• Nobuyuki Katakami, Toshiyuki Harada, Toru Murata, Katsunori Shinozaki, Masakazu Tsutsumi, Takaaki Yokota, Masatsugu Arai, Yukio Tada, Masaru Narabayashi, and Narikazu Boku.
• Nobuyuki Katakami, Institute of Biomedical Research and Innovation, Kobe; Toshiyuki Harada, Japan Community Healthcare Organization Hokkaido Hospital, Sapporo; Toru Murata, Aichi Hospital, Okazaki; Katsunori Shinozaki, Hiroshima Prefectural Hospital, Hiroshima; Masakazu Tsutsumi, Hitachi General Hospital, Hitachi; Takaaki Yokota, Masatsugu Arai, and Yukio Tada, Shionogi & Co Ltd, Osaka; Masaru Narabayashi, Cancer Institute Hospital of Japanese Foundation for Cancer Research; and Narikazu Boku, National Cancer Center Hospital, Tokyo, Japan.
• J. Clin. Oncol. 2017 Dec 1; 35 (34): 3859-3866.

AbstractPurpose 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.

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