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Multiple sclerosis
Research paper
Comparison of fingolimod, dimethyl fumarate and teriflunomide for multiple sclerosis
  1. Tomas Kalincik1,2,
  2. Eva Kubala Havrdova3,
  3. Dana Horakova3,
  4. Guillermo Izquierdo4,
  5. Alexandre Prat5,6,
  6. Marc Girard5,6,
  7. Pierre Duquette5,6,
  8. Pierre Grammond7,
  9. Marco Onofrj8,
  10. Alessandra Lugaresi9,10,
  11. Serkan Ozakbas11,
  12. Ludwig Kappos12,
  13. Jens Kuhle12,
  14. Murat Terzi13,
  15. Jeannette Lechner-Scott14,15,
  16. Cavit Boz16,
  17. Francois Grand'Maison17,
  18. Julie Prevost18,
  19. Patrizia Sola19,
  20. Diana Ferraro19,
  21. Franco Granella20,21,
  22. Maria Trojano22,
  23. Roberto Bergamaschi23,
  24. Eugenio Pucci24,
  25. Recai Turkoglu25,
  26. Pamela A McCombe26,
  27. Vincent Van Pesch27,
  28. Bart Van Wijmeersch28,
  29. Claudio Solaro29,
  30. Cristina Ramo-Tello30,
  31. Mark Slee31,
  32. Raed Alroughani32,
  33. Bassem Yamout33,
  34. Vahid Shaygannejad34,
  35. Daniele Spitaleri35,
  36. José Luis Sánchez-Menoyo36,
  37. Radek Ampapa37,
  38. Suzanne Hodgkinson38,
  39. Rana Karabudak39,
  40. Ernest Butler40,
  41. Steve Vucic41,
  42. Vilija Jokubaitis42,
  43. Tim Spelman42,
  44. Helmut Butzkueven42,43,44
  1. 1 CORe, Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
  2. 2 Department of Neurology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
  3. 3 Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague, Czech Republic
  4. 4 Hospital Universitario Virgen Macarena, Sevilla, Spain
  5. 5 Montreal, Quebec, Hopital Notre-Dame, Canada
  6. 6 CHUM and Universite de Montreal, Montreal, Quebec, Canada
  7. 7 CISSS de Chaudière-Appalaches, Levis, Quebec, Canada
  8. 8 Department of Neuroscience, Imaging, and Clinical Sciences, University G d’Annunzio, Chieti, Italy
  9. 9 Bologna, IRCCS Istituto delle Scienze Neurologiche di Bologna, Italy
  10. 10 Department of Biomedical and Neuromotor Science, University of Bologna, Bologna, Italy
  11. 11 Dokuz Eylul University, Izmir, Turkey
  12. 12 Neurologic Clinic and Policlinic, Departments of Medicine and Clinical Research, University Hospital and University of Basel, Basel, Switzerland
  13. 13 Medical Faculty, 19 Mayis University, Samsun, Turkey
  14. 14 School of Medicine and Public Health, University Newcastle, Newcastle, New South Wales, Australia
  15. 15 Department of Neurology, John Hunter Hospital, Hunter New England Health, Newcastle, New South Wales, Australia
  16. 16 KTU Medical Faculty Farabi Hospital, Trabzon, Turkey
  17. 17 Neuro Rive-Sud, Quebec City, Quebec, Canada
  18. 18 CSSS Saint-Jérôme, Saint-Jerome, Quebec, Canada
  19. 19 Department of Neuroscience, Azienda Ospedaliera Universitaria, Modena, Italy
  20. 20 Department of Medicine and Surgery, University of Parma, Parma, Italy
  21. 21 Department of Emergency and General Medicine, Parma University Hospital, Parma, Italy
  22. 22 Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy
  23. 23 IRCCS Mondino Foundation, Pavia, Italy
  24. 24 UOC Neurologia, Azienda Sanitaria Unica Regionale Marche–AV3, Macerata, Italy
  25. 25 Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey
  26. 26 Royal Brisbane and Women's Hospital, University of Queensland, Brisbane, Queensland, Australia
  27. 27 Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
  28. 28 Rehabilitation and MS-Centre Overpelt and Hasselt University, Hasselt, Belgium
  29. 29 Department of Neurology, ASL3 Genovese, and Department of Rehabilitation, ML Novarese Hospital Moncrivello, Genova, Italy
  30. 30 Hospital Germans Trias i Pujol, Badalona, Spain
  31. 31 Flinders University, Adelaide, South Australia, Australia
  32. 32 Division of Neurology, Department of Medicine, Amiri Hospital, Sharq, Kuwait
  33. 33 Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center, Beirut, Lebanon
  34. 34 Isfahan University of Medical Sciences, Isfahan, Iran
  35. 35 Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino, Avellino, Italy
  36. 36 Hospital de Galdakao-Usansolo, Galdakao, Spain
  37. 37 Nemocnice Jihlava, Jihlava, Czech Republic
  38. 38 Liverpool Hospital, Liverpool, New South Wales, Australia
  39. 39 Hacettepe University, Ankara, Turkey
  40. 40 Monash Medical Centre, Melbourne, Victoria, Australia
  41. 41 Westmead Hospital, Sydney, New South Wales, Australia
  42. 42 Central Clinical School, Monash University, Melbourne, Victoria, Australia
  43. 43 Department of Neurology, The Alfred Hospital, Melbourne, Victoria, Australia
  44. 44 Department of Neurology, Box Hill Hospital, Monash University, Melbourne, Victoria, Australia
  1. Correspondence to A/Prof Tomas Kalincik, CORe, Department of Medicine, University of Melbourne, Melbourne, VIC 3050, Australia; tomas.kalincik{at}unimelb.edu.au

Abstract

Objective Oral immunotherapies have become a standard treatment in relapsing-remitting multiple sclerosis. Direct comparison of their effect on relapse and disability is needed.

Methods We identified all patients with relapsing-remitting multiple sclerosis treated with teriflunomide, dimethyl fumarate or fingolimod, with minimum 3-month treatment persistence and disability follow-up in the global MSBase cohort study. Patients were matched using propensity scores. Three pairwise analyses compared annualised relapse rates and hazards of disability accumulation, disability improvement and treatment discontinuation (analysed with negative binomial models and weighted conditional survival models, with pairwise censoring).

Results The eligible cohorts consisted of 614 (teriflunomide), 782 (dimethyl fumarate) or 2332 (fingolimod) patients, followed over the median of 2.5 years. Annualised relapse rates were lower on fingolimod compared with teriflunomide (0.18 vs 0.24; p=0.05) and dimethyl fumarate (0.20 vs 0.26; p=0.01) and similar on dimethyl fumarate and teriflunomide (0.19 vs 0.22; p=0.55). No differences in disability accumulation (p≥0.59) or improvement (p≥0.14) were found between the therapies. In patients with ≥3-month treatment persistence, subsequent discontinuations were less likely on fingolimod than teriflunomide and dimethyl fumarate (p<0.001). Discontinuation rates on teriflunomide and dimethyl fumarate were similar (p=0.68).

Conclusion The effect of fingolimod on relapse frequency was superior to teriflunomide and dimethyl fumarate. The effect of the three oral therapies on disability outcomes was similar during the initial 2.5 years on treatment. Persistence on fingolimod was superior to the two comparator drugs.

https://doi.org/10.1136/jnnp-2018-319831

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    Footnotes

    • Correction notice This article has been corrected since it was published Online First. Under heading Fingolimod versus teriflunomide: "(HR 0.77, 95% CI 0.63 to 0.95, p=0.03; figure 3C)" should read "(HR 0.77, 95% CI 0.63 to 0.95, p=0.015; figure 3C)". Under heading Fingolimod versus dimethyl fumarate: "The analysis of MRI values missing not and random" should read "The analysis of MRI values missing not at random". Figure 3C should show "fingolimod" instead of "fingolimode". Figure 3D should show "fingolimod" instead of "DMF". Under heading Persistence: "Lack of efficacy as a reason for discontinuation was reported similarly in both treatments (5% fingolimod vs 5% teriflunomide), with adverse events being less commonly reported in fingolimod (7% vs 13%…" should read: "Adverse events as a reason for discontinuation were reported similarly in both treatments (5% fingolimod vs 5% teriflunomide), with lack of efficacy being less commonly reported in fingolimod (7% vs 13%…".

    • Contributors Conception and design of the study: TK, TS, HB. Acquisition and analysis of data: TK, EKH, DH, GI, AP, MG, PD, PG, MO, AL, SO, LK, JK, MT, JLS, CB, FGM, JP, PS, DF, FG, MT, RB, EP, RT, PAMC, VVP, BVW, CS, CRT, MS, RA, BY, VS, DLS, JLSM, RA, SH, RK, EB, SV, VJ, TS, HB. Drafting a significant portion of the manuscript or figures: TK.

    • Funding This study was financially supported by the National Health and Medical Research Council of Australia (1129189, 1140766, 1080518). The MSBase Foundation is a not-for-profit organisation that receives support from Roche, Merck, Biogen, Novartis, Bayer Schering, Sanofi Genzyme and Teva. The study was conducted separately and apart from the guidance of the sponsors.

    • Competing interests TK served on scientific advisory boards for Roche, Genzyme-Sanofi, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Novartis, Biogen, Genzyme-Sanofi, Teva, BioCSL and Merck and received research support from Biogen. EKH received speaker honoraria and consultant fees from Actelion, Biogen, Celgene, Merck, Novartis, Roche, Sanofi and Teva, and support for research activities from Czech Ministry of Education (project PROGRES Q27/LF1). DH received speaker honoraria and consulting fees from Biogen, Merck, Teva, Roche, Sanofi Genzyme and Novartis, as well as support for research activities from Biogen and Czech Ministry of Education (project PROGRES Q27/LF1). GI received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Roche, Almirall and Teva. MG received consulting fees from Teva Canada Innovation, Biogen, Novartis and Genzyme Sanofi; lecture payments from Teva Canada Innovation, Novartis and EMD. He has also received a research grant from Canadian Institutes of Health Research. PD served on editorial boards and has been supported to attend meetings by EMD, Biogen, Novartis, Genzyme and TEVA Neuroscience. He holds grants from the CIHR and the MS Society of Canada and has received funding for investigator-initiated trials from Biogen, Novartis and Genzyme. PG is a Merck, Novartis, Teva-Neuroscience, Biogen and Genzyme advisory board member, consultant for Merck, received payments for lectures by Merck, Teva-Neuroscience and Canadian Multiple Sclerosis Society, and received grants for travel from Teva-Neuroscience and Novartis. AL served as a Bayer, Biogen, Merck, Novartis, Roche, Sanofi/Genzyme and Teva Advisory Board Member. She received congress and travel/accommodation expense compensations and speaker honoraria from Bayer, Biogen, Merck, Novartis, Sanofi/Genzyme, Teva and Fondazione Italiana Sclerosi Multipla (FISM). Her institutions received research grants from Novartis. LK received research support from Acorda, Actelion, Allozyne, BaroFold, Bayer Health Care, Bayer Schering, Bayhill Therapeutics, Biogen, Elan, European Union, Genmab, Gianni Rubatto Foundation, GlaxoSmithKline, Glenmark, MediciNova, Merck, Novartis, Novartis Research Foundation, Roche, Roche Research Foundation, Sanofi-Aventis, Santhera, Swiss MS Society, Swiss National Research Foundation, Teva Neuroscience, UCB and Wyeth. JK received consulting fees from Novartis, Protagen; speaker fees from the Swiss MS Society, Biogen, Novartis, Roche, Genzyme; travel expenses from Merck Serono, Novartis; grants from ECTRIMS Research Fellowship Programme, University of Basel, Swiss MS Society, Swiss National Research Foundation, Bayer (Schweiz), Genzyme and Novartis. MT received travel grants from Novartis, Bayer Schering, Merck and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. JLS accepted travel compensation from Novartis, Biogen and Merck. Her institution receives the honoraria for talks and advisory board commitment from Bayer Health Care, Biogen, Genzyme Sanofi, Merck, Novartis and Teva; has been involved in clinical trials with Biogen, Novartis and Teva. CB received conference travel support from Biogen, Novartis, Bayer Schering, Merck and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. FGM received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, Mitsubishi and ONO Pharmaceuticals. JP accepted travel compensation from Novartis, Biogen, Genzyme and Teva and speaking honoraria from Biogen, Novartis, Genzyme and Teva. PS served on scientific advisory boards for Biogen Idec and TEVA; she has received funding for travel and speaker honoraria from Biogen Idec, Merck, Teva, Sanofi Genzyme, Novartis and Bayer and research grants for her institution from Bayer, Biogen, Merck, Novartis, Sanofi and Teva. DF received travel grants and/or speaker honoraria from Merck, TEVA, Novartis, Biogen and Sanofi Genzyme. FG received an institutional research grant from Biogen and Sanofi Genzyme; served on scientific advisory boards for Biogen, Novartis, Merck, Sanofi Genzyme and Roche; received funding for travel and speaker honoraria from Biogen, Merck and Sanofi-Aventis. MT received speaker honoraria from Biogen-Idec, Bayer Schering, Sanofi Aventis, Merck, Teva, Novartis and Almirall; has received research grants for her Institution from Biogen-Idec, Merck and Novartis. RB received speaker honoraria from Bayer Schering, Biogen, Genzyme, Merck, Novartis, Sanofi-Aventis and Teva; research grants from Bayer Schering, Biogen, Merck, Novartis, Sanofi-Aventis and Teva; congress and travel/accommodation expense compensations by Almirall, Bayer Schering, Biogen, Genzyme, Merck, Novartis, Sanofi-Aventis and Teva. EP served on scientific advisory boards for Merck, Genzyme and Biogen; he has received honoraria and travel grants from Sanofi Aventis, Novartis, Biogen, Merck, Genzyme and Teva; he has received travel grants and equipment from 'Associazione Marchigiana Sclerosi Multipla e altre malattie neurologiche'. VVP received travel grants from Biogen, Bayer Schering, Genzyme, Merck, Teva and Novartis Pharma. His institution receives honoraria for consultancy and lectures from Biogen, Bayer Schering, Genzyme, Merck, Roche, Teva and Novartis Pharma as well as research grants from Novartis Pharma and Bayer Schering. BVW received research and travel grants, honoraria for MS-Expert advisor and speaker fees from Bayer Schering, Biogen, Sanofi Genzyme, Merck, Novartis, Roche and Teva. CS served on scientific advisory boards for Merck, Genzyme, Almirall and Biogen; received honoraria and travel grants from Sanofi Aventis, Novartis, Biogen, Merck, Genzyme and Teva. CRT received research funding, compensation for travel or speaker honoraria from Biogen, Novartis, Genzyme and Almirall. MS has participated in, but not received honoraria for, advisory board activity for Biogen, Merck, Bayer Schering, Sanofi Aventis and Novartis. RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi Genzyme. DLS received honoraria as a consultant on scientific advisory boards by Bayer Schering, Novartis and Sanofi-Aventis and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva and Merck. JLSM accepted travel compensation from Novartis and Biogen, speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer and Teva and has participated in a clinical trial by Biogen. RA received conference travel support from Novartis, Teva, Biogen, Bayer and Merck and has participated in a clinical trial by Biogen, Novartis, Teva and Actelion. SH received honoraria and consulting fees from Merck, Novartis, Bayer Schering and Sanofi, and travel grants from Novartis, Biogen Idec and Bayer Schering. Ricardo Fernandez Bolaños received speaking honoraria from Biogen, Novartis, Merck and Teva. VJ received conference travel support from Teva, Novartis and Merck, and speaker honoraria from Biogen. TS received honoraria for consultancy, funding for travel and compensation for serving on scientific advisory boards from Biogen and speaker honoraria from Novartis. HB served on scientific advisory boards for Biogen, Novartis and Sanofi-Aventis and has received conference travel support from Novartis, Biogen and Sanofi Aventis. He serves on steering committees for trials conducted by Biogen and Novartis, and has received research support from Merck, Novartis and Biogen.

    • Patient consent for publication Not required.

    • Ethics approval Melbourne Health Human Research Ethics Committee

    • Provenance and peer review Not commissioned; externally peer reviewed.

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