肌萎缩侧索硬化症临床试验中药效基因相互作用的荟萃分析。
Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials.
作者信息
van Eijk Ruben P A, Jones Ashley R, Sproviero William, Shatunov Aleksey, Shaw Pamela J, Leigh P Nigel, Young Carolyn A, Shaw Christopher E, Mora Gabriele, Mandrioli Jessica, Borghero Giuseppe, Volanti Paolo, Diekstra Frank P, van Rheenen Wouter, Verstraete Esther, Eijkemans Marinus J C, Veldink Jan H, Chio Adriano, Al-Chalabi Ammar, van den Berg Leonard H, van Es Michael A
机构信息
From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre (A.R.J., W.S., A.S., C.E.S., A.A.-C.), Department of Basic and Clinical Neuroscience, King's College London; Sheffield Institute for Translational Neuroscience (SITraN) (P.J.S.), University of Sheffield, South Yorkshire; Department of Clinical Neuroscience (P.N.L.), Trafford Centre for Biomedical Research, Brighton and Sussex Medical School, Falmer, Brighton; The Walton Centre NHS Trust (C.A.Y.), Liverpool, UK; Istituti Clinici Scientifici Maugeri IRCSS (G.M.), Milan; Department of Neuroscience (J.M.), Sant'Agostino-Estense Hospital and University of Modena and Reggio Emilia, Modena; Department of Neurology (G.B.), Azienda Universitario Ospedaliera di Cagliari and University of Cagliari; Istituti Clinici Scientifici Maugeri IRCSS (P.V.), Mistretta, Italy; Rijnstate Ziekenhuis (E.V.), Arnhem, the Netherlands; Rita Levi Montalcini' Department of Neuroscience (A.C.), ALS Centre, University of Torino; and Azienda Ospedaliera Città della Salute e della Scienza (A.C.), Turin, Italy.
出版信息
Neurology. 2017 Oct 31;89(18):1915-1922. doi: 10.1212/WNL.0000000000004606. Epub 2017 Oct 4.
OBJECTIVE
To assess whether genetic subgroups in recent amyotrophic lateral sclerosis (ALS) trials responded to treatment with lithium carbonate, but that the treatment effect was lost in a large cohort of nonresponders.
METHODS
Individual participant data were obtained from 3 randomized trials investigating the efficacy of lithium carbonate. We matched clinical data with data regarding the and genotype. Our primary outcome was survival at 12 months. On an exploratory basis, we assessed whether the effect of lithium depended on the genotype.
RESULTS
Clinical data were available for 518 of the 606 participants. Overall, treatment with lithium carbonate did not improve 12-month survival (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.7-1.4; = 0.96). Both the and genotype were independent predictors of survival (HR 2.4, 95% CI 1.3-4.3; = 0.006 and HR 2.5, 95% CI 1.1-5.2; = 0.032, respectively). The effect of lithium was different for carriers ( = 0.027), but not for carriers ( = 0.22). The 12-month survival probability for carriers treated with lithium carbonate improved from 40.1% (95% CI 23.2-69.1) to 69.7% (95% CI 50.4-96.3).
CONCLUSIONS
This study incorporated genetic data into past ALS trials to determine treatment effects in a genetic post hoc analysis. Our results suggest that we should reorient our strategies toward finding treatments for ALS, start focusing on genotype-targeted treatments, and standardize genotyping in order to optimize randomization and analysis for future clinical trials.
目的
评估近期肌萎缩侧索硬化症（ALS）试验中的基因亚组是否对碳酸锂治疗有反应，但在大量无反应者队列中治疗效果丧失。
方法
从3项研究碳酸锂疗效的随机试验中获取个体参与者数据。我们将临床数据与关于[具体基因]和[具体基因]基因型的数据进行匹配。我们的主要结局是12个月时的生存率。在探索性基础上，我们评估了锂的疗效是否取决于基因型。
结果
606名参与者中有518名可获得临床数据。总体而言，碳酸锂治疗并未改善12个月生存率（风险比[HR]1.0，95%置信区间[CI]0.7 - 1.4；P = 0.96）。[具体基因]和[具体基因]基因型均是生存的独立预测因素（HR分别为2.4，95%CI 1.3 - 4.3；P = 0.006和HR 2.5，95%CI 1.1 - 5.2；P = 0.032）。锂对[具体基因]携带者的疗效不同（P = 0.027），但对[具体基因]携带者无差异（P = 0.22）。接受碳酸锂治疗的[具体基因]携带者12个月生存概率从40.1%（95%CI 23.2 - 69.1）提高到69.7%（95%CI 50.4 - 96.3）。
结论
本研究将基因数据纳入既往ALS试验，以在基因事后分析中确定治疗效果。我们的结果表明，我们应重新调整针对ALS寻找治疗方法的策略，开始专注于基因型靶向治疗，并规范基因分型，以便为未来临床试验优化随机化和分析。
Zotero 插件