Long-Term Effectiveness, Safety and Tolerability of Fingolimod in Patients with Multiple Sclerosis in Real-World Treatment Settings in France: The VIRGILE Study
Tóm tắt
It is important to confirm the effectiveness and tolerability of disease-modifying treatments for relapsing–remitting multiple sclerosis (RRMS) in real-world treatment settings. This prospective observational cohort study (VIRGILE) was performed at the request of the French health authorities. The primary objective was to evaluate the effectiveness of fingolimod 0.5 mg in reducing the annualised relapse rate (ARR) in patients with RRMS. Participating neurologists enrolled all adult patients with RRMS starting fingolimod treatment between 2014 and 2016, who were followed for 3 years. Follow-up consultations took place at the investigator’s discretion. The primary outcome measure was the change in ARR at month 24 after fingolimod initiation. Relapses and adverse events were documented at each consultation; disability assessment (EDSS) and magnetic resonance imagery were performed at the investigator’s discretion. Of 1055 eligible patients, 633 patients were assessable at month 36; 405 (64.0%) were treated continuously with fingolimod for 3 years. The ARR decreased from 0.92 ± 0.92 at inclusion to 0.31 ± 0.51 at month 24, a significant reduction of 0.58 [95% CI − 0.51 to − 0.65] relapses/year (p < 0.001). Since starting fingolimod, 461 patients (60.9%) remained relapse-free at month 24 and 366 patients (55.5%) at month 36. In multivariate analysis, no previous disease-modifying treatment, number of relapses in the previous year and lower EDSS score at inclusion were associated with a greater on-treatment reduction in ARR. The mean EDSS score remained stable over the course of the study. Sixty-one out of 289 (21.1%) patients presented new radiological signs of disease activity. Treatment-related serious adverse events were lymphopenia (N = 21), bradycardia (N = 19), elevated transaminases (N = 9) and macular oedema (N = 9). The effectiveness and tolerability of fingolimod in everyday clinical practice are consistent with findings of previous phase III studies. Our study highlights the utility of fingolimod for the long-term management of patients with multiple sclerosis.
Tài liệu tham khảo
Mehling M, Kappos L, Derfuss T. Fingolimod for multiple sclerosis: mechanism of action, clinical outcomes, and future directions. Curr Neurol Neurosci Rep. 2011;11(5):492–7.
Thomas K, Proschmann U, Ziemssen T. Fingolimod hydrochloride for the treatment of relapsing remitting multiple sclerosis. Expert Opin Pharmacother. 2017;18(15):1649–60.
Bordet R, Camu W, De Seze J, Laplaud DA, Ouallet JC, Thouvenot E. Mechanism of action of s1p receptor modulators in multiple sclerosis: the double requirement. Rev Neurol (Paris). 2020;176:100–12.
Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387–401.
Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402–15.
Miller AE. Switching or discontinuing disease-modifying therapies for multiple sclerosis. Continuum (Minneap Minn). 2016;22(3):851–63.
Hansen K, Schussel K, Kieble M, et al. Adherence to disease modifying drugs among patients with multiple sclerosis in Germany: a retrospective cohort study. PLoS ONE. 2015;10(7): e0133279.
Lebrun-Frenay C, Moulignier A, Pierrot-Deseilligny C, et al. Five-year outcome in the copaxone observatory: a nationwide cohort of patients with multiple sclerosis starting treatment with glatiramer acetate in France. J Neurol. 2019;266(4):888–901.
Druart C, El Sankari S, van Pesch V. Long-term safety and real-world effectiveness of fingolimod in relapsing multiple sclerosis. Patient Relat Outcome Meas. 2018;9:1–10.
Frisell T, Forsberg L, Nordin N, et al. Comparative analysis of first-year fingolimod and natalizumab drug discontinuation among Swedish patients with multiple sclerosis. Mult Scler. 2016;22(1):85–93.
Lapierre Y, O’Connor P, Devonshire V, et al. Canadian experience with fingolimod: adherence to treatment and monitoring. Can J Neurol Sci. 2016;43(2):278–83.
Bergvall N, Lahoz R, Reynolds T, Korn JR. Healthcare resource use and relapses with fingolimod versus natalizumab for treating multiple sclerosis: a retrospective US claims database analysis. Curr Med Res Opin. 2014;30(8):1461–71.
Bergvall N, Petrilla AA, Karkare SU, et al. Persistence with and adherence to fingolimod compared with other disease-modifying therapies for the treatment of multiple sclerosis: a retrospective US claims database analysis. J Med Econ. 2014;17(10):696–707.
Achiron A, Aref H, Inshasi J, et al. Effectiveness, safety and health-related quality of life of multiple sclerosis patients treated with fingolimod: results from a 12-month, real-world, observational PERFORMS study in the Middle East. BMC Neurol. 2017;17(1):150.
Izquierdo G, Damas F, Paramo MD, Ruiz-Pena JL, Navarro G. The real-world effectiveness and safety of fingolimod in relapsing-remitting multiple sclerosis patients: an observational study. PLoS ONE. 2017;12(4): e0176174.
Guger M, Enzinger C, Leutmezer F, et al. Real-life clinical use of natalizumab and fingolimod in Austria. Acta Neurol Scand. 2018;137(2):181–7.
Ziemssen T, Lang M, Tackenberg B, et al. Real-world persistence and benefit-risk profile of fingolimod over 36 months in Germany. Neurol Neuroimmunol Neuroinflamm. 2019;6(3): e548.
Papeix C, Vukusic S, Casey R, et al. Risk of relapse after natalizumab withdrawal: results from the French TYSEDMUS cohort. Neurol Neuroimmunol Neuroinflamm. 2016;3(6): e297.
Passante N. for the TYSEDMUS STudy Group: TYSEDMUS: suivi observationnel prospectif des patients atteints de sclérose en plaques et traités par TYSABRI® (natalizumab) dans les bases des données EDMUS en France: données finales à cinq ans. Rev Neurol (Paris). 2013;169(Suppl 2):A227.
Haute Autorité de Santé: Guide Méthologique. Études en vie réelle pour l’évaluation des médicaments et dispositifs médicaux. 2011. Available from: Haute Autorité de santé – Service communication et information, 5 avenue du Stade de France, 93218 Saint-Denis, France.
European Medicines Agency. Gilenya 0.25 mg hard capsules; Gilenya 0.5mg hard capsules. Summary of product characteristics. 2011. https://www.ema.europa.eu/en/documents/product-information/gilenya-epar-product-information_en.pdf.
Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292–302.
Confavreux C, Compston DA, Hommes OR, McDonald WI, Thompson AJ. EDMUS, a European database for multiple sclerosis. J Neurol Neurosurg Psychiatry. 1992;55(8):671–6.
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33(11):1444–52.
Simeoni M, Auquier P, Fernandez O, et al. Validation of the Multiple Sclerosis International Quality of Life questionnaire. Mult Scler. 2008;14(2):219–30.
Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann Med. 2001;33(5):337–43.
Moreau T, Bungener C, Heinzlef O, et al. Anxiety and coping strategy changes in multiple sclerosis patients initiating Fingolimod: The GRACE Prospective Study. Eur Neurol. 2017;77(1–2):47–55.
Defer G, de Seze J, Bouee S, et al. Outcomes and treatment management of a French cohort suffering from multiple sclerosis: a retrospective epidemiological study. Mult Scler Relat Disord. 2018;25:276–81.
Vollmer B, Ontaneda D, Harris H, et al. Comparative discontinuation, effectiveness, and switching practices of dimethyl fumarate and fingolimod at 36-month follow-up. J Neurol Sci. 2019;407: 116498.
Ferrè L, Mogavero A, Clarelli F, et al. Early evidence of disease activity during fingolimod predicts medium-term inefficacy in relapsing-remitting multiple sclerosis. Mult Scler. 2021;27(9):1374–83.
Quirant-Sánchez B, Hervás-García JV, Teniente-Serra A, et al. Predicting therapeutic response to fingolimod treatment in multiple sclerosis patients. CNS Neurosci Ther. 2018;24(12):1175–84.
Teniente-Serra A, Hervás JV, Quirant-Sánchez B, et al. Baseline differences in minor lymphocyte subpopulations may predict response to fingolimod in relapsing-remitting multiple sclerosis patients. CNS Neurosci Ther. 2016;22(7):584–92.
Pozzilli C, Prosperini L. Clinical markers of therapeutic response to disease modifying drugs. Neurol Sci. 2008;29(Suppl 2):S211-213.
Rio J, Nos C, Tintoré M, et al. Defining the response to interferon-beta in relapsing-remitting multiple sclerosis patients. Ann Neurol. 2006;59(2):344–52.
Rio J, Rovira A, Tintore M, et al. Evaluating the response to glatiramer acetate in relapsing-remitting multiple sclerosis (RRMS) patients. Mult Scler. 2014;20(12):1602–8.
Fernández O, Baumstarck-Barrau K, Simeoni MC, Auquier P. Patient characteristics and determinants of quality of life in an international population with multiple sclerosis: assessment using the MusiQoL and SF-36 questionnaires. Mult Scler. 2011;17(10):1238–49.
Fox E, Edwards K, Burch G, et al. Outcomes of switching directly to oral fingolimod from injectable therapies: results of the randomized, open-label, multicenter, Evaluate Patient OutComes (EPOC) study in relapsing multiple sclerosis. Mult Scler Relat Disord. 2014;3(5):607–19.
Planche V, Moisset X, Morello R, et al. Improvement of quality of life and its relationship with neuropsychiatric outcomes in patients with multiple sclerosis starting treatment with natalizumab: a 3-year follow-up multicentric study. J Neurol Sci. 2017;382:148–54.
Kobelt G, Texier-Richard B, Lindgren P. The long-term cost of multiple sclerosis in France and potential changes with disease-modifying interventions. Mult Scler. 2009;15(6):741–51.
Chevalier J, Chamoux C, Hammès F, Chicoye A. Cost-effectiveness of treatments for relapsing remitting multiple sclerosis: a French societal perspective. PLoS ONE. 2016;11(3): e0150703.
Haute Autorité de Santé: Guide Méthologique. Études en vie réelle pour l’évaluation des médicaments et dispositifs médicaux. 2021. https://www.has-sante.fr/upload/docs/application/pdf/2021-06/guide_etude_en_vie_reelle_medicaments__dm.pdf. Accessed Feb 2022.