A Study to Assess Adverse Events and Change in Symptoms With Linaclotide Versus Placebo in Pediatric Subjects, Ages 2 to 5 Years, With Functional Constipation

Study Overview
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Brief Summary
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Functional constipation (FC) is a common healthcare problem in children of all ages, potentially due to genetic predisposition, inadequate fiber and fluid intake, and immobility. Currently, there are no pharmacological therapies approved for the treatment of FC. This study will assess adverse events and change in disease activity with linaclotide therapy in participants with FC. Linaclotide is an approved drug being developed for the treatment of FC in pediatric patients who meet modified Rome IV criteria for childhood FC. In Part 1 of this study, participants are placed in 1 of 2 groups, called treatment arms. Each group receives a different treatment. There is a 1 in 2 chance that participants will be assigned to placebo. All participants in Part 2 will receive linaclotide. Approximately 100 participants aged 2 to 5 years with FC will be enrolled in this study at around 45 sites worldwide. Participants will receive daily doses of oral Linaclotide capsules or matching placebo for 12 weeks in Part 1 of the study. In Part 2, the open label long-term safety extension, participants with FC who completed study intervention in Part 1 of Study M21-572 or the Phase 2 Study LIN-MD-67 will receive linaclotide for 24 weeks. There may be higher treatment burden for participants in this trial compared to their standard of care (due to study procedures). Participants will attend visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects and completing questionnaires.

Official Title
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A Phase 3, Multicenter, Randomized, Double-blind, Parallel-group, Safety and Efficacy Study of Linaclotide Versus Placebo in Pediatric Subjects, Ages 2 to 5 Years, With Functional Constipation (FC) With a 24-week Open-label Treatment Extension

Conditions
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Functional Constipation (FC), Chronic Idiopathic Constipation (CIC)

Intervention / Treatment
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* Drug: Linaclotide
* Drug: Placebo for Linaclotide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Caregiver/parent/guardian/legally authorized representative (LAR) is willing and able to comply with procedures required in this protocol, prior to the initiation of any screening or study-specific procedures. In addition, the caregiver/parent/guardian/LAR who will be completing the electronic diary (eDiary) must be able to read and understand the assessments in the eDiary device and undergo training. Participant meets modified Rome IV criteria for FC: For at least 1 month before Screening (Visit 1), 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) per week. In addition, at least once per week, participant must meet 1 or more of the following: History of retentive posturing or excessive volitional stool retention. History of painful or hard bowel movements (BMs). Presence of a large fecal mass in the rectum. History of large diameter stools. At least 1 episode of fecal incontinence per week after the acquisition of toileting skills. Exclusion Criteria: Participant history of: Celiac disease, or positive serological test for celiac disease or the condition is suspected but has not been ruled out by endoscopic biopsy Cystic fibrosis Hypothyroidism that is untreated or treated with thyroid hormone at a dose that has not been stable for at least 3 months prior to Screening (Visit 1) Down's syndrome or any other chromosomal disorder Active anal fissure (i.e., participant reports having streaks of blood on the stool or on toilet paper and/or pain/crying with BM within 2 weeks prior to Screening). (Note: anal fissures that have resolved at least 2 weeks prior to screening would not be exclusionary.) However, if in the investigator's opinion, an anal fissure(s) may be the primary cause of participant's modified Rome IV FC criteria, the participant would not be eligible to participate in the study. Anatomic malformations (e.g., imperforate anus, anal stenosis, anterior displaced anus) Intestinal nerve or muscle disorders (e.g., Hirschprung disease, visceral myopathies, visceral neuropathies) Neuropathic conditions (e.g., spinal cord abnormalities, neurofibromatosis, tethered cord, spinal cord trauma) Lead toxicity, hypercalcemia Neurodevelopmental disabilities (early-onset, chronic disorders that share the essential feature of a predominant disturbance in the acquisition of cognitive, motor, language, or social skills, which has a significant and continuing impact on the developmental progress of an individual) producing a cognitive delay that precludes comprehension and completion of the daily eDiary or other study-related questionnaires. (Note: participants are excluded if the person who will be completing the daily eDiary or other study-related questionnaires meets this criterion.) Inflammatory bowel disease Childhood functional abdominal pain syndrome Poorly treated or poorly controlled psychiatric disorders that might influence his or her ability to participate in the study Lactose intolerance that is associated with symptoms which could confound the assessments in this study History of cancer. (Note: participants with a history of cancer are allowed provided that the malignancy has been in a complete remission before Randomization (Visit 2). A complete remission is defined as the disappearance of all signs of cancer in response to treatment.) Has conditions that could interfere with drug absorption including but not limited to short bowel syndrome.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 5 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: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Linaclotide<br>Participants will receive linaclotide for 12 weeks. | Drug: Linaclotide<br>* Capsule; oral<br>|
| Experimental: Part 1 Placebo<br>Participants will receive placebo for 12 weeks. | Drug: Placebo for Linaclotide<br>* Capsule; oral<br>|
| Experimental: Part 2 Linaclotide<br>Participants who completed study intervention in Part 1 of this study or the Phase 2 Study LIN-MD-67 will receive 24 weeks of linaclotide exposure. | Drug: Linaclotide<br>* Capsule; oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in the spontaneous bowel movement (SBM) frequency rate (SBMs/week) during the double-blind study intervention period. | 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. The caregiver/parent/guardian/legally authorized representative (LAR) will complete the electronic diary (eDiary), providing data for the SBM frequency rate up to the last dose date equivalent to the 12-week SBM frequency rate. | Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in stool consistency during the double blind study intervention period | The caregiver/parent/guardian/legally authorized representative (LAR) will rate and record in an eDiary the consistency of the stool for each BM using the Bristol Stool Form 7-point scale in which 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; and 7=Watery, no solid pieces, entirely liquid. | Baseline to Week 12 | 
| Change from baseline in straining during the double-blind study intervention period | The caregiver/parent/guardian/LAR will rate and record in an eDiary the amount of straining they observe when the child passes the BM. | Baseline to Week 12 | 
| Proportion of days with fecal incontinence during the double-blind study intervention period (for participants who have acquired toileting skills during daytime and nighttime or acquired toileting skills during daytime only) | Each day the caregiver/parent/guardian/LAR will record incidents of fecal incontinence in an eDiary. | Baseline to Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Functional Constipation (FC), Linaclotide, AGN-182139, Linzess