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A randomized proof-of-mechanism trial applying the 'fast-fail' approach to evaluating κ-opioid antagonism as a treatment for anhedonia.
Nature Medicine ( IF 82.9 ) Pub Date : 2020-03-30 , DOI: 10.1038/s41591-020-0806-7
Andrew D Krystal 1, 2 , Diego A Pizzagalli 3 , Moria Smoski 2 , Sanjay J Mathew 4, 5 , John Nurnberger 6 , Sarah H Lisanby 7 , Dan Iosifescu 8 , James W Murrough 9 , Hongqiu Yang 10 , Richard D Weiner 2 , Joseph R Calabrese 11 , Gerard Sanacora 12 , Gretchen Hermes 12 , Richard S E Keefe 2 , Allen Song 2 , Wayne Goodman 4 , Steven T Szabo 2, 13 , Alexis E Whitton 3, 14 , Keming Gao 11 , William Z Potter 7
Affiliation  

The National Institute of Mental Health (NIMH) 'fast-fail' approach seeks to improve too-often-misleading early-phase drug development methods by incorporating biomarker-based proof-of-mechanism (POM) testing in phase 2a. This first comprehensive application of the fast-fail approach evaluated the potential of κ-opioid receptor (KOR) antagonism for treating anhedonia with a POM study determining whether robust target engagement favorably impacts the brain circuitry hypothesized to mediate clinical effects. Here we report the results from a multicenter, 8-week, double-blind, placebo-controlled, randomized trial in patients with anhedonia and a mood or anxiety disorder (selective KOR antagonist (JNJ-67953964, 10 mg; n = 45) and placebo (n = 44)). JNJ-67953964 significantly increased functional magnetic resonance imaging (fMRI) ventral striatum activation during reward anticipation (primary outcome) as compared to placebo (baseline-adjusted mean: JNJ-67953964, 0.72 (s.d. = 0.67); placebo, 0.33 (s.d. = 0.68); F(1,86) = 5.58, P < 0.01; effect size = 0.58 (95% confidence interval, 0.13-0.99)). JNJ-67953964, generally well tolerated, was not associated with any serious adverse events. This study supports proceeding with assessment of the clinical impact of target engagement and serves as a model for implementing the 'fast-fail' approach.

中文翻译:

一项采用“快速失败”方法评估 κ-阿片类药物拮抗作用作为快感缺乏治疗方法的随机机制验证试验。

美国国家心理健康研究所 (NIMH) 的“快速失败”方法旨在通过在第 2a 阶段纳入基于生物标志物的机制验证 (POM) 测试来改进往往具有误导性的早期药物开发方法。这是快速失败方法的首次综合应用,通过 POM 研究评估了 κ-阿片受体 (KOR) 拮抗作用治疗快感缺乏的潜力,以确定稳健的目标参与是否有利地影响假设介导临床效果的大脑回路。在这里,我们报告了一项多中心、8 周、双盲、安慰剂对照、随机试验的结果,该试验针对快感缺乏和情绪或焦虑症患者(选择性 KOR 拮抗剂(JNJ-67953964,10 毫克;n = 45)和安慰剂(n = 44))。与安慰剂相比,JNJ-67953964 显着增加了功能性磁共振成像 (fMRI) 腹侧纹状体激活(主要结果)(基线调整平均值:JNJ-67953964,0.72 (sd = 0.67);安慰剂,0.33 (sd = 0.68) );F(1,86) = 5.58,P < 0.01;效应量 = 0.58(95% 置信区间,0.13-0.99))。JNJ-67953964 一般耐受性良好,与任何严重不良事件无关。这项研究支持继续评估目标参与的临床影响,并作为实施“快速失败”方法的模型。99)). JNJ-67953964 一般耐受性良好,与任何严重不良事件无关。这项研究支持继续评估目标参与的临床影响,并作为实施“快速失败”方法的模型。99)). JNJ-67953964 一般耐受性良好,与任何严重不良事件无关。这项研究支持继续评估目标参与的临床影响,并作为实施“快速失败”方法的模型。
更新日期:2020-04-24
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