Gabapentin Enacarbil Extended-Release Versus Placebo: A Likely Responder Reanalysis of a Randomized Clinical Trial.
Gabapentin Enacarbil Extended-Release Versus Placebo: A Likely Responder Reanalysis of a Randomized Clinical Trial.
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DOI：
10.1111/acer.14414
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发表时间：
2020-09
期刊：
影响因子：
--
通讯作者：
Marmar CR
中科院分区：
文献类型：
--
作者：
Laska EM;Siegel CE;Lin Z;Bogenschutz M;Marmar CR
我们重新分析了一项为期26周的多中心随机双盲安慰剂对照临床试验，该试验旨在评估加巴喷丁前体药物加巴喷丁Enacarbil缓释剂（GE-XR）600 mg每日两次治疗酒精使用障碍的安全性和有效性。在2019年发表的原始分析（n = 338）中，GE‐XR与安慰剂没有差异。我们的目标是通过从试验数据中识别GE-XR的可能应答者来推进精准医学，并确定GE-XR是否在因果关系上上级安慰剂。再分析的主要结果指标是重度饮酒天数（ΔHDD）较基线的减少。在随机森林（RF）模型中使用基线特征（包括酒精使用、焦虑、抑郁、情绪状态、睡眠和冲动性指标），根据分配给GE-XR的指标预测GE-XR治疗的ΔHDD。使用所得RF模型获得随机分配至GE‐XR组的受试者和随机分配至安慰剂组的受试者的预测结局。GE-XR的可能应答者定义为预计减少14天或以上的患者。对于可能的应答者和整个样本，进行了GE‐XR相对于安慰剂的因果优效性检验。对于可能的应答者，GE-XR在因果关系上上级安慰剂（p < 0.0033），而对于整个样本，没有差异。可能的响应者表现出改善的结果，为百分比HDD和每周饮料的相关结果。与不太可能的反应者相比，在基线时，可能的反应者有更高的HDD;更低水平的焦虑，抑郁和一般情绪障碍;更高水平的认知和运动冲动。对于预测可能为应答者的患者子集，GE‐XR治疗具有实质性因果获益。可能应答者统计范式是一种很有前途的方法，用于分析随机临床试验，以推进个性化治疗。根据预测性基线临床特征确定可能对加巴喷丁XR有反应的AUD个体。他们的反应在因果关系上上级分配给安慰剂的匹配组。在基线时，可能的反应者有更多的酗酒天数，更低的抑郁和焦虑水平以及更高的认知和运动冲动水平。在整个样本中，不存在治疗间差异。可能应答者统计范式是分析RCT和推进精准医学的有价值方法。
We reanalyzed a multisite 26‐week randomized double‐blind placebo‐controlled clinical trial of 600 mg twice‐a‐day Gabapentin Enacarbil Extended‐Release (GE‐XR), a gabapentin prodrug, designed to evaluate safety and efficacy for treating alcohol use disorder. In the original analysis (n = 338), published in 2019, GE‐XR did not differ from placebo. Our aim is to advance precision medicine by identifying likely responders to GE‐XR from the trial data and to determine for likely responders if GE‐XR is causally superior to placebo. The primary outcome measure in the reanalysis is the reduction from baseline of the number of heavy drinking days (ΔHDD). Baseline features including measures of alcohol use, anxiety, depression, mood states, sleep, and impulsivity were used in a random forest (RF) model to predict ΔHDD to treatment with GE‐XR based on those assigned to GE‐XR. The resulting RF model was used to obtain predicted outcomes for those randomized to GE‐XR and counterfactually to those randomized to placebo. Likely responders to GE‐XR were defined as those predicted to have a reduction of 14 days or more. Tests of causal superiority of GE‐XR to placebo were obtained for likely responders and for the whole sample. For likely responders, GE‐XR was causally superior to placebo (p < 0.0033), while for the whole sample, there was no difference. Likely responders exhibited improved outcomes for the related outcomes of percent HDD and drinks per week. Compared with unlikely responders, at baseline likely responders had higher HDDs; lower levels of anxiety, depression, and general mood disturbances; and higher levels of cognitive and motor impulsivity. There are substantial causal benefits of treatment with GE‐XR for a subset of patients predicted to be likely responders. The likely responder statistical paradigm is a promising approach for analyzing randomized clinical trials to advance personalized treatment. Individuals with AUD likely to respond to Gabapentin XR were identified based on predictive baseline clinical features. Their responses were causally superior to a matched group assigned to placebo. At baseline, likely responders had more heavy drinking days, lower levels of depression and anxiety and higher levels of cognitive and motor impulsivity. In the whole sample, there were no between treatment differences. The likely responder statistical paradigm as a valuable approach to analyzing RCTs and for advancing precision medicine.
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影响因子：
2
作者：
Foster, Jared C.;Taylor, Jeremy M. G.;Ruberg, Stephen J.
通讯作者：
Ruberg, Stephen J.
影响因子：
39
作者：
Mason, Barbara J.;Quello, Susan;Begovic, Adnan
通讯作者：
Begovic, Adnan
影响因子：
5.3
作者：
Roberto, Marisa;Gilpin, Nicholas W.;Koob, George F.
通讯作者：
Koob, George F.
影响因子：
17.7
作者：
Anton, Raymond F.;Myrick, Hugh;Randall, Patrick K.
通讯作者：
Randall, Patrick K.
DOI：
10.1111/j.1530-0277.1996.tb01696.x
发表时间：
1996-12-01
影响因子：
3.2
作者：
Kranzler, HR;Burleson, JA;Babor, TF
通讯作者：
Babor, TF