Short-interval observational data to inform clinical trial design in early Huntington’s Disease
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Objectives To evaluate candidate outcomes for disease-modifying trials in Huntington's disease (HD) over 6-month, 9-month and 15-month intervals, across multiple domains. To present guidelines on rapid efficacy readouts for disease-modifying trials. Methods 40 controls and 61 patients with HD, recruited from four EU sites, underwent 3 T MRI and standard clinical and cognitive assessments at baseline, 6 and 15 months. Neuroimaging analysis included global and regional change in macrostructure (atrophy and cortical thinning), and microstructure (diffusion metrics). The main outcome was longitudinal effect size (ES) for each outcome. Such ESs can be used to calculate sample-size requirements for clinical trials for hypothesised treatment efficacies. Results Longitudinal changes in macrostructural neuroimaging measures such as caudate atrophy and ventricular expansion were significantly larger in HD than controls, giving rise to consistently large ES over the 6-month, 9-month and 15-month intervals. Analogous ESs for cortical metrics were smaller with wide CIs. Microstructural (diffusion) neuroimaging metrics ESs were also typically smaller over the shorter intervals, although caudate diffusivity metrics performed strongly over 9 and 15 months. Clinical and cognitive outcomes exhibited small longitudinal ESs, particularly over 6-month and 9-month intervals, with wide CIs, indicating a lack of precision. Conclusions To exploit the potential power of specific neuroimaging measures such as caudate atrophy in disease-modifying trials, we propose their use as (1) initial short-term readouts in early phase/proof-of-concept studies over 6 or 9 months, and (2) secondary end points in efficacy studies over longer periods such as 15 months.
Hobbs , N Z , Farmer , R E , Rees , E M , Cole , J H , Haider , S , Malone , I B , Sprengelmeyer , R H , Johnson , H , Mueller , H-P , Sussmuth , S D , Roos , R A C , Durr , A , Frost , C , Scahill , R I , Landwehrmeyer , B & Tabrizi , S J 2015 , ' Short-interval observational data to inform clinical trial design in early Huntington’s Disease ' Journal of Neurology, Neurosurgery, and Psychiatry . DOI: 10.1136/jnnp-2014-309768
Journal of Neurology, Neurosurgery, and Psychiatry
Copyright 2015, the Authors. This article has been accepted for publication in Journal of Neurology, Neurosurgery and Psychiatry following peer review. The definitive copyedited, typeset version,Hobbs NZ, Farmer RE, Rees EM, Cole JH, Haider S, Malone IB et al. Short-interval observational data to inform clinical trial design in early Huntington’s Disease. Journal of Neurology, Neurosurgery, and Psychiatry, 2015, is available online at: https://dx.doi.org/10.1136/jnnp-2014-309768
This work has been supported by the European Union—PADDINGTON project, contract no HEALTH-F2-2010-261358. RIS is supported by the CHDI/High Q Foundation, a not for profit organisation dedicated to finding treatments for Huntington's disease. This work was undertaken at UCLH/UCL, which received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. SJT acknowledges support of the National Institute for Health Research through the Dementias and Neurodegenerative Research Network, DeNDRoN
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