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

Phase 3

Completed

Conditions: Irritable Bowel Syndrome With Diarrhea

Interventions: Drug: Ibodutant 10 mg
Drug: Placebo

Registration Number: NCT02107196

Lead Sponsor: Menarini Group

Brief Summary: 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 oral ibodutant 10 mg once daily as compared to placebo in women with IBS-D over a 12-week treatment period.

Detailed Description: The study evaluates the efficacy and safety of ibodutant 10 mg, given once daily for 12 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 12 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 12-week double-blind treatment period, a 4-week randomised withdrawal (RW) period and a 2-week safety follow-up, resulting in a maximum 22-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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 535

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ibodutant 10 mg	Ibodutant 10 mg	Oral tablet to be given once daily for 12 weeks of treatment. Patients randomised to the ibodutant 10 mg arm will be re-randomised at week 13 in a 1:1 ratio to either ibodutant 10 mg or placebo for additional 4 weeks of treatment.
Placebo	Placebo	Oral tablet to be given once daily for 12 weeks of treatment. Patients randomised to the placebo arm will be mock-re-randomised (switch in blinded conditions) to ibodutant at week 13 for additional 4 weeks of treatment.

Primary Outcome Measures

Name	Time	Method
Weekly Response for Abdominal Pain Intensity AND Stool Consistency Over 12 Weeks of Treatment in at Least 50% of the Weeks of Treatment (6 Out of 12 Weeks).	12 weeks	The patient will be considered a weekly responder if she meets both of the following criteria in the same week: * Abdominal pain response: decrease in weekly average of worst abdominal pain score in the past 24 hours of at least 30% compared with baseline; * Stool consistency response: decrease of at least 50% in the number of days per week with at least one stool that has a consistency of Type 6 or 7 compared with baseline. The patients reported Bristol Stoll Chart score based on a 1 to 7 scale where 1 corresponds to hard stool and 7 corresponds to watery diarrhoea.

Secondary Outcome Measures

Name	Time	Method
Weekly Response for Abdominal Pain Intensity Over 12 Weeks of Treatment in at Least 50% of the Weeks of Treatment (6 Out of 12 Weeks).	12 weeks	The patient will be considered a weekly abdominal pain responder if she meets the following criterion: * Decrease in weekly average of worst abdominal pain score in the past 24 hours of at least 30% compared with baseline.
Weekly Response for Stool Consistency Over 12 Weeks of Treatment in at Least 50% of the Weeks of Treatment (6 Out of 12 Weeks).	12 weeks	The patient will be considered a weekly stool consistency responder if she meets the following criterion: * Decrease of at least 50% in the number of days per week with at least one stool that has a consistency of Type 6 or 7 compared with baseline. The patients reported Bristol Stool Chart score based on a 1 to 7 scale where 1 corresponds to hard stool and 7 corresponds to watery diarrhoea.
Weekly Response for Relief of Overall IBS Signs and Symptoms Over 12 Weeks of Treatment in at Least 50% of the Weeks of Treatment (6 Out of 12 Weeks).	12 weeks	The patient will be considered a weekly responder if she has an IBS degree-of-relief equal to "completely relieved/improved" or "considerably relieved/improved".
Evaluation of Rebound Effects	4 weeks	Comparison between average abdominal pain intensity (worst abdominal pain on a 0 to 10 NRS scale, where 0 corresponds to no pain and 10 corresponds to worst possible pain) and average stool consistency score (the patients reported Bristol Stool Chart score based on a 1 to 7 NRS scale where 1 corresponds to hard stool and 7 corresponds to watery diarrhoea) during the 4-week RW presented as change to baseline. The analysis only included the patients randomised to ibodutant in the 12-week treatment period and re-randomised to placebo for the 4-week RW period. Baseline was considered as the average abdominal pain intensity/stool consistency in the 2-week Run-in period.