P4A048: Efficacy and Safety of Linaclotide in Treating Functional Constipation in Pediatric Patients Aged 6–17 Years: A Phase 3, Pivotal, Randomized, Placebo-controlled Trial

Background: Functional constipation (FC) is prevalent in childhood and can severely impact quality of life, but no prescription treatments are US Food and Drug Administration (FDA)-approved for pediatric use. In adults, linaclotide (LIN), a guanylate cyclase-C agonist, is FDA-approved to treat chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. This phase 3 trial assessed the efficacy and safety of LIN vs placebo (PBO) in pediatric patients aged 6 to 17 years with FC.

Methods: This phase 3, randomized, double-blind, PBO-controlled study (NCT04026113) enrolled patients aged 6–17 years who met modified Rome III criteria for FC. Participants were randomized 1:1, stratified by age group (6–11 and 12–17 years), to receive LIN 72 mcg or PBO once daily for 12 weeks. The primary efficacy endpoint was change from baseline in 12-week spontaneous bowel movement (SBM) frequency rate (SBMs/week). The key secondary efficacy endpoint was change from baseline in 12-week stool consistency based on the Bristol Stool Form Scale. Comparisons between LIN and PBO for efficacy endpoints were conducted using an analysis of covariance (ANCOVA) model with study intervention, with age group as fixed factors and baseline value as a covariate. Adverse events (AEs), laboratory values, vital signs, and electrocardiograms were monitored.

Results: Among 328 patients who received at least 1 dose of study drug (LIN, n=164; PBO, n=164), 55.2% were female and 69.8% were White; mean age was 11 years. Overall, 145 (88.4%) in the PBO and 148 (90.2%) in the LIN group completed 12 weeks of study treatment. Treatment groups had similar baseline stool frequency (mean SBMs/week, [SD]; LIN, 1.16 [0.83]; PBO, 1.28 [0.87]). Compared with PBO, LIN-treated patients showed significant improvement from baseline in 12-week SBM frequency rate (least square means, standard error; LSM, [SE]; LIN 2.22 [0.19] vs PBO 1.05 [0.19] SBMs/week; P < 0.0001) and 12-week stool consistency (LSM, [SE]; LIN 1.11 [0.08] vs PBO 0.69 [0.08]); P = 0.0001). Sensitivity analyses and analyses of age subgroups (Figure 1) were consistent with primary analyses.
Treatment-emergent AEs (TEAEs) reported in >2% of patients were diarrhea (LIN, 4.3%; PBO, 1.8%) and COVID-19 (LIN, 2.4%; PBO, 3.0%). Both groups had similar proportions of patients with AEs: TEAEs (LIN, 17%; PBO, 21%), serious AEs (1.2% for both), and TEAEs leading to study treatment discontinuation (LIN, 1.2%; PBO, 1.8%). One AE of special interest of diarrhea was reported in a 17-year-old but it was considered not related to study drug and resolved within a day without sequelae.

Conclusion: LIN 72 mcg once daily demonstrated significant improvement in the SBM frequency rate and stool consistency in pediatric patients with FC and exhibited a favorable safety profile consistent with prior adult data and a prior pediatric phase 2 FC study.