The ALSFRS as an outcome measure in therapeutic trials and its relationship to symptom onset.
The ALSFRS as an outcome measure in therapeutic trials and its relationship to symptom onset.
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DOI：
10.3109/21678421.2016.1140786
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发表时间：
2016-07
影响因子：
2.8
通讯作者：
Turner MR
中科院分区：
文献类型：
--
作者：
Proudfoot M;Jones A;Talbot K;Al-Chalabi A;Turner MR
从报告的症状发作到诊断的ALS功能评定评分（ALSFRS）的降低用于估计疾病进展的速率。ALSFRS下降可能是非线性的或因治疗试验中的脱落而扭曲，从而降低了斜率变化作为结局指标的可靠性。PRO-ACT数据库独特地允许使用来自阴性治疗试验的历史数据来探索这些措施。在18项汇总试验中分析了功能评分的下降，比较了基于症状发作的下降率与间隔评估之间计算的下降率。考虑了减轻试验脱落影响的策略。结果显示，根据症状发作计算的进展率低估了随后的残疾累积率，尽管它比δALSFRS或δFVC的4个月间隔估计值更准确地预测生存率。典型试验持续时间内的个体ALSFRS和FVC进展呈线性。没有确定纠正试验脱落的简单解决方案，但使用δALSFRS进行插补似乎破坏性最小。总之，在症状发作后立即招募试验参与者的驱动力与入组时ALSFRS推导的进展率的可靠性降低之间存在权衡。疾病活动的客观指标作为生存为基础的终点的替代方案的需要是明确和紧迫的。
The reduction in ALS Functional Rating Score (ALSFRS) from reported symptom onset to diagnosis is used to estimate rate of disease progression. ALSFRS decline may be non-linear or distorted by drop-outs in therapeutic trials, reducing the reliability of change in slope as an outcome measure. The PRO-ACT database uniquely allows such measures to be explored using historical data from negative therapeutic trials. The decline of functional scores was analysed in 18 pooled trials, comparing rates of decline based on symptom onset with rates calculated between interval assessments. Strategies to mitigate the effects of trial drop-out were considered. Results showed that progression rate calculated by symptom onset underestimated the subsequent rate of disability accumulation, although it predicted survival more accurately than four-month interval estimates of δALSFRS or δFVC. Individual ALSFRS and FVC progression within a typical trial duration were linear. No simple solution to correct for trial drop-out was identified, but imputation using δALSFRS appeared least disruptive. In conclusion, there is a trade-off between the drive to recruit trial participants soon after symptom onset, and reduced reliability of the ALSFRS-derived progression rate at enrolment. The need for objective markers of disease activity as an alternative to survival-based end-points is clear and pressing.