A Prospective Biomarker Study in Active SPMS Subjects Treated With Cladribine Tablets

Summary

The purpose of this study is to explore the concept that biomarker sensitivity will detect activity in Multiple Sclerosis (MS) subjects and allow appropriate change in treatment to prevent dysfunction.

Timeline

Start

2020-09-16

Primary completion

2024-12

Completion

2025-12

Publications

• Background Baker D, Herrod SS, Alvarez-Gonzalez C, Zalewski L, Albor C, Schmierer K. Both cladribine and alemtuzumab may effect MS via B-cell depletion. Neurol Neuroimmunol Neuroinflamm. 2017 Jun 5;4(4):e360. doi: 10.1212/NXI.0000000000000360. eCollection 2017 Jul.
• Background Bjornevik K, Munger KL, Cortese M, Barro C, Healy BC, Niebuhr DW, Scher AI, Kuhle J, Ascherio A. Serum Neurofilament Light Chain Levels in Patients With Presymptomatic Multiple Sclerosis. JAMA Neurol. 2020 Jan 1;77(1):58-64. doi: 10.1001/jamaneurol.2019.3238.
• Background Brureau A, Blanchard-Bregeon V, Pech C, Hamon S, Chaillou P, Guillemot JC, Barneoud P, Bertrand P, Pradier L, Rooney T, Schussler N. NF-L in cerebrospinal fluid and serum is a biomarker of neuronal damage in an inducible mouse model of neurodegeneration. Neurobiol Dis. 2017 Aug;104:73-84. doi: 10.1016/j.nbd.2017.04.007. Epub 2017 Apr 6.
• Background Comi G, Cook SD, Giovannoni G, Rammohan K, Rieckmann P, Sorensen PS, Vermersch P, Hamlett AC, Viglietta V, Greenberg SJ. MRI outcomes with cladribine tablets for multiple sclerosis in the CLARITY study. J Neurol. 2013 Apr;260(4):1136-46. doi: 10.1007/s00415-012-6775-0. Epub 2012 Dec 21.
• Background Comi G, Cook S, Rammohan K, Soelberg Sorensen P, Vermersch P, Adeniji AK, Dangond F, Giovannoni G. Long-term effects of cladribine tablets on MRI activity outcomes in patients with relapsing-remitting multiple sclerosis: the CLARITY Extension study. Ther Adv Neurol Disord. 2018 Jan 23;11:1756285617753365. doi: 10.1177/1756285617753365. eCollection 2018.
• Background Edwards KR, Garten L, Button J, O'Connor J, Kamath V, Frazier C. Neurofilament light chain as an indicator of exacerbation prior to clinical symptoms in multiple sclerosis. Mult Scler Relat Disord. 2019 Jun;31:59-61. doi: 10.1016/j.msard.2019.03.016. Epub 2019 Mar 23.
• Background Freedman MS, Leist TP, Comi G, Cree BA, Coyle PK, Hartung HP, Vermersch P, Damian D, Dangond F. 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 Oct 9;3(4):2055217317732802. doi: 10.1177/2055217317732802. eCollection 2017 Oct-Dec.
• Background Feys P, Lamers I, Francis G, Benedict R, Phillips G, LaRocca N, Hudson LD, Rudick R; Multiple Sclerosis Outcome Assessments Consortium. The Nine-Hole Peg Test as a manual dexterity performance measure for multiple sclerosis. Mult Scler. 2017 Apr;23(5):711-720. doi: 10.1177/1352458517690824. Epub 2017 Feb 16.
• Background Gafson AR, Kim K, Cencioni MT, van Hecke W, Nicholas R, Baranzini SE, Matthews PM. Mononuclear cell transcriptome changes associated with dimethyl fumarate in MS. Neurol Neuroimmunol Neuroinflamm. 2018 Jun 12;5(4):e470. doi: 10.1212/NXI.0000000000000470. eCollection 2018 Jul.
• Background Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, Soelberg Sorensen P, Vermersch P, Chang P, Hamlett A, Musch B, Greenberg SJ; CLARITY Study Group. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010 Feb 4;362(5):416-26. doi: 10.1056/NEJMoa0902533. Epub 2010 Jan 20.
• Background Giovannoni G, Cook S, Rammohan K, Rieckmann P, Sorensen PS, Vermersch P, Hamlett A, Viglietta V, Greenberg S; CLARITY study group. Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis. Lancet Neurol. 2011 Apr;10(4):329-37. doi: 10.1016/S1474-4422(11)70023-0.
• Background Giovannoni G, Cutter G, Sormani MP, Belachew S, Hyde R, Koendgen H, Knappertz V, Tomic D, Leppert D, Herndon R, Wheeler-Kingshott CAM, Ciccarelli O, Selwood D, di Cantogno EV, Ben-Amor AF, Matthews P, Carassiti D, Baker D, Schmierer K. Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Mult Scler Relat Disord. 2017 Feb;12:70-78. doi: 10.1016/j.msard.2017.01.007. Epub 2017 Jan 17.
• Background Giovannoni G, Soelberg Sorensen P, Cook S, Rammohan KW, Rieckmann P, Comi G, Dangond F, Hicking C, Vermersch P. Efficacy of Cladribine Tablets in high disease activity subgroups of patients with relapsing multiple sclerosis: A post hoc analysis of the CLARITY study. Mult Scler. 2019 May;25(6):819-827. doi: 10.1177/1352458518771875. Epub 2018 May 2.
• Background Giovannoni G, Soelberg Sorensen P, Cook S, Rammohan K, Rieckmann P, Comi G, Dangond F, Adeniji AK, Vermersch P. Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study. Mult Scler. 2018 Oct;24(12):1594-1604. doi: 10.1177/1352458517727603. Epub 2017 Sep 5.
• Background Gold R, Giovannoni G, Selmaj K, Havrdova E, Montalban X, Radue EW, Stefoski D, Robinson R, Riester K, Rana J, Elkins J, O'Neill G; SELECT study investigators. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet. 2013 Jun 22;381(9884):2167-75. doi: 10.1016/S0140-6736(12)62190-4. Epub 2013 Apr 4.
• Background Gregson A, Thompson K, Tsirka SE, Selwood DL. Emerging small-molecule treatments for multiple sclerosis: focus on B cells. F1000Res. 2019 Mar 1;8:F1000 Faculty Rev-245. doi: 10.12688/f1000research.16495.1. eCollection 2019.
• Background Gunnarsson M, Malmestrom C, Axelsson M, Sundstrom P, Dahle C, Vrethem M, Olsson T, Piehl F, Norgren N, Rosengren L, Svenningsson A, Lycke J. Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab. Ann Neurol. 2011 Jan;69(1):83-9. doi: 10.1002/ana.22247. Epub 2010 Dec 8.
• Background Havrdova E, Galetta S, Hutchinson M, Stefoski D, Bates D, Polman CH, O'Connor PW, Giovannoni G, Phillips JT, Lublin FD, Pace A, Kim R, Hyde R. Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study. Lancet Neurol. 2009 Mar;8(3):254-60. doi: 10.1016/S1474-4422(09)70021-3. Epub 2009 Feb 7.
• Background Havrdova E, Arnold DL, Bar-Or A, Comi G, Hartung HP, Kappos L, Lublin F, Selmaj K, Traboulsee A, Belachew S, Bennett I, Buffels R, Garren H, Han J, Julian L, Napieralski J, Hauser SL, Giovannoni G. No evidence of disease activity (NEDA) analysis by epochs in patients with relapsing multiple sclerosis treated with ocrelizumab vs interferon beta-1a. Mult Scler J Exp Transl Clin. 2018 Mar 12;4(1):2055217318760642. doi: 10.1177/2055217318760642. eCollection 2018 Jan-Mar.
• Background Hermann R, Karlsson MO, Novakovic AM, Terranova N, Fluck M, Munafo A. The Clinical Pharmacology of Cladribine Tablets for the Treatment of Relapsing Multiple Sclerosis. Clin Pharmacokinet. 2019 Mar;58(3):283-297. doi: 10.1007/s40262-018-0695-9.
• Background Hogel H, Rissanen E, Barro C, Matilainen M, Nylund M, Kuhle J, Airas L. Serum glial fibrillary acidic protein correlates with multiple sclerosis disease severity. Mult Scler. 2020 Feb;26(2):210-219. doi: 10.1177/1352458518819380. Epub 2018 Dec 20.
• Background Hutchinson M. The only certain measure of the effectiveness of multiple sclerosis therapy is cerebrospinal neurofilament level: Commentary. Mult Scler. 2015 Sep;21(10):1242-3. doi: 10.1177/1352458515599682. Epub 2015 Aug 4. No abstract available.
• Background Kingwell E, Marriott JJ, Jette N, Pringsheim T, Makhani N, Morrow SA, Fisk JD, Evans C, Beland SG, Kulaga S, Dykeman J, Wolfson C, Koch MW, Marrie RA. Incidence and prevalence of multiple sclerosis in Europe: a systematic review. BMC Neurol. 2013 Sep 26;13:128. doi: 10.1186/1471-2377-13-128.
• Background Kuhle J, Plavina T, Barro C, Disanto G, Sangurdekar D, Singh CM, de Moor C, Engle B, Kieseier BC, Fisher E, Kappos L, Rudick RA, Goyal J. Neurofilament light levels are associated with long-term outcomes in multiple sclerosis. Mult Scler. 2020 Nov;26(13):1691-1699. doi: 10.1177/1352458519885613. Epub 2019 Nov 4.
• Background Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983 Nov;33(11):1444-52. doi: 10.1212/wnl.33.11.1444.
• 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 Leppert D, Kuhle J. Serum NfL levels should be used to monitor multiple sclerosis evolution - Yes. Mult Scler. 2020 Jan;26(1):17-19. doi: 10.1177/1352458519872921. Epub 2019 Oct 18. No abstract available.
• Background Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sorensen PS, Thompson AJ, Wolinsky JS, Balcer LJ, Banwell B, Barkhof F, Bebo B Jr, Calabresi PA, Clanet M, Comi G, Fox RJ, Freedman MS, Goodman AD, Inglese M, Kappos L, Kieseier BC, Lincoln JA, Lubetzki C, Miller AE, Montalban X, O'Connor PW, Petkau J, Pozzilli C, Rudick RA, Sormani MP, Stuve O, Waubant E, Polman CH. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014 Jul 15;83(3):278-86. doi: 10.1212/WNL.0000000000000560. Epub 2014 May 28.
• Background Marrie RA, Goldman M. Validity of performance scales for disability assessment in multiple sclerosis. Mult Scler. 2007 Nov;13(9):1176-82. doi: 10.1177/1352458507078388. Epub 2007 Jul 10.
• Background Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000 Sep 28;343(13):938-52. doi: 10.1056/NEJM200009283431307. No abstract available.
• Background Okai AF, Amezcua L, Berkovich RR, Chinea AR, Edwards KR, Steingo B, Walker A, Jacobs AK, Daizadeh N, Williams MJ; CARE-MS I, CARE-MS II, CAMMS03409, and TOPAZ Investigators. Efficacy and Safety of Alemtuzumab in Patients of African Descent with Relapsing-Remitting Multiple Sclerosis: 8-Year Follow-up of CARE-MS I and II (TOPAZ Study). Neurol Ther. 2019 Dec;8(2):367-381. doi: 10.1007/s40120-019-00159-2. Epub 2019 Oct 25.
• Background Pardo G, Jones DE. The sequence of disease-modifying therapies in relapsing multiple sclerosis: safety and immunologic considerations. J Neurol. 2017 Dec;264(12):2351-2374. doi: 10.1007/s00415-017-8594-9. Epub 2017 Sep 6.
• Background Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW; AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006 Mar 2;354(9):899-910. doi: 10.1056/NEJMoa044397.
• Background Przybek J, Gniatkowska I, Mirowska-Guzel D, Czlonkowska A. Evolution of diagnostic criteria for multiple sclerosis. Neurol Neurochir Pol. 2015;49(5):313-21. doi: 10.1016/j.pjnns.2015.07.006. Epub 2015 Aug 5.
• Background Puentes F, van der Star BJ, Boomkamp SD, Kipp M, Boon L, Bosca I, Raffel J, Gnanapavan S, van der Valk P, Stephenson J, Barnett SC, Baker D, Amor S. Neurofilament light as an immune target for pathogenic antibodies. Immunology. 2017 Dec;152(4):580-588. doi: 10.1111/imm.12797. Epub 2017 Aug 11.
• Background Rochwerg B, Almenawer SA, Siemieniuk RAC, Vandvik PO, Agoritsas T, Lytvyn L, Alhazzani W, Archambault P, D'Aragon F, Farhoumand PD, Guyatt G, Laake JH, Beltran-Arroyave C, McCredie V, Price A, Chabot C, Zervakis T, Badhiwala J, St-Onge M, Szczeklik W, Moller MH, Lamontagne F. Atraumatic (pencil-point) versus conventional needles for lumbar puncture: a clinical practice guideline. BMJ. 2018 May 22;361:k1920. doi: 10.1136/bmj.k1920. No abstract available.
• Background Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, Lublin FD, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA, Sandrock AW; SENTINEL Investigators. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006 Mar 2;354(9):911-23. doi: 10.1056/NEJMoa044396.
• Background SCHUMACHER GA, BEEBE G, KIBLER RF, KURLAND LT, KURTZKE JF, MCDOWELL F, NAGLER B, SIBLEY WA, TOURTELLOTTE WW, WILLMON TL. PROBLEMS OF EXPERIMENTAL TRIALS OF THERAPY IN MULTIPLE SCLEROSIS: REPORT BY THE PANEL ON THE EVALUATION OF EXPERIMENTAL TRIALS OF THERAPY IN MULTIPLE SCLEROSIS. Ann N Y Acad Sci. 1965 Mar 31;122:552-68. doi: 10.1111/j.1749-6632.1965.tb20235.x. No abstract available.
• Background Schwartz CE, Powell VE. The Performance Scales disability measure for multiple sclerosis: use and sensitivity to clinically important differences. Health Qual Life Outcomes. 2017 Mar 9;15(1):47. doi: 10.1186/s12955-017-0614-z.
• Background Stankiewicz JM, Weiner HL. An argument for broad use of high efficacy treatments in early multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2019 Nov 22;7(1):e636. doi: 10.1212/NXI.0000000000000636. Print 2020 Jan.
• Background Strober L, DeLuca J, Benedict RH, Jacobs A, Cohen JA, Chiaravalloti N, Hudson LD, Rudick RA, LaRocca NG; Multiple Sclerosis Outcome Assessments Consortium (MSOAC). Symbol Digit Modalities Test: A valid clinical trial endpoint for measuring cognition in multiple sclerosis. Mult Scler. 2019 Nov;25(13):1781-1790. doi: 10.1177/1352458518808204. Epub 2018 Oct 18.
• Background Scalfari A, Knappertz V, Cutter G, Goodin DS, Ashton R, Ebers GC. Mortality in patients with multiple sclerosis. Neurology. 2013 Jul 9;81(2):184-92. doi: 10.1212/WNL.0b013e31829a3388.
• Background Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998 Jan 29;338(5):278-85. doi: 10.1056/NEJM199801293380502.
• Background Montalban X, Gold R, Thompson AJ, Otero-Romero S, Amato MP, Chandraratna D, Clanet M, Comi G, Derfuss T, Fazekas F, Hartung HP, Havrdova E, Hemmer B, Kappos L, Liblau R, Lubetzki C, Marcus E, Miller DH, Olsson T, Pilling S, Selmaj K, Siva A, Sorensen PS, Sormani MP, Thalheim C, Wiendl H, Zipp F. ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis. Mult Scler. 2018 Feb;24(2):96-120. doi: 10.1177/1352458517751049. Epub 2018 Jan 20.
• Background Nielsen AS, Kinkel RP, Madigan N, Tinelli E, Benner T, Mainero C. Contribution of cortical lesion subtypes at 7T MRI to physical and cognitive performance in MS. Neurology. 2013 Aug 13;81(7):641-9. doi: 10.1212/WNL.0b013e3182a08ce8. Epub 2013 Jul 17.
• Background Kollia K, Maderwald S, Putzki N, Schlamann M, Theysohn JM, Kraff O, Ladd ME, Forsting M, Wanke I. First clinical study on ultra-high-field MR imaging in patients with multiple sclerosis: comparison of 1.5T and 7T. AJNR Am J Neuroradiol. 2009 Apr;30(4):699-702. doi: 10.3174/ajnr.A1434. Epub 2009 Jan 15.
• Background Pitt D, Boster A, Pei W, Wohleb E, Jasne A, Zachariah CR, Rammohan K, Knopp MV, Schmalbrock P. Imaging cortical lesions in multiple sclerosis with ultra-high-field magnetic resonance imaging. Arch Neurol. 2010 Jul;67(7):812-8. doi: 10.1001/archneurol.2010.148.
• Background Kister I, Bacon TE, Chamot E, Salter AR, Cutter GR, Kalina JT, Herbert J. Natural history of multiple sclerosis symptoms. Int J MS Care. 2013 Fall;15(3):146-58. doi: 10.7224/1537-2073.2012-053.
• Background Salter A, Thomas N, Tyry T, Cutter G, Marrie RA. Employment and absenteeism in working-age persons with multiple sclerosis. J Med Econ. 2017 May;20(5):493-502. doi: 10.1080/13696998.2016.1277229. Epub 2017 Jan 25.
• Background Correale J, Gaitan MI, Ysrraelit MC, Fiol MP. Progressive multiple sclerosis: from pathogenic mechanisms to treatment. Brain. 2017 Mar 1;140(3):527-546. doi: 10.1093/brain/aww258.
• 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 Jack D, Nolting A, Galazka A. Favorable outcomes after COVID-19 infection in multiple sclerosis patients treated with cladribine tablets. Mult Scler Relat Disord. 2020 Nov;46:102469. doi: 10.1016/j.msard.2020.102469. Epub 2020 Aug 27. No abstract available.

Drugs

Indications