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 24-week treatment period.
Detailed description
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 28-week re-randomised double-blind treatment 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.
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. 6. 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 the First 24 Weeks of Treatment in at Least 50% of the Weeks of Treatment (12 Out of 24 Weeks). | 24 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 (patients reported their worst abdominal pain on a 0 to 10 NRS scale, where 0 corresponds to no pain and 10 corresponds to worst possible pain); * 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 (patients reported their stool consistency response using the Bristol Stool Chart score based on a 1 to 7 NRS 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 the First 24 Weeks of Treatment in at Least 50% of the Weeks of Treatment (12 Out of 24 Weeks). | 24 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 the First 24 Weeks of Treatment in at Least 50% of the Weeks of Treatment (12 Out of 24 Weeks). | 24 weeks | The patient was considered a weekly stool consistency responder if she met 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. |
| Weekly Response for Relief of Overall IBS Signs and Symptoms Over the First 24 Weeks of Treatment in at Least 50% of the Weeks (12 Out of 24) | 24 weeks | The patient was considered a weekly responder if she has an IBS degree-of-relief equal to completely relieved/improved or considerably relieved/improved. Weekly e-diary assessment of IBS degree-of-relief of overall on signs or symptoms over the last 7 days was collected using a balanced 7-point Likert scale with 1= Completely relieved/improved, 2= Considerably relieved/improved, 3=Somewhat relieved/improved, 4= Unchanged, 5= Somewhat worse, 6=Considerably worse, 7= As bad as I can imagine. |
| Sustained Analysis of Response for Abdominal Pain AND Stool Consistency Over First 24-week Double-blind Treatment Period | 24 weeks | Weekly response for abdominal pain intensity AND stool consistency over the first 24 weeks of treatment in at least 50% of the weeks of treatment (12 out of 24 weeks) with at least 2 weeks of response in the last 4 weeks of treatment (week 21 to 24). The patient will be considered a weekly responder as defined for the primary endpoint. |
Countries
Czechia, Germany, Hungary, Latvia, Poland, Slovakia, Sweden, United Kingdom, United States
Participant flow
Recruitment details
The first patient was screened on 26th February 2014 and the first patient randomised on 24th March 2014. The last patient completed the study on 03rd November 2015. The study was conducted at 139 clinical sites in 9 countries (Czech Rep, Germany, Hungary, Latvia, Poland, Slovakia, Sweden, the USA and the United Kingdom)
Pre-assignment details
A total of 1300 patients entered a 2-week Screening period, 1072 entered the qualifying 2-week Run-in period and 558 of them were randomised. Two patients randomised to placebo never took the study medication.
Participants by arm
| Arm | Count |
|---|---|
| Ibodutant 10 mg Oral tablet to be given once daily for 24 weeks of treatment. Patients randomised to the ibodutant 10 mg arm will continue on ibodutant 10 mg for additional 28 weeks of treatment via mock-re-randomisation at week 25 .
Ibodutant 10 mg: Oral tablet, to be given once daily. | 277 |
| Placebo Oral tablet to be given once daily for 24 weeks of treatment. Patients randomised to the placebo arm will be re-randomised at week 25 in a 1:1 ratio to ibodutant or placebo for additional 28 weeks of treatment.
Placebo: Oral tablet, (identical in appearance and weight to ibodutant tablets), to be given once daily. | 279 |
| Total | 556 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 5 |
| Overall Study | Lack of Efficacy | 3 | 5 |
| Overall Study | Lost to Follow-up | 5 | 13 |
| Overall Study | Other | 4 | 0 |
| Overall Study | Physician Decision | 4 | 3 |
| Overall Study | Protocol Violation | 18 | 21 |
| Overall Study | Study terminated by Sponsor | 45 | 47 |
| Overall Study | Withdrawal by Subject | 33 | 25 |
Baseline characteristics
| Characteristic | Ibodutant 10 mg | Total | Placebo |
|---|---|---|---|
| Abdominal Pain Severity, Categorical Abdominal Pain Severity < 5 | 55 Participants | 109 Participants | 54 Participants |
| Abdominal Pain Severity, Categorical Abdominal Pain Severity ≥ 5 and < 8 | 172 Participants | 344 Participants | 172 Participants |
| Abdominal Pain Severity, Categorical Abdominal Pain Severity ≥ 8 | 50 Participants | 103 Participants | 53 Participants |
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 18 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 269 Participants | 538 Participants | 269 Participants |
| Age, Continuous | 42.6 years STANDARD_DEVIATION 12.2 | 43.2 years STANDARD_DEVIATION 12 | 43.8 years STANDARD_DEVIATION 11.8 |
| Body Mass Index, Continuous | 29.6 kg/m² STANDARD_DEVIATION 6.92 | 29.6 kg/m² STANDARD_DEVIATION 6.96 | 29.6 kg/m² STANDARD_DEVIATION 7.02 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 124 Participants | 255 Participants | 131 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 153 Participants | 301 Participants | 148 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Geographic Region Eastern Europe | 35 Participants | 65 Participants | 30 Participants |
| Geographic Region North America | 211 Participants | 425 Participants | 214 Participants |
| Geographic Region Western Europe | 31 Participants | 66 Participants | 35 Participants |
| IBS-Signs and Symptoms Score, Categorical Mild IBS | 7 Participants | 14 Participants | 7 Participants |
| IBS-Signs and Symptoms Score, Categorical Moderate IBS | 60 Participants | 118 Participants | 58 Participants |
| IBS-Signs and Symptoms Score, Categorical Severe IBS | 210 Participants | 424 Participants | 214 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 32 Participants | 60 Participants | 28 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 241 Participants | 488 Participants | 247 Participants |
| Sex: Female, Male Female | 277 Participants | 556 Participants | 279 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 75 / 277 | 82 / 279 |
| serious Total, serious adverse events | 3 / 277 | 2 / 279 |
Outcome results
Primary
Weekly Response for Abdominal Pain Intensity AND Stool Consistency Over the First 24 Weeks of Treatment in at Least 50% of the Weeks of Treatment (12 Out of 24 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 (patients reported their worst abdominal pain on a 0 to 10 NRS scale, where 0 corresponds to no pain and 10 corresponds to worst possible pain); * 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 (patients reported their stool consistency response using the Bristol Stool Chart score based on a 1 to 7 NRS scale where 1 corresponds to hard stool and 7 corresponds to watery diarrhoea).
Time frame: 24 weeks
Population: Modified ITT (mITT) Population: all patients included in the ITT population excluding patients from site 00179 (N=48), where a potential serious breach of Good Clinical Practice was reported, and site 00186 (N=34), where disqualification proceedings against the Investigator were initiated by the US Food and Drug Administration.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ibodutant 10 mg | Weekly Response for Abdominal Pain Intensity AND Stool Consistency Over the First 24 Weeks of Treatment in at Least 50% of the Weeks of Treatment (12 Out of 24 Weeks). | 51 Participants |
| Placebo | Weekly Response for Abdominal Pain Intensity AND Stool Consistency Over the First 24 Weeks of Treatment in at Least 50% of the Weeks of Treatment (12 Out of 24 Weeks). | 52 Participants |
p-value: 0.94995% CI: [0.64, 1.53]Cochran-Mantel-Haenszel
Secondary
Sustained Analysis of Response for Abdominal Pain AND Stool Consistency Over First 24-week Double-blind Treatment Period
Weekly response for abdominal pain intensity AND stool consistency over the first 24 weeks of treatment in at least 50% of the weeks of treatment (12 out of 24 weeks) with at least 2 weeks of response in the last 4 weeks of treatment (week 21 to 24). The patient will be considered a weekly responder as defined for the primary endpoint.
Time frame: 24 weeks
Population: Modified ITT (mITT) Population: all patients included in the ITT population excluding patients from site 00179 (N=48), where a potential serious breach of Good Clinical Practice was reported, and site 00186 (N=34), where disqualification proceedings against the Investigator were initiated by the US Food and Drug Administration.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ibodutant 10 mg | Sustained Analysis of Response for Abdominal Pain AND Stool Consistency Over First 24-week Double-blind Treatment Period | 50 Participants |
| Placebo | Sustained Analysis of Response for Abdominal Pain AND Stool Consistency Over First 24-week Double-blind Treatment Period | 45 Participants |
p-value: 0.56795% CI: [0.73, 1.81]Cochran-Mantel-Haenszel
Secondary
Weekly Response for Abdominal Pain Intensity Over the First 24 Weeks of Treatment in at Least 50% of the Weeks of Treatment (12 Out of 24 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: 24 weeks
Population: Modified ITT (mITT) Population: all patients included in the ITT population excluding patients from site 00179 (N=48), where a potential serious breach of Good Clinical Practice was reported, and site 00186 (N=34), where disqualification proceedings against the Investigator were initiated by the US Food and Drug Administration.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ibodutant 10 mg | Weekly Response for Abdominal Pain Intensity Over the First 24 Weeks of Treatment in at Least 50% of the Weeks of Treatment (12 Out of 24 Weeks). | 96 Participants |
| Placebo | Weekly Response for Abdominal Pain Intensity Over the First 24 Weeks of Treatment in at Least 50% of the Weeks of Treatment (12 Out of 24 Weeks). | 83 Participants |
p-value: 0.19395% CI: [0.88, 1.86]Cochran-Mantel-Haenszel
Secondary
Weekly Response for Relief of Overall IBS Signs and Symptoms Over the First 24 Weeks of Treatment in at Least 50% of the Weeks (12 Out of 24)
The patient was considered a weekly responder if she has an IBS degree-of-relief equal to completely relieved/improved or considerably relieved/improved. Weekly e-diary assessment of IBS degree-of-relief of overall on signs or symptoms over the last 7 days was collected using a balanced 7-point Likert scale with 1= Completely relieved/improved, 2= Considerably relieved/improved, 3=Somewhat relieved/improved, 4= Unchanged, 5= Somewhat worse, 6=Considerably worse, 7= As bad as I can imagine.
Time frame: 24 weeks
Population: Modified ITT (mITT) Population: all patients included in the ITT population excluding patients from site 00179 (N=48), where a potential serious breach of Good Clinical Practice was reported, and site 00186 (N=34), where disqualification proceedings against the Investigator were initiated by the US Food and Drug Administration.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ibodutant 10 mg | Weekly Response for Relief of Overall IBS Signs and Symptoms Over the First 24 Weeks of Treatment in at Least 50% of the Weeks (12 Out of 24) | 37 Participants |
| Placebo | Weekly Response for Relief of Overall IBS Signs and Symptoms Over the First 24 Weeks of Treatment in at Least 50% of the Weeks (12 Out of 24) | 29 Participants |
p-value: 0.27295% CI: [0.79, 2.26]Cochran-Mantel-Haenszel
Secondary
Weekly Response for Stool Consistency Over the First 24 Weeks of Treatment in at Least 50% of the Weeks of Treatment (12 Out of 24 Weeks).
The patient was considered a weekly stool consistency responder if she met 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.
Time frame: 24 weeks
Population: Modified ITT (mITT) Population: all patients included in the ITT population excluding patients from site 00179 (N=48), where a potential serious breach of Good Clinical Practice was reported, and site 00186 (N=34), where disqualification proceedings against the Investigator were initiated by the US Food and Drug Administration.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ibodutant 10 mg | Weekly Response for Stool Consistency Over the First 24 Weeks of Treatment in at Least 50% of the Weeks of Treatment (12 Out of 24 Weeks). | 72 Participants |
| Placebo | Weekly Response for Stool Consistency Over the First 24 Weeks of Treatment in at Least 50% of the Weeks of Treatment (12 Out of 24 Weeks). | 71 Participants |
p-value: 0.87295% CI: [0.7, 1.53]Cochran-Mantel-Haenszel