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

Chris Frost; Amy Mulick; Rachael I Scahill; Gail Owen; Elizabeth Aylward; Blair R Leavitt; Alexandra Durr; Raymund A C Roos; Beth Borowsky; Julie C Stout; Ralf Reilmann; Douglas R Langbehn; Sarah J Tabrizi; Cristina Sampaio

doi:10.1002/mds.27122

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

Journal article

Peer reviewed

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

Chris Frost, Amy Mulick, Rachael I Scahill, Gail Owen, Elizabeth Aylward, Blair R Leavitt, Alexandra Durr, Raymund A C Roos, Beth Borowsky, Julie C Stout, …

Movement disorders, Vol.32(11), pp.1610-1619

11/2017

DOI: 10.1002/mds.27122

PMID: 28906031

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Abstract

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. 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. 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. 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. © 2017 International Parkinson and Movement Disorder Society.

Outcome Assessment, Health Care - statistics & numerical data

Randomized Controlled Trials as Topic - statistics & numerical data

Humans

Middle Aged

Atrophy - pathology

Male

Models, Statistical

Huntington Disease - diagnostic imaging

Huntington Disease - therapy

Young Adult

Caudate Nucleus - diagnostic imaging

Adult

Female

Longitudinal Studies

Research Design - statistics & numerical data

Huntington Disease - physiopathology

Details

Title: Subtitle: Design optimization for clinical trials in early-stage manifest Huntington's disease
Creators: Chris Frost - Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK
Amy Mulick - Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK
Rachael I Scahill - Huntington's Disease Centre, UCL Institute of Neurology, Department of Neurodegenerative Disease, University College London, London, UK
Gail Owen - Huntington's Disease Centre, UCL Institute of Neurology, Department of Neurodegenerative Disease, University College London, London, UK
Elizabeth Aylward - Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA
Blair R Leavitt - Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
Alexandra Durr - Assistance Publique - Hôpitaux de Paris, Genetic Department, Pitié -Salpêtrière University Hospital, Paris, France
Raymund A C Roos - Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands
Beth Borowsky - Clinical Development, Neurodegenerative Diseases, Teva Pharmaceuticals, Malvern Pennsylvania, USA
Julie C Stout - School of Psychological Sciences, Monash University, Melbourne, Victoria, Australia
Ralf Reilmann - Department of Neurodegenerative Diseases and Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany
Douglas R Langbehn - Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA
Sarah J Tabrizi - Huntington's Disease Centre, UCL Institute of Neurology, Department of Neurodegenerative Disease, University College London, London, UK
Cristina Sampaio - CHDI Management, CHDI Foundation, Princeton, New Jersey, USA
Resource Type: Journal article
Publication Details: Movement disorders, Vol.32(11), pp.1610-1619
DOI: 10.1002/mds.27122
PMID: 28906031
NLM abbreviation: Mov Disord
ISSN: 0885-3185
eISSN: 1531-8257
Publisher: United States
Grant note: 200181/Z/15/Z / Wellcome Trust
Language: English
Date published: 11/2017
Academic Unit: Psychiatry; Iowa Neuroscience Institute
Record Identifier: 9984066391902771

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