MRI lesions as a surrogate for relapses in multiple sclerosis: a meta-analysis of randomised trials
MRI lesions as a surrogate for relapses in multiple sclerosis: a meta-analysis of randomised trials
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DOI：
10.1016/s1474-4422(13)70103-0
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发表时间：
2013-07-01
期刊：
影响因子：
48
通讯作者：
Bruzzi, Paolo
中科院分区：
文献类型：
--
作者：
Sormani, Maria Pia;Bruzzi, Paolo
背景2009年发表的一项复发缓解型多发性硬化症随机试验的荟萃分析显示，对Mill病变检测到的治疗效果与临床复发之间存在定量关系。我们的目的是验证这种关系，使用一个大的和独立的一组临床试验在多发性sclerosis.Methods的数据，我们搜索Medline的临床试验，评估疾病修饰药物复发缓解型多发性sclerosis发表从2008年9月1日，到2012年10月31日。我们从每个试验中提取了对MRI病变和复发的治疗效果的数据，并使用加权线性回归分析评估了这些治疗效果的对数转换相对测量的相关性。估计R-2值以量化相关性的强度，并且我们使用相互作用检验来检验与先前估计的方程的斜率差异。我们还进行了几项敏感性分析。结果我们确定了31个合格的试验，提供了18 901例复发缓解型多发性硬化症患者的数据。使用这些研究的数据得出的回归方程显示了MRI病变的同时治疗效应与复发之间的关系（斜率=0.52; R-2=0.71），与先前估计的结果基本相同（P-相互作用=0.45）。在2期和3期研究中测试相同药物的试验分析表明，在短期随访期间对MRI病变的影响（6-9个月）也可以预测在更长的随访期内对复发的影响（12-24个月），据报道，对复发的影响在95%以内，解释我们的发现表明，治疗对复发的影响可以通过该治疗对MRI病变的影响来准确预测，这意味着在特定情况下，可以考虑在未来的多发性硬化症治疗临床试验中使用Mill标记物作为主要终点，例如在测试具有众所周知作用机制的药物的仿制药或生物类似药的试验中，或在测试已批准用于成人的药物的儿科试验中。
Background A meta-analysis of randomised trials in relapsing-remitting multiple sclerosis published in 2009 showed a quantitative relation between the treatment effects detected on Mill lesions and clinical relapses. We aimed to validate that relation using data from a large and independent set of clinical trials in multiple sclerosis.Methods We searched Medline for clinical trials that assessed disease-modifying drugs for relapsing-remitting multiple sclerosis published from Sept 1,2008, to Oct 31,2012. We extracted data for the treatment effects on MRI lesions and on relapses from each trial, and the correlation of log transformed relative measures of these treatment effects was assessed with a weighted linear regression analysis. The R-2 value was estimated to quantify the strength of the correlation, and we used an interaction test to test for a difference in slope from the previously estimated equation. We also ran several sensitivity analyses.Findings We identified 31 eligible trials, which provided data for 18 901 patients with relapsing-remitting multiple sclerosis. The regression equation derived using data from these studies showed a relation between the concurrent treatment effects on MRI lesions and relapses (slope=0.52; R-2=0.71), much the same as was previously estimated (P-interaction=0.45). Analysis of trials that tested the same drugs in phase 2 and phase 3 studies showed that the effects on MRI lesions over short follow-up periods (6-9 months) can also predict the effects on relapses over longer follow-up periods (12-24 months), with reported effects on relapses that were within the 95% prediction intervals in eight of nine trials.Interpretation Our findings indicate that the effect of a treatment on relapses can be accurately predicted by the effect of that therapy on MRI lesions, implying that the use of Mill markers as primary endpoints in future clinical trials of treatments for multiple sclerosis can be considered, in specific situations, such as in trials testing generics or biosimilars of drugs with a well known mechanism of action or in paediatric trials testing drugs already approved for adults.