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Randomized Controlled Trial
. 2023 Dec;94(12):1004-1011.
doi: 10.1136/jnnp-2023-331499. Epub 2023 Jul 6.

Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis: causal inference to emulate a multiarm randomised trial

Ibrahima Diouf  1   2 , Charles B Malpas  1   3 , Sifat Sharmin  1 , Izanne Roos  1 , Dana Horakova  4   5 , Eva Kubala Havrdova  4   5 , Francesco Patti  6 , Vahid Shaygannejad  7 , Serkan Ozakbas  8 , Sara Eichau  9 , Marco Onofrj  10 , Alessandra Lugaresi  11   12 , Raed Alroughani  13 , Alexandre Prat  14   15 , Pierre Duquette  14   15 , Murat Terzi  14   15 , Cavit Boz  16   17 , Francois Grand'Maison  18 , Patrizia Sola  19 , Diana Ferraro  19 , Pierre Grammond  20 , Bassem Yamout  21   22 , Ayse Altintas  23   24 , Oliver Gerlach  25   26 , Jeannette Lechner-Scott  27   28 , Roberto Bergamaschi  29 , Rana Karabudak  30 , Gerardo Iuliano  31 , Christopher McGuigan  32 , Elisabetta Cartechini  33 , Stella Hughes  34 , Maria Jose Sa  35 , Claudio Solaro  36   37 , Ludwig Kappos  38   39 , Suzanne Hodgkinson  40 , Mark Slee  41 , Franco Granella  42 , Koen de Gans  43 , Pamela A McCombe  44 , Radek Ampapa  45 , Anneke van der Walt  46   47 , Helmut Butzkueven  46   47 , José Luis Sánchez-Menoyo  48 , Steve Vucic  49 , Guy Laureys  50 , Youssef Sidhom  51   52 , Riadh Gouider  52 , Tamara Castillo-Trivino  53 , Orla Gray  54 , Eduardo Aguera-Morales  55 , Abdullah Al-Asmi  56   57 , Cameron Shaw  58 , Talal M Al-Harbi  59 , Tunde Csepany  60 , Angel P Sempere  61 , Irene Treviño Frenk  62 , Elizabeth A Stuart  63 , Tomas Kalincik  64   3
Affiliations
Randomized Controlled Trial

Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis: causal inference to emulate a multiarm randomised trial

Ibrahima Diouf et al. J Neurol Neurosurg Psychiatry. 2023 Dec.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: MULTIPLE SCLEROSIS; STATISTICS.

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Conflict of interest statement

Competing interests: The authors report the following relationships: speaker honoraria, advisory board or steering committee fees, research support and/or conference travel support from Acthelion (EKH, RA), Almirall (MT, FG, RB, CRT, JLS-M), Bayer (MT, AL, PS, RA, MT, CB, JL-S, EP, VVP, RB, DS, RA, JO, JLSM, SH, CR, AGK, TC, NS, BT, MS, CAS), BioCSL (TK, AGK, BT), Biogen (TK, TS, DH, EKH, MT, GI, AL, MG, PD, PG, VJ, AVW, FG, PS, DF, RA, RH, CB, JLS, EP, VVP, FG, RB, RA, CRT, JP, JO, MB, JLSM, SH, CR, CSh, OGerlach, AGK, TC, BS, NS, BT, MS, HB), Biologix (RA), BMS/Celgene (EKH, AL), Genpharm (RA), Genzyme-Sanofi (TK, EKH, MT, GI, AL, MG, PD, PG, AVW, FG, PS, DF, RA, RH, MT, CB, JLS, EP, EP, VVP, FG, RB, RB, DS, CRT, JP, JO, MB, JLSM, SH, O Gerlach, AGK, HB), GSK (RA), Innate Immunotherapeutics (AGK), Lundbeck (EP), Merck / EMD (TK, DH, EKH, MT, GI, AL(Merck Serono), MG, PD, PG, VJ, AVW, PS, DF, RA, RH, MT, CB, JLS, EP, VVP, FG, RB, DS, RA, JO, MB, JLSM, CR, FM, O Gerlach, AGK, TC, BS, MS, HB), Mitsubishi (FG),Novartis (TK, TS, DH, EKH, MT, GI, AL, MG, PD, PG, VJ, AVW, FG, PS, DF, RA, RH, MT, CB, JLS, EP, VVP, FG, RB, DS, RA, CRT, JP, JO, MB, JLSM, SH, CR, FM, CSh, OG, AGK, TC, NS, BT, MS, HB), ONO Pharmaceuticals (FG), Roche (TK, EKH, AL, MT, CB, VVP, BT), Teva (TK, DH, EKH, MT, GI, AL, MG, PD, PG, VJ, FG, PS, DF, RH, MT, CB, JLS, VVP, RB, DS, RA, JP, JO, JLSM, CR, AGK, TC, MS, CAS), WebMD (TK), UCB (EP).

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