AXS-05(右美沙芬-安非他酮)治疗重度抑郁症的疗效和安全性:一项3期随机临床试验(GEMINI)

D. Iosifescu, A. Jones, C. O'gorman, C. Streicher, Samantha Feliz, M. Fava, H. Tabuteau
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引用次数: 26

摘要

目的:谷氨酸神经传递的改变与抑郁症的发病机制有关。本试验评价了口服n-甲基- d -天冬氨酸(NMDA)受体拮抗剂和σ1受体激动剂AXS-05(右美沙芬-安非他酮)治疗重度抑郁症(MDD)的疗效和安全性。方法:该双盲三期试验于2019年6月至2019年12月进行。DSM-5诊断为重度抑郁症的患者按1:1的比例随机接受右美沙芬-安非他酮(45毫克-105毫克片剂)或安慰剂,口服(1-3天每天一次,此后每天两次),持续6周。主要终点是蒙哥马利-阿斯伯格抑郁评定量表(MADRS)总分从基线到第6周的变化。其他疗效终点和变量包括第1周和第2周MADRS较基线的变化、临床缓解(MADRS评分≤10)、临床反应(MADRS评分较基线降低≥50%)、临床医生和患者评价的整体评估、抑郁症状快速量表-自评、Sheehan残疾量表和生活质量测量。结果:共有327例患者被随机化:163例右美沙芬-安非他酮组,164例安慰剂组。右美沙芬-安非他酮组和安慰剂组平均基线MADRS总分分别为33.6和33.2。从基线到第6周,右美沙芬-安非他酮组MADRS总分的最小二乘平均变化为-15.9分,安慰剂组为-12.0分(最小二乘平均差为-3.87;95%置信区间[CI], -1.39 ~ -6.36;p = .002)。右美沙芬-安非他酮在包括第1周(P = .007)和第2周(P < .001)在内的所有时间点的MADRS改善均优于安慰剂。右美沙芬-安非他酮组缓解率为39.5%,安慰剂组为17.3%(治疗差异为22.2;95% CI, 11.7 ~ 32.7;P < 0.001),临床反应分别为54.0%和34.0%(治疗差异为20.0%;95% ci, 8.4%, 31.6%;P < 0.001),第6周。大多数次要终点的结果在几乎所有时间点右美沙芬-安非他酮组均显著优于安慰剂组(例如,第6周时CGI-S最小二乘平均差值为-0.48;95% CI, -0.48 ~ -0.79;p = .002)。右美沙芬-安非他酮组最常见的不良事件是头晕、恶心、头痛、嗜睡和口干。右美沙芬-安非他酮与拟精神作用、体重增加或性功能障碍增加无关。结论:在这项针对重度抑郁症患者的三期试验中,与安慰剂相比,右美沙芬-安非他酮(AXS-05)治疗在治疗开始1周后显著改善了抑郁症状,并且通常耐受性良好。试验注册:ClinicalTrials.gov标识符:NCT04019704。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder: A Phase 3 Randomized Clinical Trial (GEMINI).
Objective: Altered glutamatergic neurotransmission has been implicated in the pathogenesis of depression. This trial evaluated the efficacy and safety of AXS-05 (dextromethorphan-bupropion), an oral N-methyl-D-aspartate (NMDA) receptor antagonist and σ1 receptor agonist, in the treatment of major depressive disorder (MDD). Methods: This double-blind, phase 3 trial, was conducted between June 2019 and December 2019. Patients with a DSM-5 diagnosis of MDD were randomized in a 1:1 ratio to receive dextromethorphan-bupropion (45 mg-105 mg tablet) or placebo, orally (once daily for days 1-3, twice daily thereafter) for 6 weeks. The primary endpoint was the change from baseline to week 6 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Other efficacy endpoints and variables included MADRS changes from baseline at week 1 and 2, clinical remission (MADRS score ≤ 10), clinical response (≥ 50% reduction in MADRS score from baseline), clinician- and patient-rated global assessments, Quick Inventory of Depressive Symptomatology-Self-Rated, Sheehan Disability Scale, and quality of life measures. Results: A total of 327 patients were randomized: 163 patients to dextromethorphan-bupropion and 164 patients to placebo. Mean baseline MADRS total scores were 33.6 and 33.2 in the dextromethorphan-bupropion and placebo groups, respectively. The least-squares mean change from baseline to week 6 in MADRS total score was -15.9 points in the dextromethorphan-bupropion group and -12.0 points in the placebo group (least-squares mean difference, -3.87; 95% confidence interval [CI], -1.39 to -6.36; P = .002). Dextromethorphan-bupropion was superior to placebo for MADRS improvement at all time points including week 1 (P = .007) and week 2 (P < .001). Remission was achieved by 39.5% of patients with dextromethorphan-bupropion versus 17.3% with placebo (treatment difference, 22.2; 95% CI, 11.7 to 32.7; P < .001), and clinical response by 54.0% versus 34.0%, respectively (treatment difference, 20.0%; 95% CI, 8.4%, 31.6%; P < .001), at week 6. Results for most secondary endpoints were significantly better with dextromethorphan-bupropion than with placebo at almost all time points (eg, CGI-S least-squares mean difference at week 6, -0.48; 95% CI, -0.48 to -0.79; P = .002). The most common adverse events in the dextromethorphan-bupropion group were dizziness, nausea, headache, somnolence, and dry mouth. Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, or increased sexual dysfunction. Conclusions: In this phase 3 trial in patients with MDD, treatment with dextromethorphan-bupropion (AXS-05) resulted in significant improvements in depressive symptoms compared to placebo starting 1 week after treatment initiation and was generally well tolerated. Trial Registration: ClinicalTrials.gov Identifier: NCT04019704.
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