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Research paper
Short-interval observational data to inform clinical trial design in Huntington's disease
  1. Nicola Z Hobbs1,
  2. Ruth E Farmer2,
  3. Elin M Rees1,
  4. James H Cole1,
  5. Salman Haider1,
  6. Ian B Malone3,
  7. Reiner Sprengelmeyer4,
  8. Hans Johnson5,
  9. Hans-Peter Mueller4,
  10. Sigurd D Sussmuth4,
  11. Raymund A C Roos6,
  12. Alexandra Durr7,
  13. Chris Frost2,
  14. Rachael I Scahill1,
  15. Bernhard Landwehrmeyer4,
  16. Sarah J Tabrizi1
  1. 1Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UK
  2. 2Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK
  3. 3Dementia Research Centre, UCL Institute of Neurology, University College London, London, UK
  4. 4Department of Neurology, Ulm University, Ulm, Germany
  5. 5Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA
  6. 6Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands
  7. 7APHP–Department of Genetics and INSERM UMR S679, ICM (Brain and Spine Institute), Salpêtrière University Hospital, Paris, France
  1. Correspondence to Dr Sarah Tabrizi, Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, Box 104, Queen Square, London WC1N 3BG, UK; s.tabrizi{at}


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.

  • MRI

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