:Background:Opioid antagonists may mitigate medication-associated weight gain and/or metabolic dysregulation. ENLIGHTEN-2 evaluated a combination of olanzapine and the opioid antagonist samidorphan (OLZ/SAM) vs olanzapine for effects on weight gain and metabolic parameters over 24 weeks in adults with stable schizophrenia.METHODS:This phase 3, double-blind study (ClinicalTrials.gov: NCT02694328) enrolled adults 18–55 yo with stable schizophrenia, randomized 1:1 to once-daily OLZ/SAM or olanzapine. Co-primary endpoints were percent change from baseline in body weight and proportion of patients with ≥10% weight gain at week 24. Waist circumference and fasting metabolic parameters were also measured. Completers could enter a 52-week open-label safety extension.RESULTS:561 patients were randomized: 550 were dosed, 538 had ≥1 post-baseline weight assessment, and 352 (64%) completed; 10.9% discontinued due to AEs. At week 24, least squares mean (SE) percent weight change from baseline was 4.21 (0.68)% with OLZ/SAM and 6.59 (0.67)% with olanzapine (difference, −2.38 [0.76]%; P=0.003). Fewer patients treated with OLZ/SAM (17.8%) had ≥10% weight gain vs olanzapine (29.8%; odds ratio=0.50; P=0.003). The change from baseline in waist circumference was significantly smaller with OLZ/SAM (P<0.001). Common AEs (≥10%) with OLZ/SAM and olanzapine were weight increased (24.8%, 36.2%), somnolence (21.2%, 18.1%), dry mouth (12.8%, 8.0%), and increased appetite (10.9%, 12.3%), respectively. Metabolic parameter changes were generally small and remained stable with long-term OLZ/SAM treatment.DISCUSSION:OLZ/SAM treatment limited weight gain associated with olanzapine. Metabolic parameter changes were generally small, similar between groups over 24 weeks, and remained stable over an additional 52 weeks of open-label OLZ/SAM treatment.Funding Acknowledgements:This study was funded by Alkermes, Inc.

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100 奥氮平/萨米多芬治疗精神分裂症：第 3 期 ENLIGHTEN-2 和随后的长期、开放标签安全性研究中的体重增加和代谢结果

：背景：阿片类拮抗剂可以减轻药物相关的体重增加和/或代谢失调。ENLIGHTEN-2 评估了奥氮平和阿片拮抗剂沙米多芬 (OLZ/SAM) 与奥氮平的组合对稳定型精神分裂症成人 24 周内体重增加和代谢参数的影响。方法：这项 3 期双盲研究（临床试验。 gov: NCT02694328) 招募了患有稳定型精神分裂症的 18-55 岁成年人，以 1:1 的比例随机分配到每日一次的 OLZ/SAM 或奥氮平。共同主要终点是体重与基线相比的百分比变化以及第 24 周体重增加≥10% 的患者比例。还测量了腰围和空腹代谢参数。完成者可以进入为期 52 周的开放标签安全延期。结果：561 名患者被随机分配：550 名被给药，538 人进行了≥1 次基线后体重评估，352 人（64%）完成；10.9% 因不良事件而停产。在第 24 周，OLZ/SAM 与基线的最小二乘平均 (SE) 体重变化百分比为 4.21 (0.68)%，奥氮平为 6.59 (0.67)%（差异，-2.38 [0.76]%；P=0.003）。与奥氮平相比，接受 OLZ/SAM 治疗的患者（17.8%）体重增加≥10%（29.8%；优势比=0.50；P=0.003）的患者更少。OLZ/SAM 与基线的腰围变化明显更小（P<0.001）。OLZ/SAM 和奥氮平的常见不良反应 (≥10%) 包括体重增加 (24.8%, 36.2%)、嗜睡 (21.2%, 18.1%)、口干 (12.8%, 8.0%) 和食欲增加 (10.9%, 12.3%），分别。长期 OLZ/SAM 治疗的代谢参数变化通常很小并且保持稳定。讨论：OLZ/SAM 治疗限制了与奥氮平相关的体重增加。