Trial Outcomes & Findings for A Safety and Efficacy Study of a Range of Linaclotide Doses Administered Orally to Children Ages 7-17 Years, With Irritable Bowel Syndrome With Constipation (NCT NCT02559817)

NCT ID: NCT02559817

Last Updated: 2020-12-28

Results Overview

SBM was defined as a BM that occurred in the absence of laxative, suppository, or enema use on the calendar day of the BM or the calendar day before the BM. SBM rate was defined as SBMs/week during the 4-week Treatment period. Participants recorded the occurrence of BMs and use of rescue medication, morning and evening, daily in an eDiary since pretreatment period. The SBM frequency rate (SBMs/week) during the analysis period for each participant were calculated as \[(total number of SBMs in the analysis period/number of days in the analysis period)\*7\]. Baseline value was based on values collected 14 days before randomization up to randomization. Change from Baseline was calculated as the SBM frequency rate during the 4-week treatment period - SBM frequency rate at baseline. A positive change from Baseline indicates improvement.

• Recruitment status: TERMINATED
• Study phase: PHASE2
• Target enrollment: 101 participants
• Primary outcome timeframe: Baseline (14 days prior to randomization and up to randomization) to week 4
• Results posted on: 2020-12-28

Participant Flow

There was a screening period of 14 to 28 days, followed by a Pretreatment period of 14 to 21 days, prior to randomization of study participants.

Participant milestones

Measure	Matching Placebo Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast Placebo liquid oral solution or placebo solid oral capsule in children 7-11 years of age Placebo solid oral capsule in children 12-17 years of age	Linaclotide Dose A Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose A: 18 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose A: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose A: 36 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Dose B Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose B: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose B: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose B: 72 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Dose C Taken once daily each evening, at least 30 minutes before their evening meal,, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose C: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose C: 145 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose C: 145 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Approved Adult Dose Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Approved Adult Dose: 290 micrograms solid oral capsule in children 12-17 years of age
Treatment Period STARTED	19	29	21	24	8
Treatment Period COMPLETED	18	27	19	22	8
Treatment Period NOT COMPLETED	1	2	2	2	0
Post-treatment Period STARTED	18	27	20	22	8
Post-treatment Period COMPLETED	18	27	20	22	8
Post-treatment Period NOT COMPLETED	0	0	0	0	0

Reasons for withdrawal

Measure	Matching Placebo Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast Placebo liquid oral solution or placebo solid oral capsule in children 7-11 years of age Placebo solid oral capsule in children 12-17 years of age	Linaclotide Dose A Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose A: 18 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose A: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose A: 36 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Dose B Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose B: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose B: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose B: 72 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Dose C Taken once daily each evening, at least 30 minutes before their evening meal,, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose C: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose C: 145 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose C: 145 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Approved Adult Dose Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Approved Adult Dose: 290 micrograms solid oral capsule in children 12-17 years of age
Treatment Period Adverse Event	1	0	1	0	0
Treatment Period Lack of Efficacy	0	1	0	0	0
Treatment Period Lost to Follow-up	0	1	0	1	0
Treatment Period Non-Compliance With Study Drug	0	0	1	0	0
Treatment Period Protocol Violation	0	0	0	1	0

Baseline Characteristics

A Safety and Efficacy Study of a Range of Linaclotide Doses Administered Orally to Children Ages 7-17 Years, With Irritable Bowel Syndrome With Constipation

Baseline characteristics by cohort

Measure	Matching Placebo n=19 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast Placebo liquid oral solution or placebo solid oral capsule in children 7-11 years of age Placebo solid oral capsule in children 12-17 years of age	Linaclotide Dose A n=29 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose A: 18 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose A: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose A: 36 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Dose B n=21 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose B: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose B: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose B: 72 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Dose C n=24 Participants Taken once daily each evening, at least 30 minutes before their evening meal,, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose C: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose C: 145 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose C: 145 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Approved Adult Dose n=8 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Approved Adult Dose: 290 micrograms solid oral capsule in children 12-17 years of age	Total n=101 Participants Total of all reporting groups
Age, Continuous	11.9 Years STANDARD_DEVIATION 2.61 • n=5 Participants	11.9 Years STANDARD_DEVIATION 2.95 • n=7 Participants	12.7 Years STANDARD_DEVIATION 3.51 • n=5 Participants	12.4 Years STANDARD_DEVIATION 3.26 • n=4 Participants	13.5 Years STANDARD_DEVIATION 1.77 • n=21 Participants	12.3 Years STANDARD_DEVIATION 3.00 • n=8 Participants
Age, Customized Age · 7 years through 11 years	8 Participants n=5 Participants	13 Participants n=7 Participants	9 Participants n=5 Participants	11 Participants n=4 Participants	0 Participants n=21 Participants	41 Participants n=8 Participants
Age, Customized Age · 12 years through 17 years	11 Participants n=5 Participants	16 Participants n=7 Participants	12 Participants n=5 Participants	13 Participants n=4 Participants	8 Participants n=21 Participants	60 Participants n=8 Participants
Sex: Female, Male Female	13 Participants n=5 Participants	19 Participants n=7 Participants	15 Participants n=5 Participants	16 Participants n=4 Participants	5 Participants n=21 Participants	68 Participants n=8 Participants
Sex: Female, Male Male	6 Participants n=5 Participants	10 Participants n=7 Participants	6 Participants n=5 Participants	8 Participants n=4 Participants	3 Participants n=21 Participants	33 Participants n=8 Participants
Race/Ethnicity, Customized White	12 Participants n=5 Participants	17 Participants n=7 Participants	15 Participants n=5 Participants	16 Participants n=4 Participants	6 Participants n=21 Participants	66 Participants n=8 Participants
Race/Ethnicity, Customized Black or African American	7 Participants n=5 Participants	10 Participants n=7 Participants	6 Participants n=5 Participants	7 Participants n=4 Participants	1 Participants n=21 Participants	31 Participants n=8 Participants
Race/Ethnicity, Customized Multiple	0 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	1 Participants n=21 Participants	4 Participants n=8 Participants
Race/Ethnicity, Customized Hispanic or Latino	4 Participants n=5 Participants	7 Participants n=7 Participants	5 Participants n=5 Participants	7 Participants n=4 Participants	3 Participants n=21 Participants	26 Participants n=8 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	15 Participants n=5 Participants	22 Participants n=7 Participants	16 Participants n=5 Participants	17 Participants n=4 Participants	5 Participants n=21 Participants	75 Participants n=8 Participants
Weight	49.87 kg STANDARD_DEVIATION 14.387 • n=5 Participants	55.22 kg STANDARD_DEVIATION 19.339 • n=7 Participants	60.13 kg STANDARD_DEVIATION 22.670 • n=5 Participants	56.80 kg STANDARD_DEVIATION 20.943 • n=4 Participants	61.93 kg STANDARD_DEVIATION 17.586 • n=21 Participants	56.14 kg STANDARD_DEVIATION 19.523 • n=8 Participants
Body Mass Index (BMI)	21.29 kg/m^2 STANDARD_DEVIATION 3.266 • n=5 Participants	23.56 kg/m^2 STANDARD_DEVIATION 5.322 • n=7 Participants	24.85 kg/m^2 STANDARD_DEVIATION 6.304 • n=5 Participants	24.57 kg/m^2 STANDARD_DEVIATION 8.517 • n=4 Participants	23.92 kg/m^2 STANDARD_DEVIATION 5.955 • n=21 Participants	23.67 kg/m^2 STANDARD_DEVIATION 6.208 • n=8 Participants

PRIMARY outcome

Timeframe: Baseline (14 days prior to randomization and up to randomization) to week 4

Population: ITT population, all participants who had at least 1 postbaseline entry on BM characteristic assessments that determined occurrences of SBMs (i.e. BM frequency and rescue medication use).

SBM was defined as a BM that occurred in the absence of laxative, suppository, or enema use on the calendar day of the BM or the calendar day before the BM. SBM rate was defined as SBMs/week during the 4-week Treatment period. Participants recorded the occurrence of BMs and use of rescue medication, morning and evening, daily in an eDiary since pretreatment period. The SBM frequency rate (SBMs/week) during the analysis period for each participant were calculated as [(total number of SBMs in the analysis period/number of days in the analysis period)*7]. Baseline value was based on values collected 14 days before randomization up to randomization. Change from Baseline was calculated as the SBM frequency rate during the 4-week treatment period - SBM frequency rate at baseline. A positive change from Baseline indicates improvement.

Outcome measures

Measure	Matching Placebo n=19 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast Placebo liquid oral solution or placebo solid oral capsule in children 7-11 years of age Placebo solid oral capsule in children 12-17 years of age	Linaclotide Dose A n=29 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose A: 18 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose A: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose A: 36 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Dose B n=21 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose B: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose B: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose B: 72 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Dose C n=23 Participants Taken once daily each evening, at least 30 minutes before their evening meal,, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose C: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose C: 145 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose C: 145 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Approved Adult Dose n=8 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Approved Adult Dose: 290 micrograms solid oral capsule in children 12-17 years of age
Change From Baseline in 4-week Overall Spontaneous Bowel Movement (SBM) Frequency Rate (SBMs/Week) During the Treatment Period	1.447 Spontaneous Bowel Movements per Week Standard Deviation 1.376	1.991 Spontaneous Bowel Movements per Week Standard Deviation 2.349	2.298 Spontaneous Bowel Movements per Week Standard Deviation 2.634	2.678 Spontaneous Bowel Movements per Week Standard Deviation 2.774	3.222 Spontaneous Bowel Movements per Week Standard Deviation 2.194

SECONDARY outcome

Timeframe: Baseline (14 days prior to randomization) to week 4

Population: ITT population, all participants who had at least 1 postbaseline entry on BM characteristic assessments that determined occurrences of SBMs (i.e. BM frequency and rescue medication use).

The abdominal pain score was measured using 5-point scale. Participants answered the questions, How much did your tummy hurt as: 0=none, 1=a tiny bit, 2=a little, 3=some, and 4=a lot. The 4-week daytime abdominal pain was calculated as the average of nonmissing scores in evening eDiary during the Treatment Period with higher value indicating greater symptom severity. Baseline value was the average of non-missing values collected 14 days before randomization. Change from Baseline was calculated as the daytime abdominal pain score during the 4-week treatment period (i.e. average of non-missing daytime scores during 4-week treatment period) - daytime abdominal pain score at baseline. A negative change from Baseline indicates improvement.

Outcome measures

Measure	Matching Placebo n=19 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast Placebo liquid oral solution or placebo solid oral capsule in children 7-11 years of age Placebo solid oral capsule in children 12-17 years of age	Linaclotide Dose A n=29 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose A: 18 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose A: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose A: 36 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Dose B n=21 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose B: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose B: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose B: 72 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Dose C n=23 Participants Taken once daily each evening, at least 30 minutes before their evening meal,, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose C: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose C: 145 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose C: 145 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Approved Adult Dose n=8 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Approved Adult Dose: 290 micrograms solid oral capsule in children 12-17 years of age
Change From Baseline in 4-week Abdominal Pain Daytime Symptoms Based on Evening Assessment of Abdominal Pain Symptoms	-0.654 Units on a Scale Standard Deviation 0.789	-0.709 Units on a Scale Standard Deviation 0.977	-0.565 Units on a Scale Standard Deviation 0.861	-0.648 Units on a Scale Standard Deviation 0.948	-1.192 Units on a Scale Standard Deviation 1.032

SECONDARY outcome

Timeframe: Baseline (14 days prior to randomization and up to randomization) to week 4

Population: ITT population, all participants who had at least 1 postbaseline entry on BM characteristic assessments that determined occurrences of SBMs (i.e. BM frequency and rescue medication use).

Participants used 7-point pediatric Bristol Stool Form (p-BSFS) scale to rate stool consistency for each BM in morning and evening eDiary where 1=small hard lumps or balls like pebbles,2=fat sausage shape but lumpy and hard,3=a sausage but with cracks on it,4=sausage or snake, smooth and soft,5=chicken nuggets, soft smooth blobs,6=oatmeal, fluffy mushy pieces,7=milkshake, watery. Scores in 4-week treatment period were calculated as mean of participants non-missing, SBM associated p-BSFS scores during 4-week treatment period. Baseline value was based on values collected 14 days before randomization up to randomization.

Outcome measures

Measure	Matching Placebo n=16 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast Placebo liquid oral solution or placebo solid oral capsule in children 7-11 years of age Placebo solid oral capsule in children 12-17 years of age	Linaclotide Dose A n=24 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose A: 18 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose A: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose A: 36 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Dose B n=16 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose B: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose B: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose B: 72 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Dose C n=22 Participants Taken once daily each evening, at least 30 minutes before their evening meal,, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose C: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose C: 145 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose C: 145 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Approved Adult Dose n=8 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Approved Adult Dose: 290 micrograms solid oral capsule in children 12-17 years of age
Change From Baseline in 4-week Stool Consistency	0.653 Units on a Scale Standard Deviation 0.949	1.200 Units on a Scale Standard Deviation 1.068	1.502 Units on a Scale Standard Deviation 1.272	2.054 Units on a Scale Standard Deviation 1.349	1.345 Units on a Scale Standard Deviation 0.813

SECONDARY outcome

Timeframe: Baseline (14 days prior to randomization and up to randomization) to week 4

Population: ITT population, all participants who had at least 1 postbaseline entry on BM characteristic assessments that determined occurrences of SBMs (i.e. BM frequency and rescue medication use).

Severity of straining was scored on 5-point scale for question-When you pooped, how hard did you push? The score ranges from 0= not hard at all,1= I pushed a tiny bit hard,2= I pushed a little hard,3= I pushed hard,4= I pushed very hard with higher scores indicating more severe straining. Participants recorded degree of straining for each BM in morning and evening eDiary. Scores during 4-week treatment period were calculated as mean of participant's non-missing, SBM associated straining scores during 4-week treatment period.

Outcome measures

Measure	Matching Placebo n=17 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast Placebo liquid oral solution or placebo solid oral capsule in children 7-11 years of age Placebo solid oral capsule in children 12-17 years of age	Linaclotide Dose A n=24 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose A: 18 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose A: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose A: 36 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Dose B n=16 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose B: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose B: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose B: 72 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Dose C n=22 Participants Taken once daily each evening, at least 30 minutes before their evening meal,, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose C: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose C: 145 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose C: 145 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Approved Adult Dose n=8 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Approved Adult Dose: 290 micrograms solid oral capsule in children 12-17 years of age
Change From Baseline in 4-week Severity of Straining	-0.576 Units on a Scale Standard Deviation 0.915	-0.782 Units on a Scale Standard Deviation 1.187	-0.859 Units on a Scale Standard Deviation 0.993	-1.222 Units on a Scale Standard Deviation 0.972	-1.236 Units on a Scale Standard Deviation 1.042

SECONDARY outcome

Timeframe: Baseline (14 days prior to randomization) to week 4

Population: ITT population, all participants who had at least 1 postbaseline entry on BM characteristic assessments that determined occurrences of SBMs (i.e. BM frequency and rescue medication use).

Participants recorded their assessment of abdominal bloating in the evening eDiary. Participants answered the question: How big and full did your tummy feel? on a scale, where: 0=none, 1=a tiny bit, 2=a little, 3=medium or 4=very, with a higher score indicating more severe bloating. Baseline value was the average of values collected 14 days before randomization. The 4-week daytime abdominal bloating symptoms were calculated as the average of non-missing scores reported in the evening eDiary during the treatment period. Change from Baseline was calculated as the 4-week daytime abdominal bloating score during the treatment period - daytime abdominal bloating score at baseline. A negative change from Baseline indicates improvement.

Outcome measures

Measure	Matching Placebo n=19 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast Placebo liquid oral solution or placebo solid oral capsule in children 7-11 years of age Placebo solid oral capsule in children 12-17 years of age	Linaclotide Dose A n=29 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose A: 18 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose A: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose A: 36 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Dose B n=21 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose B: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose B: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose B: 72 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Dose C n=22 Participants Taken once daily each evening, at least 30 minutes before their evening meal,, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose C: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose C: 145 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose C: 145 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Approved Adult Dose n=8 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Approved Adult Dose: 290 micrograms solid oral capsule in children 12-17 years of age
Change From Baseline in 4-week Abdominal Bloating Daytime Symptoms Based on Evening Assessment	-0.438 Units on a Scale Standard Deviation 0.754	-0.486 Units on a Scale Standard Deviation 0.974	-0.515 Units on a Scale Standard Deviation 0.992	-0.440 Units on a Scale Standard Deviation 0.823	-0.595 Units on a Scale Standard Deviation 1.284

SECONDARY outcome

Timeframe: Baseline (14 days prior to randomization and up to randomization) to week 4

Population: ITT population, all participants who had at least 1 postbaseline entry on BM characteristic assessments that determined occurrences of SBMs (i.e. BM frequency and rescue medication use).

SBM was defined as a BM that occurred in the absence of laxative, suppository, or enema use on the calendar day of the BM or the calendar day before the BM. A CSBM was an SBM that was associated with a sense of complete evacuation. Participants recorded their assessment of the sensation of incomplete evacuation for each BM in the morning and evening eDiary. The 4-week overall CSBM frequency rate was calculated as [total number of CSBMs in the analysis period/number of days in the analysis period]*7). Baseline value was based on values collected 14 days before randomization and up to randomization. Change from Baseline was calculated as the CSBM frequency rate during the 4-week treatment period - CSBM frequency rate at baseline. A positive change from Baseline indicates improvement.

Outcome measures

Measure	Matching Placebo n=19 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast Placebo liquid oral solution or placebo solid oral capsule in children 7-11 years of age Placebo solid oral capsule in children 12-17 years of age	Linaclotide Dose A n=29 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose A: 18 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose A: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose A: 36 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Dose B n=21 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose B: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose B: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose B: 72 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Dose C n=23 Participants Taken once daily each evening, at least 30 minutes before their evening meal,, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose C: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose C: 145 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose C: 145 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Approved Adult Dose n=8 Participants Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Approved Adult Dose: 290 micrograms solid oral capsule in children 12-17 years of age
Change From Baseline in 4-week Overall Complete Spontaneous Bowel Movement (CSBM) Frequency Rate (CSBMs Per Week)	0.825 CSBMs per Week Standard Deviation 1.211	0.644 CSBMs per Week Standard Deviation 1.029	1.167 CSBMs per Week Standard Deviation 1.822	1.721 CSBMs per Week Standard Deviation 2.292	2.358 CSBMs per Week Standard Deviation 2.199

Adverse Events

Matching Placebo

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Linaclotide Dose A

Serious events: 1 serious events

Other events: 6 other events

Deaths: 0 deaths

Linaclotide Dose B

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Linaclotide Dose C

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Linaclotide Approved Adult Dose

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Measure	Matching Placebo n=19 participants at risk Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast Placebo liquid oral solution or placebo solid oral capsule in children 7-11 years of age Placebo solid oral capsule in children 12-17 years of age	Linaclotide Dose A n=29 participants at risk Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose A: 18 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose A: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose A: 36 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Dose B n=21 participants at risk Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose B: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose B: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose B: 72 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Dose C n=24 participants at risk Taken once daily each evening, at least 30 minutes before their evening meal,, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose C: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose C: 145 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose C: 145 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Approved Adult Dose n=8 participants at risk Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Approved Adult Dose: 290 micrograms solid oral capsule in children 12-17 years of age
Immune system disorders Anaphylactic Reaction	5.3% 1/19 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	0.00% 0/29 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	0.00% 0/21 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	0.00% 0/24 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	0.00% 0/8 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.
Gastrointestinal disorders Faecaloma	0.00% 0/19 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	3.4% 1/29 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	0.00% 0/21 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	0.00% 0/24 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	0.00% 0/8 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.

Other adverse events

Measure	Matching Placebo n=19 participants at risk Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast Placebo liquid oral solution or placebo solid oral capsule in children 7-11 years of age Placebo solid oral capsule in children 12-17 years of age	Linaclotide Dose A n=29 participants at risk Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose A: 18 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose A: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose A: 36 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Dose B n=21 participants at risk Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose B: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose B: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose B: 72 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Dose C n=24 participants at risk Taken once daily each evening, at least 30 minutes before their evening meal,, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Dose C: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg Dose C: 145 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg Dose C: 145 micrograms solid oral capsule in children 12-17 years of age	Linaclotide Approved Adult Dose n=8 participants at risk Taken once daily each evening, at least 30 minutes before their evening meal, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast. Approved Adult Dose: 290 micrograms solid oral capsule in children 12-17 years of age
Gastrointestinal disorders Diarrhoea	0.00% 0/19 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	13.8% 4/29 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	14.3% 3/21 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	8.3% 2/24 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	12.5% 1/8 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.
Gastrointestinal disorders Abdominal pain	5.3% 1/19 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	6.9% 2/29 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	14.3% 3/21 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	4.2% 1/24 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	0.00% 0/8 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.
Gastrointestinal disorders Haematemesis	5.3% 1/19 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	0.00% 0/29 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	0.00% 0/21 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	0.00% 0/24 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	0.00% 0/8 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.
Gastrointestinal disorders Vomiting	0.00% 0/19 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	6.9% 2/29 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	0.00% 0/21 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	4.2% 1/24 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	0.00% 0/8 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.
General disorders Fatigue	5.3% 1/19 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	0.00% 0/29 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	0.00% 0/21 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	4.2% 1/24 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	0.00% 0/8 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.
Infections and infestations Otitis externa	5.3% 1/19 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	0.00% 0/29 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	0.00% 0/21 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	0.00% 0/24 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.	0.00% 0/8 • From the first dose of study treatment period (4 weeks), up to Day 30 after the last dose, for serious adverse events (SAEs) and all-cause mortality. From the first dose, up to Day 1 after the last dose, for other adverse events.

Additional Information

Therapeutic Area Head

Allergan

Phone: 714-246-4500

Email: clinicaltrials@allergan.com

Results disclosure agreements

• Principal investigator is a sponsor employee All data generated in this study are the property of the Sponsor. Publication of the results by the Investigator will be subject to mutual agreement between the Investigator and the Sponsor and will follow the Sponsor's standard operating procedures on publications.
• Publication restrictions are in place

Restriction type: OTHER