TY - JOUR
T1 - Active conventional treatment and three different biological treatments in early rheumatoid arthritis
T2 - phase IV investigator initiated, randomised, observer blinded clinical trial
AU - Hetland, Merete Lund
AU - Haavardsholm, Espen A
AU - Rudin, Anna
AU - Nordström, Dan
AU - Nurmohamed, Michael
AU - Gudbjornsson, Bjorn
AU - Lampa, Jon
AU - Hørslev-Petersen, Kim
AU - Uhlig, Till
AU - Grondal, Gerdur
AU - Østergaard, Mikkel
AU - Heiberg, Marte S
AU - Twisk, Jos
AU - Lend, Kristina
AU - Krabbe, Simon
AU - Hyldstrup, Lise Hejl
AU - Lindqvist, Joakim
AU - Hultgård Ekwall, Anna-Karin
AU - Grøn, Kathrine Lederballe
AU - Kapetanovic, Meliha
AU - Faustini, Francesca
AU - Tuompo, Riitta
AU - Lorenzen, Tove
AU - Cagnotto, Giovanni
AU - Baecklund, Eva
AU - Hendricks, Oliver
AU - Vedder, Daisy
AU - Sokka-Isler, Tuulikki
AU - Husmark, Tomas
AU - Ljoså, Maud-Kristine Aga
AU - Brodin, Eli
AU - Ellingsen, Torkell
AU - Söderbergh, Annika
AU - Rizk, Milad
AU - Olsson, Åsa Reckner
AU - Larsson, Per
AU - Uhrenholt, Line
AU - Just, Søren Andreas
AU - Stevens, David John
AU - Laurberg, Trine Bay
AU - Bakland, Gunnstein
AU - Olsen, Inge C
AU - van Vollenhoven, Ronald
AU - NORD-STAR Study Group
N1 - © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2020/12/2
Y1 - 2020/12/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85097120848&partnerID=8YFLogxK
U2 - 10.1136/bmj.m4328
DO - 10.1136/bmj.m4328
M3 - Journal article
C2 - 33268527
SN - 0959-8146
VL - 371
JO - The BMJ
JF - The BMJ
M1 - m4328
ER -