title: Short-interval observational data to inform clinical trial design in Huntington's disease.
abstract: OBJECTIVE
  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.
authors: Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UK.
authors: Nicola Z
authors: NZ
authors: Hobbs
authors: Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.
authors: Ruth E
authors: RE
authors: Farmer
authors: Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UK.
authors: Elin M
authors: EM
authors: Rees
authors: Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UK.
authors: James H
authors: JH
authors: Cole
authors: Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UK.
authors: Salman
authors: S
authors: Haider
authors: Dementia Research Centre, UCL Institute of Neurology, University College London, London, UK.
authors: Ian B
authors: IB
authors: Malone
authors: Department of Neurology, Ulm University, Ulm, Germany.
authors: Reiner
authors: R
authors: Sprengelmeyer
authors: Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA.
authors: Hans
authors: H
authors: Johnson
authors: Department of Neurology, Ulm University, Ulm, Germany.
authors: Hans-Peter
authors: HP
authors: Mueller
authors: Department of Neurology, Ulm University, Ulm, Germany.
authors: Sigurd D
authors: SD
authors: Sussmuth
authors: Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands.
authors: Raymund A C
authors: RA
authors: Roos
authors: APHP-Department of Genetics and INSERM UMR S679, ICM (Brain and Spine Institute), Salpêtrière University Hospital, Paris, France.
authors: Alexandra
authors: A
authors: Durr
authors: Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.
authors: Chris
authors: C
authors: Frost
authors: Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UK.
authors: Rachael I
authors: RI
authors: Scahill
authors: Department of Neurology, Ulm University, Ulm, Germany.
authors: Bernhard
authors: B
authors: Landwehrmeyer
authors: Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UK.
authors: Sarah J
authors: SJ
authors: Tabrizi
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002540:Cerebral Cortex / Q000473:pathology; D003071:Cognition; D018450:Disease Progression; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000473:pathology / Q000523:psychology / Q000628:therapy*; D007091:Image Processing, Computer-Assisted; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D012107:Research Design
keywords: HUNTINGTON'S; MRI