A randomized, double‐blind, placebo‐controlled trial to evaluate the efficacy, safety, and tolerability of long‐term treatment with prucalopride

Abstract

• In contrast to the results of four previous 12-week trials, this study found no significant improvement in the proportion of patients achieving three or more spontaneous complete bowel movements (SCBMs) per week over 24 weeks when treated with prucalopride compared with placebo. Despite extensive evaluation, no explanation for these null efficacy results could be found.• The aim of this randomized, placebo-controlled trial was to assess the efficacy of 24 weeks of prucalopride treatment in patients with chronic constipation.• Patients with chronic constipation who had less than three SCBMs per week were randomized to receive prucalopride 2 mg or placebo daily for 24 weeks. The primary endpoint was the proportion of patients achieving a mean of three or more SCBMs per week over the treatment period.• Overall, 361 patients were enrolled in the trial. The proportion of patients achieving the primary endpoint was not statistically different between the prucalopride and placebo groups (25.1% vs 20.7%; p = 0.367). No new safety concerns were identified. AbstractBackground Randomized trials have confirmed the efficacy of prucalopride for the treatment of chronic constipation up to 12 weeks. This study aimed to assess the efficacy of prucalopride over a 24-week period (ClinicalTrials.gov: NCT01424228). Methods Adults with chronic constipation and ≤2 spontaneous complete bowel movements (SCBMs)/week were randomized to receive prucalopride 2 mg or placebo daily for 24 weeks. The primary endpoint was the proportion of patients achieving a mean of ≥3 SCBMs/week over the treatment period, assessed using daily e-diaries. Secondary outcomes and safety parameters were assessed throughout the study. Key Results Overall, 361 patients were randomized and received prucalopride or placebo. Baseline characteristics were similar in the prucalopride (N = 181) and placebo (N = 180) groups. Mean age was 48.9 years (standard deviation, 16.0) and most patients were women.

ThePAC‐SYMquestionnaire for chronic constipation: defining the minimal important difference

“…This analysis used integrated data from six phase 3 and 4, multicentre, double‐blind, randomised, placebo‐controlled, parallel‐group trials of the efficacy and safety of prucalopride in patients with chronic constipation, performed across three continents (Table 1; ClinicalTrials.gov identifiers: SPD555‐302 [NCT01147926], SPD555‐401 [NCT01424228], PRU‐CRC‐3001 [NCT01116206], PRU‐USA‐13 [NCT00485940], PRU‐USA‐11 [NCT00483886] and PRU‐INT‐6 [NCT00488137]) 11, 23, 24, 25, 26, 27. The designs of these trials were similar and have been described in detail previously 11, 23, 24, 25, 26, 27…”

“…The designs of these trials were similar and have been described in detail previously 11, 23, 24, 25, 26, 27…”

New and Investigational Agents for Irritable Bowel Syndrome

“…Adverse events were generally minor with headache being the most common (21 % randomized to the active treatment group) [17]. In a recent trial, however, prucalopride did not show statistically significant improvement in primary or secondary outcomes compared with placebo over the 12-or 24-week treatment period [18]. The reason for this failure to relieve constipation in one recent trial is unclear.…”

An update on prucalopride in the treatment of chronic constipation

“…Of particular importance are seven pivotal multicenter, double-blind, phase III and IV, placebo-controlled randomized clinical studies which are summarized in Table 1. [37][38][39][40][41][42][43] The first three of these trials, [37][38][39] which formed the basis for applications for regulatory approval in several jurisdictions, had a similar study protocol and included adult patients (>18 years) of either sex with chronic idiopathic constipationdefined as two or fewer spontaneous complete bowel movements (SCBMs) per week for at least 6 months before the screening visit. In addition, the enrolled patients were required to have either hard/very hard stools, a sensation of incomplete evacuation or straining with defecation with at least 25% of bowel movements.…”

“…To date and despite an extensive evaluation, a plausible explanation for the inconsistency between the results of this trial and the previous large pivotal studies has yet to emerge. 36,43 However, until future studies demonstrate continued efficacy over longer treatment periods, the long-term efficacy of prucalopride must be questioned.…”