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Comparing switch to ocrelizumab, cladribine or natalizumab after fingolimod treatment cessation in multiple sclerosis
  1. Chao Zhu1,
  2. Zhen Zhou2,
  3. Izanne Roos3,4,
  4. Daniel Merlo1,
  5. Tomas Kalincik3,4,
  6. Serkan Ozakbas,5,
  7. Olga Skibina1,6,
  8. Jens Kuhle7,
  9. Suzanne Hodgkinson8,
  10. Cavit Boz9,
  11. Raed Alroughani10,
  12. Jeannette Lechner-Scott11,12,
  13. Michael Barnett13,
  14. Guillermo Izquierdo14,
  15. Alexandre Prat15,
  16. Dana Horakova16,
  17. Eva Kubala Havrdova16,
  18. Richard Macdonell17,
  19. Francesco Patti18,19,
  20. Samia Joseph Khoury20,
  21. Mark Slee21,
  22. Rana Karabudak22,
  23. Marco Onofrj23,
  24. Vincent Van Pesch24,
  25. Julie Prevost25,
  26. Mastura Monif1,6,
  27. Vilija Jokubaitis1,6,
  28. Anneke van der Walt1,6,
  29. Helmut Butzkueven1,6
  30. on behalf of the MSBase Study Group
  1. 1 Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
  2. 2 Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
  3. 3 Clinical Outcomes Research Unit, Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
  4. 4 Department of Neurology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
  5. 5 Dokuz Eylul University, İzmir, Turkey
  6. 6 Department of Neurology, Alfred Hospital, Melbourne, Victoria, Australia
  7. 7 Neurologic Clinic and Policlinic, Departments of Medicine and Clinical Research, University Hospital and University of Basel, Basel, Switzerland
  8. 8 Departments of Nephrology and Neurology, Liverpool Hospital, Sydney, New South Wales, Australia
  9. 9 KTU Medical Faculty Farabi Hospital, Trabzon, Turkey
  10. 10 Division of Neurology, Amiri Hospital, Sharq, Kuwait
  11. 11 Department of Neurology, John Hunter Hospital, Newcastle, New South Wales, Australia
  12. 12 School of Medicine and Public Health, University Newcastle, Newcastle, New South Wales, Australia
  13. 13 Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia
  14. 14 Hospital Universitario Virgen Macarena, Sevilla, Spain
  15. 15 Hôpital Notre Dame, CHUM and Universite de Montreal, Montreal, Québec, Canada
  16. 16 Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague, Czech Republic
  17. 17 Austin Health, Melbourne, Victoria, Australia
  18. 18 Department of Medical and Surgical Sciences and Advanced Technologies, GF Ingrassia, Catania, Italy
  19. 19 Multiple Sclerosis Center, University of Catania, Catania, Italy
  20. 20 Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center, Beirut, Lebanon
  21. 21 Flinders University, Adelaide, South Australia, Australia
  22. 22 Department of Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
  23. 23 Department of Neuroscience, Imaging, and Clinical Sciences, University G. d'Annunzio, Chieti, Italy
  24. 24 Cliniques Universitaires Saint-Luc, Brussels, Belgium
  25. 25 Centre integre de sante et de services sociaux des Laurentides point de service de Saint-Jerome, Saint-Jerome, Quebec, Canada
  1. Correspondence to Dr Chao Zhu, Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia; Chao.Zhu{at}


Background To compare the effectiveness and treatment persistence of ocrelizumab, cladribine and natalizumab in patients with relapsing–remitting multiple sclerosis switching from fingolimod.

Methods Using data from MSBase registry, this multicentre cohort study included subjects who had used fingolimod for ≥6 months and then switched to ocrelizumab, cladribine or natalizumab within 3 months after fingolimod discontinuation. We analysed relapse and disability outcomes after balancing covariates using an inverse-probability-treatment-weighting method. Propensity scores for the three treatments were obtained using multinomial-logistic regression. Due to the smaller number of cladribine users, comparisons of disability outcomes were limited to natalizumab and ocrelizumab.

Results Overall, 1045 patients switched to ocrelizumab (n=445), cladribine (n=76) or natalizumab (n=524) after fingolimod. The annualised relapse rate (ARR) for ocrelizumab was 0.07, natalizumab 0.11 and cladribine 0.25. Compared with natalizumab, the ARR ratio (95% confidence interval [CI]) was 0.67 (0.47 to 0.96) for ocrelizumab and 2.31 (1.30 to 4.10) for cladribine; the hazard ratio (95% CI) for time to first relapse was 0.57 (0.40 to 0.83) for ocrelizumab and 1.18 (0.47 to 2.93) for cladribine. Ocrelizumab users had an 89% lower discontinuation rate (95% CI, 0.07 to 0.20) than natalizumab, but also a 51% lower probability of confirmed disability improvement (95% CI, 0.32 to 0.73). There was no difference in disability accumulation.

Conclusion After fingolimod cessation, ocrelizumab and natalizumab were more effective in reducing relapses than cladribine. Due to the low ARRs in all three treatment groups, additional observation time is required to determine if statistical difference in ARRs results in long-term disability differences.


Data availability statement

Data are available upon reasonable request. In principle, patient-level data sharing is possible. However, permission from each contributing data controller is required.

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Data availability statement

Data are available upon reasonable request. In principle, patient-level data sharing is possible. However, permission from each contributing data controller is required.

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  • Contributors Guarantor: CZ. Concept and design: CZ, AvdW and HB. Acquisition, analysis or interpretation of data: CZ, ZZ, AvdW and HB. Drafting of the manuscript: CZ. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: CZ and ZZ. Administrative, technical or material support: AvdW and HB. Supervision: AvdW and HB.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests CZ, OS, RM, AP, JK, MO, RK, SO, DM, IR and ZZ report no disclosures. VJ received conference travel support from Merck and Roche and speaker’s honoraria from Biogen and Roche outside of the submitted work. She receives research support from the Australian National Health and Medical Research Grant and MS Research Australia. MB received conference travel support from Biogen and Novartis. His institution has received research support from Biogen, Merck and Novartis. TK received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. JL-S received travel compensation from Novartis, Biogen, Roche and Merck. Her institution receives the honoraria for talks and advisory board commitment and research grants from Biogen, Merck, Roche, TEVA and Novartis. SJK received compensation for scientific advisory board activity from Merck and Roche. SH received honoraria and consulting fees from Novartis, Bayer Schering and Sanofi, and travel grants from Novartis, Biogen Idec and Bayer Schering. MS participated in, but not received honoraria for, advisory board activity for Biogen, Merck, Bayer Schering, Sanofi Aventis and Novartis. AvdW served on advisory boards and receives unrestricted research grants from Novartis, Biogen, Merck and Roche. She has received speaker’s honoraria and travel support from Novartis, Roche and Merck. She also received grant support from the National Health and Medical Research Council of Australia and MS Research Australia. VVP has received travel grants from Merck Healthcare KGaA (Darmstadt, Germany), Biogen, Sanofi, Bristol Meyer Squibb, Almirall and Roche. His institution has received research grants and consultancy fees from Roche, Biogen, Sanofi, Merck Healthcare KGaA (Darmstadt, Germany), Bristol Meyer Squibb, Janssen, Almirall and Novartis Pharma. JP received travel compensation from Novartis, Biogen, Genzyme and Teva, and speaking honoraria from Biogen, Novartis, Genzyme and Teva. 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. EKH received honoraria/research support from Biogen, Merck Serono, Novartis, Roche and Teva. GI received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Roche, Almirall and Teva. FP received speaker honoraria and advisory board fees from Almirall, Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme and TEVA. He received research funding from Biogen, Merck, FISM (Fondazione Italiana Sclerosi Multipla), Reload Onlus Association and University of Catania. RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme. CB received conference travel support from Biogen, Novartis, Bayer-Schering, Merck and Teva; he participated in Sanofi Aventis, Roche and Novartis clinical trials. MM has served on advisory board for Merck, has received speaker honoraria from Merck and Biogen. Her institution receives funding from Merck, Australian National Health Medical Research Council, Brain Foundation, Charles and Sylvia Viertel Foundation, Bethlehem Griffith Foundation and MS Research Australia. HB has received institutional (Monash University) funding from Biogen, F. Hoffmann-La Roche Ltd, Merck, Alexion, CSL and Novartis; has carried out contracted research for Novartis, Merck, F. Hoffmann-La Roche Ltd and Biogen; has taken part in speakers’ bureaus for Biogen, Genzyme, UCB, Novartis, F. Hoffmann-La Roche Ltd and Merck; has received personal compensation from Oxford Health Policy Forum for the Brain Health Steering Committee.

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

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