Trial Outcomes & Findings for A Trial of Linaclotide 290 μg in Patients With Irritable Bowel Syndrome With Constipation (IBS-C) (NCT NCT03573908)

Last Updated: 2020-12-01

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

614 participants

Primary outcome timeframe

Baseline (14 days before randomization up to the time of randomization), Treatment Period (Weeks 1-12)

Results posted on

2020-12-01

Participant Flow

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.

Participant milestones

Participant milestones
Measure	Placebo Participants were randomized to receive placebo to linaclotide orally once daily for 12 weeks during the Treatment Period.	Linaclotide 290 µg Participants were randomized to receive linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period.	Placebo -> Linaclotide 290 µg Participants who received placebo orally once daily for 12 weeks during the Treatment Period were switched to receive linaclotide 290 µg for 4 weeks during the Randomized Withdrawal Period.	Linaclotide 290 µg -> Placebo Participants who received linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period were rerandomized to receive placebo for 4 weeks in the Randomized Withdrawal Period.	Linaclotide 290 µg -> Linaclotide 290 µg Participants who received linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period were rerandomized to continue linaclotide 290 µg for 4 weeks in the Randomized Withdrawal Period.
Treatment Period STARTED	308	306	0	0	0
Treatment Period COMPLETED	284	280	0	0	0
Treatment Period NOT COMPLETED	24	26	0	0	0
Randomized Withdrawal Period STARTED	0	0	280	138	139
Randomized Withdrawal Period COMPLETED	0	0	272	136	137
Randomized Withdrawal Period NOT COMPLETED	0	0	8	2	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants were randomized to receive placebo to linaclotide orally once daily for 12 weeks during the Treatment Period.	Linaclotide 290 µg Participants were randomized to receive linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period.	Placebo -> Linaclotide 290 µg Participants who received placebo orally once daily for 12 weeks during the Treatment Period were switched to receive linaclotide 290 µg for 4 weeks during the Randomized Withdrawal Period.	Linaclotide 290 µg -> Placebo Participants who received linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period were rerandomized to receive placebo for 4 weeks in the Randomized Withdrawal Period.	Linaclotide 290 µg -> Linaclotide 290 µg Participants who received linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period were rerandomized to continue linaclotide 290 µg for 4 weeks in the Randomized Withdrawal Period.
Treatment Period Adverse Event	4	9	0	0	0
Treatment Period Protocol Violation	1	0	0	0	0
Treatment Period Withdrawal by Subject	7	5	0	0	0
Treatment Period Lost to Follow-up	7	6	0	0	0
Treatment Period Pregnancy	1	0	0	0	0
Treatment Period Other, Not Specified	4	6	0	0	0
Randomized Withdrawal Period Adverse Event	0	0	3	0	0
Randomized Withdrawal Period Withdrawal by Subject	0	0	0	0	2
Randomized Withdrawal Period Lost to Follow-up	0	0	1	0	0
Randomized Withdrawal Period Other, Not Specified	0	0	4	2	0

Baseline Characteristics

A Trial of Linaclotide 290 μg in Patients With Irritable Bowel Syndrome With Constipation (IBS-C)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=308 Participants Participants randomized to receive placebo to linaclotide orally once daily for 12 weeks during the Treatment Period.	Linaclotide 290 µg n=306 Participants Participants randomized to receive linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period.	Total n=614 Participants Total of all reporting groups
Age, Continuous	46.8 years STANDARD_DEVIATION 14.2 • n=5 Participants	46.5 years STANDARD_DEVIATION 14.6 • n=7 Participants	46.7 years STANDARD_DEVIATION 14.4 • n=5 Participants
Sex: Female, Male Female	255 Participants n=5 Participants	241 Participants n=7 Participants	496 Participants n=5 Participants
Sex: Female, Male Male	53 Participants n=5 Participants	65 Participants n=7 Participants	118 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	81 Participants n=5 Participants	87 Participants n=7 Participants	168 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	227 Participants n=5 Participants	219 Participants n=7 Participants	446 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	198 Participants n=5 Participants	189 Participants n=7 Participants	387 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	70 Participants n=5 Participants	76 Participants n=7 Participants	146 Participants n=5 Participants
Race/Ethnicity, Customized Asian	35 Participants n=5 Participants	36 Participants n=7 Participants	71 Participants n=5 Participants
Race/Ethnicity, Customized Other, Not Specified	5 Participants n=5 Participants	5 Participants n=7 Participants	10 Participants n=5 Participants
Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain)	6.46 score on a scale STANDARD_DEVIATION 1.60 • n=5 Participants	6.39 score on a scale STANDARD_DEVIATION 1.63 • n=7 Participants	6.42 score on a scale STANDARD_DEVIATION 1.61 • n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=306 Participants Participants randomized to receive placebo to linaclotide orally once daily for 12 weeks during the Treatment Period.	Linaclotide 290 µg n=306 Participants Participants randomized to receive linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period.
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	-1.898 score on a scale Standard Error 0.111

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	Placebo n=306 Participants Participants randomized to receive placebo to linaclotide orally once daily for 12 weeks during the Treatment Period.	Linaclotide 290 µg n=306 Participants Participants randomized to receive linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period.
Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score Change from BL threshold: -9.0	0.0 percentage of participants	0.3 percentage of participants
Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score Change from BL threshold: -8.0	0.0 percentage of participants	0.7 percentage of participants
Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score Change from BL threshold: -7.0	0.3 percentage of participants	1.3 percentage of participants
Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score Change from BL threshold: -6.0	0.3 percentage of participants	2.3 percentage of participants
Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score Change from BL threshold: -5.0	2.3 percentage of participants	6.2 percentage of participants
Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score Change from BL threshold: -4.0	4.9 percentage of participants	14.4 percentage of participants
Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score Change from BL threshold: -3.0	11.4 percentage of participants	24.5 percentage of participants
Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score Change from BL threshold: -2.0	23.9 percentage of participants	40.2 percentage of participants
Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score Change from BL threshold: -1.0	42.8 percentage of participants	58.8 percentage of participants

SECONDARY outcome

Timeframe: Baseline (14 days before randomization up to the time of randomization), Treatment Period (Weeks 1-12)

Population: Intent to Treat Population: all randomized participants.

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.

Outcome measures

Outcome measures
Measure	Placebo n=308 Participants Participants randomized to receive placebo to linaclotide orally once daily for 12 weeks during the Treatment Period.	Linaclotide 290 µg n=306 Participants Participants randomized to receive linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period.
Percentage of 6/12 Week Abdominal Score Responders (Responder Rate)	23.4 percentage of participants Interval 18.8 to 28.5	40.5 percentage of participants Interval 35.0 to 46.3

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=308 Participants Participants randomized to receive placebo to linaclotide orally once daily for 12 weeks during the Treatment Period.	Linaclotide 290 µg n=306 Participants Participants randomized to receive linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period.
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	-0.925 score on a scale Standard Error 0.087
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	-1.423 score on a scale Standard Error 0.104
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 0.110	-1.592 score on a scale Standard Error 0.112
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	-1.731 score on a scale Standard Error 0.117
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	-1.891 score on a scale Standard Error 0.120
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	-2.014 score on a scale Standard Error 0.124
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	-2.073 score on a scale Standard Error 0.126
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 0.130	-2.110 score on a scale Standard Error 0.131
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	-2.181 score on a scale Standard Error 0.130
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 0.130	-2.197 score on a scale Standard Error 0.132
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	-2.288 score on a scale Standard Error 0.132
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	-2.347 score on a scale Standard Error 0.135

Adverse Events

Placebo

Serious events: 2 serious events

Other events: 15 other events

Deaths: 0 deaths

Linaclotide 290 µg

Serious events: 4 serious events

Other events: 26 other events

Deaths: 0 deaths

Linaclotide 290 µg -> Linaclotide 290 µg

Serious events: 1 serious events

Other events: 5 other events

Deaths: 0 deaths

Linaclotide 290 µg -> Placebo

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Placebo -> Linaclotide 290 µg

Serious events: 1 serious events

Other events: 21 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=308 participants at risk Participants randomized to receive placebo to linaclotide orally once daily for 12 weeks during the Treatment Period.	Linaclotide 290 µg n=306 participants at risk Participants randomized to receive linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period.	Linaclotide 290 µg -> Linaclotide 290 µg n=138 participants at risk Participants who received linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period were rerandomized to continue linaclotide 290 µg for 4 weeks in the Randomized Withdrawal Period.	Linaclotide 290 µg -> Placebo n=137 participants at risk Participants who received linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period were rerandomized to receive placebo for 4 weeks in the Randomized Withdrawal Period.	Placebo -> Linaclotide 290 µg n=279 participants at risk Participants who received placebo orally once daily for 12 weeks during the Treatment Period were switched to receive linaclotide 290 µg for 4 weeks during the Randomized Withdrawal Period.
Psychiatric disorders Bipolar disorder	0.00% 0/308 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.33% 1/306 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/138 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/137 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/279 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.32% 1/308 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/306 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/138 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/137 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/279 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.
Nervous system disorders Cerebral infarction	0.32% 1/308 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/306 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/138 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/137 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/279 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.
Nervous system disorders Hemiparaesthesia	0.00% 0/308 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.33% 1/306 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/138 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/137 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/279 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.
Renal and urinary disorders Nephrolithiasis	0.00% 0/308 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.33% 1/306 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/138 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/137 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/279 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine leiomyoma	0.00% 0/308 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.33% 1/306 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/138 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/137 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/279 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.
Blood and lymphatic system disorders Anaemia	0.00% 0/308 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/306 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.72% 1/138 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/137 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/279 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.
Gastrointestinal disorders Vomiting	0.00% 0/308 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/306 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/138 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/137 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.36% 1/279 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.

Other adverse events

Other adverse events
Measure	Placebo n=308 participants at risk Participants randomized to receive placebo to linaclotide orally once daily for 12 weeks during the Treatment Period.	Linaclotide 290 µg n=306 participants at risk Participants randomized to receive linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period.	Linaclotide 290 µg -> Linaclotide 290 µg n=138 participants at risk Participants who received linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period were rerandomized to continue linaclotide 290 µg for 4 weeks in the Randomized Withdrawal Period.	Linaclotide 290 µg -> Placebo n=137 participants at risk Participants who received linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period were rerandomized to receive placebo for 4 weeks in the Randomized Withdrawal Period.	Placebo -> Linaclotide 290 µg n=279 participants at risk Participants who received placebo orally once daily for 12 weeks during the Treatment Period were switched to receive linaclotide 290 µg for 4 weeks during the Randomized Withdrawal Period.
Gastrointestinal disorders Diarrhoea	1.6% 5/308 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	4.6% 14/306 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	2.2% 3/138 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	1.5% 2/137 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	5.7% 16/279 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.
Infections and infestations Nasopharyngitis	2.9% 9/308 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	1.6% 5/306 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	1.4% 2/138 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	1.5% 2/137 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	1.4% 4/279 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.
Nervous system disorders Headache	0.97% 3/308 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	2.6% 8/306 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/138 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.00% 0/137 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.	0.36% 1/279 • Treatment Period: from first dose of study drug during the Treatment Period to the earlier of: the day after last dose of the Treatment Period and the Day before the first dose of the Randomized Withdrawal (RW) Period. Median duration of treatment was 85 days for both arms during this period. RW Period: from first dose of study drug during the RW Period until the day after the date of the last dose of RW treatment. Median duration of treatment was 29 days for all 3 arms during this period. Participants in the RW Population (ie, re-randomized or allocated to study drug for the RW Period) who received at least 1 dose of RW treatment were included in the RW Safety Population.

Additional Information

Vanessa Chong

Ironwood Pharmaceuticals, Inc.

Phone: (617) 374-3923

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee PI may publish or disclose the results of the study 24 months after final data lock provided that sponsor can review the publication prior to public release, sponsor can request removal of confidential information of sponsor (not including results of trial), and sponsor can request a publication delay in order to protect potentially patentable information. Furthermore, if a publication committee is developing an initial publication, PI is to delay disclosure until that publication is published.
Publication restrictions are in place

Restriction type: OTHER