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Safety and efficacy of rituximab versus dimethyl fumarate in patients with relapsing-remitting multiple sclerosis or clinically isolated syndrome in Sweden: a rater-blinded, phase 3, randomised controlled trial.
Svenningsson, Anders; Frisell, Thomas; Burman, Joachim; Salzer, Jonatan; Fink, Katharina; Hallberg, Susanna; Hambraeus, Joakim; Axelsson, Markus; Nimer, Faiez Al; Sundström, Peter; Gunnarsson, Martin; Johansson, Rune; Mellergård, Johan; Rosenstein, Igal; Ayad, Ahmad; Sjöblom, Irina; Risedal, Anette; de Flon, Pierre; Gilland, Eric; Lindeberg, Jonas; Shawket, Fadi; Piehl, Fredrik; Lycke, Jan.
Afiliação
  • Svenningsson A; Department of Clinical Sciences, Karolinska Institutet Danderyd Hospital, Stockholm, Sweden; Department of Neurology, Danderyd Hospital AB, Stockholm, Sweden. Electronic address: anders.svenningsson@ki.se.
  • Frisell T; Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
  • Burman J; Department of Neuroscience, Uppsala University, Uppsala, Sweden.
  • Salzer J; Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
  • Fink K; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Academic Specialist Centre, Stockholm Health Services, Stockholm, Sweden.
  • Hallberg S; Department of Clinical Sciences, Karolinska Institutet Danderyd Hospital, Stockholm, Sweden; Department of Neurology, Danderyd Hospital AB, Stockholm, Sweden.
  • Hambraeus J; Section of Neurology, Department of Medicine, Falun Hospital, Falun, Sweden.
  • Axelsson M; Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
  • Nimer FA; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Academic Specialist Centre, Stockholm Health Services, Stockholm, Sweden.
  • Sundström P; Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
  • Gunnarsson M; Department of Neurology, Örebro University, Örebro, Sweden.
  • Johansson R; Department of Neurology and Rehabilitation, Karlstad Hospital, Karlstad, Sweden.
  • Mellergård J; Department of Neurology, Linköping University Hospital, Linköping, Sweden; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
  • Rosenstein I; Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden; Department of Neurology, Borås Hospital, Borås, Sweden.
  • Ayad A; Department of Neurology, Capio St Göran Hospital, Stockholm, Sweden.
  • Sjöblom I; Section of Neurology, Department of Medicine, Gävle Hospital, Gävle, Sweden.
  • Risedal A; Section of Neurology, Department of Medicine, Helsingborg Hospital, Helsingborg, Sweden.
  • de Flon P; Section of Neurology, Department of Medicine, Östersund Hospital, Östersund, Sweden.
  • Gilland E; Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden; Section of Neurology, Department of Medicine, Kungsbacka Hospital, Kungsbacka, Sweden.
  • Lindeberg J; Section of Neurology, Department of Medicine, Nyköping Hospital, Nyköping, Sweden.
  • Shawket F; Department of Clinical Sciences, Karolinska Institutet Danderyd Hospital, Stockholm, Sweden; Department of Neurology, Danderyd Hospital AB, Stockholm, Sweden.
  • Piehl F; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Academic Specialist Centre, Stockholm Health Services, Stockholm, Sweden.
  • Lycke J; Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
Lancet Neurol ; 21(8): 693-703, 2022 08.
Article em En | MEDLINE | ID: mdl-35841908
ABSTRACT

BACKGROUND:

B-cell depleting therapies are highly efficacious in relapsing-remitting multiple sclerosis but one such therapy, rituximab, is not approved for multiple sclerosis and no phase 3 trial data are available. We therefore examined the safety and efficacy of rituximab compared with dimethyl fumarate in patients with relapsing-remitting multiple sclerosis to obtain data that might allow inclusion of rituximab in treatment guidelines.

METHODS:

RIFUND-MS was a multicentre, rater-blinded, active-comparator, phase 3, randomised controlled trial done at 17 Swedish university and community hospitals. Key inclusion criteria for participants were age 18-50 years; relapsing-remitting multiple sclerosis or clinically isolated syndrome according to prevailing McDonald criteria; 10 years or less since diagnosis; untreated or only exposed to interferons or glatiramer acetate; and with clinical or neuroradiological disease activity in the past year. Patients were automatically randomly assigned (11) by the treating physician using a randomisation module in the Swedish multiple sclerosis registry, without stratification, to oral dimethyl fumarate 240 mg twice daily or to intravenous rituximab 1000 mg followed by 500 mg every 6 months. Relapse evaluation, Expanded Disability Status Scale rating, and assessment of MRI scans were done by examining physicians and radiologists masked to treatment allocation. The primary outcome was the proportion of patients with at least one relapse (defined as subacute onset of new or worsening neurological symptoms compatible with multiple sclerosis with a duration of more than 24 h and preceded by at least 30 days of clinical stability), assessed in an intention-to-treat analysis using log-binomial regression with robust standard errors. This trial is registered at ClinicalTrials.gov, NCT02746744.

FINDINGS:

Between July 1, 2016, and Dec 18, 2018, 322 patients were screened for eligibility, 200 of whom were randomly assigned to a treatment group (100 assigned to rituximab and 100 assigned to dimethyl fumarate). The last patient completed 24-month follow-up on April 21, 2021. 98 patients in the rituximab group and 97 patients in the dimethyl fumarate group were eligible for the primary outcome analysis. Three (3%) patients in the rituximab group and 16 (16%) patients in the dimethyl fumarate group had a protocol-defined relapse during the trial, corresponding to a risk ratio of 0·19 (95% CI 0·06-0·62; p=0·0060). Infusion reactions (105 events [40·9 per 100 patient-years]) in the rituximab group and gastrointestinal reactions (65 events [47·4 per 100 patient-years]) and flush (65 events [47·4 per 100 patient-years]) in the dimethyl fumarate group were the most prevalent adverse events. There were no safety concerns.

INTERPRETATION:

RIFUND-MS provides evidence that rituximab given as 1000 mg followed by 500 mg every 6 months is superior to dimethyl fumarate in preventing relapses over 24 months in patients with early relapsing-remitting multiple sclerosis. Health economic and long-term safety studies of rituximab in patients with multiple sclerosis are needed.

FUNDING:

Swedish Research Council.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Esclerose Múltipla Recidivante-Remitente / Esclerose Múltipla Tipo de estudo: Clinical_trials / Guideline Limite: Adolescent / Adult / Humans / Middle aged País/Região como assunto: Europa Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Esclerose Múltipla Recidivante-Remitente / Esclerose Múltipla Tipo de estudo: Clinical_trials / Guideline Limite: Adolescent / Adult / Humans / Middle aged País/Região como assunto: Europa Idioma: En Ano de publicação: 2022 Tipo de documento: Article