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

NCT03649061 | Completed Phase 4 Results DMC

• 2 other identifiers: KCE-160022017-004054-41
• Study Type: interventional
• Target: 276
• Locations: 1 country
• Sites: 19

Brief Summary

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.

Conditions

Arthritis, Rheumatoid

Keywords

COBRA-Slim; Accelerated access to anti-TNF; treat to target; remission induction

Outcome Measures

Primary Outcomes (1)

• Area Under Curve (AUC) of Disease Activity Score Based on a 28 Jointcount and C-reactive Protein (DAS28CRP)

  Analysis was based on an intention to treat population, which focused on all patients randomized into the study, irrespective if they actually received the randomized treatment. Fifty-five patients were allocated to Standard COBRA-Slim and 55 to COBRA-Slim Bio-induction. This measure is an indication of the total disease-activity over time or long-term effectiveness, a higher area under the curve indicates a higher disease activity over time and so a lower effectiveness over the time frame of the trial. The scale range for the duration of the trial (104 weeks) is 0.0 to 977.6 * remission: value below 270.4 * low disease activity: from 270.4 till 332.8 (included) * moderate disease activity: above 332.8 till 530.4 * high disease activity: above 530.4

  baseline, w4, w8, w16, w24, w32, w40, w52, w64, w78, w92 and w104

Secondary Outcomes (8)

• Proportion of Insufficient Responders Achieving Remission (DAS28CRP<2.6) 28 Weeks After Randomization (Short Term Efficacy) to Either COBRA-Slim Bio-Induction or Standard COBRA-Slim Induction

  From randomization till 28 weeks after randomization.

• Proportion of Patients in Remission Defined as DAS28CRP<2.6

  at week 104

• Proportion of Patients Achieving a EULAR Response

  at 28 weeks after randomization

• Proportion of Patients Achieving a EULAR Response

  at week 104

• Health Assessment Questionnaire (HAQ) Response

  at 28 weeks after randomization

Study Arms (2)

standard COBRA-Slim induction

ACTIVE COMPARATOR

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)

COBRA-Slim Bio-induction

EXPERIMENTAL

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

Interventions

Etanercept 50 MG/ML DRUG

Etanercept 50mg subcutaneous (SC) weekly added for 24 weeks to COBRA-Slim scheme

COBRA-Slim Bio-induction

Leflunomide 10 milligram (MG) DRUG

Leflunomide 10mg PO daily added to the COBRA-Slim scheme

standard COBRA-Slim induction

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• P. Verschueren: lead
• Belgium Health Care Knowledge Centre: collaborator

Study Sites (19)

Imelda Ziekenhuis Bonheiden

Bonheiden, Antwerpen, 2820, Belgium

Location

AZ Herentals

Herentals, Antwerpen, 2200, Belgium

Location

ZNA Jan Palfijn

Merksem, Antwerpen, 2170, Belgium

Location

GHdC Saint Joseph

Gilly, Henegouwen, 6060, Belgium

Location

Reuma centrum Genk

Genk, Limburg, 3600, Belgium

Location

Reuma Clinic Genk

Genk, Limburg, 3600, Belgium

Location

Reuma Instituut Hasselt

Hasselt, Limburg, 3500, Belgium

Location

CHU UCL Namur ASBL Site Godinne

Yvoir, Namur, 5530, Belgium

Location

OLV Ziekenhuis Aalst

Aalst, Oost Vlaanderen, 9300, Belgium

Location

Regionaal Ziekenhuis Heilig Hart Leuven

Leuven, Vlaams Brabant, 3000, Belgium

Location

UZ Leuven

Leuven, Vlaams Brabant, 3000, Belgium

Location

AZ Jan Portaels

Vilvoorde, Vlaams Brabant, 1800, Belgium

Location

AZ St Lucas Brugge

Bruges, West Vlaanderen, 8310, Belgium

Location

AZ Sint Jan Brugge

Bruges, West-Vlaanderen, 8000, Belgium

Location

CHU Saint Pierre

Brussels, 1000, Belgium

Location

Cliniques Universitaire Saint Luc (UCL)

Brussels, 1000, Belgium

Location

Hôpital Erasme-ULB

Brussels, 1070, Belgium

Location

UZ Brussel

Brussels, 1090, Belgium

Location

CHU Liège

Liège, 4000, Belgium

Location

Related Publications (14)

• Van der Elst K, De Cock D, Vecoven E, Arat S, Meyfroidt S, Joly J, Moons P, Verschueren P, Westhovens R, CareRA Study Group. Are illness perception and coping style associated with the delay between symptom onset and the first general practitioner consultation in early rheumatoid arthritis management? An exploratory study within the CareRA trial. Scand J Rheumatol. 2016;45(3):171-8. doi: 10.3109/03009742.2015.1074278. Epub 2015 Sep 23.

  PMID: 26399601 BACKGROUND

• Verschueren P, Esselens G, Westhovens R. Predictors of remission, normalized physical function, and changes in the working situation during follow-up of patients with early rheumatoid arthritis: an observational study. Scand J Rheumatol. 2009 May-Jun;38(3):166-72. doi: 10.1080/03009740802484846.

  PMID: 19169906 BACKGROUND

• Verschueren P, Westhovens R. The use of glucocorticoids in early rheumatoid arthritis. Rheumatology (Oxford). 2018 Aug 1;57(8):1316-1317. doi: 10.1093/rheumatology/kex271. No abstract available.

  PMID: 28968687 RESULT

• Verschueren P, De Cock D, Corluy L, Joos R, Langenaken C, Taelman V, Raeman F, Ravelingien I, Vandevyvere K, Lenaerts J, Geens E, Geusens P, Vanhoof J, Durnez A, Remans J, Vander Cruyssen B, Van Essche E, Sileghem A, De Brabanter G, Joly J, Meyfroidt S, Van der Elst K, Westhovens R. Effectiveness of methotrexate with step-down glucocorticoid remission induction (COBRA Slim) versus other intensive treatment strategies for early rheumatoid arthritis in a treat-to-target approach: 1-year results of CareRA, a randomised pragmatic open-label superiority trial. Ann Rheum Dis. 2017 Mar;76(3):511-520. doi: 10.1136/annrheumdis-2016-209212. Epub 2016 Jul 18.

  PMID: 27432356 RESULT

• De Cock D, Van der Elst K, Meyfroidt S, Verschueren P, Westhovens R. The optimal combination therapy for the treatment of early rheumatoid arthritis. Expert Opin Pharmacother. 2015;16(11):1615-25. doi: 10.1517/14656566.2015.1056735. Epub 2015 Jun 10.

  PMID: 26058860 RESULT

• Verschueren P, De Cock D, Corluy L, Joos R, Langenaken C, Taelman V, Raeman F, Ravelingien I, Vandevyvere K, Lenaerts J, Geens E, Geusens P, Vanhoof J, Durnez A, Remans J, Vander Cruyssen B, Van Essche E, Sileghem A, De Brabanter G, Joly J, Van der Elst K, Meyfroidt S, Westhovens R; CareRA study group. Patients lacking classical poor prognostic markers might also benefit from a step-down glucocorticoid bridging scheme in early rheumatoid arthritis: week 16 results from the randomized multicenter CareRA trial. Arthritis Res Ther. 2015 Apr 9;17(1):97. doi: 10.1186/s13075-015-0611-8.

  PMID: 25889222 RESULT

• Meyfroidt S, Van der Elst K, De Cock D, Joly J, Westhovens R, Hulscher M, Verschueren P. Patient experiences with intensive combination-treatment strategies with glucocorticoids for early rheumatoid arthritis. Patient Educ Couns. 2015 Mar;98(3):384-90. doi: 10.1016/j.pec.2014.11.011. Epub 2014 Nov 20.

  PMID: 25483574 RESULT

• Verschueren P, De Cock D, Corluy L, Joos R, Langenaken C, Taelman V, Raeman F, Ravelingien I, Vandevyvere K, Lenaerts J, Geens E, Geusens P, Vanhoof J, Durnez A, Remans J, Vander Cruyssen B, Van Essche E, Sileghem A, De Brabanter G, Joly J, Meyfroidt S, Van der Elst K, Westhovens R. Methotrexate in combination with other DMARDs is not superior to methotrexate alone for remission induction with moderate-to-high-dose glucocorticoid bridging in early rheumatoid arthritis after 16 weeks of treatment: the CareRA trial. Ann Rheum Dis. 2015 Jan;74(1):27-34. doi: 10.1136/annrheumdis-2014-205489. Epub 2014 Oct 30.

  PMID: 25359382 RESULT

• Meyfroidt S, van Hulst L, De Cock D, Van der Elst K, Joly J, Westhovens R, Hulscher M, Verschueren P. Factors influencing the prescription of intensive combination treatment strategies for early rheumatoid arthritis. Scand J Rheumatol. 2014;43(4):265-72. doi: 10.3109/03009742.2013.863382. Epub 2014 Feb 24.

  PMID: 24559216 RESULT

• Westhovens R, Verschueren P. Rheumatoid arthritis: defining remission in patients with RA in clinical practice. Nat Rev Rheumatol. 2012 Aug;8(8):445-7. doi: 10.1038/nrrheum.2012.111. Epub 2012 Jul 3. No abstract available.

  PMID: 22751567 RESULT

• Verschueren P, Westhovens R. Optimal care for early RA patients: the challenge of translating scientific data into clinical practice. Rheumatology (Oxford). 2011 Jul;50(7):1194-200. doi: 10.1093/rheumatology/ker131. Epub 2011 Mar 30.

  PMID: 21454307 RESULT

• Durez P, Malghem J, Nzeusseu Toukap A, Depresseux G, Lauwerys BR, Westhovens R, Luyten FP, Corluy L, Houssiau FA, Verschueren P. Treatment of early rheumatoid arthritis: a randomized magnetic resonance imaging study comparing the effects of methotrexate alone, methotrexate in combination with infliximab, and methotrexate in combination with intravenous pulse methylprednisolone. Arthritis Rheum. 2007 Dec;56(12):3919-27. doi: 10.1002/art.23055.

  PMID: 18050189 RESULT

• Boers M, Verhoeven AC, Markusse HM, van de Laar MA, Westhovens R, van Denderen JC, van Zeben D, Dijkmans BA, Peeters AJ, Jacobs P, van den Brink HR, Schouten HJ, van der Heijde DM, Boonen A, van der Linden S. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet. 1997 Aug 2;350(9074):309-18. doi: 10.1016/S0140-6736(97)01300-7.

  PMID: 9251634 RESULT

• Bertrand D, Joly J, Neerinckx B, Durez P, Lenaerts J, Joos R, Thevissen K, Zwaenepoel T, Vanhoof J, Di Romana S, Taelman V, Van Essche E, Corluy L, Ribbens C, Vanden Berghe M, Devinck M, Ajeganova S, Durnez A, Boutsen Y, Margaux J, Peene I, Van Offel J, Doumen M, Pazmino S, De Meyst E, Kulyk M, Creten N, Westhovens R, Verschueren P; CareRA2020 Study group. Effectiveness of methotrexate and bridging glucocorticoids with or without early introduction of a 6-month course of etanercept in early RA: results of the 2-year, pragmatic, randomised CareRA2020 trial. RMD Open. 2024 Aug 7;10(3):e004535. doi: 10.1136/rmdopen-2024-004535.

  PMID: 39117445 DERIVED

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

Etanercept

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)

Immunoglobulin Fc Fragments; Immunoglobulin Fragments; Peptide Fragments; Peptides; Amino Acids, Peptides, and Proteins; Immunoglobulin Constant Regions; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Serum Globulins; Globulins; Receptors, Tumor Necrosis Factor; Receptors, Cytokine; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins

Results Point of Contact

• Title: Prof. Dr. Patrick Verschueren
• Organization: UZLeuven

patrick.verschueren@uzleuven.be

+3216342541

Study Officials

• Patrick Verschueren, MD, PhD

  UZ Leuven

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. Dr.

Model Details: 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.

Study Record Dates

• First Submitted: July 30, 2018
• First Posted: August 28, 2018
• Study Start: June 8, 2018
• Primary Completion: July 1, 2022
• Study Completion: July 1, 2022
• Last Updated: June 19, 2025
• Results First Posted: June 19, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

BE (19)