Colon to Rectum
Lancet Gastroenterol Hepatol. 2024;9(3):238–50
Efficacy and safety of linaclotide in treating functional constipation in pediatric patients: A randomized, double-blind, placebo-controlled, multicenter, phase 3 trial
Background: Linaclotide, a guanylate cyclase C agonist, has been approved in the USA for the treatment of chronic idiopathic constipation and irritable bowel syndrome with predominant constipation in adults. The authors aimed to assess the efficacy and safety of linaclotide in pediatric patients aged 6–17 years with functional constipation.
Methods: This randomized, double-blind, placebo-controlled, multicenter, phase 3 study was done at 64 clinic or hospital sites in 7 countries (USA, Canada, Israel, Italy, the Netherlands, Ukraine, and Estonia). Patients aged 6–17 years who met modified Rome III criteria for functional constipation were randomly assigned (1:1), with a block size of 4 and stratified by age (6–11 years and 12–17 years), to receive either oral linaclotide 72 μg or placebo once daily for 12 weeks. Participants, investigators, and data assessors were masked to assignment. The primary efficacy end point was change from baseline (CFB) in the 12-week frequency rate of spontaneous bowel movements (SBMs; occurring in the absence of rescue medication on the calendar day of or before the bowel movement) per week and the secondary efficacy end point was CFB in stool consistency over the 12-week treatment period; efficacy and safety were analyzed in all patients in the randomized population who received at least 1 dose of study intervention (modified intention-to-treat population and safety population, respectively).
Findings: Between October 1, 2019, and March 21, 2022, 330 patients were enrolled and randomly assigned to linaclotide (n = 166) or placebo (n = 164). Two patients in the linaclotide group did not receive any treatment; thus, efficacy and safety end points were assessed in 328 patients (164 patients in each group). 293 patients (89%) completed the 12-week treatment period (148in the linaclotide group and 145 in the placebo group). 181 of 328 patients (55%) were female and 147 (45%) were male. At baseline, the mean frequency rate for SBMs was 1.28 SBMs per week (standard deviation [SD] 0.87) for placebo and 1.16 SBMs per week (SD 0.83) for linaclotide, increasing to 2.29 SBMs per week (SD 1.99) for placebo and 3.41 SBMs per week (SD 2.76) for linaclotide during intervention. Compared with placebo (least-squares mean [LSM] CFB 1.05 SBMs per week [standard error [SE] 0.19]), patients treated with linaclotide showed significant improvement in SBM frequency (LSM CFB 2.22 SBMs per week [SE 0.19]; LSM CFB difference 1.17 SBMs per week [95% confidence interval {CI}: 0.65–1.69]; p < 0.0001). Linaclotide also significantly improved stool consistency over placebo (LSM CFB 1.11 [SE 0.08] vs. 0.69 [SE 0.08]; LSM CFB difference 0.42 [95% CI: 0.21–0.64]; p = 0.0001). The most reported treatment-emergent adverse event (TEAE) by patients treated with linaclotide was diarrhea (7/164 [4%] vs. 3/164 patients [2%] in the placebo group) and by patients treated with placebo was COVID-19 (5 [3%] vs. 4 [2%] in the linaclotide group). The most frequent treatment-related TEAE was diarrhea (linaclotide: 6 patients [4%]; placebo: 2 patients [1%]). One serious adverse event of special interest (treatment-related severe diarrhea resulting in dehydration and hospitalization) occurred in a female patient aged 17 years in the linaclotide group; this case resolved without sequelae after administration of intravenous fluids. No deaths occurred during the study.
Interpretation: Linaclotide is an efficacious and well tolerated treatment for functional constipation in pediatric patients and has subsequently been approved by the US Food and Drug Administration for this indication.