RT Journal Article SR Electronic T1 Short-interval observational data to inform clinical trial design in Huntington's disease JF Journal of Neurology, Neurosurgery & Psychiatry JO J Neurol Neurosurg Psychiatry FD BMJ Publishing Group Ltd SP 1291 OP 1298 DO 10.1136/jnnp-2014-309768 VO 86 IS 12 A1 Nicola Z Hobbs A1 Ruth E Farmer A1 Elin M Rees A1 James H Cole A1 Salman Haider A1 Ian B Malone A1 Reiner Sprengelmeyer A1 Hans Johnson A1 Hans-Peter Mueller A1 Sigurd D Sussmuth A1 Raymund A C Roos A1 Alexandra Durr A1 Chris Frost A1 Rachael I Scahill A1 Bernhard Landwehrmeyer A1 Sarah J Tabrizi YR 2015 UL http://jnnp.bmj.com/content/86/12/1291.abstract AB 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.