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.

• Register: EUCTR
• Last refreshed on: 14 August 2012
• Main ID: EUCTR2011-004720-35-SE
• Date of registration: 22/12/2011
• Prospective Registration: Yes
• Primary sponsor: The Karolinska Institute, ClinTRID
• Public 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.
• Scientific 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. - NORD-STAR
• Date of first enrolment: 28/05/2012
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-004720-35
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 4

Countries of recruitment

Sweden

Contacts

• Name: Central Study Coordinating Team
• Affiliation: The Karolinska Institute

• Name: Central Study Coordinating Team
• Affiliation: The Karolinska Institute

Key inclusion & exclusion 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 (Appendix D). (Patients should also be classified according to the 1987-revised ACR-classification criteria, without this being an inclusion criteria) (Appendix C).
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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

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:
a. Successfully treated cutaneous squamous cell or basal cell carcinoma
b. Localized carcinoma in situ of the cervix
c. 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. Subject has a history of clinically significant drug or alcohol usage in the last year.
19. Subject has a chronic widespread pain syndrome.
20. Subject is considered by the investigator, for any reason, to be an unsuitable candidate for the study.
21. Subject is unwilling to comply with the study protocol.
22. Screening clinical laboratory analyses show any of the following abnormal laboratory results:
a. Aspartate transaminase (AST) or alanine transaminase (ALT) > 1.75 times upper limit of normal (ULN).
b. Positive serum human chorionic gonadotropin (hCG).
c. Positive tests for hepatitis B surface antigen (HBsAg) or hepatitis C serology indicative of current infection.
d. Creatinine level

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Rheumatoid arthritis (RA)
MedDRA version: 14.1 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395 - Musculoskeletal and connective tissue disorders

Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

Intervention(s)

Trade Name: Cimzia
Pharmaceutical Form: Injection

Trade Name: Orencia
Pharmaceutical Form: Solution for injection in pre-filled syringe

Trade Name: RoActemra
Pharmaceutical Form: Infusion

Pharmaceutical Form: Tablet
INN or Proposed INN: METHOTREXATE
CAS Number: 59-05-2
Concentration unit: mg milligram(s)
Concentration type: range
Concentration number: 20-25

Trade Name: Metoject
Pharmaceutical Form:

Pharmaceutical Form: Tablet
CAS Number: 446-86-6
Other descriptive name: AZATHIOPRINE
Concentration unit: mg/kg milligram(s)/kilogram
Concentration type: range
Concentration number: 2-2,5

Pharmaceutical Form: Tablet
INN or Proposed INN: LEFLUNOMIDE
CAS Number: 75706-12-6
Concentration unit: mg milligram(s)
Concentration type: range
Concentration number: 10-20

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: A. 24 weeks from baseline
B. 24 weeks after the dose was first reduced
C. 56 weeks from baseline

Main Objective: The objective of this study is to assess and compare 1) the proportion of subjects who achieve remission with active conventional therapy (ACT) versus three different biologic therapies; and 2) two alternative de-escalation strategies in patients who respond to first-line therapy.

Primary end point(s): A. Treatment Part 1: The primary efficacy outcome is the proportion of patients in remission at week 24 from baseline according to CDAI.

B. 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.

C. The primary efficacy outcome is the progression of total Sharp van der Heijde score after 56 weeks from baseline.

Secondary Objective:

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Clinical outcomes are relevant at all time points (vistits between 2-12 weeks of duration throughout the study)

Radiographic outcomes are relevant at all time points (vistits between 2-12 weeks of duration throughout the study)

Secondary end point(s): Clinical outcomes
1. CDAI/SDAI/2010 ACR/EULAR remission at all time points
2. ACR20/ACR50/ACR70/ACR-hybrid
3. DAS28 (based on ESR)
•values
•DAS28-ESR based disease categories
•EULAR responses
4. DAS28-CRP
•values
•DAS28-CRP based disease categories
•EULAR responses
5. SDAI, CDAI values
6. Core set variables (66/68 joint count)
7. FACIT fatigue score and VAS fatigue
8. WPAI
9. EQ5D
10. HAQ
11. SF36
12. Patient VAS for general health and pain assessment
13. Physician VAS for general health assessment

Radiographic outcomes
Change in modified total Sharp score, modified Sharp erosion score, modified Sharp joint space narrowing score, the proportion of patients without radiographic progression (defined as change in total modified Sharp score <= 0) and the reduction of predicted progression according to the published ”POPERA” model

Secondary ID(s)

NCT01491815

NORD-STAR

Source(s) of Monetary Support

Vetenskapsrådet

SLL (Stockholms Läns Landsting)