• Nobuyuki Katakami, Koji Oda, Katsunori Tauchi, Ken Nakata, Katsunori Shinozaki, Takaaki Yokota, Yura Suzuki, Masaru Narabayashi, and Narikazu Boku.
• Nobuyuki Katakami, Institute of Biomedical Research and Innovation, Kobe; Koji Oda, Aichi Cancer Center, Aichi; Katsunori Tauchi, Aizawa Hospital, Nagano; Ken Nakata, Sakai City Medical Center; Takaaki Yokota and Yura Suzuki, Shionogi & Co, Ltd, Osaka; Katsunori Shinozaki, Hiroshima Prefectural Hospital, Hiroshima; Masaru Narabayashi, Cancer Institute Hospital of Japanese Foundation for Cancer Research; and Narikazu Boku, National Cancer Center Hospital, Tokyo, Japan.
• J. Clin. Oncol. 2017 Jun 10; 35 (17): 1921-1928.

AbstractPurpose This randomized, double-blind, multicenter study aimed to determine the dose of naldemedine, a peripherally-acting μ-opioid receptor antagonist, for future trials by comparing the efficacy and safety of three doses of naldemedine versus placebo in patients with cancer and opioid-induced constipation. Methods Patients ≥ 18 years old with cancer, an Eastern Cooperative Oncology Group performance status ≤ 2, who had been receiving a stable regimen of opioid analgesics for ≥ 2 weeks, had at least one constipation symptom despite laxative use, and no more than five spontaneous bowel movements (SBMs) during the past 14 days, were randomly assigned (1:1:1:1) to oral, once-daily naldemedine 0.1, 0.2, or 0.4 mg, or placebo, for 14 days. The primary end point was change in SBM frequency per week from baseline during the treatment period. Secondary end points included SBM responder rates, change from baseline in the frequency of SBM without straining, and complete SBM. Safety was also assessed. Results Of 227 patients who were randomly assigned, 225 were assessed for efficacy (naldemedine 0.1 mg, n = 55; 0.2 mg, n = 58; 0.4 mg, n = 56; placebo, n = 56) and 226 for safety. Change in SBM frequency (primary end point) was higher with all naldemedine doses versus placebo ( P < .05 for all comparisons), as were SBM responder rates and change in complete SBM frequency. Change in SBM frequency without straining was significantly improved with naldemedine 0.2 and 0.4 (but not 0.1) mg versus placebo (at least P < .05). Treatment-emergent adverse events were more common with naldemedine (0.1 mg: 66.1%; 0.2 mg: 67.2%; 0.4 mg: 78.6%) than placebo (51.8%); the most common treatment-emergent adverse event was diarrhea. Conclusion Fourteen-day treatment with naldemedine significantly improved opioid-induced constipation in patients with cancer and was generally well tolerated. Naldemedine 0.2 mg was selected for phase III studies.

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