Refining eligibility criteria for amyotrophic lateral sclerosis clinical trials
Van Eijk, Ruben P.A.; Westeneng, Henk Jan; Nikolakopoulos, Stavros; Verhagen, Iris E.; Van Es, Michael A.; Eijkemans, Marinus J.C.; Van Den Berg, Leonard H.
(2019) Neurology, volume 92, issue 5, pp. E451 - E460
(Article)
Abstract
Objective To assess the effect of eligibility criteria on exclusion rates, generalizability, and outcome heterogeneity in amyotrophic lateral sclerosis (ALS) clinical trials and to assess the value of a risk-based inclusion criterion. Methods A literature search was performed to summarize the eligibility criteria of clinical trials. The extracted criteria were
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applied to an incidence cohort of 2,904 consecutive patients with ALS to quantify their effects on generalizability and outcome heterogeneity. We evaluated the effect of a risk-based selection approach on trial design using a personalized survival prediction model. Results We identified 38 trials. A large variability exists between trials in all patient characteristics for enrolled patients (p < 0.001), except for the proportion of men (p = 0.21). Exclusion rates varied widely (from 14% to 95%; mean 59.8%; 95% confidence interval 52.6%-66.7%). Stratification of the eligible populations into prognostic subgroups showed that eligibility criteria lead to exclusion of patients in all prognostic groups. Eligibility criteria neither reduce heterogeneity in survival time (from 22.0 to 20.5 months, p = 0.09) nor affect between-patient variability in functional decline (from 0.62 to 0.65, p = 0.25). In none of the 38 trials were the eligibility criteria found to be more efficient than the prediction model in optimizing sample size and eligibility rate. Conclusions The majority of patients with ALS are excluded from trial participation, which questions the generalizability of trial results. Eligibility criteria only minimally improve homogeneity in trial endpoints. An individualized risk-based criterion could be used to balance the gains in trial design and loss in generalizability.
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Keywords: Clinical Neurology, Journal Article
ISSN: 0028-3878
Publisher: Lippincott Williams and Wilkins
Note: Funding Information: The Netherlands Organization for Health Research and Development (Vici scheme), and The Netherlands Organization for Health Research and Development (Sampling and Biomarker Optimization and Harmonization in ALS and Other Motor Neuron Diseases [SOPHIA], Survival, Trigger and Risk, Epigenetic, Environmental, and Genetic Targets for Motor Neuron Health [STRENGTH], A Programme for ALS Care in Europe [ALS-CarE] project), funded through the EU Joint Programme—Neurodegenerative Disease Research), and serving on the Scientific Advisory Board for Biogen, Cytoki-netics, Prinses Beatrix SpierFonds, and the Thierry Latran Foundation. Go to Neurology.org/N for full disclosures. Funding Information: R. van Eijk, H. Westeneng, S. Nikolakopoulos, I. Verhagen, and M. van Es report no disclosures relevant to the manuscript. M. Eijkemans received grants from The Netherlands Organization for Health Research and Development (Veni scheme), the Thierry Latran Foundation, and The Netherlands ALS Foundation (Stichting ALS Nederland). He received travel grants from Baxalta and serves on the biomedical research advisory panel of the UK Motor Neurone Disease Association. L. van den Berg reports grants from The Netherlands ALS Foundation, Publisher Copyright: © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
(Peer reviewed)