Welcome to Journal Presentation
Chairperson:
Dr. Satya Ranjan Sutradhar
Associate Prof. & Head Dept. of Medicine
Mymensingh Medical College
Speaker: Dr. Al-Rizwan Russel
IMO, MU-2 MMCH
1
THE TITLE
Rifaximin Therapy for Patients
with Irritable Bowel Syndrome
without Constipation
Original Article
New England Journal of Medicine 2011;364:22-32.
Authors:Mark Pimentel, Anthony Lembo,William D. Chey at el.
2
Background
 Evidence
suggests that gut flora
may play an important role in the
pathophysiology of the irritable
bowel syndrome (IBS). The Study
evaluated rifaximin, a minimally
absorbed antibiotic, as treatment
for IBS.
3
Purpose of this study


The irritable bowel syndrome (IBS) is a
functional gastrointestinal disorder
characterized by recurring symptoms
of abdominal pain, bloating, and
altered bowel function in the absence
of structural, inflammatory, or
biochemical abnormalities.
IBS often does not respond to current
treatment options.
4
Purpose…contd..


Patients with IBS may have alterations in the
intestinal microbiota, thus leading
investigators to consider targeting the
intestinal microbiota for the treatment of this
condition. Rifaximin is an oral, nonsystemic,
broad-spectrum antibiotic that targets the
gut and is associated with a low risk of
bacterial resistance.
Given the limitations of available therapies,
there is an unmet medical need for novel
therapeutic approaches.
5
Methods

In two identically designed, doubleblind, phase 3, placebo-controlled
trials (TARGET 1 and TARGET 2),
where patients who had IBS without
constipation were randomly assigned
to either rifaximin at a dose of 550 mg
or placebo, three times daily for 2
weeks, and were followed for an
additional 10 weeks.
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End Points

Methods contd…..
Primary:-
the proportion of patients who had adequate
relief of global IBS symptoms (Self reported
relief of symptoms for at least 2 of the first 4
weeks after treatment)

Secondary:
the proportion of patients who had adequate
relief of IBS-related bloating

Other secondary end points:
Abdominal pain, and stool consistency.
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Inclusion Criteria
1.
2.
3.
4.
Methods contd…..
At least 18 years of age
Had undergone a colonoscopic examination
within the previous 2 years.
Had received a diagnosis of and had current
symptoms of IBS (as assessed according to
the Rome II diagnostic criteria), in particular,
symptoms of abdominal pain and discomfort.
Did not have adequate relief of global IBS
symptoms and of IBS-related bloating at
both the time of screening and the time of
randomization.
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Exclusion criteria
1.
2.
3.
4.
5.
6.
7.
8.
Methods contd…..
Constipation-predominant IBS
A history of inflammatory bowel disease
Diabetes
Unstable thyroid disease
Previous abdominal surgery (other than
cholecystectomy or appendectomy)
Human immunodeficiency virus infection
Renal or hepatic disease.
Taking alosetron,warfarin,tegaserod,
lubiprostone or antipsychotic, antispasmodic,
antidiarrheal, probiotic, or narcotic drugs or if
they had taken antibiotics within the previous
14 days or rifaximin within 60 days.
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Methods contd…..





After a screening phase of 7 to 13 days,
eligible patients were randomly assigned
The randomization code was computergenerated,
After completing the 14-day study-treatment
period, patients were evaluated for 10
additional weeks.
Study visits were conducted on days 1, 7, 14,
28, and 84,
Patients were monitored by means of
telephone calls on days 42, 56, and 70.
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Statistical Analysis


The Study estimated the sample size for each
study assuming that 40% of the patients in the
placebo group and 55% in the rifaximin group
would meet the criteria for the primary end
point for at least 2 of the first 4 weeks after
treatment.
With these assumptions, a sample of 300
patients would be needed in each group for the
studies to have 95% power to show the 15percentage-point difference between the
groups, at a significance level of 0.05.
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Statistical Analysis.


Contd…
All efficacy and safety analyses were
performed on a modified intention-to-treat
population, which included all patients who
received at least one dose of the study
drug.
Binary data (i.e., data on the proportion of
patients who had or did not have adequate
relief of symptoms) were analyzed with
the use of logistic regression.
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Statistical Analysis. Contd…


Spearman correlation analyses were
applied to determine whether the weekly
assessments of adequate relief paralleled
the pattern seen with the daily
assessments.
Safety data were summarized with the
use of descriptive statistics.
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Results

A total of 1260 patients were enrolled in the studies
(623 patients in TARGET 1 and 637 in TARGET 2) and
underwent randomization at one of 179 investigative
sites in the United States (1217 patients) and Canada
(43 patients)

The studies were conducted in parallel from June 2008
through August 2009.

More than 90% of the patients completed the entire 12week study.

The rate of adherence to the study drug, defined as the
use of at least 70% of the dispensed tablets, was at
least 97% in both study groups.
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Efficacy during the Primary Evaluation Period
(Weeks 3 to 6)
1.

Adequate Relief of Global IBS Symptoms
Significantly more patients in the rifaximin
group than in the placebo group met the
criteria for the primary end point of adequate
relief of global IBS symptoms for at least 2 of
the first 4 weeks after treatment (40.8% vs.
31.2%, P = 0.01, in TARGET 1; 40.6% vs.
32.2%, P = 0.03, in TARGET 2; 40.7% vs.
31.7%, P<0.001, in the two studies
combined)
Figure-1
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Figure 1. Analyses of Primary and Key Secondary End points
Efficacy outcome
Proportion of pts with a response
Odds ratio
(95% CI)
P value for
Treatment
Effects
Primary End point
Weekly Global IBS symptoms
Placebo
No./Total no.
Rifaximin
No./Total no.
TARGET-1
98/314
126/309
1.53
0.01
TARGET-2
103/320
128/315
1.45
0.03
Combined
201/634
254/624
1.49
<0.001
Secondary End points
Daily Global IBS Symptoms
TARGET-1
96/314
132/309
1.76
<0.001
TARGET-2
91/320
119/315
1.59
0.007
Combined
187/634
251/624
1.61
<0.001
The odds ratios for relief of symptoms during the primary evaluation period (weeks 3 through 6 of the study)
are shown for the modified intention-to-treat population (with the use of the last-observation-carried forward
approach).
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Efficacy during the Primary Evaluation Period (Weeks 3 through 6)
…contd…
2. Adequate Relief of IBS-Related Bloating
Significantly more patients in the rifaximin
group than in the placebo group met the
criteria for the key secondary end point,
adequate relief of IBS related bloating for at
least 2 of the first 4 weeks after treatment
(39.5% vs. 28.7%, P = 0.005, in TARGET 1;
41.0% vs. 31.9%, P = 0.02, in TARGET 2;
40.2% vs. 30.3%, P<0.001, in the two
studies combined)
Figure-2
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Figure 3. Analyses of Primary and Key Secondary End points
Efficacy
outcome
Proportion of pts with a
response
Odds ratio
(95% CI)
P value for
Treatment
Effects
Daily IBS Related Bloating
Placebo
No./Total no.
Rifaximin
No./Total no.
TARGET-1
102/314
121/309
1.41
0.05
TARGET-2
99/320
137/315
1.76
<0.001
Combined
201/634
258/624
1.52
<0.001
Weekly IBS related Bloating
TARGET-1
90/314
122/309
1.62
0.005
TARGET-2
102/320
129/315
1.49
0.02
Combined
192/634
251/624
1.25
<0.001
The odds ratios for relief of symptoms during the primary evaluation period (weeks 3 through 6 of the
study) are shown for the modified intention-to-treat population (with the use of the last-observation-carried
forward approach).
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Efficacy during the Primary Evaluation Period (Weeks 3 through
6) …contd…
3.
Relief of IBS-Related Abdominal Pain
and Loose or Watery Stools
A significantly greater proportion of
patients in the rifaximin group than in
the placebo group had relief of IBSrelated abdominal pain and
discomfort during the primary
evaluation period (44.3% vs. 36.3%,
P = 0.03, in TARGET 1; 42.9% vs.
34.4%, P = 0.02, in TARGET 2)
Figure-3
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Figure 3. Analyses of Primary, Key Secondary End points
Efficacy
outcome
Proportion of pts with a
response
Odds ratio
(95% CI)
P value for
Treatmen
t Effects
Daily IBS-related abdominal pain
Placebo
No./Total no.
Rifaximin
No./Total no.
TARGET-1
114/314
137/309
1.45
0.03
TARGET-2
110/320
135/315
1.46
0.02
Combined
224/634
272/624
1.42
0.003
Daily stool consistency
TARGET-1
212/314
244/309
1.80
0.002
TARGET-2
206/320
233/315
1.57
0.01
Combined
418/634
477/624
1.67
<0.001
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Efficacy during the Entire Study Period
(Months 1 - 3)
1.
Durability of Response on the Basis of
Weekly Assessment
In analyses of the monthly response evaluated
on the basis of weekly assessments, more
patients in the rifaximin group than in the
placebo group in both studies had adequate
relief of global IBS symptoms within the first
month, with continued relief during the first 2
months and during all 3 months in both studies
(P = 0.05 in TARGET 1, P = 0.005 in TARGET 2,
and P<0.001 in the two studies combined, for
relief during all 3 months)
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2.

Durability of Response on the
Basis of Daily Assessment
The analyses of monthly response
evaluated on the basis of daily
assessments also support a durable
response to rifaximin in patients with IBS
over the course of 3 months. (P = 0.003
in TARGET 1, P = 0.01 in TARGET 2, and
P<0.001 in the two studies combined)
and of IBS-related bloating (P = 0.01 in
TARGET 1, P<0.001 in TARGET 2, and
P<0.001 in the two studies combined)
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Safety

The safety profile of rifaximin was similar
to that of placebo . Serious adverse events
were recorded in 10 patients in the
rifaximin group (1.6%) and 15 patients in
the placebo group (2.4%). There were no
cases of Clostridium difficile–associated
diarrhea or ischemic colitis. No deaths
were reported.
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Discussion


1
Treating IBS is important because the
symptoms cause substantial
impairment in health-related quality of
life, leading to increased use of health
resources and reduced work
productivity.
These two studies showed that a short
course of rifaximin leads to sustained
amelioration of the symptoms of IBS
without constipation in a subgroup of
affected patients.
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Adverse Events during the 12-Week Study
25
Conclusions

In summary, the results of these two
studies showed that treatment with
rifaximin at a dose of 550 mg three
times daily for 14 days provides better
relief of symptoms of IBS than does
placebo for up to 10 weeks after
completion of therapy.
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Defining abdominal pain and stool consistency

1.
2.
3.
4.
5.
6.
7.
Likert scoring system for abdominal pain: avg 2.5
0 indicating not at all;
1- hardly;
2- somewhat;
3- moderately;
4- a good deal;
5- a great deal;
6- a very great deal
Average daily consistency of their stools as 3.5 or
more on a 5-point scale for stool consistency (with 1
indicating very hard; 2, hard; 3, formed; 4, loose; and
5,watery) over the course of at least 7 days.
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