Irritable Bowel Syndrome With Diarrhea (IBS-D)
Conditions
Keywords
Abdominal pain, Diarrhea, Irritable Bowel Syndrome
Brief summary
To evaluate the safety and tolerability, treatment effect on abdominal pain, and dose response of MD-7246 administered orally to patients with diarrhea-predominant irritable bowel syndrome (IBS-D).
Interventions
DRUGMD-7246
Oral tablet
DRUGPlacebo
Matching oral tablet
Sponsors
Allergan Sales, LLC
Ironwood Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient meets the Rome IV criteria for diagnosis of IBS-D * Patient maintains a minimum level of compliance with daily diary * Female patients of childbearing potential must agree to use one of the following methods of birth control: 1. Hormonal contraception 2. Double-barrier method 3. Maintenance of a monogamous relationship with a male partner who has been surgically sterilized by vasectomy
Exclusion criteria
* Patient has clinically significant findings on a physical examination and/or clinical laboratory tests * Patient has symptoms of or been diagnosed with a medical condition that may contribute to abdominal pain * Patient has a structural abnormality of the gastrointestinal (GI) tract or a disease or condition that can affect GI motility * Patient has any protocol-excluded or clinically significant medical or surgical history that could confound the study assessments NOTE: Additional inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Abdominal Pain at Its Worst on a NRS Through the Treatment Period | Baseline, up to Week 12 (end of the Treatment Period) | Abdominal pain is measured daily in an eDiary, using an 11-point NRS, where 0 is anchored with no abdominal pain and 10 is anchored with worst possible abdominal pain. The postbaseline weekly abdominal pain score is the average of the non-missing daily abdominal pain at its worst scores during a week (Weeks 1-12) if there are at least 4 daily scores entered into the eDiary during the week. Weekly change from baseline was calculated for each week as the weekly score minus the baseline score. Mixed model repeated measures (MMRM) results are based on a repeated measures analysis with treatment, analysis week, and treatment-by-week interaction as fixed effects and baseline as covariate. An unstructured covariance structure was used to model intra-subject correlation with subjects as a random effect. Baseline is derived from the eDiary data collected daily in the Pretreatment Period, specifically the period of time from 14 days before randomization up to the time of randomization. |
| Percentage of Participants Who Were 6/12 Week Abdominal Pain 30% Change Responders | Baseline through Week 12 | A 6/12 Week Abdominal Pain 30% Responder was a participant who had a decrease from baseline of ≥30% in the weekly abdominal pain score for that week for at least 6 out of the 12 weeks of the Treatment Period; for any week, a participant with \< 4 daily abdominal pain scores available was considered a non-responder for that week. Abdominal pain is measured daily in an eDiary, using an 11-point NRS, where 0 is anchored with no abdominal pain and 10 is anchored with worst possible abdominal pain. The postbaseline weekly abdominal pain score is the average of the non-missing daily abdominal pain at its worst scores during a week (Weeks 1-12) if there are at least 4 daily scores entered into the eDiary during the week. |
Countries
United States
Participant flow
Pre-assignment details
This study included a Pretreatment Period, 14 to 21 days immediately before randomization. During this period, participants underwent symptomatic assessments in an electronic diary (eDiary); those who satisfied all entry criteria based on these assessments entered the Treatment Period and were randomized to 1 of 4 treatments: MD-7246 300, 600, or 1200 μg or placebo (1:1:1:1). Of the 515 participants in the Pretreatment Period, 127 were not randomized.
Participants by arm
| Arm | Count |
|---|---|
| Placebo 4 matching placebo oral tablets once daily (QD) for 12 weeks | 97 |
| MD-7246 300 μg 1 MD-7246 300-μg oral tablet and 3 matching placebo oral tablets QD for 12 weeks | 97 |
| MD-7246 600 μg 2 MD-7246 300-μg oral tablets and 2 matching placebo oral tablets QD for 12 weeks | 97 |
| MD-7246 1200 μg 4 MD-7246 300-μg oral tablets QD for 12 weeks | 97 |
| Total | 388 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 3 | 4 |
| Overall Study | Lost to Follow-up | 4 | 1 | 4 | 3 |
| Overall Study | Noncompliance With Study drug | 0 | 1 | 0 | 0 |
| Overall Study | Other Not specified | 0 | 2 | 2 | 2 |
| Overall Study | Pregnancy | 0 | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 4 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | MD-7246 1200 μg | MD-7246 600 μg | MD-7246 300 μg |
|---|---|---|---|---|---|
| Abdominal Pain at Its Worst at Each Week on a Numerical Rating Scale (NRS) | 6.22 units on a scale STANDARD_DEVIATION 1.236 | 6.12 units on a scale STANDARD_DEVIATION 1.164 | 6.24 units on a scale STANDARD_DEVIATION 1.169 | 5.95 units on a scale STANDARD_DEVIATION 1.129 | 6.05 units on a scale STANDARD_DEVIATION 1.112 |
| Age, Continuous | 43.4 years STANDARD_DEVIATION 13.12 | 43.9 years STANDARD_DEVIATION 14.04 | 45.1 years STANDARD_DEVIATION 14.58 | 42.2 years STANDARD_DEVIATION 14.38 | 45.0 years STANDARD_DEVIATION 14.04 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 24 Participants | 89 Participants | 13 Participants | 29 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 73 Participants | 299 Participants | 84 Participants | 68 Participants | 74 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 13 Participants | 50 Participants | 14 Participants | 9 Participants | 14 Participants |
| Race/Ethnicity, Customized Black or African American | 11 Participants | 51 Participants | 14 Participants | 12 Participants | 14 Participants |
| Race/Ethnicity, Customized Caucasian | 72 Participants | 283 Participants | 67 Participants | 75 Participants | 69 Participants |
| Race/Ethnicity, Customized Multiple Races | 0 Participants | 3 Participants | 2 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Female | 66 Participants | 264 Participants | 68 Participants | 67 Participants | 63 Participants |
| Sex: Female, Male Male | 31 Participants | 124 Participants | 29 Participants | 30 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 97 | 0 / 97 | 0 / 97 | 0 / 97 |
| other Total, other adverse events | 27 / 97 | 28 / 97 | 42 / 97 | 52 / 97 |
| serious Total, serious adverse events | 0 / 97 | 0 / 97 | 0 / 97 | 1 / 97 |
Outcome results
Primary
Change From Baseline in Abdominal Pain at Its Worst on a NRS Through the Treatment Period
Abdominal pain is measured daily in an eDiary, using an 11-point NRS, where 0 is anchored with no abdominal pain and 10 is anchored with worst possible abdominal pain. The postbaseline weekly abdominal pain score is the average of the non-missing daily abdominal pain at its worst scores during a week (Weeks 1-12) if there are at least 4 daily scores entered into the eDiary during the week. Weekly change from baseline was calculated for each week as the weekly score minus the baseline score. Mixed model repeated measures (MMRM) results are based on a repeated measures analysis with treatment, analysis week, and treatment-by-week interaction as fixed effects and baseline as covariate. An unstructured covariance structure was used to model intra-subject correlation with subjects as a random effect. Baseline is derived from the eDiary data collected daily in the Pretreatment Period, specifically the period of time from 14 days before randomization up to the time of randomization.
Time frame: Baseline, up to Week 12 (end of the Treatment Period)
Population: Modified Intent-to-Treat (mITT) Population: all randomized participants who received at least 1 dose of study drug. Participants with an assessment at Baseline and during the treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Abdominal Pain at Its Worst on a NRS Through the Treatment Period | -2.01 units on a scale | Standard Error 0.179 |
| MD-7246 300 μg | Change From Baseline in Abdominal Pain at Its Worst on a NRS Through the Treatment Period | -1.93 units on a scale | Standard Error 0.179 |
| MD-7246 600 μg | Change From Baseline in Abdominal Pain at Its Worst on a NRS Through the Treatment Period | -1.58 units on a scale | Standard Error 0.182 |
| MD-7246 1200 μg | Change From Baseline in Abdominal Pain at Its Worst on a NRS Through the Treatment Period | -1.95 units on a scale | Standard Error 0.18 |
p-value: 0.746795% CI: [-0.42, 0.58]MMRM
p-value: 0.094195% CI: [-0.07, 0.93]MMRM
p-value: 0.809895% CI: [-0.44, 0.56]MMRM
Primary
Percentage of Participants Who Were 6/12 Week Abdominal Pain 30% Change Responders
A 6/12 Week Abdominal Pain 30% Responder was a participant who had a decrease from baseline of ≥30% in the weekly abdominal pain score for that week for at least 6 out of the 12 weeks of the Treatment Period; for any week, a participant with \< 4 daily abdominal pain scores available was considered a non-responder for that week. Abdominal pain is measured daily in an eDiary, using an 11-point NRS, where 0 is anchored with no abdominal pain and 10 is anchored with worst possible abdominal pain. The postbaseline weekly abdominal pain score is the average of the non-missing daily abdominal pain at its worst scores during a week (Weeks 1-12) if there are at least 4 daily scores entered into the eDiary during the week.
Time frame: Baseline through Week 12
Population: Modified Intent-to-Treat (mITT) Population: all randomized participants who received at least 1 dose of study drug. Participants with an assessment at Baseline and during the treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Were 6/12 Week Abdominal Pain 30% Change Responders | 55.7 percentage of participants |
| MD-7246 300 μg | Percentage of Participants Who Were 6/12 Week Abdominal Pain 30% Change Responders | 56.7 percentage of participants |
| MD-7246 600 μg | Percentage of Participants Who Were 6/12 Week Abdominal Pain 30% Change Responders | 44.3 percentage of participants |
| MD-7246 1200 μg | Percentage of Participants Who Were 6/12 Week Abdominal Pain 30% Change Responders | 48.5 percentage of participants |
95% CI: [-12.9, 15]
95% CI: [-25.3, 2.6]
95% CI: [-21.2, 6.8]
p-value: 0.885295% CI: [0.591, 1.839]Cochran-Mantel-Haenszel
p-value: 0.115295% CI: [0.36, 1.117]Cochran-Mantel-Haenszel
p-value: 0.315795% CI: [0.425, 1.317]Cochran-Mantel-Haenszel