Neuroprotection trial design in progressive supranuclear palsy: challenges and solutions

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.

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.

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.

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.