{
  "abstract": "Background Target trial emulation (TTE) offers a formal framework for causal inference using observational data, but its validity must be evaluated in each research domain by replicating randomised clinical trials (RCTs). We aimed to replicate eight RCTs evaluating the efficacy of disease-modifying therapies (DMTs) in multiple sclerosis (MS) using French registry data.Methods This multicentre, retrospective, observational study was conducted using data extracted in December 2023 from the Observatoire Français de la Sclérose en Plaques (OFSEP) database. For each emulated trial, patients were included when they initiated one of the DMT evaluated in the corresponding RCT and met its inclusion criteria. Clinical outcomes were the annualised relapse rate and 3-month confirmed Expanded Disability Status Scale progression. Radiological outcomes were new/enlarged T2-lesions and new gadolinium-enhanced T1-lesions on a brain MRI. A targeted maximum likelihood estimator was used to estimate the treatment effect adjusted for confounding factors between groups and corrected for censoring and missing outcome assessment.Results 14 111 patients were included in eight emulated trials: ASSESS (fingolimod vs glatiramer acetate), BEYOND (interferon beta vs glatiramer acetate), CONFIRM (dimethyl fumarate (DMF) vs glatiramer acetate), OPERA (ocrelizumab vs interferon beta), REGARD (interferon beta vs glatiramer acetate), RIFUND-MS (rituximab vs DMF), TENERE (teriflunomide vs interferon beta) and TRANSFORMS (fingolimod vs interferon beta). Treatment effects estimated in emulated trials were concordant with RCT findings in seven of eight trials for relapse rate, and in all six trials assessing disability progression. Radiological outcomes were more challenging to replicate; concordance was achieved in three of five trials for new T2-lesions, and one of four trials for new gadolinium-enhanced T1-lesions.Conclusion The combined use of a TTE methodology and high-quality registry data is a valid tool to evaluate treatment effectiveness in MS.",
  "authors": [
    {
      "affiliations": [
        "Hospices Civils de Lyon, Service de Neurologie, sclérose en plaques, pathologies de la myéline et neuroinflammation, Bron, France",
        "Université Lyon 1, CNRS, Laboratoire de Biométrie et Biologie Évolutive UMR 5558, Villeurbanne, France",
        "Service de Biostatistique-Bioinformatique, Hospices Civils de Lyon, Lyon, France"
      ],
      "name": "Antoine Gavoille"
    },
    {
      "affiliations": [
        "Université Lyon 1, CNRS, Laboratoire de Biométrie et Biologie Évolutive UMR 5558, Villeurbanne, France",
        "Service de Biostatistique-Bioinformatique, Hospices Civils de Lyon, Lyon, France"
      ],
      "name": "Mikail Nourredine"
    },
    {
      "affiliations": [
        "Hospices Civils de Lyon, Service de Neurologie, sclérose en plaques, pathologies de la myéline et neuroinflammation, Bron, France",
        "Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France",
        "Observatoire Français de la Sclérose en Plaques, Centre de Recherche en Neurosciences de Lyon, INSERM 1028 et CNRS UMR 5292, Lyon, France",
        "Eugène Devic EDMUS Foundation Against Multiple Sclerosis, F-69677, Bron Cedex, France"
      ],
      "name": "Fabien Rollot"
    },
    {
      "affiliations": [
        "Hospices Civils de Lyon, Service de Neurologie, sclérose en plaques, pathologies de la myéline et neuroinflammation, Bron, France",
        "Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France",
        "Observatoire Français de la Sclérose en Plaques, Centre de Recherche en Neurosciences de Lyon, INSERM 1028 et CNRS UMR 5292, Lyon, France",
        "Eugène Devic EDMUS Foundation Against Multiple Sclerosis, F-69677, Bron Cedex, France"
      ],
      "name": "Romain Casey"
    },
    {
      "affiliations": [
        "Department of Neurology, Nancy University Hospital, Nancy, Lorraine, France",
        "Université de Lorraine, Inserm, INSPIIRE, Nancy, France",
        "CHRU de Nancy, Université de Lorraine, Inserm, CIC 1433 EC, Nancy, France"
      ],
      "name": "Guillaume Mathey"
    },
    {
      "affiliations": [
        "Department of Neurology, University Hospital of Rennes, Rennes, France",
        "Empenn U1228, University of Rennes, Inria, CNRS, Inserm, IRISA UMR 6074, Rennes, France"
      ],
      "name": "Anne Kerbrat"
    },
    {
      "affiliations": [
        "CHU de Toulouse, CRC-SEP, department of Neurology, Toulouse Cedex 9, France",
        "Université Toulouse III, Infinity, INSERM UMR1291 - CNRS UMR5051, Toulouse Cedex 3, France"
      ],
      "name": "Jonathan Ciron"
    },
    {
      "affiliations": [
        "CHU de Strasbourg, Department of Neurology and Clinical Investigation Center, CIC 1434, INSERM 1434, Strasbourg, France"
      ],
      "name": "Jérôme De Sèze"
    },
    {
      "affiliations": [
        "Sorbonne Universités, UPMC Paris 06, Brain and Spine Institute, ICM, Hôpital de la Pitié Salpêtrière, Inserm UMR S 1127, CNRS UMR 7225, and Department of Neurology, AP-HP, Paris, France"
      ],
      "name": "Bruno Stankoff"
    },
    {
      "affiliations": [
        "Département de neurologie, Hôpital Pitié-Salpêtrière, APHP, F-75013 Paris",
        "Centre de Ressources et de Compétences SEP, Paris, Île-de-France, France"
      ],
      "name": "Elisabeth Maillart"
    },
    {
      "affiliations": [
        "Department of Neurology, Service Pathologies inflammatoires du système nerveux central, CRC-SEP, University Hospital of Bordeaux, Bordeaux, France",
        "INSERM U1215, Neurocentre Magendie, Bordeaux University, Bordeaux, France"
      ],
      "name": "Aurelie Ruet"
    },
    {
      "affiliations": [
        "CHU de Montpellier, MS Unit, F-34295 Montpellier Cedex 5, France",
        "University of Montpellier (MUSE), Montpellier, France"
      ],
      "name": "Pierre Labauge"
    },
    {
      "affiliations": [
        "Hôpital Saint Vincent de Paul, Department of Neurology, Lille, France"
      ],
      "name": "Arnaud Kwiatkowski"
    },
    {
      "affiliations": [
        "CHU Lille, CRCSEP Lille, Univ Lille, U1172, Lille, France"
      ],
      "name": "Helene Zephir"
    },
    {
      "affiliations": [
        "Hôpital Fondation A. de Rothschild, Department of Neurology, F-75000 Paris, France",
        "Université Paris-Cité, Paris, France"
      ],
      "name": "Caroline Papeix"
    },
    {
      "affiliations": [
        "CHU de Caen, MS expert centre, Department of Neurology, Normandy University, Caen, France"
      ],
      "name": "Gilles Defer"
    },
    {
      "affiliations": [
        "Department of Neurology, Centre Hospitalier Universitaire Pasteur2, Université Nice Côte d’Azur, UR2CA_URRIS, Nice, France"
      ],
      "name": "Christine Lebrun-Frenay"
    },
    {
      "affiliations": [
        "CHU de Dijon, Department of Neurology, EA4184, Dijon, France"
      ],
      "name": "Thibault Moreau"
    },
    {
      "affiliations": [
        "Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, CIC INSERM 1413, Service de Neurologie, Nantes, France"
      ],
      "name": "David-Axel Laplaud"
    },
    {
      "affiliations": [
        "CHU de Besançon, Service de Neurologie, Besançon, France"
      ],
      "name": "Eric Berger"
    },
    {
      "affiliations": [
        "CHU Clermont-Ferrand, Department of Neurology, Clermont-Ferrand, France",
        "Université Clermont Auvergne, Inserm, Neuro-Dol, Clermont-Ferrand, France"
      ],
      "name": "Pierre Clavelou"
    },
    {
      "affiliations": [
        "Department of Neurology, Nimes University Hospital, Nimes Cedex 9, France",
        "IGF, University of Montpellier, CNRS, INSERM, Montpellier Cedex 5, France"
      ],
      "name": "Eric Thouvenot"
    },
    {
      "affiliations": [
        "Hôpital de Poissy, Department of Neurology, CRC SEP-IDF-Ouest, Poissy, France"
      ],
      "name": "Olivier Heinzlef"
    },
    {
      "affiliations": [
        "Aix Marseille Univ, APHM, Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie, Marseille, France"
      ],
      "name": "Jean Pelletier"
    },
    {
      "affiliations": [
        "CHU d’Amiens, Department of Neurology, Amiens, France"
      ],
      "name": "Abdullatif Al Khedr"
    },
    {
      "affiliations": [
        "CHU Grenoble Alpes, Department of Neurology, Neurology MS Clinic Grenoble, Grenoble Alpes university hospital, La Tronche, France",
        "T-RAIG, TIMC-IMAG, Grenoble Alpes University, La Tronche, France"
      ],
      "name": "Olivier Casez"
    },
    {
      "affiliations": [
        "CHU de Rouen, Department of Neurology, Rouen, France"
      ],
      "name": "Bertrand Bourre"
    },
    {
      "affiliations": [
        "APHP, Hôpital Henri Mondor, Department of neurology, Créteil, France"
      ],
      "name": "Abir Wahab"
    },
    {
      "affiliations": [
        "CHU de Limoges, Hôpital Dupuytren, Department of Neurology, Limoges, France"
      ],
      "name": "Laurent Magy"
    },
    {
      "affiliations": [
        "CHU de Reims, CRC-SEP, Department of neurology, Reims Cedex, France"
      ],
      "name": "Solène Moulin"
    },
    {
      "affiliations": [
        "CHU de Saint-Étienne, Hôpital Nord, Department of Neurology, Saint-Étienne, France"
      ],
      "name": "Jean-Philippe Camdessanché"
    },
    {
      "affiliations": [
        "CHU de Tours, Hôpital Bretonneau, CRC SEP and Department of Neurology, Tours, France"
      ],
      "name": "Ines Doghri"
    },
    {
      "affiliations": [
        "APHP, Hôpital Kremlin Bicêtre, Department of Neurology, Le Kremlin Bicêtre, France"
      ],
      "name": "Mariana Sarov"
    },
    {
      "affiliations": [
        "Department of neurology, Hôpital Pierre Delafontaine, Centre Hospitalier de Saint-Denis, Saint-Denis, France"
      ],
      "name": "Karolina Hankiewicz"
    },
    {
      "affiliations": [
        "Hôpital NOVO, site Pontoise, Department of Neurology, Pontoise, France"
      ],
      "name": "Corinne Pottier"
    },
    {
      "affiliations": [
        "CHU La Milétrie, Hôpital Jean Bernard, Department of neurology, Poitiers, France",
        "INSERM CIC 1402, Poitiers, France"
      ],
      "name": "Amélie Dos Santos"
    },
    {
      "affiliations": [
        "CH de Gonesse, Department of neurology, Gonesse, France"
      ],
      "name": "Eric Manchon"
    },
    {
      "affiliations": [
        "Hôpital Foch, Department of neurology, Suresnes, France",
        "ALTE University, Tbilisi, Georgia"
      ],
      "name": "Maia Tchikviladze"
    },
    {
      "affiliations": [
        "Université Lyon 1, CNRS, Laboratoire de Biométrie et Biologie Évolutive UMR 5558, Villeurbanne, France",
        "Service de Biostatistique-Bioinformatique, Hospices Civils de Lyon, Lyon, France"
      ],
      "name": "Muriel Rabilloud"
    },
    {
      "affiliations": [
        "Université Lyon 1, CNRS, Laboratoire de Biométrie et Biologie Évolutive UMR 5558, Villeurbanne, France",
        "Service de Biostatistique-Bioinformatique, Hospices Civils de Lyon, Lyon, France"
      ],
      "name": "Fabien Subtil"
    },
    {
      "affiliations": [
        "Hospices Civils de Lyon, Service de Neurologie, sclérose en plaques, pathologies de la myéline et neuroinflammation, Bron, France",
        "Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France",
        "Observatoire Français de la Sclérose en Plaques, Centre de Recherche en Neurosciences de Lyon, INSERM 1028 et CNRS UMR 5292, Lyon, France",
        "Eugène Devic EDMUS Foundation Against Multiple Sclerosis, F-69677, Bron Cedex, France"
      ],
      "name": "Sandra Vukusic"
    }
  ],
  "title": "Target trial emulation to replicate randomised clinical trials using registry data in multiple sclerosis",
  "uid": "a4bc99c7-cbee-59c2-99d2-84a690a3ccca"
}