This is a Randomized, Double-blind, Placebo-controlled, Multicenter, Parallel-group Study of the Efficacy and Safety of 2 Weight-based Treatment Groups of Plecanatide Versus Placebo in Children and Adolescent Participants 6 to Less Than 18 Years of Age With FC

Summary

The goal of this clinical trial is to learn if plecanatide can treat functional constipation in children and adolescents aged 6 to less than 18 years. It will also learn about the safety and pharmacokinetics of plecanatide in this population. The main questions it aims to answer are: * Does plecanatide increase the number of spontaneous bowel movements compared to placebo after 8 weeks of treatment? * What medical problems do participants experience when taking plecanatide? Researchers will compare low-dose plecanatide and high-dose plecanatide to placebo to see if plecanatide improves bowel movement frequency, stool consistency, and constipation-related symptoms. Participants will: * Complete a screening period with daily electronic diary entries to record bowel movements, symptoms, and rescue medication use * Take plecanatide or placebo by mouth once daily for 8 weeks * Continue daily electronic diary entries throughout the study * Attend clinic visits for physical exams, laboratory tests, and assessments of symptoms and safety * Provide blood samples for pharmacokinetic and safety evaluations * Complete questionnaires about constipation symptoms and quality of life

Detailed Description

This Phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel-group study is designed to evaluate the efficacy, safety, and pharmacokinetics (PK) of plecanatide administered orally once daily in pediatric participants with functional constipation (FC). Approximately 180 participants will be enrolled at up to 30 investigational sites in the United States and randomized in a 1:1:1 ratio to receive low-dose plecanatide, high-dose plecanatide, or matching placebo. Randomization will be stratified by age group (6 to 11 years and 12 to less than 18 years) and sex. Background and Rationale Functional constipation is a common condition in children and adolescents and is characterized by infrequent bowel movements, hard stool consistency, and associated symptoms such as straining and abdominal discomfort. Available treatment options in the pediatric population are limited, and there remains a need for additional therapies. Plecanatide is an orally administered guanylate cyclase-C (GC-C) agonist that acts locally in the gastrointestinal tract to increase intestinal fluid secretion and transit. Clinical studies in adults with chronic idiopathic constipation have demonstrated improvements in bowel movement frequency and stool consistency, as well as an acceptable safety profile. The current study is designed to evaluate plecanatide in a pediatric population using a weight-based dosing approach intended to achieve exposure levels comparable to those associated with efficacy in adults. Study Design The study consists of three periods: a Screening/Baseline Period, an 8-week Treatment Period, and a Post-treatment Follow-up Period. The total duration of participation is approximately 14 weeks (98 days). During the Screening/Baseline Period (up to 28 days), participants and/or caregivers complete daily assessments using an electronic diary (eDiary) to record bowel movements, stool characteristics, and constipation-related symptoms. Data from the eDiary are used to establish baseline values and confirm eligibility prior to randomization. Participants who meet all eligibility criteria are randomized on Day 1 and enter the Treatment Period. Study drug is administered once daily for 8 weeks. Participants are required to continue daily eDiary entries throughout the Treatment Period to capture bowel movement frequency, stool consistency, symptom severity, and use of rescue medication. Following completion of the Treatment Period, participants enter a 2-week Post-treatment Follow-up Period, during which eDiary assessments continue. A final study visit is conducted at the end of follow-up. Treatment and Randomization Participants are randomized via an interactive web-based system to receive low-dose plecanatide, high-dose plecanatide, or placebo. Dose assignment is based on treatment group and participant body weight at the time of randomization in order to achieve predefined weight-based dosing ranges. Study drug is administered orally once daily, preferably in the morning, with or without food. Participants who are unable to swallow tablets may have the study drug administered in a suitable alternative form as described in the protocol. A rescue medication (bisacodyl) is provided for use if a participant has not had a bowel movement for at least 72 hours. Use of rescue medication is recorded in the eDiary and is subject to protocol-defined limitations. Efficacy Evaluations Efficacy evaluations are based primarily on data collected through the eDiary and participant-reported outcome (PRO) instruments administered at study visits. The primary efficacy variable is the change from baseline in spontaneous bowel movement (SBM) frequency at Week 8. Secondary efficacy variables include responder endpoints based on SBM and complete spontaneous bowel movement (CSBM) frequency, stool consistency assessed using the Bristol Stool Form Scale (BSFS) or modified BSFS, and changes from baseline in constipation-related symptoms. Additional assessments include time to first bowel movement, use of rescue medication, and global and symptom-specific PRO measures. Safety Evaluations Safety is monitored throughout the study by assessment of adverse events (AEs), clinical laboratory parameters, vital signs, physical examinations, and electrocardiograms (ECGs). Gastrointestinal events, including diarrhea, are of particular interest due to the mechanism of action of plecanatide. Criteria for dose interruption or discontinuation are specified in the protocol for participants experiencing clinically significant adverse events. Treatment-emergent adverse events, serious adverse events, and discontinuations due to adverse events will be summarized descriptively by treatment group. Pharmacokinetic Assessments Pharmacokinetic evaluations include measurement of plasma concentrations of plecanatide and its metabolite at specified time points following dosing. Given the minimal systemic absorption observed in prior studies, PK analyses are exploratory and are intended to further characterize exposure in the pediatric population. Statistical Considerations Approximately 30 participants per treatment group within each age cohort are planned. The sample size is considered sufficient for evaluation of the primary objective in this Phase 2b study. The primary efficacy analysis will be performed on the intent-to-treat population using a mixed-effects model for repeated measures, including treatment group, time, and relevant baseline covariates. Secondary endpoints will be analyzed using appropriate statistical methods based on endpoint type. Safety analyses will be performed on the safety population and will be summarized descriptively. Data Collection and Study Conduct Study data are collected using electronic case report forms (eCRFs) and participant eDiaries. Compliance with study procedures, including study drug administration and diary completion, is monitored throughout the study. The study is conducted in accordance with the principles of Good Clinical Practice (GCP), applicable regulatory requirements, and institutional review board or ethics committee approval. Written informed consent and, where applicable, assent are obtained prior to participation.

Eligibility Criteria

Interventions