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Neuromuscular
Original research
Critical design considerations for time-to-event endpoints in amyotrophic lateral sclerosis clinical trials
  1. Ruben P A van Eijk1,2,
  2. Stavros Nikolakopoulos2,
  3. Kit C B Roes2,
  4. Bas M Middelkoop1,
  5. Toby A Ferguson3,
  6. Pamela J Shaw4,
  7. P Nigel Leigh5,
  8. Ammar Al-Chalabi6,
  9. Marinus J C Eijkemans2,
  10. Leonard H van den Berg1
  1. 1 Department of Neurology, Brain Center Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The Netherlands
  2. 2 Biostatistics & Research Support, Julius Centre for Health Sciences and Primary Care, Utrecht, The Netherlands
  3. 3 Department of Neurology Research and Early Clinical Development, Biogen Inc, Cambridge, Massachusetts, USA
  4. 4 Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
  5. 5 Department of Clinical Neuroscience, Trafford Centre for Biomedical Research, Brighton and Sussex Medical School, Brighton, UK
  6. 6 Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London, London, UK
  1. Correspondence to Dr Ruben P A van Eijk, Department of Neurology, UMC Utrecht Brain Center Rudolf Magnus, Utrecht 3584 CG, The Netherlands; R.P.A.vanEijk-2{at}umcutrecht.nl

Abstract

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.

  • time-to-event endpoints
  • parametric survival
  • trial design
  • amyotrophic lateral sclerosis

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jnnp-2019-320998

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    Footnotes

    • Contributors RPAvE, SN: study concept, design, analysis, interpretation of data and drafting manuscript. KCBR, MJCE: study concept, design, analysis and interpretation of data. BMM: design and critical revision of manuscript for intellectual content. TAF, PJS, PNL, AA-C: acquisition of data, critical revision of manuscript for intellectual content. LHvdB: study supervision and critical revision of manuscript for intellectual content.

    • Funding This study was funded by the Netherlands ALS Foundation (Project TRICALS-Reactive).

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information.

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