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 (LIN-MD-63)

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

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.

Study Overview

• Status: Terminated
• Conditions: Irritable Bowel Syndrome With Constipation
• Intervention / Treatment: Drug: Matching Placebo; Drug: Linaclotide Dose A; Drug: Linaclotide Dose B; Drug: Linaclotide Dose C; Drug: Linaclotide Approved Adult Dose

• Study Type: Interventional
• Enrollment (Actual): 101
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • Children's Hospital of Western Ontario
    • Vaughan, Ontario, Canada, L4L 4Y7
      • Physician's Clinical Research Inc.
• United States
  • Arkansas
    • Hot Springs, Arkansas, United States, 71913
      • HealthStar Research, LLC
    • Little Rock, Arkansas, United States, 72212
      • Applied Research Center of Arkansas
  • California
    • Anaheim, California, United States, 92805
      • Advanced Research Center - Site 069
    • Corona, California, United States, 92879
      • Kindred Medical Institute for Clinical Trials, LLC
    • Costa Mesa, California, United States, 92626
      • WCCT Global, LLC
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Los Angeles, California, United States, 90017
      • ACTCA, Inc
    • Paramount, California, United States, 90723
      • Center for Clinical Trials, LLC
    • San Francisco, California, United States, 94143
      • University of California at San Francisco
  • Florida
    • Miami, Florida, United States, 33135
      • Advanced Medical Research Center
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Children's Center for Digestive Health Care LLC
    • Stockbridge, Georgia, United States, 30281
      • Sleepcare Clinical Research Institute
  • Illinois
    • Peoria, Illinois, United States, 61602
      • Methodist Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children at Indiana University Health
  • Kansas
    • Wichita, Kansas, United States, 67205
      • Heartland Research Associates, LLC
  • Louisiana
    • Shreveport, Louisiana, United States, 71118
      • Willis-Knighton Physician Network
  • Maryland
    • Silver Spring, Maryland, United States, 20910
      • Certified Research Consultants Virgo/Carter Pediatrics
  • Mississippi
    • Jackson, Mississippi, United States, 39202
      • GI Associates and Endoscopy Center
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
  • Nebraska
    • Boys Town, Nebraska, United States, 68010
      • Boys Town National Research Hospital
    • Lincoln, Nebraska, United States, 68505
      • Midwest Children Health Research Institute
    • Lincoln, Nebraska, United States, 68516
      • Midwest Children Health Research Institute
  • New Jersey
    • Morristown, New Jersey, United States, 07962
      • Goryeb Children's Hospital
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center and Morgan Stanley Children's Hospital of New York
  • North Carolina
    • Asheboro, North Carolina, United States, 27203
      • Asheboro Research Associates - Site 022
    • Raleigh, North Carolina, United States, 27609
      • Capital Pediatrics and Adolescent Center PLLC
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Dayton, Ohio, United States, 45414
      • Ohio Pediatric Research Association
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73103
      • IPS Research Company
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19134
      • St. Christopher's Hospital for Children
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
    • Pittsburgh, Pennsylvania, United States, 15236
      • Preferred Primary Care Physicians, Inc.
    • Scottdale, Pennsylvania, United States, 15683
      • Frontier Clinical Research, LLC
    • Smithfield, Pennsylvania, United States, 15478
      • Montgomery Medical Inc.
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29414
      • Coastal Pediatric Research
    • Mount Pleasant, South Carolina, United States, 29464
      • Coastal Pediatrics Associates
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
    • Houston, Texas, United States, 77090
      • Houston Clinical Research Associates
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital/Baylor College Medicine
    • San Antonio, Texas, United States, 78215
      • Sun Research Institute
    • Waxahachie, Texas, United States, 75165
      • ClinPoint Trials
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Children's Hospital of The King's Daughters
    • Roanoke, Virginia, United States, 24013
      • Virginia Tech Carilion School of Medicine Pediatric Gastroenterology
  • Washington
    • Tacoma, Washington, United States, 98405
      • Multicare Institute for Research and Innovation
  • Wisconsin
    • Summit, Wisconsin, United States, 53066
      • Aurora Health Care, Aurora Medical Center in Summit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Linaclotide Dose A; 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; Other Names: Linzess
Experimental: Linaclotide Dose B; 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; Other Names: Linzess
Experimental: Linaclotide Dose C; 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; Other Names: Linzess
Experimental: Linaclotide Approved Adult Dose; 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; Other Names: Linzess
Placebo Comparator: Matching Placebo; 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; Other Names: Linzess

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Forest Laboratories
• Collaborators: Ironwood Pharmaceuticals, Inc.
• Investigators: Study Chair: Anna Muslin, Forest Laboratories, LLC, an Allergan Affiliate

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2015
• Primary Completion (Actual): August 30, 2019
• Study Completion (Actual): August 30, 2019

Study Registration Dates

• First Submitted: September 23, 2015
• First Submitted That Met QC Criteria: September 23, 2015
• First Posted (Estimate): September 24, 2015

Study Record Updates

• Last Update Posted (Actual): December 28, 2020
• Last Update Submitted That Met QC Criteria: December 23, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: Irritable Bowel Syndrome with Constipation in children; Linzess
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Disease; Signs and Symptoms, Digestive; Gastrointestinal Diseases; Colonic Diseases, Functional; Colonic Diseases; Intestinal Diseases; Syndrome; Irritable Bowel Syndrome; Constipation; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents; Guanylyl Cyclase C Agonists; Enzyme Activators; Linaclotide
• Other Study ID Numbers: LIN-MD-63

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No