Confirmed 6-Month Disability Improvement and Worsening Correlate with Long-term Disability Outcomes in Alemtuzumab-Treated Patients with Multiple Sclerosis: Post Hoc Analysis of the CARE-MS Studies.
Alemtuzumab
Confirmed disability improvement
Confirmed disability worsening
Disease-modifying therapy
Expanded Disability Status Scale
Functional systems
Multiple sclerosis
Journal
Neurology and therapy
ISSN: 2193-8253
Titre abrégé: Neurol Ther
Pays: New Zealand
ID NLM: 101637818
Informations de publication
Date de publication:
Dec 2021
Dec 2021
Historique:
received:
01
04
2021
accepted:
03
06
2021
pubmed:
25
6
2021
medline:
25
6
2021
entrez:
24
6
2021
Statut:
ppublish
Résumé
In the 2-year CARE-MS trials (NCT00530348; NCT00548405) in patients with relapsing-remitting multiple sclerosis, alemtuzumab showed superior efficacy versus subcutaneous interferon beta-1a. Efficacy was maintained in two consecutive extensions (NCT00930553; NCT02255656). This post hoc analysis compared disability outcomes over 9 years among alemtuzumab-treated patients according to whether they experienced confirmed disability improvement (CDI) or worsening (CDW) or neither CDI nor CDW. CARE-MS patients were randomized to receive two alemtuzumab courses (12 mg/day; 5 days at baseline; 3 days at 12 months), with additional as-needed 3-day courses in the extensions. CDI or CDW were defined as ≥ 1.0-point decrease or increase, respectively, in Expanded Disability Status Scale (EDSS) score from core study baseline confirmed over 6 months, assessed in patients with baseline EDSS score ≥ 2.0. Improved or stable EDSS scores were defined as ≥ 1-point decrease or ≤ 0.5-point change (either direction), respectively, from core study baseline. Functional systems (FS) scores were also assessed. Of 511 eligible patients, 43% experienced CDI and 34% experienced CDW at any time through year 9 (patients experiencing both CDI and CDW were counted in each individual group); 29% experienced neither CDI nor CDW. At year 9, patients with CDI had a -0.58-point mean EDSS score change from baseline; 88% had stable or improved EDSS scores. Improvements occurred across all FS, primarily in sensory, pyramidal, and cerebellar domains. Patients with CDW had a +1.71-point mean EDSS score change; 16% had stable or improved EDSS scores. Patients with neither CDI nor CDW had a -0.10-point mean EDSS score change; 98% had stable or improved EDSS scores. CDI achievement at any point during the CARE-MS studies was associated with improved disability at year 9, highlighting the potential of alemtuzumab to change the multiple sclerosis course. Conversely, CDW at any point was associated with worsened disability at year 9.
Identifiants
pubmed: 34165694
doi: 10.1007/s40120-021-00262-3
pii: 10.1007/s40120-021-00262-3
pmc: PMC8571457
doi:
Types de publication
Journal Article
Langues
eng
Pagination
803-818Informations de copyright
© 2021. The Author(s).
Références
Conradsson D, Ytterberg C, von Koch L, Johansson S. Changes in disability in people with multiple sclerosis: a 10-year prospective study. J Neurol. 2018;265(1):119–26.
doi: 10.1007/s00415-017-8676-8
Sutliff MH. Contribution of impaired mobility to patient burden in multiple sclerosis. Curr Med Res Opin. 2010;26(1):109–19.
doi: 10.1185/03007990903433528
Chalmer TA, Baggesen LM, Norgaard M, et al. Early versus later treatment start in multiple sclerosis: a register-based cohort study. Eur J Neurol. 2018;25(10):1262-e110.
doi: 10.1111/ene.13692
Stankiewicz JM, Weiner HL. An argument for broad use of high efficacy treatments in early multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2020;7(1):e636.
doi: 10.1212/NXI.0000000000000636
Harding K, Williams O, Willis M, et al. Clinical outcomes of escalation vs early intensive disease-modifying therapy in patients with multiple sclerosis. JAMA Neurol. 2019;76(5):536–41.
doi: 10.1001/jamaneurol.2018.4905
Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012;380(9856):1819–28.
doi: 10.1016/S0140-6736(12)61769-3
Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012;380(9856):1829–39.
doi: 10.1016/S0140-6736(12)61768-1
Giovannoni G, Cohen JA, Coles AJ, et al. Alemtuzumab improves preexisting disability in active relapsing-remitting MS patients. Neurology. 2016;87(19):1985–92.
doi: 10.1212/WNL.0000000000003319
Havrdova E, Arnold DL, Cohen JA, et al. Alemtuzumab CARE-MS I 5-year follow-up: durable efficacy in the absence of continuous MS therapy. Neurology. 2017;89(11):1107–16.
doi: 10.1212/WNL.0000000000004313
Coles AJ, Cohen JA, Fox EJ, et al. Alemtuzumab CARE-MS II 5-year follow-up: efficacy and safety findings. Neurology. 2017;89(11):1117–26.
doi: 10.1212/WNL.0000000000004354
Comi G, Alroughani R, Bass AD, et al. Alemtuzumab maintains efficacy on clinical and MRI disease activity outcomes, including slowing of brain volume loss, over 9 years in RRMS patients: CARE-MS II follow-up (TOPAZ study). Presented at: 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Stockholm, Sweden, September 11–13 2019.
Montalban X, Arnold DL, Boyko AN, et al. Alemtuzumab maintains efficacy on clinical and MRI disease activity outcomes, including slowing of brain volume loss, over 9 years in RRMS patients: CARE-MS I follow-up (TOPAZ study). Presented at: 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Stockholm, Sweden, September 11–13 2019.
Ziemssen T, Bass AD, Berkovich R, et al. Efficacy and safety of alemtuzumab through 9 years of follow-up in patients with highly active disease: post hoc analysis of CARE-MS I and II patients in the TOPAZ extension study. CNS Drugs. 2020;34(9):973–88.
doi: 10.1007/s40263-020-00749-x
Bielekova B, Tintore M. Sustained reduction of MS disability: new player in comparing disease-modifying treatments. Neurology. 2016;87(19):1966–7.
doi: 10.1212/WNL.0000000000003314
Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1995;45(7):1268–76.
doi: 10.1212/WNL.45.7.1268
Phillips JT, Giovannoni G, Lublin FD, et al. Sustained improvement in Expanded Disability Status Scale as a new efficacy measure of neurological change in multiple sclerosis: treatment effects with natalizumab in patients with relapsing multiple sclerosis. Mult Scler. 2011;17(8):970–9.
doi: 10.1177/1352458511399611
Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017;376(3):221–34.
doi: 10.1056/NEJMoa1601277
Le Page E, Leray E, Taurin G, et al. Mitoxantrone as induction treatment in aggressive relapsing remitting multiple sclerosis: treatment response factors in a 5 year follow-up observational study of 100 consecutive patients. J Neurol Neurosurg Psychiatry. 2008;79(1):52–6.
doi: 10.1136/jnnp.2007.124958
Alsop JC, Bergvall N, Cornelissen C, Vormfelde SV, Medin J, Ziemssen T. Confirmed disability improvement in patients with active multiple sclerosis treated with fingolimod versus brace: a matched comparison of treatments from the PANGAEA and PEARL registry studies. Value Health. 2015;18:A750.
doi: 10.1016/j.jval.2015.09.2900
Kurtzke JF. Patterns of neurologic involvement in multiple sclerosis. Neurology. 1989;39(9):1235–8.
doi: 10.1212/WNL.39.9.1235
Gandek B, Sinclair SJ, Kosinski M, Ware JE Jr. Psychometric evaluation of the SF-36 health survey in Medicare managed care. Health Care Financ Rev. 2004;25(4):5–25.
pubmed: 15493441
pmcid: 4194895
Ware J Jr, Kosinski M, Bjorner J, Turner-Bowker D, Gandek B, Maruish M. User’s manual for the 36v2
Arroyo R, Bury DP, Guo JD, et al. Impact of alemtuzumab on health-related quality of life over 6 years in CARE-MS II trial extension patients with relapsing-remitting multiple sclerosis. Mult Scler. 2020;26(8):955–63.
doi: 10.1177/1352458519849796
EuroQoL Research Foundation. EQ-5D-3L user guide. 2018. https://euroqol.org/publications/user-guides . Accessed Aug 25, 2020.
Cella DF, Dineen K, Arnason B, et al. Validation of the functional assessment of multiple sclerosis quality of life instrument. Neurology. 1996;47(1):129–39.
doi: 10.1212/WNL.47.1.129
Kalincik T, Cutter G, Spelman T, et al. Defining reliable disability outcomes in multiple sclerosis. Brain. 2015;138(Pt 11):3287–98.
doi: 10.1093/brain/awv258
Leray E, Yaouanq J, Le Page E, et al. Evidence for a two-stage disability progression in multiple sclerosis. Brain. 2010;133(Pt 7):1900–13.
doi: 10.1093/brain/awq076
Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl J Med. 2000;343(20):1430–8.
doi: 10.1056/NEJM200011163432001
Scott TF, Hackett CT, Quigley MR, Schramke CJ. Relapsing multiple sclerosis patients treated with disease modifying therapy exhibit highly variable disease progression: a predictive model. Clin Neurol Neurosurg. 2014;127:86–92.
doi: 10.1016/j.clineuro.2014.09.008
Paz Soldan MM, Novotna M, Abou Zeid N, et al. Relapses and disability accumulation in progressive multiple sclerosis. Neurology. 2015;84(1):81–8.
doi: 10.1212/WNL.0000000000001094
Lizak N, Lugaresi A, Alroughani R, et al. Highly active immunomodulatory therapy ameliorates accumulation of disability in moderately advanced and advanced multiple sclerosis. J Neurol Neurosurg Psychiatry. 2017;88(3):196–203.
doi: 10.1136/jnnp-2016-313976
Goldman MD, Motl RW, Rudick RA. Possible clinical outcome measures for clinical trials in patients with multiple sclerosis. Ther Adv Neurol Disord. 2010;3(4):229–39.
doi: 10.1177/1756285610374117
Frischer JM, Bramow S, Dal-Bianco A, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009;132(Pt 5):1175–89.
doi: 10.1093/brain/awp070
Coles AJ, Arnold DL, Bass AD, et al. Efficacy and safety of alemtuzumab over 6 years: final results of the 4-year CARE-MS extension trial. Ther Adv Neurol Disord. 2020. https://doi.org/10.1177/1756286420982134 .
doi: 10.1177/1756286420982134
Jones J, Anderson J, Phuah C, et al. Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity. Brain. 2010;133(8):2232–47.
doi: 10.1093/brain/awq176
Scott TF, You X, Foulds P. Functional system scores provide a window into disease activity occurring during a multiple sclerosis treatment trial. Neurol Res. 2011;33(5):549–52.
doi: 10.1179/1743132810Y.0000000017
Scott T, Wang P, You X, Mann M, Sperling B. Relationship between sustained disability progression and functional system scores in relapsing-remitting multiple sclerosis: analysis of placebo data from four randomized clinical trials. Neuroepidemiology. 2015;44(1):16–23.
doi: 10.1159/000369621
Fox EJ, Wynn D, Coles AJ, Palmer J, Margolin DH, CAMMS Investigators. Alemtuzumab improves neurological functional systems in treatment-naive relapsing-remitting multiple sclerosis patients. J Neurol Sci. 2016;363:188–94.
doi: 10.1016/j.jns.2016.02.025
Hauser SL, Bar-Or A, Cohen JA, et al. Ofatumumab versus teriflunomide in multiple sclerosis. N Engl J Med. 2020;383(6):546–57.
doi: 10.1056/NEJMoa1917246
Signori A, Boffa G, Bovis F, et al. Prevalence of disability improvement as a potential outcome for multiple sclerosis trials. Mult Scler. 2020. https://doi.org/10.1177/1352458520936236 (Online ahead of print).
doi: 10.1177/1352458520936236
pubmed: 32589486
Wiendl H, Spelman T, Butzkueven H, et al. Real-world disability improvement in patients with relapsing-remitting multiple sclerosis treated with natalizumab in the Tysabri Observational Program. Mult Scler. 2020. https://doi.org/10.1177/1352458520926869 .
doi: 10.1177/1352458520926869
pubmed: 33150829
pmcid: 8414828