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

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


Title: Active conventional treatment and three different biological treatments in early rheumatoid arthritis : Phase IV investigator initiated, randomised, observer blinded clinical trial
Author: Hetland, Merete Lund   orcid.org/0000-0003-4229-6818
Haavardsholm, Espen A.
Rudin, Anna
Nordström, Dan
Nurmohamed, Michael
Gudbjornsson, Bjorn   orcid.org/0000-0003-4631-6505
Lampa, Jon
Hørslev-Petersen, Kim
Uhlig, Till
Grondal, Gerdur
... 33 more authors Show all authors
Date: 2020-12-02
Language: English
Scope:
University/Institute: Landspitali - The National University Hospital of Iceland
Department: Faculty of Medicine
Internal Medicine and Emergency Services
Series: The BMJ; 371()
ISSN: 0959-8146
DOI: https://doi.org/10.1136/bmj.m4328
Subject: Medicine (all)
URI: https://hdl.handle.net/20.500.11815/3394

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Citation:

Hetland , M L , Haavardsholm , E A , Rudin , A , Nordström , D , Nurmohamed , M , Gudbjornsson , B , Lampa , J , Hørslev-Petersen , K , Uhlig , T , Grondal , G , Østergaard , M , Heiberg , M S , Twisk , J , Lend , K , Krabbe , S , Hyldstrup , L H , Lindqvist , J , Hultgård Ekwall , A K , Grøn , K L , Kapetanovic , M , Faustini , F , Tuompo , R , Lorenzen , T , Cagnotto , G , Baecklund , E , Hendricks , O , Vedder , D , Sokka-Isler , T , Husmark , T , Ljoså , M K A , Brodin , E , Ellingsen , T , Söderbergh , A , Rizk , M , Olsson , Å R , Larsson , P , Uhrenholt , L , Just , S A , Stevens , D J , Laurberg , T B , Bakland , G , Olsen , I C & Van Vollenhoven , R 2020 , ' Active conventional treatment and three different biological treatments in early rheumatoid arthritis : Phase IV investigator initiated, randomised, observer blinded clinical trial ' , The BMJ , vol. 371 , m4328 . https://doi.org/10.1136/bmj.m4328

Abstract:

AbstractObjective 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.

Description:

Funding was obtained through public sources: Academy of Finland (grant No 258536), Finska Läkaresällskapet, grant from the South-Eastern Health Region, Norway, HUCH Institutional grant, Finland (grant No 1159005), Icelandic Society for Rheumatology, interregional grant from all health regions in Norway, NordForsk (grant No 70945), Regionernes Medicinpulje, Denmark (grant No 14/217), Stockholm County Council, Sweden (grant No 20100490), Swedish Medical Research Council (grant No C0634901, D0342301, 2015-00891_5), Swedish Rheumatism Association, The Research Fund of University Hospital, Reykjavik, Iceland (A2015017). UCB supported the work in the context of an investigator initiated study where UCB provided certolizumab pegol at no cost. UCB had no role in study design, collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit for publication. Bristol-Myers Squibb (BMS) provided abatacept at no cost. In addition, the Karolinska Institute received several unrestricted grants from BMS; these were subsequently transferred to the principal investigators of Denmark, Finland, and the Netherlands to help defray various trial related costs at the local level. BMS had no role in study design, collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit for publication. The final manuscript was provided for courtesy review to UCB and BMS in line with Good Publication Practice (GPP3). We confirm the independence of researchers from funders and that all authors, external and internal, had full access to all of the data (including statistical reports and tables) in the study and can take responsibility of the integrity of the data and the accuracy of the data analysis. Publisher Copyright: ©

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