U.S. patent application number 16/992671 was filed with the patent office on 2020-11-26 for methods of treating eosinophilic esophagitis.
The applicant listed for this patent is Adare Pharmaceuticals US, L.P.. Invention is credited to Gail M. COMER, Brian A. MELTZER.
Application Number | 20200368147 16/992671 |
Document ID | / |
Family ID | 1000005016483 |
Filed Date | 2020-11-26 |
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United States Patent
Application |
20200368147 |
Kind Code |
A1 |
MELTZER; Brian A. ; et
al. |
November 26, 2020 |
METHODS OF TREATING EOSINOPHILIC ESOPHAGITIS
Abstract
The present disclosure provides methods of treating inflammation
of the upper gastrointestinal tract, especially the esophagus, by
administering an oral corticosteroid. In some cases, the methods
include treating eosinophilic esophagitis (EoE) by administering an
oral corticosteroid in an induction phase and a maintenance phase
to improve peak eosinophilic counts and symptoms. In embodiments,
the methods include treating EoE by administering the oral
corticosteroid at nighttime and/or while the patient is lying
down.
Inventors: |
MELTZER; Brian A.; (Wilton,
CT) ; COMER; Gail M.; (Phoenixville, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Adare Pharmaceuticals US, L.P. |
Lawrence viiie |
NJ |
US |
|
|
Family ID: |
1000005016483 |
Appl. No.: |
16/992671 |
Filed: |
August 13, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16131812 |
Sep 14, 2018 |
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16992671 |
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15680301 |
Aug 18, 2017 |
10105315 |
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16131812 |
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62489292 |
Apr 24, 2017 |
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62461317 |
Feb 21, 2017 |
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62376703 |
Aug 18, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/56 20130101;
A61K 31/565 20130101; A61K 9/006 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/56 20060101 A61K031/56; A61K 31/565 20060101
A61K031/565 |
Claims
1. A method of topically treating eosinophilic esophagitis (EoE) in
a patient in need thereof, comprising administering an effective
amount of budesonide in an induction phase and a maintenance phase,
wherein: an induction dose of about 1 mg to about 2 mg of
budesonide is administered in the induction phase; and a
maintenance dose of about 0.5 mg to about 1 mg of budesonide is
administered in the maintenance phase.
2. The method of claim 1, wherein the induction dose is about 1 mg
or about 2 mg of budesonide.
3. The method of claim 1, wherein the maintenance dose is about 0.5
mg or about 1 mg of budesonide.
4. The method of claim 1, wherein the total daily dose of
budesonide administered in the induction phase is about 2 mg.
5. The method of claim 1, wherein the total daily dose of
budesonide administered in the maintenance phase is about 1 mg.
6. The method of claim 1, wherein the induction dose is greater
than the maintenance dose.
7. The method of claim 1, wherein the induction dose is
administered twice a day (b.i.d).
8. The method of claim 1, wherein the maintenance dose is
administered twice a day (b.i.d).
9. The method of claim 1, wherein the induction phase lasts between
about 1 and about 12 weeks.
10. The method of claim 1, wherein the induction phase results in
improvement in peak eosinophilic counts in at least one esophageal
biopsy and/or no worsening of symptoms.
11. The method of claim 1, wherein after the induction phase the
patient experiences esophageal inflammation.
12. The method of claim 1, wherein the induction phase results in
reduction of esophageal inflammation measured by one or more of a
reduction in eosinophil count, an increase in dysphagia-free days,
a reduction in episodes of dysphagia, improvement in EREFS score,
EndoFLIP documentation of improved esophageal compliance,
evaluation of biomarkers, a decrease in episodes of food impaction,
an improvement in EEsAI scores (patient, physician, endoscopy,
pathology scores), EoE-QOL-A, Visual Dysphagia Questionnaire (VDQ),
Avoidance Modification and Slow Eating (AMS) scores, or
histology.
13. The method of claim 1, wherein the corticosteroid is formulated
as a solid composition.
14. The method of claim 13, wherein the solid composition is an
effervescent tablet.
15. A method of topically treating eosinophilic esophagitis (EoE)
in a patient in need thereof, the method comprising: administering
at least one induction dose of budesonide in an amount of about 1
mg to about 2 mg during an induction phase; and based upon patient
response, subsequently administering at least one maintenance dose
of budesonide in an amount of about 0.5 mg to about 1 mg during
maintenance phase.
16. The method of claim 15, wherein after the induction phase, the
patient suffers from esophageal inflammation, and then administers
at least one maintenance dose of budesonide.
17. The method of claim 15, wherein the induction dose is about 1
mg or about 2 mg of budesonide.
18. The method of claim 15, wherein the maintenance dose is about
0.5 mg or about 1 mg.
19. The method of claim 15, wherein the total daily dose of
budesonide administered in the induction phase is about 2 mg.
20. The method of claim 15, wherein the total daily dose of
budesonide administered in the maintenance phase is about 1 mg.
21. The method of claim 15, wherein the induction dose is greater
than the maintenance dose.
22. The method of claim 15, wherein the induction dose is
administered twice a day (b.i.d.).
23. The method of claim 15, wherein the maintenance dose is
administered twice a day (b.i.d.).
24. The method of claim 15, wherein the induction phase lasts
between about 1 and about 12 weeks.
25. The method of claim 15, wherein the maintenance dose is
administered after recurrence of active symptoms of EoE.
26. The method of claim 15, wherein after the induction phase, the
patient exhibits active symptoms of EoE.
27. The method of claim 15, wherein after the induction phase the
patient experiences esophageal inflammation.
28. The method of claim 15, wherein the budesonide is administered
in an effervescent tablet.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation of U.S. patent
application Ser. No. 16/131,812, filed Sep. 14, 2018, which is a
continuation of U.S. patent application Ser. No. 15/680,301, filed
on Aug. 18, 2017 (now U.S. Pat. No. 10,105,315, issued Oct. 23,
2018), which claims priority to U.S. Provisional Application No.
62/489,292, filed Apr. 24, 2017; U.S. Provisional Application No.
62/461,317, filed Feb. 21, 2017; and U.S. Provisional Application
No. 62/376,703, filed Aug. 18, 2016, the entire contents of each of
which are hereby incorporated by reference in their entirety for
all purposes.
BACKGROUND
[0002] Esophageal inflammation disorders such as eosinophilic
esophagitis (EoE), a disease characterized by high levels of
eosinophils in the esophagus, as well as basal zonal hyperplasia,
is increasingly being diagnosed in children and adults. Many
aspects of the disease remain unclear including its etiology,
natural history, and optimal therapy. EoE affects all age groups
but most frequently individuals between 20 and 50 years of age.
Symptoms of EoE often mimic those of gastroesophageal reflux
disease (GERD) and include vomiting, dysphagia, pain and food
impaction. The disease is painful, leads to difficulty swallowing,
and predisposes patients to other complications. EoE is often
misdiagnosed for GERD, causing delay in adequate treatment for EoE
patients.
[0003] Currently, no topically administered anti-inflammatory
medications are approved for the treatment of conditions associated
with inflammation of the upper portion of the gastrointestinal
tract, particularly the inflammatory conditions of the esophagus,
such as EoE. Although systemic treatments with corticosteroids such
as prednisolone are effective, these therapeutics are associated
with significant adverse effects such as suppression of the
hypothalamo-pituitary-adrenal (HPA) axis as reflected in salivary
Cortisol levels, generalized suppression of immune function, and
particularly in children, troubling side-effects from long term
systemic exposure include growth retardation.
SUMMARY OF THE INVENTION
[0004] The present disclosure provides methods of administering
pharmaceutical compositions comprising a low-dose topically active
corticosteroid to treat, prevent, ameliorate, or delay the symptoms
and/or inflammation associated with a gastrointestinal inflammatory
disorder. In some embodiments, the gastrointestinal inflammatory
disorder is in the esophagus. In some embodiments, the
gastrointestinal inflammatory disorder is eosinophilic
esophagitis.
[0005] In some embodiments, the present disclosure provides methods
of treating eosinophilic esophagitis (EoE) in a patient in need
thereof, comprising administrating an oral corticosteroid in an
induction phase and a maintenance phase. In some embodiments, the
induction phase results in improvement in Peak eosinophilic (Eos)
counts in at least one esophageal biopsy, and the treatment (e.g.
during the induction phase) results in no worsening of patient mean
weekly scores in a patient-reported outcome assessment which
includes the assessment of dysphagia-free days. In some
embodiments, the patient exhibits substantial improvement in
esophageal function and morphology, including lessening of
esophageal furrows, lessening of esophageal focal narrowing,
increased esophageal diameter, increased esophageal compliance,
increased esophageal body distensibility, increased ease
swallowing, reduced edema, improved vascularity, reduction of
rings, decrease or absence of exudate, and/or absence of
stricture.
[0006] In some embodiments, the present disclosure provides methods
of treating eosinophilic esophagitis (EoE) in a patient in need
thereof, comprising administrating an oral corticosteroid in an
induction phase and a maintenance phase, wherein the induction
phase does not result in substantial improvement in Peak
eosinophilic counts in at least one esophageal biopsy. In some
embodiments, the patient experiences at least one episode of food
impaction in the induction phase. In some embodiments, the patient
exhibits active symptoms of EoE during the induction phase. In some
embodiments, the induction phase results in a histological response
of .gtoreq.15 peak eosinophils per high power field (HPF). In some
embodiments, the patient exhibits no substantial improvement in
esophageal function and/or morphology during the induction phase.
In some embodiments, following the ineffective induction phase,
treatment is continued resulting in the patient exhibiting an
improvement in Peak eosinophilic counts in at least one esophageal
biopsy, and the continued treatment results in no worsening of
patient mean weekly scores in a patient-reported outcome
assessment, which includes the assessment of dysphagia-free
days.
[0007] In some embodiments, the maintenance phase comprises a dose
at least equal to, more than or less than the induction phase. In
some embodiments the induction and maintenance doses are between
about 1.5 mg and about 3 mg, e.g. administered once or twice
daily.
[0008] In some embodiments, the induction phase comprises
administration for at least about 6 weeks, for at least about 8
weeks, for at least about 10 weeks, or for at least about 12 weeks.
In some embodiments, administration occurs twice per day. In some
embodiments, the induction phase results in a histological response
of <6 peak Eos per HPF. In some embodiments, the induction phase
results in no episodes of food impaction.
[0009] In some embodiments, the patient in maintenance therapy does
not relapse with active symptoms of EoE. In some embodiments, the
maintenance does is substantially the same or less than the
induction dose. In some embodiments, the maintenance dose is higher
than the induction dose. In some embodiments, the patient in the
withdrawal phase does not relapse with active symptoms of EoE. In
some embodiments, the patient remains in withdrawal phase until
active symptoms of EoE recur. In some embodiments, after recurrence
of active symptoms of EoE, the patient receives an induction dose
of an oral corticosteroid. In some embodiments, after recurrence of
active symptoms of EoE, the patient receives a maintenance dose of
an oral corticosteroid. In some embodiments, after recurrence of
active symptoms of EoE, the patient receives an induction dose of
an oral corticosteroid followed by a maintenance dose.
[0010] In some embodiments, the present disclosure provides for
administering the oral corticosteroid composition to a patient
while laying down. In some embodiments, the corticosteroid is
administered to the patient while laying down and prior to going to
sleep (e.g., about 1 minute, about 5 minutes, about 10 minutes,
about 15 minutes, or about 30 minutes, inclusive of all values
therein). In some embodiments, the pharmaceutical composition is
administered to the patient at least about 2 hours after the
evening meal. In some embodiments, the corticosteroid is
administered to the patient at least about 4 hours after the
evening meal.
[0011] In some embodiments, the corticosteroid is formulated in an
orally dissolving dosage form. In some embodiments, the
corticosteroid is selected from the group consisting of budesonide,
fluticasone, flunisolide, ciclesonide, mometasone, beclomethasone,
tixocortol and salts, or esters and mixtures thereof. In some
embodiments, the orally dissolving dosage form is a tablet or
wafer. In some embodiments, the corticosteroid is deposited
topically in the upper gastrointestinal tract. In some embodiments,
the patient has previously been administered proton pump inhibitor
(PPI) therapy. In some embodiments, the patient has previously been
administered PPI therapy for eight weeks. In some embodiments, the
PPI therapy was not effective to substantially improve one or more
symptoms of EoE. In some embodiments, the patient has previously
not been administered PPI therapy.
[0012] In some embodiments, the present disclosure provides methods
for assessing the suitability of subjects for a clinical trial to
measure the effect of an oral corticosteroid on EoE after
administration in both an induction phase and a maintenance phase,
wherein the recruitment of subjects into the clinical trial is
assessed based on (i) patients having Peak eosinophil counts per
HPF of greater than 15, and (ii) prior treatment with a PPI over at
least about 8 weeks had not been effective to substantially improve
one or more symptoms of EoE.
[0013] In some embodiments, the present disclosure provides for a
method of treating EoE in a patient in need thereof, comprising
administering an oral corticosteroid to the patient, wherein the
patient is lying down when the oral corticosteroid is administered
or the patient lays down immediately after administration of the
oral corticosteroid. In other embodiments, the present disclosure
provides for a composition comprising an oral corticosteroid for
use in the treatment of EoE in a patient in need thereof, wherein
the patient is lying down when the composition is administered or
the patient lays down after immediately after administration of the
composition. In still other embodiments, the present disclosure
provides for the use of composition comprising an oral
corticosteroid for the manufacture of a medicament for the
therapeutic application in EoE in a patient in need thereof,
wherein the patient is lying down when the medicament is
administered or the patient lays down immediately after
administration of the medicament.
[0014] In various embodiments, the present disclosure provides for
methods (or compositions for use in methods) for topically treating
EoE in patient in need thereof with an oral corticosteroid, said
methods comprising: (a) administering the oral corticosteroid while
the patient is lying down or immediately prior to the patient lying
down. In embodiments, a therapeutically effective amount of the
oral corticosteroid contacts the esophagus, thereby topically
treating EoE.
[0015] In embodiments, the lying down is in a supine, prone, or
laterally recumbent position. In embodiments, the oral
corticosteroid is administered about 30 minutes or less before
target sleep time. In embodiments, the oral corticosteroid is
administered at least about 30 minutes after a meal. In
embodiments, the patient does not eat or drink for at least about
30 minutes after administration the oral corticosteroid.
[0016] In embodiments, the oral corticosteroid is administered: (i)
once daily; or (ii) twice daily, wherein the first daily dose is
administered while the subject remains upright. In embodiments, the
corticosteroid has a systemic bioavailability of less than or equal
to about 20% of its dose. In embodiments, the oral corticosteroid
provides an average maximum blood plasma concentration (Cmax) of
less than or equal to about 500 pg/mL after oral administration of
about 0.01 mg to about 20 mg of the oral corticosteroid. In
embodiments, the oral corticosteroid provides an average
AUC.sub.0-24 of less than or equal to about 3,000 pg*h/mL after
oral administration of about 0.01 mg to about 20 mg of the oral
corticosteroid. In embodiments, the oral corticosteroid is
budesonide, fluticasone, flunisolide, ciclesonide, mometasone or
beclomethasone, or a pharmaceutically acceptable salt, solvent,
ester, polymorph or prodrug thereof. In embodiments, the oral
corticosteroid is formulated: (i) as a liquid composition; (ii) as
a solid composition; (iii) to form a solution or suspension prior
to oral administration; or (iv) to form a solution, suspension or
gel after oral administration, wherein (i)-(iv) delivers a
therapeutically effective amount of the oral corticosteroid to the
esophagus. In embodiments, (i) the liquid composition is in the
form of a solution, suspension or slurry; and (ii) the solid
composition is in the form of a gel, lozenge, lollipop,
effervescent tablet, powder, granules or an orally disintegrating
composition. In embodiments, the orally disintegrating composition
is a tablet, wafer, film, or lyophilized matrix. In embodiments,
the orally disintegrating composition is a tablet comprising: (a)
the oral corticosteroid in an amount of from about 1.5 mg to about
7.5 mg; (b) a pharmaceutically acceptable carrier combined with the
corticosteroid; and (c) rapidly dispersing microgranules, wherein
the orally disintegrating tablet disintegrates within 60 seconds
when tested using the USP <701> method for disintegration
time.
[0017] In embodiments, the patient has a Cmax of the oral
corticosteroid of less than or equal to about 200 pg/mL following
oral administration 1.5 mg to about 7.5 mg of the oral
corticosteroid. In embodiments, the oral corticosteroid is
fluticasone propionate, and the lying down patient has a Cmax
within the range of about 80% to about 125% of about 15 pg/mL to
about 45 pg/mL following oral administration of 6 mg fluticasone
propionate or 3 mg of fluticasone propionate to a lying down
patient. In embodiments, the Cmax of the corticosteroid for the
laying down patient is lower than the Cmax of the oral
corticosteroid for a fed patient that is upright and does not lay
down immediately after administration of the oral corticosteroid.
In embodiments, the Cmax of the oral corticosteroid for the lying
down patient is lowered by about 10% to about 30% compared to the
Cmax of the oral corticosteroid for a fed patient that is upright
and does not lay down immediately after administration of the oral
corticosteroid.
[0018] In embodiments, the average time to reach a maximum blood
plasma concentration (Tmax) is in the range of about 80% to about
125% of about 12 h to about 15 h. In embodiments, the Tmax of the
corticosteroid for the lying down patient is delayed compared to
the Tmax of the oral corticosteroid for a patient that is upright
and does not lay down immediately after administration of the oral
corticosteroid. In embodiments, the Tmax of the corticosteroid for
the lying down patient is delayed by at least about 1 hour compared
to the average Tmax of the oral corticosteroid for a patient that
is upright and does not lay down immediately after administration
of the oral corticosteroid. In embodiments, the Tmax of the
corticosteroid for the lying down patient is delayed by an amount
of time in the range of about 4 h to about 9 h compared to the Tmax
of the oral corticosteroid for a patient that is upright and does
not lay down immediately after administration of the oral
corticosteroid.
[0019] In embodiments, after 12 weeks of daily administration of
the oral corticosteroid, esophageal inflammation is reduced as
measured by a reduction in eosinophil count, an increase in
dysphagia-free days, a reduction in episodes of dysphagia,
improvement in EREFS score, EndoFLIP documentation of improved
esophageal compliance, evaluation of biomarkers, a decrease in
episodes of food impaction, an improvement in EEsAI scores
(patient, physician, endoscopy, pathology scores), EoE-QOL-A,
Visual Dysphagia Questionnaire (VDQ), Avoidance Modification and
Slow Eating (AMS) scores, or histology. In embodiments, the
patient's eosinophil count is reduced by at least about 50%.
[0020] In embodiments, the patient has a lactose allergy or starch
allergy.
BRIEF DESCRIPTION OF THE FIGURES
[0021] FIG. 1 shows an exemplary schematic overview of Parts 1 and
2 of a Phase 2b study design and depicts screening and run-in in
Part 1 (induction stage), and randomized withdrawal in Part 2.
[0022] FIG. 2 shows an exemplary schematic overview of Part 3
(maintenance) and follow-up of a Phase 2b study.
[0023] FIG. 3 shows another an exemplary schematic overview of
Parts 1 and 2 of a Phase 2b study design and depicts screening and
run-in in Part 1 (induction stage), and randomized withdrawal in
Part 2.
[0024] FIG. 4 shows another shows an exemplary schematic overview
of Part 3 (maintenance) and follow-up of a Phase 2b study.
[0025] FIG. 5 shows a study schematic providing an overview of the
treatment each subject will receive throughout the FLUTE study.
[0026] FIG. 6 shows the Mean Linear Plasma Concentration-Time
Profile of APT-1011 (Fluticasone Proprionate) for fed, fasted, and
HS administration.
[0027] FIG. 7 shows the Mean Logarithmic Plasma Concentration-Time
Profile of APT-1011 (Fluticasone Proprionate) for fed, fasted, and
HS administration.
[0028] FIG. 8 shows Spaghetti Plots of APT-1011 (Fluticasone
Proprionate) (Fasted conditions).
[0029] FIG. 9 shows Spaghetti Plots of APT-1011 (Fluticasone
Proprionate) (Fed conditions)
[0030] FIG. 10 shows Spaghetti Plots of APT-1011 (Fluticasone
Proprionate) (HS conditions).
DETAILED DESCRIPTION
[0031] Gastrointestinal inflammatory disorders, such as
Eosinophilic esophagitis (EoE), an allergic/immune condition where
the subject suffers from inflammation and/or swelling of the
esophagus, affect a patient's ability to swallow food and can
consequently cause malnutrition and failure to thrive. Typically,
eosinophils are not found in the esophagus, but in EoE these cells
accumulate and produce swelling that reduces the interior diameter
of the esophagus making swallowing and eating very difficult. Often
patients experience episodes of food impaction where food becomes
lodged in the patient's esophagus, which can require emergency
treatment. Because of the difficulty swallowing, and fear of food
impaction, many patients with EoE limit themselves to eating soft
foods such as yogurt, soups, and smoothies. In severe cases of EoE
patients receive parenteral nutrition (e.g. intravenous feeding),
which can provide required sustenance but limits the patient's
activities and can lead to increased infection at the site of the
catheter.
[0032] EoE most commonly occurs in Caucasian males and can occur at
any age, with the symptoms varying with age. Infants and toddlers
suffering from EoE may refuse food, fail to thrive, or experience
"reflux" and/or vomiting. Young children typically report
heartburn/reflux, abdominal pain, vomiting, food avoidance, and/or
poor growth. For adults, the hallmark symptom is dysphagia (trouble
swallowing), and EoE is implicated in over 50% of food impactions.
Adult patients less commonly exhibit heartburn or chest pain.
Adults with EoE also exhibit altered eating behavior such as
dietary modifications, slow eating, excessive chewing, and
increased consumption of liquids with food.
[0033] While the causes of EoE are not known, many EoE patients
have a family history of allergies, asthma, and/or symptoms of
allergic disorders (e.g. asthma, allergic rhinitis, atopic
dermatitis, and food allergy). Additionally, environmental
allergens such as dust mites, animals, pollen, and molds may play a
role in the development of EoE. Because of the link between EoE and
allergies, especially food allergies, elimination of the allergen
may help alleviate symptoms. However, these types of elimination
can be difficult to achieve.
[0034] While there are no medications currently approved to treat
EoE, some medications such as glucocorticosteroids, leukotriene
antagonists, mast cell stabilizers, immunomodulators, biologics,
and small molecules can help alleviate symptoms. Proton Pump
Inhibitors (PPI) which control the amount of acid produced, have
also been used to treat patients' symptoms, but may not reduce the
amount of inflammation in the patient. Further, recent studies have
linked long-term PPI use to dementia, making their use in EoE
patients less desirable. Endoscopic therapy (dilation) may also be
used to alleviate symptoms, but this too has no effect on the
underlying inflammation causing the esophageal swelling.
[0035] While these therapies may help alleviate symptoms in some
patients for a time, they often fall short of treatment of EoE. For
example, current topical steroid medications are not optimal, with
5-50% of patients classified as non-responders. Similarly, diet
elimination which requires significant endoscopic surveillance of
the patient shows about 30% non-response rate.
[0036] New methods of not only alleviating the symptoms of
esophageal inflammatory disorders such as EoE, but also addressing
the inflammation causing the symptoms are required. The present
disclosure provides methods of administering pharmaceutical
compositions comprising a topically active corticosteroid to treat
the symptoms and/or inflammation associated with a gastrointestinal
inflammatory disorder. Pharmaceutical compositions comprising a
topically active corticosteroid for use in such methods are also
herein disclosed.
[0037] In various embodiments, the methods disclosed herein include
at least two phases: an induction phase and a maintenance phase.
During the induction phase, patients are administered a dosage of a
pharmaceutical composition of the disclosure. Based upon patient
response at the end of the induction phase (e.g. a histologic
response and no worsening of symptoms or episodes of food
impaction), the patient may enter the maintenance phase. The dose
of the pharmaceutical composition may be the same or different
during the maintenance and induction phases. Upon an amelioration
or decrease of symptoms, the patient may also enter a withdrawal
phase, and receive no doses of the pharmaceutical composition until
symptoms recur.
[0038] The present disclosure provides methods of treating
eosinophilic esophagitis (EoE) in a patient in need thereof,
comprising administrating an oral corticosteroid in an induction
phase and a maintenance phase, where the induction phase results in
improvement in Peak eosinophilic counts in at least one esophageal
biopsy and the treatment results in no worsening of patient mean
weekly scores in a patient-reported outcome assessment which
includes the assessment of dysphagia-free days.
[0039] Unless defined otherwise, all technical and scientific terms
herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this disclosure belongs.
Although any methods and materials, similar or equivalent to those
described herein, can be used in the practice or testing of the
present disclosure, the preferred methods and materials are
described herein.
[0040] It should be understood that singular forms such as "a,"
"an," and "the" are used throughout this application for
convenience, however, except where context or an explicit statement
indicates otherwise, the singular forms are intended to include the
plural. All numerical ranges should be understood to include each
and every numerical point within the numerical range, and should be
interpreted as reciting each and every numerical point
individually. The endpoints of all ranges directed to the same
component or property are inclusive, and intended to be
independently combinable.
[0041] As used herein, the word "include," and its variants, is
intended to be non-limiting, such that recitation of items in a
list is not to the exclusion of other like items that may also be
useful in the materials, compositions, devices, and methods of this
technology. Similarly, the terms "can" and "may" and their variants
are intended to be non-limiting, such that recitation that an
embodiment can or may comprise certain elements or features does
not exclude other embodiments of the present technology that do not
contain those elements or features. Although the open-ended term
"comprising," as a synonym of terms such as including, containing,
or having, is used herein to describe and claim the disclosure, the
present technology, or embodiments thereof, may alternatively be
described using more limiting terms such as "consisting of" or
"consisting essentially of" the recited ingredients.
[0042] The term "drug", "active" or "active pharmaceutical
ingredient" as used herein includes a pharmaceutically acceptable
and topically acting corticosteroid, pharmaceutically acceptable
salts, esters, solvates (including hydrates), polymorphs,
stereoisomers, and/or prodrugs, and mixtures thereof. The terms
"salts" refers to the product formed by the reaction of a suitable
inorganic or organic acid with the "free base" form of the drug.
Suitable acids include those having sufficient acidity to form a
stable salt, for example acids with low toxicity such as the salt
approved for use in humans or animals. Non-limiting examples of
acids that may be used to form salts of an orally active drug,
include inorganic acids, e.g., HCl, H3PO4 H2SO4. Non-limiting
examples of organic acids include alkyl sulfonic acids and
propionic acid.
[0043] The terms "pharmaceutical composition" and "pharmaceutical
dosage form," are used interchangeably herein to refer to an oral
dosage form (suspension, solution, powder, solid, etc.) which can
be used to administer a corticosteroid. Non-limiting examples of
dosage forms include an orally disintegrating composition, such as
a tablet, a lyophilized matrix, a film, and a wafer, liquid
composition, a gel, a slurry, a lozenge, a lollipop, sachet, an
effervescent tablet, and the like.
[0044] The term "oral corticosteroid" and "corticosteroid" are used
interchangeably to refer to a corticosteroid which is administered
orally, e.g., in a pharmaceutical composition described herein.
[0045] The terms "orally disintegrating dosage form", "orally
disintegrating tablet", "orally dispersing tablet", or "ODT" refer
to a solid dosage form/tablet of the present disclosure, which
disintegrates rapidly in the oral cavity of a patient after
administration, without chewing, to form a suspension comprising
the corticosteroid. The rate of oral disintegration can vary, but
is significantly faster than the rate of oral disintegration of
conventional solid dosage forms or chewable solid dosage forms
(i.e., tablets or capsules) which are intended to be swallowed
immediately after administration.
[0046] As used herein, the terms "treating," "treatment" and
"treat" include (i) preventing a particular disease or disorder
from occurring in a subject who may be predisposed to the disease
or disorder but has not yet been diagnosed as having it; (ii)
curing, treating, or inhibiting the disease, i.e., arresting its
development; or (iii) ameliorating the disease by reducing or
eliminating symptoms, conditions, and/or by causing regression of
the disease. In some embodiments, "treating," "treatment" and
"treat" may include administering a therapeutically effective
regimen as defined herein.
[0047] The term "about", as used herein to refer to a numerical
quantity, includes "exactly" plus or minus up to 10% of that
referenced numeric indication. When the term "about" is used in
reference to a range of values, the term "about" refers to both the
minimum and maximum value of the range (e.g., "about 1-50 .mu.m"
means "about 1 .mu.m to about 50 .mu.m"). The term "intimately
associated", as used herein to describe the spatial relationship
between two or more components of a composition refers to
components that are intimately mixed, such as, for example, in
mixtures, coatings and matrices.
[0048] Unless indicated otherwise, all percentages and ratios are
calculated by weight. Unless indicated otherwise, all percentages
and ratios are calculated based on the total composition.
[0049] The term "having no significant systemic glucocorticoid or
mineralocorticoid activity", as used herein refers to
corticosteroid compositions which do not provide a generalized
effect in the body through absorption into the circulation, but do
provide local effects through topical contact with a diseased
tissue. Examples include fluticasone, flunisolide, budesonide,
circlesone, mometasone, tixocortol, and beclomethasone.
Corticosteroids which have high systemic glucocorticoid potencies
when administered orally include e.g., hydrocortisone, prednisone,
prednisolone, methylprednisolone, dexamethasone, betamethasone,
etc. or mineralocorticoid potencies (e.g., alsosterone).
Corticosteroids which typically have systemic glucocorticoid or
mineralocorticoid activity when administered orally can also be
used in the diluted compositions of the present disclosure, wherein
the systemic uptake of the corticosteroid is reduced or
suppressed.
[0050] A "histologic responder" may be defined as a subject who
achieves a histologic response of peak eosinophils/HPF
number.ltoreq.6 (as primary determinant). HPF may be defined as a
standard area of 0.237 square millimeters in a microscope with
40.times. lens and 22 mm ocular.
[0051] A "histologic non-responder" may be defined as a subject who
does not have a histologic response (i.e., do not achieve a
histologic response of peak eosinophils/HPF number.ltoreq.6).
[0052] Subjects who develop food impaction with or without
esophageal dilatation anytime during a study may be considered
"treatment failures".
Pharmaceutical Compositions and Administration
[0053] The pharmaceutical compositions used in (or for use in) the
methods described herein can be any dosage form which can be used
to topically administer a therapeutic agent (e.g., corticosteroid)
to the esophagus. Suitable dosage forms include liquid compositions
(e.g., solutions, suspensions, and slurries), gels, and solid
compositions which form a liquid or gel after oral administration.
For example, orally disintegrating compositions (e.g., ODT, film,
lyophilize matrix, or wafer), lozenges, and lollipops can from a
solution, suspension, or gel comprising the therapeutic agent in
the oral cavity of the patient, and after the solution or
suspension is swallowed, the corticosteroid dissolved or suspended
therein contacts the esophagus as the liquid traverses the
esophageal tract. In a preferred embodiment, the pharmaceutical
composition is in the form of an ODT.
[0054] In some embodiments, the present disclosure provides an oral
solid pharmaceutical composition comprising a corticosteroid (e.g.,
about 10 mg or less, including 7.5 mg, 6.0 mg, 4.5 mg, 3.0 mg, 1.5
mg, or 0.75 mg) and at least one pharmaceutically acceptable
carrier, wherein the corticosteroid is combined with (e.g.,
adsorbed onto or suspended in) the pharmaceutically acceptable
carrier. In some embodiments, the drug is present in an amount of
less than about 5% (weight of drug/weight of composition),
particularly less than 3% by weight. The pharmaceutical
compositions disclosed herein can be formulated as an orally
disintegrating tablet (hereafter referred to as an ODT) that
disintegrates within 60 seconds (e.g., within 30 seconds) when
tested using the USP <701> Disintegration Test, and/or
disintegrates within 60 seconds when placed in the oral cavity of a
human.
[0055] In some embodiments, the corticosteroid used in the
compositions and methods described herein is a topically acting
corticosteroid. In some embodiments, the corticosteroid has low or
substantially no systemic effect. In some embodiments,
corticosteroids that have low or no systemic effects are those
which have no significant systemic glucocorticoid or
mineralocorticoid activity after oral administration in humans.
Corticosteroid with "no significant systemic glucocorticoid or
mineralocorticoid activity after oral administration in humans"
refer to corticosteroids, or pharmaceutical compositions comprising
corticosteroids, which have less than about 20% systemic
glucocorticoid or mineralocorticoid activity after oral
administration, e.g., less than about 15%, less than about 10%,
less than about 5%, less than about 5%, less than about 4%, less
than about 3%, less than about 2%, or less than about 1%. Systemic
glucocorticoid or mineralocorticoid activity can be determined
using methods known in the art, such as by measuring morning
cortisol levels.
[0056] In some embodiments, corticosteroids for use in the methods
and compositions described herein have a systemic bioavailability
of less than or equal to about 20% of the administered dose.
Non-limiting examples of oral corticosteroids that have a
bioavailability of less than or equal to about 20% include
fluticasone, flunisolide, budesonide, circlesone, mometasone,
tixocortol, and beclomethasone, and pharmaceutically acceptable
salts, solvates, esters, polymorphs or prodrugs thereof. In
preferred embodiments, the oral corticosteroid used in the methods
and compositions described herein is fluticasone propionate.
[0057] In some embodiments, the oral corticosteroids for use in the
methods and compositions described herein are formulated to provide
a pharmacokinetic profile which reduces the likelihood that a
patient will experience side effects associated with systemic
corticosteroid administration, including, but not limited to,
osteoporosis, weight gain, immune system suppression (i.e.,
increased incidence of infections), high blood pressure,
hyperglycaemia, muscle weekness, skin problems (e.g., poor healing
of injuries, thinning of skin, easy bruising, stretchmarks, etc.)
mood and behavioral changes, increased risk of developing
cataracts, and increased risk of duodenal ulcers. That is, the
pharmacokinetic profile of a corticosteroid can be modified to
provide an average maximum plasma concentration (Cmax), an average
time to reach the maximum plasma concentration (Tmax), and/or AUC
that reduces systemic side effects. Pharmacokinetic profile can be
measured by methods known in the art, for example the methods
described in Example 5.
[0058] In some embodiments, oral corticosteroids for use in the
methods and compositions described herein are formulated to provide
an average maximum blood plasma concentration (Cmax) of less than
or equal to about 10,000 pg/mL after oral administration of about
0.01 mg to about 20 mg of the oral corticosteroid, e.g., about
9,000 pg/mL, about 8,000 pg/mL, about 7,000 pg/mL, about 6,000
pg/mL, about 5,000 pg/mL, about 4,000 pg/mL, about 3,000 pg/mL,
about 2,000 pg/mL, about 1,000 pg/mL, about 900 pg/mL, about 800
pg/mL, about 700 pg/mL, about 600 pg/mL, or about 500 pg/mL,
inclusive of all values and subranges therebetween. In preferred
embodiments, the oral corticosteroid is formulated to provide a
Cmax of less than or equal to about 500 pg/mL after oral
administration of about 0.01 mg to about 20 mg of the oral
corticosteroid.
[0059] In some embodiments, oral corticosteroids for use in the
methods and compositions described herein are formulated to provide
an average AUC.sub.0-24 of less than or equal to about 15,000
pg*h/mL after oral administration of about 0.01 mg to about 20 mg
of the oral corticosteroid, e.g., about 14,000 pg*h/mL, about
13,000 pg*h/mL, about 12,000 pg*h/mL, about 11,000 pg*h/mL, about
10,000 pg*h/mL, about 9,000 pg*h/mL, about 8,000 pg*h/mL, about
7,000 pg*h/mL, about 6,000 pg*h/mL, about 5,000 pg*h/mL, about
4,000 pg*h/mL, about 3,000 pg*h/mL, about 2,000 pg*h/mL, about
1,000 pg*h/mL, inclusive of all values and subranges therebetween.
In preferred embodiments, oral corticosteroids for use in the
methods and compositions described herein are formulated to provide
an average AUC.sub.0-24 of less than or equal to about 3,000
pg*h/mL after oral administration of about 0.01 mg to about 20 mg
of the oral corticosteroid.
[0060] In some embodiments, the pharmaceutical compositions
described herein can be formulated to reduce systemic
bioavailability, glucocorticoid activity, and/or mineralocorticoid
activity (or combinations thereof) of the oral corticosteroid
following oral administration. Reducing systemic bioavailability
may allow the corticosteroid to exhibit local therapeutic effects,
rather than being absorbed systemically. For example, a
corticosteroid which otherwise has high systemic bioavailability
(systemic bioavailability of e.g., >20%) can be formulated in an
ion-exchange resin to reduce systemic bioavailability while
increasing local therapeutic effects.
[0061] Salts, solvates, polymorphs, and prodrugs can be used to
modify corticosteroids that otherwise have a systemic
bioavailability of greater than about 20% to provide a "topically
activing corticosteroid" having less than about 20% systemic
activity and greater than about 80% local effect by decreasing the
systemic bioavailability of the corticosteroid.
[0062] Non-limiting examples of corticosteroids which can be
modified (e.g., by forming a salt or prodrug, or formulating the
oral corticosteroid in an ion-exchange resin) to reduce systemic
bioavailability and increase local effects, include hydrocortisone,
prednisone, prednisolone. methylprednisolone, dexamethasone,
betamethasone, alsosterone, and the like.
[0063] The compositions of the present disclosure may include a
water soluble or water-swellable pharmaceutically acceptable
excipient, such as bio-gelling or bioadhesive polymer that will
enhance bioadherence of the corticosteroid to the inflamed
esophageal mucosa.
[0064] Suitable topically acting corticosteroids which may be
included in the pharmaceutical composition of the present
disclosure include budesonide, fluticasone, flunisolide,
ciclesonide, mometasone, beclomethasone, tixocortol and salts,
esters, solvates, polymorphs, or prodrugs, and mixtures
thereof.
[0065] In preferred embodiments, the composition of the present
disclosure comprises fluticasone (e.g. fluticasone propionate). In
preferred embodiments, the pharmaceutical composition is an ODT
comprising fluticasone or a pharmaceutically acceptable salt
thereof (e.g., fluticasone propionate). In other embodiments, the
composition of the present disclosure comprises budesonide. In
certain other embodiments, the composition of the present
disclosure comprises ciclesonide.
[0066] In some embodiments, the corticosteroid may be in the form
of crystals having a mean particle size of about 100 .mu.m or less,
about 75 .mu.m or less, about 50 .mu.m or less, more particularly
about 25 .mu.m or less, or about 15 .mu.m or less. Particular
embodiments of the disclosure provide the corticosteroid is
micronized in order to achieve a mean particle size of less than
about 10 .mu.m, less than about 8 .mu.m or less, less than about 6
.mu.m, or particularly, less than about 4 .mu.m.
[0067] Alternatively, such crystals may have an average size in the
sub-micron range (e.g., average particle size of about <1
.mu.m), i.e., may be as nanoparticles (e.g., average particle size
in the range of about 1-100 nm). In some embodiments, the
corticosteroid may be present in an amorphous form, for example in
association with a stabilizing agent which limits drug
recrystallization, e.g., polyvinylpyrrolidone (PVP), hydroxypropyl
methylcellulose (HPMC), hydroxypropyl cellulose,
hydroxyethylcellulose; Soluplus.RTM., Kollidon.RTM. VA64, sodium
lauryl sulphate, Tween surfactants, Eudragit.RTM. EPO polymer, and
mixtures thereof.
[0068] The amount of corticosteroid present in the pharmaceutical
compositions of the present disclosure is selected so as to
maximize the therapeutic benefit from topical administration while
minimizing side effects from systemic absorption. In the case of
solid pharmaceutical compositions of the present disclosure, the
amount of corticosteroid in the composition is less than about 5%
w/w (weight of drug/weight of composition). In some embodiments the
amount of corticosteroid in the pharmaceutical composition is less
than about 4%. In another embodiment it is less than about 3%. In
some embodiments it is less than about 2%, less than about 1.5%,
less than about 1%, less than about 0.5% by weight or less. In some
embodiments the amount of corticosteroid in the pharmaceutical
composition is between about 0.50 mg and about 18 mg. In some
embodiments the amount of corticosteroid in the pharmaceutical
composition is between about 0.75 mg and about 12 mg. In some
embodiments the amount of corticosteroid in the pharmaceutical
composition is between about 1.5 mg and about 9 mg. In still other
embodiments, the amount of corticosteroid is about 0.01 mg, about
0.05 mg, about 0.1 mg, about 0.15 mg, about 0.1 mg, about 0.2 mg,
about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about
0.45 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.75 mg,
about 0.8 mg, about 1 mg, about 1.5 mg, about 2 mg, about 3 mg,
about 4 mg, about 4.5 mg, about 5 mg, about 6 mg, about 7 mg, about
8 mg, about 9 mg, about 10 mg, about 12 mg, about 18 mg, inclusive
of all ranges and sub-ranges there between.
[0069] In preferred embodiments, the amount of corticosteroid in
the pharmaceutical composition disclosed herein (e.g., ODT) is the
range of from about 1.5 mg to about 7.5 mg, including about 3.0 mg,
about 4.5 mg, and about 6.0 mg. In preferred embodiments, the
pharmaceutical composition is an ODT and the corticosteroid is
present in an amount of about 1.5 mg. In other preferred
embodiments, the pharmaceutical composition is an ODT and the
corticosteroid is present in an amount of about 3.0 mg. In still
other preferred embodiments, the pharmaceutical composition is an
ODT and the corticosteroid is present in an amount of about 4.5 mg.
In yet other preferred embodiments, the pharmaceutical composition
is an ODT and the corticosteroid is present in an amount of about
6.0 mg. In some other preferred embodiments, the pharmaceutical
composition is an ODT and the corticosteroid is present in an
amount of about 7.5 mg.
[0070] In some embodiments, the rapidly disintegrating composition
of the disclosure may comprise pharmaceutically acceptable
excipients which swell, dissolve or otherwise facilitate
disintegration of the orally disintegrating dosage form (e.g. an
ODT, film, lyophilized matrix, or wafer) providing a smooth viscous
suspension containing micronized corticosteroid particles to coat
inflammatory esophageal mucosa to treat eosinophilic esophagitis.
Examples of such pharmaceutically acceptable excipients include
disintegrants or rapidly dispersing microgranules as described
herein. As used herein, the term "rapidly dispersing microgranules"
refers to granules comprising particles of at least one sugar
alcohol and/or saccharide in combination with particles of at least
one disintegrant, which are formed in a granulator. In embodiments,
the corticosteroid (e.g., micronized corticosteroid particles) may
be granulated with the alcohol and/or saccharide particles.
Alternatively, in some embodiments, the corticosteroid (e.g.,
micronized corticosteroid particles) can be combined with the
pharmaceutically acceptable carrier, and then blended with the
rapidly dispersing microgranules comprising particles of at least
one sugar alcohol and/or saccharide in combination with particles
of at least one disintegrant.
[0071] In certain embodiments of the present disclosure the total
weight of the dosage form is kept in the range of from 300 to 900
mg to incorporate as much rapidly dispersing microgranules
comprising at least one sugar alcohol and/or saccharide in
combination with at least one disintegrant, as possible to maximize
eosinophilic esophagitis surface coating with micronized
corticosteroid. In some embodiments, the rapidly dispersing
microgranules comprise at least one disintegrant in combination
with a sugar alcohol and/or a saccharide. The amount of sugar
alcohol and/or saccharide in the rapidly dispersing granules ranges
from about 99%-90%, or about 95%-90% of the total weight of the
disintegrant-containing granules, including all ranges and
sub-ranges there between. In some embodiments, the average particle
size of a sugar alcohol and/or saccharide is about 30 .mu.m or
less, for example about 1-30 .mu.m, about 5-30 .mu.m, about 5-25
.mu.m, about 5-20 .mu.m, about 5-15 .mu.m, about 5-10 .mu.m, about
10-30 .mu.m, about 10-25 .mu.m, about 10-20 .mu.m, about 10-15
.mu.m, about 15-30 .mu.m, about 15-25 .mu.m, about 15-20 .mu.m,
about 20-30 .mu.m, about 20-25 .mu.m, or about 25-30 .mu.m.
[0072] In some embodiments, the dosage form has total weight of 300
mg and contain about 0.05 mg (0.16%), about 0.75 mg (0.25% w/w),
about 1.5 mg (0.5% w/w), about 3 mg (1% w/w), about 4.5 mg (1.5%) ,
about 6 mg (2% w/w), about 7.5 mg (2.5% w/w), about 9 mg (3% w/w),
about 12 mg (4% w/w), about 16 mg (5%) of the corticosteroid.
[0073] In some embodiments, the dosage forms has total weight of
600 mg and contain about 0.75 mg (0.125% w/w), about 1.5 mg (0.25%
w/w), about 3 mg (0.5% w/w), about 4.5 mg (0.75%), about 6 mg (0.1%
w/w), about 7.5 mg (1.25% w/w), about 9 mg (1.5% w/w), about 12 mg
(2% w/w), about 18 mg (3% w/w) of the corticosteroid. In some
embodiments, the topically acting corticosteroid is fluticasone
propionate and it is in the range of about 0.05 to about 15 mg in
the pharmaceutical composition at a drug content of from about
0.16% to 5% by weight of the composition.
[0074] In some embodiments, the fluticasone propionate is in the
range of about 0.75 to about 7.5 mg in the composition at a drug
content of from about 0.25% to 2.5% by weight in the
composition.
[0075] In some embodiments, the fluticasone propionate is in the
range of 0.05 to about 18 mg in the composition at a drug content
of from about 0.125% to 5% by weight in the composition.
[0076] The pharmaceutically acceptable carrier used in the mixture
of the present disclosure is suitable for combining with the drug
(e.g., adsorption of the drug, or dissolution of suspension of the
drug in the pharmaceutically acceptable carrier), it should have
the properties of an excellent carrier for dry blends providing
blend flowability and workability and preventing the segregation.
It may concur in providing corticosteroid content uniformity.
Suitable pharmaceutically acceptable carriers include, but are not
limited to, microcrystalline cellulose, silicified microcrystalline
cellulose, pregelatinized starch, corn starch, colloidal silica, or
amorphous magnesium aluminum silicate (commercially available as
VEEGUM.TM. or NEUSILIN.TM.). In preferred embodiments, the
pharmaceutical carrier for the adsorption of the corticosteroid is
silicified microcrystalline cellulose. It is preferably silicified
microcrystalline cellulose which is composed of intimately
associated microcrystalline cellulose and colloidal silicon dioxide
particles, (PROSOLV.RTM. SMCC: MCC, 98% and CSD, 2%). The use of
this ingredient in the composition of the disclosure improves the
flow and blending properties of the corticosteroid mixture;
improved blend uniformity/homogeneity and physical stability of the
formulations during storage until their final processing into
finished dosage forms such as tablets or capsules, i.e., to avoid
or minimize potential de-mixing and segregation of corticosteroid
microparticles is also achieved. The presence of this carrier in
admixture with the active also ensures reproducibility of
preparations of the composition of the disclosure (in particular
with the applied technology of direct tableting). In some
embodiments, a low-dose corticosteroid blend with the carrier
showing high blend uniformity, low-segregation potential and
excellent flowability is disclosed. This blend is particularly
suitable for producing a rapidly disintegrating diluted
corticosteroid composition. In some embodiments, of the disclosure
the blend comprises fluticasone propionate adsorbed on silicified
microcrystalline cellulose, and rapidly dispersing
microgranules.
[0077] In embodiments, the pharmaceutically acceptable carrier for
absorption of the corticosteroid is micronized. In some
embodiments, the micronized pharmaceutically acceptable carrier has
a diameter of less than about 20 microns, e.g., less than about 15
microns, less than about 10 microns, less than about 9 microns,
less than about 8 microns, less than about 7 microns, less than
about 6 microns, less than about 5 microns, less than about 4
microns, less than about 3 microns, less than about 2 microns, or
less than about 1 micron. In particular embodiments, the micronized
pharmaceutically acceptable carrier has a diameter of less about 5
microns.
[0078] In some embodiments, the pharmaceutically acceptable carrier
is present in the pharmaceutical composition (e.g., ODT) an amount
in the range of about 1 w/w to about 20% w/w, e.g., about 2%, about
3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%,
about 10%, about 11%, about 12%, about 13%, about 14%, about 15%,
about 16%, about 17%, about 18%, or about 19%, inclusive of all
values and subranges therein. In preferred embodiments, the
pharmaceutically carrier is present in the pharmaceutical
composition (e.g, ODT) an amount in the range of about 10% w/w.
[0079] In some embodiments, combining the corticosteroid with the
pharmaceutically acceptable carrier provides a batch of orally
disintegrating compositions having a corticosteroid content
uniformity within the range of about 85% to about 115% of the
corticosteroid dosage on the label (e.g., 1.5-7.5 mg, including 1.5
mg, 3.0 mg, 4.5 mg, 6.0 mg, and 7.0 mg). In some embodiments, the
batch has a corticosteroid content uniformity within the range of
about 90% to about 110% of the corticosteroid dosage on the label,
or within the range of about 95% to about 105%, or about 96% to
about 104%, or about 97% to about 103%, or about 98% to about 102%,
or about 99% to about 101%.
[0080] In some embodiments, the rate of disintegration of the
disintegrating compositions of the present disclosure (e.g., ODT,
wafer, lyophilized matrix, film, etc) in the oral cavity of an
individual can be on the order of about 60 seconds or less, about
50 seconds or less, about 40 seconds or less, about 30 seconds or
less, about 20 seconds or less, or about 10 seconds or less.
[0081] In some embodiments, the rate of disintegration of the
disintegrating compositions of the present disclosure (e.g., ODT,
wafer, lyophilized matrix, film, etc) measured using the USP
<701> Disintegration Test is about 60 seconds or less, about
45 seconds or less, about 30 seconds or less, about 20 seconds or
less, or about 10 seconds or less.
[0082] In addition to the corticosteroid and the carrier, the blend
of the compositions or the oral dosage forms of the present
disclosure may contain further pharmaceutically acceptable
ingredients which swell, dissolve or otherwise facilitate
disintegration. Such ingredients can include, but are not limited
to, a disintegrant, a sugar alcohol, a saccharide, or a mixture
thereof, a water-soluble polymeric binder, a bio-gelling or a
bioadhesive polymer, which can retain the corticosteroid particle
adhered onto the inflamed esophageal tissues longer than in its
absence.
[0083] In some embodiments, the present disclosure provides a solid
pharmaceutical composition comprising a corticosteroid and a
pharmaceutically acceptable bio-gelling polymer which enables
longer retention of the corticosteroid at the inflamed esophageal
tissues. The ingredient herein called "bio-gelling polymer" or
"bio-adhesive agent" is an agent which promote adhesion of the
corticosteroid to biological surfaces, especially the inflamed
mucosa through gelling under GI tract physiological conditions, for
example, upon contact with physiological fluids and/or at
physiological temperature, and includes, but is not limited to, the
bio-gelling polymers listed below.
[0084] The bio-gelling polymer may be a thermosensitive polymer.
Suitable thermosensitive polymers include polyacrylamides, such as
poly(N-isopropylacrylamide), as well as poly(ether-ester)
copolymers, such as poly(ethylene glycol-(DL-lactic
acid-co-glycolic acid)-ethylene glycol). Such thermosensitive
polymers can partially or fully cover the inflamed esophageal
tissues while keeping the corticosteroid particle(s) close or in
intimate contact with the inflamed tissues, thereby increasing the
topical contact of the corticosteroid with the inflamed
tissues.
[0085] In some embodiments, the compositions of the present
disclosure include a bioadhesive agent such as a lipid or a
polymer. Examples of such lipids are glycerphospholipids such as
phosphatidyl choline, and diacyl glycerols such as glycerol
dioleate. Examples of bioadhesive polymers include chitosan,
polyorthoesters, and copolymers, terpolymers and mixtures
thereof.
[0086] In some embodiments, the solid pharmaceutical compositions
of the present disclosure include an adhesive agent. Suitable
adhesive agents include, but are not limited to, sucrose aluminum
sulfate complex, chitosan and derivatives such as
trimethylchitosan, polyvinylpyrrolidone, methylcellulose,
hydroxypropyl cellulose, cross-linked polyacrylic acid copolymers,
polyvinylpyrrolidone, vinylpyrrolidone-polyvinyl acetate copolymer
(e.g., Kollidon.RTM. VA 64 from BASF), Soluplus.RTM., poly(ethylene
glycol 6000-vinylcaprolactam-vinyl acetate) (13:57:30) copolymer
from BASF), polyvinyl alcohol, polyethylene oxide, polyamide,
alginic acid and its salts, carrageenan, xanthan gum,
ammoniomethacrylate copolymers, CARBOPOL polymers, maltodextrins,
pectins, sucralose, and combinations thereof. In certain
embodiments of the solid pharmaceutical compositions of the present
disclosure, the corticosteroid and the adhesive agent are
intimately associated. In some embodiments, the solid
pharmaceutical composition comprises corticosteroid surrounded or
encapsulated by the adhesive agent. In some embodiments, the solid
pharmaceutical composition comprises corticosteroid disposed on the
surface of the adhesive agent. In still other embodiments, the
solid pharmaceutical composition comprises corticosteroid mixed or
granulated with the adhesive agent.
[0087] In certain embodiments, the solid pharmaceutical composition
includes any solid dosage form which disintegrates rapidly in the
mouth to form a suspension of powdered corticosteroid, which is
hypothesized to coat or adhere onto the inflamed esophageal mucosa
when swallowed.
[0088] In some embodiments, the composition of the present
disclosure is in the form of an ODT. The ODT comprises the drug in
an amount less than about 5% (weight of drug/weight of composition)
and a pharmaceutically acceptable carrier, wherein the composition
has no significant systemic glucocorticoid or mineralocorticoid
activity after oral administration in humans. The drug particles,
(e.g., a corticosteroid as described herein optionally coated or
optionally combined with an adhesive agent as described herein) are
combined with rapidly dispersing microgranules. Rapidly dispersing
microgranules comprise a sugar alcohol, a saccharide, or a mixture
thereof and a disintegrant alone or a disintegrant in combination
with a pharmaceutically acceptable additive with multi-functional
activity (e.g., pregelatinized starch, hydroxypropylcellulose or
the like).
[0089] A non-limiting list of suitable disintegrants for the
rapidly dispersing microgranules includes crospovidone
(cross-linked PVP), sodium starch glycolate, cross-linked sodium
carboxymethylcellulose, calcium silicate, and low substituted
hydroxypropyl cellulose.
[0090] The amount of disintegrant in the ODT is typically in the
range of about 1% to about 10% by weight.
[0091] Sugar alcohols are hydrogenated forms of carbohydrates in
which the carbonyl group (i.e., aldehyde or ketone) has been
reduced to a primary or secondary hydroxyl group. Non-limiting
examples of suitable sugar alcohols for the rapidly dispersing
granules of the pharmaceutical compositions of the present
disclosure include e.g., arabitol, isomalt, erythritol, glycerol,
lactitol, mannitol, sorbitol, xylitol, maltitol, and mixtures
thereof.
[0092] The term "saccharide" is synonymous with the term "sugars",
and includes but is not limited to, monosaccharides such as
glucose, fructose and ribose, and disaccharides such as sucrose,
lactose, maltose, trehalose, and cellobiose. Non-limiting examples
of suitable saccharides for use in the compositions of the present
disclosure include e.g., lactose, sucrose, maltose, and mixtures
thereof. In preferred embodiments, the composition does not include
lactose. In some embodiments, the rapidly dispersing granules
comprise at least one disintegrant in combination with a sugar
alcohol. In some embodiments, the rapidly dispersing granules
comprise at least one disintegrant in combination with a
saccharide. In some embodiments, the disintegrant-containing
granules comprise at least one disintegrant in combination with a
sugar alcohol and a saccharide.
[0093] The amount of sugar alcohol and/or saccharide in the rapidly
dispersing granules ranges from about 99%-90%, or about 95%-90% of
the total weight of the disintegrant-containing granules, including
all ranges and sub-ranges there between.
[0094] The amount of sugar alcohol and/or saccharide in the ODT
ranges from about 30% to about 70% by weight.
[0095] In some embodiments, the average particle size of a sugar
alcohol and/or saccharide is 30 .mu.m or less, for example about
1-30 .mu.m, about 5-30 .mu.m, about 5-25 .mu.m, about 5-20 .mu.m,
about 5-15 .mu.m, about 5-10 .mu.m, about 10-30 .mu.m, about 10-25
.mu.m, about 10-20 .mu.m, about 10-15 .mu.m 15-30 .mu.m, about
15-25 .mu.m, about 15-20 .mu.m, about 20-30 .mu.m, about 20-25
.mu.m, or about 25-30 .mu.m.
[0096] The ratio of the disintegrant to the sugar alcohol,
saccharide, or mixture thereof in the rapidly dispersing
microgranules ranges from about 90/10 to about 99/01, for example
about 90/10, about 91/9, about 92/8, about 93/7, about 94/6, about
95/5, about 96/4, about 97/3, about 98/2, about 99/1 , inclusive of
all values, ranges, and sub-ranges there between.
[0097] The rapidly dispersing microgranules present in the ODT help
rapid disintegration of the tablet when placed in the oral cavity,
creating a smooth suspension containing the corticosteroid drug
particles. It is desirable to incorporate sufficient amount of
rapidly dispersing microgranules to coat extensively the esophageal
mucosa. This creates a content uniformity problem in these low-dose
ODTs (for example, 300 mg ODT containing 12 mg or less of a
corticosteroid). Typically, this problem is overcome by
granulation, which involves spraying a dilute solution of the
corticosteroid on to an excipient powder bed. The drug particles
are embedded in the granules and consequently may not become
exposed to the inflamed mucosa, resulting in being poorly
efficacious. It has been surprisingly observed that it is possible
not only to achieve desired content uniformity but also to enhance
the probability of largely keeping the corticosteroid drug
particles exposed to the inflamed mucosa by adsorbing micronized
topically acting corticosteroid drug particles onto the
pharmaceutically acceptable carrier (such as silicified
microcrystalline cellulose) prior to blending with rapidly
dispersing microgranules and other excipients and compressing into
ODTs.
[0098] The dosage form as described herein may also include
pharmaceutically acceptable excipients typically used in
disintegrating tablet formulations such as fillers, diluents,
glidants, disintegrants, binders and lubricants.
[0099] Examples of suitable fillers, diluents and/or binders
include, but are not limited to, lactose (e.g. spray-dried lactose,
such as FAST-FLO.RTM.), microcrystalline cellulose (various grades
of Avicel.RTM., CEOLUS.RTM.), hydroxypropylcellulose,
L-hydroxypropylcellulose (low substituted), low molecular weight
hydroxypropyl methylcellulose (HPMC) (e.g., Methocel.TM. E, F and K
from Dow Chemical, MetholoseE SH from Shin-Etsu, Ltd),
hydroxyethylcellulose, sodium carboxymethylcellulose,
carboxymethylhydroxyethylcellulose and other cellulose derivatives,
sucrose, agarose, sorbitol, mannitol, dextrins, maltodextrins,
starches or modified starches (including potato starch, maize
starch and rice starch), calcium phosphate (e.g., basic calcium
phosphate, calcium hydrogen phosphate, dicalcium phosphate
hydrate), calcium sulfate, calcium carbonate, sodium alginate and
collagen. The preferred filler for the composition of the
disclosure is mannitol such as spray dried mannitol.
[0100] Examples of suitable disintegrants include, but are not
limited to, crospovidone (cross-linked PVP), sodium starch
glycolate, cross-linked sodium carboxymethylcellulose, calcium
silicate, and low substituted hydroxypropyl cellulose. The
preferred disintegrant for the composition of the disclosure is
crospovidone.
[0101] Specific examples of glidants and lubricants include stearic
acid, magnesium stearate, calcium stearate or other metallic
stearates, talc, glyceryl behenate, colloidal silica, com starch,
and optionally magnesium stearate or sodium stearyl fumarate
(lubricant intragranularly mixed or used externally to lubricate
die and punch surfaces). The preferred glidant for the composition
of the disclosure is colloidal silica and preferred lubricant is
sodium stearyl fumarate.
[0102] In some embodiments, the methods and compositions described
herein can be used to treat a patient suffering from EoE who also
has a lactose allergy and/or a starch allergy. Pharmaceutical
formulations comprising lactose can aggravate a lactose allergy in
a patient suffering from such, and this can cause increased
discomfort in patients also suffering from EoE. In certain
embodiments, the pharmaceutical compositions described herein do
not include lactose. Similarly, pharmaceutical formulations
comprising starch can aggravate a starch allergy in a patient
suffering from such, and this can cause increased discomfort in
patients also suffering from EoE. In certain embodiments, the
pharmaceutical compositions described herein do not include starch.
In further preferred embodiments, the pharmaceutical compositions
described herein do not include lactose and sucrose.
[0103] The solid pharmaceutical compositions of the present
disclosure can include other dosage forms besides an ODT, a wafer,
a film, or other solid dosage form which disintegrates rapidly in
the mouth to form a suspension or dispersion of a corticosteroid,
which can readily be swallowed to coat the mucosal surface of
eosinophilic esophagitis.
[0104] For example, wafers can include dried or lyophilized
compositions such as orally disintegrating or dissolving dosage
forms prepared using Zydis.RTM. lyophilization technology (e.g., as
described in U.S. Pat. No. 6,316,027), containing a corticosteroid
as the active pharmaceutical ingredient. Film dosage forms can
include edible films such as those described in U.S. Pat. No.
6,596,298 or U.S. Pat. No. 6,740,332, containing a corticosteroid
as the active pharmaceutical ingredient. In some embodiments, the
solid composition comprises a lyophilized matrix, wherein the
lyophilized matrix comprises corticosteroid, the carrier and
excipient. Suitable excipients include, but are not limited to,
mannitol, xylitol, sorbitol, maltol, maltitol, lactose, sucrose,
maltose, and combinations thereof.
[0105] Topical administration of a corticosteroid to the oral
cavity of individuals has been associated with candidiasis
infection and oral thrush. While the disclosure is designed so as
to be less prone to promoting such infections, in some embodiments
of the disclosure, the pharmaceutical composition may include an
antifungal agent. Suitable antifungal agents include, but are not
limited, to mitotic inhibitor antifungals, pyrimidine analog
antifungals, polyene antifungals, benzimidazole antifungals,
imidazole antifungals, polyene antifungals, triazole antifungals,
thiazole antifungals, allylamine antifungals, echinocandin
antifungals, and other "uncategorized" antifungals recognized in
the art that do not fall within any of the above categories (e.g.,
tolnaflate and ciclopirox). For example, suitable antifungal agents
which may be included in the solid pharmaceutical compositions of
the present disclosure include, but are not limited to, abafungin,
amorolfine, anidulafungin, bifonazole, butenafine, butoconazole,
candicin, caspofungin, ciclopirox, clotrimazole, econazole,
fenticonazole, filipin, fluconazole, flucytosine, griseofulvin,
isavuconizole, isoconazole, itraconazole, ketoconazole, micafungin,
miconazole, miconazole nitrate, naftifine, natamycin, nystatin,
oxiconazole, posaconazole, pramiconazole, ravuconazole, rimocidin,
setaconizole, sulconazole, terbafine, terconazole, tioconazole,
tolnaftate, undecylenic acid, and voriconazole.
[0106] In some embodiments, pharmaceutical compositions of the
present disclosure include an antiviral agent. Antiviral agents
which may be included in the solid pharmaceutical compositions of
the present disclosure include interferons, nucleoside and
nucleotide reverse transcriptase inhibitors, non-nucleoside reverse
transcriptase inhibitors, protease inhibitors, integrase
inhibitors, fusion inhibitors, maturation inhibitors, guanosine
analogs, puridine analogs, pyrimidine analogs, and other
"uncategorized" antiviral drugs recognized in the art which do not
fall within any of the above classes (e.g., foscarnet and
miltefosine). For example, suitable antiviral agents which may be
included in the solid pharmaceutical compositions of the present
disclosure include, but are not limited to, abacavir, aciclovir
(also known as acyclovir), adefovir, amantadine, amdoxovir,
amprenavir, aplaviroc, apricitabine, arbidol, atazanavir,
bevirimat, BMS-488043, boceprevir, brivudine, cidofovir, DCM205,
docosanol, delavirdine, didanosine, durunavir, efavirenz,
elvitegravir, elvucitabine, emtricitabine, enfuvirtide,
epigallocatechin gallate, etravirine, famciclovir, fosamprenavir,
ganciclocvir, globoidnan A, griffithsin, ibalizumab, idoxuridine,
indinavir, lamivudine, lopinavir, loviride, maraviroc, nelfinavir,
nevirapine, oseltamivir, pegylated interferon alpha-2a, pegylated
interferon alpha-2b, penciclovir, peramivir, plerixafor, PRO 140,
racivir, raltegrvir, ritonavir, ribavirin, rimantadine,
rlipivirine, saquinavir, stampidine, stavudine, tenofovir,
tipranavir, TNX-355, trifluridine, tromantadine, valaciclovir,
valganciclovir, vicriviroc, vidarabione, viramidine, vivecon,
zalcitabine, zanamivir, and zidovudine.
[0107] Tablet dosage forms, including ODT dosage forms, comprising
the low dosage strength of a topically acting corticosteroid (e.g.,
corticosteroids having systemic bioavailability of less or equal to
about 20% of the dose, or corticosteroids which are formulated to
reduce systemic bioavailability, each of which are described above)
and a pharmaceutically acceptable carrier, wherein the drug is in
amount less than about 5% (weight drug/weight of composition),
disintegrate in less than about 30 sec (USP method), and have a low
friability in order to have sufficient durability to withstand
handling, shipping, and/or packaging in push-through blister
packaging. In some embodiments, friability of the ODT dosage form
described herein is less than about 1%, e.g., less than about 0.9%,
less than about 0.8%, less than about 0.7%, less than about 0.6%,
less than about 0.5%, less than about 0.4%, less than about 0.3%,
etc., inclusive of all ranges and sub-ranges there between).
[0108] In preferred embodiments, the ODT used in (or for use in) in
the methods described herein comprises: a corticosteroid in an
amount of from about 0.25% to about 2.5% w/w (or about 0.75 mg to
about 7.5 mg); a pharmaceutically acceptable carrier in an amount
of from about 5% to about 15% w/w (or about 20 mg to about 40 mg);
and rapidly dispersing microgranules in an amount of from about 40%
to about 60% w/w (or about 125 mg to about 175 mg), wherein the
rapidly dispersing microgranules comprise a ratio of sugar
alcohol/saccharide to disintegrant of about 90:10 to about 99:1. In
embodiments, the ODT optionally further comprises: a disintegrant
in an amount of about 5% to about 10% w/w (or about 5 mg to 20 mg
to about 30 mg); a sugar alcohol or saccharide in an amount of
about 20% to about 40% w/w (or about 80 mg to about 100 mg); and
optional excipients.
[0109] Preferred embodiments of the pharmaceutical formulation
disclosed herein are described in Table 1 or Table 2.
TABLE-US-00001 TABLE 1 Compositions of compressible blends of
Fluticasone ODTs, 1.5 and 3 mg Fluticasone ODTs ODT 1.5 mg 3 mg
Ingredients (%/tablet) (mg/tablet) (%/tablet) (mg/tablet)
Micronized 0.50 1.50 1.0 3.00 Fluticasone Propionate USP Colloidal
Silicon 0.30 0.90 0.30 0.90 Dioxide NF Silicified 10.00 30.00 10.00
30.00 Microcrystalline Cellulose NF Crospovidone NF 7.50 22.50 7.50
22.50 Sucralose NF 0.40 1.20 0.40 1.20 Spray-dried 30.30 90.90
29.80 89.40 Mannitol USP Rapidly Dispersing 50.00 150.00 50.00
150.0 Granules Sodium Stearyl 1.00 3.00 1.00 3.00 Fumarate NF Total
100.00 300.0 100.00 300.0
TABLE-US-00002 TABLE 2 Compositions of compressible blends of
Fluticasone ODTs, 0.75 mg, 4.5 mg, 6 mg Fluticasone ODTs ODT 0.75
mg 4.5 mg 6.0 mg Ingredients (%/tablet) (mg/tablet) (mg/tablet)
(mg/tablet) Micronized 0.25 0.75 4.50 6.00 Fluticasone Propionate
USP Colloidal Silicon 0.30 0.90 0.90 0.90 Dioxide NF Silicified
10.00 30.0 30.00 30.00 Microcrystalline Cellulose NF Crospovidone
NF 7.50 22.50 22.50 22.50 Sucralose NF 0.40 1.20 1.20 1.20
Spray-dried 30.05 90.15 86.40 84.90 Mannitol USP Rapidly 50.00
150.00 150.00 150.0 Dispersing Granules Sodium Stearyl 1.50 4.50
4.50 4.50 Fumarate NF Total 100.00 300.0 300.0 300.0
Gastrointestinal Inflammation and Methods of Treatment
[0110] Treatment with topically acting corticosteroid (e.g.,
fluticasone propionate) results in fewer side-effects than other
treatments, for example a highly systemically acting
corticosteroid. Upon administration of a pharmaceutical composition
of the present disclosure to a patient, the composition
disintegrates in the patient's oral cavity, and contacts the
esophagus without being absorbed systemically, thus limiting
systemic effects.
[0111] In some embodiments, the present disclosure provides methods
of treating the symptoms associated with an inflammatory disorder
of the intestinal tract. In some embodiments, the present
disclosure provides methods of treating inflammation associated
with an inflammatory gastrointestinal disorder. In some embodiments
the present disclosure provides methods of treating both symptoms
and inflammation associated an inflammatory gastrointestinal
disorder. In some embodiments, the inflammatory gastrointestinal
disorder affects the upper gastrointestinal tract. In some
embodiments, the upper gastrointestinal tract is the esophagus.
[0112] In some embodiments, the oral corticosteroid contacts and/or
is deposited in the upper part of the gastrointestinal tract. In
some embodiments, the oral corticosteroid contacts and/or is
deposited in the esophagus. In some embodiments, the oral
corticosteroid contacts and/or is deposited in the distal portion
of the esophagus. In some embodiments, the pharmaceutical
composition contacts and/or is deposited in the proximal portion of
the esophagus. In some embodiments, the oral corticosteroid
contacts and/or is deposited in a substantially equivalent amount
in the distal and proximal portion of the esophagus.
[0113] Inflammatory gastrointestinal disorders which may be treated
according to the present disclosure include, but are not limited
to, inflammation of the esophagus, inflammation of the glottis,
inflammation of the epiglottis, inflammation of the tonsils,
inflammation of the oropharynx, eosinophilic esophagitis (EoE),
gastroesophageal reflux disease (GERD), non-erosive reflux disease
(NERD), erosive esophagitis, Barrett's esophagus, eosinophilic
gastroenteritis, hypereosinophilic syndrome, corrosive (caustic)
chemical esophagitis, radiation-induced esophagitis,
chemotherapy-induced esophagitis, transient drug-induced
esophagitis (also known as medication esophagitis), persistent
drug-induced esophagitis, Crohn's disease of the esophagus, and
pseudomembranous esophagitis. In some embodiments, the present
disclosure includes a method for treating a food allergy with an
identified allergen, e.g., "atopic IBS", and "atopic bowel". In
some embodiments, the present disclosure includes a method for
treating a patient having one or more of the above gastrointestinal
disorders, wherein the patient also has a lactose allergy and/or a
starch allergy. In some embodiments, the inflammatory
gastrointestinal disorder is eosinophilic esophagitis (EoE). In
some embodiments, the present disclosure includes a method for
treating a patient EoE, wherein the patient also a lactose allergy
and/or a starch allergy.
[0114] In some embodiments, the pharmaceutical compositions
disclosed herein are administered until symptoms and/or
inflammation associated with gastrointestinal inflammation are
treated. In some embodiments, the pharmaceutical compositions
disclosed herein continue to be administered after symptoms and/or
inflammation associated with gastrointestinal inflammation are
treated. In some embodiments, the symptom is dysphagia, episodes of
food impaction, feelings of having a lump in one's throat, and/or
increased eosinophil count in the esophagus.
[0115] The treatment of gastrointestinal inflammation may be
measured by any means known in the art. For example, tests used to
evaluate patients with esophageal inflammation such as EoE include,
but are not limited to, biopsies, evaluation of symptoms (e.g.
through patient reported outcome (PRO) or physician questionnaire),
quality of life measurements, determination of Dysphagia-Free-Days
in a patient, endoscopy (e.g. EREFS), esophageal compliance and/or
improvement in esophageal remodeling (e.g. using a suitable
diagnostic test such as EndoFLIP (available from Crospon Inc.),
evaluation of biomarkers, decrease in peak eosinophil count,
decrease in food impaction, EEsAI, Strong Dysphagia Index (DSQ),
MDQ-30, EoE-QOL-A, VDQ (Visual Dysphagia Questionnaire), Avoidance
Modification and Slow Eating (AMS) scores, and/or histology.
[0116] In some embodiments, patient response to treatment is
determined by measuring changes in one or more questionnaire scores
with a biological response such as histology score (e.g. eosinophil
count). Reliance on patient reported symptoms may yield false
positive results as patients may modify their behavior to reduce
incidents of dysphagia (e.g. avoiding problematic foods or other
behavior modifications such as increased chewing or liquid
consumption) which can alter questionnaire score regardless of
whether biological symptoms have improved.
[0117] In some embodiments, patient response is evaluated by
assessing histology scores in a patient. In some embodiments the
histology score is assessed by one or more different histologic
features, including but not limited to, eosinophil inflammation,
basal zone hyperplasia, dilated intercellular spaces, lamina
propria fibrosis, eosinophil abscess, surface layering, surface
epithelial alteration, and dyskeratotic epithelial cells.
[0118] In some embodiments, administration of the oral
corticosteroid according to the methods disclosed herein reduces a
histology score in a treated patient compared to an untreated
patient or the same patient before treatment. In some embodiments,
the histology score is measured in a treated patient between week 1
and year 10. In some embodiments, administration of the
pharmaceutical compositions disclosed herein reduces a histology
score at about week 1, about week 2, about week 3, about week 4,
about week 5, about week 6, about week 7, about week 8, about week
9, about week 10, about week 20, about week 30, about week 40,
about week 50, about week 60, about week 70, about week 80, about
week 90, about week 100, about year 1, about year 2, or about year
3 compared with the histology score in an untreated patient or the
same patient before treatment. In some embodiments, administration
of the pharmaceutical compositions disclosed herein reduces a
histology score for about 1 week, about 1 month, about 2 months,
about 3 months, about 4 months, about 5 months, about 6 months,
about 1 year, about 2 years, about 5 years, or about 10 years, or
more compared with the histology score in an untreated patient or
the same patient before treatment.
[0119] In some embodiments, a histology score is reduced by about
1%, about 5%, about 10%, about 20%, about 30%, about 40%, about
50%, about 60%, about 70%, about 80%, about 90%, or about 100%
compared with the histology score in an untreated patient or the
same patient before treatment. In some embodiments, administration
of the pharmaceutical compositions disclosed herein reduces the
histology score by about 1%, about 5%, about 10%, about 20%, about
30%, about 40%, about 50%, about 60%, about 70%, about 80%, about
90%, or about 100% at about week 1, about week 2, about week 3,
about week 4, about week 5, about week 6, about week 7, about week
8, about week 9, about week 10, about week 20, about week 30, about
week 40, about week 50, about week 60, about week 70, about week
80, about week 90, about week 100, about year 1, about year 2, or
about year 3 compared with the histology score in an untreated
patient or the same patient before treatment. In some embodiments,
administration of the pharmaceutical compositions disclosed herein
reduces the histology score by about 1%, about 5%, about 10%, about
20%, about 30%, about 40%, about 50%, about 60%, about 70%, about
80%, about 90%, or about 100% for about 1 week, about 1 month,
about 2 months, about 3 months, about 4 months, about 5 months,
about 6 months, about 1 year, about 2 years, about 5 years, or
about 10 years or more compared with the histology score in an
untreated patient or the same patient before treatment.
[0120] In some embodiments, administration of the oral
corticosteroid according to the methods disclosed herein reduces
peak eosinophil (per high power field (HPF), e.g., as described in
Example 2) in at least one biopsy in a treated patient compared to
peak eosinophil per HPF in an untreated patient or the same patient
before treatment. In some embodiments, administration of the
pharmaceutical compositions disclosed herein reduces peak
eosinophil in at least one biopsy to less than 15/HPF. In some
embodiments, administration of the pharmaceutical compositions
disclosed herein reduces peak eosinophil in at least one biopsy in
a treated patient to less than about 14/HPF, less than about
13/HPF, less than about 12/HPF, less than about 11/HPF, less than
about 10/HPF, less than about 9/HPF, less than about 8/HPF, less
than about 7/HPF, less than about 6/HPF, less than about 5/HPF,
less than about 4/HPF, less than about 3/HPF, less than about
2/HPF, less than about 1/HPF, or less (e.g. 0) in the patient. In
some embodiments, administration of the pharmaceutical compositions
disclosed herein reduce peak eosinophil in at least one biopsy to
less than 1 HPF in the patient. In some embodiments, the reduction
of peak eosinophil in at least one biopsy in a treated patient is
measured between about week 1 and about year 10. In some
embodiments, the reduction of peak eosinophil is measured at about
week 1, about week 2, about week 3, about week 4, about week 5,
about week 6, about week 7, about week 8, about week 9, about week
10, about week 20, about week 30, about week 40, about week 50,
about week 60, about week 70, about week 80, about week 90, about
week 100, about year 1, about year 2, or about year 3. In some
embodiments, administration of the pharmaceutical compositions
disclosed herein reduces peak eosinophil in at least one biopsy to
less than about 14/HPF, less than about 13/HPF, less than about
12/HPF, less than about 11/HPF, less than about 10/HPF, less than
about 9/HPF, less than about 8/HPF, less than about 7/HPF, less
than about 6/HPF, less than about 5/HPF, less than about 4/HPF,
less than about 3/HPF, less than about 2/HPF, less than about 1/HPF
or less (e.g. 0) in the patient at about week 1, about week 2,
about week 3, about week 4, about week 5, about week 6, about week
7, about week 8, about week 9, about week 10, about week 20, about
week 30, about week 40, about week 50, about week 60, about week
70, about week 80, about week 90, about week 100, about year 1,
about year 2, or about year 3. In some embodiments, administration
of the pharmaceutical compositions disclosed herein reduces peak
eosinophil in at least one biopsy to less than about 14/HPF, less
than about 13/HPF, less than about 12/HPF, less than about 11/HPF,
less than about 10/HPF, less than about 9/HPF, less than about
8/HPF, less than about 7/HPF, less than about 6/HPF, less than
about 5/HPF, less than about 4/HPF, less than about 3/HPF, less
than about 2/HPF, less than about 1/HPF or less (e.g. 0) in the
patient for about 1 week, about 1 month, about 2 months, about 3
months, about 4 months, about 5 months, about 6 months, about 1
year, about 2 years, about 5 years, or about 10 years, or more
[0121] In some embodiments, administration of the oral
corticosteroid according to the methods disclosed herein reduces
peak eosinophil (per high power field (HPF), e.g., as described in
Example 2) in at least one biopsy in a treated patient compared to
peak eosinophil per HPF in an untreated patient or the same patient
before treatment by at least about 10%, e.g., about 15%, about 20%,
about 25%, about 30%, about 35%, about 40%, about 45%, about 50%,
about 55%, about 60%, about 65%, about 70%, about 75%, about 80%,
about 85%, about 90%, about 91%, about 92%, about 93%, about 94%,
about 95%, about 96%, about 97%, about 98%, or about 99%, inclusive
of all values and subranges therebetween. In particular
embodiments, the peak eosinophil count is reduced by an amount in
the range of about 50% to about 99%, e.g., about 55%, about 60%,
about 65%, about 70%, about 75%, about 80%, about 85%, about 90%,
about 91%, about 92%, about 93%, about 94%, about 95%, about 96%,
about 97%, about 98%, inclusive of all values and subranges
therebetween.
[0122] In some embodiments, administration of the pharmaceutical
compositions disclosed herein reduces peak eosinophil in at least
one biopsy from a treated patient at week 12, week 26, or week 52.
In some embodiments, administration of the pharmaceutical
compositions disclosed herein reduces peak eosinophil in at least
one biopsy from a treated patient to less than about 6/HPF at week
12, week 26, or week 52. In some embodiments, administration of the
pharmaceutical compositions disclosed herein reduces peak
eosinophil in all tested biopsies from a treated patient at week
12, week 26, or week 52. In some embodiments, administration of the
pharmaceutical compositions disclosed herein reduces peak
eosinophil in all tested biopsies from a treated patient to less
than about 6/HPF at week 12, week 26, or week 52.
[0123] In some embodiments, administration of the pharmaceutical
compositions disclosed herein reduce mean score in a patient
questionnaire completed by the patient or a physician. In some
embodiments, the questionnaire is Eosinophilic Esophagitis Activity
Index (EEsAI), which can use either a 7-day recall period or a
daily recall period to monitor the severity and frequency of
dysphagia and any dietary modifications. In some embodiments, the
questionnaire is Dysphagia Symptom Questionnaire (DSQ), which is a
daily symptom diary used to monitor dysphagia frequency. In some
embodiments, the questionnaire is a customized patient-reported
outcome assessment which includes the assessment of dysphagia-free
days. In some embodiments, the total score of a questionnaire such
as the EEsAI or PROSE are used in combination with other patient
assessments to measure patient response to treatment. In some
embodiments, the correlation of questionnaire score with
improvement in histological measurements (e.g. eosinophil count)
indicates patient response to treatment.
[0124] In some embodiments, the mean questionnaire score is
measured in a treated patient between week 1 and year 10. In some
embodiments, administration of the pharmaceutical compositions
disclosed herein reduces the mean questionnaire score at about week
1, about week 2, about week 3, about week 4, about week 5, about
week 6, about week 7, about week 8, about week 9, about week 10,
about week 20, about week 30, about week 40, about week 50, about
week 60, about week 70, about week 80, about week 90, about week
100, about year 1, about year 2, or about year 3 compared with the
mean questionnaire score in an untreated patient or the same
patient before treatment. In some embodiments, administration of
the pharmaceutical compositions disclosed herein reduces the mean
questionnaire score for about 1 week, about 1 month, about 2
months, about 3 months, about 4 months, about 5 months, about 6
months, about 1 year, about 2 years, about 5 years, or about 10
years or more compared with the mean questionnaire score in an
untreated patient or the same patient before treatment. In some
embodiments, the mean questionnaire score is reduced by about 1%,
about 5%, about 10%, about 20%, about 30%, about 40%, about 50%,
about 60%, about 70%, about 80%, about 90%, or about 100% compared
with the mean questionnaire score in an untreated patient or the
same patient before treatment. In some embodiments, administration
of the pharmaceutical compositions disclosed herein reduces the
mean questionnaire score by about 1%, about 5%, about 10%, about
20%, about 30%, about 40%, about 50%, about 60%, about 70%, about
80%, about 90%, or about 100% at about week 1, about week 2, about
week 3, about week 4, about week 5, about week 6, about week 7,
about week 8, about week 9, about week 10, about week 20, about
week 30, about week 40, about week 50, about week 60, about week
70, about week 80, about week 90, about week 100, about year 1,
about year 2, or about year 3 compared with the mean questionnaire
score in an untreated patient or the same patient before treatment.
In some embodiments, administration of the pharmaceutical
compositions disclosed herein reduces the mean questionnaire score
by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%,
about 50%, about 60%, about 70%, about 80%, about 90%, or about
100% for about 1 week, about 1 month, about 2 months, about 3
months, about 4 months, about 5 months, about 6 months, about 1
year, about 2 years, about 5 years, or about 10 years or more
compared with the mean questionnaire score in an untreated patient
or the same patient before treatment.
[0125] In some embodiments, the patient questionnaire is EEsAI. In
some embodiments, administration of the pharmaceutical compositions
disclosed herein reduces mean EEsAI score to less than 20. In some
embodiments, administration of the pharmaceutical compositions
disclosed herein reduces mean EEsAI score of a treated patient to
less than about 19, less than about 18, less than about 17, less
than about 16, less than about 15 less than about 14, less than
about 13, less than about 12, less than about 11, less than about
10, less than about 9, less than about 8, less than about 7, less
than about 6, less than about 5, less than about 4, less than about
3, less than about 2, less than about 1, or about 0. In some
embodiments, the reduction of mean EEsAI score in a treated patient
is measured between about week 1 and about year 10. In some
embodiments, the reduction of mean EEsAI score is measured at about
week 1, about week 2, about week 3, about week 4, about week 5,
about week 6, about week 7, about week 8, about week 9, about week
10, about week 20, about week 30, about week 40, about week 50,
about week 60, about week 70, about week 80, about week 90, about
week 100, about year 1, about year 2, or about year 3. In some
embodiments, administration of the pharmaceutical compositions
disclosed herein reduces mean EEsAI score to less than about 20,
less than about 19, less than about 18, less than about 17, less
than about 16, less than about 15, less than about 14, less than
about 13, less than about 12, less than about 11, less than about
10, less than about 9, less than about 8, less than about 7, less
than about 6, less than about 5, less than about 4, less than about
3, less than about 2, less than about 1, or less (e.g. 0) at about
week 1, about week 2, about week 3, about week 4, about week 5,
about week 6, about week 7, about week 8, about week 9, about week
10, about week 20, about week 30, about week 40, about week 50,
about week 60, about week 70, about week 80, about week 90, about
week 100, about year 1, about year 2, or about year 3. In some
embodiments, administration of the pharmaceutical compositions
disclosed herein reduces mean EEsAI score to less than about 20,
less than about 19, less than about 18, less than about 17, less
than about 16, less than about 15, less than about 14, less than
about 13, less than about 12, less than about 11, less than about
10, less than about 9, less than about 8, less than about 7, less
than about 6, less than about 5, less than about 4, less than about
3, less than about 2, less than about 1, or less (e.g. 0) for about
1 week, about 1 month, about 2 months, about 3 months, about 4
months, about 5 months, about 6 months, about 1 year, about 2
years, about 5 years, or about 10 years, or more.
[0126] In some embodiments, administration of the pharmaceutical
compositions disclosed herein reduces mean EEsAI score in a treated
patient at week 12, week 26, or week 52. In some embodiments,
administration of the pharmaceutical compositions disclosed herein
reduces mean EEsAI score in a treated patient to less than about 20
at week 12, week 26, or week 52.
[0127] In some embodiments, administration of the pharmaceutical
compositions disclosed herein reduce mean EoE Endoscopic Reference
Score (EREFS) in a treated patient, which measures edema (e.g.
decreased vascularity or pallot), rings present, exudates (e.g.
white plaques), furrows, and/or stricture in the esophagus
according to Table 3. In some embodiments, the EREFS score in a
patient correlates with histologic response (e.g. eosinophil count)
and EREFS score can be used in conjunction with histologic response
to measure patient response to treatment.
TABLE-US-00003 TABLE 3 EREFS Score Assessment Characteristic Grade
0 Grade 1 Grade 2 Grade 3 Edema (loss Distinct Decreased Absent
vascular markings) vascularity Rings None Mild Moderate Severe
(trachealization) (ridges) (distinct (cannot rings) pass endoscope)
Exudate (white None Mild Severe plaques) (.ltoreq.10% (.gtoreq.10%
surface surface area) area) Furrows (vertical None Mild Severe
lines) (depth) Stricture Absent Present
[0128] In some embodiments, the compositions and methods disclosed
herein reduce the EREFS score for edema to 1 or 0. In some
embodiments, the compositions and methods disclosed herein reduce
the EREFS score for rings to 2, 1, or 0. In some embodiments, the
compositions and methods disclosed herein reduce the EREFS score
for exudates to 1, or 0. In some embodiments, the compositions and
methods disclosed herein reduce the EREFS score for exudates to 1,
or 0. In some embodiments, the compositions and methods disclosed
herein reduce the EREFS score for furrows to 1, or 0. In some
embodiments, the compositions and methods disclosed herein
substantially remove strictures.
[0129] In some embodiments, administration of the pharmaceutical
compositions disclosed herein reduces the mean EREFS score to less
than about 10, about 9, about 8, about 7, about 6, about 5, about
4, about 3, about 2, about 1, or about zero in a treated patient.
In some embodiments, the mean EREFS score is measured in a treated
patient between week 1 and year 10. In some embodiments,
administration of the pharmaceutical compositions disclosed herein
reduces the EREFS score at about week 1, about week 2, about week
3, about week 4, about week 5, about week 6, about week 7, about
week 8, about week 9, about week 10, about week 20, about week 30,
about week 40, about week 50, about week 60, about week 70, about
week 80, about week 90, about week 100, about year 1, about year 2,
or about year 3. In some embodiments, administration of the
pharmaceutical compositions disclosed herein reduces the mean EREFS
score for about 1 week, about 1 month, about 2 months, about 3
months, about 4 months, about 5 months, about 6 months, about 1
year, about 2 years, about 5 years, or about 10 years or more in a
treated patient. In some embodiments, administration of the
pharmaceutical compositions disclosed herein reduces the mean EREFS
score to less than about 10, about 9, about 8, about 7, about 6,
about 5, about 4, about 3, about 2, about 1, or about zero at about
week 1, about week 2, about week 3, about week 4, about week 5,
about week 6, about week 7, about week 8, about week 9, about week
10, about week 20, about week 30, about week 40, about week 50,
about week 60, about week 70, about week 80, about week 90, about
week 100, about year 1, about year 2, or about year 3. In some
embodiments, administration of the pharmaceutical compositions
disclosed herein reduces the mean EREFS score to less than about
10, about 9, about 8, about 7, about 6, about 5, about 4, about 3,
about 2, about 1, or about zero for about 1 week, about 1 month,
about 2 months, about 3 months, about 4 months, about 5 months,
about 6 months, about 1 year, about 2 years, about 5 years, or
about 10 years or more in a treated patient.
[0130] In some embodiments, administration of the pharmaceutical
compositions disclosed herein reduces mean EREFS score in a treated
patient at about week 12, about week 26, or about week 52.
[0131] In some embodiments, administration of the pharmaceutical
compositions disclosed herein reduces episodes of dysphagia in a
treated patient. In some embodiments, reduction of episodes of
dysphagia in a treated patient is measured by determining
Dysphagia-Free-Days in the patient. In some embodiments,
improvement in Dysphagia-Free-Days in a patient is measured in
conjunction with other patient measurements such as improved
histologic scores (e.g. eosinophil counts) to measure patient
response to treatment. In some embodiments, administration of the
pharmaceutical compositions disclosed herein reduce dysphagia in a
treated patient compared with episodes of dysphagia in an untreated
subject or in the same patient before treatment. In some
embodiments, administration of the pharmaceutical compositions
disclosed herein reduce episodes of dysphagia to fewer than about 6
per week. In some embodiments, administration of the pharmaceutical
compositions disclosed herein reduces episodes of dysphagia to
fewer than 6 per week over a time period of two weeks. In some
embodiments, administration of the pharmaceutical compositions
disclosed herein reduces episodes of dysphagia to fewer than about
6 per week, about 5 per week, about 4 per week, about 3 per week,
about 2 per week, about one per week, or none per week. In some
embodiments, administration of the pharmaceutical compositions
disclosed herein reduces episodes of dysphagia to fewer than about
6 per week, about 5 per week, about 4 per week, about 3 per week,
about 2 per week, about one per week, or none per week over a time
period of two weeks.
[0132] In some embodiments, episodes of dysphagia are reduced by up
to about 100%. In some embodiments, episodes of dysphagia are
reduced by up to about 1%, about 5%, about 10%, about 20%, about
30%, about 40%, about 50%, about 60%, about 70%, about 80%, about
90%, or about 100% compared with episodes of dysphagia in an
untreated patient or the same patient before treatment. In some
embodiments, dysphagia is eliminated. In some embodiments,
dysphagia is assessed in a treated patient between week 1 and year
10. In some embodiments, administration of the pharmaceutical
compositions disclosed herein reduces episodes of dysphagia at
about week 1, about week 2, about week 3, about week 4, about week
5, about week 6, about week 7, about week 8, about week 9, about
week 10, about week 20, about week 30, about week 40, about week
50, about week 60, about week 70, about week 80, about week 90,
about week 100, about year 1, about year 2, or about year 3. In
some embodiments, administration of the pharmaceutical compositions
disclosed herein reduces dysphagia for about 1 week, about 1 month,
about 2 months, about 3 months, about 4 months, about 5 months,
about 6 months, about 1 year, about 2 years, about 5 years, or
about 10 years or more compared with the number of episodes of
dysphagia in an untreated patient or the patient before treatment.
In some embodiments, episodes of dysphagia are reduced by up to
about 1%, about 5%, about 10%, about 20%, about 30%, about 40%,
about 50%, about 60%, about 70%, about 80%, about 90%, or about
100% compared with episodes of dysphagia in an untreated patient or
the same patient before treatment at about week 1, week 2, about
week 3, about week 4, about week 5, about week 6, about week 7,
about week 8, about week 9, about week 10, about week 20, about
week 30, about week 40, about week 50, about week 60, about week
70, about week 80, about week 90, about week 100, about year 1,
about year 2, or about year 3. In some embodiments, episodes of
dysphagia are reduced by up to about 1%, about 5%, about 10%, about
20%, about 30%, about 40%, about 50%, about 60%, about 70%, about
80%, about 90%, or about 100% compared with episodes of dysphagia
in an untreated patient or the same patient before treatment for
about 1 week, about 1 month, about 2 months, about 3 months, about
4 months, about 5 months, about 6 months, about 1 year, about 2
years, about 5 years, or about 10 years or more compared with the
number of episodes of dysphagia in an untreated patient or the
patient before treatment.
[0133] In some embodiments, administration of the pharmaceutical
compositions disclosed herein reduces episodes of dysphagia in a
treated patient at week 12, week 26, or week 52 compared with
episodes of dysphagia in an untreated patient or the same patient
before treatment.
[0134] In some embodiments, administration of the pharmaceutical
compositions disclosed herein reduces food impaction in a treated
patient compared with episodes of food impaction in an untreated
patient or in the same patient before treatment. In some
embodiments, administration of the pharmaceutical compositions
disclosed herein reduces episodes of food impaction to fewer than 4
per week. In some embodiments, administration of the pharmaceutical
compositions disclosed herein reduces episodes of food impaction to
fewer than 4 per week over a time period of two weeks. In some
embodiments, administration of the pharmaceutical compositions
disclosed herein reduces episodes of food impaction to fewer than
about 4 per week, about 3 per week, about 2 per week, about one per
week, or none per week. In some embodiments, administration of the
pharmaceutical compositions disclosed herein reduces episodes of
food impaction to fewer than about 4 per week, about 3 per week,
about 2 per week, about one per week, or none per week over a time
period of two weeks.
[0135] In some embodiments, episodes of food impaction are reduced
by up to about 100%. In some embodiments, episodes of food
impaction are reduced by up to about 1%, about 5%, about 10%, about
20%, about 30%, about 40%, about 50%, about 60%, about 70%, about
80%, about 90%, or about 100% compared with episodes of food
impaction in an untreated patient or the same patient before
treatment. In some embodiments, food impaction is eliminated. In
some embodiments, episodes of food impaction are assessed in a
treated patient between week 1 and year 10. In some embodiments,
administration of the pharmaceutical compositions disclosed herein
reduces episodes of food impaction at about week 1, about week 2,
about week 3, about week 4, about week 5, about week 6, about week
7, about week 8, about week 9, about week 10, about week 20, about
week 30, about week 40, about week 50, about week 60, about week
70, about week 80, about week 90, about week 100, about year 1,
about year 2, or about year 3. In some embodiments, administration
of the pharmaceutical compositions disclosed herein reduces
episodes of food impaction for about 1 week, about 1 month, about 2
months, about 3 months, about 4 months, about 5 months, about 6
months, about 1 year, about 2 years, about 5 years, or about 10
years or more compared with the number of episodes of food
impaction in an untreated patient or the same patient before
treatment. In some embodiments, episodes of food impaction are
reduced by up to about 1%, about 5%, about 10%, about 20%, about
30%, about 40%, about 50%, about 60%, about 70%, about 80%, about
90%, or about 100% compared with episodes of food impaction in an
untreated patient or the same patient before treatment at about
week 1, about week 2, about week 3, about week 4, about week 5,
about week 6, about week 7, about week 8, about week 9, about week
10, about week 20, about week 30, about week 40, about week 50,
about week 60, about week 70, about week 80, about week 90, about
week 100, about year 1, about year 2, or about year 3. In some
embodiments, episodes of food impaction are reduced by up to about
1%, about 5%, about 10%, about 20%, about 30%, about 40%, about
50%, about 60%, about 70%, about 80%, about 90%, or about 100%
compared with episodes of food impaction in an untreated patient or
the same patient before treatment for about 1 week, about 1 month,
about 2 months, about 3 months, about 4 months, about 5 months,
about 6 months, about 1 year, about 2 years, about 5 years, or
about 10 years or more compared with the number of episodes of food
impaction in an untreated patient or the same patient before
treatment.
[0136] In some embodiments, administration of the pharmaceutical
compositions disclosed herein reduces episodes of food impaction in
a treated patient at week 12, week 26, or week 52 compared with
food impaction in an untreated patient or the same patient before
treatment.
[0137] In some embodiments, administration of the pharmaceutical
compositions disclosed herein reduces Global EoE score in a treated
patient compared with Global EoE score in an untreated patient or
in the same patient before treatment.
[0138] In some embodiments, the reduction of Global EoE score in a
treated patient is measured between about week 1 and about year 10.
In some embodiments, administration of the pharmaceutical
compositions disclosed herein reduces Global EoE score at about
week 1, about week 2, about week 3, about week 4, about week 5,
about week 6, about week 7, about week 8, about week 9, about week
10, about week 20, about week 30, about week 40, about week 50,
about week 60, about week 70, about week 80, about week 90, about
week 100, about year 1, about year 2, or about year 3 compared with
an untreated patient or the same patient before treatment. In some
embodiments, administration of the pharmaceutical compositions
disclosed herein reduces Global EoE score for about 1 week, about 1
month, about 2 months, about 3 months, about 4 months, about 5
months, about 6 months, about 1 year, about 2 years, about 5 years,
or about 10 years compared with the Global EoE score in an
untreated patient or the patient before treatment. In some
embodiments, Global EoE score is reduced by up to about 1%, about
5%, about 10%, about 20%, about 30%, about 40%, about 50%, about
60%, about 70%, about 80%, about 90%, or about 100% compared with
Global EoE score in an untreated patient or the same patient before
treatment commenced.
[0139] In some embodiments, administration of the pharmaceutical
compositions disclosed herein reduces Global EoE score by up to
about 1%, about 5%, about 10%, about 20%, about 30%, about 40%,
about 50%, about 60%, about 70%, about 80%, about 90%, or about
100% compared with Global EoE score in an untreated patient or the
same patient before treatment at about week 1, about week 2, about
week 3, about week 4, about week 5, about week 6, about week 7,
about week 8, about week 9, about week 10, about week 20, about
week 30, about week 40, about week 50, about week 60, about week
70, about week 80, about week 90, about week 100, about year 1,
about year 2, or about year 3. In some embodiments, administration
of the pharmaceutical compositions disclosed herein reduces Global
EoE score by up to about 1%, about 5%, about 10%, about 20%, about
30%, about 40%, about 50%, about 60%, about 70%, about 80%, about
90%, or about 100% compared with Global EoE score in an untreated
patient or the same patient before treatment for about 1 week,
about 1 month, about 2 months, about 3 months, about 4 months,
about 5 months, about 6 months, about 1 year, about 2 years, about
5 years, or about 10 years, or more.
[0140] Global EoE is scored on a scale of 0 to 10, with 0
representing no EoE symptoms, and 10 representing most severe EoE
symptoms. In some embodiments, administration of the pharmaceutical
compositions disclosed herein reduces Global EoE score in a treated
subject to less than about 5. In some embodiments, administration
of the pharmaceutical compositions disclosed herein reduces Global
EoE score to less than about 10, less than about 9, less than about
8, less than about 7, less than about 6, less than about 5, less
than about 4, less than about 3, less than about 2, less than about
1, or about 0. In some embodiments, administration of the
pharmaceutical compositions disclosed herein reduces Global EoE
score in a treated subject to less than about 10, less than about
9, less than about 8, less than about 7, less than about 6, less
than about 5, less than about 4, less than about 3, less than about
2, less than about 1, or about 0 at about week 1, week 2, about
week 3, about week 4, about week 5, about week 6, about week 7,
about week 8, about week 9, about week 10, about week 20, about
week 30, about week 40, about week 50, about week 60, about week
70, about week 80, about week 90, about week 100, about year 1,
about year 2, or about year 3. In some embodiments, administration
of the pharmaceutical compositions disclosed herein reduces Global
EoE score in a treated subject to less than about 10, less than
about 9, less than about 8, less than about 7, less than about 6,
less than about 5, less than about 4, less than about 3, less than
about 2, less than about 1, or about 0 for about 1 week, about 1
month, about 2 months, about 3 months, about 4 months, about 5
months, about 6 months, about 1 year, about 2 years, about 5 years,
or about 10 years, or more.
[0141] In some embodiments, administration of the pharmaceutical
compositions disclosed herein reduces Global EoE score in a treated
patient at about week 12, about week 26, or about week 52 compared
with Global EoE score in an untreated patient or the same patient
before treatment.
[0142] In some embodiments, administration of the pharmaceutical
compositions disclosed herein improves characteristics as measured
by endoscopy (e.g. EndoFlip) in a treated patient compared with an
untreated patient or the same patient before treatment commenced.
These characteristics include, but are not limited to esophagus
diameter, esophageal compliance, focal narrowing of the esophagus,
esophageal body distensibility, esophageal body cross-sectional
areas (CSA), and intra-luminal diameter.
[0143] In some embodiments, the characteristics as measured by
endoscopy are assessed in a treated patient between week 1 and year
10. In some embodiments, administration of the pharmaceutical
compositions disclosed herein improves characteristics as measured
by endoscopy at about week 1, about week 2, about week 3, about
week 4, about week 5, about week 6, about week 7, about week 8,
about week 9, about week 10, about week 20, about week 30, about
week 40, about week 50, about week 60, about week 70, about week
80, about week 90, about week 100, about year 1, about year 2, or
about year 3 compared with an untreated patient or the same patient
before treatment. In some embodiments, administration of the
pharmaceutical compositions disclosed herein improves
characteristics as measured by endoscopy for about 1 week, about 1
month, about 2 months, about 3 months, about 4 months, about 5
months, about 6 months, about 1 year, about 2 years, about 5 years,
or about 10 years or more compared with an untreated patient or the
same patient before treatment. In some embodiments, characteristics
as measured by endoscopy are improved by up to about 100%. In some
embodiments, characteristics as measured by endoscopy are improved
by up to about 1%, about 5%, about 10%, about 20%, about 30%, about
40%, about 50%, about 60%, about 70%, about 80%, about 90%, or
about 100% compared with an untreated patient or the same patient
before treatment. In some embodiments, administration of the
pharmaceutical compositions disclosed herein improves
characteristics as measured by endoscopy by up by about 1%, about
5%, about 10%, about 20%, about 30%, about 40%, about 50%, about
60%, about 70%, about 80%, about 90%, or about 100% compared with
an untreated patient or the same patient before treatment at about
week 1, about week 2, about week 3, about week 4, about week 5,
about week 6, about week 7, about week 8, about week 9, about week
10, about week 20, about week 30, about week 40, about week 50,
about week 60, about week 70, about week 80, about week 90, about
week 100, about year 1, about year 2, or about year 3. In some
embodiments, administration of the pharmaceutical compositions
disclosed herein improves characteristics as measured by endoscopy
by up by about 1%, about 5%, about 10%, about 20%, about 30%, about
40%, about 50%, about 60%, about 70%, about 80%, about 90%, or
about 100% compared with EndoFlip score in an untreated patient or
the same patient before treatment for about 1 week, about 1 month,
about 2 months, about 3 months, about 4 months, about 5 months,
about 6 months, about 1 year, about 2 years, about 5 years, or
about 10 years or more.
[0144] In some embodiments, administration of the pharmaceutical
compositions disclosed herein improves characteristics as measured
by endoscopy in a treated patient at week 12, week 26, or week 52
compared with an untreated patient or the same patient before
treatment.
[0145] In some embodiments, administration of the pharmaceutical
compositions disclosed reduces the number of episodes associated
with EoE experienced by a patient over a period of time.
Non-limiting examples of such episodes include difficulty
swallowing a pill or food. The occurrence of such episodes may be
reported by the patient as a feeling of discomfort after swallowing
a pill or food, and may be measured after each instance of
swallowing a pill or food or over a 24 hour period or more. Any
method can be used to assess or report patient discomfort,
including PROSE.
[0146] In some embodiments, the number of episodes occurring over
said period of time is reduced by at least 1 episode, at least 2
episodes, at least 3 episodes, at least 4 episodes, at least 5
episodes, at least 6 episodes, at least 7 episodes, at least 8
episodes, at least 9 episodes, at least 10 episodes, at least 11
episodes, at least 12 episodes, at least 13 episodes, at least 14
episodes, at least 15 episodes, at least 16 episodes, at least 17
episodes, at least 18 episodes, at least 19 episodes, or at least
20 episodes, least 21 episodes, at least 22 episodes, at least 23
episodes, at least 24 episodes, at least 25 episodes, at least 26
episodes, at least 27 episodes, at least 28 episodes, at least 29
episodes, or at least 30 episodes, least 31 episodes, at least 32
episodes, at least 33 episodes, at least 34 episodes, at least 35
episodes, at least 36 episodes, at least 37 episodes, at least 38
episodes, at least 39 episodes, or at least 40 episodes, least 41
episodes, at least 42 episodes, at least 43 episodes, at least 44
episodes, at least 45 episodes, at least 46 episodes, at least 47
episodes, at least 48 episodes, at least 49 episodes, or at least
50 episodes. In some embodiments, the time period is about 1 week,
about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6
weeks, about 7 weeks, about 8 weeks, about 9, weeks about 10 weeks,
about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks,
about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks,
about 100 weeks, about 1 year, about 2 years, or about 3 years.
Dosing and Administration
[0147] The oral corticosteroids disclosed herein may be
administered in any appropriate dose and using any suitable
pharmaceutical composition. While one of skill in the art can
determine the desirable dose in each case, a suitable dose of the
therapeutic agent for achievement of therapeutic benefit, may, for
example, be in a range of about 1 microgram (.mu.g) to about 100
milligrams (mg) per kilogram body weight of the recipient per day,
preferably in a range of about 10 .mu.g to about 50 mg per kilogram
body weight per day and most preferably in a range of about 10
.mu.g to about 50 mg per kilogram body weight per day. In some
embodiments, the pharmaceutical composition is administered at a
low dose, e.g., about 20 mg or less. In some embodiments, the oral
corticosteroid is administered at about 1 mg per kilogram body
weight per day, about 3 mg per kilogram body weight per day, and/or
about 9 mg per kilogram body weight per day. The desired dose may
be presented as one dose or two or more sub-doses administered at
appropriate intervals throughout the day. These sub-doses can be
administered in unit dosage forms, for example, containing from
about 10 .mu.g to about 1000 mg, preferably from about 0.05 mg to
about 20 mg, and most preferably from about 0.5 mg to about 7.5 mg.
In some embodiments, the pharmaceutical composition is administered
in a unit dosage form of 0.75 mg, 1.5 mg, 3.0 mg, 4.5 mg, 6.0 mg,
or 7.5.
[0148] In some embodiments, the pharmaceutical composition
described herein (e.g., a liquid or solid composition comprising an
oral corticosteroid) is administered to a patient once a day at
bedtime (HS). In some embodiments, the pharmaceutical composition
is administered to a patient twice a day (BID). In some
embodiments, the pharmaceutical composition is administered to a
patient once in the morning and once in the evening. In some
embodiments, the pharmaceutical composition is administered on an
empty stomach (e.g. at least 2 hours after eating or at least 1
hour before eating; or at least 30 minutes before or after eating).
In some embodiments, the pharmaceutical composition is administered
to a patient 30 minutes before breakfast and 30 minutes before
bedtime. In some embodiments, administering the pharmaceutical
composition before bedtime decreases systemic adsorption of the
oral corticosteroid compared to systemic adsorption observed after
daytime dosing.
[0149] Thus, in some embodiments, the pharmaceutical composition is
administered during the evening between about 7 pm and about 10 pm,
e.g., at about 7 pm, 7:30 pm, about 8 pm, about 8:30 pm, about 9
pm, or about 9:30 pm, inclusive of all values and subranges
therebetween. In some embodiments, the pharmaceutical composition
is administered about 30 minutes before the target sleep time. The
term "target sleep time" can mean the time of day that the patient
anticipates going to bed.
[0150] Preliminary investigations of therapeutic efficacy in
treating EoE following conventional oral administration of the oral
corticosteroid (i.e., while the patient is upright) revealed higher
eosinophil clearance in the proximal portion esophagus (e.g.,
closer to the oral cavity) and lower eosinophil clearance in the
distal portion of the esophagus (e.g., closer to the stomach).
Without being bound by theory, these results suggested increased
contact of the corticosteroid with the proximal esophageal tissue,
and decreased contact of the corticosteroid with the distal
esophageal tissue. Various experiments were performed in an attempt
to improve contact of the corticosteroid with the distal esophagus.
It was surprisingly discovered that administering the oral
corticosteroid while the patient is lying down increases eosinophil
clearance in the distal esophagus while maintaining high eosinophil
clearance in the proximal esophagus. Without being bound by theory,
contact of the corticosteroid with the distal esophagus is
increased when the corticosteroid is administered while the patient
is lying down, because drug transit through the esophagus is driven
primarily by peristalsis, whereas adopting an upright position
decreases contact of the oral corticosteroid with the distal
esophagus because drug transit is driven primarily by gravity and
the continuous flow of fluids down the esophagus.
[0151] Contact of the corticosteroid with the esophagus can be
observed directly by conducting a scintigraphy study as described
in Example 6. Alternatively, contact of the corticosteroid with the
esophagus can be determined indirectly by measuring eosinophil
clearance in the proximal and distal portions of the esophagus. For
example, eosinophil clearance can be determined by measuring the
eosinophil count in the proximal and distal esophagus before
treatment (cells/mm.sup.2 of the high power field) to establish a
baseline and comparing said baseline to the eosinophil count in the
proximal and distal esophagus measured after 8-weeks of treatment,
as described in Example 2.
[0152] Accordingly, in particular embodiments, the oral
corticosteroid is administered once daily, at nighttime while the
patient is lying down (or wherein the patient lays down immediately
after oral administration). In other particular embodiments, the
oral corticosteroid is administered twice daily, wherein the
patient may remain upright during the first daily dose and the
patient is lying down for the second daily dose (or the patient
lays down immediately after oral administration). In further
embodiments, the patient is lying down for both daily doses.
[0153] In certain embodiments, the pharmaceutical composition is
administered to a patient while the patient is lying down or
immediately prior to the patient lying down, e.g., within about 1
second, about 2 seconds, about 3 seconds, about 4 seconds, about 5
seconds, about 6 seconds, about 7 seconds, about 8 seconds, about 9
seconds, about 10 seconds, about 15 seconds, about 20 seconds,
about 25 seconds, about 30 seconds, about 35 seconds, about 40
seconds, about 45 seconds, about 50 seconds, about 60 seconds,
about 1.1 minutes, about 1.2 minutes, about 1.3 minutes, about 1.4
minutes, about 1.5 minutes, about 1.6 minutes, about 1.7 minutes,
about 1.8 minutes, about 1.9 minutes, about 2.0 minutes, about 2.5
minutes, about 3 minutes, about 4 minutes, or about 5 minutes prior
to the patient lying down, inclusive of all values and ranges
therebetween.
[0154] In various embodiments, the pharmaceutical composition is
administered HS while the patient is lying down (or the patient
lays down immediately following administration). In other
embodiments, the pharmaceutical composition is administrated during
daytime (e.g., BID or QD administration), while the patient is
lying down (or the patient lays down immediately following
administration). In various embodiments, the patient remains lying
down following administration for an amount of time sufficient for
topical deposition and/or contact of the corticosteroid onto the
esophagus to treat inflammation thereof (e.g., a time sufficient to
result in improvement of EoE using the measurements described
herein, such as a reduction in episodes of dysphagia). In some such
embodiments, the patient remains lying down following
administration for an amount of time in the range of from about 1
minute to about 8 hours, including about 5 minutes, about 10
minutes, about 15 minutes, about 20 minutes, about 25 minutes,
about 30 minutes, about 35 minutes, about 40 minutes, about 45
minutes, about 50 minutes, about 55 minutes, about 1 hr, about 1.1
hr, about 1.2 hr, about 1.3 hr, about 1.4 hr, about 1.5 hr, about
1.6 hr, about 1.7 hr, about 1.8 hr, or about 1.9 hr, about 2 hrs,
about 2.1 hr, about 2.2 hr, about 2.3 hr, about 2.4 hr, about 2.5
hr, about 2.6 hr, about 2.7 hr, about 2.8 hr, or about 2.9 hr,
about 3 hrs, about 3.1 hr, about 3.2 hr, about 3.3 hr, about 3.4
hr, about 3.5 hr, about 3.6 hr, about 3.7 hr, about 3.8 hr, or
about 3.9 hr, about 4 hrs, about 4.1 hr, about 4.2 hr, about 4.3
hr, about 4.4 hr, about 4.5 hr, about 4.6 hr, about 4.7 hr, about
4.8 hr, about 4.9 hr, about 5 hrs, about 5.1 hr, about 5.2 hr,
about 5.3 hr, about 5.4 hr, about 5.5 hr, about 5.6 hr, about 5.7
hr, about 5.8 hr, about 5.9 hr about 6 hrs, about 6.1 hr, about 6.2
hr, about 6.3 hr, about 6.4 hr, about 6.5 hr, about 6.6 hr, about
6.7 hr, about 6.8 hr, or about 6.9 hr, about 7 hrs, about 7.1 hr,
about 7.2 hr, about 7.3 hr, about 7.4 hr, about 7.5 hr, about 7.6
hr, about 7.7 hr, about 7.8 hr, or about 7.9 hr, inclusive of all
values and subranges therebetween. In embodiments in which the
pharmaceutical composition is administered during daytime, the
patient remains lying down for an amount of time in the range of
from about 1 minute to about 60 minutes, including about 5 minutes,
about 10 minutes, about 15 minutes, about 20 minutes, about 25
minutes, about 30 minutes, about 35 minutes, about 40 minutes,
about 45 minutes, about 50 minutes, about 55 minutes, inclusive of
all values and subranges therebetween. In certain embodiments, the
patient remains lying down for about 5 to about 10 minutes.
[0155] As used herein, "lying down," "lays down," and derivations
and variants thereof, refer to a patient adopting a supine, prone,
or laterally recumbent position, as on a bed or on the ground, or a
substantially horizontal body position, whereby the corticosteroid
(upon swallowing) contacts the esophagus and topically deposits the
corticosteroid on esophagus, e.g., at the site of inflammation. As
used herein, "substantially horizontal" refers to a body position
which at least 10.degree. less than vertical, e.g., less than about
15.degree., less than about 20.degree., less than about 25.degree.,
less than about 30.degree., less than about 35.degree., less than
about 40.degree., less than about 45.degree., less than about
50.degree., less than about 55.degree., less than about 65.degree.,
less than about 70.degree., less than about 75.degree., less than
about 80.degree., less than about 85.degree., or about 90.degree.
from vertical, inclusive of all values and ranges therebetween. For
example, when the composition is formulated as an ODT, the ODT
rapidly disintegrates in the mouth of the supine patient to form a
suspension comprising the corticosteroid which is swallowed. The
suspension then traverses the esophagus of the patient, providing
topical contact of the corticosteroid on the esophagus to topically
treat inflammation thereof. As used herein, "upright" refers to a
patient adopting essentially any other position, including, but not
limited to, standing or sitting.
[0156] In some embodiments, the pharmaceutical composition is
administered to a patient at bedtime. In some embodiments, the
pharmaceutical composition is administered to a patient at bedtime
while the patient is lying down. In some embodiments, the
pharmaceutical composition is administered to the patient while
lying down and prior to sleep (e.g., about 1 minute to about 1 hour
before going to sleep, e.g., about 1 minute, about 5 minutes, about
10 minutes, about 15 minutes, about 20 minutes, about 25 minutes,
about 30 minutes, about 35 minutes, about 40 minute, about 45
minutes, about 50 minutes, about 55 minutes, inclusive of all
values therein). In preferred embodiments, the pharmaceutical
composition is administered to a lying down patient about 30
minutes before bedtime. In some embodiments, the pharmaceutical
composition is administered to a patient after the evening meal,
e.g., from about 1 minute to about 5 hours after the evening meal
(e.g., about 5 minutes, about 10 minutes, about 15 minutes, about
20 minutes, about 25 minutes, about 30 minutes, about 35 minutes,
about 40 minute, about 45 minutes, about 50 minutes, about 55
minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5
hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5
hours, inclusive of all values and subranges therebetween. In
preferred embodiments, the pharmaceutical composition is
administered at least about 30 minutes after the evening meal.
[0157] In some embodiments, administering the pharmaceutical
composition comprising a corticosteroid while the patient is lying
down increases contact of the corticosteroid with the upper
gastrointestinal tract (e.g., the esophagus), while also decreasing
systemic absorption of the corticosteroid. Thus, in embodiments,
administering the pharmaceutical composition while the patient is
lying improves efficacy, and (in further embodiments) reduces side
effects associated with systemic administration of
corticosteroids.
[0158] Transit time of a liquid pharmaceutical composition in the
esophagus is generally in the range of about 1 to about 5 seconds.
Without being limited by theory, administration of a pharmaceutical
composition described herein while the patient is lying down
increases the residence time (also referred to as dwell time) of
the corticosteroid in the esophagus, which increases the time
required for the corticosteroid to reach the stomach, and decreases
the amount of the corticosteroid that reaches the stomach and is
absorbed systemically. In some embodiments, increased residence
time of the corticosteroid in the esophagus increases contact of
the corticosteroid with the esophagus. In some embodiments,
residence time of the corticosteroid on the esophagus and/or
contact of the corticosteroid with the esophagus is increased in a
lying down patient compared to the residence time of the
corticosteroid when administering in a similar composition while
the patient is upright.
[0159] In some embodiments, the residence time of the
corticosteroid on the esophagus following administration while the
patient is lying down is in the range of from about 1 second to
about 5 minutes, e.g., about 2 seconds, about 3 seconds, about 5
seconds, about 6 seconds, about 7 seconds, about 8 seconds, about 9
seconds, about 10 seconds, about 15 seconds, about 20 seconds,
about 25 seconds, about 30 seconds, about 35 seconds, about 40
seconds, about 45 seconds, about 50 seconds, about 55 seconds,
about 60 seconds, about 65 seconds, about 70 seconds, about 75
seconds, about 80 seconds, about 85 seconds, about 90 seconds about
95 seconds, about 100 seconds, about 105 seconds, about 110
seconds, about 115 seconds, about 120 seconds, about 125 seconds,
about 130 seconds, about 135 seconds, about 140 seconds, about 145
seconds, about 150 seconds, about 155 seconds, about 160 seconds,
about 165 seconds, about 170 seconds, about 175 seconds, about 180
seconds, about 185 seconds, about 190 seconds about 195 seconds,
about 200 seconds, 205 seconds, about 210 seconds, about 215
seconds, about 220 seconds, about 225 seconds, about 230 seconds,
about 235 seconds, about 240 seconds, about 245 seconds, about 250
seconds, about 255 seconds, about 260 seconds, about 265 seconds,
about 270 seconds, about 275 seconds, about 280 seconds, about 285
seconds, about 290 seconds, or about 295 seconds, inclusive of all
values and subranges therebetween. In particular embodiments, the
traverse time of the corticosteroid on the esophagus following
administration while the patient is lying down is in the range of
about 5 seconds to about 60 seconds.
[0160] In some embodiments, administering the pharmaceutical
composition while the patient is lying down increases the residence
time of the corticosteroid in the esophagus (compared to the
residence time of the corticosteroid in the esophagus when the
patient is upright) by about 5 seconds, about 10 seconds, about 15
seconds, about 20 seconds, about 25 seconds, about 30 seconds,
about 35 seconds, about 40 seconds, about 45 seconds, about 50
seconds, about 55 seconds, about 60 seconds, about 65 seconds,
about 70 seconds, about 75 seconds, about 80 seconds, about 85
seconds, about 90 seconds about 95 seconds, about 100 seconds,
about 105 seconds, about 110 seconds, about 115 seconds, about 120
seconds, about 125 seconds, about 130 seconds, about 135 seconds,
about 140 seconds, about 145 seconds, about 150 seconds, about 155
seconds, about 160 seconds, about 165 seconds, about 170 seconds,
about 175 seconds, about 180 seconds, about 185 seconds, about 190
seconds about 195 seconds, about 200 seconds, 205 seconds, about
210 seconds, about 215 seconds, about 220 seconds, about 225
seconds, about 230 seconds, about 235 seconds, about 240 seconds,
about 245 seconds, about 250 seconds, about 255 seconds, about 260
seconds, about 265 seconds, about 270 seconds, about 275 seconds,
about 280 seconds, about 285 seconds, about 290 seconds, about 295
seconds, or about 300 seconds. In particular embodiments, the
residence time of the corticosteroid on the esophagus following
administration while the patient is lying down is increased by an
amount of time in the range of from about 5 seconds to about 60
seconds.
[0161] In some embodiments, the average time to reach the maximum
blood plasma concentration of the corticosteroid (T.sub.max) for
the lying down patient is the range of about 80% to about 125% of
about 8 hr to about 20 hr, e.g, about 4.0 hr, about 4.5 hr, about 5
hr, about 5.5 hr, about 6 hr, about 6.6 hr, about 7 hr, about 7.5
hr, about 8 hr, about 8.5 hr, about 9.0 hr, about 9.5 hr, about
10.0 hr, about 10.5 hr, about 11 hr, about 11.5 hr, about 12 hr,
about 12.5 hr, about 13 hr, about 13.5 hr, about 14hr, about 14.5
hr, about 15 hr, about 15.5 hr, about 16 hr, about 16.5 hr, about
17 hr, about 17.5 hr, about 18 hr, about 18.5 hr, about 19 hr,
about 19.5 hr, about 20 hr, about 20.5 hr, about 21 hr, about 21.5
hr, or about 22 hr, about 22.5 hr, about 23 hr, or about 23.5 hr,
about 24 hr, about 24.5 hr, about 25 hr, about 25.5 hr, or about 26
hr, inclusive of all values and subranges therebetween. In
preferred embodiments, the Tmax of the oral corticosteroid for the
lying down patient is the range of about 80% to about 125% of about
14 hr.+-.6 hr, inclusive of all values and subranges
therebetween.
[0162] In some embodiments, the lying down patient's T.sub.max of
the oral corticosteroid is increased by an amount of time in the
range of from about 1 hr to about 15 hr compared to the Tmax of an
upright patent (e.g., AM fed or fasted conditions), e.g., about 1.5
hr, about 2.5 hr, about 3hr, about 3.5 hr, about 4 hr, about 4.5
hr, about 5 hr, about 5.5 hr, about 6 hr, about 6.5 hr, about 7 hr,
about 7.5 hr, about 8 hr, about 8.5 hr, about 9 hr, about 9.5 hr,
about 10 hr, about 10.5 hr, about 11 hr, about 11.5 hr, about 12
hr, about 12.5 hr, about 13 hr, about 13.5 hr, about 14hr, about
14.5 hr, inclusive of all values and subranges therebetween.
[0163] In some embodiments, the T.sub.max of the oral
corticosteroid when administered to an upright patient in a fed
state (and the patient does not lay down immediately thereafter) is
in the range of about 80% to about 125% of about 1 hr to about 10
hr, e.g., about 1.5 hr, about 2.5 hr, about 3hr, about 3.5 hr,
about 4 hr, about 4.5 hr, about 5 hr, about 5.5 hr, about 6 hr,
about 6.5 hr, about 7 hr, about 7.5 hr, about 8 hr, about 8.5 hr,
about 9 hr, about 9.5 hr, about 10 hr, about 10.5 hr, about 11 hr,
about 11.5 hr, about 12 hr, about 12.5 hr, about 13 hr, inclusive
of all values and subranges therebetween.
[0164] In some embodiments, the T.sub.max of the oral
corticosteroid when administered to an upright patient in a fasted
state (and the patient does not lay down immediately thereafter) is
in the range of about 80% to about 125% of about 2 hr to about 30
hr, e.g., about 1 hr, about 1.5 hr, about 2.5 hr, about 3hr, about
3.5 hr, about 4 hr, about 4.5 hr, about 5 hr, about 5.5 hr, about 6
hr, about 6.5 hr, about 7 hr, about 7.5 hr, about 8 hr, about 8.5
hr, about 9 hr, about 9.5 hr, about 10 hr, about 10.5 hr, about 11
hr, about 11.5 hr, about 12 hr, about 12.5 hr, about 13 hr, about
13.5 hr, about 14 hr, about 14.5 hr, about 15 hr, about 15.5 hr,
about 16 hr, about 16.5 hr, about 17 hr, about 17.5 hr, about 18
hr, about 18.5 hr, about 19 hr, about 19.5 hr, about 20 hr, about
20.5 hr, about 21 hr, about 21.5 hr, about 22 hr, about 22.5 hr,
about 23 hr, about 23.5 hr, about 24 hr, about 24.5 hr, about 25
hr, about 25.5 hr, about 26 hr, about 26.5 hr, about 27 hr, about
27.5 hr, about 28 hr, about 28.5 hr, about 29 hr, about 29.5 hr,
about 30 hr, about 30.5 hr, about 31 hr, about 31.5 hr, about 32
hr, about 32.5 hr, about 33 hr, inclusive of all values and
subranges therebetween.
[0165] Conventionally, food usually delays T.sub.max, and therefore
T.sub.max for the fed state are usually larger than fasted state
T.sub.max. However, the pharmacokinetic studies revealed that
fasted state T.sub.max values are larger than fed state T.sub.max.
Thus, in some embodiments, fasted state T.sub.max are larger than
fed state T.sub.max by about 1 hr, about 1.5 hr, about 2 hr, about
2.5 hr, about 3 hr, about 3.5 hr, about 4 hr, about 4.5 hr, about 5
hr, about 5.5 hr, about 6 hr, about 6.5 hr, about 7 hr, about 7.5
hr, about 8 hr, about 8.5 hr, about 9 hr, about 9.5 hr, about 10
hr, about 10.5 hr, about 11 hr, about 11.5 hr, about 12 hr, about
12.5 hr, about 13 hr, about 13.5 hr, about 14 hr, about 14.5 hr,
about 15 hr, about 15.5 hr, about 16 hr, about 16.5 hr, about 17
hr, about 17.5 hr, about 18 hr, about 18.5 hr, about 19 hr, about
19.5 hr, about 20 hr, or more.
[0166] Due to the topical contact of the oral corticosteroid with
the esophagus, and the use of corticosteroids having low (or
modified to have low) systemic bioavailability, the methods and
compositions described herein are able to treat EoE with blood
plasma levels of the corticosteroid that are surprisingly low. A
benefit of low blood plasma levels of the corticosteroid is a
reduction or avoidance of side effects associated with systemic
administration of corticosteroids. Thus, in some embodiments, the
methods and compositions described herein topically administer a
corticosteroid to the upper gastrointestinal tract (e.g., the
esophagus) in an effective amount of the corticosteroid to
topically treat inflammation thereof (e.g., EoE). In some
embodiments, the oral corticosteroid provides an average maximum
blood plasma concentration (Cmax) of less than or equal to about
1000 pg/mL after oral administration of about 0.01 mg to about 20
mg of the oral corticosteroid, e.g., less than or equal to about
about 950 pg/mL, about 900 pg/mL, about 850 pg/mL, about 800 pg/mL,
about 750 pg/mL, about 700 pg/mL, about 650 pg/mL, about 600 pg/mL,
about 550 pg/mL, about 500 pg/mL, about 450 pg/mL, about 400 pg/mL,
about 350 pg/mL, about 300 pg/mL, about 250 pg/mL, about 200 pg/mL,
about 150 pg/mL, about 100 pg/mL, or about 50 pg/mL. In preferred
embodiments, the oral corticosteroid provides a Cmax of less than
or equal to about 500 pg/mL after oral administration of about 0.01
mg to about 20 mg of the oral corticosteroid.
[0167] In preferred embodiments, the lying down patient's C.sub.max
is within the range of about 80% to about 125% of about 15 pg/mL to
about 40 pg/mL following administration of 6 mg of fluticasone
propionate while the patient is lying down, e.g., about 10 pg/mL,
about 11 pg/mL, about 12 pg/mL, about 13 pg/mL, about 14 pg/mL,
about 15 mg/mL, about 16 pg/mL, about 17 pg/mL, about 18 pg/mL,
about 19 pg/mL, about 20 pg/mL, about 21 pg/mL, about 22 pg/mL,
about 23 pg/mL, about 24 pg/mL, about 25 pg/mL, about 26 pg/mL,
about 27 pg/mL, about 28 pg/mL, about 29 pg/mL, about 30 pg/mL,
about 31 pg/mL, about 32 pg/mL, about 33 pg/mL, about 34 pg/mL,
about 35 pg/mL, about 36 pg/mL, about 37 pg/mL, about 38 pg/mL,
about 39 pg/mL, about 40 pg/mL, about 41 pg/mL, about 42 pg/mL,
about 43 pg/mL, about 44 pg/mL, about 45 pg/mL, about 46 pg/mL,
about 47 pg/mL, about 48 pg/mL, about 49 pg/mL, about 50 pg/mL,
about 51 pg/mL, about 52 pg/mL, about 53 pg/mL, about 54 pg/mL, or
about 55 pg/mL, inclusive of all values and subranges therebetween.
In some embodiments, the low blood plasma levels achieved to treat
EoE also reduces side effects associated with systemic
administration of corticosteroids. For example, in embodiments
involving HS administration, topical delivery of the corticosteroid
decreases systemic administration and associated side effect even
though HS administration is generally known to increase systemic
absorption.
[0168] In some embodiments, a lying down patient's C.sub.max of the
oral corticosteroid is at least about 1% lower compared to the fed
patient's C.sub.max of the oral corticosteroid for a fed patient
that is upright and does not lay down immediately after
administration of the oral corticosteroid, e.g., at least about 2%,
at least about 3%, at least about 4%, at least about 5%, at least
about 6%, at least about 7%, at least about 8%, at least about 9%,
at least about 10%, at least about 11%, at least about 12%, at
least about 13%, at least about 14%,at least about 15%, at least
about 16%, at least about 17%, at least about 18%, at least about
19%, at least about 20%, at least about 25%, at least about 30%, at
least about 35%, at least about 40%, at least about 45%, or at
least about 50%, inclusive of all values and subranges
therebetween.
[0169] In some embodiments, the oral corticosteroid provides and an
average AUC.sub.0-24 of less than or equal to about 10,000 pg*h/mL
after oral administration of about 0.01 mg to about 20 mg of the
oral corticosteroid, e.g., about 9,000 pg*h/mL, about 8,000
pg*h/mL, about 7,000 pg*h/mL, about 6,000 pg*h/mL, about 5,000
pg*h/mL, about 4,000 pg*h/mL, about 3,000 pg*h/mL, about 2,000
pg*h/mL, about 1,000 pg*h/mL, about 900 pg*h/mL, about 800 pg*h/mL,
about 700 pg*h/mL, about 600 pg*h/mL, about 500 pg*h/mL, about 400
pg*h/mL, about 300 pg*h/mL, about 200 pg*h/mL, or about 100
pg*h/mL. In particular embodiments, the oral corticosteroid
provides and an average AUC.sub.0-24 of less than or equal to about
3,000 pg*h/mL after oral administration of about 0.01 mg to about
20 mg of the oral corticosteroid.
[0170] In some embodiments, the patient's AUC.sub.0-24 (pg*h/mL) is
within the range of about 80% to about 125% of about 50 pgh/mL to
about 1,000 pgh/mL following administration of 1.5, 3.0, 4.5, 6.0
or 7.5 mg of fluticasone propionate while the patient is lying
down, e.g., about 10 pgh/mL, about 20 pgh/mL, about 30 pgh/mL,
about 40 pgh/mL, about 50 pgh/mL, about 60 pgh/mL, about 70 pgh/mL,
about 80 pgh/mL, about 90 pgh/mL, about 100 pgh/mL, about 110
pgh/mL, about 120 pgh/mL, about 130 pgh/mL, about 140 pgh/mL, about
150 pgh/mL, about 160 pgh/mL, about 170 pgh/mL, about 180 pgh/mL,
about 190 pgh/mL, about 200 pgh/mL, about 210 pgh/mL, about 220
pgh/mL, about 230 pgh/mL, about 240 pgh/mL, about 250 pgh/mL, about
260 pgh/mL, about 270 pgh/mL, about 280 pgh/mL, about 290 pgh/mL,
about 300 pgh/mL, about 310 pgh/mL, about 320 pgh/mL, about 330
pgh/mL, about 340 pgh/mL, about 350 pgh/mL, about 360 pgh/mL, about
370 pgh/mL, about 380 pgh/mL, about 390 pgh/mL, about 400 pgh/mL,
about 410 pgh/mL, about 420 pgh/mL, about 430 pgh/mL, about 440
pgh/mL, about 450 pgh/mL, about 460 pgh/mL, about 470 pgh/mL, about
480 pgh/mL, about 490 pgh/mL, about 500 pgh/mL, about 510 pgh/mL,
about 520 pgh/mL, about 530 pgh/mL, about 540 pgh/mL, about 550
pgh/mL, about 560 pgh/mL, about 570 pgh/mL, about 580 pgh/mL, about
590 pgh/mL, about 600 pgh/mL, about 610 pgh/mL, about 620 pgh/mL,
about 630 pgh/mL, about 640 pgh/mL, about 650 pgh/mL, about 660
pgh/mL, about 670 pgh/mL, about 680 pgh/mL, about 690 pgh/mL, about
700 pgh/mL, about 710 pgh/mL, about 720 pgh/mL, about 730 pgh/mL,
about 740 pgh/mL, about 750 pgh/mL, about 760 pgh/mL, about 770
pgh/mL, about 780 pgh/mL, about 790 pgh/mL, about 800 pgh/mL, about
810 pgh/mL, about 820 pgh/mL, about 830 pgh/mL, about 840 pgh/mL,
about 850 pgh/mL, about 860 pgh/mL, about 870 pgh/mL, about 880
pgh/mL, about 890 pgh/mL, about 900 pgh/mL, about 910 pgh/mL, about
920 pgh/mL, about 930 pgh/mL, about 940 pgh/mL, about 950 pgh/mL,
about 960 pgh/mL, about 970 pgh/mL, about 980 pgh/mL, about 990
pgh/mL, about 1000 pgh/mL, about 1010 pgh/mL, about 1020 pgh/mL,
about 1030 pgh/mL, about 1040 pgh/mL, about 1050 pgh/mL, about 1060
pgh/mL, about 1070 pgh/mL, about 1080 pgh/mL, about 1090 pgh/mL,
about 1100 pgh/mL, about 1110 pgh/mL, about 1120 pgh/mL, about 1130
pgh/mL, about 1140 pgh/mL, about 1150 pgh/mL, about 1160 pgh/mL,
about 1170 pgh/mL, about 1180 pgh/mL, about 1190 pgh/mL, about 1200
pgh/mL, about 1210 pgh/mL, about 1220 pgh/mL, about 1230 pgh/mL,
about 1240 pgh/mL, about 1250 pgh/mL, about 1260 pgh/mL, about 1270
pgh/mL, about 1280 pgh/mL, about 1290 pgh/mL,about 1300 pgh/mL,
inclusive of all values and subranges therebetween.
[0171] In some embodiments, the patient's AUC.sub.0-24 (pg*h/mL) is
within the range of about 80% to about 125% of about 50 pgh/mL to
about 1,000 pgh/mL following administration of 1.5, 3.0, 4.5, 6.0
or 7.5 mg of fluticasone propionate while the patient is upright
(AM dosing in the fed or fasted state), e.g., about 10 pgh/mL,
about 20 pgh/mL, about 30 pgh/mL, about 40 pgh/mL, about 50 pgh/mL,
about 60 pgh/mL, about 70 pgh/mL, about 80 pgh/mL, about 90 pgh/mL,
about 100 pgh/mL, about 110 pgh/mL, about 120 pgh/mL, about 130
pgh/mL, about 140 pgh/mL, about 150 pgh/mL, about 160 pgh/mL, about
170 pgh/mL, about 180 pgh/mL, about 190 pgh/mL, about 200 pgh/mL,
about 210 pgh/mL, about 220 pgh/mL, about 230 pgh/mL, about 240
pgh/mL, about 250 pgh/mL, about 260 pgh/mL, about 270 pgh/mL, about
280 pgh/mL, about 290 pgh/mL, about 300 pgh/mL, about 310 pgh/mL,
about 320 pgh/mL, about 330 pgh/mL, about 340 pgh/mL, about 350
pgh/mL, about 360 pgh/mL, about 370 pgh/mL, about 380 pgh/mL, about
390 pgh/mL, about 400 pgh/mL, about 410 pgh/mL, about 420 pgh/mL,
about 430 pgh/mL, about 440 pgh/mL, about 450 pgh/mL, about 460
pgh/mL, about 470 pgh/mL, about 480 pgh/mL, about 490 pgh/mL, about
500 pgh/mL, about 510 pgh/mL, about 520 pgh/mL, about 530 pgh/mL,
about 540 pgh/mL, about 550 pgh/mL, about 560 pgh/mL, about 570
pgh/mL, about 580 pgh/mL, about 590 pgh/mL, about 600 pgh/mL, about
610 pgh/mL, about 620 pgh/mL, about 630 pgh/mL, about 640 pgh/mL,
about 650 pgh/mL, about 660 pgh/mL, about 670 pgh/mL, about 680
pgh/mL, about 690 pgh/mL, about 700 pgh/mL, about 710 pgh/mL, about
720 pgh/mL, about 730 pgh/mL, about 740 pgh/mL, about 750 pgh/mL,
about 760 pgh/mL, about 770 pgh/mL, about 780 pgh/mL, about 790
pgh/mL, about 800 pgh/mL, about 810 pgh/mL, about 820 pgh/mL, about
830 pgh/mL, about 840 pgh/mL, about 850 pgh/mL, about 860 pgh/mL,
about 870 pgh/mL, about 880 pgh/mL, about 890 pgh/mL, about 900
pgh/mL, about 910 pgh/mL, about 920 pgh/mL, about 930 pgh/mL, about
940 pgh/mL, about 950 pgh/mL, about 960 pgh/mL, about 970 pgh/mL,
about 980 pgh/mL, about 990 pgh/mL, about 1000 pgh/mL, about 1010
pgh/mL, about 1020 pgh/mL, about 1030 pgh/mL, about 1040 pgh/mL,
about 1050 pgh/mL, about 1060 pgh/mL, about 1070 pgh/mL, about 1080
pgh/mL, about 1090 pgh/mL, about 1100 pgh/mL, about 1110 pgh/mL,
about 1120 pgh/mL, about 1130 pgh/mL, about 1140 pgh/mL, about 1150
pgh/mL, about 1160 pgh/mL, about 1170 pgh/mL, about 1180 pgh/mL,
about 1190 pgh/mL, about 1200 pgh/mL, about 1210 pgh/mL, about 1220
pgh/mL, about 1230 pgh/mL, about 1240 pgh/mL, about 1250 pgh/mL,
about 1260 pgh/mL, about 1270 pgh/mL, about 1280 pgh/mL, about 1290
pgh/mL,about 1300 pgh/mL, inclusive of all values and subranges
therebetween.
[0172] In some embodiments, the patient's AUC.sub.0-24 (pg*h/mL) is
within the range of about 80% to about 125% of about 250 pgh/mL to
about 475 pgh/mL following administration of 6 mg of fluticasone
propionate while the patient is lying down, e.g., about 150 pgh/mL,
about 160 pgh/mL, about 170 pgh/mL, about 180 pgh/mL, about 190
pgh/mL, about 200 pgh/mL, about 210 pgh/mL, about 220 pgh/mL, about
230 pgh/mL, about 240 pgh/mL, about 250 pgh/mL, about 260 pgh/mL,
about 270 pgh/mL, about 280 pgh/mL, about 290 pgh/mL, about 300
pgh/mL, about 310 pgh/mL, about 320 pgh/mL, about 330 pgh/mL, about
340 pgh/mL, about 350 pgh/mL, about 360 pgh/mL, about 370 pgh/mL,
about 380 pgh/mL, about 390 pgh/mL, about 400 pgh/mL, about 410
pgh/mL, about 420 pgh/mL, about 430 pgh/mL, about 440 pgh/mL, about
450 pgh/mL, about 460 pgh/mL, about 470 pgh/mL, about 480 pgh/mL,
about 490 pgh/mL, about 500 pgh/mL, about 510 pgh/mL, about 520
pgh/mL, about 530 pgh/mL, about 540 pgh/mL, about 550 pgh/mL, about
560 pgh/mL, about 570 pgh/mL, about 580 pgh/mL, about 590 pgh/mL,
about 600 pgh/mL inclusive of all values and subranges
therebetween.
[0173] In some embodiments, the patient's AUC.sub.0-24 (pg*h/mL) is
within the range of about 80% to about 125% of about 250 pgh/mL to
about 475 pgh/mL following administration of 6 mg of fluticasone
propionate while the patient is upright, e.g., about 150 pgh/mL,
about 160 pgh/mL, about 170 pgh/mL, about 180 pgh/mL, about 190
pgh/mL, about 200 pgh/mL, about 210 pgh/mL, about 220 pgh/mL, about
230 pgh/mL, about 240 pgh/mL, about 250 pgh/mL, about 260 pgh/mL,
about 270 pgh/mL, about 280 pgh/mL, about 290 pgh/mL, about 300
pgh/mL, about 310 pgh/mL, about 320 pgh/mL, about 330 pgh/mL, about
340 pgh/mL, about 350 pgh/mL, about 360 pgh/mL, about 370 pgh/mL,
about 380 pgh/mL, about 390 pgh/mL, about 400 pgh/mL, about 410
pgh/mL, about 420 pgh/mL, about 430 pgh/mL, about 440 pgh/mL, about
450 pgh/mL, about 460 pgh/mL, about 470 pgh/mL, about 480 pgh/mL,
about 490 pgh/mL, about 500 pgh/mL, about 510 pgh/mL, about 520
pgh/mL, about 530 pgh/mL, about 540 pgh/mL, about 550 pgh/mL, about
560 pgh/mL, about 570 pgh/mL, about 580 pgh/mL, about 590 pgh/mL,
about 600 pgh/mL inclusive of all values and subranges
therebetween.
[0174] In some embodiments, the pharmaceutical composition is
administered to a patient at least about 2 hours after the evening
meal (with no snacks) while the patient is lying down. In some
embodiments, the pharmaceutical composition is administered to a
patient at least about 4 hours after the evening meal (with no
snacks) while the patient is lying down. In some embodiments, the
pharmaceutical composition is administered to a patient within
about 2 hours after the evening meal (with no snacks) while the
patient is lying down. In some embodiments, the pharmaceutical
composition is administered to a patient within about 4 hours after
the evening meal (with no snacks) while the patient is lying down.
In some embodiments, after administration of the pharmaceutical
composition while the patient is lying down, the patient goes to
sleep. In some embodiments, after administration of the
pharmaceutical composition while the patient is lying down, the
patient does not rise for at least one hour.
[0175] In some embodiments, the patient holds the pharmaceutical
composition in the oral cavity for a length of time sufficient to
swallow the composition (e.g., about 1 second, about 2 seconds,
about 3 seconds, about 4 seconds, about 5 seconds, about 6 seconds,
about 7 seconds, about 8 seconds, about 9 seconds, or about 10
seconds). In other embodiments, the patient holds the
pharmaceutical composition in the oral cavity for a length of time
sufficient to allow the pharmaceutical composition to dissolve in
the saliva. One skilled in the art will appreciate that the length
of time necessary for the pharmaceutical composition depends, in
part, on the dosage form. For example, orally disintegrating
compositions disintegrate in saliva within about 60 seconds (e.g.,
about 50 seconds, about 40 seconds, about 30 seconds, about 20
seconds, or about 10 seconds) to form a suspension which is then
swallowed. In embodiments in which the pharmaceutical composition
is a lozenge or lollipop, the lozenge or lollipop may remain in the
patient's oral cavity for about 1 minute, about 2 minute, about 3
minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7
minutes, about 8 minutes, about 9 minutes, or about 10 minutes.
[0176] In some embodiments, the pharmaceutical composition is
administered to a patient from one to five times a day. In some
embodiments, the pharmaceutical composition is administered to a
patient at least once a day, at least twice a day, at least three
times a day, at least 4 times a day, or at least five times a day.
In some embodiments, the pharmaceutical composition is administered
to a patient at least one to five times a day for one week to 10
years or more. In some embodiments, the pharmaceutical composition
is administered to a patient at least once a day, at least twice a
day, at least three times a day, at least 4 times a day, or at
least five times a day for at least one week, at least two weeks,
at least three weeks, at least four weeks, at least five weeks, at
least six weeks, at least seven weeks, at least eight weeks, at
least nine weeks, at least ten weeks, at least fifteen weeks, at
least twenty weeks, at least thirty weeks, at least forty weeks, at
least fifty weeks, at least fifty-two weeks, at least sixty weeks,
at least seventy weeks, at least eighty weeks, at least ninety
weeks, or at least one hundred weeks or more. In some embodiments,
the pharmaceutical composition is administered to a patient
indefinitely. In some embodiments, the pharmaceutical composition
is administered twice a day for at least about 6 weeks, at least
about 8 weeks, at least about 10 weeks, or at least about 12 weeks.
In some embodiments, the pharmaceutical composition is administered
twice a day during the induction and/or maintenance phase. In some
embodiments, the pharmaceutical composition is administered twice a
day for at least about 6 weeks, at least about 8 weeks, at least
about 10 weeks, or at least about 12 weeks during the induction
phase.
[0177] In some embodiments, the pharmaceutical composition is
administered to a patient at 0.75 mg, 1.5 mg, 3.0 mg, 4.5 mg, or
6.0 mg at least once a day, at least twice a day, at least three
times a day, at least four times a day, or at least five times a
day. In some embodiments, the pharmaceutical composition is
administered to a patient at the same dose multiple times a day. In
some embodiments, the pharmaceutical composition is administered to
a patient at the same dose at least twice a day, at least three
times a day, at least 4 times a day, or at least five times a day.
In some embodiments, the pharmaceutical composition is administered
to a patient at the same dose two to five times a day for one week
to 10 years or more. In some embodiments, the pharmaceutical
composition is administered to a patient at least at the same dose
at least twice a day, at least three times a day, at least 4 times
a day, or at least five times a day for at least one week, at least
two weeks, at least three weeks, at least four weeks, at least five
weeks, at least six weeks, at least seven weeks, at least eight
weeks, at least nine weeks, at least ten weeks, at least fifteen
weeks, at least twenty weeks, at least thirty weeks, at least forty
weeks, at least fifty weeks, at least fifty-two weeks, at least
sixty weeks, at least seventy weeks, at least eighty weeks, at
least ninety weeks, or at least one hundred weeks or more or
indefinitely.
[0178] In some embodiments, the pharmaceutical composition is
administered twice a day at different doses. In some embodiments,
the pharmaceutical composition is administered twice a day, with
the morning dose being greater than the evening dose. In some
embodiments, the pharmaceutical composition is administered twice a
day, with the morning dose being less than the evening dose.
[0179] In some embodiments, the patient is administered different
doses of the pharmaceutical composition depending on the phase of
the regimen. For example, the regimen may be divided into at least
induction, treatment, withdrawal, or maintenance phase. In some
embodiments, the regimen includes at least one of these phases. In
some embodiments, the regimen includes a combination of one or more
of these phases. In some embodiments, the regimen includes all of
these phases.
[0180] In some embodiments, the regimen includes induction and
withdrawal. In some embodiments, the regimen includes multiple
cycles of induction and withdrawal as needed. In some embodiments,
the regimen includes multiple cycles of induction and withdrawal
repeated indefinitely. In some embodiments, the induction period
does not result in a recurrence of symptoms.
[0181] The regimen phases may be any appropriate duration. In some
embodiments, the induction phase lasts between about 1 and about 10
weeks, about 12 weeks, about 15 weeks, about 20 weeks, about 30
weeks, about 40 weeks, or about 50 weeks. In some embodiments, the
induction phase lasts about 14 weeks. In some embodiments, the
withdrawal phase lasts between about 1 and about 10 weeks, about 15
weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50
weeks, about 1 year, about 2 years, about 5 years, about 10 years
or indefinitely. In some embodiments, the withdrawal phase lasts
until symptoms recur. In some embodiments, the withdrawal phase
lasts about 14 weeks. In some embodiments, the maintenance phase
lasts between about 1 and about 15 weeks, about 20 weeks, about 30
weeks, about 40 weeks, about 50 weeks, about 1 year, about 2 years,
about 5 years, about 10 years or more. In some embodiments, the
maintenance phase lasts about 28 weeks. In some embodiments, the
maintenance phase is an indefinite duration.
[0182] In some embodiments, the patient is administered a greater
dose in one or more regimen phases compared to the others. In some
embodiments, the patient is administered the same dose in one or
more regimen phases. In some embodiments, the patient is
administered the same dose in every regimen phases. In some
embodiments, the patient is administered no dose during one or more
phases.
[0183] In some embodiments, the patient is administered a greater
dose during the induction stage compared to the maintenance stage.
In some embodiments, the patient is administered a smaller dose
during the induction stage compared to the maintenance stage. In
some embodiments, the patient is administered no dose during either
the induction or maintenance stage. In some embodiments, the
patient is administered no dose during both the induction and
maintenance stages. In some embodiments, the patient is
administered the same dose during the induction and maintenance
stages. In some embodiments, the patient is administered
substantially the same dose during the induction and maintenance
stages. In some embodiments, the patient is administered 3.0 mg BID
during the induction stage, and 1.5 mg BID during the maintenance
stage. In some embodiments, the patient is administered 3.0 mg BID
during the induction stage, and 1.5 mg HS during the maintenance
stage. In some embodiments, the patient is administered 1.5 mg BID
during the induction stage, and 3.0 mg BID during the maintenance
stage. In some embodiments, the patient is administered 1.5 mg HS
during the induction stage, and 3.0 mg BID during the maintenance
stage. In some embodiments, the patient is administered 1.5 mg BID
during both the induction and maintenance stages. In some
embodiments, the patient is administered 1.5 mg HS during the
induction and maintenance stages. In some embodiments, the patient
is administered 3.0 mg BID during the induction and maintenance
stages. In some embodiments, the patient is administered 6.0 mg BID
during the induction stage, and 3.0 or 1.5 mg BID during the
maintenance stage. In some embodiments, the patient is administered
6.0 mg BID during the induction stage, and 3.0 or 1.5 mg HS during
the maintenance stage. In some embodiments, the patient is
administered 1.5 or 3.0 mg BID during the induction stage, and 6.0
mg BID during the maintenance stage. In some embodiments, the
patient is administered 1.5 or 3.0 mg HS during the induction
stage, and 6.0 mg BID during the maintenance stage. In some
embodiments, the patient is administered 6.0 or 3.0 mg BID during
both the induction and maintenance stages. In some embodiments, the
patient is administered 6.0 or 3.0 mg HS during the induction and
maintenance stages. In some embodiments, the patient is
administered 6.0 mg BID during the induction and maintenance
stages.
[0184] In some embodiments, the patient is not co-administered a
strong cytochrome P4503A4 inhibitor. In some embodiments, the
patient is not co-administered ritonavir or ketoconazole.
[0185] In certain embodiments, the patient is a human, but in other
embodiments may be a non-human mammal, such as a domesticated pet
(e.g., dog or cat), or livestock or farm animal (e.g., horse, cow,
sheep, or pig).
Patient Populations
[0186] Any patient diagnosed with, or presumed to be suffering from
an inflammatory gastrointestinal disorder, may be administered the
pharmaceutical compositions of the present disclosure. In some
embodiments, the patient is an adult. In some embodiments, the
patient is an adolescent. In some embodiments, the patient is a
child. In some embodiments, the patient is an infant.
[0187] In some embodiments, the inflammatory gastrointestinal
disorder is EoE. The patient may be diagnosed using any appropriate
measures in the art. In some embodiments, the patient is diagnosed
with EoE based on symptoms, histology, and/or failed documentation
on proton pump inhibitors. In some embodiments, the patient
received PPI therapy prior to administration of a pharmaceutical
composition of the present disclosure. In some embodiments, the
patient did not receive PPI therapy prior to administration of a
pharmaceutical composition of the present disclosure. In some
embodiments, the patient failed to improve after 8 weeks of
high-dose (e.g. 40 mg) PPI. A lack of response to PPI therapy may
be defined as Peak eosinophil count.gtoreq.15/HPF in at least one
biopsied location after 8 weeks of treatment with a high dose PPI.
In some embodiments, the failure of PPI therapy is documented
before administration of a pharmaceutical composition of the
present disclosure. In some embodiments, the failure of PPI therapy
is documented subsequently to administration of a pharmaceutical
composition of the present disclosure. In some embodiments,
patients which did not respond to previous PPI therapy are
administered a high dose of the oral corticosteroid according to
(or for use in) the methods disclosed herein, such as 6.0 mg, 7.5
mg, or more (e.g., about 9.0 mg to about 20 mg, including about 9
mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14
mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, and about
19 mg, inclusive of all values and subranges therebetween).
[0188] In some embodiments, the patient diagnosed with EoE has an
esophageal stricture. In some embodiments, said patient is
administered a high dose of the oral corticosteroid according to
(or for use in) the methods disclosed herein, such as 6.0 mg, 7.5
mg, or more (e.g., about 9.0 mg to about 20 mg, including about 9
mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14
mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, and about
19 mg, inclusive of all values and subranges therebetween).
[0189] In some embodiments, the patient diagnosed with EoE has a
severe food allergy (e.g., a lactose or starch allergy). In some
embodiments, said patient is administered a high dose of the oral
corticosteroid according to (or for use in) the methods disclosed
herein, such as 6.0 mg, 7.5 mg, or more (e.g., about 9.0 mg to
about 20 mg, including about 9 mg, about 10 mg, about 11 mg, about
12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17
mg, about 18 mg, and about 19 mg, inclusive of all values and
subranges therebetween).
[0190] In some embodiments, the patient has been diagnosed with EoE
by histological analysis. In some embodiments, the patient is
diagnosed as having .gtoreq.15 peak eosinophil count per HPF
(400.times. magnification) in at least one biopsy. In some
embodiments, there are at minimum of 6 biopsies taken from the
patient. In some embodiments, at least 3 biopsies are taken from
each of the proximal and the distal esophagus.
[0191] In some embodiments, the patient is diagnosed as having EoE
by their EEsAI, Global EoE, EREFS, PROSE, and/or measurement of
esophageal characteristics via endoscopy (e.g. EndoFlip). In some
embodiments, the patient is diagnosed as having EoE based on a
7-day recall EEsAI score of >30. In some embodiments, the
patient is diagnosed as having EoE based on a 7-day recall Global
EoE score of .gtoreq.5. In some embodiments, the patient is
diagnosed has having EoE based on the EREFS score which scores
endoscopic characteristics (see Table 3). In some embodiments EoE
is diagnosed in a patient scoring above Grade 0 in any of the five
characteristics disclosed in Table 3.
[0192] In some embodiments, the patient is diagnosed as having EoE
based on symptoms, including but not limited to episodes of food
impaction, episodes of food impaction requiring endoscopy, food
avoidance, vomiting, reflux, and/or dysphagia. In some embodiments,
the patient is diagnosed as having EoE based on dysphagia
(difficulty swallowing). In some embodiments, the patient is
diagnosed as having EoE based on experiencing dysphagia at least 3
times per week within 2 weeks.
[0193] Patient outcome and response to administration with a
pharmaceutical composition of the present disclosure may be
monitored or measured using any appropriate means in the art (e.g.
endoscopy, histology, questionnaires).
[0194] Patients who exhibit an improvement of symptoms and/or
histologic response after treatment commences are categorized as
Responders. In some embodiments, patients who exhibit <15 peak
eosinophils/HPF are categorized as Responders. In some embodiments,
patients who exhibit <6 peak eosinophils/HPF are categorized as
Responders. In some embodiments, patients who exhibit <6 peak
eosinophils/HPF and no worsening of symptoms (e.g. no increase in
weekly EEsAI score compared to baseline; stricture requiring
dilation) are categorized as Responders. In some embodiments,
patients who exhibit <6 peak eosinophils/HPF and no episodes of
food impaction are categorized as Responders. In some embodiments,
Responders exhibit evidence of inflammatory endoscopic remission
such as an absence of white exudate and/or furrows. In some
embodiments, Responders exhibit evidence of fibrotic remission
including an absence of strictures and rings or moderate to severe
rings. In some embodiments, Responders exhibit improved
vascularity. In some embodiments, Responders exhibit improved
biomarkers (e.g. IL-5, IgE levels).
[0195] In some embodiments, patients who are categorized as
Responders enter the maintenance stage of the regimen. In some
embodiments, patients who are categorized as Responders are
administered a different dose of a pharmaceutical composition of
the present disclosure after categorization. In some embodiments,
Responders receive a greater dose after categorization after
categorization. In some embodiments, Responders receive a smaller
dose after categorization. In some embodiments, Responders receive
the same dose after categorization. In some embodiments, Responders
receive substantially the same dose after categorization.
[0196] In some embodiments, the patient is classified as a
responder if the pharmaceutical compositions disclosed herein are
administered in an induction phase and a maintenance phase, and
during the induction phase improvement in Peak eosinophilic counts
in at least one esophageal biopsy and/or at least no worsening of
patient mean weekly EESAI scores are observed, and where the
maintenance phase comprises a dose at least equal to, more than or
less than the induction phase.
[0197] Patients who do not meet the definition of Responder as
disclosed above are categorized as Non-Responders. Patients whose
histologic score and/or symptoms worsen are categorized as Relapse.
In some embodiments, patients whose histologic score and/or
symptoms worsen at any point during treatment are categorized as
Relapse. In some embodiments, patients who experience food
impaction requiring endoscopy and/or clinically-significant
worsening of symptoms are categorized as Relapse. In some
embodiments, patients who are categorized as Non-Responders or
Relapsers are administered a different dose of a pharmaceutical
composition of the present disclosure after categorization. In some
embodiments, Non-Responders and/or Relapsers receive a greater dose
after categorization. In some embodiments, Non-Responders and/or
Relapsers receive a smaller dose after categorization. In some
embodiments, Non-Responders and/or Relapsers receive the same dose
after categorization. In some embodiments, Non-Responders and/or
Relapsers receive substantially the same dose after
categorization.
[0198] In some embodiments, the patient is classified as a
responder if the pharmaceutical compositions disclosed herein are
administered in an induction phase and a maintenance phase, and
during the induction phase no improvement in Peak eosinophilic
counts in at least one esophageal biopsy and/or worsening of
patient mean weekly EESAI scores are observed, and where the
maintenance phase comprises a dose at least equal to, more than or
less than the induction phase.
[0199] In some embodiments, the present disclosure provides methods
for assessing the suitability of subjects for a clinical trial to
measure the effect of an oral corticosteroid on EoE, after
administration in both an induction phase and a maintenance phase.
In some embodiments, the recruitment of subjects into the clinical
trial is assessed on patient's eosinophil count and prior
treatment. In some embodiments, the patients selected for the
clinical trial have Peak eosinophil counts per HPF of greater than
about 6, greater than about 10, greater than about 15, or greater
than about 20. In some embodiments, the patients selected for the
clinical trial have Peak eosinophil counts per HPF of greater than
about 15. In some embodiments, the patients selected for the
clinical trial have failed prior treatment. In some embodiments,
the prior treatment was administration of a PPI over at least about
8 weeks that had not been effective to substantially improve one or
more symptoms of EoE.
Purpose-Bound Products
[0200] In keeping with the foregoing, the present disclosure
provides an oral corticosteroid for use in a method of treating EoE
in a patient, wherein the oral corticosteroid is administered
immediately prior to the patient lying down or whilst the patient
is lying down. In embodiments, a therapeutically effective amount
of the oral corticosteroid contacts the patient's esophagus. The
term "therapeutically effective amount" can mean an amount capable
of eliciting beneficial biological activity in vivo and, in an
embodiment, capable of treating EoE as measured using any of the
metrics disclosed herein. The doses of oral corticosteroid
disclosed herein suitably deliver a therapeutically effective
amount of the oral corticosteroid to a patient.
[0201] The oral corticosteroid, method of treating and patient can
all be as described herein. Indeed, any and all of the features as
described herein for the disclosed compositions, methods of
treatment, dosing, administration and patient populations can be
employed in connection with the disclosed purpose-bound products.
Any and all combinations of such features are explicitly
encompassed by the disclosed invention, except combinations where
at least some of such features are mutually exclusive.
[0202] Thus, in embodiments, the lying down may be in a supine,
prone or laterally recumbent position.
[0203] The oral corticosteroid may be administered about 30 minutes
or less before target sleep time. The oral corticosteroid may be
administered at least about 30 minutes after a meal. In an
embodiment, the patient may not eat or drink for at least about 30
minutes after administration of the oral corticosteroid.
[0204] The oral corticosteroid may be administered once daily. It
may be administered twice daily, the first daily dose being
administered whilst the patient remains upright.
[0205] The oral corticosteroid may be administered in a dose of
from about 0.01 mg to about 20 mg. The oral corticosteroid may be
fluticasone propionate, administered in a dose of from about 1.5 mg
to about 7.5 mg, and preferably about 1.5, 3.0, 4.5, 6.0 or 7.5
mg.
[0206] In an embodiment, the patient may have a lactose allergy or
a starch allergy.
[0207] The oral corticosteroid may have a systemic bioavailability
of less than or equal to about 20%, less than about 15%, less than
about 10%, less than about 5% or less than about 1% of its
dose.
[0208] The oral corticosteroid may provide an average maximum blood
plasma concentration (Cmax) of less than or equal to about 500
pg/mL after oral administration of from about 0.01 mg to about 20
mg of the oral corticosteroid.
[0209] The oral corticosteroid may provide an average AUC.sub.0-24
of less than or equal to about 3,000 pg*h/mL of after oral
administration of from about 0.01 mg to about 20 mg of the oral
corticosteroid.
[0210] In embodiments the oral corticosteroid may be budesonide,
fluticasone, flunisolide, ciclesonide, mometasone, tixocortol or
beclomethasone, or a pharmaceutically acceptable salt, solvate,
ester, polymorph or prodrug thereof.
[0211] In an embodiment, the oral corticosteroid may be formulated
as a liquid composition. In another embodiment, it may be
formulated as a solid composition. It may be formulated to form a
solution or suspension prior to oral administration. It may be
formulated to form a solution, suspension or gel upon oral
administration. If formulated as a liquid composition, the oral
corticosteroid may be in the form of a solution, suspension or
slurry. If formulated as a solid composition, the oral
corticosteroid may be in the form of a gel, lozenge, lollipop,
effervescent tablet, powder, granules or an orally disintegrating
composition. The orally disintegrating composition may be in the
form of a tablet, wafer, film or lyophilized matrix.
[0212] In an embodiment, the oral corticosteroid is formulated as
an orally disintegrating tablet comprising the oral corticosteroid
in an amount of from about 1.5 mg to about 7.5 mg, a
pharmaceutically acceptable carrier combined with the
corticosteroid, and rapidly dispersing microgranules, wherein the
orally disintegrating tablet disintegrates within 60 seconds when
tested using the USP <701> Disintegration Test.
[0213] In an embodiment, the patient may have a Cmax of the oral
corticosteroid of less than or equal to about 200 pg/mL following
oral administration of from about 1.5 mg to about 7.5 mg of the
oral corticosteroid.
[0214] The average time to reach a maximum blood plasma
concentration (Tmax) of the oral corticosteroid may be in the range
of from about 80% to about 125% of from about 12 h to about 15
h.
[0215] In an embodiment, the oral corticosteroid may be fluticasone
propionate and the Cmax may be within the range of from about 80%
to about 125% of from about 15 pg/mL to about 40 pg/mL following
administration of 6 mg of fluticasone propionate or 3 mg of
fluticasone propionate.
[0216] In embodiments, after 12 weeks of daily administration of
the oral corticosteroid, esophageal inflammation may be reduced as
measured by a reduction in eosinophil count, an increase in
dysphagia-free days, a reduction in episodes of dysphagia,
improvement in EREFS score, EndoFLIP documentation of improved
esophageal compliance, evaluation of biomarkers, a decrease in
episodes of food impaction, an improvement in EEsAI scores
(patient, physician, endoscopy, pathology scores), EoE-QOL-A,
Visual Dysphagia Questionnaire (VDQ), Avoidance Modification and
Slow Eating (AMS) scores, or histology.
[0217] In an embodiment, the patient's eosinophil count may be
reduced by at least about 50%.
Combination Therapies
[0218] The one or more therapeutic agents may be "co-administered",
i.e., administered together in a coordinated fashion to a subject,
either as separate pharmaceutical compositions or admixed in a
single pharmaceutical composition. By "co-administered", the one or
more therapeutic agents may also be administered simultaneously
with the present pharmaceutical compositions, or be administered
separately, including at different times and with different
frequencies. The one or more therapeutic agents may be administered
by any known route, such as orally, intravenously, intramuscularly,
nasally, subcutaneously, intra-vaginally, intra-rectally, and the
like; and the therapeutic agent may also be administered by any
conventional route.
[0219] When two or more medicines are used in combination, dosage
of each medicine is commonly identical to the dosage of the
medicine when used independently, but when a medicine interferes
with metabolism of other medicines, the dosage of each medicine is
properly adjusted. Each medicine may be administered simultaneously
or separately in an appropriate time interval.
[0220] The pharmaceutical compositions disclosed herein may be
co-administered with various therapies used to treat, prevent,
delay, and/or ameliorate inflammatory conditions of the
gastrointestinal tract, including but not limited to inflammation
of the esophagus, inflammation of the glottis, inflammation of the
epiglottis, inflammation of the tonsils, inflammation of the
oropharynx, eosinophilic esophagitis (EoE), gastroesophageal reflux
disease (GERD), non-erosive reflux disease (NERD), erosive
esophagitis, Barrett's esophagus, eosinophilic gastroenteritis,
hypereosinophilic syndrome, corrosive (caustic) chemical
esophagitis, radiation-induced esophagitis, chemotherapy-induced
esophagitis, transient drug-induced esophagitis (also known as
medication esophagitis), persistent drug-induced esophagitis,
Crohn's disease of the esophagus, and pseudomembranous
esophagitis.
[0221] The one or more therapeutic agents may be any compound,
molecule, or substance that exerts therapeutic effect to a subject
in need thereof.
[0222] In some embodiments, the pharmaceutical compositions
disclosed herein are co-administered with one or more
corticosteroids. Suitable corticosteroids include, but are not
limited to hydrocortisone, prednisone, prednisolone,
methylprednisolone, dexamethasone, betamethasone, etc. or
mineralocorticoid potencies (e.g., alsosterone), budesonide,
fluticasone, flunisolide, ciclesonide, mometasone, beclomethasone,
tixocortol and salts, or esters and mixtures thereof.
[0223] In some embodiments, the pharmaceutical compositions
disclosed herein are co-administered with one or more proton pump
inhibitors (PPI). Suitable PPIs include, but are not limited to,
omeprazole, lansoprazole, dexlansoprazole, rabeprazole,
pantoprazole, and esomeprazole. In some embodiments the PPI is
administered at high doses.
[0224] In some embodiments, the pharmaceutical compositions
disclosed herein are co-administered with an antifungal agent.
Suitable antifungal agents include, but are not limited to mitotic
inhibitor antifungals, pyrimidine analog antifungals, polyene
antifungals, benzimidazole antifungals, imidazole antifungals,
polyene antifungals, triazole antifungals, thiazole antifungals,
allylamine antifungals, echinocandin antifungals, and other
"uncategorized" antifungals recognized in the art that do not fall
within any of the above categories (e.g., tolnaflate and
ciclopirox). For example, suitable antifungal agents which may be
included in the solid pharmaceutical compositions of the present
disclosure include abafungin, amorolfine, anidulafungin,
bifonazole, butenafine, butoconazole, candicin, caspofungin,
ciclopirox, clotrimazole, econazole, fenticonazole, filipin,
fluconazole, flucytosine, griseofulvin, isavuconizole, isoconazole,
itraconazole, ketoconazole, micafungin, miconazole, miconazole
nitrate, naftifine, natamycin, nystatin, oxiconazole, posaconazole,
pramiconazole, ravuconazole, rimocidin, setaconizole, sulconazole,
terbafine, terconazole, tioconazole, tolnaftate, undecylenic acid,
and voriconazole.
[0225] In other embodiments, pharmaceutical compositions disclosed
herein are co-administered with an antiviral agent. Antiviral
agents which may be used in the present disclosure include, but are
not limited to, interferons, nucleoside and nucleotide reverse
transcriptase inhibitors, non-nucleoside reverse transcriptase
inhibitors, protease inhibitors, integrase inhibitors, fusion
inhibitors, maturation inhibitors, guanosine analogs, puridine
analogs, pyrimidine analogs, and other "uncategorized" antiviral
drugs recognized in the art which do not fall within any of the
above classes (e.g., foscarnet and miltefosine). For example,
suitable antifungal agents which may be included in the solid
pharmaceutical compositions of the present disclosure include
abacavir, aciclovir (also known as acyclovir), adefovir,
amantadine, amdoxovir, amprenavir, aplaviroc, apricitabine,
arbidol, atazanavir, bevirimat, BMS-488043, boceprevir, brivudine,
cidofovir, DCM205, docosanol, delavirdine, didanosine, durunavir,
efavirenz, elvitegravir, elvucitabine, emtricitabine, enfuvirtide,
epigallocatechin gallate, etravirine, famciclovir, fosamprenavir,
ganciclocvir, globoidnan A, griffithsin, ibalizumab, idoxuridine,
indinavir, lamivudine, lopinavir, loviride, maraviroc, nelfinavir,
nevirapine, oseltamivir, pegylated interferon alpha-2a, pegylated
interferon alpha-2b, penciclovir, peramivir, plerixafor, PRO 140,
racivir, raltegrvir, ritonavir, ribavirin, rimantadine,
rlipivirine, saquinavir, stampidine, stavudine, tenofovir,
tipranavir, TNX-355, trifluridine, tromantadine, valaciclovir,
valganciclovir, vicriviroc, vidarabione, viramidine, vivecon,
zalcitabine, zanamivir, and zidovudine.
[0226] In some embodiments, the pharmaceutical compositions
disclosed herein are co-administered with one or more
immunosuppressants. Suitable immunosuppressants include, but are
not limited to, cyclosporine, tacrolimus, prednisolone,
hydrocortisone, sirolimus, everolimus, azathioprine, mycophenolic
acid, methotrexate, basiliximab, daclizumab, rituximab,
anti-thymocyte globulin, and anti-lymphocyte globulin.
Kits
[0227] The disclosure also provides kits for the treatment of
gastrointestinal inflammatory disorders. In some embodiments, the
kits include a pharmaceutical composition of the present disclosure
(fluticasone propionate, ODT) in unit dosage form. In some
embodiments, the kits include 1.5 mg or 3.0 mg of a pharmaceutical
composition of the present disclosure. In some embodiments, the
kits include a maintenance dosage of a pharmaceutical composition
of the present disclosure. In some embodiments, the kits include an
induction dosage of a pharmaceutical composition of the present
disclosure. In some embodiments, the kits include both an induction
and a maintenance dosage of a pharmaceutical composition of the
present disclosure. The kit can further include a label or printed
instructions instructing the use of described reagents. The kit can
further include a treatment to be tested.
INCORPORATION BY REFERENCE
[0228] All publications, patents, and patent publications cited are
incorporated by reference herein in their entirety for all
purposes.
[0229] This application incorporates by reference the following
publications and applications in their entireties for all purposes:
U.S. Pat. No. 8,771,729 filed Oct. 1, 2010; US 2016/0206627 filed
Sep. 5, 2014, U.S. 61/874,450 filed Sep. 6, 2013, WO 2015/034678
filed Aug. 21, 2014, and WO 2015/035114 filed Sep. 5, 2014.
[0230] This disclosure is further illustrated by the following
non-limiting examples.
EXAMPLES
Example 1
A Randomized, Double Blind Dose-Ranging Study of Fluticasone
Propionate Oral Dissolving Tablet
[0231] This Phase 2b study will enroll 320 patients with
eosinophilic esophagitis (EoE) between the ages of 14-75. To be
eligible for the study, patients must have a diagnosis of EoE
(>15 peak eosinophil per HPF) after proven failure of 8 weeks or
more of high-dose (i.e. 40 mg BID esomeprazole) proton pump
inhibitor (PPI). PPI therapy may be continued during the study only
if the subject was on PPI therapy at the time of enrolling in the
study. No new initiation of, nor alteration of PPI therapy is
allowed during the study. Subjects must also be symptomatic and
have a 7-day recall Global EoE symptom score of .gtoreq.5 and a
7-day recall EEsAI score of >20 to enter the placebo run-in, and
an increased EEsAI score based upon a daily diary.
[0232] Primary Objectives: To evaluate the efficacy of fluticasone
propionate oral disintegrating tablet (APT-1011) in adolescents and
adults with eosinophilic esophagitis (EoE).
[0233] Secondary Objectives: To evaluate the safety of APT-1011
(fluticasone propionate, ODT) in adolescents and adults with EoE.
To define the dose-response of APT-1011. To evaluate the
pharmacokinetics (PK) of APT-1011 in patients with EoE. To evaluate
the effect of Treatment-Withdrawal, including time to relapse and
effect of re-treatment. To evaluate maintenance of efficacy of
treatment and long-term safety. To evaluate the effects on
endoscopic appearance using the EoE Endoscopic Reference Score
(ERES).
[0234] Study Rationale and Design: Doses from 1.5 mg HS to 3.0 BID
will be explored to define the exposure-response of APT-1011 and
the minimum effective dose. This is a randomized, double-blind,
placebo-controlled dose-ranging study of three daily doses (1.5 mg,
3 mg, and 6 mg) of APT-1011 administered as 1.5 mg HS, 1.5 mg BID,
or 3.0 mg BID compared to matching placebo. The impact of treatment
withdrawal, re-treatment, and long-term maintenance will also be
evaluated.
[0235] The formulations of APT-1011 (fluticasone propionate, ODT)
used in the clinical trials are listed in the following tables.
TABLE-US-00004 Fluticasone ODTs ODT 1.5 mg 3 mg Ingredients
(%/tablet) (mg/tablet) (%/tablet) (mg/tablet) Micronized 0.50 1.50
1.0 3.00 Fluticasone Propionate USP Colloidal Silicon 0.30 0.90
0.30 0.90 Dioxide NF Silicified 10.00 30.00 10.00 30.00
Microcrystalline Cellulose NF Crospovidone NF 7.50 22.50 7.50 22.50
Sucralose NF 0.40 1.20 0.40 1.20 Spray-dried 30.30 90.90 29.80
89.40 Mannitol USP Rapidly Dispersing 50.00 150.00 50.00 150.0
Granules Sodium Stearyl 1.00 3.00 1.00 3.00 Fumarate NF Total
100.00 300.0 100.00 300.0
TABLE-US-00005 Fluticasone ODTs ODT 0.75 mg 4.5 mg 6.0 mg
Ingredients (%/tablet) (mg/tablet) (mg/tablet) (mg/tablet)
Micronized 0.25 0.75 4.50 6.00 Fluticasone Propionate USP Colloidal
Silicon 0.30 0.90 0.90 0.90 Dioxide NF Silicified 10.00 30.0 30.00
30.00 Microcrystalline Cellulose NF Crospovidone NF 7.50 22.50
22.50 22.50 Sucralose NF 0.40 1.20 1.20 1.20 Spray-dried 30.05
90.15 86.40 84.90 Mannitol USP Rapidly 50.00 150.00 150.00 150.0
Dispersing Granules Sodium Stearyl 1.50 4.50 4.50 4.50 Fumarate NF
Total 100.00 300.0 300.0 300.0
[0236] Dosing: For 3 dosing groups, APT-1011 will be provided as
blinded tablets in dose strengths of 1.5 mg and 3.0 mg. For the
fourth dosing group there will be a matching placebo. Tablets will
be administered BID--30 minutes before breakfast and HS (at
bedtime). Note that in the 1.5 mg dosing group, subjects will
receive placebo tablets 30 minutes before breakfast, and 1.5 mg
APT-1011 HS (at bedtime). To maintain the blind, all tablets will
be labeled for "before breakfast" and "bedtime" administration.
[0237] Screening: Subjects will be screened with upper endoscopy
(EGD) at 2-4 weeks. Subjects who meet other inclusion criteria and
have .gtoreq.15 peak eosinophil per HPF and have a global symptom
score of >5 and a 7-day recall EEsAI score of >20 may enter
the placebo run-in. Subjects who have an increased EEsAI score
based upon a daily diary, >80% compliance daily diary, and
>90% compliance with study drug and meet all the other inclusion
criteria will be randomized. Subjects will be randomized 1:1:1:1 to
3 active doses and placebo.
[0238] The study will be conducted in three parts as shown in FIGS.
1 and 2. Part 1 and Part 2 represent a Treatment-Withdrawal Design.
In Part 1, treatment efficacy is assessed. In Part 2, the effect of
withdrawal is assessed including Time to Relapse and difference in
relapse rates between active treatment and placebo.
[0239] Part 1: Treatment (Day 1 to week 14). Subjects will be
stratified by age (<18 and .gtoreq.18 years) and by concomitant
PPI use during the study ("yes" or "no"); then randomly assigned to
1 of the 4 dosing groups (ratio: 1:1:1:1).
[0240] All subjects will come in monthly for routine visits, and
for unscheduled visits should symptoms worsen between visits.
Subjects will be treated for 12 weeks and undergo an EGD to assess
histologic and endoscopic improvement. Symptom improvement will be
assessed on an ongoing basis. EoE Responders, defined as subjects
who achieve a histologic response of <6 Peak Eos per HPF, and no
worsening of symptoms (e.g. an increase in weekly EEsAI score
compared to baseline) or episodes of food impaction will be
re-randomized to Part 2 at week 14. Non-Responders, defined as
subjects who do not meet the definition of Response, will receive
open-label (OL) 3 mg BID until week 28 with an EGD at week 28. EoE
Responders at the end of the OL period will be eligible to enter
Part 3. Non-responders to OL treatment will enter a 2-week
follow-up period.
[0241] Part 2: Treatment-Withdrawal (week 14 to week 28). EoE
Responders from Part 1 will be randomized to either continue their
dose or receive placebo in a 3:1 randomization. Placebo responders,
which are expected to be few, will remain on placebo. Subjects who
experience a worsening of symptoms (e.g. return to baseline weekly
EEsAI score or complain of symptoms worsening) or food impaction
will undergo endoscopy at an unscheduled visit. Subjects with food
impaction requiring endoscopy or a stricture requiring dilation
will enter the 2-week follow-up period and exit the study. Subjects
deemed to be a relapse will be returned to their previous dose,
except those previously on placebo who will receive 3 mg BID.
Subjects who relapse on Study Drug will also receive 3 mg BID to
avoid unblinding the study. The relapsers will enter Part 3. All
subjects in the study at weeks 12, 26 and 52 will undergo
endoscopy. EoE Responders at week 28 will continue to Part 3.
Non-responders at the end of Part 2 will receive 3 mg BID when they
enter Part 3.
[0242] Part 3: Maintenance (week 28 to week 54). Non-Responders
from Part 1 who respond to open-label 3 mg BID will continue on
this dose in Part 3. Note that this group will not participate in
Part 2. EoE responders from Part 2 will continue on the same dose.
Relapsers and non-responders from Part 2 will receive 3 mg BID in
Part 3. Subjects who relapse (e.g. experience food impaction
requiring endoscopy or clinically-significant worsening of
symptoms) in Part 3 will undergo an unscheduled endoscopy, enter
the 2-week follow-up, and exit the study. All continuing subjects
will undergo endoscopy at week 52 and complete their final on
treatment visit at week 54.
[0243] Follow-up: (2-weeks after last dose). All subjects must have
a final endoscopy within 3 weeks prior to entering follow-up.
Exceptions include withdrawal of consent or contra-indication to
endoscopy. Reasons for entering follow-up include completing week
54, adverse event requiring early withdrawal including food
impaction requiring endoscopy, failed to respond to open-label 3 mg
BID, or relapsed in Part 3.
[0244] Pharmacokinetics: All doses of APT-1011 will be administered
twice daily 30 minutes before breakfast and bedtime with the
exception of the 1.5 mg dose, which will be administered HS at
bedtime or 30 minutes before breakfast. A population PK analysis
will be performed based on a combination of serial and sparse
plasma concentration data.
[0245] Population PK: Sparse PK samples will be collected from all
subjects (excluding subject +/-3 days) of repeat dosing. On Week 4,
Day 1 (+/-3 days) of the repeat-dose period, PK samples will be
collected no more than 15 minutes prior to the morning dose, and at
0.5, 1.5, and 3 hours following the morning dose. The time of the
night-time dosing (e.g. bedtime) along with actual PK sampling time
will be documented.
[0246] Intensive PK Subset to be performed in Part 1: At selected
sites, 24 evaluable subjects (6 subjects per dose group) will
undergo intensive serial PK sampling following a single dose on
Week 1, Day 1 and following repeat-dose administration on Week 4,
Day 1 (+/-3 days). On the morning of Week 1, Day 1, subjects will
receive a single dose of APT-1011 and PK samples will be collected
no more than 15 minutes prior to the AM dose and at 0.5, 1, 2, 4,
8, 24, and 48 hours following dose administration. NOTE: the
48-hour sample should be collected following the single dose and
prior to the start of the repeat-dose period. This sample would be
collected on the visit when subjects return to receive medication
for the repeat-dose outpatient period.
[0247] The repeat-dose period will start following collection of
the 48-hour PK sample on Week 1 Day 3. On Week 4, Day 1 (+/-3 days)
of the repeat-dose period PK samples will be collected no more than
15 minutes prior to AM dose and at 0.5, 1, 2, 4, 8 and 12 hours
post AM dose, immediately prior to PM dose. NOTE: the 12-hour post
AM dose PK sample is `Optional`. The 12-hour PK sample should be
collected immediately prior to the PM dose. Time of dosing (bedtime
the preceding night and following morning) along with actual PK
sampling times will be documented).
[0248] Study Duration: This study has an anticipated recruitment
period of 12 months. Subjects who enter and complete the study
(Part 1, Part 2 and Part 3) will be in the study for up to 15
months.
[0249] Study Population: The study will enroll approximately 320
adolescent and adult subjects diagnosed with EoE who meet the entry
criteria and will randomize subjects into 1 of 4 dosing groups
(including placebo) of 80 subjects per dosing group.
[0250] Inclusion Criteria: Male and female subjects between the
ages of 14 and 75 inclusive. Patients must have a diagnosis or
presumptive diagnosis of EoE, including those patients with
relapse, must be confirmed by symptoms and histology; by historical
documentation of failed treatment on 8 weeks or more of high-dose
(e.g. 40 mg BID) proton pump inhibitor (PPI) either prior to
initial diagnosis or documented subsequently. A lack of response to
PPI therapy is defined as a peak eosinophil count.gtoreq.15 per HPF
in at least one biopsied location after the 8 weeks of high dose
treatment. PPI therapy may be continued during the study only if
the subject was on PPI therapy at the time of biopsies from the
screening endoscopy. No new initiation of, nor alteration of PPI
therapy is allowed during the study.
[0251] Subjects must have evidence of eosinophilic esophagitis
defined by the PEAK esophageal mucosal eosinophil count.gtoreq.15
per high-powered field (HPF, 400.times. magnification) in at least
1 of the esophageal sites biopsied (.gtoreq.3 biopsies from each
the proximal and the distal esophagus; a minimum of 6 total
biopsies). Biopsies are to be obtained no more than 30 days prior
to the Screening Visit, and slides must be received by the central
pathologist within 30 days after the Screening Visit or 2 weeks
prior to randomization. Eligibility will be based solely on the
central pathologist's assessment.
[0252] The subjects must have a 7-day recall Global EoE
score.gtoreq.5, as measured on a scale from 0 to 10 (0 representing
no symptoms and 10 representing most severe symptoms).
[0253] Subjects must have 7-day recall EEsAI score>20 to enter
the placebo run-in. For randomization, an increased EEsAI score
based upon a daily diary is required and clinical symptoms of
dysphagia (difficulty swallowing) at least 3 times per week within
2 weeks.
[0254] Exclusion Criteria: Known contraindication, hypersensitivity
or intolerance to corticosteroids; any physical, mental, or social
condition, history of illness or laboratory abnormality that in the
investigator's judgment might interfere with study procedures or
the ability of the subject to adhere to and complete the study;
presence of oral or esophageal mucosal infection of any type; any
condition affecting the esophageal mucosa or altering esophageal
motility other than EoE including erosive esophagitis, hiatus
hernia longer than 3 cm, and Barrett's esophagus; use of systemic,
oral or parenteral corticosteroids within 30 days, or inhaled or
extended use of high-potency dermal topical corticosteroids within
30 days prior to: the esophageal biopsy required for entrance to
this study or EGD if done during the pre-screening period; morning
(0700 to 0800 hours, or as close to that window as possible) serum
cortisol level.ltoreq.5 .mu.g/dL (138 nmol/L); a plasma cortisol
level of <18 .mu.g/mL (497 nmol/L) at 60 minutes with
adrenocorticotropic hormone (ACTH) stimulation test using 250 .mu.g
cosyntropin, consumption of grapefruit juice during the treatment
is prohibited; use of biologic immunomodulators within the past 6
months; use of calcineurin inhibitors, purine analogues
(azathioprine, 6-mercaptopurine) within the past 3 months;
contraindication to EGD or esophageal biopsy or narrowing of the
esophagus precluding EGD with a standard 9 mm endoscope;
gastrointestinal bleeding within 1 month prior to the Screening
Visit or between the Screening Visit and the Randomization Visit;
current chronic infection, immunosuppression, or immunodeficiency;
history or presence of Crohn's disease, celiac disease, or other
inflammatory disease of the gastrointestinal tract including
eosinophilic gastroenteritis; current alcohol or drug abuse; female
subjects who are pregnant or breastfeeding; sexually active females
of child-bearing potential who do not agree to follow highly
effective contraceptive methods during the study including the
follow-up period. (abstinence is acceptable for adolescents);
female subjects with surgical menopause or menopause confirmed by
FSH do not require contraception or pregnancy testing during the
study; participation in a clinical study involving an
investigational drug within 30 days of the Screening Visit.
[0255] Methodology/Study Procedures are shown in Tables 4-7.
[0256] Primary Efficacy Endpoints: There are 2 co-primary efficacy
endpoints for EoE Response
[0257] The percentage of subjects with a PEAK eosinophil
count<6/HPF at all biopsied esophageal locations at Week 12 and
change from baseline in mean weekly EEsAI score. EoE Endoscopic
Response and no worsening of the mean weekly EEsAI score will be
the basis for entering Part 2.
[0258] Secondary Efficacy Endpoints: EoE Response will be assessed
also at week 26 with comparisons to placebo to assess the impact of
treatment-withdrawal. EoE Response will also be assessed at week 52
by dose and subgroup. EoE Remission and Response will also be
assessed after 12 weeks of OL treatment in non-responders to Part
1.
[0259] Sustained EoE Response will be assessed at Weeks 24 and 52
for subjects remaining on the same dose: Assessment of Relapse and
Treatment Failure; non-Response at each endoscopic endpoint;
relapse on Placebo in Part 2; percentage of subjects requiring
emergency endoscopic food disimpaction by dose and part of the
study; percentage of subjects requiring esophageal dilation.
[0260] The effect of re-treatment will be assessed by assessing EoE
Response in Part 2 Relapsers at week 52 by treatment group.
[0261] The percent of subjects with PEAK Eos per HPF<1 and
<15 at all major time points where EoE Response is assessed
[0262] The percent of subjects with mean weekly EEsAI score<20
at all major time points where EoE Response is assessed
[0263] Endoscopic changes will be based upon the EREFS score based
on 5 endoscopic features: edema, furrowing, exudates, rings,
strictures and physician assessment of overall disease activity
(absent, mild, moderate, severe): the percentage of subjects with
overall assessment of `improved`, `no change` and `worsened` from
baseline (Screening Visit) at Week 12, 26 and 52 as well as at the
end of OL treatment of non-responders from Part 1; the change from
baseline in 7-day Global EoE Score which will be assessed before
run-in, baseline, week 12, week 26 and week 52.
[0264] Pharmacokinetic Endpoints: Steady-state Population PK
(sparse PK and intensive PK) analyses; single-dose PK analyses.
[0265] Exploratory Endpoints: Collin's Histologic Score for EoE for
all biopsies performed, the change from baseline will be assessed;
evaluation of quality of life based on the EoE-QOL-A at week 12,
26, 52 and week 12 of OL treatment by dose and subgroup; patient's
assessment of symptoms compared to the previous visit. This
Question will be assessed at weeks 8, 12, 18, 26, 30 and 52.
[0266] Safety: Safety will be assessed by monitoring and recording
all treatment-emergent adverse events (TEAEs), TEAEs leading to
withdrawal and serious adverse events (SAEs). All TEAEs will be
coded based upon the MedDRA version 14.0 classification of adverse
events (AEs) and classified by severity (mild, moderate, severe)
and relatedness to study drug (related or not related) by the
Investigator. TEAEs occurring within 2 days of a dose change will
be attributed to the previous dose. This time of attribution may be
altered based on the half-life of the dose. Physical examinations
will be performed to document the baseline condition of the subject
and to highlight changes related. to AEs. Vital signs will also be
assessed at all visits and clinically significant deviations will
be reported.
[0267] Routine laboratory tests will be performed throughout the
study including hematology, blood chemistry, urinalysis,
electrocardiograms (ECGs) as indicated in the Schedules of
Assessments. Clinically significant changes in laboratory tests or
ECGs will be summarized.
[0268] Cortisol Issues: Abnormal AM cortisol, urinary glucose or
serum glucose would necessitate following the subject to
resolution. CRFs should capture presence or absence of known
glucocorticoid AEs such as moon facies, acne, hirsutism, mood
swings, insomnia or depression. ICF should highlight that stress
steroids may be required during significant medical illnesses. ACTH
stimulation test (cosyntropin 250 mcg) should be performed at
baseline and Week 12, early withdrawal and at week 52 for all
subjects. ACTH test should be performed in all subjects with plasma
cortisol>5 mcg/dL (138 mmol/L). All subjects with positive tests
should be excluded. Any positive results at the end of treatment
should be followed to recovery of adrenal function. The number of
subjects discontinuing for HPA suppression or positive ACTH
stimulation tests will be summarized. The Sponsor will provide each
site and investigator with guidelines for safety follow-up and
document restoration of adrenal function in all subjects
demonstrating evidence of hypercorticism or HPA axis suppression
during the course of the study. Subjects under age 18 will be
evaluated for growth parameters such as height, weight, body mass
index (BMI) and corresponding z-scores. The safety endpoints of
interest are: frequency of treatment emergent adverse events
(TEAEs), TEAEs leading to withdrawal and treatment-emergent serious
adverse events (SAEs), as well as the percentage of subjects with
serum cortisol level.ltoreq.5 .mu.g/dL (138 nmol/L) or positive
ACTH stimulation test (serum cortisol<18 .mu.g/mL (497 nmol/L)
at 60 minutes). The number of subjects discontinuing for HPA axis
suppression will be recorded.
[0269] Statistical Methods: Sample Size Determination: For Part 1,
sample size determination is based on the planned comparisons
between each dosing group with respect to EOE Response: 1) the
percentage of subjects with a peak eosinophil count<6
Eosinophil/HPF at all biopsied esophageal locations at Week 12; and
2) Change from baseline in EEsAI score. If for the present study,
after 12 weeks of treatment, the percentage of placebo treated
subjects with a peak eosinophil count<6/HPF at all biopsied
esophageal locations is assumed to be 15% for placebo and 60% for
active arms with an expected delta of 45. For the mean weekly EEsAI
score, the EoE Response for symptoms at week 12, we assume a
placebo rate of 35% with an expected efficacy of 65% in the active
arms with an expected delta of 30%. Based upon an equal
randomization, approximately 60% of subjects will enter Part 2 of
the study. In order to ensure that the sample size is sufficient to
detect a delta of 30% in Part 1 and to ensure sufficient subjects
enter PART 2 for analysis assuming 20% of active and 80% of placebo
develop a symptomatic relapse, a minimum of 320 subjects will be
enrolled (80 per arm). With 320 per arm, assuming and overall
dropout rate of 20%, we assume that approximately 35 subjects per
active arm will be evaluable for assessment of sustained remission
at week 52.
[0270] The primary analysis population for efficacy is the
intent-to-treat (ITT) population, defined as all randomized
subjects. The analysis population for safety is the safety
population, defined as all subjects who receive at least one dose
of study drug. The single-dose PK population will be defined as all
subjects in the ITT population of PART 1 who are randomized to one
of the three APT-1011 dosing groups, take their first dose of
APT-1011, and have at least one PK sample included in the final
single-dose population PK analysis. The steady-state PK population
will be defined as all subjects in the ITT population of PART 1 who
are randomized to one of the three APT-1011 arms, take their dose
of APT-1011 that corresponds to the steady-state PK sampling
period, and have at least one PK sample included in the final
steady-state population PK analysis. Additional per protocol
analysis populations who complete Parts 1, 2, and 3 and OL
treatment may be defined in the Statistical Analysis Plan (SAP).
Baseline and demographic information will be summarized using
descriptive statistics for continuous and ordinal variables (e.g.,
age, weight, height) and counts and percentages for categorical
variables (e.g., sex, race).
[0271] Primary Efficacy for Part 1
[0272] There are two co-primary efficacy endpoints for PART 1: the
percentage of subjects with a peak eosinophil count<6/HPF at all
biopsied esophageal locations at Week 12; and the change from
baseline in mean weekly EEsAI score at week 12. To preserve the
overall level of significance at 0.05 for the study, each of the
two co-primary efficacy endpoints will be assessed at the 0.05
level.
[0273] For each co-primary endpoint, the primary treatment
comparisons of interest are the comparisons of each APT-1011 dosing
group versus placebo. The efficacy hypotheses of APT-1011 versus
placebo will be tested in the following order:
[0274] H.sub.0: .mu. of APT-1011 3.0 mg BID=.mu. of placebo
[0275] H.sub.0: .mu. of APT-1011 1.5 mg BID=.mu. of placebo
[0276] H.sub.0: .mu. of APT-1011 1.5 mg HS=.mu. of placebo
[0277] where .mu. denotes the proportion of subjects with a peak
eosinophil count<15/HPF at all biopsied esophageal locations at
Week 12 for one co-primary efficacy end-point and denotes the
change from baseline in mean weekly EEsAI score at Week 12 for the
other co-primary efficacy endpoint.
[0278] The statistical testing will begin with the comparison of
APT-1011 3.0 mg BID vs. placebo with respect to each of the two
co-primary efficacy endpoints. If both comparisons are
statistically significant at the 0.05 level, the next lower dose
will be tested vs. placebo for both co-primary efficacy endpoints.
The procedure stops after the first pair-wise comparison yields a
non-statistically significant result for one or both of the
co-primary efficacy endpoints. Since statistical testing of
treatment differences between APT-1011 and placebo is to be
performed by means of a priori ordered hypotheses, no adjustment of
the significance level for multiplicity is required.
[0279] The pair-wise comparisons between each APT-1011 arm and
placebo with respect to the proportion of subjects with a peak
eosinophil count<6/HPF at all biopsied esophageal locations at
Week 12 will be performed using the Cochran-Mantel-Haenszel (CMH)
test adjusting for the two randomization stratification factors:
age group and PPI use; and also geographic region (North America;
non-North America). The pair-wise comparisons between each APT-1011
arm and placebo with respect to the change from baseline in mean
weekly EEsAI score at week 12 will be performed by comparing the
corresponding least squares means from an analysis of covariance
(ANCOVA) with treatment, the two randomization stratification
factors, and the geographic region in the model as fixed effects
and the baseline SQ score as a covariate. The method will be used
to adjust for multiple comparisons. The sample size has been
increased accordingly.
[0280] If superiority of at least one of the APT-1011 dose groups
over placebo is demonstrated for the two co-primary endpoints, the
dose-response relationship will be assessed for the two co-primary
endpoints with total daily dose among the explanatory variables in
the appropriate statistical models.
[0281] Efficacy for OL Treatment
[0282] A similar approach will be taken as in Part 1 for
non-responders from Part 1 who receive OL treatment with 3.0 mg
BID.
[0283] Efficacy for Part 2
[0284] There is one primary efficacy endpoint for PART 2, the
percentage of subjects who relapse on or before the end of the
double-blind treatment in PART 2, defined as a return to baseline
in EEsAI score or a verbal complaint that "My symptoms have
worsened and are about the same as when I entered the study") and a
peak eosinophil count.gtoreq.15/HPF in at least one biopsied
esophageal location on or before the end of the assessment at week
26 Part 2. To preserve the overall level of significance at 0.05
for the study, the statistical testing for the efficacy endpoint in
PART 2 will be performed only if statistical significance in favor
of at least one APT-1011 dosing group over placebo is demonstrated
for the two PART 1 co-primary efficacy endpoints. The efficacy
hypothesis of APT-1011 3.0 mg QD versus placebo is as follows:
[0285] H.sub.0: .mu. of APT-1011 3.0 mg QD=.mu. of placebo
[0286] where .mu. denotes the proportion of subjects who relapse on
or before the end of the 12-week double-blind treatment in PART 2.
The test will be conducted at the 0.05 level of significance using
the CMH test adjusting for the two randomization stratification
factors (from Part 1), geographic region, and the prior treatment
the subject was on before being randomized into double-blind
treatment in PART 2. The prior treatments are placebo, APT-1011 1.5
mg QD, 1.5 mg BID, and 3.0 mg BID for randomized subjects in Part
1.
[0287] Efficacy for Part 3
[0288] Sustained EoE Response will be assessed in the subgroup of
subjects who achieved EoE Response in Part 1 and Part 2 and who
complete the week 52 evaluations.
[0289] Secondary and Exploratory Efficacy
[0290] Statistical tests to compare each APT-1011 dosing group to
placebo will be performed for the secondary efficacy endpoints, but
the corresponding p-values will be considered as descriptive rather
than inferential. The secondary endpoints will be analyzed in the
same manner as described above for the primary efficacy endpoints,
namely, using CMH test for categorical endpoints and ANCOVA for
change or percentage change from baseline endpoints, except for the
endpoint of time to relapse after initiation of double-blind
treatment in PART 2, which will be analyzed using Kaplan-Meier
methods. No statistical testing of exploratory efficacy endpoints
will be performed.
[0291] Safety
[0292] The incidence of TEAEs will be summarized by system organ
class and preferred term. Separate summaries by maximum severity
and relationship to study drug will be provided. The incidence of
TEAEs leading to withdrawal from the study and treatment-emergent
SAEs will also be summarized. In subjects who change dose groups,
the TEAEs will be attributed to the previous dose, if they occur
within 2 days of the change. The attribution period may be altered
depending on the half-life of the dose. Clinically significant
changes of potential clinical interest in clinical tests will be
summarized including hematology, chemistry, urinalysis, ECG,
cortisol, vital signs, growth-related assessments for adolescents,
and bone mineral density. No statistical testing of safety
endpoints will be performed. Shift tables may be performed, if
needed.
[0293] Pharmacokinetics and Pharmacodynamics Analysis
[0294] In this study, all doses of APT-1011 will be administered
twice daily (before breakfast and at bedtime) with the exception of
1.5 mg daily, which will be administered QD at bedtime with placebo
administered after breakfast. A population PK analysis will be
performed based on a combination of serial and sparse plasma
concentration data. Previous serial PK data for APT-1011 may be
included in this analysis to facilitate development of a base PK
model.
[0295] Population PK analysis will be performed using the nonlinear
mixed-effects software, NONMEM, Version 7.2.0 or later (ICON
Development Solutions, Ellicott City, Md.) or other appropriate
nonlinear mixed-effects modeling software. The structural PK model
will include CL/F and V/F as fixed-effect parameters. In addition,
the between-subject (intersubject) variability in the parameter
estimates and the random residual error in the data will be
estimated with appropriate error models. The optimal base model
will be selected according to the standard criteria such as minimum
objective function value and diagnostic plots. Given the relatively
small number of subjects in this study, a covariate analysis is not
planned. The relevant information from bioanalytical and clinical
databases (e.g., dosing times and sampling times) will be extracted
and integrated for generation of the population PK input file(s).
All possible efforts will be made to capture any missing
information. Any additional information obtained regarding missing
data and the procedures followed to handle any missing data will be
documented and discussed in the clinical study report. After the
final model is constructed, secondary parameters such as AUC and
Cmax will be calculated to characterize the extent of FP systemic
exposure. Additional simulations may be performed, as necessary, to
inform decision making for future studies. In general, the
simulation step will include creation of data files using dummy
subjects with desired sampling times and dosing regimens, running
simulation with desired number of replicates using the final model
output parameters in the control file. The output from the final
population models including appropriate diagnostic plots, listings,
and summaries of PK parameters will be generated. In addition,
graphical and tabular presentations of any PK simulations will be
produced.
[0296] As data permit, exploratory analyses assessing the
relationship between systemic exposure to FP and changes in
cortisol levels also may be performed as described above. Potential
exploratory PK/PD analyses will be used to facilitate selection of
safe and effective doses for future studies.
TABLE-US-00006 TABLE 4 Schedule of Assessments: Screening through
PART 1 VISIT Run- Week Week Week Week Unscheduled Early Screening
In Randomization 4 8 12 14 Visit.sup.c Withdrawal.sup.b Assessments
and DAY Procedures -56 to -29 -28 to -1 1 28 .+-. 3 56 .+-. 3 84
.+-. 3 98 .+-. 3 zz Informed X consent signed Inclusion/exclusion X
.sup. X.sup.d criteria Demographics, X medical, surgical history,
medication history Concomitant X X X X X X X X medication(s)
Physical X X X X X X X examination Vital signs X X X X X X X X
Chemistry; X X X X X X X Hematology; LFTs Serum cortisol X X X X X
Results.sup.f optional.sup. X (AMfasting).sup.e Urinalysis X X X X
X X X Electrocardiogram - X X X X Standard 12- lead Population
.sup. X.sup.g .sup. X.sup.g .sup. X.sup.g .sup. X.sup.g .sup.
X.sup.g Pharmacokinetics Pre-Dose Intensive PK .sup. X.sup.h .sup.
X.sup.h Pre-Dose EGD with X X X.sup.m multiple esophageal
biopsies.sup.a, i EndoFlip will be performed at selected sites at
the time of endoscopy as part of a substudy Urine X X X X X X
pregnancy test for women of CBP Menopausal women FSH at screening
only ACTH X X Optional.sup.k X stimulation test (250 .mu.g).sup.k
Adverse X X X X X X X X X events Global EoE X X X Score 7-day EEsAI
X X X X X X X EEsAI Daily X X X X X X X EoE-QOL-A X X X X X and
Global EoE Symptoms Bone Age.sup.m X Study Drug X X X X X Dispensed
All placebo BID Drug return X X X X X X and accountability (Study
Drug compliance assessment) Daily Diary X Compliance Assessment
.sup.aEndoscopy may be performed at a separate visit. Results of
histology will be required at randomization and week 14.
.sup.bPatient should be seen in the office within 7 days of
determination of the need to withdraw the patient. If this is not
possible due to an SAE or other unforeseen circumstance, visit may
be completed with a phone visit with the patient or family member.
Documentation of why the patient could not come in should be placed
in the patient record. .sup.cThe reason for an unscheduled visit
will guide procedures, at the discretion of the PI.
.sup.dConfirmation that the patient still meets inclusion/exclusion
criteria based upon Daily EEsAI in addition to other criteria
.sup.eTo be drawn as close as possible to 0800 hours. Patients must
be fasting for an eight (8)-hour period prior to the serum cortisol
assessments. Blood may be drawn for AM Serum Cortisol +/-2 days of
scheduled visit to accommodate accurate timing. Other blood draws
scheduled for the visit may be done at the same time. .sup.fIf
abnormal serum cortisol level is reported at Final on treatment
Visit; additional monitoring and ACTH test may be required. .sup.gA
sample will be obtained at Week 4 in all subjects excluding those
in the intensive PK subset, no more than 15 minutes prior to the AM
dose and at 0.5, 1.5 and 3 hours following the AM dose. The time of
the PM dose (bedtime preceding) and AM dose along with actual PK
sampling will be documented. .sup.hApproximately 6 subjects per
dose group will undergo intensive PK at selected sites between
Weeks 2 and 4: PK samples will be collected no more than 15 minutes
prior to AM dose and at 0.5, 1, 2, 4, 8 and 12 hours post AM dose,
immediately prior to PM dose. NOTE: the 12-hour post AM dose PK
sample is `Optional`. The 12-hour PK sample should be collected
immediately prior to the PM dose. The time of the PM dose (bedtime
preceding) and AM dose along with actual PK sampling will be
documented. .sup.iCan be done up to 30 days prior to Screening
Visit (in absence of systemic or inhaled, intranasal or
high-potency dermal topical corticosteroids within these 30 days
prior to the Screening Visit). If a previous histology is
considered not acceptable, an additional Screening Visit must be
scheduled to perform EGD and biopsies during the Screening Period.
The results from the central pathologist must be available before
randomization. EREFS must be available or able to be performed from
an endoscopy report for any standard of care endoscopies as well.
.sup.jIf the patient is withdrawing from the study due to lack of
efficacy or other reasons, the Investigator may perform an EGD, if
clinically indicated. .sup.kAll subjects undergo a 250 .mu.g ACTH
stimulation test at baseline and EOT or at early withdrawal. An
ACTH simulation test will also be performed during the study at an
optional visit for subjects whose serum cortisol level is confirmed
by two blood draws as .ltoreq.5 .mu.g/dL (138 nmol/L) or if they
have signs and symptoms of hypercortism to assess for
hypophyseal-pituitary-adrenal (HPA) axis suppression of potential
clinical concern. .sup.lBone age to be performed on all adolescents
(<18 years of age at randomization); exceptions include female
subjects who have completed their linear growth or male subject who
have not completed their liner growth by 18 years of age, at the
discretion of the PI.
TABLE-US-00007 TABLE 5 Schedule of Assessments: PART 2 VISIT Week
14 Week Week Week Week Unscheduled Early Randomization 18 22 26 28
Visit.sup.c Withdrawal.sup.b Assessments and DAY Procedures 98 + 3
126 .+-. 3 154 .+-. 3 192 .+-. 3 220 .+-. 3 zz EoE Responder in X
PART 1 No contraindications to continue >80% compliant with
diary >90% compliant with drug Concomitant TR Week 12 X X X X X
X medication(s) Physical TR Week 12 X X X X examination Vital signs
TR week 12 X X X X X X Chemistry; TR week 12 X X X X X Hematology;
LFTs Serum cortisol (AM TR week 12 X X X Results.sup.f
optional.sup. X fasting).sup.e Urinalysis TR week 12 X X X X X
Electrocardiogram - TR week 12 X X Standard 12-lead Population
Pharmacokinetics (Needed?) EGD with multiple TR Week 12 Results X
esophageal biopsies.sup.a, i EndoFlip at selected sites as part of
a substudy ACTH stimulation TR Week 12 X Results Optional.sup.k X
test (250 .mu.g).sup.k Adverse events X X X X X X X 7-day EEsAI X X
X X X X X EEsAI Daily X X X X X GlobalEoEScore X X X EoE-QOL-A and
X X X Global EoE Symptoms Study Drug X X X X Dispensed Drug return
and X X X X X accountability (Study Drug compliance assessment)
TABLE-US-00008 TABLE 6 Schedule of Assessments: OL Treatment VISIT
Week Week Week Week Week Unscheduled Early 14 18 22 26 28
Visit.sup.c Withdrawal.sup.b Assessments and DAY Procedures 98 + 3
126 .+-. 3 154 .+-. 3 192 .+-. 3 220 .+-. 3 zz Eo ENON-Responder in
X PART 1 >80% compliant with diary >90% compliant with study
drug Concomitant medication(s) TR X X X X X from Part 1 Physical
examination TR X X X X X from Part 1 Vital signs TR X X X X X from
Part 1 Chemistry; Hematology; TR X X X X X LFTs from Part 1 Serum
cortisol (AM TR X X X Results.sup.f optional.sup. X fasting).sup.e
from Part 1 Urinalysis TR X X X X X from Part 1 Electrocardiogram -
TR X X Standard 12-lead from Part 1 Population Pharmacokinetics
(Needed?) Intensive PK (Needed?) EGD with multiple TR X esophageal
biopsies.sup.a, i from EndoFlip at selected sites as Part 1 part of
substudy Urine pregnancy test for X X X X X women of CBP ACTH
stimulation test (250 .mu.g).sup.k X Optional.sup.k X Adverse
events X X X X X X X 7-day EEsAI X X X X X X X EEsAI Daily X X X X
X Global EoE Score X X X EoE-QOL-A and Global X X X EoE Symptoms
Study Drug Dispensed X X X X Drug return and X X X X X
accountability (Study Drug compliance assessment)
TABLE-US-00009 TABLE 7 Schedule of Assessments: PART 3 VISIT
Follow- up Any Week 28 subject Randomization Week with Or assigned
Week 36, 40, Week Week Unscheduled Early Early dose 32 44, 48 52 54
Visit.sup.c Withdrawal.sup.b Withdrawal DAY 2 weeks Assessments and
after last Procedures 220 + 3 126 .+-. 3 154 .+-. 3 192 .+-. 3 220
.+-. 3 dose Inclusion X Criteria for PART 3.sup.o Concomitant TR
week X X X X X X medication(s) 26 Physical TR week X X X X X X
examination 26 Vital signs TR week X X X X X X 26 Chemistry; TR
week X X X X X X Hematology; 26 LFTs Serum cortisol TR week X X X
Results.sup.f optional.sup. X X (AM fasting).sup.e 26 Urinalysis TR
week X X X X X X 26 Electrocardiogram - TR week X X X Standard 26
12-lead Population Pharmacokinetics (Needed?) EGD with TR week X
Results X multiple 26 esophageal biopsies.sup.a, i Urine X X X X X
X pregnancy test for women of CBP ACTH X Results Optional.sup.k X
stimulation test (250 .mu.g).sup.k Adverse events X X X X X X X
7-day EEsAI X X X X X X X EEsAI Daily X X X X X X X Global EoE X X
X Score EoE-QOL-A X X X and Global EoE Symptoms Study Drug X X X X
Dispensed Drug return X X X X X X and accountability (compliance
assessment) a-m see previous footnotes .sup.oSubjects meet
Inclusion Criteria for PART 3 Complete PART 2 as a Responder -
continue on same dose Complete PART 2 as a Non-Responder - Assigned
to 3 mg BID Relapse on Placebo - return to prior dose in PART 3
Relapse in PART 2 on placebo - Assigned to 3 mg BID in PART 3
Complete OL Treatment as a Responder - Continue 3 mg BID Complete
OL Treatment as a Non-Responder - Exit Study and enter Follow-up
Period
Example 2
A Randomized, Double-Blind, Placebo-Controlled Trial of a
Fluticasone Propionate Orally Disintegrating Tablet in Adult and
Adolescent Patients with Eosinophilic Esophagitis: A Phase 1/2a
Safety and Tolerability Study
[0297] BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is a
chronic immune-mediated disease characterized by presence of tissue
eosinophilia and symptoms of esophageal dysfunction. This was the
first clinical study of APT-1011, fluticasone propionate (FP) a
novel orally disintegrating tablet (ODT), that evaluated the
tolerability and safety of 2 dosing regimens of APT-1011 compared
to placebo (PBO) in adolescent and adult EoE patients.
[0298] METHODS: Subjects were randomized 1:1:1 to receive either
APT-1011 1.5 mg BID [BID] (n=8), APT-1011 3.0 mg QD [QD] (n=8), or
PBO (n=8). Patients underwent esophago-gastro-duodenoscopy (EGD)
with esophageal biopsy at baseline (BL) and end of treatment [EOT]
(week 8) to assess change in median eosinophil count. Secondary
endpoints included improvement in endoscopic features as measured
by the EoE Endoscopic Reference Score (EREFS), and Patient Global
Assessment of Disease Severity (PatGA). Safety was also
assessed.
[0299] RESULTS: Twenty four subjects (including 9 adolescent
patients, 3 in each treatment arm) completed the 8-week
double-blind period. Baseline and EOT median esophageal eosinophil
counts (cells/mm.sup.2 of the high power field), median EREFS
score, as well as median PatGA for PBO, BID and QD groups are shown
(Table 8). At EOT, the median esophageal eosinophil counts were
significantly decreased from BL in biopsies of patients given
APT-1011 (both regimens) but not in those of patients given
placebo. There was a significant reduction in the 1 median EREFS
(when compared to BL) in both groups of patients given APT-1011,
but not placebo. There was a significant improvement in Patient
Global Assessment of Disease Severity in patients given APT-1011
BID (trend in group given QD), but not placebo. Table 8 shows the
median (and IQR) esophageal eosinophil counts as well as median
EREFS score. P-value of <0.05 is considered to be
significant.
TABLE-US-00010 TABLE 8 Eosinophil counts EREFS score PatGA PBO BL
459 (286-609) 6.5 (4.5-7.5) 4.0 (4.0-6.5) APT-1011 1.5 379
(289-563) 6.0 (2.5-9.0) 3.0 (2.0-6.0) mg BID BL APT-1011 3.0 378
(224-458) 6.0 (4.5-7.5) 4.5 (2.0-6.5) mg QD BL PBO EOT 323
(200-523) 5.0 (3.0-7.0) 3.5 (3.0-5.0) APT-1011 1.5 0 (0-60) 2.0
(0.5-3.0) 0.5 (0-2.5) mg BID EOT APT-1011 3.0 23 (0-109) 2.5
(2.0-3.5) 2.0 (1.0-3.0) mg QD EOT p-values PBO 0.3261 0.5347 0.1167
(BL vs EOT) p-values BID 0.0002 0.0088 0.0104 (BL vs EOT) p-values
QD 0.0111 0.0019 0.0563 (BL vs EOT)
[0300] The rates of treatment emergent adverse events (TEAEs) were
75% (PBO), 75% (APT-1011) (QD). All TEAEs were of mild intensity
except for 1 each of moderate fatigue and moderate depression by 1
subject in the placebo group.
[0301] CONCLUSIONS: Eight-week treatment with APT-1011 is well
tolerated. Use of APT-1011 in adult and adolescent EoE patients led
to significant reduction in esophageal eosinophilia and
improvements in the severity of EoE-associated endoscopic
findings.
Example 3
A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging, and
Maintenance Study of APT-1011 in Adolescents and Adults with
Eosinophilic Esophagitis (EoE)
[0302] Primary Objective: Evaluate the efficacy of APT-1011 in
adolescents and adults with eosinophilic esophagitis (EoE).
[0303] Secondary Objectives: To evaluate the safety of APT-1011 in
adolescents and adults with EoE; To define the dose-response of
APT-1011; To select a dose(s) for Phase 3; To evaluate individual
pharmacokinetics of APT-1011 in a subset of adults and adolescents
with EoE; To evaluate the population pharmacokinetics (PopPK) of
APT-1011 in patients with EoE; Evaluate maintenance of efficacy and
long-term safety; To evaluate the effects on endoscopic appearance
using the EoE Endoscopic Reference Score (EREFs) (Hirano 2015; van
Rhijn 2014); Evaluate change from baseline of the 7-day EEsAI and
Global EoE Symptom Score.
[0304] Safety Objectives: To determine the safety profile of acute
and chronic administration of FP and its effects on the HP
axis.
[0305] Exploratory Objectives: Evaluate the change from baseline in
the EoE Histology Scoring System (EoEHSS) score (Collins 2016); To
evaluate Quality of Life via the Adult Eosinophilic Esophagitis
Quality of Life Questionnaire (EoE-QoL-A). (Taft 2011); Evaluate
Symptoms compared to prior visit(s) (7 scale); To evaluate
PK/PD(cortisol) and exposure-response (efficacy) relationships.
[0306] Study Rationale: Doses from 1.5 mg HS to 3.0 mg BID will be
explored to define the exposure-response of APT-1011 and the
minimum effective dose while remaining below any clinically
significant hypothalamic-pituitary-adrenal (HPA) axis effects.
[0307] Study Design
[0308] This is a randomized, double-blind, placebo-controlled
dose-ranging study of 3 total daily doses (1.5, 3 and 6 mg) of
APT-1011 administered as 1.5 mg HS, 1.5 mg BID, and 3.0 mg BID
compared to matching placebo in 320 adult and adolescent subjects
with EoE. Maintenance of efficacy and long-term safety will also be
evaluated.
[0309] Eligible subjects will be 14-75 years of age (inclusive) and
have a diagnosis of EoE (.gtoreq.15 Peak Eos per HPF) after proven
failure of 8 weeks or more of high-dose (i.e. twice daily dosing)
proton pump inhibitor (PPI). Subjects who have not had an adequate
trial of PPI therapy should have this performed BEFORE screening
for this study. PPI therapy may be continued during the study only
if the subject was on PPI therapy at the time of signing an
informed consent. No new initiation of, nor alteration of PPI
therapy is allowed during the study. Subjects must also be
symptomatic with dysphagia and have a 7-day recall Global EoE
symptom score of >3 AND report at least 3 episodes of dysphagia
in the past 7 days AND no exclusions for the study to enter the
2-week baseline symptom assessment. The subjects must report
dysphagia at least 3 episodes per week for each of the two weeks of
the baseline symptom assessment in the daily diary to be eligible
for randomization.
[0310] In PART 1, subjects will be stratified by age (<18 and
.gtoreq.18 years) and by concomitant PPI use during the study
("yes" or "no"); then randomly assigned to 1 of the 4 dosing groups
(ratio: (1.7):1:1:1).
[0311] All subjects will come in monthly for routine visits, and
for unscheduled visits should symptoms worsen between visits.
[0312] The study will be conducted in several parts:
[0313] Screening:
[0314] 1-4 weeks including upper endoscopy (EGD)
[0315] Baseline Symptom Assessment: 2 weeks
[0316] have a Global EoE symptom score of >3 AND report at least
3 dysphagia episodes in the past 7 days AND have no exclusions for
the study may enter the baseline symptom assessment
[0317] Randomization: Subjects must report at least 3 dysphagia
episodes per week for each of the two weeks of the baseline symptom
assessment in the daily diary, have >75% compliance with daily
diary and have .gtoreq.15 Peak Eos per HPF and meet all the other
inclusion and exclusion criteria will be randomized. Subjects will
be randomized 1.7:3 for placebo to active doses. Response adaptive
randomization will be used among the active doses which will be
updated at each interim analysis.
[0318] Subjects will be stratified by age and current PPI use.
[0319] The overall protocol is shown in FIGS. 3 and 4. PART 1
represents induction of EoE response and PARTS 2 and 3 will assess
maintenance.
[0320] Open-label treatment will be offered to non-responders in
PART 1.
[0321] PART 1: Treatment (Day 1 to Week 14)
[0322] Subjects will be treated for 12 weeks and undergo an EGD to
assess histologic and endoscopic improvement. Symptom improvement
will be assessed on an ongoing basis. EoE Responders, defined as
subjects who achieve a histologic response of =<6 Peak Eos per
HPF and no worsening of symptoms (i.e. no increase in dysphagia
based upon the daily diary compared to baseline) or episode of food
impaction, will enter the PART 2 maintenance at week 14. This part
will incorporate an adaptive sample size and response adaptive
randomization within active arms. Interim analyses will be
conducted frequently after 160 subjects are randomized, in which
randomization probabilities are modified and early stopping
criteria evaluated.
[0323] Open-Label (OL) Treatment (Weeks 14 to 28)
[0324] Non-responders (subjects who do not have a histologic
response and/or have worsening of their dysphagia) at week 14 will
receive open-label (OL) 3 mg BID until week 28 with an EGD at week
28, and then if they are responders at the end of the OL period
(same definition as above), they will be eligible to enter PART 3.
Non-responders to OL treatment will enter a 2-week follow-up period
and then exit the study.
[0325] PART 2: Maintenance (Week 14 to Week 28)
[0326] EoE Responders (histologic response and no worsening of
dysphagia) from PART 1 will continue on their same dose as in PART
1. Placebo responders, which are expected to be few, will remain on
placebo. Either worsening of dysphagia or food impaction will
prompt an endoscopy at an unscheduled visit. After the endoscopy,
all "relapsers" will immediately enter PART 3 except those with
food impaction requiring endoscopy or stricture requiring dilation.
Subjects with food impaction requiring endoscopy or a stricture
requiring dilatation will enter the 2-week follow-up period and
exit the study. All subjects in the study at week 26 will undergo
endoscopy. EoE Responders at week 28 will continue to PART 3.
Non-responders at the end of PART 2 or early relapsers will receive
3 mg BID when they enter PART 3.
[0327] PART 3: Maintenance (Week 28 to Week 54)
[0328] Non-Responders from PART 1 who respond to open-label 3 mg
BID will continue on this dose in PART 3. Note that this group will
not participate in PART 2.
[0329] EoE Responders from PART 2 will continue on the same
dose.
[0330] Non-responders and early relapsers from PART 2 will receive
open-label 3 mg BID in PART 3.
[0331] Subjects who relapse (food impaction requiring endoscopy or
clinically-significant recurrent symptoms) in PART 3 will undergo
an unscheduled endoscopy and enter the 2-week follow-up and exit
the study.
[0332] All continuing subjects will undergo endoscopy at week 52
and complete their final on treatment visit at week 54.
[0333] Follow-Up (2 Weeks After Last Dose)
[0334] All subjects must have a final endoscopy within 3 weeks
prior to entering follow-up. Exceptions include: withdrawal of
consent or contra-indication to endoscopy. Reasons for entering
follow-up: Completed week 54; Adverse event requiring early
withdrawal including food impaction requiring endoscopy; Failed to
respond to open-label 3 mg BID; Relapsed in PART 3.
[0335] Pharmacokinetics: In this study, the 1.5 mg BID and 3.0 mg
BID doses of APT-1011 will be administered at least 30 minutes
AFTER breakfast and at bedtime, (at least 2 hours after the evening
meal). The 1.5 mg dose will be administered at bedtime (at least 2
hours after the evening meal). Subjects receiving the 1.5 mg dose
will receive placebo in the morning at least 30 minutes AFTER
breakfast. No food or drink will be permitted for at least 1 hour
after dosing.
[0336] A combination of intensive PK sampling from a subset of
subjects and sparse PK sampling from the remaining subjects will be
collected to characterize FP exposure in the patient population.
Non compartmental analysis (NCA) will be performed on the intensive
PK data and a population PK analysis will be performed based on a
combination of intensive serial and sparse plasma concentration
data.
[0337] Intensive PK: Intensive PK serial sampling will be performed
at baseline and at Steady-State in a subset of adult subjects (8
per dose group) and in a subset of adolescent subjects
(approximately 5 per dose group) at pre-specified PK sites. These
subjects will take the daily dose (both tablets) on Day 1. Blood
samples for determination of fluticasone plasma concentrations will
be collected pre-dose and at 0.5, 1, 2, 4, 8, and 12 hours
following the morning dose on Day 1 and Week 4. Steady-state
samples may be collected at the Week 8 or 12 visit if the subject
cannot stay for 12 hours on Week 4. Collection of intensive PK
samples over a 12-hour period is related to the BID dosing schedule
and the need to avoid an in-patient stay for these EoE
patients.
[0338] Sparse PK: Sparse PK samples will be collected from all
adult and adolescent subjects (excluding subjects in the intensive
PK Subset). A baseline pre-dose sample will be taken prior to
dosing on Day 1. At Weeks 4, 8 and 12 of repeat dosing the subjects
will take their AM dose at home and will have two samples taken
during their scheduled visit. One sample will be taken upon arrival
to the site and another sample taken 1 to 1.5 hours later
immediately prior to leaving the site. The time of dosing the prior
evening (bedtime of preceding night) and the time of the morning
dosing (the day of planned visit) will be recorded. The actual PK
sampling times also will be documented. Sites will be encouraged to
vary site visits throughout the day. Due to the variability of site
visits, the sparse PK samples will be taken to typically cover a
large portion of the 12-hour post-dosing period.
[0339] Study Duration: This study has an anticipated recruitment
period of approximately 12-18 months. Subjects who enter and
complete the study (PART 1, PART 2 and PART 3) will be in the study
for up to 14 months.
[0340] Study Population: The study uses an adaptive sample size,
with a range of 160 to 320 adult subjects diagnosed with EoE who
meet the entry criteria. The study is expected to enroll
approximately 25% females and 5% elderly subjects.
[0341] Inclusion Criteria:
[0342] Male and female subjects.gtoreq.14 and .ltoreq.75 years of
age at the time of informed consent.
[0343] Have signed the informed consent form (ICF) (parent or
guardian must sign when applicable) and assent form (required for
adolescents under 18 or legal age of majority per local law) and
willing and able to adhere to all study procedures.
[0344] Diagnosis or presumptive diagnosis of EoE, must be confirmed
by symptoms, and histology; and by historical documentation of
failed treatment on 8 weeks or more of high-dose) proton pump
inhibitor (PPI). (i.e. 20 mg BID omeprazole or 20-40 mg BID of an
approved prescription PPI. Maintenance or OTC doses are too low)
Documentation of PPI failure prior to initial diagnosis OR by
documentation of PPI failure at the time of screening. A lack of
response to PPI therapy is defined as a peak eosinophil
count.gtoreq.15/HPF in at least one biopsied location AFTER the 8
weeks of high dose treatment. PPI therapy may be continued during
the study only if the subject was on PPI therapy at the time of
biopsies from the screening endoscopy. Subjects on PPI's may either
stop them after the endoscopy or reduce the dose as long as this is
BEFORE the baseline run in period. After this dose change the
subjects must remain on a stable dose after that. Once a PPI is
stopped it may not be restarted. No new initiation of PPI therapy
is allowed during the study.
[0345] Have evidence of eosinophilic esophagitis defined by the
PEAK esophageal mucosal eosinophil count.gtoreq.15 per high-powered
field (HPF, 400.times. magnification (0.3 mm.sup.2) in at least 1
of the esophageal sites biopsied (.gtoreq.3 biopsies from each the
proximal and the distal esophagus; a minimum of 6 total biopsies).
Additional mid esophageal biopsies may be taken at the
investigator's discretion. Biopsies are to be obtained and must be
received by the central pathologist within 30 days AFTER the
Screening Visit or 2 weeks prior to randomization and before
starting the baseline period. Eligibility will be based solely on
the central pathologist's assessment. Optional biopsies may be
taken and processed locally for local use if specified in the local
ICF. The subjects must have a 7-day recall Global EoE score>3;
Subjects must report at least 3 dysphagia episodes per week for
each week of the Baseline Symptom Assessment; Willing and able to
adhere to study related treatment regimens, procedures and visit
schedule.
[0346] Exclusion Criteria: Known contraindication, hypersensitivity
or intolerance to corticosteroids. Any physical, mental, or social
condition, history of illness or laboratory abnormality that in the
investigator's judgment might interfere with study procedures or
the ability of the subject to adhere to and complete the study.
Presence of oral or esophageal mucosal infection of any type. Any
mouth or dental condition that prevents normal eating. Any
condition affecting the esophageal mucosa or altering esophageal
motility other than EoE including erosive esophagitis (LA grade B
or higher), hiatus hernia longer than 3 cm, Barrett's esophagus,
and achalasia. Use of systemic, oral or parenteral corticosteroids
within 30 days, or inhaled or extended use of high-potency dermal
topical corticosteroids within 30 days prior to: The esophageal
biopsy required for entrance to this study; EGD if done during the
pre-screening period. Use of swallowed/topical steroids within 30
days. Initiation of an elimination diet or elemental diet within 30
days of screening. No dietary therapy may be started during the
study. Morning (0700 to 0800 hours, or as close to that window as
possible) serum cortisol level.ltoreq.5 .mu.g/dL (138 nmol/L). A
serum cortisol level of <18 ug/mL (497 nmol/L) at 60 minutes
with adrenocorticotropic hormone (ACTH) stimulation test using 250
.mu.g cosyntropin. Consumption of grapefruit juice during the
treatment is prohibited. Use of biologic immunomodulators within
the past 6 months. Use of calcineurin inhibitors, purine analogues
(azathioprine, 6-mercaptopurine) within the past 3 months.
Contraindication to esophagogastroduoendoscopy (EGD) or esophageal
biopsy or narrowing of the esophagus precluding EGD with a standard
9 mm endoscope. Overt gastrointestinal bleeding within 1 month
prior to the Screening Visit or between the Screening Visit and the
Randomization Visit. Current chronic infection, immunosuppression,
or immunodeficiency. History or presence of Crohn's disease, celiac
disease, or other inflammatory disease of the gastrointestinal
tract including eosinophilic gastroenteritis. Current alcohol or
drug abuse. Female subjects who are pregnant or breastfeeding.
Sexually active females of child-bearing potential who do not agree
to follow highly effective contraceptive methods during the study
including the follow-up period. Abstinence is acceptable for
adolescents. Female subjects with surgical menopause or menopause
confirmed by FSH do not require contraception or pregnancy testing
during the study. Participation in a clinical study involving an
investigational drug within 30 days of the Screening Visit.
[0347] Study Drug Administration: For 3 dosing groups, APT-1011
(fluticasone propionate, ODT) will be provided as blinded tablets
in dose strengths of 1.5 mg and 3.0 mg. For the fourth dosing group
there will be a matching placebo. Tablets will be administered
BID--30 minutes AFTER breakfast and HS (at bedtime) at least 2
hours after the evening meal. Note that in the 1.5 mg dosing group,
subjects will receive placebo tablets 30 minutes AFTER breakfast,
and 1.5 mg APT-1011 HS. To maintain the blind, all tablets will be
labeled for "AFTER breakfast" and "BEDTIME" administration. The
subjects should not eat or drink for 1 hour after study drug
administration. The BEDTIME dose should be administered after all
drinks and snacks and tooth brushing and immediately before going
to bed.
[0348] Primary Efficacy Endpoints at Week 12:
[0349] There are two co-primary efficacy endpoints for EOE
RESPONSE: PEAK eosinophil count=<6/HPF at all biopsied
esophageal locations and change from baseline in dysphagia episodes
over the prior 14 days
[0350] Secondary Efficacy Endpoints:
[0351] Change from baseline in Dysphagia-Free Days over the
previous 14 days; EoE Sustained Response will be assessed at Weeks
26 and 52 with the Co-Primary Endpoint; Change from baseline in
7-day Global EoE Score will be assessed before the baseline symptom
assessment, baseline, Week 12, Week 26 and Week 52. 7-day Global
EoE symptom score will be assessed at each visit. Change from
baseline in EREFS score at Weeks 12, 26 and 52. Endoscopic changes
will be based upon the EREFS score based on 5 endoscopic features:
edema, furrowing, exudates, rings, strictures. Percent of subjects
with PEAK Eos per HPF<1 and <15 at all major time points
where EoE Response is assessed Change from baseline in 7-day EEsAI
score and percent of subjects with mean weekly EEsAI score<20
and change from baseline in sub scores will be assessed at Weeks
12, 26 and 52. 7-day EEsAI will be assessed at each visit.
[0352] Assessment of Relapse and Treatment Failure
[0353] (a) Non-Response at each endoscopic time point
[0354] (b) Percentage of subjects requiring emergency endoscopic
food disimpaction by dose and part of the study.
[0355] (c) Percentage of subjects requiring esophageal
dilation.
[0356] OL Treatment: EoE Response (Co-Primary above) will also be
assessed after 12 weeks of OL treatment in non-responders to PART
1.
[0357] Pharmacokinetic Endpoints
[0358] The following PK parameters will be calculated for the
intensively-sampled PK subjects using noncompartmental methods, as
data permit: Cmax, Tmax, AUC.sub.0-12, CLss/F and Accumulation
Ratio.
[0359] Population pharmacokinetic parameters including oral
clearance (CL/F) and volume of distribution (V/F) will be
estimated, as data permit. Additional parameters will be estimated,
as appropriate, based on the final structural pharmacokinetic
model.
[0360] Exploratory Endpoints:
[0361] EoE Histology Scoring System for all biopsies performed.
Change from baseline will be assessed. Evaluation of quality of
life based on the EoE-QoL-A at Week 12, 26, 52 and Week 12 of OL
treatment by dose and subgroup. Patient's assessment of symptoms
compared to the previous visit. This question will be assessed at
Weeks 8, 12, 18, 26, 36 and 52. Evaluation of PK/PD (cortisol) and
exposure-response (efficacy) relationships.
[0362] Safety Endpoints: Safety will be assessed by monitoring and
recording all treatment-emergent adverse events (TEAEs), TEAEs
leading to withdrawal and Serious adverse events (SAEs). All TEAEs
will be coded based upon the MedDRA version 14.0 classification of
adverse events (AEs) and classified by severity (mild, moderate,
severe) and relatedness to study drug (related or not related) by
the Investigator. TEAEs occurring within 3 days of a dose change
will be attributed to the previous dose. Physical examinations will
be performed to document the baseline condition of the subject and
to highlight changes related. to AEs. Vital signs will also be
assessed at all visits and clinically significant deviations will
be reported.
[0363] Routine laboratory tests will be performed throughout the
study including hematology, blood chemistry, urinalysis,
electrocardiograms (ECGs) as indicated in the Schedules of
Assessments. Clinically significant changes in laboratory tests or
ECGs will be summarized.
[0364] Cortisol Issues: Abnormal AM cortisol, urinary glucose or
serum glucose would necessitate following the subject to resolution
CRFs should capture presence or absence of known glucocorticoid AEs
such as moon facies, acne, hirsutism, mood swings, insomnia or
depression. ICF should highlight that stress steroids may be
required during significant medical illnesses. ACTH stimulation
test (cosyntropin 250 mcg) should be performed at baseline and Week
12, early withdrawal and at Week 52 for all subjects. ACTH test
should be performed in all subjects with AM serum cortisol>5
mcg/dL (138 mmol/L). All subjects with positive tests should be
excluded. Any positive results at the end of treatment should be
followed to recovery of adrenal function. The number of subjects
discontinuing for HPA suppression or positive ACTH stimulation
tests will be summarized. Subjects under age 18 will be evaluated
for growth parameters such as height, weight, body mass index (BMI)
and corresponding z-scores. Tanner stage and bone age will also be
determined in adolescents less than 18 who have not completed their
linear growth.
[0365] The safety endpoints of interest are: frequency of treatment
emergent adverse events (TEAEs), TEAEs leading to withdrawal and
treatment-emergent serious adverse events (SAEs), as well as the
percentage of subjects with serum cortisol level<5 .mu.g/dL
(.ltoreq.138 nmol/L) or positive ACTH stimulation test (serum
cortisol<18 ug/mL (497 nmol/L) at 60 minutes). The number of
subjects discontinuing for HPA axis suppression will be
recorded.
[0366] Statistical Methods
[0367] Sample Size Determination
[0368] PART 1 incorporates an adaptive sample size that ranges
between 160 and 320 adult patients. Frequent interim analyses will
be conducted after at least 160 subjects are randomized in which
success and futility criteria are evaluated. If evidence of
treatment efficacy with respect to co-primary outcomes is
sufficiently low, the trial may stop early for futility. If the
predictive probability of obtaining sufficient evidence to
demonstrate treatment efficacy is very high, the trial may stop
accrual for expected success, with a decisive analysis performed
when all enrolled patients have completed 12 weeks of follow-up
(Broglio 2014). Simulations are used to calculate the expected
sample size, Type 1 error, and statistical power under a variety of
assumed treatment profiles (to be provided in SAP).
[0369] It is anticipated that approximately 60% of subjects will
enter PART 2 of the study. Given a minimum of 102 patients on
active treatment in PART 1, at least 61 patients are expected to
enter PART 2. Approximately 17 placebo responders are expected to
enter PART 2. It is anticipated that 70% of the placebo responders
and approximately 20% of those on active treatment may relapse
prior to Week 26. Approximately 82 subjects on active treatment are
expected to enter PART 3.
[0370] In addition, assuming a 20% dropout rate into PART 3, at
least 66 subjects (22 per dose) are expected to be evaluable on the
active treatment arms for the assessment of sustained remission at
Week 52, and at least 4 patients are expected on control. This
provides a minimum expected power of 73% for comparing sustained
remission rates of 80% versus 20% for each active dose versus
control, and a minimum expected power of 80% for comparing the
pooled active treatment remission rates versus control. However,
the primary focus of PART 3 will be descriptive in nature.
[0371] Statistical Methodology
[0372] Summary statistics will be presented in tabular form by dose
group and subgroups, as applicable) or each PART of the study
including the OL treatment.
[0373] The primary analysis population for efficacy is the
intent-to-treat (ITT) population, defined as all randomized
subjects. The analysis population for safety is the safety
population, defined as all subjects who receive at least one dose
of study drug. The single-dose PK population will be defined as all
subjects in the ITT population of PART 1 who are randomized to one
of the three APT-1011 dosing groups, take their first dose of
APT-1011, and have at least one PK sample included in the final
single-dose population PK analysis. The steady-state PK population
will be defined as all subjects in the ITT population of PART 1 who
are randomized to one of the three APT-1011 arms, take their dose
of APT-1011 that corresponds to the steady-state PK sampling
period, and have at least one PK sample included in the final
steady-state population PK analysis. Additional per protocol
analysis populations who complete PARTs 1, 2, and 3 and OL
treatment may be defined in the Statistical Analysis Plan
(SAP).
[0374] Baseline and demographic information will be summarized
using descriptive statistics for continuous and ordinal variables
(e.g., age, weight, height) and counts and percentages for
categorical variables (e.g., sex, race).
[0375] Pharmacokinetics and Pharmacodynamics Analysis
[0376] In this study, the 1.5 mg BID and 3.0 mg BID doses will be
administered at least 30 minutes AFTER breakfast and at bedtime (at
least 2 hours after the evening meal). The 1.5 mg HS dose will be
administered at bedtime (at least 2 hours after the evening meal).
Subjects receiving 1.5 mg HS daily will also receive placebo at
least 30 minutes after breakfast.
[0377] Using the PK data from the intensely sampled subjects, PK
parameters for FP will be calculated by noncompartmental methods
when possible, as follows:
[0378] Cmax: Maximum observed concentration, observed by inspection
of individual study participant plasma concentration time
plots.
[0379] Tmax: Time of maximum observed concentration, obtained
directly from the observed concentration time data
[0380] AUC0-12: The area under the plasma concentration time curve,
from time 0 to the 12 hours post-dose, calculated by a combination
of linear and logarithmic trapezoidal methods (Linear up/log down
method).
[0381] CLss/F Apparent Clearance at Steady-State
[0382] Accumulation Ratio Accumulation ratio calculated from
AUC0-12 at steady state and AUC0-12 after single dosing
[0383] Individual and mean plasma concentration time curves (both
linear and semi-log) will be generated. Detailed methodology for
summary statistics of the concentration data and the PK parameters
will be documented in the SAP.
[0384] A Population PK analysis will be performed based on a
combination of serial and sparse plasma concentration data.
Previous serial PK data for APT-1011 (Studies PR-023 and
Food-effect) may be included in this analysis to facilitate
development of a base PK model.
[0385] Population PK parameters including oral clearance (CL/F) and
volume of distribution (V/F) will be estimated, as data permit.
Additional parameters will be estimated, as appropriate, based on
the final structural PK model.
[0386] The output from the final population models including
appropriate diagnostic plots, listings, and summaries of PK
parameters will be generated. In addition, graphical and tabular
presentations of any PK simulations will be produced. A separate
PopPK report will be generated and linked to the clinical study
report.
[0387] As data permit, exploratory analyses assessing the
relationship between systemic exposure to FP and changes in
cortisol levels also may be performed as described above.
Additional exploratory exposure-response analyses may be performed
based upon the co-primary endpoint or its components to facilitate
selection of safe and effective doses for future studies and
clinical use.
TABLE-US-00011 TABLE 9 Schedule of Assessments: Screening through
PART 1 VISITS Baseline Unscheduled Early Screening Symptoms
Randomization Week 4 Week 8 Week 12 Week 14 Visit .sup.C Withdrawal
.sup.b Assessments and DAY Procedures -42 to -14 -14 to -1 1 28
.+-. 3 56 .+-. 3 84 .+-. 3 98 + 3 zz Informed consent signed X No
exclusion criteria X Global EoE Symptom Score >3 >=3
dysphagia episodes in prior 7 days Inclusion/exclusion X X .sup.
X.sup.d criteria Demographics, X medical, surgical history,
medication history Concomitant X X X X X X medication(s) Physical
examination X X X X X X X Tanner stage if age < 18 X Vital signs
X X X X X X X X Chemistry; Hematology X X X X X X X Serum cortisol
(AM X X X X X Results.sup.f Optional X fasting).sup.e Urinalysis X
X X X X X X Electrocardiogram - X X X X Standard 12-lead Population
.sup. X.sup.g .sup. X.sup.g .sup. X.sup.g .sup. X.sup.g
Pharmacokinetics Pre-Dose Intensive PK .sup. X.sup.h .sup. X.sup.h
EGD with multiple X Pre-Dose X X.sup.m esophagealbiopsies.sup.a, i
Urine pregnancy test X X X X X Optional X for women of CBP
Menopausal women FSH at screening only ACTH stimulation X X
Optional.sup.K X test (250 .mu.g).sup.k Adverse events X X X X X X
X X X GlobalEoEScore X X X X X 7-day EEsAI X X X X X X X X Daily
Diary X X X X X X X Symptoms X X X compared to prior visit
EoE-QoL-A X X X X X Bone Age.sup.l X Study Drug X X X X Dispensed
Drug return and X X X X X accountability (Study Drug compliance
assessment) Daily Diary X Compliance Assessment .sup.aEndoscopy may
be performed at a separate visit. Results of histology will be
required at randomization and Week 14. .sup.b Patient should be
seen in the office within 7 days of determination of the need to
withdraw the patient. If this is not possible due to an SAE or
other unforeseen circumstance, visit may be completed with a phone
visit with the patient or family member. Documentation of why the
patient could not come to the site should be placed in the patient
record. .sup.C The reason for an unscheduled visit will guide
procedures, at the discretion of the PI. .sup.dConfirmation that
the patient still meets inclusion/exclusion criteria based upon
>3 episodes of dysphagia per week based upon the daily diary for
the previous 14 days in addition to other inclusion/exclusion
criteria including histology .sup.eTo be drawn as close as possible
to 0800 hours. Patients must be fasting for an eight (8)-hour
period prior to the serum cortisol assessments. Blood may be drawn
for AM Serum Cortison +/-2 days of scheduled visit to accommodate
accurate timing. Other blood draws scheduled for the visit may be
done at the same time. .sup.fIf abnormal serum cortisol level is
reported at Final on treatment Visit; additional monitory and ACTH
test may be required. See Safty sEction .sup.gSparse PK samples
will be obtained from all subjects excluding those in the intensive
PK subset. A baseline, pre-dose sample will be collected on Day 1,
prior to the first dose. At Weeks 4, 8, and 12 of repeat dosing the
subjects will take their morning dose at home and will have two
samples taken during their scheduled visit. One sample will be
taken upon arrival to the site and another sample taken 1 to 1.5
hours later, immediately prior to leaving the site. The time of
dosing the prior evening (bedtime of preceding night) and the time
of the morning dosing (the day of planned visit) will be recorded.
The actual PK sampling times also will be documented.
.sup.hApproximately 8 adult subjects and 5 adolescents per dose
group will undergo intensive PK sampling at selected sites. After
taking both doses (AM and HS Tablets), Intensive PK samples will be
collected on Day 1 and Week 4. At each of these visits, PK samples
will be collected predose (no more than 15 minutes prior to AM
dose) and at 0.5, 1, 2, 4, 8 and 12 hours post AM dose. The PK
samples planned for Week 4 may be collected at the Week 8 or Week
12 visit if the subject cannot stay for 12 hours on Week 4.
.sup.iCan be done up to 30 days prior to Screening Visit (in
absence of systemic or inhaled, intranasal or high-potency dermal
topical corticosteroids within these 30 days prior to the Screening
Visit). EREFS must be done and 3 biopsies taken from at least 2
levels of the esophagus. .sup.jIf the patient is withdrawing from
the study due to lack of efficacy or other reasons, the
Investigator may perform an EGD, if clinically indicated. .sup.KAll
subjects undergo a 250 .mu.g ACTH stimulation test at baseline and
EOT or at early withdrawal. An ACTH simulation test will also be
performed during the study at an optional visit for subjects whose
serum cortisol level is confirmed by two blood draws as .ltoreq.5
.mu.g/dL (138 nmol/L) or if they have signs and symptoms of
hypercortism to assess for hypothalamic-pituitary-adrenal (IPA)
axis suppression of potential clinical concern. .sup.lBone age to
be performed on all adolescents (<18 years of age at
randomization); exceptions include female subjects who have
completed their linear growth or male subject who have not
completed their liner growth by 18 years of age, at the discretion
of the PI.
TABLE-US-00012 TABLE 10 Schedule of Assessments: PART 2 VISIT Week
14 Unscheduled Early Randomization Week 18 Week 22 Week 26 Week 28
Visit .sup.C Withdrawal .sup.b DAY Assessments and Procedures 98 +
3 126 .+-. 3 154 .+-. 3 192 .+-. 3 220 .+-. 3 zz EoE Responder in
PART 1 No X contra-indications to continue Concomitant
medication(s) Data Transfer X X X X X X Physical examination Data
Transfer X X X X Vital signs Data Transfer X X X X X X Chemistry;
Hematology Data Transfer X X X X X Serum cortisol (AM
fasting).sup.e Data Transfer X X X Results.sup.f Optional X
Urinalysis Data Transfer X X X X X Electrocardiogram - Standard
Data Transfer X X 12-lead EGD with multiple esophageal Data
Transfer Results X biopsies.sup.a, i Urine Pregnancy Test for women
Data Transfer X X X X X Optional of CBP ACTH stimulation test (250
.mu.g).sup.k Data Transfer X Results .sup. Optional.sup.k X Adverse
events Data Transfer X X X X X X 7-day EEsAI Data Transfer X X X X
X X Daily Diary Data Transfer X X X X Global EoE Score Data
Transfer X X Symptoms compared to previous Data Transfer X X visit
EoE-QoL-A Data Transfer X X Study Drug Dispensed X X X X Drug
return and accountability X X X X X (Study Drug compliance
assessment) Schedule of Assessments: OL Treatment VISIT Unscheduled
Early Week 14 Week 18 Week 22 Week 26 Week 28 Visit .sup.C
Withdrawal .sup.b DAY Assessments and Procedures 98 + 3 126 .+-. 3
154 .+-. 3 192 .+-. 3 220 .+-. 3 zz EoE Non-Responder in PART 1 X
Concomitant medication(s) Data Transfer X X X X X Physical
examination Data Transfer X X X X X Vital signs Data Transfer X X X
X X Chemistry; Hematology Data Transfer X X X X X Serum cortisol
(AM fasting).sup.e Data Transfer X X X Results.sup.f Optional X
Urinalysis Data Transfer X X X X X Electrocardiogram - Standard
Data Transfer X X 12-lead EGD with multiple esophageal Data
Transfer X biopsies.sup.a, i Urine pregnancy test for women Data
Transfer X X X X of CBP ACTH stimulation test (250 .mu.g).sup.k
Data. Transfer X .sup. Optional.sup.k X Adverse events Data
Transfer X X X X X X 7-day EEsAI Data Transfer X X X X X X Daily
Diary Data Transfer X X X X Global EoE Score Data Transfer X X
Symptoms compared to previous Data Transfer X X X visit EoE-QoL-A
Data Transfer X Study Drug Dispensed X X X X Drug return and
accountability X X X X X (Study Drug compliance assessment)
TABLE-US-00013 TABLE 11 Schedule of Assessment: PART 3 VISIT
Follow-up Week 28 Any Subject Randomization Unscheduled Early with
Early or assigned dose Week 36 Week 44 Week 52 Week 54 Visit .sup.C
Withdrawal .sup.b Withdrawal DAY 2 weeks after Assessments and
Procedures 220 + 3 126 .+-. 3 154 .+-. 3 192 .+-. 3 220 .+-. 3 last
dose Inclusion Criteria for PART 3.sup.o X Concomitant
medication(s) Data Transfer X X X X X X Physical examination Data
Transfer X X X X X X Vital signs Data Transfer X X X X X X
Chemistry; Hematology Data Transfer X X X X X X Serum cortisol (AM
fasting).sup.e Data Transfer X X X Results.sup.f Optional X X
Urinalysis Data Transfer X X X X X X Electrocardiogram - Standard
Data Transfer X X X X 12-lead EGD with multiple esophageal Data
Transfer X Results X biopsies.sup.a, i Urine pregnancy test for
women Data Transfer X X X Optional X X of CBP ACTH stimulation test
(250 .mu.g).sup.k Data. Transfer X Results .sup. Optional.sup.k X
Adverse events Data Transfer X X X X X X 7-day EEsAI Data Transfer
X X X X X X Daily Diary Data Transfer X X X X X X X Global EoE
Score Data Transfer X X Symptoms compared to previous Data Transfer
X X visit EoE-QoL-A Data Transfer X X Study Drug Dispensed X X X X
Drug return and accountability X X X X X X (Study Drug compliance
assessment) Footnotes: a-m see previous footnotes .sup.oSubjects
meet Inclusion Criteria for PART 3: Complete PART 2 as a Responder
- continue on same dose; Complete PART 2 as a Non-Responder -
Assigned to 3 mg BID; Relapse on Placebo - return to prior dose
from PART 1 when entering PART 3; Relapse PART 2 on placebo -
Assigned to 3 mg BID in PART 3; Complete OL Treatment as a
Responder - Continue 3 mg BID; C
Example 4
FLUTicasone in Eosinophilic Esophagitis (FLUTE): A Randomized,
Double-Blind, Placebo-Controlled, Dose Ranging, and Maintenance
Study of APT-1011 in Subjects with Eosinophilic Esophagitis
[0388] Primary Objective: The primary objective of the study is to
evaluate the efficacy (histological response) of APT-1011 in adults
(.gtoreq.18 years of age) with eosinophilic esophagitis (EoE).
[0389] Secondary Objectives: The secondary objectives of the study
are as follows: To define the dose-response of APT-1011; To select
a dose(s) of APT-1011 for Phase 3; To evaluate the effect of
APT-1011 on histology and endoscopic appearance; To evaluate
maintenance of efficacy and long-term safety of APT-1011; To
evaluate the population pharmacokinetics (PopPK) of APT-1011; To
evaluate the effect of APT-1011 on dysphagia episodes.
[0390] Exploratory Objectives: The exploratory objectives of the
study are as follows:
[0391] To evaluate the effect of APT-1011 on dysphagia and other
symptoms of EoE; To evaluate quality of life; To evaluate
symptomatology over time; To evaluate the pharmacokinetic
(PK)/pharmacodynamic (PD) relationship (with cortisol as the
primary endpoint); To evaluate the dose-response relationship for
the histological response and symptom response; To derive a scoring
structure, and various endpoints from the Patient Reported Outcome
Symptoms of EoE (PROSE); To evaluate the measurement properties of
the PROSE, including reliability, construct validity, sensitivity
to change; To produce guidelines for interpreting clinically
meaningful change and derive the cut-off for treatment response on
the PROSE, or a responder definition.
[0392] Study Design
[0393] This is a randomized, double-blind, placebo-controlled
dose-ranging study of 4 total daily doses of APT-1011 versus
placebo in 100 adult subjects (.gtoreq.18 years of age) diagnosed
with EoE.
[0394] During the single-blind run-in/baseline symptom assessment,
the subjects will receive placebo 30 minutes after breakfast and
hora somni (HS; at bedtime). Four doses of study drug will be
administered: Placebo 30 minutes after breakfast and 1.5 mg hora
somni (HS; at bedtime) APT-1011, 1.5 mg twice daily (BID) (30
minutes after breakfast and at bedtime; total daily dose of 3 mg)
APT-1011, Placebo 30 minutes after breakfast and 3 mg HS (at
bedtime), and 3 mg BID (30 minutes after breakfast and at bedtime;
total daily dose of 6 mg) APT-1011, and matching placebo
administered 30 minutes after breakfast and HS (at bedtime).
[0395] The 100 subjects will be randomized in a 1:1:1:1:1 to
receive placebo or one of the active doses into Part 1 of the
study. As described below, the treatment that a subject receives in
Part 2 depends on their histologic response status at Week 12.
[0396] Randomization will occur in a double-blind manner using an
integrated Interactive Web Response System (IWRS), and will be
stratified by the presence or absence of a history of or current
esophageal strictures at Screening and history of a prior positive
steroid response to any corticosteroid treatment previously
received to treat the subject's EoE captured with demography.
[0397] Efficacy (including sustained EoE response and
patient-reported outcomes), safety, and PK of APT-1011 will be
examined.
[0398] FLUTE will be conducted in several parts (Screening [4
weeks], followed by a 4-week single-blind placebo run-in and
Baseline Symptom Assessment, and 2 treatment parts [Part 1 and Part
2]), with a Follow-up Visit to occur 2 weeks after the final dose
of study drug. Screening will take up to 28 days. The
esophagogastroduodenoscopy (EGD) to determine eligibility
(Inclusion Criterion #7: evidence of EOE as defined by .gtoreq.15
PEAK eosinophils/high-power field [HPF] with at least 5-6 biopsies
including both proximal and distal specimens [3 each]) will be
completed during the Screening Period and the biopsies must be
received by the central pathologist by the times noted in this
inclusion criterion. To enter the 4-weeks Baseline Symptom
Assessment, the subject must satisfy all eligibility criteria
including the Global EoE score>3 (Inclusion Criterion #5),
except those to be confirmed during this phase (Inclusion Criterion
#7: evidence of EOE as defined by .gtoreq.15 PEAK eosinophils/HPF
with at least 5-6 biopsies including both proximal and distal
specimens [3 each]; Inclusion Criterion #8: in the daily diary,
report episodes of dysphagia.gtoreq.3 days per week during the last
2 weeks of the 4-week Baseline Symptom Assessment; Inclusion
Criterion #9: completion of episode entries on at least 5 of out of
each 7 days during the 4-week Baseline Symptom Assessment; and
Exclusion Criterion #23: a serum cortisol level<18 .mu.g/dL (497
nmol/L) at 60 minutes with adrenocorticotropic hormone [ACTH]
stimulation test using 250 .mu.g cosyntropin [i.e., a positive
result on the ACTH stimulation test]). The subjects will be
dispensed placebo along with their electronic diary at the
beginning of the 4-week placebo run-in/Baseline Symptom
Assessment.
[0399] During the 4-week Baseline Symptom Assessment, baseline
symptom severity will be determined and the ability of the subject
to be compliant with diary entries will be assessed. The subjects
must have .gtoreq.15 PEAK eosinophils/HPF on their esophageal
biopsies to be randomized. In order to ensure that a diagnosis can
be made, at least 5-6 biopsies from both the proximal and distal (3
each) should be taken. The presence or absence of a history of or
current esophageal stricture on the EGD along with a history of a
prior positive response to any corticosteroids treatment previously
received to treat the subject's EoE captured with demography will
be stratification variables at randomization.
[0400] Following confirmation of these eligibility criteria,
eligible subjects may be randomized as described above.
[0401] During treatment, all subjects will return to the site
approximately monthly for scheduled visits and for unscheduled
visits due to significant adverse events or worsening of symptoms
including food impaction.
[0402] Definitions of Histologic Response, Histologic Non-Response,
and Treatment Failure.
[0403] Response or non-responsive status will be assessed 2 weeks
prior to the planned end of treatment for Part 1 (Week 12), and
Part 2 (Weeks 26 and 52).
[0404] A histologic responder will be defined as a subject who
achieves a histologic response of peak eosinophils/HPF
number.ltoreq.6 (as primary determinant). HPF will be defined as a
standard area of 0.235 square millimeters in a microscope with
40.times. lens and 22 mm ocular.
[0405] A histologic non-responder will be defined as a subject who
does not have a histologic response (i.e., do not achieve a
histologic response of peak eosinophils/HPF number.ltoreq.6).
[0406] Subjects who develop food impaction with or without
esophageal dilatation anytime during the study will be considered
treatment failures and complete early termination assessments and
exit the study after the 2 week post-treatment follow-up period.
Subjects who voluntarily withdraw from the study due to worsening
symptoms before the week 12 evaluation or later in the study will
also be considered treatment failures. Every effort should be made
to perform an EGD in subjects wishing to withdraw due to worsening
symptoms. They also must complete the early termination assessments
and exit the study after a 2-week post-treatment follow-up
period.
[0407] Part 1: Induction (Day 1 to Week 14)
[0408] During Part 1, subjects will be treated for 14 weeks with
study drug (FIG. 5). At Week 12, the subjects will undergo a
response assessment, including EGD to assess endoscopic and
histologic status.
[0409] Histologic responders and histologic non-responders (at Week
12) will enter Part 2.
[0410] Part 2: Maintenance (Week 14 to Week 52)
[0411] In Part 2, all subjects classified as histologic responders
at Week 12 will continue to be treated according to the dosing
group to which they were randomized for Part 1 for an additional 14
weeks, beginning at Week 14 (FIG. 5). Subjects may continue on this
dose for up to 9 months after the completion of Part 1.
[0412] Subjects who are histologic non-responders at Week 12 will
receive single-blind 3 mg BID in Part 2.
[0413] At Week 26, subjects will undergo a response assessment,
including EGD to assess histologic response. Symptoms will also be
assessed. The 14 days prior Week 26 will be compared to the 14 days
prior to Randomization. Subjects who are histologic non-responders
will stop treatment at Week 28 and enter the 2 week follow-up and
exit the study. Histologic responders will continue on the same
dose.
[0414] Subjects who complete the study at Week 52 will undergo a
response assessment, including EGD to assess endoscopic and
histologic status. Symptoms will also be assessed. The 14 days
prior Week 52 will be compared to the 14 days prior to
Randomization.
[0415] Subjects will complete a Follow up Visit 2 weeks after the
final dose of study drug.
[0416] Follow-Up Visit
[0417] Subjects will complete a Follow-up Visit for 1 or more of
the following reasons: Subject completed treatment at Week 52
(following EGD); Subject experienced an adverse event (AE)
requiring early discontinuation, including food impaction requiring
EGD; Subject with histologic non-response at week 26 including
subjects on single-blind 3 mg BID; Subject with worsening symptoms
who voluntarily withdraws during the study. The Follow-up Visit
will occur 2 weeks after the subject takes the final dose of study
drug. All subjects must have a final EGD within 3 weeks prior to
completing the Follow up Visit unless the subject withdraws consent
or has a contraindication to EGD.
[0418] Pharmacokinetics
[0419] Sparse PK sampling will be performed to characterize
fluticasone propionate (FP) exposure in the study population. PopPK
analysis will be performed on sparse plasma concentration data.
[0420] Pharmacokinetic samples will be collected from subjects in
all 5 dosing groups to maintain the blind. Samples collected from
subjects in the placebo dosing group will not be analyzed. Samples
collected from the subjects on active doses will be analyzed for
PopPK results.
[0421] For this sparse PK sampling, a pre-dose sample will be
collected on Day 1. At Week 4, Week 8, and Week 12, subjects will
take their "after breakfast" dose as scheduled on the day of the
visit (most likely at home) and 2 samples will be taken during
their scheduled visit: upon arrival to the site and approximately 1
to 1.5 hours after first sample (immediately prior to leaving the
site). Sites will be encouraged to book subject visits throughout
the day. Due to this variability, the sparse PK samples are
expected to represent a large portion of the 12 hour post-dosing
interval.
[0422] Planned Number of Subjects
[0423] Approximately 100 subjects will be randomized into Part 1 in
a 1:1:1:1:1 fashion stratified by presence or absence of a history
of or current esophageal stricture and a history of a prior
positive steroid response to any corticosteroids treatment
previously received to treat the subject's EoE.
[0424] While both genders will be encouraged to enroll, it is
expected that approximately 25% of subjects enrolled will be
female. Although subjects are allowed to be up to 75 years old, it
is expected that 5% of enrolled subjects will be geriatric
(.gtoreq.65 years).
[0425] No interim analyses are planned.
[0426] Inclusion Criteria:
[0427] Subjects must satisfy all of the following criteria:
[0428] Before entering 4-week Baseline Symptom Assessment: Male or
female between .gtoreq.18 and .ltoreq.75 years of age at the time
of informed consent; Signed the informed consent form (ICF) and
willing and able to adhere to all study procedures; Diagnosis or
presumptive diagnosis of EoE; Diagnosis of EoE must be confirmed by
symptoms, histology, and historical documentation of failed
treatment on .gtoreq.8 weeks of high-dose proton pump inhibitors
(PPI). For the purposes of FLUTE, high dose PPI is defined as 20 mg
BID omeprazole or 20 to 40 BID mg of any marketed PPI; maintenance
doses of PPIs are not acceptable. A lack of response to PPI therapy
is defined as .gtoreq.15 PEAK eosinophils/HPF with at least 5
biopsies including both proximal and distal specimens after 8 weeks
of high dose PPI treatment.
[0429] Documentation of PPI failure prior to initial diagnosis or
by documentation of PPI failure at the time of Screening is
required. The subjects may be pre-screened but should not be
consented, sign an ICF, or be offered participation in FLUTE if
they have not met the diagnostic criteria for EoE that requires
that they fail an 8-week trial of high dose PPIs EXCEPT those that
have taken PPIs for 8 weeks will use the EGD within the study for
this documentation. The Investigator and potential subject must
make the decision to complete a PPI trial independent of any
considerations of the study. There is insufficient time to do the 8
week trial within the current study. Should a subject be consented
in error and screen fails due to this point, they may be
re-screened as described in the protocol. Have a subject reported
history of .gtoreq.3 episodes of dysphagia (difficulty with food
going down) in the 7 days prior to Screening; Have a 7-day recall
Global EoE Symptom Score>3; at baseline (EoE score must remain
>3 at each of Visits 1, 2 and 3 before randomization). This will
be performed on paper during the Screening visit; Willing and able
to adhere to study related treatment regimens, procedures, and
visit schedule;
[0430] Before randomization: To be determined prior to
randomization: have evidence of EoE, as defined by .gtoreq.15 PEAK
eosinophils/HPF with at least 5-6 biopsies including both proximal
and distal specimens (3 each); No EGDs and biopsies performed
outside FLUTE are acceptable for meeting eligibility criteria.
Optional biopsies may be taken and processed locally for local use
if specified in the local ICF. Biopsies are to be obtained PRIOR to
the 4-week Baseline Symptom Assessment. Eligibility from a
histological perspective will be based solely on the central
pathologist's assessment.
[0431] To be determined prior to randomization: in the daily diary,
report at least 3 episodes of dysphagia (difficulty with food going
down) for each of the last 7 days during the last 2 weeks of the
4-week Baseline Symptom Assessment;
[0432] To be determined prior to randomization: completion of
episode entries on at least 5 out of each 7 days during the last 14
days of the 4-week Baseline Symptom Assessment.
[0433] Exclusion Criteria:
[0434] Subjects will not be entered in FLUTE for any of the
following reasons:
[0435] Before entering 4-week Baseline Symptom Assessment: Have
known contraindication, hypersensitivity, or intolerance to
corticosteroids; Have any physical, mental, or social condition or
history of illness or laboratory abnormality that in the
Investigator's judgment might interfere with study procedures or
the ability of the subject to adhere to and complete the study;
Presence of oral or esophageal mucosal infection of any type; Have
any mouth or dental condition that prevents normal eating; Have any
condition affecting the esophageal mucosa or altering esophageal
motility other than EoE, including erosive esophagitis (grade B or
higher as per the Los Angeles Classification of Gastroesophageal
Reflux Disease), hiatus hernia longer than 3 cm, Barrett's
esophagus, and achalasia; Use of systemic (oral or parenteral)
corticosteroids within 60 days prior to Screening, use of
inhaled/swallowed corticosteroids within 30 days prior to
Screening, or extended use of high-potency dermal topical
corticosteroids within 30 days prior to Screening; Initiation of an
elimination diet or elemental diet within 30 days before Screening;
Morning (0700 to 0800 hours, or as close to that window as
possible) serum cortisol level.ltoreq.5 .mu.g/dL (138 nmol/L); Use
of biologic immunomodulators in the 24 weeks prior to Screening;
Use of calcineurin inhibitors or purine analogues (azathioprine, 6
mercaptopurine) in the 12 weeks prior to Screening; Use of potent
cytochrome P450 (CYP) 3A4 inhibitors (e.g., ritonavir and
ketoconazole) in the 12 weeks prior to Screening; Have a
contraindication to or factors that substantially increase the risk
of EGD or esophageal biopsy or have narrowing of the esophagus that
precludes EGD with a standard 9 mm endoscope; Have history of an
esophageal stricture requiring dilatation with the previous 12
weeks prior to Screening; Subjects who have initiated, discontinued
or changed dosage regimen of PPIs, H2 antagonists, antacids or
antihistamines for any condition such as GERD for allergic rhinitis
within 4 weeks prior to qualifying endoscopy. These drugs must
remain constant throughout the study. Infection with hepatitis B,
hepatitis C, or human immunodeficiency virus (to be tested during
Screening);
[0436] The following parameters will be utilized to determine
hepatitis B and hepatitis C infection: positive for hepatitis B
surface antigen [HBsAg], total hepatitis B core antibody [anti
HBc], or hepatitis C virus antibody. However, subjects who are
positive for hepatitis B surface antibody, but negative for HBsAg
and anti HBc, will be eligible.
[0437] Have gastrointestinal (GI) bleeding within 4 weeks prior to
Screening or between the Screening Visit and the Randomization
Visit; Have current (>30 days) chronic infection,
immunosuppression, or immunodeficiency; Have history or presence of
Crohn's disease, celiac disease, or other inflammatory disease of
the GI tract, including eosinophilic gastroenteritis; Have current
alcohol or drug abuse in the opinion of the Investigator; Female
subjects who are pregnant, breastfeeding, or planning to become
pregnant during the study; Serum pregnancy test at Screening and
urine pregnancy test during 4-week Baseline Symptom Assessment in
women of childbearing potential must be negative. Sexually active
females of childbearing potential who do not agree to follow highly
effective contraceptive methods through the Follow up Visit; For
systemic contraceptive, use must be stable for .gtoreq.28 days
prior to Screening. Female subjects with surgical menopause or
menopause confirmed by follicle stimulating hormone/luteinizing
hormone do not require contraception or pregnancy testing during
the study. Participation in a clinical study involving an
investigational product within 30 days (or 5 half-lives, whichever
is longer) of Screening;
[0438] Before Randomization
[0439] A serum cortisol level<18 .mu.g/mL (497 nmol/dL) at 60
minutes with adrenocorticotropic hormone (ACTH) stimulation test
using 250 .mu.g cosyntropin (i.e., a positive result on the ACTH
stimulation test).
[0440] Test Product, Dose and Mode of Administration:
[0441] APT-1011 is an orally disintegrating tablet that includes FP
as its active ingredient.
[0442] For the purposes of this protocol, the term study drug is
used to refer to any blinded medication administered (i.e., any
dosage of APT-1011 or placebo).
[0443] Subjects will be instructed to take the study drug orally,
with no water or other liquids. The tablet should be placed in the
mouth and manipulated between the tongue and the roof of the mouth
and allowed to disintegrate completely on the subject's tongue. It
should be swallowed when fully disintegrated, without biting or
chewing. No rinsing with water or liquids is to be allowed after
administration.
[0444] Dosing will occur in the morning ("after breakfast;"
.gtoreq.30 minutes after breakfast) and at bedtime ("at bedtime;"
.gtoreq.2 hours after the evening meal). The "at bedtime" dose of
study drug will be administered immediately prior to sleep, while
lying in bed. All eating, drinking, and tooth brushing should be
completed prior to dosing.
[0445] Study drug will be administered BID (30 minutes after
breakfast and at bedtime) in all parts of the study. During the
placebo run-in, the subjects will receive placebo BID. In the HS
groups, the subjects will receive placebo in the morning 30 minutes
after breakfast and their doses at bedtime. Placebo subjects after
randomization will receive placebo BID.
[0446] Subjects in the 1.5 mg BID APT-1011, 3 mg BID APT-1011, and
placebo dosing groups will take the same study drug for the "after
breakfast" and "at bedtime" doses. Subjects in the 1.5 mg HS and 3
mg HS APT 1011 groups will take placebo "after breakfast" and 1.5
mg or 3 mg APT 1011 "at bedtime."
[0447] Subjects should refrain from oral intake of solids or
liquids for .gtoreq.1 hour after dosing.
[0448] Criteria for Evaluation:
[0449] Efficacy will be assessed histologically (eosinophils per
HPF), endoscopically (Eosinophilic Esophagitis Endoscopic Reference
Score [EREFs]), clinically as an exploratory endpoint (via the
PROSE completed for each dysphagia episode and at the end of each
day), and the following additional patient-reported outcomes:
Global EoE Symptom Score, Patient Global Impression of Severity
(PGIS) and Patient Global Impression of Change (PGIC), 7-day recall
Eosinophilic Esophagitis Activity Index (EEsAI) total and
subscores, and subject's assessment of symptoms. Health Related
Quality of Life (HRQoL) will be assessed as an exploratory endpoint
by the Adult Eosinophilic Esophagitis Quality of Life Questionnaire
(EoE-QoL-A).
[0450] Primary efficacy endpoint: The following primary efficacy
endpoint will be evaluated at Week 12 to assess EoE response:
[0451] Histology: percentage of subjects with PEAK eosinophils/HPF
number.ltoreq.6 after assessing at least 5-6 biopsies from the
proximal and distal esophagus (.about.3 each) where the HPF area is
235 square microns (40 magnification lens with a 22 mm ocular).
[0452] Secondary efficacy endpoints: The following secondary
efficacy endpoints will be evaluated:
[0453] EoE sustained response: percentage of subjects who met the
primary endpoint at Week 12 and maintained the primary endpoint at
Week 26 and Week 52;
[0454] Change from baseline EREFs at Week 12, Week 26, and Week
52;
[0455] Endoscopic changes will as per the EREFs evaluation based on
the following endoscopic features: edema, rings, exudates, furrows,
stricture, and several miscellaneous features (crepe paper
esophagus, narrow caliber esophagus, and esophageal erosions).
[0456] Percentage of subjects with a peak eosinophils/HPF
number<1 and <15 at Week 12, Week 26, and Week 52;
[0457] Change from baseline Global EoE Symptom Score accessed prior
to randomization, which will be assessed for the 7-day period prior
to the following study visits: Week 4, Week 8, Week 12, Week 18,
Week 22, Week 26, Week 28, Week 36, Week 44, and Week 52;
[0458] Dysphagia: Change in the number of dysphagia episodes at
baseline (14-day period prior to randomization) compared with the
14-day period prior to the time point of interest (Week 12, Week
26, and Week 52)
[0459] Change from baseline 7-day recall EEsAI total score at Week
12, Week 26, and Week 52;
[0460] Change from baseline 7-day recall EEsAI subscores at Week
12, Week 26, and Week 52;
[0461] Percentage of subjects with mean 7-day recall EEsAI total
score<20 at Week 12, Week 26, and Week 52;
[0462] Change from baseline PGIS assessed prior to randomization to
those assessed at Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44 and
52;
[0463] PGIC at weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and
52.
[0464] Assessment of treatment failure and relapse, including:
[0465] Percentage of histologic non-responders by dose at Week 12,
Week 26, and Week 52;
[0466] Percentage of subjects requiring emergency endoscopic food
disimpaction by dose before Week 14, between Week 14 and Week 28,
and between Week 28 and Week 52;
[0467] Percentage of subjects requiring esophageal dilation by
dosing group and part of the study.
[0468] Exploratory efficacy endpoints: The following exploratory
efficacy endpoints will be evaluated:
[0469] Dysphagia: Change in the number of dysphagia episodes at
baseline (14-day period prior to randomization) compared with the
14 day period prior to the time point of interest (Weeks 12, 26 and
52).
[0470] Change from baseline in dysphagia-free days during the 14
day period prior to the following study visits: Week 12, Week 26,
and Week 52;
[0471] EoE sustained response (dysphagia): percentage of all
subjects who met the dysphagia secondary endpoint at Week 12 and
maintained a dysphagia-related response at Week 26 and Week 52;
[0472] Evaluation of PK/PD (cortisol) and exposure-response
(efficacy) relationships;
[0473] Subject's assessment of symptoms compared with the previous
visit at Week 4, Week 8, Week 12, Week 14, Week 18, Week 22, Week
26, Week 28, Week 36, Week 44, Week 52, and the Early Termination
Visit (if applicable);
[0474] Evaluation of HRQoL based on the EoE-QoL-A at randomization,
Week 12, Week 26, Week 52 for all subjects by dose and
subgroup;
[0475] Subjects receiving single-blind (to subject) treatment (in
Part 2) will be tabulated separately.
[0476] Percentage of subjects who were classified as histologic
non-responders at Week 12 and have a peak eosinophils/HPF
number.ltoreq.6 at all biopsied esophageal locations at Week 26 and
Week 52;
[0477] Change from baseline dysphagia episodes during the 14 day
period prior to Week 26 and Week 52 for subjects who were
classified as non-responders at Week 12;
[0478] Percentage of subjects who were classified as histologic
non-responders at Week 12 and meet the primary endpoint at Week 26
and Week 52;
[0479] A scoring structure, and various endpoints will be derived
from the DEDI.
[0480] Psychometric measurement properties of the PROSE will be
evaluated;
[0481] Anchor and distribution analyses to evaluate meaningful
changes on the PROSE.
[0482] Adverse Events
[0483] Any AE or concurrent illness experienced by a subject during
any portion of FLUTE must be described in detail and be fully
evaluated by the Investigator. The Investigator is responsible for
recording all AEs observed or reported during the study, regardless
of causality and/or clinical significance.
[0484] Safety will be assessed by monitoring and recording all
treatment-emergent adverse events (TEAEs), TEAEs leading to
discontinuation, and serious adverse events (SAEs). All TEAEs will
be coded using the Medical Dictionary for Regulatory Activities
version 14.0 classification and classified by severity (mild,
moderate, or severe). Relatedness to study drug (related or not
related) will be reported for SAEs only by the Investigator.
Treatment-emergent adverse events occurring within 3 days of a dose
change will be attributed to the previous dose.
[0485] APT-1011 (fluticasone proprionate ODT) a minimally absorbed
corticosteroid is expected to act topically in the esophagus.
Because of this, there is potential for decreased efficacy if the
subject swallows water soon after dosing. Since the use of
fluticasone has only been rarely associated with oral candidiasis,
there will be no need to do swish and spit since this could
inadvertently be associated with swallowed water.
[0486] Oral and esophageal candidiasis will however be considered
AEs of special interest. Subjects may remain in the study during
the treatment for these AEs. The investigator may allow swish and
spit 30 minutes after dosing for these subjects. Subjects must be
instructed not to swallow the rinsing water.
[0487] Symptoms of hypercorticism (See below) are also AEs of
special interest.
[0488] Laboratory Tests
[0489] Routine laboratory tests and assessments will be performed
throughout the study, including hematology, blood chemistry,
urinalysis, and electrocardiograms (ECGs). Clinically significant
changes in laboratory tests or ECGs will be summarized.
[0490] Physical Examination and Vital Signs
[0491] Physical examinations will be performed to document the
baseline condition of the subject and to highlight changes related
to AEs. Vital signs will also be assessed and clinically
significant deviations will be reported.
[0492] Cortisol-Related Findings
[0493] All subjects will undergo a 250 .mu.g ACTH stimulation test
during the 4-week Baseline Symptom Assessment following receipt of
the morning serum cortisol level during the Screening period. This
test will also be administered at Week 12 (Visit 6), Week 26 (Visit
10), and Week 52 (Visit 14).
[0494] At all visits (scheduled or unscheduled), specific attention
will be given to potential changes related to corticosteroids, as
well as symptoms of hypercorticism. Should a subject undergo
surgery or trauma during the study, particular care should be taken
in observing subjects for evidence of inadequate adrenal
response.
[0495] If hypercorticism or adrenal suppression are suspected, an
adequate work-up should be performed to confirm or rule out these
findings. Specifically, to monitor for hypothalamic pituitary
adrenal (HPA) axis suppression of potential clinical concern, a 250
.mu.g ACTH simulation test will also be performed after Screening
if any of the following occur:
[0496] During routine laboratory testing completed for the study,
the subject has a morning serum cortisol level.ltoreq.5 .mu.g/dL
(138 nmol/L) (confirmed by 2 blood draws), including at the last
on-treatment visit for a subject and, if applicable, Early
Termination Visit;
[0497] The subject reports symptoms of hypercorticism;
[0498] The subject discontinues due to HPA axis suppression.
[0499] A positive result for the ACTH stimulation test is defined
as serum cortisol level<18 .mu.g/dL (497 nmol/L) at 60 minutes
after treatment with 250 .mu.g cosyntropin. This result is
exclusionary if it occurs at Screening/4 week Baseline Symptom
Assessment and requires follow-up through recovery of adrenal
function if it occurs thereafter. Treatment for HPA axis
suppression is discussion in the full protocol. The Sponsor will
provide guidelines for safety follow-up and document of restoration
of adrenal function in all subjects demonstrating evidence of
hypercorticism or HPA axis suppression during the course of the
study.
[0500] Electrocardiogram
[0501] Electrocardiograms signs will be assessed and clinically
significant deviations will be reported.
[0502] Safety endpoints: The safety endpoints of interest are:
[0503] Frequency of TEAEs;
[0504] TEAEs leading to discontinuation;
[0505] Treatment-emergent SAEs;
[0506] Percentage of subjects with serum cortisol level.ltoreq.5
.mu.g/dL (.ltoreq.138 nmol/L) or positive ACTH stimulation test
(serum cortisol<18 .mu.g/mL [.ltoreq.497 nmol/L] at 60
minutes);
[0507] The number of subjects discontinuing for HPA axis
suppression will be recorded.
[0508] Frequency of oral and esophageal candidiasis.
[0509] Pharmacokinetic variables: The following PopPK parameters
will be estimated using sparse sampling, as data permit: Oral
clearance; Volume of distribution. Additional PopPK parameters will
be estimated, as appropriate, based on the final structural PK
model.
[0510] Statistical Methods:
[0511] Sample size determination: Part 1 will include a sample size
with a range of 100 subjects, in which 20 patients are randomized
to 1.5 mg HS, 1.5 mg BID, 3 mg HS, 3 mg BID, and placebo
(1:1:1:1:1). Based on these randomization ratios, approximately 80%
of all subjects in Part 1 will be treated with an APT-1011 dosing
regimen and approximately 20% of all subjects in Part 1 will be
treated with placebo.
[0512] Analysis Populations:
[0513] The All Enrolled Population includes all subjects who signs
an ICF and are enrolled into the study. The Safety Population
includes all subjects who receive .gtoreq.1 dose of the study drug.
The Intent-to-treat (ITT) Population includes all subjects who
receive .gtoreq.1 dose of study drug and have .gtoreq.1 efficacy
assessment post-dose. A subject who is enrolled in the study and
receives study drug, but fails to complete treatment will be
considered a dropout. The Sparse PK Subgroup includes all subjects
who have .gtoreq.1 quantifiable PK sample collected for sparse PK
evaluations.
[0514] Additional analysis populations (e.g., Per Protocol
Populations including subjects who complete Part 1, Part 2 Weeks 26
and 52) may be defined in the Statistical Analysis Plan.
[0515] Statistical Methodology:
[0516] Subject characteristics: Baseline and demographic
information will be summarized using descriptive statistics for
continuous and ordinal variables (e.g., age and weight) and counts
and percentages for categorical variables (presence or absence of
strictures, prior response to steroids, sex and race).
[0517] Primary Efficacy Analysis for Part 1
[0518] Let p.sub.0 be the proportion of patients who meet histology
response for placebo, and let p.sub.j be the proportion of patients
who meet histology response for dose j, with j=1,2,3,4
corresponding to 1.5 mg HS, 1.5 mg BID, 3 mg HS and 3 mg BID doses,
respectively. There are 4 hypotheses corresponding to the 4 active
doses, which will be tested using a gatekeeping strategy to
preserve Type I error for each analysis.
[0519] 1) Primary Hypothesis #1
[0520] H.sub.0: p.sub.4.ltoreq.p.sub.0
[0521] H.sub.1: p.sub.4=p.sub.0
[0522] A Chi-square test of proportions will be used to test
primary hypothesis #1, i.e 3 mg BID vs. placebo. If the
corresponding p-value is less than or equal to 0.05, the null
hypothesis will be rejected, and subsequently the following
hypothesis will be tested:
[0523] 2) Primary Hypothesis #2
[0524] H.sub.0: p.sub.3.ltoreq.p.sub.0
[0525] H.sub.1: p.sub.3=p.sub.0
[0526] A Chi-square test of proportions will be used to test
primary hypothesis #2, i.e 3 mg HS vs. placebo. If the
corresponding p-value is less than or equal to 0.05, the null
hypothesis will be rejected, and subsequently the following
hypothesis will be tested:
[0527] 3) Primary Hypothesis #3
[0528] H.sub.0: p.sub.2.ltoreq.p.sub.0
[0529] H.sub.1: p.sub.2=p.sub.0
[0530] A Chi-square test of proportions will be used to test
primary hypothesis #3, i.e 1.5 mg BID vs. placebo. If the
corresponding p-value is less than or equal to 0.05, the null
hypothesis will be rejected, and subsequently the following
hypothesis will be tested:
[0531] 4) Primary Hypothesis #4
[0532] H.sub.0: p.sub.1.ltoreq.p.sub.0
[0533] H.sub.1: p.sub.1=p.sub.0
[0534] A Chi-square test of proportions will be used to test
primary hypothesis #4, i.e 1.5 mg HS vs. placebo. If the
corresponding p-value is less than or equal to 0.05, the null
hypothesis will be rejected.
[0535] Note the gate-keeping strategy only allows formal hypothesis
testing of 1.5 mg HS or 1.5 mg BID if the higher doses meet
statistical significance.
[0536] Efficacy Analysis for Part 2
[0537] Sustained EoE response will be assessed in subjects who
complete both Part 1 and Part 2 and complete Week 26 and 52
evaluations. This will be assessed by the primary endpoint. Other
measures of efficacy will be assessed at Week 26. Efficacy will be
summarized for histologic non-responders from Part 1 who are
treated in Part 2. Other measures of efficacy will be assessed at
Week 52.
[0538] Secondary and Exploratory Efficacy Analysis
[0539] Statistical tests to compare each APT-1011 dosing group with
placebo will be performed for the secondary efficacy endpoints, but
the corresponding p-values will be considered as descriptive rather
than inferential.
[0540] The secondary endpoints will be analyzed via a
Cochran-Mantel-Haenzel (CMH) test for categorical endpoints and
analysis of covariance for change from baseline endpoints, except
for the endpoint of time to relapse after initiation of
double-blind treatment in Part 2, which will be analyzed using
Kaplan-Meier methods.
[0541] No statistical testing of exploratory efficacy endpoints
will be performed.
[0542] Safety Analyses
[0543] The incidence of TEAEs will be summarized by system organ
class and preferred term. Separate summaries by maximum severity
(all AEs) and relationship to study drug (SAEs only) will be
provided. The incidence of TEAEs leading to discontinuation from
the study and treatment-emergent SAEs will also be summarized. In
subjects who change dosing groups, the TEAEs will be attributed to
the previous dose, if they occur within 3 days of the change.
[0544] Clinically significant changes of potential clinical
interest in clinical tests will be summarized including hematology,
chemistry, urinalysis, ECG, cortisol, vital signs, and bone mineral
density. No statistical testing of safety endpoints will be
performed. Shift tables may be produced, if needed. The number of
subjects discontinuing due to HPA axis suppression or positive ACTH
stimulation tests will be summarized.
[0545] Population Pharmacokinetics
[0546] A PopPK analysis will be performed based on sparse plasma
concentration data. It will be performed using the nonlinear
mixed-effects software, NONMEM, Version 7.2.0 or later (ICON
Development Solutions, Ellicott City, Md.) or other appropriate
nonlinear mixed-effects modeling software. The structural PK model
will include oral clearance and volume of distribution as
fixed-effect parameters. Additionally, the intersubject variability
in the parameter estimates and the random residual error in the
data will be estimated with appropriate error models. The optimal
base model will be selected according to the standard criteria such
as minimum objective function value and diagnostic plots. A
separate PopPK report will be generated as an appendix to the
clinical study report.
[0547] Exploratory PK/PD Analysis
[0548] As data permit, exploratory PK/PD analyses assessing the
relationship between systemic exposure to FP and changes in
cortisol levels also may be performed as described above.
Additional exploratory PK/PD analyses may be performed to
facilitate selection of safe and effective doses for future studies
and clinical use.
[0549] Study Rationale and Risk-Benefit Analysis
[0550] The purpose of FLUTicasone in Eosinophilic esophagitis
(FLUTE) is to examine 3 total daily doses of APT-1011 to define the
exposure-response of APT-1011 and the minimum effective dose while
minimizing any clinically significant HPA axis effects. APT-1011 is
expected to offer the following advantages for patients with EoE:
Oral administration is generally more acceptable and more reliable
in terms of accurate dose administration. Currently, the only
available formulation of FP is a metered dose inhaler that is
sprayed into the mouth and swallowed by the patient. Oral
administration of APT-1011 has very low bioavailability even
compared with similar compounds such as budesonide, which further
reduces its potential for systemic corticosteroid toxicity, while
it may be more potent on a mg basis.
[0551] The current study represents the first dose ranging study of
APT-1011. Given its low bioavailability, it is unlikely that
APT-1011 will have any significant systemic corticosteroid
effects.
TABLE-US-00014 TABLE 12 Schedule of Events (Screening, 4-week
Placebo Run-in/Baseline Symptom Assessment, and Part 1) VISIT Visit
2 (4-week Visit 6 Baseline Visit 4 Visit 5 (Week 12) Early Visit 1
Symptom Visit 3 (Week (Week (Response Visit 7 Unscheduled
Termination (Screening) Assessment) (Randomization) 4) 8)
Assessment) .sup.a (Week 14 .sup.a) Visit .sup.b Visit .sup.c DAY
-28 to -1 (Site Visit to Assessments and Occur Procedures -56 to
-28 Day -28) 1 28 .+-. 2 56 .+-. 2 84 .+-. 2 98 + 2 zz ICF signed X
Confirm entry to X 4-week Baseline Symptom Assessment .sup.d
Inclusion/exclusion X X .sup. X .sup.e criteria Demographics; X
medical, surgical, and medication history Concomitant X X X X X X X
X X medication(s) Physical X X X X X X X X examination .sup.f Vital
signs .sup.g X X X X X X X X X Chemistry and X X X X X X X X
hematology Serum cortisol X X X X X X .sup.i Optional X (morning
fasting) .sup.h Urinalysis X X X X X X X 12-lead ECG X X X X PopPK
.sup.j X X X X (pre-dose) EGD (with EREFs), X X .sup. X .sup.n
including collection of multiple Pregnancy test for X X X X X X X
Optional X women of (serum) (urine) (urine) (urine) (urine) (urine)
(urine) (urine) childbearing potential (menopausal women FSH at
Screening only) .sup.o ACTH stimulation .sup. X .sup.p X .sup.
Optional .sup.q Optional.sup.r test (250 .mu.g) AEs X X X X X X X X
X .sup.s Global EoE .sup. X.sup.t X X X X X X Optional X Symptom
Score 7-day EEsAI X X X PGIC X X X X Optional X PGIS X X X X X X
.sup. Optional .sup.u X EoE-QoL-A X X X Training for daily .sup.
X.sup.v diary Daily diary X X X X X X X Study drug X X X X X X
dispensed Drug return and X X X X X X accountability and study drug
compliance assessment Reason for X discontinuation Abbreviations:
ACTH = adrenocorticotropic hormone; AE = adverse event; ECG =
electrocardiogram; eCRF = electronic case report form; EEsAI =
Eosinophilic Esophagitis Activity Index; EGD =
esophagogastroduodenoscopy; EoE = eosinophilic esophagitis;
EoE-QoL-A = Adult Eosinophilic Esophagitis Quality of Life
Questionnaire; EREFs = Eosinophilic Esophagitis Endoscopic
Reference Score; FSH = follicle-stimulating hormone; HPA =
hypothalamic-pituitary-adrenal; ICF = informed consent form; PGIC =
Patient Global Impression of Change; PGIS = Patient Global
Impression of Severity; PK = pharmacokinetic(s); popPK = population
pharmacokinetic(s); SAE = serious adverse event. .sup.a Data and
samples collected for Week 14 in the Part 1 Schedule of Events will
also apply for this visit in the Part 2 Schedule of Events (as
applicable) and procedures will not be repeated. Histologic
non-responders at Week 12 will receive single-blind 3 mg BID in
Part 2. .sup.b The reason for an unscheduled visit will guide
procedures, at the discretion of the Investigator. .sup.c The
subject should be seen at the site within 7 days of determination
of the need to discontinue. If this is not possible due to an SAE
or other unforeseen circumstance, it may be completed with a phone
visit with the subject or a family member. The eCRF should document
why the subject was not available for an on-site visit. .sup.d As
described in Section 4.1.4, to enter the 4-week Baseline Symptom
Assessment, subjects must meet all inclusion criteria including the
Global EoE score >3 (Inclusion Criterion #5) except those to be
assessed during the 4-week Baseline Symptom Assessment (Inclusion
Criterion #7: evidence of EoE as defined by .gtoreq.15 PEAK
eosinophils/HPF, Inclusion Criterion #8: in the daily diary, report
episodes of dysphagia .gtoreq.3 days per 7 days during the last 14
days of the 4-week Baseline Symptom Assessment, Inclusion Criterion
#9: completion of the daily diary on at least 5 out of each 7 days
during the last 14 days of the Baseline Symptom Assessment, and
Exclusion Criterion #23: serum cortisol level <18 .mu.g/dL (497
nmol/L) at 60 minutes with adrenocorticotropic hormone (ACTH)
stimulation test using 250 .mu.g cosyntropin [i.e., a positive
result on the ACTH stimulation test]). .sup.e Confirmation that the
subject meets eligibility criteria include the following to be
confirmed during the 4-week Baseline Symptom Assessment: Inclusion
Criterion #7: evidence of EoE as defined by .gtoreq.15 PEAK
eosinophils/HPF, Inclusion Criterion #8: in the daily diary, report
episodes of dysphagia .gtoreq.3 days per 7 days during the last 14
days of the 4-week Baseline Symptom Assessment, Inclusion Criterion
#9: completion of the daily diary on at least 5 out of each 7 days
during the last 14 days of the Baseline Symptom Assessment, and
Exclusion Criterion #23: serum cortisol level <18 .mu.g/dL (497
nmol/L) at 60 minutes with ACTH stimulation test using 250 .mu.g
cosyntropin (i.e., a positive result on the ACTH stimulation test).
.sup.f Physical examination will include assessments of height at
screening (Day 1 only), weight, general appearance, head and neck,
eyes and ears, nose and throat, chest, lungs, heart, abdomen,
extremities and joints, lymph nodes, skin, and neurological
examination. Body Mass Index (BMI) will be calculated on Day 1.
.sup.g Vital signs to be collected include pulse, respiratory rate,
temperature (.degree. C.; after a 5-minute rest in sitting
position), and blood pressure (measured from the same arm
throughout the study). .sup.h To be drawn 0700 to 0800 hours, or as
close to that window as possible. Subjects must be fasting for an
8-hour period prior to the serum cortisol assessments. Blood may be
drawn for serum cortisol (morning fasting) .+-.3 days of scheduled
visit to accommodate accurate timing. If desired, other blood draws
scheduled for the visit may be done at the same time. .sup.i If
abnormal serum cortisol level is reported at the last on-treatment
visit for a subject, additional monitoring and ACTH test may be
required (see Section 6.3.4). .sup.j Sparse PK samples will be
performed in all subjects. A sample will be collected pre-dose on
Day 1. At Week 4, Week 8, and Week 12, subjects will take their
"after breakfast" dose at home and 2 samples will be taken during
their scheduled visit: upon arrival to the site and 1 to 1.5 hours
after first sample (immediately prior to leaving the site).
Subjects should write down the time they took the morning dose and
inform the site staff. The time of the "after breakfast" dose (day
of the planned visit) and the time of the immediately preceding "at
bedtime" dose (evening prior to planned visit) will be recorded.
Actual PK sampling times will be documented. .sup.k It is expected
that the EGD will typically be performed during a separate time
from other procedures for a given time point. Both EGD and any
other procedures indicated for a study visit must be completed
within the window for that study visit. For Screening, the EGD must
be completed after the ICF is signed and .gtoreq.2 weeks before the
date of expected randomization. .sup.l During the EGD, the
endoscopist will complete the EREFs and ~3 biopsies will be
obtained from both the proximal and the distal esophagus (total of
5-6 biopsies). The pathologist will assess histology. .sup.m The
EGD to determine eligibility must be performed before entry into
the 4-week (28 day) single-blind run-in/Baseline Symptom
Assessment. Pathology for EGD biopsies may also be assessed during
the 4-week Baseline Symptom Assessment (or earlier if possible).
.sup.n If the subject discontinues from the study due to lack of
efficacy or other reasons, the Investigator may perform an EGD, if
clinically indicated. .sup.o A serum pregnancy test will be
performed at Screening and urine pregnancy tests thereafter.
Pregnancy testing in women of childbearing potential must be
negative (see Section 6.3.2.1). .sup.p All subjects undergo a 250
.mu.g ACTH stimulation test as part of eligibility assessments.
This evaluation will be completed following receipt of the morning
serum cortisol level during the Screening period. This must be
performed before entry into the 4-week (28 day) single-blind
run-in/Baseline Symptom Assessment. A positive ACTH stimulation
test (serum cortisol level <18 .mu.g/dL (497 nmol/L) at 60
minutes after treatment with 250 .mu.g cosyntropin) will be
exclusionary (see Exclusion Criterion #9: use of biologic
immunomodulators in the 24 weeks prior to Screening in Section
4.2.2). .sup.q A 250 .mu.g ACTH simulation test will be performed
(at an unscheduled visit) to assess for HPA axis suppression of
potential clinical concern as follows: 1) Any time a subject has a
morning serum cortisol level .ltoreq.5 .mu.g/dL (138 nmol/L)
(confirmed by 2 blood draws) 2) Any time a subject reports symptoms
of hypercorticism (Appendix 6) .sup.rSubjects who discontinue from
the study due to evidence of HPA axis suppression will undergo a
250 .mu.g ACTH stimulation test at the Early Termination Visit.
.sup.s For the Early Termination Visit, the Investigator should
record any occurrence of AEs (14 .+-. 5 days after
discontinuation). Subjects discontinued for HPA issues should be
followed until resolution. .sup.tGlobal EoE symptom score at
Screening will be completed on paper. EoE score must remain >3
at each of Visits 1, 2 and 3 before randomization, or the subject
will be considered a screen failure. .sup.u Only if visit is
related to EoE change in symptoms. .sup.vRecording in the daily
diary will not start until 28 days prior to planned date of
randomization.
TABLE-US-00015 TABLE 13 Schedule of Events Part 2 VISIT Visit 10
(Week 26) Early Visit 7 Visit 8 Visit 9 (Response Visit 11
Unscheduled Termination (Week 14) (Week 18) (Week 22) Assessment)
.sup.a (Week 28 .sup.a) Visit .sup.b Visit .sup.c DAY Assessments
and Procedures 98 + 2 126 .+-. 2 154 .+-. 2 182 .+-. 2 196 + 2 zz
Histologic Responder/Non-Responders in Part 1 X (no
contraindications to continue) Concomitant medication(s) X X X X X
X X Physical examination .sup.d X X X X X Vital signs .sup.e X X X
X X X X Chemistry and hematology X X X X X X Serum cortisol
(morning fasting) .sup.f X X X X .sup. X .sup.g Optional X
Urinalysis X X X X X 12-lead ECG X X EGD (with EREFs), including
collection of X X .sup. X .sup.j multiple Urine pregnancy test for
women of X X X X X Optional X childbearing potential ACTH
stimulation test (250 .mu.g) .sup.k X .sup. Optional .sup.k
Optional .sup.l AEs X X X X X X .sup. X .sup.m Global EoE Symptom
Score X X X X X Optional X 7-day EEsAI X X PGIC X X X X X Optional
X PGIS X X X X X .sup. Optional .sup.n X EoE-QoL-A X X Daily diary
X X X X X Study drug dispensed X (if needed X X X X for dosin g
group change) Drug return and accountability and study drug X X X X
X compliance assessment Reason for discontinuation X Abbreviations:
ACTH = adrenocorticotropic hormone; AE = adverse event; ECG =
electrocardiogram; eCRF = electronic case report form; EEsAI =
Eosinophilic Esophagitis Activity Index; EGD =
esophagogastroduodenoscopy; EoE = eosinophilic esophagitis;
EoE-QoL-A = Adult Eosinophilic Esophagitis Quality of Life
Questionnaire; EREFs = Eosinophilic Esophagitis Endoscopic
Reference Score; HPA = hypothalamic-pituitary-adrenal; PGIC =
Patient Global Impression of Change; PGIS = Patient Global
Impression of Severity; SAE = serious adverse event. .sup.a Data
and samples collected for Week 28 in the Part 1 Schedule of Events
will also apply for this visit in the Part 2 Schedule of Events in
Table 4-3 (as applicable) and procedures will not be repeated. At
Week 26 subjects who are histologic non-responders will stop
treatment at Week 28 and enter the 2- week Follow-up period.
Histologic responders continue on the same dose. .sup.b The reason
for an unscheduled visit will guide procedures, at the discretion
of the Investigator. .sup.c The subject should be seen at the site
within 7 days of determination of the need to discontinue. If this
is not possible due to an SAE or other unforeseen circumstance, it
may be completed with a phone visit with the subject or a family
member. The eCRF should document why the subject was not available
for an on-site visit. .sup.d Physical examination will include
assessments of weight, general appearance, head and neck, eyes and
ears, nose and throat, chest, lungs, heart, abdomen, extremities
and joints, lymph nodes, skin, and neurological examination. .sup.e
Vital signs to be collected include pulse, respiratory rate,
temperature (.degree. C.; after a 5-minute rest in sitting
position), and blood pressure (measured from the same arm
throughout the study). .sup.f To be drawn 0700 to 0800 hours, or as
close to that window as possible. Subjects must be fasting for an 8
hour period prior to the serum cortisol assessments. Blood may be
drawn for serum cortisol (morning fasting) .+-.3 days of scheduled
visit to accommodate accurate timing. If desired, other blood draws
scheduled for the visit may be done at the same time. .sup.g If
abnormal serum cortisol level is reported at the last on-treatment
visit for a subject, additional monitoring and ACTH test may be
required (see Section 6.3.4). .sup.h It is expected that the EGD
will typically be performed during a separate time from other
procedures for a given time point. Both EGD and any other
procedures indicated for a study visit must be completed within the
window for that study visit. For Screening, the EGD must be
completed after the ICF is signed and .gtoreq.2 weeks before the
date of expected randomization. .sup.i During the EGD, the
endoscopist will complete the EREFs and ~3 biopsies will be
obtained from both the proximal and the distal esophagus (total of
5-6 biopsies). The pathologist will assess histology. .sup.j If the
subject is discontinuation from the study due to lack of efficacy
or other reasons, the Investigator may perform an EGD, if
clinically indicated. .sup.k A 250 .mu.g ACTH simulation test will
be performed (at an unscheduled visit) to assess for HPA axis
suppression of potential clinical concern as follows: 1) Any time a
subject has a morning serum cortisol level .ltoreq.5 .mu.g/dL (138
nmol/L) (confirmed by 2 blood draws) 2) Any time a subject reports
symptoms of hypercorticism (Appendix 6). .sup.l Subjects who
discontinue from the study due to evidence of HPA axis suppression
will undergo a 250 .mu.g ACTH stimulation test at the Early
Termination Visit. .sup.m For the Early Termination Visit, the
Investigator should record any occurrence of AEs (14 .+-. 5 days
after discontinuation). Subjects discontinued for HPA issues should
be followed until resolution. .sup.n Only if visit is related to
EoE change in symptoms.
TABLE-US-00016 TABLE 14 Schedule of Events (Part 2 and follow up
visit) VISIT Visit 14 (Week 52) Early Visit 11 Visit 12 Visit 13
(Response Unscheduled Termination (Week 28) (Week 36) (Week 44)
Assessment) Visit .sup.a Visit .sup.b Follow-up DAY Visit 2 weeks
after last dose of Assessments and Procedures 196 + 2 252 .+-. 2
308 .+-. 2 364 .+-. 2 study drug Histologic responders at Week 26
.sup.c X Responder status X Concomitant medication(s) X X X X X X X
Physical examination .sup.d X X X X X X Vital signs .sup.e X X X X
X X X Chemistry and hematology X X X X X X Serum cortisol (morning
fasting).sup.f X X X .sup. X .sup.g Optional X X Urinalysis X X X X
X X 12-lead ECG X X X EGD (with EREFs), including .sup. X .sup.k X
.sup. X .sup.j collection of multiple esophageal biopsies to be
assessed histologically .sup.h,i Urine pregnancy test for women X X
X X Optional X X of childbearing potential ACTH stimulation test
(250 .mu.g) X .sup. Optional .sup.k Optional .sup.l AEs X X X X X
.sup. X .sup.m Global EoE Symptom Score X X X X Optional X 7-day
EEsAI X X PGIC X X X X Optional X PGIS X X X X .sup. Optional
.sup.n X EoE-QoL-A X X Daily diary X X X X X Study drug dispensed X
(if needed X X for dosing group change) Drug return accountability
and X X X X X X study drug compliance assessment Reason for
discontinuation X Abbreviations: ACTH = adrenocorticotropic
hormone; AE = adverse event; ECG = electrocardiogram; eCRF =
electronic case report form; EEsAI = Eosinophilic Esophagitis
Activity Index; EGD = esophagogastroduodenoscopy; EoE =
eosinophilic esophagitis; EoE-QoL-A = Adult Eosinophilic
Esophagitis Quality of Life Questionnaire; EREFs = Eosinophilic
Esophagitis Endoscopic Reference Score; HPA =
hypothalamic-pituitary-adrenal; PGIC = Patient Global Impression of
Change; PGIS = Patient Global Impression of Severity; SAE = serious
adverse event. .sup.a The reason for an unscheduled visit will
guide procedures, at the discretion of the Investigator. .sup.b The
subject should be seen at the site within 7 days of determination
of the need to discontinue. If this is not possible due to an SAE
or other unforeseen circumstance, it may be completed with a phone
visit with the subject or a family member. The eCRF should document
why the subject was not available for an on-site visit. .sup.c
Histologic responders will continue on the same dose. Histologic
non-responders at Week 26 will stop treatment at Week 28 and enter
the 2-week follow-up period. .sup.d Physical examination will
include assessments of weight, general appearance, head and neck,
eyes and ears, nose and throat, chest, lungs, heart, abdomen,
extremities and joints, lymph nodes, skin, and neurological
examination. .sup.e Vital signs to be collected include pulse,
respiratory rate, temperature (.degree. C.; after a 5-minute rest
in sitting position), and blood pressure (measured from the same
arm throughout the study). .sup.fTo be drawn 0700 to 0800 hours, or
as close to that window as possible. Subjects must be fasting for
an 8 hour period prior to the serum cortisol assessments. Blood may
be drawn for serum cortisol (morning fasting) .+-.3 days of
scheduled visit to accommodate accurate timing. If desired, other
blood draws scheduled for the visit may be done at the same time.
.sup.g If abnormal serum cortisol level is reported at the last
on-treatment visit for a subject, additional monitoring and ACTH
test may be required (see Section 6.3.4). .sup.h It is expected
that the EGD will typically be performed during a separate time
from other procedures for a given time point. Both EGD and any
other procedures indicated for a study visit must be completed
within the window for that study visit. For Screening, the EGD must
be completed after the ICF is signed and .gtoreq.2 weeks before the
date of expected randomization. .sup.i During the EGD, the
endoscopist will complete the EREFs and ~3 biopsies will be
obtained from both the proximal and the distal esophagus (total of
5-6 biopsies). The pathologist will assess histology. The subject
will be treated with study drug through completion of the EGD
associated with the Week 52 visit. .sup.j If the subject is
discontinued from the study due to lack of efficacy or other
reasons, the Investigator may perform an EGD, if clinically
indicated. .sup.k A 250 .mu.g ACTH simulation test will be
performed (at an unscheduled visit) to assess for HPA axis
suppression of potential clinical concern as follows: 1) Any time a
subject has a morning serum cortisol level .ltoreq.5 .mu.g/dL (138
nmol/L) (confirmed by 2 blood draws) 2) Any time a subject reports
symptoms of hypercorticism (Appendix 6). .sup.l Subjects who
discontinue from the study due to evidence of HPA axis suppression
will undergo a 250 .mu.g ACTH stimulation test at the Early
Termination Visit. .sup.m For the Early Termination Visit, the
Investigator should record any occurrence of AEs (14 .+-. 5 days
after discontinuation). Subjects discontinued for HPA issues should
be followed until resolution. .sup.n Only if visit is related to
EoE change in symptoms.
[0552] Screening
[0553] The Screening Period is 4 weeks (28 days). Along with the
reports confirming the subject's primary diagnosis of EoE, the
Investigator will assess eligibility criteria (see Section 4.2.1
and Section 4.2.2) of the subject based on Screening results. The
Global EoE score must be >3 for the subject to continue in the
study.
[0554] The EGD procedures to determine eligibility (see Inclusion
Criterion #7: have evidence of EoE, as defined by .gtoreq.15 PEAK
eosinophils/HPF. In order to ensure that a diagnosis can be made,
at least 5-6 biopsies should be taken including both proximal and
distal specimens [-3 each]) will be completed during the Screening
Period and the biopsies must be received by the central pathologist
by the times noted in this inclusion criterion. EGD must be
performed prior to Visit 2 (4-week Baseline Symptom
Assessment).
[0555] ACTH stimulation test must also be performed prior to Visit
2 (4-week Baseline Symptom Assessment).
[0556] With Medical Monitor approval, a subject may be rescreened
once if the previous reason for screen failure is no longer present
or the subject withdrew due to personal or family reasons that have
since resolved. If a subject is rescreened, a new informed consent
form (ICF) will be signed and assigned a new number. All tests and
assessments must be repeated.
[0557] 4-Week Baseline Symptom Assessment (Placebo Run-In)
[0558] To enter this phase, subjects must: [0559] Meet all
inclusion criteria that are possible to assess prior to the 4-week
Baseline Symptom Assessment including the Global EoE score>3
(Inclusion Criterion #5; EoE score must remain >3 at each of
Visits 1, 2 and 3 before randomization, or the subject will be
considered a screen failure) except those to be assessed during the
4-week Baseline Symptom Assessment: Inclusion Criterion #7:
evidence of EOE as defined by .gtoreq.15 PEAK eosinophils/HPF;
Inclusion Criterion #8: in the daily diary, report episodes of
dysphagia.gtoreq.3 days per 7 days during the last 14 days of the
4-week Baseline Symptom Assessment; Inclusion Criterion #9:
completion of the daily diary on at least 5 out of each 7 days
during the last 14 days of the Baseline Symptom Assessment; [0560]
Meet no exclusion criteria that will be assessed prior to the
4-week Baseline Symptom Assessment (i.e., all except Exclusion
Criteria #23: a serum cortisol level<18 .mu.g/dL (497 nmol/L) at
60 minutes with adrenocorticotropic hormone [ACTH] stimulation test
using 250 .mu.g cosyntropin [i.e., a positive result on the ACTH
stimulation test]).
[0561] The subject will complete a site visit at the beginning of
the 4-week Baseline Symptom Assessment to complete procedures and
assessments noted in Table 4-1.
[0562] During the 4-week Baseline Symptom Assessment, baseline
symptom severity will be determined and the ability of the subject
to be compliant with diary entries will be assessed. Pathology for
EGD biopsies may also be assessed (or earlier if possible).
[0563] Randomization
[0564] Confirmation of Eligibility:
[0565] To be eligible for randomization, subjects must satisfy all
inclusion/exclusion criteria, including the following inclusion
criteria that are expected to be confirmed during the 4-week
Baseline Symptom Assessment: Inclusion Criterion #7: evidence of
EOE as defined by .gtoreq.15 PEAK eosinophils/HPF; Inclusion
Criterion #8: in the daily diary, report episodes of
dysphagia.gtoreq.3 days per 7 days during the last 14 days of the
4-week Baseline Symptom Assessment; Inclusion Criterion #9:
completion of the daily diary on at least 5 out of each 7 days
during the last 14 days of the Baseline Symptom Assessment and
Exclusion Criteria #23: a serum cortisol level<18 .mu.g/dL (497
nmol/L) at 60 minutes with adrenocorticotropic hormone (ACTH)
stimulation test using 250 .mu.g cosyntropin (i.e., a positive
result on the ACTH stimulation test).
[0566] If the Investigator confirms eligibility criteria are met,
he or she will randomize the subject using the Interactive Web
Response System (IWRS). The IWRS will confirm the eligibility of
the subject pertaining to histology (i.e., confirm histological
evidence of the EoE diagnosis as per Inclusion Criterion #7:
evidence of EOE as defined by .gtoreq.15 PEAK eosinophils/HPF), and
provide the randomization number to the Investigator and the
Sponsor.
[0567] Randomization Scheme:
[0568] A total of 100 adult subjects will be randomized to 1 of 4
doses of APT-1011 (1.5 mg HS, 1.5 mg BID, 3 mg HS, and 3 mg BID) or
placebo. Subjects in the HS treatment groups will receive placebo
30 minutes after breakfast in order to maintain the blind.
[0569] Randomization will occur in a double-blind manner using an
integrated IWRS, and will be stratified by the presence or absence
of a history of or current esophageal stricture at Screening and
history of a prior positive steroid response to any corticosteroid
treatment previously received to treat the subject's EoE captured
with demography. Randomization for subjects in Part 1 will be
stratified by use, such that a comparable percentage of subjects
during the study will be allocated to each of the 5 dosing
groups.
[0570] Treatment
[0571] FIG. 5 provides an overview of the treatment each subject
will receive is determined throughout FLUTE (based on responder
status). Symptom improvement or deterioration will be assessed on
an ongoing basis.
[0572] Induction (Day 1 to Week 14)
[0573] During Part 1, subjects will receive their randomized
treatment for 14 weeks.
[0574] At Week 12, the subjects will undergo a response assessment,
including EGD to assess endoscopic and histologic status. The
process overview in Section 6.2 will be followed to determine
responder status (as defined in Section 4.1.1) and inform the site
thereof. Symptoms will also be assessed. The 14 days prior to Week
12 will be compared to the 14 days prior to Randomization.
[0575] Histologic responders and non-responders (at Week 12) will
enter Part 2 (see Section 4.1.6.2).
[0576] Maintenance (Week 14 to Week 52)
[0577] In Part 2, all subjects classified as histologic responders
at Week 12 will continue to be treated according to the dosing
group to which they were randomized for Part 1. Subjects may
continue on this dose for up to 9 months after the completion of
Part 1.
[0578] Subjects who are histologic non-responders (see Section
4.1.1) at Week 12 will receive single-blind 3 mg BID in Part 2.
[0579] At Week 26, subjects will undergo an EGD with biopsy, to
assess histologic response. The process overview in Section 6.2
will be followed to determine responder status (as defined in
Section 4.1.1) and inform the site thereof. Symptoms will also be
assessed. All subjects classified as histologic responders will
continue to be treated according to the dosing group to which they
were randomized for Part 1 up to Week 52. The 14 days prior to Week
26 will be compared to the 14 days prior to Randomization.
[0580] Subjects who are histologic non-responders (see Section
4.1.1) at Week 26 will stop treatment at Week 28 and enter the
2-week follow-up period and exit the study.
[0581] Subjects who complete the study at Week 52 will undergo a
response assessment, including EGD to assess endoscopic and
histologic status. The process overview in Section 6.2 will be
followed to determine responder status (as defined in Section
4.1.1) and inform the site thereof. Symptoms will also be assessed.
The subject will be treated with study drug through completion of
the EGD associated with the Week 52 visit. The 14 days prior to
Week 52 will be compared to the 14 days prior to Randomization.
[0582] Subjects will complete a Follow-up Visit 2 weeks after the
final dose of study drug (see Section 4.1.8).
[0583] Efficacy, Safety, and Pharmacokinetic Assessments
[0584] Baseline and demographic data to be collected include age,
gender, weight, race (Caucasian, Black, Asian, Native American, or
other), ethnicity (Hispanic, Non-Hispanic, or other), and smoking
status.
[0585] Efficacy and Patient-Reported Outcome Assessments
[0586] Esophagogastroduodenoscopy: For the purposes of the current
study, it is expected that the esophagus will be the focus of EGD
procedures.
[0587] Whenever possible, the same endoscopist should be used for
all EGDs performed for the study.
[0588] Multiple Esophageal Biopsies
[0589] A minimum of 3 biopsies will be obtained from both the
proximal and the distal esophagus (total of .gtoreq.6 biopsies)
during the EGD. Care should be taken to obtain biopsies that are of
sufficient size and are opaque. Additional attempts should be made
if suboptimal biopsies are taken. It is suggested that biopsies be
obtained 1 at a time to achieve optimal results.
[0590] All biopsies should be stored at room temperature.
[0591] Eosinophilic Esophagitis Histology
[0592] A central pathologist will evaluate all esophageal biopsies
and count the peak number of eosinophils/HPF. From a histological
perspective, the eligibility requirements are described in
Inclusion Criterion (e.g. have evidence of EoE, as defined by
.gtoreq.15 PEAK eosinophils/HPF with at least 5-6 biopsies
including both proximal and distal specimens [3 each]).
[0593] Eosinophilic Esophagitis Endoscopic Reference Score
[0594] The endoscopist will record the observed Eosinophilic
Esophagitis Endoscopic Reference Score (EREFs)27 that assesses
edema, furrowing, exudates, rings, strictures, several
miscellaneous features, and physician assessment of overall disease
activity (absent; mild; moderate; severe) at each EGD. The EREFs
has been shown to be a reliable diagnostic tool to both diagnose
EoE and to assess the response to treatment.
[0595] The endoscopist will complete a worksheet for the EREFs, and
data will be transferred to the appropriate eCRF by the site
clinical staff/study coordinator. The worksheet should be retained
at the site as a source document.
[0596] Daily Diary
[0597] A daily diary will be completed by the subject to assess the
presence of dysphagia and questions related to its severity and
associated pain. The diary will be completed by the subject daily
throughout the study.
[0598] These data will be self-reported electronically by the
subject, transferred automatically to the electronic
patient-reported outcome (ePRO) vendor, and transmitted thereafter
to the clinical database.
[0599] Global Eosinophilic Esophagitis Symptom Score
[0600] For the Global EoE Symptom Score, the subject will respond
to the following:
[0601] On a scale from 0 to 10 (0 representing no symptoms and 10
representing most severe symptoms), how severe were your
eosinophilic esophagitis symptoms over the past 7 days?
[0602] These data will be self-reported electronically by the
subject, transferred automatically to the ePRO vendor, and
transmitted thereafter to the clinical database.
[0603] 7-Day Recall Eosinophilic Esophagitis Symptom Assessment
Index
[0604] Symptoms will be assessed using the 7-day recall EEsAI
questionnaire periodically and both total and subscores will be
calculated. The subscores will include symptoms such as dysphagia,
food avoidance and modification, and painful swallowing
(odynophagia).
[0605] Additional questions used as anchors for the 7-day recall
EEsAI score will also be assessed. These data will be self-reported
on paper by the subject and transmitted thereafter to the clinical
database by the site.
[0606] Subject Assessment of Symptoms
[0607] The following Patient Global Impression of Change (PGIC)
questions will be asked to examine the subject's assessment of
symptoms:
[0608] Compared with the beginning of the study, before you started
the treatment, your EoE symptoms today are: Much worse; Moderately
worse; A little worse; Stayed the same; A little improved;
Moderately improved; Much improved. Please think of all your
symptoms due to EoE and make an overall statement by choosing 1 of
the options above.
[0609] Compared with the beginning of the study, before you started
the treatment, your difficulty with food or pills going down today
is: Much worse; Moderately worse; A little worse; Stayed the same;
A little improved; Moderately improved; Much improved. Please think
of your difficulty with food or pills going down and make an
overall statement by choosing 1 of the options above.
[0610] These data will be self-reported electronically by the
subject, transferred automatically to the ePRO vendor, and
transmitted thereafter to the clinical database.
[0611] Subject Assessment of Symptom Severity
[0612] The following questions about patient global impression of
symptom severity (PGIS) will be asked to examine the subject's
assessment of severity:
[0613] Please choose the response that best describes the severity
of your EoE symptoms over the past week (check one response): None;
Mild; Moderate; Severe; Very Severe. Please think of all your
symptoms due to EoE and make an overall statement of their severity
by choosing 1 of the options above.
[0614] Please choose the response that best describes the severity
of your difficulty with food or pills going down over the past week
(check one response): None; Mild; Moderate; Severe; Very Severe.
Please think of your difficulty with food or pills going down and
make an overall statement of its severity by choosing 1 of the
options above.
[0615] These data will be self-reported electronically by the
subject, transferred automatically to the ePRO vendor, and
transmitted thereafter to the clinical database.
[0616] Adult Eosinophilic Esophagitis Quality of Life
Questionnaire
[0617] The Adult Eosinophilic Esophagitis Quality of Life
Questionnaire (EoE-QOL-A)29 is an assessment that may be
administered directly to subjects to determine how EoE impacts
their quality of life. It includes 30 questions on a 5-point Likert
scale; questions represent 5 factors: eating/diet impact, social
impact, emotional impact, disease anxiety, and choking anxiety and
has been validated to correlate with established health related
quality of life measures. Higher scores indicate better quality of
life.
[0618] These data will be self-reported electronically by the
subject, transferred automatically to the ePRO vendor, and
transmitted thereafter to the clinical database.
[0619] Efficacy Endpoints
[0620] Primary Efficacy Endpoint: The following primary efficacy
endpoint will be evaluated at Week 12 to assess EoE response:
[0621] Histology: percentage of subjects with a PEAK
eosinophils/HPF number.ltoreq.6 after assessing at least 5-6
biopsies from the proximal and distal esophagus where the HPF area
is 0.235 square millimeters (40 magnification lens with a 22 mm
ocular).
[0622] Secondary Efficacy Endpoints
[0623] The following secondary efficacy endpoints will be
evaluated: EoE sustained response: percentage of subjects who met
the primary endpoint (histology) at Week 12 and maintained the
primary endpoint at Week 26 and Week 52; Change from baseline EREFs
at Week 12, Week 26, and Week 52; Endoscopic changes will as per
the EREFs evaluation based on the following endoscopic features:
edema, rings, exudates, furrows, stricture, and several
miscellaneous features (crepe paper esophagus, narrow caliber
esophagus, and esophageal erosions); Percentage of subjects with a
peak eosinophils/HPF number<1 and <15 at Week 12, Week 26,
and Week 52; Change from baseline Global EoE Symptom Score, which
will be assessed for the 7 day period prior to the following study
visits: Week 12, Week 26, and Week 52; Dysphagia: Change in the
number of dysphagia episodes at baseline (14-day period prior to
randomization) compared with the 14-day period prior to the time
point of interest (Week 12, Week 26 and Week 52); Change from
baseline 7-day recall EEsAI total score at Week 12, Week 26, and
Week 52; Change from baseline 7-day recall EEsAI sub scores at Week
12, Week 26, and Week 52; Percentage of subjects with mean 7-day
recall EEsAI total score<20 at Week 12, Week 26, and Week 52;
Change from baseline PGIS assessed prior to randomization at Weeks
4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52; PGIC at Weeks 4, 8,
12, 14, 18, 22, 26, 28, 36, 44, and 52. Assessment of treatment
failure and relapse, including: Percentage of non-responders by
dose at before Week 14, between Week 14 and 28, and between Week 28
and 52; Percentage of subjects requiring emergency endoscopic food
dis-impaction by dose at Week 12, Week 26, and Week 52; Percentage
of subjects requiring esophageal dilation by dosing group and part
of the study.
[0624] Exploratory Efficacy Endpoints
[0625] The following exploratory efficacy endpoints will be
evaluated:
[0626] Dysphagia: Change in the number of dysphagia episodes at
baseline (14-day period prior to randomization) compared with the
14 day period prior to the time point of interest (Weeks 12, 26 and
52). Change from baseline in dysphagia-free days during the 14 day
period prior to the following study visits: Week 4, Week 8. Week
12, Week 14, Week 18, Week 22, Week 26, Week 28, Week 36, Week 44,
and Week 52; EoE sustained response (dysphagia): percentage of all
subjects who met the dysphagia secondary endpoint at Week 12 and
maintained a dysphagia-related response at Week 26 and Week 52;
Evaluation of PK/PD (cortisol) and exposure-response (efficacy)
relationships; Subject's assessment of symptoms compared with the
previous visit at Week 4, Week 8, Week 12, Week 14, Week 18, Week
22, Week 26, Week 28, Week 36, Week 44, Week 52, and the Early
Termination Visit (if applicable); Evaluation of HRQoL based on the
EoE-QoL-A at baseline, Week 12, Week 26, Week 52 for all subjects
by dose and subgroup; Subjects receiving single-blind (to subject)
treatment (Part 2) will be tabulated separately.
[0627] Percentage of subjects who were classified as histologic non
responders at Week 12 and have a peak eosinophils/HPF
number.ltoreq.6 at all biopsied esophageal locations at Week 26 and
Week 52;
[0628] Change from baseline dysphagia episodes during the 14 day
period prior to Week 26 and Week 52 for subjects who were
classified as non responders at Week 12;
[0629] Percentage of subjects who were classified as histologic
non-responders at Week 12 and meet the primary endpoint at Week 26
and Week 52.
[0630] A scoring structure, and various endpoints will be derived
from the DEDI. The populations to be analyzed will be detailed in
the Statistical Analysis Plan (SAP). Subgroup analyses may be
performed based upon age, gender, PPI status, and other study
subpopulations.
Example 5
A Phase 1 Study to Assess the Pharmacokinetics, Safety and
Tolerability of a Single Dose of Fluticasone Propionate
Administered Under Fed or Fasted Conditions or at Bedtime in a
Randomized Three-Way Crossover Design
[0631] Primary Objective: The plasma pharmacokinetics (PK) of
Fluticasone propionate (FP) after administration under Fed or
Fasted conditions in the morning were evaluated.
[0632] Secondary Objectives: The plasma (PK) of FP after
administration at bedtime (HS) were evaluated. The
safety/tolerability of the administration of a single dose of FP in
male and female healthy adult volunteers when administered under
fasted, fed, or HS conditions were evaluated.
[0633] Primary Endpoint: FP Cmax, AUClast, and Tmax after
administration of FP under fed and fasted conditions for morning
dose administration were assessed.
[0634] Secondary Endpoints: FP AUC0-24, AUCinf, AUCext, .lamda.z,
t1/2, CL/F, and Vz/F after administration of FP under fed and
fasted conditions were assessed. FP AUC0-24, AUCinf, AUCext,
.lamda.z, t1/2, CL/F, and Vz/F after administration of FP under HS
administration were assessed. Additional PK parameters were
calculated as needed to adequately characterize the
pharmacokinetics of FP following morning (fasted and fed) or HS
dosing. Incidence of treatment-emergent Adverse Events (AEs), AEs
leading to withdrawal, and Serious Adverse Events (SAEs) grouped by
system organ class (SOC) were calculated as needed. Clinically
significant abnormal values for clinical laboratory, AM cortisol
(.ltoreq.138 nmol/L), urinalysis, vital signs, and
electrocardiogram (ECG) findings were measured as needed.
[0635] Study Design and Duration: This study was a randomized,
single-dose, three-way crossover study evaluating the effects of 6
mg FP administered in the morning (AM) under fed or fasted
conditions or before bedtime (HS), 4 hours after the evening meal.
A total of 24 subjects were enrolled and randomized to one of six
sequences to receive each of the three treatments over the three
periods with a 7-day washout between doses. The three treatments
included administration of 6 mg of FP (2.times.3 mg orally
disintegrating tablets) under the following conditions:
[0636] A. Fasted: 6.0 mg of APT-1011 (e.g. FP) (Two 3 mg oral
dissolving tablets) after an overnight fast (at least 10 hours),
with fast continuing 4 hours post-dose
[0637] B. Fed: 6.0 mg APT-1011 (Two 3 mg oral dissolving tablets)
30 minutes after the start of a high fat breakfast.
[0638] C. HS: 6.0 mg APT-1011 (Two 3 mg oral dissolving tablets) at
bedtime approximately 4 hours after the standard evening meal.
[0639] Subjects on the "Fasted" treatment (Treatment A), were
administered 6.0 mg of APT-1011 after an overnight fast of at least
10 hours. These subjects continued fasting for at least 4 hours
post-dose.
[0640] Subjects on the "Fed" treatment (Treatment B) began a
high-fat breakfast 30 minutes after an overnight fast of at least
10 hours. Subjects were administered 6.0 mg of APT-1011, 30 minutes
after initiation of the high-fat breakfast.
[0641] Subjects on the "HS" treatment (Treatment C) consumed a
standard meal approximately 4 hours prior to bedtime. Subjects were
administered 6.0 mg of ATP-1011 immediately prior to bedtime (4
hours following the standard meal). Subjects were administered the
dose of FP while laying down.
[0642] Randomization (Day 1): Subjects were randomized to one of
six sequences (See Table 15) to receive a single dose of each
treatment over three periods, with a 7-day washout between
doses.
TABLE-US-00017 TABLE 15 Sequence N Period 1 Period 2 Period 3 1 4 A
B C 2 4 B C A 3 4 C A B 4 4 A C B 5 4 C B A 6 4 B A C
[0643] Treatment Periods: For each period, subjects were
in-patients for 5 days (Days 0-4, Days 7-11, Days 14-18) with PK
samples collected over 72 hours following each dose. Subjects were
checked-in to the CRU the evening prior to each dosing (Day 0, 7,
and 14) and received treatment according to the sequence on which
they were randomized on Day 1. APT-1011 was administered as single
doses on Days 1, 8, and 15. All meals (AM and 4 hours prior to
bedtime) were standardized for all subjects and all periods.
Subjects completed these meals within 30 minutes. Serial plasma
samples for FP PK were collected pre-dose and at 0.5, 1, 2, 3, 4,
5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 60, and 72 hours
following each dose. Subjects dosed HS followed the same PK
schedule with PK samples scheduled relative to the bedtime
dose.
[0644] Subjects were discharged from the CRU following PK sampling
and safety assessments for each treatment period (Day 4, Day 11,
Day 18).
[0645] Follow-Up (Day 25.+-.2 days): After Period 3, subjects
returned to the clinic within 7 days (.+-.2 days) of discharge from
the clinical research unit for follow-up criteria.
[0646] Inclusion Criteria: Female and male subjects were eligible
for inclusion in this study only if all of the following criteria
applied:
[0647] 1. Subject was healthy based on evaluation of medical
history, physical examination, clinical laboratory tests and
12-lead ECG. Subjects with history of mild acute or chronic medical
illness or laboratory parameters outside the normal reference range
were included only if the Investigator agree that the finding is
unlikely to introduce additional risk and will not interfere with
study procedures.
[0648] 2. An Institutional Review Board (IRB)-approved informed
consent was signed and dated prior to any study-related
activities.
[0649] 3. Subject was between the ages of 18 and 55 years,
inclusive.
[0650] 4. Female subject of child-bearing potential had a negative
urine pregnancy test or had surgical sterilization, had been
diagnosed infertile, or was post-menopausal prior to randomization.
Females of childbearing potential must have been willing to
practice adequate birth control from at least 28 days prior to the
first administration of the study drug, during the study and for at
least 30 days after the last dose of the study drug to be
eligible.
[0651] 5. Male subjects who engaged in sexual activity must have
agreed to use a condom and spermicide during the study.
[0652] 6. Body mass index between 19 and 30 kg/m2
(weight/[height]2), inclusive.
[0653] 7. Normal (or abnormal but clinically insignificant)
laboratory values present at Screening.
[0654] 8. Subject had the ability to understand the requirements of
the study and a willingness to comply with all study
procedures.
[0655] 9. Subject had not consumed and agrees to abstain from
taking any dietary supplements, herbal therapies, or
non-prescription drugs (except as authorized by the Investigator)
for 7 days prior to 1st CRU admission (for Period 1) through
Follow-Up.
[0656] 10. Subject had not consumed and agreed to abstain from
taking any prescription drugs (except as authorized by the
Investigator) for 28 days prior to 1st CRU admission (for Period 1)
through Follow-Up.
[0657] 11. Subject had not consumed alcohol-containing beverages
for 3 days prior to 1st CRU admission (for Period 1) through
Follow-Up.
[0658] 12. Subject agreed to abstain from consuming caffeine- or
chocolate-containing products from CRU admission to discharge of
each period.
[0659] 13. Subject agreed to abstain from strenuous physical
activity from signing of the informed consent form to the final
follow up visit.
[0660] Key Exclusion Criteria: A subject was not eligible for
inclusion in this study if any of the following criteria
applied:
[0661] 1. Had a history of asthma requiring occasional use of
inhaled corticosteroids.
[0662] 2. Had a recent (within 30 days) history of corticosteroid
use, including but not limited to intranasal, inhaled, dermal,
ophthalmological, or intra-articular routes of administration.
[0663] 3. Had a history of illicit drug abuse in the past year or
current evidence of such abuse in the opinion of the Investigator
based on criteria established in DSM-IV.
[0664] 4. Used tobacco products within 3 months before Day 1 of
this study
[0665] 5. Had positive findings on urine drug screen or positive
cotinine test.
[0666] 6. Had a history of regular alcohol consumption within 6
months of the study defined as an average weekly intake of >14
drinks/week for men or >10 drinks/week for women. One drink is
equivalent to 12 g alcohol--5 ounces (150 mL) of wine or 12 ounces
(360 mL) of beer or 1.5 ounces (45 mL) of 80-proof distilled
spirits. An ethanol breath test was administered twice and used to
document lack of ethanol use at Screening and Day 0 and was
exclusionary if positive.
[0667] 7. Was positive (i.e., evidence of current infection) for
human immunodeficiency virus (HIV), hepatitis B and/or hepatitis C
on Screening assessments.
[0668] 8. Female subject who was pregnant or lactating.
[0669] 9. Male subject whose partner was known to be pregnant.
[0670] 10. Had an acute illness within 28 days of first CRU
admission.
[0671] 11. Had any history of tuberculosis and/or prophylaxis for
tuberculosis
[0672] 12. Had donated plasma in the previous 7 days before Day 1
of this study
[0673] 13. Had donated 500 mL or more of blood (Canadian Blood
Services, Hema-Quebec, clinical studies, etc.) in the previous 56
days before day 1 of this study
[0674] 14. Had taken an inducer or inhibitor of Cytochrome P450 3A
(CYP3A) enzymes within 28 days of the first dose.
[0675] 15. Had taken grapefruit juice within 7 days of the first
dose.
[0676] 16. Had participated in an investigational drug study within
the 30 days prior to first CRU admission or subject has had less
than 5 half-lives washout of any prior investigational drug prior
to first CRU admission (whichever is longer).
[0677] 17. Had any physical, mental, or social condition, history
of illness or laboratory abnormality that, in the investigator's
judgment, might interfere with study procedures or the ability of
the subject to adhere to and complete the study.
[0678] 18. Clinical laboratory tests indicated the presence of
clinically relevant renal or hepatic insufficiency in the opinion
of the Investigator.
[0679] 19. Had a history of any gastrointestinal, renal, or hepatic
conditions that could impact absorption or metabolism/elimination
of the investigational compound.
[0680] 20. Could not or would not consume contents of standard high
fat meal due to dietary preferences or restrictions
[0681] 21. Had a history of sensitivity to the study medication
(Fluticasone propionate or other corticosteroids) or components
thereof, or a history of drug or other allergy (such as eggs) that,
in the opinion of the Investigator, contraindicates
participation.
Analysis
[0682] Pharmacokinetics: Derived plasma-PK-parameter descriptive
statistics were summarized by treatment. To assess the PK of FP in
the fasted (reference) and fed (test) states, an analysis of
variance (ANOVA) with fixed effect term for treatment (fed or
fasted status), fixed effect term for Period (1, 2, 3), fixed
effect term for sequence (ABC, BCA, CAB, CBA, ACB, BAC) and subject
within sequence as a random effect was performed on log-transformed
AUClast, AUC0-24, AUCinf, and Cmax. Relative bioavailability was
estimated by exponentiating the difference in least-squares means
(test-reference) and the associated 90% confidence interval (CI).
Additional comparisons were assessed between HS dosing and Fed and
Fasted administration.
TABLE-US-00018 TABLE 16 PK Parameter Description Cmax Maximum
observed plasma concentration, obtained directly from the observed
concentration versus time data Tmax Time of maximum concentration
(h), obtained directly from the observed concentration versus time
data AUClast Area under the plasma concentration-time curve from
time 0 to time of last measurable plasma concentration AUCinf Area
under the plasma concentration-time curve from 0-time extrapolated
to infinity AUCext The percentage of the AUC that is extrapolated
beyond the last measurable concentration AUC0-24 Area under the
plasma concentration-time curve from time 0 to 24 hours post-dose
.lamda.z Apparent plasma terminal-phase elimination rate constant
t1/2 Elimination half-life Vz/F Apparent volume of distribution,
terminal phase CL/F Apparent systemic clearance Additional PK
parameters may be calculated as necessary to adequately
characterize the PK profile of APT-1011.
[0683] FP concentrations were summarized using descriptive
statistics (including n, mean, SD, coefficient of variation (CV %),
median, minimum, and maximum) for each treatment.
[0684] The following PK parameters were estimated by
noncompartmental methods from plasma samples. Below limit of
quantitation concentrations were treated as zero for all PK
analyses. All deviations from the scheduled sampling time of 2
minutes or more were taken into consideration for evaluation of the
PK parameters. In the case where concentrations of FP could not be
determined due to clinical or bioanalytical reasons, these values
were set to missing for the pharmacokinetic analysis.
[0685] The trapezoidal rule was used to estimate the area under the
curve (linear trapezoidal linear interpolation) and the terminal
phase were estimated by maximizing the coefficient of determination
estimated from the log-linear regression model. However,
disposition parameters were not estimated for individual
concentration-time profiles where the terminal log-linear phase
cannot be reliably characterized.
[0686] If a pre-dose concentration of FP was detected, the
subject's data was included in the pharmacokinetic analysis without
adjustment, if the pre-dose concentration was equal to or less than
5% of the Cmax value of the corresponding period. If the pre-dose
concentration was greater than 5% of the Cmax value, the subject
was dropped from all pharmacokinetic evaluations.
[0687] Given the low expected systemic bioavailability of FP
(.about.1%) it was possible that some PK parameters were not
reliably calculated due to low plasma FP concentrations (e.g.,
concentrations that are BLQ). Whenever possible, PK parameters were
calculated.
[0688] Derived plasma-PK-parameter descriptive statistics were
tabulated by treatment. Descriptive statistics for PK parameters
included the arithmetic and geometric mean, CV %, SD of the
arithmetic mean, median, minimum, maximum, and n, as
appropriate.
[0689] To assess the PK of FP, an analysis of variance (ANOVA) with
fixed effect term for treatment, fixed effect term for Period (1,
2, 3), fixed effect term for sequence (ABC, BCA, CAB, CBA, ACB,
BAC) and subject within sequence as a random effect was performed
on loge-transformed AUClast, AUC0-24, AUCinf, and Cmax. Relative
bioavailability was estimated by exponentiating the difference in
least-squares means (test-reference) and the associated 90%
confidence interval (CI).
[0690] Food Effect Analysis: The 90% confidence interval for the
exponential of the difference in LSmeans between B (fed) and A
(fasted) was calculated for the ln-transformed parameters (Test to
Reference ratio of geometric LSmeans).
[0691] HS vs Fasted Analysis: The 90% confidence interval for the
exponential of the difference in LSmeans between C (HS) and A
(fasted) was calculated for the ln-transformed parameters (Test to
Reference ratio of geometric LSmeans).
[0692] HS vs Fed Analysis: The 90% confidence interval for the
exponential of the difference in LSmeans between C (HS) and B (fed)
was calculated for the ln-transformed parameters (Test to Reference
ratio of geometric LSmeans).
[0693] Statistical analyses were generated using SAS.RTM. (version
9).
[0694] Sample Size: Using an estimate of 54% as determined by using
an overall estimate of variability of 60%, and assuming the
intra-subject variability is estimated to be about 10% less. Then
for a two-sided 90% confidence interval for a normal mean, a sample
size of 24 yields a half-width of at most 0.25 with a conditional
probability of 0.98.
[0695] Rationale for the Current Study: The approach to treatment
of EoE with oral administration of APT-1011 was to provide topical
esophageal exposure of FP while minimizing systemic exposure and
associated systemic pharmacologic effects. Previous studies
demonstrated a significantly decreased exposure when the drug was
administered after breakfast; for example administration of
APT-1011 after a high-fat meal significantly decreased systemic
exposure compared to administration in the fasted state.
Additionally, administration of APT-1011 as 6 mg QD resulted in
approximately the same dose-normalized, steady-state systemic
exposure (AUCtau/Dose) as a 3 mg BID regimen. However, the data
were highly variable, with the between-subject variability (CV %
Geo mean) of FP AUC(0-24 h) following single-dose
administration>55%.
[0696] The previous PK study demonstrated significantly lower drug
levels with QD administration compared to the same dose divided and
administered BID. The reason for this is unclear.
[0697] The current study assessed the effect of food on APT-1011
pharmacokinetics. APT-1011 exposures were compared when a morning
dose is administered in either the fasted state or 30 minutes after
initiating a high fat meal. Additionally, the current study
characterized the pharmacokinetics of APT-1001 when administered as
a single dose at bedtime (HS).
[0698] This study provides guidance on administration of the drug
relative to food and time of day of dosing.
Treatments
[0699] Treatments Administered: Study drug was administered by
qualified study staff only in accordance with the procedures
described in this protocol. All doses of APT-1011 were be 6 mg,
administered as two 3 mg orally disintegrating tablets. All
subjects were instructed to take the study drug tablet orally
without water or other liquids. Subjects placed both study drug
tablets on the upper surface of the tongue and gently massaged the
study drug tablet between the tongue and the roof of the mouth
until it disintegrated sufficiently to allow normal swallowing with
saliva over the course of one to five minutes. Subjects were
instructed not to chew or crush the study drug tablet and not to
swallow any portion of the intact study-drug tablet before it has
fully dissolved. Subjects did not drink for at least 1 hour after
dosing and did not eat for at least 4 hours after dosing.
[0700] Due to the low bioavailability of APT-1011, a dose of 6 mg
was selected for this study. Based on previous data, FP
concentrations following a 6 mg dose provide detectable plasma
levels of FP at most time points using the proposed bioanalytical
assay.
Selection and Timing of Dose for Each Subject
[0701] All doses of APT-1011 were 6 mg, administered as two 3 mg
orally disintegrating tablets simultaneously. For the Fasted
treatment (Treatment A), subjects were dosed following an overnight
fast of at least 10 hours. A standard meal was provided 4 hours
after dosing. For the Fed treatment (Treatment B), subjects started
a high-fat, high-calorie meal after an overnight fast of at least
10 hours, and 30 minutes prior to dosing. The meal was consumed
within 30 minutes or less.
[0702] For the HS treatment, subjects were administered APT-1011
approximately 4 hours after a standard meal with no snacks after
dinner. After administering the drug, the subject immediately laid
down and did not get up for at least 1 hour.
Pharmacokinetics
[0703] Collecting, Processing, and Shipping Pharmacokinetic
Samples: Blood samples (6 mL per sample) were drawn and processed
for plasma. The yield of plasma (.about.3 mL) was subdivided into 2
samples (.about.1.5 mL each). One of these samples was and the
other was stored at .ltoreq.-20.degree. C. at the CRU until
completion of the study.
[0704] Bioanalytical method for Fluticasone propionate
quantitation: Fluticasone propionate concentrations were measured
using an LC/MS/MS method validated in accordance with US regulatory
guidelines. The method was developed starting from 1 mL of plasma
collected from blood containing potassium oxalate/sodium fluoride
as anticoagulant/preservative. The method is linear over the
nominal concentration range of 1.00 to 500 pg/mL. The limit of
quantitation is 1 pg/mL20. Samples from all subjects were
analyzed.
Assessment of Safety
[0705] Safety assessments included the following: Adverse events,
both reported and observed, regardless of severity or seriousness;
Body weight; Vital sign measurements (blood pressure, heart rate,
temperature, respiration rate); ECG findings; Clinical laboratory
tests and urinalysis; Physical examination findings.
[0706] Clinical Laboratory Tests: The clinical laboratories tests
were as follows. Hematology, blood chemistry, coagulation, and
urinalysis was performed at Screening, on Day 0 (CRU admission), at
12 hours postdose of each period, before CRU discharge of each
period, and at the Follow-up visit.
[0707] Hematology: Red blood cell (RBC) count, hemoglobin,
hematocrit, mean corpuscular volume (MCV), mean corpuscular
hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC),
white blood cell (WBC) count and differential, absolute neutrophil
count (ANC), and platelet count.
[0708] Blood Chemistry/Coagulation: Alanine aminotransferase (ALT;
SGPT) and Aspartate aminotransferase (AST; SGOT), total bilirubin,
direct bilirubin, blood urea nitrogen (BUN), creatinine, alkaline
phosphatase, sodium, potassium, calcium, chloride, glucose, and
albumin
[0709] Urine pregnancy test: Urine .beta.-hCG test in women at
screening, check-in for each period (i.e. Day 0, Day 7, Day 14) and
Follow-up.
[0710] Follicle Stimulating Hormone (FSH)/Luteinizing Hormone (LH)
test: This test was performed in all menopausal women including
surgical menopause.
[0711] Urinalysis: Urinalysis included macroscopic analysis and
microscopic analysis only when indicated by dipstick. Analyses
included: Color, Turbidity, Specific Gravity, pH, Glucose, Protein,
Ketones, Urobilinogen, Bilirubin, Blood, Nitrite, and Leukocyte
Esterase.
[0712] Serology: HIV Ag/Ab Combo, Hepatitis B (HBsAg (B) (hepatitis
B)) and Hepatitis C (HCV (C)) (performed at Screening only).
[0713] Urine Drug Screen: Urine for a drug screening test was
collected from all subjects during the screening period and on Day
0, Day 7, and Day 14. The sample was tested for the presence of
cotinine, cocaine, tetrahydrocannabinol, barbiturates,
amphetamines, benzodiazepines, and opiates. Subjects with positive
urine drug screen test results for any of the above substances were
excluded from this study.
[0714] Ethanol Breath Test: Alcohol consumption was not permitted
within 3 days of first CRU admission through Follow-up. An ethanol
breath test was performed at Screening and at CRU admission of each
period (i.e., Day 0, Day 7 and Day 14). Subjects with positive
ethanol breath test results at Screening were not enrolled in the
study to avoid inadvertent enrollment of a subject with chronic
alcoholism. Subjects with positive ethanol breath test results on
Day 0 (CRU admission) were also excluded from further participation
in the study.
[0715] Adverse Events
[0716] A Serious Adverse Event (SAE) was defined as any untoward
medical occurrence that at any dose: Results in death; Is
life-threatening; Requires inpatient hospitalization or
prolongation of existing hospitalization excepting hospital
admissions due to administrative reasons (e.g., the subject has no
transportation home) or hospitalization for elective treatment of a
pre-existing condition that did not worsen during the study unless
a complication occurs during the hospitalization; Results in
permanent or significant disability/incapacity; or Results in
congenital anomaly/birth defect.
[0717] Results
[0718] FIGS. 6 and 7 show the mean plasma concentrations of
APT-1011 (Fluticasone Propionate) administration in fasted, fed,
and HS treatment regimens. FIGS. 8-10 show spaghetti plots of the
plasma concentrations of APT-1011 (Fluticasone Propionate)
administration in fasted (FIG. 8), fed (FIG. 9), and HS (FIG. 10)
conditions. Surprisingly, HS administration to a patient laying
down before sleep shows a sustained level of drug. Instead of a
sharp, quick peak as observed in fed and fasted administration, HS
administration in a prone position lead to a sustained
concentration of APT-1011 in the patient's blood. This may be due
to prolonged exposure to the distal esophagus. This long exposure
in the distal esophagus has the added advantage of also reducing
systemic exposure to APT-1011, which is expected to decrease
adverse side effects.
[0719] A total of 24 participants enrolled and 22 (92%) completed
the study. A summary of the PK parameters by test group is
presented in Table 18. AM dosing was associated with a higher rate
of absorption under fed compared to fasted conditions. Following a
high fat meal, there was a higher peak concentration (C.sub.max:
ratio [90% CI]=120.65% [99.84%-145.79%]), and a faster time to peak
concentration, as compared to the fasted state (T.sub.max: fed=5.00
h; fast=10.00 h). However, lower total exposure in the fed compared
to the fasted state (AUC.sub.last: ratio [90% CI]=76.97%
[67.64%-87.59%]) was observed. HS dosing was found to slow the rate
of absorption as compared to AM dosing conditions. Specifically,
the time to peak concentration with HS (T.sub.max=14 h) was longer
than with AM dosing (T.sub.max: fast=10 h, fed=5 h). HS dosing was
associated with higher overall exposure (AUC.sub.inf: ratio [90%
CI]=122.36% [107.02%-139.88%] and lower C.sub.max (C.sub.max: ratio
[90% CI]=67.79% [56.29%-81.64%]) as compared to the fed regimen. As
compared to the fasted regimen, HS dosing yielded lower overall
exposure (AUC.sub.inf: ratio [90% CI]=87.00% [75.24%-100.59%] and
lower C.sub.max (C.sub.max: ratio [90% CI]=81.78% [67.93%-98.47%]).
Across all dosing regimens, the C.sub.max of fluticasone with
APT-1011 ranged from 5.97-200 pg/mL.
[0720] No AEs of special interest (AESI), no serious adverse events
(SAE), and no deaths were reported for any of the subjects enrolled
in this study. No subject was withdrawn by the investigator for
safety reasons.
[0721] A total of 12 treatment-emergent adverse events (TEAEs) were
reported by 7 (29%) of the 24 subjects who participated in this
study. Of these events, 4 occurred after administration of
Treatment A, 1 after administration of Treatment B, and the other 7
after administration of Treatment C. All TEAEs were deemed mild in
severity. Most TEAEs were considered possibly related (92%) to
treatment.
[0722] The TEAEs reported in this study were experienced with a low
incidence, by 1 subject per treatment group (5% for Treatment A, 5%
for Treatment B, and 4% for Treatment C). These included: nausea,
chest discomfort, upper respiratory tract infection, and headache
for Treatment A, chest discomfort for Treatment B, and
constipation, oral herpes, dizziness, vessel puncture site bruise,
aspartate aminotransferase increased, nasal congestion, and hot
flush for Treatment C.
[0723] The incidence of TEAEs was of 9% for Treatment A, 5% for
Treatment B, and 22% for Treatment C. Drug-related TEAEs were
reported with a similar trend as the total TEAE incidence: 9% for
Treatment A, 5% for Treatment B, and 17% for Treatment C.
[0724] Generally, the abnormal clinical laboratory values were
marginally higher or lower than their reference ranges and were
mostly considered non-clinically significant by the investigator.
However, one subject showed an abnormal aspartate aminotransferase
result at poststudy visit, which was considered clinically
significant by the investigator and reported as a mild TEAE
(increased aspartate aminotransferase). The last treatment
administered to this subject was Treatment C. The event outcome was
unknown at the end of the study; the subject was lost to
follow-up.
[0725] Overall, the means of laboratory parameters, vital signs,
and ECGs for the different treatments were comparable. In addition,
the mean for all subjects at screening and post-study of evaluated
parameters were comparable.
[0726] Furthermore, there were no clinically significant
abnormalities in the vital signs and ECGs of the subjects in this
study.
[0727] Overall, the most common answers in the palatability
assessments were "Like, a little", and "Neither like not
dislike".
[0728] Conclusion
[0729] Oral APT-1011 was safe and well-tolerated when administered
under AM fasted, AM fed, or HS conditions to healthy subjects.
[0730] This phase 1 study demonstrated that systemic exposure of FP
is confirmed to be very low following oral APT-1011 administration
(total dose 6 mg) under fast, fed and at bedtime dosing. PK
sampling allowed for accurate estimation of the elimination
profile. Therefore, comparison of extent of systemic exposure over
24 hours, 72 hours and infinity was performed.
[0731] Peak values were comparable between morning-fast and HS
dosing, however maximal concentrations were reached more rapidly
when APT-1011 was administered with a high fat meal.
[0732] The interindividual variability (CV %) for C.sub.max was the
highest for the HS regimen followed by the morning-fast and fed
regimens. Based on the expected low bioavailability of this
formulation (expected minimum systemic exposure), this high level
of variability observed was expected.
[0733] The food effect and time of day effect are inversely
proportional to the peak exposure of FP when compared to the
morning-fast dosing. When compared to the morning-fast regimen,
maximum peak exposure was 20% higher for the morning-fed regimen
and 19% lower for the HS administration. A lower rate of absorption
is suggested when APT-1011 is given at bedtime, while a higher rate
of absorption is observed when given in the morning with a high fat
meal.
[0734] While there was faster absorption of APT-1011 under fed
conditions and slower absorption at bedtime, overall absorption of
fluticasone with this formulation is low (<200 pg/mL). Slower
absorption with HS dosing suggests a potential for longer dwell
times in the esophagus; the relationship of bedtime dosing with
histological efficacy in both the proximal and distal portions of
the esophagus will be explored in future studies of APT-1011 in
EoE.
[0735] Overall, a food effect was observed as C.sub.max and AUC
ratios and/or 90% CI were not all within the pre-defined standard
range of 80.00-125.00%.
[0736] Also, complete absence of time of day effect on
bioavailability of FP could not be established as lower bounds of
the 90% CI for C.sub.max and AUC.sub.inf were below the pre-defined
standard range of 80.00%.
[0737] The overall extent of systemic exposure over 72 hours
(AUC.sub.last) was about 24% lower for the fed dosing as compared
to a non-statistically significant decrease of 8% when given HS
when compared to the morning-fast administration.
[0738] The extrapolated extent of systemic exposure to infinity
(AUC.sub.inf) was lower for both regimens (fed; decrease of 29%,
and HS; decrease of 13%) when compared the morning-fast dosing.
[0739] Finally, HS regimen showed a higher decrease in exposure
(33% decreases in C.sub.max) when compared to the morning-fed
regimen than with the morning-fast regimen. Also, the extent of
exposure over 72 hours and extrapolated to infinity was around 20%
higher at bedtime vs morning-fed suggesting that bedtime
administration has a more sustained exposure with lower maximum
peaks over time.
[0740] Summaries of the pharmacokinetic parameters for the Fast,
Fed, and HS studies are provided in Tables 18-21.
TABLE-US-00019 TABLE 18 Summary of Plasma FP Pharmacokinetic
Parameters Treatment A Treatment B Treatment C (Test Fast) (Test
Fed) (Test HS) N = 22.sup.b,d N = 21.sup.e N = 23.sup.c,f Geometric
(Geometric Geometric (Geometric Geometric (Geometric PARAMETER Mean
C.V. %) Mean C.V. %) Mean C.V. %) C.sub.max (pg/mL) 31.1 (103.6)
34.2 (102.3) 23.8 (111.9) T.sub.max (hours).sup.a 10.00
(2.00-30.00) 5.00 (1.00-10.00) 14.00 (2.00-20.00) AUC.sub.last
775.049 (94.6) 548.933 (111.1) 669.695 (98.3) (pg h/mL)
AUC.sub.0-24 366.607 (115.8) 361.277 (105.5) 359.541 (100.5) (pg
h/mL) AUC.sub.inf 1044.308 (90.1) 587.890 (107.2) 726.451 (100.2)
(pg h/mL) AUC.sub.ext (%) 7.13 (77.9) 5.82 (51.5) 4.91 (47.5)
.lamda..sub.Z (hours.sup.-1) 0.0362 (32.5) 0.0370 (23.7) 0.0474
(21.2) t.sub.1/2 (hours) 19.14 (32.5) 18.72 (23.7) 14.61 (21.2)
CL/F (L/hour) 5745.43 (90.1) 10205.99 (107.2) 8259.33 (100.2)
V.sub.z/F (L) 158611.12 (99.9) 275613.92 (126.6) 174108.33 (106.1)
.sup.aMedian and range are presented .sup.bn = 17 for AUC.sub.inf,
AUC.sub.ext, CL/F, VZ/F, .lamda..sub.Z, and T.sub.half .sup.cn = 21
for AUC.sub.inf, AUC.sub.ext, CL/F, VZ/F, .lamda..sub.Z, and
T.sub.half .sup.dsubjects 001, 002, 004-018, and 020-024
.sup.esubjects 001, 003-007, 009-018, and 020-024 .sup.fsubjects
001, 003-024
TABLE-US-00020 TABLE 19 Summary of the Statistical Analysis of FP -
Food Effect GEOMETRIC LSMEANS.sup.a INTRA- Treatment B Treatment A
90% CONFIDENCE SUBJECT (Test Fed) (Test Fast) RATIO LIMITS (%)
PARAMETER C.V. (%) (n = 21).sup.b,d (n = 21).sup.c,e (%) LOWER
UPPER C.sub.max 37.1 37.7 31.3 120.65 99.84 145.79 AUC.sub.0-24
23.1 402.404 367.351 109.54 97.12 123.55 AUC.sub.last 24.9 607.477
789.234 76.97 67.64 87.59 AUC.sub.inf 24.9 650.820 915.302 71.10
61.46 82.26 .sup.aunits are pg/mL for C.sub.max and pg h/mL for
AUC.sub.0-24, AUC.sub.last and AUC.sub.inf .sup.bn = 20 for
AUC.sub.inf .sup.cn = 16 for AUC.sub.inf .sup.dsubjects 001,
004-007, 009-018, and 020-024 .sup.esubjects 001, 004-018, and
020-024
TABLE-US-00021 TABLE 20 Summary of the Statistical Analysis of FP -
Fast vs HS Regimen GEOMETRIC LSMEANS.sup.a INTRA- Treatment C
Treatment A 90% CONFIDENCE SUBJECT (Test HS) (Test Fast) RATIO
LIMITS (%) PARAMETER C.V. (%) (n = 22).sup.b,d (n = 21).sup.c,e (%)
LOWER UPPER C.sub.max 37.1 25.6 31.3 81.78 67.93 98.47 AUC.sub.0-24
23.1 389.137 367.351 105.93 94.14 119.19 AUC.sub.last 24.9 729.171
789.234 92.39 81.39 104.87 AUC.sub.inf 24.9 796.317 915.302 87.00
75.24 100.59 .sup.aunits are pg/mL for C.sub.max and pg h/mL for
AUC.sub.0-24, AUC.sub.last and AUC.sub.inf .sup.bn = 20 for
AUC.sub.inf .sup.cn = 16 for AUC.sub.inf .sup.dsubjects 001,
003-018, and 020-024 .sup.esubjects 001, 004-018, and 020-024
TABLE-US-00022 TABLE 21 Summary of the Statistical Analysis of FP-
Fed vs HS Regimen GEOMETRIC LSMEANS.sup.a INTRA- Treatment C
Treatment B 90% CONFIDENCE SUBJECT (Test HS) (Test Fed) RATIO
LIMITS (%) PARAMETER C.V. (%) (n = 22).sup.b,c (n = 21).sup.b,d (%)
LOWER UPPER C.sub.max 37.1 25.6 37.7 67.79 56.29 81.64 AUC.sub.0-24
23.1 389.137 402.404 96.70 85.93 108.83 AUC.sub.last 24.9 729.171
607.477 120.03 105.72 136.28 AUC.sub.inf 24.9 796.317 650.820
122.36 107.02 139.88 .sup.aunits are pg/mL for C.sub.max and pg
h/mL for AUC.sub.0-24, AUC.sub.last and AUC.sub.inf .sup.bn = 20
for AUC.sub.inf .sup.csubjects 001, 003-018, and 020-024
.sup.dsubjects 001, 004-007, 009-018, and 020-024
Example 6
Scintigraphy Study of Anatomical Contact of Oral Corticosteroid
Following Oral Administration to a Lying Down Patient Compared to
an Upright Patient
[0741] The oral corticosteroid (e.g., fluticasone propionate) will
be radiolabeled by attaching radioisotopes, and the corticosteroid
will be formulated in a pharmaceutical composition, such as an
orally disintegrating tablet. The radiolabeled oral corticosteroid
will be administered to the patient while the patient is lying
down. Independently, radiolabeled oral corticosteroid will be
administered to the patient while the patient is upright.
[0742] The radioisotopes emit gamma radiation. External detectors
(gamma cameras) capture the gamma radiation emitted from the
radiolabeled corticosteroid as it traverses the esophagus which are
converted to images. The location and relative amount of the
corticosteroid in the distal and proximal esophagus for the lying
down patient versus the upright patient can measured from said
images.
[0743] The results of the scintigraphy study will indicate that
similar amounts of the corticosteroid contact the proximal and
distal esophagus when the oral corticosteroid is administered to a
lying down patient, whereas an upright patient has a higher amount
of corticosteroid in the proximal esophagus compared to the distal
esophagus.
* * * * *