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

Published:August 22, 2022DOI:https://doi.org/10.1016/j.msard.2022.104143

      Highlights

      • Neurologic damage usually begins well before MS can be diagnosed.
      • Many radiologically isolated syndrome (RIS) patients go on to develop MS.
      • The CELLO trial will evaluate whether short-term ocrelizumab can prevent RIS from becoming MS.
      • Biospecimens collected in CELLO will help define the immunobiology of preclinical MS.

      Abstract

      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

      Keywords

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      References

        • Amato M.P.
        • Hakiki B.
        • Goretti B.
        • et al.
        Association of MRI metrics and cognitive impairment in radiologically isolated syndromes.
        Neurology. 2012; 78: 309-314
        • Avasarala J.
        • Yousuf F.
        Radiologically isolated syndrome is antiquated amidst evolving McDonald criteria for multiple sclerosis.
        CNS Spectr. 2021; 26: 307-309
        • Baker D.
        • MacDougall A.
        • Kang A.S.
        • Schmierer K.
        • Giovannoni G.
        • Dobson R.
        CD19 B cell repopulation after ocrelizumab, alemtuzumab and cladribine: implications for SARS-CoV-2 vaccinations in multiple sclerosis.
        Mult. Scler. Relat. Disord. 2021; 57103448
        • Baker D.
        • Pryce G.
        • James L.K.
        • Marta M.
        • Schmierer K
        The ocrelizumab phase II extension trial suggests the potential to improve the risk: benefit balance in multiple sclerosis.
        Mult. Scler. Relat. Disord. 2020; 44102279
        • Barkhof F.
        • Filippi M.
        • Miller D.H.
        • et al.
        Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis.
        Brain. 1997; 120: 2059-2069
        • Barr T.A.
        • Shen P.
        • Brown S.
        • et al.
        B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6-producing B cells.
        J. Exp. Med. 2012; 209: 1001-1010
        • Beltran E.
        • Gerdes L.A.
        • Hansen J.
        • et al.
        Early adaptive immune activation detected in monozygotic twins with prodromal multiple sclerosis.
        J. Clin. Invest. 2019; 129: 4758-4768
        • Benedict R.H.
        • DeLuca J.
        • Phillips G.
        • et al.
        Validity of the Symbol Digit Modalities Test as a cognition performance outcome measure for multiple sclerosis.
        Mult. Scler. 2017; 23: 721-733
        • Bjornevik K.
        • Munger K.L.
        • Cortese M.
        • et al.
        Serum Neurofilament Light Chain Levels in Patients With Presymptomatic Multiple Sclerosis.
        JAMA Neurol. 2020; 77: 58-64
        • Brown J.W.L.
        • Coles A.
        • Horakova D.
        • et al.
        Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis.
        JAMA. 2019; 321: 175-187
        • Cella D.
        • Lai J.S.
        • Nowinski C.J.
        • et al.
        Neuro-QOL: brief measures of health-related quality of life for clinical research in neurology.
        Neurology. 2012; 78: 1860-1867
        • Cohen M.
        • Romero G.
        • Bas J.
        • et al.
        Monitoring CD27+ memory B-cells in neuromyelitis optica spectrum disorders patients treated with rituximab: results from a bicentric study.
        J. Neurol. Sci. 2017; 373: 335-338
        • Colucci M.
        • Carsetti R.
        • Serafinelli J.
        • et al.
        Prolonged Impairment of Immunological Memory After Anti-CD20 Treatment in Pediatric Idiopathic Nephrotic Syndrome.
        Front. Immunol. 2019; 10: 1653
        • Comi G.
        • Martinelli V.
        • Rodegher M.
        • et al.
        Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial.
        Lancet. 2009; 374: 1503-1511
        • Cortese M.
        • Riise T.
        • Bjornevik K.
        • et al.
        Preclinical disease activity in multiple sclerosis: a prospective study of cognitive performance prior to first symptom.
        Ann. Neurol. 2016; 80: 616-624
        • De Stefano N.
        • Giorgio A.
        • Tintore M.
        • et al.
        Radiologically isolated syndrome or subclinical multiple sclerosis: MAGNIMS consensus recommendations.
        Mult. Scler. 2018; 24: 214-221
        • Disanto G.
        • Adiutori R.
        • Dobson R.
        • et al.
        Serum neurofilament light chain levels are increased in patients with a clinically isolated syndrome.
        J. Neurol. Neurosurg. Psychiatry. 2016; 87: 126-129
        • Disanto G.
        • Barro C.
        • Benkert P.
        • et al.
        Serum Neurofilament light: a biomarker of neuronal damage in multiple sclerosis.
        Ann. Neurol. 2017; 81: 857-870
        • Freedman M.S.
        • Leist T.P.
        • Comi G.
        • et al.
        The efficacy of cladribine tablets in CIS patients retrospectively assigned the diagnosis of MS using modern criteria: results from the ORACLE-MS study.
        Mult Scler J Exp Transl Clin. 2017; 32055217317732802
        • Hakiki B.
        • Goretti B.
        • Portaccio E.
        • Zipoli V.
        • Amato M.P.
        Subclinical MS': follow-up of four cases.
        Eur. J. Neurol. 2008; 15: 858-861
        • Hauser S.L.
        • Bar-Or A.
        • Comi G.
        • et al.
        Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis.
        N. Engl. J. Med. 2017; 376: 221-234
        • Havrdova E.
        • Arnold D.L.
        • Cohen J.A.
        • et al.
        Alemtuzumab CARE-MS I 5-year follow-up: durable efficacy in the absence of continuous MS therapy.
        Neurology. 2017; 89: 1107-1116
        • Herold K.C.
        • Bundy B.N.
        • Long S.A.
        • et al.
        An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes.
        N. Engl. J. Med. 2019; 381: 603-613
        • Iaffaldano P.
        • Lucisano G.
        • Patti F.
        • et al.
        Transition to secondary progression in relapsing-onset multiple sclerosis: definitions and risk factors.
        Mult. Scler. 2021; 27: 430-438
        • Jacobs L.D.
        • Beck R.W.
        • Simon J.H.
        • et al.
        Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group.
        N. Engl. J. Med. 2000; 343: 898-904
        • Kappos L.
        • Freedman M.S.
        • Polman C.H.
        • et al.
        Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial.
        Lancet Neurol. 2009; 8: 987-997
        • Kappos L.
        • Polman C.H.
        • Freedman M.S.
        • et al.
        Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes.
        Neurology. 2006; 67: 1242-1249
        • Labiano-Fontcuberta A.
        • Martinez-Gines M.L.
        • Aladro Y.
        • et al.
        A comparison study of cognitive deficits in radiologically and clinically isolated syndromes.
        Mult. Scler. 2016; 22: 250-253
        • Lebrun C.
        • Blanc F.
        • Brassat D.
        • Zephir H.
        • de Seze J.
        Cfsep. Cognitive function in radiologically isolated syndrome.
        Mult. Scler. 2010; 16: 919-925
        • Lebrun-Frenay C.
        • Kantarci O.
        • Siva A.
        • et al.
        Radiologically Isolated Syndrome: 10-Year Risk Estimate of a Clinical Event.
        Ann. Neurol. 2020; 88: 407-417
        • Li R.
        • Rezk A.
        • Miyazaki Y.
        • et al.
        Proinflammatory GM-CSF–producing B cells in multiple sclerosis and B cell depletion therapy.
        Sci. Transl. Med. 2015; 7 (310ra166-310ra166)
        • Lunemann J.D.
        • Ruck T.
        • Muraro P.A.
        • Bar-Or A.
        • Wiendl H.
        Immune reconstitution therapies: concepts for durable remission in multiple sclerosis.
        Nat. Rev. Neurol. 2020; 16: 56-62
        • Maarouf A.
        • Rico A.
        • Boutiere C.
        • et al.
        Extending rituximab dosing intervals in patients with MS during the COVID-19 pandemic and beyond?.
        Neurol. Neuroimmunol. Neuroinflamm. 2020; 7
        • Matute-Blanch C.
        • Villar L.M.
        • Alvarez-Cermeno J.C.
        • et al.
        Neurofilament light chain and oligoclonal bands are prognostic biomarkers in radiologically isolated syndrome.
        Brain. 2018; 141: 1085-1093
        • Montalban X.
        • Hauser S.L.
        • Kappos L.
        • et al.
        Ocrelizumab versus placebo in primary progressive multiple sclerosis.
        N. Engl. J. Med. 2017; 376: 209-220
        • Muto K.
        • Matsui N.
        • Unai Y.
        • et al.
        Memory B cell resurgence requires repeated rituximab in myasthenia gravis.
        Neuromuscul. Disord. 2017; 27: 918-922
        • Nielsen N.M.
        • Westergaard T.
        • Rostgaard K.
        • et al.
        Familial risk of multiple sclerosis: a nationwide cohort study.
        Am. J. Epidemiol. 2005; 162: 774-778
        • Nissimov N.
        • Hajiyeva Z.
        • Torke S.
        • et al.
        B cells reappear less mature and more activated after their anti-CD20-mediated depletion in multiple sclerosis.
        Proc. Natl. Acad. Sci. U. S. A. 2020; 117: 25690-25699
        • Oh J.
        • Suthiphosuwan S.
        • Sati P.
        • et al.
        Cognitive impairment, the central vein sign, and paramagnetic rim lesions in RIS.
        Mult. Scler. 2021; 13524585211002097
        • Okuda D.T.
        • Mowry E.M.
        • Beheshtian A.
        • et al.
        Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome.
        Neurology. 2009; 72: 800-805
        • Okuda D.T.
        • Mowry E.M.
        • Cree B.A.
        • et al.
        Asymptomatic spinal cord lesions predict disease progression in radiologically isolated syndrome.
        Neurology. 2011; 76: 686-692
        • Okuda D.T.
        • Siva A.
        • Kantarci O.
        • et al.
        Radiologically isolated syndrome: 5-year risk for an initial clinical event.
        PLoS ONE. 2014; 9: e90509
        • Okuda D.T.
        Unanticipated demyelinating pathology of the CNS.
        Nat. Rev. Neurol. 2009; 5: 591-597
        • Ramesh A.
        • Schubert R.D.
        • Greenfield A.L.
        • et al.
        A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis.
        Proc. Natl. Acad. Sci. U. S. A. 2020; 117: 22932-22943
        • Sati P.
        • Oh J.
        • Constable R.T.
        • et al.
        The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis Cooperative.
        Nat. Rev. Neurol. 2016; 12: 714-722
        • Song J.
        • Westerlind H.
        • McKay K.A.
        • et al.
        Familial risk of early- and late-onset multiple sclerosis: a Swedish nationwide study.
        J. Neurol. 2019; 266: 481-486
        • Thompson A.J.
        • Banwell B.L.
        • Barkhof F.
        • et al.
        Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria.
        Lancet Neurol. 2018; 17: 162-173
        • Thompson A.J.
        • Reingold S.C.
        • Cohen J.A.
        International Panel on Diagnosis of Multiple S. Applying the 2017 McDonald diagnostic criteria for multiple sclerosis - Authors' reply.
        Lancet Neurol. 2018; 17: 499-500
        • Tintore M.
        • Cobo-Calvo A.
        • Carbonell P.
        • et al.
        Effect of Changes in MS Diagnostic Criteria Over 25 Years on Time to Treatment and Prognosis in Patients With Clinically Isolated Syndrome.
        Neurology. 2021; 97: e1641-e1652
        • Tornatore C.
        • Phillips J.T.
        • Khan O.
        • Miller A.E.
        • Hughes M.
        Consensus opinion of US neurologists on practice patterns in RIS, CIS, and RRMS: evolution of treatment practices.
        Neurol. Clin. Pract. 2016; 6: 329-338
        • Vanderlugt C.L.
        • Miller S.D.
        Epitope spreading in immune-mediated diseases: implications for immunotherapy.
        Nat. Rev. Immunol. 2002; 2: 85-95
        • van Lierop Z.Y.
        • Toorop A.A.
        • van Ballegoij W.J.
        • et al.
        Personalized B-cell tailored dosing of ocrelizumab in patients with multiple sclerosis during the COVID-19 pandemic.
        Mult. Scler. 2021; 13524585211028833
        • Wijnands J.M.A.
        • Kingwell E.
        • Zhu F.
        • et al.
        Health-care use before a first demyelinating event suggestive of a multiple sclerosis prodrome: a matched cohort study.
        Lancet Neurol. 2017; 16: 445-451
        • Wijnands J.M.A.
        • Zhu F.
        • Kingwell E.
        • et al.
        Prodrome in relapsing-remitting and primary progressive multiple sclerosis.
        Eur. J. Neurol. 2019; 26: 1032-1036
        • Yuan A.
        • Nixon R.A.
        Neurofilament proteins as biomarkers to monitor neurological diseases and the efficacy of therapies.
        Front Neurosci. 2021; 15689938
        • Yusuf F.
        • Wijnands J.M.
        • Kingwell E.
        • et al.
        Fatigue, sleep disorders, anaemia and pain in the multiple sclerosis prodrome.
        Mult. Scler. 2021; 27: 290-302