Increasing the efficiency of clinical trials in neurodegenerative disorders using group sequential trial designs - PubMed 22/10/23, 0:22

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Review J Clin Epidemiol. 2018 Jun:98:80-88. doi: 10.1016/j.jclinepi.2018.02.013.

Epub 2018 Feb 24.

Increasing the efficiency of clinical trials in

neurodegenerative disorders using group sequential
trial designs
Ruben P A van Eijk 1 , Stavros Nikolakopoulos 2 , Toby A Ferguson 3, Dawei Liu 3,

Marinus J C Eijkemans 2 , Leonard H van den Berg 4

Affiliations
PMID: 29486281 DOI: 10.1016/j.jclinepi.2018.02.013

Abstract
Objectives: Clinical trials in neurodegenerative disorders are facing high futility rates and rising
development costs. We aim to review and exemplify the value of group sequential trial designs (i.e.,
designs with one or more prospectively planned interim analyses) within the field of amyotrophic
lateral sclerosis.

Study design and setting: We reviewed the literature to identify sequentially conducted trials.
Subsequently, we reanalyzed the dexpramipexole trial (EMPOWER), a classically designed and
conducted trial involving 942 participants, by sequentially monitoring the functional questionnaire
and survival endpoint. Finally, we simulated the performance of the sequential methodology under
different treatment effects.

Results: Only six (12%) randomized, placebo-controlled trials incorporated stopping rules for both
futility and superiority. Despite its high enrollment rate, sequential reanalysis of the EMPOWER
study reduced the total trial duration with 140 days (23.4%, 95% confidence interval [CI] 13.2-
34.4%), the number of follow-ups with 2,688 visits (23.6%, 95% CI 11.3-38.6%), and the total drug
exposure time with 73,377 days (20.6%, 95% CI 9.8-35.9%). The functional questionnaire
considerably increased the heterogeneity in the test statistics, which may negatively affect
sequential monitoring.

Conclusion: Group sequential trials can result in important reductions in the trial duration, which
could make clinical trials more ethical by reducing the patients' exposure to noneffective
treatments or by limiting their time on placebo.

Keywords: ALSFRS-R; Amyotrophic lateral sclerosis; Clinical trials; Group sequential trial designs;
Methods; Neurodegenerative diseases; Survival.

Copyright © 2018 Elsevier Inc. All rights reserved.

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