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Tytuł pozycji:

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

Tytuł :
Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial.
Autorzy :
Hetland ML; Copenhagen Center for Arthritis Research (COPECARE) and DANBIO, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark .; Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Haavardsholm EA; Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.
Rudin A; Rheumatology Clinic, Sahlgrenska University Hospital, Gothenburg, Sweden.; Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy of University of Gothenburg, Gothenburg, Sweden.
Nordström D; Division of Rheumatology, Helsinki University Hospital, Helsinki, Finland.; University of Helsinki, Helsinki, Finland.
Nurmohamed M; Amsterdam Rheumatology and Immunology Center, Reade, Netherlands.; Department of Rheumatology and Amsterdam Rheumatology Center, Amsterdam University Medical Centers, Amsterdam, Netherlands.
Gudbjornsson B; Landspitali University Hospital, Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Lampa J; Department of Medicine, Rheumatology Unit, Center for Molecular Medicine (CMM), Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
Hørslev-Petersen K; Danish Hospital for Rheumatic Diseases, University Hospital of Southern Denmark, Sønderborg, Denmark.; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark.
Uhlig T; Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.; University of Oslo, Oslo, Norway.
Grondal G; Landspitali University Hospital, Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Østergaard M; Copenhagen Center for Arthritis Research (COPECARE) and DANBIO, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark.; Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Heiberg MS; Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.
Twisk J; Department of Epidemiology and Biostatistics, Amsterdam University Medical Centres, Amsterdam, Netherlands.
Lend K; Department of Medicine, Rheumatology Unit, Center for Molecular Medicine (CMM), Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
Krabbe S; Copenhagen Center for Arthritis Research (COPECARE) and DANBIO, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark.; Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Hyldstrup LH; Copenhagen Center for Arthritis Research (COPECARE) and DANBIO, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark.; Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Lindqvist J; Department of Medicine, Rheumatology Unit, Center for Molecular Medicine (CMM), Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
Hultgård Ekwall AK; Rheumatology Clinic, Sahlgrenska University Hospital, Gothenburg, Sweden.; Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy of University of Gothenburg, Gothenburg, Sweden.
Grøn KL; Copenhagen Center for Arthritis Research (COPECARE) and DANBIO, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark.
Kapetanovic M; Section of Rheumatology, Department of Clinical Sciences Lund, Skåne University Hospital, Lund and Malmö, Sweden.
Faustini F; Department of Medicine, Rheumatology Unit, Center for Molecular Medicine (CMM), Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
Tuompo R; Division of Rheumatology, Helsinki University Hospital, Helsinki, Finland.; University of Helsinki, Helsinki, Finland.
Lorenzen T; Department of Rheumatology, Silkeborg University Clinic, Silkeborg, Denmark.
Cagnotto G; Department of Rheumatology, Skåne University Hospital, Malmö, Sweden.; Rheumatology, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
Baecklund E; Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Hendricks O; Danish Hospital for Rheumatic Diseases, University Hospital of Southern Denmark, Sønderborg, Denmark.
Vedder D; Amsterdam Rheumatology and Immunology Center, Reade, Netherlands.
Sokka-Isler T; Department of Medicine and University of Eastern Finland, Jyväskylä Central Hospital, Jyväskylä, Finland.
Husmark T; Department of Rheumatology, Falu Hospital, Falun, Sweden.
Ljoså MA; Department of Rheumatology, Ålesund Hospital, Ålesund, Norway.
Brodin E; Department of Rheumatology, Haukeland University Hospital, Bergen, Norway.
Ellingsen T; Rheumatology Research Unit, Odense University Hospital, Southern University of Denmark, Denmark.
Söderbergh A; Department of Rheumatology, Örebro University Hospital, Örebro, Sweden.
Rizk M; Rheumatology Clinic, Västmanlands Hospital Västerås, Sweden.
Olsson ÅR; Department of Rheumatology, Linköping University Hospital, Sweden.
Larsson P; Academic Specialist Center, Stockholm, Sweden.
Uhrenholt L; Department of Rheumatology, Aalborg University Hospital, Aalborg, Denmark.
Just SA; Section of Rheumatology, Department of Medicine, Svendborg Hospital OUH, Denmark.
Stevens DJ; Department of Rheumatology, St Olav's Hospital, University Hospital of Trondheim, Trondheim, Norway.
Laurberg TB; Department of Rheumatology, Aarhus University Hospital, Denmark.
Bakland G; Department of Rheumatology, University Hospital of North Norway, Tromsø, Norway.
Olsen IC; Department of Research Support for Clinical Trials, Oslo University Hospital, Norway.
van Vollenhoven R; Department of Rheumatology and Amsterdam Rheumatology Center, Amsterdam University Medical Centers, Amsterdam, Netherlands.; Department of Medicine, Rheumatology Unit, Center for Molecular Medicine (CMM), Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
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Corporate Authors :
NORD-STAR study group
Źródło :
BMJ (Clinical research ed.) [BMJ] 2020 Dec 02; Vol. 371, pp. m4328. Date of Electronic Publication: 2020 Dec 02.
Typ publikacji :
Clinical Trial, Phase IV; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't
Język :
English
Imprint Name(s) :
Original Publication: London : British Medical Association
MeSH Terms :
Antirheumatic Agents/*therapeutic use
Arthritis, Rheumatoid/*drug therapy
Biological Products/*therapeutic use
Glucocorticoids/*therapeutic use
Methotrexate/*therapeutic use
Abatacept/therapeutic use ; Adult ; Aged ; Anti-Citrullinated Protein Antibodies/immunology ; Antibodies, Monoclonal, Humanized/therapeutic use ; Arthritis, Rheumatoid/immunology ; C-Reactive Protein/immunology ; Certolizumab Pegol/therapeutic use ; Denmark ; Drug Therapy, Combination ; Early Medical Intervention ; Female ; Finland ; Humans ; Hydroxychloroquine/therapeutic use ; Injections, Intra-Articular ; Male ; Middle Aged ; Netherlands ; Norway ; Prednisolone/therapeutic use ; Rheumatoid Factor/immunology ; Severity of Illness Index ; Single-Blind Method ; Sulfasalazine/therapeutic use ; Sweden ; Treatment Outcome
References :
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Ann Rheum Dis. 2015 Jan;74(1):27-34. (PMID: 25359382)
Trials. 2017 Apr 4;18(1):161. (PMID: 28376912)
Ann Rheum Dis. 2014 Jul;73(7):1331-9. (PMID: 24788619)
Ann Rheum Dis. 2014 Apr;73(4):654-61. (PMID: 23434570)
Ann Rheum Dis. 2008 Nov;67(11):1516-23. (PMID: 18625622)
Ann Rheum Dis. 2012 Jul;71(7):1190-6. (PMID: 22454398)
BMJ. 2010 Mar 23;340:c869. (PMID: 20332511)
Arthritis Rheum. 2008 Sep;58(9):2642-51. (PMID: 18759292)
Arthritis Rheum. 2012 Sep;64(9):2824-35. (PMID: 22508468)
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Arthritis Rheum. 2006 May;54(5):1401-9. (PMID: 16645967)
Ann Rheum Dis. 2013 Oct;72(10):1613-20. (PMID: 23687260)
Arthritis Rheum. 2010 Sep;62(9):2569-81. (PMID: 20872595)
Ann Rheum Dis. 2017 Jan;76(1):96-104. (PMID: 27165179)
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Lancet. 2009 Aug 8;374(9688):459-66. (PMID: 19665644)
Lancet. 2016 Dec 3;388(10061):2763-2774. (PMID: 27863807)
Arthritis Rheum. 2011 Mar;63(3):573-86. (PMID: 21294106)
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Arthritis Rheum. 1998 Oct;41(10):1845-50. (PMID: 9778226)
Lancet. 2017 Jun 10;389(10086):2304-2316. (PMID: 28502609)
Arthritis Rheum. 2004 Nov;50(11):3432-43. (PMID: 15529377)
Ann Rheum Dis. 1995 Dec;54(12):944-7. (PMID: 8546524)
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BMJ. 2020 Jul 7;370:m2288. (PMID: 32636183)
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Contributed Indexing :
Investigator: A Bengtsson; A Gülfe; AB Aga; A Blanken; A Schlemmer; A Kononoff; C Turesson; C Dackhammar; C Gentline; D Glinatsi; E Lindqvist; EM Hauge; E Hermansson; E Grenholm; E Af Klint; E Rødevand; F Markros; H Rezaei; HM Lindegaard; H Relas; H Valleala; I Qirjazo; IM Jensen Hansen; J Rutanen; JK Pedersen; J Rathmann; J Back; J Wallman; J Carlestam; J Einarsson; J Lysholm; K Öberg; K Almehed; K Mykkänen; L Karlberg; M Hemberg; MK Stilling-Vinther; M Leirisalo-Repo; M Hameed; N Vivar; O Kaipiainen-Seppänen; P Olsson; P Linge; P Lindell; PN Jensen; P Parmanne; R Østgård; S Dieperink; SN Christiansen; S Exarchou; T Saleh; T Olofsson; T Bruun; V Rantalaiho; Y Borgas
Molecular Sequence :
ClinicalTrials.gov NCT01491815
Substance Nomenclature :
0 (Anti-Citrullinated Protein Antibodies)
0 (Antibodies, Monoclonal, Humanized)
0 (Antirheumatic Agents)
0 (Biological Products)
0 (Glucocorticoids)
3XC8GUZ6CB (Sulfasalazine)
4QWG6N8QKH (Hydroxychloroquine)
7D0YB67S97 (Abatacept)
9007-41-4 (C-Reactive Protein)
9009-79-4 (Rheumatoid Factor)
9PHQ9Y1OLM (Prednisolone)
I031V2H011 (tocilizumab)
UMD07X179E (Certolizumab Pegol)
YL5FZ2Y5U1 (Methotrexate)
Entry Date(s) :
Date Created: 20201203 Date Completed: 20201222 Latest Revision: 20201222
Update Code :
20210301
PubMed Central ID :
PMC7708829
DOI :
10.1136/bmj.m4328
PMID :
33268527
Czasopismo naukowe
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.
(© 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.)

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