• van Eijk Ruben P A RPA 0000-0002-7132-5967 Department of Neurology, Brain Center Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The Nether, Stavros Nikolakopoulos, Roes Kit C B KCB Biostatistics & Research Support, Julius Centre for Health Sciences and Primary Care, Utrecht, The Netherlands., Bas M Middelkoop, Toby A Ferguson, Pamela J Shaw, P Nigel Leigh, Ammar Al-Chalabi, Eijkemans Marinus J C MJC Biostatistics & Research Support, Julius Centre for Health Sciences and Primary Care, Utrecht, The Netherlands., and Leonard H van den Berg.
• Department of Neurology, Brain Center Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The Netherlands R.P.A.vanEijk-2@umcutrecht.nl.
• J. Neurol. Neurosurg. Psychiatr. 2019 Dec 1; 90 (12): 1331-1337.

BackgroundFunding and resources for low prevalent neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) are limited, and optimising their use is vital for efficient drug development. In this study, we review the design assumptions for pivotal ALS clinical trials with time-to-event endpoints and provide optimised settings for future trials.MethodsWe extracted design settings from 13 completed placebo-controlled trials. Optimal assumptions were estimated using parametric survival models in individual participant data (n=4991). Designs were compared in terms of sample size, trial duration, drug use and costs.ResultsPrevious trials overestimated the hazard rate by 18.9% (95% CI 3.4% to 34.5%, p=0.021). The median expected HR was 0.56 (range 0.33-0.66). Additionally, we found evidence for an increasing mean hazard rate over time (Weibull shape parameter of 2.03, 95% CI 1.93 to 2.15, p<0.001), which affects the design and planning of future clinical trials. Incorporating accrual time and assuming an increasing hazard rate at the design stage reduced sample size by 33.2% (95% CI 27.9 to 39.4), trial duration by 17.4% (95% CI 11.6 to 23.3), drug use by 14.3% (95% CI 9.6 to 19.0) and follow-up costs by 21.2% (95% CI 15.6 to 26.8).ConclusionsImplementing distributional knowledge and incorporating accrual at the design stage could achieve large gains in the efficiency of ALS clinical trials with time-to-event endpoints. We provide an open-source platform that helps investigators to make more accurate sample size calculations and optimise the use of their available resources.© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

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