Prospective, randomized, controlled, proof-of-concept study of the ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients
Beck DE, Sweeney WB, McCarter MD
International Journal of Colorectal Disease (2014) · n=114
Median time to first tolerated meal was 25.3 hours with ipamorelin versus 32.6 hours with placebo — a seven-hour edge in the expected direction, but p = 0.15, and the rigorous indication trial that should have made ipamorelin a prescription drug fell short of statistical significance.
This is the most rigorous randomized controlled trial of ipamorelin in humans — a multicenter, double-blind, placebo-controlled Phase 2 proof-of-concept study conducted by what was then Helsinn Therapeutics (developing ipamorelin as an indication for postoperative ileus). Adults undergoing small- or large-bowel resection by open or laparoscopic surgery were randomized to receive intravenous ipamorelin at 0.03 mg/kg twice daily versus placebo, beginning on postoperative day 1 and continuing for up to 7 days or until hospital discharge. One hundred seventeen patients were enrolled; 114 comprised the safety and modified intent-to-treat populations. The pre-specified primary endpoint was time from first dose to tolerance of a standardized solid meal. Median time to first tolerated meal was 25.3 hours in the ipamorelin arm versus 32.6 hours in the placebo arm — a numerical separation of approximately seven hours in the expected direction, but the p-value of 0.15 did not reach statistical significance. Key and secondary efficacy analyses showed no significant differences between arms. Treatment-emergent adverse events occurred in 87.5% of ipamorelin patients and 94.8% of placebo patients, comparable in nature and severity. The trial concluded that ipamorelin at this dose and schedule was well tolerated but did not show a statistically significant clinical benefit in postoperative ileus.
The trial is the closest thing to a regulatory-grade efficacy study ever conducted on ipamorelin, and it is a negative trial on its prespecified primary endpoint. Critics have argued the trial was underpowered to detect the observed effect size; with N = 114 and a seven-hour delta against a heterogeneous bowel-resection cohort, statistical power was modest. The dose chosen (0.03 mg/kg IV twice daily) was selected from prior Phase 1 and Phase 2a work and may not represent the optimal dose-and-schedule combination — particularly given ipamorelin's short half-life, more frequent or continuous dosing might plausibly have produced a stronger signal. Heterogeneity in surgical approach (open versus laparoscopic), bowel-resection extent, and post-op care pathways across centers adds noise. The sponsor's development program for ipamorelin in postoperative ileus was effectively discontinued after this trial, and ipamorelin has not been pursued by Helsinn or its successors for any prescription indication since. Industry sponsorship is disclosed.
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