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

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of linaclotide for the treatment of Irritable Bowel syndrome with Constipation (IBS-C), in children age 7-17 years. This study includes up to a 4-week Screening Period, and a 2 to 3-week Pretreatment Period. Patients age 7-11 will receive oral liquid or oral solid capsule and patients 12-17 will receive solid oral capsule formulation. Children ages 7-11 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 IBS-C.

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, A Multicenter, Randomized, Double-blind, Placebo-controlled Safety and Efficacy Study of a Range of Linaclotide Doses Administered Orally to Children Ages 7-17 Years, With Irritable Bowel Syndrome With Constipation (IBS-C) (ie, Fulfill Rome III Criteria for Child/Adolescent IBS and Fulfill Modified Rome III Criteria for Child/Adolescent Functional Constipation

Conditions
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Irritable Bowel Syndrome With Constipation

Intervention / Treatment
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* Drug: Linaclotide Dose A
* Drug: Linaclotide Dose B
* Drug: Linaclotide Dose C
* Drug: Linaclotide Approved Adult Dose
* Drug: Matching Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient weighs at least 18 kg (39.7 lbs) Patient meets Rome III criteria for child/adolescent IBS: at least once per week for at least 2 months before Screening Visit, the patient 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: a) Improvement with defecation b) Onset associated with a change in frequency of stool c) Onset associated with a change in form (appearance) of stool Patient meets modified Rome III criteria for child/adolescent Functional Constipation (FC): For at least 2 months before the Screening Visit, the patient 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 fecal mass in the rectum d) History of large diameter stools that may obstruct the toilet Patient is willing to discontinue any laxatives used before the Pretreatment Visit in favor of the protocol-permitted rescue medicine Patient 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 Patient or parent/guardian/LAR or caregiver is compliant with eDiary by completing both the morning and evening assessments for 10 out of the 14 days immediately preceding the Randomization Visit Exclusion Criteria: Patient 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 Patient has required manual disimpaction anytime prior to randomization or disimpaction during in-patient hospitalization within one year prior to randomization Patient is unable to tolerate the placebo during rhe Screening Period

Ages Eligible for Study
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Minimum Age: 7 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 |
| --- | --- |
| Experimental: Linaclotide Dose A<br>Taken once daily each morning at least 30 minutes before breakfast, 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 | Drug: Linaclotide Dose A<br> <br> * Other names: Linzess;|
| Experimental: Linaclotide Dose B<br>Taken once daily each morning at least 30 minutes before breakfast, 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 | Drug: Linaclotide Dose B<br> <br> * Other names: Linzess;|
| Experimental: Linaclotide Dose C<br>Taken once daily each morning at least 30 minutes before breakfast, 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 | Drug: Linaclotide Dose C<br> <br> * Other names: Linzess;|
| Experimental: Linaclotide Approved Adult Dose<br>Taken once daily each morning at least 30 minutes before breakfast, 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 | Drug: Linaclotide Approved Adult Dose<br> <br> * Other names: Linzess;|
| Placebo Comparator: Matching Placebo<br>Taken once daily each morning at least 30 minutes before breakfast, 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 | Drug: Matching Placebo<br> <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 in 4-week Overall Spontaneous Bowel Movement (SBM) Frequency Rate (SBMs/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. 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. | Baseline (14 days prior to randomization and up to randomization) to week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in 4-week Abdominal Pain Daytime Symptoms Based on Evening Assessment of Abdominal Pain Symptoms | 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. | Baseline (14 days prior to randomization) to week 4 | 
| Change From Baseline 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 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. | Baseline (14 days prior to randomization and up to randomization) to week 4 | 
| Change From Baseline in 4-week 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. Scores during 4-week treatment period were calculated as mean of participant's non-missing, SBM associated straining scores during 4-week treatment period. | Baseline (14 days prior to randomization and up to randomization) to week 4 | 
| Change From Baseline 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. | Baseline (14 days prior to randomization) to week 4 | 
| Change From Baseline in 4-week Overall Complete Spontaneous Bowel Movement (CSBM) Frequency Rate (CSBMs Per Week) | 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. | Baseline (14 days prior to randomization and up to randomization) to week 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Irritable Bowel Syndrome with Constipation in children, Linzess