Active Conventional Therapy Compared to Three Different Biologic Treatments in Early Rheumatoid Arthritis With Subsequent Dose Reduction
NCT ID: NCT01491815
Last Updated: 2022-07-08
Study Results
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Basic Information
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UNKNOWN
PHASE4
812 participants
INTERVENTIONAL
2012-12-14
2023-12-31
Brief Summary
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1. the proportion of subjects who achieve remission with ACT versus three different biologic therapies (Certolizumab-pegol, Abatacept or Tocilizumab)
2. two alternative de-escalation strategies in patients who respond to first-line therapy.
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Detailed Description
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371 of the included patients have entered treatment part 2, 256 patients have exited the study after treatment part 1, 207 patients have had early termination and 322 patients have completed the full study.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
SINGLE
Study Groups
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Active conventional therapy (ACT)
Non-biological DMARD's: Methotrexate plus steroids or Methotrexate plus Sulphasalazine and Hydroxychloroquine and steroids
Non-biological DMARD's
Methotrexate: 25mg/week. SSZ: 2 g/day. HCQ: 35 mg/kg/week (Finland and Denmark) Methotrexate: 25mg/week. Prednisolone 20 mg/day tapered in 9 weeks to 5 mg/day, discontinued after 9 months. (Sweden, Norway, Iceland, and the Netherlands)
Biologic agent 1
Cimzia: Certolizumab-pegol plus Methotrexate and steroids
Cimzia
Certolizumab-pegol: 200 mg s.c. every other week. Methotrexate: 25mg/week
Biologic agent 2
Orencia: Abatacept plus Methotrexate and steroids
Orencia
Abatacept: 125 mg s.c. every week. Methotrexate: 25mg/week
Biologic agent 3
RoActemra: Tocilizumab plus Methotrexate and steroids
RoActemra
Tocilizumab is given as 4-weekly infusions at dosage 8 mg/kg or 162 mg in solution s.c. every week.
Methotrexate: 25mg/week
Interventions
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Non-biological DMARD's
Methotrexate: 25mg/week. SSZ: 2 g/day. HCQ: 35 mg/kg/week (Finland and Denmark) Methotrexate: 25mg/week. Prednisolone 20 mg/day tapered in 9 weeks to 5 mg/day, discontinued after 9 months. (Sweden, Norway, Iceland, and the Netherlands)
Cimzia
Certolizumab-pegol: 200 mg s.c. every other week. Methotrexate: 25mg/week
Orencia
Abatacept: 125 mg s.c. every week. Methotrexate: 25mg/week
RoActemra
Tocilizumab is given as 4-weekly infusions at dosage 8 mg/kg or 162 mg in solution s.c. every week.
Methotrexate: 25mg/week
Eligibility Criteria
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Inclusion Criteria
3. \<24 months from arthritis symptom debut (symptom duration will be registered).
4. Subject must have DAS28 (CRP) \> 3.2.
5. ≥ 2 swollen joints AND ≥ 2 tender joints.
6. Subject must fulfill one of the following three criteria: RF positive OR ACPA positive OR CRP \>10 mg/L.
7. Female subject is either not of childbearing potential (postmenopausal, surgically sterile etc.), or is of childbearing potential and practicing one of the following methods of birth control throughout the study and for 150 days after study completion:
* Intrauterine device (IUD)
* Contraceptives (oral, parenteral, patch) for three months prior to study drug administration)
* A vasectomized partner
8. Female subjects of childbearing potential must have a negative serum pregnancy test at the Screening visit.
9. Subject is judged to be in good general health as determined by the principal investigator based upon the results of medical history, laboratory profile, physical examination, chest X-ray (CXR), and 12-lead electrocardiogram (ECG) performed at Screening.
10. Subjects must be able and willing to provide written informed consent and comply with the requirements of this study protocol.
11. Subjects must be able and willing to self-administer s.c. injections or have a qualified person available to administer s.c. injections.
Exclusion Criteria
2. Current active inflammatory joint disease other than RA.
3. Subjects has had a dose of prednisone (or equivalent) \>7.5 mg/day or has had a dose change within the preceding 4 weeks.
4. Subject has been treated with intra-articular or parenteral administration of corticosteroids in the preceding 4 weeks. Inhaled corticosteroids for stable medical conditions are allowed.
5. Subject has undergone joint surgery within the preceding two months (at joints to be assessed within the study).
6. Subject has chronic arthritis diagnosed before age 17 years.
7. Subject has a history of an allergic reaction or significant sensitivity to constituents of study drugs.
8. Subject has been treated with any investigational drug within one month prior to screening visit.
9. Active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization within 4 weeks of screening.
10. Subject has a poorly controlled medical condition, such as uncontrolled diabetes, unstable heart disease, congestive heart failure, recent cerebrovascular accidents and any other condition which, in the opinion of the investigator, would put the subject at risk by participation in the study.
11. Subject has a history of clinically significant hematologic (e.g., severe anemia, leukopenia, thrombocytopenia), renal or liver disease (e.g., fibrosis, cirrhosis, hepatitis).
12. Subject has history of neurologic symptoms suggestive of central nervous system (CNS) demyelinating disease and/or diagnosis of central demyelinating disease.
13. Subject has history of cancer or lymphoproliferative disease. Allowable exceptions:
1. Successfully treated cutaneous squamous cell or basal cell carcinoma
2. Localized carcinoma in situ of the cervix
3. Curatively treated malignancy (treatment terminated) \> 5 years prior to screening
14. Subject has a history of listeriosis, histoplasmosis, untreated TB, persistent chronic infections, or recent active infections requiring hospitalization or treatment with intravenous (iv) anti-infectives within 30 days or oral anti-infectives within 14 days prior to the BL visit.
15. Subjects will be evaluated for latent TB infection with a PPD or QuantiFERON test and X-ray. Subjects with evidence for latent TB will not be enrolled but first assessed according to local guidelines.
16. Subject is known to have immune deficiency, history of Human Immunodeficiency Virus (HIV) or is otherwise severely immunocompromised.
17. Female subject who is pregnant or breast-feeding or considering becoming pregnant during the study or within 150 days after the last dose of study medication.
18. Men who are planning to father a child during the time they are included in the study
19. Subject has a history of clinically significant drug or alcohol usage in the last year.
20. Subject has a chronic widespread pain syndrome.
21. Subject is considered by the investigator, for any reason, to be an unsuitable candidate for the study.
22. Subject is unwilling to comply with the study protocol.
23. Screening clinical laboratory analyses show any of the following abnormal laboratory results:
1. Aspartate transaminase (AST) or alanine transaminase (ALT) \> 1.75 times upper limit of normal (ULN).
2. Positive serum human chorionic gonadotropin (hCG).
3. Positive tests for hepatitis B surface antigen (HBsAg) or hepatitis C serology indicative of current infection.
4. Creatinine levels \> 2x the ULN. If creatinine 1-2 times ULN, check GFR.
5. Hemoglobin \< 90 g/L.
6. Absolute neutrophil count (ANC) \< 1.5 x 10\^3/microL.
7. Serum total bilirubin \> 1.5 mg/dL (\>26 micromol/L).
18 Years
ALL
No
Sponsors
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Karolinska Institutet
OTHER
Responsible Party
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Ronald van Vollenhoven, prof.
Principal Investigator
Principal Investigators
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Ronald van Vollenhoven, MD, Prof.
Role: PRINCIPAL_INVESTIGATOR
The Karolinska Institute
Locations
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Aalborg University Hospital
Aalborg, , Denmark
Aarhus University Hospital
Aarhus, , Denmark
Rigshospitalet
Copenhagen, , Denmark
Odense University Hospital
Odense, , Denmark
Silkeborg University Clinic
Silkeborg, , Denmark
Svendborg Hospital OUH
Svendborg, , Denmark
University Hospital of Southern Denmark
Sønderborg, , Denmark
Helsinki University Central Hospital
Helsinki, , Finland
Central Finland Central Hospital
Jyväskylä, , Finland
Kuopio University Hospital
Kuopio, , Finland
Tampere University Hospital
Tampere, , Finland
Landspitali University Hospital
Reykjavik, , Iceland
Reade
Amsterdam, , Netherlands
Ålesund Hospital
Ålesund, , Norway
Haukeland University Hospital
Bergen, , Norway
Diakonhjemmet Hospital
Oslo, , Norway
University Hospital of North Norway
Tromsø, , Norway
St. Olav's Hospital
Trondheim, , Norway
Falu Hospital
Falun, , Sweden
Sahlgrenska University Hospital
Gothenburg, , Sweden
The Karolinska University Hospital
Huddinge, , Sweden
Linköping University Hospital
Linköping, , Sweden
Skåne University Hospital
Lund, , Sweden
Skåne University Hospital
Malmo, , Sweden
Örebro University Hospital
Örebro, , Sweden
The Karolinska University Hospital
Solna, , Sweden
Academic Specialist Center
Stockholm, , Sweden
The Karolinska Institutet
Stockholm, , Sweden
Uppsala University Hospital
Uppsala, , Sweden
Västmanlands Hospital
Västerås, , Sweden
Countries
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References
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Lend K, Twisk JW, Kumar N, Dijkshoorn B, Lampa J, Rudin A, Hetland ML, Uhlig T, Nordstrom D, Ostergaard M, Gudbjornsson B, Sokka-Isler T, Grondal G, Horslev-Petersen K, Nurmohamed MT, Frostegard J, van Vollenhoven RF. Glucocorticoid treatment in early rheumatoid arthritis is independently associated with increased PCSK9 levels: data from a randomised controlled trial. RMD Open. 2025 Jun 5;11(2):e005129. doi: 10.1136/rmdopen-2024-005129.
Lend K, Lampa J, Padyukov L, Hetland ML, Heiberg MS, Nordstrom DC, Nurmohamed MT, Rudin A, Ostergaard M, Haavardsholm EA, Horslev-Petersen K, Uhlig T, Sokka-Isler T, Gudbjornsson B, Grondal G, Frazzei G, Christiaans J, Wolbink G, Rispens T, Twisk JWR, van Vollenhoven RF. Association of rheumatoid factor, anti-citrullinated protein antibodies and shared epitope with clinical response to initial treatment in patients with early rheumatoid arthritis: data from a randomised controlled trial. Ann Rheum Dis. 2024 Nov 14;83(12):1657-1665. doi: 10.1136/ard-2024-226024.
Dubovyk V, Vasileiadis GK, Fatima T, Zhang Y, Kapetanovic MC, Kastbom A, Rizk M, Soderbergh A, Zhao SS, van Vollenhoven RF, Hetland ML, Haavardsholm EA, Nordstrom D, Nurmohamed MT, Gudbjornsson B, Lampa J, Ostergaard M, Heiberg MS, Sokka-Isler T, Grondal G, Lend K, Horslev-Petersen K, Uhlig T, Rudin A, Maglio C. Obesity is a risk factor for poor response to treatment in early rheumatoid arthritis: a NORD-STAR study. RMD Open. 2024 Apr 4;10(2):e004227. doi: 10.1136/rmdopen-2024-004227.
Ostergaard M, van Vollenhoven RF, Rudin A, Hetland ML, Heiberg MS, Nordstrom DC, Nurmohamed MT, Gudbjornsson B, Ornbjerg LM, Boyesen P, Lend K, Horslev-Petersen K, Uhlig T, Sokka T, Grondal G, Krabbe S, Lindqvist J, Gjertsson I, Glinatsi D, Kapetanovic MC, Aga AB, Faustini F, Parmanne P, Lorenzen T, Giovanni C, Back J, Hendricks O, Vedder D, Rannio T, Grenholm E, Ljosa MK, Brodin E, Lindegaard H, Soderbergh A, Rizk M, Kastbom A, Larsson P, Uhrenholt L, Just SA, Stevens DJ, Bay Laurbjerg T, Bakland G, Olsen IC, Haavardsholm EA, Lampa J; NORD-STAR study group. Certolizumab pegol, abatacept, tocilizumab or active conventional treatment in early rheumatoid arthritis: 48-week clinical and radiographic results of the investigator-initiated randomised controlled NORD-STAR trial. Ann Rheum Dis. 2023 Oct;82(10):1286-1295. doi: 10.1136/ard-2023-224116. Epub 2023 Jul 9.
Stockfelt M, Lundell AC, Hetland ML, Ostergaard M, Uhlig T, Heiberg MS, Haavardsholm EA, Nurmohamed MT, Lampa J, Nordstrom D, Petersen KH, Gudbjornsson B, Grondal G, Aldridge J, Andersson K, Blennow K, Zetterberg H, van Vollenhoven R, Rudin A. Plasma interferon-alpha is associated with double-positivity for autoantibodies but is not a predictor of remission in early rheumatoid arthritis-a spin-off study of the NORD-STAR randomized clinical trial. Arthritis Res Ther. 2021 Jul 13;23(1):189. doi: 10.1186/s13075-021-02556-1.
Hetland ML, Haavardsholm EA, Rudin A, Nordstrom D, Nurmohamed M, Gudbjornsson B, Lampa J, Horslev-Petersen K, Uhlig T, Grondal G, Ostergaard M, Heiberg MS, Twisk J, Lend K, Krabbe S, Hyldstrup LH, Lindqvist J, Hultgard Ekwall AK, Gron KL, Kapetanovic M, Faustini F, Tuompo R, Lorenzen T, Cagnotto G, Baecklund E, Hendricks O, Vedder D, Sokka-Isler T, Husmark T, Ljosa MA, Brodin E, Ellingsen T, Soderbergh A, Rizk M, Olsson AR, Larsson P, Uhrenholt L, Just SA, Stevens DJ, Laurberg TB, Bakland G, Olsen IC, van Vollenhoven R; NORD-STAR study group. Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial. BMJ. 2020 Dec 2;371:m4328. doi: 10.1136/bmj.m4328.
Glinatsi D, Heiberg MS, Rudin A, Nordstrom D, Haavardsholm EA, Gudbjornsson B, Ostergaard M, Uhlig T, Grondal G, Horslev-Petersen K, van Vollenhoven R, Hetland ML. Head-to-head comparison of aggressive conventional therapy and three biological treatments and comparison of two de-escalation strategies in patients who respond to treatment: study protocol for a multicenter, randomized, open-label, blinded-assessor, phase 4 study. Trials. 2017 Apr 4;18(1):161. doi: 10.1186/s13063-017-1891-x.
Study Documents
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Document Type: Study Protocol
Publication of the protocol. Glinatsi et al. Trials (2017) 18:161
View DocumentOther Identifiers
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2011-004720-35
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
2011/2069-31/4
Identifier Type: OTHER
Identifier Source: secondary_id
NORD-STAR
Identifier Type: -
Identifier Source: org_study_id
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