ArticlesPotential endpoints for clinical trials in premanifest and early Huntington's disease in the TRACK-HD study: analysis of 24 month observational data
Introduction
Since 2008, TRACK-HD has recorded the earliest stages of the neurodegenerative processes in presymptomatic and mild-to-moderately symptomatic individuals who carry a Huntington's disease (HD) expansion mutation in the HTT gene.1, 2 As HD is monogenetic, fully penetrant, and characterised by a long premanifest phase, it provides an opportunity for therapeutic intervention many years before overt symptom onset, when reversal or prevention of neural dysfunction might still be possible.3, 4 Several candidate treatments with potential disease-modifying effects are being tested.3 Selective reduction of mutant HTT expression is being explored in preclinical studies, and compounds suggested to promote clearance of mutant HTT are being studied in phase 1b and phase 2a trials.3 Nevertheless, so far there have been no successful disease-modifying phase 3 trials in HD; such trials ultimately rely on the development of objective and quantitative outcome measures. Therefore, it is highly desirable to validate measures that allow efficacy testing over relatively short intervals, with a practical number of participants who might best respond to therapeutic interventions—namely, those in the earliest stages of the disease.3
Observational studies, such as TRACK-HD,1 have reported baseline cross-sectional findings in early HD; both TRACK-HD and PREDICT-HD5 have also identified subtle differences in individuals many years before predicted clinical onset, known as the premanifest or prodromal stage.6 Impairment has been detected with cognitive tests of emotion recognition and working memory,1, 7, 8 psychomotor processing,8 and visuomotor integration,9 as well as quantitative motor tests of involuntary movements,10 finger tapping,11 grip force,12 tongue protrusion force, and saccadic function.1 However, these data represent cross-sectional changes that might result from an accumulation of pathogenic events that began at least 10–20 years before presentation of disease,13 and thus they are naturally poor estimates of the rate of progression across the shorter periods typical of clinical trials. In TRACK-HD we have previously reported significant progressive white-matter, regional, and whole-brain atrophy, accompanied by deterioration in involuntary choreatic movements and visuomotor integration, over 12 months in people with premanifest and early HD.2 Other studies have shown regional brain atrophy,14 deterioration in a finger tapping task,15 and cognitive decline over 24 months in a premanifest HD population.16, 17, 18
The aim of the study is to establish a battery of sensitive and specific clinical and biological markers of disease progression. We assess which measures show change during the natural course of HD and might therefore be sensitive to therapeutic intervention, are reproducible, and are reliable across many sites over 24 months. We estimate sample sizes that might inform the design of future clinical trials and we assess the functional relevance of these measures. Although modalities such as volumetric imaging might show highly sensitive disease-related change and responses to treatment, they do not necessarily relate to a functional improvement, which is essential to establish drug efficacy. We aimed to establish the relation between such readouts and their functional effect on the disease.
Section snippets
Participants
We assessed longitudinal data collected at baseline, 12 months, and 24 months with 3T MRI, clinical, cognitive, quantitative motor, oculomotor, and neuropsychiatric assessments. Assessments were done at sites in Leiden (Netherlands), London (UK), Paris (France), and Vancouver (Canada). Our inclusion criteria have been described previously (webappendix).1 We divided premanifest gene carriers at the baseline group median (10·8 years) for predicted years to diagnosis13 into preHD-A (further from
Results
Of the 366 participants enrolled at baseline, 347 (95%) completed the 12 month follow-up assessment and 332 (91%) completed the 24 month follow-up assessment (table 1). At 24 months, ten controls (8%), one preHD-A participant (2%), five preHD-B participants (9%), five HD1 participants (7%), and five HD2 participants (11%) had withdrawn, and a further eight participants were unable to attend but remained in the study. We analysed all data according to baseline subgroup. However, at 24 months, 12
Discussion
A major goal of TRACK-HD has been to discover potential outcome measures for therapeutic trials in HD. By use of highly standardised data collection across multiple sites, masked quality control, and centralised independent statistical analysis, we document assessments from many domains showing detectable disease-related change over 24 months. Thus, here we propose outcome measures suitable for proof-of-concept and phase 2 and 3 studies of potential disease-modifying drugs in early HD. These
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