Design optimization for clinical trials in early-stage manifest Huntington's disease

the TRACK-HD Investigators

Research output: Contribution to journalArticle

Abstract

Objectives: The purpose of this study was to inform the design of randomized clinical trials in early-stage manifest Huntington's disease through analysis of longitudinal data from TRACK-Huntington's Disease (TRACK-HD), a multicenter observational study. Methods: We compute sample sizes required for trials with candidate clinical, functional, and imaging outcomes, whose aims are to reduce rates of change. The calculations use a 2-stage approach: first using linear mixed models to estimate mean rates of change and components of variability from TRACK-HD data and second using these to predict sample sizes for a range of trial designs. Results: For each outcome, the primary drivers of the required sample size were the anticipated treatment effect and the duration of treatment. Extending durations from 1 to 2 years yielded large sample size reductions. Including interim visits and incorporating stratified randomization on predictors of outcome together with covariate adjustment gave more modest, but nontrivial, benefits. Caudate atrophy, expressed as a percentage of its baseline, was the outcome that gave smallest required sample sizes. Discussion: Here we consider potential required sample sizes for clinical trials estimated from naturalistic observation of longitudinal change. Choice among outcome measures for a trial must additionally consider their relevance to patients and the expected effect of the treatment under study. For all outcomes considered, our results provide compelling arguments for 2-year trials, and we also demonstrate the benefits of incorporating stratified randomization coupled with covariate adjustment, particularly for trials with caudate atrophy as the primary outcome. The benefits of enrichment are more debatable, with statistical benefits offset by potential recruitment difficulties and reduced generalizability.

Original languageEnglish (US)
Pages (from-to)1610-1619
Number of pages10
JournalMovement Disorders
Volume32
Issue number11
DOIs
StatePublished - Nov 1 2017
Externally publishedYes

Fingerprint

Huntington Disease
Sample Size
Clinical Trials
Social Adjustment
Random Allocation
Atrophy
Multicenter Studies
Observational Studies
Linear Models
Therapeutics
Randomized Controlled Trials
Observation
Outcome Assessment (Health Care)

Keywords

  • trial design Huntington's

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Design optimization for clinical trials in early-stage manifest Huntington's disease. / the TRACK-HD Investigators.

In: Movement Disorders, Vol. 32, No. 11, 01.11.2017, p. 1610-1619.

Research output: Contribution to journalArticle

the TRACK-HD Investigators. / Design optimization for clinical trials in early-stage manifest Huntington's disease. In: Movement Disorders. 2017 ; Vol. 32, No. 11. pp. 1610-1619.
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abstract = "Objectives: The purpose of this study was to inform the design of randomized clinical trials in early-stage manifest Huntington's disease through analysis of longitudinal data from TRACK-Huntington's Disease (TRACK-HD), a multicenter observational study. Methods: We compute sample sizes required for trials with candidate clinical, functional, and imaging outcomes, whose aims are to reduce rates of change. The calculations use a 2-stage approach: first using linear mixed models to estimate mean rates of change and components of variability from TRACK-HD data and second using these to predict sample sizes for a range of trial designs. Results: For each outcome, the primary drivers of the required sample size were the anticipated treatment effect and the duration of treatment. Extending durations from 1 to 2 years yielded large sample size reductions. Including interim visits and incorporating stratified randomization on predictors of outcome together with covariate adjustment gave more modest, but nontrivial, benefits. Caudate atrophy, expressed as a percentage of its baseline, was the outcome that gave smallest required sample sizes. Discussion: Here we consider potential required sample sizes for clinical trials estimated from naturalistic observation of longitudinal change. Choice among outcome measures for a trial must additionally consider their relevance to patients and the expected effect of the treatment under study. For all outcomes considered, our results provide compelling arguments for 2-year trials, and we also demonstrate the benefits of incorporating stratified randomization coupled with covariate adjustment, particularly for trials with caudate atrophy as the primary outcome. The benefits of enrichment are more debatable, with statistical benefits offset by potential recruitment difficulties and reduced generalizability.",
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