Randomized Phase III and Extension Studies of Naldemedine in Patients With Opioid-Induced Constipation and Cancer

Abstract

Purpose Opioid-induced constipation (OIC) is a frequent and debilitating adverse effect (AE) of opioids-common analgesics for cancer pain. We investigated the efficacy and safety of a peripherally acting μ-opioid receptor antagonist, naldemedine (S-297995), for OIC, specifically in patients with cancer. Patients and Methods This phase III trial consisted of a 2-week, randomized, double-blind, placebo-controlled study (COMPOSE-4) and an open-label, 12-week extension study (COMPOSE-5). In COMPOSE-4, eligible adults with OIC and cancer were randomly assigned on a 1:1 basis to receive once-daily oral naldemedine 0.2 mg or placebo. The primary end point was the proportion of spontaneous bowel movement (SBM) responders (≥ 3 SBMs/week and an increase of ≥ 1 SBM/week from baseline). The primary end point of COMPOSE-5 was safety. Results In COMPOSE-4, 193 eligible patients were randomly assigned to naldemedine (n = 97) or placebo (n = 96). The proportion of SBM responders in COMPOSE-4 was significantly greater with naldemedine than with placebo (71.1% [69 of 97 patients] v 34.4% [33 of 96 patients]; P < .0001). A greater change from baseline was observed with naldemedine than with placebo in the frequency of SBMs/week (5.16 v 1.54; P < .0001), SBMs with complete bowel evacuation/week (2.76 v 0.71; P < .0001), and SBMs without straining/week (3.85 v 1.17; P = .0005). In COMPOSE-4, more patients treated with naldemedine than with placebo reported treatment-emergent AEs (TEAEs) (44.3% [43 of 97 patients] v 26.0% [25 of 96 patients]; P = .01); in COMPOSE-5, 105 (80.2%) of 131 of patients reported TEAEs. Diarrhea was the most frequently reported TEAE in COMPOSE-4 (19.6% [19 of 97 patients] v 7.3% [seven of 96 patients] with naldemedine v placebo) and COMPOSE-5 (18.3% [24 of 131 patients] with naldemedine). Naldemedine was not associated with signs or symptoms of opioid withdrawal and had no notable impact on opioid-mediated analgesia. Conclusion Once-daily oral naldemedine 0.2 mg effectively treated OIC and was generally well tolerated in patients with OIC and cancer.

Medical Therapy of Constipation: Current Standards and Beyond

“…A new oral PAMORA, naldemedine, which has also demonstrated good efficacy and tolerability in a large clinical trial program [33][34][35], has recently been approved by the FDA and is currently undergoing licensing application at the EMA.…”

Peripherally acting μ‐opioid antagonist for the treatment of opioid‐induced constipation: Systematic review and meta‐analysis

“…A total of 7715 patients with 4100 AEs were reported in 26 RCTs . Overall, there were significantly increased AEs in patients given PAMORA (RR, 1.10; 95% CI, 1.06–1.15; P < 0.00001; Fig.…”

“…Ultimately, 51 articles, including 31 RCTs, met our inclusion criteria. [14][15][16] Figure 1 shows the screening process and reasons for excluding studies.…”

“…Crossover and cluster RCTs were excluded to avoid heterogeneity. We regarded SBM (defined as a bowel movement without a rescue laxative taken within the past 24 h) as the same disease concept as a rescue‐free bowel movement (defined as a bowel movement where no laxatives were used during the prior 24 h).…”

Reduction in pain: Is it worth the gain? The effect of opioids on the GI tract

“…When OTC laxatives fail to treat constipation, prescription treatments should be considered. Currently, the drugs approved for the treatment of OIC are peripheral acting μ‐opioid receptor antagonist (PAMORA) medications methylnaltrexone, naldemedine, naloxegol, fixed dose oxycodone:naloxone, and the chloride‐type II agonist lubiprostone . Prucalopride, a 5‐HT4 agonist, also appears to improve symptoms associated with OIC though it has not been approved for this indication …”