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
{"title":"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》。","authors":"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","doi":"10.4088/JCP.24m15265","DOIUrl":null,"url":null,"abstract":"<p><p><b>Objective:</b> To test esmethadone (REL-1017) as adjunctive treatment in patients with major depressive disorder (MDD) and inadequate response to standard antidepressants.</p><p><p><b>Methods:</b> In this phase 3, double-blind, placebo-controlled trial, outpatients with MDD (<i>DSM-5</i>) 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).</p><p><p><b>Results:</b> 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 (<i>P</i> = .154; Cohen effect size [ES] = 0.21). Remission rates were 22.1% and 13.2% (<i>P</i> = .076), and response rates were 39.8% and 27.2% (<i>P</i> = .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 (<i>P</i> = .051; ES =0.29). In post hoc analyses of patients with baseline MADRS ≥35 in the ITT population (n = 112), MD was 6.9; <i>P</i> = .0059; ES = 0.57, and for the PP population (n = 98), MD was 7.9; <i>P</i> = .0015; ES = 0.69. Adverse events (AEs) were predominantly mild or moderate and transient, with no significant differences between groups.</p><p><p><b>Conclusions:</b> 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.</p><p><p><b>Trial Registration:</b> ClinicalTrials.gov identifier: NCT04688164.</p>","PeriodicalId":50234,"journal":{"name":"Journal of Clinical Psychiatry","volume":"85 3","pages":""},"PeriodicalIF":4.5000,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"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.\",\"authors\":\"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\",\"doi\":\"10.4088/JCP.24m15265\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b>Objective:</b> To test esmethadone (REL-1017) as adjunctive treatment in patients with major depressive disorder (MDD) and inadequate response to standard antidepressants.</p><p><p><b>Methods:</b> In this phase 3, double-blind, placebo-controlled trial, outpatients with MDD (<i>DSM-5</i>) 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).</p><p><p><b>Results:</b> 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 (<i>P</i> = .154; Cohen effect size [ES] = 0.21). Remission rates were 22.1% and 13.2% (<i>P</i> = .076), and response rates were 39.8% and 27.2% (<i>P</i> = .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 (<i>P</i> = .051; ES =0.29). In post hoc analyses of patients with baseline MADRS ≥35 in the ITT population (n = 112), MD was 6.9; <i>P</i> = .0059; ES = 0.57, and for the PP population (n = 98), MD was 7.9; <i>P</i> = .0015; ES = 0.69. Adverse events (AEs) were predominantly mild or moderate and transient, with no significant differences between groups.</p><p><p><b>Conclusions:</b> 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.</p><p><p><b>Trial Registration:</b> ClinicalTrials.gov identifier: NCT04688164.</p>\",\"PeriodicalId\":50234,\"journal\":{\"name\":\"Journal of Clinical Psychiatry\",\"volume\":\"85 3\",\"pages\":\"\"},\"PeriodicalIF\":4.5000,\"publicationDate\":\"2024-06-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Clinical Psychiatry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.4088/JCP.24m15265\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PSYCHIATRY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Clinical Psychiatry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.4088/JCP.24m15265","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PSYCHIATRY","Score":null,"Total":0}
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.
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.
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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.
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