Randomized Phase III and Extension Studies of Naldemedine in Patients With Opioid-Induced Constipation and Cancer
Randomized Phase III and Extension Studies of Naldemedine in Patients With Opioid-Induced Constipation and Cancer
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DOI：
10.1200/jco.2017.73.0853
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发表时间：
2017-12-01
影响因子：
45.3
通讯作者：
Boku, Narikazu
中科院分区：
文献类型：
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作者：
Katakami, Nobuyuki;Harada, Toshiyuki;Boku, Narikazu
阿片类药物是治疗癌症疼痛的常用镇痛药，阿片类药物引起的便秘（OIC）是一种常见的不良反应。我们调查的有效性和安全性的外周作用的M-阿片受体拮抗剂，naldemedine（S-297995），OIC，特别是在cancer.Patients和MethodsThis阶段III试验包括一个2周，随机，双盲，安慰剂对照研究（COMPOSSE-4）和一个开放标签，12周的扩展研究（COMPOSSE-5）。在COMPOSE-4中，符合条件的OIC和癌症成人按1：1的比例随机分配接受每日一次口服纳地美定0.2 mg或安慰剂。主要终点是自发性排便（SBM）应答者的比例（>= 3 SBM/周，较基线增加>= 1 SBM/周）。COMPOSE-5的主要终点是safety.ResultsIn COMPOSE-4，193名符合条件的患者被随机分配到纳地美丁（n = 97）或安慰剂（n = 96）。化合物-4中SBM应答者的比例在纳地美定组显著高于安慰剂组（71.1% [97例患者中的69例] vs 34.4% [96例患者中的33例]; P < .0001）。与安慰剂组相比，纳地美汀组的SBM/周频率（5.16 v1.54; P < .0001）、SBM伴完全排便/周频率（2.76 v0.71; P < .0001）和SBM无劳损/周频率（3.85 v1.17; P = .0005）较基线变化更大。在COMPOSSE-4中，与安慰剂相比，更多接受纳地美定治疗的患者报告了治疗后出现的AE（TEAE）（44.3% [97例患者中的43例] vs 26.0% [96例患者中的25例]; P = 0.01）;在COMPOSSE-5中，131例患者中的105例（80.2%）报告了TEAE。腹泻是COMPOSE-4（19.6% [19/97例患者] vs 7.3% [7/96例患者]，纳德美定vs安慰剂）和COMPOSE-5（18.3% [24/131例患者]，纳德美定）中最常报告的TEAE。纳二甲双胍与阿片类药物戒断的体征或症状无关，对阿片类药物介导的镇痛作用无显著影响。结论每日一次口服纳二甲双胍0.2 mg有效治疗OIC，并且在OIC和癌症患者中耐受性良好。(C)2017年美国临床肿瘤学会
PurposeOpioid-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 m-opioid receptor antagonist, naldemedine (S-297995), for OIC, specifically in patients with cancer.Patients and MethodsThis 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.ResultsIn 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.ConclusionOnce-daily oral naldemedine 0.2 mg effectively treated OIC and was generally well tolerated in patients with OIC and cancer. (C) 2017 by American Society of Clinical Oncology