Potential endpoints for clinical trials in premanifest and early Huntington's disease in the TRACK-HD study: analysis of 24 month observational data

Summary

Background

TRACK-HD is a prospective observational biomarker study in premanifest and early Huntington's disease (HD). In this report we define a battery of potential outcome measures for therapeutic trials.

Methods

We assessed longitudinal data collected at baseline, 12 months, and 24 months at sites in Leiden (Netherlands), London (UK), Paris (France), and Vancouver (Canada). Participants were individuals without HD but carrying the mutant HTT gene (ie, premanifest HD), patients with early HD, and healthy control individuals matched by age and sex to the combined HD groups. Data were collected with 3T MRI, clinical, cognitive, quantitative motor, oculomotor, and neuropsychiatric assessments. We estimated adjusted, between-group differences in rates of change in these measures and concomitant longitudinal effect sizes.

Findings

Longitudinal data were available for 116 control individuals, 117 premanifest gene carriers, and 116 participants with early HD. Significantly greater progressive grey-matter, white-matter, whole-brain, and regional atrophy was recorded in the premanifest and early HD groups than in the control group. Effect sizes for atrophy rates between participants with early HD and controls were largest in the caudate (2·04, 95% CI 1·68 to 2·48) and white matter (1·70, 1·40 to 2·08). Functional, quantitative motor, and cognitive measures deteriorated to a greater extent in the early HD group than in controls, with the largest effect size in the symbol digit modality test (1·00, 0·67 to 1·27). In the early HD group, changes in structural imaging and various cognitive and quantitative motor scores were associated with worsening total motor score (TMS) and total functional capacity (TFC). In the premanifest group, despite significant declines in regional and overall brain volumes, few functional variables showed significant 24 month change compared with controls; TMS, emotion recognition, and speeded tapping were exceptions. Premanifest individuals with progression, predefined as an increase in TMS score of 5 points or more, any TFC decline, or a new diagnostic confidence score of 4, exhibited higher rates of brain atrophy and deterioration on some quantitative motor tasks compared with other premanifest participants.

Interpretation

On the basis of longitudinal effect size, we recommend several objective outcome measures for clinical trials in participants with early HD. Hypothetical treatment effects defined by slower longitudinal changes in these measures would be detectable over a realistic timescale with practical sample sizes. The restricted 24 month cognitive or motor decline in the premanifest sample illustrates the greater challenge in trial design for this group.

Funding

CHDI/HighQ Foundation Inc.

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.