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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

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THE TITLE

Rifaximin Therapy for Patients with Irritable Bowel Syndrome

without Constipation

Original ArticleNew England Journal of Medicine 2011;364:22-32.

Authors:-Mark Pimentel, Anthony Lembo,William D. Chey at el.

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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.

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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.

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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.

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Methods

In two identically designed, double-blind, 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 Methods contd…..

1. At least 18 years of age2. Had undergone a colonoscopic examination

within the previous 2 years.3. 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.

4. 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 Methods contd…..

1. Constipation-predominant IBS2. A history of inflammatory bowel disease 3. Diabetes4. Unstable thyroid disease5. Previous abdominal surgery (other than

cholecystectomy or appendectomy) 6. Human immunodeficiency virus infection 7. Renal or hepatic disease. 8. 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 computer-generated,

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 15-percentage-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 12-week 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

PlaceboNo./Total no.

RifaximinNo./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 <0.001The 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

PlaceboNo./Total no.

RifaximinNo./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 IBS-related 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 Treatment Effects

Daily IBS-related abdominal pain

PlaceboNo./Total no.

RifaximinNo./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 AssessmentIn 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

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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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Likert scoring system for abdominal pain: avg 2.51. 0 indicating not at all; 2. 1- hardly; 3. 2- somewhat; 4. 3- moderately; 5. 4- a good deal; 6. 5- a great deal;7. 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.

Defining abdominal pain and stool consistency