Johanna B Andersen1, Sifat Sharmin2, Mathilde Lefort3, Nils Koch-Henriksen4, Finn Sellebjerg5, Per Soelberg Sørensen6, Claudia C Hilt Christensen7, Peter V Rasmussen8, Michael B Jensen9, Jette L Frederiksen10, Stephan Bramow5, Henrik K Mathiesen6, Karen I Schreiber5, Dana Horakova11, Eva K Havrdova11, Raed Alroughani12, Guillermo Izquierdo13, Sara Eichau13, Serkan Ozakbas14, Francesco Patti15, Marco Onofrj16, Alessandra Lugaresi17, Murat Terzi18, Pierre Grammond19, Francois Grand Maison20, Bassem Yamout21, Alexandre Prat22, Marc Girard22, Pierre Duquette22, Cavit Boz23, Maria Trojano24, Pamela McCombe25, Mark Slee26, Jeannette Lechner-Scott27, Recai Turkoglu28, Patrizia Sola29, Diana Ferraro29, Franco Granella30, Vahid Shaygannejad31, Julie Prevost32, Olga Skibina33, Claudio Solaro34, Rana Karabudak35, Bart V Wijmeersch36, Tunde Csepany37, Daniele Spitaleri38, Steve Vucic39, Romain Casey40, Marc Debouverie41, Gilles Edan42, Jonathan Ciron43, Aurélie Ruet44, Jérôme D Sèze45, Elisabeth Maillart46, Hélène Zephir47, Pierre Labauge48, Gilles Defer49, Christine Lebrun50, Thibault Moreau51, Eric Berger52, Pierre Clavelou53, Jean Pelletier54, Bruno Stankoff55, Olivier Gout56, Eric Thouvenot57, Olivier Heinzlef58, Abdullatif Al-Khedr59, Bertrand Bourre60, Olivier Casez61, Philippe Cabre62, Alexis Montcuquet63, Abir Wahab64, Jean-Philippe Camdessanché65, Aude Marousset66, Ivania Patry67, Karolina Hankiewicz68, Corinne Pottier69, Nicolas Maubeuge70, Céline Labeyrie71, Chantal Nifle72, Emmanuelle Leray3, David A Laplaud73, Helmut Butzkueven74, Tomas Kalincik75, Sandra Vukusic76, Melinda Magyari77. 1. The Danish Multiple Sclerosis Registry, Department of Neurology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark. Electronic address: johanna.balslev.andersen@regionh.dk. 2. CORe, Department of Medicine, University of Melbourne, Melbourne, Australia; Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia. 3. Rennes University, EHESP, REPERES - EA 7449, F-35000 Rennes, France; Univ Rennes, CHU Rennes, Inserm, CIC 1414 (Centre d'Investigation Clinique de Rennes), F-35000 Rennes, France. 4. Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark. 5. The Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet Glostrup, Denmark. 6. The Danish Multiple Sclerosis Center, Department of Neurology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark. 7. Department of Neurology Aalborg University Hospital, Multiple Sclerosis Unit. 8. Aarhus University Hospital, Neurology, PPJ Boulevard, DK-8200 Aarhus N. 9. Department of Neurology, University Hospital of Northern Sealand. 10. Danish Multiple Sclerosis Centre, Dept. of Neurology, Copenhagen University Hospital, Rigshospitalet in Glostrup, 2600 Glostrup, Denmark. 11. Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague, Czech Republic. 12. Division of Neurology, Department of Medicine, Amiri Hospital, Sharq, Kuwait. 13. Hospital Universitario Virgen Macarena, Sevilla, Spain. 14. Dokuz Eylul University, Konak/Izmir, Turkey. 15. GF Ingrassia Department, University of Catania, Catania, Policlinico G Rodolico, Italy. 16. Department of Neuroscience, Imaging, and Clinical Sciences, University G. d'Annunzio, Chieti, Italy. 17. Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy. 18. Medical Faculty, 19 Mayis University, Samsun, Turkey. 19. CISSS Chaudiere-Appalache, Levis, Canada. 20. Neuro Rive-Sud, Quebec, Canada. 21. Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center, Beirut, Lebanon. 22. Hopital Notre Dame, Montreal, Canada, CHUM and Universite de Montreal, Montreal, Canada. 23. KTU Medical Faculty Farabi Hospital, Trabzon, Turkey. 24. Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy. 25. University of Queensland, Brisbane, Australia, Royal Brisbane and Women's Hospital. 26. Flinders University, Adelaide, Australia. 27. School of Medicine and Public Health, University Newcastle, Newcastle, Australia; Department of Neurology, John Hunter Hospital, Hunter New England Health, Newcastle, Australia. 28. Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey. 29. Department of Neuroscience, Azienda Ospedaliera Universitaria, Modena, Italy. 30. Department of Medicine and Surgery, University of Parma, Parma, Italy; Department of Emergency and General Medicine, Parma University Hospital, Parma, Italy. 31. Isfahan University of Medical Sciences, Isfahan, Iran. 32. CSSS Saint-Jerome, Saint-Jerome, Canada. 33. Monash University, Melbourne, Australia. 34. Department of Neurology, ASL3 Genovese, Genova, Italy; Department of Rehabilitaiton, ML Novarese Hospital Moncrivello. 35. Hacettepe University, Ankara, Turkey. 36. Rehabilitation and MS-Centre Overpelt and Hasselt University, Hasselt, Belgium. 37. Department of Neurology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary. 38. Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino, Avellino, Italy. 39. Westmead Hospital, Sydney, Australia. 40. Service de neurologie, sclérose en plaques, pathologies de la myéline et neuro-inflammation, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, 69677 Lyon/Bron, France; Centre des Neurosciences de Lyon, Observatoire Français de la Sclérose en Plaques, INSERM 1028 et CNRS UMR5292, 69003 Lyon, France ; Université Claude Bernard Lyon 1, Faculté de médecine Lyon Est, F-69000 Lyon, France, Eugene Devic EDMUS Foundation, 69677 Lyon/Bron, France. 41. Centre hospitalier régional universitaire de Nancy, Hôpital central, Service de neurologie, Nancy, France. 42. Centre hospitalier universitaire de Rennes, Hôpital Pontchaillou, Service de neurologie, Rennes, France. 43. Centre hospitalier universitaire de Toulouse, Hôpital Purpan, Service de neurologie inflammatoire et neuro-oncologie, Toulouse, France. 44. Centre hospitalier universitaire de Bordeaux, Hôpital Pellegrin, Service de neurologie, Bordeaux, France. 45. Hôpitaux universitaire de Strasbourg, Hôpital de Hautepierre, Service des maladies inflammatoires du système nerveux - neurologie, Strasbourg, France. 46. Assistance publique des hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Service de neurologie, Paris, France. 47. Centre hospitalier universitaire de Lille, Hôpital Salengro, Service de neurologie D, Lille, France. 48. Centre hospitalier universitaire de Montpellier, Hôpital Gui de Chauliac, Service de neurologie, Montpellier, France. 49. Centre hospitalier universitaire de Caen Normandie, Service de neurologie, Hôpital Côte de Nacre, Caen, France. 50. Centre hospitalier universitaire de Nice, Université Nice Côte d'Azur, Hôpital Pasteur, Service de neurologie, Nice, France. 51. Centre hospitalier universitaire Dijon Bourgogne, Hôpital François Mitterrand, Service de neurologie, maladies inflammatoires du système nerveux et neurologie générale, Dijon, France. 52. Centre hospitalier régional universitaire de Besançon, Hôpital Jean Minjoz, Service de neurologie, Besançon, France. 53. Centre hospitalier universitaire de Clermont-Ferrand, Hôpital Gabriel-Montpied, Service de neurologie, Clermont-Ferrand, France. 54. Assistance publique des hôpitaux de Marseille, Centre hospitalier de la Timone, Service de neurologie et unité neuro-vasculaire, Marseille, France. 55. Assistance publique des hôpitaux de Paris, Hôpital Saint-Antoine, Service de neurologie, Paris, France. 56. Fondation Adolphe de Rothschild de l'œil et du cerveau, Service de neurologie, Paris, France. 57. Centre hospitalier universitaire de Nîmes, Hôpital Carémeau, Service de neurologie, Nîmes, France. 58. Centre hospitalier intercommunal de Poissy Saint-Germain-en-Laye, Service de neurologie, Poissy, France. 59. Centre hospitalier universitaire d'Amiens Picardie, Site sud, Service de neurologie, Amiens, France. 60. Centre hospitalier universitaire Rouen Normandie, Hôpital Charles-Nicolle, Service de neurologie, Rouen, France. 61. Centre hospitalier universitaire Grenoble-Alpes, Site nord, Service de neurologie, Grenoble/La Tronche, France. 62. Centre hospitalier universitaire de Martinique, Hôpital Pierre Zobda-Quitman, Service de Neurologie, Fort-de-France, France. 63. Centre hospitalier universitaire Limoges, Hôpital Dupuytren, Service de neurologie, Limoges, France. 64. Hôpital Henri Mondor, Department of Neurology, F-94000 Créteil, France. 65. Centre hospitalier universitaire de Saint-Étienne, Hôpital Nord, Service de neurologie, Saint-Étienne, France. 66. Centre hospitalier régional universitaire de Tours, Hôpital Bretonneau, Service de neurologie, Tours, France. 67. Centre hospitalier sud francilien, Service de neurologie, Corbeil-Essonnes, France. 68. Centre hospitalier de Saint-Denis, Hôpital Casanova, Service de neurologie, Saint-Denis, France. 69. Centre hospitalier de Pontoise, Service de neurologie, Pontoise, France. 70. Centre hospitalier universitaire de Poitiers, Site de la Milétrie, Service de neurologie, Poitiers, France. 71. Assistance publique des hôpitaux de Paris, Hôpital Bicêtre, Service de neurologie, Le Kremlin-Bicêtre, France. 72. Centre hospitalier de Versailles, Hôpital André-Mignot, Service de neurologie, Le Chesnay, France. 73. CHU de Nantes, Service de Neurologie & CIC015 INSERM, F-44093 Nantes, France; INSERM CR1064, F-44000 Nantes, France. 74. Central Clinical School, Monash University, Melbourne, Australia; Department of Neurology, The Alfred Hospital, Melbourne, Australia; Department of Neurology, Box Hill Hospital, Monash University, Melbourne, Australia. 75. CORe, Department of Medicine, University of Melbourne, Melbourne, Australia; Melbourne MS Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia. 76. The Danish Multiple Sclerosis Registry, Department of Neurology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark; The Danish Multiple Sclerosis Center, Department of Neurology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark. 77. The Danish Multiple Sclerosis Registry, Department of Neurology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark; The Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet Glostrup, Denmark.
Abstract
BACKGROUND: Natalizumab and fingolimod were the first preparations recommended for disease breakthrough in priorly treated relapsing-remitting multiple sclerosis. Of three published head-to-head studies two showed that natalizumab is the more effective to prevent relapses and EDSS worsening. METHODS: By re-analyzing original published results from MSBase, France, and Denmark using uniform methodologies, we aimed at identifying the effects of differences in methodology, in the MS-populations, and at re-evaluating the differences in effectiveness between the two drugs. We gained access to copies of the individual amended databases and pooled all data. We used uniform inclusion/exclusion criteria and statistical methods with Inverse Probability Treatment Weighting. RESULTS: The pooled analyses comprised 968 natalizumab- and 1479 fingolimod treated patients. The on-treatment natalizumab/fingolimod relapse rate ratio was 0.77 (p=0.004). The hazard ratio (HR) for a first relapse was 0.82 (p=0.030), and the HR for sustained EDSS improvement was 1.4 (p=0.009). There were modest differences between each of the original published studies and the replication study, but the conclusions of the three original studies remained unchanged: in two of them natalizumab was more effective, but in the third there was no difference between natalizumab and fingolimod. CONCLUSION: The results were largely invariant to the epidemiological and statistical methods but differed between the MS populations. Generally, the advantage of natalizumab was confirmed.
BACKGROUND:Natalizumab and fingolimod were the first preparations recommended for disease breakthrough in priorly treated relapsing-remitting multiple sclerosis. Of three published head-to-head studies two showed that natalizumab is the more effective to prevent relapses and EDSS worsening. METHODS: By re-analyzing original published results from MSBase, France, and Denmark using uniform methodologies, we aimed at identifying the effects of differences in methodology, in the MS-populations, and at re-evaluating the differences in effectiveness between the two drugs. We gained access to copies of the individual amended databases and pooled all data. We used uniform inclusion/exclusion criteria and statistical methods with Inverse Probability Treatment Weighting. RESULTS: The pooled analyses comprised 968 natalizumab- and 1479 fingolimod treated patients. The on-treatment natalizumab/fingolimod relapse rate ratio was 0.77 (p=0.004). The hazard ratio (HR) for a first relapse was 0.82 (p=0.030), and the HR for sustained EDSS improvement was 1.4 (p=0.009). There were modest differences between each of the original published studies and the replication study, but the conclusions of the three original studies remained unchanged: in two of them natalizumab was more effective, but in the third there was no difference between natalizumab and fingolimod. CONCLUSION: The results were largely invariant to the epidemiological and statistical methods but differed between the MS populations. Generally, the advantage of natalizumab was confirmed.
Authors: M Lefort; S Sharmin; J B Andersen; M Magyari; T Kalincik; E Leray; S Vukusic; R Casey; M Debouverie; G Edan; J Ciron; A Ruet; J De Sèze; E Maillart; H Zephir; P Labauge; G Defer; C Lebrun-Frenay; T Moreau; E Berger; P Clavelou; J Pelletier; B Stankoff; O Gout; E Thouvenot; O Heinzlef; A Al-Khedr; B Bourre; O Casez; P Cabre; A Montcuquet; A Wahab; J P Camdessanché; A Maurousset; H Ben Nasr; K Hankiewicz; C Pottier; N Maubeuge; D Dimitri-Boulos; C Nifle; D A Laplaud; D Horakova; E K Havrdova; R Alroughani; G Izquierdo; S Eichau; S Ozakbas; F Patti; M Onofrj; A Lugaresi; M Terzi; P Grammond; F Grand'Maison; B Yamout; A Prat; M Girard; P Duquette; C Boz; M Trojano; P McCombe; M Slee; J Lechner-Scott; R Turkoglu; P Sola; D Ferraro; F Granella; V Shaygannejad; J Prevost; D Maimone; O Skibina; K Buzzard; A Van der Walt; R Karabudak; B Van Wijmeersch; T Csepany; D Spitaleri; S Vucic; N Koch-Henriksen; F Sellebjerg; P S Soerensen; C C Hilt Christensen; P V Rasmussen; M B Jensen; J L Frederiksen; S Bramow; H K Mathiesen; K I Schreiber; H Butzkueven Journal: BMC Med Res Methodol Date: 2022-05-30 Impact factor: 4.612