jnnp-2019-320998.full.pdf (1.83 MB)
Critical design considerations for time-to-event endpoints in amyotrophic lateral sclerosis clinical trials
Version 2 2023-06-07, 08:23
Version 1 2023-06-07, 06:35
journal contribution
posted on 2023-06-07, 08:23 authored by Ruben P A van Eijk, Stavros Nikolakopoulos, Kit C B Roes, Bas M Middelkoop, Toby A Ferguson, Pamela J Shaw, Nigel LeighNigel Leigh, Ammar Al-Chalabi, Marinus J C Eijkemans, Leonard H van den BergBackground: Funding 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. Methods: We 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. Results: Previous 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). Conclusions: Implementing 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.
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Publication status
- Published
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- Published version
Journal
Journal of Neurology, Neurosurgery and PsychiatryISSN
0022-3050Publisher
BMJ Publishing GroupExternal DOI
Department affiliated with
- BSMS Neuroscience Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2019-06-19First Open Access (FOA) Date
2019-07-15First Compliant Deposit (FCD) Date
2019-06-19Usage metrics
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