EFFICACY AND SAFETY OF LINACLOTIDE IN TREATING FUNCTIONAL CONSTIPATION IN PEDIATRIC PATIENTS AGED 6-17 YEARS: A PHASE 3 PIVOTAL RANDOMIZED PLACEBO-CONTROLLED TRIAL

Introduction: Chronic nausea and abdominal pain are debilitating symptoms that often co-exist in children with functional abdominal pain disorders (FAPD). Standard medical therapy (SMT) includes the off-label medications, cyproheptadine and amitriptyline. While several pediatric studies have demonstrated the benefits of percutaneous electrical nerve field stimulation (PENFS) in children with FAPD, no study has compared outcomes of PENFS to SMT. We aimed to compare improvements in abdominal pain, nausea and disability using validated measures between these treatments.
Methods: The electronic medical records (demographic data and medical history) of patients aged 11-21 years who met the Rome 4 criteria for a FAPD and had been treated with 4 weeks of PENFS, cyproheptadine or amitriptyline were reviewed. Outcomes were evaluated using validated questionnaires collected as part of clinical care at baseline and follow-up within 3 months (FU) and included: Abdominal Pain Index (API), Nausea Severity Scale (NSS), and the Functional Disability Inventory (FDI).
Results: Of the 101 patients, 35% had functional dyspepsia and had IBS each while 30% had functional abdominal pain. Of these, 49 (48%) were treated with PENFS, 31 (31%) with cyproheptadine and 21 (21%) with amitriptyline and median ages in these groups were 17 (15-19), 16 (15-18) and 15 (11-16) years respectively. In all three groups, majority were females (75%, 90% and 52% respectively).
In the PENFS group, API (p=0.001), NSS (0.05) and FDI (p=0.04) were lower at FU compared with baseline. All scores decreased but were not significant in the cyproheptadine group. API scores decreased at FU in the amitriptyline group (p=0.03). Examining each outcome longitudinally, the API and NSS scores were lowest in the PENFS group. The FDI scores however, were lowest in the amitriptyline group.
Comparing outcomes between groups, API scores were significantly lower in PENFS versus cyproheptadine (p=0.04) but not between PENFS and amitriptyline (p=0.64, figure 1). The NSS scores were significantly lower in PENFS vs. cyproheptadine (p<0.001), between PENFS vs. amitriptyline (p<0.001) and in amitriptyline vs. cyproheptadine (p=0.04). The FDI scores were only lower in the amitriptyline vs. cyproheptadine group (p=0.03).
Conclusion: In children with FAPD, PENFS showed improvements in abdominal pain, nausea and disability while amitriptyline showed improvements in abdominal pain within 3 months of treatment. PENFS was more effective than SMT in reducing nausea scores within 3-month follow-up. PENFS was also more effective than cyproheptadine in improving abdominal pain scores but did not differ from amitriptyline. Amitriptyline improved disability scores more than cyproheptadine.

Introduction: 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 μg 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 μg 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.