Sustainability of Linaclotide Response in Chronic Idiopathic Constipation Patients: A Post-hoc Pooled Analysis of Two Phase 3 Trials

Abstract

Introduction: Linaclotide (LIN), a guanylate cyclase-C agonist, is approved in the US at a dose of 145 μg for treatment of chronic idiopathic constipation (CIC) in adults. Approval was based on two phase 3, randomized, placebo-controlled trials; the primary efficacy endpoint was met in each. Clinicians and regulatory agencies are increasingly interested in sustainability of CIC treatment response. The aims of this post-hoc analysis were to assess sustained response to LIN and examine differences between sustained responders and primary-efficacy (12-week) responders in the phase 3 trials. Methods: CIC patients were randomized 1:1:1 to receive placebo (PBO), or LIN 145 μg or 290 μg once daily for 12 weeks. Patient populations were pooled across the two nearly identical trials by treatment. Weekly response was defined as ≥3 complete, spontaneous bowel movements (CSBMs)/week and an increase from baseline of ≥1 CSBM/week; patients without CSBM data (missing or discontinued before that week) were considered weekly nonresponders. Both the 12-week and the sustained responder definitions required weekly response for ≥9 of 12 weeks. In addition, sustained responders must have had a weekly response for ≥3 of the last 4 treatment weeks. 12-week responder and sustained responder rates were evaluated; frequency of weekly response in the last 4 of 12 weeks was analyzed by the frequency of weekly response in the first 8 weeks. Sustained responder rates were also analyzed in the individual trials. Results: The pooled analysis included 423 PBO, 430 LIN 145 μg, and 418 LIN 290 μg patients; 4.7% of PBO patients were 12-week responders compared to 18.6% of LIN 145 μg patients (p < 0.0001) and 20.3% of LIN 290 μg patients (p < 0.0001). Sustained responder rates were 4.3% of PBO patients compared to 16.3% of LIN 145 μg patients (p < 0.0001) and 18.7% of LIN 290 μg patients (p < 0.0001); differences versus PBO were significant in each trial (Table 1). Of the 12-week responders who were not sustained responders, the majority had a weekly response for 2 of the last 4 weeks (Table 2).Table 1: Responder Rates: 12-Week Responders and Sustained RespondersTable 2: Frequency of Weekly Response in the Last 4 of 12 Treatment Weeks by Frequency in the First 8 Weeks Pooled PopulationConclusion: In this post-hoc pooled analysis of two 12-week phase 3 CIC trials, significantly more LIN patients than PBO patients showed sustained response in CSBM frequency. The efficacy results demonstrated by sustained responders are similar to those demonstrated by the 12-week primary efficacy responder endpoint; in that 87.5% of LIN 145 μg and 91.8% of LIN 290 μg patients meeting the 12-week responder definition were also sustained responders.