Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial

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DOI

  • Merete Lund Hetland, Københavns Universitet
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  • Espen A. Haavardsholm, Diakonhjemmet Hospital
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  • Anna Rudin, University of Gothenburg
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  • Dan Nordström, University of Helsinki
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  • Michael Nurmohamed, Amsterdam Rheumatology and Immunology Center, University of Amsterdam
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  • Bjorn Gudbjornsson, Landspitali University Hospital, University of Iceland
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  • Jon Lampa, Karolinska Institutet
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  • Kim Hørslev-Petersen, University Hospital of Southern Denmark, Syddansk Universitet
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  • Till Uhlig, Diakonhjemmet Hospital, University of Oslo
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  • Gerdur Grondal, Landspitali University Hospital, University of Iceland
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  • Mikkel Østergaard, Københavns Universitet
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  • Marte S. Heiberg, Diakonhjemmet Hospital
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  • Jos Twisk, University of Amsterdam
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  • Kristina Lend, Karolinska Institutet
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  • Simon Krabbe, Københavns Universitet
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  • Lise Hejl Hyldstrup, Københavns Universitet
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  • Joakim Lindqvist, Karolinska Institutet
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  • Anna Karin Hultgård Ekwall, University of Gothenburg
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  • Kathrine Lederballe Grøn, Københavns Universitet
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  • Meliha Kapetanovic, Lund University
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  • Francesca Faustini, Karolinska Institutet
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  • Riitta Tuompo, University of Helsinki
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  • Tove Lorenzen
  • Giovanni Cagnotto, Lund University, Lund University Diabetes Centre
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  • Eva Baecklund, Uppsala University
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  • Oliver Hendricks, University Hospital of Southern Denmark
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  • Daisy Vedder, Amsterdam Rheumatology and Immunology Center
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  • Tuulikki Sokka-Isler, University of Eastern Finland
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  • Tomas Husmark, Falun Central Hospital
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  • Maud Kristine Aga Ljoså, Ålesund Hospital
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  • Eli Brodin, University of Bergen
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  • Torkell Ellingsen, Syddansk Universitet
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  • Annika Söderbergh, Örebro University
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  • Milad Rizk, Västmanlands Hospital Västerås
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  • Åsa Reckner Olsson, Linköping University
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  • Per Larsson, Academic Specialist Center
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  • Line Uhrenholt, Aalborg Universitet
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  • Søren Andreas Just, Syddansk Universitet
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  • David John Stevens, Norwegian University of Science and Technology
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  • Trine Bay Laurberg
  • Gunnstein Bakland, University Hospital of North Norway
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  • Inge C. Olsen, University of Oslo
  • ,
  • Ronald van Vollenhoven, University of Amsterdam, Karolinska Institutet
  • ,
  • NORD-STAR study group

OBJECTIVE: To evaluate and compare benefits and harms of three biological treatments with different modes of action versus active conventional treatment in patients with early rheumatoid arthritis. DESIGN: Investigator initiated, randomised, open label, blinded assessor, multiarm, phase IV study. SETTING: Twenty nine rheumatology departments in Sweden, Denmark, Norway, Finland, the Netherlands, and Iceland between 2012 and 2018. PARTICIPANTS: Patients aged 18 years and older with treatment naive rheumatoid arthritis, symptom duration less than 24 months, moderate to severe disease activity, and rheumatoid factor or anti-citrullinated protein antibody positivity, or increased C reactive protein. INTERVENTIONS: Randomised 1:1:1:1, stratified by country, sex, and anti-citrullinated protein antibody status. All participants started methotrexate combined with (a) active conventional treatment (either prednisolone tapered to 5 mg/day, or sulfasalazine combined with hydroxychloroquine and intra-articular corticosteroids), (b) certolizumab pegol, (c) abatacept, or (d) tocilizumab. MAIN OUTCOME MEASURES: The primary outcome was adjusted clinical disease activity index remission (CDAI≤2.8) at 24 weeks with active conventional treatment as the reference. Key secondary outcomes and analyses included CDAI remission at 12 weeks and over time, other remission criteria, a non-inferiority analysis, and harms. RESULTS: 812 patients underwent randomisation. The mean age was 54.3 years (standard deviation 14.7) and 68.8% were women. Baseline disease activity score of 28 joints was 5.0 (standard deviation 1.1). Adjusted 24 week CDAI remission rates were 42.7% (95% confidence interval 36.1% to 49.3%) for active conventional treatment, 46.5% (39.9% to 53.1%) for certolizumab pegol, 52.0% (45.5% to 58.6%) for abatacept, and 42.1% (35.3% to 48.8%) for tocilizumab. Corresponding absolute differences were 3.9% (95% confidence interval -5.5% to 13.2%) for certolizumab pegol, 9.4% (0.1% to 18.7%) for abatacept, and -0.6% (-10.1% to 8.9%) for tocilizumab. Key secondary outcomes showed no major differences among the four treatments. Differences in CDAI remission rates for active conventional treatment versus certolizumab pegol and tocilizumab, but not abatacept, remained within the prespecified non-inferiority margin of 15% (per protocol population). The total number of serious adverse events was 13 (percentage of patients who experienced at least one event 5.6%) for active conventional treatment, 20 (8.4%) for certolizumab pegol, 10 (4.9%) for abatacept, and 10 (4.9%) for tocilizumab. Eleven patients treated with abatacept stopped treatment early compared with 20-23 patients in the other arms. CONCLUSIONS: All four treatments achieved high remission rates. Higher CDAI remission rate was observed for abatacept versus active conventional treatment, but not for certolizumab pegol or tocilizumab versus active conventional treatment. Other remission rates were similar across treatments. Non-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. The results highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids, with nominally better results for abatacept, in treatment naive early rheumatoid arthritis. TRIAL REGISTRATION: EudraCT2011-004720-35, NCT01491815.

OriginalsprogEngelsk
Artikelnummerm4328
TidsskriftBMJ (Clinical research ed.)
Vol/bind371
ISSN0959-8146
DOI
StatusUdgivet - dec. 2020

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