Irritable Bowel Syndrome With Diarrhea
Conditions
Keywords
Irritable Bowel Syndrome, Colon, irritable, Bowel disease, Diarrhea
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.
Interventions
DRUGIbodutant 10 mg
Oral tablet, to be given once daily.
DRUGPlacebo
Oral tablet, (identical in appearance and weight to ibodutant tablets), to be given once daily.
Sponsors
Menarini Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Bulgaria, Czechia, France, Germany, Italy, Poland, Romania, Russia, Spain, United Kingdom, United States
Participant flow
Recruitment details
The first patient was screened on 27th February 2014 and the first patient randomized on 21st March 2014. The last patient completed the study on 22nd June 2015. The study was conducted at 158 clinical sites in 11 countries (Bulgaria, Czech Republic, France, Germany, Italy, Poland, Romania, Russia, Spain, the USA and the United Kingdom).
Pre-assignment details
A total of 1237 patients entered a 2-week Screening period, 1034 entered the qualifying 2-week Run-in period and 535 of them were randomised. After completion of the double-blind 12-week treatment, 453 patients entered into the Randomised Withdrawal (RW) period.
Participants by arm
| Arm | Count |
|---|---|
| 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.
Ibodutant 10 mg: Oral tablet, to be given once daily. | 271 |
| 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.
Placebo: Oral tablet, (identical in appearance and weight to ibodutant tablets), to be given once daily. | 264 |
| Total | 535 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 12-week Treatment Period | Adverse Event | 6 | 3 |
| 12-week Treatment Period | Lack of Efficacy | 2 | 1 |
| 12-week Treatment Period | Lost to Follow-up | 3 | 6 |
| 12-week Treatment Period | Physician Decision | 0 | 1 |
| 12-week Treatment Period | Protocol Violation | 7 | 8 |
| 12-week Treatment Period | Reason Missing | 11 | 8 |
| 12-week Treatment Period | Withdrawal by Subject | 15 | 12 |
| 4-week Randomized Withdrawal (RW) Period | Adverse Event | 2 | 0 |
| 4-week Randomized Withdrawal (RW) Period | Protocol Violation | 2 | 0 |
| 4-week Randomized Withdrawal (RW) Period | Reason Missing | 18 | 5 |
| 4-week Randomized Withdrawal (RW) Period | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo | Ibodutant 10 mg |
|---|---|---|---|
| Abdominal Pain Severity Score <5 | 83 participants | 37 participants | 46 participants |
| Abdominal Pain Severity Score >=5 to <8 | 363 participants | 187 participants | 176 participants |
| Abdominal Pain Severity Score >=8 | 89 participants | 40 participants | 49 participants |
| Age, Continuous | 43.1 years STANDARD_DEVIATION 12.65 | 43.8 years STANDARD_DEVIATION 12.47 | 42.5 years STANDARD_DEVIATION 12.81 |
| Gender Female | 535 Participants | 264 Participants | 271 Participants |
| Gender Male | 0 Participants | 0 Participants | 0 Participants |
| IBS-SSS Score Mild IBS (<175) | 8 participants | 6 participants | 2 participants |
| IBS-SSS Score Missing | 3 participants | 2 participants | 1 participants |
| IBS-SSS Score Moderate IBS (175 to <300) | 79 participants | 44 participants | 35 participants |
| IBS-SSS Score Severe IBS (>=300) | 445 participants | 212 participants | 233 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 285 participants | 136 participants | 149 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 250 participants | 128 participants | 122 participants |
| Region of Enrollment Europe | 135 participants | 66 participants | 69 participants |
| Region of Enrollment North America | 400 participants | 198 participants | 202 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 35 / 271 | 33 / 264 |
| serious Total, serious adverse events | 0 / 271 | 2 / 264 |
Outcome results
Primary
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).
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.
Time frame: 12 weeks
Population: The primary efficacy analysis was performed on the modified ITT population (n=437): all patients included in the ITT population excluding patients from one site, where a potential serious breach of GCP was reported, and from another site, where disqualification proceedings against the Investigator were confirmed by the FDA.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibodutant 10 mg | 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). | 35.7 Percentage of Responders |
| Placebo | 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). | 34.7 Percentage of Responders |
Secondary
Evaluation of Rebound Effects
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.
Time frame: 4 weeks
Population: modified RW population: only patients randomised to ibodutant in the 12-week treatment period and re-randomized to placebo for the 4-week RW period (excluding patients from one site, where a potential serious breach of GCP was reported, and another site, where disqualification proceedings against the Investigator were confirmed by FDA).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ibodutant 10 mg | Evaluation of Rebound Effects | 4-week RW-Bristol Stool Scale (NRS, 1 - 7 points) | -1.38 units on a scale | Standard Deviation 1.37 |
| Ibodutant 10 mg | Evaluation of Rebound Effects | Baseline-Abdominal Pain Score (NRS, 0-10 points) | 6.53 units on a scale | Standard Deviation 1.6 |
| Ibodutant 10 mg | Evaluation of Rebound Effects | 4-week RW-Abdominal Pain Score (NRS, 0-10 points) | -3.11 units on a scale | Standard Deviation 2.21 |
| Ibodutant 10 mg | Evaluation of Rebound Effects | Baseline-Bristol Stool Scale (NRS, 1 - 7 points) | 6.05 units on a scale | Standard Deviation 0.52 |
Secondary
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).
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.
Time frame: 12 weeks
Population: The secondary efficacy analysis was performed on the modified ITT population (n=437): all patients included in the ITT population excluding patients from one site, where a potential serious breach of GCP was reported, and from another site, where disqualification proceedings against the Investigator were confirmed by the FDA.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibodutant 10 mg | 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). | 48.0 percentage of responders |
| Placebo | 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). | 47.7 percentage of responders |
Secondary
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).
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.
Time frame: 12 weeks
Population: The secondary efficacy analysis was performed on the modified ITT population (n=437): all patients included in the ITT population excluding patients from one site, where a potential serious breach of GCP was reported, and from another site, where disqualification proceedings against the Investigator were confirmed by the FDA.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibodutant 10 mg | 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). | 21.3 percentage of responders |
| Placebo | 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). | 19.0 percentage of responders |
Secondary
Weekly Response for Stool Consistency Over 12 Weeks of Treatment in at Least 50% of the Weeks of Treatment (6 Out of 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.
Time frame: 12 weeks
Population: The secondary efficacy analysis was performed on the modified ITT population (n=437): all patients included in the ITT population excluding patients from one site, where a potential serious breach of GCP was reported, and from another site, where disqualification proceedings against the Investigator were confirmed by the FDA.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibodutant 10 mg | Weekly Response for Stool Consistency Over 12 Weeks of Treatment in at Least 50% of the Weeks of Treatment (6 Out of 12 Weeks). | 44.8 percentage of responders |
| Placebo | Weekly Response for Stool Consistency Over 12 Weeks of Treatment in at Least 50% of the Weeks of Treatment (6 Out of 12 Weeks). | 43.1 percentage of responders |