52-Week Efficacy and Safety Study of Ibodutant in Women With Irritable Bowel Syndrome With Diarrhea (IBS-D)

The study evaluates the efficacy and safety of ibodutant 10 mg, given once daily for 24
weeks in comparison with placebo in female IBS-D patients. Randomisation to ibodutant and
placebo will be 1:1. Efficacy is evaluated in terms of weekly response for abdominal pain
intensity and stool consistency over 24 weeks of treatment in at least 50% of the weeks of
treatment.

The clinical phase of the study comprises up to 2 weeks of screening for patient's
eligibility, a 2-week run-in period (treatment-free) for IBS severity assessment, a first
24-week double-blind treatment period, a second 26-week re-randomised treatment period
period and a 2-week safety follow-up, resulting in a maximum 58-week overall duration of the
study for each patient.

Patients report their IBS-related symptoms daily in a telephone-based electronic diary from
run-in until end of treatment.

Inclusion Criteria:

- At screening:

- Female patients aged 18 years or older.

- Clinical diagnosis of IBS-D according to the following symptoms-based criteria
as per Rome III modular questionnaire criteria:

1. Recurrent abdominal pain or discomfort for at least 3 days per month in the
last 3 months associated with at least 2 of the following characteristics:
a) improvement with defecation; b) onset associated with a change in the
frequency of stool; c) onset associated with a change in form (appearance)
of stool.

2. Symptom-onset at least 6 months prior to diagnosis.

3. Loose or watery stools at least 25% of the time in the last 3 months AND
hard or lumpy stools less than 25% of the time in the last 3 months.

4. Additional criterion: 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 a positive family history of
colorectal cancer: normal results from colonoscopy/flexible sigmoidoscopy
performed within the last 5 years.

- For patients aged 65 years or older: absence of ischaemic colitis, microscopy
colitis or any other organic gastrointestinal disease as evidenced by the
results of a colonoscopy/flexible sigmoidoscopy with biopsy performed within 6
months.

- For women of childbearing potential: Use of a highly effective contraceptive
method with a failure rate <1% per year throughout the entire study period.

- Physical examination without clinically relevant abnormalities during screening.

- No clinically relevant abnormalities in 12-Lead ECG or in laboratory findings.

- Mentally competent, able to give written informed consent, and compliant to
undergo all visits and procedures.

- Unrestricted access to a touch-tone telephone.

- Willingness to refrain from using loperamide within 3 days prior to run-in visit
and during the run-in period.

Additional criteria at randomisation:

- During both weeks of the run-in period:

1. A weekly average of worst abdominal pain in the past 24 hours with a score of
≥3.0 on a 0 to 10 point scale.

2. At least one bowel movement on each day.

3. A weekly average of at least 3 bowel movements per day.

4. At least one stool with a consistency of Type 6 or Type 7 according to the
Bristol Stool Scale (BSS) on at least 2 days per week.

5. Less than 2 bowel movements with a consistency of Type 1 or Type 2 according to
the BSS per week.

- Adequate compliance with the e-diary recording procedure defined as at least 11 of 14
days (≥75%) of the nominal daily data entry.

Exclusion Criteria:

- Male gender.

- Diagnosis of IBS with a subtype of constipation, mixed IBS, or un-subtyped IBS.

- Colonic or major abdominal surgery, any other major abdominal surgery or elective
major surgery planned or expected during the study.

- History of organic GI abnormalities, inflammatory bowel diseases, complicated
diverticulosis, ischaemic colitis, microscopic colitis.

- History of pancreatitis, active biliary duct disease, cholecystitis or symptomatic
gallbladder stone disease in the previous 6 months.

- History of gluten enteropathy or lactose intolerance.

- Current or previous diagnosis of neoplasia.

- History of endometriosis.

- History of positive tests for ova or parasites, or clostridium difficile toxin or
occult blood in the stool in the previous 6 months.

- History of human immunodeficiency virus infection.

- History of major cardiovascular events in the previous 6 months.

- Uncontrolled hypertension, insulin-dependent diabetes mellitus or abnormal thyroid
function.

- Major psychiatric or neurological disorders or unstable medical condition which may
compromise the efficacy and safety assessments.

- Evidence of clinically significant hepatic disease, severe renal insufficiency or
anemia.

- Relevant changes in dietary habits, lifestyle, or exercise regimen in the previous 2
months.

- Use of prohibited concurrent medication within the previous month such as
antibiotics, antimuscarinic drugs, drugs enhancing GI motility and analgesics.

- Pregnancy or breastfeeding.

- Inability to understand or collaborate throughout the study.

- Participation in other clinical studies in the previous 4 weeks or concurrent
enrollment in a clinical study.

- Any condition that would compromise the well-being of the patient.