Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis: causal inference to emulate a multiarm randomised trial.
Journal: Journal of neurology, neurosurgery, and psychiatry
Volume: 94
Issue: 12
Year of Publication: 2023
Affiliated Institutions:
CORe, Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia.
Department of Neurology, Center of Clinical Neuroscience, Charles University, Praha, Czech Republic.
Department of Medical and Surgical Sciences and Advanced Technologies, University of Catania 'G.F. Ingrassia', Catania, Italy.
Department of Neurology, Isfahan University of Medical Sciences, Isfahan, Iran (the Islamic Republic of).
Dokuz Eylul University, İzmir, Turkey.
Neurology, Hospital Universitario Virgen Macarena, Sevilla, Spain.
Deptartment of Neuroscience, Imaging, and Clinical Sciences, Gabriele d'Annunzio University of Chieti and Pescara, Chieti, Italy.
UOSI Riabilitazione Sclerosi Multipla, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
Division of Neurology, Department of Medicine, Amiri Hospital, Kuwait City, Kuwait.
CHUM MS Center, Montreal, Quebec, Canada.
School of Medicine, Ondokuz Mayis Universitesi, Samsun, Turkey.
Neuro Rive-Sud, Greenfield Park, Quebec, Canada.
Department of Neuroscience, Azienda Ospedaliero-Universitaria di Modena, Modena, Italy.
CISSS de Chaudiere-Appalaches, Levis, Quebec, Canada.
Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center, Beirut, Lebanon.
Department of Neurology, Koc Universitesi, Istanbul, Turkey.
Department of Neurology, Zuyderland Medical Centre Sittard-Geleen, Sittard-Geleen, The Netherlands.
University of Newcastle Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
Foundation National Neurological Institute C Mondino Institute for Hospitalization and Care Scientific, Pavia, Italy.
Department of Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
Ospedali Riuniti di Salerno, Salerno, Italy.
Department of Neurology, St Vincent's University Hospital, Dublin, Ireland.
UOC Neurologia, Azienda Sanitaria Unica Regionale Marche - AV, Macerata, Italy.
Royal Victoria Hospital, Belfast, UK.
Department of Neurology, Centro Hospitalar de São João, Porto, Portugal.
Department of Neurology, ASL Genovese, Genova, Italy.
Research Center for Clinical Neuroimmunology and Neuroscience Basel (RCNB) and MS Center, Neurologic Clinic and Policlinic, Departments of Head, Spine and Neuromedicine and Clinical Research, University Hospital Basel, Basel, Switzerland.
Liverpool Hospital, Sydney, New South Wales, Australia.
Flinders University, Adelaide, South Australia, Australia.
Department of Medicine and Surgery, University of Parma, Parma, Italy.
Groene Hart Ziekenhuis, Gouda, The Netherlands.
UQCCR, The University of Queensland, Brisbane, Queensland, Australia.
Nemocnice Jihlava, Jihlava, Czech Republic.
Department of Neurology, Alfred Hospital, Melbourne, Victoria, Australia.
Department of Neurology, Galdakao-Usansolo Hospital, Galdakao, Spain.
Westmead Hospital, Westmead, New South Wales, Australia.
Universitair Ziekenhuis Gent, Gent, Belgium.
Department of Neurology, Razi University Hospital, Tunis, Tunisia.
Department of Neurology, University of Tunis El Manar, Tunis, Tunisia.
Instituto de Investigacion Sanitaria Biodonostia, Hospital Universitario de Donostia, San Sebastian, Spain.
South and East Belfast Health and Social Services Trust, Belfast, UK.
Neurology, Hospital Universitario Reina Sofia, Cordoba, Spain.
Department of Medicine, Sultan Qaboos University Hospital, Seeb, Oman.
University Hospital Geelong, Geelong, Victoria, Australia.
Department of Neurology, King Fahad Specialist Hospital-Dammam, Khobar, Saudi Arabia.
Department of Neurology, University of Debrecen, Debrecen, Hungary.
Department of Neurology, Hospital General de Alicante, Alicante, Spain.
Department of Neurology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico.
Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.
CORe, Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia tomas.kalincik@unimelb.edu.au.
Abstract summary
Simultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly used therapies over 5 years.Data from 74 centres in 35 countries were sourced from MSBase. For each patient, the first eligible intervention was analysed, censoring at change/discontinuation of treatment. The compared interventions included natalizumab, fingolimod, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate and no treatment. Marginal structural Cox models (MSMs) were used to estimate the average treatment effects (ATEs) and the average treatment effects among the treated (ATT), rebalancing the compared groups at 6-monthly intervals on age, sex, birth-year, pregnancy status, treatment, relapses, disease duration, disability and disease course. The outcomes analysed were incidence of relapses, 12-month confirmed disability worsening and improvement.23 236 eligible patients were diagnosed with RRMS or clinically isolated syndrome. Compared with glatiramer acetate (reference), several therapies showed a superior ATE in reducing relapses: natalizumab (HR=0.44, 95% CI=0.40 to 0.50), fingolimod (HR=0.60, 95% CI=0.54 to 0.66) and dimethyl fumarate (HR=0.78, 95% CI=0.66 to 0.92). Further, natalizumab (HR=0.43, 95% CI=0.32 to 0.56) showed a superior ATE in reducing disability worsening and in disability improvement (HR=1.32, 95% CI=1.08 to 1.60). The pairwise ATT comparisons also showed superior effects of natalizumab followed by fingolimod on relapses and disability.The effectiveness of natalizumab and fingolimod in active RRMS is superior to dimethyl fumarate, teriflunomide, glatiramer acetate and interferon beta. This study demonstrates the utility of MSM in emulating trials to compare clinical effectiveness among multiple interventions simultaneously.
Authors & Co-authors:
Diouf Ibrahima I
Malpas Charles B CB
Sharmin Sifat S
Roos Izanne I
Horakova Dana D
Kubala Havrdova Eva E
Patti Francesco F
Shaygannejad Vahid V
Ozakbas Serkan S
Eichau Sara S
Onofrj Marco M
Lugaresi Alessandra A
Alroughani Raed R
Prat Alexandre A
Duquette Pierre P
Terzi Murat M
Boz Cavit C
Grand'Maison Francois F
Sola Patrizia P
Ferraro Diana D
Grammond Pierre P
Yamout Bassem B
Altintas Ayse A
Gerlach Oliver O
Lechner-Scott Jeannette J
Bergamaschi Roberto R
Karabudak Rana R
Iuliano Gerardo G
McGuigan Christopher C
Cartechini Elisabetta E
Hughes Stella S
Sa Maria Jose MJ
Solaro Claudio C
Kappos Ludwig L
Hodgkinson Suzanne S
Slee Mark M
Granella Franco F
de Gans Koen K
McCombe Pamela A PA
Ampapa Radek R
van der Walt Anneke A
Butzkueven Helmut H
Sánchez-Menoyo José Luis JL
Vucic Steve S
Laureys Guy G
Sidhom Youssef Y
Gouider Riadh R
Castillo-Trivino Tamara T
Gray Orla O
Aguera-Morales Eduardo E
Al-Asmi Abdullah A
Shaw Cameron C
Al-Harbi Talal M TM
Csepany Tunde T
Sempere Angel P AP
Treviño Frenk Irene I
Stuart Elizabeth A EA
Kalincik Tomas T
Study Outcome
Source Link: Visit source