TY - JOUR
T1 - Critical design considerations for time-to-event endpoints in amyotrophic lateral sclerosis clinical trials
AU - van Eijk, Ruben P A
AU - Nikolakopoulos, Stavros
AU - Roes, Kit C B
AU - Middelkoop, Bas M
AU - Ferguson, Toby A
AU - Shaw, Pamela J
AU - Leigh, P Nigel
AU - Al-Chalabi, Ammar
AU - Eijkemans, Marinus J C
AU - van den Berg, Leonard H
N1 - Funding Information:
Funding This study was funded by the netherlands als Foundation (Project Tricals-reactive).
Funding Information:
This study was funded by the Netherlands ALS Foundation (Project TRICALS-Reactive).
Publisher Copyright:
© 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.
PY - 2019/12
Y1 - 2019/12
N2 - 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.
AB - 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.
KW - amyotrophic lateral sclerosis
KW - parametric survival
KW - time-to-event endpoints
KW - trial design
UR - http://www.scopus.com/inward/record.url?scp=85068746359&partnerID=8YFLogxK
U2 - 10.1136/jnnp-2019-320998
DO - 10.1136/jnnp-2019-320998
M3 - Article
C2 - 31292200
SN - 0022-3050
VL - 90
SP - 1331
EP - 1337
JO - Journal of neurology, neurosurgery, and psychiatry
JF - Journal of neurology, neurosurgery, and psychiatry
IS - 12
ER -