A Safety and Efficacy Study of a Range of Linaclotide Doses Administered Orally to Children Ages 6-17 Years Who Fulfill Modified Rome III Criteria for Child/Adolescent Functional Constipation (FC)

Study Overview
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Brief Summary
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The purpose of this study was to evaluate dose response of the safety and efficacy of linaclotide for the treatment of functional constipation (FC), in children age 6-17 years. This study includes up to a 4-week Screening Period, and a 2 to 3-week Pretreatment Period. Participants age 6-11 years will receive oral liquid formulation and participants 12-17 years will receive solid oral capsule or liquid oral solution. Children ages 6-11 years meeting the entry criteria will be randomized to 1 of 3 doses of linaclotide or placebo for 4 weeks. Children ages 12-17 years meeting the entry criteria will be randomized to 1 of 4 doses of linaclotide or placebo for 4 weeks. This 4-week study will assess the effects of linaclotide on bowel movement frequency, as well as other bowel symptoms of FC.

Official Title
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A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Safety and Efficacy Study of a Range of Linaclotide Doses Administered Orally to Children, Ages 6 to 17 Years, Who Fulfill Modified Rome III Criteria for Child/Adolescent Functional Constipation (FC)

Conditions
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Functional Constipation in Children Ages 6-17 Years

Intervention / Treatment
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* Drug: Placebo
* Drug: LIN Dose A
* Drug: LIN Dose B
* Drug: LIN Dose C
* Drug: LIN 145 µg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant weighs at least 18 kg (kilograms) (39.7 lbs) Participant meets modified Rome III criteria for child/adolescent FC: For at least 2 months before the Screening Visit, the participant has had 2 or fewer defecations (with each defecation occurring in the absence of any laxative, suppository, or enema use during the preceding 24 hours) in the toilet per week. In addition, at least once per week, patient meets 1 or more of the following: a) History of retentive posturing or excessive volitional stool retention b) History of painful or hard bowel movements (BMs) c) Presence of a large faecal mass in the rectum d) History of large diameter stools that may obstruct the toilet e) At least one episode of fecal incontinence per week Participant is willing to discontinue any laxatives used before the Pretreatment Visit in favor of the protocol-permitted rescue medicine Participant has an average of fewer than 3 spontaneous BMs (SBMs) per week during the 14 days before the randomization day and up to the randomization. An SBM is defined as a BM that occurs in the absence of laxative, enema, or suppository use on the calendar day of the BM or the calendar day before the BM Participant or participant/guardian/legally authorized representative (LAR) or caregiver is compliant with electronic diary (eDiary) by completing both the morning and evening assessments for 10 out of the 14 days immediately preceding the Randomization Visit Exclusion Criteria: Participant meets Rome III criteria for Child/Adolescent irritable bowel syndrome (IBS): At least once per week for at least 2 months before the Screening Visit, the participant has experienced abdominal discomfort (an uncomfortable sensation not described as pain) or pain associated with 2 or more of the following at least 25% of the time: 1. Improvement with defecation 2. Onset associated with a change in frequency of stool 3. Onset associated with a change in form (appearance) of stool Participant reports having more than 1 loose, mushy stool (eDiary-recorded stool consistency of 6 on the Pediatric Bristol Stool Form Scale [p-BSFS]) or any watery stool (eDiary-recorded stool consistency of 7 on the p-BSFS) with any SBM that occurred in the absence of laxative use on the calendar day of the BM or the calendar day before the BM during the 14 days before the randomization day and up to the randomization Select medical history or conditions that may be related to other causes of constipation or may interfere with safety and efficacy analyses Participant has required manual or hospital-based disimpassion any time prior to randomization Participant is unable to tolerate the placebo during the Screening Period

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants aged 6 to 11 or 12 to 17 years received matching placebo linaclotide (LIN), 30 minutes before evening meal, once daily for 4 weeks. Administered as liquid oral solution for participants 6 to 11 years of age and solid oral capsule or liquid oral solution for participants 12 to 17 years of age. | Drug: Placebo<br>* Participants received matching placebo LIN liquid solution or solid capsules, orally, 30 minutes before evening meal, once daily for 4 weeks.<br>|
| Experimental: LIN Dose A (9 ug or 18 ug)<br>Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 9 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 18 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks. | Drug: LIN Dose A<br>* Participants received LIN 9 or 18 ug liquid solution or solid capsules, orally, 30 minutes before evening meal, once daily for 4 weeks.<br>* Other names: LINZESS;|
| Experimental: LIN Dose B (18 ug or 36 ug)<br>Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 36 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks. | Drug: LIN Dose B<br>* Participants received LIN 18 or 36 ug liquid solution or solid capsules, orally, 30 minutes before evening meal, once daily for 4 weeks.<br>* Other names: LINZESS;|
| Experimental: LIN Dose C (36 ug or 72 ug)<br>Participants aged 6 to 11 years with weight 18 to <35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 72 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 72 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks. | Drug: LIN Dose C<br>* Participants received LIN 36 or 72 ug liquid solution or solid capsules, orally, 30 minutes before evening meal, once daily for 4 weeks.<br>* Other names: LINZESS;|
| Experimental: LIN 145 µg<br>Participants aged 12 to 17 years received LIN 145 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks. | Drug: LIN 145 µg<br>* Participants received LIN 145 µg, liquid solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.<br>* Other names: LINZESS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline (CFB) in 4-week Overall Spontaneous Bowel Movement (SBM) Frequency Rate During the Treatment Period | 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. Least squares mean (LSM) and standard error (SE) were calculated using analysis of covariance (ANCOVA) method. | Baseline (14-day prior to randomization and up to randomization) to Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline (CFB) in 4-week Daytime Abdominal Pain | 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. LSM and SE were calculated using ANCOVA method. | Baseline (14-day prior to randomization) to Week 4 | 
| Change From Baseline (CFB) in 4-week Stool Consistency | 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 by 2 approaches-1) following derivation similar in earlier adult studies, mean of participants non-missing, SBM associated p-BSFS scores during 4-week treatment period (adult derivation),2) observed weighted average of daily p-BSFS scores during that period. Daily p-BSFS score was average of non-missing morning and/or evening assessments of p-BSFS score from SBMs reported by participants on that specific day. Baseline value was based on values collected 14 days before randomization up to randomization. LSM and SE were calculated using ANCOVA method. | Baseline (14-day prior to randomization and up to randomization) to Week 4 | 
| Change From Baseline (CFB) in 4-week of Severity of Straining | 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. Data was derived as adult derivation and weighted average. Scores during 4-week treatment period were calculated following two approaches - (1) following derivation similar in earlier adult studies, as mean of participant's non-missing, SBM associated straining scores during 4-week treatment period (adult derivation) and (2) as observed weighted average of daily straining scores during that period. Daily straining score was the average of non-missing morning and/or evening assessments of straining score from the SBMs reported by the participants on that specific day. LSM and SE were calculated using ANCOVA method. | Baseline (14-day prior to randomization and up to randomization) to Week 4 | 
| Change From Baseline (CFB) in 4-week Abdominal Bloating Daytime Symptoms Based on Evening Assessment | 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. LSM and SE were calculated using ANCOVA method. | Baseline (14-day prior to randomization) to Week 4 | 
| Change From Baseline (CFB) in 4-week Overall Complete Spontaneous Bowel Movement Frequency Rate (CSBM/Week) During the Treatment Period | 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. LSM and SE were calculated using ANCOVA method. | Baseline (14-day prior to randomization and up to randomization) to Week 4 | 
| Change From Baseline in 4-week Fecal Incontinence Daytime Symptoms Based on Evening Assessment | Participants recorded the presence of incontinence episodes in daytime daily since pre-treatment period (14-day prior to randomization) in the evening eDiary for participants randomized following protocol amendment #3. The 4-week daytime fecal incontinence was calculated as the mean of non-missing participant scores reported in the evening eDiary during the Treatment Period. Baseline value was the average of values collected 14 days before randomization. Change from Baseline was calculated as the 4-week fecal incontinence daytime symptoms during the treatment period - fecal incontinence daytime symptoms at baseline. A negative change from Baseline indicates improvement. No data is reported for LIN 145 μg as it was an exploratory arm group. | Baseline (14-day prior to randomization) to Week 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Functional constipation in children, LINZESS