Neuroprotection trial design in progressive supranuclear palsy: challenges and solutions

Area of Science:

• Neuroscience
• Clinical Trials
• Neurology

Background:

• Progressive supranuclear palsy (PSP) presents unique challenges for clinical trial design due to its rarity, diagnostic difficulty, and quantitative assessment limitations.
• Designing effective neuroprotection trials for PSP requires addressing these inherent complexities.

Purpose of the Study:

• To review and identify key elements of neuroprotection trial methodology for PSP.
• To formulate a new minimum clinically important difference (MCID) for PSP to serve as a potential outcome milestone.
• To propose strategies for reducing trial size and cost.

Main Methods:

• Review of existing and emerging outcome measures for PSP, including the PSP Rating Scale (PSPRS) and its variations (PSPRS-15, PSPRS-10).
• Evaluation of advanced assessment tools such as magnetic resonance imaging (MRI) volumetry and wearable movement-sensitive devices.
• Exploration of innovative trial designs including platform, futility, basket, factorial, adaptive, and multistage approaches.
• Consideration of customized endpoints, baseline predictor stratification, and milestone-based assessments.

Main Results:

• The PSPRS remains a validated measure, but shorter versions (PSPRS-15, -10) show promise.
• MRI volumetry and wearable devices offer objective quantitative data.
• Various adaptive and innovative trial designs can enhance efficiency.
• A newly calculated MCID for PSP can serve as a valuable outcome milestone.

Conclusions:

• Specific assessment tools, used individually or in combination, can significantly reduce the sample size (N) and cost of PSP neuroprotection trials.
• Implementing these optimized methodologies can accelerate the development of effective treatments for PSP.