Efficacy and Safety of Mifepristone in the Treatment of Male US Veterans With Posttraumatic Stress Disorder: A Phase 2a Randomized Clinical Trial.
Efficacy and Safety of Mifepristone in the Treatment of Male US Veterans With Posttraumatic Stress Disorder: A Phase 2a Randomized Clinical Trial.
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DOI：
10.1001/jamanetworkopen.2023.10223
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发表时间：
2023-05-01
影响因子：
13.8
通讯作者：
Reda, Domenic J.
中科院分区：
文献类型：
--
作者：
Golier, Julia A.;Li, Xue;Bizien, Marcel;Hurley, Robin A.;Bechard, Brendan W.;Kimbrell, Timothy;Flory, Janine D.;Baker, Dewleen G.;Yehuda, Rachel;Reda, Domenic J.
是否有证据表明糖皮质激素受体拮抗剂米非司酮治疗男性退伍军人创伤后应激障碍的临床疗效？在这项随机临床试验中，80名患有创伤后应激障碍的男性退伍军人（41名接受米非司酮，39名接受安慰剂）接受短期米非司酮治疗（每天600 mg，持续7天），在4周和12周时米非司酮与安慰剂的临床反应率差异小于用于定义疗效的预定临床边界。这些结果不支持在该异质性人群中进行该方案III期试验的适应症。这项2a期随机临床试验比较了患有创伤后应激障碍的男性退伍军人对米非司酮和安慰剂的临床反应，以确定是否有临床疗效的信号。迄今为止，没有精神药理学治疗已被发现是统一有效的退伍军人与创伤后应激障碍（PTSD）;新的目标和方法，需要治疗这种致残性疾病。研究糖皮质激素受体拮抗剂米非司酮治疗PTSD男性退伍军人是否产生临床疗效信号。这项2a期、双盲、平行组随机临床试验于2012年11月19日（开始招募）至2016年11月16日（最终随访）在美国退伍军人事务部进行。参与者是患有慢性PTSD的男性退伍军人，筛选时临床医生管理PTSD量表评分为50或更高。共有181名退伍军人同意参加。在2014年8月至2017年5月期间进行了统计分析。参与者以1：1的比例随机接受米非司酮（600 mg）或匹配的安慰剂口服7天。临床结局是退伍军人在4周和12周随访时是否达到临床应答状态（临床医生管理PTSD量表总分较基线降低≥30%）。根据二元统计选择规则，治疗组与对照组应答者比例的差异15%将是临床相关差异。PTSD和相关症状的自我报告措施也得到了。测定神经内分泌结果和米非司酮的血浆水平。在整个研究期间评估安全性。主要分析基于多重插补技术，以解决缺失的结局数据;因此，一些受试者人数可能不显示为整数。共有81名退伍军人入组并随机分组。排除1名随机错误的参与者，80名参与者被纳入改良的意向治疗分析（41名随机分配到米非司酮组，39名随机分配到安慰剂组）。平均（SD）年龄为43.1（13.7）岁。在使用多重插补技术的分析中，米非司酮组和安慰剂组分别有15.6（38.1%）和12.1（31.1%）例患者在4周时有临床应答。临床应答者比例的组间差异（7.0%）小于预定义的界值15%，表明存在临床疗效信号。在一项探索性分析中，在无创伤性脑损伤（TBI）终身史的亚组中，米非司酮与安慰剂的反应差异（7.0 [50.0%] vs 3.0 [27.3%];差异，22.7%）在4周时超过了疗效界限，并持续到12周。相比之下，在患有PTSD和终身TBI的退伍军人中，米非司酮的反应率在12周时低于安慰剂（7.4 [27.4%] vs 13.5 [48.3%];差异为-20.9%）。这项研究没有检测到米非司酮600 mg/d治疗慢性PTSD男性退伍军人1周的疗效信号。因此，本研究不支持在该人群中进行III期试验。米非司酮治疗PTSD的未来研究可能对那些没有TBI史或终生头部创伤基础率低的样本感兴趣。ClinicalTrials.gov标识符：NCT 01946685
Is there evidence of a signal for clinical efficacy for the glucocorticoid receptor antagonist mifepristone in the treatment of male veterans with posttraumatic stress disorder? In this randomized clinical trial of short-term mifepristone treatment (600 mg per day for 7 days) in 80 male veterans with posttraumatic stress disorder (41 receiving mifepristone and 39 receiving placebo), the difference in the clinical response rate to mifepristone vs placebo at 4 and 12 weeks was less than the predefined clinical margin used to define efficacy. These results do not support an indication for a phase 3 trial of this regimen in this heterogeneous population. This phase 2a randomized clinical trial compares the clinical response to mifepristone and placebo in male veterans with posttraumatic stress disorder to determine whether there is a signal for clinical efficacy. To date, no psychopharmacologic treatment has been found to be uniformly effective in veterans with posttraumatic stress disorder (PTSD); novel targets and approaches are needed to treat this disabling disorder. To examine whether treatment with the glucocorticoid receptor antagonist mifepristone yields a signal for clinical efficacy in male veterans with PTSD. This phase 2a, double-blind, parallel-group randomized clinical trial was conducted from November 19, 2012 (accrual started), through November 16, 2016 (final follow-up), within the US Department of Veterans Affairs. Participants were male veterans with chronic PTSD and a screening Clinician-Administered PTSD Scale score of 50 or higher. A total of 181 veterans consented to participation. Statistical analysis was conducted between August 2014 and May 2017. Participants were randomized in a 1:1 ratio to mifepristone (600 mg) or matched placebo taken orally for 7 days. The clinical outcome was whether a veteran achieved a clinical response status (a reduction of ≥30% of total Clinician-Administered PTSD Scale score from baseline) at 4- and 12-week follow-up. On the basis of a binary statistical selection rule, a difference in the proportion of treatment vs control group responders of 15% would be a clinically relevant difference. Self-report measures of PTSD and associated symptoms were also obtained. Neuroendocrine outcomes and plasma levels of mifepristone were measured. Safety was assessed throughout the study. The primary analysis was based on a multiple imputation technique to address missing outcome data; thus, some participant numbers may not appear as whole numbers. A total of 81 veterans were enrolled and randomized. Excluding 1 participant randomized in error, 80 were included in the modified intention-to-treat analysis (41 randomized to mifepristone and 39 to placebo). The mean (SD) age was 43.1 (13.7) years. A total of 15.6 (38.1%) in the mifepristone group and 12.1 (31.1%) in the placebo group were clinical responders at 4 weeks in the analysis using the multiple imputation technique. The group difference in the proportion of clinical responders (7.0%) was less than the predefined margin of 15% indicating signal for clinical efficacy. In an exploratory analysis, the difference in response to mifepristone vs placebo in the subgroup with no lifetime history of traumatic brain injury (TBI) (7.0 [50.0%] vs 3.0 [27.3%]; difference, 22.7%) exceeded the efficacy margin at 4 weeks and was sustained at 12 weeks. In contrast, in veterans with PTSD and lifetime TBI, the response rate to mifepristone was lower than placebo at 12 weeks (7.4 [27.4%] vs 13.5 [48.3%]; difference, −20.9%). This study did not detect a signal for efficacy for mifepristone at 600 mg/d for 1 week in male veterans with chronic PTSD. Thus, this study does not support a phase 3 trial in this population. Future studies of mifepristone for the treatment of PTSD may be of interest in those without a history of TBI or in samples with a low base rate of lifetime head trauma. ClinicalTrials.gov Identifier: NCT01946685
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影响因子：
2.9
作者：
Block T;Petrides G;Kushner H;Kalin N;Belanoff J;Schatzberg A
通讯作者：
Schatzberg A
影响因子：
--
作者：
Davis LL;Whetsell C;Hamner MB;Carmody J;Rothbaum BO;Allen RS;Al Bartolucci ABPP;Southwick SM;Bremner JD
通讯作者：
Bremner JD
DOI：
10.3109/10401230009147096
发表时间：
2000-06-01
期刊：
Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists
影响因子：
--
作者：
Hertzberg, M A;Feldman, M E;Davidson, J R
通讯作者：
Davidson, J R
影响因子：
--
作者：
Golier, Julia A;Caramanica, Kimberly;Yehuda, Rachel
通讯作者：
Yehuda, Rachel
DOI：
10.1176/appi.ajp.2011.10111704
发表时间：
2011-12
期刊：
The American journal of psychiatry
影响因子：
--
作者：
Posner K;Brown GK;Stanley B;Brent DA;Yershova KV;Oquendo MA;Currier GW;Melvin GA;Greenhill L;Shen S;Mann JJ
通讯作者：
Mann JJ