Trial Outcomes & Findings for Linaclotide Safety and Efficacy in 2 to 5-Year-Old Participants With Functional Constipation (NCT NCT04110145)

Last Updated: 2022-04-26

Results Overview

A SBM was defined as a bowel movement (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. Each day the caregiver recorded the number of SBMs in the last 24 hours in an electronic diary (eDiary). The SBM frequency rate (SBMs/week) during the analysis period for each participant was 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

COMPLETED

Study phase

PHASE2

Target enrollment

35 participants

Primary outcome timeframe

Baseline (14 days prior to randomization) to Day 29

Results posted on

2022-04-26

Participant Flow

Participants were randomized in a 3:1 ratio to receive ascending doses of linaclotide Cohorts 1-3 (18/36/72 μg) to determine the highest dose to be safe or placebo and in a 5:1 ratio for the Final Cohort (72 μg) safe dose or placebo.

Participant milestones

Participant milestones
Measure	Cohort 1 (Linaclotide 18 μg) Linaclotide 18 microgram (μg), capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Cohort 2 (Linaclotide 36 μg) Linaclotide 36 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Cohort 3 (Linaclotide 72 μg) Linaclotide 72 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Final Cohort (Linaclotide 72 μg) Linaclotide at the highest dose tested/determined to be safe (72 μg), capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Placebo Pooled Matching placebo, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period pooled from Cohorts 1, 2, 3, and Final Cohort.
Double-Blind Treatment Period (4 Weeks) STARTED	7	7	6	7	8
Double-Blind Treatment Period (4 Weeks) COMPLETED	7	7	6	6	8
Double-Blind Treatment Period (4 Weeks) NOT COMPLETED	0	0	0	1	0
Post-Treatment Period (1 Week) STARTED	7	7	5	6	8
Post-Treatment Period (1 Week) COMPLETED	7	7	5	6	8
Post-Treatment Period (1 Week) NOT COMPLETED	0	0	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort 1 (Linaclotide 18 μg) Linaclotide 18 microgram (μg), capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Cohort 2 (Linaclotide 36 μg) Linaclotide 36 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Cohort 3 (Linaclotide 72 μg) Linaclotide 72 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Final Cohort (Linaclotide 72 μg) Linaclotide at the highest dose tested/determined to be safe (72 μg), capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Placebo Pooled Matching placebo, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period pooled from Cohorts 1, 2, 3, and Final Cohort.
Double-Blind Treatment Period (4 Weeks) Site Terminated by the Sponsor	0	0	0	1	0

Baseline Characteristics

Linaclotide Safety and Efficacy in 2 to 5-Year-Old Participants With Functional Constipation

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1 (Linaclotide 18 μg) n=7 Participants Linaclotide,18 μg, capsules, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Cohort 2 (Linaclotide 36 μg) n=7 Participants Linaclotide, 36 μg, capsules, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Cohort 3 (Linaclotide 72 μg) n=6 Participants Linaclotide, 72 μg, capsules, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Final Cohort (Linaclotide 72 μg) n=7 Participants Linaclotide at the highest dose tested/determined to be safe (72 μg), capsules, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Placebo Pooled n=8 Participants Matching placebo once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period pooled from Cohorts 1, 2, 3, and Final Cohort.	Total n=35 Participants Total of all reporting groups
Age, Continuous	3.6 years n=5 Participants	3.3 years n=7 Participants	4.0 years n=5 Participants	3.6 years n=4 Participants	3.5 years n=21 Participants	3.6 years n=10 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants	0 Participants n=4 Participants	4 Participants n=21 Participants	16 Participants n=10 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	4 Participants n=7 Participants	1 Participants n=5 Participants	7 Participants n=4 Participants	4 Participants n=21 Participants	19 Participants n=10 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants	4 Participants n=4 Participants	3 Participants n=21 Participants	14 Participants n=10 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	6 Participants n=5 Participants	5 Participants n=7 Participants	2 Participants n=5 Participants	3 Participants n=4 Participants	5 Participants n=21 Participants	21 Participants n=10 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
Race (NIH/OMB) Black or African American	5 Participants n=5 Participants	4 Participants n=7 Participants	2 Participants n=5 Participants	2 Participants n=4 Participants	3 Participants n=21 Participants	16 Participants n=10 Participants
Race (NIH/OMB) White	2 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants	5 Participants n=4 Participants	5 Participants n=21 Participants	19 Participants n=10 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants

PRIMARY outcome

Timeframe: Baseline (14 days prior to randomization) to Day 29

Population: mITT Population included all Randomized Population who received at least 1 dose of double-blind study intervention and who had at least 1 postbaseline entry on BM characteristic assessments that determine occurrences of SBMs.

Outcome measures

Outcome measures
Measure	Cohort 1 (Linaclotide 18 μg) n=7 Participants Linaclotide,18 μg, capsules, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Cohort 2 (Linaclotide 36 μg) n=7 Participants Linaclotide, 36 μg, capsules, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Cohort 3 (Linaclotide 72 μg) n=6 Participants Linaclotide, 72 μg, capsules, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Final Cohort (Linaclotide 72 μg) n=7 Participants Linaclotide at the highest dose tested/determined to be safe (72 μg), capsules, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Placebo Pooled n=8 Participants Matching placebo once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period pooled from Cohorts 1, 2, 3, and Final Cohort.
Change From Baseline in 4-week Overall Spontaneous Bowel Movement (SBM) Frequency Rate (SBMs/Week) During the Study Intervention Period of Each Cohort Baseline	1.379 SBMs per week Standard Deviation 1.095	0.621 SBMs per week Standard Deviation 0.365	0.724 SBMs per week Standard Deviation 0.953	1.034 SBMs per week Standard Deviation 0.809	1.267 SBMs per week Standard Deviation 1.062
Change From Baseline in 4-week Overall Spontaneous Bowel Movement (SBM) Frequency Rate (SBMs/Week) During the Study Intervention Period of Each Cohort Change from Baseline to Day 29	3.100 SBMs per week Standard Deviation 5.251	0.032 SBMs per week Standard Deviation 0.508	3.603 SBMs per week Standard Deviation 2.867	1.574 SBMs per week Standard Deviation 1.933	0.482 SBMs per week Standard Deviation 0.773

PRIMARY outcome

Timeframe: Baseline (14 days prior to randomization) to Day 29

The caregiver rated and recorded in an eDiary the consistency of the stool for each bowel movement using the Bristol Stool Form 7-point scale where: 1=Separate hard lumps, like nuts (hard to pass); 2=Sausage-shaped, but lumpy; 3=Like a sausage but with cracks on its surface; 4=Like a sausage or snake, smooth and soft; 5=Soft blobs with clear cut edges (easy to pass); 6=Fluffy pieces with ragged edges, a mushy stool; 7=Watery, no solid pieces. Entirely liquid. Baseline value was based on values collected 14 days before randomization up to randomization. A participant's stool consistency score for the treatment period was the average of the nonmissing consistency scores from the BMs recorded by the caregiver during the 4-week treatment period.

Outcome measures

Outcome measures
Measure	Cohort 1 (Linaclotide 18 μg) n=5 Participants Linaclotide,18 μg, capsules, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Cohort 2 (Linaclotide 36 μg) n=5 Participants Linaclotide, 36 μg, capsules, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Cohort 3 (Linaclotide 72 μg) n=3 Participants Linaclotide, 72 μg, capsules, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Final Cohort (Linaclotide 72 μg) n=7 Participants Linaclotide at the highest dose tested/determined to be safe (72 μg), capsules, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Placebo Pooled n=7 Participants Matching placebo once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period pooled from Cohorts 1, 2, 3, and Final Cohort.
Change From Baseline in 4-week Stool Consistency Reported by the Caregiver During the Study Intervention Period of Each Cohort Baseline	1.633 score on a scale Standard Deviation 0.461	1.700 score on a scale Standard Deviation 0.447	2.733 score on a scale Standard Deviation 1.079	2.021 score on a scale Standard Deviation 0.793	2.024 score on a scale Standard Deviation 0.641
Change From Baseline in 4-week Stool Consistency Reported by the Caregiver During the Study Intervention Period of Each Cohort Change from Baseline to Day 29	0.917 score on a scale Standard Deviation 1.360	1.600 score on a scale Standard Deviation 1.294	1.687 score on a scale Standard Deviation 2.779	1.716 score on a scale Standard Deviation 1.689	0.596 score on a scale Standard Deviation 0.937

PRIMARY outcome

Timeframe: Baseline (14 days prior to randomization) to Day 29

The caregiver rated and recorded in an eDiary the amount of straining they observed when the child passed the BM (1=Not at all; 2=Yes a little; 3=Yes a lot; I don't know). Baseline value was based on values collected 14 days before randomization up to randomization. A participant's straining score for the treatment period was the average of the nonmissing straining scores from the BMs recorded by the caregiver during the 4-week treatment period. A negative change from Baseline indicates improvement.

Outcome measures

Outcome measures
Measure	Cohort 1 (Linaclotide 18 μg) n=5 Participants Linaclotide,18 μg, capsules, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Cohort 2 (Linaclotide 36 μg) n=5 Participants Linaclotide, 36 μg, capsules, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Cohort 3 (Linaclotide 72 μg) n=3 Participants Linaclotide, 72 μg, capsules, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Final Cohort (Linaclotide 72 μg) n=7 Participants Linaclotide at the highest dose tested/determined to be safe (72 μg), capsules, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Placebo Pooled n=7 Participants Matching placebo once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period pooled from Cohorts 1, 2, 3, and Final Cohort.
Change From Baseline in 4-week Straining Reported by the Caregiver During the Study Intervention Period of Each Cohort Baseline	2.310 straining score Standard Deviation 0.410	2.600 straining score Standard Deviation 0.379	2.600 straining score Standard Deviation 0.361	2.571 straining score Standard Deviation 0.426	2.548 straining score Standard Deviation 0.658
Change From Baseline in 4-week Straining Reported by the Caregiver During the Study Intervention Period of Each Cohort Change from Baseline to Day 29	-0.370 straining score Standard Deviation 0.631	-0.320 straining score Standard Deviation 0.325	-0.769 straining score Standard Deviation 0.884	-0.996 straining score Standard Deviation 0.759	-0.334 straining score Standard Deviation 0.360

PRIMARY outcome

Timeframe: 29 Days

Each day the caregiver recorded in an eDiary if the child had a bowel movement accident (Yes; No; I don't know). The percentage of days with fecal incontinence for the treatment period was the average of the nonmissing incidences of fecal incontinence recorded by the caregiver during the 4-week treatment period.

Outcome measures

Outcome measures
Measure	Cohort 1 (Linaclotide 18 μg) n=5 Participants Linaclotide,18 μg, capsules, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Cohort 2 (Linaclotide 36 μg) n=6 Participants Linaclotide, 36 μg, capsules, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Cohort 3 (Linaclotide 72 μg) n=5 Participants Linaclotide, 72 μg, capsules, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Final Cohort (Linaclotide 72 μg) n=5 Participants Linaclotide at the highest dose tested/determined to be safe (72 μg), capsules, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.	Placebo Pooled n=6 Participants Matching placebo once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period pooled from Cohorts 1, 2, 3, and Final Cohort.
Percentage of Days With Fecal Incontinence During the Study Intervention Period (for Participants Who Have Acquired Toileting Skills During the Daytime and Nighttime or Acquired Toileting Skills During Daytime Only) Within Each Cohort	0.007 percentage of days Standard Deviation 0.016	0.065 percentage of days Standard Deviation 0.107	0.091 percentage of days Standard Deviation 0.063	0.009 percentage of days Standard Deviation 0.019	0.000 percentage of days Standard Deviation 0.000

PRIMARY outcome

Timeframe: First dose of study drug intervention to within 1 week of last dose (Up to 45 days)

Population: Safety Population included all participants in the Randomized Population who received at least 1 dose of double-blind study intervention.

An Adverse Event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease. A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that: results in death, is immediately life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, and/or causes a congenital anomaly/birth defect. A TEAE is an AE that begins or worsens after receiving study drug. Safety Population included all participants in the Randomized Population who received at least 1 dose of double-blind study intervention.