Short-interval observational data to inform clinical trial design in Huntington's disease.


Hobbs, NZ; Farmer, RE; Rees, EM; Cole, JH; Haider, S; Malone, IB; Sprengelmeyer, R; Johnson, H; Mueller, HP; Sussmuth, SD; Roos, RA; Durr, A; Frost, C; Scahill, RI; Landwehrmeyer, B; Tabrizi, SJ; (2015) Short-interval observational data to inform clinical trial design in Huntington's disease. Journal of neurology, neurosurgery, and psychiatry. ISSN 0022-3050 DOI: 10.1136/jnnp-2014-309768

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Abstract

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.<br/> 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.<br/> 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.<br/> 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.<br/>

Item Type: Article
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Medical Statistics
Faculty of Epidemiology and Population Health > Dept of Non-Communicable Disease Epidemiology
PubMed ID: 25669748
Web of Science ID: 365859500004
URI: http://researchonline.lshtm.ac.uk/id/eprint/2118833

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