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

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
.