title: Challenges assessing clinical endpoints in early Huntington disease.
abstract: The basic aim of this study was to evaluate the current accepted standard clinical endpoint for the earliest-studied HD participants likely to be recruited into clinical trials. As the advent of genetic testing for HD, it is possible to identify gene carriers before the diagnosis of disease, which opens up the possibility of clinical trials of disease-modifying treatments in clinically asymptomatic persons. Current accepted standard clinical endpoints were examined as part of a multinational, 32-site, longitudinal, observational study of 786 research participants currently in the HD prodrome (gene-positive but not clinically diagnosed). Clinical signs and symptoms were used to prospectively predict functional loss as assessed by current accepted standard endpoints over 8 years of follow-up. Functional capacity measures were not sensitive for HD in the prodrome; over 88% scored at ceiling. Prospective evaluation revealed that the first functional loss was in their accustomed work. In a survival analysis, motor, cognitive, and psychiatric measures were all predictors of job change. To our knowledge, this is the first prospective study ever conducted on the emergence of functional loss secondary to brain disease. We conclude that future clinical trials designed for very early disease will require the development of new and more sensitive measures of real-life function.
authors.affiliation: Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242-1000, USA. jane-paulsen@uiowa.edu
authors.forename: Jane S
authors.initials: JS
authors.lastname: Paulsen
authors.forename: Chiachi
authors.initials: C
authors.lastname: Wang
authors.forename: Kevin
authors.initials: K
authors.lastname: Duff
authors.forename: Roger
authors.initials: R
authors.lastname: Barker
authors.forename: Martha
authors.initials: M
authors.lastname: Nance
authors.forename: Leigh
authors.initials: L
authors.lastname: Beglinger
authors.forename: David
authors.initials: D
authors.lastname: Moser
authors.forename: Janet K
authors.initials: JK
authors.lastname: Williams
authors.forename: Sheila
authors.initials: S
authors.lastname: Simpson
authors.forename: Douglas
authors.initials: D
authors.lastname: Langbehn
authors.forename: Daniel P
authors.initials: DP
authors.lastname: van Kammen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002986:Clinical Trials as Topic; D023381:Endpoint Determination / Q000379:methods*; D005260:Female; D005820:Genetic Testing; D006801:Humans; D006816:Huntington Disease / Q000175:diagnosis / Q000235:genetics / Q000628:therapy*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged