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.
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.
摘要：
目的：测试艾司美沙酮（REL-1017）作为对标准抗抑郁药反应不足的重度抑郁症（MDD）患者的辅助治疗。
方法：在此阶段3，双盲，安慰剂对照试验,在2020年12月至2022年12月之间,MDD(DSM-5)门诊患者被随机分为每日口服艾司美沙酮(第1天75mg,然后在第2天至第28天每天25mg)或安慰剂组.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。符合方案(PP)群体包括没有影响评估的主要方案偏差的完成者。事后分析包括患有重度抑郁症（基线MADRS评分≥35）的参与者。
结果：对于ITT分析(n=227)，艾司美沙酮（n=113）的平均CFB为15.1（SD11.3），安慰剂（n=114）的平均CFB为12.9（SD10.4），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）。缓解率分别为22.1%和13.2%(P=0.076)，艾司美沙酮和安慰剂的缓解率分别为39.8%和27.2%(P=0.044)，分别。对于PP分析(n=198)，艾司美沙酮（n=101）的平均CFB为15.6（SD11.2），安慰剂（n=97）的平均CFB为12.5（SD9.9），MD为3.1（P=.051；ES=0.29）。在ITT人群中基线MADRS≥35的患者的事后分析中(n=112)，MD为6.9；P=.0059；ES=0.57，对于PP群体（n=98），MD为7.9；P=.0015；ES=0.69。不良事件（AE）主要是轻度或中度和短暂的，组间无显著差异。
结论：未达到主要终点。依美沙酮在PP中显示出比在ITT分析中更强的功效，差异不归因于影响治疗依从性的AE。在对重度抑郁症患者的事后分析中出现了显着疗效。美沙酮耐受性良好,与以前的研究一致。
试验注册：ClinicalTrials.gov标识符：NCT04688164。
方法：在此阶段3，双盲，安慰剂对照试验,在2020年12月至2022年12月之间,MDD(DSM-5)门诊患者被随机分为每日口服艾司美沙酮(第1天75mg,然后在第2天至第28天每天25mg)或安慰剂组.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。符合方案(PP)群体包括没有影响评估的主要方案偏差的完成者。事后分析包括患有重度抑郁症（基线MADRS评分≥35）的参与者。
结果：对于ITT分析(n=227)，艾司美沙酮（n=113）的平均CFB为15.1（SD11.3），安慰剂（n=114）的平均CFB为12.9（SD10.4），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）。缓解率分别为22.1%和13.2%(P=0.076)，艾司美沙酮和安慰剂的缓解率分别为39.8%和27.2%(P=0.044)，分别。对于PP分析(n=198)，艾司美沙酮（n=101）的平均CFB为15.6（SD11.2），安慰剂（n=97）的平均CFB为12.5（SD9.9），MD为3.1（P=.051；ES=0.29）。在ITT人群中基线MADRS≥35的患者的事后分析中(n=112)，MD为6.9；P=.0059；ES=0.57，对于PP群体（n=98），MD为7.9；P=.0015；ES=0.69。不良事件（AE）主要是轻度或中度和短暂的，组间无显著差异。
结论：未达到主要终点。依美沙酮在PP中显示出比在ITT分析中更强的功效，差异不归因于影响治疗依从性的AE。在对重度抑郁症患者的事后分析中出现了显着疗效。美沙酮耐受性良好,与以前的研究一致。
试验注册：ClinicalTrials.gov标识符：NCT04688164。
