Active Conventional Therapy Compared to Three Different Biologic Treatments in Early Rheumatoid Arthritis With Subsequent Dose Reduction

NCT01491815 | Unknown Phase 4 DMC

• 3 other identifiers: NORD-STAR2011-004720-352011/2069-31/4
• Study Type: interventional
• Target: 812
• Locations: 6 countries
• Sites: 30

Brief Summary

This is an international (Sweden, Finland, Norway, Denmark, Iceland and the Netherlands) trial designed to compare the safety and efficacy of active conventional therapy (ACT) and three biologic treatments in subjects with early rheumatoid arthritis (RA). The global aim of this study is to assess and compare

1. 1.the proportion of subjects who achieve remission with ACT versus three different biologic therapies (Certolizumab-pegol, Abatacept or Tocilizumab)
2. 2.two alternative de-escalation strategies in patients who respond to first-line therapy.

Conditions

Rheumatoid Arthritis

Outcome Measures

Primary Outcomes (3)

• The proportion of patients in remission at week 24 from baseline according to CDAI

  Treatment Part 1: The primary efficacy outcome is the proportion of patients in remission at week 24 from BL according to CDAI

  24 weeks from BL

• The proportion of patients in remission at week 24 after dose-reduction according to CDAI

  Treatment Part 2: The primary efficacy outcome is the proportion of patients in remission according to CDAI, at the time point 24 weeks after the dose was first reduced

  24 weeks after dose-reduction

• The radiographic progression of total Sharp van der Heijde score after 48 weeks from baseline

  The primary efficacy outcome is the progression of total Sharp van der Heijde score after 48 weeks from BL

  48 weeks from BL

Study Arms (4)

Active conventional therapy (ACT)

ACTIVE COMPARATOR

Non-biological DMARD's: Methotrexate plus steroids or Methotrexate plus Sulphasalazine and Hydroxychloroquine and steroids

Drug: Non-biological DMARD's

Biologic agent 1

ACTIVE COMPARATOR

Cimzia: Certolizumab-pegol plus Methotrexate and steroids

Biological: Cimzia

Biologic agent 2

ACTIVE COMPARATOR

Orencia: Abatacept plus Methotrexate and steroids

Biological: Orencia

Biologic agent 3

ACTIVE COMPARATOR

RoActemra: Tocilizumab plus Methotrexate and steroids

Biological: RoActemra

Interventions

Non-biological DMARD's DRUG

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)

Active conventional therapy (ACT)

Cimzia BIOLOGICAL

Certolizumab-pegol: 200 mg s.c. every other week. Methotrexate: 25mg/week

Biologic agent 1

Orencia BIOLOGICAL

Abatacept: 125 mg s.c. every week. Methotrexate: 25mg/week

Biologic agent 2

RoActemra BIOLOGICAL

Tocilizumab is given as 4-weekly infusions at dosage 8 mg/kg or 162 mg in solution s.c. every week. Methotrexate: 25mg/week

Biologic agent 3

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject is ≥18 years of age.
• \<24 months from arthritis symptom debut (symptom duration will be registered).
• Subject must have DAS28 (CRP) \> 3.2.
• ≥ 2 swollen joints AND ≥ 2 tender joints.
• Subject must fulfill one of the following three criteria: RF positive OR ACPA positive OR CRP \>10 mg/L.
• 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
• Female subjects of childbearing potential must have a negative serum pregnancy test at the Screening visit.
• 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.
• Subjects must be able and willing to provide written informed consent and comply with the requirements of this study protocol.
• Subjects must be able and willing to self-administer s.c. injections or have a qualified person available to administer s.c. injections.

You may not qualify if:

• Subject has been previously treated with disease modifying antirheumatic drugs (DMARDs) for rheumatic diseases.
• Current active inflammatory joint disease other than RA.
• Subjects has had a dose of prednisone (or equivalent) \>7.5 mg/day or has had a dose change within the preceding 4 weeks.
• 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.
• Subject has undergone joint surgery within the preceding two months (at joints to be assessed within the study).
• Subject has chronic arthritis diagnosed before age 17 years.
• Subject has a history of an allergic reaction or significant sensitivity to constituents of study drugs.
• Subject has been treated with any investigational drug within one month prior to screening visit.
• Active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization within 4 weeks of screening.
• 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.
• Subject has a history of clinically significant hematologic (e.g., severe anemia, leukopenia, thrombocytopenia), renal or liver disease (e.g., fibrosis, cirrhosis, hepatitis).
• Subject has history of neurologic symptoms suggestive of central nervous system (CNS) demyelinating disease and/or diagnosis of central demyelinating disease.
• Subject has history of cancer or lymphoproliferative disease. Allowable exceptions:
• Successfully treated cutaneous squamous cell or basal cell carcinoma
• Localized carcinoma in situ of the cervix

Sponsors & Collaborators

• Karolinska Institutet: lead

Study Sites (30)

Aalborg University Hospital

Aalborg, Denmark

Location

Aarhus University Hospital

Aarhus, Denmark

Location

Rigshospitalet

Copenhagen, Denmark

Location

Odense University Hospital

Odense, Denmark

Location

Silkeborg University Clinic

Silkeborg, Denmark

Location

Svendborg Hospital OUH

Svendborg, Denmark

Location

University Hospital of Southern Denmark

Sønderborg, Denmark

Location

Helsinki University Central Hospital

Helsinki, Finland

Location

Central Finland Central Hospital

Jyväskylä, Finland

Location

Kuopio University Hospital

Kuopio, Finland

Location

Tampere University Hospital

Tampere, Finland

Location

Landspitali University Hospital

Reykjavik, Iceland

Location

Reade

Amsterdam, Netherlands

Location

Ålesund Hospital

Ålesund, Norway

Location

Haukeland University Hospital

Bergen, Norway

Location

Diakonhjemmet Hospital

Oslo, Norway

Location

University Hospital of North Norway

Tromsø, Norway

Location

St. Olav's Hospital

Trondheim, Norway

Location

Falu Hospital

Falun, Sweden

Location

Sahlgrenska University Hospital

Gothenburg, Sweden

Location

The Karolinska University Hospital

Huddinge, Sweden

Location

Linköping University Hospital

Linköping, Sweden

Location

Skåne University Hospital

Lund, Sweden

Location

Skåne University Hospital

Malmo, Sweden

Location

Örebro University Hospital

Örebro, Sweden

Location

The Karolinska University Hospital

Solna, Sweden

Location

Academic Specialist Center

Stockholm, Sweden

Location

The Karolinska Institutet

Stockholm, Sweden

Location

Uppsala University Hospital

Uppsala, Sweden

Location

Västmanlands Hospital

Västerås, Sweden

Location

Related Publications (7)

• 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.

  PMID: 40480650 DERIVED

• 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.

  PMID: 39079894 DERIVED

• 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.

  PMID: 38580350 DERIVED

• 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.

  PMID: 37423647 DERIVED

• 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.

  PMID: 34256800 DERIVED

• 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.

  PMID: 33268527 DERIVED

• 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.

  PMID: 28376912 DERIVED

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

Certolizumab Pegol; Abatacept; tocilizumab

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Polyethylene Glycols; Polymers; Macromolecular Substances; Immunoglobulin Fab Fragments; Immunoglobulin Fragments; Peptide Fragments; Peptides; Amino Acids, Peptides, and Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Serum Globulins; Globulins; Immunoconjugates

Study Officials

• Ronald van Vollenhoven, MD, Prof.

  The Karolinska Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 8, 2011
• First Posted: December 14, 2011
• Study Start: December 14, 2012
• Primary Completion: July 1, 2023
• Study Completion: December 1, 2023
• Last Updated: July 8, 2022

Record last verified: 2022-07

Data Sharing

• IPD Sharing: Will not share

Locations

DK (7); IC (1); NL (1); NO (5); FI (4); SE (12)