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

7 juli 2022 uppdaterad av: Ronald van Vollenhoven, prof., Karolinska Institutet

A Multicenter, Randomized, Open-label, Blinded-assessor, Phase 4 Study in Patients With Early Rheumatoid Arthritis to Compare Active Conventional Therapy Versus Three Biologic Treatments, and Two De-escalation Strategies in Patients Who Respond to Treatment

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. 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.

Studieöversikt

Status

Aktiv, inte rekryterande

Betingelser

Intervention / Behandling

Detaljerad beskrivning

After completed enrollment a total of 812 patients were included in the study.

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.

Studietyp

Interventionell

Inskrivning (Faktisk)

812

Fas

  • Fas 4

Kontakter och platser

Det här avsnittet innehåller kontaktuppgifter för dem som genomför studien och information om var denna studie genomförs.

Studieorter

  • Danmark
      • Aalborg, Danmark
        • Aalborg University Hospital
      • Aarhus, Danmark
        • Aarhus University Hospital
      • Copenhagen, Danmark
        • Rigshospitalet
      • Odense, Danmark
        • Odense University Hospital
      • Silkeborg, Danmark
        • Silkeborg University Clinic
      • Svendborg, Danmark
        • Svendborg Hospital OUH
      • Sønderborg, Danmark
        • University Hospital of Southern Denmark
  • Finland
      • Helsinki, Finland
        • Helsinki University Central Hospital
      • Jyväskylä, Finland
        • Central Finland Central Hospital
      • Kuopio, Finland
        • Kuopio University Hospital
      • Tampere, Finland
        • Tampere University Hospital
  • Island
      • Reykjavík, Island
        • Landspitali University Hospital
  • Nederländerna
      • Amsterdam, Nederländerna
        • Reade
  • Norge
      • Bergen, Norge
        • Haukeland University Hospital
      • Oslo, Norge
        • Diakonhjemmet Hospital
      • Tromsø, Norge
        • University Hospital of North Norway
      • Trondheim, Norge
        • St. Olav's Hospital
      • Ålesund, Norge
        • Ålesund Hospital
  • Sverige
      • Falun, Sverige
        • Falu Hospital
      • Gothenburg, Sverige
        • Sahlgrenska University Hospital
      • Huddinge, Sverige
        • The Karolinska University Hospital
      • Linköping, Sverige
        • Linköping University Hospital
      • Lund, Sverige
        • Skane University Hospital
      • Malmö, Sverige
        • Skane University Hospital
      • Solna, Sverige
        • The Karolinska University Hospital
      • Stockholm, Sverige
        • Academic Specialist Center
      • Stockholm, Sverige
        • The Karolinska Institutet
      • Uppsala, Sverige
        • Uppsala University Hospital
      • Västerås, Sverige
        • Västmanlands Hospital
      • Örebro, Sverige
        • Örebro University Hospital

Deltagandekriterier

Forskare letar efter personer som passar en viss beskrivning, så kallade behörighetskriterier. Några exempel på dessa kriterier är en persons allmänna hälsotillstånd eller tidigare behandlingar.

Urvalskriterier

Åldrar som är berättigade till studier

18 år och äldre (Vuxen, Äldre vuxen)

Tar emot friska volontärer

Nej

Kön som är behöriga för studier

Allt

Beskrivning

Inclusion Criteria:

  1. Subject is ≥18 years of age.
  2. Subject has a diagnosis of RA as defined by the newly established ACR/EULAR criteria, 2010. (Patients should also be classified according to the 1987-revised ACR-classification criteria, without this being an 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:

  1. Subject has been previously treated with disease modifying antirheumatic drugs (DMARDs) for rheumatic diseases.
  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).

Studieplan

Det här avsnittet ger detaljer om studieplanen, inklusive hur studien är utformad och vad studien mäter.

Hur är studien utformad?

Designdetaljer

  • Primärt syfte: Behandling
  • Tilldelning: Randomiserad
  • Interventionsmodell: Parallellt uppdrag
  • Maskning: Enda

Vapen och interventioner

Deltagargrupp / Arm
Intervention / Behandling
Aktiv komparator: Active conventional therapy (ACT)
Non-biological DMARD's: Methotrexate plus steroids or Methotrexate plus Sulphasalazine and Hydroxychloroquine and steroids
Läkemedel: 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)
Aktiv komparator: Biologic agent 1
Cimzia: Certolizumab-pegol plus Methotrexate and steroids
Biologisk: Cimzia
Certolizumab-pegol: 200 mg s.c. varannan vecka. Metotrexat: 25mg/vecka
Aktiv komparator: Biologic agent 2
Orencia: Abatacept plus Methotrexate and steroids
Biologisk: Orencia
Abatacept: 125 mg s.c. varje vecka. Metotrexat: 25mg/vecka
Aktiv komparator: Biologic agent 3
RoActemra: Tocilizumab plus Methotrexate and steroids
Biologisk: 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

Vad mäter studien?

Primära resultatmått

Resultatmått
Åtgärdsbeskrivning
Tidsram
The proportion of patients in remission at week 24 from baseline according to CDAI
Tidsram: 24 weeks from BL
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
Tidsram: 24 weeks after dose-reduction
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
Tidsram: 48 weeks from BL
The primary efficacy outcome is the progression of total Sharp van der Heijde score after 48 weeks from BL
48 weeks from BL

Samarbetspartners och utredare

Det är här du hittar personer och organisationer som är involverade i denna studie.

Sponsor

Karolinska Institutet

Utredare

  • Huvudutredare: Ronald van Vollenhoven, MD, Prof., The Karolinska Institute

Publikationer och användbara länkar

Den som ansvarar för att lägga in information om studien tillhandahåller frivilligt dessa publikationer. Dessa kan handla om allt som har med studien att göra.

Allmänna publikationer

Studieavstämningsdatum

Dessa datum spårar framstegen för inlämningar av studieposter och sammanfattande resultat till ClinicalTrials.gov. Studieposter och rapporterade resultat granskas av National Library of Medicine (NLM) för att säkerställa att de uppfyller specifika kvalitetskontrollstandarder innan de publiceras på den offentliga webbplatsen.

Studera stora datum

Studiestart (Faktisk)

14 december 2012

Primärt slutförande (Förväntat)

1 juli 2023

Avslutad studie (Förväntat)

1 december 2023

Studieregistreringsdatum

Först inskickad

8 december 2011

Först inskickad som uppfyllde QC-kriterierna

12 december 2011

Första postat (Uppskatta)

14 december 2011

Uppdateringar av studier

Senaste uppdatering publicerad (Faktisk)

8 juli 2022

Senaste inskickade uppdateringen som uppfyllde QC-kriterierna

7 juli 2022

Senast verifierad

1 juli 2022

Mer information

Termer relaterade till denna studie

Ytterligare relevanta MeSH-villkor

Andra studie-ID-nummer

  • NORD-STAR
  • 2011-004720-35 (EudraCT-nummer)
  • 2011/2069-31/4 (Annan identifierare: Regional Ethical Review Board)

Plan för individuella deltagardata (IPD)

Planerar du att dela individuella deltagardata (IPD)?

NEJ

Studiedata/dokument

  1. Studieprotokoll
    Informationskommentarer: Publication of the protocol. Glinatsi et al. Trials (2017) 18:161

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