U.S. patent application number 16/391438 was filed with the patent office on 2020-02-27 for methods of treating hepatic encephalopathy.
The applicant listed for this patent is Salix Pharmaceuticals, Ltd. Invention is credited to Enoch Bortey, William Forbes, Kunal Merchant, Audrey Shaw.
Application Number | 20200061032 16/391438 |
Document ID | / |
Family ID | 45067069 |
Filed Date | 2020-02-27 |
![](/patent/app/20200061032/US20200061032A1-20200227-C00001.png)
![](/patent/app/20200061032/US20200061032A1-20200227-C00002.png)
![](/patent/app/20200061032/US20200061032A1-20200227-C00003.png)
![](/patent/app/20200061032/US20200061032A1-20200227-C00004.png)
![](/patent/app/20200061032/US20200061032A1-20200227-D00000.png)
![](/patent/app/20200061032/US20200061032A1-20200227-D00001.png)
![](/patent/app/20200061032/US20200061032A1-20200227-D00002.png)
![](/patent/app/20200061032/US20200061032A1-20200227-D00003.png)
![](/patent/app/20200061032/US20200061032A1-20200227-D00004.png)
![](/patent/app/20200061032/US20200061032A1-20200227-D00005.png)
![](/patent/app/20200061032/US20200061032A1-20200227-D00006.png)
View All Diagrams
United States Patent
Application |
20200061032 |
Kind Code |
A1 |
Forbes; William ; et
al. |
February 27, 2020 |
METHODS OF TREATING HEPATIC ENCEPHALOPATHY
Abstract
The application describes treatment of hepatic encephalopathy
using gastrointestinal specific antibiotics. One example of a
gastrointestinal specific antibiotic is rifaximin. The instant
application also provides methods for determining if a subject has
a neurological condition or hepatic encephalopathy by determining
the critical flicker frequency and/or the venous ammonia level of
the subject at two or more time points. The invention further
provides methods for treating these subjects.
Inventors: |
Forbes; William; (Raleigh,
NC) ; Merchant; Kunal; (Durham, NC) ; Bortey;
Enoch; (Chapel Hill, NC) ; Shaw; Audrey;
(Durham, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Salix Pharmaceuticals, Ltd |
Bridgewater |
NJ |
US |
|
|
Family ID: |
45067069 |
Appl. No.: |
16/391438 |
Filed: |
April 23, 2019 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
15824209 |
Nov 28, 2017 |
10314828 |
|
|
16391438 |
|
|
|
|
15212720 |
Jul 18, 2016 |
9855254 |
|
|
15824209 |
|
|
|
|
13914074 |
Jun 10, 2013 |
9421195 |
|
|
15212720 |
|
|
|
|
12964847 |
Dec 10, 2010 |
|
|
|
13914074 |
|
|
|
|
12792658 |
Jun 2, 2010 |
|
|
|
12964847 |
|
|
|
|
12572344 |
Oct 2, 2009 |
|
|
|
12792658 |
|
|
|
|
61316796 |
Mar 23, 2010 |
|
|
|
61307417 |
Feb 23, 2010 |
|
|
|
61306935 |
Feb 22, 2010 |
|
|
|
61305854 |
Feb 18, 2010 |
|
|
|
61262525 |
Nov 18, 2009 |
|
|
|
61102349 |
Oct 2, 2008 |
|
|
|
61183513 |
Jun 2, 2009 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G16H 20/10 20180101;
Y02A 90/22 20180101; Y02A 90/10 20180101; A61P 25/00 20180101; A61K
31/7016 20130101; A61K 31/437 20130101; A61P 31/00 20180101; G06Q
50/22 20130101; A61P 1/16 20180101; A61K 45/06 20130101; A61K
31/437 20130101; A61K 2300/00 20130101; A61K 31/7016 20130101; A61K
2300/00 20130101 |
International
Class: |
A61K 31/437 20060101
A61K031/437; G06Q 50/22 20060101 G06Q050/22; A61K 45/06 20060101
A61K045/06; A61K 31/7016 20060101 A61K031/7016 |
Claims
1-74. (canceled)
75. A method of reducing the risk of overt hepatic encephalopathy
(HE) recurrence in a subject, comprising administering about 1100
mg of rifaximin daily to the subject, wherein the subject has had
two or more HE episodes within 12-months prior to the
administration of rifaximin.
76. The method of claim 75, wherein the rifaximin is administered
orally.
77. The method of claim 75, wherein the 550 mg of rifaximin is
administered twice daily.
78. The method of claim 75, further comprising administering
lactulose.
79. A method of reducing the risk of overt hepatic encephalopathy
(HE) recurrence in a subject, comprising administering 550 mg of
rifaximin twice a day to the subject for a period of at least 6
months, wherein the subject has had two or more HE episodes within
12-months prior to the administration of rifaximin.
80. The method of claim 79, wherein the rifaximin is administered
orally.
81. The method of claim 79, further comprising administering
lactulose.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 15/824,209, filed Nov. 28, 2017, which is a continuation of
U.S. application Ser. No. 15/212,720, filed Jul. 18, 2016, now U.S.
Pat. No. 9,855,254, which is a continuation of U.S. application
Ser. No. 13/914,074, filed Jun. 10, 2013, now U.S. Pat. No.
9,421,195, which is a continuation of U.S. application Ser. No.
12/964,847 filed Dec. 10, 2010, which is a continuation of U.S.
application Ser. No. 12/792,658, filed Jun. 2, 2010, which is a
continuation-in-part of U.S. application Ser. No. 12/572,344, filed
Oct. 2, 2009 which claims the benefit of U.S. Provisional
Application Ser. No. 61/102,349, filed Oct. 2, 2008. U.S.
application Ser. No. 12/792,658 also claims the benefit of U.S.
Provisional Application No. 61/183,513 filed Jun. 2, 2009; U.S.
Provisional Application No. 61/262,525, filed Nov. 18, 2009; U.S.
Provisional Application No. 61/305,854, filed Feb. 18, 2010; U.S.
Provisional Application No. 61/306,935, filed Feb. 22, 2010; U.S.
Provisional Application No. 61/307,417, filed Feb. 23, 2010; and
U.S. Provisional Application No. 61/316,796, filed Mar. 23, 2010.
The entire contents of each of the aforementioned applications is
hereby expressly incorporated herein by reference.
BACKGROUND
[0002] Hepatic encephalopathy (HE) is caused by a reversible
decrease in neurologic function associated with liver failure and
portosystemic venous shunting. HE occurs in 1 of every 3 cases of
cirrhosis, in cases of fulminant hepatic failure reported in the
United States (US), and is present in nearly half of patients
reaching end-stage liver disease. It may occur at any age, but the
peaks parallel those of fulminant liver disease (peak=40's), and
cirrhosis (peak=late 50's).
[0003] The incidence of HE is likely to increase with the incidence
of hepatitis C in the general population and cirrhotics in aging
patients. Acute HE signifies a serious prognosis with a 40%
likelihood of survival for 1 year. There is a need in the art for a
compositions and methods for treating and preventing HE.
[0004] Moreover, methods of predicting a breakthrough HE event or
for determining when to prophylactically treat a subject prior to
the occurrence of a breakthrough event are necessary in the
art.
SUMMARY
[0005] Provided herein are compositions and methods for the
prevention and treatment of hepatic encephalopathy.
[0006] One embodiment is a method of treating or preventing hepatic
encephalopathy (HE) in a subject comprising administering to a
subject a gastrointestinal (GI) specific antibiotic. In one
embodiment the GI specific antibiotic is rifaximin. In another
embodiment, the rifaximin is 1100 mg/day of rifaximin.
[0007] Another embodiment is a method of decreasing a subject's
risk of a hepatic encephalopathy HE breakthrough episode by
administering a GI specific antibiotic to a subject suffering from
HE.
[0008] Yet another embodiment is a method of maintaining remission
of hepatic encephalopathy in a subject by administering a GI
specific antibiotic to a subject suffering from HE.
[0009] Still another embodiment is a method of reducing the
frequency of hospitalization visits by an HE patient, comprising
administering a GI specific antibiotic to a subject suffering from
HE.
[0010] In one embodiment, the GI specific antibiotic is
administered to the subject with lactulose, prior to treatment with
lactulose, or following treatment with lactulose. In one embodiment
the subject or a health care worker is advised to administer the GI
specific antibiotic with lactulose.
[0011] In one embodiment the subject or a health care worker is
advised by a pharmaceutical label or insert to administer the GI
specific antibiotic with lactulose in order to maintain remission
of HE, or to decrease the risk for episodes of overt HE.
[0012] In one embodiment, the subject or health care worker is
advised to administer two 550 mg tablets of rifaximin twice daily
with lactulose. Lactulose use may be titrated over time so that the
subject maintains 2-3 soft stool bowel movements per day. In one
embodiment the lactulose is administered in 15 ml dosages, wherein
each 15 ml dosage contains 10 mg of lactulose.
[0013] In one embodiment, subjects in need of treatment for HE and
having a Child-Pugh grade of A or B are treated with a GI specific
antibiotic.
[0014] In another embodiment, subjects in need of treatment for HE
having a Child-Pugh grade of A or B are treated with a GI specific
antibiotic in combination with lactulose.
[0015] In another embodiment, subjects having a Child-Pugh grade of
A or B, or their health care worker, are advised that they should
be treated with a GI specific antibiotic. The advice can be oral or
written advice, such as on a pharmaceutical label or package
insert.
[0016] In another embodiment, subjects having a Child-Pugh grade of
A or B, or their health care worker, are advised that they should
be treated with a GI specific antibiotic in combination with
lactulose.
[0017] In one embodiment, a subject in need of treatment for HE and
having a Child-Pugh grade of less than C is treated with a GI
specific antibiotic. In one embodiment, a subject in need of
treatment for HE and having a Child-Pugh grade of less than C is
treated with a GI specific antibiotic and lactulose.
[0018] In another embodiment, a subject in need of treatment for
HE, or their health care worker is advised of the risk for
anaphylaxis prior to treatment with a GI specific antibiotic.
[0019] In one embodiment, subjects in need of treatment for HE and
having a MELD score of 25 or less are treated with a GI specific
antibiotic.
[0020] In another embodiment, subjects in need of treatment for HE
having a MELD score of 25 or less are treated with a GI specific
antibiotic in combination with lactulose.
[0021] In another embodiment, subjects having a MELD score of 25 or
less are advised that they should be treated with a GI specific
antibiotic. The advice can be oral or written advise, such as on a
pharmaceutical label or package insert.
[0022] In another embodiment, subjects having a MELD score of 25 or
less are advised that they should be treated with a GI specific
antibiotic in combination with lactulose.
[0023] The novel methods and devices presented herein are based in
part on the finding of a correlation between CFF and/or venous
ammonia concentration and the occurrence of breakthrough HE events.
Moreover, the novel methods and devices are also based on the
discovery that the time weighted average CFF and/or venous ammonia
concentration is an accurate predictor of breakthrough HE events
and prognosis of subjects with HE.
[0024] Accordingly, in one aspect provided herein are methods of
diagnosing hepatic encephalopathy (HE) in a subject by determining
the critical flicker frequency (CFF) of a subject at two or more
time points, wherein a decrease in the CFF is indicative that the
subject has hepatic encephalopathy. In a related embodiment, the
CFF comprises the CFF time weighted average. In another related
embodiment, the CFF time weighted average comprises less than about
24 Hz.
[0025] In another aspect, provided herein are methods of
determining a subject's risk of an HE breakthrough event, by
determining the critical flicker frequency (CFF) of a subject at
two or more time points, wherein a decrease in the CFF is
indicative that the subject has an increased risk of a HE
breakthrough event. In a related embodiment, the CFF comprises the
CFF time weighted average. In another related embodiment, the CFF
time weighted average comprises less than about 24 Hz. In another
embodiment, a CFF time weighted average of 10 Hz is indicative that
the subject has the greatest chance of a HE breakthrough event.
[0026] In another aspect, provided herein are methods of
determining the prognosis of a subject having HE, by determining
the critical flicker frequency (CFF) of a subject at two or more
time points, wherein a decrease in the CFF is indicative that the
subject has a poor prognosis. In a related embodiment, the CFF
comprises the CFF time weighted average. In another related
embodiment, the CFF time weighted average comprises less than about
24 Hz, or less than about 20 Hz.
[0027] In another aspect, provided herein are methods of treating
or preventing an HE event, by determining the critical flicker
frequency (CFF) of a subject at two or more time points,
administering to a subject having a decrease in the CFF average
between the time points an effective amount of a GI specific
antibiotic, (e.g., rifaximin), thereby treating or preventing an HE
event. In another embodiment, the subject is administered a GI
specific antibiotic when the CFF time weighted average is less than
20 Hz.
[0028] In one embodiment, the subject is also administered
lactulose. In another embodiment, the risk is increased as compared
to a control subject without HE.
[0029] In related embodiments, the two or more time points occur
within one week, four weeks, six months, or more.
[0030] In another aspect provided herein are methods of diagnosing
hepatic encephalopathy (HE) in a subject by determining the venous
ammonia levels of a subject at two or more time points, wherein an
increase in the venous ammonia levels is indicative that the
subject has hepatic encephalopathy.
[0031] In one embodiment, the venous ammonia level comprises the
time weighted average venous ammonia levels. In another embodiment,
the time weighted average venous ammonia level comprises more than
about 100 .mu.mol/L.
[0032] In another aspect, provided herein are methods of
determining a subject's risk of an HE breakthrough event, by
determining the venous ammonia levels of a subject at two or more
time points, wherein an increase in the venous ammonia levels is
indicative that the subject has an increased risk of a HE
breakthrough event.
[0033] In one embodiment, the venous ammonia level comprises the
time weighted average venous ammonia levels. In another embodiment,
the time weighted average venous ammonia level comprises more than
about 100 .mu.mol/L.
[0034] In another aspect, provided herein are methods of
determining the prognosis of a subject having HE, by determining
the venous ammonia level of a subject at two or more time points,
wherein an increase in the venous ammonia level is indicative that
the subject has a poor prognosis.
[0035] In one embodiment, the venous ammonia level comprises the
time weighted average venous ammonia levels. In another embodiment,
the time weighted average venous ammonia level comprises more than
about 100 .mu.mol/L, or more than about 110 .mu.mol/L.
[0036] In another aspect, provided herein are methods of treating
or preventing an HE event, by determining the venous ammonia level
of a subject at two or more time points, administering to a subject
having an increase in the venous ammonia level between the time
points an effective amount of Rifaximin, thereby treating or
preventing an HE event.
[0037] In one embodiment, the venous ammonia level comprises the
time weighted average venous ammonia levels. In another embodiment,
the time weighted average venous ammonia level comprises more than
about 100 .mu.mol/L.
[0038] In another embodiment, the methods further comprise
administering lactulose.
[0039] In related embodiments, the two or more time points occur
within one week, two weeks, three weeks, four weeks, five weeks,
six weeks, eight weeks, six months, or more. Also included are time
points at any time in between the points.
[0040] In another aspect, provided herein are methods of treating a
subject having HE comprising administering to the subject an
effective amount of a GI specific antibiotic, e.g., rifaximin,
thereby treating the subject.
[0041] In related embodiments, the GI specific antibiotic, e.g.,
rifaximin, is administered for greater than 365 days, greater than
730 days, greater than 1095 days, or for the remainder of the life
of the subject.
[0042] In another aspect provided herein are methods of diagnosing
a neurological disease in a subject, by determining the critical
flicker frequency (CFF) of a subject at two or more time points,
wherein a decrease in the CFF is indicative that the subject has a
neurological disease. The decrease may be between any two time
points. For example, between the first and second time points,
between the first and third time points, between the first and
fourth time points, between the second and third time points,
between the second and fourth time points and the like.
[0043] In a related embodiment, the CFF comprises the CFF time
weighted average.
[0044] In another embodiment, the neurological disease or disorder
comprises Alzheimer's disease or Parkinson's disease. Also included
are diseases in which the CFF is modulated in a subject. Modulated,
as used herein includes increases or decreasing from a baseline or
a change from any measurement, even if not baseline for the
subject. The baseline for a subject may be determined when a
subject not experiencing an HE event or other neurological event,
when a subject has recovered or is in remission from an HE event or
other neurological event.
[0045] In another aspect, provided herein are methods of
determining the prognosis of a subject having a neurological
disease, by determining the critical flicker frequency (CFF) of a
subject at two or more time points, wherein a decrease in the CFF
is indicative that the subject has a poor prognosis. Poor
prognosis, as used herein, includes a prognosis that life
expectancy is less than prior prognosis.
[0046] In a related embodiment, the CFF comprises the CFF time
weighted average. In another embodiment, the neurological disease
or disorder comprises Alzheimer's disease, Parkinson's disease,
trauma, migraine, chronic headache, insomnia and other sleep
disorders, and/or epilepsy.
[0047] In related embodiments, the two or more time points occur
within one week, four weeks, six months, or more.
[0048] In another aspect, provided herein are computerized methods
for identifying subjects having a neurological disease by
maintaining a database of CFFs for subjects at various time points
and stages of disease progression, comparing the results of an
individuals CFF results taken at two or more time points to the
database, obtaining the diagnosis of a neurological disease from
the computer if subject has CFF results that decrease between
measurements.
[0049] In one embodiment, the CFF comprises the CFF time weighted
average. In another embodiment the CFF time weighted average or a
second or subsequent time point comprises less than about 24 Hz. In
another embodiment, the methods further comprise controlling a
printing device to print a report based on the results of the
method.
[0050] In another aspect, provided herein are business methods for
decreasing healthcare costs, comprising determining the critical
flicker frequency (CFF) of a subject at two or more time points,
storing patient information on a computer processor, determining if
the subject has a neurological disease by determining if the CFF
value has decreased between time points, and treating the subject
as necessary to avoid or delay hospitalization.
[0051] In another aspect, provided herein are business methods for
decreasing healthcare costs comprising determining the critical
flicker frequency (CFF) of a subject at two or more time points,
storing patient information on a computer processor, determining if
the subject has hepatic encephalopathy by determining if the CFF
value has decreased between time points, treating the subject as
necessary to avoid or delay hospitalization.
[0052] A device for determining the risk of an HE event,
comprising, a "flicker box," a measurement device to CFF, and a
computer with an algorithm. In another embodiment, the method
further comprises a memory device capable of storing CFF data.
BRIEF DESCRIPTION OF THE DRAWINGS
[0053] FIG. 1 is a line graph comparing lactulose daily use between
subjects taking placebos and subjects taking rifaximin.
[0054] FIG. 2 is a line graph showing Kaplan Meier estimates of the
distribution of time to a breakthrough HE event.
[0055] FIG. 3 is a line graph showing Kaplan Meier estimates of the
distribution of time to a first HE related hospitalization.
[0056] FIG. 4 is a line graph showing Kaplan Meier estimates of the
distribution of time to a first increase in Conn scores.
[0057] FIG. 5 is a line graph showing Kaplan Meier estimates of the
distribution of time to a first increase in an Asterixis grade.
[0058] FIG. 6 depicts the time to first breakthrough overt HE
episode (up to 6 months of treatment, day 170 in the first study)
(ITT Population).
[0059] FIG. 7 is a comparison of time to first breakthrough overt
HE episode in the first study (rifaximin versus placebo groups) and
the second study (new to rifaximin group).
[0060] FIG. 8 depicts a comparison of time to first breakthrough
over the episode during placebo experience (the first study) and
after crossover to rifaximin experience (the second study) among
the first study placebo subjects who started rifaximin in the
second study.
[0061] FIG. 9 depicts the time to first HE-related hospitalization
(up to 6 months of treatment, day 170, in the first study).
[0062] FIG. 10 depicts the time to first HE-caused hospitalization
in the first study (ITT population).
[0063] FIG. 11 depicts the time to First Increase in Conn Score (up
to 6 months of treatment, day 170, the first study) (ITT
Population).
[0064] FIG. 12 depicts the time to first Increase in asterixis
grade (up to 6 months of treatment, day 170, the first study) (ITT
Population).
[0065] FIG. 13 depicts the Kaplan Meier estimates of distribution
of time to first breakthrough HE for continuing rifaximin subjects
who did not have an HE episode in the first study vs placebo.
[0066] FIGS. 14A-B depict CLDQ results, as measured by Twa, between
the rifaximin and placebo groups in the frequency distributions of
Twa scores for the fatigue domain and overall domain.
[0067] FIG. 15 shows the pathogenesis of HE.
[0068] FIG. 16 shows the clinical presentation of HE. The
classification was by the 1998 WCOG Working Group. Adapted from
Ferenci P, et al. Hepatology. 2002; 35:716-721.
[0069] FIG. 17 shows the HESA adaptation of Conn Score.
[0070] FIG. 18 shows the impact of HE on the patient and
caregiver.
[0071] FIG. 19 depicts HE hospitalizations and economic impact.
[0072] FIG. 20 shows the influence of Liver Impairment on Rifaximin
PK.
[0073] FIG. 21 demonstrates that rifaximin exposure is
significantly lower than other antibiotic exposures. Well et al.,
Int J Antimicrob Agents 10 (1998) 31-38. In patients with greatest
liver impairment, rifaximin exposure is >200-fold lower than
rifampin exposure; >35-fold lower than norfloxacin exposure; and
.gtoreq.10-fold lower than neomycin exposure.
[0074] FIG. 22 shows drug interactions with midazolam and
rifaximin. No significant inhibition of CYP enzymes,
P-glycoprotein, or BSEP. Portosystemic shunting in liver impairment
may reduce liver exposure.
[0075] FIG. 23 shows the effect on blood ammonia. Rifaximin 1200
mg/day for 5-10 days decreased blood ammonia (p<0.0001).
Corresponding improvement in HE grade (p<0.0001), neurological,
neuropsychiatric, and psychometric parameters. Correlation between
ammonia reduction over time and HE was examined.
[0076] FIG. 24 depicts the Kaplan-Meier Event-Free Curves in HE
Study (Time to First Breakthrough-HE Episode up to 6 Months of
Treatment, Day 170) (ITT Population).
[0077] FIG. 25 depicts Kaplan-Meier Event-Free Curves in Pivotal HE
Study (Time to First HE-Related Hospitalization in HE Study up to 6
Months of Treatment, Day 170) (ITT Population).
[0078] FIG. 26 is a line graph showing the time to First
Breakthrough HE Episode.
[0079] FIG. 27 is a chart showing hazard ratios for the risk of
experiencing breakthrough overt HE (rifaximin group divided by
placebo group) for each subgroup.
[0080] FIG. 28 is a line graph illustrating a time to First
HE-Related Hospitalization.
[0081] FIG. 29 is a bar chart illustrating that lactulose use
between a control group and a group taking rifaximin was the
same.
[0082] FIG. 30 is a chart illustrating that there was a consistency
of treatment affect across various subgroups that were administered
rifaximin.
[0083] FIG. 31 depicts the distribution of time-weighted average
CFF results by breakthrough overt HE status.
[0084] FIG. 32 depicts receiver operating characteristic curve for
CFF results in the prediction of breakthrough overt HE.
[0085] FIG. 33 depicts the distribution of time-weighted average
venous ammonia concentrations results by breakthrough overt HE
status.
[0086] FIG. 34 depicts receiver operating characteristic curve for
venous ammonia levels in the prediction of breakthrough overt
HE.
DETAILED DESCRIPTION
[0087] Hepatic encephalopathy, also known as hepatic coma or
portal-systemic encephalopathy (PSE), is a serious, rare, complex,
episodic, neuropsychiatric syndrome associated with advanced liver
disease. Hepatic encephalopathy is a formidable burden on the
patient, his/her family, and the healthcare system; and the current
standard of care is inadequate. Overt, episodic HE is common among
patients with liver cirrhosis. The condition is rare among
individuals in the overall, general population. Overt HE episodes
are debilitating, can present without warning, render the patient
incapable of self-care, and frequently result in hospitalization.
The frequency of hospitalizations due to HE increased since 1993 to
over 40,000 patients in 2003; and in 2004, 50,962 patients were
hospitalized with a principal diagnosis of HE.
[0088] The main pathogenesis of HE is related to nitrogenous
substances derived from the gut adversely affecting brain function.
The most influential of these compounds is thought to be ammonia, a
byproduct of protein digestion that is normally detoxified by the
liver. Correlation of blood levels with mental state in cirrhosis,
however, is inaccurate, in part, because the blood-brain barrier
permeability to ammonia is increased in patients with HE. Other
gut-derived toxins have also been proposed as being responsible for
HE.
[0089] In patients with chronic liver disease, the occurrence of
hepatic encephalopathy is associated with a low quality of life
compared to age-matched patients without HE. Overt HE episodes are
debilitating, can present without warning, render the patient
incapable of self-care, and frequently result in hospitalization.
Patients with HE experience symptoms including fatigue, daytime
sleepiness, and lack of awareness (Conn score 1); and confusion and
disorientation (Conn score 2) that significantly interfere with
day-to-day function and decreased ability for self care. Often,
this lack of self care leads to improper nutrition and
non-adherence to therapy and further escalates into more severe
symptoms such as increased somnolence, gross disorientation and
stupor (Conn score 3) or coma (Conn score 4).
[0090] A history of overt HE episodes and the severity of HE
episodes were also found to be predictive of decreased survival in
patients with chronic liver disease. In patients with liver
cirrhosis and a history of overt HE episodes, survival probability
was 42% at 1 year and 23% at 3 years after experiencing an HE
episode. In another analysis, the occurrence of an HE episode of
Conn score 2 in patients with cirrhosis was associated with a
4-fold increase in the risk of death.
[0091] The inventors of the instant application have determined
that there is a correlation between CFF and venous ammonia
concentration and the occurrence of breakthrough HE events.
Moreover, the inventors have determined that time weighted average
CFF or venous ammonia concentration is an accurate predictor of
breakthrough HE events and prognosis of subjects with HE. In
another embodiment, the inventors have determined that subjects who
continue taking Rifaximin for a long duration of time, e.g.,
greater than 1.5 years, continue to see beneficial results, e.g.,
decreased incidence of breakthrough HE events.
[0092] In certain embodiments, provided herein are methods for
determining if a subject has a neurological disease or HE. The
methods of the invention rely on determining the critical flicker
frequency or the venous ammonia level.
[0093] Critical flicker frequency, also called CFF, can be
determined, for example, by standard methods known in the art.
Moreover, commercial instruments are available to measure CFF,
which are known by those skilled in the art.
[0094] Critical flicker frequency tests utilize, for example, the
correlation between cerebral processing of oscillatory visual
stimuli and CNS impairment due to increased HE severity. This test
identifies a frequency at which a flickering light is perceived by
a subject as a steady light. A decline in this frequency has been
associated with increasing severity of HE. In one example, circular
light pulses with a 1:1 ratio between the visual impulse and the
interval were used with decreasing frequency in gradual steps of
0.5 to 0.1 Hz/second. The frequency of the white light, which is
initially generated as a high-frequency pulse (50 Hz) and which
gives the patient the impression of a steady light, can be reduced
gradually until the subject had the impression that the steady
light had changed to a flicker. The subject registered this change
by pressing a hand-held switch. The flicker frequencies can be
measured multiple times and the mean values for each subject can be
calculated.
[0095] In some embodiments, CFF values are tracked over time for
each subject.
[0096] From these values the area under the CFF versus time curve
(AUC) could be calculated using calculations that are standard in
the art. For example, AUC can be calculated using the trapezoidal
rule. To use the trapezoidal rule, data points are connected by
straight line segments, perpendiculars are erected from the
abscissa to each data point, and the sum of the areas of the
triangles and trapezoids so constructed is computed and equals the
AUC.
[0097] To accurately describe the variation in the CFF over time
for each subject the time-weighted average (twa) can be computed.
To calculated the twa, the results of the CFF test over time or the
venous ammonia levels are expressed as:
twa = AUC T , ##EQU00001##
where T is the exposure time. Thus, twa describes the average CFF
and/or venous ammonia level effect between multiple time
points.
[0098] The correlation between twa and the presence or absence of
breakthrough HE episode can be analyzed with analysis of variance
and Spearman rank correlation coefficient. Additionally, a ROC
curve analysis can be performed to evaluate the accuracy of the twa
to discriminate between the presence or absence of breakthrough
episodes. A ROC analysis for the data collected in the Examples
demonstrated that the methodology is a highly accurate predictor of
HE.
[0099] These toxic compounds gain access to the systemic
circulation as a result of decreased hepatic function or
portal-systemic shunts. Once in brain tissue, the compounds produce
alterations of neurotransmission that affect consciousness and
behavior. HE is attributed to global central nervous system
depression from nitrogenous compounds that result in excitation of
gamma-aminobutyric acid (GABA) and decreased neurotransmission of
glutamate.
[0100] Precipitating factors include azotemia (29%), sedatives,
tranquilizers, analgesics (24%), gastrointestinal bleeding (18%),
excess dietary protein (9%), metabolic alkalosis (11%), infection
(3%), constipation (3%). Surgery, particularly transjugular
intrahepatic portal-systemic shunt (TIPS) procedures, also may
precipitate HE. HE due to unknown causes accounts for only 2% of
cases.
[0101] Initial manifestations are subclinical and require
psychometric testing for diagnosis. There are 4 progressive stages
of impairment known as the West Haven criteria (or Conn score)
which range from Stage 0 (Lack of detectable changes in
personality) to Stage 4 (Coma, decerebrate posturing, dilated
pupils) as discussed in more detail below.
[0102] HE is manifested as a continuum of psychomotor dysfunction,
impaired memory, increased reaction time, sensory abnormalities,
poor concentration and in severe forms, as coma. Changes may be
observed in personality, consciousness, behavior and neuromuscular
function. Neurologic signs may include hyperreflexia, rigidity,
myoclonus and asterixis (coarse "flapping" muscle tremor).
Cognitive tasks such as connecting numbers with lines can be
abnormal. Fetor hepaticus (sweet breath odor) may be present.
Electroencephalogram (EEG) tracings show nonspecific slow,
triphasic wave activity mainly over the frontal areas. Prothrombin
time may be prolonged and not correctable with Vitamin K. A
computed tomography scan of the head may be normal or show general
atrophy. Finally, signs of liver disease such as jaundice and
ascites may be noted.
[0103] Diagnosis of HE is made on the basis of medical history, and
physical and mental status examinations with the required clinical
elements being knowledge of existent liver disease, precipitating
factor(s), and/or prior history of HE. An EEG may show slow-wave
activity, even in mild cases. An elevated serum ammonia level is
characteristic but not essential, and correlates poorly with the
level of encephalopathy Management of patients with chronic HE
includes 1) provision of supportive care, 2) identification and
removal of precipitating factors, 3) reduction of nitrogenous load
from the gut, and 4) assessment of the need for long term therapy.
The nitrogenous load from the gut is typically reduced using
non-absorbable disaccharide (lactulose) and/or antibiotics.
[0104] Lactulose is considered a first-line treatment in the United
States. Lactulose is metabolized by the intestinal bacteria of the
colon, which leads to reduced fecal pH, then to a laxative effect,
and finally to fecal elimination. The reduced fecal pH ionizes
ammonia (NH.sub.3) to the ammonium ion (NH.sub.4.sup.+) which is
used by the bacteria for amino acid and protein synthesis. This
lowers the serum ammonia levels and improves mental function.
[0105] Conventional therapy aims to lower the production and
absorption of ammonia. Lactulose is typically used in doses of
30-60 g daily. However, the dose can be titrated up to 20-40 g
TID-QID to affect 2-3 semi-formed bowel movements per day. If
lactulose cannot be administered orally or per nasogastric tube,
for example to patients with stage 3 and 4 HE, it may be given as a
300 cc (200 g) retention enema.
[0106] For acute encephalopathy, lactulose can be administered
either orally, by mouth or through a nasogastric tube, or via
retention enemas. The usual oral dose is 30 g followed by dosing
every 1 to 2 hours until evacuation occurs. At that point, dosing
is adjusted to attain two or three soft bowel movements daily.
[0107] Lactulose for is readily available over-the-counter. A
convenient and relatively tasteless formulation, often referred to
in the trade as "lactulose powder for oral solution" can be
obtained, for example, from Bertek Pharmaceuticals, Sugarland, Tex.
as Kristalose.RTM. in 10 and 20 gm packets. The lactulose syrups
commonly sold as laxatives include Cephulac.RTM., Chronulac.RTM.,
Cholac.RTM., and Enulose.RTM. These syrups can be substituted for
lactulose powder by using sufficient syrup to provide the desired
dosage of lactulose; typically, the named syrups contain about 10
gm lactulose in 15 ml of syrup.
[0108] Broad-spectrum, GI-active antibiotics including neomycin,
metronidazole, vancomycin and paromomycin have been used with or
without lactulose. Current guidelines recommend neomycin at 1 to 2
g/day by mouth with periodic renal and annual auditory monitoring
or metronidazole at 250. Lactulose can induce diarrhea leading to
dehydration, a precipitating factor of HE. Additionally, compliance
with lactulose is limited by patient dislike of its overly sweet
taste. In addition, a dosing schedule that is linked to bowel
habits and side effects of flatulence, bloating, diarrhea (which
leads to dehydration), and acidosis make lactulose difficult to use
long-term.
[0109] Antibiotic use in treatment of HE is hampered by toxicity
associated with long-term use. Specifically, systemic absorption of
neomycin, metronidazole and ampicillin has led to rare cases of
nephrotoxicity, ototoxicity, S. enterocolitis, and/or development
of resistant bacterial strains. Additionally, neomycin inhibits
only aerobic bacteria. Metronidazole is metabolized slowly in
patients with hepatic dysfunction, has a potential for alcohol
interactions (disulfiram-like effect), and high blood levels may
result in seizures.
[0110] One gastrointestinal specific antibiotic is rifaximin.
Rifaximin is a nonaminoglycoside, semisynthetic antibiotic derived
from rifamycin O. It is a non-systemic, non-absorbed,
broad-spectrum, oral antibiotic specific for enteric pathogens of
the GI tract. Rifaximin was found to be advantageous in treatment
of HE relative to previously used antibiotics; e.g., negligible
systemic absorption (<0.4%) regardless of food intake or
presence of GI disease and exhibits no plasma accumulation with
high or repeat doses. The lack of systemic absorption makes
rifaximin safe and well tolerated, thus improving patient
compliance and reducing side effects associated with currently
known treatments.
[0111] Rifaximin (INN; see The Merck Index, XIII Ed., 8304) is an
antibiotic belonging to the rifamycin class of antibiotics, e.g., a
pyrido-imidazo rifamycin. Rifaximin exerts its broad antibacterial
activity, for example, in the gastrointestinal tract against
localized gastrointestinal bacteria that cause infectious diarrhea,
irritable bowel syndrome, small intestinal bacterial overgrowth,
Crohn's disease, and/or pancreatic insufficiency. It has been
reported that rifaximin is characterized by a negligible systemic
absorption, due to its chemical and physical characteristics
(Descombe J. J. et al. Pharmacokinetic study of rifaximin after
oral administration in healthy volunteers. Int J Clin Pharmacol
Res, 14 (2), 51-56, (1994)).
[0112] Rifaximin is described in Italian Patent IT 1154655 and EP
0161534. EP patent 0161534 discloses a process for rifaximin
production using rifamycin O as the starting material (The Merck
Index, XIII Ed., 8301). U.S. Pat. No. 7,045,620 B1 discloses
polymorphic forms of rifaximin. The applications and patents
referred to here are incorporated herein by reference in their
entirety for all purposes
[0113] A rifamycin class antibiotic is, for example, a compound
having the structure of Formula I:
##STR00001##
wherein A may be the structure A.sub.1:
##STR00002## [0114] or the structure A.sub.2
##STR00003##
[0114] wherein, -x- is a covalent chemical bond or nil; R is
hydrogen or acetyl;
[0115] R.sub.1 and R.sub.2 independently represent hydrogen,
(C.sub.1-4) alkyl, benzyloxy, mono- and di-(C.sub.1-3)
alkylamino-(C.sub.1-4) alkyl, (C.sub.1-3)alkoxy-(C.sub.1-4)alkyl,
hydroxymethyl, hydroxy-(C.sub.2-4)-alkyl, nitro or R.sub.1 and
R.sub.2 taken together with two consecutive carbon atoms of the
pyridine nucleus form a benzene ring unsubstituted or substituted
by one or two methyl or ethyl groups; R.sub.3 is a hydrogen atom or
nil; with the proviso that, when A is A.sub.1, -x- is nil and
R.sub.3 is a hydrogen atom; with the further proviso that, when A
is A.sub.2, -x- is a covalent chemical bond and R.sub.3 is nil.
[0116] Also described herein is a compound as defined above,
wherein A is A.sub.1 or A.sub.2 as above indicated, -x- is a
covalent chemical bond or nil, R is hydrogen or acetyl, R.sub.1 and
R.sub.2 independently represent hydrogen, (C.sub.1-4)alkyl,
benzyloxy, hydroxy-(C.sub.2-4) alkyl, di-(C.sub.1-3)
alkylamino-(C.sub.1-4) alkyl, nitro or R.sub.1 and R.sub.2 taken
together with two consecutive carbon atoms of the pyridine nucleus
form a benzene ring and R.sub.3 is a hydrogen atom or nil; with the
proviso that, when A is A.sub.1, -x- is nil and R.sub.3 is a
hydrogen atom; with the further proviso that, when A is A.sub.2,
-x- is a covalent chemical bond and R.sub.3 is nil.
[0117] Also described herein is a compound as defined above,
wherein A is A.sub.1 or A.sub.2 as above indicated, -x- is a
covalent chemical bond or nil, R is acetyl, R.sub.1 and R.sub.2
independently represent hydrogen, (C.sub.1-4) alkyl or R.sub.1 and
R.sub.2 taken together with two consecutive carbon atoms of the
pyridine nucleus form a benzene ring and R.sub.3 is a hydrogen atom
or nil; with the proviso that, when A is A.sub.1, -x- is nil and
R.sub.3 is a hydrogen atom; with the further proviso that, when A
is A.sub.2, -x- is a covalent chemical bond and R.sub.3 is nil.
[0118] Also described herein is a compound as defined above, which
is 4-deoxy-4'-methyl-pyrido[1',2'-1,2]imidazo [5,4-c]rifamycin SV.
Also described herein is a compound as defined above, which is
4-deoxy-pyrido [1',2':1,2]imidazo [5,4-c]rifamycin SV.
[0119] Also described herein is a compound as defined above,
wherein A is as described above, -x- is a covalent chemical bond or
nil; R is hydrogen or acetyl; R.sub.1 and R.sub.2 independently
represent hydrogen, (C.sub.1-4) alkyl, benzyloxy, mono- and
di-(C.sub.1-3)alkylamino(C.sub.1-4)alkyl, (C.sub.1-3)alkoxy-
(C.sub.1-4)alkyl, hydroxymethyl, hydroxy-(C.sub.2-4)-alkyl, nitro
or R.sub.1 and R.sub.2 taken together with two consecutive carbon
atoms of the pyridine nucleus form a benzene ring unsubstituted or
substituted by one or two methyl or ethyl groups; R.sub.3 is a
hydrogen atom or nil; with the proviso that, when A is A.sub.1, -x-
is nil and R.sub.3 is a hydrogen atom; with the further proviso
that, when A is A.sub.2, -x- is a covalent chemical bond and
R.sub.3 is nil.
[0120] Rifaximin is a compound having the structure of formula
II:
##STR00004##
[0121] In certain embodiments, the antibiotic comprises one or more
of a rifamycin, aminoglycoside, amphenicol, ansamycin,
.beta.-Lactam, carbapenem, cephalosporin, cephamycin, monobactam,
oxacephem, lincosamide, macrolide, polypeptide, tetracycline, or a
2,4-diaminopyrimidine class antibiotic. Exemplary antibiotics of
these classes are listed below.
[0122] Rifaximin exerts a broad antibacterial activity in the
gastrointestinal tract against localized gastrointestinal bacteria
that cause infectious diarrhea, including anaerobic strains. It has
been reported that rifaximin is characterized by a negligible
systemic absorption, due to its chemical and physical
characteristics (Descombe J. J. et al. Pharmacokinetic study of
rifaximin after oral administration in healthy volunteers. Int J
Clin Pharmacol Res, 14 (2), 51-56, (1994)).
[0123] Without wishing to be bound by any particular scientific
theories, rifaximin acts by binding to the beta-subunit of the
bacterial deoxyribonucleic acid-dependent ribonucleic acid (RNA)
polymerase, resulting in inhibition of bacterial RNA synthesis. It
is active against numerous gram (+) and (-) bacteria, both aerobic
and anaerobic. In vitro data indicate rifaximin is active against
species of Staphylococcus, Streptococcus, Enterococcus, and
Enterobacteriaceae. Bacterial reduction or an increase in
antimicrobial resistance in the colonic flora does not frequently
occur and does not have a clinical importance. Rifaximin is
currently approved in 17 countries outside the US and was licensed
by the Food and Drug Administration (FDA) for the US in May
2004.
[0124] It is to be understood that both the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not restrictive of the invention as
claimed. In this application, the use of the singular includes the
plural unless specifically stated otherwise. In this application,
the use of "or" means "and/or" unless stated otherwise.
Furthermore, the use of the term "including", as well as other
forms, such as "includes" and "included", is not limiting. Also,
terms such as "element" or "component" encompass both elements and
components comprising one unit and elements and components that
comprise more than one subunit unless specifically stated
otherwise. Also, the use of the term "portion" can include part of
a moiety or the entire moiety.
[0125] All documents, or portions of documents, cited in this
application, including but not limited to patents, patent
applications, articles, books, and treatises, are hereby expressly
incorporated by reference in their entirety for any purpose.
[0126] One embodiment is a method of treating or preventing hepatic
encephalopathy (HE) by administering a therapeutically effective
amount of a gastrointestinal (GI) specific antibiotic to a subject.
Examples of gastrointestinal antibiotics as used herein include
rifamycin class antibiotics, such as rifaximin.
[0127] Embodiments of the invention relate to the discovery of the
efficacy of gastrointestinal (GI) specific antibiotics for the
treatment and prevention of Hepatic Encephalopathy. Embodiments
relate to the use of GI specific antibiotics to prevent the onset
of HE symptoms and also to lengthen the time to a first
breakthrough HE episode. In one embodiment, the time to a first
breakthrough HE episode was measured by an increase of the Conn
score to Grade .gtoreq.2 (e.g., 0 or 1 to .gtoreq.2) or a Conn and
asterixis score increase of one grade each for those subjects that
have a baseline Conn Score of 0. In another embodiment, the time to
breakthrough HE episode was measured by the time to any increase
from baseline in either the Conn score (mental state grade) or
asterixis grade, with Kaplan-Meier estimates of cumulative
proportions of subjects with any increase at Days 28, 56, 84, 112,
140, and 168.
[0128] Another embodiment was a measurement of the time to a first
HE-related hospitalization or the time to development of
spontaneous bacterial peritonitis (SBP). Another embodiment was a
mean change from baseline in blood ammonia concentration over time
or a mean change from baseline in critical flicker frequency values
over time. An additional embodiment was indicated by a mean daily
lactulose consumption over time, shifts from baseline in Conn
scores over time; or shifts from baseline in asterixis grades over
time. Unless otherwise specified, a shift of a value is the change
of that value from a baseline value.
[0129] Other measures of efficacy of the treatments described
herein included mean change from baseline in Chronic Liver Disease
Questionnaire (CLDQ) scores over time; mean change from baseline in
Epworth Sleepiness Scale scores over time; and proportion of
subjects who have an Epworth Sleepiness Scale score >10. The
evaluation of severity of persistent hepatic encephalopathy may
also be based, for example, on Conn scores.
[0130] In another embodiment, a subject suffering from, susceptible
to or in remission from hepatic encephalopathy (HE) can be
administered a rifamycin class antibiotic for between about 24
weeks and 24 months. In treating HE, the rifamycin class antibiotic
may be administered to the subject for 12 months and longer, for
example for a subject's entire life span. In one embodiment, the
antibiotic is administered daily until the death of the
subject.
[0131] In one embodiment, the invention relates to a method of
decreasing a subject's risk of having a breakthrough event by
administering to the subject a GI specific antibiotic. In one
embodiment, the for subjects having a last HE episode equal to or
greater than 90 days prior to starting on treatment, the risk of
failure occurrence was reduced by 58%. In another embodiment, the
risk of failure occurrence was reduced by between about 30-70%. In
another embodiment, the risk was reduced by about 40% to 70%. In
one embodiment the invention relates to decreasing the risk for
episodes of overt hepatic encephalopathy in patients suffering from
HE. In one embodiment, the patients are over 18 years of age.
[0132] In one embodiment, for subjects having a last HE episode
more than 90 days prior to administration of a GI specific
antibiotic, the risk of failure occurrence was decreased by between
about 60%. In another embodiment, the risk of failure occurrence
was decreased by between about 2%-80%.
[0133] In another embodiment, for subjects having two or fewer HE
episodes in the six months prior to starting on treatment, the risk
of a breakthrough HE episode was decreased by about a 56%. In one
embodiment, the risk of a breakthrough HE episode was decreased by
between about a 20%-70%.
[0134] In another embodiment, for subjects having greater than two
HE episodes in the six months prior to starting on treatment, the
risk of a breakthrough HE episode was reduced by about 63%. In
another embodiment, the risk was reduced by about 30%-80%.
[0135] In one embodiment, the therapeutically effective amount of a
gastrointestinal (GI) specific antibiotic comprises from between
about 1000 mg to about 1200 mg/day.
[0136] In one embodiment, the therapeutically effective amount of a
gastrointestinal (GI) specific antibiotic comprises from between
about 1100 mg to about 1200 mg/day.
[0137] According to one embodiment, the therapeutically effective
amount of a gastrointestinal (GI) specific antibiotic comprises
about 1150 mg/day.
[0138] In another embodiment, the therapeutically effective amount
is a dosage regimen of one capsule or tablet of the formulation two
times each day, wherein each tablet comprises about 550 mg of the
gastrointestinal (GI) specific antibiotic, such as rifaximin.
[0139] In one embodiment, the therapeutically effective amount is a
dosage regimen of two capsules or tablets three times each day,
wherein each capsule comprises about 200 mg of the gastrointestinal
(GI) specific antibiotic.
[0140] In one embodiment, the therapeutically effective amount is a
dosage of 275 mg of a gastrointestinal (GI) specific antibiotic
administered four times per day. In another embodiment, 275 mg of a
gastrointestinal (GI) specific antibiotic is administered as two
dosage forms two times per day.
[0141] Another embodiment is a method of maintaining remission of
HE in a subject by administering a GI specific antibiotic to the
subject.
[0142] Another embodiment is a method of increasing time to
hospitalization for treatment of HE by administering to the subject
a GI specific antibiotic. In one embodiment, the administration of
a GI specific antibiotic reduces hospitalization frequency by about
48%. In another embodiment, a GI specific antibiotic reduces
hospitalization frequency by from between about 13% to about
69%.
[0143] In one embodiment, treatment with the gastrointestinal (GI)
specific antibiotic maintains remission of HE in the subject.
[0144] In one embodiment, the GI specific antibiotic is
administered to the subject for six months, one year, two to three
years or daily until the subject's death.
[0145] In one embodiment, a Conn score for the subject is improved
over baseline following administration of a GI specific
antibiotic.
[0146] In one embodiment, a quality of life (QoL) measurement is
improved from baseline with administration of a GI specific
antibiotic over a course of treatment with rifaximin. In one
embodiment, the improvised quality is an improvement in the AUC or
TWA of the Chronic Liver Disease Questionnaire (CLDQ).
[0147] In one embodiment, the GI specific antibiotic is
administered to the subject with lactulose, prior to treatment with
lactulose, or following treatment with lactulose. In one embodiment
the subject or a health care worker is advised to administer the GI
specific antibiotic with lactulose. In one embodiment the subject
or a health care worker is advised by a pharmaceutical label or
insert to administer the GI specific antibiotic with lactulose in
order to maintain remission of HE, or to decrease the risk for
episodes of overt HE. In one embodiment, the subject or health care
worker is advised to administer two 550 mg tablets of rifaximin
twice daily with lactulose. Lactulose use may be titrated over time
so that the subject maintains 2-3 soft stool bowel movements per
day. In one embodiment the lactulose is administered in 15 ml
dosages, wherein each 15 ml dosage contains 10 mg of lactulose. In
a typical titration, the subject may start on one dosage, or a
partial dosage, per day and then move up in 15 ml dosages over time
until they reach an end point of 2-3 soft stool bowel movements per
day.
[0148] In one embodiment, subjects in need of treatment for HE and
having a Child-Pugh grade of A or B are treated with a GI specific
antibiotic. In another embodiment, subjects in need of treatment
for HE having a Child-Pugh grade of A or B are treated with a GI
specific antibiotic in combination with lactulose. In another
embodiment, subjects having a Child-Pugh grade of A or B, or their
health care worker, are advised that they should be treated with a
GI specific antibiotic. The advice can be oral or written advice,
such as on a pharmaceutical label or package insert. In another
embodiment, subjects having a Child-Pugh grade of A or B, or their
health care worker, are advised that they should be treated with a
GI specific antibiotic in combination with lactulose. In one
embodiment, a subject in need of treatment for HE and having a
Child-Pugh grade of less than C is treated with a GI specific
antibiotic. In one embodiment, a subject in need of treatment for
HE and having a Child-Pugh grade of less than C is treated with a
GI specific antibiotic and lactulose.
[0149] In another embodiment, a subject in need of treatment for
HE, or their health care worker is advised of the risk for
anaphylaxis prior to treatment with a GI specific antibiotic.
[0150] In one embodiment, the GI specific antibiotic is
administered with one or more of align, alinia, Lactulose, pentasa,
cholestyramine, sandostatin, vancomycin, lactose, amitiza, flagyl,
zegerid, prevacid, or miralax.
[0151] In one embodiment, following treatment with GI specific
antibiotic, a Conn score (mental state grade) of a subject
decreases.
[0152] In one embodiment, following treatment with a GI specific
antibiotic, a Conn score increase from baseline is increased.
[0153] In one embodiment, following treatment with a GI specific
antibiotic, a delay in time to an increase in Conn score is about
54%. For example, the percentage delay in time to increase in Conn
score may be between about 30% to about 70%.
[0154] In another embodiment, administration of the GI specific
antibiotic prevents an increase in Conn score. For example,
administration of the GI specific antibiotic increases the time to
an increase from baseline in a Conn score.
[0155] In one embodiment, administration of the GI specific
antibiotic results in an increase of time to an increase from
baseline in an asterixis grade.
[0156] In another embodiment, administration of the GI specific
antibiotic results in a delay in the time to increase in asterixis
grade.
[0157] In another embodiment, administration of the GI specific
antibiotic results in an increase in time to first HE-related
hospitalization.
[0158] In another embodiment, administration of the GI specific
antibiotic results in an increase in the time to development of
spontaneous bacterial peritonitis (SBP).
[0159] In another embodiment, administration of the GI specific
antibiotic results in a decrease in blood ammonia concentration
from baseline after administration of rifaximin. For example, the
decrease in blood ammonia concentration may be from baseline to 170
days of about 6 .mu.g/dL.
[0160] In another embodiment, administration of the GI specific
antibiotic results in an increase in critical flicker frequency
values from baseline after administration of rifaximin.
[0161] In another embodiment, administration of the GI specific
antibiotic results in a decrease in daily lactulose consumption
from baseline over time after administration with rifaximin.
[0162] In another embodiment, administration of the GI specific
antibiotic results in a decrease in daily lactulose consumption is
from between about 7 doses of lactulose to about 2 doses of
lactulose.
[0163] In another embodiment, administration of the GI specific
antibiotic results in a lactulose use that initially increases from
baseline. For example, the lactulose use may be from between about
1 and about 30 days.
[0164] In another embodiment, administration of the GI specific
antibiotic results in a shift in baseline in Conn scores over time
after administration of rifaximin. For example, the shift in
baseline in Conn scores may be from between about 1 to about 2.
[0165] In another embodiment, administration of the GI specific
antibiotic results in a shift from baseline in asterixis grades
over time.
[0166] In another embodiment, administration of the GI specific
antibiotic results in a change from baseline in Chronic Liver
Disease Questionnaire (CLDQ) scores over time.
[0167] In another embodiment, administration of the GI specific
antibiotic results in a change from baseline in Epworth Sleepiness
Scale scores over time after administration of rifaximin.
[0168] As is known, the Model for End-Stage Liver Disease (MELD)
score can be utilized to predict liver disease severity based on
serum creatinine, serum total bilirubin, and the international
normalized ratio for prothrombin time INR. The MELD score and has
been shown to be useful in predicting mortality in patients with
compensated and decompensated cirrhosis. The maximum score given
for MELD is 40. All values higher than 40 are given a score of
40.
[0169] In another embodiment, subjects having a MELD level of
between about 1 to 24 responded to treatment for HE using
administration of the GI specific. In another embodiment, subjects
having a MELD level less than or equal to 10 responded to treatment
with GI specific antibiotics. In another embodiment, subjects
having a MELD level between 11 and 18 respond to treatment with GI
specific antibiotics. In another embodiment, subjects having a MELD
level between 19 and 24 respond to treatment with GI specific
antibiotics. In one embodiment, subjects in need of treatment for
HE and having a MELD score of 25 or less are treated with a GI
specific antibiotic. In another embodiment, subjects in need of
treatment for HE having a MELD score of 25 or less are treated with
a GI specific antibiotic in combination with lactulose. In another
embodiment, subjects having a MELD score of 25 or less are advised
that they should be treated with a GI specific antibiotic. The
advice can be oral or written advise, such as on a pharmaceutical
label or package insert. In another embodiment, subjects having a
MELD score of 25 or less are advised that they should be treated
with a GI specific antibiotic in combination with lactulose.
[0170] One embodiment of the invention is a method of treating or
preventing HE by administering 1100 mg of rifaximin per day to a
patient for more than 28 days.
[0171] Another embodiment is a method of decreasing lactulose use
in a subject.
[0172] This method includes: administering rifaximin to a subject
daily that is being treated with lactulose, and tapering lactulose
consumption. For example, the lactulose consumption may be reduced
by 1, 2, 3, 4, 5, 6 or more unit dose cups of lactulose from a
baseline level. Alternatively, the lactulose use may be reduced by
5, 10, 15, 20, 25, 30, 34, 40, 45, 50, 55, 60, 65, or 70 g
lactulose from a baseline level. In one embodiment, the baseline
use of lactulose is no use.
[0173] One embodiment of the invention is a method of maintaining
remission of HE in a subject comprising administering 550 mg of
rifaximin twice a day (BID) to the subject.
[0174] Another embodiment is a method of increasing time to
hospitalization for treatment of HE comprising, administering to a
subject 550 mg of rifaximin two times per day (BID).
[0175] The term "administration" or "administering" includes routes
of introducing a GI specific antibiotic to a subject to perform
their intended function. Examples of routes of administration that
may be used include injection (subcutaneous, intravenous,
parenterally, intraperitoneally, intrathecal), oral, inhalation,
rectal and transdermal. The pharmaceutical preparations may be
given by forms suitable for each administration route. For example,
these preparations are administered in tablets or capsule form, by
injection, inhalation, eye lotion, eye drops, ointment,
suppository, etc. administration by injection, infusion or
inhalation; topical by lotion or ointment; and rectal by
suppositories. Oral administration is preferred. The injection can
be bolus or can be continuous infusion. Depending on the route of
administration, a GI specific antibiotic can be coated with or
disposed in a selected material to protect it from natural
conditions that may detrimentally effect its ability to perform its
intended function. A GI specific antibiotic can be administered
alone, or in conjunction with either another agent or agents as
described above or with a pharmaceutically-acceptable carrier, or
both. A GI specific antibiotic can be administered prior to the
administration of the other agent, simultaneously with the agent,
or after the administration of the agent. Furthermore, a GI
specific antibiotic can also be administered in a proform, which is
converted into its active metabolite, or more active metabolite in
vivo.
[0176] Administration "in combination with" one or more further
therapeutic agents includes simultaneous (concurrent) and
consecutive administration in any order.
[0177] 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 will vary depending upon the age, weight and
mammalian species treated, the particular compounds employed, and
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.
Typically, human clinical applications of products are commenced at
lower dosage levels, with dosage level being increased until the
desired effect is achieved.
[0178] As used herein, an "increase" or "decrease" in a
measurement, unless otherwise specified, is typically in comparison
to a baseline value. For example, an increase in time to
hospitalization for subjects undergoing treatment may be in
comparison to a baseline value of time to hospitalization for
subjects that are not undergoing such treatment. In some instances
an increase or decrease in a measurement can be evaluated based on
the context in which the term is used.
[0179] "Carriers" as used herein include pharmaceutically
acceptable carriers, excipients, or stabilizers which are nontoxic
to the cell or mammal being exposed thereto at the dosages and
concentrations employed. Often the physiologically acceptable
carrier is an aqueous pH buffered solution. Examples of
physiologically acceptable carriers include buffers such as
phosphate, citrate, and other organic acids; antioxidants including
ascorbic acid; low molecular weight (less than about 10 residues)
polypeptide; proteins, such as serum albumin, gelatin, or
immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone;
amino acids such as glycine, glutamine, asparagine, arginine or
lysine; monosaccharides, disaccharides, and other carbohydrates
including glucose, mannose, or dextrins; chelating agents such as
EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming
counterions such as sodium; and/or nonionic surfactants such as
TWEEN, polyethylene glycol (PEG).
[0180] The term "effective amount" includes an amount effective, at
dosages and for periods of time necessary, to achieve the desired
result, e.g., sufficient to treat or prevent HE in a patient or
subject. An effective amount of a GI specific antibiotic may vary
according to factors such as the disease state, age, and weight of
the subject, and the ability of a GI specific antibiotic to elicit
a desired response in the subject.
[0181] Dosage regimens may be adjusted to provide the optimum
therapeutic response. An effective amount is also one in which any
toxic or detrimental effects (e.g., side effects) of a GI specific
antibiotic are outweighed by the therapeutically beneficial
effects.
[0182] "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.
[0183] Such improvement or change may be observed in treated
subjects as compared to subjects not treated with rifaximin, 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, including, e.g., a quality of life assessment such
as a Chronic Liver Disease Questionnaire (CLDQ), a slowed
progression of a disease(s) or condition(s), a reduced severity of
a disease(s) or condition(s), or a suitable assay(s) for the level
or activity(ies) of a biomolecule(s), cell(s) or by detection of HE
episodes in a subject. Amelioration may be transient, prolonged or
permanent or it may be variable at relevant times during or after a
GI specific antibiotic 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 a GI specific antibiotic to about 28 days,
or 1, 3, 6, 9 months or more after a subject(s) has received such
treatment.
[0184] 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 a GI specific
antibiotic, 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, e.g., by the subject's
self assessment, by a clinician's assessment or by conducting an
appropriate assay or measurement, including, e.g., quality of life
assessments or suitable assays for the level or activity of
molecules, cells or cell migration within a subject. Modulation may
be transient, prolonged or permanent or it may be variable at
relevant times during or after a GI specific antibiotic 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 a GI
specific antibiotic to about 3, 6, 9 months or more after a
subject(s) has received a GI specific antibiotic.
[0185] The term "modulate" may also refer to increases or decreases
in the activity of a cell in response to exposure to a GI specific
antibiotic, e.g., the inhibition of proliferation and/or induction
of differentiation of at least a sub-population of cells in an
animal such that a desired end result is achieved, e.g., a
therapeutic result of GI specific antibiotic used for treatment may
increase or decrease over the course of a particular treatment.
[0186] The term "obtaining" as in "obtaining a GI specific
antibiotic" is intended to include purchasing, synthesizing or
otherwise acquiring a GI specific antibiotic. The phrases
"parenteral administration" and "administered parenterally" as used
herein includes, for example, modes of administration other than
enteral and topical administration, usually by injection, and
includes, without limitation, intravenous, intramuscular,
intraarterial, intrathecal, intracapsular, intraorbital,
intracardiac, intradermal, intraperitoneal, transtracheal,
subcutaneous, subcuticular, intraarticulare, subcapsular,
subarachnoid, intraspinal and intrasternal injection and
infusion.
[0187] The language "a prophylactically effective amount" of a
compound refers to an amount of a GI specific antibiotic which is
effective, upon single or multiple dose administration to the
subject, in preventing or treating HE.
[0188] Pharmaceutical Preparations
[0189] Embodiments also provide pharmaceutical compositions,
comprising an effective amount of a rifaximin described herein and
a pharmaceutically acceptable carrier. In a further embodiment, the
effective amount is effective to treat a bacterial infection,
Crohn's disease, hepatic encephalopathy, antibiotic associated
colitis, and/or diverticular disease in a subject further suffering
from hepatic insufficiency.
[0190] Embodiments also provide pharmaceutical compositions
comprising rifaximin and a pharmaceutically acceptable carrier.
Doses may be selected, for example on the basis of desired amounts
of systemic adsorption, elimination half-life, serum concentration
and the like. Embodiments of the pharmaceutical composition 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. One composition 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.
[0191] In an embodiment, rifaximin is administered to the subject
using a pharmaceutically-acceptable formulation, e.g., a
pharmaceutically-acceptable formulation that provides sustained
delivery of the rifaximin to a subject for at least 12 hours, 24
hours, 36 hours, 48 hours, one week, two weeks, three weeks, or
four weeks after the pharmaceutically-acceptable formulation is
administered to the subject.
[0192] 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 of the present invention 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.
[0193] The phrase "pharmaceutically acceptable" refers to rifaximin
compositions containing rifaximin 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.
[0194] 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 is preferably
"acceptable" in the sense of being compatible with the other
ingredients of the formulation and not injurious to the subject.
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.
[0195] 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.
[0196] 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.
[0197] Compositions containing a rifaximin forms disclosed herein
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 well 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.
[0198] Generally, out of one hundred %, this amount will range from
about 1% to about ninety-nine % of active ingredient, preferably
from about 5% to about 70%, most preferably from about 10% to about
30%.
[0199] Methods of preparing these compositions include the step of
bringing into association a rifaximin with the carrier and,
optionally, one or more accessory ingredients. In general, the
formulations are prepared by uniformly and intimately bringing into
association a rifaximin with liquid carriers, or finely divided
solid carriers, or both, and then, if necessary, shaping the
product.
[0200] Compositions suitable for oral administration may be in the
form of capsules, cachets, pills, tablets, lozenges (using a
flavored basis, usually sucrose and acacia or tragacanth), powders,
granules, or as a solution or a suspension in an aqueous or
non-aqueous liquid, or as an oil-in-water or water-in-oil liquid
emulsion, or as an elixir or syrup, or as pastilles (using an inert
base, such as gelatin and glycerin, or sucrose and acacia) and/or
as mouth washes and the like, each containing a predetermined
amount of a rifaximin as an active ingredient. A compound may also
be administered as a bolus, electuary or paste.
[0201] The term "pharmaceutical agent composition" (or agent or
drug) as used herein refers to a chemical compound, composition,
agent or drug capable of inducing a desired therapeutic effect when
properly administered to a patient. It does not necessarily require
more than one type of ingredient.
[0202] The compositions may be in the form of tablets, capsules,
powders, granules, lozenges, liquid or gel preparations. Tablets
and capsules for oral administration may be in a form suitable for
unit dose presentation and may contain conventional excipients.
Examples of these are: binding agents such as syrup, acacia,
gelatin, sorbitol, tragacanth, and polyvinylpyrrolidone; fillers
such as lactose, sugar, maize-starch, calcium phosphate, sorbitol
or glycine; tableting lubricants, such as magnesium stearate,
silicon dioxide, talc, polyethylene glycol or silica;
disintegrants, such as potato starch; or acceptable wetting agents,
such as sodium lauryl sulfate. The tablets may be coated according
to methods well known in normal pharmaceutical practice.
[0203] Oral liquid preparations may be in the form of, for example,
aqueous or oily suspensions, solutions, emulsions, syrups or
elixirs, or may be presented as a dry product for reconstitution
with water or other suitable vehicle before use. Such liquid
preparations may contain conventional additives such as suspending
agents, e.g., sorbitol, syrup, methyl cellulose, glucose syrup,
gelatin, hydrogenated edible fats, emulsifying agents, e.g.,
lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles
(including edible oils), e.g., almond oil, fractionated coconut
oil, oily esters such as glycerine, propylene glycol, or ethyl
alcohol; preservatives such as methyl or propyl p-hydroxybenzoate
or sorbic acid, and, if desired, conventional flavoring or coloring
agents.
[0204] The phrases "systemic administration," "administered
systemically," "peripheral administration," and "administered
peripherally," as used herein mean the administration of a GI
specific antibiotic, drug or other material, such that it enters
the subject's system and, thus, is subject to metabolism and other
like processes, for example, subcutaneous administration.
[0205] The language "therapeutically effective amount" of a GI
specific antibiotic refers to an amount of a GI specific antibiotic
which is effective, upon single or multiple dose administration to
the subject, in inhibiting the bacterial growth and/or invasion, or
in decreasing symptoms, such as HE episodes, relating to bacterial
growth in a subject. "Therapeutically effective amount" also refers
to the amount of a therapy (e.g., a composition comprising a GI
specific antibiotic), which is sufficient to reduce the severity of
HE in a subject.
[0206] As used herein, the terms "prevent," "preventing," and
"prevention" refer to the prevention of the recurrence, onset, or
development HE episodes or more symptoms of HE. Preventing includes
protecting against the occurrence and severity of HE episodes.
[0207] As used herein, the term "prophylactically effective amount"
refers to the amount of a therapy (e.g., a composition comprising a
GI specific antibiotic) which is sufficient to result in the
prevention of the development, recurrence, or onset of HE episodes
or to enhance or improve the prophylactic effect(s) of another
therapy.
[0208] "Rifaximin", as used herein, includes solvates and
polymorphous forms of the molecule, including, for example,
.alpha., .beta., .gamma., .delta., .epsilon., .zeta. and amorphous
forms of rifaximin. These forms are described in more detail, for
example, in U.S. Ser. No. 11/873,841; U.S. Ser. No. 11/658,702; EP
05 004 635.2, filed 3 May 2005; U.S. Pat. No. 7,045,620; U.S.
61/031,329; and G. C. Viscomi, et al., CrystEngComm, 2008, 10,
1074-1081 (April 2008). Each of these references is hereby
incorporated by reference in entirety.
[0209] The forms of rifaximin can be advantageously used in the
production of medicinal preparations having antibiotic activity,
containing rifaximin, for both oral and topical use. The medicinal
preparations for oral use may contain rifaximin a or R or .gamma.
together with other excipients, for example diluting agents such as
mannitol, lactose and sorbitol; binding agents such as starchs,
gelatines, sugars, cellulose derivatives, natural gums and
polyvinylpyrrolidone; lubricating agents such as talc, stearates,
hydrogenated vegetable oils, polyethylenglycol and colloidal
silicon dioxide; disintegrating agents such as starchs, celluloses,
alginates, gums and reticulated polymers; coloring, flavoring and
sweetening agents.
[0210] Medicinal preparations may contain gastrointestinal specific
antibiotics together with usual excipients, such as white
petrolatum, white wax, lanoline and derivatives thereof, stearylic
alcohol, red iron oxide, propylene glycol, talc, sodium lauryl
sulfate, ethers of fatty polyoxyethylene alcohols, disodium
edentate, glycerol palmitostearate, esters of fatty polyoxyethylene
acids, sorbitan monostearate, glyceryl monostearate, propylene
glycol monostearate, hypromellose, polyethylene glycols, sodium
starch glycolate, methylcellulose, hydroxymethyl propylcellulose,
sodium carboxymethylcellulose, microcrystalline cellulose,
colloidal aluminium and magnesium silicate, titanium dioxide,
propylene glycol, colloidal silicon dioxide, or sodium
alginate.
[0211] As used herein, "breakthrough HE," includes, for example, an
increase of the Conn score to Grade .gtoreq.2 (e.g., 0 or 1 to
.gtoreq.2) or a Conn and Asterixis score increase of 1 grade each
for those subjects that have a baseline Conn score of 0.
[0212] As used herein, "time to the first breakthrough HE episode,"
includes, for example, the duration between the date of first
administration of rifaximin and the date of first breakthrough HE
episode.
[0213] As used herein, the term "breakthrough HE event", is
intended to include a marked, clinically significant deterioration
in neurological function caused by toxic substances accumulating in
the blood that cause a deleterious effect on self care, and often
leads to hospitalization. Breakthrough HE event is also defined as
an increase of a Conn Score to .gtoreq.2 (i.e., 0 or 1 to
.gtoreq.2) or a Conn score and asterixis grade increase of 1 each
for those subjects that have a baseline Conn score of 0.
[0214] Provided herein are methods for determining if a subject has
a neurological condition by determining the CFF of a subject at two
or more time points. In exemplary embodiments, time points can be
1, 2, 3, 4, 5, 6 or 7 days apart; or 2, 3, or 4 weeks apart; or 2,
3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months apart or any time point in
between any two values. In other embodiments, a subject may be
monitored at routine intervals for life.
[0215] The methods of the invention provide that a decrease in CFF
between two or more time points is indicative that the probability
of an HE breakthrough event is approaching. Moreover, if a subject
has a CFF twa value at a time point that is less than 24 Hz, it is
indicative that the subject has an increased probability of an HE
event. Therefore, a decrease between CFF in two or more time points
or a twa of 24 Hz or less is indicative that the subject has HE,
has an increased chance of an HE breakthrough event, and/or should
be treated with Rifaximin. Accordingly, based on the data collected
to date, in one embodiment provided herein are methods of
determining if a subject has HE, of predicting the occurrence of a
breakthrough HE event, or determining the prognosis of a subject by
determining a subject's CFF is below 24 Hz, wherein a CFF below 24
Hz is indicative that the subject has HE, is likely to have a
breakthrough HE event, or has a poor prognosis. In certain
embodiments, a CFF of less than 24 Hz is indicative that a GI
specific antibiotic, e.g., rifaximin, should be administered.
[0216] Provided herein are prognostic methods based on determining
the CFF or twa CFF wherein a twa CFF of less than 24 is indicative
of poor prognosis, or wherein a decrease in CFF or twa CFF between
measurements at different time points is indicative of poor
prognosis. Poor prognosis includes the survival of the subject for
less than 2, 3, 4, 5, 6, 7, 8 or more years or as described herein
or in the opinion of a healthcare professional, the subject or a
person observing the subject.
[0217] In other embodiments, provided herein are method for
determining if a subject has HE or has an increased risk of having
a HE breakthrough event by measuring the venous ammonia level in a
subject at two or more time points, wherein an increase in the
venous ammonia level is indicative that the subject has HE, has an
increased chance of an HE breakthrough event, and/or should be
treated with a GI specific antibiotic, e.g., rifaximin. In certain
embodiments the venous ammonia level is a time weighted average
venous ammonia level.
[0218] Venous ammonia concentration can be measured using methods
that are known to one of skill in the art. The accuracy of ammonia
determination is dependent on sample collection. Whole blood is
preferred. In one specific method described herein, blood is
collect blood from a stasis-free vein into an EDTA evacuated tube.
The sample is placed in ice immediately after collecting and
mixing. The sample is placed in a cold environment, e.g., on ice,
for approximately ten minutes and then centrifuged. The plasma is
separated from the sample within fifteen minutes of collection and
frozen. Hemolyzed samples should not be used for further
analysis.
[0219] The frozen sample is subjected to an enzymatic assay to
determine the amount of ammonia present in the sample. The sample
containing ammonia is mixed with .alpha.-ketoglutarate and reduced
nicotinamide adenine dinucleotide phosphate (NADPH) to form
L-glutamate and NADP and water. The reaction is catalyzed by
glutamate dehydrogenase. The results are determined
spectrophotometrically by monitoring the decrease in absorbance at
340 nm due to the oxidation of NADPH. This decrease is proportional
to the ammonia concentration.
[0220] In other embodiments, provided herein are methods for
determining if a subject has a neurological condition by measuring
the CFF between two or more time points. A decrease in the CFF
between time points is indicative that a subject has a neurological
condition. In certain embodiments, the CFF is the twa of CFF
events.
[0221] According to one embodiment of the teachings of the present
invention, provided herein are a database having a data structure
which contains a number of CFF or venous ammonia levels from
subjects. Similarly, at least one of the databases includes a data
structure which maintains a number of relationships between the CFF
or venous ammonia levels and the disease state of the subjects and
that defines the business rules for performing the methods of the
present invention. These business rules can include defined methods
for determining if a subject has HE or is at risk of having a
breakthrough HE event. Likewise, the business rules can include
defined methods for determining if a subject has a neurological
condition. The diagnosis or prognosis can be optionally selected
using the novel software of the systems and methods of the present
invention. In this scenario, the systems and methods, including the
novel program configurations, will automatically perform the
methods of the present invention without additional user input.
[0222] Provided herein are methods for determining if a subject has
a neurological condition by determining the CFF of a subject at two
or more time points.
[0223] In particular, one such additional method provided herein
includes novel software including a number of program modules or
components located on a server within the system for creating and
populating a database for use in the diagnostic or prognostic
methods of the invention. In other words, in one embodiment, the
systems and methods provide for the creation and management of a
particular policy and policy management for a particular client.
One of ordinary skill in the art will understand upon reading this
disclosure that the various embodiments include novel software
including a number of program modules or components located on the
computer based system or network of the present invention, e.g.
servers, sending remote clients, and receiving remote clients, for
facilitating the methods of the present invention.
[0224] As used herein, "time to first HE-related hospitalization,"
includes, for example, the duration between the first dose of
rifaximin and the date of first HE-related hospitalization.
[0225] As used herein, "time to an increase from baseline in the
Conn score" includes, for example, the duration between the first
dose of rifaximin and the date of first increase in Conn score.
[0226] As used herein, "time to an increase from baseline in the
asterixis grade", includes, for example, the duration between the
first dose of rifaximin and the date of first increase in asterixis
grade.
[0227] As used herein, "mean change from baseline in the fatigue
domain score of Chronic Liver Disease Questionnaire (CLDQ), at end
of treatment (EOT)" is the mean score with a baseline from before
the first administration of rifaximin.
[0228] As used herein, "mean change from baseline in blood ammonia
concentration at EOT," includes the mean score with a baseline from
before the first administration of rifaximin.
[0229] As used herein, the "time to diagnosis of spontaneous
bacterial peritonitis (SBP)," includes, for example, the duration
between the first dose of rifaximin and the date of first episode
of SBP.
[0230] As used herein, the "mean change from baseline at each
post-baseline in critical flicker frequency values," is measured,
for example, from a baseline established before the first
administration of rifaximin.
[0231] "GI specific antibiotic," and "GI antibiotic" as used herein
include antibiotic known to have an effect on GI disease. For
example, a rifamycin class antibiotic (e.g., rifaximin), neomycin,
metronidazole, teicoplanin, ciprofloxacin, doxycycline,
tetracycline, augmentin, cephalexin, penicillin, ampicillin,
kanamycin, rifamycin, vancomycin, rifaximin, and combinations
thereof are useful GI specific antibiotics. Even more preferable
are GI specific antibiotics with low systemic absorption, for
example, rifaximin. Low systemic absorption includes, for example,
less than 10% absorption, less than 5% absorption, less than 1%
absorption and less than 0.5% absorption. Low systemic absorption
also includes, for example, from between about 0.01-1% absorption,
from between about 0.05-1% absorption, from between about 0.1-1%
absorption, from between about 1-10% absorption, or from between
about 5-20% absorption.
[0232] As used herein, "subject" includes organisms which are
capable of suffering from a bowel disorder or other disorder
treatable by rifaximin or who could otherwise benefit from the
administration of a rifaximin as described herein, such as human
and non-human animals. Preferred human animals include human
subjects. The term "non-human animals" of the invention includes
all vertebrates, e.g., mammals, e.g., rodents, e.g., mice, and
non-mammals, such as non-human primates, e.g., sheep, dog, cow,
chickens, amphibians, reptiles, etc. Susceptible to a bowel
disorder is meant to include subjects at risk of developing a bowel
disorder or bowel infection, e.g., subjects suffering from hepatic
failure or decreased haepatic function, immune suppression,
subjects that have been exposed to other subjects with a bacterial
infection, physicians, nurses, subjects traveling to remote areas
known to harbor bacteria that causes travelers' diarrhea, etc.
[0233] The language "a prophylactically effective amount" of a
compound refers to an amount of a compound of the invention of
formula I, formula II, or otherwise described herein which is
effective, upon single or multiple dose administration to the
subject, in preventing or treating hepatic encephalopathy.
[0234] Another embodiment includes articles of manufacture that
comprise, for example, a container holding a pharmaceutical
composition suitable for oral administration of rifaximin in
combination with printed labeling instructions providing a
discussion of when a particular dosage form extends remission of HE
or prevents or delays future episodes of HE. The dosage can be
modified for administration to a subject suffering from HE, or
include labeling for administration to a subject suffering from HE.
Exemplary dosage forms and administration protocols are described
infra. The composition will be contained in any suitable container
capable of holding and dispensing the dosage form and which will
not significantly interact with the composition and will further be
in physical relation with the appropriate labeling. The labeling
instructions may be consistent with the methods of treatment as
described hereinbefore. The labeling may be associated with the
container by any means that maintain a physical proximity of the
two, by way of non-limiting example, they may both be contained in
a packaging material such as a box or plastic shrink wrap or may be
associated with the instructions being bonded to the container such
as with glue that does not obscure the labeling instructions or
other bonding or holding means.
[0235] In one embodiment, the instructions will inform and/or
advise a health care worker, prescribing physician, a pharmacist,
or a subject that they should advise a patient suffering from
hepatic encephalopathy that administration of rifaximin may induce
cytochrome P450. In another embodiment, the instructions will
inform the subject and/or the healthcare provider that there is an
extended time to remission or relapse of subjects that take
rifaximin. In another embodiment, the instructions will inform the
subject and/or the healthcare worker or provider that rifaximin
does not significantly alter the C.sub.max, AUC.sub.0-t, or
AUC.sub.0-.infin., of midazolam. In another embodiment, the
instructions will inform the subject and/or the healthcare worker
or provider that rifaximin does not increase the risk of QT
prolongation.
[0236] Packaged compositions are also provided, and may comprise a
therapeutically effective amount of rifaximin tablets or capsules.
Kits are also provided herein, for example, kits for treating HE in
a subject. The kits may contain, for example, rifaximin and
instructions for use when treating a subject for an HE. The
instructions for use may contain prescribing information, dosage
information, storage information, and the like.
[0237] Kits may include pharmaceutical preparations of the GI
specific antibiotics along with pharmaceutically acceptable
solutions, carriers and excipients.
[0238] Forms of rifaximin can be advantageously used in the
production of medicinal preparations having antibiotic activity,
containing rifaximin, for both oral and topical use. The medicinal
preparations for oral use may contain one or more forms of
rifaximin (for example, .alpha. or .beta. or .gamma.) together with
other excipients, for example diluting agents such as mannitol,
lactose and sorbitol; binding agents such as starchs, gelatines,
sugars, cellulose derivatives, natural gums and
polyvinylpyrrolidone; lubricating agents such as talc, stearates,
hydrogenated vegetable oils, polyethylenglycol and colloidal
silicon dioxide; disintegrating agents such as starchs, celluloses,
alginates, gums and reticulated polymers; coloring, flavoring and
sweetening agents.
[0239] Solid preparations of gastrointestinal specific antibiotics
administrable by the oral route include for instance coated and
uncoated tablets, soft and hard gelatin capsules, sugar-coated
pills, lozenges, wafer sheets, pellets and powders in sealed
packets.
[0240] Medicinal preparations may contain gastrointestinal specific
antibiotics together with usual excipients, such as white
petrolatum, white wax, lanoline and derivatives thereof, stearylic
alcohol, red iron oxide, propylene glycol, talc, sodium lauryl
sulfate, ethers of fatty polyoxyethylene alcohols, disodium
edentate, glycerol palmitostearate, esters of fatty polyoxyethylene
acids, sorbitan monostearate, glyceryl monostearate, propylene
glycol monostearate, hypromellose, polyethylene glycols, sodium
starch glycolate, methylcellulose, hydroxymethyl propylcellulose,
sodium carboxymethylcellulose, microcrystalline cellulose,
colloidal aluminium and magnesium silicate, titanium dioxide,
propylene glycol, colloidal silicon dioxide, or sodium
alginate.
[0241] West Haven Criteria (Conn Score):
[0242] Measurements of change in mental status may be done, for
example, by the Conn score (also known as the West Haven score).
The Conn score has been widely used as a measure of mental state in
HE studies and is based on the criteria of Parsons- Smith as
modified by Conn. Asterixis will not be considered when assessing
the subject's status using the Conn scoring criteria listed
below.
[0243] The scale used in the Conn scoring system is provided below.
[0244] Grade 0=No personality or behavioral abnormality detected
[0245] Grade 1=Trivial lack of awareness, euphoria or anxiety;
shortened attention span; impairment of addition or subtraction
[0246] Grade 2=Lethargy; disorientation for time; obvious
personality change; inappropriate behavior [0247] Grade
3=Somnolence to semi-stupor, responsive to stimuli; confused; gross
disorientation; bizarre behavior [0248] Grade 4=Coma; unable to
test mental state
[0249] HE is defined as a spectrum of neuropsychiatric
abnormalities seen in patients with liver dysfunction, diagnosed
after routine exclusion of other known neurologic disease. HE is a
major complication of liver cirrhosis, affecting 30-45% patients.
In 2006, the CDC listed cirrhosis as the 12th leading cause of
death by disease in the U.S. HE affects the patient's
consciousness, personality, intellect and neuromuscular function,
and may range from a minimal disturbance in cognition, to coma.
[0250] In the gut, enteric bacteria act on nitrogen-containing
substrates to generate ammonia. FIG. 15 represents the situation in
unaffected HE subjects: ammonia is removed from the blood as it
passes through the liver where it is converted to urea, and
excreted by the kidneys. In cirrhosis, ammonia from the intestines
bypasses the damaged liver as a result of vascular shunts. This
increases blood ammonia, which passes into the brain generating
glutamine from the amino acid glutamate. The excess glutamine
causes many deleterious effects on brain function; it inhibits
neurotransmission, interferes with mitochondrial energy metabolism,
and causes swelling of astrocytes.
[0251] The clinical presentation of HE is classified according to
the scheme shown in FIG. 16. HE associated with Cirrhosis--the most
common by far--is type C. HE Type C is sub-classified into
episodic, persistent and minimal categories. Episodic and
persistent varieties are clinically readily apparent conditions,
and hence are denoted as Overt. Episodic HE presents with
impairment in all the neurological functions mentioned above. As
the term episodic implies, there are periods between episodes when
no distinctive symptoms are seen. Episodes may be precipitated by
factors such as constipation, infection, dehydration, GI hemorrhage
and certain medications. If the cause is not immediately
identified, the episode is referred to as spontaneous.
[0252] HE episodes are usually reversible with treatment--but
they're often recurring. HE is a clinical diagnosis made by some
tools, including the West Haven, or Conn, Score. In use for about
30 years, The HESA scoring algorithm (FIG. 17) is a relatively new
tool used for accurate assignment of Conn criteria. Neuromuscular
dysfunction can be measured by eliciting asterixis, or flapping
tremor. Blood ammonia levels are often measured to support the
diagnosis. Neurophysiological tests, such as critical flicker
frequency and EEG, are potentially very useful to support the
clinical findings. The Conn criteria use an increasing grade to
associate with increasing neurological impairment, (ranging from
0=no impairment to 4=coma) [0253] Grades 1, 2, and 3 represent an
worsening in impairment in: [0254] Consciousness--ranging from a
trivial lack of awareness to somnolence; [0255] impairment in
intellectual ability and alterations in personality [0256] This
assessment can be conducted quickly, requires minimal intervention
from the examiner or cooperation from the patient, [0257] And we
often use information from family or caregivers to help gauge the
severity of HE episodes when the patient is confused.
[0258] While patients with grade 1 HE can be managed at home by a
caregiver, any escalation to grade 2 or higher may require
hospitalization and even management in intensive care. The Conn
criteria use an increasing grade to associate with increasing
neurological impairment, (ranging from 0=no impairment to 4=coma).
Grades 1, 2, and 3 represent an worsening in impairment in:
consciousness; intellectual ability and alterations in personality.
This assessment can be conducted quickly, requires minimal
intervention from the examiner or cooperation from the patient,
information from family or caregivers is often used to gauge the
severity of HE episodes.
[0259] While patients with grade 1 HE can be managed at home by a
caregiver, any escalation to grade 2 or higher may require
hospitalization and even management in intensive care.
[0260] There is a similar grading system for asterixis. If an HE
patient is asked to hold out their hands just so, a jerky so called
asterixis or flapping tremor will be observed. The number of beats
is counted and scored from zero for none to four for almost
continuous flapping. This is a simple test but requires a
cooperative and conscious patient.
[0261] HE presents a vicious cycle of dysfunction and disability
that has a dramatic effect on patients, their families and the
healthcare system. Early on, impairments in behavior, personality,
intellect and consciousness affect the patient's social and family
life and ability to hold employment. As the condition worsens, it
impacts capacity for self care, medication compliance, lack of
compliance further intensifies HE symptoms and frequency of
episodes. As a result, patients may need in-home assistance and
often land in the ER or hospital beds. Severe HE can be a life
threatening event, but it more commonly devastates the QOL of
patients and their families; some caregivers liken the experience
to caring for unpredictably episodic Alzheimer's disease. Impact on
caregiver is shown in FIG. 18.
[0262] In terms of the impact on healthcare, the number of HE
discharges more than doubled between 1993 to 2007. See FIG. 19.
Costs increased--from about 13 k to 30 k per hospitalization. So,
the goals for HE Therapy include, for example, bringing acute
episodes to quick resolution, and preventing recurrent episodes. To
achieve these goals, we need a safe and effective therapy that is
well tolerated for long-term treatment. There are serious
limitations to the long-term use of the currently approved
therapies. The most common, Lactulose, a non-absorbable
disaccharide, targets the gut flora responsible for ammonia
production. It exerts its effects mainly by purging, with frequent
bowel movements. Lactulose therapy relies on dose self-titration,
aim is for 2-3 loose stools a day--unfortunately this goal is often
exceeded. At ten unpredictable loose stools per day, leaving
home--even for a short walk to the store--may become impossible or
embarrassing. Patients go on disability because of Lactulose rather
than the HE it was prescribed for. Severe diarrhea can cause
dehydration and electrolyte abnormalities that may even precipitate
an HE episode. Nausea is not uncommon. Understandably, these
factors can lead to poor adherence and limit long term use.
[0263] Another approved treatment is neomycin. However, long-term
use is severely limited by its damaging side effects which include
nephrotoxicity and sensorineural hearing loss--for which patients
with advanced liver disease are most susceptible. Not surprisingly,
the safety profile of neomycin is not conducive to long-term
therapy. Given the limitations with both lactulose and
neomycin--there clearly is an unmet medical need for a safe,
effective, and well-tolerated long-term therapy. Hepatic
encephalopathy is a serious neurological complication of advanced
liver disease that disrupts quality of life, ability for self care
and compliance, and results in frequent hospitalization
[0264] There are limited therapeutic options for HE and there
remains an unmet medical need for a safe, effective, and
well-tolerated therapy for long-term treatment. There has not been
a new treatment for this debilitating disease for 30 years.
Physicians have been sufficiently impressed with the efficacy,
tolerability and safety data on rifaximin- and their favorable
experience with this drug, even prior to the exciting new trial
data you will see today--to make rifaximin quite possibly the most
widely used antibiotic therapy for HE.
[0265] Study 3001 was designed to continuously monitor patients to
ensure the validity and completeness of HE breakthrough capture.
Following screening, subjects entered a treatment period that
included weekly visits and/or phone calls with patients and
caregivers. Subjects were followed for the protocol specified 168
days. Complete capture of breakthrough events as well as mortality
and provided assurance of the validity of the study outcome.
Narratives for each subject experiencing HE breakthrough, AE's
resulting in termination, SAEs or death were provided in the NDA.
Key entry criteria included: [0266] Patients with advanced liver
disease, [0267] Presenting with at least 2 episodes of HE within 6
months of screening; documented in medical records with a severity
equivalent to a Conn score .gtoreq.2; [0268] At both screening and
baseline, subjects had a Conn score of 0 or 1, a MELD less than or
equal to 25 and were required to have a caregiver who assented to
the patient's participation; [0269] Patients were excluded if they
had a condition that could interfere with the protocol assessments,
used alcohol within 14 days, sedatives within 7 days or evidence of
current drug dependence;
[0270] HESA combines both the clinical components of Conn and
neuropsychological tests. Administration requires .about.45
minutes. It was used as a tool to establish consistent scoring of
Conn across study centers. It provided a continuous reinforcement
of standards and definitions
[0271] FIG. 17 succinctly covers the clinical assessments and
neuropsychological testing of HESA. Rifaximin provided a
significant, protective effect as demonstrated by a 58% reduction
in the risk of breakthrough HE with a highly significant p-value.
The benefit of rifaximin is striking in that 78% of the patients
now had zero events over 6 months. This is in contrast to the
placebo group where only 54% maintain remission from HE. In a sick
population who suffers from frequent adverse events, restricted
living and a shortened life span, rifaximin is able to provide a
meaningful benefit by preventing deterioration in their mental
status and motor skills.
[0272] There were a total of 104 events recorded from 299
participating patients. For the components, we are using
descriptive statistics using proportion analysis meeting the
condition. 86 events, or 83% of the total events, consisted of
patients experiencing a Conn Score of >=2, 37% placebo and 20%
rifaximin, resulting in a highly significant p-value.
[0273] Eighteen (18) events, or 17% of the total events, are
included in this next category of patients experiencing a worsening
of Conn and asterixis grade of 1 each. 9% of placebo and 2% of
rifaximin, also providing a highly significant p-value.
[0274] Consistency of effect aids in determining whether the
benefit is derived from one or a few subgroups or if the effect is
seen generally across all patient subgroups. Importantly, we tested
for a treatment by subgroup interaction to ascertain homogeneity in
response across subgroups. None of the subgroups tested for a
significant interaction. Hazard ratios less than 1 indicate that
the outcome favors rifaximin and greater than 1 favors placebo. The
result seen in all subgroups consistently reflect the clinical
benefit in favor of rifaximin. This consistency of outcome, coupled
with the absence of a subgroup by treatment interaction, support
the robustness of the overall treatment effect.
[0275] This effect is maintained across subgroups of varying
degrees of severity as it relates to MELD and Child-Pugh. Again,
there is no subgroup by treatment interaction here and the estimate
of the treatment effect is approximately the same across all
groups. In total, the subgroup analyses demonstrate the remarkable
consistency of the risk reduction seen in the Primary Endpoint
analysis across all groups.
[0276] The analysis of the time to HE-related hospitalization
results in a 50% reduction in risk with a significant p-value. A
large proportion of HE episodes resulted either in direct
hospitalization or occurred during the hospitalization. It was
shown that time to HE-caused hospitalization (defined as time to
hospitalization directly resulting from HE), and time to all-cause
hospitalization were reduced with rifaximin, and these analyses
show 56% and 30% reductions in risk respectively.
[0277] Other endpoints included, for example, the time to first
worsening in Conn or Asterixis Scores regardless of whether that
change led to a breakthrough HE event; patient reported Quality of
life, in particular fatigue, using the CLDQ; changes in blood
ammonia, believed to be the primary neurotoxin responsible for the
HE; and the Critical flicker frequency. The time to first time
worsening in Conn Score reflects a 54% reduction in risk. Time to
worsening of asterixis or hand flapping, shows a 35% reduction with
a trending p-value. These data represent the changes in each domain
throughout the course of the trial. The results demonstrate that
rifaximin treated patients feel better. The questionnaire uses a
7-point Likert scale with 1=All the time and 7 being none of the
time. Thus, greater values represent better quality of life. The
change seen here in each subscale suggests a movement on each scale
of 1 category improvement over placebo. The changes we see in
ammonia and CFF are statistically significant and reflect
improvement in favor of rifaximin. These results support the
treatment effect of rifaximin.
[0278] Analyses were undertaken to assess the sensitivity and
specificity of breakthrough HE. Patients with lower CFF and fatigue
assessments, and a higher blood ammonia concentration had a greater
likelihood of experiencing an HE breakthrough. These data provide
further evidence that the primary endpoint is objective and
clinically meaningful. For 3002, breakthrough HE data were
collected to provide supportive information regarding rifaximin's
effect of preventing recurrence of HE.
[0279] Three populations were treated in study 3002, including,
rifaximin-treated patients from Study 3001; crossover
placebo-treated patients from Study 3001; and new HE patients.
[0280] Rifaximin subjects who maintained remission throughout 3001
demonstrated continued benefit during their participation in 3002.
The incidence of breakthrough HE for rifaximin subjects was lower
than the 3001 placebo group demonstrating a 90% reduction in the
risk of breakthrough HE. Note that approximately 60% of these
patients remain free of breakthrough after almost 3 years. 82
placebo treated subjects from the 3001 study were enrolled in 3002
and were followed for breakthrough. Once in the open-label and
receiving rifaximin, we see a 79% risk reduction compared to their
experience in the 3001 trial.
[0281] The all Rifaximin population demonstrates a 2.6-fold
increase risk of all-cause mortality for subjects who achieved a
Conn score of at least 2.
[0282] The following example will discuss new and novel aspects of
rifaximin: [0283] In vitro and in vivo pharmacological actions of
rifaximin that may contribute to its clinical benefit; [0284]
Rifaximin's ADME properties, including pharmacokinetics and its
excretory and metabolic fate; and [0285] Drug-drug interaction
studies.
[0286] Mechanistically, rifaximin binds to the beta-subunit of
bacterial DNA dependent RNA polymerase resulting in inhibition of
bacterial RNA synthesis. In vivo, rifaximin ameliorates bacterial
diarrheal symptoms and the majority of the dose is not absorbed and
it concentrates in the gut, with high gut lumen concentrations,
approximately 8000 .mu.g/g of stool. Interestingly, treatment of
travelers' diarrhea occurs without significant alteration to the
overall intestinal pathogen burden.
[0287] In vitro, rifaximin has multiple effects at subinhibitory
concentrations, including, for example, increasing plasmid cured,
reducing plasmid transfer, and reducing virulence.
[0288] We have observed effects of rifaximin on mammalian cells,
including, for example, detoxification pathways such as P-gp and
3A4 may be upregulated in the gut. Rifaximin renders epithelial
cells resistant to bacterial colonization and internalization
independent of the effects on bacteria and reduces production and
absorption of gut-derived neurotoxins, the primary example being
ammonia, which lead to HE in liver-impaired patients.
[0289] In this example, 50 patients treated with rifaximin 1200
mg/day showed statistically significant blood ammonia reduction.
This reduction was accompanied by significant improvement in
overall HE grade and individual measures of HE. While discrete
blood ammonia concentrations may be variable, serial measurements
in individual patients have been associated with HE severity.
[0290] Rifaximin is a member of the rifamycin class of antibiotics.
The functional group shown in green differentiates rifaximin from
other rifamycins and leads to gut-specific activity.
[0291] Rifaximin is categorized as BCS 4; poorly soluble and poorly
absorbed. It is also a substrate of P-glycoprotein, an efflux
transporter. These properties result in very low oral absorption.
The small fraction that is absorbed is cleared by three mechanisms:
billiary, metabolic and renal. Rifaximin undergoes first pass
elimination via biliary excretion as unchanged rifaximin. There is
one known metabolite; nearly undetectable in healthy subjects, and
very low in HE patients, approximately 2.5% of parent exposure. In
both healthy and liver disease subjects, rifaximin renal clearance
is <0.4%. Orally administered rifaximin is eliminated almost
entirely as unchanged rifaximin in the feces. Steady-state
rifaximin pharmacokinetics was examined in healthy subjects and in
liver impaired subjects. Exposure is quite low in all populations
studied.
[0292] In healthy volunteers, mean Cmax is less than 4 ng/mL. See
FIG. 20. As liver impairment increases, AUC and Cmax increase
correspondingly. Even at their highest, exposures remain low, in
the ng/mL range. Increased exposure in liver impaired patients is
well described in the literature, and may be attributed to several
factors, including, for example, protein binding, reduced liver
blood flow and reduced metabolic capability. Limited access to the
liver due to blood flow shunting around the liver, and reduced
metabolism due to impaired hepatocyte enzyme activity, may reduce
hepatic clearance. Either or both of the latter two factors may be
responsible for reducing clearance of rifaximin and increasing
exposure in liver impaired patients.
[0293] To put this exposure into further perspective see FIG. 21
which shows rifaximin data in comparison with other antibiotics, on
a log scale because of the wide differences.
[0294] Patients with greatest liver impairment and highest plasma
exposure have rifaximin levels more than 200-fold lower than those
achieved with a systemic antibiotic, like rifampin--shown in blue.
It's also more than 10-fold lower than exposures observed with oral
neomycin--shown here in pink--which is considered to be
non-absorbed. Norfloxacin also is used commonly in this population,
for SBP prophylaxis; it's a systemic antibiotic with plasma
exposures greater than 35-fold higher than rifaximin. The potential
for rifaximin to cause drug-drug interactions was explored here.
Rifaximin does not significantly inhibit any major P450 drug
metabolizing enzyme, P-glycoprotein, or BSEP in subjects with
normal liver function.
[0295] Knowing that other members of this class can cause
interactions by upregulating important drug metabolizing enzymes,
particularly CYP3A4, we examined the potential for this induction
in clinical studies. Rifaximin's effect on midazolam, a classic
CYP3A4 substrate, was studied in healthy volunteers. After 16 days
of rifaximin 550 mg TID, a dose 50% higher than that used for HE,
midazolam's AUC was reduced by 10%. See FIG. 22. In contrast,
rifampin reduces midazolam AUC by 95% in similar experiments. This
difference reflects not only an in vitro potency difference between
rifampin and rifaximin, but an in vivo disposition difference
between the two compounds in terms of rifaximin's low liver and
systemic exposure. Based on these data we do not anticipate
clinically significant drug interactions in subjects with normal
liver function. In summary, in vitro and in vivo data indicate that
rifaximin has bacteriostatic mechanisms as well as the ability to
reduce bacterial adhesion and virulence. It lowers ammonia levels
(See FIG. 23), which is linked to improvement in HE patients. The
essential distinction between rifaximin and other rifamycins is its
extremely low solubility and oral absorption, resulting in
gut-targeted therapeutic effects and limited systemic exposure.
Although liver disease leads to increased systemic exposure of
rifaximin, the highest exposures seen with rifaximin are
substantially lower than what's observed with other systemic and
unabsorbed oral antibiotics. With this low systemic exposure comes
a minimized drug-drug interaction risk.
[0296] Embodiments of the invention relate to all of the topical
preparations, for instance ointments, pomades, creams, gels and
lotions.
[0297] In solid dosage forms of rifaximin for oral administration
(capsules, tablets, pills, dragees, powders, granules and the
like), the active ingredient is typically mixed with one or more
pharmaceutically-acceptable carriers, such as sodium citrate or
dicalcium phosphate, and/or any of the following: (1) fillers or
extenders, such as starches, lactose, sucrose, glucose, mannitol,
and/or silicic acid; (2) binders, such as, for example,
carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,
sucrose and/or acacia; (3) humectants, such as glycerol; (4)
disintegrating agents, such as agar-agar, calcium carbonate, potato
or tapioca starch, alginic acid, certain silicates, and sodium
carbonate; (5) solution retarding agents, such as paraffin; (6)
absorption accelerators, such as quaternary ammonium compounds; (7)
wetting agents, such as, for example, acetyl alcohol and glycerol
monostearate; (8) absorbents, such as kaolin and bentonite clay;
(9) lubricants, such as talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate, and mixtures
thereof; and (10) colouring agents. In the case of capsules,
tablets and pills, the pharmaceutical compositions may also
comprise buffering agents. Solid compositions of a similar type may
also be employed as fillers in soft and hard-filled gelatin
capsules using such excipients as lactose or milk sugars, as well
as high molecular weight polyethylene glycols and the like.
[0298] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared using binder (for example, gelatin or hydroxypropylmethyl
cellulose), lubricant, inert diluent, preservative, disintegrant
(for example, sodium starch glycolate or cross-linked sodium
carboxymethyl cellulose), surface-active or dispersing agent.
Molded tablets may be made by molding in a suitable machine a
mixture of the powdered active ingredient moistened with an inert
liquid diluent.
[0299] The tablets, and other solid dosage forms of the
pharmaceutical compositions described herein, such as dragees,
capsules, pills and granules, may optionally be scored or prepared
with coatings and shells, such as enteric coatings and other
coatings well known in the pharmaceutical-formulating art. They may
also be formulated so as to provide slow or controlled release of
the active ingredient therein using, for example,
hydroxypropylmethyl cellulose in varying proportions to provide the
desired release profile, other polymer matrices, liposomes and/or
microspheres. They may be sterilized by, for example, filtration
through a bacteria-retaining filter, or by incorporating
sterilizing agents in the form of sterile solid compositions which
can be dissolved in sterile water, or some other sterile injectable
medium immediately before use. These compositions may also
optionally contain opacifying agents and may be of a composition
that they release the active ingredient(s) only, or preferentially,
in a certain portion of the gastrointestinal tract, optionally, in
a delayed manner. Examples of embedding compositions which can be
used include polymeric substances and waxes. The active ingredient
can also be in micro-encapsulated form, if appropriate, with one or
more of the above-described excipients.
[0300] Liquid dosage forms for oral administration of rifaximin
include 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.
[0301] In addition to inert diluents, the oral compositions can
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, coloring, perfuming and
preservative agents.
[0302] Suspensions, in addition to rifaximin 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.
[0303] Pharmaceutical compositions for rectal or vaginal
administration may be presented as a suppository, which may be
prepared by mixing rifaximin with one or more suitable
nonirritating excipients or carriers comprising, for example, cocoa
butter, polyethylene glycol, a suppository wax or a salicylate, and
which is solid at room temperature, but liquid at body temperature
and, therefore, will melt in the rectum or vaginal cavity and
release the active agent.
[0304] Compositions which are suitable for vaginal administration
also include pessaries, tampons, creams, gels, pastes, foams or
spray formulations containing such carriers as are known in the art
to be appropriate.
[0305] Dosage forms for the topical or transdermal administration
of rifaximin includes powders, sprays, ointments, pastes, creams,
lotions, gels, solutions, patches and inhalants. Rifaximin may be
mixed under sterile conditions with a pharmaceutically-acceptable
carrier, and with any preservatives, buffers, or propellants which
may be required.
[0306] Ointments, pastes, creams and gels may contain, in addition
to rifaximin, 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.
[0307] Powders and sprays can contain, in addition to rifaximin,
excipients such as lactose, talc, silicic acid, aluminium
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.
[0308] Rifaximin can be alternatively administered by aerosol. This
is accomplished by preparing an aqueous aerosol, liposomal
preparation or solid particles containing the compound. A
non-aqueous (e.g., fluorocarbon propellant) suspension could be
used. Sonic nebulizers are preferred because they minimize exposing
the agent to shear, which can result in degradation of the
compound.
[0309] An aqueous aerosol is made, for example, by formulating an
aqueous solution or suspension of the agent together with
conventional pharmaceutically-acceptable carriers and stabilizers.
The carriers and stabilizers vary with the requirements of the
particular compound, but typically include non-ionic surfactants
(Tweens.RTM., Pluronics.RTM., or polyethylene glycol), innocuous
proteins like serum albumin, sorbitan esters, oleic acid, lecithin,
amino acids such as glycine, buffers, salts, sugars or sugar
alcohols. Aerosols generally are prepared from isotonic
solutions.
[0310] Pharmaceutical compositions suitable for parenteral
administration may comprise rifaximin in combination with one or
more pharmaceutically-acceptable sterile isotonic aqueous or
nonaqueous solutions, dispersions, suspensions or emulsions, or
sterile powders which may be reconstituted into sterile injectable
solutions or dispersions just prior to use, which may contain
antioxidants, buffers, bacteriostats, solutes which render the
formulation isotonic with the blood of the intended recipient or
suspending or thickening agents.
[0311] Examples of suitable aqueous and non-aqueous carriers which
may be employed in the pharmaceutical compositions include 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.
[0312] These compositions may also contain adjuvants such as
preservatives, wetting agents, emulsifying agents and dispersing
agents. Prevention of the action of microorganisms may be ensured
by the inclusion of various antibacterial and antifungal agents,
for example, paraben, chlorobutanol, phenol sorbic acid, and the
like. It may also be desirable to include isotonic agents, such as
sugars, sodium chloride, and the like into the compositions. In
addition, prolonged absorption of the injectable pharmaceutical
form may be brought about by the inclusion of agents which delay
absorption such as aluminum monostearate and gelatin.
[0313] In some cases, to prolong the effect of a drug, it is
desirable to alter the absorption of the drug. This may be
accomplished by the use of a liquid suspension of crystalline, salt
oramorphous material having poor water solubility. The rate of
absorption of the drug may then depend on its rate of dissolution
which, in turn, may depend on crystal size and crystalline form.
Alternatively, delayed absorption of a drug form is accomplished by
dissolving or suspending the drug in an oil vehicle.
[0314] Injectable depot forms are made by forming microencapsule
matrices of rifaximin in biodegradable polymers such as
polylactide-polyglycolide. Depending on the ratio of drug to
polymer, and the nature of the particular polymer employed, the
rate of drug release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the drug in liposomes or microemulsions which are
compatible with body tissue.
[0315] When the rifaximin is administered as a pharmaceutical, to
humans and animals, it can be given per se or as a pharmaceutical
composition containing, for example, 0.1 to 99.5% (more preferably,
0.5 to 90%) of active ingredient in combination with a
pharmaceutically-acceptable carrier.
[0316] Regardless of the route of administration selected rifaximin
which may be used in a pharmaceutical compositions of the present
invention, is formulated into pharmaceutically-acceptable dosage
forms by methods known to those of skill in the art.
[0317] Actual dosage levels and time course of administration of
the active ingredients in the pharmaceutical compositions may be
varied so as to obtain an amount of the active ingredient which is
effective to achieve the desired therapeutic response for a
particular subject, composition, and mode of administration,
without being toxic to the subject. An exemplary dose range is from
25 to 3000 mg per day.
[0318] XIFAXAN, a tradename for rifaximin, is approved for the
following two uses:
[0319] 1) Traveler's diarrhea: Rifaximin 200 mg are indicated for
the treatment of patients (.gtoreq.12 years of age) with travelers'
diarrhea caused by noninvasive strains of Escherichia coli.
Rifaximintablets should not be used in patients with diarrhea
complicated by fever or blood in the stool or diarrhea due to
pathogens other than Escherichia coli.
[0320] 2) Hepatic encephalopathy: Rifaximin tablets 550 mg are
indicated for the maintenance of remission of hepatic
encephalopathy in patients .gtoreq.18 years of age.
[0321] To reduce the development of drug-resistant bacteria and
maintain the effectiveness of rifaximin, and other antibacterial
drugs, rifaximin when used to treat infection should be used only
to treat or prevent infections that are proven or strongly
suspected to be caused by susceptible bacteria. When culture and
susceptibility information are available, they should be considered
in selecting or modifying antibacterial therapy. In the absence of
such data, local epidemiology and susceptibility patterns may
contribute to the empiric selection of therapy.
[0322] XIFAXAN, a tradename for rifaximin, is approved for the
following two uses:
[0323] 1) Travelers' Diarrhea
[0324] Rifaximin 200 mg is indicated for the treatment of patients
(.gtoreq.12 years of age) with travelers' diarrhea caused by
noninvasive strains of Escherichia coli.
[0325] Rifaximin should not be used in patients with diarrhea
complicated by fever or blood in the stool or diarrhea due to
pathogens other than Escherichia coli.
[0326] 2) Hepatic Encephalopathy
[0327] Rifaximin 550 mg is indicated for reduction in risk of overt
hepatic encephalopathy (HE) recurrence in patients .gtoreq.18 years
of age. In the trials of rifaximin for HE, 91% of the patients were
using lactulose concomitantly. Differences in the treatment effect
of those patients not using lactulose concomitantly could not be
assessed.
[0328] Rifaximin has not been studied in patients with MELD (Model
for End-Stage Liver Disease) scores >25, and only 8.6% of
patients in the controlled trial had MELD scores over 19. There is
increased systemic exposure in patients with more severe hepatic
dysfunction.
[0329] Rifaximin can be administered orally with or without food.
For treatment of travelers' diarrhea patients should take one 200
mg tablet three times a day for 3 days. For hepatic encephalopathy
patients should take one 550 mg tablet two times a day.
[0330] Rifaximin tablets are contraindicated in patients with a
hypersensitivity to rifaximin, any of the rifamycin antimicrobial
agents, or any of the components in rifaximin tablets.
Hypersensitivity reactions have included exfoliative dermatitis,
angioneurotic edema, and anaphylaxis.
[0331] Rifaximin was not found to be effective in patients with
diarrhea complicated by fever and/or blood in the stool or diarrhea
due to pathogens other than Escherichia coli. Discontinue rifaximin
use if diarrhea symptoms get worse or persist more than 24-48 hours
and alternative antibiotic therapy should be considered.
[0332] Rifaximin is not effective in cases of travelers' diarrhea
due to Campylobacter jejuni. The effectiveness of rifaximin in
travelers' diarrhea caused by Shigella spp. and Salmonella spp. has
not been proven. Rifaximin should not be used in patients where
Campylobacter jejuni, Shigella spp., or Salmonella spp. may be
suspected as causative pathogens.
[0333] Clostridium difficile-associated diarrhea (CDAD) has been
reported with use of nearly all antibacterial agents, including
rifaximin, and may range in severity from mild diarrhea to fatal
colitis. Treatment with antibacterial agents alters the normal
flora of the colon which may lead to overgrowth of C.
difficile.
[0334] C. difficile produces toxins A and B which contribute to the
development of CDAD. Hypertoxin producing strains of C. difficile
cause increased morbidity and mortality, as these infections can be
refractory to antimicrobial therapy and may require colectomy. CDAD
must be considered in all patients who present with diarrhea
following antibiotic use. Careful medical history is necessary
since CDAD has been reported to occur over two months after the
administration of antibacterial agents.
[0335] If CDAD is suspected or confirmed, ongoing antibiotic use
not directed against C. difficile may need to be discontinued.
Appropriate fluid and electrolyte management, protein
supplementation, antibiotic treatment of C. difficile, and surgical
evaluation should be instituted as clinically indicated.
[0336] Prescribing rifaximin for travelers' diarrhea in the absence
of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the
patient and increases the risk of the development of drug-resistant
bacteria.
[0337] There is increased systemic exposure in patients with severe
hepatic impairment. Animal toxicity studies did not achieve
systemic exposures that were seen in patients with severe hepatic
impairment. The clinical trials were limited to patients with MELD
scores <25. Therefore, caution should be exercised when
administering rifaximin to patients with severe hepatic impairment
(Child-Pugh C).
[0338] The safety of rifaximin 200 mg taken three times a day was
evaluated in patients with travelers' diarrhea consisting of 320
patients in two placebo-controlled clinical trials with 95% of
patients receiving three or four days of treatment with rifaximin.
The population studied had a mean age of 31.3 (18-79) years of
which approximately 3% were .gtoreq.65 years old, 53% were male and
84% were White, 11% were Hispanic.
[0339] Discontinuations due to adverse reactions occurred in 0.4%
of patients. The adverse reactions leading to discontinuation were
taste loss, dysentery, weight decrease, anorexia, nausea and nasal
passage irrigation.
[0340] All adverse reactions for rifaximin 200 mg three times daily
that occurred at a frequency .gtoreq.2% in the two
placebo-controlled trials combined are provided in Table 26. (These
include adverse reactions that may be attributable to the
underlying disease.)
[0341] The following adverse reactions, presented by body system,
have also been reported in <2% of patients taking rifaximin in
the two placebo-controlled clinical trials where the 200 mg tablet
was taken three times a day for travelers' diarrhea. The following
includes adverse reactions regardless of causal relationship to
drug exposure:
TABLE-US-00001 TABLE 29 All Adverse Events With an Incidence
.gtoreq. 2% Among Patients Receiving XIFAXAN Tablets, 600 mg/day,
in Placebo-Controlled Studies Number (%) of Patients XIFAXAN MedDRA
Tablets, 600 mg/day Placebo Preferred Term (N = 320) N = 228
Flatulence 36 (11.3%) 45 (19.7%) Headache 31 (9.7%) 21 (9.2%)
Abdominal Pain NOS 23 (7.2%) 23 (10.1%) Rectal Tenesmus 23 (7.2%)
20 (8.8%) Defacation Urgency 19 (5.9%) 21 (9.2%) Nausea 17 (5.3%)
19 (8.3%) Constipation 12 (3.8%) 8 (3.5%) Pyrexia 10 (3.1%) 10
(4.4%) Vomiting NOS 7 (2.2%) 4 (1.8%)
[0342] Blood and Lymphatic System Disorders: Lymphocytosis,
monocytosis, neutropenia
[0343] Ear and Labyrinth Disorders: Ear pain, motion sickness,
tinnitus
[0344] Gastrointestinal Disorders: Abdominal distension, diarrhea
NOS, dry throat, fecal abnormality NOS, gingival disorder NOS,
inguinal hernia NOS, dry lips, stomach discomfort
[0345] General Disorders and Administration Site Conditions: Chest
pain, fatigue, malaise, pain NOS, weakness
[0346] Infections and Infestations: Dysentery NOS, respiratory
tract infection NOS, upper respiratory tract infection NOS
[0347] Injury and Poisoning: Sunburn
[0348] Investigations: Aspartate aminotransferase increased, blood
in stool, blood in urine, weight decreased
[0349] Metabolic and Nutritional Disorders: Anorexia,
dehydration
[0350] Musculoskeletal, Connective Tissue, and Bone Disorders:
Arthralgia, muscle spasms, myalgia, neck pain
[0351] Nervous System Disorders: Abnormal dreams, dizziness,
migraine NOS, syncope, loss of taste
[0352] Psychiatric Disorders: Insomnia
[0353] Renal and Urinary Disorders: Choluria, dysuria, hematuria,
polyuria, proteinuria, urinary frequency
[0354] Respiratory, Thoracic, and Mediastinal Disorders: Dyspnea
NOS, nasal passage irritation, nasopharyngitis, pharyngitis,
pharyngolaryngeal pain, rhinitis NOS, rhinorrhea
[0355] Skin and Subcutaneous Tissue Disorders: Clamminess, rash
NOS, sweating increased; and
[0356] Vascular Disorders: Hot flashes.
[0357] Hepatic Encephalopathy
[0358] The data described below reflect exposure to rifaximin 550
mg in 348 patients, including 265 exposed for 6 months and 202
exposed for more than a year (mean exposure was 364 days). The
safety of rifaximin 550 mg taken two times a day for reducing the
risk of overt hepatic encephalopathy recurrence in adult patients
was evaluated in a 6-month placebo-controlled clinical trial
(n=140) and in a long term follow-up study (n=280). The population
studied had a mean age of 56.26 (range: 21-82) years; approximately
20% of the patients were .gtoreq.65 years old, 61% were male, 86%
were White, and 4% were Black. Ninety-one percent of patients in
the trial were taking lactulose concomitantly. All adverse
reactions that occurred at an incidence .gtoreq.5% and at a higher
incidence in rifaximin 550 mg-treated subjects than in the placebo
group in the 6-month trial are provided in Table 27. (These include
adverse events that may be attributable to the underlying
disease.)
TABLE-US-00002 TABLE 30 Adverse Events Occurring in .gtoreq. 5% of
Patients Receiving XIFAXAN and at a Higher Incidence Than Placebo
Adverse Events Occurring in .gtoreq. 5% of Patients Receiving
XIFAXAN and at a Higher Incidence Than Placebo Number (%) of
Patients XIFAXAN Tablets 550 mg BIB Placebo MedDRA Preferred Term N
= 140 N = 159 Edema peripheral 21 (15.0%) 13 (8.2%) Nausea 20
(14.3%) 21 (13.2%) Dizziness 18 (12.9%) 13 (8.2%) Fatigue 17
(12.1%) 18 (11.3%) Ascites 16 (11.4%) 15 (9.4%) Muscle spasms 13
(9.3%) 11 (6.9%) Pruritus 13 (9.3%) 10 (6.3%) Abdominal pain 12
(8.6%) 13 (8.2%) Abdominal distension 11 (7.9%) 12 (7.5%) Anemia 11
(7.9%) 6 (3.8%) Cough 10 (7.1%) 11 (6.9%) Depression 10 (7.1%) 8
(5.0%) Insomnia 10 (7.1%) 11 (6.9%) Nasopharyngitis 10 (7.1%) 10
(6.3%) Abdominal pain upper 9 (6.4%) 8 (5.0%) Arthralgia 9 (6.4%) 4
(2.5%) Back pain 9 (6.4%) 10 (6.3%) Constipation 9 (6.4%) 10 (6.3%)
Dyspnea 9 (6.4%) 7 (4.4%) Pyrexia 9 (6.4%) 5 (3.1%) Rash 7 (5.0%) 6
(3.8%)
[0359] The following adverse reactions, presented by body system,
have also been reported in the placebo-controlled clinical trial in
greater than 2% but less than 5% of patients taking rifaximin 550
mg taken orally two times a day for hepatic encephalopathy. The
following includes adverse events occurring at a greater incidence
than placebo, regardless of causal relationship to drug
exposure.
[0360] Ear and Labyrinth Disorders: Vertigo;
[0361] Gastrointestinal Disorders: Abdominal pain lower, abdominal
tenderness, dry mouth, esophageal variceal bleed, stomach
discomfort.
[0362] General Disorders and Administration Site Conditions: Chest
pain, generalized edema, influenza like illness, pain NOS
[0363] Infections and Infestations: Cellulitis, pneumonia,
rhinitis, upper respiratory tract infection NOS
[0364] Injury, Poisoning and Procedural Complications: Contusion,
fall, procedural pain Investigations: Weight increased
[0365] Metabolic and Nutritional Disorders: Anorexia, dehydration,
hyperglycemia, hyperkalemia, hypoglycemia, hyponatremia
[0366] Musculoskeletal, Connective Tissue, and Bone Disorders:
Myalgia, pain in extremity
[0367] Nervous System Disorders: Amnesia, disturbance in attention,
hypoathesia, memory impairment, tremor
[0368] Psychiatric Disorders: Confusional state
[0369] Respiratory, Thoracic, and Mediastinal Disorders: Epistaxis;
and
[0370] Vascular Disorders: Hypotension.
[0371] The following adverse reactions have been identified during
post approval use of rifaximin. Because these reactions are
reported voluntarily from a population of unknown size, estimates
of frequency cannot be made. These reactions have been chosen for
inclusion due to either their seriousness, frequency of reporting
or causal connection to rifaximin.
[0372] Infections and Infestations
[0373] Cases of C. difficile-associated colitis have been
reported.
[0374] Hypersensitivity reactions, including exfoliative
dermatitis, rash, angioneurotic edema (swelling of face and tongue
and difficulty swallowing), urticaria, flushing, pruritus and
anaphylaxis have been reported. These events occurred as early as
within 15 minutes of drug administration.
[0375] In vitro studies have shown that rifaximin did not inhibit
cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and
CYP3A4 at concentrations ranging from 2 to 200 ng/mL. Rifaximin is
not expected to inhibit these enzymes in clinical use.
[0376] An in vitro study has suggested that rifaximin induces
CYP3A4. However, in patients with normal liver function, rifaximin
at the recommended dosing regimen is not expected to induce CYP3A4.
It is unknown whether rifaximin can have a significant effect on
the pharmacokinetics of concomitant CYP3A4 substrates in patients
with reduced liver function who have elevated rifaximin
concentrations.
[0377] An in vitro study suggested that rifaximin is a substrate of
P-glycoprotein. It is unknown whether concomitant drugs that
inhibit P-glycoprotein can increase the systemic exposure of
rifaximin.
[0378] Rifaximin was teratogenic in rats at doses of 150 to 300
mg/kg (approximately 2.5 to 5 times the clinical dose for
travelers' diarrhea [600 mg/day], and approximately 1.3 to 2.6
times the clinical dose for hepatic encephalopathy [1100 mg/day],
adjusted for body surface area). Rifaximin was teratogenic in
rabbits at doses of 62.5 to 1000 mg/kg (approximately 2 to 33 times
the clinical dose for travelers' diarrhea [600 mg/day], and
approximately 1.1 to 18 times the clinical dose for hepatic
encephalopathy [1100 mg/day], adjusted for body surface area).
These effects include cleft palate, agnatha, jaw shortening,
hemorrhage, eye partially open, small eyes, brachygnathia,
incomplete ossification, and increased thoracolumbar vertebrae.
[0379] Reproduction studies have been performed in rats at doses up
to 2.5 to 5.0 times (adjusted for body surface area) the human
dose, and in rabbits at doses up to 2.0 to 33.0 times (adjusted for
body surface area) the human dose and have revealed no evidence of
impaired fertility or harm to the fetus due to rifaximin.
[0380] Two studies evaluated the pharmacokinetics of rifaximin in
patients with hepatic impairment. In the first study mMean (SD)
peak rifaximin plasma concentrations of 13.5 (14.8) ng/mL were
detected in hepatic encephalopathy patients 3 hours after
administration of the first dose of administered rifaximin 800 mg
three times daily for 7 days; Lless than 0.1% of the administered
dose was recovered in urine after 7 days. Because of the limited
systemic absorption of rifaximin, no specific dosing adjustments
are recommended for patients with hepatic insufficiency. In the
second study, patients were administered rifaximin 550 mg two times
a day. Mean (SD) rifaximin steady-state systemic exposure values
(Cmax) in those with hepatic impairment grades of Child-Pugh A and
Child-Pugh B were 19.5 (11.4) ng/mL and 25.1 (12.6) ngh/mL
(approximately 5.7- and 7.4-fold higher, respectively, than
steady-state Cmax values observed in healthy individuals). This
increase in systemic exposure to rifaximin in patients with hepatic
impairment does not require a dosing adjustment with rifaximin due
to its gastrointestinal local action and low systemic
bioavailability.
[0381] Exemplary dosages of contain rifaximin, a non-aminoglycoside
semi-synthetic, nonsystemic antibiotic derived from rifamycin SV.
Rifaximin is a structural analog of rifampin. The chemical name for
rifaximin is:
(2S,16Z,18E,20S,21S,22R,23R,24R,25S,26S,27S,28E)-5,6,21,23,25-pentahydrox-
y-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-[1,11,13-
]trienimino)benzofuro
[4,5-e]pyrido[1,2-a]-benzimidazole-1,15(2H)-dione,25-acetate. The
empirical formula is C.sub.43H.sub.51N.sub.3O.sub.11 and its
molecular weight is 785.9.
[0382] Exemplary rifaximin tablets for oral administration are
film-coated and contain 200 mg or 550 mg of rifaximin. Each tablet
contains colloidal silicon dioxide, disodium edetate, glycerol
palmitostearate, hypromellose, microcrystalline cellulose,
propylene glycol, red iron oxide, sodium starch glycolate, talc,
and titanium dioxide.
[0383] The dose-response relationship for rifaximin efficacy in
reducing the severity of hepatic encephalopathy (HE) was
established in a double-blind dose-ranging study (600, 1200, or
2400 mg total daily dose for 7 days) in patients with Grade 1, 2,
or 3 HE, improvements from baseline were observed in all groups, as
measured by an index measuring multiple HE symptoms; mean changes
(improvements) in symptom index scores were -0.064, -0.103, and
-0.107 in groups receiving total daily doses of 600 mg, 1200 mg,
and 2400 mg, respectively.
[0384] The mean plasma pharmacokinetic parameters of rifaximin in
14 healthy subjects after a single oral 400 mg dose given as
2.times.200 mg doses and a single 550 mg dose in 12 healthy
subjects under fed and fasting conditions are summarized in Table
31.
TABLE-US-00003 TABLE 31 Effect of Food on the Mean .+-. S.D.
Pharmacokinetic Parameters Single 400 mg Dose of Rifaximin (N = 14)
Table 41 Effect of Food on the Mean .+-. S.D. Pharmacokinetic
Parameters Single 400 mg Single 550 mg Dose of Rifaximin Dose of
Rifaximin (N - 14) (N = 12) Parameter Fasting Fed Fasting Fed
C.sub.max (ng/mL) 3.80 .+-. 1.32 9.63 .+-. 5.93 4.04 .+-. 1.51 4.76
.+-. 4.25 T.sub.max (h) 1.21 .+-. 0.47 1.90 .+-. 1.52 0.75 1.50
(0.50-2.05)* (0.50-4.08)* Half-Life (h) 5.85 .+-. 4.34 5.95 .+-.
1.88 1.83 .+-. 1.38 4.84 .+-. 1.34 AUC (ng.cndot.h/mL) 18.35 .+-.
9.48 34.70 .+-. 9.23 11.1 .+-. 4.15 22.5 .+-. 12.0
[0385] Rifaximin can be administered with or without food. Because
systemic absorption of rifaximin was low minimal in both the
fasting state and when administered within 30 minutes of a high-fat
breakfast, rifaximin can be administered with or without food.
[0386] 14C-Rifaximin was administered as a single dose to 4 healthy
male subjects. The mean overall recovery of radioactivity in the
urine and feces of 3 subjects during the 168 hours after
administration was 96.94.+-.5.64% of the dose. Radioactivity was
excreted almost exclusively in the feces (96.62.+-.5.67% of the
dose), with only a small proportion of the dose (mean 0.32% of the
dose) excreted in urine. Analysis of fecal extracts indicated that
rifaximin was being excreted as unchanged drug. The amount of
radioactivity in urine (<0.4% of the dose) suggests that
rifaximin is poorly absorbed from the gastrointestinal tract and is
almost exclusively and completely excreted in feces as unchanged
drug. Mean rifaximin pharmacokinetic parameters were Cmax
4.3.+-.2.8 ng/mL and AUCt 19.5.+-.16.5 ngh/mL with a median Tmax of
1.25 hours.
[0387] Travelers' Diarrhea
[0388] Systemic absorption of rifaximin (200 mg three times daily)
was evaluated in 13 subjects challenged with shigellosis on Days 1
and 3 of a three-day course of treatment. Rifaximin plasma
concentrations and exposures were low and variable. There was no
evidence of accumulation of rifaximin following repeated
administration for 3 days (9 doses). Peak plasma rifaximin
concentrations after 3 and 9 consecutive doses ranged from 0.81 to
3.4 ng/mL on Day 1 and 0.68 to 2.26 ng/mL on Day 3. Similarly,
AUC.sub.0-last estimates were 6.95.+-.5.15 ngh/mL on Day 1 and
7.83.+-.4.94 ngh/mL on Day 3. Rifaximin is not suitable for
treating systemic bacterial infections because of limited systemic
exposure after oral administration.
[0389] Hepatic Encephalopathy
[0390] After a single dose and multiple doses of rifaximin 550 mg
in healthy subjects, the mean time to reach peak plasma
concentrations was about an hour. The pharmacokinetic (PK)
parameters were highly variable and the accumulation ratio based on
AUC was 1.37.
[0391] The pharmacokinetics of patients with hepatic impairment
(hepatic impairment grades of Child-Pugh A and Child-Pugh B) taking
rifaximin 550 mg two times a day were evaluated in an open-label
rifaximin study. Rifaximin exposure values (AUCt) in subjects with
Child-Pugh score A and B (118 and 161 ngh/mL, respectively) were
approximately 9.6- and 13.1-fold higher than that observed in
healthy subjects following two times a day oral doses of 550 mg
(12.3 ngh/mL), respectively. Intersubject variabilites in the
pharmacokinetics of healthy subjects were generally similar to
those measured in subjects with hepatic impairment.
[0392] Rifaximin can be administered with or without food.
[0393] Animal pharmacokinetic studies have demonstrated that 80% to
90% of orally administered rifaximin is concentrated in the gut
with less than 0.2% in the liver and kidney, and less than 0.01% in
other tissues. In adults with infectious diarrhea treated with
rifaximin 800 mg daily for three days, concentrations of rifaximin
in stools averaged .about.8000 .mu.g/g the day after treatment
ended.
[0394] In a mass balance study, after administration of 400 mg
.sup.14C-rifaximin orally to healthy volunteers, of the 96.94%
total recovery, 96.62% of the administered radioactivity was
recovered in feces almost exclusively as the unchanged drug and
0.32% was recovered in urine mostly as metabolites with 0.03% as
the unchanged drug. Rifaximin accounted for 18% of radioactivity in
plasma. This suggests that the absorbed rifaximin undergoes
metabolism with minimal renal excretion of the unchanged drug. The
enzymes responsible for metabolizing rifaximin are unknown.
[0395] In a separate study, rifaximin was detected in the bile
after cholecystectomy in patients with intact gastrointestinal
mucosa, suggesting biliary excretion of rifaximin.
[0396] Hepatic Impairment The systemic exposure of rifaximin was
markedly elevated in patients with hepatic impairment compared to
healthy subjects. The mean AUC in patients with Child-Pugh Class C
hepatic impairment was 2-fold higher than in patients with
Child-Pugh Class A hepatic impairment (see Table 28).
[0397] In vitro drug interaction studies have shown that rifaximin,
at concentrations ranging from 2 to 200 ng/mL, did not inhibit
human hepatic cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19,
2D6, 2E1, and 3A4. In an in vitro hepatocyte induction model,
rifaximin was shown to induce cytochrome P450 3A4 (CYP3A4), an
isoenzyme which rifampin is known to induce. Two clinical drug-drug
interaction studies using midazolam and an oral contraceptive
containing ethinyl estradiol and norgestimate demonstrated that
rifaximin (200 mg TID for 3 days) did not alter the
pharmacokinetics of these drugs, and rifaximin 550 mg TID for 7 or
14 days resulted in only slightly reduced exposure to midazolam
following a single oral midazolam dose.
[0398] In an in vitro study, rifaximin was shown to induce CYP3A4
at the concentration of 0.2 .mu.M.
[0399] An in vitro study suggests that rifaximin is a substrate of
P-glycoprotein. In the presence of P-glycoprotein inhibitor
verapamil, the efflux ratio of rifaximin was reduced greater than
50% in vitro. The effect of P-glycoprotein inhibition on rifaximin
was not evaluated in vivo.
[0400] The inhibitory effect of rifaximin on P-gp transporter was
observed in an in vitro study. The effect of rifaximin on P-gp
transporter was not evaluated in vivo.
[0401] The effect of rifaximin 200 mg administered orally every 8
hours for 3 days and for 7 days on the pharmacokinetics of a single
dose of either midazolam 2 mg intravenous or midazolam 6 mg orally
was evaluated in healthy subjects. No significant difference was
observed in the metrics of systemic exposure or elimination of
intravenous or oral midazolam or its major metabolite,
1'-hydroxymidazolam, between midazolam alone or together with
rifaximin. Therefore, rifaximin was not shown to significantly
affect intestinal or hepatic CYP3A4 activity for the 200 mg three
times a day dosing regimen.
[0402] After rifaximin 550 mg was administered three times a day
for 7 days and 14 days to healthy subjects, the mean AUC of single
midazolam 2 mg orally was 3.8% and 8.8% lower, respectively, than
when midazolam was administered alone. The mean C.sub.max of
midazolam was also decreased by 4-5% when rifaximin was
administered for 7-14 days prior to midazolam administration. This
degree of interaction is not considered clinically meaningful.
[0403] The effect of rifaximin on CYP3A4 in patients with impaired
liver function who have elevated systemic exposure is not
known.
[0404] Oral Contraceptives Containing 0.07 mg Ethinyl Estradiol and
0.5 mg Norgestimate
[0405] The oral contraceptive study utilized an open-label,
crossover design in 28 healthy female subjects to determine if
rifaximin 200 mg orally administered three times a day for 3 days
(the dosing regimen for travelers' diarrhea) altered the
pharmacokinetics of a single dose of an oral contraceptive
containing 0.07 mg ethinyl estradiol and 0.5 mg norgestimate.
Results showed that the pharmacokinetics of single doses of ethinyl
estradiol and norgestimate were not altered by rifaximin.
[0406] In vitro study data suggest that rifaximin is a substrate
for P-glycoprotein. Rifaximinis a weak inhibitor of P-gp; at
concentrations (50 .mu.M) significantly higher than those
anticipated in plasma following oral dose administration, rifaximin
only partially inhibited transport of a model P-gp substrate.
Therefore, no clinically significant interactions with other drugs
affected by P-glycoprotein are anticipated.
[0407] Rifaximin is excreted primarily in the feces. After oral
administration of 400 mg 14C398 rifaximin to healthy volunteers,
approximately 97% of the dose was recovered in feces, almost
entirely as unchanged drug, and 0.32% was recovered in the
urine.
[0408] Rifaximin is a non-aminoglycoside semi-synthetic antibiotic
derived from rifamycin SV; it is a structural analog of rifampin.
The mechanism of action of rifaximin depends on the inhibition of
DNA-dependent RNA polymerase of the target microorganisms, leading
to the suppression of initiation of chain formation in RNA
synthesis.
[0409] The lower rate of eradication of fecal pathogens in patients
treated with rifaximin compared with fluoroquinolones and
aminoglycosides and lack of alteration of gut flora indicate a
unique mechanism of action. Rifaximin may alter virulence factors
of enteric bacterial pathogens without killing them, as has been
seen with subtherapeutic levels of drugs and colonization fimbriae
of enterotoxigenic E. coli. Rifaximin caused morphological
alterations in both susceptible and resistant bacterial strains at
concentrations as low as 1/32 of the MIC.1Rifaximin reduced the
viability and virulence of resistant bacteria, suggesting that if
in vivo pathogens are exposed to sub-MICs of the drug, not only are
their physiological functions compromised, but gene virulence and
antibiotic resistance are not fully expressed.
[0410] Rifaximin has in vitro antimicrobial activity against
numerous Gram-positive and Gram-negative bacteria, such as
Escherichia coli. Animal and human studies demonstrate negligible
systemic rifaximin absorption (<1%) after oral
administration.
[0411] The negligible systemic absorption of rifaximin from the
gastrointestinal tract minimizes the potential adverse events
associated with systemically absorbed antibiotics. Rifaximin is
delivered at high concentrations to the gastrointestinal tract,
which is the therapeutic site of action.
[0412] Rifaximin acts by binding to the beta-subunit of bacterial
DNA-dependent RNA polymerase resulting in inhibition of bacterial
RNA synthesis.
[0413] Escherichia coli has been shown to develop resistance to
rifaximin in vitro. However, the clinical significance of such an
effect has not been studied.
[0414] Rifaximin is a structural analog of rifampin. Organisms with
high rifaximin minimum inhibitory concentration (MIC) values also
have elevated MIC values against rifampin. Cross-resistance between
rifaximin and other classes of antimicrobials has not been
studied.
[0415] Rifaximin has been shown to be active against the following
pathogen in clinical studies of infectious diarrhea as described in
herein.
[0416] For HE, rifaximin is thought to have an effect on the
gastrointestinal flora.
[0417] In vitro susceptibility testing was performed according to
the National Committee for Clinical Laboratory Standards (NCCLS)
agar dilution method M7-A612. However, the correlation between
susceptibility testing and clinical outcome has not been
determined.
[0418] Escherichia coli has been shown to develop resistance to
rifaximin in vitro. However, the clinical significance of such an
effect has not been studied. Rifaximin is a structural analog of
rifampin. Organisms with high rifaximin minimum inhibitory
concentration (MIC) values also have elevated MIC values against
rifampin. Cross resistance between rifaximin and other classes of
antimicrobials has not been studied.
[0419] Malignant schwannomas in the heart were significantly
increased in male Crl:CD.RTM. (SD) rats that received rifaximin by
oral gavage for two years at 150 to 250 mg/kg/day (doses equivalent
to 2.4 to 4 times the recommended dose of 200 mg three times daily
for travelers' diarrhea, and equivalent to 1.3 to 2.2 times the
recommended dose of 550 mg twice daily for hepatic encephalopathy,
based on relative body surface area comparisons). There was no
increase in tumors in Tg.rasH2 mice dosed orally with rifaximin for
26 weeks at 150 to 2000 mg/kg/day (doses equivalent to 1.2 to 16
times the recommended daily dose for travelers' diarrhea and
equivalent to 0.7 to 9 times the recommended daily dose for hepatic
encephalopathy, based on relative body surface area
comparisons).
[0420] The carcinogenic potential of rifaximin was examined in a 2
year study with CD rats. Daily oral administration of at dose
levels ranging from 20, 50, to 250 mg/kg/day produced no evidence
of a carcinogenic effect.
[0421] Similarly, in a study with Tg.rasH2 mice daily oral
administration by gavage with rifaximin at doses up to 1500
mg/kg/day (males) and 2000 mg/kg/day (females) for 26-weeks did not
increase the incidence of tumors when compared to vehicle
control.
[0422] Rifaximin was not genotoxic in the bacterial reverse
mutation assay, chromosomal aberration assay, rat bone marrow
micronucleus assay, rat hepatocyte unscheduled DNA synthesis assay,
or the CHO/HGPRT mutation assay. There was no effect on fertility
in male or female rats following the administration of rifaximin at
doses up to 300 mg/kg (approximately 5 times the clinical dose of
600 mg/day, and approximately 2.6 times the clinical dose of 1100
mg/day, adjusted for body surface area).
[0423] Results from multiple-dose oral toxicity studies in rats,
rabbits, and dogs showed negligible toxic effects of rifaximin at
doses ranging from 6 to 68 times the clinical dose for travelers'
diarrhea (600 mg/day) for durations of up to 39 weeks.
[0424] In a 26-week study with Tg.rasH2 mice orally administered
rifaximin at doses up to 1500 mg/kg/day (males) and 2000 mg/kg/day
(females) 2/25 female mice at 2000 mg/kg day presented ruffled fur
and hunched appearance in low incidence that did not reach
statistical significance.
[0425] Oral administration of rifaximin for 3-6 months produced
hepatic proliferation of connective tissue in rats (50 mg/kg/day)
and fatty degeneration of liver in dogs (100 mg/kg/day). However,
plasma drug levels were not measured in these studies.
[0426] Subsequently, rifaximin was studied at doses as high as 300
mg/kg/day in rats for 6 months and 1000 mg/kg/day in dogs for 9
months, and no signs of hepatotoxicity were observed. The maximum
plasma AUC.sub.0-8 hr values from the 6 month rat and 9 month dog
toxicity studies (range: 42-127 ngh/mL) was lower than the maximum
plasma AUC.sub.0-8 hr values in cirrhotic patients (range: 19-306
ngh/mL).
[0427] The efficacy of rifaximin given as 200 mg orally taken three
times a day for 3 days was evaluated in 2 randomized, multi-center,
double-blind, placebo-controlled studies in adult subjects with
travelers' diarrhea. One study was conducted at clinical sites in
Mexico, Guatemala, and Kenya (Study 1). The other study was
conducted in Mexico, Guatemala, Peru, and India (Study 2). Stool
specimens were collected before treatment and 1 to 3 days following
the end of treatment to identify enteric pathogens.
[0428] The predominant pathogen in both studies was Escherichia
coli.
[0429] The clinical efficacy of rifaximin was assessed by the time
to return to normal, formed stools and resolution of symptoms. The
primary efficacy endpoint was time to last unformed stool (TLUS)
which was defined as the time to the last unformed stool passed,
after which clinical cure was declared. Table 32 displays the
median TLUS and the number of patients who achieved clinical cure
for the intent to treat (ITT) population of Study 1. The duration
of diarrhea was significantly shorter in patients treated with
rifaximin than in the placebo group. More patients treated with
rifaximin were classified as clinical cures than were those in the
placebo group.
TABLE-US-00004 TABLE 32 Clinical Response in Study 1 (ITT
population) XIFAXAN Placebo Estimate (n = 125) (n = 129) (97.5% CI)
P-Value Median 32.5 58.6 1.78.sup.a 0.0002 TLUS (1.26, 2.50)
(hours) Clinical 99 (79.2) 78 (60.5) 18.7.sup.b 0.001 cure, n (%)
(5.3, 32.1) .sup.aHazard Ratio .sup.bDifference in rates
[0430] Microbiological eradication (defined as the absence of a
baseline pathogen in culture of stool after 72 hours of therapy)
rates for Study 1 are presented in Table 30 for patients with any
pathogen at baseline and for the subset of patients with
Escherichia coli at baseline. Escherichia coli was the only
pathogen with sufficient numbers to allow comparisons between
treatment groups.
[0431] Even though rifaximin had microbiologic activity similar to
placebo, it demonstrated a clinically significant reduction in
duration of diarrhea and a higher clinical cure rate than placebo.
Therefore, patients should be managed based on clinical response to
therapy rather than microbiologic response.
TABLE-US-00005 TABLE 33 Microbiologic Eradication Rates in Study 1
Subjects with a Baseline Pathogen Rifaximin Placebo Overall 48/70
(68.6) 41/61 (67.2) E. coli 38/53 (71.7) 40/54 (74.1)
[0432] The results of Study 2 supported the results presented for
Study 1. In addition, this study also provided evidence that
subjects treated with rifaximin with fever and/or blood in the
stool at baseline had prolonged TLUS. These subjects had lower
clinical cure rates than those without fever or blood in the stool
at baseline. Many of the patients with fever and/or blood in the
stool (dysentery-like diarrheal syndromes) had invasive pathogens,
primarily Campylobacter jejuni, isolated in the baseline stool.
[0433] Also in this study, the majority of the subjects treated
with rifaximin who had Campylobacter jejuni isolated as a sole
pathogen at baseline failed treatment and the resulting clinical
cure rate for these patients was 23.5% (4/17). In addition to not
being different from placebo, the microbiologic eradication rates
for subjects with Campylobacter jejuni isolated at baseline were
much lower than the eradication rates seen for Escherichia
coli.
[0434] In an unrelated open-label, pharmacokinetic study of oral
rifaximin 200 mg taken every 8 hours for 3 days, 15 adult subjects
were challenged with Shigella flexneri 2a, of whom 13 developed
diarrhea or dysentery and were treated with rifaximin. Although
this open-label challenge trial was not adequate to assess the
effectiveness of rifaximin in the treatment of shigellosis, the
following observations were noted: eight subjects received rescue
treatment with ciprofloxacin either because of lack of response to
rifaximin treatment within 24 hours (2), or because they developed
severe dysentery (5), or because of recurrence of Shigella flexneri
in the stool (1); five of the 13 subjects received ciprofloxacin
although they did not have evidence of severe disease or
relapse.
[0435] The efficacy of rifaximin 550 mg taken orally two times a
day was evaluated in a randomized, placebo-controlled,
double-blind, multi-center 6-month trial of adult subjects from the
U.S., Canada and Russia who were defined as being in remission
(Conn score of 0 or 1) from hepatic encephalopathy (HE). Eligible
subjects had 2 2 episodes of HE associated with chronic liver
disease in the previous 6 months.
[0436] A total of 299 subjects were randomized to receive either
rifaximin (n=140) or placebo (n=159) in this study. Patients had a
mean age of 56 years (range, 21-82 years), 81%<65 years of age,
61% were male and 86% White. At baseline, 67% of patients had a
Conn score of 0 and 68% had an asterixis grade of 0. Patients had
MELD scores of either .ltoreq.10 (27%) or 11 to 18 (64%) at
baseline. No patients were enrolled with a MELD score of >25.
Nine percent of the patients were Child-Pugh Class C. Lactulose was
concomitantly used by 91% of the patients in each treatment arm of
the study. Per the study protocol, patients were withdrawn from the
study after experiencing a breakthrough HE episode. Other reasons
for early study discontinuation included: adverse reactions
(rifaximin 6%; placebo 4%), patient request to withdraw (rifaximin
4%; placebo 6%) and other (rifaximin 7%; placebo 5%).
[0437] The primary endpoint was the time to first breakthrough
overt HE episode. A breakthrough overt HE episode was defined as a
marked deterioration in neurological function and an increase of
Conn score to Grade .gtoreq.2. In patients with a baseline Conn
score of 0, a breakthrough overt HE episode was defined as an
increase in Conn score of 1 and asterixis grade of 1.
[0438] Breakthrough overt HE episodes were experienced by 31 of 140
subjects (22%) in the rifaximin group and by 73 of 159 subjects
(46%) in the placebo group during the 6-month treatment period.
Comparison of Kaplan-Meier estimates of event-free curves showed
rifaximin significantly reduced the risk of HE breakthrough by 58%
during the 6-month treatment period. Presented below in FIG. 24 is
the Kaplan-Meier event-free curve for all subjects (n=299) in the
study.
[0439] When the results were evaluated by the following demographic
and baseline characteristics, the treatment effect of rifaximin 550
mg in reducing the risk of breakthrough overt HE recurrence was
consistent for: sex, baseline Conn score, duration of current
remission and diabetes. The differences in treatment effect could
not be assessed in the following subpopulations due to small sample
size: non-White (n=42), baseline MELD>19 (n=26), Child-Pugh C
(n=31), and those without concomitant lactulose use (n=26).
[0440] FIG. 25 shows hazard ratios for the risk of experiencing
breakthrough overt HE (rifaximin group divided by placebo group)
for each subgroup, 95% confidence intervals as determined by the
Cox proportional hazards model. P-values for differences between
the rifaximin and placebo groups were determined by log rank
test.
[0441] HE-related hospitalizations were reported for 19 of 140
subjects (14%) and 36 of 159 subjects (23%) in the rifaximin and
placebo groups, respectively. Rifaximin had a significant reduction
of risk against HE-related hospitalization during the 6-month
treatment period; hazard ratio in the rifaximin group relative to
placebo was 0.500 (95% CI: 0.287 to 0.873) (p=0.0129). Subjects in
the rifaximin group had a 50% reduction in the risk of
hospitalization due to HE during the 6-month treatment period when
compared with placebo. See FIG. 26: Time to First HE-Related
Hospitalization in HE Study (up to 6 Months of Treatment, Day 170)
(ITT Population).
[0442] HE-related hospitalizations (hospitalizations directly
resulting from HE, or hospitalizations complicated by HE) were
reported for 19 of 140 subjects (14%) and 36 of 159 subjects (23%)
in the rifaximin and placebo groups respectively. rifaximin had a
significant reduction of risk against HE-related hospitalization
during the 6-month treatment period; hazard ratio in the rifaximin
group relative to placebo was 0.500 (95% CI: 0.287 to 0.873)
(p=0.0129). Subjects in the rifaximin group had a 50% reduction in
the risk of hospitalization due to HE during the 6-month treatment
period when compared with placebo. See FIG. 26: Time to First
HE-Related Hospitalization in HE Study (up to 6 Months of
Treatment, Day 170) (ITT Population).
[0443] Comparison of Kaplan-Meier estimates of event-free curves
showed rifaximin significantly reduced the risk of HE-related
hospitalizations by 50% during the 6-month treatment period.
Comparison of Kaplan-Meier estimates of event-free curves is shown
in FIG. 25.
[0444] Methods for dilution antimicrobial susceptibility tests for
bacteria that grow aerobically. National Committee for Clinical
Laboratory Standards, Sixth Edition, Wayne Pa. Approved Standard
NCCLS Document M7-A6 Jan. 2003; 23 (2).
[0445] Highly significant protective effects of rifaximin were
observed with respect to time to any increase from baseline in Conn
score and time to any increase from baseline in asterixis grade
when analyzed independently; hazard ratio in the rifaximin group
relative to placebo was 0.463 (95% CI: 0.312 to 0.685)
(p<0.0001) for the risk of experiencing an increase in Conn
score (ie, worsening in mental status) and 0.646 (95% CI: 0.414 to
1.008) (p=0.0523) for the risk of experiencing an increase in
asterixis grade (ie, worsening in neuromotor functioning) during
the 6-month treatment period.
[0446] Because lactulose was the most frequently used concomitant
medicine, an analysis was undertaken to analyze lactulose use at
baseline and during the study to ensure that rifaximin treatment
effect was not modified. At baseline and during the trial,
lactulose use between the rifaximin and control groups was no
different. Thus, results of the study showing efficacy of rifaximin
were not influenced by the use of lactulose.
[0447] In addition, patient subgroups were analyzed by MELD and
Child-Pugh analyses to determine any differences between the
treatment group and the rifaximin group. It was found that the
positive effects of rifaximin were not limited by liver disease
severity. In addition, it was also found that there was no
significant interaction across subgroups. Accordingly, all these
analyses demonstrated a risk reduction in favor of rifaximin. FIG.
28 illustrates that there was a consistency of treatment affect
across all the various subgroups that were administered
rifaximin.
[0448] Clostridium difficile-associated diarrhea (CDAD) has been
reported with use of nearly all antibacterial agents, including
rifaximin, and may range in severity from mild diarrhea to fatal
colitis. Treatment with antibiotics alters the normal flora of the
colon which may lead to C. difficile. Patients can develop watery
and bloody stools (with or without stomach cramps and fever) even
as late as two or more months after having taken the last dose of
the antibiotic. If diarrhea occurs after therapy or does not
improve or worsens during therapy, advise patients to contact a
physician as soon as possible.
[0449] Patients should be informed that in patients with severe
hepatic impairment (Child-Pugh C) there is an increase in systemic
exposure to rifaximin.
EXAMPLES
[0450] It should be appreciated that embodiments of the invention
should not be construed to be limited to the examples, which are
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: Effects of Rifaximin on Subjects with Hepatic
Insufficiency
[0451] Subjects were instructed to take one tablet of 550 mg of
rifaximin by mouth 2 times per day--approximately every 12 hours.
The rifaximin may be co-administered with other medications, for
example, lactulose, antidepressants, anti-inflammatory, methadone,
prescription and non-prescription sleep aids (e.g., Lunesta.TM.
(eszopiclone) and Ambien.RTM. (zolpidem tartrate)), and
antihistamines, diuretics, laxatives or stool softeners, neurontin
(gabapentin) and lyrica (pregabalin).
[0452] Lactulose use was optional for subjects. For subjects who
used lactulose, it was titrated to a dose during the 3 to 7-day
observation period according to accepted medical practice.
[0453] Asterixis Grade
[0454] Asterixis (flapping tremor) was determined with the subject
holding both arms and forearms extended with wrists dorsiflexed and
fingers open for .gtoreq.30 seconds. Asterixis was measured on a
continuum of 5 grades, e.g., grades 0 and 4=no abnormal movement
vs. almost continuous flapping motions, respectively as shown
below:
Grade 0=No tremors; Grade 1=Rare flapping motions; Grade
2=Occasional, irregular flaps; Grade 3=Frequent flaps; and Grade
4=Almost continuous flapping motions.
[0455] Efficacy in regard to asterixis grade was measured as time
to any increase from baseline in asterixis grade. Time to an
increase in asterixis grade was computed as the number of days from
the first dose of rifaximin to the initial occurrence of an
increase from baseline in asterixis grade.
Breakthrough HE Episode
[0456] Relative risk of experiencing a breakthrough HE episode
(e.g., Conn score Grade .gtoreq.2, (e.g., 0 or 1 to .gtoreq.2) or a
Conn and asterixis score increase of 1 grade each) for each subject
in the trial taking either rifaximin or the placebo was measured.
The analysis compared time to first breakthrough HE episode for
rifaximin versus placebo using survival analysis methods. Time to
first breakthrough HE episode was computed as the number of days
from the first dose of rifaximin to the initial occurrence of
breakthrough HE (e.g., Conn score Grade .gtoreq.2, or a Conn and
asterixis score increase of 1 grade each).
[0457] Change in mental status was measured by the Conn score (also
known as the West Haven score). The Conn score has been widely used
as a measure of mental state in HE studies and is based on the
criteria of Parsons- Smith as modified by Conn. The scale used in
the Conn scoring system is described above.
[0458] Subjects had a Conn score of 0 or 1. An increase in the Conn
score of greater than or equal to grade 2 was considered as a
breakthrough HE episode.
Hepatic Encephalopathy Scoring Algorithm (HESA)
[0459] The Hepatic Encephalopathy Scoring Algorithm (HESA) is a
method that uses both clinical and neuropsychological assessments
to assess mental status. The Algorithm has been validated
previously and has been correlated with the Conn criteria.
[0460] The CFF test is recognized as a quantitative measure of CNS
dysfunction and that utilizes the correlation between cerebral
processing of oscillatory visual stimuli and its subsequent
impairment due to increased HE severity. The CFF test was
administered, and statistically significant greater improvement in
CFF results were observed in rifaximin subjects when compared with
placebo (p=0.0320).
[0461] The Critical Flicker Frequency (CFF) was assessed for each
subject at screening, baseline, visits 3 through 14 and the end of
study visit using the Lafayette Flicker Fusion (Lafayette
Instrument Company, Inc). Circular light pulses with a 1:1 ratio
between the visual impulse and the interval were used with
decreasing frequency in gradual steps of 0.5 to 0.1 Hz/second. The
frequency of the white light, which is initially generated as a
high-frequency pulse (50 Hz) and which gives the patient the
impression of a steady light, was reduced gradually until the
patient had the impression that the steady light had changed to a
flicker. The patient registered this change by pressing a hand-held
switch. The flicker frequencies were measured 8 times and from
these data, the mean values for each patient were calculated. The
process was conducted in a quiet, semi-darkened room without
distracting noises and took about 10 minutes.
[0462] Critical Flicker Frequency scores The critical flicker
frequency (CFF) was assessed for each subject using a specialized
CFF instrument. The CFF is the frequency at which the subject
observes a constant light transition to a flickering light and is
measured in Hertz (Hz). CFF is an objective assessment of mental
status. A CFF value of 39 Hz has been shown to be the threshold for
separation between subjects who have manifest HE (e.g.,
Conn.gtoreq.1) and those without HE symptoms (e.g., Conn=0), with a
lower CFF value indicating more severe HE.sup.(43).
[0463] The CFF was measured on a continuous scale and was the mean
of 8 separate fusion-to-flicker transition tests performed in rapid
succession.
Ammonia Concentrations
[0464] Venous blood samples (10 mL) were collected and ammonia
concentrations were obtained by methods known in the art.
[0465] Time to increase from baseline in either the Conn score
(mental state grade) or asterixis grade
[0466] To analyze the time to a first breakthrough HE episode,
survival analysis methods were used to assess the effectiveness of
the rifaximin treatment on the time to increase from baseline in
either the Conn score (mental state grade) or asterixis grade.
[0467] Time to increase in either the Conn score or asterixis grade
was computed as the number of days from the first dose of rifaximin
to the initial occurrence of either an increase from baseline in
Conn score or asterixis grade. The analysis of time to increase in
either Conn score or asterixis grade were based on the comparison
of time to event between rifaximin and placebo.
Time to First HE-Related Hospitalization
[0468] The effect of rifaximin on time to first HE-related
hospitalization was determined. Time to first HE-related
hospitalization was computed as the number of days from the first
dose of rifaximin to the first hospitalization for an HE related
event. The analysis of time to first HE-related hospitalization was
based on the comparison of time to hospitalization between
rifaximin and placebo.
Time to Development of Spontaneous Bacterial Peritonitis
[0469] The effect of rifaximin on time to development of
spontaneous bacterial peritonitis (SBP) was determined. Time to
development of SBP was computed as the number of days from the
first dose of rifaximin to the time of peritoneal fluid collection
that resulted in a positive test for SBP. The analysis of time to
development of SBP was based on the comparison of time to event
between rifaximin and placebo.
[0470] Mean Change from Baseline in Blood Ammonia Concentration and
Critical Flicker Frequency Values Over Time
[0471] Mean values and mean changes from baseline in blood ammonia
concentration and critical flicker frequency values were collected.
Analyses of blood ammonia concentrations and critical flicker
frequency values were based upon quantitative values (not
qualitative grades). Treatment differences for mean change from
baseline in these parameters was estimated using a mixed effects
model with fixed effects for time and baseline value.
Mean Daily Lactulose Consumption Over Time
[0472] A subject's daily lactulose consumption was used to compute
mean daily lactulose consumption for each month. Treatment
differences for mean change from baseline in mean daily lactulose
consumption were estimated.
CLDQ
[0473] The CLDQ includes 29 items in the following six domains:
abdominal symptoms (three items), fatigue (five items), systemic
symptoms (five items), activity (three items), emotional function
(eight items), and worry (five items). Summary scores for the CLDQ
overall and each of the six domains were computed and summarized at
baseline and Days 28, 56, 84, 112, 140 and 168 using descriptive
statistics. Treatment differences for mean change in overall score
and domain scores from baseline to Days 28, 56, 84, 112, 140 and
168 were collected summarized and compared between treatments.
[0474] Treatment differences for mean change from baseline to EOT
were determined as the change from baseline at EOT in fatigue
domain score of Chronic Liver Disease Questionnaire (CLDQ).
Similarly, the mean change from baseline in blood ammonia
concentration at EOT was also determined.
Assessment of Quality of Life
[0475] The SF-36, Chronic Liver Disease Questionnaire (CLDQ), and
Epworth Sleepiness Scale were used to measure health related
quality of life. The 29 item CLDQ questionnaire consists of the
following domains: fatigue, activity, emotional function, abdominal
symptoms, systemic symptoms, and worry.
Epworth Sleepiness Scale
[0476] Total scores for the Epworth Sleepiness Scale were computed
and summarized at baseline and Days 28, 56, 84, 112, 140 and 168
using descriptive statistics. Treatment differences for mean change
in total scores from baseline to Days 28, 56, 84, 112, 140 and 168
were summarized and compared between treatments.
[0477] FIG. 1 is a line graph showing Lactulose daily use between
subjects taking placebos and subjects taking rifaximin as described
above.
[0478] FIG. 2 is a line graph showing Kaplan Meier estimates of the
distribution of time to a breakthrough HE event for the placebo
group and the rifaximin group. As indicated there was an increased
time to breakthrough HE events for subjects taking rifaximin in
comparison to subjects taking the placebo.
[0479] FIG. 3 is a line graph showing Kaplan Meier estimates of the
distribution of time to a first HE related hospitalization. As
indicated there was an increased time to hospitalization for
subjects taking rifaximin in comparison to the placebo group.
[0480] FIG. 4 is a line graph showing Kaplan Meier estimates of the
distribution of time to a first increase in Conn scores. As
indicated there was an increased time to the first increase in Conn
scores for subjects taking rifaximin in comparison to the placebo
group.
[0481] FIG. 5 is a line graph showing Kaplan Meier estimates of the
distribution of time to a first increase in Asterixis grade. As
indicated there was an increased time to the first increase in
Asterixis grade for subjects taking rifaximin in comparison to the
placebo group.
Example 2
[0482] The following tables provide further evidence supporting the
advantageous use of GI specific antibiotics, such as rifaximin, to
treat subjects suffering from HE.
TABLE-US-00006 TABLE 1 Time to Onset of Breakthrough HE Episode
Placebo 550 mg Rifaximin BID (N = 159) (N = 140) Cumulative
Conditional Cumulative Conditional At Occurrences Occurrences
Probability of At Occurrences Occurrences Probability of Days Risk
of Events of Events Events (SE) Survival Risk of Events of Events
Events (SE) Survival [0-28) 158 20 20 0.13 (0.03) 1.0000 140 13 13
0.09 (0.02) 1.0000 [28-56) 137 23 43 0.17 (0.03) 0.8734 126 4 17
0.03 (0.02) 0.9071 [56-84) 113 14 57 0.12 (0.03) 0.7262 120 6 23
0.05 (0.02) 0.8783 [84-140) 98 10 67 0.10 (0.03) 0.6363 112 7 30
0.06 (0.02) 0.8344 [140-168) 84 6 73 0.07 (0.03) 0.5713 98 1 31
0.01 (0.01) 0.7820 >=168 38 0 73 0.00 (0.00) 0.5305 46 0 31 0.00
(0.00) 0.7740 Harzard Ratio: 0.421 95% CI: (0.276, 0.641) p-value:
<.0001
TABLE-US-00007 TABLE 2 Time to Onset of Breakthrough HE Episode by
Baseline Conn Score Level Placebo 550 mg Rifaximin BID (N = 107) (N
= 93) Cumulative Conditional Cumulative Conditional At Occurrences
Occurrences Probability of At Occurrences Occurrences Probability
of Days Risk of Events of Events Events (SE) Survival Risk of
Events of Events Events (SE) Survival [0-28) 107 13 13 0.12 (0.03)
1.0000 93 11 11 0.12 (0.03) 1.0000 [28-56) 93 16 29 0.17 (0.04)
0.8779 81 3 14 0.04 (0.02) 0.8817 [56-84) 77 7 36 0.09 (0.03)
0.7269 77 1 15 0.01 (0.01) 0.8491 [84-140) 69 5 41 0.07 (0.03)
0.6608 75 3 18 0.04 (0.02) 0.8380 [140-168) 61 4 45 0.07 (0.03)
0.6129 68 1 19 0.01 (0.01) 0.8042 >=168 27 0 45 0.00 (0.00)
0.5724 32 0 19 0.00 (0.00) 0.7924 Harzard Ratio: 0.441 95% CI:
(0.258, 0.754) p-value: 0.0028
TABLE-US-00008 TABLE 3 Time to Onset of Breakthrough HE Episode by
Prior Lactulose Use Placebo 550 mg Rifaximin BID (N = 142) (N =
123) Cumulative Conditional Cumulative Conditional At Occurrences
Occurrences Probability of At Occurrences Occurrences Probability
of Days Risk of Events of Events Events (SE) Survival Risk of
Events of Events Events (SE) Survival [0-28) 141 19 19 0.13 (0.03)
1.0000 123 12 12 0.10 (0.03) 1.0000 [28-56) 121 21 40 0.17 (0.03)
0.8652 110 4 16 0.04 (0.02) 0.9024 [56-84) 100 13 53 0.13 (0.03)
0.7151 104 5 21 0.05 (0.02) 0.8696 [84-140) 86 10 63 0.12 (0.03)
0.6221 97 7 28 0.07 (0.03) 0.8278 [140-168) 73 5 68 0.07 (0.03)
0.5498 84 1 29 0.01 (0.01) 0.7678 >=168 33 0 68 0.00 (0.00)
0.5121 39 0 29 0.00 (0.00) 0.7586 Harzard Ratio: 0.424 95% CI:
(0.274, 0.655) p-value: 0.0001
TABLE-US-00009 TABLE 4 Time to Onset of First HE-Related
Hospitalization Placebo (N = 159) 550 mg Rifaximin BID Conditional
(N = 140) Conditional Cumulative Probability Cumulative Probability
At Occurrences Occurrences of At Occurrences Occurrences of Events
Days Risk of Events of Events Events (SE) Survival Risk of Events
of Events (SE) Survival [0-28) 154 11 11 0.07 (0.02) 1.0000 138 6 6
0.04 (0.02) 1.0000 [28-56) 131 14 25 0.11 (0.03) 0.9286 125 4 10
0.03 (0.02) 0.9564 [56-84) 106 7 32 0.07 (0.02) 0.8293 113 5 15
0.04 (0.02) 0.9258- [84-140) 86 8 40 0.09 (0.03) 0.7743 100 5 20
0.05 (0.02) 0.8848 [140-168) 66 2 42 0.03 (0.02) 0.7023 86 3 23
0.04 (0.02) 0.8402 >=168 30- 0 42 0.00 (0.00) 0.6810 39 0 23
0.00 (0.00) 0.8108 Hazard Ratio: 0.521 958 CI: (0.313, 0.868)
p-value: 0.0107
TABLE-US-00010 TABLE 5 Time to Any Increase from Baseline in Conn
Score Placebo 550 mg Rifaximin BID (N = 159) (N = 140) Cumulative
Conditional Cumulative Conditional At Occurrences Occurrences
Probability of At Occurrences Occurrences Probability of Days Risk
of Events of Events Events (SE) Survival Risk of Events of Events
Events (SE) Survival [0-28) 156 26 26 0.17 (0.03) 1.0000 139 17 17
0.12 (0.03) 1.0000 [28-56) 125 21 47 0.17 (0.03) 0.8333 119 5 22
0.04 (0.02) 0.8777 [56-84) 100 15 62 0.15 (0.04) 0.6928 109 9 31
0.08 (0.03) 0.8407 [84-140) 80 10 72 0.13 (0.04) 0.5883 94 5 36
0.05 (0.02) 0.7713 [140-168) 62 5 77 0.08 (0.03) 0.5143 79 0 36
0.00 (0.00) 0.7302 >=168 27 0 77 0.00 (0.00) 0.4729 37 1 37 0.03
(0.03) 0.7302 Harzard Ratio: 0.463 95% CI: (0.312, 0.685) p-value:
<.0001
TABLE-US-00011 TABLE 6 Time to Onset of Breakthrough HE Episode by
Baseline MELD Score Level Placebo 550 mg Rifaximin BID (N = 44) (N
= 34) Cumulative Conditional Cumulative Conditional At Occurrences
Occurrences Probability of At Occurrences Occurrences Probability
of Days Risk of Events of Events Events (SE) Survival Risk of
Events of Events Events (SE) Survival [0-28) 44 2 2 0.05 (0.03)
1.0000 34 1 1 0.03 (0.03) 1.0000 [28-56) 42 4 6 0.10 (0.05) 0.9545
33 0 1 0.00 (0.00) 0.9706 [56-84) 38 1 7 0.03 (0.03) 0.8636 32 0 1
0.00 (0.00) 0.9706 [84-140) 37 3 10 0.08 (0.04) 0.8409 32 1 2 0.03
(0.03) 0.9706 [140-168) 33 4 14 0.12 (0.06) 0.7727 28 0 2 0.00
(0.00) 0.9398 >=168 14 0 14 0.00 (0.00) 0.6791 13 0 2 0.00
(0.00) 0.9398 Harzard Ratio: 0.171 95% CI: (0.039, 0.754) p-value:
0.0197
TABLE-US-00012 TABLE 7 Time to Onset of Breakthrough HE Episode by
Baseline MELD Score Level Placebo 550 mg Rifaximin BID (N = 86) (N
= 85) -- -- Conditional Conditional Cumulative Probability
Cumulative Probability At Occurrences Occurrences of Events At
Occurrences Occurrences of Events Days Risk of Events of Events
(SE) Survival Risk of Events of Events (SE) Survival [0-28) 86 15
15 0.18 (0.04) 1.0000 85 8 8 0.09 (0.03) 1.0000 [28-56) 70 13 28
0.19 (0.05) 0.8246 77 2 10 0.03 (0.02) 0.9059 [56-84) 56 11 39 0.20
(0.05) 0.6703 73 3 13 0.04 (0.02) 0.8822 [84-140) 45 7 46 0.16
(0.05) 0.5387 68 6 19 0.09 (0.03) 0.8459 [140-168) 36 2 48 0.06
(0.04) 0.4539 58 1 20 0.02 (0.02) 0.7713 >=168 16 0 48 0.00
(0.00) 0.4284 27 0 20 0.00 (0.00) 0.7580 Harzard Ratio: 0.329 95%
CI: (0.195, 0.556) p-value: <.0001
TABLE-US-00013 TABLE 8 Time to Onset of Breakthrough HE Episode by
Baseline MELD Score Level Placebo 550 mg Rifaximin BID (N = 14) (N
= 11) Cumulative Conditional Cumulative Conditional At Occurrences
Occurrences Probability of At Occurrences Occurrences Probability
of Days Risk of Events of Events Events (SE) Survival Risk of
Events of Events Events (SE) Survival [0-28) 14 3 3 0.21 (0.11)
1.0000 11 1 1 0.09 (0.09) 1.0000 [28-56) 11 4 7 0.36 (0.15) 0.7857
10 0 1 0.00 (0.00) 0.9091 [56-84) 7 2 9 0.29 (0.17) 0.5000 10 3 4
0.30 (0.14) 0.9091 [84-140) 5 0 9 0.00 (0.00) 0.3571 7 0 4 0.00
(0.00) 0.6364 [140-168) 4 0 9 0.00 (0.00) 0.3571 7 0 4 0.00 (0.00)
0.6364 >=168 2 0 9 0.00 (0.00) 0.3571 3 0 4 0.00 (0.00) 0.6364
Harzard Ratio: 0.403 95% CI: (0.123, 1.313) p-value: 0.1315
TABLE-US-00014 TABLE 9 Time to Onset of Breakthrough HE Episode by
Prior Lactulose Use Placebo 550 mg Rifaximin BID (N = 134) (N =
127) Cumulative Conditional Cumulative Conditional At Occurrences
Occurrences Probability of At Occurrences Occurrences Probability
of Days Risk of Events of Events Events (SE) Survival Risk of
Events of Events Events (SE) Survival [0-28) 134 18 18 0.13 (0.03)
1.0000 127 12 12 0.09 (0.03) 1.0000 [28-56) 115 20 38 0.17 (0.04)
0.8652 114 4 16 0.04 (0.02) 0.9055 [56-84) 95 14 52 0.15 (0.04)
0.7147 108 6 22 0.06 (0.02) 0.8737- [84-140 80 9 61 0.11 (0.04)
0.6094 100 6 28 0.06 (0.02) 0.8252 [140-168) 68 5 66 0.07 (0.03)
0.5408 88 1 29 0.01 (0.01) 0.7754 >=168 31 0 66 0.00 (0.00)
0.5011 41 0 29 0.00 (0.00) 0.7666 Hazard Ratio: 0.399 95% CI:
(0.258, 0.618) p-value: <.0001
TABLE-US-00015 TABLE 10 Time to Any Increase from Baseline in
Asterixis Grade Placebo 550 mg Rifaximin BID (N = 159) (N = 140)
Cumulative Conditional Cumulative Conditional At Occurrences
Occurrences Probability of At Occurrences Occurrences Probability
of Days Risk of Events of Events Events (SE) Survival Risk of
Events of Events Events (SE) Survival [0-28) 154 20 20 0.13 (0.03)
1.0000 137 13 13 0.10 (0.03) 1.0000 [28-56) 120 15 35 0.13 (0.03)
0.8697 116 7 20 0.06 (0.02) 0.9048 [56-84) 91 4 39 0.04 (0.02)
0.7610 101 7 27 0.07 (0.03) 0.8499 [84-140) 76 6 45 0.08 (0.03)
0.7275 87 3 30 0.03 (0.02) 0.7910 [140-168) 61 4 49 0.07 (0.03)
0.6701 74 1 31 0.01 (0.01) 0.7637 >=168 27 1 50 0.04 (0.04)
0.6262 34 1 32 0.03 (0.03) 0.7534 Harzard Ratio: 0.646 95% CI:
(0.414, 1.008) p-value: 0.0523
TABLE-US-00016 TABLE 11 Mean Change from Baseline in Blood Ammonia
Concentration (.mu.g/dL) 550 mg Assessment Placebo Rifaximin BID
Time (N = 159) (N = 140) P-value Day 28 n 126 121 Mean 89.3 88.4 SD
48.19 49.02 Median 87.0 74.0 Min 2 25 Max 315 326 Change from
Baseline to Day 28 n 117 117 0.6268 Mean -1.1 -2.1 SD 48.32 44.37
Median 1.0 -2.0 Min -252 -164 Max 133 176
TABLE-US-00017 TABLE 12 Mean Change from Baseline in Critical
Flicker Frequency Test (Hz) 550 mg Assessment Placebo Rifaximin BID
Time (N = 159) (N = 140) P-value Day 140 N 70 87 Mean 38.7 38.7 SD
5.47 4.76 Median 38.8 38.9 Min 26 27 Max 50 49 Change from Baseline
to Day 140 n 70 87 0.0266 Mean 1.1 1.4 SD 4.10 4.84 Median 0.9 1.5
Min -12 -15 Max 12 12
TABLE-US-00018 TABLE 13 Mean Change from Baseline in Critical
Flicker Frequency Test (Hz) 550 mg Rifaximin Assessment Placebo BID
Time (N = 159) (N = 140) P-value EOT n 155 139 Mean 37.6 37.8 SD
5.98 4.88 Median 37.9 37.8 Min 21 25 Max 50 49 Change from Baseline
to EOT n 155 139 0.0320 Mean 0.4 0.9 SD 4.70 4.75 Median 0.2 0.1
Min -12 -14 Max 16 11
TABLE-US-00019 TABLE 14 Number of Subjects in Each Level of Change
from Baseline in Conn Score by Treatment Group 550 mg Odds Ratio
Assessment Placebo Rifaximin BID (550 mg Rifaximin 95% CI for P-
Time Statistics (N = 159) (N = 140) BID/Placebo) Odds Ratio value
Change from Baseline to EOT -1 n (%) 18 (11.5%) 26 (18.7%) 2.46
(1.49, 4.09) 0.0005 0 n (%) 100 (63.7%) 101 (72.7%) 1 n (%) 29
(18.5%) 10 (7.2%) 2 n (%) 9 (5.7%) 2 (1.4%) 3 n (%) 1 (0.6%) 0 n
157 139 Mean 0.2 -0.1 SD 0.74 0.56 Median 0.0 0.0 Min -1 -1 Max 3
2
TABLE-US-00020 TABLE 15 Number of Subjects in Each Level of Change
from Baseline in Asterixis Grade by Treatment Group Odds Ratio
Placebo 550 mg Rifaximin (550 mg Assessment (N = BID Rifaximin 95%
CI for Time Statistics 159) (N = 140) BID/Placebo) Odds Ratio
P-value Change from Baseline to EOT -2 n (%) 1 1 (0.7%) 1.88 (1.10,
3.23) 0.0207 (0.6%) -1 n (%) 14 18 (12.9%) (8.9%) 0 n (%) 114 108
(77.7%) (72.6%) 1 n (%) 18 10 (7.2%) (11.5%) 2 n (%) 8 2 (1.4%)
(5.1%) 3 n (%) 1 0 (0.6%) 4 n (%) 1 0 (0.6%) n 157 139 Mean 0.2 0.0
SD 0.76 0.54 Median 0.0 0.0 Min -2 -2 Max 4 2
TABLE-US-00021 TABLE 16 Mean Change from Baseline for Epworth
Sleepiness Total Score 550 mg Rifaximin Assessment Placebo BID Time
(N = 159) (N = 140) P-value Day 28 N 91 87 Mean 9.1 10.0 SD 4.84
5.51 Median 8.0 9.0 Min 0 0 Max 21 23 Change from Baseline to Day
28 N 90 86 0.0593 Mean -1.1 -0.2 SD 4.79 3.53 Median -1.0 0.0 Min
-17 -14 Max 14 7 5
TABLE-US-00022 TABLE 17 Time to Onset of First HE-Related
Hospitalization Placebo 550 mg Rifaximin BID (N = 159) (N = 140) --
-- Cumulative Conditional Cumulative Conditional At Occurrences
Occurrences Probability of At Occurrences Occurrences of
Probability of Days Risk of Events of Events Events (SE) Survival
Risk of Events Events Events (SE) Survival [0-28) 155 11 11 0.07
(0.02) 1.0000 139 4 4 0.03 (0.01) 1.0000 [28-56) 132 12 23 0.09
(0.03) 0.9288 130 4 8 0.03 (0.02) 0.9711 [56-84) 108 7 30 0.06
(0.02) 0.8440 119 4 12 0.03 (0.02) 0.9411 [84-140) 88 4 34 0.05
(0.02) 0.7893 106 5 17 0.05 (0.02) 0.9094 [140-168) 72 2 36 0.03
(0.02) 0.7535 92 2 19 0.02 (0.02) 0.8665 >=168 34 0 36 0.00
(0.00) 0.7325 43 0 19 0.00 (0.00) 0.8475 Harzard Ratio: 0.500 95%
CI: (0.287, 0.873) p-value: 0.0129
Example 3: CYP3A4 is not Induced by Rifaximin
[0483] Induction of CYP3A4 by rifaximin was observed based on
decreased midazolam AUC by .about.25%. A higher systemic exposure
is expected in a majority of the target patient population.
[0484] When rifaximin was orally administered at high doses (1650
mg/day) for at least 7 days, the mean C.sub.max, AUC.sub.0-t, and
AUC.sub.0-.infin. of midazolam were reduced by <25%. Rifaximin
is a potential CYP3A4 inducer, in vitro studies have shown it to
have a lower induction potency than rifampin. (The estimated
intestinal lumen concentration of rifaximin is approximately 5
.mu.M. In the in vitro study, CYP3A4 activity was induced 1.7-fold
and 1.8-fold at rifaximin 1 .mu.M and 10 .mu.M; at the same
concentrations, rifampin induced CYP3A4 3.7-fold and 4-fold,
respectively. Furthermore, rifaximin's gut-targeted distribution is
believed to limit its CYP3A4 induction mechanism to the intestine,
sparing hepatic induction as a result of low systemic exposure.
That is, there is a separation of intestinal and hepatic induction
for rifaximin This is shown in studies disclosed herein in humans
receiving rifaximin, as supported by the absence of induction when
either intravenous or oral midazolam was administered following
rifaximin 200 mg TID for up to 7.
[0485] Without wishing to be bound by any particular scientific
theory, it is thought that any risk of hepatic CYP3A4 induction
likely is further mitigated in hepatically impaired patients, for
whom significant fractions of portal blood flow are shunted around
the liver;.sup.3 therefore, their increased systemic exposure
should be accompanied by a proportional decrease in exposure to
hepatocytes and the patients should incur no net increase in risk
of hepatic CYP3A4 induction.
Example 4: Drug Interaction Studies
[0486] Two clinical drug-drug interaction studies were conducted
with the rifaximin 200 mg tablet and one drug-drug interaction
study with the 550 mg tablet. Two studies using midazolam, a known
substrate for CYP3A4, and 1 study using an oral contraceptive
containing ethinyl estradiol and norgestimate were conducted to
assess the effect of rifaximin on the pharmacokinetics of these
drugs. Based on the results of these studies and in vitro induction
and inhibition studies using human liver fractions, no clinically
relevant drug interactions are anticipated with rifaximin.
[0487] Although in vitro studies demonstrated the potential of
rifaximin to interact with cytochrome P450 3A4 (CYP3A4), a clinical
drug-drug interaction study demonstrated that rifaximin did not
significantly affect the pharmacokinetics of midazolam either
presystemically or systemically. An additional clinical drug-drug
interaction study showed no effect of rifaximin on the presystemic
metabolism of an oral contraceptive containing ethinyl estradiol
and norgestimate. Therefore, clinical interactions with drugs
metabolized by human cytochrome P450 isoenzymes are not
expected.
[0488] Two studies have been performed to evaluate the potential
for drug interactions with midazolam. The first was an open-label,
randomized, crossover, drug-interaction trial designed to assess
the effect of rifaximin 200 mg administered orally (PO) every 8
hours (Q8H) for 3 days and every 8 hours for 7 days, on the
pharmacokinetics of a single dose of either midazolam 2 mg
intravenous (IV) or midazolam 6 mg PO. No significant difference
was observed in the metrics of systemic exposure or elimination of
IV or PO midazolam or its major metabolite, 1'-hydroxymidazolam,
between midazolam alone or together with rifaximin. Therefore,
rifaximin was not shown to significantly affect intestinal or
hepatic CYP3A4 activity.
[0489] The second study, an open-label, drug-interaction study
examined the effect of rifaximin, 550 mg three times daily, on
orally administered (PO) midazolam 2 mg when dosed for 7 and 14
consecutive days. In this study rifaximin was shown to be a weak
inducer of CYP3A4; given the low systemic exposure of rifaximin,
this interaction is believed to be limited to the gastrointestinal
tract. This induction is both dose- and dosing-duration dependent.
When rifaximin was orally administered at high doses (1650 mg/day)
for at least 7 days, the mean C.sub.max, AUC.sub.0-t, and
AUC.sub.0-.infin. of midazolam were reduced by <25%.
[0490] In vitro hERG potency and in vitro protein binding of
rifaximin. In the in vitro hERG studies, rifaximin concentrations
up to 300 .mu.M failed to achieve 50% inhibition of the hERG
potassium current. Due to rifaximin precipitation at 300 .mu.M, the
IC.sub.50 was estimated to be greater than 100 .mu.M. In fact, 50%
inhibition could not be achieved; at 100 .mu.M, mean inhibition was
34.5%. The highest C.sub.max observed in a hepatically impaired
patient in a study was 52.2 ng/mL (0.0664 .mu.M); the highest free
fraction observed in a subset of plasma samples from patients
enrolled in this study was 44.7%. Using these numbers, the highest
anticipated free plasma exposure would be 0.03 .mu.M, which
represents a reduction of .gtoreq.3000-fold in comparison with the
highest concentration at which rifaximin could be tested in the
hERG experiments. This safety margin greatly exceeds the 30-fold
separation between hERG IC.sub.50 and unbound C.sub.max that is
commonly associated with minimization of risk of clinical QT
prolongation.
Example 5: Time to First Breakthrough Event
[0491] An efficacy parameter for a first study was the occurrence
of an episode of breakthrough overt HE during treatment.
Breakthrough overt HE episodes were measured by using the Conn
score (or West Haven grade), and the asterixis grade. A
breakthrough overt HE episode, as defined for the first study, was
a marked, clinically significant deterioration in neurological
function that can result in a deleterious effect on self care, and
lead to hospitalization. The efficacy endpoint, time to first
breakthrough overt HE episode, showed a highly significant
protective effect of rifaximin (p<0.0001 for between-group
difference in relative risk). Rifaximin treatment resulted in a
57.9% reduction, when compared with placebo, in the risk of
experiencing breakthrough overt HE during the 6-month treatment
period.
[0492] In addition, this study also showed that the time to first
breakthrough overt HE also showed a highly significant protective
effect of rifaximin when analyzed in separate geographic regions,
North America versus Russia.
[0493] Rifaximin treatment results in fewer overt HE episodes that
may otherwise incapacitate the patient, may alleviate the burden on
family members who are required to care for the patient, and
reduces the burden of hospitalization in this patient population
and the healthcare system.
[0494] In a second study, similar results were shown, for example,
the second study with respect to time to first breakthrough overt
HE episode: the Kaplan-Meier estimates of time to first
breakthrough overt HE episode were similar between the rifaximin
group in the first study and new rifaximin subjects in this second
study.
[0495] Also, similar proportions of subjects had breakthrough overt
HE in the rifaximin group of the first study (22%, 31 of 140
[rifaximin group]) and in the new rifaximin group of the second
study (27.6%, 54 of 196).
[0496] Additionally, when the first study placebo subjects crossed
over to rifaximin therapy by entering the second study, a
protective effect of rifaximin was observed: the first study a 70%
reduction in risk of experiencing breakthrough overt HE during
rifaximin treatment in the second study when compared with their
prior placebo experience in the first study. This reduction took
place in spite of the aging and presumably progressing nature of
the population with chronic liver disease.
[0497] The second study also showed that the protective effect of
rifaximin was durable: the estimate of time-to-first breakthrough
HE demonstrated long-term maintenance of remission from
breakthrough HE when rifaximin subjects in remission after
participation in the first study were followed in the second study
(up to 680 days of rifaximin therapy; median exposure durations
were 168 days in the first study and 253 days in the second study).
The incidence of breakthrough HE episode for these rifaximin
subjects relative to the first study placebo was lower, an
indication of fewer breakthrough HE episodes with rifaximin
treatment.
[0498] A critical flicker frequency (CFF) assessment, a recognized
quantitative measure of CNS dysfunction, was an efficacy endpoint
in the first study. CFF tests utilize the correlation between
cerebral processing of oscillatory visual stimuli and CNS
impairment due to increased HE severity. This test identifies a
frequency at which a flickering light is perceived as steady. A
decline in this frequency has been associated with increasing
severity of HE. Likewise, elevation in blood ammonia, another
endpoint in the first study, is a quantitative assessment
associated with the CNS effects underlying overt HE.
[0499] Comparisons of changes from baseline to end of study in CFF
results and in venous ammonia levels showed statistically
significant, greater improvement over the course of the study in
the rifaximin group when compared to placebo (p=0.0320 for CFF
changes and p=0.0391 for venous ammonia changes). In the first
study, a correlation between CFF results and breakthrough overt HE
(primary efficacy measure) was noted. Venous ammonia levels were
found to be correlated to the occurrence of breakthrough overt HE
in the first study.
[0500] Results for other efficacy endpoints also demonstrated
protective effects of rifaximin. In particular, the other efficacy
endpoint of time to first HE-related hospitalization showed a
reduction in risk for rifaximin subjects.
[0501] In the first study, the analysis of time to first HE-related
hospitalization (e.g., hospitalization directly resulting from HE
or hospitalization complicated by HE) demonstrated that the
reduction in risk of hospitalization due to HE was 50% in the
rifaximin group, when compared with placebo, during the 6-month
treatment period. The HE-related hospitalization rate was 0.38
event/person exposure years (PEY), rifaximin versus 0.78 event/PEY,
placebo after normalization to exposure.
[0502] In the first study, the risk of HE-caused hospitalization
(e.g., hospitalization directly resulting from HE only) was reduced
by 56% in the rifaximin group when compared with placebo. The
HE-caused hospitalization rate was 0.30 events/PEY in the rifaximin
group versus 0.72 event/PEY in the placebo group.
[0503] In the first study, the risk of all-cause hospitalization
rate was reduced by 30% in the rifaximin group when compared to
placebo. The all-cause hospitalization rate was 0.92 events/PEY in
the rifaximin group versus 1.31 event/PEY in the placebo group.
[0504] In the second study, the low HE-caused hospitalization rate
was maintained at rates consistent with those in the first study:
HE-caused hospitalization rate was 0.29 event/PEY and all cause
hospitalization in the second study was 0.66 event/PEY. The
consistently low HE-related/HE-caused hospitalization rate in
rifaximin-treated subjects in the first study and in the second
study was at least partly a result of maintaining remission from
demonstrated HE in subjects with end-stage liver disease.
[0505] Hepatic encephalopathy is associated with a low quality of
life compared to age-matched patients without HE. Patients with HE
experience symptoms including fatigue, daytime sleepiness, and lack
of awareness (Conn score 1); and confusion and disorientation (Conn
score 2) that significantly interfere with day-to-day function and
decreased ability for self care. Often, this lack of self care can
lead to improper nutrition and non-adherence to therapy and can
further escalate into more severe symptoms such as increased
somnolence, gross disorientation and stupor, which require
hospitalization. Rifaximin treatment protects against HE
related/caused hospitalization, thereby improving the functional
status for the patient and benefitting his/her caregiver; and
reducing the economic cost related to liver cirrhosis and
associated HE.
[0506] There are limited treatment options in the United States for
patients with recurrent HE. Neomycin sulfate is only approved for
the adjunctive therapy in hepatic coma. Conventional therapy aims
to lower the production and absorption of ammonia. Nonabsorbable
disaccharides, eg, lactulose or lactitol, are typically used as
first-line therapy for HE. There is evidence that nonabsorbable
disaccharides lower plasma levels of ammonia by changing nitrogen
metabolism in colonic flora and increasing fecal excretion of
nitrogen. Broadspectrum, GI-active antibiotics including neomycin,
metronidazole, vancomycin, and paromomycin have been used with or
without lactulose. These antibiotics appear to act indirectly by
inhibiting the splitting of urea by deaminating bacteria, thus
reducing the production of ammonia and other potential toxins.
Current guidelines recommend (not FDA approved) antibiotic therapy
with neomycin or metronidazole as an alternative to treatment with
nonabsorbable disaccharides.
[0507] Common side effects of nonabsorbable disaccharide (e.g.,
lactulose) therapy include an unpleasant taste that can hinder
treatment compliance, a dosing schedule that is linked to bowel
habits, and GI side effects such as bloating, abdominal cramps, and
diarrhea. Diarrhea resulting in dehydration has been reported with
the use of lactulose, a significant consequence for patients with
HE as electrolyte abnormalities can worsen HE and lead to renal
dysfunction.
[0508] The use of systemically absorbed antibiotics such as
neomycin in the treatment of HE is hampered by ototoxicity and
nephrotoxicity associated with long-term use. The incidence of
aminoglycoside-induced nephrotoxicity is substantially greater in
patients with advanced liver disease than in patients without liver
disease. The frequency of aminoglycoside-induced nephrotoxicity in
the general population is 3% to 11%. Leitman reported that
nephrotoxicity occurred in 73% of patients with liver disease
versus 34% of patients without liver disease who received
aminoglycosides by intravenous administration during
hospitalization; and Cabrera reported that renal tubular damage or
functional renal impairment was observed in 60% of
aminoglycoside-treated cirrhotic patients (intravenous
administration during hospitalization). Additionally, a high
mortality rate and sustained renal damage were noted in cirrhotic
patients who developed aminoglycoside-induced renal tubular damage.
Therefore, aminoglycosides are now widely considered as
contraindicated in patients with advanced liver disease.
[0509] Rifaximin is an attractive therapy for the treatment of
patients with HE because of its demonstrated effectiveness,
favorable safety profile, and because of disadvantages of systemic
aminoglycosides and nonabsorbable disaccharides.
[0510] Rifaximin has a broad spectrum of in vitro antibacterial
activity against both Gram-positive and Gram-negative bacteria and
against aerobic and anaerobic isolates.
[0511] Since rifaximin is poorly absorbed after oral
administration, the drug is selectively active in the
gastrointestinal tract. Additionally, there is a low risk of
drug-drug interactions with the use of rifaximin. Rifaximin has a
lower rate of fecal eradication of pathogens compared with other
commonly used antibacterial drugs and causes minimal alterations in
gut flora suggesting that rifaximin has a different mechanism of
action than other commonly used drugs in enteric bacterial
infection, such as the fluoroquinolones. The risk of the
development of antibiotic resistance is low during chronic
treatment with rifaximin when compared to other systemic
antibiotics such as neomycin, possibly because resistance is
mediated by a mutation in host cell DNA and is not plasmid
based.
[0512] In a retrospective chart review, the numbers and durations
of hospitalizations due to HE, the total cost of therapy, and HE
endpoints (asterixis grade, Conn score) were found to be
dramatically reduced when compared to lactulose treatment in
patients with HE who received lactulose daily for 6 months and then
received rifaximin daily for 6 months.
[0513] The first study was designed to overcome the limitations of
previous studies reported in the literature (e.g., heterogeneous
subject populations, small population size, short durations, and
insufficient endpoints for mental status).
[0514] First, treatment duration was increased to 6 months. This
longer duration was planned to allow for a greater number of
subjects to experience an HE episode than if the study was limited
to <6 weeks. Also, the longer treatment duration provided an
opportunity to evaluate the long-term safety of rifaximin in
subjects with chronic hepatic cirrhosis and associated recurrent,
overt, episodic HE. The study investigated consequences of HE with
respect to patient care and economic cost by measuring
hospitalizations due to HE episodes as a key secondary efficacy
endpoint.
[0515] To evaluate overt HE episodes by using clinically relevant
criteria in the first study and study the second study, mental
status impairment was measured by using Conn score (West Haven
criteria) and the severity of neuromotor abnormalities was measured
by asterixis grade. The Conn score ranges from Stage 0 (lack of
detectable changes in personality) to Stage 4 (coma, decerebrate
posturing, dilated pupils). The Conn score is the recommended and
widely used gold standard for grading the severity of impaired
mental status in overt HE. Asterixis (flapping tremor) is a
neuromotor symptom of overt HE that increases in severity with
worsening neurological impairment.
[0516] The control group for the first study received matched
placebo tablets in parallel with rifaximin treatments in the active
group. The second study was an ongoing open-label,
treatment-extension study to evaluate the long-term safety of
rifaximin 550 mg BID in subjects with a history of recurrent,
episodic, overt HE. In addition to safety measurements, Conn scores
and asterixis grades were assessed during the course of the study
to measure the protective effect of rifaximin against breakthrough
overt HE during treatment for up to approximately 1 year in
subjects who completed up to 6 months of rifaximin treatment in the
first study and then entered the second study; in subjects who
received placebo in the first study and crossed over to rifaximin
treatment in the second study; and in patients with a history of HE
who entered the second study as new subjects.
[0517] The dosage regimen used (550 mg BID) was based on past
clinical experience with rifaximin in patients with HE and other
subject populations. In several previous studies, rifaximin was
safe and effective in subjects with HE at a dose of 1200 mg per day
with or without concomitant lactulose. In a 6-month study of
rifaximin versus neomycin (14 days on-treatment and 14 days
off-treatment per month),.sup.8 rifaximin 1200 mg/day and neomycin
(3 g/day) had comparable efficacy in patients with HE.
Aminoglycoside antibiotics are contraindicated in patients with
advanced liver disease because of the risk of nephrotoxicity.
[0518] An efficacy endpoint was the time to first breakthrough
overt HE episode. A breakthrough overt HE episode was defined as an
increase of Conn score to Grade .gtoreq.2 (e.g., 0 or 1 to
.gtoreq.2) or an increase in Conn and asterixis score of 1 grade
each for those subjects who entered the study with a Conn score of
0. Time to breakthrough overt HE episode was the duration from time
of first dose of study drug to the first breakthrough overt HE
episode. Subjects who completed the study and did not experience a
breakthrough overt HE episode were censored at the time of their
6-month visit. Subjects who terminated early for reasons other than
breakthrough overt HE were contacted at 6 months from randomization
to determine if subjects had experienced a breakthrough overt HE
episode or other outcome (e.g., mortality status); and, if the
subject had no breakthrough overt HE event prior to contact, he/she
was censored at the time of contact. Therefore, complete capture
was achieved for breakthrough overt HE episodes up to 6 months
postrandomization. Subjects in the study had .gtoreq.2 episodes of
overt HE equivalent to Conn score .gtoreq.2 within 6 months prior
to screening (i.e., subjects had documented recurrent, overt HE).
At the baseline assessment, subjects were in remission with a Conn
score of 0 or 1. A breakthrough overt HE episode, as defined above,
was a marked deterioration in neurological function.
[0519] Other efficacy endpoints in the first study included, for
example:
1. Time to first HE-related hospitalization; 2. Time to any
increase from baseline in Conn score (mental state grade); 3. Time
to any increase from baseline in asterixis grade; 4. Mean change
from baseline in fatigue domain scores on the CLDQ at end of
treatment; and 5. Mean change from baseline in venous ammonia
concentration at end of treatment.
[0520] Presented herein are the results of the first study and
second study. The first study was a double-blind, randomized,
placebo-controlled study evaluating the efficacy and safety of
rifaximin 550 mg BID as compared to placebo. Subjects in remission
from demonstrated recurrent, overt, episodic HE associated with
chronic, hepatic cirrhosis were randomized on Day 0 (Visit 2)
according to a 1:1 ratio to receive rifaximin 550 mg BID or placebo
for 6 months. The primary efficacy endpoint was the time to
breakthrough overt HE. Breakthrough overt HE was defined as an
increase of Conn score to Grade .gtoreq.2 (e.g., 0 or 1 to
.gtoreq.2) or an increase in Conn and asterixis score of 1 grade
each for those subjects who entered the study with a Conn score of
0. Subjects discontinued from the study at the time of breakthrough
overt HE episode. After participation in the first study, subjects
had the option to enroll in the open-label, treatment-extension
study (the second study).
[0521] A total of 299 subjects were randomized to receive rifaximin
(140 subjects) or placebo (159 subjects). All randomized subjects
received at least 1 dose of study drug. A total of 251 (84%) (116
[rifaximin], 135 [placebo]) subjects completed the study as
specified in the protocol (e.g., completed 6 months of treatment or
withdrew from the study at the time of breakthrough overt HE).
[0522] Subjects in the study had .gtoreq.2 episodes of overt HE
equivalent to Conn score .gtoreq.2 within 6 months prior to
screening (e.g., subjects had recurrent, overt HE). At the baseline
assessment, subjects were in remission with a Conn score of 0 or 1.
A breakthrough overt HE episode was a marked deterioration in
neurological function. Breakthrough overt HE episodes were
experienced by 31 of 140 subjects in the rifaximin group and by 73
of 159 subjects in the placebo group during the 6-month treatment
period (up to Day 170). Comparison of Kaplan-Meier estimates of
time to breakthrough overt HE between groups showed a protective
effect of rifaximin (p<0.0001). These data show that rifaximin
treatment resulted in a 57.9% reduction, when compared with
placebo, in the risk of experiencing breakthrough overt HE.
[0523] Rifaximin treatment results in fewer overt HE episodes that
may otherwise incapacitate the patient, may alleviate the burden on
family members who are required to care for the patient, and
reduces the burden of hospitalization in this patient population
and the healthcare system.
[0524] The following prognostic factors were found to be predictors
of breakthrough overt HE episodes: baseline age (p=0.0160), MELD
score (p=0.0003), duration of current verified remission
(p=0.1089), and number of prior HE episodes (p=0.0022). These data
show that rifaximin treatment, resulted in a 60% reduction, when
compared with placebo, in the risk of experiencing a breakthrough
overt HE episode during the course of this study (p<0.0001).
[0525] Time to first HE-related hospitalization; and the
frequencies of HE-related and all-cause hospitalizations Hepatic
encephalopathy-related hospitalizations (hospitalization directly
resulting from HE or hospitalization complicated by HE) were
reported for 19 of 140 subjects and 36 of 159 subjects in the
rifaximin and placebo groups, respectively. Rifaximin had a
protective effect against HE-related hospitalization during the
6-month treatment period. Subjects in the rifaximin group had a 50%
reduction in the risk of hospitalization due to HE during the
6-month treatment period when compared with placebo. The HE-related
hospitalization rate was 0.38 events/PEY in the rifaximin group
versus 0.78 event/PEY in the placebo group.
[0526] Hepatic encephalopathy-caused hospitalizations
(hospitalization directly resulting from HE only) were reported for
15 of 140 subjects and 33 of 159 subjects in the rifaximin and
placebo groups, respectively. Rifaximin had a significant
protective effect against HE-caused hospitalization during the
6-month treatment period; hazard ratio in the rifaximin group
relative to placebo was 0.438 (95% CI: 0.238 to 0.807) (p=0.0064)
for the risk of HE-caused hospitalization. Subjects in the
rifaximin group had a 56% reduction in the risk of hospitalization
due to HE during the 6-month treatment period when compared with
placebo. The HE-caused hospitalization rate was 0.30 events/PEY in
the rifaximin group versus 0.72 event/PEY in the placebo group.
[0527] All-cause hospitalization was also lower in the rifaximin
group (46 of 140) than in the placebo group (60 of 159) (30%
reduction in the rifaximin group compared with placebo). The all
cause hospitalization rate, after normalizing for subject exposure,
was 0.90 events/PEY in the rifaximin group and 1.26 event/PEY in
the placebo group. The HE-related hospitalization rate was 0.38
event/PEY in the rifaximin group and 0.78 event/PEY in the placebo
group. Rifaximin treatment protects against HE-related
hospitalization, thereby improving the quality of life for the
patient and for his/her caregiver, and reducing the economic cost
related to liver cirrhosis and associated HE.
[0528] Time to any increase from baseline in Conn score and time to
any increase from baseline in asterixis grade Protective effects of
rifaximin were observed with respect to both of these endpoints
when analyzed independently; hazard ratio in the rifaximin group
relative to placebo was 0.463 (95% CI: 0.312 to 0.685)
(p<0.0001) for the risk of experiencing an increase in Conn
score and 0.646 (95% CI: 0.414 to 1.008) (p=0.0523) for the risk of
experiencing an increase in asterixis grade during the 6-month
treatment period.
[0529] Changes from baseline in venous ammonia levels at end of
treatment Subjects in the rifaximin group had greater reductions in
venous ammonia levels when compared to placebo-treated subjects
(p=0.0391).
[0530] Venous ammonia levels, a quantitative assessment that is
associated with the CNS effects underlying overt HE, was found to
be highly correlated to the occurrence of breakthrough overt HE as
determined by the clinical evaluation of Conn score (or a
combination of Conn score and asterixis grade).
[0531] Tracking of Conn scores and asterixis grades: changes from
baseline in Conn scores and asterixis grades A favorable treatment
effect of rifaximin was observed, when compared with placebo, with
respect to the proportions of subjects who had changes of -1
(improvement) or 0 (no change); or 1, 2, or 3 (worsening) in Conn
score from baseline to end of treatment (last postbaseline
assessment or assessment at time of breakthrough HE). In the
rifaximin group compared to placebo, higher proportions of subjects
experienced Conn score changes of -1 or no change (77.1% versus
53.9%) and lower proportions of subjects had Conn score changes of
1, 2, 3, or 4. Thus, treatment with rifaximin was more effective
than placebo in the prevention of worsening of Conn score (2.46
times versus placebo, p=<0.0001).
[0532] For changes from baseline to end of treatment in asterixis
grade, significantly higher proportions of subjects in the
rifaximin group versus the placebo group had changes from baseline
in asterixis grades of -2, -1, and 0 (88.5% versus 77.0%), and
significantly lower proportions of subjects had changes of 1, 2, 3,
or 4 (11.6% versus 23.2%). Thus, treatment with rifaximin was more
effective than placebo in the prevention of worsening of asterixis
grade (1.92 times versus placebo, p=0.0262).
[0533] Changes from baseline in CFF results Increases in CFF
results represent improvement in neurological function in patients
with HE..sup.10,11 Subjects in the rifaximin group had
significantly greater increases in CFF results from baseline to end
of treatment when compared with placebo. Mean changes (.+-.standard
deviation [SD]) in CFF results were 0.945 (.+-.4.75) in the
rifaximin group versus 0.355 (.+-.4.70) in the placebo group
(p=0.0320 for between-group difference). Similar to venous ammonia
levels, CFF was shown to be highly predictive of breakthrough
HE.
[0534] Median exposure to study drug was 168 days (range: 10 to
178) in the rifaximin group and 110 days (range: 6 to 176) in the
placebo group. A total of 64 subjects (33 [rifaximin] and 31
[placebo]) received treatment for 141 to 168 days and 98 subjects
(57 [rifaximin] and 41 [placebo]) received treatment for >168
days. Duration of exposure results are consistent with the finding
that lower proportions of subjects in the rifaximin group than in
the placebo group experienced breakthrough overt HE resulting in
study discontinuation (per protocol, subjects discontinued from the
study after breakthrough overt HE).
[0535] The percentages of subjects who had treatment-emergent AEs,
severe TEAEs, drug-related TEAEs, treatment-emergent SAEs, TEAEs
resulting discontinuation, and who died were similar between
placebo and rifaximin groups. A total of 79.9% of subjects (239 of
299) experienced TEAEs during the course of the study. The most
common TEAEs (e.g., in .gtoreq.10% of total subjects [combined
placebo plus rifaximin]) experienced by subjects were the
following: diarrhea (10.7% [rifaximin] versus 13.2% [placebo]),
nausea (14.3% versus 13.2%), peripheral edema (15% versus 8.2%),
fatigue (12.1% versus 11.3%), dizziness (12.9% versus 8.2%),
ascites (11.4% versus 9.4%), and headache (10% versus 10.7%).
[0536] The second study is an ongoing open-label,
treatment-extension study evaluating the long-term safety of
rifaximin 550 mg BID in subjects with a history of recurrent,
overt, episodic HE. All eligible subjects had a history of overt HE
episodes with a documented severity equivalent to Conn score
.gtoreq.2 within 12 months prior to screening (.gtoreq.1 qualifying
episode was required), a Conn score of .ltoreq.2 at the baseline
assessment, and either participated in the first study or were new
subjects. Unlike the first study, subjects were not required to
withdraw from the study after experiencing a breakthrough overt HE
episode.
[0537] A total of 267 subjects were enrolled and 208 were active at
the time of the interim clinical cutoff. Additional data were
collected for the interim report up to the time of database
freeze.
[0538] Conn scores and asterixis grades were assessed during the
course of the study. Therefore, it was possible to determine time
to breakthrough overt HE episode for subjects who completed 6
months of rifaximin treatment in the first study and then entered
the second study, subjects who received placebo in the first study
and then started rifaximin in the second study, and in new subjects
who started rifaximin therapy in the second study. In subjects who
took rifaximin for up to 680 days (1.9 years), breakthrough overt
HE episodes during the treatment period were experienced by 72 of
266 subjects (27.1%) overall: 54 of 196 subjects (27.6%) in the new
rifaximin group and 18 of 70 subjects (25.7%) in the continuing
rifaximin group.
[0539] Time-to-first-breakthrough HE profiles were similar between
the rifaximin group in the first study and the new rifaximin group
in the second study. A durable protective effect of rifaximin was
observed in subjects who received rifaximin starting in the first
study and continuing in the second study (median exposures to
rifaximin were 168 days in the first study and 253 days in the
second study) A total of 133 of 266 subjects were hospitalized for
any cause: 98 in the new rifaximin group, and 35 in the continuing
rifaximin group. Normalizing for subject exposure, this represents
a hospitalization rate of 0.60 event/PEY. A total of 59 were
hospitalized due HE episodes (e.g., HE-caused). Normalizing for
subject exposure, this represents an HE-caused hospitalization rate
of 0.29 event/PEY. The low HE-caused hospitalization rate was
consistent between rifaximin therapy in the second study (0.29
event/PEY) and in the first study rifaximin (0.30 event/PEY) at
least partly as a result of maintaining remission from demonstrated
HE in subjects with end-stage liver disease. Tracking of Conn
scores and asterixis grades: changes from baseline in Conn scores
and asterixis grades Conn scores were generally maintained or
improved with rifaximin use up to 18 months. At the last visit,
70.7% of subjects (188 of 266 subjects) had no change and 20.3% (54
of 266) had improvements in Conn scores compared with baseline,
indicating that mental status was maintained or improved in the
majority of subjects (91%) over the treatment period. Of the 84
subjects (70 new rifaximin and 14 continuing rifaximin) who entered
the study with Conn scores of 1, 2, or 3 (e.g., those subjects for
whom measurable improvement was possible), 54 subjects
(54/84=64.3%) showed a 1-grade (47 subjects; 56.0%) or 2-grade (7
subjects; 8.3%) improvement from baseline at the last visit
recorded for the interim analysis. All subjects were capable of
worsening over time, and 24/266 subjects (9.0%) did so by 1 or 2
grades.
[0540] Like Conn scores, asterixis grades were generally maintained
or improved with rifaximin use up to 18 months. At the last visit,
77.1% of subjects (205 of 266 subjects) had no change and 16.2% (43
of 266) had improvements in asterixis scores compared with
baseline, indicating that neuromotor symptoms associated with
increasing neurological impairment were maintained in 83.3% of
subjects over the treatment period. Of the 67 subjects (55 new
rifaximin and 12 continuing rifaximin) who entered the study with
asterixis scores of 1, 2, or 3 (e.g., those subjects for whom
improvement was possible), 43 subjects (43/67=64.2%) showed a 1-
(34 subjects; 50.7%), 2- (4 subjects; 6.0%), or 3-grade (5
subjects; 7.5%) improvement from baseline at the last visit
recorded for this interim analysis. All subjects were capable of
worsening over time, and 18/266 subjects (6.8%) did so by 1, 2, or
4 grades; the incidence of worsening asterixis grades were similar
between the new (12/196 subjects; 6.1%) and continuing (6/70
subjects; 8.6%) rifaximin groups.
[0541] Median exposures in study the second study were 253 days
(range: 7 to 680) in the new rifaximin group (subjects who received
placebo in the first study or subjects who did not participate in
the first study), 265.5 days (range: 10 to 673) in the continuing
rifaximin group (subjects who received rifaximin in the first study
and the second study), and 255 days (range: 7 to 680) in the all
rifaximin group (all subjects who received rifaximin in the second
study). At the time of this interim analysis, most subjects had
received rifaximin for 6 to <9 months (21.4%) or 9 to <12
months (32.3%).
[0542] At the time of this interim analysis, TEAEs were reported in
230 subjects (86.5%). The most common TEAEs (e.g., in .gtoreq.10%
of total subjects) experienced by subjects were the following:
peripheral edema (15.8%); urinary tract infection and nausea (12.8%
each); and abdominal pain and ascites (10.5% each). Note that signs
and symptoms associated with HE were not considered AEs unless they
met the definition of an SAE, so the number of subject with HE
counted in efficacy analysis (72 subjects; 27.1%) is higher than
that counted for the safety analyses (57 subjects; 21.4%).
[0543] Most TEAEs were mild or moderate in intensity, with 40.2% of
subjects experiencing at least 1 TEAE that was judged by the
investigator to be severe. The incidence of TEAEs considered
related to study drug was comparable between the new rifaximin
group (7.7%) and the continuing rifaximin group (7.1%).
Treatment-emergent SAEs were experienced by 47.4% of subjects.
[0544] FIG. 1 illustrates Kaplan-Meier estimates of time to first
breakthrough overt HE episode by treatment group in the ITT
population. Table 18 presents Kaplan-Meier estimates of the
proportions of subjects who experienced breakthrough overt HE over
the course of the Treatment Period and results of statistical
analyses. Subjects who completed the study and did not experience a
breakthrough overt HE event were censored at the time of their
6-month visit. Subjects who terminated early for reasons other than
breakthrough overt HE (eg, liver transplant, AE, subject request)
were contacted at 6 months from date of randomization to determine
if subjects had experienced a breakthrough overt HE episode or
other outcome (e.g., mortality status). Subjects without
breakthrough overt HE were censored at the time of contact or
death, whichever was earlier. Therefore, complete capture was
achieved for breakthrough overt HE episodes up to 6 months.
TABLE-US-00023 TABLE 18 The First Study: Kaplan-Meier Estimates and
Statistical Analyses of Time to First Breakthrough Overt HE (up to
6 Months of Treatment, Day 170) (ITT Population) Placebo (N = 159)
Rifaximin (N = 140) Probability Probability Cumulative of no
Cumulative of no Treatment Number number Event breakthrough Number
number Event breakthrough interval At of of probability overt At of
of probability overt (days) Risk.sup.a events.sup.b events
(SE).sup.c HE.sup.d Risk.sup.a events.sup.b events (SE).sup.c
HE.sup.d 0 to <28 158 20 20 0.13 1.0000 140 13 13 0.09 1.0000
(0.03) (0.02) 28 to <56 137 23 43 0.17 0.8734 126 4 17 0.03
0.9071 (0.03) (0.02) 56 to <84 113 14 57 0.12 0.7262 120 6 23
0.05 0.8783 (0.03) (0.02) 84 to <140 98 10 67 0.10 0.6363 112 7
30 0.06 0.8344 (0.03) (0.02) 140 to <168 84 6 73 0.07 0.5713 98
1 31 0.01 0.7820 (0.03) (0.01) .gtoreq.168 38 0 73 0 0.5305 46 0 31
0 0.7740 Hazard ratio: 0.421.sup.e 95% CI: (0.276, 0.641) p-value
<0.0001 .sup.aNumber of subjects at risk during the treatment
interval, estimated using the life table method. Assuming that
censored cases were at risk for half of the interval, they only
counted for half in figuring the number at risk. .sup.bNumber of
events occurring during the treatment interval. .sup.cEstimate of
the probability of experiencing breakthrough overt HE during the
treatment interval. Standard error (SE) estimated by using
Greenwood's formula. .sup.dEstimate of the probability of no
breakthrough overt HE until at least the beginning of the next
treatment interval. .sup.eHazard ratio estimate (hazard of
breakthrough overt HE in the rifaximin group compared with the
placebo group) determined from the Cox proportional hazards model.
P-value based on the Score statistic.
[0545] Breakthrough overt HE episodes were experienced by 31 of 140
subjects in the rifaximin group and by 73 of 159 subjects in the
placebo group during the 6-month period since randomization (up to
Day 170). Comparison of Kaplan-Meier estimates of time to
breakthrough overt HE between groups showed a protective effect of
rifaximin (p<0.0001). These data show that rifaximin treatment
resulted in a 57.9% reduction, when compared with placebo, in the
risk of experiencing breakthrough overt HE during the course of
this study. Rifaximin treatment results in fewer overt HE episodes
that may otherwise incapacitate the patient, may alleviate the
burden on family members who are required to care for the patient,
and reduces the burden of hospitalization in this patient
population and the healthcare system.
[0546] To investigate the potential effect of prognostic factors on
breakthrough overt HE episode, the following prognostic factors
were examined:
Sex (male vs. female);
Age;
[0547] Race (white vs. non-white); Analysis Region (North American
vs. Russia);
MELD Level;
Conn Score (0 vs. 1);
[0548] Diabetes at Baseline (Yes vs. No); Duration of current
verified remission; and Number of HE Episodes within the past 6
months prior to randomization.
[0549] Strong independent predictors of breakthrough overt HE
episodes were the baseline age (p=0.0160), MELD score (p=0.0003),
duration of current verified remission (p=0.1089), and number of
prior HE episodes (p=0.0022).
[0550] These data show that rifaximin treatment, after adjusting
for significant prognostic factors, resulted in a 60% reduction,
when compared with placebo, in the risk of experiencing a
breakthrough overt HE episode during the course of this study. The
most influential prognostic factors were age (p=0.0315) and
baseline MELD score (p=0.0003).
[0551] The results indicate that the highly significant protective
effect of rifaximin (p<0.0001) against breakthrough overt HE
episodes was maintained in the presence of statistically
significant competing factors.
[0552] In the second study, median exposures were 253 days (range:
7 to 680) in the new rifaximin group (subjects who received placebo
in the first study or subjects who did not participate in the first
study), 265.5 days (range: 10 to 673) in the continuing rifaximin
group (subjects who received rifaximin in the first study and the
second study), and 255 days (range: 7 to 680) in the all rifaximin
group (all subjects who received rifaximin in the second study
[0553] In subjects who took rifaximin for up to 680 days (1.9
years), breakthrough overt HE episodes during the treatment period
were experienced by 72 of 266 subjects (27.1%) overall: 54 of 196
subjects (27.6%) in the new rifaximin group and 18 of 70 subjects
(25.7%) in the continuing rifaximin group. FIG. 2 compares subjects
who participated in the double-blind, randomized the first study
with new rifaximin subjects in the long-term, open-label study, the
second study.
[0554] The Kaplan-Meier estimates of time to first breakthrough
overt HE episode were similar between the rifaximin group in the
first study and new rifaximin subjects in the second study. Also,
similar proportions of subjects had breakthrough overt HE in the
rifaximin group of the first study (22%, 31 of 140 [rifaximin
group]) and in the new rifaximin group of the second study (27.6%,
54 of 196). Adjusted for exposure, rates of breakthrough HE
episodes were 0.62 events/PEY in the rifaximin group from the first
study compared to 0.38 events/PEY for new rifaximin subjects in the
second study. These data demonstrate that protection against
breakthrough overt HE in subjects who received rifaximin was
consistent between the 2 studies.
[0555] Note for FIG. 7, the survival distribution estimate on
y-axis represents the proportion of subjects without breakthrough
overt HE.
[0556] The first study data on time to first breakthrough overt HE
episode are shown for the rifaximin group (small dashes) and the
placebo group (straight line). The second study data on time to
first breakthrough overt HE episode in the new rifaximin group are
shown in large dashes.
[0557] In FIG. 8, the first study placebo subjects were followed
after they crossed over to rifaximin therapy in the second study.
Breakthrough overt HE was experienced by 15 of 82 during rifaximin
treatment versus 39 of 82 during placebo treatment. A striking
protective effect of rifaximin was observed in the comparison of
Kaplan-Meier estimates of time to first breakthrough overt HE
between placebo experience in the first study and rifaximin
experience in the second study. The hazard ratio of rifaximin to
placebo was 0.302 (95% CI: 0.166 to 0.549, p<0.0001 for between
group difference in relative risk). This result represents 70%
reduction in risk of experiencing breakthrough overt HE during
rifaximin treatment in the second study when compared with their
prior placebo experience in the first study.
[0558] Note for FIG. 8, the survival distribution estimate on
y-axis represents the proportion of subjects without breakthrough
overt HE. the first study data on time to first breakthrough overt
HE episode are shown in the left panel for the placebo group. The
right panel shows time to first breakthrough overt HE in the second
study among the first study placebo subjects (n=82) who crossed
over to rifaximin therapy in the second study. The vertical line
between the left and right panels marks the end of the double-blind
study and start of the open-label study.
[0559] FIG. 9 illustrates time to first HE-related hospitalization
(e.g., hospitalization directly resulting from HE or
hospitalization caused by HE) by treatment group in the ITT
population in the first study. Table 19 presents estimates of the
proportions of subjects who had their first HE-related
hospitalization over the course of the Treatment Period and results
of statistical analyses. Subjects who discontinued prior to
hospitalization due to HE and prior to completion of the 6-month
treatment period were censored at the time of discontinuation.
Hepatic encephalopathy-related hospitalizations were reported for
19 of 140 subjects and 36 of 159 subjects in the rifaximin and
placebo groups, respectively. Rifaximin had a protective effect
against HE-related hospitalization during the 6-month treatment
period; hazard ratio in the rifaximin group relative to placebo was
0.500 (95% CI: 0.287 to 0.873) (p=0.0129) for the risk of
HE-related hospitalization. This hazard ratio represents a 50%
reduction, when compared with placebo, in the risk of
hospitalization due to HE during the 6-month treatment period.
Consistent with these results, the HE-related hospitalization rate
was 51% lower (0.38 event/PEY, rifaximin versus 0.78 event/PEY,
placebo) in the rifaximin group in the first study, after
normalization to exposure.
[0560] Note for FIG. 9, the survival distribution estimate on
y-axis represents the proportion of subjects without HE-related
hospitalization. Dashed line represents rifaximin group and solid
line represents placebo group. Open circles and open triangles
represent censored subjects. Subjects who discontinued prior to
hospitalization due to HE and prior to completion of the 6-month
treatment period were censored at the time of discontinuation.
Hepatic encephalopathy-related hospitalization was recorded on the
HE-related hospitalization CRF.
TABLE-US-00024 TABLE 19 The First Study: Kaplan-Meier Estimates and
Statistical Analyses of Time to First HE-Related Hospitalization
(up to 6 Months of Treatment, Day 170) (ITT Population) Placebo (N
= 159) Rifaximin (N = 140) Probability Probability Cumulative of no
Cumulative of no Treatment Number number Event HE- Number number
Event HE- interval At of of probability related At of of
probability related (days) Risk.sup.a events.sup.b events
(SE).sup.c hospitalization.sup.d Risk.sup.a events.sup.b events
(SE).sup.c hospitalization.sup.d 0 to <28 155 11 11 0.07 1.0000
139 4 4 0.03 1.0000 (0.02) (0.01) 28 to <56 132 12 23 0.09
0.9288 130 4 8 0.03 0.9711 (0.03) (0.02) 56 to <84 108 7 30 0.06
0.8440 119 4 12 0.03 0.9411 (0.02) (0.02) 84 to <140 88 4 34
0.05 0.7893 106 5 17 0.05 0.0904 (0.02) (0.02) 140 to <168 72 2
36 0.03 0.7535 92 2 19 0.02 0.8665 (0.02) (0.02) .gtoreq.168 34 0
36 0 0.7525 43 0 19 0 0.8475 Abbreviations: CI = confidence
interval; SE = standard error. .sup.aNumber of subjects at risk
during the treatment interval, estimated using the life table
method. Assuming that censored cases were at risk for half of the
interval, they only counted for half in figuring the number at
risk. .sup.bNumber of events occurring during the treatment
interval. .sup.cEstimate of the probability of experiencing
HE-related hospitalization during the treatment interval. Standard
error (SE) estimated by using Greenwood's formula. .sup.dEstimate
of the probability of no HE-related hospitalization until at least
the beginning of the next treatment interval. .sup.eHazard ratio
estimate (hazard of HE-related hospitalization in the rifaximin
group compared with the placebo group) determined from the Cox
proportional hazards model. P-value based on the Score
statistic.
[0561] The effect of rifaximin therapy on HE-caused
hospitalizations (e.g., hospitalization directly resulting from HE
only) was also determined. FIG. 5 illustrates time to first
HE-caused hospitalizations by treatment group in the first
study.
[0562] Hepatic encephalopathy-caused hospitalizations were reported
for 15 of 140 subjects and 33 of 159 subjects in the rifaximin and
placebo groups, respectively. Rifaximin had a significant
protective effect against HE-caused hospitalization during the
6-month treatment period; hazard ratio in the rifaximin group
relative to placebo was 0.438 (95% CI: 0.238 to 0.807) (p=0.0064)
for the risk of HE-caused hospitalization. Subjects in the
rifaximin group had a 56% reduction in the risk of hospitalization
due to HE during the 6-month treatment period when compared with
placebo. The HE-caused hospitalization rate was 0.30 events/PEY in
the rifaximin group versus 0.72 event/PEY in the placebo group.
[0563] Note for FIG. 10, the survival distribution estimate on
y-axis represents the proportion of subjects without HE-caused
hospitalizations. Dashed line represents rifaximin group and solid
line represents placebo group. Open circles and open triangles
represent censored subjects. Subjects who discontinued prior to
hospitalization were censored at the time of discontinuation.
[0564] The effect of rifaximin therapy on all-cause
hospitalizations was also determined. In the double-blind the first
study, 46 of 140 rifaximin subjects and 60 of 159 placebo subjects
were hospitalized due to any SAE. The risk of all-cause
hospitalization was reduced by 30% in the rifaximin group when
compared to placebo (p=0.0793 for between-group difference in
relative risk). The all-cause hospitalization rate was 0.92
events/PEY in the rifaximin group versus 1.31 event/PEY in the
placebo group. These data demonstrated that rifaximin treatment
reduced the burden of HE-related/caused hospitalization when
compared to placebo treatment in the first study. Also, a low
HE-related/caused hospitalization rate was consistently observed
during rifaximin therapy in the first study (0.38 event/PEY) and in
the second study (0.29 event/PEY), at least partly as a result of
maintaining remission from demonstrated HE in subjects with
end-stage liver disease.
[0565] FIG. 11 illustrates time to any increase from baseline in
Conn score by treatment group in the ITT population. Table 20
presents estimates of the proportions of subjects who had any
increase in Conn score over the course of the Treatment Period and
results of statistical analyses. Subjects who discontinued prior to
experiencing an increase in Conn score and prior to completion of
the 6-month treatment period were censored at the time of
discontinuation. By evaluating the time to any increase from
baseline in Conn score, it was possible to compare the earliest
worsening in mental status between subjects in the rifaximin and
placebo treatment groups, even if the worsening did not reach the
definition of breakthrough HE (eg, increase inConn score from 0 to
1). Increases in Conn score were reported for 37 of 140 subjects
and 77 of 159 subjects in the rifaximin and placebo groups,
respectively. A highly significant protective effect of rifaximin
was observed; hazard ratio in the rifaximin group relative to
placebo was 0.463 (95% CI: 0.312 to 0.685) (p<0.0001) for the
risk of experiencing an increase in Conn score (e.g., worsening in
mental status) during the 6-month treatment period.
TABLE-US-00025 TABLE 20 The First Study: Kaplan-Meier Estimates and
Statistical Analyses of Time to First Increase in Conn Score (up to
6 Months of Treatment, Day 170) (ITT Population) Placebo (N = 159)
Rifaximin (N = 140) Probability Probability Cumulative of no
Cumulative of no Treatment Number number Event increase Number
number Event increase interval At of of probability in Conn At of
of probability in Conn (days) Risk.sup.a events.sup.b events
(SE).sup.c score.sup.d Risk.sup.a events.sup.b events (SE).sup.c
score.sup.d 0 to <28 156 26 26 0.17 1.0000 139 17 17 0.012
1.0000 (0.03) (0.03) 28 to <56 125 21 47 0.17 0.8333 119 5 22
0.04 0.8777 (0.03) (0.02) 56 to <84 100 15 62 0.15 0.6928 109 9
31 0.08 0.8407 (0.04) (0.03) 84 to <140 80 10 72 0.13 0.5883 94
5 36 0.05 0.7713 (0.04) (0.02) 140 to <168 62 5 77 0.08 0.5143
79 0 36 0 0.7302 (0.03) .gtoreq.168 27 0 77 0 0.4729 37 1 37 0.03
0.7302 (0.03) Abbreviations: CI = confidence interval; SE =
standard error. .sup.aNumber of subjects at risk during the
treatment interval, estimated using the life table method.
.sup.bNumber of events occurring during the treatment interval.
Assuming that censored cases were at risk for half of the interval,
they only counted for half in figuring the number at risk.
.sup.cKaplan-Meier estimate of the probability of experiencing an
increase in Conn score during the treatment interval. Standard
error (SE) estimated by using Greenwood's formula. .sup.dEstimate
of the probability of no increase in Conn score until at least the
beginning of the next treatment interval. .sup.eHazard ratio
estimate (hazard of experiencing an increase in Conn score in the
rifaximin group compared with the placebo group) determined from
the Cox proportional hazards model. P-value based on the Score
statistic.
[0566] FIG. 12 illustrates time to any increase from baseline in
asterixis grade by treatment group in the ITT population in the
first study. Table 21 presents estimates of the proportions of
subjects who had any increase in asterixis grade over the course of
the Treatment Period and results of statistical analyses. Subjects
who discontinued prior to experiencing an increase in asterixis
grade and prior to completion of the 6-month treatment period were
censored at the time of discontinuation.
[0567] By evaluating the time to any increase from baseline in
asterixis grade, it was possible to compare the earliest worsening
in neuromotor functioning between subjects in the rifaximin and
placebo treatment groups. Increases in asterixis grade were
reported for 32 of 140 subjects and 50 of 159 subjects in the
rifaximin and placebo groups, respectively. A protective effect of
rifaximin against an increase in asterixis grade (e.g., worsening
in neuromotor functioning) was observed that showed a trend toward
statistical significance; hazard ratio in the rifaximin group
relative to placebo was 0.646 (95% CI: 0.414 to 1.008) (p=0.0523)
for the risk of experiencing an increase in asterixis grade during
the 6-month treatment period.
TABLE-US-00026 TABLE 21 The First Study: Kaplan-Meier Estimates and
Statistical Analyses of Time to First Increase in Asterixis Grade
(up to 6 Months of Treatment, Day 170) (ITT Population) Placebo (N
= 159) Rifaximin (N = 140) Probability Probability of no of no
Cumulative increase Cumulative increase Treatment Number number
Event in Number number Event in interval At of of probability
asterixis At of of probability asterixis (days) Risk.sup.a
events.sup.b events (SE).sup.c grade.sup.d Risk.sup.a events.sup.b
events (SE).sup.c grade.sup.d 0 to <28 154 20 20 0.13 1.0000 137
13 13 0.10 1.0000 (0.03) (0.03) 28 to <56 120 15 35 0.13 0.8697
116 7 20 0.06 0.9048 (0.03) (0.02) 56 to <84 91 4 39 0.04 0.7610
101 7 27 0.07 0.8499 (0.02) (0.03) 84 to <140 76 6 45 0.08
0.7275 87 3 30 0.03 0.7910 (0.03) (0.02) 140 to <168 61 4 49
0.07 0.6701 74 1 31 0.01 0.7637 (0.03) (0.01) .gtoreq.168 27 1 50
0.04 0.6262 34 1 32 0.03 0.7534 (0.04) (0.03) Abbreviations: CI =
confidence interval; SE = standard error. .sup.aNumber of subjects
at risk during the treatment interval, estimated using the life
table method. Assuming that censored cases were at risk for half of
the interval, they only counted for half in figuring the number at
risk. .sup.bNumber of events occurring during the treatment
interval. .sup.cEstimate of the probability of experiencing an
increase in asterixis grade during the treatment interval. Standard
error (SE) estimated by using Greenwood's formula. .sup.dEstimate
of the probability of no increase in asterixis grade until at least
the beginning of the next treatment interval. .sup.eHazard ratio
estimate (hazard of experiencing an increase in asterixis grade in
the rifaximin group compared with the placebo group) determined
from the Cox proportional hazards model. P-value based on the Score
statistic.
[0568] Subjects ranked their level of fatigue by using a 7-point
scale from the worst response (1, high degree of fatigue) the best
response (7, minimal fatigue). Minimal differences between placebo
and rifaximin groups were observed in the changes from baseline in
CLDQ fatigue scores. Mean (SD) fatigue scores were 3.34 (1.406)
versus 3.28 (1.326) at baseline and 3.51 (1.529) versus 3.57
(1.527) in the placebo and rifaximin groups, respectively. Because
of altered mental and neuromotor status, it was not possible for
subjects to complete the CLDQ assessment during an overt HE
breakthrough episode.
[0569] Table 22 summarizes changes from baseline to end of
treatment in venous ammonia level by treatment group in the first
study.
[0570] In the first study, venous ammonia levels were highly
variable over the course of the study. However, subjects in the
rifaximin group had significantly greater reductions in venous
ammonia levels when compared to placebo-treated subjects
(p=0.0391). Venous ammonia levels, a quantitative assessment that
is associated with the CNS effects underlying overt HE, was shown
to be highly predictive of the occurrence of breakthrough overt HE
as determined by the clinical evaluation of Conn score (or a
combination of Conn score and asterixis grade), thereby
underscoring the reliability and clinical relevance of the primary
efficacy measure. The significant correlation of the primary
efficacy endpoint to a venous ammonia levels demonstrates the
reliability and clinical relevance of the primary efficacy measure
in the first study.
TABLE-US-00027 TABLE 22 The First Study: Mean (SD) Changes from
Baseline in Venous Ammonia Level by Treatment Group (ITT
Population) Placebo Placebo N = 159 N = 140 (.mu.g/dL) (.mu.g/dL)
Baseline n = 146 n = 132 Mean (SD) ammonia level 90.3 (52.48) 87.9
(47.76) End of treatment n = 141 n = 132 Mean (SD) ammonia level
88.4 (45.75) 83.9 (45.02) Change from baseline n = 131 n = 125 to
end of treatment Mean (SD) change in -0.3 (58.13) -5.7 (46.77)
ammonia level
[0571] Note: Baseline value was the last available value prior to
first dose of study drug, and end of treatment value was the last
available post-baseline value during the treatment period.
[0572] The Second Study
[0573] In the second study, Conn scores were generally maintained
or improved with rifaximin use up to 18 months. At the last visit,
70.7% of subjects (188 of 266 subjects) had no change and 20.3% (54
of 266) had improvements in Conn scores compared with baseline,
indicating that mental status was maintained or improved in the
majority of subjects (91%) over the treatment period. Like Conn
scores, asterixis grades were generally maintained or improved with
rifaximin use up to 18 months. At the last visit, 77.1% of subjects
(205 of 266 subjects) had no change and 16.2% (43 of 266) had
improvements in asterixis scores compared with baseline, indicating
that neuromotor symptoms associated with increasing neurological
impairment were maintained in 83.3% of subjects over the treatment
period. The last visit for the second study is the last visit
recorded for the interim analysis.
[0574] Maintenance or improvement in Conn scores were observed for
>85% of subjects during rifaximin treatment for up to 840 days;
mean (.+-.SD) exposure for all rifaximin experience was 273.8
(160.92) days (exposure results are present in detail in the ISS,
Module 5.3.5.3.2). A total of 65.5% of subjects (220 of 337) had no
change in Conn score and 21.1% (71 of 337) had improvements in Conn
score from baseline to last visit. Similarly, maintenance or
improvements in asterixis grades were observed for >90% of
subjects during rifaximin treatment. No change from baseline in
asterixis grade was reported for 75.2% of subjects (252 of 337),
and 17.3% had improvements.
[0575] Of the 118 subjects who entered the study with a Conn score
of .gtoreq.1, e.g., those subjects for whom improvement was
possible, 62.2% (71 of 118) showed an improvement from baseline to
Conn score 0 at last assessment. Also, of the 99 subjects who
entered with an asterixis grade of .gtoreq.1, ie those subjects for
whom improvement in asterixis grade was possible, 58.6% (58 of 99)
showed improvement in asterixis grade from baseline to end of
study.
[0576] Changes from baseline in Conn scores and asterixis grades to
last visit were similar among new rifaximin subjects in the second
study (e.g., started rifaximin in 3002), continuing rifaximin
subjects (e.g., received rifaximin in the first study and in the
second study), and all rifaximin experience subjects (e.g.,
received rifaximin in the first study or in the second study).
[0577] These results support those from the first study, in which
treatment with rifaximin was significantly more effective than
placebo in the prevention of worsening of Conn score (2.46 times
versus placebo, p<0.0001) and in the prevention of worsening of
asterixis grade (1.92 times versus placebo, p=0.0262).
[0578] Changes from baseline in CFF results (the first study)
Increases in CFF results represent improvement in neurological
function in patients with HE. Subjects in the rifaximin group had
significantly greater increases in CFF results from baseline to end
of treatment when compared with placebo (Table 23). Mean changes
(.+-.SD) in CFF results were 0.945 (.+-.4.75) in the rifaximin
group versus 0.355 (.+-.4.70) in the placebo group (p=0.0320 for
between-group difference).
[0579] Similar to the correlation for venous ammonia levels, there
was a strong correlation between the quantitative assessment of CFF
results and the occurrence of breakthrough overt HE.
TABLE-US-00028 TABLE 23 Mean (SD) Changes from Baseline in CFF Test
Results by Treatment Group (ITT Population) Placebo Rifaximin N =
159 N = 140 (Hz) (Hz) Baseline n = 159 n = 140 Mean (SD) CFF result
37.41 (6.03) 36.90 (5.47) End of treatment n = 155 n = 139 Mean
(SD) CFF result 37.60 (5.98) 37.81 (4.88) Change from baseline to
end of treatment n = 155 n = 139 Mean (SD) change in CFF result
0.355 (4.70) 0.945 (4.75) Note: Baseline value was the last
available value prior to first dose of study drug, and end of
treatment value was the last available post-baseline value during
the treatment period.
[0580] A retrospective chart review was performed for 145 patients
with HE who received lactulose 30 mL twice daily for .gtoreq.6
months followed by treatment with rifaximin 400 mg 3 times/day for
.gtoreq.6 months. Dramatic differences were observed in favor of
rifaximin treatment. Compliance of .gtoreq.75% was significantly
better during rifaximin treatment than during lactulose treatment;
92% versus 31% of patients received .gtoreq.75% of scheduled
rifaximin and lactulose doses, respectively. Total number of
hospitalizations, duration of hospitalizations, HE endpoints, and
cost of therapy were compared between the 2 treatment regimens.
Significantly fewer hospitalizations (0.5 versus 1.6) and days
hospitalized (2.5 versus 7.3 days) were reported for rifaximin
treatment versus lactulose treatment (p<0.001), and
hospitalization charges per patient were $14,222 compared with
$56,635 during rifaximin and lactulose treatments,
respectively.
[0581] With respect to HE endpoints at the end of the treatment
periods, asterixis was reported for 63% (rifaximin) versus 93%
(lactulose) of patients (p<0.001), and Conn scores of 3 or 4
were observed for 6% (rifaximin) versus 25% (lactulose)
(p<0.001). In addition, significantly more patients had
diarrhea, flatulence, and abdominal pain during lactulose therapy
than during rifaximin therapy (p<0.001).
[0582] Hospitalizations and cost of therapy were analyzed in a
chart review of 39 liver transplant patients who presented with HE
Conn scores of 2 during the interval from January 2004 to November
2005. Twenty-four patients were treated with lactulose and 15 were
treated with rifaximin. Nineteen hospitalizations were reported for
the lactulose group and 3 hospitalizations for the rifaximin group.
The average length of stay was significantly shorter in the
rifaximin group than in the lactulose group (3.5 days [range, 3-4]
versus 5.0 days [range, 3 to 10] [p<0.001]). The average annual
total cost of treatment (hospitalization, emergency room visit, and
drug cost) per patient was $7958 for the rifaximin group and
$13,285 for the lactulose group. Although the cost of rifaximin was
substantially higher than the cost of lactulose, total cost of
treatment (hospitalization plus drug cost) was 1.67-fold higher in
patients who were treated with lactulose.
[0583] Durability of Rifaximin Treatment Effect Data from the
second study provide information on the long-term durability of
rifaximin for the protection against breakthrough overt HE
episodes. Rifaximin treated subjects from the first study who were
in remission at the end of the first study (6 months treatment)
were followed during open-label study the second study (n=60). Time
to first breakthrough HE episode is shown for the rifaximin
rollover subjects (the first study plus the second study) and the
first study placebo subjects in FIG. 15. The incidence of
breakthrough overt HE in these rollover rifaximin subjects was
compared to placebo subjects in the first study. The incidence of
breakthrough HE episode for rifaximin subjects was dramatically
lower than the first study placebo group (ratio of rollover
rifaximin to placebo was 0.0797 after adjusting for exposure time,
p<0.0001 for difference between rifaximin and placebo.
[0584] These results demonstrated that rifaximin had a durable
protective effect beginning in the first study and continuing in
the second study (median exposures to rifaximin were 168 days in
the first study and 253 days in the second study).
[0585] Note for FIG. 13, the survival distribution estimate on
y-axis represents the proportion of subjects without breakthrough
overt HE. Dashed lines represents rifaximin treated subjects from
the first study who were in remission at the end of the first study
(6 months treatment) and were followed during open-label study the
second study (n=60), and solid line represents the placebo group in
the first study. The vertical line marks the end of the
double-blind study and start of the open-label study. Open circles
represent censored subjects in the first study placebo group and
open triangles represent censored subjects in the continuing
rifaximin group. Subjects who discontinued prior to the first
breakthrough overt HE episode were censored at the time of
discontinuation.
[0586] Unlike the first study, in which subjects were discontinued
from the study after experiencing their first breakthrough overt HE
episode, subjects had the option of continuing rifaximin therapy in
the second study after experiencing breakthrough overt HE.
Therefore, the incidence of breakthrough overt HE over time during
rifaximin therapy was evaluated. Table 24 presents breakthrough
overt HE episodes by total number of HE episodes during the course
of the study.
[0587] In the all rifaximin group, 27.1% of subjects (72 of 266)
had .gtoreq.1 breakthrough overt HE episode. Of the 72 subjects
with breakthrough HE, most had 1 (44 subjects) or 2 (18 subjects)
episodes. Ten subjects had 3 or more breakthrough HE episodes in
the second study.
TABLE-US-00029 TABLE 24 the second study: Breakthrough Overt HE
Episodes by Number of Repeat Episodes New Continuing All Rifaximin
Rifaximin Rifaximin N = 196 N = 70 N = 266 n (%) n (%) n (%)
Subjects with .gtoreq. 1 breakthrough 54 (27.6) 18 (25.7) 72 (27.1)
overt HE episode Total number of HE episodes.sup.a during the
study: 1 34 (17.3) 10 (14.3) 44 (16.5) 2 12 (6.1) 6 (8.6) 18 (6.8)
3 4 (2.0) 0 4 (1.5) 4 1 (0.5) 1 (1.4) 2 (0.8) 5 1 (0.5) 0 1 (0.4) 6
0 1 (1.4) 1 (0.4) 10 2 (1.0) 0 2 (0.8) Abbreviation: HE = hepatic
encephalopathy .sup.aNumber of HE episodes. Subjects were counted
only once for each number of overt HE episodes. For example, if a
subject experienced 3 episodes, he/she was included in the row
showing 3 episodes only, and was not also counted in the rows for 2
and 1 episodes.
[0588] Effect of Rifaximin on the Incidence of Overt HE Episodes
(HE burden) The effect of rifaximin therapy on the incidence of
overt HE episodes (e.g., burden of HE), the numbers of HE episodes
in the first study or the second study were compared to the numbers
of HE episodes in the absence of rifaximin therapy. The 6-month
interval prior to the first study or the 12-month interval prior to
the second study was compared against rifaximin therapy in either
study. The time of participation in the first study did not reflect
experience in the absence of rifaximin therapy, therefore, for
subjects who rolled over to the second study without an HE episode
in the first study, the 12-month interval prior to the second study
was used for comparison. Most subjects in the second study (152 of
266) were also in the first study. Overt HE episodes in the second
study were combined with the first study because, unlike the first
study, subjects in the second study had the option of remaining on
rifaximin after experiencing their first breakthrough HE episode.
The numbers of overt HE episodes experienced during the 6-month or
12-month intervals prior to the first study or prior to the second
study were known. While 30.8% of subjects had >2 HE episodes
during the 6-month or 12-month interval prior to rifaximin therapy,
only 3.6% of subjects had >2 HE episodes during rifaximin
therapy for up to 840 days (median exposure=253 days [.about.8
months]) in the first study plus the second study. This difference
in the incidence of HE episodes while subjects were receiving
rifaximin when compared to the absence of rifaximin therapy
suggests a strong effect of rifaximin in relieving the burden of
overt HE episodes in patients with recurrent, overt HE associated
severe liver disease.
[0589] Hepatic encephalopathy is a serious, rare, complex,
episodic, neuropsychiatric syndrome associated with advanced liver
disease. Hepatic encephalopathy is a formidable burden on the
patient, his/her family, and the healthcare system. Overt HE
episodes are debilitating, render the patient incapable of
self-care, and frequently result in hospitalization. Rifaximin has
been granted orphan drug status for the HE indication because the
disease is serious and chronically debilitating, and there is a low
incidence of HE in the general population. Also, there is an unmet
medical need for patients with HE because of limitations of the
current standard of care.
[0590] Without wishing to be bound by any specific scientific
theories, it is believed that the mechanism of action of rifaximin
depends on the inhibition of DNA-dependent RNA polymerase of the
target microorganisms, leading to the suppression of initiation of
chain formation in RNA synthesis. Rifaximin has a lower rate of
fecal eradication of pathogens compared with other commonly used
antibacterial drugs and causes minimal alterations in gut flora
suggesting that rifaximin has a different mechanism of action than
other commonly used drugs in enteric bacterial infection, such as
the fluoroquinolones. The antibacterial properties of rifaximin
appear to result from bactericidal activity at rifaximin
concentrations greater than or equal to the MIC, and from
alterations in bacterial morphology and physiological functioning,
which have been observed at sub-MIC concentrations.
[0591] It was unexpectedly discovered herein, that the risk of the
development of antibiotic resistance is low during chronic
treatment with rifaximin when compared to other systemic
antibiotics such as neomycin. The low risk of antibiotic resistance
during rifaximin therapy is likely due to the fact that resistance
to rifaximin is not plasmid-mediated but instead requires a stable
mutation in host cell DNA; therefore, dissemination of resistance
and cross-resistance to other antibiotics by plasmid-based
mechanisms are eliminated. Also, bacteria at sites outside of the
GI tract are not exposed to appreciable selective pressure because
of negligible systemic concentrations of rifaximin. Additionally,
microbiological data from a study of patients with ulcerative
colitis who were receiving high doses of rifaximin showed that
rifaximin-resistant bacterial colonies generated during in vivo
exposure to rifaximin were unstable and susceptibility returned
after a brief period of treatment interruption.
[0592] Rifaximin treatment results in fewer overt HE episodes that
may otherwise incapacitate the patient, may alleviate the burden on
family members who are required to care for the patient, and
reduces the burden of hospitalization in this patient population
and the healthcare system. The following are results from the
second study with respect to time to first breakthrough overt HE
episode: The protective effect was reproducible: the time to first
breakthrough overt HE episode results were similar between the
rifaximin group in the first study and new rifaximin subjects in
the second study; and 22% and 27.6% had breakthrough overt HE in
the first study rifaximin group and the second study new rifaximin
group, respectively. Adjusted for exposure, rates of breakthrough
HE episodes were 0.62 events/PEY in the rifaximin group from the
first study compared to 0.38 events/PEY for new rifaximin subjects
in the second study. These data demonstrate that protection against
breakthrough overt HE in subjects who received rifaximin was
consistent between the 2 studies. Additionally, when the first
study placebo subjects crossed over to rifaximin therapy by
entering the second study, a striking protective effect of
rifaximin was observed in the comparison of Kaplan-Meier estimates
of time to first breakthrough overt HE between placebo experience
in the first study and rifaximin experience in the second study.
The hazard ratio of rifaximin to placebo was 0.302 (95% CI: 0.166
to 0.549, p<0.0001 for between group difference in relative
risk). This result represents 70% reduction in risk of experiencing
breakthrough overt HE during rifaximin treatment in the second
study when compared with their prior placebo experience in the
first study. This reduction took place in spite of the aging and
presumably progressing nature of the population with chronic liver
disease.
[0593] The protective effect was durable: the Kaplan-Meier estimate
of time-to-first breakthrough HE demonstrated long-term maintenance
of remission from breakthrough HE when rifaximin subjects in
remission after participation in the first study were followed in
the second study (up to 680 days of rifaximin therapy; median
exposure durations were 168 days in the first study and 253 days in
the second study). The incidence of breakthrough HE episode for
these rifaximin subjects relative to the first study placebo was
dramatically low, an indication of fewer breakthrough HE episodes
with rifaximin treatment (p<0.0001 for difference in relative
risk between rifaximin and placebo).
[0594] Results for other efficacy endpoints also demonstrated
statistically significant protective effects of rifaximin. In the
first study, the analysis of time to first HE-related
hospitalization (e.g., hospitalization directly resulting from HE
or hospitalization complicated by HE) demonstrated that the
reduction in risk of hospitalization due to HE was 50% in the
rifaximin group, when compared with placebo, during the 6-month
treatment period (p=0.0129 for between-group difference in relative
risk). In the first study, the risk of HE-caused hospitalization
(e.g., hospitalization directly resulting from HE only) was reduced
by 56% (p=0.0064 for between-group difference in relative risk),
and the risk of all-cause hospitalization was reduced by 30% in the
rifaximin group compared with the placebo group (p=0.0793 for
between-group difference in relative risk). In the first study, the
risk of all-cause hospitalization rate was reduced by 30% in the
rifaximin group when compared to placebo (p=0.0793 for
between-group difference in relative risk). The all-cause
hospitalization rate was 0.92 events/PEY in the rifaximin group
versus 1.31 event/PEY in the placebo group.
[0595] In the second study, the low HE-caused hospitalization rate
was maintained at rates consistent with those in the first study:
HE-caused hospitalization rate was 0.29 event/PEY and all cause
hospitalization in the second study was 0.66 event/PEY. The
consistently low HE-related/HE-caused hospitalization rate in
rifaximin-treated subjects in the first study and in the second
study was at least partly a result of maintaining remission from
demonstrated HE in subjects with end-stage liver disease.
[0596] Improved Quality of Life in HE Subjects Administered
Rifaximin HE is manifested as a continuum of mental status
deterioration, psychomotor dysfunction, impaired memory, increased
reaction time, sensory abnormalities, poor concentration,
disorientation, and in severe forms, coma. Patients with HE
experience symptoms that have adverse consequences for the
patient's health-related quality of life, and result in a decreased
ability for self care. The Chronic Liver Disease Questionnaire
(CLDQ) is a validated instrument for measuring health-related
quality of life in subjects with chronic liver disease. The mean
change from baseline in CLDQ fatigue domain scores at end of
treatment was 1 of 5 key secondary endpoints in this study.
Additionally, mean change from baseline in CLDQ scores (overall
score and each domain score) at each postbaseline assessment and at
end of treatment was one of the tertiary efficacy endpoints
prespecified in the study protocol.
[0597] The CLDQ was administered at Baseline, Days 28, 56, 84, 112,
and 140, and at Day 168 or end of treatment. The CLDQ includes 29
items in the following 6 domains: abdominal symptoms (three items),
fatigue (five items), systemic symptoms (five items), activity
(three items), emotional function (eight items), and worry (five
items). Scores in the fatigue subdomain were highly correlated with
liver disease severity as determined by clinical assessments.
Therefore, the fatigue subdomain was chosen as a key secondary
endpoint for the study.
[0598] Subjects ranked their level of fatigue by using a 7-point
scale from the worst response (1, high degree of fatigue) the best
response (7, minimal fatigue). Other domains and the overall score
were also ranked on a 7-point scale with higher scores indicating
better quality of life and lower scores reflecting lower quality of
life. For example, 1 of the 5 fatigue items was `How much time have
you been fatigued during the last 2 weeks?` Response options were
`all of the time,` `most of the time,` `a good bit of the time,`
`some of the time,` `a little of the time,` `hardly any of the
time,` and `none of the time.` These were graded as 1 (worst degree
of fatigue), 2, 3, 4, 5, 6, and 7 (no fatigue), respectively.
[0599] In contrast to the change from baseline analysis, the AUC
analysis presented below includes CLDQ results over the subject's
complete time of participation in the study.
[0600] Area Under the Curve and Time-Weighted Average (Twa)
Analysis of Chronic Liver Disease Questionnaire Results
[0601] In the an original analysis of the study data, minimal
differences between placebo and rifaximin groups were observed in
the changes from baseline in CLDQ fatigue scores and in other CLDQ
domain scores. Mean (SD) fatigue scores were 3.34 (1.406) versus
3.28 (1.326) at baseline and 3.51 (1.529) versus 3.57 (1.527) at
last assessment in the placebo and rifaximin groups,
respectively.
[0602] In this example, CLDQ responses were tracked over time for
each subject and an area under the curve (AUC) was determined. For
those subjects who had breakthrough HE episodes, CLDQ data reflect
experience prior to the breakthrough episode. Because all subjects
did not stay in the study for the same length of time, the AUC was
normalized by exposure time (T), referred to as Time-weighted
average (Twa) as given below:
Twa = AUC T , ##EQU00002##
[0603] Thus, Twa describes the average CLDQ response from baseline
through the course of the trial, normalized to duration of
exposure.
[0604] As shown below in FIG. 14A-B, there is a distinct separation
in CLDQ results, as measured by Twa, between the rifaximin and
placebo groups in the frequency distributions of Twa scores for the
fatigue domain and overall domain. The shift in the frequency
distribution toward higher scores in the rifaximin subjects
indicates better responses; ie, improved overall quality of life
results and less fatigue for the rifaximin group when compared with
the placebo group. Similar between-group differences favoring the
rifaximin group were observed in the frequency distributions for
additional CLDQ domains.
[0605] Table 25 summarizes Twa results for the CLDQ overall domain
scores and CLDQ fatigue domain scores by treatment group in the
Intent-to-Treat (ITT) population. Time-weighted average scores for
the fatigue domain and overall domain were significantly higher in
the rifaximin group than in the placebo group (p=0.0087 [fatigue
domain] and p=0.0093 [overall domain] for between-group differences
in favor of the rifaximin group). Time-weighted average scores for
other CLDQ domains were also significantly higher in the rifaximin
group than in the placebo group (p=0.0090 [abdominal symptoms],
p=0.0160 [systemic symptoms], p=0.0022 [activity], p=0.0065
[emotional function], and p=0.0436 [worry] for between-group
differences in favor of the rifaximin group.
[0606] The differences in mean Twa scores between treatment groups
(rifaximin minus placebo) were 0.72 for the fatigue domain and 0.75
for the overall domain. A difference of 0.5 points is considered
important and a difference of 0.8 points is considered `large` when
using a 7-point scale for quality-of-life measurements.
[0607] Pertinent findings from the literature comparing subjects
with no cirrhosis, Child-Pugh A, and Child-Pugh C liver disease
suggest that differences of 0.5 to 1.0 in CLDQ scores are
clinically significant. Mean differences in overall domain scores
in subjects with no cirrhosis compared with subjects with
Child-Pugh A (no cirrhosis minus Child-Pugh A) were 0.6 in subjects
in the United States and 0.3 in a study of subjects in Spain.
Greater mean differences in overall domain scores were reported for
the transition from no cirrhosis to Child-Pugh C (no cirrhosis
minus Child-Pugh C): 1.3 difference in the United States study and
1.0 difference in the Spain study.
TABLE-US-00030 TABLE 25 Area Under the Curve and Time-Weighted
Average for CLDQ Results (ITT Population) CLDQ results Rifaximin
Placebo parameter N = 140 N = 159 P-value.sup.a Fatigue domain
Baseline score n = 81 n = 86 Mean (SD) 3.37 (1.304) 3.46 (1.363)
Median (min, max) 3.40 (1.0, 5.8) 3.40 (1.4, 6.4) Twa (score) n =
82 n = 86 Mean (SD) 3.242 (1.7619) 2.522 (1.7538) p = 0.0087 Median
(min, max) 3.600 (0.29, 6.51) 2.365 (0.27, 6.25) Overall domain
Baseline score n = 82 n = 87 Mean (SD) 4.18 (1.184) 4.31 (1.058)
Median (min, max) 4.25 (1.6, 6.7) 4.29 (1.7, 6.6) Twa (score) n =
83 n = 87 Mean (SD) 3.692 (1.8607) 2.943 (1.8480) p = 0.0093 Median
(min, max) 4.249 (0.39, 6.70) 2.926 (0.46, 6.63)
Conclusions for CLDQ Analyses
[0608] When CLDQ results from the study were analyzed over the
duration of exposure to study drug by calculation of Twa, subjects
in the rifaximin group had significantly less fatigue and
significantly greater overall quality of life than subjects in the
placebo group. For example, mean (.+-.SD) Twa fatigue scores were
3.24 (1.76) in the rifaximin group and 2.42 (1.75) in the placebo
group (p=0.0087 in favor of the rifaximin group). Significant
differences in Twa CLDQ results in favor of the rifaximin group
were also observed for the overall CLDQ domain score (p=0.0093),
and for each of the other component domains of the CLDQ, including
abdominal symptoms (p=0.0090), systemic symptoms (p=0.0160),
activity (p=0.0022), emotional function (p=0.0065), and worry
(p=0.0436).
[0609] Importantly, these data demonstrate that rifaximin treatment
resulted in significantly improved quality of life compared to
placebo over a 6-month treatment period in subjects with hepatic
cirrhosis and recurrent, overt HE, prior to experiencing a new
onset overt HE and performed without data impugnation. This
demonstrates that the patients in this study reported improvement
in every domain relative to the placebo group. The observed
statistically significant difference between the rifaximin and
placebo groups agrees with the clinically significant differences
reported for subjects with increasing severity of liver disease as
measured by Child-Pugh score.
Correlation of CFF to Breakthrough Overt HE
[0610] As a test of the reliability and clinical relevance of the
primary endpoint, the quantitative results for CFF were tested for
correlation to the occurrence of breakthrough overt HE (primary
efficacy measure), which was determined on the basis of clinical
symptoms using Conn score (or a combination of Conn score and
asterixis grade).
[0611] The CFF values were tracked over time for each subject and
it was noted that on average, subjects who experienced a
breakthrough HE had lower test values than subjects who did not
experience a breakthrough event. And it was further noted that the
area under the CFF versus time curve (AUC) could be used to
accurately describe the variation in the CFF over time for each
subject as a Time-weighted average (twa). Since all subjects did
not stay in the study for the same length of time, the twa was
normalized by exposure time (T).
[0612] The results of the CFF test over time were expressed as:
twa = AUC T , ##EQU00003## [0613] where T is the exposure time.
Thus, twa describes the average CFF effect through the trial.
[0614] The correlation between twa and the presence or absence of
breakthrough HE episode was analyzed with analysis of variance and
Spearman rank correlation coefficient. Additionally, a ROC curve
analysis was performed to evaluate the accuracy of the twa to
discriminate between the presence or absence of breakthrough
episodes. In a ROC curve, the true positive rate (Sensitivity) is
plotted against the false positive rate (1-Specificity). A
diagnostic test with perfect discrimination has a ROC plot that
passes through the upper left corner (100% sensitivity, 100%
specificity). Therefore the closer the ROC plot to the upper left
corner, the higher the overall accuracy of the test.
[0615] FIGS. 31 and 32 and Table 26 demonstrate that the difference
between the frequency distributions of twa corresponding to the
presence (mean=12.5 Hz) and absence of breakthrough HE events
(mean=32.7 Hz) was statistically significant (p<0.0001). Also,
mean twa correlated with presence or absence of breakthrough HE
episode (Spearman correlation coefficient=-0.62; p<0.0001).
TABLE-US-00031 TABLE 26 Area Under the Curve and Time-Weighted
Average for CFF Results (ITT Population) CFF results
Non-breakthrough HE Breakthrough HE parameter N = 195 N = 104
P-Value.sup.a AUC.sub.(1-168 days) n = 194 n = 99 (Hz .times. day)
Mean (SD) 5455.07 (1918.260) 2090.24 (1648.022) Median (min, max)
6037.0 (137.4, 8189.4) 1610.2 (175.7, 7092.9) twa (HZ).sup.b n =
194 n = 99 Mean (SD) 32.67 (11.487) 12.52 (9.868) p < 0.0001
Median (min, max) 36.2 (0.8, 49.0) 9.6 (1.1, 42.5) CFF: critical
flicker frequency; AUC: area under the ammonia concentration versus
time curve; twa: time-weighted average .sup.ap-value calculated
using ANCOVA model with effects for treatment and analysis region
as covariates. .sup.bSpearman's correlation for twa to presence or
absence of breakthrough HE equals -0.62; p < 0.0001
[0616] The ROC curve analysis of twa for the diagnosis of
breakthrough HE by CFF showed an area under the curve value of 0.88
(95% CI 0.84-0.92). Values close to 1, and the appearance of the
ROC plot closer to the upper left corner, are considered
diagnostically significant.
[0617] Thus, CFF, which is an accepted, physiologically relevant,
quantitative measure associated with HE, was shown to be highly
predictive of breakthrough HE as defined by as an increase of Conn
score to Grade .gtoreq.2 (ie, 0 or 1 to .gtoreq.2) or an increase
in Conn and asterixis score of 1 grade each for those subjects who
entered the study with a Conn score of 0. The fact that this
quantitative measure discriminates in a highly statistically
significant manner demonstrates the reliability and clinical
relevance of the primary efficacy measure.
Example 6: Correlation of the Venous Ammonia Levels to HE
Breakthrough Events
[0618] Subjects administered rifaximin had significantly greater
reductions in venous ammonia levels when compared to
placebo-treated subjects (p=0.0391, see Table 27). Venous ammonia
levels were assessed at Screening, Baseline, Day 28, Day 84, and
Day 168/end-of-treatment.
TABLE-US-00032 TABLE 27 Mean (SD) Changes from Baseline in Venous
Ammonia Level by Treatment Group (ITT Population) Placebo Rifaximin
N = 159 N = 140 (.mu.g/dL) (.mu.g/dL) P-Value.sup.a Baseline n =
146 n = 132 Mean (SD) ammonia level 90.3 (52.48) 87.9 (47.76) End
of treatment n = 141 n = 132 Mean (SD) ammonia level 88.4 (45.75)
83.9 (45.02) Change from baseline to n = 131 n = 125 end of
treatment Mean (SD) change in -0.3 (58.13) -5.7 (46.77) p = 0.0391
ammonia level Note: Baseline value was the last available value
prior to first dose of study drug, and end of treatment value was
the last available postbaseline value during the treatment period.
.sup.aP-value was calculated using analysis of covariance with
effects for treatment and analysis region, and baseline as a
covariate.
[0619] Blood ammonia levels, a quantitative assessment that is
associated with the CNS effects underlying overt HE, was found to
be highly correlated to the occurrence of breakthrough overt HE as
determined by clinical evaluation. This high degree of correlation
was consistent with the correlation between CFF results and the
occurrence of breakthrough overt HE.
[0620] The venous ammonia laboratory values were tracked over time
for each subject. To normalize by exposure time, a twa value was
calculated similarly to the CFF analysis.
[0621] The correlation between the ammonia twa and the presence or
absence of breakthrough HE episode was analyzed as described for
the CFF.
[0622] FIG. 33 and Table 28 show that the difference between the
frequency distributions of twa corresponding to the presence
(mean=102.4 .mu.mol/L) and absence of breakthrough HE events
(mean=85.4 .mu.mol/L) was statistically significant (p=0.0079).
Also, mean twa correlated with presence or absence of breakthrough
HE episode (Spearman correlation coefficient of 0.22,
p=0.0005).
TABLE-US-00033 TABLE 28 Area Under the Curve and Time-Weighted
Average for Venous Ammonia Concentrations (ITT Population) Venous
ammonia Non-breakthrough Breakthrough concentration HE HE P-
parameter N = 195 N = 104 Value.sup.a AUC.sub.(1-28 days) 11 = 173
n = 68 (.mu.mol/L .times. day) Mean (SD) 2304.83 (1211.428) 2763.93
(1160.357) Median 2038.5 (499.5, 2787.8 (999.0, (min, max) 9153.0)
7681.5) twa (.mu.mol/L).sup.b n = 173 n = 68 P = 0.0079 Mean (SD)
85.36 (44.87) 102.37 (42.98) Median 75.5 (18.5, 339.0) 103.25
(37.0, 284.5) (min, max) AUC: area under the ammonia concentration
versus time curve; twa: time-weighted average. .sup.ap-value
calculated using ANCOVA model with effects for treatment and
analysis region as covariates. .sup.bSpearman's correlation for twa
to presence or absence of breakthrough HE equals 0.22; p =
0.0005
[0623] The ROC curve analysis of twa for the diagnosis of
breakthrough HE by venous ammonia levels, showed an area under the
curve value of 0.64 (95% CI 0.57-0.72) (See FIG. 34). Values close
to 1, and the appearance of the ROC plot closer to the upper left
corner, are considered diagnostically significant.
[0624] Thus, venous ammonia level, which is an accepted
physiologically relevant quantitative measure associated with HE,
was shown to be highly predictive of breakthrough HE as defined by
as an increase of Conn score to Grade .gtoreq.2 (ie, 0 or 1 to
.gtoreq.2) or an increase in Conn and asterixis score of 1 grade
each for those subjects who entered the study with a Conn score of
0. The fact that this quantitative measure discriminates in a
highly statistically significant manner the presence or absence of
breakthrough HE attests to the reliability and clinical relevance
of the primary efficacy measure.
INCORPORATION BY REFERENCE
[0625] The contents of all references, patents, pending patent
applications and published patents, cited throughout this
application are hereby expressly incorporated by reference.
EQUIVALENTS
[0626] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
herein. Such equivalents are intended to be encompassed by the
following claims.
* * * * *