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

The primary objective of this Phase 3, multicenter, randomized, double-blind, parallel-group study is to evaluate the **safety** and **efficacy** of 12 weeks of **linaclotide** therapy compared to placebo in pediatric subjects aged 2 to 5 years with **Functional Constipation** (FC) who meet modified Rome IV criteria. This is clinically relevant as it aims to address the therapeutic needs of young children suffering from FC, a condition that can significantly impact quality of life and may lead to further complications if untreated. Additionally, the study seeks to assess the long-term safety of linaclotide in subjects who have completed the initial study intervention or a related study, LIN-MD-67, thereby providing insights into the sustained use of linaclotide in this population.

The clinical trial involves a total of **102 participants** diagnosed with **Functional Constipation**. The study population consists of pediatric subjects aged between 24 months and 5 years and 11 months, inclusive of both **male and female** participants. The trial specifically targets a vulnerable population, as it includes young children. Participants were selected based on their compliance with the modified Rome IV criteria for childhood functional constipation, which includes having two or fewer defecations per week for at least one month prior to screening. The general health status of the participants is assessed to ensure no clinically significant conditions that could pose a safety concern or interfere with the study assessments. Lifestyle considerations such as the discontinuation of any laxatives prior to the intervention are required, with the use of protocol-permitted rescue medicine. The trial aims to evaluate the safety and efficacy of linaclotide therapy over a 12-week period, followed by an assessment of its long-term safety in those who complete the initial study phase.

The clinical trial is a **Phase 3**, multicenter, randomized, double-blind, parallel-group study designed to evaluate the safety and efficacy of **Linaclotide** compared to placebo in pediatric subjects aged 2 to 5 years with **Functional Constipation**. The trial consists of two parts: Part 1 involves a 12-week double-blind treatment period, and Part 2 includes a 24-week open-label treatment extension to assess long-term safety. The trial is expected to conclude by November 2025, with recruitment having commenced in August 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, health status, and meeting modified Rome IV criteria for childhood functional constipation. Following successful screening, participants will be randomized to receive either Linaclotide or placebo in a double-blind manner. The primary endpoint is the change from baseline in the 12-week spontaneous bowel movement (SBM) frequency rate, as observed by the primary caregiver. Secondary endpoints include changes in stool consistency, straining, and the proportion of days with fecal incontinence.

Study visits will include regular follow-up assessments to monitor safety and efficacy, with data collected through caregiver observations and eDiary entries. The end-of-study visit will occur after the completion of the open-label extension, or earlier if the participant withdraws or is withdrawn from the study. Conditions that may lead to early termination include adverse events, non-compliance with the study protocol, or withdrawal of consent by the caregiver. The expected length of participant involvement is up to 36 weeks, encompassing both the double-blind and open-label phases.

The clinical trial involves the administration of **Linaclotide**, an experimental medication, to evaluate its safety and efficacy in pediatric subjects aged 2 to 5 years with **functional constipation**. Linaclotide is formulated as a **capsule** and is classified as an agonist of **guanylate cyclase C (GC-C)**. The medication is administered orally, with a maximum daily dose of 72 micrograms and a total maximum dose of 2592 micrograms over a treatment period of up to 36 weeks. The active substance, linaclotide, is a protein of other origin, and the product is manufactured by AbbVie Deutschland GmbH & Co. KG. The trial aims to assess the effects of 12 weeks of linaclotide therapy compared to a placebo, followed by a 24-week open-label treatment extension to evaluate long-term safety.

In addition to the experimental treatment, the study includes a **placebo** group to serve as a comparator. The placebo is designed to mimic the appearance of the linaclotide capsule but does not contain any active substance. The placebo is used to ensure the double-blind nature of the trial, allowing for an unbiased comparison of the safety and efficacy outcomes between the linaclotide and placebo groups. The placebo administration follows the same oral route and dosing schedule as the linaclotide treatment to maintain consistency across the study arms.

The efficacy of Linaclotide in treating **Functional Constipation** in pediatric subjects aged 2 to 5 years will be assessed through a Phase 3, multicenter, randomized, double-blind, parallel-group study. The primary endpoint for evaluating efficacy is the change from baseline in the 12-week spontaneous bowel movement (SBM) frequency rate, as observed by the primary caregiver during the double-blind study intervention period. Secondary endpoints include changes from baseline in 12-week stool consistency and straining, as well as the proportion of days with fecal incontinence during the double-blind study intervention period for subjects who have acquired toileting skills.

Data collection will involve observations made by the primary caregiver, with efficacy parameters being measured at baseline and throughout the 12-week double-blind intervention period. The study will utilize an eDiary to record the frequency of SBMs, stool consistency, and straining, ensuring accurate and consistent data collection. The analysis will focus on comparing the changes in these parameters between the Linaclotide and placebo groups to determine the efficacy of the treatment.