A Study to Assess Adverse Events and Change in Disease Activity in Pediatric Participants (Age 6 Months to <2 Years) With Functional Constipation Who Are Treated With Linaclotide

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 3 groups, which occur consecutively. Each group receives a different dosage of linaclotide. In Part 2 of the study, participants will be randomly assigned to receive either linaclotide or placebo. There is a 1 in 2 chance that participants will be assigned to placebo. Approximately 30 pediatric participants 6 months to less than 2 years of age with FC will be enrolled in the study at about 25 sites worldwide. Participants will receive oral solution of linaclotide prepared from capsule by parent/guardian once daily for 4 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 regular 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 2 Dose Finding Study Evaluating the Safety and Efficacy of Linaclotide in Pediatric Subjects 6 Months to Less Than 2 Years of Age With Functional Constipation (FC).

Conditions
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Functional Constipation

Intervention / Treatment
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* Drug: Linaclotide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals must be 6 months to less than 1 year and 11 months old, at the time the legally authorized representative (LAR)/parent/guardian signs the informed consent in alignment with local requirements. The LAR/parent/guardian who will be completing the electronic diary (eDiary) is able to read and understand the assessments in the eDiary device and must undergo training. Participant meets modified Rome IV criteria for functional constipation (FC): for at least 1 month before Screening (Visit 1), the participant must meet 2 or more of the following: 2 or fewer defecations per week (with each defecation occurring in the absence of any laxative, suppository, or enema use during the preceding 24 hours) History of excessive volitional stool retention History of painful or hard bowel movements (BMs) History of large-diameter stools Presence of a large fecal mass in the rectum LAR/Parent/Guardian is willing to discontinue any laxatives used before the Preintervention Visit in favor of the protocol-permitted rescue medicine. Exclusion Criteria: Participant has conditions that could interfere with drug absorption, including, but not limited to, short bowel syndrome. History of clinically significant medical conditions or any other reason that the investigator determines would interfere with the individual's participation in this study or would make the participant an unsuitable candidate to receive study drug. Participant has 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 (investigator has confirmed an active anal fissure and participant reports known anal fissure symptoms [i.e., streaks of blood on the stool or on diaper or toilet paper and pain/crying with bowel movement 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 subject 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 of the LAR/Parent/Guardian/Caregiver who will be completing the eDiary (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. Inflammatory bowel disease 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 enrollment/randomization (Visit 3). A complete remission is defined as the disappearance of all signs of cancer in response to treatment)

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 23 Months

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 Dose A<br>Linaclotide Dose A capsules, mixed with water and administered orally, once daily for 4 weeks | Drug: Linaclotide<br>* Capsule; oral<br>* Other names: Linzess;|
| Experimental: Part 1, Linaclotide Dose B<br>Linaclotide Dose B capsules, mixed with water and administered orally, once daily for 4 weeks | Drug: Linaclotide<br>* Capsule; oral<br>* Other names: Linzess;|
| Experimental: Part 1, Linaclotide Dose C<br>Linaclotide Dose C capsules, mixed with water and administered orally, once daily for 4 weeks | Drug: Linaclotide<br>* Capsule; oral<br>* Other names: Linzess;|
| Experimental: Part 2, Linaclotide<br>Participants will receive Linaclotide capsules mixed with water and administered orally in Part 2 for 4 weeks. | Drug: Linaclotide<br>* Capsule; oral<br>* Other names: Linzess;|
| Experimental: Part 2, Placebo<br>Participants will receive placebo capsules mixed with water and administered orally in Part 2 for 4 weeks. | Drug: Placebo<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 overall Spontaneous Bowel Movement (SBM) frequency rate (SBMs/week) during the 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 4-week SBM frequency rate. | Baseline to Week 4 | 
| Change from baseline in stool consistency (Bristol Stool Form Scale) during the 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 4 | 
| Change from baseline in straining during the 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 4 | 
| Number of Participants with Adverse Events (AEs) | An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study. | Up to Week 5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Linaclotide, pediatric functional constipation, Linzess