Ghrelin Agonist TZP-101/Ulimorelin Accelerates Gastrointestinal Recovery Independently of Opioid Use and Surgery Type: Covariate Analysis of Phase 2 Data

BACKGROUND: Delayed recovery of gastrointestinal (GI) motility is a common complication following surgery. TZP-101/ulimorelin is a macrocyclic peptidomimetic ghrelin receptor agonist with GI promotility effects that significantly accelerates time to recovery of GI motility compared to placebo following partial colectomy. It is also well tolerated. The objectives of this analysis were to identify predictors of GI motility recovery in patients undergoing partial colectomy and to evaluate whether these factors affect ulimorelin acceleration of GI recovery. METHODS: Covariate analysis assessed the effect of eight variables—age, sex, body mass index, type of surgery (right colectomy, left colectomy, other), duration of surgery, blood loss, total opioid consumption, country—on recovery of GI motility in 236 patients randomized to ulimorelin (n = 168) or placebo (n = 68). The primary endpoint was the recovery of GI function (time from the end of surgery to first bowel movement). Stepwise regression identified a parsimonious model of the smallest subset of variables best predicting GI recovery. RESULTS: Recovery was shorter for segmental/subtotal colectomies vs. right colectomies (P = 0.016) and longer with increased total opioid use (P = 0.037). The remaining variables had no statistically significant effect on GI recovery. Effects of ulimorelin 480 μg/kg (the most effective dose) on time to GI tract recovery remained statistically and clinically significant (hazard ratio = 1.81, P = 0.014) when adjusted for surgery type and/or total opioid use. CONCLUSIONS: Two factors, type of surgery and total opioid use, independently modified times to recovery of GI motility following partial large bowel resection surgery. Acceleration of recovery of GI motility by ulimorelin was independent of these factors.