Clinical trial NCT01491815: Active Conventional Therapy Compared to Three Different Biologic Treatments in Early Rheumatoid Arthritis With Subsequent Dose Reduction
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Rheumatoid Arthritis
Lead sponsor: Karolinska Institutet
Sponsor class: OTHER
First posted: 2011-12-14
Enrollment: 812
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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. 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.

Detailed description: 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.

Eligibility criteria: 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).

Primary outcomes:
measure: The proportion of patients in remission at week 24 from baseline according to CDAI
timeFrame: 24 weeks from BL
measure: The proportion of patients in remission at week 24 after dose-reduction according to CDAI
timeFrame: 24 weeks after dose-reduction
measure: The radiographic progression of total Sharp van der Heijde score after 48 weeks from baseline
timeFrame: 48 weeks from BL
Secondary outcomes:
Other outcomes:
Locations:
city: Aalborg
country: Denmark
facility: Aalborg University Hospital
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Odense
country: Denmark
facility: Odense University Hospital
city: Silkeborg
country: Denmark
facility: Silkeborg University Clinic
city: Svendborg
country: Denmark
facility: Svendborg Hospital OUH
city: Sønderborg
country: Denmark
facility: University Hospital of Southern Denmark
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital
city: Jyväskylä
country: Finland
facility: Central Finland Central Hospital
city: Kuopio
country: Finland
facility: Kuopio University Hospital
city: Tampere
country: Finland
facility: Tampere University Hospital
city: Reykjavík
country: Iceland
facility: Landspitali University Hospital
city: Amsterdam
country: Netherlands
facility: Reade
city: Bergen
country: Norway
facility: Haukeland University Hospital
city: Oslo
country: Norway
facility: Diakonhjemmet Hospital
city: Tromsø
country: Norway
facility: University Hospital of North Norway
city: Trondheim
country: Norway
facility: St. Olav's Hospital
city: Ålesund
country: Norway
facility: Ålesund Hospital
city: Falun
country: Sweden
facility: Falu Hospital
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital
city: Huddinge
country: Sweden
facility: The Karolinska University Hospital
city: Linköping
country: Sweden
facility: Linköping University Hospital
city: Lund
country: Sweden
facility: Skåne University Hospital
city: Malmö
country: Sweden
facility: Skåne University Hospital
city: Solna
country: Sweden
facility: The Karolinska University Hospital
city: Stockholm
country: Sweden
facility: Academic Specialist Center
city: Stockholm
country: Sweden
facility: The Karolinska Institutet
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
city: Västerås
country: Sweden
facility: Västmanlands Hospital
city: Örebro
country: Sweden
facility: Örebro University Hospital
Study officials:
affiliation: The Karolinska Institute
name: Ronald van Vollenhoven, MD, Prof.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.