Impact of Ocrelizumab on Cerebrospinal Fluid Biomarkers at Multiple Sclerosis Onset

Summary

Newly diagnosed relapsing multiple sclerosis (MS) and high risk clinically isolated syndrome (CIS) patients will be treated with ocrelizumab at disease onset to see if treatment favorably alters CSF markers of chronic inflammation.

Timeline

Start

2020-08-30

Primary completion

2026-12

Completion

2027-07

Publications

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• Background Dobson R, Ramagopalan S, Davis A, Giovannoni G. Cerebrospinal fluid oligoclonal bands in multiple sclerosis and clinically isolated syndromes: a meta-analysis of prevalence, prognosis and effect of latitude. J Neurol Neurosurg Psychiatry. 2013 Aug;84(8):909-14. doi: 10.1136/jnnp-2012-304695. Epub 2013 Feb 21.
• Background Howell OW, Reeves CA, Nicholas R, Carassiti D, Radotra B, Gentleman SM, Serafini B, Aloisi F, Roncaroli F, Magliozzi R, Reynolds R. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain. 2011 Sep;134(Pt 9):2755-71. doi: 10.1093/brain/awr182. Epub 2011 Aug 11.
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• Background Alping P, Frisell T, Novakova L, Islam-Jakobsson P, Salzer J, Bjorck A, Axelsson M, Malmestrom C, Fink K, Lycke J, Svenningsson A, Piehl F. Rituximab versus fingolimod after natalizumab in multiple sclerosis patients. Ann Neurol. 2016 Jun;79(6):950-8. doi: 10.1002/ana.24651. Epub 2016 Apr 20.
• Background Rommer PS, Dorner T, Freivogel K, Haas J, Kieseier BC, Kumpfel T, Paul F, Proft F, Schulze-Koops H, Schmidt E, Wiendl H, Ziemann U, Zettl UK; GRAID investigators. Safety and Clinical Outcomes of Rituximab Treatment in Patients with Multiple Sclerosis and Neuromyelitis Optica: Experience from a National Online Registry (GRAID). J Neuroimmune Pharmacol. 2016 Mar;11(1):1-8. doi: 10.1007/s11481-015-9646-5. Epub 2015 Nov 20.
• Background Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Montalban X, Rammohan KW, Selmaj K, Traboulsee A, Wolinsky JS, Arnold DL, Klingelschmitt G, Masterman D, Fontoura P, Belachew S, Chin P, Mairon N, Garren H, Kappos L; OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2017 Jan 19;376(3):221-234. doi: 10.1056/NEJMoa1601277. Epub 2016 Dec 21.
• Background Klein C, Lammens A, Schafer W, Georges G, Schwaiger M, Mossner E, Hopfner KP, Umana P, Niederfellner G. Epitope interactions of monoclonal antibodies targeting CD20 and their relationship to functional properties. MAbs. 2013 Jan-Feb;5(1):22-33. doi: 10.4161/mabs.22771. Epub 2012 Dec 4.
• Background Kappos L, Li D, Calabresi PA, O'Connor P, Bar-Or A, Barkhof F, Yin M, Leppert D, Glanzman R, Tinbergen J, Hauser SL. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet. 2011 Nov 19;378(9805):1779-87. doi: 10.1016/S0140-6736(11)61649-8. Epub 2011 Oct 31.
• Background Sorensen PS, Lisby S, Grove R, Derosier F, Shackelford S, Havrdova E, Drulovic J, Filippi M. Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: a phase 2 study. Neurology. 2014 Feb 18;82(7):573-81. doi: 10.1212/WNL.0000000000000125. Epub 2014 Jan 22.
• Background Bar-Or A, Grove RA, Austin DJ, Tolson JM, VanMeter SA, Lewis EW, Derosier FJ, Lopez MC, Kavanagh ST, Miller AE, Sorensen PS. Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: The MIRROR study. Neurology. 2018 May 15;90(20):e1805-e1814. doi: 10.1212/WNL.0000000000005516. Epub 2018 Apr 25.
• Background Weinshenker BG, Bass B, Rice GP, Noseworthy J, Carriere W, Baskerville J, Ebers GC. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain. 1989 Feb;112 ( Pt 1):133-46. doi: 10.1093/brain/112.1.133.
• Background Tremlett H, Zhao Y, Devonshire V; UBC Neurologists. Natural history comparisons of primary and secondary progressive multiple sclerosis reveals differences and similarities. J Neurol. 2009 Mar;256(3):374-81. doi: 10.1007/s00415-009-0039-7. Epub 2009 Mar 18.
• Background Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl J Med. 2000 Nov 16;343(20):1430-8. doi: 10.1056/NEJM200011163432001.
• Background Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O'Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011 Feb;69(2):292-302. doi: 10.1002/ana.22366.
• Background Ontaneda D, Thompson AJ, Fox RJ, Cohen JA. Progressive multiple sclerosis: prospects for disease therapy, repair, and restoration of function. Lancet. 2017 Apr 1;389(10076):1357-1366. doi: 10.1016/S0140-6736(16)31320-4. Epub 2016 Nov 24.
• Background Hawker K, O'Connor P, Freedman MS, Calabresi PA, Antel J, Simon J, Hauser S, Waubant E, Vollmer T, Panitch H, Zhang J, Chin P, Smith CH; OLYMPUS trial group. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009 Oct;66(4):460-71. doi: 10.1002/ana.21867.
• Background Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, de Seze J, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Rammohan KW, Selmaj K, Traboulsee A, Sauter A, Masterman D, Fontoura P, Belachew S, Garren H, Mairon N, Chin P, Wolinsky JS; ORATORIO Clinical Investigators. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017 Jan 19;376(3):209-220. doi: 10.1056/NEJMoa1606468. Epub 2016 Dec 21.
• Background Dyson JK, Jopson L, Ng S, Lowery M, Harwood J, Waugh S, Valappil M, McPherson S. Improving testing for hepatitis B before treatment with rituximab. Eur J Gastroenterol Hepatol. 2016 Oct;28(10):1172-8. doi: 10.1097/MEG.0000000000000689.
• Background Lee J, Park JY, Huh KH, Kim BS, Kim MS, Kim SI, Ahn SH, Kim YS. Rituximab and hepatitis B reactivation in HBsAg-negative/anti-HBc-positive kidney transplant recipients. Nephrol Dial Transplant. 2017 May 1;32(5):906. doi: 10.1093/ndt/gfx048. No abstract available.
• Background Seto WK, Wong DK, Chan TS, Hwang YY, Fung J, Liu KS, Gill H, Lam YF, Cheung KS, Lie AK, Lai CL, Kwong YL, Yuen MF. Association of Hepatitis B Core-Related Antigen With Hepatitis B Virus Reactivation in Occult Viral Carriers Undergoing High-Risk Immunosuppressive Therapy. Am J Gastroenterol. 2016 Dec;111(12):1788-1795. doi: 10.1038/ajg.2016.436. Epub 2016 Sep 20.
• Background Clifford DB, Ances B, Costello C, Rosen-Schmidt S, Andersson M, Parks D, Perry A, Yerra R, Schmidt R, Alvarez E, Tyler KL. Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis. Arch Neurol. 2011 Sep;68(9):1156-64. doi: 10.1001/archneurol.2011.103. Epub 2011 May 9.
• Background Hauser SL. The Charcot Lecture | beating MS: a story of B cells, with twists and turns. Mult Scler. 2015 Jan;21(1):8-21. doi: 10.1177/1352458514561911. Epub 2014 Dec 5.
• Background Harding K, Williams O, Willis M, Hrastelj J, Rimmer A, Joseph F, Tomassini V, Wardle M, Pickersgill T, Robertson N, Tallantyre E. Clinical Outcomes of Escalation vs Early Intensive Disease-Modifying Therapy in Patients With Multiple Sclerosis. JAMA Neurol. 2019 May 1;76(5):536-541. doi: 10.1001/jamaneurol.2018.4905.
• Background Brown JWL, Coles A, Horakova D, Havrdova E, Izquierdo G, Prat A, Girard M, Duquette P, Trojano M, Lugaresi A, Bergamaschi R, Grammond P, Alroughani R, Hupperts R, McCombe P, Van Pesch V, Sola P, Ferraro D, Grand'Maison F, Terzi M, Lechner-Scott J, Flechter S, Slee M, Shaygannejad V, Pucci E, Granella F, Jokubaitis V, Willis M, Rice C, Scolding N, Wilkins A, Pearson OR, Ziemssen T, Hutchinson M, Harding K, Jones J, McGuigan C, Butzkueven H, Kalincik T, Robertson N; MSBase Study Group. Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis. JAMA. 2019 Jan 15;321(2):175-187. doi: 10.1001/jama.2018.20588.
• Background Ontaneda D, Tallantyre EC, Raza PC, Planchon SM, Nakamura K, Miller D, Hersh C, Craner M, Bale C, Chaudhry B, Gunzler DD, Love TE, Gerry S, Coles A, Cohen JA, Evangelou N. Determining the effectiveness of early intensive versus escalation approaches for the treatment of relapsing-remitting multiple sclerosis: The DELIVER-MS study protocol. Contemp Clin Trials. 2020 Aug;95:106009. doi: 10.1016/j.cct.2020.106009. Epub 2020 Apr 19.
• Background raditional Versus Early Aggressive Therapy for Multiple Sclerosis Trial (TREAT-MS) Johns Hopkins University NCT03500328
• Background University of California, San Francisco MS-EPIC Team; Cree BAC, Hollenbach JA, Bove R, Kirkish G, Sacco S, Caverzasi E, Bischof A, Gundel T, Zhu AH, Papinutto N, Stern WA, Bevan C, Romeo A, Goodin DS, Gelfand JM, Graves J, Green AJ, Wilson MR, Zamvil SS, Zhao C, Gomez R, Ragan NR, Rush GQ, Barba P, Santaniello A, Baranzini SE, Oksenberg JR, Henry RG, Hauser SL. Silent progression in disease activity-free relapsing multiple sclerosis. Ann Neurol. 2019 May;85(5):653-666. doi: 10.1002/ana.25463. Epub 2019 Mar 30.
• Background Warnke C, Stettner M, Lehmensiek V, Dehmel T, Mausberg AK, von Geldern G, Gold R, Kumpfel T, Hohlfeld R, Maurer M, Stangel M, Straeten V, Limmroth V, Weber T, Kleinschnitz C, Wattjes MP, Svenningsson A, Olsson T, Hartung HP, Hermsen D, Tumani H, Adams O, Kieseier BC. Natalizumab exerts a suppressive effect on surrogates of B cell function in blood and CSF. Mult Scler. 2015 Jul;21(8):1036-44. doi: 10.1177/1352458514556296. Epub 2014 Nov 12.
• Background Larsson D, Akerfeldt T, Carlson K, Burman J. Intrathecal immunoglobulins and neurofilament light after autologous haematopoietic stem cell transplantation for multiple sclerosis. Mult Scler. 2020 Oct;26(11):1351-1359. doi: 10.1177/1352458519863983. Epub 2019 Jul 26.
• Background Rejdak K, Stelmasiak Z, Grieb P. Cladribine induces long lasting oligoclonal bands disappearance in relapsing multiple sclerosis patients: 10-year observational study. Mult Scler Relat Disord. 2019 Jan;27:117-120. doi: 10.1016/j.msard.2018.10.006. Epub 2018 Oct 10.
• Background Leist TP, Comi G, Cree BA, Coyle PK, Freedman MS, Hartung HP, Vermersch P, Casset-Semanaz F, Scaramozza M; oral cladribine for early MS (ORACLE MS) Study Group. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol. 2014 Mar;13(3):257-67. doi: 10.1016/S1474-4422(14)70005-5. Epub 2014 Feb 4.
• Background https://www.emdserono.com/content/dam/web/corporate/non-images/country-specifics/us/pi/mavenclad-pi.pdf
• Background https://www.gene.com/download/pdf/ocrevus_prescribing.pdf.

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Indications