Proudfoot Malcolm, Jones Ashley, Talbot Kevin, Al-Chalabi Ammar, Turner Martin R
a Nuffield Department of Clinical Neuroscience , University of Oxford and.
b Department of Clinical Neuroscience , Institute of Psychiatry, King's College London , London SE5 8AF , UK.
Amyotroph Lateral Scler Frontotemporal Degener. 2016 Jul-Aug;17(5-6):414-25. doi: 10.3109/21678421.2016.1140786. Epub 2016 Feb 11.
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.
从报告的症状出现到诊断时肌萎缩侧索硬化功能评分（ALSFRS）的降低用于估计疾病进展速度。在治疗试验中，ALSFRS的下降可能是非线性的，或者会因患者退出而受到扭曲，从而降低了斜率变化作为结果指标的可靠性。PRO-ACT数据库独特地允许使用阴性治疗试验的历史数据来探索此类指标。对18项汇总试验中的功能评分下降情况进行了分析，比较了基于症状出现的下降率与间隔评估之间计算出的下降率。还考虑了减轻试验退出影响的策略。结果表明，根据症状出现计算出的进展速度低估了随后残疾累积的速度，不过它比δALSFRS或δFVC的四个月间隔估计更准确地预测了生存率。在典型试验持续时间内，个体的ALSFRS和FVC进展呈线性。未找到校正试验退出的简单解决方案，但使用δALSFRS进行插补似乎干扰最小。总之，在症状出现后尽快招募试验参与者的需求与入组时基于ALSFRS得出的进展速度可靠性降低之间存在权衡。显然迫切需要疾病活动的客观标志物来替代基于生存的终点指标。
