Evidence map›Paper›PMID 31292200›Full record

ArticleJournal of neurology, neurosurgery, and psychiatry2019

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

Ruben P A van Eijk, Stavros Nikolakopoulos, Kit C B Roes, Bas M Middelkoop, Toby A Ferguson, Pamela J Shaw, P Nigel Leigh, Ammar Al-Chalabi, Marinus J C Eijkemans, Leonard H van den Berg

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of neurology, neurosurgery, and psychiatry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
11citing papers in PubMed, 1 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

11 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Pooled it
  2. Review
  3. Article
  4. Article
  5. Article
  6. Article
  7. Article
  8. Review
  9. Article
  10. Article
  11. TDP-43 proteinopathies: a new wave of neurodegenerative diseases.Journal of neurology, neurosurgery, and psychiatry · 2020
    Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

10 authors.

Ruben P A van EijkDepartment of Neurology, Brain Center Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The Netherlands R.P.A.vanEijk-2@umcutrecht.nl.ORCID 0000-0002-7132-5967
Stavros NikolakopoulosBiostatistics & Research Support, Julius Centre for Health Sciences and Primary Care, Utrecht, The Netherlands.
Kit C B RoesBiostatistics & Research Support, Julius Centre for Health Sciences and Primary Care, Utrecht, The Netherlands.
Bas M MiddelkoopDepartment of Neurology, Brain Center Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The Netherlands.
Toby A FergusonDepartment of Neurology Research and Early Clinical Development, Biogen Inc, Cambridge, Massachusetts, USA.
Pamela J ShawSheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
P Nigel LeighDepartment of Clinical Neuroscience, Trafford Centre for Biomedical Research, Brighton and Sussex Medical School, Brighton, UK.
Ammar Al-ChalabiDepartment of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.
Marinus J C EijkemansBiostatistics & Research Support, Julius Centre for Health Sciences and Primary Care, Utrecht, The Netherlands.
Leonard H van den BergDepartment of Neurology, Brain Center Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The Netherlands.

Funding

Medical Research Council MR/L501529/1Medical Research Council MR/R024804/1Motor Neurone Disease Association ALCHALABI-TALBOT/APR14/926-794
6 · The paper itself

Abstract

backgroundFunding 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.

methodsWe 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.

resultsPrevious 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).

conclusionsImplementing 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.

Indexed as

Research DesignAdultAmyotrophic Lateral SclerosisClinical Trials as TopicEndpoint DeterminationFemaleHumansMaleQuality of LifeRiluzoleRiluzoleamyotrophic lateral sclerosisparametric survivaltime-to-event endpointstrial design

Identifiers

PMID31292200
PMCPMC6902062

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.