Neuroprotection trial design in progressive supranuclear palsy: challenges and solutions

INTRODUCTION: We review the specific challenges posed to neuroprotective trial design by progressive supranuclear palsy (PSP), a rare disorder difficult to diagnose and to assess quantitatively. METHODS: Focusing on reducing the size and cost of trials, we review elements of PSP neuroprotection trial methodology and formulate a new minimum clinically important difference (MCID) for PSP to be used as a potential outcome milestone. RESULTS: While the original, 28-item version of the PSP Rating Scale (PSPRS) remains the best-validated and most widely published clinical outcome measure, promising improvements include the PSPRS-15 and -10; magnetic resonance imaging (MRI) volumetry; wearable movement-sensitive devices; platform, futility, basket, factorial, adaptive, and multistage designs; customized endpoints; baseline predictor stratification; and the replacement of a continuous disability scale with attainment of milestones, possibly including our newly calculated MCID. DISCUSSION: The specific assessment tools we deem most valuable could be used individually or in combination to reduce the required N and cost of PSP neuroprotection trials.