Chronic Constipation, Constipation
Conditions
Keywords
Chronic Constipation, Abdominal Bloating, Linaclotide
Brief summary
The purpose of this study is to evaluate the efficacy and safety of linaclotide compared with placebo in patients with chronic constipation (CC) and prominent abdominal bloating. This study includes an up to 3-week screening period and a 2-3 week pretreatment period. Patients who are eligible will be randomized to one of two doses of linaclotide or placebo for 12 weeks. This 12-week study will assess the effects of linaclotide on bowel movement frequency, as well as other abdominal and bowel symptoms of CC.
Interventions
oral capsule, taken once daily each morning at least 30 minutes before breakfast
oral capsule, taken once daily each morning at least 30 minutes before breakfast
DRUGMatching placebo
oral capsule, taken once daily each morning at least 30 minutes before breakfast
Sponsors
Ironwood Pharmaceuticals, Inc.
Forest Laboratories
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Patient has completed a colonoscopy according to the American Gastroenterological Association criteria with no clinically significant findings * Patient has successfully completed protocol procedures (with no clinically significant findings) * Patient meets protocol criteria for Chronic Constipation(CC): \< 3 bowel movements per week and reports one or more of the following symptoms for at least 12 weeks: 1. Straining during more than 25% of BMs 2. Lumpy or hard stools during more than 25% of BMs 3. Sensation of incomplete evacuation during more than 25% of BMs * Patient demonstrates continued chronic constipation and bloating through Pretreatment Period * Patient is compliant with Interactive voice response System (IVRS)
Exclusion criteria
* Patient has a history of loose or watery stools * Patient has symptoms of or been diagnosed with Irritable Bowel Syndrome (IBS) * 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 would limit the patient's ability to complete or participate in this clinical trial or could confound the study assessments
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 9/12 Week Complete Spontaneous Bowel Movement (CSBM) 3+1 Responder | 12-week treatment period | A 9/12 Week CSBM 3+1 Responder is a patient who is a CSBM 3+1 Weekly Responder for at least 9 out of the 12 weeks of the Treatment Period. A CSBM 3+1 Weekly Responder is a patient who had a CSBM Weekly Frequency Rate that was 3 or greater and increased by 1 or more from baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 12-Week Abdominal Bloating | Baseline and 12-week treatment period | Abdominal Bloating was measured daily using an 11-point Numerical Rating Scale (NRS) where a value of 0 represents no abdominal bloating and a value of 10 represents very severe abdominal bloating. The abdominal bloating score from Baseline is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization up to the time of randomization (Visit 3, Day 1). The change from baseline in 12-Week Abdominal Bloating score is the difference between the average nonmissing daily patient assessments of abdominal bloating scores during the 14 day Baseline period, and the average of the nonmissing daily patient assessments of abdominal bloating scores reported during the 12 week Treatment Period. |
| Percent Change From Baseline in 12-week Abdominal Bloating | Baseline and 12-week treatment period | Abdominal Bloating was measured daily using an 11-point Numerical Rating Scale (NRS) where a value of 0 represents no abdominal bloating and a value of 10 represents very severe abdominal bloating. The abdominal bloating score from Baseline is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). The percent change from baseline in 12-Week Abdominal Bloating score is the percentage difference between the average nonmissing daily patient assessments score of abdominal bloating scores during the 14 day Baseline period, and the average of the nonmissing daily patient assessments of abdominal bloating scores reported during the 12 week Treatment Period. |
| Percent Change From Baseline in Abdominal Bloating at Week 12 | Baseline and Week 12 | Abdominal bloating was measured daily using an 11-point Numerical Rating Scale (NRS) where a value of 0 represents no abdominal bloating and a value of 10 represents very severe abdominal bloating. The abdominal bloating score from Baseline is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). The percent change from baseline at Week 12 in Abdominal Bloating score is the percentage difference between the average nonmissing daily patient assessments of abdominal bloating scores during the 14 day Baseline period, and the average of the nonmissing daily patient assessments of abdominal bloating scores reported during Week 12. |
| 6/12 Week Abdominal Bloating 30% Responder | 12-week treatment period | A patient was a 6/12 week abdominal bloating 30% responder if, for at least 6 weeks of the 12-week treatment period, that patient's improvement from baseline in the weekly abdominal bloating score was ≥ 30% from baseline. |
| Change From Baseline in 12-week CSBM Frequency Rate | Baseline and 12-week treatment period | A patient's 12-week CSBM frequency rate from Baseline is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's 12-week CSBM frequency rate was the CSBM rate (CSBMs/week) calculated over the 12 weeks of the treatment period. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison. |
| Change From Baseline in CSBM Frequency Rate at Week 1. | Baseline and Week 1 | A patient's CSBM frequency rate from Baseline is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's CSBM frequency rate at week 1 was the CSBM rate (CSBMs/week) calculated over that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison. |
| Change From Baseline in CSBM Frequency Rate at Week 4. | Baseline and Week 4 | A patient's CSBM frequency rate from Baseline is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's CSBM frequency rate at week 4 was the CSBM rate (CSBMs/week) calculated over that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison. |
| Change From Baseline in CSBM Frequency Rate at Week 8 | Baseline and Week 8 | A patient's CSBM frequency rate from Baseline is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's CSBM frequency rate at week 8 was the CSBM rate (CSBMs/week) calculated over that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison. |
| Change From Baseline in CSBM Frequency Rate at Week 12 | Baseline and Week 12 | A patient's CSBM frequency rate from Baseline is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's CSBM frequency rate at week 12 was the CSBM rate (CSBMs/week) calculated over that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison. |
| Change From Baseline in 12-Week SBM Frequency Rate | 12-week treatment period | A patient's Baseline SBM frequency rate is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's 12-week SBM frequency rate was the SBM rate (SBMs/week) calculated over the 12 weeks of the treatment period. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison. |
| Change From Baseline in SBM Frequency Rate at Week 1 | Baseline and Week 1 | A patient's baseline SBM frequency rate is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's SBM frequency rate at week 1 was the SBM rate (SBMs/week) calculated over that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison. |
| 9/12 Week Complete Spontaneous Bowel Movement (CSBM) 3+1 Responder | 12-week treatment period | A 9/12 Week CSBM 3+1 Responder is a patient who is a CSBM 3+1 Weekly Responder for at least 9 out of the 12 weeks of the Treatment Period. A CSBM 3+1 Weekly Responder is a patient who had a CSBM Weekly Frequency Rate that was 3 or greater and increased by 1 or more from baseline. |
| Change From Baseline in SBM Frequency Rate at Week 8 | Baseline and Week 8 | A patient's baseline SBM frequency rate is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's SBM frequency rate at Week 8 was the SBM rate (SBMs/week) calculated over that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison. |
| Change From Baseline in SBM Frequency Rate at Week 12 | Baseline and Week 12 | A patient's baseline SBM frequency rate is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's SBM frequency rate at week 12 was the SBM rate (SBMs/week) calculated over that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison. |
| Change From Baseline in the Number of Days With a Spontaneous Bowel Movement (SBM) | Baseline and 12-week treatment period | A patient's baseline number of days with a Spontaneous Bowel Movement (SBM) was calculated as the number of days with at least 1 Spontaneous Bowel Movement (SBM), derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's number of days with a SBM during the Treatment Period was calculated as the number of days with at least 1 Spontaneous Bowel Movement (SBM), divided by treatment duration (in days), and multiplied by 7. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison. |
| SBM Within 24 Hours After the First Dose of Investigational Product | 24 hours from first dose of investigational product (Day 1) | The proportion of patients with a SBM within 24 hours of first taking investigational product in each linaclotide dose group was compared with the proportion in the placebo group using the Cochran-Mantel-Haenszel (CMH) test controlling for geographic region. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison. |
| Time to Spontaneous Bowel Movement (SBM) After the First Dose of Investigational Product | 12-week treatment period | Time to first SBM after the first dose of investigation product was defined as the number of hours between the time of the first dose of investigational product to the occurrence of the first SBM. Patients who did not achieve an SBM were considered censored, with time to censoring defined as the number of hours elapsing from the time of the first dose of investigational product was taken to the end of the day of the last dose, at 12:00 AM (24:00 military time). Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison. |
| Change From Baseline in 12-week Stool Consistency | Baseline and 12-week treatment period | Stool consistency was measured using the 7-point Bristol Stool Form Scale (BSFS): 1. = separate hard lumps like nuts \[difficult to pass\] 2. = sausage shaped but lumpy 3. = like a sausage but with cracks on surface 4. = like a sausage or snake, smooth and soft 5. = soft blobs with clear-cut edges \[passed easily\] 6. = fluffy pieces with ragged edges, a mushy stool 7. = watery, no solid pieces \[entirely liquid\] A patient's BSFS score for the baseline period (14 days before randomization, up to the time of randomization) and for the 12-week treatment period, was the average of the nonmissing BSFS scores from the SBMs reported by the patient during the respective baseline and treatment periods. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison. |
| Change From Baseline in Stool Consistency at Week 12 | Baseline and Week 12 | Stool consistency was measured using the 7-point Bristol Stool Form Scale (BSFS): 1. = separate hard lumps like nuts \[difficult to pass\] 2. = sausage shaped but lumpy 3. = like a sausage but with cracks on surface 4. = like a sausage or snake, smooth and soft 5. = soft blobs with clear-cut edges \[passed easily\] 6. = fluffy pieces with ragged edges, a mushy stool 7. = watery, no solid pieces \[entirely liquid\] A patient's BSFS score for the baseline period (14 days before randomization, up to the time of randomization) and at week 12, was the average of the nonmissing BSFS scores from the SBMs reported by the patient during the respective baseline period and during Week 12. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison. |
| Change From Baseline in 12-week Severity of Straining | Baseline and 12-week treatment period | Severity of straining was measured using a 5-point ordinal scale, where of value of 1 is not at all and a value of 5 is an extreme amount. A patient's straining score for baseline was derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's straining score for the treatment period was the average of the nonmissing straining scores from the SBMs reported by the patient during the 12-week treatment period. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison. |
| Change From Baseline in Severity of Straining at Week 12 | Baseline and Week 12 | Severity of straining was measured using a 5-point ordinal scale, where of value of 1 is not at all and a value of 5 is an extreme amount. A patient's straining score for baseline was derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's straining score at Week 12 was the average of the nonmissing straining scores from the SBMs reported by that patient during analysis Week 12. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison. |
| 9/12 Week Mild Straining and Diarrhea-free Responder | 12-week treatment period | A patient was a 9/12 week mild straining and diarrhea-free responder if that patient met the weekly criterion for at least 9 weeks of the 12-week treatment period. A patient was considered to have met the weekly criterion in a given week if that patient had a nonmissing average straining score ≤ 2 (where a value of 1 represents no straining, an a value of 5 represents an extreme amount of straining), and the patient had no diarrhea adverse event (AE) reported for that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison. |
| Change From Baseline in SBM Frequency Rate at Week 4 | Baseline and Week 4 | A patient's baseline SBM frequency rate is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's SBM frequency rate at Week 4 was the SBM rate (SBMs/week) calculated over that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison. |
Countries
Canada, United States
Participant flow
Recruitment details
Patient recruitment occurred at 136 study sites in the US and 5 study sites in Canada over a 6 month period from August of 2012 to February of 2013.
Pre-assignment details
Enrolled participants had up to 21 days of screening (screening period) to determine eligibility for entry into the study's pretreatment period. After an additional 14 to 21 days of pretreatment, those patients meeting entry criteria were randomized for 12 weeks of double-blind treatment.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching placebo
Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast | 173 |
| Linaclotide 145 Micrograms Linaclotide 145 micrograms
Linaclotide 145 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast | 153 |
| Linaclotide 290 Micrograms Linaclotide 290 micrograms
Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast | 160 |
| Total | 486 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 11 | 7 | 15 |
| Overall Study | Lack of Efficacy | 9 | 4 | 2 |
| Overall Study | Lost to Follow-up | 5 | 3 | 7 |
| Overall Study | Other Reason | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 15 | 13 | 6 |
| Overall Study | Withdrawal by Subject | 5 | 5 | 10 |
Baseline characteristics
| Characteristic | Linaclotide 290 Micrograms | Total | Placebo | Linaclotide 145 Micrograms |
|---|---|---|---|---|
| Age, Continuous | 47.5 Years STANDARD_DEVIATION 13.6 | 47.3 Years STANDARD_DEVIATION 13.2 | 46.3 Years STANDARD_DEVIATION 13.4 | 48.3 Years STANDARD_DEVIATION 12.6 |
| Age, Customized Age 18 to 39 years | 43 participants | 133 participants | 53 participants | 37 participants |
| Age, Customized Age 40 to 64 years | 99 participants | 307 participants | 104 participants | 104 participants |
| Age, Customized Age ≥ 65 years | 18 participants | 46 participants | 16 participants | 12 participants |
| BMI (Body Mass Index), mean | 29.83 kilograms per meter squared STANDARD_DEVIATION 6.57 | 29.12 kilograms per meter squared STANDARD_DEVIATION 6.23 | 28.43 kilograms per meter squared STANDARD_DEVIATION 6.03 | 29.17 kilograms per meter squared STANDARD_DEVIATION 6.03 |
| Height, mean | 164.37 cm STANDARD_DEVIATION 7.07 | 164.70 cm STANDARD_DEVIATION 8.08 | 164.87 cm STANDARD_DEVIATION 8.65 | 164.85 cm STANDARD_DEVIATION 8.44 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 participants | 1 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 4 participants | 3 participants | 1 participants |
| Race/Ethnicity, Customized Black or African American | 47 participants | 148 participants | 47 participants | 54 participants |
| Race/Ethnicity, Customized Hispanic | 25 participants | 70 participants | 26 participants | 19 participants |
| Race/Ethnicity, Customized Non-Hispanic | 135 participants | 416 participants | 147 participants | 134 participants |
| Race/Ethnicity, Customized Other | 0 participants | 4 participants | 3 participants | 1 participants |
| Race/Ethnicity, Customized White | 112 participants | 329 participants | 120 participants | 97 participants |
| Region of Enrollment Canada | 8 participants | 22 participants | 8 participants | 6 participants |
| Region of Enrollment United States | 152 participants | 464 participants | 165 participants | 147 participants |
| Sex/Gender, Customized Female | 148 participants | 445 participants | 159 participants | 138 participants |
| Sex/Gender, Customized Male | 12 participants | 41 participants | 14 participants | 15 participants |
| Weight, mean | 80.53 kg STANDARD_DEVIATION 18.2 | 79.12 kg STANDARD_DEVIATION 18.5 | 77.59 kg STANDARD_DEVIATION 19.19 | 79.39 kg STANDARD_DEVIATION 18.01 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 12 / 173 | 25 / 153 | 33 / 160 |
| serious Total, serious adverse events | 2 / 173 | 4 / 153 | 2 / 160 |
Outcome results
Primary
9/12 Week Complete Spontaneous Bowel Movement (CSBM) 3+1 Responder
A 9/12 Week CSBM 3+1 Responder is a patient who is a CSBM 3+1 Weekly Responder for at least 9 out of the 12 weeks of the Treatment Period. A CSBM 3+1 Weekly Responder is a patient who had a CSBM Weekly Frequency Rate that was 3 or greater and increased by 1 or more from baseline.
Time frame: 12-week treatment period
Population: 487 patients were randomized to treatment (Randomized Population). The Safety population consists of 486 randomized patients who received at least one dose of study drug. The Intent to Treat (ITT) population consists of 483 patients in the Safety population with valid post-baseline efficacy data. Reported outcome data is based on the ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | 9/12 Week Complete Spontaneous Bowel Movement (CSBM) 3+1 Responder | Responder | 13 participants |
| Placebo | 9/12 Week Complete Spontaneous Bowel Movement (CSBM) 3+1 Responder | Nonresponder | 158 participants |
| Linaclotide 290 Micrograms | 9/12 Week Complete Spontaneous Bowel Movement (CSBM) 3+1 Responder | Responder | 24 participants |
| Linaclotide 290 Micrograms | 9/12 Week Complete Spontaneous Bowel Movement (CSBM) 3+1 Responder | Nonresponder | 129 participants |
p-value: 0.026495% CI: [1.09, 4.56]Cochran-Mantel-Haenszel
Secondary
6/12 Week Abdominal Bloating 30% Responder
A patient was a 6/12 week abdominal bloating 30% responder if, for at least 6 weeks of the 12-week treatment period, that patient's improvement from baseline in the weekly abdominal bloating score was ≥ 30% from baseline.
Time frame: 12-week treatment period
Population: 487 patients were randomized to treatment (Randomized Population). The Safety population consists of 486 randomized patients who received at least one dose of study drug. The Intent to Treat (ITT) population consists of 483 patients in the Safety population with valid post-baseline efficacy data. Reported outcome data is based on the ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | 6/12 Week Abdominal Bloating 30% Responder | Responder | 50 participants |
| Placebo | 6/12 Week Abdominal Bloating 30% Responder | Nonresponder | 121 participants |
| Linaclotide 290 Micrograms | 6/12 Week Abdominal Bloating 30% Responder | Responder | 62 participants |
| Linaclotide 290 Micrograms | 6/12 Week Abdominal Bloating 30% Responder | Nonresponder | 91 participants |
| Linaclotide 290 Micrograms | 6/12 Week Abdominal Bloating 30% Responder | Nonresponder | 90 participants |
| Linaclotide 290 Micrograms | 6/12 Week Abdominal Bloating 30% Responder | Responder | 69 participants |
Secondary
9/12 Week Complete Spontaneous Bowel Movement (CSBM) 3+1 Responder
A 9/12 Week CSBM 3+1 Responder is a patient who is a CSBM 3+1 Weekly Responder for at least 9 out of the 12 weeks of the Treatment Period. A CSBM 3+1 Weekly Responder is a patient who had a CSBM Weekly Frequency Rate that was 3 or greater and increased by 1 or more from baseline.
Time frame: 12-week treatment period
Population: 487 patients were randomized to treatment (Randomized Population). The Safety population consists of 486 randomized patients who received at least one dose of study drug. The Intent to Treat (ITT) population consists of 483 patients in the Safety population with valid post-baseline efficacy data. Reported outcome data is based on the ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | 9/12 Week Complete Spontaneous Bowel Movement (CSBM) 3+1 Responder | Responder | 13 participants |
| Placebo | 9/12 Week Complete Spontaneous Bowel Movement (CSBM) 3+1 Responder | Nonresponder | 158 participants |
| Linaclotide 290 Micrograms | 9/12 Week Complete Spontaneous Bowel Movement (CSBM) 3+1 Responder | Responder | 26 participants |
| Linaclotide 290 Micrograms | 9/12 Week Complete Spontaneous Bowel Movement (CSBM) 3+1 Responder | Nonresponder | 133 participants |
Secondary
9/12 Week Mild Straining and Diarrhea-free Responder
A patient was a 9/12 week mild straining and diarrhea-free responder if that patient met the weekly criterion for at least 9 weeks of the 12-week treatment period. A patient was considered to have met the weekly criterion in a given week if that patient had a nonmissing average straining score ≤ 2 (where a value of 1 represents no straining, an a value of 5 represents an extreme amount of straining), and the patient had no diarrhea adverse event (AE) reported for that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.
Time frame: 12-week treatment period
Population: 487 patients were randomized to treatment (Randomized Population). The Safety population consists of 486 randomized patients who received at least one dose of study drug. The Intent to Treat (ITT) population consists of 483 patients in the Safety population with valid post-baseline efficacy data. Reported outcome data is based on the ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | 9/12 Week Mild Straining and Diarrhea-free Responder | Responder | 15 participants |
| Placebo | 9/12 Week Mild Straining and Diarrhea-free Responder | Nonresponder | 156 participants |
| Linaclotide 290 Micrograms | 9/12 Week Mild Straining and Diarrhea-free Responder | Responder | 38 participants |
| Linaclotide 290 Micrograms | 9/12 Week Mild Straining and Diarrhea-free Responder | Nonresponder | 115 participants |
| Linaclotide 290 Micrograms | 9/12 Week Mild Straining and Diarrhea-free Responder | Responder | 27 participants |
| Linaclotide 290 Micrograms | 9/12 Week Mild Straining and Diarrhea-free Responder | Nonresponder | 132 participants |
Secondary
Change From Baseline in 12-Week Abdominal Bloating
Abdominal Bloating was measured daily using an 11-point Numerical Rating Scale (NRS) where a value of 0 represents no abdominal bloating and a value of 10 represents very severe abdominal bloating. The abdominal bloating score from Baseline is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization up to the time of randomization (Visit 3, Day 1). The change from baseline in 12-Week Abdominal Bloating score is the difference between the average nonmissing daily patient assessments of abdominal bloating scores during the 14 day Baseline period, and the average of the nonmissing daily patient assessments of abdominal bloating scores reported during the 12 week Treatment Period.
Time frame: Baseline and 12-week treatment period
Population: 487 patients were randomized to treatment (Randomized Population). The Safety population consists of 486 randomized patients who received at least one dose of study drug. The Intent to Treat (ITT) population consists of 483 patients in the Safety population with valid post-baseline efficacy data. Reported outcome data is based on the ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 12-Week Abdominal Bloating | -1.583 units on a scale | Standard Deviation 1.988 |
| Linaclotide 290 Micrograms | Change From Baseline in 12-Week Abdominal Bloating | -2.476 units on a scale | Standard Deviation 2.315 |
| Linaclotide 290 Micrograms | Change From Baseline in 12-Week Abdominal Bloating | -2.456 units on a scale | Standard Deviation 2.24 |
Secondary
Change From Baseline in 12-week CSBM Frequency Rate
A patient's 12-week CSBM frequency rate from Baseline is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's 12-week CSBM frequency rate was the CSBM rate (CSBMs/week) calculated over the 12 weeks of the treatment period. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.
Time frame: Baseline and 12-week treatment period
Population: 487 patients were randomized to treatment (Randomized Population). The Safety population consists of 486 randomized patients who received at least one dose of study drug. The Intent to Treat (ITT) population consists of 483 patients in the Safety population with valid post-baseline efficacy data. Reported outcome data is based on the ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 12-week CSBM Frequency Rate | 1.020 CSBMs per week | Standard Deviation 1.596 |
| Linaclotide 290 Micrograms | Change From Baseline in 12-week CSBM Frequency Rate | 2.309 CSBMs per week | Standard Deviation 2.832 |
| Linaclotide 290 Micrograms | Change From Baseline in 12-week CSBM Frequency Rate | 2.292 CSBMs per week | Standard Deviation 2.79 |
Secondary
Change From Baseline in 12-Week SBM Frequency Rate
A patient's Baseline SBM frequency rate is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's 12-week SBM frequency rate was the SBM rate (SBMs/week) calculated over the 12 weeks of the treatment period. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.
Time frame: 12-week treatment period
Population: 487 patients were randomized to treatment (Randomized Population). The Safety population consists of 486 randomized patients who received at least one dose of study drug. The Intent to Treat (ITT) population consists of 483 patients in the Safety population with valid post-baseline efficacy data. Reported outcome data is based on the ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 12-Week SBM Frequency Rate | 1.480 SBMs per week | Standard Deviation 2.198 |
| Linaclotide 290 Micrograms | Change From Baseline in 12-Week SBM Frequency Rate | 3.481 SBMs per week | Standard Deviation 3.085 |
| Linaclotide 290 Micrograms | Change From Baseline in 12-Week SBM Frequency Rate | 3.550 SBMs per week | Standard Deviation 3.382 |
Secondary
Change From Baseline in 12-week Severity of Straining
Severity of straining was measured using a 5-point ordinal scale, where of value of 1 is not at all and a value of 5 is an extreme amount. A patient's straining score for baseline was derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's straining score for the treatment period was the average of the nonmissing straining scores from the SBMs reported by the patient during the 12-week treatment period. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.
Time frame: Baseline and 12-week treatment period
Population: 487 patients were randomized to treatment (Randomized Population). The Safety population consists of 486 randomized patients who received at least one dose of study drug. The Intent to Treat (ITT) population consists of 483 patients in the Safety population with valid post-baseline efficacy data. Reported outcome data is based on the ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 12-week Severity of Straining | -0.812 units on a scale | Standard Deviation 0.941 |
| Linaclotide 290 Micrograms | Change From Baseline in 12-week Severity of Straining | -1.495 units on a scale | Standard Deviation 0.938 |
| Linaclotide 290 Micrograms | Change From Baseline in 12-week Severity of Straining | -1.512 units on a scale | Standard Deviation 1.027 |
Secondary
Change From Baseline in 12-week Stool Consistency
Stool consistency was measured using the 7-point Bristol Stool Form Scale (BSFS): 1. = separate hard lumps like nuts \[difficult to pass\] 2. = sausage shaped but lumpy 3. = like a sausage but with cracks on surface 4. = like a sausage or snake, smooth and soft 5. = soft blobs with clear-cut edges \[passed easily\] 6. = fluffy pieces with ragged edges, a mushy stool 7. = watery, no solid pieces \[entirely liquid\] A patient's BSFS score for the baseline period (14 days before randomization, up to the time of randomization) and for the 12-week treatment period, was the average of the nonmissing BSFS scores from the SBMs reported by the patient during the respective baseline and treatment periods. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.
Time frame: Baseline and 12-week treatment period
Population: 487 patients were randomized to treatment (Randomized Population). The Safety population consists of 486 randomized patients who received at least one dose of study drug. The Intent to Treat (ITT) population consists of 483 patients in the Safety population with valid post-baseline efficacy data. Reported outcome data is based on the ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 12-week Stool Consistency | 0.797 units on a scale | Standard Deviation 1.129 |
| Linaclotide 290 Micrograms | Change From Baseline in 12-week Stool Consistency | 1.925 units on a scale | Standard Deviation 1.358 |
| Linaclotide 290 Micrograms | Change From Baseline in 12-week Stool Consistency | 2.304 units on a scale | Standard Deviation 1.47 |
Secondary
Change From Baseline in CSBM Frequency Rate at Week 1.
A patient's CSBM frequency rate from Baseline is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's CSBM frequency rate at week 1 was the CSBM rate (CSBMs/week) calculated over that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.
Time frame: Baseline and Week 1
Population: 487 patients were randomized to treatment (Randomized Population). The Safety population consists of 486 randomized patients who received at least one dose of study drug. The Intent to Treat (ITT) population consists of 483 patients in the Safety population with valid post-baseline efficacy data. Reported outcome data is based on the ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in CSBM Frequency Rate at Week 1. | 0.641 CSBMs per week | Standard Deviation 1.543 |
| Linaclotide 290 Micrograms | Change From Baseline in CSBM Frequency Rate at Week 1. | 1.984 CSBMs per week | Standard Deviation 3.784 |
| Linaclotide 290 Micrograms | Change From Baseline in CSBM Frequency Rate at Week 1. | 1.746 CSBMs per week | Standard Deviation 2.842 |
Secondary
Change From Baseline in CSBM Frequency Rate at Week 12
A patient's CSBM frequency rate from Baseline is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's CSBM frequency rate at week 12 was the CSBM rate (CSBMs/week) calculated over that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.
Time frame: Baseline and Week 12
Population: 487 patients were randomized to treatment (Randomized Population). The Safety population consists of 486 randomized patients who received at least one dose of study drug. The Intent to Treat (ITT) population consists of 483 patients in the Safety population with valid post-baseline efficacy data. Reported outcome data is based on the ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in CSBM Frequency Rate at Week 12 | 1.074 CSBMs per week | Standard Deviation 1.893 |
| Linaclotide 290 Micrograms | Change From Baseline in CSBM Frequency Rate at Week 12 | 2.272 CSBMs per week | Standard Deviation 2.801 |
| Linaclotide 290 Micrograms | Change From Baseline in CSBM Frequency Rate at Week 12 | 2.488 CSBMs per week | Standard Deviation 3.01 |
Secondary
Change From Baseline in CSBM Frequency Rate at Week 4.
A patient's CSBM frequency rate from Baseline is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's CSBM frequency rate at week 4 was the CSBM rate (CSBMs/week) calculated over that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.
Time frame: Baseline and Week 4
Population: 487 patients were randomized to treatment (Randomized Population). The Safety population consists of 486 randomized patients who received at least one dose of study drug. The Intent to Treat (ITT) population consists of 483 patients in the Safety population with valid post-baseline efficacy data. Reported outcome data is based on the ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in CSBM Frequency Rate at Week 4. | 1.063 CSBMs per week | Standard Deviation 2.176 |
| Linaclotide 290 Micrograms | Change From Baseline in CSBM Frequency Rate at Week 4. | 2.756 CSBMs per week | Standard Deviation 3.662 |
| Linaclotide 290 Micrograms | Change From Baseline in CSBM Frequency Rate at Week 4. | 2.678 CSBMs per week | Standard Deviation 3.552 |
Secondary
Change From Baseline in CSBM Frequency Rate at Week 8
A patient's CSBM frequency rate from Baseline is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's CSBM frequency rate at week 8 was the CSBM rate (CSBMs/week) calculated over that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.
Time frame: Baseline and Week 8
Population: 487 patients were randomized to treatment (Randomized Population). The Safety population consists of 486 randomized patients who received at least one dose of study drug. The Intent to Treat (ITT) population consists of 483 patients in the Safety population with valid post-baseline efficacy data. Reported outcome data is based on the ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in CSBM Frequency Rate at Week 8 | 1.347 CSBMs per week | Standard Deviation 2.438 |
| Linaclotide 290 Micrograms | Change From Baseline in CSBM Frequency Rate at Week 8 | 2.803 CSBMs per week | Standard Deviation 4.034 |
| Linaclotide 290 Micrograms | Change From Baseline in CSBM Frequency Rate at Week 8 | 2.319 CSBMs per week | Standard Deviation 2.989 |
Secondary
Change From Baseline in SBM Frequency Rate at Week 1
A patient's baseline SBM frequency rate is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's SBM frequency rate at week 1 was the SBM rate (SBMs/week) calculated over that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.
Time frame: Baseline and Week 1
Population: 487 patients were randomized to treatment (Randomized Population). The Safety population consists of 486 randomized patients who received at least one dose of study drug. The Intent to Treat (ITT) population consists of 483 patients in the Safety population with valid post-baseline efficacy data. Reported outcome data is based on the ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in SBM Frequency Rate at Week 1 | 1.840 SBMs per week | Standard Deviation 2.52 |
| Linaclotide 290 Micrograms | Change From Baseline in SBM Frequency Rate at Week 1 | 4.168 SBMs per week | Standard Deviation 4.547 |
| Linaclotide 290 Micrograms | Change From Baseline in SBM Frequency Rate at Week 1 | 4.125 SBMs per week | Standard Deviation 4.229 |
Secondary
Change From Baseline in SBM Frequency Rate at Week 12
A patient's baseline SBM frequency rate is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's SBM frequency rate at week 12 was the SBM rate (SBMs/week) calculated over that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.
Time frame: Baseline and Week 12
Population: 487 patients were randomized to treatment (Randomized Population). The Safety population consists of 486 randomized patients who received at least one dose of study drug. The Intent to Treat (ITT) population consists of 483 patients in the Safety population with valid post-baseline efficacy data. Reported outcome data is based on the ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in SBM Frequency Rate at Week 12 | 1.288 SBMs per week | Standard Deviation 2.221 |
| Linaclotide 290 Micrograms | Change From Baseline in SBM Frequency Rate at Week 12 | 3.085 SBMs per week | Standard Deviation 3.399 |
| Linaclotide 290 Micrograms | Change From Baseline in SBM Frequency Rate at Week 12 | 2.983 SBMs per week | Standard Deviation 3.616 |
Secondary
Change From Baseline in SBM Frequency Rate at Week 4
A patient's baseline SBM frequency rate is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's SBM frequency rate at Week 4 was the SBM rate (SBMs/week) calculated over that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.
Time frame: Baseline and Week 4
Population: 487 patients were randomized to treatment (Randomized Population). The Safety population consists of 486 randomized patients who received at least one dose of study drug. The Intent to Treat (ITT) population consists of 483 patients in the Safety population with valid post-baseline efficacy data. Reported outcome data is based on the ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in SBM Frequency Rate at Week 4 | 1.420 SBMs per week | Standard Deviation 2.882 |
| Linaclotide 290 Micrograms | Change From Baseline in SBM Frequency Rate at Week 4 | 4.045 SBMs per week | Standard Deviation 4.172 |
| Linaclotide 290 Micrograms | Change From Baseline in SBM Frequency Rate at Week 4 | 3.872 SBMs per week | Standard Deviation 4.563 |
Secondary
Change From Baseline in SBM Frequency Rate at Week 8
A patient's baseline SBM frequency rate is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's SBM frequency rate at Week 8 was the SBM rate (SBMs/week) calculated over that week. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.
Time frame: Baseline and Week 8
Population: 487 patients were randomized to treatment (Randomized Population). The Safety population consists of 486 randomized patients who received at least one dose of study drug. The Intent to Treat (ITT) population consists of 483 patients in the Safety population with valid post-baseline efficacy data. Reported outcome data is based on the ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in SBM Frequency Rate at Week 8 | 1.638 SBMs per week | Standard Deviation 3.093 |
| Linaclotide 290 Micrograms | Change From Baseline in SBM Frequency Rate at Week 8 | 3.674 SBMs per week | Standard Deviation 3.784 |
| Linaclotide 290 Micrograms | Change From Baseline in SBM Frequency Rate at Week 8 | 3.785 SBMs per week | Standard Deviation 3.925 |
Secondary
Change From Baseline in Severity of Straining at Week 12
Severity of straining was measured using a 5-point ordinal scale, where of value of 1 is not at all and a value of 5 is an extreme amount. A patient's straining score for baseline was derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's straining score at Week 12 was the average of the nonmissing straining scores from the SBMs reported by that patient during analysis Week 12. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.
Time frame: Baseline and Week 12
Population: 487 patients were randomized to treatment (Randomized Population). The Safety population consists of 486 randomized patients who received at least one dose of study drug. The Intent to Treat (ITT) population consists of 483 patients in the Safety population with valid post-baseline efficacy data. Reported outcome data is based on the ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Severity of Straining at Week 12 | -1.021 units on a scale | Standard Deviation 1.184 |
| Linaclotide 290 Micrograms | Change From Baseline in Severity of Straining at Week 12 | -1.654 units on a scale | Standard Deviation 0.97 |
| Linaclotide 290 Micrograms | Change From Baseline in Severity of Straining at Week 12 | -1.686 units on a scale | Standard Deviation 1.117 |
Secondary
Change From Baseline in Stool Consistency at Week 12
Stool consistency was measured using the 7-point Bristol Stool Form Scale (BSFS): 1. = separate hard lumps like nuts \[difficult to pass\] 2. = sausage shaped but lumpy 3. = like a sausage but with cracks on surface 4. = like a sausage or snake, smooth and soft 5. = soft blobs with clear-cut edges \[passed easily\] 6. = fluffy pieces with ragged edges, a mushy stool 7. = watery, no solid pieces \[entirely liquid\] A patient's BSFS score for the baseline period (14 days before randomization, up to the time of randomization) and at week 12, was the average of the nonmissing BSFS scores from the SBMs reported by the patient during the respective baseline period and during Week 12. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.
Time frame: Baseline and Week 12
Population: 487 patients were randomized to treatment (Randomized Population). The Safety population consists of 486 randomized patients who received at least one dose of study drug. The Intent to Treat (ITT) population consists of 483 patients in the Safety population with valid post-baseline efficacy data. Reported outcome data is based on the ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Stool Consistency at Week 12 | 0.845 units on a scale | Standard Deviation 1.439 |
| Linaclotide 290 Micrograms | Change From Baseline in Stool Consistency at Week 12 | 2.061 units on a scale | Standard Deviation 1.478 |
| Linaclotide 290 Micrograms | Change From Baseline in Stool Consistency at Week 12 | 2.358 units on a scale | Standard Deviation 1.687 |
Secondary
Change From Baseline in the Number of Days With a Spontaneous Bowel Movement (SBM)
A patient's baseline number of days with a Spontaneous Bowel Movement (SBM) was calculated as the number of days with at least 1 Spontaneous Bowel Movement (SBM), derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). A patient's number of days with a SBM during the Treatment Period was calculated as the number of days with at least 1 Spontaneous Bowel Movement (SBM), divided by treatment duration (in days), and multiplied by 7. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.
Time frame: Baseline and 12-week treatment period
Population: 487 patients were randomized to treatment (Randomized Population). The Safety population consists of 486 randomized patients who received at least one dose of study drug. The Intent to Treat (ITT) population consists of 483 patients in the Safety population with valid post-baseline efficacy data. Reported outcome data is based on the ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Number of Days With a Spontaneous Bowel Movement (SBM) | 1.086 Days per week | Standard Deviation 1.595 |
| Linaclotide 290 Micrograms | Change From Baseline in the Number of Days With a Spontaneous Bowel Movement (SBM) | 2.279 Days per week | Standard Deviation 1.83 |
| Linaclotide 290 Micrograms | Change From Baseline in the Number of Days With a Spontaneous Bowel Movement (SBM) | 2.143 Days per week | Standard Deviation 1.78 |
Secondary
Percent Change From Baseline in 12-week Abdominal Bloating
Abdominal Bloating was measured daily using an 11-point Numerical Rating Scale (NRS) where a value of 0 represents no abdominal bloating and a value of 10 represents very severe abdominal bloating. The abdominal bloating score from Baseline is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). The percent change from baseline in 12-Week Abdominal Bloating score is the percentage difference between the average nonmissing daily patient assessments score of abdominal bloating scores during the 14 day Baseline period, and the average of the nonmissing daily patient assessments of abdominal bloating scores reported during the 12 week Treatment Period.
Time frame: Baseline and 12-week treatment period
Population: 487 patients were randomized to treatment (Randomized Population). The Safety population consists of 486 randomized patients who received at least one dose of study drug. The Intent to Treat (ITT) population consists of 483 patients in the Safety population with valid post-baseline efficacy data. Reported outcome data is based on the ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in 12-week Abdominal Bloating | -22.65 percentage change of NRS score | Standard Deviation 29.19 |
| Linaclotide 290 Micrograms | Percent Change From Baseline in 12-week Abdominal Bloating | -34.52 percentage change of NRS score | Standard Deviation 31.79 |
| Linaclotide 290 Micrograms | Percent Change From Baseline in 12-week Abdominal Bloating | -34.22 percentage change of NRS score | Standard Deviation 30.65 |
Secondary
Percent Change From Baseline in Abdominal Bloating at Week 12
Abdominal bloating was measured daily using an 11-point Numerical Rating Scale (NRS) where a value of 0 represents no abdominal bloating and a value of 10 represents very severe abdominal bloating. The abdominal bloating score from Baseline is derived from the Interactive Voice Response System (IVRS) daily diary data collected in the Pretreatment Period, specifically the period of time from 14 days before randomization, up to the time of randomization (Visit 3, Day 1). The percent change from baseline at Week 12 in Abdominal Bloating score is the percentage difference between the average nonmissing daily patient assessments of abdominal bloating scores during the 14 day Baseline period, and the average of the nonmissing daily patient assessments of abdominal bloating scores reported during Week 12.
Time frame: Baseline and Week 12
Population: Reported outcome data is based on the 483 patient Intent-to-Treat Population. The distribution of each of the linaclotide groups was compared, in a pair-wise manner, to the placebo group using the two-sample Kolmogorov-Smirnov test.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Abdominal Bloating at Week 12 | -31.41 percentage change in abdominal bloating | Standard Deviation 40.78 |
| Linaclotide 290 Micrograms | Percent Change From Baseline in Abdominal Bloating at Week 12 | -45.43 percentage change in abdominal bloating | Standard Deviation 37.56 |
| Linaclotide 290 Micrograms | Percent Change From Baseline in Abdominal Bloating at Week 12 | -47.12 percentage change in abdominal bloating | Standard Deviation 33.55 |
p-value: 0.0054Kolmogorov-Smirnov
p-value: 0.0012Kolmogorov-Smirnov
Secondary
SBM Within 24 Hours After the First Dose of Investigational Product
The proportion of patients with a SBM within 24 hours of first taking investigational product in each linaclotide dose group was compared with the proportion in the placebo group using the Cochran-Mantel-Haenszel (CMH) test controlling for geographic region. Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.
Time frame: 24 hours from first dose of investigational product (Day 1)
Population: 487 patients were randomized to treatment (Randomized Population). The Safety population consists of 486 randomized patients who received at least one dose of study drug. The Intent to Treat (ITT) population consists of 483 patients in the Safety population with valid post-baseline efficacy data. Reported outcome data is based on the ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | SBM Within 24 Hours After the First Dose of Investigational Product | Responder | 72 participants |
| Placebo | SBM Within 24 Hours After the First Dose of Investigational Product | Nonresponder | 99 participants |
| Linaclotide 290 Micrograms | SBM Within 24 Hours After the First Dose of Investigational Product | Responder | 94 participants |
| Linaclotide 290 Micrograms | SBM Within 24 Hours After the First Dose of Investigational Product | Nonresponder | 59 participants |
| Linaclotide 290 Micrograms | SBM Within 24 Hours After the First Dose of Investigational Product | Responder | 94 participants |
| Linaclotide 290 Micrograms | SBM Within 24 Hours After the First Dose of Investigational Product | Nonresponder | 65 participants |
p-value: 0.000695% CI: [0.086, 0.3]Cochran-Mantel-Haenszel
p-value: 0.002295% CI: [0.064, 0.227]Cochran-Mantel-Haenszel
Secondary
Time to Spontaneous Bowel Movement (SBM) After the First Dose of Investigational Product
Time to first SBM after the first dose of investigation product was defined as the number of hours between the time of the first dose of investigational product to the occurrence of the first SBM. Patients who did not achieve an SBM were considered censored, with time to censoring defined as the number of hours elapsing from the time of the first dose of investigational product was taken to the end of the day of the last dose, at 12:00 AM (24:00 military time). Only the Placebo versus Linaclotide 145 micrograms arm comparison is a secondary measure type for this outcome measure. The additional data for the Linaclotide 290 micrograms arm (a pre-specified additional outcome measure) is presented here for ease of comparison.
Time frame: 12-week treatment period
Population: 487 patients were randomized to treatment (Randomized Population). The Safety population consists of 486 randomized patients who received at least one dose of study drug. The Intent to Treat (ITT) population consists of 483 patients in the Safety population with valid post-baseline efficacy data. Reported outcome data is based on the ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Spontaneous Bowel Movement (SBM) After the First Dose of Investigational Product | 28.07 Hours |
| Linaclotide 290 Micrograms | Time to Spontaneous Bowel Movement (SBM) After the First Dose of Investigational Product | 12.53 Hours |
| Linaclotide 290 Micrograms | Time to Spontaneous Bowel Movement (SBM) After the First Dose of Investigational Product | 19.35 Hours |
p-value: 0.005495% CI: [1.09, 1.72]Log Rank
p-value: 0.04795% CI: [0.99, 1.55]Log Rank