The CELLO trial: Protocol of a planned phase 4 study to assess the efficacy of Ocrelizumab in patients with radiologically isolated syndrome.

Background: Patients with radiologically isolated syndrome (RIS) exhibit CNS lesions suggestive of multiple sclerosis (MS) in the absence of overt neurological symptoms characteristic of the disease. They may have concurrent brain atrophy, subtle cognitive impairment, and intrathecal inflammation. At least half ultimately develop MS, cementing RIS as preclinical MS for many. However, high-quality data, including immunologic biomarkers, to guide treatment decisions in this population are lacking. Early intervention with ocrelizumab, a humanized monoclonal antibody approved for relapsing and primary progressive MS that targets CD20 ⁺ B-cells, may affect disease course and improve long-term outcomes. The objective of this study is to describe the protocol for CELLO, a clinical trial assessing the effect of ocrelizumab on RIS.
Methods: The CELLO clinical trial, a phase 4, multicenter, randomized, double-blind, placebo-controlled study conducted as an academic-industry collaboration, aims to (1) assess the efficacy of ocrelizumab in patients with RIS and (2) identify biomarkers indicative of emerging autoimmunity as well as immune recovery after transient B-cell depletion. The study will enroll 100 participants across ≥15 sites. Participants will be aged 18 to 40 years, have RIS (defined as meeting 2017 revised McDonald criteria for dissemination in space), and have either been diagnosed with RIS within the last 5 years or have had new brain lesions identified within 5 years of study entry. A screening program of first-degree relatives of patients with MS will be used to boost recruitment. Eligible patients will be randomized 1:1 to receive 3 courses of ocrelizumab or placebo at baseline, week 24, and week 48. Patients will subsequently be followed up for ≥3 years. The primary outcome is time to development of new radiological or clinical evidence of MS. Secondary and exploratory objectives will investigate neuroimaging, serological and immunologic biomarkers, cognitive function, and patient-reported outcomes. A substudy using single-cell RNA sequencing to characterize blood and CSF immune cells will assess markers associated with conversion to clinical MS.
Conclusion: The CELLO study will improve the understanding of B-cell biology in early MS disease pathophysiology, characterize the emergence of CNS autoimmunity, and provide evidence to inform treatment decision-making for individuals with RIS.
Clinicaltrials: GOV: NCT04877457.
Competing Interests: Declaration of competing interest EEL has received honoraria for consulting for EMD Serono, Biogen, Alexion, Genzyme, Genentech, Janssen, NGM, and TG Therapeutics. She has received honoraria for speaking at Efficient CME, MJH Life Sciences, PRIME education, and DKBmed. She has received travel support for the ACTRIMS Forum meeting. She has participated on the data and safety monitoring board (DSMB) for a fenebrutinib study (Genentech). She serves on a steering committee for Genentech and on the board of directors for ACTRIMS and serves as an assistant editor for Annals of Neurology. She has received research support from National Institutes of Health (NIH) K23107624, Race to Erase MS, Robert Leet and Clara Guthrie Patterson Trust, and UL1 TR001863. LHH has received research funding paid to her institution from Biogen. She has received honoraria for consulting for Novartis, Genzyme, Genentech, EMD Serono, TG Therapeutics, Horizon, Greenwich, Alexion, and Bristol Myers Squibb. She has received honoraria for speaking for Bristol Myers Squibb, Genzyme, and Genentech. She has participated on the advisory boards for Novartis, Genentech, and EMD Serono. EMM has received research support paid to her institution from Biogen, Genentech, and Teva. She has received royalties for editorial duties from UpToDate. She is a DSMB member of the National Institute of Allergy and Infectious Diseases DSMB and TRIM trial. SAG has received research support paid to her institution from Genentech and NIH National Institute of Neurological Disorders and Stroke. EA has received research funding paid to his institution from Genentech, Biogen, TG Therapeutics, Patient-Centered Outcomes Research Initiative, National MS Society, the National Institutes of Health, and the Rocky Mountain MS Center. He has received honoraria for consulting paid to his institution for Actelion, Alexion, Bayer, Biogen, Celgene/BMS, EMD Serono, Genentech, Novartis, Sanofi, and TG Therapeutics. AHC has received research support from the Conrad N. Hilton Foundation and Race to Erase MS. She has received honoraria for consulting for Biogen, EMD Serono, Janssen, Bristol Myers Squibb, Greenwich Biosciences, Novartis, Genentech, TG Therapeutics, and Horizon Pharmaceuticals. She has received honoraria for speaking at Neurology Grand Rounds (UCLA, Swedish Medical Center, Washington University School of Medicine, University of New Mexico, University of Miami Miller School of Medicine, Massachusetts General Hospital, and Brigham and Women's Hospital), the Consortium of Multiple Sclerosis Centers Annual meeting, and for the Hillel Panitch Memorial Lecture and the John Jay Dystel Prize lecture. She has also received travel costs for nonvirtual presentations as well as support to attend ACTRIMS Forum 2022, the Consortium of Multiple Sclerosis Centers Annual Meeting 2021, and ECTRIMS 2019. She has a patent issued for 15,060–630 (015,875). She serves on the scientific advisory board for evobrutinib (EMD Serono) and for the OBOE study (Genentech). She serves as the Secretary of the Consortium of Multiple Sclerosis Centers and is the Chair of the Program Committee for ACTRIMS 2020–2022. DAH has received honoraria for consulting for Repertoire Immune Medicines, Biogen, F. Hoffmann-La Roche Ltd, Viela Bio, Compass Therapeutics, Sonoma, Proclara Biosciences, GlaxoSmithKline, EcoR1, EMD Serono, NexImmune, and Biohaven Pharmaceuticals. He has received research support paid to his institution from Genentech. J Pei, J Priest, CR and RWC are employees of Genentech, Inc., and shareholders of F. Hoffmann-La Roche Ltd.
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