COBRA-Slim With or Without Fast Access to TNF Blockade for Remission Induction in Early RA

Study Overview
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Brief Summary
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In the Care in Rheumatoid Arthritis (CareRA) trial (NCT01172639) about 70% of early RA patients are in remission at the 2 year evaluation point independent of the combination scheme used. Interesting to see is that the 30% of insufficient responders can be identified in an early stage of the treatment course. The purpose of the present study is to investigate if, for patients with an insufficient response to a COBRA-Slim regimen, accelerated access to a short course of anti-TNF therapy already early after treatment initiation (from w8 until w32) could improve outcomes compared to a more traditional treat to target sequence.

Official Title
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Effectiveness of a Combination of Methotrexate and a Step Down Glucocorticoid Regimen (COBRA-Slim) for Remission Induction in Patients With Early Rheumatoid Arthritis (RA), With or Without Fast Access to 24 Weeks of Tumor Necrosis Factor (TNF) Blockade in Insufficient Responders, a Randomized, Multicenter, Pragmatic Trial

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Drug: Etanercept 50 MG/ML
* Drug: Leflunomide 10 milligram (MG)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years and older Diagnosis of RA as defined by the American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) 2010 criteria for early RA Early RA defined by a diagnosis made ≤ 1 year ago. Use a reliable method of contraception for women of childbearing potential to be evaluated as in daily clinical practice Able and willing to give written informed consent and to participate in the study Understanding and able to write Dutch or French Exclusion Criteria: Previous treatment with: Methotrexate (MTX) or leflunomide cyclophosphamide, azathioprine or cyclosporine sulphasalazine (SSZ) for more than 3 weeks hydroxychloroquine for more than 6 weeks oral Glucocorticoids (GC) for more than 4 weeks within 4 months before screening oral GC at a daily dosage of more than 10 mg prednisone equivalent within 4 weeks before baseline oral GC at a daily dosage equal to or less than 10 mg prednisone equivalent within 2 weeks before baseline intra-articular GC within 4 weeks before BL an investigational drug for the treatment/prevention of RA History of chronic heart failure History of severe infections or chronic infection History of malignant neoplasm within 5 years Contra indications for GC Contra indications for TNF blocking agents Contra indications for MTX or leflunomide Psoriatic Arthritis Underlying cardiac, pulmonary, metabolic, renal or gastrointestinal conditions, chronic or latent infectious diseases or immune deficiency which in the opinion of the investigator places the patient at an unacceptable risk for participation in the study Pregnancy, breastfeeding or no use of a reliable method of contraception for woman of childbearing potential (as in daily clinical practice) Alcohol or drug abuse Active tuberculosis (TB) Latent TB unless adequate prophylactic treatment is given according to local guidelines No access to the Belgian Health Insurance system-

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Insufficient responders to a COBRA-Slim strategy, defined as not reaching low disease activity based on DAS28 CRP from week 8 until week 32 or not reaching remission based on DAS28 CRP at week 32, will be randomly assigned to one of the two arms. Randomization will be balanced according to time-point of randomization, baseline (BL) disease activity and Anti-Citrullinated Protein Antibody (ACPA) and Rheumatoid Factor (RF) status to ensure comparability of the treatment groups with respect to these prognostic variables.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: standard COBRA-Slim induction<br>Leflunomide 10mg PO daily added to the COBRA-Slim scheme (Methotrexate 15 mg PO weekly, Step down scheme of GC: 30-20-12,5-10-7,5-5 mg prednisone PO daily, each for 7 days except for the lowest dose of 5 mg, this will be maintained until w28 and then tapered to 2.5 mg daily for two weeks before stopping completely.) | Drug: Leflunomide 10 milligram (MG)<br>* Leflunomide 10mg PO daily added to the COBRA-Slim scheme<br>|
| Experimental: COBRA-Slim Bio-induction<br>Etanercept 50mg subcutaneous (SC) weekly added for 24 weeks to COBRA-Slim scheme (Methotrexate 15 mg PO weekly, Step down scheme of GC: 30-20-12,5-10-7,5-5 mg prednisone PO daily, each for 7 days except for the lowest dose of 5 mg, this will be maintained until w28 and then tapered to 2.5 mg daily for two weeks before stopping completely.) | Drug: Etanercept 50 MG/ML<br>* Etanercept 50mg subcutaneous (SC) weekly added for 24 weeks to COBRA-Slim scheme<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under Curve (AUC) DAS28 C reactive protein (CRP) |  | over 104 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Remission | DAS28 CRP<2.6 | at 28 weeks after randomization | 
| Remission | DAS28 CRP<2.6 | at week 104 | 
| EULAR response |  | at 28 weeks after randomization | 
| EULAR response |  | at week 104 | 
| Health Assessment Questionnaire (HAQ) response | HAQ measures physical function as reported by the patient, total score range from 0-3 of which higher scores represent worse physical function. | at 28 weeks after randomization | 
| Health Assessment Questionnaire (HAQ) response | HAQ measures physical function as reported by the patient, total score range from 0-3 of which higher scores represent worse physical function. | at week 104 | 
| Radiographic progression |  | at week 52 | 
| Radiographic progression |  | at week 104 | 
| Analysis of reported (Serious) Adverse Reactions | (Serious) Adverse Reactions will be captured by the investigator using his/her clinical judgement. Number of events will be analysed and described in total and per patient | over 104 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COBRA-Slim, Accelerated access to anti-TNF, treat to target, remission induction