U.S. patent application number 13/294307 was filed with the patent office on 2012-05-03 for methods and compositions for treating hiv-associated diarrhea.
Invention is credited to Enoch Bortey, Pravin Chaturvedi, William Forbes, Steven King.
Application Number | 20120107370 13/294307 |
Document ID | / |
Family ID | 45994461 |
Filed Date | 2012-05-03 |
United States Patent
Application |
20120107370 |
Kind Code |
A1 |
Forbes; William ; et
al. |
May 3, 2012 |
METHODS AND COMPOSITIONS FOR TREATING HIV-ASSOCIATED DIARRHEA
Abstract
Presented herein are methods for treating diarrhea by
administering to a patient in need thereof, an inhibitor of
chloride-ion transport in an amount sufficient to treat diarrhea.
Treatment of diarrhea includes the treatment of the diarrhea as
well as the pain, abdominal discomfort and other symptoms
associated with diarrhea. In one embodiment, the inhibitor of
chloride-ion transport is crofelemer.
Inventors: |
Forbes; William; (Raleigh,
NC) ; Bortey; Enoch; (Chapel Hill, NC) ; King;
Steven; (Moss Beach, CA) ; Chaturvedi; Pravin;
(Andover, MA) |
Family ID: |
45994461 |
Appl. No.: |
13/294307 |
Filed: |
November 11, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13285397 |
Oct 31, 2011 |
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13294307 |
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61408622 |
Oct 31, 2010 |
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61409335 |
Nov 2, 2010 |
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61416249 |
Nov 22, 2010 |
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61434379 |
Jan 19, 2011 |
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Current U.S.
Class: |
424/400 ;
514/456 |
Current CPC
Class: |
A61P 25/04 20180101;
A61P 1/12 20180101; A61P 31/18 20180101; A61K 31/353 20130101; A61P
1/00 20180101; A61K 31/05 20130101 |
Class at
Publication: |
424/400 ;
514/456 |
International
Class: |
A61K 31/353 20060101
A61K031/353; A61P 1/12 20060101 A61P001/12; A61K 9/00 20060101
A61K009/00 |
Claims
1. A method of treating HIV associated diarrhea or highly active
antiretroviral therapy (HAART) associated diarrhea in an HIV
positive subject, comprising: administering about 250 mg of
crofelemer to a subject in need thereof.
2. The method of claim 1, wherein treating HIV associated diarrhea
or HAART associated diarrhea comprises the subject having a
decrease in the number of bowel movements per day, a decrease in
the number of watery bowel movements per day, a decrease in the
daily abdominal pain or discomfort score, an improvement in the
daily stool consistency score, a decrease in the number of days per
week that a subject experiences urgency, or a decrease in the
number of days per week that a subject experiences fecal
incontinence.
3. The method of claim 1, wherein the subject is administered 125
mg crofelemer two times per day.
4. The method of claim 1, wherein the administering comprises from
between about 1 month to about 6 months.
5. The method of claim 1, wherein treating results in two or fewer
watery bowel movements per week.
6. The method of claim 1, wherein the crofelemer is administered
for at least 8 days.
7. The method of claim 1, wherein the crofelemer is administered
from between 8 days to 24 weeks.
8. The method of claim 1, wherein the administering comprises about
6 months.
9. The method of claim 1, wherein the administering comprises about
6 months or longer.
10. The method of claim 1, wherein the administering is for the
duration of the HIV infection.
11. The method of claim 1, wherein a response to treatment
increases after the crofelemer has been administered for longer
than 4 months.
12. The method of claim 1, wherein the subject has previously been
administered protease inhibitors.
13. The method of claim 1, wherein the crofelemer is isolated from
a Croton species or a Calophyllum species.
14. The method of claim 13, wherein the crofelemer is isolated from
Croton sakutaris, Croton gossypifolius, Croton palanostima, Croton
lechleri, Croton erythrochilus or Croton draconoides.
15. The method of claim 1, wherein the crofelemer is enteric
coated.
16. A method of treating highly active antiretroviral therapy
(HAART) associated diarrhea in an HIV positive subject, comprising:
administering about 250 mg to about 1000 mg per day; administering
about 250 mg per day; administering about 500 mg per day;
administering about 1000 mg per day; administering about 125 mg two
times per day; administering about 250 mg two times per day; or
administering about 500 mg two times per day of crofelemer to a
subject in need thereof.
17. The method of claim 16, wherein treating HAART associated
diarrhea comprises the subject having a decrease in the number of
bowel movements per day, a decrease in the number of watery bowel
movements per day, a decrease in the daily abdominal pain or
discomfort score, an improvement in the daily stool consistency
score, a decrease in the number of days per week that a subject
experiences urgency, or a decrease in the number of days per week
that a subject experiences fecal incontinence.
18. The method of claim 16, wherein treating results in two or
fewer watery bowel movements per week.
19. The method of claim 16, wherein the administering comprises
from between about 1 month to about 6 months.
20. The method of claim 16, wherein a response to treatment
increases after the crofelemer has been administered for longer
than 4 months.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 13/285,397, filed Oct. 31, 2011 which claims benefit of U.S.
Provisional Application No. 61/408,622, filed Oct. 31, 2010; U.S.
Provisional Application No. 61/409,335, filed Nov. 2, 2010; U.S.
Provisional Application No. 61/416,249, filed Nov. 22, 2010; and
U.S. Provisional Application No. 61/434,379, filed Jan. 19, 2011.
The entire contents of each of these applications is hereby
incorporated in herein by reference.
BACKGROUND
[0002] Diarrhea remains an important problem for HIV-infected
subjects in the highly active antiretroviral therapy (HAART) era,
impacting negatively on quality of life, despite the extensive use
of anti-diarrheals. Causes are many and include HIV enteropathy,
overgrowth of unusual microbial agents, common enteric pathogens
malignancy, and adverse effects of HAART therapy itself (Kartalija
1999).
[0003] While definitions and methods of reporting vary, it is
estimated that around half of all HIV-AIDS subjects will have
diarrhea at some point during their illness. Although the incidence
of diarrhea did not change during the introduction of HAART, the
etiologies of diarrhea changed significantly with an increase of
noninfectious causes and a decrease in opportunistic infectious
causes.
[0004] Managing diarrhea will assist in improving overall efficacy
of anti-viral drug therapies, as well as quality of life, and
controlling weight loss in HIV-positive subjects. Diarrhea may
result in reduced antiretroviral compliance and/or necessitate
switching ARV regimens. Diarrhea has also been associated with
reduced antiretroviral drug levels, suggesting that adequate
treatment will improve the absorption of ARV medication. On a
population-wide basis, adherence to drug treatment regimens and
maintenance of adequate ARV levels are important for minimizing the
development of drug resistant strains of the virus. Therefore,
drug-related diarrhea in HIV-positive subjects represents an
important and unmet clinical need requiring more effective
management. Currently prescribed therapies are only partially
effective or are plagued by unacceptable side effects such as
constipation and the potential for addiction. The development of a
drug for the treatment of HIV-associated diarrhea with a low
potential for drug-drug interactions, effects on drug metabolism,
or abuse potential would provide an important benefit for
HIV-infected subjects.
SUMMARY
[0005] Disclosed herein are methods of preventing, ameliorating
and/or treating diarrhea. In one embodiment, the methods presented
herein prevent, ameliorate or treat HIV-associated diarrhea and
highly active antiretroviral therapy (HAART) associated
diarrhea.
[0006] In one aspect, presented herein are methods of treating HIV
associated diarrhea or highly active antiretroviral therapy (HAART)
associated diarrhea in an HIV positive subject, comprising:
administering about 250 mg to about 1000 mg per day; administering
about 250 mg per day; administering about 500 mg per day;
administering about 1000 mg per day; administering about 125 mg two
times per day; administering about 250 mg two times per day; or
administering about 500 mg two times per day of crofelemer to a
subject in need thereof.
[0007] In one aspect, presented herein are methods of treating
stool consistency in an HIV positive subject, comprising:
administering about 250 mg to about 1000 mg per day; administering
about 250 mg per day; administering about 500 mg per day;
administering about 1000 mg per day; administering about 125 mg two
times per day; administering about 250 mg two times per day; or
administering about 500 mg two times per day of crofelemer to a
subject in need thereof.
[0008] In one aspect, presented herein are methods of improving
stool consistency in an HIV positive subject, comprising:
administering about 250 mg to about 1000 mg per day; administering
about 250 mg per day; administering about 500 mg per day;
administering about 1000 mg per day; administering about 125 mg two
times per day; administering about 250 mg two times per day; or
administering about 500 mg two times per day of crofelemer to a
subject in need thereof.
[0009] In one aspect, presented herein are methods of alleviating
watery diarrhea in an HIV positive subject, comprising:
administering about 250 mg to about 1000 mg per day; administering
about 250 mg per day; administering about 500 mg per day;
administering about 1000 mg per day; administering about 125 mg two
times per day; administering about 250 mg two times per day; or
administering about 500 mg two times per day of crofelemer to a
subject in need thereof.
[0010] In one aspect, presented herein are methods of decreasing
the number of bowel movements per day in an HIV positive subject,
comprising: administering about 250 mg to about 1000 mg per day;
administering about 250 mg per day; administering about 500 mg per
day; administering about 1000 mg per day; administering about 125
mg two times per day; administering about 250 mg two times per day;
or administering about 500 mg two times per day of crofelemer to a
subject in need thereof.
[0011] In one embodiment, the administering is from between about 1
month and about 5 months. In one embodiment, the administering is
from between about 1 month and about 6 months. In one embodiment,
the administering comprises about 6 months. In another embodiment,
the administering comprises 6 months or longer.
[0012] In one embodiment, the administering is from between about 3
days and 5 months. In one embodiment, the administering is from
between about 3 days and 6 months.
[0013] In one embodiment, improvement of symptoms begins on day
3.
[0014] In one embodiment, improvement of symptoms increases with a
longer duration of administration after day 3.
[0015] In one embodiment, the subject is of Caucasian or Hispanic
descent.
[0016] In one embodiment, the crofelemer is administered for at
least 8 days.
[0017] In one embodiment, the crofelemer is administered from
between 8 days and 24 weeks or 8 days and 26 weeks.
[0018] In one embodiment, a subject is considered treated if the
subject demonstrates one or more of a decrease in the number of
bowel movements per day, a decrease in the number of watery bowel
movements per day, a improvement in the daily abdominal score for
pain or discomfort, an improvement in the score for daily stool
consistency, a decrease in stool consistency score (from watery to
formed), a decrease in the number of days per week that subjects
experienced urgency, a decrease in the number of days per week that
subjects experienced fecal incontinence, or a decrease in the
unscheduled visit for a significant worsening of diarrhea.
[0019] In one embodiment, a subject is considered treated if the
subject demonstrates an improvement in the score for daily stool
consistency.
[0020] In one embodiment, a subject is considered treated if the
subject demonstrates a decrease in stool consistency.
[0021] In one embodiment, a subject is considered treated if the
subject demonstrates a decrease in the number of watery bowel
movements per day.
[0022] In one embodiment, subject is considered treated if the
subject demonstrates a decrease in the number of bowel movements
per day.
[0023] In one embodiment, symptoms increased or decreased are
measured from a baseline.
[0024] In one embodiment, the administering is for about 5 months.
In another embodiment, the administering is for about 6 months.
[0025] In one embodiment, the administering is about 5 months or
longer. In another embodiment, the administering is about 6 months
or longer.
[0026] In one embodiment, the administering is for the duration of
the HIV infection.
[0027] In one embodiment, the response to treatment increases after
the crofelemer has been administered for longer than 4 months.
[0028] Other embodiments are disclosed infra.
DESCRIPTION OF THE FIGURES
[0029] FIG. 1 shows subjects with clinical response in the
crossover to placebo-free phase of the safety population.
[0030] FIG. 2 shows subjects with stool consistency response in the
crossover to placebo-free phase in the safety population.
[0031] FIG. 3 depicts a subgroup analysis showing the treatment
difference in percentage of responders (crofelemer 125 mg BID vs.
placebo) with associated confidence intervals and p-values.
DETAILED DESCRIPTION
[0032] The methods disclosed herein involved the administration of
effective amounts of a proanthocyanidin polymer, e.g., crofelemer,
to subjects having, for example, HIV associated diarrhea or highly
active antiretroviral therapy (HAART) associated diarrhea.
[0033] Proanthocyanidins are a group of condensed tannins. Crude
extracts from medicinal plants, for example, Pycanthus angolenis
and Baphia nitida, have been shown to have antidiarrheal qualities
in animal tests (Onwukaeme and Anuforo, 1993, Discovery and
Innovation, 5:317; Onwukaeme and Lot, 1991, Phytotherapy Res.,
5:254). Crude extracts which contain tannins, in particular
extracts from carob pods and sweet chestnut wood, have been
proposed as treatments or prophylactics (U.S. Pat. No. 5,043,160;
European Patent No. 481,396).
[0034] Proanthocyanidins are comprised of at least two or more
monomer units that may be of the same or different monomeric
structure. The monomer units (generally termed
"leucoanthocyanidin") are generally monomeric flavonoids which
include catechins, epicatechins, gallocatechins, galloepicatechins,
flavanols, flavonols, and flavan-3,4-diols, leucocyanidins and
anthocyanidins. Therefore, the polymer chains are based on
different structural units, which create a wide variation of
polymeric proanthocyanidins and a large number of possible isomers
(Hemingway et al., 1982, J. C. S. Perkin, 1:1217). Larger polymers
of the flavonoid 3-ol units are predominant in most plants, and are
found with average molecular weights above 2,000 daltons,
containing 6 or more units (Newman et al., 1987, Mag. Res. Chem.,
25:118).
[0035] Proanthocyanidin polymers are found in a wide variety of
plants, particularly those with a woody habit of growth (e.g.,
Croton spp. and Calophyllum spp.). A number of different Croton
tree species, including Croton sakutaris, Croton gossypifolius,
Croton palanostima, Croton lechleri, Croton erythrochilus and
Croton draconoides, found in South America, produce a red viscous
latex sap called Sangre de Drago or "Dragon's Blood". U.S. Pat. No.
5,211,944 first described the isolation of an aqueous soluble
proanthocyanidin polymer composition from Croton spp. and the use
of the composition as an antiviral agent (See also Ubillas et al.,
1994, Phytomedicine, 1:77). The proanthocyanidin polymer
composition was shown to have antiviral activity against a variety
of viruses including, respiratory syncytial, influenza,
parainfluenza and herpes viruses. U.S. Pat. No. 5,211,944 also
discloses the isolation of an aqueous soluble proanthocyanidin
polymer composition from Calophyllum inophylum and the use of this
composition as an antiviral agent.
[0036] Exemplary proanthocyanidin polymer compositions useful in
the methods presented herein are preferably isolated from a Croton
spp. or Calophyllum spp. by any method known in the art. For
example, the proanthocyanidin polymer composition may be isolated
from a Croton spp. or Calophyllum spp. by the method disclosed in
U.S. Pat. No. 5,211,944 or in Ubillas et al., 1994, Phytomedicine
1: 77-106.
[0037] Proanthocyanidin polymer compositions useful in the methods
presented herein may also be made in vitro using synthetic
techniques.
[0038] In one specific embodiment, a proanthocyanidin polymer
composition useful in the methods presented herein is
crofelemer.
[0039] Crofelemer is an oligomeric proanthocyanidin extracted and
purified from the red, viscous latex of the plant Croton lechleri
of the family Euphorbiace. The plant is widely distributed
throughout tropical Central America and South America and is widely
recognized by ethnobotanists and local healers for its medicinal
properties (McRae 1988), including for the treatment of diarrhea.
Crofelemer is believed to exert its anti-diarrhea effect through
luminal blockade of CFTR (cystic fibrosis transmembrane conductance
regulator) chloride (Cl--) channel. Crofelemer has demonstrated in
vitro activity against cholera toxin, forskolin, E. coli LT and STa
toxin-mediated Cl-secretion, and to normalize electrolyte and fluid
accumulation in CT-treated mice (Gabriel 1999, Fischer 2004, Adam
2005) via its effects on the CFTR channel. Crofelemer also
significantly improved the secretory diarrhea in humans due to
enterotoxigenic E. coli (DiCesare 2002), which is also thought to
evoke secretory diarrhea through activation of CFTR (Kunzelmann
2002). Blockade of the CFTR channel could be anticipated to have
negative consequences in man, even mimicking cystic fibrosis.
However, crofelemer has virtually no systemic bioavailability in
humans. When studied, the results indicated that there was little
or no absorption of crofelemer from the GI tract, and that
crofelemer was well tolerated by normal male subjects. Thus, the
site of action of crofelemer is topical in the gastrointestinal
tract.
[0040] Crofelemer (CAS 148465-45-6) is an oligomeric
proanthocyanidin of varying chain lengths derived from the Dragon's
Blood Croton lecheri of the family Euphorbiaceae. Crofelemer has an
average molecular weight of between approximately 1500 daltons and
approximately 2900 daltons.
[0041] The monomers comprising crofelemer comprise catechin,
epicatechin, gallocatechin, and epigallocatechin. The chain length
of crofelemer ranges from about 3 to about 30 units with an average
chain length of about 8 units. The structure of crofelemer is shown
below.
##STR00001##
Wherein the average n=6.
[0042] Another method for isolating crofelemer can be found in U.S.
Patent Publication No. 2005/0019389, the contents of which are
expressly incorporated herein.
[0043] In other embodiments, a raw latex obtained from a Croton
species or a Calophyllum species or an extract obtained from a
Croton species or a Calophyllum species are useful in the methods
presented herein. Exemplary extracts are described in Persinos et
al., 1979, J. Pharma. Sci. 68:124 and Sethi, 1977, Canadian J.
Pharm. Sci. 12:7.
[0044] "Ameliorate," "amelioration," "improvement" or the like
refers to, for example, a detectable improvement or a detectable
change consistent with improvement that occurs in a subject or in
at least a minority of subjects, e.g., in at least about 2%, 5%,
10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%,
95%, 98%, 100% or in a range between about any two of these values.
Such improvement or change may be observed in treated subjects as
compared to subjects not treated with crofelemer, where the
untreated subjects have, or are subject to developing, the same or
similar disease, condition, symptom or the like. Amelioration of a
disease, condition, symptom or assay parameter may be determined
subjectively or objectively, e.g., self assessment by a subject(s),
by a clinician's assessment or by conducting an appropriate assay
or measurement. Amelioration may be transient, prolonged or
permanent or it may be variable at relevant times during or after
crofelemer is administered to a subject or is used in an assay or
other method described herein or a cited reference, e.g., within
timeframes described infra, or about 1 hour after the
administration or use of crofelemer to about 7 days, 2 weeks, 28
days, or 1, 3, 6, 9 months or more after a subject(s) has received
such treatment.
[0045] The "modulation" of, e.g., a symptom, level or biological
activity of a molecule, or the like, refers, for example, that the
symptom or activity, or the like is detectably increased or
decreased. Such increase or decrease may be observed in treated
subjects as compared to subjects not treated with crofelemer, where
the untreated subjects have, or are subject to developing, the same
or similar disease, condition, symptom or the like. Such increases
or decreases may be at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%,
40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 100%, 150%, 200%,
250%, 300%, 400%, 500%, 1000% or more or within any range between
any two of these values. Modulation may be determined subjectively
or objectively. Modulation may be transient, prolonged or permanent
or it may be variable at relevant times during or after crofelemer
is administered to a subject or is used in an assay or other method
described herein or a cited reference, e.g., within times descried
infra, or about 1 hour of the administration or use of crofelemer
to about 2 weeks, 28 days, 3, 6, 9 months or more after a
subject(s) has received crofelemer.
[0046] The language "a prophylactically effective amount" of a
compound refers to an amount of crofelemer which is effective, upon
single or multiple dose administration to the subject, in
preventing or treating diarrhea, e.g., HIV-associated diarrhea.
[0047] As used herein, "subject" includes organisms which are
capable of suffering from HIV associated diarrhea or HAART
associated diarrhea or who could otherwise benefit from the
administration of crofelemer as described herein, such as humans
and non-human animals. The term "non-human animals" includes all
vertebrates, e.g., mammals such as non-human primates, other
mammals, e.g., rodents, and sheep, dog, and cow, at risk for HIV
associated diarrhea or HAART associated diarrhea. A subject at risk
for HIV associated diarrhea or HAART associated diarrhea is meant
to include a subject at risk of developing or contracting an HIV
infection
[0048] The language "a prophylactically effective amount" of a
compound refers to an amount of crofelemer which is effective, upon
single or multiple dose administration to the subject, in
preventing or treating the diarrhea.
[0049] The term "administration" or "administering" includes routes
of introducing crofelemer to a subject to perform their intended
function. Examples of routes of administration that may be used
include injection, oral, inhalation, vaginal, rectal and
transdermal. The pharmaceutical preparations may be given by forms
suitable for each administration route. For example, these
preparations are administered in tablet or capsule form, by
injection, inhalation, ointment, or suppository. Administration may
also be by injection, infusion or inhalation; topical by lotion or
ointment; and rectal by suppositories. Oral administration is
preferred. Depending on the route of administration, crofelemer can
be coated with or disposed in a selected material to protect it
from natural conditions that may detrimentally affect its ability
to perform its intended function. Crofelemer can be administered
alone, or in conjunction with either another agent or agents as
described above or with a pharmaceutically-acceptable carrier, or
both. Exemplary enteric coated forms of crofelemer are described
in, for example, U.S. Pat. No. 7,556,831.
[0050] Administration "in combination with" one or more further
therapeutic agents includes simultaneous (concurrent) and
consecutive administration in any order.
[0051] As will be readily apparent to one skilled in the art, the
useful in vivo dosage to be administered and the particular mode of
administration may vary depending upon the age, weight and
mammalian species treated, the particular compounds employed,
and/or the specific use for which these compounds are employed. The
determination of effective dosage levels, that is the dosage levels
necessary to achieve the desired result, can be accomplished by one
skilled in the art using routine pharmacological methods and in
consultation with the data presented herein. In regard to
crofelemer, it may be advantageous to administer 125 mg crofelemer
two times per day to treat watery diarrhea if fewer watery stools
are desired over a week. It is also advantageous to treat with 500
mg two times per day if an improvement in stool consistency is
desired.
[0052] The term "obtaining" as in "obtaining crofelemer" is
intended to include purchasing, synthesizing, isolating, extracting
or otherwise acquiring crofelemer.
[0053] The language "a prophylactically effective amount" of a
compound refers to an amount of crofelemer which is effective, upon
single or multiple dose administration to the subject, in
preventing or treating an indication. In one embodiment, the
indication is HIV-associated diarrhea.
Methods of Treatment
[0054] Provided herein are methods of treating, preventing, or
alleviating diarrhea or the symptoms caused by HIV infection or
HAART therapy for HIV infection comprising administering to a
subject in need thereof an effective amount of crofelemer.
Exemplary diarrhea that can be treated or prevented using the
methods presented herein include HIV associated diarrhea or highly
active antiretroviral therapy (HAART) associated diarrhea.
[0055] In one embodiment, treating HIV-associated diarrhea includes
an improvement of the following symptoms of HIV associated diarrhea
or HAART associated diarrhea, including, for example, a decrease in
the number of bowel movements per day (frequency), a decrease in
the number of watery bowel movements per day, a decrease in symptom
frequency (urgency, fecal incontinence), a decrease in symptom
severity (abdominal pain or discomfort), a decrease in daily stool
consistency score (watery to formed), or a decrease in stool
consistency leading to formed stools from watery stools.
[0056] In one specific embodiment, treatment is defined as two or
less watery bowel movements per week. More specifically, treatment
is defined as two or less watery bowel movements per week during at
least two of the four weeks of treatment with crofelemer.
[0057] In other specific embodiments, treatment can also include,
for example, one or more of a decrease in the number of bowel
movements per day, a decrease in the number of watery bowel
movements per day, a improvement in the daily abdominal score for
pain or discomfort, an improvement in the score for daily stool
consistency, a decrease in the number of days per week that
subjects experienced urgency, a decrease in the number of days per
week that subjects experienced fecal incontinence, or a decrease in
the unscheduled visit for a significant worsening of diarrhea.
[0058] In one aspect, provided herein are methods of treating HIV
associated diarrhea or highly active antiretroviral therapy (HAART)
associated diarrhea in an HIV positive subject. Treatment of the
diarrhea can include, for example, one or more of a decrease in the
number of bowel movements per day, a decrease in the number of
watery bowel movements per day, a improvement in the daily
abdominal score for pain or discomfort, an improvement in the score
for daily stool consistency, a decrease in stool consistency, a
decrease in the number of days per week that subjects experienced
urgency, a decrease in the number of days per week that subjects
experienced fecal incontinence, or a decrease in the unscheduled
visit for a significant worsening of diarrhea.
[0059] In one aspect, provided herein are methods of treating stool
consistency in an HIV positive subject, wherein a subject is
considered treated if there is an improvement in the score for
daily stool consistency and/or a decrease in stool consistency
score a measured throughout the day or days or weeks. This decrease
may be measured from a baseline. The baseline may be determined in
the days to week prior to treatment with crofelemer. Treatment
comprises administering about 250 mg to about 1000 mg per day;
administering about 250 mg per day; administering 1000 mg per day;
administering about 125 mg two times per day; or administering
about 500 mg two times per day of crofelemer to a subject in need
thereof.
[0060] In one aspect, provided herein are methods of improving
stool consistency in an HIV positive subject wherein a subject is
considered treated if there is an improvement in stool consistency
and/or a decrease in stool consistency throughout the day or days
or weeks. This increase may be measured from a baseline. The
baseline may be determined in the days to week prior to treatment
with crofelemer. Treatment comprises administering about 250 mg to
about 1000 mg per day; administering about 250 mg per day;
administering 1000 mg per day; administering about 125 mg two times
per day; or administering about 500 mg two times per day of
crofelemer to a subject in need thereof.
[0061] In one aspect, provided herein are methods of alleviating
watery diarrhea in an HIV positive subject, wherein a subject is
considered treated if the subject experiences a decrease in the
number of watery bowel movements per day and/or over days, a week
or weeks of administration of crofelemer. This decrease may be
measured from a baseline. The baseline may be determined in the
days to week prior to treatment with crofelemer. Treatment
comprises administering about 250 mg to about 1000 mg per day;
administering about 250 mg per day; administering 1000 mg per day;
administering about 125 mg two times per day; or administering
about 500 mg two times per day of crofelemer to a subject in need
thereof.
[0062] In one aspect, presented herein are methods a decreasing the
number of bowel movements per day, wherein a subject is considered
treated if there is a decrease in the number of bowel movements per
day as measured from a baseline. The baseline may be determined in
the days to week prior to treatment with crofelemer. Treatment
comprises administering about 250 mg to about 1000 mg per day;
administering about 250 mg per day; administering 1000 mg per day;
administering about 125 mg two times per day; or administering
about 500 mg two times per day of crofelemer to a subject in need
thereof.
[0063] Crofelemer may be administered, for example, once a day,
twice a day, three times a day, or four times or more often as
necessary per day. Crofelemer may be administered in doses, for
example of from about between 25 mg BID to about 3000 mg TID,
preferably crofelemer is administered from between about 125 mg to
about 1000 mg per day. In another embodiment, crofelemer is
administered between 125 mg BID to about 500 mg BID depending of
symptoms. In another embodiment, crofelemer is administered as 125
mg BID. In another embodiment, crofelemer is administered as 500 mg
BID. Crofelemer may be administered orally, for example, in tablet
form, powered form, liquid form or in capsules.
[0064] In exemplary embodiments, the subject is administered 250,
500, or 1000 mg/day of crofelemer.
[0065] In specific embodiments, the subject is administered 125,
250 or 500 mg p.o. b.i.d (orally twice per day). Other appropriate
dosages for methods may be determined by health care professionals
or by the subject. The amount of crofelemer administered daily may
be increased or decreased based on the weight, age, health, sex or
medical condition of the subject. One of skill in the art would be
able to determine the proper dose for a subject based on this
disclosure and the data presented in the Examples, which
follow.
[0066] In other embodiments, the subject is treated with crofelemer
for 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 or more weeks or 26
or more weeks. In one embodiment, the subject is administered
crofelemer for the duration of the disease. Length of treatment may
vary depending on the type and length of disease and the proper
length of treatment may be easily determined by one of skill in the
art having the benefit of this disclosure. Treatment may be prior
to infection, during infection, or after suspected infection and
for a period of time suggested by a medical professional to reduce
or eliminate diarrhea.
[0067] Subjects in need thereof include subjects having or that are
susceptible to or who have I-IIV-associated diarrhea or HAART
associated diarrhea.
[0068] As used herein, a therapeutically effective amount means an
amount effective, when administered to a human or non-human
subject, to provide a therapeutic benefit such as an amelioration
of symptoms, e.g., an amount effective to decrease the symptoms
HIV-associated diarrhea.
[0069] According to certain embodiments, crofelemer may be
administered in combination with other compounds, including for
example, anti-diarrheal agents or anti-HIV agents, including, for
example, anti-retroviral agents.
[0070] According to one aspect, provided herein are methods of
treating HIV associated diarrhea or highly active antiretroviral
therapy (HAART) associated diarrhea in an HIV positive subject that
has previously used protease inhibitors, comprising: administering
about 250 mg to about 1000 mg per day; administering about 250 mg
per day; administering about 500 mg per day; administering about
1000 mg per day; administering about 125 mg two times per day;
administering about 250 mg two times per day; or administering
about 500 mg two times per day of crofelemer to a male subject in
need thereof. As used herein, "previously used" includes, for
example, subjects who have used protease inhibitors (PIs) prior to
crofelemer therapy or overlapping with crofelemer therapy, but the
PI use began prior to the first dose of crofelemer therapy.
Pharmaceutical Preparations
[0071] Also provided herein are pharmaceutical compositions,
comprising an effective amount of a crofelemer described herein and
a pharmaceutically acceptable carrier. In a further embodiment, the
effective amount is effective to treat HIV-associated diarrhea
and/or HAART associated diarrhea.
[0072] Examples of the preparation and use of crofelemer have been
described in U.S. Pat. No. 7,556,831, US Patent Publication
20070254050 and US Patent Publication 20080031984, all of which are
incorporated herein by reference in their entirety.
[0073] One embodiment includes pharmaceutical compositions
comprising crofelemer and a pharmaceutically acceptable
carrier.
[0074] The pharmaceutical compositions described herein may further
comprise excipients, for example, one or more of a diluting agent,
binding agent, lubricating agent, disintegrating agent, coloring
agent, flavoring agent or sweetening agent. Compositions may be
formulated for selected coated and uncoated tablets, hard and soft
gelatin capsules, sugar-coated pills, lozenges, wafer sheets,
pellets and powders in sealed packet. For example, compositions may
be formulated for topical use, for example, ointments, pomades,
creams, gels and lotions.
[0075] In certain embodiments, these pharmaceutical compositions
are suitable for topical or oral administration to a subject. In
other embodiments, as described in detail below, the pharmaceutical
compositions may be specially formulated for administration in
solid or liquid form, including those adapted for the following:
(1) oral administration, for example, drenches (aqueous or
non-aqueous solutions or suspensions), tablets, boluses, powders,
granules, pastes; (2) parenteral administration, for example, by
subcutaneous, intramuscular or intravenous injection as, for
example, a sterile solution or suspension; (3) topical application,
for example, as a cream, ointment or spray applied to the skin; (4)
intravaginally or intrarectally, for example, as a pessary, cream
or foam; or (5) aerosol, for example, as an aqueous aerosol,
liposomal preparation or solid particles containing the
compound.
[0076] The phrase "pharmaceutically acceptable" refers to
crofelemer as described herein, compositions containing crofelemer,
and/or dosage forms which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of human
beings and animals without excessive toxicity, irritation, allergic
response, or other problem or complication, commensurate with a
reasonable benefit/risk ratio.
[0077] The phrase "pharmaceutically-acceptable carrier" includes
pharmaceutically-acceptable material, composition or vehicle, such
as a liquid or solid filler, diluent, excipient, solvent or
encapsulating material, involved in carrying or transporting the
subject chemical from one organ, or portion of the body, to another
organ, or portion of the body. Each carrier must be "acceptable" in
the sense of being compatible with the other ingredients of the
formulation and not injurious to the patient. Some examples of
materials which can serve as pharmaceutically-acceptable carriers
include: (1) sugars, such as lactose, glucose and sucrose; (2)
starches, such as corn starch and potato starch; (3) cellulose, and
its derivatives, such as sodium carboxymethyl cellulose, ethyl
cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt;
(6) gelatin; (7) talc; (8) excipients, such as cocoa butter and
suppository waxes; (9) oils, such as peanut oil, cottonseed oil,
safflower oil, sesame oil, olive oil, corn oil and soybean oil;
(10) glycols, such as propylene glycol; (11) polyols, such as
glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,
such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering
agents, such as magnesium hydroxide and aluminum hydroxide; (15)
alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18)
Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer
solutions; and (21) other non-toxic compatible substances employed
in pharmaceutical formulations.
[0078] Wetting agents, emulsifiers and lubricants, such as sodium
lauryl sulfate and magnesium stearate, as well as coloring agents,
release agents, coating agents, sweetening, flavoring and perfuming
agents, preservatives and antioxidants can also be present in the
compositions.
[0079] Examples of pharmaceutically-acceptable antioxidants
include: (1) water soluble antioxidants, such as ascorbic acid,
cysteine hydrochloride, sodium bisulfate, sodium metabisulfite,
sodium sulfite and the like; (2) oil-soluble antioxidants, such as
ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated
hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol,
and the like; and (3) metal chelating agents, such as citric acid,
ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid,
phosphoric acid, and the like.
[0080] Compositions containing crofelemer include those suitable
for oral, nasal, topical (including buccal and sublingual), rectal,
vaginal, aerosol and/or parenteral administration. The compositions
may conveniently be presented in unit dosage form and may be
prepared by any methods known in the art of pharmacy. The amount of
active ingredient which can be combined with a carrier material to
produce a single dosage form will vary depending upon the host
being treated, the particular mode of administration. The amount of
active ingredient which can be combined with a carrier material to
produce a single dosage form will generally be that amount of the
compound which produces a therapeutic effect. Generally, out of one
hundred percent, this amount will range from about 0.01% to about
99% of active ingredient, for example, from about 5% to about 70%,
or from about 10% to about 30%.
[0081] Liquid dosage forms for oral or rectal administration of
crofelemer may include, for example, pharmaceutically-acceptable
emulsions, microemulsions, solutions, suspensions, syrups and
elixirs. In addition to the active ingredient, the liquid dosage
forms may contain inert diluents commonly used in the art, such as,
for example, water or other solvents, solubilizing agents and
emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, oils (in particular,
cottonseed, groundnut, corn, germ, olive, castor and sesame oils),
glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty
acid esters of sorbitan, and mixtures thereof.
[0082] Suspensions, in addition to crofelemer may contain
suspending agents as, for example, ethoxylated isostearyl alcohols,
polyoxyethylene sorbitol and sorbitan esters, microcrystalline
cellulose, aluminum metahydroxide, bentonite, agar-agar and
tragacanth, and mixtures thereof. Dosage forms for the topical or
transdermal administration ofcrofelemer can include, for example,
powders, sprays, ointments, pastes, creams, lotions, gels,
solutions, patches and inhalants. The ointments, pastes, creams and
gels may contain, in addition to crofelemer, excipients, such as
animal and vegetable fats, oils, waxes, paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones,
bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to a croflemer,
excipients such as lactose, talc, silicic acid, aluminum hydroxide,
calcium silicates and polyamide powder, or mixtures of these
substances. Sprays can additionally contain customary propellants,
such as chlorofluorohydrocarbons and volatile unsubstituted
hydrocarbons, such as butane and propane.
[0083] Examples of suitable aqueous and non-aqueous carriers which
may be employed in the pharmaceutical compositions can include, for
example, water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), and suitable mixtures
thereof, vegetable oils, such as olive oil, and injectable organic
esters, such as ethyl oleate. Proper fluidity can be maintained,
for example, by the use of coating materials, such as lecithin, by
the maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0084] In one embodiment, crofelemer is enteric coated so as to
protect it from degradation by the acidic conditions of the stomach
and/or from interactions with proteins, such as pepsin, present in
the stomach, e.g., an enteric protected formulation. In a specific
embodiment, crofelemer is in tablet form. In yet another
embodiment, the tablet is enteric coated, e.g., Eudragit.RTM.. In
one embodiment, crofelemer is formulated as an enteric coated bead
or granule in an enteric coated capsule shell. In another
embodiment, crofelemer is formulated in a delayed release
composition.
[0085] In certain embodiments, the composition is formulated with a
compound or compounds which neutralize stomach acid. Alternatively,
the pharmaceutical composition containing the composition is
administered either concurrent with or subsequent to or after
administration of a pharmaceutical composition which neutralize
stomach acid. Compounds, such as antacids, which are useful for
neutralizing stomach acid include, but are not limited to, aluminum
carbonate, aluminum hydroxide, bismuth subnitrate, bismuth
subsalicylate, calcium carbonate, dihydroxyaluminum sodium
carbonate, magaldrate, magnesium carbonate, magnesium hydroxide,
magnesium oxide, and mixtures thereof. Compounds that are able to
reduce the secretion of stomach acid and/or are able to reduce the
acidity of stomach fluid are well known in the art and include, but
are not limited to, antacids (aluminum hydroxide, aluminum
carbonate, aluminum glycinate, magnesium oxide, magnesium
hydroxide, magnesium carbonate, calcium carbonate, sodium
bicarbonate), stomach acid blockers and a combination of any of the
foregoing. In general, any drug that has been approved for sale by
the relevant government agency and is able to reduce the production
of stomach acid and/or reduce the acidity of stomach fluid can be
administered in combination with an inhibitor molecule, such as
crofelemer, in accordance with the methods presented herein.
[0086] In a particular embodiment where crofelemer is not enteric
coated, crofelemer is formulated with one or more compounds that
are able to reduce the secretion of stomach acid and/or able to
reduce the acidity of stomach fluid. In an exemplary embodiment,
crofelemer is formulated in a controlled release (delayed release)
composition, such as Merck GEM, Alza OROS, wax matrix (release is
primarily delayed until after the formulation passes out of the
stomach and into the intestine).
[0087] Also provided herein are pharmaceutical formulations of
crofelemer comprising the composition along with a pharmaceutically
acceptable vehicle, at a dose which is therapeutically effective at
treating HIV associated diarrhea or HAART associated diarrhea. In
one embodiment, a directly compressible crofelemer (e.g., that can
be directly compressed, without excipients, into a tablet of
pharmaceutically acceptable hardness and friability) compressed
into a tablet, optionally with a lubricant, such as but not limited
to magnesium stearate, is enteric coated. These formulations can be
prepared by methods known in the art, see, e.g. methods described
in Remington's Pharmaceutical Sciences, 18th Ed., ed. Alfonso R.
Gennaro, Mack Publishing Co., Easton, Pa., 1990.
[0088] In a specific embodiment, the proanthocyanidin polymer
composition comprises crofelemer (CAS 148465-45-6).
[0089] In a more another embodiment, a composition is enteric
coated. Enteric coatings are those coatings that remain intact in
the stomach, but will dissolve and release the contents of the
dosage form once it reaches the small intestine. A large number of
enteric coatings are prepared with ingredients that have acidic
groups such that, at the very low pH present in the stomach, i.e.
pH 1.5 to 2.5, the acidic groups are not ionized and the coating
remains in an undissociated, insoluble form. At higher pH levels,
such as in the environment of the intestine, the enteric coating is
converted to an ionized form, which can be dissolved to release the
inhibitor molecule. Other enteric coatings remain intact until they
are degraded by enzymes in the small intestine, and others break
apart after a defined exposure to moisture, such that the coatings
remain intact until after passage into the small intestines.
[0090] Polymers which are useful for the preparation of enteric
coatings include, but are not limited to, shellac, starch and
amylose acetate phthalates, styrene-maleic acid copolymers,
cellulose acetate succinate, cellulose acetate phthalate (CAP),
polyvinylacetate phthalate (PVAP), hydroxypropylmethylcellulose
phthalate (grades HP-50 and HP-55), ethylcellulose, fats, butyl
stearate, and methacrylic acid-methacrylic acid ester copolymers
with acid ionizable groups. In one embodiment, the pharmaceutical
composition contains a polymeric proanthocyanidin composition and
the enteric coating polymer Eudragit.RTM.. L 30D, an anionic
copolymer of methacrylic acid and methyl acrylate with a mean
molecular weight of 250,000 Daltons. In another embodiment, the
enteric coating polymer is Eudragit.RTM.. L 30D-55. Application of
the enteric coating to the crofelemer composition can be
accomplished by any method known in the art for applying enteric
coatings. For example, but not by way of limitation, the enteric
polymers can be applied using organic solvent based solutions
containing from 5 to 10% w/w polymer for spray applications and up
to 30% w/w polymer for pan coatings. Solvents that are commonly in
use include, but are not limited to, acetone, acetone/ethyl acetate
mixtures, methylene chloride/methanol mixtures, and tertiary
mixtures containing these solvents. Some enteric polymers, such as
methacrylic acid-methacrylic acid ester copolymers can be applied
using water as a dispersant. The volatility of the solvent system
must be tailored to prevent sticking due to tackiness and to
prevent high porosity of the coating due to premature spray drying
or precipitation of the polymer as the solvent evaporates.
[0091] In another embodiment, the pharmaceutical composition
comprising crofelemer is formulated as enteric coated granules or
powder (microspheres with a diameter of 300-5001) provided in
either hard shell gelatin capsules or suspended in an oral solution
for pediatric administration. The enteric coated powder or granules
may also be mixed with food, particularly for pediatric
administration.
[0092] The granules and powder can be prepared using any method
known in the art, such as but not limited to, crystallization,
spray-drying or any method of comminution, for example, using a
high speed mixer/granulator. Exemplary formulations may be found,
for example, in the following US patents and applications U.S. Pat.
No. 7,341,744; U.S. Ser. No. 11/510,152; and U.S. Ser. No.
12/175,131.
[0093] Regardless of the route of administration selected,
crofelemer is formulated into pharmaceutically-acceptable dosage
forms by methods known to those of skill in the art.
[0094] In combination therapy treatment, both the compounds and the
other drug agent(s) are administered to mammals (e.g., humans, male
or female) by methods known in the art. The agents may be
administered in a single dosage form or in separate dosage forms.
Effective amounts of the other therapeutic agents are well known to
those skilled in the art. However, it is well within the skilled
artisan's purview to determine the other therapeutic agent's
optimal effective-amount range. In one embodiment in which another
therapeutic agent is administered to an animal, the effective
amount of the compound is less than its effective amount in case
the other therapeutic agent is not administered. In another
embodiment, the effective amount of the agent is less than its
effective amount in case the compound is not administered. In this
way, undesired side effects associated with high doses of either
agent may be minimized. Other potential advantages (including
without limitation improved dosing regimens and/or reduced drug
cost) will be apparent to those skilled in the art.
[0095] In various embodiments, the therapies (e.g., prophylactic or
therapeutic agents) are administered less than 5 minutes apart,
less than 30 minutes apart, 1 hour apart, at about 1 hour apart, at
about 1 to about 2 hours apart, at about 2 hours to about 3 hours
apart, at about 3 hours to about 4 hours apart, at about 4 hours to
about 5 hours apart, at about 5 hours to about 6 hours apart, at
about 6 hours to about 7 hours apart, at about 7 hours to about 8
hours apart, at about 8 hours to about 9 hours apart, at about 9
hours to about 10 hours apart, at about 10 hours to about 11 hours
apart, at about 11 hours to about 12 hours apart, at about 12 hours
to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours
apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52
hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84
hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours
part. In one or more embodiments, two or more therapies are
administered within the same patient's visit.
Kits
[0096] Kits are also provided herein, for example, kits for
treating a diarrhea, e.g., HIV-associated diarrhea in a subject.
The kits may contain, for example, crofelemer or a pharmaceutical
composition comprising crofelemer and instructions for use. The
instructions for use may contain prescribing information, dosage
information, storage information, and the like.
[0097] Label instructions include, for example, instructions to
take the crofelemer for at least 3 days for the treatment of HIV
associated or HAART associated diarrhea. The instructions could
also read, for example, take from between 125 mg BID to 500 mg BID
of crofelemer until resolution of symptoms or for 24 weeks for
treatment or HIV-associated diarrhea. The instructions could also
read, for example, take 125 mg BID of crofelemer until resolution
of symptoms or for 24 weeks for treatment or HIV-associated
diarrhea. The instructions could also read, for example, take 500
mg BID of crofelemer until resolution of symptoms or for 24 weeks
for treatment or HIV-associated diarrhea.
[0098] Label instructions may further or alternately include, for
example, instructions to take the crofelemer from between 125 mg
BID to 500 mg BID of crofelemer until resolution of symptoms or for
26 weeks for treatment or HIV-associated diarrhea. The instructions
could also read, for example, take 125 mg BID of crofelemer until
resolution of symptoms or for 26 weeks for treatment or
HIV-associated diarrhea. The instructions could also read, for
example, take 250 mg BID of crofelemer until resolution of symptoms
or for 26 weeks for treatment or HIV-associated diarrhea. The
instructions could also read, for example, take 500 mg BID of
crofelemer until resolution of symptoms or for 26 weeks for
treatment or HIV-associated diarrhea.
EXAMPLES
[0099] It should be appreciated that the invention should not be
construed to be limited to the example, which is now described;
rather, the invention should be construed to include any and all
applications provided herein and all equivalent variations within
the skill of the ordinary artisan.
Example 1
Pulmonary Effects of Orally Administered Crofelemer in Rats
[0100] Three treatment groups of eight male rats were administered
Crofelemer at respective dose levels of 60, 200, and 600 mg/kg. An
additional group of eight male rats served as control animals and
were administered the vehicle, purified water. Crofelemer and
vehicle were administered at a dose volume of 10 mL/kg. One
additional group of eight male rats received the positive control
article, baclofen, at a dose level of 100 mg/kg and a dose volume
of 15 mL/kg. Crofelemer, positive control article, and vehicle were
administered to all groups via oral gavage.
[0101] Observations for mortality, morbidity, injury, and the
availability of food and water were conducted at least twice daily
for all animals. Clinical observations were conducted prior to
dosing, approximately 1 hour postdose, and following completion of
the pulmonary monitoring periods (approximately 4 hours postdose).
Body weights were measured and recorded prior to dosing (Day 1).
Pulmonary function (respiratory rate, tidal volume, and minute
volume) was monitored for approximately 1 hour prior to dosing to
establish baseline and for approximately 4 hours postdose.
Following the pulmonary monitoring periods, all animals were
euthanized and the carcasses were discarded without further
evaluation.
[0102] Crofelemer, administered orally to male rats at doses of 60,
200, and 600 mg/kg did not produce any effects on mortality or any
of the quantitative respiratory endpoints over the course of the
study. With respect to the basic respiratory endpoints evaluated in
this study, oral administration of Crofelemer produced no adverse
effects in rats at doses up to and including 60 mg/kg.
Example 2
13-Week Oral Toxicity Study of Crofelemer Administered to Mice
[0103] Three treatment groups of 15 male and 15 female mice were
administered Crofelemer at respective dose levels of 40, 400, and
1200 mg/kg/day. One additional group of 15 animals/sex served as
the control and received the vehicle, purified water. The vehicle
or Crofelemer was administered to all groups at a dose volume of 10
mL/kg. Additionally, four groups of eight or 39 animals/sex/group
served as toxicokinetic (TK) animals and received the control or
Crofelemer in the same manner as the main study groups at
respective dose levels of 0, 40, 400, or 1200 mg/kg/day. Due to
mortalities, the main study and TK animals at 1200 mg/kg/day were
administered Crofelemer for up to 55 or 56 days, respectively.
[0104] Observations for morbidity, mortality, injury, and the
availability of food and water were conducted twice daily for all
animals. Detailed clinical observations for clinical signs were
conducted weekly on all main study animals. Body weights were
measured and recorded weekly on all animals. Food consumption was
measured and recorded weekly on all main study animals.
Ophthalmoscopic examinations were conducted pretest and prior to
necropsy for all main study animals. Blood samples for clinical
pathology evaluations were collected from main study animals in
extremis and at termination. Blood samples for determination of the
plasma concentrations of Crofelemer were collected from designated
TK animals at designated time points on Days 1, 56, and 91. After
blood collection, the TK animals were euthanized and the carcasses
were discarded, with the exception of designated animals at 1200
mg/kg/day. The toxicokinetic parameters were determined for
Crofelemer from concentration time data in the test species. At
study termination, necropsy examinations were performed and organ
weights were recorded for all main study animals and designated TK
animals at 1200 mg/kg/day. Tissues were microscopically examined
for main study animals at 0, 400, and 1200 mg/kg/day. Beginning on
Day 7, a limited gross necropsy examination was performed on any TK
animal euthanized in extremis or found dead in an effort to
determine the cause of death. Tissues were collected and preserved
for possible future examination from main study animals at 40
mg/kg/day and designated TK animals at 1200 mg/kg/day.
[0105] Twice-daily oral gavage administration of Crofelemer at 0,
40, or 400 mg/kg/day for 13 weeks or 1200 mg/kg/day for 8 weeks in
mice was only tolerated in females at 40 mg/kg/day.
[0106] Crofelemer-related mortalities were evident in a single male
at 40 mg/kg/day and in both sexes at 400 and 1200 mg/kg/day.
Crofelemer-related body weight effects were evident at .gtoreq.400
mg/kg/day in both sexes, and food consumption effects were evident
at 40 mg/kg/day in females and .gtoreq.400 mg/kg/day in both sexes.
Clinical pathology, organ weight, and macroscopic effects were
observed in both sexes at 1200 mg/kg/day. Due to mortality at 40
mg/kg/day, there was no No-Observed-Adverse-Effect-Level (NOAEL) in
males; however, the NOAEL was determined to be 40 mg/kg/day in
females.
Example 3
Neurobehavioral Evaluation of Orally Administered Crofelemer in
Rats
[0107] Three treatment groups of six male rats were administered
Crofelemer at respective dose levels of 60, 200, and 600 mg/kg. One
additional group of six male rats served as the control and
received the vehicle, purified water. Another additional group of
six male rats received the positive control article, chlorpromazine
hydrochloride, at a dose level of 20 mg/kg. Crofelemer, positive
control article, or vehicle was administered to all groups once via
oral gavage at a dose volume of 10 mL/kg.
[0108] Observations for morbidity, mortality, injury, and the
availability of food and water were conducted at least twice daily
for all animals. Clinical observations were conducted following
each functional observational battery (FOB) examination. FOB
evaluations were conducted predose and at approximately 1 and 24
hours postdose. Body weights were measured and recorded prior to
dosing on Day 1. At study termination, all animals were euthanized
and the carcasses were discarded without further evaluation.
[0109] Crofelemer administered orally to male rats at doses of 60,
200, and 600 mg/kg did not produce any effects on mortality,
clinical observations, body weight, or any of the neurobehavioral
measures tested. Therefore, with respect to the basic
neurobehavioral endpoints evaluated in this study, oral
administration of Crofelemer produced no effects in rats at doses
up to and including 600 mg/kg.
Example 4
Effects of Orally Administered Crofelemer on Gut Motility Function
in the Rat
[0110] Three treatment groups of eight male rats were administered
Crofelemer at respective dose levels of 60, 200, and 600 mg/kg. One
additional group of eight male rats received the positive control
article, morphine, at a dose level of 20 mg/kg. An additional group
of eight male rats served as the control and received the vehicle,
purified water. The vehicle, positive control article, or
Crofelemer was administered to all groups via oral gavage once on
Day 1 of the study at a dose volume of 10 mL/kg. Approximately 1
hour after administration, the test meal, 5% charcoal suspension in
10% Acacia in deionized water, was administered to all animals via
oral gavage at a dose volume of 10 mL/kg.
[0111] Observations for morbidity, mortality, injury, and the
availability of food (except during fasting periods) and water were
conducted at least twice daily for all animals. Clinical
observations were conducted prior to dosing, and prior to
termination. Body weights were measured and recorded prior to
dosing on Day 1. Approximately 30 minutes following test meal
administration all animals were euthanized, the small intestine was
surgically removed, and the total intestine length and the distance
the charcoal traveled were both measured. The carcasses were
discarded without further evaluation.
[0112] Crofelemer, administered orally to male rats at doses of 60,
200, or 600 mg/kg did not produce mortality or any clinical
observations. Crofelemer-related, dose-dependent decreases in
gastrointestinal propulsion were noted in all Crofelemer-treated
groups; however, statistically significant decreases were only
noted following the 200 and 600 mg/kg doses. Due to low recovery
values, the dose levels actually administered to the animals in the
60 and 200 mg/kg groups were 51 and 169 mg/kg, respectively.
Example 5
Cardiovascular Effects of Orally Administered Crofelemer in the
Beagle Dog
[0113] The same four male beagle dogs were administered the control
article, placebo tablets in gelatin number 12 Torpac lock ring
gelatin capsules (0 mg/kg), and Crofelemer at dose levels of
approximately 60, 200, and 600 mg/kg according to a modified Latin
square design, with one animal/sex/treatment dosing each week
followed by at least a 7 day washout period between
administrations, until each animal received all treatments. The
control article and Crofelemer were administered to all animals
orally via gelatin capsule.
[0114] The animals were previously surgically instrumented with
radio transmitters for measurement of body temperature, blood
pressure, heart rate, and the electrocardiogram (ECG). Body
temperature, systolic, diastolic, and mean arterial blood
pressures, heart rate, and ECG parameters (QRS duration and the RR,
PR, and QT intervals) were monitored continuously from at least 2
hours prior to dosing until at least 20 hours postdose. Nine days
prior to the first administration, untreated animals were
continuously monitored for cardiovascular endpoints for at least 22
hours. These data were used in the calculation of the corrected QT
interval throughout the study.
[0115] Observations for morbidity, mortality, injury, and the
availability of food and water were conducted at least twice daily
for all animals. Clinical observations were conducted prior to
dosing and following completion of the cardiovascular monitoring
period. Body weights were measured and recorded on the day prior to
each administration. At study termination, the animals were
transferred to the stock colony.
[0116] Crofelemer administered orally to male dogs at doses of 60,
200, and 600 mg/kg did not produce mortality nor any effects on the
ECG over the course of the study. Following doses of 200 and 600
mg/kg the test article produced clinical observations of red,
black, or brown feces; soft, watery, and/or mucoid feces; and/or
black or brown material below the cage (fecal material). Therefore,
with respect to all the physiological parameters evaluated as a
part of this cardiovascular study, a
no-observable-adverse-effect-level (NOAEL) of 600 mg/kg has been
established.
Example 6
Effects of Crofelemer on Herg K.sup.+ Currents in Hek-293 Cells
[0117] The hERG channel was stably expressed in a subclone
(HEK-293/hERG) of the HEK-293 cell line. The effect of Crofelemer
was measured on the maximum amplitude of the tail current. This
parameter was determined from current traces obtained from
voltage-clamped HEK-293/hERG cells, using patch-clamp techniques in
the whole cell configuration.
[0118] Crofelemer was tested at 5 concentrations for the first set
of experiments: 0.001 .mu.M, 0.01 .mu.M, 0.1 .mu.M, 1.0 .mu.M, and
10.0 .mu.M and 6 concentrations for the second set of experiments:
0.1 .mu.M, 0.3 .mu.M, 1 .mu.M, 3 .mu.M, 10 .mu.M, and 30 .mu.M.
Positive control article was tested at 10 .mu.M. Negative control
article was deionized water.
[0119] Crofelemer inhibited hERG tail current in a dose-dependent
manner. The estimated 1050 values were 1.79 .mu.M for the first set
of experiments and 1.75 .mu.M for the second set of experiments.
Cisapride (positive control, 10 .mu.M) inhibited hERG tail current
by an average of 99.67% and 100.47% for the first and second sets
of experiments respectively, which is consistent with its known
pharmacological action.
Example 7
Effects of Food on the PK of Crofelemer 500 Mg
[0120] A total of 28 subjects were to be enrolled into this study.
Subjects were randomized on Day 1 at a 1:1 ratio to Group 1 (fasted
then fed) or Group 2 (fed then fasted). Randomization was
stratified by sex. Each subject received a single dose of
crofelemer 500 mg (administered orally as 2.times.250 mg tablets)
with a high fat meal (crofelemer fed) and after fasting (crofelemer
fasted). The fasted/fed study periods were separated by 7 days. The
sequence of fasted/fed or fed/fasted dosing on Days 1 and 8 were
determined by randomization on Day 1.
[0121] Blood samples for PK analyses of crofelemer were collected
pre-dose and up to 48 hours post-dose following both fasted and fed
single-dose treatment administrations.
[0122] During the food effect study period, subjects fasted
overnight (no food for approximately 9.5 hours) prior to
administration of a high fat breakfast (crofelemer fed) or fasted
overnight for 10 hours prior to administration of the single dose
of study drug (crofelemer fasted).
[0123] Assessments of the treatment regimen on the relative
bioavailability of crofelemer were based on comparisons of plasma
concentrations of crofelemer across each study phase. Whole blood
samples were drawn at the following times (actual blood collection
times were recorded in the source/eCRF): Days 1 and 8: pre-dose
(approximately 1 hour before dosing), and at 0.5, 1, 2, 4, 6, 8,
10, 12, 16, 24, 30, 36, 42, and 48 hours post-dose.
[0124] A pharmacokinetic/pharmacodynamic (PK/PD) analysis was
intended to be performed using all subjects who had paired ECG and
plasma concentrations for crofelemer. The PK/PD
pharmacokinetic-pharmacodynamic analysis was not done due to
insufficient pharmacokinetic PK data.
[0125] This analysis was also designed to assess the relationship
between the concentration of crofelemer and QTcF. However, only 3
samples were found to have concentrations above the LLOQ of 50
ng/mL so the relationship of crofelemer concentration to QTcF could
not be assessed.
[0126] The mean baseline corrected change in heart rate showed a
decrease in heart rate of -1.1 bpm and -1.0 bpm for crofelemer
fasting and fed, respectively, at 4 hours. The mean baseline
corrected change in heart rate showed an increase in heart rate of
3.5 bpm and 1.6 bpm for crofelemer fasting and fed, respectively,
at 12 hours. The heart rate changes were of no clinical
significance. There were no tachycardic or bradycardic outliers on
crofelemer fasting or fed.
Example 8
Efficacy and Safety of Crofelemer for the Treatment of HIV
Associated Diarrhea
[0127] This study was conducted to determine if treatment with
Crofelemer 125 mg, 250 mg and 500 mg orally (p.o.) twice daily
improves the frequency, consistency, and urgency of bowel movements
in subjects with HIV-associated diarrhea compared to placebo. Male
or female subjects aged .gtoreq.18 years, with HIV-1 infection
confirmed by standard serological tests and/or viral load and
history of diarrhea of at least 1 month duration
[0128] The study was a randomized, double-blind, parallel-group,
placebo-controlled, multicenter study The study was done in two
stages. Both stages consisted of a 10+4 day, single-blind, placebo
screening phase; followed by randomization and a 31-day,
double-blind, placebo-controlled treatment phase; and concluded
with a 20-week placebo-free extension phase. In Stage I (dose
selection stage), the double-blind phase had four arms: three doses
of crofelemer (125 mg b.i.d., 250 mg b.i.d., and 500 mg b.i.d.) and
placebo b.i.d. The chance of receiving crofelemer or placebo was
3:1 (1:1:1:1 ratio). Subjects on crofelemer rolling over into the
extension phase remained on their same dose, or if on placebo was
re-randomized to one of the three aforementioned doses. After Stage
I is completed an interim analysis was conducted and the dose of
crofelemer that appears to work better, be safer, and/or better
tolerated than the others, was selected to use exclusively in Stage
II. Stage II will have only two arms in the double blind,
placebo-controlled treatment phase: the selected dose of crofelemer
(crofelemer 125 mg) and placebo. The chances of receiving
crofelemer or placebo will be 1:1. All subjects rolling over into
the 20-week placebo-free extension phase in Stage II were assigned
the previously selected dose of crofelemer. During both Stage I and
Stage II, subjects will first enter a single-blind placebo
screening phase lasting 10+4 days during which time bowel movement
frequency, consistency, and urgency was measured. Antiretroviral
therapy and therapy for associated conditions (including
prophylactic antibiotics for Pneumocystis carinii (PCP) or
infection must have remained at a constant level from four weeks
prior to screening through the placebo-controlled treatment phase.
Any changes in antiretroviral therapy during any point in the study
must be reported to the site and documented on the subject's case
report form.
[0129] The key efficacy analyses were based on the data from the
4-week efficacy assessment period of the placebo-controlled
treatment phase. Analysis of the primary endpoint was based on the
Intent to Treat (ITT) population and will compare the proportion of
responders in the placebo group to the proportion of responders in
the crofelemer 125 mg group. The primary efficacy endpoint was
clinical response, defined as two or less watery bowel movements
per week, during at least two of the four weeks of the 4-week
efficacy assessment period in the ITT population. The secondary
efficacy variables during the 4-week efficacy assessment period in
the ITT population were: [0130] The number of bowel movements per
day [0131] The number of watery bowel movements per day; [0132] The
score for daily abdominal pain or discomfort; [0133] The score for
daily stool consistency; [0134] The number of days per week that
subjects experienced urgency; [0135] The number of days per week
that subjects experienced fecal incontinence; and [0136] Proportion
of subjects undergoing an unscheduled visit for a significant
worsening or clinically significant exacerbation of diarrhea during
the 4-week efficacy assessment period.
[0137] This study consisted of a dose-selection stage, an interim
analysis period, and a dose-assessment stage.
Stage I: Dose-selection stage
[0138] Subjects were randomized 1:1:1:1, at approximately 50
subjects per treatment group: crofelemer 125 mg p.o. b.i.d.;
crofelemer 250 mg p.o. b.i.d.; crofelemer 500 mg p.o. b.i.d.; and
placebo p.o. b.i.d.
[0139] Crofelemer 125 mg, 250 mg, and 500 mg, or matching placebo,
was administered as a tablet combination orally twice daily with
fluids at least one half hour before the morning and evening
meals.
[0140] The double-blind, placebo-controlled treatment phase
consisted of an initial 3-day run-in period (Days -3 to -1)
followed by a 4-week efficacy assessment period (Days 1 to 28). The
run-in period assured that the effects of study medication were
established before the 4-week efficacy assessment period is
commenced.
[0141] Subjects who completed the placebo-controlled treatment
phase entered a 20-week placebo-free extension phase. Subjects in
the Crofelemer 125 mg p.o. b.i.d., Crofelemer 250 mg p.o. b.i.d or
Crofelemer 500 mg b.i.d. groups continued to receive these
therapies throughout the placebo-free treatment phase; subjects who
received placebo were re-randomized to receive either Crofelemer
125 mg p.o. b.i.d, Crofelemer 250 mg p.o. b.i.d. or 500 mg p.o.
b.i.d (1:1:1). There was no risk of placebo during the 20-week
extension phase, and subjects were permitted ad libitum (prn) use
of ADM.
[0142] Stage I ended when about 50 subjects were randomized to each
of the four treatment groups. Enrollment was stopped at
approximately 50 subjects per treatment group until the interim
analysis and decision for Stage II are completed.
Interim Analysis
[0143] An interim analysis was performed when approximately 50
subjects (actual totals in the Tables, which follow) were
randomized to each of four treatment groups and completed the
placebo-controlled treatment period or terminate the study (not in
either case to include the 14-day post-dosing telephone call for
assessment of adverse events). Based upon an assessment of efficacy
and safety, subjects were select to continue one of the crofelemer
doses along with placebo into Stage II.
Stage II: Dose-Assessment Stage
[0144] Once the interim analysis was completed, enrollment resumed.
Subjects were screened for eligibility for randomization based on
the criteria in Stage I. Subjects who enter the double-blind,
placebo-controlled treatment phase in Stage II were randomized to
one of two treatment groups: crofelemer 125 mg p.o. b.i.d. or
placebo p.o. b.i.d.
[0145] Crofelemer 125 mg, 250 mg, and 500 mg, or matching placebo,
was administered as a tablet combination orally twice daily with
fluids at least one half hour before the morning and evening
meals.
[0146] An objective of the dose-assessment stage was to determine
the proportion of HIV-positive subjects experiencing relief of
diarrhea with crofelemer 125 mg p.o. b.i.d. compared to placebo
p.o. b.i.d. during the placebo-controlled treatment phase. Other
objectives were to evaluate the effects of crofelemer 125 mg p.o.
b.i.d. vs. placebo on:
[0147] i. Number of bowel movements per day (frequency)
[0148] ii. Number of watery bowel movements per day
[0149] iii. Symptom frequency (urgency, fecal incontinence)
[0150] iv. Symptom severity (abdominal pain or discomfort); and
[0151] v. Daily stool consistency score.
[0152] The ratio of randomization to crofelemer 125 mg p.o. b.i.d
or placebo p.o. b.i.d was 1:1. Subjects who completed the
double-blind treatment phase participated in the 20-week,
placebo-free extension phase and received crofelemer 125 mg p.o.
b.i.d. Subjects who enrolled in Stage I, and who received either
crofelemer 125 mg p.o. b.i.d., 250 mg p.o. b.i.d. or 500 mg p.o.
b.i.d, remained on their previously assigned dose. However,
subjects were re-assigned to crofelemer 125 mg p.o. b.i.d. if, in
the opinion of the investigator, the response to or tolerance to
their current dose was inadequate. Treatment remained blinded
during this treatment period, including the possibility that
subjects were switched to the same dose they had initially been
taking.
[0153] All study procedures performed in Stage I were otherwise be
identical to Stage II.
[0154] Subjects randomized during Stages I and II were combined and
included in sample size calculations and analysis of efficacy and
safety.
[0155] The following criteria were used for collecting data to
evaluate the efficacy of crofelemer on HIV-associated diarrhea.
Study Diary (IVRS) Definitions
[0156] Diarrhea, includes, frequent loose or watery bowel movements
Bowel movement is defined as a trip to the bathroom with evacuation
of stool; number of bowel movements means number of trips to the
bathroom with evacuation of [0157] Watery bowel movement is defined
as stool that can be poured; [0158] Loose bowel movement is defined
as soft blobs with no shape or form; [0159] Formed bowel movement
is defined as a stool like a soft sausage; [0160] Hard bowel
movement is defined as a stool like a hard or lumpy sausage; and
[0161] Very hard bowel movement is defined as hard lumps or nuts
that are hard to pass.
[0162] Urgency is defined as having to rush to the bathroom for a
bowel movement Fecal incontinence is defined as leaking or passing
stool at unwanted times (two teaspoons or more of stool).
[0163] Abdominal pain or discomfort is defined as pain, cramping,
or bloating that is uncomfortable and/or interrupts normal
activities.
Stool Samples
[0164] Each sample collected was analyzed as follows:
[0165] Visit 0 [0166] Clostridium difficile toxin; [0167] Enteric
pathogens, O&P examination; [0168] Giardia-specific antigen by
EIA; [0169] Modified acid-fast stain for Cryptosporidium,
Cyclospora, and Isospora; [0170] Lactoferrin (qualitative); and
[0171] Occult blood.
[0172] Visit 3 [0173] Clostridium difficile toxin; [0174] Enteric
pathogens, O&P examination; [0175] Giardia-specific antigen by
EIA; and [0176] Modified acid-fast stain for Cryptosporidium,
Cyclospora, and Isospora.
[0177] Visits 4, 5, 6, 7 and 8 [0178] Clostridium difficile toxin;
[0179] Enteric pathogens, O&P examination [0180]
Giardia-specific antigen by EIA [0181] Modified acid-fast stain for
Cryptosporidium, Cyclospora, and Isospora
Analysis of the Primary Efficacy Variable
[0182] The primary efficacy endpoint is clinical response; subjects
are classified responders if they reported two or less watery bowel
movements per week, during at least two of the four weeks of the
efficacy assessment period of the placebo-controlled treatment
phase.
Analysis of Secondary Efficacy Variables
[0183] For every subject, a mean baseline, a mean for Weeks 1 to 4,
and change from baseline will be calculated for the following
variables: [0184] Number of bowel movements per day; [0185] Number
of watery bowel movements per day; [0186] Daily abdominal pain or
discomfort score; [0187] Daily stool consistency score; [0188] The
number of days per week that subjects experienced urgency; and
[0189] The number of days per week that subjects experienced fecal
incontinence.
[0190] Each of the secondary continuous variables will be analyzed
as percent change from baseline.
[0191] The daily abdominal pain or discomfort score were assigned
scores as follows: none=0, mild=1, moderate=2, severe=3, that is
the greater the score the worse the pain or discomfort. Stool
consistencies will be assigned scores as follows: 1=very hard,
2=hard, 3=formed, 4=loose, 5=watery for each bowel movement.
[0192] The stool consistency score was computed from the mean of
these scores each day.
[0193] Table 1 below shows the baseline characteristics for the
placebo-controlled treatment phase, including the diagnosed cause
of diarrhea, the CD4 cell count and the CD4 cell category. This
table demonstrates that the subjects in each group were
similar.
TABLE-US-00001 TABLE 1 Baseline Characteristics in the
Placebo-Controlled Treatment Phase Crofelmer Crofelmer Crofelmer
Baseline Disease Placebo 125 mg * 250 mg 500 mg All Crofelmer
Characteristics (N = 138) (N = 138) (N = 54) (N = 47) (N = 239)
Cause of diarrhea Antiretroviral therapy 104 (75.4%) 104 (75.4%) 37
(68.5%) 30 (63.8%) 171 (71.5%) HIV infection of intestine 33
(23.9%) 32 (23.2% 15 (27.8%) 15 (31.9%) 62 (25.9%) Other 1 (0.7%) 2
(1.4%) 2 (3.7%) 2 (4.3%) 6 (2.5%) CD4 cell counts n 138 137 54 46
237 Mean 530.5 497.8 425.2 481.7 478.1 SD 244.79 230.88 226.13
275.18 239.81 Median 518.5 479.0 374.0 421.5 429.0 Min 76 111 100
149 100 Max 1298 1183 1095 1734 1734 CD4 cell Category <404 39
(28.3%) 55 (39.9%) 29 (53.7%) 21 (44.7%) 105 (3.9%) >=404 99
(71.7%) 32 (59.4%) 25 (46.3%) 25 (53.2%) 132 (55.2%; [1] Baseline
was the average of daily data from the 7 days prior to first dose
day of randomized study drug. [2] Baseline was the average of daily
stool consistency scores from the 7 days prior to first dose day of
randomized study drug. The daily score = (1*# of very hard stools +
2*# of hard stools + 3*# of formed stools + 4*# of loose stools +
5*# of watery stools)/(# of total stools). [3] Baseline was the
average of daily scores from the 7 days prior to first dose day of
randomized study drug, none = 0, mild = 1, moderate = 2, severe =
3. [4] Baseline = 7*A/B, A = # of days with event during the 7 days
prior to first dose day of randomized study drug, B = # of days
with non-missing assessments.
[0194] Table 2 below shows additional baseline characteristics of
the placebo-controlled treatment phase, including use of
antibiotics during the study.
TABLE-US-00002 TABLE 2 Baseline Characteristics of the
Placebo-Controlled Treatment Phase Crofelmer Crofelmer Crofelmer
Baseline Disease Placebo 125 mg* 250 mg 500 mg All Crofelmer
Characteristics (N = 138) (N = 138) (N = 54) (N = 47) (N = 239) Use
of a new antibiotic regimen during placebo-controlled treatment
phase Yes 14 (10.1%) 9 (6.5%) 2 (3.7%) 1 (2.1%) 12 (5.0%) No 124
(89.9%) 129 (92.5%) 52 (96.3%) 46 (97.9%) 227 (95.0%)
Tables 3 and 3a below show the percentage of subjects with clinical
response, e.g., improvement of watery diarrhea, in the
placebo-controlled treatment phase, and the change in response from
baseline as a function of time, respectively. As can be seen from
Table 3, all three treatment groups from Stage I were statistically
significant for treatment of watery diarrhea, as well at the
combined group of subjects dosed 125 mg in both stages. Table 3a
sets forth data indicating that, regardless of treatment group, the
primary endpoint (Clinical Response) demonstrated responsiveness by
consistently correlating with other daily assessments collected in
the study for changes in symptoms scoring. Responders, i.e.,
subjects with .ltoreq.2 watery stools per week, had significantly
greater improvements in daily symptom severity scores than
non-responders at each week during the course of the study.
TABLE-US-00003 TABLE 3 Primary Efficacy Endpoint: Percentage of
Subjects with Clinical Response in the Placebo-Controlled Treatment
Phase Crofelmer Crofelmer Crofelmer Placebo 125 mg* 250 mg 500 mg
(N = 138) (N = 136) (N = 54) (N = 46) Stage I Responder - n/Ni (%)
1/50 9/44 5/54 9/46 (2.0%) (20.5%) (9.3%) (19.6%) Treatment 18.5%
7.3% 17.6% Difference (vs. Placebo) 1-Sided 97.5% CI (1) (6.0%,
.sup.00) (-1.7%, .sup.00) (5.3%, .sup.00) 1-Sided P-value 0.0019
0.0563 0.0024 (vs. Placebo) [1] Combined Responder - n/Ni (%)
11/138 24/136 (8.0%) (17.6%) Treatment 9.6% Difference (vs.
Placebo) 1-Sided 97.5% CI (1) (1.2%,.sup.00) 1-Sided P-value 0.0096
(vs. Placebo) [1]
TABLE-US-00004 TABLE 3A Responsiveness of the Primary Endpoint
(Clinical Response) - Clinical Response.sup.a: Clinical
Response.sup.a: Weekly Responder Weekly Non-Responder Difference
Week Mean Change from Mean Change from Responder - Daily Question
Baseline (.+-.SD) Baseline (.+-.SD) Non-Responder p-value Week 1
Daily Watery Stools -1.75 (0.901) -0.51 (1.296) -1.24 <0.0001
Daily Stool Consistency.sup.b -1.08 (0.589) -0.19 (0.381) -0.90
<0.0001 Daily Abdominal Pain.sup.c -0.41 (0.651) -0.11 (0.493)
-0.30 0.0217 Urgency.sup.d -2.97 (2.299) -0.75 (1.908) -2.22
<0.0001 Fecal Incontinence.sup.e -1.48 (2.007) -0.43 (1.867)
-1.06 0.0144 Daily Stool Frequency -1.13 (1.299) -0.31 (1.810)
-0.83 <0.0001 Week 2 Daily Watery Stools -2.03 (1.184) -0.53
(1.392) -1.50 <0.0001 Daily Stool Consistency.sup.b -1.14
(0.672) -0.17 (0.379) -0.97 <0.0001 Daily Abdominal Pain.sup.c
-0.61 (0.701) -0.12 (0.494) -0.49 <0.0001 Urgency.sup.d -2.79
(2.418) -0.79 (2.014) -2.00 <0.0001 Fecal Incontinence.sup.e
-1.71 (2.071) -0.44 (1.982) -1.27 <0.0001 Daily Stool Frequency
-1.18 (1.331) -0.34 (1.851) -0.83 <0.0001 Week 3 Daily Watery
Stools -2.00 (1.280) -0.65 (1.408) -1.35 <0.0001 Daily Stool
Consistency.sup.b -1.20 (0.734) -0.22 (0.382) -0.98 <0.0001
Daily Abdominal Pain.sup.c -0.51 (0.668) -0.17 (0.517) -0.34 0.0016
Urgency.sup.d -3.41 (2.215) -0.98 (2.253) -2.43 <0.0001 Fecal
Incontinence.sup.e -1.65 (2.228) -0.64 (2.121) -1.01 0.0015 Daily
Stool Frequency -1.20 (1.314) -0.41 (1.992) -0.79 <0.0001 Week 4
Daily Watery Stools -1.89 (1.058) -0.68 (1.430) -1.21 <0.0001
Daily Stool Consistency.sup.b -1.07 (0.645) -0.24 (0.410) -0.83
<0.0001 Daily Abdominal Pain.sup.c -0.48 (0.658) -0.19 (0.533)
-0.28 0.0058 Urgency.sup.d -3.11 (2.411) -0.99 (2.166) -2.12
<0.0001 Fecal Incontinence.sup.e -1.75 (2.140) -0.57 (2.085)
-1.18 <0.0001 Daily Stool Frequency -1.07 (1.086) -0.43 (2.039)
-0.64 <0.0001 .sup.aClinical response in a week was defined as
.ltoreq. 2 watery stools during a given week. .sup.bStool
consistency response was defined as <4 daily stool consistency
score during a given week .sup.cAbdominal pain and discomfort
score: 0 = none, 1 = mild, 2 = moderate, and 3 = severe.
.sup.dNumber of days per week with urgency = 7 * A/B, where A = #
of days with urgency in the week, and B = # of days with
assessments in the week. .sup.eNumber of days per week with fecal
incontinence = 7 * A/B, where A = # of days with fecal incontinence
in the week, and B = # of days with assessments in the week.
.sup.fP-values were obtained from a Wilcoxon rank-sum test for
comparison of the responder vs. non-responder groups.
[0195] Table 4 below shows the number of weeks of clinical response
of subjects in the study. As shown below, the subjects dosed with
500 mg BID had more weeks of response to the treatment.
TABLE-US-00005 TABLE 4 Number of Weeks with Clinical Response in
the Placebo-Controlled Treatment Phase Number of Crofelmer
Crofelmer Crofelmer Weeks Placebo 125 mg* 250 mg 500 mg Responded
(N = 138) (N = 136) (N = 54) (N = 46) Stage I Number of N = 50 N =
44 N = 54 N = 46 Subjects 0 week 43 (86.0%) 32 (72.7%) 41 (75.9%)
25 (60.9%) 1 week 6 (12.0%) 2 (4.5%) 8 (14.8%) 9 (19.6%) 2 weeks 2
(4.5%) 2 (3.7%) 4 (8.7%) 3 weeks 4 (9.1%) 2 (3.7%) 4 (8.7%) 4 weeks
1 (2.0%) 3 (6.8%) 1 (1.9%) 1 (2.2%) Crofelemer vs. Placebo [1] Odds
Ratio 2.41 2.02 4.21 95% CI (0.84, 6.87) (0.74, 5.56) (1.56, 11.33)
p-value 0.1011 0.1727 0.0045
[0196] Table 5 below shows subjects with clinical response by
month. As can be seen from the Table, responding subjects and
response rate increases the longer a subject was administered
crofelemer.
TABLE-US-00006 TABLE 5 Subjects with Monthly Clinical Response by
Month in the Placebo-Free Extension Phase Crofelmer Crofelmer
Crofelmer 125 mg* 250 mg 500 mg All Crofelemer Responders in
Placebo- (N = 219) (N = 68) (N = 50) (N = 337) free Extension Phase
n (%) n (%) n (%) n (%) Month 1 87/218 (39.9%) 19/68 (27.9%) 14/50
(28.0%) 120/336 (35.7%) Month 2 99/208 (47.6%) 31/60 (51.7%) 19/48
(39.6%) 149/316 (47.2%) Month 3 111/198 (56.1%) 30/58 (51.7%) 17/47
(36.2%) 158/303 (52.1%) Month 4 99/178 (55.6%) 27/54 (50.0%) 20/44
(45.5%) 146/276 (52.9%) Month 5 90/155 (58.1%) 30/53 (56.6%) 17/42
(40.5%) 137/250 (54.8%)
[0197] Table 6 below shows the percent of subjects with stool
consistency response to crofelemer. As can be seen from Table 6,
subjects administered 500 mg and 250 mg BID responded better than
did the 125 mg BID or the 250 mg BID.
TABLE-US-00007 TABLE 6 Percentage of Subjects with Stool
Consistency Response in the Placebo-Controlled Treatment Phase
Crofelmer Crofelmer Crofelmer Placebo 125 mg* 250 mg 500 mg (N =
138) (N = 136) (N = 54) (N = 46) Stage I Responder - 11/50 14/44
20/54 23/46 n/Ni (%) (22.0%) (31.8%) (37.0%) (50.0%) Treatment 9.8%
15.0% 28.0% Difference vs. Placebo 1-Sided 97.5% (-8.1%, .sup.00)
(-2.6%, .sup.00) (-8.8%, .sup.00) CI [1] 1-Sided P-value 0.1412
0.0470 0.0021 (vs. lacebo) [1] Combined Responder - 49/186 53/136
n/Ni (%) (35.5%) (39.0%) Treatment 3.5% Difference vs. Placebo
1-Sided 97.5% [-5.0%, .sup.00) CI [1] 1-Sided P-value 0.1428 (vs.
lacebo) [1]
[0198] Table 7 below shows the number of months of clinical
response by subjects on crofelemer in the study. Table 7 again
demonstrates that the longer the treatment, the better the response
to treatment.
TABLE-US-00008 TABLE 7 Number of Months with Clinical Response in
the Placebo-Free Extension Phase Number of Crofelmer Crofelmer
Crofelmer Weeks 125 mg* 250 mg 500 mg Responded (N = 219) (N = 66)
(N = 50) 0 month 69 (31.5%) 25 (36.8%) 25 (50.0%) 1 month 31
(14.2%) 6 (8.8%) 4 (8.0%) 2 months 19 (8.7%) 10 (14.7%) 4 (8.0%) 3
months 29 (13.2%) 7 (10.3%) 3 (6.0%) 4 months 25 (11.4%) 10 (14.7%)
4 (8.0%) 5 months 46 (21.0%) 10 (14.7%) 10 (20.0%)
[0199] Table 8 below shows the percentage of Caucasian and Hispanic
subjects and all other races with clinical response. This table
demonstrates that the Caucasian and Hispanic populations receiving
crofelemer responded well to treatment.
TABLE-US-00009 TABLE 8 Percentage of Subjects with Clinical
Response by Race in the Placebo-Controlled Treatment Phase
Crofelmer Crofelmer Crofelmer Placebo 125 mg* 250 mg 500 mg Race:
White/Hispanic (N = 83) (N = 84) (N = 44) (N = 38) Stage I
Responder - n/Ni (%) 0/36 (0.0%) 7/31 (22.6%) 3/44 (6.8%) 8/38
(21.1%) Treatment Difference vs. 22.6% 6.5% 21.1% Placebo [95% CI]
[7.9%, 37.3%] [-0.6%, 14.3%] [8.14%, 34.0%] P-value vs. Placebo [1]
0.0030 0.2481 0.0053 Combined Responder - n/Ni (%) 6/83 (7.2%)
19/84 (22.6%) Treatment Difference vs. 15.4% Placebo [95% CI]
[4.9%, 25.9%] P-value (vs. Placebo) [1] 0.0083 Crofelmer Crofelmer
Crofelmer Placebo 125 mg* 250 mg 500 mg Race: Other (N = 55) (N =
52) (N = 10) (N = 8) Stage I Responder - n/Ni (%) 1/14 (7.1%) 2/13
(15.4%) 2/10 (20.0%) 1/8 (12.5%) Treatment Difference vs. 8.2%
12.9% 5.4% Placebo [95% CI] [-15.6%, 32.0%] [-15.4%, 41.1%]
[-21.2%, 32.0%] P-value vs. Placebo [1] 0.5956 0.5504 1.0000
Combined Responder - n/Ni (%) 5/55 (9.1%) 5/52 (9.6%) Treatment
Difference vs. 0.5% Placebo [95% CI] [-10.5%, 11.6%] P-value (vs.
Placebo) [1] 1.0000 Note: Clinical response was defined as <=2
watery stools per week during at least 2 of the 4 efficacy
assessment weeks. Note: Percentage is based on Ni, number of
subjects entered the stage or combine.
[0200] In another study, 400 subjects with chronic HIV associated
diarrhea were treated with crofelemer or placebo for 7 days in an
inpatient setting. Crofelemer was given at doses of 250 mg and 500
mg enteric-coated tablets or 500 mg enteric-coated beads four times
daily, compared to a matching placebo. Subjects who responded to
treatment were continued in a three-week blinded outpatient phase.
The difference in decreased stool weight between subjects receiving
crofelemer and subjects receiving placebo was not statistically
significant by the primary efficacy analysis.
[0201] However, reanalysis of these data revealed that
approximately 50% of the study population did not have watery
diarrhea at study entry. Evaluation of the population with watery
diarrhea and urgency at baseline revealed statistically significant
improvement in stool frequency and weight (p<0.05) with
treatment. Changes in abnormal (watery and loose) stools were even
greater, with significant (p<0.015) improvements in abnormal
stool weight and frequency observed at Day 7. Approximately 3 days
were necessary for the anti-diarrheal effects of crofelemer to
stabilize.
[0202] Table 9 below shows additional supportive data showing that
crofelemer 125 mg, 250 mg and 500 mg were efficacious at treating
HIV associated diarrhea.
TABLE-US-00010 TABLE 9 Primary Efficacy Endpoint Percentage of
Subjects with Clinical Response* Crofelemer Crofelemer Crofelemer
Placebo 125 mg 250 mg 500 mg (N = 138) (N = 136) (N = 54) (N = 46)
Stage 1 Responder 1/50 9/44 5/54 9/46 (2.0%) (20.5%) (9.3%) (19.6%)
Treatment 18.50% 7.30% 17.60% Difference Stage 2 Responder 10/88
15/92 (11.4%) (16.3%) Treatment 4.90% Difference Combined Responder
11/138 24/136 (8.0%) (17.6%) Treatment 9.60% Difference 1-Sided
97.5% CI [1.2%, .infin.) 1-Sided P-value 0.0096 (vs. Placebo)
*.ltoreq.2 watery BM/wk during .gtoreq.2 of 4 wks of the 4-wk
placebo controlled period
[0203] Table 10 below shows that crofelemer is particularly
efficacious in treating males with HIV associated diarrhea.
Additional subgroup analysis is show in FIG. 1. The primary
endpoint was analyzed in subgroups defined by demographics and
baseline characteristics to assess the consistency of the treatment
effect. FIG. 1 provides a summary of each of these subgroup
analyses, showing the treatment difference in percentage of
responders (crofelemer 125 mg BID vs. placebo) with associated
confidence intervals and p-values. As shown in the figure,
consistent efficacy was observed across subgroups; a higher
percentage of subjects treated with crofelemer 125 mg BID
experienced clinical response compared with placebo in all
subgroups analyzed.
TABLE-US-00011 TABLE 10 Effects Across Demographic & Baseline
Characteristics - Gender* Crofelemer 125 mg Placebo (N = 138) (N =
136) Gender: Male Responder - n/Ni (%) 9/116 (7.8%) 22/115 (19.1%)
Treatment Difference vs Placebo 11.40% [95% CI] [2.7%, 20.1%]
P-value vs Placebo 0.0124 Gender: Female Responder - n/Ni (%) 2/22
(9.1%) 2/21 (9.5%) Treatment Difference vs Placebo 0.40% [95% CI]
[-16.9%, 17.8%] P-value vs Placebo 1 *Clinical response was defined
as <=2 watery stools per week during at least 2 of the 4
efficacy assessment weeks. Intent-to-Treat Population.
[0204] According to one aspect, provided herein are methods of
treating HIV associated diarrhea or highly active antiretroviral
therapy (HAART) associated diarrhea in a male HIV positive subject,
comprising: administering about 250 mg to about 1000 mg per day;
administering about 250 mg per day; administering about 500 mg per
day; administering about 1000 mg per day; administering about 125
mg two times per day; administering about 250 mg two times per day;
or administering about 500 mg two times per day of crofelemer to a
male subject in need thereof.
[0205] Below, Table 11 shows that subject taking protease
inhibitors responded particularly well to treatment with
crofelemer.
TABLE-US-00012 TABLE 11 Effects Across Demographic & Baseline
Characteristics - Prior use of Protease Inhibitors* Crofelemer 125
mg Placebo (N = 138) (N = 136) Use of PI at Screening - Yes:
Responder - n/Ni (%) 6/97 (6.2%) 15/86 (17.4%) Treatment Difference
vs Placebo 11.30% [95% CI] [1.9%, 20.6%] P-value vs Placebo 0.0204
Use of PI at Screening - No: Responder - n/Ni (%) 5/41 (12.2%) 9/50
(18.0%) Treatment Difference vs Placebo 5.80% [95% CI] [-8.8%,
20.4%] P-value vs Placebo 0.5638 *Clinical response was defined as
<=2 watery stools per week during at least 2 of the 4 efficacy
assessment weeks. Intent-to-Treat Population
[0206] According to one aspect, provided herein are methods of
treating HIV associated diarrhea or highly active antiretroviral
therapy (HAART) associated diarrhea in an HIV positive subject that
lies previously used protease inhibitors, comprising: administering
about 250 mg to about 1000 mg per day; administering about 250 mg
per day; administering about 500 mg per day; administering about
1000 mg per day; administering about 125 mg two times per day;
administering about 250 mg two times per day; or administering
about 500 mg two times per day of crofelemer to a male subject in
need thereof. As used herein, "previously used" includes, for
example, subjects who have used protease inhibitors (PIs) prior to
crofelemer therapy or overlapping with crofelemer therapy, but the
PI use began prior to the first dose of crofelemer therapy.
TABLE-US-00013 TABLE 12 Secondary Efficacy Endpoints
Intent-to-Treat Population Watery BMs/day No treatment differences
between 125 mg vs. Pbo Stage 1: numerically greater in 500 mg vs.
Pbo (-0.91/day vs. -0.62/day; p = 0.0713) Stool consistency
Significant improvement for 125 mg vs. Pbo score (-0.35 vs. -0.25;
p = 0.0168) Daily abd No treatment differences between 125 mg vs.
Pbo pain/discomfort Stage 1: 125 mg vs. Pbo (-0.35 vs. -0.13; p =
0.0170) Days/wk with urgency No treatment differences between 125
vs. Pbo Days/wk with fecal Numerical differences for 125 mg vs. Pbo
incontinence (-0.96 vs. -0.55; p = 0.0643) BMs/day No treatment
differences between 125 mg vs. Pbo
[0207] FIG. 1 and Table 13 show subjects with clinical response in
the crossover to placebo-free phase of the safety population.
PC=Placebo-controlled Phase and PF=Placebo-free Phase. This data
shows that subjects previously on placebo had a sharp increase in
efficacy when they were crossed-over onto 125 mg crofelemer. This
data also demonstrates that crofelemer efficacy continued to rise
with length of use.
TABLE-US-00014 TABLE 13 Subjects with Clinical Response Crossover
to Placebo-Free Phase, Safety Population Crofelemer Crofelemer
Crofelemer Placebo 125 mg 250 mg 500 mg Month Statistic.sup.1 (N =
126) (N = 99) (N = 15) (N = 12) Month 1 Responder - n/Ni (%) 11/126
36/99 3/15 2/12 (16.7%) (8.7%) (36.4%) (20.0%) Odds Ratio (95% CI)
0.17 (0.09, 0.32) P-value (vs. Placebo in <.0001 PC) Month 2
Responder - n/Ni (%) 42/95 8/15 2/12 (16.7%) (44.2%) (53.3%) Odds
Ratio (95% CI) 0.12 (0.06, 0.24) P-value (vs. Placebo in <.0001
PC) Month 3 Responder - n/Ni (%) 48/89 5/14 2/11 (18.2%) (53.9%)
(35.7%) Odds Ratio (95% CI) 0.07 (0.03, 0.15) P-value (vs. Placebo
in <.0001 PC) Month 4 Responder - n/Ni (%) 43/77 5/13 2/9
(22.2%) (55.8%) (38.5%) Odds Ratio (95% CI) 0.07 (0.03, 0.15)
P-value (vs. Placebo in <.0001 PC) Month 5 Responder - n/Ni (%)
37/67 6/13 1/8 (12.5%) (55.2%) (46.2%) Odds Ratio (95% CI) 0.07
(0.03, 0.16) P-value (vs. Placebo in <.0001 PC) .sup.1Ratio of
responders and p value obtained from parameter estimates with
effect for treatment and region.
TABLE-US-00015 TABLE 14 Subjects with Stool Consistency Response*
Intent-to-Treat Population Crofelemer Crofelemer Crofelemer Placebo
125 mg 250 mg 500 mg (N = 138) (N = 136) (N = 54) (N = 46) Stage 1
Responder 11/50 13/44 20/54 23/46 (22.0%) (31.8%) (37.0%) (50.0%)
Treatment 9.80% 15.00% 28.00% Difference Stage 2 Responder 38/88
39/92 (43.2%) (42.4%) Treatment -0.80% Difference Combined
Responder 49/138 53/136 (35.5%) (39.0%) Treatment 3.50% Difference
*<4 stool consistency score at least 2 of the 4 efficacy
assessment weeks.
[0208] FIG. 2 and Table 14 show subjects with stool consistency
response in the crossover to placebo-free phase in the safety
population. PC=Placebo-controlled Phase and PF=Placebo-free Phase.
This data shows that subjects previously on placebo had a sharp
increase in efficacy when they were crossed-over onto 125 mg
crofelemer. This data also demonstrates that crofelemer efficacy
continued to rise with length of use.
TABLE-US-00016 TABLE 15 Subjects With Abnormal ECG Findings Safety
Population Crofelemer Crofelemer Crofelemer All Placebo 125 mg 250
mg 500 mg Crofelemer Characteristic, n (%) (N = 137) (N = 130) (N =
54) (N = 42) (N = 226) Post Baseline Abnormal 35 (25.5%) 34 (26.2%)
18 (33.3%) 13 (31.0%) 65 (28.8%) ECG Finding.sup.1 QT Interval
(msec) >450 with Baseline .ltoreq.450 2 (1.5%) 4 (3.1%) 1 (1.9%)
0 5 (2.2%) >480 with Baseline .ltoreq.480 1 (0.7%) 0 1 (1.9%) 0
1 (0.4%) >500 with Baseline .ltoreq.500 0 0 1 (1.9%) 0 1 (0.4%)
Change from Baseline 30-60 9 (6.6%) 4 (3.1%) 6 (11.1%) 3 (7.1%) 13
(5.8%) Change from Baseline >60 4 (2.9%) 1 (0.8%) 2 (3.7%) 0 3
(1.3%) QT Interval Linear Regression Correction (msec) >450 with
Baseline .ltoreq.450 2 (1.5%) 4 (3.1%) 1 (1.9%) 0 5 (2.2%) >480
with Baseline .ltoreq.480 1 (0.7%) 0 1 (1.9%) 0 1 (0.4%) >500
with Baseline .ltoreq.500 0 0 1 (1.9%) 0 1 (0.4%) Change from
Baseline 30-60 7 (5.1%) 4 (3.1%) 6 (11.1%) 3 (7.1%) 13 (5.8%)
Change from Baseline >60 4 (2.9%) 1 (0.8%) 2 (3.7%) 0 3 (1.3%)
QT Interval Fridericias's Correction (msec) >450 with Baseline
.ltoreq.450 6 (4.4%) 1 (0.8%) 2 (3.7%) 0 3 (1.3%) >480 with
Baseline .ltoreq.480 1 (0.7%) 1 (0.8%) 0 0 1 (0.4%) >500 with
Baseline .ltoreq.500 1 (0.7%) 0 0 0 0 Change from Baseline 30-60 3
(2.2%) 5 (3.8%) 2 (3.7%) 1 (2.4%) 8 (3.5%) Change from Baseline
>60 4 (2.9%) 0 1 (1.9%) 0 1 (0.4%) QT Interval Bazett's
Correction (msec) >450 with Baseline .ltoreq.450 8 (5.8%) 4
(3.1%) 2 (3.7%) 0 6 (2.7%) >480 with Baseline .ltoreq.480 2
(1.5%) 2 (1.5%) 1 (1.9%) 0 3 (1.3%) >500 with Baseline
.ltoreq.500 2 (1.5%) 0 0 0 0 Change from Baseline 30-60 7 (5.1%) 8
(6.2%) 3 (5.6%) 1 (2.4%) 12 (5.3%) Change from Baseline >60 3
(2.2%) 1 (0.8%) 1 (1.9%) 0 2 (0.9%)
[0209] Table 15 demonstrates that crofelemer is safe to be given to
subjects and that there are no QT Interval issues associated with
use. This is surprising and advantageous over other molecules used
to treat diarrhea and IBS, which are know to be associated with QT
issues.
[0210] From the above data and Figures, it has been demonstrated
that the proportion of clinical responders was significantly higher
in the crofelemer 125 mg group compared with placebo (p=0.0096;
Combined data). Subjects switching from placebo to crofelemer upon
conclusion of the placebo-controlled phase achieved rates of
clinical response of between 36.4% and 55.8% for each of the 5
months of the placebo-free phase (p<0.0001; for data collected
prior to lock). Stool consistency scores improved significantly in
subjects receiving 125 mg crofelemer compared with placebo
(p=0.0168; Combined data). Days per week that subjects experienced
fecal incontinence decreased in subjects receiving 125 mg
crofelemer compared with placebo (p=0.0643; Combined data). It is
also demonstrated that crofelemer was well tolerated and
demonstrated a safety profile comparable to placebo and no
clinically important differences in safety assessments have been
identified.
TABLE-US-00017 TABLE 16 Dose-Ranging Study for treatment of d-IBS:
All Randomized Subjects Design: P2, R, DB, PC, Dose-Ranging Study
for treatment of d-IBS Treatment: 125, 250, 500 mg Crofelemer
b.i.d. or Pbo for 12 weeks N: 125 mg: 62, 250 mg: 60, 250 mg: 62,
Pbo: 61 Primary Endpoint Daily stool consistency Outcome: ROME
Foundation Definition.sup.1 Month 1 = 2.6% Treatment .DELTA., 125
mg dose Month 2 = 9.0% Month 3 = 10.7% All 3 months: Odds Ratio
1.51 (0.78, 2.92) FDA Definition.sup.2 Month 1 = 0.6% Treatment
.DELTA., 125 mg dose Month 2 = 2.2% Month 3 = -4.4% All 3 months:
Odds Ratio 1.09 (0.54, 2.20) .sup.1ROME Foundation Stool
consistency weekly responder: Subjects with <25% days with loose
or watery stools in a given week. Based on Ad Hoc Table 1.1
.sup.2FDA Stool consistency weekly responder: Subjects with a
weekly average stool consistency score <4 (4 = Loose stool)
[0211] Table 16 demonstrates that crofelemer is an efficacious
treatment for d-IBS. It also demonstrates that crofelemer is an
efficacious treatment for treating abnormal stool consistency
associated with d-IBS.
[0212] In one embodiment, crofelemer is administered to treat
abnormal stool consistency associated with d-IBS for at least one
month.
[0213] In one embodiment, crofelemer is administered to treat
abnormal stool consistency associated with d-IBS from between one
month and two months or longer. In one embodiment, crofelemer is
administered to treat abnormal stool consistency associated with
d-IBS from between about one month and about three months or
longer.
[0214] In one embodiment, crofelemer is administered to treat
abnormal stool consistency associated with d-IBS for at least one
month at about 125 mg b.i.d. In one embodiment, crofelemer is
administered to treat abnormal stool consistency associated with
d-IBS from between one month and two months or longer at about 125
mg b.i.d. In one embodiment, crofelemer is administered to treat
abnormal stool consistency associated with d-IBS from between one
month and three months or longer at about 125 mg b.i.d.
TABLE-US-00018 TABLE 17 Dose-Ranging Study for treatment of d-IBS
All Randomized Female Subjects Design: P2, R, DB, PC, Dose-Ranging
Study for treatment of d-IBS Treatment: 125, 250, 500 mg Crofelemer
b.i.d. or Pbo for 12 weeks N (125 mg 125 mg: 46, Pbo: 46 females):
Primary Daily stool consistency Endpoint Outcome: ROME Foundation
Definition.sup.1 Month 1 = 6.5% Treatment .DELTA., 125 mg dose
Month 2 = 10.8% Month 3 = 10.8% All 3 months: Odds Ratio 1.88
(0.87, 4.06) FDA Definition.sup.2 Month 1 = -2.1% Treatment
.DELTA., 125 mg dose Month 2 = 2.2% Month 3 = -4.4% All 3 months:
Odds Ratio 1.20 (0.52, 2.75) .sup.1ROME Foundation Stool
consistency weekly responder: Subjects with <25% days with loose
or watery stools in a given week. Based on Ad Hoc Table 1.1
.sup.2FDA Stool consistency weekly responder: Subjects with a
weekly average stool consistency score <4 (4 = Loose stool)
[0215] Table 17 demonstrates that crofelemer is an efficacious
treatment for d-IBS, especially to treat d-IBS in females. It also
demonstrates that crofelemer is an efficacious treatment for
treating abnormal stool consistency associated with d-IBS, and
especially to treat abnormal stool consistency associated with
d-IBS in females.
[0216] In one embodiment, crofelemer is administered to treat
abnormal stool consistency associated with d-IBS in females for at
least one month at 125 mg b.i.d. In one embodiment, crofelemer is
administered to treat abnormal stool consistency associated with
d-IBS in females from between one month and two months at about 125
mg b.i.d. In one embodiment, crofelemer is administered to treat
abnormal stool consistency associated with d-IBS in females from
between one month and three months or longer at about 125 mg
b.i.d.
TABLE-US-00019 TABLE 18 Dose-Ranging Study for treatment of d-IBS
in females All Randomized Subjects Design: P2, R, DB, PC,
Dose-Ranging Study for treatment of d-IBS in females Treatment: 125
mg Crofelemer b.i.d. or Pbo for 12 weeks N: 125 mg: 120, Pbo: 120
Primary Endpoint Daily abdominal pain.sup.1 Outcome: Placebo (N =
120) 125 mg (N = 120) P-value Month 1 66 (55.0%) 75 (62.5%) 0.2316
Month 2 61 (50.8%) 82 (68.3%) 0.0059 Month 3 65 (54.2%) 79 (65.8%)
0.0662 All 3 Months Odds Ratio: 1.67 (1.03, 2.70); p = 0.0357
.sup.1Abdominal pain weekly responder is defined as subjects with
at least 30% improvement compared to baseline abdominal pain score
in a given week
[0217] Table 18 demonstrates that crofelemer is an efficacious
treatment for d-IBS, especially to treat d-IBS in females. It also
demonstrates that crofelemer is an efficacious treatment for
treating abdominal pain associated with d-IBS, and especially to
treat abdominal pain associated with d-IBS in females.
[0218] In one embodiment, crofelemer is administered to treat d-IBS
for at least one month.
[0219] In one embodiment, crofelemer is administered to treat d-IBS
from between one month and two months or longer. In one embodiment,
crofelemer is administered to treat d-IBS from between about one
month and about three months or longer.
[0220] In one embodiment, crofelemer is administered to treat d-IBS
for at least one month at about 125 mg b.i.d. In one embodiment,
crofelemer is administered to treat d-IBS from between one month
and two months or longer at about 125 mg b.i.d. In one embodiment,
crofelemer is administered to treat d-IBS from between one month
and three months or longer at about 125 mg b.i.d.
[0221] In one embodiment, crofelemer is administered to treat d-IBS
in females for at least one month at 125 mg b.i.d. In one
embodiment, crofelemer is administered to treat d-IBS in females
from between one month and two months at about 125 mg b.i.d. In one
embodiment, crofelemer is administered to treat d-IBS in females
from between one month and three months or longer at about 125 mg
b.i.d.
[0222] In one embodiment, crofelemer is administered to treat
abdominal pain associated with d-IBS for at least one month.
[0223] In one embodiment, crofelemer is administered to treat
abdominal pain associated with d-IBS from between one month and two
months or longer. In one embodiment, crofelemer is administered to
treat abdominal pain associated with d-IBS from between about one
month and about three months or longer.
[0224] In one embodiment, crofelemer is administered to treat
abdominal pain associated with d-IBS for at least one month at
about 125 mg b.i.d. In one embodiment, crofelemer is administered
to treat abdominal pain associated with d-IBS from between one
month and two months or longer at about 125 mg b.i.d. In one
embodiment, crofelemer is administered to treat abdominal pain
associated with d-IBS from between one month and three months or
longer at about 125 mg b.i.d.
[0225] In one embodiment, crofelemer is administered to treat
abdominal pain associated with d-IBS in females for at least one
month at 125 mg b.i.d. In one embodiment, crofelemer is
administered to treat abdominal pain associated with d-IBS in
females from between one month and two months at about 125 mg
b.i.d. In one embodiment, crofelemer is administered to treat
abdominal pain associated with d-IBS in females from between one
month and three months or longer at about 125 mg b.i.d.
Example 10
A Double-blind, Randomized, Placebo-Controlled, Phase II Study to
Assess the Safety and Efficacy of Orally Administered Crofelemer
for the Symptomatic Treatment of Diarrhea in Acquired
Immunodeficiency Syndrome (AIDS) Patients
[0226] This study was a randomized, double-blind, multicenter (2
study sites), placebo-controlled, parallel-group study designed to
assess the efficacy and safety of crofelemer 500 mg beads in
subjects with HIV-associated diarrhea.
[0227] The primary objectives of the study were to evaluate the
safety and efficacy of orally administered crofelemer for 96 hours
for the symptomatic treatment of diarrhea in AIDS patients.
[0228] The secondary objectives were 1) to characterize stool
chloride ion concentration and daily stool chloride output in AIDS
patients with diarrhea, 2) to compare stool chloride ion
concentration and daily stool chloride output in AIDS patients with
diarrhea treated with crofelemer or placebo, and 3) to assess stool
consistency in AIDS patients with diarrhea treated with crofelemer
or placebo.
[0229] There were 3 assessment periods during the study: 1) a
24-hour in-patient screening period to ensure that the subjects met
all of the study criteria, during which baseline stool weight was
assessed; 2) a 4-day inpatient treatment period, during which all
subjects received their assigned treatment 4 times per day (Days
1-4); subjects were discharged from the hospital after 96 hours of
treatment if clinically stable); and 3) a follow-up visit 7-9 days
after discharge from the hospital. The use of ADM was not allowed
during the study.
[0230] Efficacy measurements included assessments of stool weight
and frequency, abnormal stool frequency, DGIS, MORE, body weight,
time to diarrhea recurrence, and number of early dropouts (prior to
completion of 4 days of treatment).
[0231] Efficacy endpoints in this study were as follows:
[0232] The primary efficacy endpoint in this study was the change
in total daily stool weight during the Treatment Period. The
secondary efficacy endpoints of the study were abnormal stool
frequency, defined as watery or soft stools (change in daily
abnormal stool frequency), stool frequency (change in daily stool
frequency), DGIS (change from baseline in DGIS for each day [Days 1
through 4]), stool chloride concentration (mg chloride/g stool
weight; change in daily stool chloride concentration) and measure
of relief scores, where MORE was the maximum of: a) time from the
start of treatment period to the first abnormal stool, b) the
maximum time between abnormal stools, or c) the time between the
last abnormal stool and the end of the treatment period.
[0233] The DGIS was the daily sum of mean symptom scores for each
of 7 symptoms (nausea, vomiting, abdominal pain and/or cramps,
excess gas, urgency, tenesmus, and incontinence) scored 4 times per
day. Symptoms were rated on a 4-point scale from 0=absent to
3=severe.
[0234] A total of 85 subjects were enrolled into the study at 2
study sites. Two of subjects in each of the 2 treatment groups
withdrew before completion of the in-patient treatment period.
[0235] All randomized subjects (n=85) received at least 1 dose of
study drug and were included in efficacy analyses.
TABLE-US-00020 TABLE 19 Demographics: Crofelemer Characteristic
Placebo 500 mg Beads Category or Statistic (n = 42) (n = 43) Age,
Years Mean (.+-.SD) 38.9 (7.6) 41.0 (8.8) Median 36 40 Min, Max 27,
55 21, 60 Sex, n (%) Male 41 (97.6)) 42 (97.7) Female 1 (2.4) 1
(2.3) Race, n (%) Caucasian 26 (61.9) 32 (74.4) Hispanic 7 (16.7) 6
(14.0) African American 7 (16.7) 5 (11.6) Other 2 (5.0) 0
Abbreviations: ITT = intent-to-treat; Max = maximum; Min = minimum,
SD = standard deviation.
[0236] The number of unformed (i.e., soft or watery) stools/day at
baseline (screening [Day 0]) and during the week prior to baseline,
and disease severity are presented in Table. Mean (.+-.SD) unformed
stools/day at baseline was 5.5 (3.3) in the placebo group and 4.6
(2.6) in the crofelemer group. Most subjects had mild (3-4
stools/day) or moderate (5-8 stools/day) disease severity at
baseline. Five subjects in the crofelemer group and 4 subjects in
the placebo group had severe diarrhea (>9 stools/day).
TABLE-US-00021 TABLE 20 Baseline Diarrhea Assessments: (ITT
Population) Crofelemer Characteristic Placebo 500 mg Beads Category
or Statistic (n = 42) (n = 43) Unformed Stools During 24 Hours
Prior to First Dose of Study Drug (Screening [Day 0]), Stools/Day
Mean (.+-.SD) 5.6 (2.9) 4.6 (2.5) Median 5 4 Min, Max 1, 6 0, 10
Unformed Stools During the Week Prior to First Dose of Study Drug
(Screening [Day 0]), Stools/Day Mean (.+-.SD) 5.5 (2.9) 5.1 (2.3)
Median 6 5 Min, Max 1, 15 2, 10 Diarrhea Severity, n (%) Mild (3-4
stools/day) 10 (40.0) 15 (57.1) Moderate (5-8 stools/day) 13 (52.0)
8 (30.8) Severe (>9 stools/day) 2 (8.0) 3 (11.5) Abbreviations:
ITT = intent-to-treat; Max = maximum; Min = minimum, SD = standard
deviation.
[0237] Concomitant antiretroviral medications were received by
majority of subjects (71 of 85): 36 of 42 (85.7%) in the placebo
group and 35 of 43 (81.4%) in the crofelemer group. Protease
inhibitors were taken by 69.4% of subjects. The concomitant use of
antiretrovirals, including protease inhibitors, was balanced
between groups.
[0238] The primary efficacy analysis was change in total daily
stool weight during the 4-day in-patient treatment period. The
primary endpoint of reduction in stool weight is an appropriate
measure of the extent of watery diarrhea in patients with
HIV-associated diarrhea due to high water content in the diarrhea
experienced by these patients.
[0239] As shown in Table 21, there were significantly greater
decreases in stool weight from baseline to Day 4 (last treatment
day) in the crofelemer group compared with placebo (p=0.0335 by
generalized linear model) in the ITT population. The repeated
measures analysis of longitudinal data over the course of the 4-day
Treatment Period did not show significant improvements in the
crofelemer group compared to placebo; p=0.4108 for changes in total
stool weight.
TABLE-US-00022 TABLE 21 Change in Stool Weight Crofelemer Placebo
500 mg Beads p-value In-Patient Period (n = 42) (n = 43) (vs.
Placebo).sup.a Stool Weight at Baseline (g) Mean (.+-.SD) 730.9
(720.14) 861.3 (604.67) 0.3832 Median 547.0 707.7 Min, Max 206,
4701 220, 3407 Categories of Stool Weight at Baseline, n (%) Low
(.ltoreq.740 g) 28 (66.7) 24 (55.8) 0.2725 High (>740 g) 14
(33.3) 19 (44.2) Change in Stool Weight: Baseline to Day 4 (g) Mean
(.+-.SD) -192.4 (381.57) -401.3 (531.65) 0.0335 Median -232.8
-267.5 Min, Max -1319, 683 -1815, 854 Abbreviations: ITT =
intent-to-treat; Max = maximum; Min = minimum, SD = standard
deviation. .sup.aP-value for baseline mean comparison is from
generalized linear model with analysis center as a covariate.
P-value for baseline percentage comparison is from CMH test with
analysis center as a covariate. The estimates and p values are from
the generalized linear model for the change from baseline result,
with independent variables: treatment, analysis center, baseline
category (value = Low for .ltoreq.740 g and High for >740 g in
stool weight), and the interaction between treatment and baseline
category (if p value >0.15, the interaction term was not
included).
[0240] The effect of crofelemer in decreasing stool weight was more
pronounced in the subgroup of subjects with baseline stool weight
>740 g when compared to subjects with baseline stool weight
.ltoreq.740 g (p-values for differences relative to placebo were
0.0202 [>740 g subgroup] versus 0.6820 [.ltoreq.740 g
subgroup]).
[0241] There were significantly greater decreases from baseline in
stool weight at Day 3 in the crofelemer group compared with placebo
(p=0.0128).
Secondary Efficacy Results
[0242] Significantly greater decreases in the frequency of abnormal
stools (i.e., watery or soft stools) from baseline to Day 4 were
observed in the crofelemer group compared with placebo (p=0.0069 by
generalized-linear model) in the ITT population. The repeated
measures analysis of longitudinal data over the course of the
Treatment Period also indicates significantly greater reductions in
the crofelemer group compared with placebo; p=0.0330 for changes in
abnormal stool frequency. In addition, subjects in the crofelemer
group had significantly greater decreases in abnormal stool
frequency from baseline to Day 2 (p=0.0454) and from baseline to
Day 3 (p=0.0064) compared with subjects in the placebo group.
TABLE-US-00023 TABLE 22 Abnormal Stool Frequency Crofelemer Placebo
500 mg Beads p-value In-Patient Period (n = 42) (n = 43) (vs.
Placebo).sup.a Abnormal Stool (soft or watery stool) Frequency at
Baseline; abnormal stools/day Mean (.+-.SD) 4.8 (2.12) 4.9 (2.58)
0.9933 Median 4.0 4.0 Min, Max 3, 12 2, 14 Categories of Abnormal
Stool Frequency at Baseline, n (%) Low (.ltoreq.5/day) 30 (71.4) 32
(74.4) 0.7847 High (>5/day) 12 (28.6) 11 (25.6) Change in
Abnormal Stool Frequency: Baseline to Day 4; abnormal stools/day
Mean (.+-.SD) -2.1 (1.94) -2.8 (2.23) 0.0069 Median -2.0 -3.0 Min,
Max -6, 4 -11, 2 Abbreviations: ITT = intent-to-treat; Max =
maximum; Min = minimum, SD = standard deviation. .sup.aP-value for
baseline mean comparison is from generalized linear model with
analysis center as a covariate. P-value for baseline percentage
comparison is from CMH test with analysis center as a covariate.
The estimates and p values are from the generalized linear model
for the change from baseline result, with independent variables:
treatment, analysis center, baseline category (value = Low for
.ltoreq.5/day and High for >5/day in abnormal stool frequency),
and the interaction between treatment and baseline category (if p
value >0.15, the interaction term was not included).
[0243] The effect of crofelemer in decreasing abnormal stool
frequency was more pronounced in the subgroup with high abnormal
stool counts at baseline (>5/day) compared to the subgroup with
low abnormal stool counts at baseline (.ltoreq.5/day; p-values for
differences relative to placebo were 0.0041 [>5/day subgroup]
versus 0.8184 [.ltoreq.5/day subgroup])
[0244] Significantly greater decreases in stool frequency (i.e.,
formed, watery, and soft stools) from baseline to Day 4 were
observed in the crofelemer group compared with placebo (p=0.0046 by
generalized-linear model) in the ITT population (Table 23). The
repeated measures analysis of longitudinal data over the course of
the Treatment Period also indicates significantly greater
reductions in the crofelemer group compared with placebo; p=0.0236
for changes in stool frequency.
[0245] The effect of crofelemer in decreasing stool frequency was
more pronounced in the subgroup with high stool counts at baseline
(>5/day) compared to the subgroup with low stool counts at
baseline (.ltoreq.5/day) (p-values for differences relative to
placebo were 0.0019 [>5/day subgroup] versus 0.7912
[.ltoreq.5/day subgroup]).
TABLE-US-00024 TABLE 23 Stool Frequency Crofelemer Placebo 500 mg
Beads p-value In-Patient Period (n = 42) (n = 43) (vs.
Placebo).sup.a Stool Frequency at Baseline; stools/day Mean
(.+-.SD) 5.1 (2.22) 5.0 (2.46) 0.8442 Median 4.0 4.0 Min, Max 3, 12
2, 14 Categories of Stool Frequency at Baseline, n (%) Low
(.ltoreq.5/day) 27 (64.3) 32 (74.4) 0.2850 High (>5/day) 15
(35.7) 11 (25.6) Change in Stool Frequency: Baseline to Day 4;
stools/day Mean (.+-.SD) -1.7 (1.92) -2.5 (2.45) 0.0116 Median -2.0
-2.5 Min, Max -5, 5 -10, 2 Abbreviations: ITT = intent-to-treat;
Max = maximum; Min = minimum, SD = standard deviation.
.sup.aP-value for baseline mean comparison is from generalized
linear model with analysis center as a covariate. P-value for
baseline percentage comparison is from CMH test with analysis
center as a covariate. The estimates and p values are from the
generalized linear model for the change from baseline result, with
independent variables: treatment, analysis center, baseline
category (value = Low for .ltoreq.5/day and High for >5/day in
stool frequency), and the interaction between treatment and
baseline category (if p value >0.15, the interaction term was
not included).
[0246] The crofelemer group had significantly greater decreases in
stool frequency from baseline to Day 2 (p=0.0223) and from baseline
to Day 3 (p=0.0140) compared with placebo.
[0247] Daily Gastrointestinal Symptom Score
[0248] In a repeated measures analysis of longitudinal data over
the course of the in-patient period (i.e., changes from baseline at
each day during Days 1-4), a statistical trend indicating greater
improvements in DGIS scores was observed in the crofelemer group
compared with placebo (p=0.0559).
[0249] Stool Chloride Concentrations
[0250] Stool chloride concentrations were measured in this study
because the antisecretory, antidiarrheal effect of crofelemer is
likely due to the inhibition of CFTR channel and CACC in the GI
lumen; this inhibition blocks luminal Cl.sup.- secretion and
accompanying high volume water loss in secretory diarrhea (Fischer
2004; Tradtrantip 2010); thus reduced luminal Cl.sup.- secretion
should result in lower stool chloride concentrations. Subjects in
the crofelemer group had significantly greater reductions in stool
chloride concentrations from baseline to Day 4 when compared with
placebo (p=0.0024 by generalized linear model) among subjects with
stool chloride data (placebo n=25, crofelemer n=26). Mean (.+-.SD)
changes from baseline to Day 4 were 0.123 (0.7138) mg/g in the
placebo group and -0.245 (0.5556) mg/g in the crofelemer group.
[0251] All publications, patents, and patent applications cited
herein are hereby incorporated herein by reference in their
entirety.
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