Design optimization for clinical trials in early stage manifest Huntington’s Disease 1 Design optimization for clinical trials in early stage manifest Huntington’s disease Chris Frost MA, DipStat a , Amy Mulick MSc a , Rachael I. Scahill PhD b , Gail Owen PhD b , Elizabeth Aylward PhD c , Blair R. Leavitt MDCM d , Alexandra Durr MD e , Raymund A. C. Roos MD, PhD f , Beth Borowsky PhD g , Julie C. Stout PhD h , Ralf Reilmann MD i , Douglas R. Langbehn MD, PhD j , Sarah J. Tabrizi MD, PhD b , Cristina Sampaio MD, PhD k and the TRACK-HD Investigators a Department of Medical Statistics, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK b UCL Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK c Center for Integrative Brain Research, Seattle Children's Research Institute Seattle, WA 98195-7115 d Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada e ICM - Institut du Cerveau et de la Moelle Epinière, INSERM U1127, CNRS UMR7225, Sorbonne Universités – UPMC Université Paris VI UMR_S1127and APHP, Genetic department, Pitié-Salpêtrière University Hospital, Paris, France f Department of Neurology, Leiden University Medical Centre, 2300RC Leiden, The Netherlands g CHDI Management Inc/CHDI Foundation, Princeton, USA; and Clinical Development, Neurodegenerative Diseases, Teva Pharmaceuticals, Malvern, USA h School of Psychological Sciences, Monash University, Melbourne, Victoria, Australia i George Huntington Institute, Technology Park Muenster, Johann-Krane-Weg 27, 48149 Muenster, Institute for Clinical Radiology, University of Muenster, Albert Schweitzer Campus 1 – Building A1, 48149 Muenster, Germany and Department of Neurodegenerative Diseases and Hertie-Institute for Clinical Brain Research, University of Tuebingen, Hoppe-Seyler Str. 3, 72076 Tuebingen, Germany j Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242, USA k CHDI Management Inc/CHDI Foundation, Princeton, USA