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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. THE TITLE.

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  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. Inclusion Criteria 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.

  9. Exclusion criteria 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. Efficacy during the Primary Evaluation Period (Weeks 3 to 6) • 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

  16. Figure 1. Analyses of Primary and Key Secondary End points The odds ratios for relief ofsymptoms 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).

  17. 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

  18. Figure 3. Analyses of Primary and Key Secondary End points The odds ratios for relief ofsymptoms 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).

  19. Efficacy during the Primary Evaluation Period (Weeks 3 through 6) …contd… • 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

  20. Figure 3. Analyses of Primary,Key Secondary End points

  21. 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)

  22. 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)

  23. 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.

  24. 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.

  25. Adverse Events during the 12-Week Study

  26. 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.

  27. Defining abdominal pain and stool consistency • 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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