Efficacy and Safety of Esmethadone (REL-1017) in Patients With Major Depressive Disorder and Inadequate Response to Standard Antidepressants: A Phase 3 Randomized Controlled Trial.

IF 4.5 2区医学 Q1 PSYCHIATRY Journal of Clinical Psychiatry Pub Date : 2024-06-17 DOI:10.4088/JCP.24m15265

Maurizio Fava, Stephen M Stahl, Luca Pani, Sara De Martin, Andrew J Cutler, Vladimir Maletic, Charles W Gorodetzky, Frank J Vocci, Frank L Sapienza, Thomas R Kosten, Cornelia Kröger, Paggard Champasa, Cedric O'Gorman, Clotilde Guidetti, Andrea Alimonti, Stefano Comai, Andrea Mattarei, Franco Folli, David Bushnell, Sergio Traversa, Charles E Inturrisi, Paolo L Manfredi, Marco Pappagallo

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Abstract

Objective: To test esmethadone (REL-1017) as adjunctive treatment in patients with major depressive disorder (MDD) and inadequate response to standard antidepressants.

Methods: In this phase 3, double-blind, placebo-controlled trial, outpatients with MDD (DSM-5) were randomized to daily oral esmethadone (75 mg on day 1, followed by 25 mg daily on days 2 through 28) or placebo between December 2020 and December 2022. The primary efficacy measure was change from baseline (CFB) to day 28 in the Montgomery-Asberg Depression Rating Scale (MADRS) score. The intent-to-treat (ITT) population included all randomized participants. The per-protocol (PP) population included completers without major protocol deviations impacting assessment. Post hoc analyses included participants with severe depression (baseline MADRS score ≥35).

Results: For the ITT analysis (n = 227), mean CFB was 15.1 (SD 11.3) for esmethadone (n = 113) and 12.9 (SD 10.4) for placebo (n = 114), with a mean difference (MD) of 2.3, which was not statistically significant (P = .154; Cohen effect size [ES] = 0.21). Remission rates were 22.1% and 13.2% (P = .076), and response rates were 39.8% and 27.2% (P = .044) with esmethadone and placebo, respectively. For the PP analysis (n = 198), mean CFB was 15.6 (SD 11.2) for esmethadone (n = 101) and 12.5 (SD 9.9) for placebo (n = 97), with an MD of 3.1 (P = .051; ES =0.29). In post hoc analyses of patients with baseline MADRS ≥35 in the ITT population (n = 112), MD was 6.9; P = .0059; ES = 0.57, and for the PP population (n = 98), MD was 7.9; P = .0015; ES = 0.69. Adverse events (AEs) were predominantly mild or moderate and transient, with no significant differences between groups.

Conclusions: The primary end point was not met. Esmethadone showed stronger efficacy in PP than in ITT analyses, with the discrepancy not attributable to AEs impacting treatment adherence. Significant efficacy occurred in post hoc analyses of patients with severe depression. Esmethadone was well tolerated, consistent with prior studies.

Trial Registration: ClinicalTrials.gov identifier: NCT04688164.

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艾司美沙酮（REL-1017）对标准抗抑郁药无效的重度抑郁症患者的疗效和安全性：3期随机对照试验》。

目的：测试艾司美沙酮（REL-1017）对重度抑郁症（MDD）患者的辅助治疗效果：测试艾司美沙酮（REL-1017）作为重度抑郁障碍（MDD）患者的辅助治疗药物以及对标准抗抑郁药的不良反应：在这项3期双盲安慰剂对照试验中，患有MDD（DSM-5）的门诊患者在2020年12月至2022年12月期间随机接受每日口服艾司美沙酮（第1天75毫克，第2天至第28天每天25毫克）或安慰剂治疗。主要疗效指标是蒙哥马利-阿斯伯格抑郁量表（MADRS）评分从基线（CFB）到第28天的变化。意向治疗（ITT）人群包括所有随机参与者。按方案（PP）人群包括未出现影响评估的重大方案偏差的完成者。事后分析包括患有严重抑郁症的参与者（基线 MADRS 评分≥35）：在ITT分析（n = 227）中，艾司美沙酮（n = 113）和安慰剂（n = 114）的平均CFB分别为15.1（SD 11.3）和12.9（SD 10.4），平均差异（MD）为2.3，无统计学意义（P = .154；科恩效应大小[ES] = 0.21）。艾司美沙酮和安慰剂的缓解率分别为22.1%和13.2%（P = .076），反应率分别为39.8%和27.2%（P = .044）。在PP分析（n = 198）中，艾司美沙酮（n = 101）和安慰剂（n = 97）的平均CFB分别为15.6（SD 11.2）和12.5（SD 9.9），MD为3.1（P = .051；ES =0.29）。对基线MADRS≥35的患者进行事后分析，ITT人群（n = 112）的MD为6.9；P = .0059；ES = 0.57，PP人群（n = 98）的MD为7.9；P = .0015；ES = 0.69。不良事件（AEs）主要为轻度或中度和一过性，组间无显著差异：结论：主要终点未达到。艾司美沙酮在PP分析中比ITT分析中显示出更强的疗效，这种差异不能归因于影响治疗依从性的不良反应。在对严重抑郁症患者进行的事后分析中，疗效显著。艾司美沙酮的耐受性良好，与之前的研究结果一致：试验注册：ClinicalTrials.gov identifier：NCT04688164。

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来源期刊

Journal of Clinical Psychiatry 医学-精神病学

CiteScore

7.40

自引率

1.90%

发文量

审稿时长

3-8 weeks

期刊介绍： For over 75 years, The Journal of Clinical Psychiatry has been a leading source of peer-reviewed articles offering the latest information on mental health topics to psychiatrists and other medical professionals.The Journal of Clinical Psychiatry is the leading psychiatric resource for clinical information and covers disorders including depression, bipolar disorder, schizophrenia, anxiety, addiction, posttraumatic stress disorder, and attention-deficit/hyperactivity disorder while exploring the newest advances in diagnosis and treatment.