Evolution of Lesions that Shrink or Disappear into Cerebrospinal Fluid (Atrophied T2 Lesion Volume) in Primary-Progressive Multiple Sclerosis: Results from the Phase III ORATORIO Study
Robert Zivadinov1,2, Jinglan Pei3, David Clayton3, Donna Goldman3, Ryan Winger3, Deepa Ramasamy1, Michael Dwyer1,2, Niels Bergsland1
1Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, 2Center for Biomedical Imaging at Clinical Translational Science Institute, University at Buffalo, State University of New York, 3Genentech, Inc.
Objective:
To investigate the effect of ocrelizumab versus placebo over 120 weeks on the evolution of atrophied T2-lesion volume (aT2-LV) in primary-progressive multiple sclerosis (PPMS) in a double-blind, randomized, phase 3, placebo-controlled study (ORATORIO; NCT01194570).
Background:
Atrophied T2-LV is an exploratory imaging marker in MS reflecting the volume of periventricular lesions subsumed into cerebrospinal fluid (CSF). This MRI biomarker has been shown to be sensitive to MS progression. Accumulation of aT2-LV is 3- to 5-fold higher in progressive compared to relapsing MS, making it an interesting endpoint for PPMS trials. This is one of the first applications of aT2-LV in an interventional, multicenter study with a 2-year treatment duration. 
Design/Methods:
This exploratory post-hoc, MRI-blinded analysis evaluated 732 PPMS patients participating in ORATORIO randomized to ocrelizumab (488) or placebo (244). Atrophied T2-LV was calculated using T1-weighted and FLAIR acquisitions by overlaying baseline T2-lesion masks on follow-up CSF maps at 24, 48 and 120 weeks. Treatment group comparisons were performed using mixed effect model with repeated measures on log-transformed data. Covariates included baseline T2-LV, EDSS, gadolinium-enhancing lesions, geographical region and age (≤/>45).  Sensitivity analysis was performed to account for the influence of unavoidable longitudinal changes to MRI acquisition factors. 
Results:

Accumulation of aT2-LV in the placebo group (366.1mm3, 120 weeks) was consistent with progressive MS in previous reports. In comparison, ocrelizumab treatment significantly slowed accumulation of aT2-LV (319.4mm3, p=0.013). Similar results were obtained when scanner model, software and protocol changes were included, as additional covariates in the model (p=0.029).

Conclusions:

Ocrelizumab showed a significant effect of reducing aT2-LV in PPMS. Additionally, aT2-LV was not affected by scanner-related changes. These data suggest that ocrelizumab may favorably impact mechanisms underlying progressive biology of MS; however, further investigations are needed to validate the connection between aT2-LV and its pathobiology, and to better understand individual clinical relevance.