The impact of relapse definition and measures of durability on MS clinical trial outcomes.
The impact of relapse definition and measures of durability on MS clinical trial outcomes.
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DOI：
10.1177/13524585231157211
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发表时间：
2023-04
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试验指标的定义对于准确捕获结局和交叉试验可比性至关重要，特别是对于衍生指标。使用CombiRx，检查复发定义对终点的影响，并评价复发缓解型多发性硬化（RRMS）进展指标的持久性。CombiRx复发类型通过扩展残疾状态量表（EDSS）增加的存在或时间来区分。使用最广泛的复发定义，在试验期间未复发的患者中评估进展终点。耐久性比较研究结束时和恶化时的EDSS。将复发定义扩大到最具包容性的定义，使所有组的年复发率（ARR）增加了3倍，并使不依赖于复发活动的进展（PIRA）（定义为6个月确认的残疾恶化（6 M CDW）而无复发）减少了44%。PIRA和PIA（进展独立于任何炎症活动）均不能保证持续恶化，研究结束时分别有43%和40%的患者改善。多变量分析显示，两个CDW事件，而不是复发，预测持久性患者满足6个月CDW。复发定义的严格性影响了绝对ARR和RRMS中的复合终点。尽管复发定义最宽泛，但试验中43%符合PIRA的患者没有持续恶化，这表明应考虑复发定义和持久性，以避免高估RRMS试验中的进展。
Definitions of trial measures are consequential to accurately capturing outcomes and cross-trial comparability, particularly for derivative measures. Using CombiRx, examine the impact of relapse definition on endpoints and evaluate the durability of progression measures in Relapsing Remitting Multiple Sclerosis (RRMS). CombiRx relapse types were distinguished by the presence or timing of Expanded Disability Status Scale (EDSS) increase. Using the broadest definition of relapse, progression endpoints were assessed in patients without relapses on trial. Durability compared EDSS at study end and time of worsening. Broadening relapse definition to the most inclusive definition increased annualized relapse rate (ARR) threefold in all arms and decreased progression independent of relapse activity (PIRA), defined as 6-month confirmed disability worsening (6M CDW) without relapse, by 44%. Neither PIRA nor PIA (progression independent of any inflammatory activity) guaranteed durable worsening, with 43% and 40%, respectively, improving by end of study. Multivariate analysis showed two CDW events, not relapse, predicted durability among patients meeting 6M CDW. The stringency of relapse definition impacted absolute ARR and composite endpoints in RRMS. Despite the most generous relapse definition, 43% of patients meeting PIRA on trial did not have durable worsening suggesting that relapse definition and durability should be considered to avoid overestimating progression in RRMS trials.
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影响因子：
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作者：
Rudick, Richard A.;Lee, Jar-Chi;You, Xiaojun
通讯作者：
You, Xiaojun
影响因子：
2.5
作者：
Healy BC;Engler D;Glanz B;Musallam A;Chitnis T
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影响因子：
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Polman CH
影响因子：
11.2
作者：
Cree, Bruce A. C.;Hollenbach, Jill A.;Hauser, Stephen L.
通讯作者：
Hauser, Stephen L.
影响因子：
29
作者：
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通讯作者：
Ebers, George C.