Irritable Bowel Syndrome Characterized by Constipation
Conditions
Brief summary
To evaluate the efficacy on abdominal symptoms (abdominal bloating, abdominal discomfort, and abdominal pain) and safety of linaclotide 290 μg administered orally to patients with IBS-C.
Detailed description
This study consists of a 12-week Treatment Period followed by 4-week Randomized Withdrawal (RW) Period.
Interventions
DRUGLinaclotide
Oral capsule
DRUGPlacebo
Matching placebo oral capsule
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 has no clinically significant findings on a physical examination and clinical laboratory tests * Female patients of childbearing potential must agree to use one of the following methods of birth control: 1. Hormonal contraception 2. Double-barrier birth control 3. Maintenance of a monogamous relationship with a male partner who has been surgically sterilized by vasectomy * Patient meets protocol criteria for diagnosis of IBS-C * Patient demonstrates continued IBS-C symptoms through Pretreatment Period * Patient maintains a minimum level of compliance with daily diary
Exclusion criteria
* Patient has history of loose or watery stools * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Throughout the Treatment Period | Baseline (14 days before randomization up to the time of randomization), Treatment Period (Weeks 1-12) | A participant's daily abdominal score was calculated as the average of daily e-diary abdominal pain, abdominal bloating and abdominal discomfort scores, each based on an 11-point scale of 0 (none) and 10 (worst possible). Baseline abdominal score was 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. The participant's abdominal score was averaged on a weekly basis, and each weekly change from baseline was calculated for the treatment period and used as the dependent variable in the mixed model with repeated measures (MMRM) model. MMRM results are based on a model with treatment, analysis week, region and treatment-by-week interaction as fixed effects and baseline as a covariate. An unstructured covariance structure was used to model intra-subject correlation with subjects as a random effect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score | Baseline (14 days before randomization up to the time of randomization), Treatment Period (Weeks 1-12) | A participant's daily abdominal score was calculated as the average of daily e-diary abdominal pain, abdominal bloating and abdominal discomfort scores, each based on an 11-point scale of 0 (none) and 10 (worst possible). Baseline abdominal score was 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. The 12-week abdominal score was the average of the non-missing abdominal scores reported over the course of the treatment period. Change from baseline (BL) was calculated as the 12-week score minus the baseline score. The table presents the percentage of participants whose 12-week change from baseline was less than or equal to the threshold value of the score change (cumulative distribution of change). |
| Percentage of 6/12 Week Abdominal Score Responders (Responder Rate) | Baseline (14 days before randomization up to the time of randomization), Treatment Period (Weeks 1-12) | A 6/12 week abdominal score responder is a participant who meets the weekly abdominal score responder criteria for at least 6 out of the 12 weeks of the Treatment Period. For each week in the Treatment Period, a weekly abdominal score responder is a participant who has an improvement from baseline of at least 2 points (ie, a -2 point change from baseline) in the respective weekly abdominal score. If a participant did not have at least 4 completed eDiary entries for a particular Treatment Period week, the participant was not considered a responder for that week. A participant's daily abdominal score was calculated as the average of daily e-diary abdominal pain, abdominal bloating and abdominal discomfort scores, each based on an 11-point scale of 0 (none) and 10 (worst possible). The participant's abdominal score was averaged on a weekly basis, and each weekly change from baseline was calculated for the treatment period. |
| Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Baseline (14 days before randomization up to the time of randomization), Weeks 1-12 | A participant's daily abdominal score was calculated as the average of daily e-diary abdominal pain, abdominal bloating and abdominal discomfort scores, each based on an 11-point scale of 0 (none) and 10 (worst possible). Baseline abdominal score was 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. The participant's abdominal score was averaged on a weekly basis, and each weekly change from baseline was calculated for the treatment period and used as the dependent variable in the mixed model with repeated measures (MMRM) model. MMRM results are based on a model with treatment, analysis week, region and treatment-by-week interaction as fixed effects and baseline as a covariate. An unstructured covariance structure was used to model intra-subject correlation with subjects as a random effect. |
Countries
United States
Participant flow
Pre-assignment details
Treatment Period (TP, 12 weeks): Participants were randomized 1:1 to linaclotide 290 μg or placebo once daily. Randomized Withdrawal Period (4 weeks): * Participants randomized to linaclotide 290 μg during TP were rerandomized 1:1 to linaclotide 290 μg or placebo * Participants randomized to placebo during TP were allocated to linaclotide 290 μg.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants randomized to receive placebo to linaclotide orally once daily for 12 weeks during the Treatment Period. | 308 |
| Linaclotide 290 µg Participants randomized to receive linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period. | 306 |
| Total | 614 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Randomized Withdrawal Period | Adverse Event | 0 | 0 | 3 | 0 | 0 |
| Randomized Withdrawal Period | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 |
| Randomized Withdrawal Period | Other, Not Specified | 0 | 0 | 4 | 2 | 0 |
| Randomized Withdrawal Period | Withdrawal by Subject | 0 | 0 | 0 | 0 | 2 |
| Treatment Period | Adverse Event | 4 | 9 | 0 | 0 | 0 |
| Treatment Period | Lost to Follow-up | 7 | 6 | 0 | 0 | 0 |
| Treatment Period | Other, Not Specified | 4 | 6 | 0 | 0 | 0 |
| Treatment Period | Pregnancy | 1 | 0 | 0 | 0 | 0 |
| Treatment Period | Protocol Violation | 1 | 0 | 0 | 0 | 0 |
| Treatment Period | Withdrawal by Subject | 7 | 5 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Linaclotide 290 µg | Placebo |
|---|---|---|---|
| Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) | 6.42 score on a scale STANDARD_DEVIATION 1.61 | 6.39 score on a scale STANDARD_DEVIATION 1.63 | 6.46 score on a scale STANDARD_DEVIATION 1.6 |
| Age, Continuous | 46.7 years STANDARD_DEVIATION 14.4 | 46.5 years STANDARD_DEVIATION 14.6 | 46.8 years STANDARD_DEVIATION 14.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 168 Participants | 87 Participants | 81 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 446 Participants | 219 Participants | 227 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 71 Participants | 36 Participants | 35 Participants |
| Race/Ethnicity, Customized Black or African American | 146 Participants | 76 Participants | 70 Participants |
| Race/Ethnicity, Customized Caucasian | 387 Participants | 189 Participants | 198 Participants |
| Race/Ethnicity, Customized Other, Not Specified | 10 Participants | 5 Participants | 5 Participants |
| Sex: Female, Male Female | 496 Participants | 241 Participants | 255 Participants |
| Sex: Female, Male Male | 118 Participants | 65 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 308 | 0 / 306 | 0 / 138 | 0 / 137 | 0 / 279 |
| other Total, other adverse events | 15 / 308 | 26 / 306 | 5 / 138 | 4 / 137 | 21 / 279 |
| serious Total, serious adverse events | 2 / 308 | 4 / 306 | 1 / 138 | 0 / 137 | 1 / 279 |
Outcome results
Primary
Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Throughout the Treatment Period
A participant's daily abdominal score was calculated as the average of daily e-diary abdominal pain, abdominal bloating and abdominal discomfort scores, each based on an 11-point scale of 0 (none) and 10 (worst possible). Baseline abdominal score was 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. The participant's abdominal score was averaged on a weekly basis, and each weekly change from baseline was calculated for the treatment period and used as the dependent variable in the mixed model with repeated measures (MMRM) model. MMRM results are based on a model with treatment, analysis week, region and treatment-by-week interaction as fixed effects and baseline as a covariate. An unstructured covariance structure was used to model intra-subject correlation with subjects as a random effect.
Time frame: Baseline (14 days before randomization up to the time of randomization), Treatment Period (Weeks 1-12)
Population: Intent to Treat Population: all randomized participants. Two participants were excluded from the analysis due to missing scores.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Throughout the Treatment Period | -1.182 score on a scale | Standard Error 0.109 |
| Linaclotide 290 µg | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Throughout the Treatment Period | -1.898 score on a scale | Standard Error 0.111 |
Comparison: The overall family-wise Type I error rate for the primary and secondary outcome measures were controlled at the α=0.05 level by employing a fixed-sequence testing procedure. Outcome measures were tested using 10 hypotheses, each comparing linaclotide versus placebo, in the sequence of presentation of statistical analyses in this record. If the hypothesis comparing the 2 groups was statistically significant (α=0.05), then the next hypothesis was to be tested; otherwise, testing would stop.p-value: <0.000195% CI: [-0.998, -0.433]MMRM
Secondary
Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score
A participant's daily abdominal score was calculated as the average of daily e-diary abdominal pain, abdominal bloating and abdominal discomfort scores, each based on an 11-point scale of 0 (none) and 10 (worst possible). Baseline abdominal score was 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. The 12-week abdominal score was the average of the non-missing abdominal scores reported over the course of the treatment period. Change from baseline (BL) was calculated as the 12-week score minus the baseline score. The table presents the percentage of participants whose 12-week change from baseline was less than or equal to the threshold value of the score change (cumulative distribution of change).
Time frame: Baseline (14 days before randomization up to the time of randomization), Treatment Period (Weeks 1-12)
Population: Intent to Treat Population: all randomized participants. Participants with available 12-week abdominal score.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score | Change from BL threshold: -8.0 | 0.0 percentage of participants |
| Placebo | Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score | Change from BL threshold: -4.0 | 4.9 percentage of participants |
| Placebo | Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score | Change from BL threshold: -6.0 | 0.3 percentage of participants |
| Placebo | Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score | Change from BL threshold: -3.0 | 11.4 percentage of participants |
| Placebo | Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score | Change from BL threshold: -7.0 | 0.3 percentage of participants |
| Placebo | Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score | Change from BL threshold: -2.0 | 23.9 percentage of participants |
| Placebo | Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score | Change from BL threshold: -5.0 | 2.3 percentage of participants |
| Placebo | Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score | Change from BL threshold: -1.0 | 42.8 percentage of participants |
| Placebo | Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score | Change from BL threshold: -9.0 | 0.0 percentage of participants |
| Linaclotide 290 µg | Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score | Change from BL threshold: -1.0 | 58.8 percentage of participants |
| Linaclotide 290 µg | Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score | Change from BL threshold: -9.0 | 0.3 percentage of participants |
| Linaclotide 290 µg | Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score | Change from BL threshold: -8.0 | 0.7 percentage of participants |
| Linaclotide 290 µg | Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score | Change from BL threshold: -7.0 | 1.3 percentage of participants |
| Linaclotide 290 µg | Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score | Change from BL threshold: -6.0 | 2.3 percentage of participants |
| Linaclotide 290 µg | Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score | Change from BL threshold: -5.0 | 6.2 percentage of participants |
| Linaclotide 290 µg | Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score | Change from BL threshold: -4.0 | 14.4 percentage of participants |
| Linaclotide 290 µg | Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score | Change from BL threshold: -3.0 | 24.5 percentage of participants |
| Linaclotide 290 µg | Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score | Change from BL threshold: -2.0 | 40.2 percentage of participants |
Comparison: The overall family-wise Type I error rate for the primary and secondary outcome measures were controlled at the α=0.05 level by employing a fixed-sequence testing procedure. Outcome measures were tested using 10 hypotheses, each comparing linaclotide versus placebo, in the sequence of presentation of statistical analyses in this record. If the hypothesis comparing the 2 groups was statistically significant (α=0.05), then the next hypothesis was to be tested; otherwise, testing would stop.p-value: <0.000195% CI: [-0.88, -0.35]Wilcoxon Rank Sum Test
Secondary
Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period
A participant's daily abdominal score was calculated as the average of daily e-diary abdominal pain, abdominal bloating and abdominal discomfort scores, each based on an 11-point scale of 0 (none) and 10 (worst possible). Baseline abdominal score was 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. The participant's abdominal score was averaged on a weekly basis, and each weekly change from baseline was calculated for the treatment period and used as the dependent variable in the mixed model with repeated measures (MMRM) model. MMRM results are based on a model with treatment, analysis week, region and treatment-by-week interaction as fixed effects and baseline as a covariate. An unstructured covariance structure was used to model intra-subject correlation with subjects as a random effect.
Time frame: Baseline (14 days before randomization up to the time of randomization), Weeks 1-12
Population: Intent to Treat Population: all randomized participants. Participants with an assessment at given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Change from Baseline at Week 1 | -0.490 score on a scale | Standard Error 0.085 |
| Placebo | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Change from Baseline at Week 2 | -0.795 score on a scale | Standard Error 0.102 |
| Placebo | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Change from Baseline at Week 3 | -0.908 score on a scale | Standard Error 0.11 |
| Placebo | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Change from Baseline at Week 4 | -1.048 score on a scale | Standard Error 0.115 |
| Placebo | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Change from Baseline at Week 5 | -1.123 score on a scale | Standard Error 0.118 |
| Placebo | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Change from Baseline at Week 6 | -1.183 score on a scale | Standard Error 0.122 |
| Placebo | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Change from Baseline at Week 7 | -1.315 score on a scale | Standard Error 0.125 |
| Placebo | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Change from Baseline at Week 8 | -1.446 score on a scale | Standard Error 0.13 |
| Placebo | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Change from Baseline at Week 9 | -1.478 score on a scale | Standard Error 0.129 |
| Placebo | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Change from Baseline at Week 10 | -1.478 score on a scale | Standard Error 0.13 |
| Placebo | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Change from Baseline at Week 11 | -1.444 score on a scale | Standard Error 0.131 |
| Placebo | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Change from Baseline at Week 12 | -1.480 score on a scale | Standard Error 0.133 |
| Linaclotide 290 µg | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Change from Baseline at Week 11 | -2.288 score on a scale | Standard Error 0.132 |
| Linaclotide 290 µg | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Change from Baseline at Week 1 | -0.925 score on a scale | Standard Error 0.087 |
| Linaclotide 290 µg | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Change from Baseline at Week 7 | -2.073 score on a scale | Standard Error 0.126 |
| Linaclotide 290 µg | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Change from Baseline at Week 2 | -1.423 score on a scale | Standard Error 0.104 |
| Linaclotide 290 µg | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Change from Baseline at Week 10 | -2.197 score on a scale | Standard Error 0.132 |
| Linaclotide 290 µg | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Change from Baseline at Week 3 | -1.592 score on a scale | Standard Error 0.112 |
| Linaclotide 290 µg | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Change from Baseline at Week 8 | -2.110 score on a scale | Standard Error 0.131 |
| Linaclotide 290 µg | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Change from Baseline at Week 4 | -1.731 score on a scale | Standard Error 0.117 |
| Linaclotide 290 µg | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Change from Baseline at Week 12 | -2.347 score on a scale | Standard Error 0.135 |
| Linaclotide 290 µg | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Change from Baseline at Week 5 | -1.891 score on a scale | Standard Error 0.12 |
| Linaclotide 290 µg | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Change from Baseline at Week 9 | -2.181 score on a scale | Standard Error 0.13 |
| Linaclotide 290 µg | Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period | Change from Baseline at Week 6 | -2.014 score on a scale | Standard Error 0.124 |
Comparison: Week 3. Not part of the fixed-sequence testing procedure.p-value: <0.000195% CI: [-0.969, -0.398]MMRM
Comparison: Week 12. The overall family-wise Type I error rate for primary and secondary outcome measures were controlled at the α=0.05 level by employing a fixed-sequence testing procedure. Outcome measures were tested using 10 hypotheses, each comparing linaclotide versus placebo, in the sequence of presentation of statistical analyses in this record. If the hypothesis comparing the 2 groups was statistically significant (α=0.05), then the next hypothesis was to be tested; otherwise, testing would stop.p-value: <0.000195% CI: [-1.219, -0.515]MMRM
Comparison: Week 10. The overall family-wise Type I error rate for primary and secondary outcome measures were controlled at the α=0.05 level by employing a fixed-sequence testing procedure. Outcome measures were tested using 10 hypotheses, each comparing linaclotide versus placebo, in the sequence of presentation of statistical analyses in this record. If the hypothesis comparing the 2 groups was statistically significant (α=0.05), then the next hypothesis was to be tested; otherwise, testing would stop.p-value: <0.000195% CI: [-1.062, -0.376]MMRM
Comparison: Week 8. The overall family-wise Type I error rate for primary and secondary outcome measures were controlled at the α=0.05 level by employing a fixed-sequence testing procedure. Outcome measures were tested using 10 hypotheses, each comparing linaclotide versus placebo, in the sequence of presentation of statistical analyses in this record. If the hypothesis comparing the 2 groups was statistically significant (α=0.05), then the next hypothesis was to be tested; otherwise, testing would stop.p-value: 0.000295% CI: [-1.007, -0.322]MMRM
Comparison: Week 6. The overall family-wise Type I error rate for primary and secondary outcome measures were controlled at the α=0.05 level by employing a fixed-sequence testing procedure. Outcome measures were tested using 10 hypotheses, each comparing linaclotide versus placebo, in the sequence of presentation of statistical analyses in this record. If the hypothesis comparing the 2 groups was statistically significant (α=0.05), then the next hypothesis was to be tested; otherwise, testing would stop.p-value: <0.000195% CI: [-1.151, -0.511]MMRM
Comparison: Week 4. The overall family-wise Type I error rate for primary and secondary outcome measures were controlled at the α=0.05 level by employing a fixed-sequence testing procedure. Outcome measures were tested using 10 hypotheses, each comparing linaclotide versus placebo, in the sequence of presentation of statistical analyses in this record. If the hypothesis comparing the 2 groups was statistically significant (α=0.05), then the next hypothesis was to be tested; otherwise, testing would stop.p-value: <0.000195% CI: [-0.982, -0.383]MMRM
Comparison: Week 2. The overall family-wise Type I error rate for primary and secondary outcome measures were controlled at the α=0.05 level by employing a fixed-sequence testing procedure. Outcome measures were tested using 10 hypotheses, each comparing linaclotide versus placebo, in the sequence of presentation of statistical analyses in this record. If the hypothesis comparing the 2 groups was statistically significant (α=0.05), then the next hypothesis was to be tested; otherwise, testing would stop.p-value: <0.000195% CI: [-0.888, -0.368]MMRM
Comparison: Week 1. The overall family-wise Type I error rate for primary and secondary outcome measures were controlled at the α=0.05 level by employing a fixed-sequence testing procedure. Outcome measures were tested using 10 hypotheses, each comparing linaclotide versus placebo, in the sequence of presentation of statistical analyses in this record. If the hypothesis comparing the 2 groups was statistically significant (α=0.05), then the next hypothesis was to be tested; otherwise, testing would stop.p-value: <0.000195% CI: [-0.641, -0.228]MMRM
Comparison: Week 5. Not part of the fixed-sequence testing procedure.p-value: <0.000195% CI: [-1.076, -0.46]MMRM
Comparison: Week 7. Not part of the fixed-sequence testing procedure.p-value: <0.000195% CI: [-1.086, -0.431]MMRM
Comparison: Week 9. Not part of the fixed-sequence testing procedure.p-value: <0.000195% CI: [-1.043, -0.363]MMRM
Comparison: Week 11. Not part of the fixed-sequence testing procedure.p-value: <0.000195% CI: [-1.189, -0.498]MMRM
Secondary
Percentage of 6/12 Week Abdominal Score Responders (Responder Rate)
A 6/12 week abdominal score responder is a participant who meets the weekly abdominal score responder criteria for at least 6 out of the 12 weeks of the Treatment Period. For each week in the Treatment Period, a weekly abdominal score responder is a participant who has an improvement from baseline of at least 2 points (ie, a -2 point change from baseline) in the respective weekly abdominal score. If a participant did not have at least 4 completed eDiary entries for a particular Treatment Period week, the participant was not considered a responder for that week. A participant's daily abdominal score was calculated as the average of daily e-diary abdominal pain, abdominal bloating and abdominal discomfort scores, each based on an 11-point scale of 0 (none) and 10 (worst possible). The participant's abdominal score was averaged on a weekly basis, and each weekly change from baseline was calculated for the treatment period.
Time frame: Baseline (14 days before randomization up to the time of randomization), Treatment Period (Weeks 1-12)
Population: Intent to Treat Population: all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of 6/12 Week Abdominal Score Responders (Responder Rate) | 23.4 percentage of participants |
| Linaclotide 290 µg | Percentage of 6/12 Week Abdominal Score Responders (Responder Rate) | 40.5 percentage of participants |
95% CI: [9.9, 24.4]
Comparison: The overall family-wise Type I error rate for the primary and secondary outcome measures were controlled at the α=0.05 level by employing a fixed-sequence testing procedure. Outcome measures were tested using 10 hypotheses, each comparing linaclotide versus placebo, in the sequence of presentation of statistical analyses in this record. If the hypothesis comparing the 2 groups was statistically significant (α=0.05), then the next hypothesis was to be tested; otherwise, testing would stop.p-value: <0.000195% CI: [1.55, 3.12]Cochran-Mantel-Haenszel