Ibodutant for Relief of Irritable Bowel Syndrome With Diarrhoea (IBS-D) (IRIS-2)

• Response for Relief of Overall IBS Symptoms and of Abdominal Pain/Discomfort at the End of 8 Weeks of Treatment, Where the Response is Defined as at Least 4 Weeks With Satisfactory Relief During 8 Weeks of Treatment (50% Rule) in the ITT Population [ Time Frame: Eight weeks ] [ Designated as safety issue: No ]

  Weekly binary questions (yes/no) from IV/WRS diary records: "Did you have satisfactory relief of your overall IBS symptoms during the last week?" and "Did you have satisfactory relief of your abdominal pain or discomfort during the last week?"

  Responder: Report of satisfactory overall IBS symptom relief ="Yes" and of satisfactory abdominal pain/discomfort relief = "Yes" 4/8 weeks with at least 2 consecutive weeks of satisfactory relief during Week 5 to Week 8(50% rule)

• Quality of Life Changes (Using EuroQoL EQ-5D Questionnaire) [ Time Frame: Eight weeks ] [ Designated as safety issue: No ]
  Change in EQ-5D Quality of Life (visual analogue scale) score at the end of 8 weeks of treatment versus baseline (at randomisation). EQ-5D quality of life visual analogue scale ranges from "0"= worst imaginable health state to "100"=best imaginable health state.

• Response for satisfactory relief of overall IBS symptoms and of abdominal pain/discomfort satisfactory relief during 8 weeks of treatment-(50% rule) [ Time Frame: Eight weeks ] [ Designated as safety issue: No ]

  Weekly binary questions (yes/no): "Did you have satisfactory relief of your overall IBS symptoms during the last week?" and "Did you have satisfactory relief of your abdominal pain or discomfort during the last week?"

  Responder: Report of satisfactory overall IBS symptom relief ="Yes" and of satisfacory abdominal pain/discomfort relief = "Yes" 4/8 weeks with at least 2 consecutive weeks of satisfactory relief during Week 5 to Week 8(50% rule)

• Quality of Life Changes (using EuroQoL EQ-5D questionnaire) [ Time Frame: Eight weeks ] [ Designated as safety issue: No ]
  Change in EQ-5D score at the end of 8 weeks of treatment versus baseline (at randomisation).

• Subgroup Analysis: Response for Relief of Overall IBS Symptoms and of Abdominal Pain/Discomfort According to the 75% Rule in the Female ITT Population [ Time Frame: Eight weeks ] [ Designated as safety issue: No ]

  Weekly binary questions (yes/no) from IV/WRS diary records: "Did you have satisfactory relief of your overall IBS symptoms during the last week?" and "Did you have satisfactory relief of your abdominal pain or discomfort during the last week?"

  Responder: Report of satisfactory overall IBS symptom relief ="Yes" and of satisfactory abdominal pain/discomfort relief = "Yes" 6/8 weeks (75% rule)

• Subgroup Analysis: Response for Relief of Overall IBS Symptoms and of Abdominal Pain/Discomfort According to the 75% Rule in the Male ITT Population [ Time Frame: Eight weeks ] [ Designated as safety issue: No ]

  Weekly binary questions (yes/no) from IV/WRS diary records: "Did you have satisfactory relief of your overall IBS symptoms during the last week?" and "Did you have satisfactory relief of your abdominal pain or discomfort during the last week?"

  Responder: Report of satisfactory overall IBS symptom relief ="Yes" and of satisfactory abdominal pain/discomfort relief = "Yes" 6/8 weeks (75% rule)

Irritable Bowel Syndrome with diarrhoea (IBS-D) is a functional gastrointestinal disorder characterised by chronic or recurrent abdominal pain or discomfort and diarrhoea. This trial aims at the evaluation of the efficacy and safety of the neurokinin type 2 receptor antagonist Ibodutant in improving IBS-D symptoms.

The study evaluates the efficacy and safety of three doses of ibodutant, given once daily for 8 weeks versus placebo in IBS-D patients. Efficacy is evaluated in terms of overall symptom relief and abdominal pain/discomfort relief after 8 weeks of treatment. The clinical phase of the study comprises a 2-week run-in period (treatment-free),an 8-week double-blind treatment period and a 2-week treatment withdrawal period, resulting in a 10-week overall duration of the study for each patient.

Patients report their IBS-related symptoms daily in an electronic diary (web-and telephone based)during all periods of the study.

• Drug: Ibodutant
  Oral tablet, low dose, once daily, for 8 weeks
  Other Name: Code: MEN 15596
• Drug: Ibodutant
  Oral tablet, intermediate dose, once daily, for 8 weeks
  Other Name: Code: MEN 15596
• Drug: Ibodutant
  Oral tablet, high dose, once daily, for 8 weeks
  Other Name: Code: MEN 15569
• Drug: Placebo
  Oral tablet, (identical in appearance and weight to Ibodutant tablets), once daily, for 8 weeks
  Other Name: Sugar pill

• Experimental: Ibodutant low dose
  Oral tablet, to be given once daily in fasting conditions.
  Intervention: Drug: Ibodutant
• Experimental: Ibodutant intermediate dose
  Oral tablet, to be given once daily in fasting conditions.
  Intervention: Drug: Ibodutant
• Experimental: Ibodutant high dose
  Oral tablet, to be given once daily in fasting conditions.
  Intervention: Drug: Ibodutant
• Placebo Comparator: Placebo
  Oral tablet, to be given once daily in fasting conditions.
  Intervention: Drug: Placebo

Inclusion Criteria:

At start of the run-in period:

• Male or female patients aged 18 - 70 years with a clinical diagnosis of IBS-D according to the Rome III criteria:

• Recurrent abdominal pain/discomfort for at least 3 days per month in the last 3 months associated with at least 2 of the following characteristics:

  1. improvement with defecation;
  2. onset associated with a change in the frequency of stool;
  3. onset associated with a change in form (appearance) of stool.
• Symptom-onset at least 6 months prior to diagnosis.
• Loose/watery stools at least 25% of the time in the last 3 months AND hard/lumpy stools less than 25% of the time in the last 3 months.
• More than 3 bowel movements per day at least 25% of the time in the last 3 months.
• For patients older than 50 years OR patients with positive family history of colorectal cancer: Normal results from colonoscopy or flexible sigmoidoscopy.
• Mentally competent, able to give written informed consent.
• For women of childbearing potential: Use of a highly effective contraceptive method throughout the entire study period and up to 30 days post-treatment.
• Normal physical examination or without clinically relevant abnormalities.

At randomisation:

-Confirmation of IBS-D severity in terms of bowel movement frequency and abdominal pain intensity along the 2-week run-in period.

Exclusion criteria:

• Organic abnormalities of the gastrointestinal tract, including history of colonic or major abdominal surgery.
• History of gluten enteropathy.
• Lactose intolerance as assessed by response to diet.
• History of positive tests for ova or parasites, or occult blood in the stool.
• Previous diagnosis of diabetes mellitus (either type 1 or 2).
• Unstable medical condition.
• Major psychiatric, neurological, or cardiovascular disorders, or uncontrolled metabolic disease.
• Relevant changes in dietary habits, lifestyle, or exercise regimen in the previous 2 months.
• Use of concurrent medication with drugs known to interfere with gastro-intestinal motility or sensitivity.
• Pregnancy or breastfeeding.