A set of objective, validated measures for assessing new treatments for Huntington's disease (HD) in phase 2 and 3 clinical trials has been identified. The findings, published Online first in The Lancet Neurology, should increase the likelihood of success of future trials of new drugs to delay the onset and reduce the severity of HD.
"HD research is at a critical point, with new drugs in the later stages of development, and we propose a battery of assessments for use in clinical trials in people with early HD. Hypothetical treatment effects defined by slower longitudinal changes in these measures should be detectable over a realistic timescale with practical sample sizes. These new tools provide a key contribution towards our ultimate aim of establishing effective treatments for this devastating condition"*, explains lead author Sarah Tabrizi from University College London's Institute of Neurology, London, UK.
Currently, clinical drug trials for HD treatments rely on the unified Huntington's disease rating scale (UHDRS) as the standard outcome measure. But this scale has limited reliability and sensitivity and might therefore not be ideal for measuring meaningful changes in disease progression within a short time period, and more robust methods of testing potential therapies are needed.
The TRACK-HD study was established to identify measures (biomarkers) that could be used to more accurately measure and predict the progression of HD, by comparing a series of techniques to assess motor function, behaviour, cognition, and advanced brain imaging. The study enrolled 366 individuals from Canada, France, the Netherlands, and the UK—120 presymptomatic carriers of the HD gene mutation, 123 patients with early symptomatic HD, and 123 healthy controls.
In January 2011, the TRACK-HD investigators reported changes across a wide range of neuroimaging and clinical measures in presymptomatic individuals over 12 months, including progressive reduction in white matter and whole-brain volume, and cognitive and motor function decline.
Here they report the 24 month follow-up of patients with the goal of establishing the ability of these measures to track disease progression when used annually and to calculate their effect sizes, to assess potential sensitivity and efficiency.
Measures derived from brain imaging techniques were the most effective at detecting disease progression over 24 months. Measures of brain atrophy increased at a significantly higher, measurable rate, in both individuals without noticeable symptoms and those with early HD, and provide the strongest outcome measure for both stages of the disease. But, the authors note, which measures have causal links to functional decline need to be identified.
In early HD there was also significant deterioration in functional, cognitive, and motor function over 24 months compared with controls. Speeded tapping was the most sensitive of the motor assessments and outperformed the more commonly used UHDRS measures.
The authors conclude: "Future studies to investigate the validity of the markers as indicators of clinically meaningful and potentially reversible progression will advance the development of treatments for this devastating neurodegenerative disease."
In a Comment, Karl Kieburtz from University of Rochester, New York, USA, says: "With methods that have improved precision and predictability, sample size and trial duration estimates should decrease. These methods, coupled with trial designs created to identify and discard unhelpful interventions rapidly, should accelerate the process of finding effective treatments for HD and other neurodegenerative diseases."
Dr Ed Wild, UCL, Institute of Neurology, London, UK. T) +44 (0)207 611 0125 or +44 (0) 7779251463 (mobile) Professor Sarah Tabrizi, UCL, Institute of Neurology, London, UK. Available from Friday 2 December T) +44 (0) 203 448 4434 E) s.tabrizi@ucl.ac.uk
Dr Karl Kieburtz from University of Rochester, New York, USA.T) +1 585 275 8911 E) Karl.Kieburtz@chet.rochester.edu
Notes to Editors: *Quote direct from author and cannot be found in text of Article.
Journal
The Lancet Neurology