Background Two recent randomized, placebo-controlled phase II/III trials (clinicaltrials.gov: NCT01110720, NCT01049399) of davunetide and tideglusib in progressive supranuclear palsy (PSP) generated prospective, 1-year longitudinal datasets of high-resolution T1-weighted 3D MRI. Objectives Develop a quantitative MRI disease progression measurement for clinical trials. Methods We performed a fully automated quantitative MRI analysis employing atlas-based volumetry and provide sample size calculations based on data collected in N=99 PSP patients, assigned to placebo in these trials. Based on individual volumes of N=44 brain compartments and structures at baseline and 52 weeks follow-up, means and standard deviations of annualized percentage volume changes were used to estimate standardized effect sizes and the required sample sizes per group for future two-armed, placebo-controlled therapeutic trials. Results The highest standardized effect sizes were found for midbrain, frontal lobes, and third ventricle. Using the annualized percentage volume change of these structures to detect a 50% change in the 1-year progression (80% power, significance level 5%) required lower numbers of patients per group [third ventricle, N=32; midbrain, N=37; frontal lobe, N= 43] than the best clinical scale (PSP rating scale total score, N=58). A combination of volume changes in these three structures reduced the number of required patients to only N=20 and correlated best with the progression in the clinical scales. Conclusions We propose the 1-year change in the volumes of third ventricle, midbrain, and frontal lobe as combined imaging read-out for clinical trials in PSP, requiring the least number of patients for detecting efficacy to reduce brain atrophy.

Introduction There are no effective treatments for progressive supranuclear palsy (PSP). Volumetric MRI (vMRI) may be a useful surrogate outcome measure in PSP clinical trials. The goal of the study was to evaluate the potential of vMRI to correlate with clinical outcomes from an international clinical trial population. Methods PSP patients (n = 198) from the AL-108-231 trial who had high quality vMRI and Progressive Supranuclear Palsy Rating Scale (PSPRS), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Schwab and England Activities of Daily Living (SEADL), Color Trails Test, Geriatric Depression Screen (GDS) and one year Clinician Global Impression of Change (CGIC) data from the baseline and 52 week visits were included. Linear regression was used to relate baseline values and annual clinical rating scale changes to annual regional vMRI changes (whole brain, ventricular, midbrain and superior cerebellar peduncle volumes). Results Effect sizes (Cohen's d) measuring disease progression over one year were largest for vMRI (midbrain [1.27] and ventricular volume [1.31]) but similar to PSPRS (1.26). After multiple comparison adjustment, annual changes in PSPRS, RBANS, SEADL, Color Trails Test, GDS and one year CGIC were modestly correlated with annual vMRI changes (p < 0.05). Baseline neuropsychological status on RBANS (p = 0.019) and Color Trails (p < 0.01) predicted annual midbrain atrophy rates. Conclusion Standard vMRI measurements are sensitive to disease progression in large, multicenter PSP clinical trials, but are not well correlated with clinical changes. vMRI changes may be useful as supportive endpoints in PSP trials.

Structured Abstract Introduction Despite the widespread use of the PSP rating scale it is not known what change in this scale is meaningful for patients. Methods We analyzed data from a large clinical trial in PSP-Richardson’s syndrome (AL-108-231) to calculate minimal clinically important worsening. This was defined as the difference in mean change of PSP rating scale in subjects rated ‘a little worse’ and those rated ‘unchanged’ on the Clinicians’ Global Impression of Change Scale. A multivariate analysis using logistic regression assessed the relationship between clinical worsening, PSP rating scale, depression and activities of daily living. Results The minimal clinically important worsening on the PSP rating scale was 5.7 points, corresponding to the mean decline over six months in the trial. Changes in activities of daily living and PSP rating scale were significantly associated with clinical worsening. Conclusion Clinically meaningful change is measurable on the PSP rating scale over six months.

Introduction Clinical and MRI measurements can track disease progression in PSP, but many have not been extensively evaluated in multicenter clinical trials. We identified optimal measures to capture clinical decline and predict disease progression in multicenter PSP trials. Methods Longitudinal clinical rating scales, neuropsychological test scores, and volumetric MRI data from an international, phase 2/3 clinical trial of davunetide for PSP (intent to treat population, n=303) were used to identify measurements with largest effect size, strongest correlation with clinical change, and best ability to predict dropout or clinical decline over one year as measured by PSP Rating Scale (PSPRS). Results Baseline cognition as measured by Repeatable Battery for Assessing Neuropsychological Status (RBANS) was associated with attrition, but had only a small effect. PSPRS and Clinical Global Impression (CGI) had the largest effect size for measuring change. Annual change in CGI, RBANS, color trails, and MRI midbrain and ventricular volumes were most strongly correlated with annual PSPRS and had the largest effect sizes for detecting annual change. At baseline, shorter disease duration, more severe depression, and lower performance on RBANS and executive function tests were associated with faster worsening of the PSPRS in completers. With dropouts included, SEADL, RBANS, and executive function tests had significant effect on PSPRS trajectory of change. Conclusion Baseline cognitive status and mood influence the rate of disease progression in PSP. Multiple clinical, neuropsychological, and volumetric MRI measurements are sensitive to change over one year in PSP and appropriate for use in multicenter clinical trials.