CELLO: a phase IV, multicenter, randomized, doubleblind, placebo-controlled study assessing efficacy of ocrelizumab in radiologically isolated syndrome

INTRODUCTION: People with radiologically isolated syndrome (RIS) display MRI features consistent with CNS demyelination but lack overt neurologic symptoms characteristic of MS. Similar to established MS, RIS subjects exhibit CNS lesions, brain atrophy, cognitive impairment, and intrathecal inflammation; at least half go on to develop definite MS, cementing RIS as pre‐clinical MS for many. However, high quality data, including immunologic biomarkers, to stratify risk and guide treatment decisions in this population are lacking. Early intervention with ocrelizumab (OCR), a humanized monoclonal antibody approved for relapsing and primary progressive MS that selectively targets CD20+ B cells, may impact disease course and improve long‐term outcomes. OBJECTIVES: Report the study design of CELLO, a phase IV, multicenter, randomized, double‐blind, placebo‐controlled study to assess the efficacy of OCR in delaying development of new radiologic or clinical evidence of MS in subjects with RIS. METHODS: The study population will comprise people aged 18‐40 with RIS, defined by asymptomatic CNS lesions fulfilling the 2017 McDonald criteria for dissemination in space. Eligible subjects will be randomized 1:1 to receive three courses of OCR or placebo at baseline, week 24 and week 48 and subsequently followed for a minimum of three years. The primary outcome is time to development of new radiologic or clinical evidence of MS. Secondary and exploratory objectives are to investigate neuroimaging, serologic and immunologic biomarkers, cognitive function, and patient reported outcomes. A sub‐study using single‐cell RNA sequencing to characterize blood and CSF immune cells will assess markers associated with conversion to clinical MS. RESULTS: Enrollment will begin July 2021 with a planned total of 100 patients. CONCLUSIONS: This study aims to improve the understanding of B cell biology in early disease pathophysiology, characterize the emergence of CNS autoimmunity, and provide evidence to support treatment initiation at the earliest stage of MS.