Critical design considerations for time-to-event endpoints in amyotrophic lateral sclerosis clinical trials

van Eijk, Ruben P A, Nikolakopoulos, Stavros, Roes, Kit C B, Middelkoop, Bas M, Ferguson, Toby A, Shaw, Pamela J, Leigh, P Nigel, Al-Chalabi, Ammar, Eijkemans, Marinus J C and van den Berg, Leonard H (2019) Critical design considerations for time-to-event endpoints in amyotrophic lateral sclerosis clinical trials. Journal of Neurology, Neurosurgery and Psychiatry. ISSN 0022-3050

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Background: 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.

Item Type: Article
Keywords: time-to-event endpoints; parametric survival; trial design; amyotrophic lateral sclerosis
Schools and Departments: Brighton and Sussex Medical School > Neuroscience
Subjects: R Medicine > RC Internal medicine > RC0321 Neurosciences. Biological psychiatry. Neuropsychiatry > RC0346 Neurology. Diseases of the nervous system Including speech disorders
Depositing User: Patricia Butler
Date Deposited: 19 Jun 2019 12:00
Last Modified: 15 Jul 2019 13:30

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