title: The ALSFRS as an outcome measure in therapeutic trials and its relationship to symptom onset.
abstract: 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.
authors: a Nuffield Department of Clinical Neuroscience , University of Oxford and.
authors: Malcolm
authors: M
authors: Proudfoot
authors: b Department of Clinical Neuroscience , Institute of Psychiatry, King's College London , London SE5 8AF , UK.
authors: Ashley
authors: A
authors: Jones
authors: a Nuffield Department of Clinical Neuroscience , University of Oxford and.
authors: Kevin
authors: K
authors: Talbot
authors: b Department of Clinical Neuroscience , Institute of Psychiatry, King's College London , London SE5 8AF , UK.
authors: Ammar
authors: A
authors: Al-Chalabi
authors: a Nuffield Department of Clinical Neuroscience , University of Oxford and.
authors: Martin R
authors: MR
authors: Turner
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis* / Q000401:mortality; D004185:Disability Evaluation; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D017063:Outcome Assessment, Health Care; D015203:Reproducibility of Results; D012720:Severity of Illness Index; D013997:Time Factors
keywords: Motor neuron disease; clinical trial; modelling; prognosis; survival