Safety and efficacy of linaclotide in children aged 2–5 years with functional constipation: Phase 2, randomized study

Abstract Objectives Linaclotide, a guanylate cyclase‐C agonist, was recently approved in the United States for the treatment of children 6–17 years of age with functional constipation (FC). This study evaluated the dose‐response, safety, and efficacy of 4 weeks of linaclotide compared with placebo in children 2–5 years of age with FC. Methods In this phase 2, randomized, double‐blind, placebo‐controlled, multidose study, 35 children with FC (based on Rome III criteria) were randomized 3:1 to receive linaclotide (18, 36, or 72 μg, for groups 1, 2, and 3, respectively) and 5:1 to receive linaclotide 9, 18, 36, or 72 μg (group 4), or matching placebo. Key endpoints were the changes from baseline in overall spontaneous bowel movement (SBM) frequency (SBMs/week), stool consistency, and straining, as well as the proportion of days with fecal incontinence during the study intervention period. Adverse events (AEs) were recorded. Results Of the randomized patients, 34 (97.1%) completed the treatment period and 33 (94.3%) completed the posttreatment period. Mean change from baseline over the treatment period for three of the four key efficacy endpoints showed greater improvement in the linaclotide 72 μg group versus placebo. A dose‐response trend was seen for stool consistency in patients receiving linaclotide. Four patients randomized to linaclotide experienced treatment‐emergent AEs, one of which was treatment‐related (mild diarrhea). All AEs were mild or moderate and none were severe. Conclusions Linaclotide was well tolerated in this pediatric population and an efficacy trend was seen with linaclotide 72 μg versus placebo.