Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial. (2nd December 2020)

• Record Type: Journal Article
• Authors: Hetland, Merete Lund; Haavardsholm, Espen A; Rudin, Anna; Nordström, Dan; Nurmohamed, Michael; Gudbjornsson, Bjorn; Lampa, Jon; Hørslev-Petersen, Kim; Uhlig, Till; Grondal, Gerdur; Østergaard, Mikkel; Heiberg, Marte S; Twisk, Jos; Lend, Kristina; Krabbe, Simon; Hyldstrup, Lise Hejl; Lindqvist, Joakim; Hultgård Ekwall, Anna-Karin; Grøn, Kathrine Lederballe; Kapetanovic, Meliha; Faustini, Francesca; Tuompo, Riitta; Lorenzen, Tove; Cagnotto, Giovanni; Baecklund, Eva; Hendricks, Oliver; Vedder, Daisy; Sokka-Isler, Tuulikki; Husmark, Tomas; Ljoså, Maud-Kristine Aga; Brodin, Eli; Ellingsen, Torkell; Söderbergh, Annika; Rizk, Milad; Olsson, Åsa Reckner; Larsson, Per; Uhrenholt, Line; Just, Søren Andreas; Stevens, David John; Laurberg, Trine Bay; Bakland, Gunnstein; Olsen, Inge C; van Vollenhoven, Ronald;
• Other Names: author non-byline.; Bengtsson Anders author non-byline.; Gülfe Anders author non-byline.; Aga Anna-Birgitte author non-byline.; Blanken Annelies author non-byline.; Schlemmer Annette author non-byline.; Kononoff Aulikki author non-byline.; Turesson Carl author non-byline.; Dackhammar Christina author non-byline.; Gentline Cidem author non-byline.; Glinatsi Daniel author non-byline.; Lindqvist Elisabet author non-byline.; Hauge Ellen-Margrethe author non-byline.; Hermansson Elsa author non-byline.; Grenholm Emma author non-byline.; af Klint Erik author non-byline.; Rødevand Erik author non-byline.; Markros Fredrik author non-byline.; Rezaei Hamed author non-byline.; Lindegaard Hanne Merete author non-byline.; Relas Heikki author non-byline.; Valleala Heikki author non-byline.; Qirjazo Ilia author non-byline.; Jensen Hansen Inger Marie author non-byline.; Rutanen Jarno author non-byline.; Pedersen Jens Kristian author non-byline.; Rathmann Jens author non-byline.; Back Johan author non-byline.; Wallman Johan author non-byline.; Carlestam Johanna author non-byline.; Einarsson Jon author non-byline.; Lysholm Jörgen author non-byline.; Öberg Kajsa author non-byline.; Almehed Katarina author non-byline.; Mykkänen Kati author non-byline.; Karlberg Lena author non-byline.; Hemberg Malin author non-byline.; Stilling-Vinther Maria K author non-byline.; Leirisalo-Repo Marjatta author non-byline.; Hameed Mohaned author non-byline.; Vivar Nancy author non-byline.; Kaipiainen-Seppänen Oili author non-byline.; Olsson Peter author non-byline.; Linge Petrus author non-byline.; Lindell Pia author non-byline.; Jensen Pia Neuer author non-byline.; Parmanne Pinja author non-byline.; Østgård René author non-byline.; Dieperink Sabine author non-byline.; Christiansen Sara Nysom author non-byline.; Exarchou Sofia author non-byline.; Saleh Thiab author non-byline.; Olofsson Tor author non-byline.; Bruun Trude author non-byline.; Rantalaiho Vappu author non-byline.; Borgas Ylva author non-byline.;
• Is Part Of: BMJ. Volume 371(2020)
• Publication Date: 2020-12-02
• Subjects: Medicine -- Periodicals; Medicine -- Periodicals; Medicine; Periodicals; 610
• DOI: 10.1136/bmj.m4328
• Languages: English
• ISSNs: 0007-1447

Abstract

Abstract: 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 .