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Published on: March 11, 2020
Short-interval observational data to inform clinical trial design in Huntington's disease
Nicola Z Hobbs1, Ruth E Farmer2, Elin M Rees1
1Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UK.
Insights
Neuroimaging measures like caudate atrophy show promise for Huntington's disease (HD) trials. These markers offer reliable efficacy readouts over 6-15 months, aiding in faster drug development.
Area of Science:
- Neuroscience
- Neurology
- Medical Imaging
Background:
- Huntington's disease (HD) is a progressive neurodegenerative disorder.
- Developing disease-modifying therapies requires sensitive outcome measures for clinical trials.
- Current outcome measures may lack precision for short-term efficacy assessments.
Purpose of the Study:
- To evaluate candidate outcomes for Huntington's disease (HD) clinical trials across 6, 9, and 15-month intervals.
- To establish guidelines for rapid efficacy readouts in disease-modifying HD trials.
- To determine the utility of neuroimaging and clinical measures as trial endpoints.
Main Methods:
- Recruited 61 HD patients and 40 controls from four EU sites.
- Conducted 3 Tesla MRI, clinical, and cognitive assessments at baseline, 6, and 15 months.
- Analyzed longitudinal changes in brain macrostructure (atrophy, cortical thinning) and microstructure (diffusion metrics), calculating effect sizes (ES).
Main Results:
- Significant longitudinal macrostructural changes (caudate atrophy, ventricular expansion) in HD patients yielded large ES over 6-15 months.
- Cortical metrics and microstructural diffusion metrics showed smaller ES, especially over shorter intervals.
- Clinical and cognitive outcomes demonstrated small longitudinal ES with wide confidence intervals, indicating limited precision.
Conclusions:
- Caudate atrophy and related neuroimaging measures are powerful outcome candidates for HD trials.
- Propose using these neuroimaging measures as initial short-term readouts (6-9 months) in early-phase studies.
- Recommend these measures as secondary endpoints in longer-term (15 months) efficacy studies.
Objectives:
To evaluate candidate outcomes for disease-modifying trials in Huntington's disease (HD) over 6-month, 9-month and 15-month intervals, across multiple domains. To present guidelines on rapid efficacy readouts for disease-modifying trials.
Methods:
40 controls and 61 patients with HD, recruited from four EU sites, underwent 3 T MRI and standard clinical and cognitive assessments at baseline, 6 and 15 months. Neuroimaging analysis included global and regional change in macrostructure (atrophy and cortical thinning), and microstructure (diffusion metrics). The main outcome was longitudinal effect size (ES) for each outcome. Such ESs can be used to calculate sample-size requirements for clinical trials for hypothesised treatment efficacies.
Results:
Longitudinal changes in macrostructural neuroimaging measures such as caudate atrophy and ventricular expansion were significantly larger in HD than controls, giving rise to consistently large ES over the 6-month, 9-month and 15-month intervals. Analogous ESs for cortical metrics were smaller with wide CIs. Microstructural (diffusion) neuroimaging metrics ESs were also typically smaller over the shorter intervals, although caudate diffusivity metrics performed strongly over 9 and 15 months. Clinical and cognitive outcomes exhibited small longitudinal ESs, particularly over 6-month and 9-month intervals, with wide CIs, indicating a lack of precision.
Conclusions:
To exploit the potential power of specific neuroimaging measures such as caudate atrophy in disease-modifying trials, we propose their use as (1) initial short-term readouts in early phase/proof-of-concept studies over 6 or 9 months, and (2) secondary end points in efficacy studies over longer periods such as 15 months.
