Trial Outcomes & Findings for Safety and Efficacy of Linaclotide in Patients With Chronic Constipation and Prominent Abdominal Bloating (NCT NCT01642914)

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

487 participants

Primary outcome timeframe

12-week treatment period

Results posted on

2016-04-26

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	Placebo Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 145 Micrograms Linaclotide 145 micrograms Linaclotide 145 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
Overall Study STARTED	173	154	160
Overall Study COMPLETED	127	122	120
Overall Study NOT COMPLETED	46	32	40

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 145 Micrograms Linaclotide 145 micrograms Linaclotide 145 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
Overall Study Lost to Follow-up	5	3	7
Overall Study Other Reason	1	0	0
Overall Study Adverse Event	11	7	15
Overall Study Lack of Efficacy	9	4	2
Overall Study Protocol Violation	15	13	6
Overall Study Withdrawal by Subject	5	5	10

Baseline Characteristics

Safety and Efficacy of Linaclotide in Patients With Chronic Constipation and Prominent Abdominal Bloating

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=173 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 145 Micrograms n=153 Participants Linaclotide 145 micrograms Linaclotide 145 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=160 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Total n=486 Participants Total of all reporting groups
Age, Continuous	46.3 Years STANDARD_DEVIATION 13.4 • n=5 Participants	48.3 Years STANDARD_DEVIATION 12.6 • n=7 Participants	47.5 Years STANDARD_DEVIATION 13.6 • n=5 Participants	47.3 Years STANDARD_DEVIATION 13.2 • n=4 Participants
Age, Customized Age 18 to 39 years	53 participants n=5 Participants	37 participants n=7 Participants	43 participants n=5 Participants	133 participants n=4 Participants
Age, Customized Age 40 to 64 years	104 participants n=5 Participants	104 participants n=7 Participants	99 participants n=5 Participants	307 participants n=4 Participants
Age, Customized Age ≥ 65 years	16 participants n=5 Participants	12 participants n=7 Participants	18 participants n=5 Participants	46 participants n=4 Participants
Sex/Gender, Customized Male	14 participants n=5 Participants	15 participants n=7 Participants	12 participants n=5 Participants	41 participants n=4 Participants
Sex/Gender, Customized Female	159 participants n=5 Participants	138 participants n=7 Participants	148 participants n=5 Participants	445 participants n=4 Participants
Race/Ethnicity, Customized White	120 participants n=5 Participants	97 participants n=7 Participants	112 participants n=5 Participants	329 participants n=4 Participants
Race/Ethnicity, Customized Black or African American	47 participants n=5 Participants	54 participants n=7 Participants	47 participants n=5 Participants	148 participants n=4 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	1 participants n=4 Participants
Race/Ethnicity, Customized Asian	3 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	4 participants n=4 Participants
Race/Ethnicity, Customized Other	3 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	4 participants n=4 Participants
Race/Ethnicity, Customized Hispanic	26 participants n=5 Participants	19 participants n=7 Participants	25 participants n=5 Participants	70 participants n=4 Participants
Race/Ethnicity, Customized Non-Hispanic	147 participants n=5 Participants	134 participants n=7 Participants	135 participants n=5 Participants	416 participants n=4 Participants
Region of Enrollment United States	165 participants n=5 Participants	147 participants n=7 Participants	152 participants n=5 Participants	464 participants n=4 Participants
Region of Enrollment Canada	8 participants n=5 Participants	6 participants n=7 Participants	8 participants n=5 Participants	22 participants n=4 Participants
Weight, mean	77.59 kg STANDARD_DEVIATION 19.19 • n=5 Participants	79.39 kg STANDARD_DEVIATION 18.01 • n=7 Participants	80.53 kg STANDARD_DEVIATION 18.20 • n=5 Participants	79.12 kg STANDARD_DEVIATION 18.50 • n=4 Participants
Height, mean	164.87 cm STANDARD_DEVIATION 8.65 • n=5 Participants	164.85 cm STANDARD_DEVIATION 8.44 • n=7 Participants	164.37 cm STANDARD_DEVIATION 7.07 • n=5 Participants	164.70 cm STANDARD_DEVIATION 8.08 • n=4 Participants
BMI (Body Mass Index), mean	28.43 kilograms per meter squared STANDARD_DEVIATION 6.03 • n=5 Participants	29.17 kilograms per meter squared STANDARD_DEVIATION 6.03 • n=7 Participants	29.83 kilograms per meter squared STANDARD_DEVIATION 6.57 • n=5 Participants	29.12 kilograms per meter squared STANDARD_DEVIATION 6.23 • n=4 Participants

PRIMARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=171 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=153 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
9/12 Week Complete Spontaneous Bowel Movement (CSBM) 3+1 Responder Responder	13 participants	24 participants	—
9/12 Week Complete Spontaneous Bowel Movement (CSBM) 3+1 Responder Nonresponder	158 participants	129 participants	—

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=171 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=159 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
9/12 Week Complete Spontaneous Bowel Movement (CSBM) 3+1 Responder Responder	13 participants	26 participants	—
9/12 Week Complete Spontaneous Bowel Movement (CSBM) 3+1 Responder Nonresponder	158 participants	133 participants	—

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=171 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=153 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=159 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
Change From Baseline in 12-Week Abdominal Bloating	-1.583 units on a scale Standard Deviation 1.988	-2.476 units on a scale Standard Deviation 2.315	-2.456 units on a scale Standard Deviation 2.240

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=171 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=153 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=159 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
Percent Change From Baseline in 12-week Abdominal Bloating	-22.65 percentage change of NRS score Standard Deviation 29.19	-34.52 percentage change of NRS score Standard Deviation 31.79	-34.22 percentage change of NRS score Standard Deviation 30.65

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=135 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=121 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=118 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
Percent Change From Baseline in Abdominal Bloating at Week 12	-31.41 percentage change in abdominal bloating Standard Deviation 40.78	-45.43 percentage change in abdominal bloating Standard Deviation 37.56	-47.12 percentage change in abdominal bloating Standard Deviation 33.55

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=171 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=153 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=159 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
6/12 Week Abdominal Bloating 30% Responder Responder	50 participants	62 participants	69 participants
6/12 Week Abdominal Bloating 30% Responder Nonresponder	121 participants	91 participants	90 participants

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=171 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=153 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=159 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
Change From Baseline in 12-week CSBM Frequency Rate	1.020 CSBMs per week Standard Deviation 1.596	2.309 CSBMs per week Standard Deviation 2.832	2.292 CSBMs per week Standard Deviation 2.790

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=171 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=153 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=159 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
Change From Baseline in CSBM Frequency Rate at Week 1.	0.641 CSBMs per week Standard Deviation 1.543	1.984 CSBMs per week Standard Deviation 3.784	1.746 CSBMs per week Standard Deviation 2.842

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=164 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=144 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=145 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
Change From Baseline in CSBM Frequency Rate at Week 4.	1.063 CSBMs per week Standard Deviation 2.176	2.756 CSBMs per week Standard Deviation 3.662	2.678 CSBMs per week Standard Deviation 3.552

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=147 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=133 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=131 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
Change From Baseline in CSBM Frequency Rate at Week 8	1.347 CSBMs per week Standard Deviation 2.438	2.803 CSBMs per week Standard Deviation 4.034	2.319 CSBMs per week Standard Deviation 2.989

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=137 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=126 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=124 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
Change From Baseline in CSBM Frequency Rate at Week 12	1.074 CSBMs per week Standard Deviation 1.893	2.272 CSBMs per week Standard Deviation 2.801	2.488 CSBMs per week Standard Deviation 3.010

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=171 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=153 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=159 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
Change From Baseline in 12-Week SBM Frequency Rate	1.480 SBMs per week Standard Deviation 2.198	3.481 SBMs per week Standard Deviation 3.085	3.550 SBMs per week Standard Deviation 3.382

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=171 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=153 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=159 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
Change From Baseline in SBM Frequency Rate at Week 1	1.840 SBMs per week Standard Deviation 2.520	4.168 SBMs per week Standard Deviation 4.547	4.125 SBMs per week Standard Deviation 4.229

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=164 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=144 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=145 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
Change From Baseline in SBM Frequency Rate at Week 4	1.420 SBMs per week Standard Deviation 2.882	4.045 SBMs per week Standard Deviation 4.172	3.872 SBMs per week Standard Deviation 4.563

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=147 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=133 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=131 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
Change From Baseline in SBM Frequency Rate at Week 8	1.638 SBMs per week Standard Deviation 3.093	3.674 SBMs per week Standard Deviation 3.784	3.785 SBMs per week Standard Deviation 3.925

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=137 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=126 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=124 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
Change From Baseline in SBM Frequency Rate at Week 12	1.288 SBMs per week Standard Deviation 2.221	3.085 SBMs per week Standard Deviation 3.399	2.983 SBMs per week Standard Deviation 3.616

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=171 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=153 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=159 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
Change From Baseline in the Number of Days With a Spontaneous Bowel Movement (SBM)	1.086 Days per week Standard Deviation 1.595	2.279 Days per week Standard Deviation 1.830	2.143 Days per week Standard Deviation 1.780

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=171 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=153 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=159 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
SBM Within 24 Hours After the First Dose of Investigational Product Responder	72 participants	94 participants	94 participants
SBM Within 24 Hours After the First Dose of Investigational Product Nonresponder	99 participants	59 participants	65 participants

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=171 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=153 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=159 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
Time to Spontaneous Bowel Movement (SBM) After the First Dose of Investigational Product	28.07 Hours Interval 24.02 to 43.27	12.53 Hours Interval 7.03 to 21.18	19.35 Hours Interval 9.81 to 23.02

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=160 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=137 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=137 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
Change From Baseline in 12-week Stool Consistency	0.797 units on a scale Standard Deviation 1.129	1.925 units on a scale Standard Deviation 1.358	2.304 units on a scale Standard Deviation 1.470

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=116 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=105 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=99 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
Change From Baseline in Stool Consistency at Week 12	0.845 units on a scale Standard Deviation 1.439	2.061 units on a scale Standard Deviation 1.478	2.358 units on a scale Standard Deviation 1.687

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=160 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=136 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=137 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
Change From Baseline in 12-week Severity of Straining	-0.812 units on a scale Standard Deviation 0.941	-1.495 units on a scale Standard Deviation 0.938	-1.512 units on a scale Standard Deviation 1.027

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=116 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=105 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=99 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
Change From Baseline in Severity of Straining at Week 12	-1.021 units on a scale Standard Deviation 1.184	-1.654 units on a scale Standard Deviation 0.970	-1.686 units on a scale Standard Deviation 1.117

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=171 Participants Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=153 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=159 Participants Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
9/12 Week Mild Straining and Diarrhea-free Responder Responder	15 participants	38 participants	27 participants
9/12 Week Mild Straining and Diarrhea-free Responder Nonresponder	156 participants	115 participants	132 participants

Adverse Events

Placebo

Serious events: 2 serious events

Other events: 12 other events

Deaths: 0 deaths

Linaclotide 145 Micrograms

Serious events: 4 serious events

Other events: 25 other events

Deaths: 0 deaths

Linaclotide 290 Micrograms

Serious events: 2 serious events

Other events: 33 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=173 participants at risk Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 145 Micrograms n=153 participants at risk Linaclotide 145 micrograms Linaclotide 145 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=160 participants at risk Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
Nervous system disorders brain stem infarction	0.58% 1/173 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada	0.00% 0/153 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada	0.00% 0/160 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada
Gastrointestinal disorders abdominal pain	0.58% 1/173 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada	0.65% 1/153 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada	0.00% 0/160 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada
Infections and infestations Clostridium difficile colitis	0.00% 0/173 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada	0.65% 1/153 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada	0.00% 0/160 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada
Neoplasms benign, malignant and unspecified (incl cysts and polyps) uterine leiomyoma	0.00% 0/173 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada	0.65% 1/153 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada	0.00% 0/160 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada
General disorders non-cardiac chest pain	0.00% 0/173 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada	0.65% 1/153 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada	0.00% 0/160 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada
Infections and infestations gastroenteritis viral	0.00% 0/173 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada	0.00% 0/153 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada	0.62% 1/160 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada
Infections and infestations pneumonia	0.00% 0/173 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada	0.00% 0/153 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada	0.62% 1/160 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada
Blood and lymphatic system disorders anaemia	0.00% 0/173 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada	0.00% 0/153 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada	0.62% 1/160 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada
Infections and infestations upper respiratory tract infection	0.00% 0/173 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada	0.00% 0/153 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada	0.62% 1/160 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada

Other adverse events

Other adverse events
Measure	Placebo n=173 participants at risk Matching placebo Matching placebo: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 145 Micrograms n=153 participants at risk Linaclotide 145 micrograms Linaclotide 145 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast	Linaclotide 290 Micrograms n=160 participants at risk Linaclotide 290 micrograms Linaclotide 290 micrograms: oral capsule, taken once daily each morning at least 30 minutes before breakfast
Gastrointestinal disorders Diarrhoea	2.3% 4/173 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada	5.9% 9/153 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada	16.9% 27/160 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada
Infections and infestations Upper respiratory tract infection	2.9% 5/173 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada	5.9% 9/153 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada	3.1% 5/160 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada
Infections and infestations Sinusitis	1.7% 3/173 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada	5.9% 9/153 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada	1.2% 2/160 • Adverse event reporting occurred over a 10 month period from August of 2012 to June of 2013 at 141 study sites in the United States and Canada

Additional Information

Steven Shiff, Executive Director, Clinical Development

Forest Research Institute

Phone: 201-427-8000

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee All data generated in this trial will be the property of Forest Research Institute, Inc. and Ironwood Pharmaceuticals, Inc. An integrated clinical and statistical report will be prepared at the completion of the trial. Publication of the results by the Investigator will be subject to mutual agreement between the Investigator, Ironwood Pharmaceuticals, Inc., and Forest Research Institute, Inc.
Publication restrictions are in place

Restriction type: OTHER