Disability as an outcome in MS clinical trials
Disability as an outcome in MS clinical trials
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DOI：
10.1212/01.wnl.0000313034.46883.16
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发表时间：
2008-08-26
期刊：
影响因子：
9.9
通讯作者：
Noseworthy, J. H.
中科院分区：
文献类型：
--
作者：
Ebers, G. C.;Heigenhauser, L.;Noseworthy, J. H.
背景资料：关于多发性硬化症（MS）治疗的长期效果的推断是基于短期试验中研究的替代标志物。预防进行性残疾是关键的治疗目标，但在试验背景下对其测量仍然没有经过验证的定义。与此同时，MS试验继续缩短，并依赖于未经验证的替代品。由于目前还没有改善持续性残疾的治疗声明，因此安慰剂/对照组中残疾的恶化必须发生才能显示出对该结局的有效性。方法：我们在31项随机临床试验的安慰剂组的独特数据库中检查了MS个体患者长期残疾进展的广泛使用的临床替代物。二级进展性MS试验中治疗效果的检测受到残疾测量中噪音的影响。而现有的措施可以部分验证继发进展型MS，这是不是在复发缓解型MS的情况下，在这里，广泛使用的治疗失败的定义的检查表明，残疾进展的可能性并不比类似定义的改善。复发缓解型患者的短期干预试验中疾病进展的现有定义反映了随机变化，测量误差和缓解relapses.Conclusion：复发缓解型多发性硬化症试验中使用的不懈残疾的临床替代品不能被验证。试验太短或残疾程度变化太小，无法衡量关键结果。这些分析强调了确定慢性病治疗有效性的困难。
Background: Inferences about long-term effects of therapies in multiple sclerosis (MS) have been based on surrogate markers studied in short-term trials. Preventing progressive disability is the key therapeutic goal but there remains no validated definition for its measurement in a trial context. Meanwhile, MS trials continue to shorten and to depend on unvalidated surrogates. Since there have been no treatment claims for improving unremitting disability, worsening of disability in the placebo/control arm must occur for effectiveness on this outcome to be shown.Methods: We examined widely-used clinical surrogates of long-term disability progression in individual patients with MS within a unique database from the placebo arms of 31 randomized clinical trials.Results: Detection of treatment effects in secondary progressive MS trials is undermined by noise in disability measurement. Whereas existing measures can be partially validated in secondary progressive MS, this is not the case in relapsing-remitting MS. Here, examination of widely used definitions of treatment failure demonstrated that disability progression was no more likely than similarly defined improvement. Existing definitions of disease progression in short-term intervention trials in relapsing-remitting patients reflect random variation, measurement error, and remitting relapses.Conclusion: Clinical surrogates of unremitting disability used in trials of relapsing-remitting multiple sclerosis cannot be validated. Trials have been too short or degrees of disability change too small to measure the key outcomes. These analyses highlight the difficulty in determining effectiveness of therapy in chronic diseases.