Clinical trial NCT03649061: COBRA-Slim With or Without Fast Access to TNF Blockade for Remission Induction in Early RA
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Arthritis, Rheumatoid
Keywords: COBRA-Slim
Accelerated access to anti-TNF
treat to target
remission induction
Lead sponsor: Universitaire Ziekenhuizen KU Leuven
Sponsor class: OTHER
Collaborators: name: Belgium Health Care Knowledge Centre
First posted: 2018-08-28
Enrollment: 284
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

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.


Eligibility criteria: 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-

Primary outcomes:
measure: Area Under Curve (AUC) DAS28 C reactive protein (CRP)
timeFrame: over 104 weeks
Secondary outcomes:
measure: Remission
timeFrame: at 28 weeks after randomization
measure: Remission
timeFrame: at week 104
measure: EULAR response
timeFrame: at 28 weeks after randomization
measure: EULAR response
timeFrame: at week 104
measure: Health Assessment Questionnaire (HAQ) response
timeFrame: at 28 weeks after randomization
measure: Health Assessment Questionnaire (HAQ) response
timeFrame: at week 104
measure: Radiographic progression
timeFrame: at week 52
measure: Radiographic progression
timeFrame: at week 104
measure: Analysis of reported (Serious) Adverse Reactions
timeFrame: over 104 weeks
Other outcomes:
Locations:
city: Bonheiden
country: Belgium
facility: Imelda Ziekenhuis Bonheiden
state: Antwerpen
city: Herentals
country: Belgium
facility: AZ Herentals
state: Antwerpen
city: Merksem
country: Belgium
facility: ZNA Jan Palfijn
state: Antwerpen
city: Gilly
country: Belgium
facility: GHdC Saint Joseph
state: Henegouwen
city: Genk
country: Belgium
facility: Reuma centrum Genk
state: Limburg
city: Genk
country: Belgium
facility: Reuma Clinic Genk
state: Limburg
city: Hasselt
country: Belgium
facility: Reuma Instituut Hasselt
state: Limburg
city: Yvoir
country: Belgium
facility: CHU UCL Namur ASBL Site Godinne
state: Namur
city: Aalst
country: Belgium
facility: OLV Ziekenhuis Aalst
state: Oost Vlaanderen
city: Leuven
country: Belgium
facility: Regionaal Ziekenhuis Heilig Hart Leuven
state: Vlaams Brabant
city: Leuven
country: Belgium
facility: UZ Leuven
state: Vlaams Brabant
city: Vilvoorde
country: Belgium
facility: AZ Jan Portaels
state: Vlaams Brabant
city: Brugge
country: Belgium
facility: AZ St Lucas Brugge
state: West Vlaanderen
city: Brugge
country: Belgium
facility: AZ Sint Jan Brugge
state: West-Vlaanderen
city: Brussels
country: Belgium
facility: UZ Brussel
city: Brussel
country: Belgium
facility: CHU Saint Pierre
city: Brussel
country: Belgium
facility: Cliniques Universitaire Saint Luc (UCL)
city: Brussel
country: Belgium
facility: Hôpital Erasme-ULB
city: Liège
country: Belgium
facility: CHU Liège
Study officials:
affiliation: UZ Leuven
name: Patrick Verschueren, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.