Clinical trial NCT03649061
Conditions: Arthritis, Rheumatoid
Keywords: COBRA-Slim Accelerated access to anti-TNF treat to target remission induction
Sponsor: P. Verschueren
Start date: 2018-06-08; Completion date: 2022-07-01
Enrollment: 276 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Detailed description:

Arms: arm 1: 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.) arm 2: 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.)
Interventions: intervention 1: Etanercept 50 MG/ML intervention 2: Leflunomide 10 milligram (MG)
Intervention descriptions: intervention 1: Etanercept 50mg subcutaneous (SC) weekly added for 24 weeks to COBRA-Slim scheme intervention 2: Leflunomide 10mg PO daily added to the COBRA-Slim scheme

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol 
Version 4.1 
CareRA2020 
29/04/2020 
EudraCT number:2017-004054-41 
KCE number: KCE-16002 
 
 
- 1 - 
 
 
 
 
 
 
 
 
 
 
CareRA2020: 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. 
 
 
 
 
 


Clinical Study Protocol 
Version 4.1 
CareRA2020 
29/04/2020 
EudraCT number:2017-004054-41 
KCE number: KCE-16002 
 
 
- 2 - 
 
Table of content 
Table of content ........................................................................................................................ 2 
General Information ................................................................................................................ 6 
Title Page ...................................................................................................................... 6 
Signature page ............................................................................................................... 7 
Signature on behalf of the sponsor/ Chief Investigator (CI) ......................................... 7 
Investigator Protocol signature Page ............................................................................. 8 
Key trial contacts .......................................................................................................... 9 
Trial Summary CareRA2020 ................................................................................................ 11 
Funding and support in kind................................................................................................. 17 
Financial support ......................................................................................................... 17 
Support in kind ............................................................................................................ 17 
Role of study sponsor .................................................................................................. 17 
Roles and responsibilities of trial management committees/groups & individuals ......... 17 
Study team and management group (STMG): ............................................................ 17 
Trial Steering Committee (TSC): ................................................................................ 17 
Chief investigator (CI) ................................................................................................ 18 
Local investigator ........................................................................................................ 18 
Protocol contributors ............................................................................................................. 18 
Key words ................................................................................................................................ 19 
List of Abbreviations .............................................................................................................. 19 
Trial flow chart ....................................................................................................................... 21 
Study protocol ......................................................................................................................... 23 
1 
Background and Rationale ....................................................................................... 23 
2 
Objectives and outcome measures/endpoints ......................................................... 24 
Primary objective ........................................................................................................ 24 
Secondary objectives................................................................................................... 24 
Other secondary exploratory objectives:..................................................................... 24 
Outcome measures/endpoints ..................................................................................... 25 
3 
Study design ............................................................................................................... 26 
Overall design ............................................................................................................. 26 
Initial protocol-based treat to target period (BL until w32): ....................................... 27 
Further protocol-based treat to target period (w32 until w104): ................................. 27 
CareRA2020 adaptation schedule ............................................................................... 28 
General rules for treatment adaptations during the study from baseline until w104 .. 29 
Important points to consider: ...................................................................................... 29 
Use of GC during the protocol: ................................................................................... 29 
Guidance on NSAID and analgesic use ...................................................................... 29 


Clinical Study Protocol 
Version 4.1 
CareRA2020 
29/04/2020 
EudraCT number:2017-004054-41 
KCE number: KCE-16002 
 
 
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Treatment failure during study .................................................................................... 30 
Treatment toxicity during study .................................................................................. 30 
4 
Study setting .............................................................................................................. 30 
Participating Centers ................................................................................................... 30 
5 
Study population ....................................................................................................... 31 
Number of patients and assignment to treatment groups ............................................ 31 
Inclusion criteria ......................................................................................................... 31 
Exclusion criteria ........................................................................................................ 31 
6 
Trial Procedures ........................................................................................................ 32 
Recruitment ................................................................................................................. 32 
Screening ..................................................................................................................... 32 
Consent ....................................................................................................................... 33 
The randomization scheme ......................................................................................... 33 
Method of implementing the allocation sequence ...................................................... 33 
Blinding ....................................................................................................................... 34 
Unblinding .................................................................................................................. 34 
Visits  ....................................................................................................................... 34 
BL data (w0) ............................................................................................................... 35 
Trial assessments......................................................................................................... 35 
Withdrawal of patients ................................................................................................ 37 
7 
Study related procedures .......................................................................................... 37 
Laboratory tests: .......................................................................................................... 37 
Medical history and demographic data ....................................................................... 37 
Clinical and Rheumatologic examination ................................................................... 38 
Tuberculosis (TB) screening: ...................................................................................... 38 
Patient Reported Outcomes (PROs) ............................................................................ 38 
End of trial .................................................................................................................. 38 
Study discontinuation .................................................................................................. 39 
Time schedule ............................................................................................................. 39 
8 
Trial medication ........................................................................................................ 39 
Name and description of investigational medicinal product(s) .................................. 39 
Name and description of each Non-Investigational Medicinal Product (NIMP) ........ 40 
Legal status of the drugs ............................................................................................. 40 
Summary of Product Characteristics (SmPC) ............................................................. 40 
Drug storage and supply ............................................................................................. 40 
Preparation and labelling of Investigational Medicinal Product ................................. 40 
Dosage schedules and modifications .......................................................................... 40 
Known drug reactions and interaction with other therapies ....................................... 40 
Relevant medication .................................................................................................... 40 
Trial restrictions .......................................................................................................... 41 


Clinical Study Protocol 
Version 4.1 
CareRA2020 
29/04/2020 
EudraCT number:2017-004054-41 
KCE number: KCE-16002 
 
 
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Assessment of compliance .......................................................................................... 41 
9 
Pharmacovigilance .................................................................................................... 41 
Definition of an adverse event .................................................................................... 41 
Definition of an adverse reaction (AR) ....................................................................... 41 
Adverse event of interest ............................................................................................. 42 
Laboratory Abnormalities: .......................................................................................... 42 
Definition of a Serious Adverse Event or Serious Adverse Reaction......................... 42 
Definition of a suspected unexpected serious adverse event (SUSAR) ...................... 42 
Collecting and Reporting of adverse events: .............................................................. 43 
Reporting of adverse events that meet seriousness criteria: ....................................... 43 
Safety committees ....................................................................................................... 45 
Pregnancy reporting .................................................................................................... 46 
Reporting urgent safety measures ............................................................................... 46 
10 
Statistics and data analysis ....................................................................................... 46 
Sample size calculation ............................................................................................... 46 
Planned recruitment rate ............................................................................................. 47 
Subject populations ..................................................................................................... 48 
Statistical analysis plan ............................................................................................... 48 
Flow Diagram ............................................................................................................. 50 
Primary outcome analysis ........................................................................................... 50 
Statement regarding use of intention to treat (ITT) analysis ...................................... 52 
Description of any non-statistical methods that might be used (e.g. qualitative 
methods)......................................................................................................... 52 
Secondary outcome analysis ....................................................................................... 52 
Adjusted analysis ........................................................................................................ 53 
Interim analysis and criteria for the premature termination of the trial ...................... 54 
Procedure(s) to account for missing or spurious data ................................................. 54 
Regarding trial planning and conduct: ........................................................................ 54 
Follow-up after Treatment Discontinuation: ............................................................... 54 
Other statistical considerations. .................................................................................. 55 
Economic evaluation ................................................................................................... 55 
11 
Data handling ............................................................................................................ 55 
Data collection tools and source document identification .......................................... 55 
Case report forms ........................................................................................................ 55 
Data handling and record keeping .............................................................................. 56 
12 
Study monitoring, audit and inspection .................................................................. 56 
13 
Archiving of Documentation .................................................................................... 56 
14 
Confidentiality ........................................................................................................... 58 
15 
Ethical and regulatory considerations .................................................................... 58 
Independent Ethics Committee (IEC) review& reports .............................................. 58 
Peer review .................................................................................................................. 58 


Clinical Study Protocol 
Version 4.1 
CareRA2020 
29/04/2020 
EudraCT number:2017-004054-41 
KCE number: KCE-16002 
 
 
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Public and Patient Involvement .................................................................................. 59 
16 
Regulatory Compliance ............................................................................................ 59 
Protocol compliance .................................................................................................... 59 
Notification of Serious Violation to GCP and/or the protocol.................................... 59 
Data protection and patient confidentiality ................................................................. 60 
Financial and other competing interests for the Chief Investigator, PIs at each site and 
committee members for the overall trial management .................................. 60 
Indemnity .................................................................................................................... 60 
Amendments ............................................................................................................... 61 
Post-trial care .............................................................................................................. 61 
Access to the final trial dataset ................................................................................... 61 
17 
Dissemination policy ................................................................................................. 61 
Dissemination policy................................................................................................... 61 
Authorship eligibility guidelines and any intended use of professional writers ......... 62 
18 
Reference List ............................................................................................................ 63 
19 
Appendices ................................................................................................................. 68 
Risk 
 ....................................................................................................................... 68 
Study management / responsibilities........................................................................... 68 
Patient registration/randomisation procedure ............................................................. 68 
Data management ........................................................................................................ 68 
Preparation and submission of amendments ............................................................... 68 
Data protection/confidentiality ................................................................................... 68 
Trial documentation and archiving ............................................................................. 68 
Authorisation of participating sites ............................................................................. 68 
Required documentation ............................................................................................. 69 
Procedure for initiating/opening a new site ................................................................ 69 
Principal Investigator responsibilities ......................................................................... 69 
Schedule of Procedures ............................................................................................... 70 
Safety Reporting Flow Chart ...................................................................................... 71 
Amendment History .................................................................................................... 71 
 
 
 


Clinical Study Protocol 
Version 4.1 
CareRA2020 
29/04/2020 
EudraCT number:2017-004054-41 
KCE number: KCE-16002 
 
 
- 6 - 
 
General Information 
 
Title Page 
 
CareRA2020: Effectiveness of a combination of methotrexate and 
a step down glucocorticoid regimen (COBRA-Slim) for remission 
induction in patients with early RA, with or without fast access to 
24 weeks of TNF blockade in insufficient responders, a 
randomized, multicenter, pragmatic trial. 
 
COBRA-Slim with or without fast access to TNF blockade for remission induction in early RA 
 
Study phase: 
IV 
 
EudraCT number: 
2017-004054-41 
 
Study n°: 
CareRA2020, version 4.1, 29/04/2020 
 
KCE number: 
KCE-16002 
 
Sponsor: 
This multi-center study is organized by the University Hospitals 
Leuven together with the investigator team of the Department of Rheumatology, Herestraat 49, 
3000 Leuven in close collaboration with other academic and peripheral rheumatology practices. 
 
It will be coordinated by Chief-Investigator: 
 
Prof. Dr. Patrick Verschueren. 
 
Department of Rheumatology, 
 
University Hospitals Leuven 
 
Herestraat 49, B-3000 Leuven, Belgium 
 
Telephone number: +32 16 34 25 41 
 
Fax number:  +32 16 34 63 46 
 
E-Mail address: patrick.verschueren@uzleuven.be 
 
 


Clinical Study Protocol 
Version 4.1 
CareRA2020 
29/04/2020 
EudraCT number:2017-004054-41 
KCE number: KCE-16002 
 
 
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Signature page 
Signature on behalf of the sponsor/ Chief Investigator (CI) 
The undersigned confirm that the following protocol has been agreed and accepted and that the 
Chief Investigator agrees to conduct the trial in compliance with the approved protocol and will 
adhere to the principles outlined in the requirements for the conduct of clinical trials in the 
European Union (EU) as provided for in " Directive 2001/20/EC” and any subsequent 
amendments, Good Clinical Practice (GCP) guidelines, the Belgian law of May 7th 2004 
regarding experiments on the human person, the Sponsor’s Standard Operating Procedures 
(SOP’s), and other regulatory requirements as amended. 
 
The undersigned agree to ensure that the confidential information contained in this document 
will not be used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of the Sponsor. 
 
The undersigned also confirm that they will make the findings of the study publically available 
through publication or other dissemination tools without any unnecessary delay and that an 
honest accurate and transparent account of the study will be given; and that any discrepancies 
from the study as planned in this protocol will be explained. 
 
For and on behalf of the Study Sponsor: 
 
Chief Investigator: 
 
 
___________________________________  
 
 
 
________________ 
Signature  
 
 
 
 
 
 
 
 
Date 
Prof. Dr. P. Verschueren 
 
 
 


Clinical Study Protocol 
Version 4.1 
CareRA2020 
29/04/2020 
EudraCT number:2017-004054-41 
KCE number: KCE-16002 
 
 
- 8 - 
 
Investigator Protocol signature Page  
I agree to: 
 
• 
Implement and conduct the trial in compliance with the approved protocol and will 
adhere to the principles outlined in the requirements for the conduct of clinical trials in the EU 
as provided for in " Directive 2001/20/EC” and any subsequent amendments, GCP guidelines, 
the Belgian law of May 7th 2004 regarding experiments on the human person, the Sponsor’s 
SOP’s, and other regulatory requirements as amended. 
 • 
Ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of the sponsor. 
 
I have read this protocol in its entirety and I agree to all aspects. 
 
 
 
___________________________________  
 
 
 
________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
 
 


Clinical Study Protocol 
Version 4.1 
CareRA2020 
29/04/2020 
EudraCT number:2017-004054-41 
KCE number: KCE-16002 
 
 
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Key trial contacts 
 
Chief Investigator (CI) 
Prof. Dr. Patrick Verschueren 
Department of Rheumatology  
University Hospitals Leuven 
Herestraat 49, B-3000 Leuven, Belgium 
Telephone number: +32 16 34 25 41 
Fax number:  +32 16 34 25 43  
E-Mail address: patrick.verschueren@uzleuven.be 
Project Manager (PM) 
Mr. Johan Joly 
Department of Rheumatology  
University Hospitals Leuven 
Herestraat 49, B-3000 Leuven, Belgium 
Telephone number: +32 16 34 02 58 
Fax number:  +32 16 34 63 46 
E-Mail address: johan.joly@uzleuven.be  
Sponsor 
University Hospitals Leuven 
Herestraat 49, B-3000 Leuven, Belgium 
Funder(s) 
Belgian Health Care Knowledge Center (KCE) 
Administrative 
Center 
Botanique, 
Doorbuilding, 
Boulevard du Jardin Botanique 55,  
B-1000 Brussels, Belgium  
Telephone number: +32 2 287 33 88 
E-Mail address: Trials@kce.fgov.be  
Clinical Trials Unit (CTU) 
Clinical Trial Center (CTC) 
University Hospitals Leuven 
Herestraat 49, B-3000 Leuven, Belgium 
Telephone number +32 16 34 19 98 
E-Mail address: ctc@uzleuven.be 
Key Protocol Contributors 
Prof. Dr. Patrick Verschueren 
Prof. Dr. René Westhovens 
Mr. Johan Joly 
Dr. Sofia Pazmino 
Mrs. Veerle Stouten 
Mrs. Kristien Van der Elst 
Mrs. Delphine Bertrand 
Department of Rheumatology  
University Hospitals Leuven 
Herestraat 49, B-3000 Leuven, Belgium 
Telephone number: +32 16 34 25 41 
Fax number:  +32 16 34 25 43 
E-Mail address: 
patrick.verschueren@uzleuven.be 
rene.westhovens@uzleuven.be  
johan.joly@uzleuven.be  
sofia.pazmino@kuleuven.be  
veerle.stouten@kuleuven.be  
kristien.vanderelst@uzleuven.be 
delphine.bertrand@kuleuven.be  


Clinical Study Protocol 
Version 4.1 
CareRA2020 
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EudraCT number:2017-004054-41 
KCE number: KCE-16002 
 
 
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Statistician 
Prof. Ben Van Calster 
Department of Development and Regeneration  
Herestraat 49, B-3000 Leuven 
E-Mail address: ben.vancalster@kuleuven.be  
Health Economics 
Prof. Steven Simoens 
Department 
of 
Clinical 
Pharmacology 
and 
Pharmacotherapy 
Herestraat 49, B-3000 Leuven 
E-Mail address: steven.simoens@kuleuven.be  
Data Manager 
Mr. Johan Joly 
Department of Rheumatology  
University Hospitals Leuven 
Herestraat 49, B-3000 Leuven, Belgium 
Telephone number: +32 16 34 02 58 
Fax number:  +32 16 34 63 46 
E-Mail address: johan.joly@uzleuven.be 
Patient representatives 
ReumaNet vzw 
Patient Expertise Centrum Reuma (PECR) 
Coordinated by Ilse De Keyser and Michell Silva 
Imperiastraat 16, B-1930 Zaventem 
Committees 
Ethics Committee and Competent Authority 
Single opinion of Ethics Committee and Competent 
Authority (Federal Agency on Medicinal and Health 
Products FAMPH) will be requested with the centralized 
procedure (Clinical Trial Regulation (CTR) 536/2014 
Pilot).  
 
Study team and management group (STMG) 
The STMG is compiled of the CI, the PM, the Clinical 
Research Assistant(s) (CRA’s) and the DM assigned to 
the protocol. This group will regularly (2 weekly) meet to 
discuss study progress and practical implications. 
 
Trial Steering Committee (TSC) 
The core of the TSC consists of the CI, the PM, the trial 
statistician and the DM assigned to the protocol. This core 
could be broadened with a representative of KCE, 
representatives 
of 
the 
sponsor 
(CTC), 
experts, 
investigators participating in the trial and patient 
representatives/researchers on request. 
This committee will meet 3 times a year. 
 
 
 
 


Clinical Study Protocol 
Version 4.1 
CareRA2020 
29/04/2020 
EudraCT number:2017-004054-41 
KCE number: KCE-16002 
 
 
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Trial Summary CareRA2020  
 
Title of the protocol 
CareRA2020: Effectiveness of a combination of methotrexate and a 
step down glucocorticoid regimen (COBRA-Slim) for remission 
induction in patients with early Rheumatoid Arthritis, with or 
without fast access to 24 weeks of TNF blockade in insufficient 
responders, a randomized, multicenter, pragmatic trial 
Internal Reference 
CareRA2020 
COBRA-Slim with or without fast access to TNF blockade for 
remission induction in early RA 
Clinical phase 
IV 
Trial design 
Randomized, multicenter, pragmatic trial 
Study Population and 
enrolment period 
A total of 442 patients is planned to be included in CareRA2020.  
The enrolment period is estimated to be open from Q2 2018 – Q2 
2020.  
Patients recently diagnosed with Rheumatoid Arthritis (RA) and 
naïve to Disease Modifying Anti Rheumatic Drug (DMARD) 
treatment will receive a remission induction therapy according to 
the COBRA-Slim regimen. Participants with an insufficient 
response (DAS28CRP >3.2) even after methotrexate dose 
optimization will be randomly assigned to 1 of 2 treatment groups 
(1:1 ratio) during a time window between week (w) 8 and w32, 
called the accelerated access period. It is expected that about 90 
patients will be eligible for randomization. Patients who do not 
meet the criteria for randomization during the accelerated access 
period (DAS28CRP ≤ 3.2), will be followed and treated to target as 
described within the protocol. 
Inclusion criteria  
- 
Age ≥ 18 years 
- 
Diagnosis of RA as defined by the American College of 
Rheumatology/ 
European 
League 
Against 
Rheumatism 
(ACR/EULAR) 2010 criteria for early RA 
- 
Early RA, defined by a diagnosis of ≤ 1 year 
- 
Use of 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 
participate in the study 
- 
Understanding and able to write Dutch or French 
 
 


Clinical Study Protocol 
Version 4.1 
CareRA2020 
29/04/2020 
EudraCT number:2017-004054-41 
KCE number: KCE-16002 
 
 
- 12 - 
Exclusion criteria 
- 
Previous treatment with: 
o Methotrexate (MTX) or leflunomide 
o cyclophosphamide, azathioprine or cyclosporine 
o sulphasalazine (SSZ) for more than 3 weeks 
o hydroxychloroquine for more than 6 weeks 
o oral glucocorticoids (GC) for more than 4 weeks within 4 
months before screening  
o oral GC at a daily dosage of more than 10 mg prednisone 
equivalent within 4 weeks before baseline 
o oral GC at a daily dosage equal to or less than 10 mg 
prednisone equivalent within 2 weeks before baseline 
o intra-articular, intravenous or intramuscular GC within 4 
weeks before BL 
o 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 TB 
- 
Latent TB unless adequate prophylactic treatment is given 
according to local guidelines 
- 
No access to the Belgian Health Insurance system  


Clinical Study Protocol 
Version 4.1 
CareRA2020 
29/04/2020 
EudraCT number:2017-004054-41 
KCE number: KCE-16002 
 
 
- 13 - 
Study design 
Initial protocol-based treat to target period (BL until w32) 
 
In this pragmatic, prospective, multicenter, randomized, controlled 
trial of 2-year duration, 442 patients with early RA (≤ 1 year), 
previously untreated with DMARDs will be included. All 
participants will receive at baseline (BL) a COBRA-Slim remission 
induction regimen, consisting of MTX 15 mg Per Os (PO) weekly, 
with a 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, which will be maintained until w28 and then tapered to 2.5 mg 
daily for 2 weeks before stopping completely).  
 
In case at any evaluation moment from w4 until w32 (not included) 
patients do not reach low disease activity (LDA = DAS28CRP≤3.2), 
the MTX dose will be increased to 20 mg PO weekly. 
 
If after this first adaptation patients still not achieve or maintain a 
sufficient response during the period from week 8 until 32 (the 
accelerated access period), they will be considered insufficient 
responders.  
 
Insufficient responders are defined as: 
- 
Patients not reaching LDA (DAS28CRP≤3.2) after the first 
adaptation (MTX increase) at any evaluation moment from week 
8 until 32  
- 
Patients not reaching remission (DAS28CRP<2.6) at the week 
32 evaluation visit irrespective of a previous MTX increase 
 
These insufficient responders will be randomly assigned to one of 
two different treatment strategies: 
 
Group 1: Standard COBRA-Slim Induction:  
Addition of leflunomide 10mg PO daily as the next step in the 
protocol-based CareRA2020 treatment adaptation scheme.   
 
Group 2: COBRA-Slim Bio-induction with accelerated access to 
anti-TNF (etanercept):  
Etanercept is defined as etanercept or its biosimilars marketed and 
reimbursed in Belgium. 
Addition of etanercept 50mg Subcutaneous (SC) weekly for a period 
of 24 weeks in this accelerated access arm as the next treatment 
adaptation. 
 


Clinical Study Protocol 
Version 4.1 
CareRA2020 
29/04/2020 
EudraCT number:2017-004054-41 
KCE number: KCE-16002 
 
 
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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. 
 
Patients who do not meet the criteria for randomization, during the 
so-called accelerated access period, will all follow the same 
Standard COBRA-Slim treatment adaptation scheme, further 
detailed in the protocol. 
 
Further protocol-based treat to target period (w32 until 104) 
 
After w32, patients will continue on the therapy assigned to their 
treatment arm. Patients not maintaining or not reaching the target of 
LDA beyond the accelerated access time window (w8-w32), will go 
to the next step in the protocol-based adaptation scheme further 
detailed in the protocol. In accordance with the latest EULAR 
recommendations patients should be further treated to a target of at 
least LDA but this can be adapted to remission at the investigators 
discretion. 
 
After completing this 2-year randomized controlled trial, all patients 
will be asked to give consent for roll over into a 3-year observational 
follow-up trial.  
 


Clinical Study Protocol 
Version 4.1 
CareRA2020 
29/04/2020 
EudraCT number:2017-004054-41 
KCE number: KCE-16002 
 
 
- 15 - 
Treatment 
adjustments during 
study 
Treat to target adaptation steps: 
If patients fail to respond (target: DAS28CRP ≤3.2), protocol-based 
treatment adjustments will be made from 4 weeks of treatment 
onwards until w104. The consecutive predefined treatment 
adaptation steps are summarized in Table 1 “CareRA2020 
Adaptation Scheme”, page 28. 
 
In the two following cases the need for treatment adaptation can be 
based on a different outcome instrument, still aiming for LDA: 
- If feet are clinically involved: DAS44 score (LDA ≤2.4) 
- In case of a recent infection: Clinical Disease Activity Index 
(CDAI) (LDA ≤10.0)  
 
No other reasons for treatment adaptations are allowed according to 
the protocol unless there is toxicity or discomfort due to protocol-
based medication intake (detailed in paragraph “Treatment toxicity 
during study“, page 30).  
 
Use of GC during the protocol: 
All patients will receive oral GC as part of the prescribed COBRA-
Slim strategy. Only the following additional glucocorticoid use is 
allowed during the study: 
- An intramuscular depot-corticoid injection on top of the protocol-
defined treatment adjustments, but not before w8 and not within 4 
weeks preceding a study visit until w104.  
- Intra-articular GC maximally once every 8 weeks, but not before 
w8 and not within 4 weeks preceding a study visit until w104. 
 
Non-Steroidal Anti Inflammatory Drug (NSAID) and analgesic 
use: 
NSAIDs and analgesics are allowed at the discretion of the treating 
physician and according to local guidelines, but not encouraged, 
during the duration of the trial. The use of this type of medication 
should be documented in the source documents and e-CRF with a 
clear indication if it was taken for RA related symptoms or not. 
 
Primary objective 
The primary objective is to compare in an early RA population 
with insufficient response (not achieving DAS28CRP≤3.2 within 32 
weeks) to COBRA-Slim remission induction, the long term 
effectiveness of accelerated access to a six-month course of anti-
TNF therapy (etanercept) within a time window from w8 up to w32, 
versus further treatment adaptation according to the standard 
COBRA-Slim strategy. 
 


Clinical Study Protocol 
Version 4.1 
CareRA2020 
29/04/2020 
EudraCT number:2017-004054-41 
KCE number: KCE-16002 
 
 
- 16 - 
Outcome measures 
Primary outcome: 
Area under the curve of DAS28CRP over 104 weeks (long term 
effectiveness) in insufficient responders randomized to either 
COBRA-Slim Bio-Induction or Standard COBRA-Slim Induction. 
 
Main secondary outcome: 
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.  
 
Other secondary and exploratory outcome measures: 
All other secondary and exploratory outcome measures on clinical 
efficacy, radiographic progression, side effects, PROs and possible 
economic analysis are detailed further in the protocol (page 25).  
They will be assessed both for the insufficient responder population, 
as for the complete study population.  
 
 
 


Clinical Study Protocol 
Version 4.1 
CareRA2020 
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EudraCT number:2017-004054-41 
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Funding and support in kind 
Financial support 
Financial support for this trial is provided by the BELGIAN HEALTH CARE 
KNOWLEDGE CENTER, Administrative Centre Botanique (Door building), Boulevard du 
Jardin Botanique 55, B-1000 Brussels, Belgium. 
 
Support in kind 
The Belgian national institute of healthcare and disability insurance (RIZIV-INAMI) is 
allowing participating investigators to prescribe etanercept, or its biosimilars marketed and 
reimbursed in Belgium, and have it reimbursed for the patient outside the current 
reimbursement rules via the TARDIS system. Only patients randomized in this trial, with their 
identifier of the trial entered into TARDIS and treated according to this protocol can benefit 
from this exception. 
 
Role of study sponsor 
University Hospitals Leuven, as mentioned in the Key Trial Contacts (page 9), shall act as 
sponsor of the Study, as defined in the Law of 2004, and shall assume all responsibilities and 
liabilities in connection therewith and procure the mandatory liability insurance coverage in 
accordance with the Law of 2004. University Hospitals Leuven shall ensure that it shall be 
mentioned in the Protocol, the Informed Consent Forms and in other relevant communication 
with the Study Subjects or the Regulatory Authorities as sponsor of the Study. University 
Hospitals Leuven acknowledges and agrees for the avoidance of doubt that KCE shall under no 
circumstances be considered as sponsor of the Study or assume any responsibilities or liabilities 
in connection therewith, and University Hospitals Leuven shall make no representations 
whatsoever in this respect.  
Roles and responsibilities of trial management committees/groups 
& individuals 
Study team and management group (STMG): 
The STMG is compiled of the CI, the PM, the Clinical Research Assistant(s) (CRA’s) and the 
DM assigned to the protocol. This group will regularly (2 weekly) meet to monitor and discuss 
daily progress of the trial and will act on identified issues. 
All remarks and decisions of the STMG will be documented in a report and stored at the 
department of Rheumatology, University Hospitals Leuven and will be shared with the sponsor 
and KCE. 
Trial Steering Committee (TSC):  
The Trial Steering Committee (TSC) will overview the trial on regular meetings (3 times a year 
the first year and 2 to 3 times a year thereafter) based on the reports of the STMG. This 
committee will monitor the course of the trial logistically, but also in terms of safety, and will 
advise the STMG if required. 
The core of the TSC consists of the chief investigator (CI), the project manager (PM), the trial 
statistician and Data Manager (DM) assigned to the protocol. In addition, a representative of 


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KCE, representatives of the CTC, experts, investigators participating in the trial and patients’ 
representatives/researchers will be invited to attend. 
All remarks and decisions of the STMG will be documented in a report that will be stored at 
the department of Rheumatology, University Hospitals Leuven and will be shared with the 
sponsor and KCE. The summary will be shared with the participating investigators. 
Chief investigator (CI) 
The CI is responsible for designing and implementing the protocol and, supported by the TSC, 
to follow-up on the conduct of the trial. CI will ensure the trial will be executed in compliance 
with the approved protocol and applicable regulatory requirements. 
The CI has an overall medical responsibility in the trial and will follow up on safety reporting. 
The CI is responsible to make the study findings publically available through publication or 
other dissemination tools without any unnecessary delay and that an honest accurate and 
transparent account of the study will be given. 
Local investigator 
The local investigator is responsible to implement and conduct the trial in compliance with the 
approved protocol and applicable regulatory requirements, the Sponsor’s SOPs, and other 
regulatory requirements as amended. 
The local investigator is bound to confidentiality and will ensure that the confidential 
information contained in this document will not be used for any purpose other than the 
evaluation or conduct of the clinical investigation. 
Except where the investigator’s signature is specifically required, it is understood that the term 
“investigator” as used in this protocol and protocol related documents refers to the investigators 
and/or appropriate study personnel that the investigators designates to perform a certain duty. 
The investigator is ultimately responsible for the conduct of all aspects of the study at the site. 
The organizing center, department of Rheumatology of the University Hospitals Leuven, will 
provide notification to the investigators of protocol and amendment approvals by regulatory 
authorities, if applicable. 
Protocol contributors 
This protocol was developed by the Trial Steering Committee (TSC), led by Chief Investigator 
(CI) Professor Patrick Verschueren, in close collaboration with the CTC of the University 
Hospital Leuven. Professor Ben Van Calster of the Department of Development and 
Regeneration KU Leuven acts as Statistician and Professor Steven Simoens of the Department 
of Clinical Pharmacology and Pharmacotherapy, as Health Economist for this trial. Wherever 
necessary adaptations were made after consultation of the KCE clinical trials team and in 
answer to questions and remarks of the KCE Trials Board.  
During protocol development, feedback from patient representatives/researchers (ReumaNet 
vzw) was included. 
Furthermore, patient researchers are engaged as scientific collaborators in the TSC, the 
supervision of the trial, data analyses and preparation of the study report. Patient partners were 
involved in the development of the informed consent form and all other information leaflets 
that were developed for this trial. Moreover, the study design and important endpoints of the 
CareRA2020 trial are inspired by the results of previous research from our research group that 
was looking into patient priorities concerning the management and treatment outcomes of RA.  


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Key words 
Early Rheumatoid Arthritis; Treatment strategies; Remission induction; Treat to target (T2T); 
COBRA; csDMARD and glucocorticoids; bDMARD 
List of Abbreviations 
AE 
Adverse Event 
ACPA 
anti Citrullinated Protein antibody 
ACR 
American College of Rheumatology 
APR 
Annual Product Report 
AR 
Adverse Reaction 
AUC 
Area under the curve 
BMI 
Body Mass Index 
BL 
Baseline 
CareRA 
Care in early Rheumatoid Arthritis trial 
CDAI 
Clinical Disease Activity Index 
CI 
Chief Investigator 
COBRA 
COmbinatie therapie Bij Reumatoïde Artritis 
CRA 
Clinical Research Associate  
CRO 
Clinical Research Organisation 
CRP 
C-Reactive Protein 
CTA 
Clinical Trial Assistant 
cta 
Clinical Trial Agreement 
CTC 
Clinical Trial Center 
CTR 
Clinical Trial Regulation 
CTU 
Clinical Trial Unit 
DAS28CRP 
Disease Activity Score based on 28 joint count and CRP 
DAS28ESR 
Disease Activity Score based on 28 joint count and ESR 
DM 
Data Manager 
DMARD 
Disease Modifying Anti Rheumatic Drug 
csDMARD 
conventional synthetic DMARD 
bDMARD 
biological DMARD 
DoA 
Delegation of Authority 
e-CRF 
electronic Case Report Form 
EC 
European Commission 
EEA 
European Economic Area 
EMA 
European Medicines Agency 
EQ5D 
EuroQuol-5-Dimensions Questionnaire 
ESR 
Erythrocyte Sedimentation Rate 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
EudraVIGILANCE 
European database for Pharmacovigilance 
EULAR 
European League against Rheumatism 
FAMPH 
Federal Agency for Medicines and Health Products 
FDA 
Food and Drug Administration 
GC 
Glucocorticoids 
GCP 
Good Clinical Practice 
GH 
General Health 
GOT 
Glutamate Oxaloacetate Transaminase 
GP 
General Practitioner 
GPT 
Glutamate Pyruvate Transaminase 
HAQ 
Health Assessment Questionnaire 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethical Committee 
IM 
Intramuscular 


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IMP 
Investigational Medicinal Product 
INAMI 
Institut national d'assurance maladie-invalidité 
ISF 
Investigator Site File 
ITT 
Intention To Treat analysis 
IU 
International Unit 
IV 
Intravenous  
IWRS 
Interactive Web Response system 
KCE 
Belgian Healthcare Knowledge Center 
LDA 
Low Disease Activity 
MA 
Marketing Authorization 
MD 
Medical Doctor 
mg 
Milligrams 
MTX 
Methotrexate 
NSAID 
Non-Steroidal Anti Inflammatory Drug 
NIMP 
Non-Investigational Medicinal Product 
PASS 
Patient Acceptable Symptom State 
PhD 
Doctor of Philosophy 
PhGA 
Physician Global Assessment 
PI 
Principal Investigator 
PM 
Project Manager 
PO 
Per Os 
PP 
Per Protocol analysis 
PRO 
Patient Reported Outcome questionnaires 
Q 
Quarter (of a year) 
RA 
Rheumatoid Arthritis 
RAID 
Rheumatoid Arthritis Impact of Disease questionnaire 
RCT 
Randomized Control Trial 
RF 
Rheumatoid Factor 
RIZIV 
Belgisch Rijksinstituut voor Ziekte- en  Invaliditeitsverzekering 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SoC 
Standard of Care 
SOP 
Standard Operating Procedure  
SmPC 
Summary of Product Characteristics  
SUSAR 
Suspected Unexpected Serious AR 
SAE 
Serious Adverse Event 
SC 
Sub Cutaneous 
SIV 
Site Initiation Visit 
SJC 
Swollen Joint Count 
SSZ 
Sulfasalazine 
STMG 
Study Team Management Group 
TARDIS 
Tool for Administrative Reimbursement Drug Information Sharing 
TB 
Tuberculosis 
T2T 
Treat to Target 
TJC 
Tender Joint Count 
TNF 
Tumor Necrosis Factor 
TSC 
Trial Steering Committee 
VAS 
Visual Analog Scale 
w 
week 
WPAI 
Work Productivity and Activity Impairment 
 
 


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Trial flow chart 
 
 


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Flowchart
Screen
BL
W4
W8
w12
W16
w20
w24
w28
w32
w36
W40
w44
w48
W52
w56
w60
w64
Randomized at W8
X
X
X
X
X
X
X
X
X
X
X
X
Randomized at W16
X
X
X
X
X
X
X
X
X
X
X
X
Randomized at W24
X
X
X
X
X
X
X
X
X
X
X
X
Randomized at W32
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Not randomized
X
X
X
X
X
X
X
X
X
X
General mandatory visit
R+28w
General optional visit
R+24w
R+16w
R+8w
randomized patients
Mandatory visits for


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Study protocol 
CareRA2020: Effectiveness of a combination of methotrexate and a step down glucocorticoid 
regimen (COBRA-Slim) for remission induction in patients with early Rheumatoid Arthritis, 
with or without accelerated access to 24 weeks of TNF blockade in insufficient responders, a 
randomized, multicenter, pragmatic trial. 
 
1 Background and Rationale 
Treatment for early Rheumatoid Arthritis (RA) has become much more successful over the last 
two decades, mainly due to the more effective use of conventional synthetic disease modifying 
anti-rheumatic drugs (csDMARD) and glucocorticoids (GC). Recently, our group demonstrated 
that so-called “combinatietherapie bij reumatoïde artritis" (COBRA) strategies combining 
csDMARDs with a step-down bridge GC schedule, starting from moderate or high dosages of 
prednisone, resulted in remission rates of up to 70%. Moreover, combining methotrexate 
(MTX) monotherapy with a step down bridge GC therapy, the COBRA-Slim regimen, appeared 
to be equally effective as combining MTX with another DMARD and GC at higher dosages, 
but with less side effects. Therefore, COBRA-Slim can be considered a first-choice initial 
treatment for the large majority of early RA patients. Nevertheless, for about 25 to 30% of 
patients the desirable treatment target cannot be achieved with this approach and according to 
the current “treat to target” principle, the medication regimen has to be adapted until it becomes 
more successful. Often, this results in many months of insufficient disease control and an 
increased risk of side effects, unfortunately resulting in a reduced quality of life but also having 
unfavorable long-term consequences in terms of functionality, structural joint integrity, 
psychosocial wellbeing and employment. This means there is an unmet need for more effective 
initial treatment strategies targeting the subgroup of insufficient responders to csDMARDs and 
GC. Given the effectiveness of the new generation of biological (b) DMARDs in refractory RA, 
a short course of these compounds could prove to be more successful than GC for remission 
induction. Apart from being efficacious, bDMARDs should of course also prove to be cost-
effective in this setting and the conditions for their cost-effectiveness should be explored 
further, depending on the RA subpopulation targeted. 
 
We propose 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. Current practice requires first the evaluation of the effectiveness of adding or 
switching to another csDMARD after failure of the initial csDMARD, mostly methotrexate, 
before a biological can be introduced. An important additional research question would be if 
providing a bDMARD to insufficient responders to the COBRA-Slim remission induction 
regimen would be cost-effective compared to continuing treatment adaptations according to the 
standard COBRA-Slim strategy, taking into account direct and indirect costs.  
 
 


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Assessment and management of risk 
This trial can be categorized as a low interventional trial according to the definition of the EU 
regulation n° 536/2014 for the following reasons: 
- 
The medication (etanercept, defined as etanercept and its biosimilars marketed and 
reimbursed in Belgium) has a Marketing Authorization in Belgium 
- 
According to the protocol the medication is used in accordance with the indication as 
mentioned in the European Marketing Authorization  
- 
Any additional diagnostic or monitoring procedures do not deviate from routine clinical 
practice, with the exception of the completion of some questionnaires  
2 Objectives and outcome measures/endpoints  
Primary objective 
To compare in an early RA population with insufficient response (not achieving 
DAS28CRP≤3.2) to COBRA-Slim remission induction, the long-term effectiveness of 
accelerated access to a 24 weeks course of anti-TNF therapy (etanercept) within a time window 
from w8 up to w32, versus further treatment adaptation according to the standard COBRA-Slim 
strategy. 
 
For this purpose, the area under the DAS28CRP curve from BL until w104 will be assessed. 
This outcome parameter is considered to be clinically very relevant, since it reflects the overall 
evolution in disease burden over the first 2 years of treatment, taking into account the speed 
and stability of the response and the need for consecutive treatment adaptations. 
Secondary objectives 
Main secondary objective 
To investigate in insufficient responders to the COBRA-Slim regimen if accelerated access to 
a six-month course of anti-TNF therapy (etanercept), is leading to improved remission rates 
when compared to conventional treatment adaptation according to the COBRA-Slim strategy, 
28 weeks after randomization into one of two treatment arms.  
Other secondary objectives: 
1. To further determine the clinical efficacy of accelerated access to etanercept versus the 
standard COBRA-Slim strategy in terms of remission rates and functionality scales. 
2. To compare radiographic progression between all treatment schemes. 
3. To evaluate the side effects of the given treatments as evaluated according to the 
regulatory guidelines for marketed products. 
4. To evaluate the primary outcome using the DAS28ESR instead of the DAS28CRP. 
Other secondary exploratory objectives: 
1. To further determine the clinical effectiveness of accelerated access to etanercept 
versus the standard COBRA-Slim strategy. 
2. To evaluate treatment response based on a set of PROs. 
3. Depending on the clinical results of the trial, a health economic analysis may be 
justified. This could be part of a health technology assessment project at KCE. Quality 
of life data as well as the national number of the participating patients are collected in 
this trial to facilitate a possible economic analysis. 
 


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All secondary and exploratory objectives will be assessed both for the insufficient responder 
population, as for the complete study population.  
Outcome measures/endpoints 
Primary outcome measure 
Area under the curve of DAS28CRP over 104 weeks (long term effectiveness) in insufficient 
responders randomized to either COBRA-Slim Bio-Induction or Standard COBRA-Slim  
Induction. 
Main secondary outcome measure 
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. 
Other secondary outcome measures 
The following analyses will be performed in the randomized early insufficient responder 
population (w8-w32) with or without accelerated access to a six-month course of etanercept. 
The same analyses will also be performed including the randomized groups of insufficient 
responders, each completed with an early responder control population. 
 
1. Clinical efficacy: 
o Remission (DAS28CRP<2.6) at w104. 
o EULAR response at 28 weeks after randomization and at w104 
o HAQ response at 28 weeks after randomization and at w104 
2. Radiographic progression: X-ray evolution at w52 and w104 compared to BL as 
reviewed and evaluated by the central team. 
3. Side effects: (S)ARs from BL until w104 
4. To evaluate the primary outcome using the DAS28ESR instead of the DAS28CRP. 
Other secondary, exploratory outcome measures: 
1. Clinical effectiveness: 
A) In the randomized early insufficient responder population (w8-w32) with or without 
accelerated access to a six-month course of etanercept. 
Effectiveness:  
o AUC of DAS28CRP/DAS28ESR during 28 weeks after randomization 
o Time to first remission during 28 weeks after randomization 
o Sustained remission = remission for at least 24 weeks (BL-w104). 
o Number of treatment changes, number of patients able to follow the protocol, 
number of patients using biologicals and/or GC at 28 weeks after randomization 
and at w104. 
o Cumulative doses of GC and analgesic use at 28 weeks after randomization and 
at w104. 
B) In the complete study population, including the randomized groups of insufficient 
responders, each completed with an early responder control population. 
Effectiveness:  
o Sustained remission = remission for at least 24 weeks (BL-w64, BL-w104, w64-
w104). 
o Number of treatment changes, number of patients able to follow the protocol, 
number of patients using biologicals and/or GC throughout the entire study 


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o Cumulative doses of GC and analgesic use throughout the entire study 
2. Treatment response in terms of PROs:  
o Patient acceptable symptom state (PASS) and RA Impact of Disease (RAID) at 
28 weeks after randomization and at w104  
o PASS at w64 and w104. 
o RAID at w 64, 104. 
3. Cost-effectiveness:  
o WPAI / EQ5D questionnaire at 28 weeks after randomization and at w104 
o Per-protocol and out-of-protocol medication use as well as the number of 
outpatient visits and occasional hospitalization 
Depending on the clinical results of the trial, a health economic analysis may be justified. 
This could be part of a health technology assessment project at KCE. Quality of life data as 
well as the national number of the participating patients are collected in this trial to facilitate 
a possible economic analysis. 
3 Study design 
Overall design 
In this pragmatic, prospective, multicenter, randomized, controlled trial of 2-year duration, 442 
patients with early RA (≤ 1 year), previously untreated with DMARDs (disease modifying anti-
rheumatic drugs), will be included. A subgroup of insufficient responders to the initial COBRA-
Slim remission induction regimen will be randomly assigned, during a time window between 
w8 and w32, to 2 different treatment strategies. 
Randomization will be balanced according to time-point of randomization, BL disease activity 
and RF/ACPA status using the minimization technique (see statistical plan). Patients who do 
not meet the criteria for randomization, during the so-called accelerated access period, will still 
follow the common adaptation strategy during the remaining part of the study. 
 
 


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Initial protocol-based treat to target period (BL until w32): 
All participants will receive at BL a COBRA-Slim remission induction regimen, which 
includes: 
- 
Methotrexate 15 mg PO weekly (starting from 10 mg weekly for 2 weeks) 
- 
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. 
 
In case at any evaluation moment from w4 until w32 (not included) patients do not reach low 
disease activity (LDA = DAS28CRP≤3.2), the MTX dose will be increased to 20 mg PO 
weekly. 
 
If after this first adaptation patients still not achieve or maintain a sufficient response during the 
period from week 8 until 32 (the accelerated access period), they will be considered insufficient 
responders.  
 
Insufficient responders are defined as: 
Patients not reaching LDA (DAS28CRP≤3.2) at any evaluation moment from week 8 until 32 
after the first adaptation (a previous MTX increase). 
Patients not reaching remission (DAS28CRP<2.6) at the week 32 evaluation visit irrespective 
of a previous MTX increase. 
 
These insufficient responders will be randomly assigned to one of two different treatment 
strategies: 
 
Group 1: Standard COBRA-Slim Induction:  
Addition of leflunomide 10mg PO daily as the next step in the protocol-based CareRA2020 
treatment adaptation scheme.   
If target of LDA is still not reached or maintained minimally 12 weeks after the initiation of 
Leflunomide, treatment has to be adapted according to the next step of the adaptation scheme. 
Group 2: COBRA-Slim Bio-induction with accelerated access to anti TNF:  
Addition of etanercept 50mg Subcutaneous (SC) weekly for a period of 24 weeks in this 
accelerated access arm as the next treatment adaptation. 
If target of LDA is still not reached or maintained minimally 12 weeks after the initiation of 
etanercept, treatment has to be adapted according to the next step of the CareRA2020 adaptation 
scheme. 
 
Randomization will be balanced according to time-point of randomization, baseline (BL) 
disease activity and Anti-Citrullinated Protein Antibody (ACPA) and/or Rheumatoid Factor 
(RF) status to ensure comparability of the treatment groups with respect to these prognostic 
variables. 
 
Patients who do not meet the criteria for randomization, during the so-called accelerated access 
period, will all follow the same CareRA2020 treatment adaptation scheme, further detailed in 
the protocol. 
Further protocol-based treat to target period (w32 until w104): 
After w32, patients will continue on the therapy assigned to their treatment. In case LDA is lost 
or still not reached during this protocol-based treat to target phase, treatment will be adapted 


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according to CareRA2020 adaptation schedule (table 1 page 28). A next adaptation is only 
allowed after the previous treatment adaptation has reached its full strength, so minimally after 
the time period specified for each adaptation step (table 2 page 28). 
 
In accordance with the latest EULAR recommendations patients should be further treated to a 
target of at least LDA but this can be adapted to remission at the investigators discretion. 
 
The minimal dose of MTX required according to protocol is 15 mg PO per week except in case 
of documented toxicity, then 7.5 mg PO or parenteral is allowed. In case MTX has to be 
discontinued, Leflunomide should be given at a dose of 20 mg PO daily or 10 mg PO in case 
of documented toxicity (see paragraph “Treatment toxicity during study”, page 30). 
CareRA2020 adaptation schedule 
As a first adaptation, from w4 onwards, MTX should be increased to 20mg weekly PO. The 
next adaptation steps are summarized in table 1. 
One exception is the w32 visit, at which a MTX dose increase is not needed, and one should 
proceed to the second adaptation step. 
After w32, adaptation of MTX or leflunomide is at the investigators discretion, but when LDA 
is not reached one should proceed to the next adaptation step. 
 
Table 1: protocol defined adaptations 
Adaptations 
Patients randomized 
to Standard COBRA-
Slim Induction 
Patients 
randomized 
to 
COBRA-Slim 
Bio-
induction with accelerated access to Etanercept  
Patients 
NOT 
randomized  
2nd  
Add 
leflunomide 
10mg/day PO 
Add etanercept 50mg/week SC for 24 weeks* 
Add 
leflunomide 
10mg/day PO 
3rd 
Replace leflunomide 
by 
etanercept 
(50mg/week 
SC*) 
(per reimbursement)  
Add leflunomide 10mg/day PO and stop etanercept 
if it has not been already stopped 
Replace 
leflunomide 
by 
etanercept 
(50mg/week SC*) (per 
reimbursement) 
4th  
Treatment 
at 
the 
discretion 
of 
the 
rheumatologist 
 
If previous response** 
to etanercept:  
Replace 
Leflunomide 
by 
etanercept 
(50mg/week SC) (per 
reimbursement) 
 
If 
NO 
previous 
response** 
to 
etanercept: 
Treatment 
at 
the 
discretion 
of 
the 
rheumatologist 
 
Treatment 
at 
the 
discretion 
of 
the 
rheumatologist 
5th  
Treatment 
at 
the 
discretion 
of 
the 
rheumatologist 
 
Treatment 
at 
the 
discretion 
of 
the 
rheumatologist 
 
Treatment 
at 
the 
discretion 
of 
the 
rheumatologist 
 
Treatment 
at 
the 
discretion 
of 
the 
rheumatologist 
 
* check for latent TB if not already done within 6 months 
** Previous response: If patient completed the 6 months course of etanercept and maintained LDA without toxicities during this period. 
 
Adaptations are only allowed after the current treatment has reached its full strength, so 
minimally after the time period specified in table 2, or in case of toxicity. 
 
Table 2: protocol defined time to next adaptation: 
Medication 
Time 
to 
be 
re-
evaluated 
Methotrexate dose increase 
At least 4 to 8 weeks 
Leflunomide initiation 
At least 12 weeks 
Etanercept or other bDMARD initiation 
 


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General rules for treatment adaptations during the study from baseline until w104 
If patients fail to achieve or maintain low disease activity (DAS28CRP≤3.2), protocol-based 
treatment adjustments will be made from 4 weeks of treatment onwards until w104. 
The only exception to this rule is at w32, the end of the remission induction phase, where 
treatment response will not be targeted at LDA but at remission (DAS28CRP<2.6). If patients 
at w32 fail to reach remission, a treatment adaptation is required, unless a previous treatment 
adaptation has not yet reached its full strength (table 2).  
In accordance with the latest EULAR recommendations patients should be further treated to a 
target of at least LDA but this can be adapted to remission at the investigators discretion after 
w32. 
 
The need to perform treatment adjustments can only be overruled if disease activity evaluated 
by DAS28CRP score is not reflecting the real clinical situation according to the rheumatologist. 
This can only be done in 2 situations: 
- In case of isolated involvement of the feet that would lead to an underestimation of disease 
activity by the DAS28CRP score, the original DAS44 score (LDA = score below or equal to 
2.4 and remission = below 1.6) has to be used to include the feet. 
- In case a recent infection would lead to an overestimation of disease activity by the 
DAS28CRP score the CDAI can be used, as this score is independent of elevated CRP (LDA = 
score below or equal to 10.0 and remission = below or equal to 2.8). 
The results of these alternative scoring systems will be automatically displayed in the e-CRF 
when the investigator indicates this special situation by ticking the specific box. 
Treatment adaptations are also allowed in the protocol in case of toxicity or discomfort due to 
protocol-based medication intake (detailed in paragraph “Treatment toxicity during study”, 
stated below). 
No other reasons for treatment adaptations are allowed according to the protocol. 
Important points to consider: 
 Investigators have to be aware that protocol specified treatment adaptations are only 
allowed after the current treatment has reached its full strength. 
 Treatment adaptations beyond the steps defined in the CareRA2020 adaptation scheme 
can be made at the discretion of the investigator, according to local regulations and good 
clinical practice 
 In all cases, patients will be followed according to the schedule of events outlined in 
this protocol. 
Use of GC during the protocol: 
All patients will receive oral GC as part of the prescribed COBRA-Slim strategy.  
During the study, the following additional glucocorticoids use is allowed: 
- 
An intramuscular depot-corticoid injection on top of these treatment adjustments, but not 
before w8 and not within 4 weeks preceding a study visit until week 104.  
- 
Intra-articular GC are allowed maximally once every 8 weeks but not before week 8, and 
not within 4 weeks preceding a study visit until week 104. 
Guidance on NSAID and analgesic use 
NSAIDs and analgesics are allowed at the discretion of the treating physician and according to 
local guidelines, but not encouraged, during the duration of the trial. When added to the 
treatment they should be documented in the source documents and e-CRF with a clear 
indication if they were taken for RA related symptoms or not and with start and end date. 


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Treatment failure during study 
In this trial, all included patients will be followed according to the protocol for the complete 
study period unless they withdraw consent, are lost to follow up or die. 
Protocol violations in relation to the therapeutic strategy will not be considered a reason to 
interrupt follow up within the CareRA2020 study. 
In case the proposed treatment schedule cannot be followed due to serious safety concerns, the 
patient will be kept in the study follow-up and treated at the discretion of the investigator, taking 
into account the interest of the patient and the feasibility of the treatment. 
These patients will also be asked to roll over into the observational follow-up study. 
Treatment toxicity during study  
In case of toxicity, actions will be taken according to good clinical practice. Toxicities will be 
documented and followed up as closely as possible. If feasible and in the patients’ best interest, 
every effort will be made to return patients to their original treatment strategy with a minimal 
csDMARD intake of 7.5 mg MTX weekly (either PO or parenteral) or 10mg Leflunomide PO 
daily. 
Patients who are not able to return to their original treatment strategy will still be followed 
within the CareRA2020 study and will be asked to participate to the observational follow-up 
study. 
4 Study setting 
The study is a multicenter pragmatic trial sponsored by the University Hospitals Leuven, 
commissioned by KCE Trials and coordinated by the Chief investigator Prof. Dr. Patrick 
Verschueren from the department of Rheumatology, University Hospitals Leuven. 
A centralized approval procedure for the independent Ethics Committee (IEC) and Competent 
Authority (FAMPH) will be used to get unique advice for the whole trial. 
Prior to enrolment of patients into this study, the final protocol, informed consent form (ICF) 
and any patient recruitment materials will be submitted to, reviewed and approved by an IEC. 
Any necessary amendments to the protocol and/or ICF will be prepared by the Rheumatology 
Department of the University Hospitals of Leuven and submitted to the IEC and FAMHP. 
 
Four different types of sites are selected: 
- 
University rheumatology centers with local support 
- 
University rheumatology centers without local support 
- 
Non-university rheumatology centers with local support (mostly group practices) 
- 
Non-university rheumatology centers without local support 
It is important to include all these types of centers in the trial in view of future generalizability 
of the study results, as the target population is seen as well in second as in third line centers. 
Every effort will be made to ensure maximal recruitment potential in all participating centers 
by collaboration with their network and referring general practitioners. 
Participating Centers 
Approximately 20 centers will participate to this trial, consisting of rheumatology departments 
in a university or non-university setting. 
 
 


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5 Study population 
Number of patients and assignment to treatment groups 
A total of 442 patients are planned to be included in this study. In case patients do not achieve 
low disease activity (DAS28CRP ≤3.2) at any evaluation moment from w8 until 32 (not 
included) despite dose adjustment of MTX, or remission (DAS28CRP<2.6) at w32, they will 
be considered insufficient responders to COBRA-Slim induction therapy (approximately 90 
patients expected) and randomly assigned to one of two treatment groups according to a 1:1 
ratio and balanced according to time-point of randomization, disease activity and RF/ACPA 
status.  
Inclusion criteria 
Patients enrolled in the study must meet the following inclusion criteria:  
- 
Age 18 years and older 
- 
Diagnosis of RA as defined by the ACR/EULAR2010 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 
Patients will be excluded from participating in the study if they meet any of the 
following exclusion criteria: 
- 
Previous treatment with: 
o MTX or leflunomide 
o cyclophosphamide, azathioprine or cyclosporine 
o sulphasalazine (SSZ) for more than 3 weeks 
o hydroxychloroquine for more than 6 weeks 
o oral GC for more than 4 weeks within 4 months before screening  
o oral GC at a daily dosage of more than 10 mg prednisone equivalent 
within 4 weeks before baseline 
o oral GC at a daily dosage equal to or less than 10 mg prednisone 
equivalent within 2 weeks before baseline 
o intra-articular, intravenous or intramuscular GC within 4 weeks 
before BL 
o 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 


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- 
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 TB 
- 
Latent TB unless adequate prophylactic treatment is given according to local 
guidelines 
- 
No access to the Belgian Health Insurance system  
6 Trial Procedures 
All procedures required in the protocol are described further; timing can be checked in the 
attached flow chart (Appendix1). Procedures are organized as either “Standard of Care (SoC)” 
or “Study Specific”. 
Some trial procedures can be adapted in case of restrictions in the usual outpatient care 
organization at the participating rheumatology centers due to governmental or local regulations. 
A typical example of such adaptations would be that regular outpatient visits would be replaced 
by telephone consultations. This measure is introduced in the context of the COVID-19 
outbreak and will be valid in case of future epidemics/events as well. Details are described 
further under the visits header. 
 
Recruitment 
Every effort will be made to gather a representative sample of patients, reflecting a normal 
distribution of an early RA population in Belgium. 
In order to achieve this, the purpose is to propose all newly or recently diagnosed early RA 
patients at the participating centers to participate in this trial. 
In- and exclusion criteria are not so restrictive towards patient recruitment. This means that all 
csDMARD naive patients, recently diagnosed with RA, can be included unless there are contra 
indications to the proposed treatment strategy. 
Data from patients who gave consent will be collected, if no consent is given, no data will be 
collected. Based on data from the CareRA trial, refusal to participate in this type of pragmatic 
trial is expected in less than 2% of patients. 
Screening 
A signed informed consent form must be obtained from each patient prior to any study-related 
procedure being performed. All test results and assessments required to establish eligibility of 
the patient must be obtained prior to enrolment and prior to dispensation of the medication. 
 
Study specific procedures:  
 Informed consent 
 Assessment of inclusion/Exclusion criteria 
 
The following information will be captured from routine clinical data (SoC): 
 Demographic data (as specified on page 37)  
 Relevant Medical history (co-morbidity shortlist) 
 Relevant Concomitant medication 
 Clinical/Rheumatologic examination 
 Joint Count TJC, SJC 
 Weight 
 Height 


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 RF and ACPA status 
 ESR and CRP 
 X-Ray hands/feet (evaluation of erosions y/n and Sharp/van der Heijde Scoring) 
 DAS28CRP/DAS28ESR 
 VAS PhGA/GH/pain/fatigue 
 TB screening (to be repeated in case bDMARD therapy starts beyond 6 months after 
initial testing). 
Consent  
The investigator will choose patients in accordance with eligibility criteria. The investigator 
will not exercise selectivity so that bias is prevented.  
 
Prior to the study, patients will receive a comprehensive explanation of the proposed treatment 
including the nature and risks of the study, other possible therapies, any known side effects of 
the medicinal products they will receive, and any other elements that are part of properly 
obtaining informed consent. Patients will be allowed sufficient time to consider participation in 
the study and their questions will be answered. 
 
Before entering the study, all patients must sign an informed consent form that complies with 
the requirements of ICH E6. By signing the informed consent form, the patient agrees to comply 
with all proposed evaluations required in the study, unless the patient withdraws voluntarily or 
is terminated from the study for any reason. 
The consent will include the registration of the national number and the study code for all 
participating patients (even if not receiving anti-TNF) in the standard trusted third party register 
used for anti-TNF RA treatment approval by RIZIV-INAMI (TARDIS), which will allow for a 
later coupling by the trusted third party of the study data with the billing data (reimbursement).  
The randomization scheme 
Patients included in the trial and not achieving low disease activity (DAS28CRP≤3.2) between 
w8 and w32 or remission (DAS28CRP<2.6) at week 32, will be randomly assigned to one of 
two treatment groups (1:1 allocation): 
- 
Group 1 stepping up to a combination of MTX with leflunomide as described in 
the standard COBRA-Slim strategy, or  
- 
Group 2 receiving accelerated access to a 6 months course of etanercept (defined 
as etanercept or its biosimilars as marketed and reimbursed in Belgium) besides 
continued MTX therapy.  
Randomization will be done electronically within the e-CRF whenever a patient is considered 
an insufficient responder within the time window from w8 until w32 included.  
The randomization process will be balanced on the margins (minimization) according to time-
point of randomization, BL disease activity and RF/ACPA status. 
 
Patients who are not considered insufficient responders within the accelerated access period 
will be further followed in the protocol. 
Method of implementing the allocation sequence 
Each clinical site will be assigned a 3-digit site number, the patient numbers will start with this 
site number followed by a 3-digit patient number starting with 001. 
At site, all study personnel (investigator and/or CTA) will be able to perform the randomization 
as long as this is clearly identified on the Delegation of Authority (DoA). 
A patient identification and randomization list will be kept at site.  


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Blinding 
No blinding is applicable in this trial, investigators and patients will know which medications 
and doses are taken. 
 
Unblinding 
Unblinding is not applicable.  
 
Visits 
In this trial two kinds of visits are defined: mandatory and optional. 
Mandatory visits have to be performed for all included patients while optional visits are 
recommended but are not obligatory. These can be performed at the investigators discretion. 
The aim of these optional visits is to check if treatment adaptations have the required effect and 
for positive reinforcement in view of compliance. 
In case patients are randomized, some optional visits are becoming mandatory (see table below) 
as will be shown in the patient schedule tab of the e-CRF. These visits are important for 
calculation of secondary outcomes. 
 
 
In case of restrictions in the usual outpatient care organization at the participating rheumatology 
centers due to governmental or local regulations (e.g. related to the outbreak of an epidemic), 
regular outpatient visits can be replaced by a telephone consultation when required to reduce 
risks for patients and health workers . 
During this telephone consultation, one should gather as much clinical data as possible with 
regards to the visit it is replacing. Patients should also be encouraged to continue completing 
their PROs. When this is done electronically, patients will be reminded of their questionnaires 
as  usual. In case these PROs are completed on paper, the site should provide patients with a 
paper version of the PROs and a prepaid envelope to return them to the site. 
During a telephone consultation, the rheumatologist cannot score patients’ joints. Therefore, it 
is suggested to provide the patients with a template for self-evaluation of the joints on 
tenderness and swelling. Literature suggests this could be a reliable alternative. The procedure 
to distribute this homunculus is the same as described for the PROs: for patients with a known 
email address by email, for the others by regular mail. 
Regular lab testing for CRP, hematology, liver- and kidney function is also a point of attention. 
During the telephone consultation it should be checked if blood sampling was done recently. If 
not, the general practitioner can be asked to take a blood sample, depending on the regulations. 
If after a telephone consultation, the investigator is convinced that the disease activity is not 
sufficiently well controlled and there is a need for treatment adaptations, a traditional 
Flowchart
Screen
BL
W4
W8
w12
W16
w20
w24
w28
w32
w36
W40
w44
w48
W52
w56
w60
w64
Randomized at W8
X
X
X
X
X
X
X
X
X
X
X
X
Randomized at W16
X
X
X
X
X
X
X
X
X
X
X
X
Randomized at W24
X
X
X
X
X
X
X
X
X
X
X
X
Randomized at W32
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Not randomized
X
X
X
X
X
X
X
X
X
X
General mandatory visit
R+28w
General optional visit
R+24w
R+16w
R+8w
randomized patients
Mandatory visits for


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consultation at the outpatient clinic might be justifiable. At that time the mandatory visit should 
be completed and a randomization procedure must be performed if required by the protocol.  
In case of an epidemic like the COVID-19 outbreak, the health of patients and coworkers are 
the first priority. On the other hand, adequate follow-up of patients, with a chronic condition 
and in need of a chronic treatment, is essential. Interruption of treatment is contraindicated, not 
for conventional nor for biological or targeted synthetic DMARDs, except in case of active 
infection or other complications and preferably on the advice of the treating rheumatologist. 
Data collected during telephone consultations will be transcribed by the sites at the correct visit 
page in the e-CRF, marking the box of the telephone visit next to the date field. This way data 
management can clearly discriminate between data collected by phone and during outpatient 
consultations. 
BL data (w0)  
The following information will be captured from routine clinical data (SoC) at Week 0 visit: 
 Clinical/Rheumatologic examination 
 Joint Count: TJC, SJC 
 Weight 
 ESR and CRP (in case screening blood samples were taken within 5 days, these values 
can be used). 
 DAS28CRP/DAS28ESR (in case screening blood samples were taken within 5 days, 
these values can be used) 
 VAS PhGA/GH/pain/fatigue 
 HAQ  
 Relevant concomitant medication 
 Relevant side effects 
 Changes in employment status 
Apart from the above information following PROs will be collected from the patients 
specifically for the study: 
 RAID 
 EQ5D/WPAI 
Trial assessments 
 (A schematic overview can be found at page 21) 
At week 4, 12, 20, 28, 48, 56, 68, 82, 95 or unscheduled visit following data are captured as 
part of routine clinical data collection (SoC):  
 Clinical/Rheumatologic examination 
 Joint Count: TJC, SJC 
 Weight 
 ESR and CRP 
 DAS28CRP/DAS28ESR 
 VAS PhGA/GH/pain/fatigue 
 Relevant concomitant medication 
 Relevant side effects 
 Changes in employment status 
 


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Randomization procedure is optional and is preferably done at the dedicated visits (w8, 16, 24 
or 32). In case randomization is required in between these visits, when LDA is not reached, it 
is allowed at week 12, 20 and 28. 
At week 8, 16, 24, 32, 40, 64, 78 and 91 following data are captured as part of routine clinical 
data collection (SoC): 
 Clinical/Rheumatologic examination 
 Changes in co-morbidities assessment (co-morbidity shortlist only at w32) 
 Joint Count: TJC, SJC 
 ESR and CRP  
 DAS28CRP/DAS28ESR 
 VAS PhGA/GH/pain/fatigue 
 HAQ  
 X-ray (Sharp/van der Heijde Score) only for w24 visit  
 Relevant concomitant medication 
 Relevant side effects 
 Changes in employment status 
Apart from the above information following PROs and assessments will be collected 
specifically for the study at these time points: 
 RAID 
 EQ5D/WPAI 
 PASS (only w64) 
 Randomization procedure in case LDA is not reached between w8 and w32, and in case 
remission is not reached at w32. This randomization procedure will be done preferable 
at the dedicated time points w8, w16, w24 or w32 but when required is also allowed in 
between these visits. This can be done with an optional procedure at visit w12, 20 or 28. 
At yearly and endpoint visits (week 36, 44, 52, 60 and 104) following data are captured as 
part of routine clinical data collection (SoC): 
 Clinical/Rheumatologic examination 
 Joint Count TJC, SJC 
 Weight 
 Changes in co-morbidities assessment (co-morbidity shortlist only at w52 and 104) 
 RF and ACPA status only at w104 
 ESR and CRP 
 X-Ray hands/feet (Sharp/van der Heijde Score) on a yearly basis 
 DAS28CRP/DAS28ESR 
 VAS PhGA/GH/pain/fatigue 
 HAQ  
 Relevant concomitant medication 
 Relevant side effects 
 Changes in employment status 
Apart from the above information following PROs and assessments will be collected 
specifically for the study at these time points: 
 RAID 
 EQ5D/WPAI 
 PASS (only w52 and 104) 


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Withdrawal of patients  
Any patient may withdraw from the study for any reason at any time. The investigator may 
withdraw any patient from the study if it is not in the patient’s best interest to continue. 
 
In this trial, all included patients will be followed according to the protocol for the complete 
study period unless they withdraw consent, are lost to follow up or die. 
Protocol violations in relation to the therapeutic strategy will not be considered a reason to 
interrupt follow up within the CareRA2020 study. 
In case the proposed treatment schedule cannot be followed due to serious safety concerns, the 
patient will be kept in the study for further follow up and treated at the discretion of the 
investigator, taking into account the interest of the patient and the feasibility of the treatment. 
 
When a patient withdraws consent, or is withdrawn from the study, regardless of the reason, 
the date of withdrawal and the reason for termination should be documented on the 
withdrawal/completion page of the e-CRF. To the extent possible, if follow up is refused by the 
patient, all evaluations as required for a yearly visit will be recorded: radiological evaluation in 
case no radiographs are available within the last 3 months preceding withdrawal and evaluation 
of RF and ACPA positivity only in case not available within the last year. 
 
Every effort should be made to determine the reason why patients fail to return for the necessary 
visits or withdraw from the study. If patients cannot be reached by phone, a letter should be 
sent requesting that contact will be made with the investigator to confirm the reason for 
withdrawal from the study. 
 
All patients followed up for 104 weeks in the CareRA2020 RCT will be asked to participate in 
the long-term observational follow-up. 
 
7 Study related procedures 
Laboratory tests: 
A routine blood sample will be performed at each visit (if not available from the GP within 5 
days of study visit). The routine laboratory tests minimally required are as follows: ESR, CRP, 
complete blood count, GOT, GPT and serum creatinine. Only ESR and CRP will be recorded 
in the e-CRF. 
RF and ACPA status will be checked at screening (in case this information is not already 
available) and at w104. 
No samples will be stored for further analysis within this protocol. 
Medical history and demographic data 
At screening, medical history and demographic data will be collected. This will include date of 
birth, gender, smoking history (never, past or current) with indication of the number of pack 
years (1 pack (25 cigarettes) daily for 1 year is 1 pack year), alcohol intake (yes or no) and 
numbers of units per week, employment status (recorded at screening, date of employment start, 
changes will be inquired at all other study visits), educational level and co-morbidity listing 
(check boxes: Cardiovascular, Respiratory, Gastrointestinal, Renal, Neurological, Cancer, 
Endocrine, Musculoskeletal, Psychiatric disorders, Metabolic disturbances, extra-articular 
manifestations of RA, other). Rheumatoid Arthritis disease characteristics including date of 
first symptoms, date of diagnosis, RF and ACPA status, presence of erosions (yes/no according 
to the rheumatologist) will be registered as well. 


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Clinical and Rheumatologic examination 
At every visit, a routine clinical and Rheumatologic examination will be done. A complete 
68/66 joint count will be done at each visit based on a simple present/absent score for pain and 
swelling. Nocturnal pain (present/not) and morning stiffness will be evaluated (yes/no; with 
specification, when present: 5, 15, 30, 45, 60, 90 min, 2-3 hours, 3-4 hours, >4 hours). 
A VAS global assessment of the disease activity by the physician will be scored (VAS PhGA). 
Tuberculosis (TB) screening: 
As patients could have accelerated access to bDMARDs, standard TB screening should be 
performed at screening and the appropriate measures should be taken according to local 
guidelines. TB screening can be done by standard PPD, or Quantiferon test, combined with a 
chest X ray. In case of latent TB, patients should start prophylactic Nicotibine treatment for 6 
months, at least 4 weeks before introducing the bDMARD. If a bDMARD needs to be started 
more than 6 months after a screening TB test is performed, TB testing should be repeated. 
Active TB is an exclusion criterion. 
Patient Reported Outcomes (PROs) 
During the trial, Patient Reported Outcomes (PROs) will be gathered by means of self-reported 
patient questionnaires. Many of these PROs are collected routinely as part of good clinical 
practice by Belgian rheumatologists (= K55 incentive). Patients will fill-out visual analogue 
scales for global assessment of the disease, pain and fatigue at every visit. The HAQ will be 
obtained to measure patients’ functional ability, while the RAID and EQ5D will be filled-out 
to evaluate patients’ perceived impact of disease. The WPAI questionnaire will be collected to 
measure work productivity and activity impairment, also in view of estimating the cost-
effectiveness of different treatment strategies. Lastly, Patient acceptable symptom state (PASS) 
will be assessed. 
PROs will be collected via an app on an electronic device or via a web-application on a personal 
computer to minimize the risk of incompleteness and transcription errors. Therefore the email 
address of the patients will be recorded in the eCRF. This email will only be accessible for the 
site staff and stored encrypted so anonymity can be guaranteed. In case patients are not able to 
work with an electronic device or are not able to connect to the web-application an option will 
be open to fill out the questionnaires on paper. 
End of trial 
The maximal duration of this study will be 108 weeks (104 weeks of treatment and a maximal 
interval of 4 weeks between screening and BL) 
 
The enrolment period will be 2 years estimated to start in Q2 2018, so the closure of the 
recruitment period is estimated at Q2 2020.  
 
The end of the RCT is estimated at Q2 2022 (LPLV, Last patient last visit). 
 
After completing this 2-year randomized controlled trial, all patients will be asked to give their 
informed consent to continue with a separate 3-year observational follow-up trial. 
 
In case of restrictions in the usual outpatient care organization at the participating rheumatology 
centers due to governmental or local regulations (e.g. related to the outbreak of an epidemic), 
the inclusion in this trial will be temporally suspended and it will resume as soon as it is allowed. 
This will impact the timelines of this trial and will delay the inclusion and “end of trial” 
timelines for the duration of the suspension period. 


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Due to the COVID-19 outbreak the inclusion is suspended from 17/03/2020 until governmental 
and local regulations allow reopening the inclusion. 
 
Study discontinuation 
The sponsor may discontinue the study in case of safety concerns or major logistic problems. 
Time schedule  
The schedule of procedures is summarized at page 22 and in the appendices (page 67). 
A maximum of 4 weeks is allowed between screening and BL visit (w0). In case a BL visit is 
done within 5 days of screening, data collected at screening and blood results can be re-used if 
the investigator expects no change. 
Every effort will be made to see patients within a time frame of one week before and one week 
after the target date until week 64. With the exception of week 8, where no time window before 
the target date is allowed. From w64 until w104 it is aimed to see patients within two weeks of 
the target date. 
At BL (w0), a list with target dates (+/- window) for each follow up visit will be created within 
the e-CRF. 
In case of restrictions in the usual outpatient care organization at the participating rheumatology 
centers due to governmental or local regulations (e.g. related to the outbreak of an epidemic), 
it will not be feasible to have all visits performed within the visit window. Every effort should 
be made to perform mandatory visits (as outpatient visit or telephone visit) as much as possible 
within the defined windows. However, getting out of window will not be considered a problem. 
 
8 Trial medication 
In this trial all patients will receive a combination of MTX and prednisone at baseline (COBRA-
Slim). According to the protocol and following the treat to target principle the therapeutic 
regimen will be adapted by adding, if necessary, another csDMARD (leflunomide) or 
bDMARD (etanercept first). 
 
All medications used in this protocol have Marketing Authorization (MA) to be used in 
Rheumatoid Arthritis. As the IMP(s) will be prescribed on-label within this trial, they will be 
used within the Marketing Authorization (MA). 
 
Etanercept, either the bio-originator etanercept or the bio-similar, is not used in conformity with 
current Belgian reimbursement criteria during the accelerated access period (w8-w32) and will 
be started in the early access group after failure of only one csDMARD instead of two.  
As RIZIV-INAMI has agreed to have this reimbursed for 24 weeks, the TARDIS system will 
be used to receive approval for prescription, marking Methotrexate as the first DMARD and 
COBRA-Slim as the second DMARD.  
 
Medications given during the trial will be prescribed as in normal daily practice and collected 
at the local pharmacy, including etanercept in the accelerated access phase. 
Name and description of investigational medicinal product(s) 
Etanercept is the IMP used in this trial, and will be prescribed generically. Etanercept is 
available as bio-originator (Enbrel). Currently one bio-similar (Benepali) is marketed and 
reimbursed in Belgium, but more may follow and can be used in this trial as etanercept. 


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License for the bio-originator (Enbrel) is held by Pfizer Limited, Ramsgate Road, Sandwich, 
Kent CT13 9NJ, UK, filed under numbers EU/1/99/126/016, EU/1/99/126/017 and 
EU/1/99/126/018. First date of MA: February 3th 2000.  
 
License for the bio-similar (Benepali) is held by Samsung UK Limited, 3000 Hillswood Drive, 
Chertsey, Surrey KT16 0RS, UK, filed under numbers EU/1/15/1074/001-004. 
 
The etanercept dose used in this protocol is 50 mg subcutaneous (SC) weekly. 
The bio-originator as well as the bio-similar of etanercept has been proven to be well tolerated 
and safe at this dose in the treatment of RA. 
SmPC for both can be found at http://bijsluiters.fagg-afmps.be/ or www.ema.europa.eu.  
Name and description of each Non-Investigational Medicinal Product (NIMP) 
Other NIMP’s used in this trial are all used within MA. 
- MTX, leflunomide, prednisone, other bDMARDs. 
- Calcium and vitamin D supplements as well as folic acid. 
SmPC for all used NIMPs can be found at http://bijsluiters.fagg-afmps.be/ or 
www.ema.europa.eu. 
Legal status of the drugs  
All Medications used in this protocol have MA to be used in Rheumatoid Arthritis. 
Summary of Product Characteristics (SmPC) 
For all drugs used in the trial, SmPCs can be found at http://bijsluiters.fagg-afmps.be/ or 
www.ema.europa.eu. 
Drug storage and supply  
As this is a pragmatic trial, all drugs, IMP and NIMP’s, will be prescribed by the investigators 
as in normal daily practice. Patients will collect prescribed drugs in their local pharmacy. The 
instructions for storage and use of the medication will follow the routine clinical practice.  
Preparation and labelling of Investigational Medicinal Product 
All medications used in this trial are ready to use or will be prepared by the patients’ local 
pharmacist. Concerning the subcutaneous administration of etanercept, either the bio-originator 
or the bio-similar, this can be delivered as prefilled syringes or injection devices (pen), so no 
preparation is required. 
Dosage schedules and modifications 
Dosage schedules and modifications according to protocol are described under section “study 
design” (table 1 page 28). 
Dosage adaptations in case of toxicity can be found in the paragraph of “treatment toxicity 
during study” (page 30). 
Patients will be provided with a medication schedule where daily treatment schedule is 
visualized. This scheme will be provided and discussed on each planned study visit together 
with the prescriptions for the next period. 
Known drug reactions and interaction with other therapies 
Can be found in the SmPC’s at http://bijsluiters.fagg-afmps.be/ and www.ema.europa.eu . 
Relevant medication 


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Additional glucocorticoids, NSAIDs or analgesics are permitted according to protocol in 
specific circumstances described under section “Study design” on page 26. 
 
In this trial only relevant medication has to be recorded in the e-CRF. Relevant medication is 
defined as medication used to treat the RA or to treat adverse reactions. A list of relevant 
medication such as, but not limited to, glucocorticoids, NSAIDs and analgesics will be recorded 
at baseline. All changes in relevant medication should be registered in the e-CRF. Also, 
indications for taking these products and their relation to disease and treatment strategy will be 
assessed. 
 
In case NSAIDs or analgesics are used, these should be recorded for effectiveness evaluation, 
especially in relation to RA and RA related pain. 
 
All study patients must receive oral folic acid supplements of minimally 1mg daily (except on 
day MTX is taken) as well as Calcium and vitamin D (minimal 1000 mg/800IU daily) as 
prophylactic treatment. 
Trial restrictions  
In- and exclusion criteria are clearly describing restrictions on inclusion of patients in the trial. 
Assessment of compliance 
Medications are prescribed according to the label and will be collected by the patients in their 
local pharmacy.  
 
At each visit, patients will be questioned about medication intake. In this protocol, patients will 
be provided with a medication schedule/diary to follow. 
In case of increased disease activity, patients will be inquired on their medication intake to pick 
up possible non-compliance. 
9 Pharmacovigilance 
Definition of an adverse event 
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient 
administered a pharmaceutical product. The occurrence does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not related to the medicinal product. 
The investigator and/or his study team will examine any patient experiencing an AE as soon as 
possible. The investigator will do whatever is medically necessary for the safety and well-being 
of the patient. 
In this trial no adverse events have to be recorded in the e-CRF unless they are categorized as 
an adverse reaction, related to RA or RA treatment, or as an adverse event of interest as 
described further in the protocol. 
 
Definition of an adverse reaction (AR) 
All untoward and unintended responses to an investigational medicinal product or to an 
experiment and, when an investigational product is concerned, related to any dose 
administered. 


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The phrase "response to an investigational medicinal product" means that a causal 
relationship between a trial medication and an AE is at least a reasonable possibility, i.e. 
the relationship cannot be ruled out. 
All cases judged by either the reporting medically qualified professional or the Sponsor as 
having a reasonable suspected causal relationship to the trial medication or to RA qualify as 
adverse reactions. 
This type of events needs to be recorded in the e-CRF. 
 
Adverse event of interest 
Adverse events of interest are defined by the protocol as major cardiac and cerebrovascular  
events, non-traumatic fractures, malignancies, severe infections, a negative outcome of a 
pregnancy and death. 
Severe infection in the context of an epidemic (e.g.. COVID-19 infection) will also be 
considered an adverse event of interest and should be reported. 
 
Laboratory Abnormalities: 
Abnormal laboratory values will be evaluated by the investigator according to normal practice. 
Any clinically significant abnormalities should be investigated. If the abnormal value represents 
an adverse reaction, then this should be recorded in the e-CRF. Other abnormal values will not 
be recorded in the e-CRF unless considered by the investigator as an adverse event of interest. 
 
Definition of a Serious Adverse Event or Serious Adverse Reaction 
All Adverse Events or Adverse Reactions that meet one of the following criteria is considered 
serious: 
 Is Fatal, resulting in death 
 Is immediately life-threatening 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
 
In addition, important medical events that not fulfill above criteria may be considered serious 
when, based upon appropriate medical judgement, they may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the outcomes listed in the definition.  
In this trial no serious adverse events have to be recorded in the e-CRF unless they are 
categorized as a serious adverse reaction, related to RA or RA treatment, or as a serious adverse 
event of interest. 
 
Definition of a suspected unexpected serious adverse event (SUSAR) 
A serious adverse reaction, the nature or severity of which is not consistent with the information 
on the experiment, and, when a clinical trial is concerned, with the applicable product 
information (in this case the patient leaflet joined to the summary of product characteristics as 
it concerns the use within the label of an authorized product).  
This type of events needs to be recorded in the e-CRF. 
 
 


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Collecting and Reporting of adverse events: 
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and evaluated for causality.  
 
In this trial only ARs and adverse events of interest, as defined above, will be captured in the 
e-CRF. 
 
Following rules apply for reporting adverse events in the e-CRF: 
- 
After informed consent has been obtained but prior to initiation of study treatment, 
only SAE of interest and ARs caused by a protocol-mandated intervention should be 
reported  
- 
After initiation of study treatment, all ARs, serious adverse reaction (SARs), SUSARs 
and (serious) adverse events of interest will be recorded in the e-CRF up to the patient’s 
final study visit.  
 
In the e-CRF all above mentioned events will be detailed with the following information: 
o Full details in medical terms and case description 
o Duration of the event 
o The action taken regarding the event 
o The outcome of the event 
o Seriousness criteria (medical judgement of the treating investigator): 
Seriousness will be evaluated for each adverse event based on the criteria 
described in the paragraph on definition of a serious adverse event. In case 
the seriousness is answered “yes” than the event should be reported within 
24h. 
o Severity Grading for Adverse Events (medical judgement of the treating 
investigator): 
Severity should be graded into one of the three classes that describe the 
clinical severity of the event as it occurred: 
 Mild (does not interfere with daily living) 
 Moderate (somewhat interferes with daily living or medications needed 
to relieve event) 
 Severe (incapacitating) 
o Causality grading (medical judgement of the treating investigator) 
Causality should be graded, to determine to what extent the investigator 
thinks the adverse event is related to the proposed strategy, prescribed drugs 
or any other protocol-mandated intervention. 
o For serious events: whether the event would be considered expected or unexpected 
according to the Reference Safety Information, which is the current version of the 
SmPc. (medical judgement of the treating investigator). 
o Outcome 
 
Adverse events and reactions should be followed by the investigator until they have returned to 
normal or stabilized. 
 
All events related to the normal disease course of RA, which are captured within the outcome 
parameters of the trial, are not considered as adverse events unless these events are considered 
by the investigator as adverse events of interest. 
Reporting of adverse events that meet seriousness criteria: 


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Only SARs, SAEs of interest and deaths that occur during this study must be reported to the 
sponsor. No other SAEs will be reported. 
 
After completion of the seriousness criteria in the e-CRF a SAE-form will automatically appear 
and should be completed by the investigator. This SAE report will then be electronically signed 
and automatically e-mailed to the Department of Rheumatology of the University Hospitals 
Leuven. In case the electronic system is unavailable, a paper copy can be used. Once the e-CRF 
is again available the information should be added as soon as possible. 
 
The investigator or site must complete this form within 24 hours (immediately) after becoming 
aware of the SAR or SAE of interest. If the investigator is not available at the time of reporting, 
the report without causality and expectedness will be provided by site staff within the prescribed 
timeframe and must be followed-up by medical assessment as soon as possible thereafter. 
 
Follow-up information must be submitted promptly within the electronic template available in 
the e-CRF. 
Staff of the coordinating center will be available to provide guidance regarding SAR or SAE of 
interest reporting.   
 
Contact Information: 
 
Prof. Dr. P. Verschueren or Prof. Dr. R. Westhovens 
 
Department of Rheumatology, University Hospitals Leuven 
 
Herestraat 49, B-3000 Leuven, Belgium 
 
Telephone number: +3216342541 
 
Fax number:  +3216342543 
 
Email addresses:  patrick.verschueren@uz.kuleuven.ac.be 
 
 
rene.westhovens@uz.kuleuven.a.be 
In case both the CI and Prof Westhovens are not available, the PM can be contacted: 
 
Mr. Johan Joly 
 
Department of Rheumatology, University Hospitals Leuven 
 
Herestraat 49, B-3000 Leuven, Belgium 
 
Telephone number: +32 16 34 02 58 
 
Fax number:  +32 16 34 63 46 
 
E-Mail address: johan.joly@uzleuven.be 
 
For this pragmatic strategy trial IMPs are used within the registered label, the chance of 
encountering a SUSAR is rather low. Nevertheless, in case this would happen, it should be 
reported within the given timeframe. 
 
The department of Rheumatology of the University hospital Leuven is responsible to report 
SAEs of interest, SUSARs and deaths to the Competent Authority and Ethical Committees 
within the defined timelines: 
- 
Immediately in case of death 
- 
7 days in case of fatal or life threatening SUSAR’s 
- 
15 days in case of all other SUSAR’s 
- 
Summary report of all SAR’s/SUSAR’s annually or final report 
 
Any case of death should also be reported by the investigators to their local Ethical Committee 
immediately on awareness.  
 


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All study-related problems will be discussed with the Trial Steering Committee (TSC), which 
will take appropriate measures if necessary. Safety information will also be included in trial 
status reports, which serve as a basis of discussion during meetings. These reports will be made 
available to investigators participating in the study.  
Safety committees 
Roles and responsibilities of Trial Steering Committee (TSC) regarding safety are described on 
page 17. 
 
 


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Pregnancy reporting 
In this trial, we exclude patients to participate when pregnant or breastfeeding at screening. As 
in daily clinical practice the issue of pregnancy in relation to the proposed treatments (SmPC) 
will be discussed thoroughly and, when required, the investigator will take appropriate 
measures. If during the course of the trial, a female participant wants to become pregnant, this 
should be discussed in advance with the PI and if required with the CI so appropriate measures 
can be taken. 
Within the first 104 weeks of the trial, planned pregnancy will however not be encouraged, and 
will be reported in the e-CRF as treatment adaptations are likely to be implemented. A 
pregnancy beyond w104 can be planned according to local guidelines. 
In case of unplanned pregnancy, the participating female, should notify the investigator 
immediately, so appropriate advice and decisions can be made. 
Pregnancy is not considered an AE unless a negative or consequential outcome is recorded for 
the mother or child/fetus. If the outcome meets the seriousness criteria, this would be considered 
a SAE of interest. 
Reporting urgent safety measures  
If any urgent safety measures are taken, the CI/Sponsor shall immediately and in any event no 
later than 3 days from the date the measures are taken, give written notice to the Competent 
Authority and Ethical Committees of the measures taken and the circumstances giving rise to 
those measures. 
10 Statistics and data analysis 
Sample size calculation 
Estimation of ratio insufficient responders versus responders w8-w32 
To properly estimate the number of patients that will belong to this w8-w32 insufficient 
responder group (target of LDA: DAS28CRP≤3.2), data from the previous CareRA trial were 
used, in which ‘COBRA-Slim’ was compared with other remission induction schemes 
(Verschueren et al, 2015). In the CareRA trial population around 25% of patients required a 
second treatment adaptation because they did not reach LDA during the remission induction 
phase after a first adaptation of MTX dose increase to 20 mg. 
Expected difference in effect 
The early insufficient responders in the previous CareRA trial had a mean AUC under the 
DAS28CRP curve of 351.3 (SD 103) after 2 years. We estimate that patients in this insufficient 
responder group, when given the opportunity to have accelerated access to a short course of 
etanercept, will have an increase in effect size, reflected by a decrease in AUC at w104 in 
comparison to the reference arm. We consider a 20% decrease in AUC (from 351 to 281) to be 
clinically relevant and assume the same standard deviation. A 20% reduction in AUC over the 
first 104 weeks of treatment would reflect an important decrease of the overall disease burden. 
Additionally, we believe that this is the minimum effect size to consider an early access to anti-
TNF to be cost-effective. 
Sample size calculation of insufficient responders 
For a superiority design, with a two-sided alpha of 0.05, the null and alternative hypotheses are:  
 
 Null hypothesis: In early insufficient responders to COBRA-Slim induction therapy, 
accelerated access to anti-TNF therapy leads to the same AUC compared to treatment 


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adaptation according to the standard COBRA-Slim strategy after 104 weeks (there is no 
difference in AUC in early insufficient responders).  𝐻0: 𝛿= 0 
 Alternative hypothesis: In early insufficient responders to COBRA-Slim induction 
therapy, accelerated access to anti-TNF therapy can be considered as superior to the 
standard COBRA-Slim strategy. 𝐻1: 𝛿≠0 
 
These are the parameters taken into account for the sample size calculation, using PASS 14 
software (PASS 14 Power Analysis and Sample Size Software, 2015. NCSS, LLC. Kaysville, 
Utah, USA, ncss.com/software/pass): 
 
 Calculation of Superiority / Test for Two means (likelihood ratio test). 
 Allocation of 1:1  
 Power of 0.80 
 α was set at 0.05.  
 Primary endpoint is AUC after 104 weeks in early insufficient responders, with a mean 
AUC of 351 (SD 103) after 104 weeks in the reference group following the traditional 
COBRA-Slim adaptation strategy, as estimated based on data from the CareRA trial. 
 Assumed 20% lower mean AUC after 104 weeks (281 (SD 103)) in the arm with 
accelerated access to etanercept.  
 
To achieve a power of 80%, 70 insufficient responders have to be randomized. Based on the 
CareRA data we expect a 21% dropout rate up until week 104. Therefore, we aim to randomize 
90 insufficient responders. As mentioned above, the insufficient responders are expected to 
represent 25% of the total population of the trial. After adjusting for the expected 6% 
screen/randomization failures, we expect that 383 patients have to be screened for the new 
CareRA2020 trial in order to randomize 90 insufficient responders. The 6% expected 
screen/randomization failures is based on CareRA data, showing 21 failures out of 400 patients. 
 
Increasing the sample size would help to account for possible influence of missing data on the 
statistical power to detect the estimated difference in effectiveness of the remission induction 
schemes (Little et al, 2012) and allow us to perform a statistically more robust exploration of 
the secondary endpoints. Realistically, a sample size of around 440 patients is feasible in 
practice (see planned recruitment rate), which would lead to the randomization of 104 patients, 
of which 82 would not drop out. This would yield 86% power. 
 
Table: Sample size calculation for primary endpoint 
 
N 
screened 
N entered  
(assuming 
6% 
screening failures) 
N 
insufficient 
responders 
(assuming 25%) 
N 
complete 
insufficient 
responders  
(assuming 21% dropout) 
Power 
383 
360 
90 
70 
80% 
442 
416 
104 
82 
86% 
Planned recruitment rate 
Every effort will be made to gather a representative sample of patients, reflecting a normal 
distribution of an early RA population in Belgium. In order to achieve this, it is aimed for to 
propose all early RA patients who are newly or recently diagnosed at the participating centers, 
to take part in this trial. In- and exclusion criteria are not too restrictive towards patient 
recruitment. This means that all csDMARD naive patients, recently diagnosed with RA, can be 
included unless there are contra indications towards the proposed treatment strategy. 


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There will be about twenty recruiting centers and the recruitment rate is expected to be around 
18 patients per month. To obtain a total sample of 440 patients we expect the needed enrolment 
period to be 24 months. Therefore, we schedule the enrolment phase to be open from Q2 2018 
until Q2 2020. Recruitment rate will be closely monitored and discussed on with sites in case 
it is lower than expected. If, however, the needed sample size is not yet reached in 24 months, 
the recruitment period will be extended. 
 
Based on data from previous research, refusal to participate in this type of pragmatic trial is less 
than 2%. Therefore, we expect consent rate to be 98%. As stated above, 
screening/randomization failure rate is estimated at 6%, because there were 21 out of 400 
patients eventually not randomized in the CareRA trial (2 due to not meeting 
inclusion/exclusion criteria, 10 due to practical reasons, 7 due to consent withdrawal and 2 due 
to loss of contact with patient).  
Subject populations 
For data analysis, we will define the insufficient responder group as ‘the efficacy population’ 
to assess efficacy of the 2 different induction schemes in this specific group.  
 
Patients who do not meet the criteria for treatment adaptation within the accelerated access 
period will be followed up separately. Using the same randomization procedure as for the w8-
w32 insufficient responders, at week 32 these patients will be randomized to two subgroups 
that will be further treated identically but will each act as a complementary responder 
subpopulation for one of the two insufficient responder subpopulations to reconstruct two 
artificial global populations, one with accelerated access to etanercept for w8-w32 insufficient 
responders and one without.  
The entire group of patients will be called ‘the effectiveness population’ to investigate the 
effectiveness of the different schemes in a general RA population as a whole. 
 
For both populations, an intention to treat, a per-protocol and safety analysis will be performed: 
 An intention to treat analysis will include all patients randomized into the study. These 
patients will be analyzed according to the treatment they are randomized to, irrespective 
of whether they actually received the treatment. 
 Per protocol analysis will include all patients randomized that did follow the initial 
allocated treatment scheme and had the required adaptations performed according to 
protocol. 
 Safety analysis will include all treated patients, taking into account the treatment that 
they actually received. Any subject randomized into the study that received at least one 
dose of study drug will be included for safety analysis. 
Statistical analysis plan 
Summary of BL data and flow of patients 
These BL variables, gathered at initiation of the COBRA-Slim remission induction regimen, 
will be used to assess comparability of the population eligible for randomization, and they will 
be reported as proportions or means with their standard deviations, when appropriate. 
 
 


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Overview of BL measurements. 
Variable 
Definition 
Measurement 
level  
Age 
 
Continuous 
BMI (kg/m2) at BL 
body mass index 
Continuous 
Gender 
 
Dichotomous 
Smoking status at BL 
Status never-ever-current 
Categorical 
Alcohol intake at BL 
consumption of any form of 
alcohol, units per week 
Ordinal 
Symptom duration at BL 
time elapsed between onset of 
symptoms and BL 
Continuous 
Disease duration at BL 
time elapsed between diagnosis 
of RA and BL 
Continuous 
Employed before symptom onset 
 
Categorical 
Employed at screening 
 
Categorical 
Comorbidities at screening 
 
Categorical 
RF positivity at BL 
rheumatoid factor 
Dichotomous 
ACPA positivity at BL 
Anti-citrullinated 
protein 
antibody 
Dichotomous 
Erosions present at BL 
 
Dichotomous 
Total TJC at BL 
tender joint count 
Continuous 
Total SJC at BL 
swollen joint count 
Continuous 
GA (0-100) at BL 
Patient global assessment 
Continuous 
Pain (0-100) at BL 
Visual analog scale of pain 
Continuous 
Fatigue (0-100) at BL 
Visual analog scale of fatigue 
Continuous 
PhGA (0-100) at BL 
physician global assessment 
Continuous 
ESR (mm/h) at BL 
erythrocyte sedimentation rate 
Continuous 
CRP (mg/l) at BL 
C-reactive protein 
Continuous 
DAS28ESR at BL 
28 joint disease activity score 
(ESR) 
Continuous 
DAS28CRP at BL 
28 joint disease activity score 
(CRP) 
Continuous 
HAQ score (0-3) at BL 
Health 
Assessment 
Questionnaire 
Continuous 
EQ5D at BL 
5 dimensions questionnaire for 
health-related quality of life 
Continuous 
RAID at BL 
RA impact of disease score 
Continuous 
PASS at BL 
Patient Acceptable Symptom 
State 
Dichotomous 
 
 


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Flow Diagram 
 
 
 
All values are an estimation taking into account the distribution present in CareRA. There were 
21 failures at screening or randomization (6%) and we expect a drop-out rate of 21%. 
Primary outcome analysis 
Primary endpoint 
Area under the curve of DAS28CRP over 104 weeks (long term effectiveness) in insufficient 
responders (w8-w32) randomized to either COBRA-Slim Bio-Induction or Standard COBRA-
Slim Induction. 
Method of analysis 
Because missing data are expected, we will use the method from Bell et al to compare AUC 
between treatment arms based on a mixed model for repeated measures (MMRM) with 
DAS28CRP as the outcome (Bell et al, 2014). The model will be adjusted for the variables used 
in the minimization algorithm for treatment assignment (moment of randomization; between 
w8 and w32 but preferably at the dedicated time points w8, w16, w24, or w32 from baseline), 
DAS28CRP at baseline, and RF/ACPA status (see table). The effect of treatment arm is 
corrected for minimization factors to obtain correct P values and confidence intervals and to 
avoid an unnecessary loss in power (Kahan & Morris, BMJ 2012).  The model will include the 
following mandatory visits: w4, w8, w16, w24, w32, w40, w52, w64, w78, w91, and w104.  
 
 


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Table: Minimization variables. 
 
Variable 
Description 
Timing of randomization 
Randomization is possible between w8 and w32 
preferably at the dedicated time points (w8, w16, w24, 
w32) 
Disease activity at baseline 
DAS28CRP score categorized as low (≤3.2), moderate 
(>3.2 to ≤5.1), or high (>5.1). 
RF and/or ACPA status 
Positive serology of either RF or ACPA versus negative 
serology for both 
 
We will report the estimated difference in AUC between study arms together with a 95% 
confidence interval. The confidence interval mainly helps to interpret the uncertainty around 
the treatment effect, but it can also reveal whether the treatment effect is statistically significant 
at the 5% level. 
Plans for handling multiple comparisons, missing data, non-compliers, spurious data and 
withdrawals in analysis 
Missing values for the primary endpoint may arise because not all measurements to derive the 
presence of remission are available, or because patients withdraw from the study. We expect 
around 21% dropouts based on the CareRA trial. Most will be lost to follow-up or due to patient 
withdrawal; occasionally patients drop out because of death or logistic reasons (Verschueren et 
al, 2016).  
 
We will compare dropout between arms. More specifically, the amount of dropout, the time 
point of dropout, and the reason for dropout will be compared (Committee for Medicinal 
Products for Human Use, 2010). If this is equal, there is less concern about systematic bias 
(Vickers & Altman, 2013). We will also compare baseline measurements and measurements at 
the randomization visit between patients who do and do not drop out up until week 104. 
 
The MMRM method assumes that data are ‘missing at random’ (MAR). This means that 
missing values are completely random conditional on other observed measurements. We 
believe that MAR is a plausible assumption. Last observation carried forward, although often 
used, is an implausible assumption and will not be considered in this trial (Mallinckrodt et al, 
2001; Jansen et al, 2006; White et al, 2012; Jiang et al, 2015). 
 
We plan two sensitivity analyses (EMA guideline): 
 
1. An alternative analysis option under the MAR assumption of missing values involves 
multiple imputation of missing DAS28CRP values. After imputation, the primary 
endpoint (AUC of DAS28-CRP over 104 weeks) will be analyzed using linear 
regression. Predictor variables in the model will be treatment arm and the minimization 
factors, which are the timing of randomization, disease activity at baseline, and RF 
and/or ACPA status.  
Multiple imputation using fully conditional specification will be used to handle missing 
data (Sterne et al, 2009; Spratt et al 2010; van Buuren 2015; Lee et al, 2016). The 
multiple imputation procedure will by default include the variables in the analysis 
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randomization (w8, w16, w24, or w32), DAS28CRP score at baseline, and RF/ACPA 
status. In addition, auxiliary variables might be included that are related to missingness 
of DAS28CRP or to the value of DAS28CRP (Spratt et al, 2010; Lee et al, 2016). This 
can increase the likelihood of the MAR assumption of missing values. Likely auxiliary 
variables are gender and age. However, we have to make sure that we do not make the 
model too large. We focus on direct imputation of DAS28CRP rather than on separate 
imputation of its four component variables (Lee et al 2016). In cases where maximum 
three of the component variables are available, we will restrict imputation of 
DAS28CRP to be eat least the value that is obtained when computing DAS28CRP based 
on the available components only. We expect DAS28CRP to have a distribution that is 
close to normality (Matsui et al, 2007; Castrejón et al, 2008). We use multiple 
imputation to generate 100 completed datasets. After multiple imputation, every 
completed dataset is analyzed in the same way, and results are combined using Rubin’s 
rules. 
 
2. Although MAR is a reasonable assumption to explain missing data, dropout may still 
be related to the DAS28CRP value that would have been observed. In this situation, 
missing values for the DAS28CRP score are said to be missing not at random (MNAR). 
We assume that MNAR missingness implies that the DAS28CRP score is not observed 
because it is poor. We plan to investigate the possible influence of MNAR missingness 
on the results. A simple approach can already be very informative (Rubin, 1987; Little, 
2009), where we add a constant d to the imputations from the primary analysis when we 
assume MNAR. This number d was obtained as follows. First, a random number δ was 
sampled from a normal distribution with the estimated standard deviation of the 
distribution of DAS28CRP at 28 weeks after randomization, and standard deviation the 
square root of this value. Then d=max(δ, 1), such that d is restricted to imply an increase 
in DAS28CRP score. After the imputations under MNAR are computed, analysis 
proceeds as usual, using Rubin’s rules to combine results. We plan to do this analysis 
once when assuming that MNAR is present in all dropouts, and once when assuming 
that MNAR is present in dropouts due to death, patient withdrawal, adverse events, or 
lack of efficacy. Of course, if dropout rate, timing, and reason are similar for both 
treatment arms, MNAR is unlikely to affect the results, and we may decide to omit this 
sensitivity analysis. 
Statement regarding use of intention to treat (ITT) analysis 
For the primary endpoint analysis, an intention to treat analysis will be performed which will 
include all patients randomized into the study. Patients will be analyzed according to the 
treatment they are randomized to, irrespective of whether they actually received the treatment. 
The use of LOCF or a complete case analysis in the presence of longitudinal data is inconsistent 
with the ITT principle (White et al, 2012). 
Description of any non-statistical methods that might be used (e.g. qualitative methods) 
We do not foresee any qualitative methods to be used. 
Secondary outcome analysis 
Main secondary outcome measure 
Proportion of early 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. Taking into account a screen failure rate of 6% and dropout rate of 


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11% at that stage in the trial, based on the CareRA data, this main secondary outcome will have 
sufficient power under the assumption that remission rate is 50% in the standard COBRA-Slim 
arm vs 80% in the experimental arm (table). 
 
Table: Sample size calculation for main secondary endpoint 
N 
screened 
N entered  
(assuming 
6% 
screening failures) 
N 
insufficient 
responders 
(assuming 25%) 
N 
complete 
insufficient responders  
(assuming 11% dropout) 
Power 
383 
360 
90 
80 
82% 
442 
416 
104 
92 
87% 
 
Assuming the MAR assumption of missing values, we plan to analyse the main secondary 
outcome measure with MMRM that is adapted for binary outcomes (O’Kelly & Ratitch, 2014). 
The model will be adjusted for the variables used in the minimization algorithm for treatment 
assignment (moment of randomization; i.e. w8, w16, w24, or w32 from baseline), DAS28CRP 
at baseline, and RF/ACPA status. For every participant, remission is measured at five visits up 
to week 28 after randomization: the randomization visit (RV), RV plus 4/8 weeks, RV plus 
12/16 weeks, RV plus 20/24 weeks, and RV plus 28 weeks (Table 4).  
 
Table 4. 
Randomization 
visit (RV) 
Weeks since baseline 
8 
16 
W24 
W32 
W36 
W44 
W52 
W60 
W8 
× 
(RV+0w) 
× 
(RV+8w) 
× 
(RV+16w) 
× 
(RV+24w) 
× 
(RV+28w) 
 
 
 
W16 
 
× 
(RV+0w) 
× 
(RV+8w) 
× 
(RV+16w) 
× 
(RV+24w) 
× 
(RV+28w) 
 
 
W24 
 
 
× 
(RV+0w) 
× 
(RV+8w) 
× 
(RV+16w) 
× 
(RV+24w) 
× 
(RV+28w) 
 
W32 
 
 
 
× 
(RV+0w) 
× 
(RV+8w) 
× 
(RV+16w) 
× 
(RV+24w) 
× 
(RV+28w) 
 
All other secondary outcomes are to be considered as explorative. We will therefore report 
effect sizes with 95% confidence intervals. These confidence intervals will only be used to 
interpret the uncertainty around the effect size, not to determine statistical significance. 
 
All secondary outcomes measures are clearly described under section 2 objectives and outcome 
measures/endpoints. 
Subgroup analyses 
Treatment response heterogeneity could be explored by adding a possible influencing factor 
and its interaction term with the treatment arm into the same linear regression model made for 
the first sensitivity analysis of the primary endpoint (Lagakos, 2006; Gabler et al, 2009). This 
method of analysis could suggest the effect of this factor on the treatment response.  
Adjusted analysis 
Minimization will be used as allocation method to ensure balance between the insufficient 
responder arms with respect to predefined factors (Altman & Bland, 2005).  Based on a 
literature search for prognostic variables of the treatment response in early RA (Cook et al 2016; 
Castrejón et al 2016; Hmamouchi et al 2014) and on data of CareRA, the following 
minimization factors were defined: timing of randomization within the 8-32 weeks accelerated 
access period (w8, w16, w24, or w32), disease activity at baseline based on DAS28CRP, RF 
and/or ACPA status. Primary analysis should be adjusted for balancing factors to obtain correct 
confidence intervals and to avoid an unnecessary loss in power (Kahan & Morris, 2012). 


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Therefore, the analysis of the primary endpoint and the main secondary endpoint will be 
adjusted for these minimization factors. 
Interim analysis and criteria for the premature termination of the trial 
The Chief Investigator and/or Steering Committee may decide to discontinue this study in case 
of safety concerns or major logistic problems. This trial uses marketed drugs, therefore we do 
not expect having to perform any interim analysis for safety or efficacy reasons. Which events 
are to be reported is described in paragraph “Collecting and reporting of relevant safety events” 
page 43.  
The outcome data, before analyzing the primary endpoint will only be seen by the TSC if 
needed. More detailed information can be found in the Pharmacovigilance section of the 
protocol. 
Procedure(s) to account for missing or spurious data  
Several strategies will be conducted to avoid having missing data as much as possible (Little et 
al, 2012; White et al, 2011). 
Regarding trial planning and conduct: 
 Prior to initiating the trial the monitor shall ensure that the investigator understands all 
requirements of the protocol and his/her regulatory responsibilities as an investigator. 
 There will be regular monitoring and support 
o The monitor will visit each clinical study site at appropriate intervals to ensure 
compliance with the protocol, to verify accuracy, completeness and correctness 
of data 
o Also centralized electronic monitoring will be performed 
 Use of an electronic Case Report Form (CRF) with built in warnings (pop-ups) when 
data is incomplete or inaccurate (e.g. DAS28CRP or DAS28ESR score should always 
be filled out before saving, systolic blood pressure should be in a specific range, etc. …) 
 Use of an Interactive Web Response System (IWRS) that will be integrated into the 
CRF: When a randomization procedure becomes mandatory, a pop-up will appear in the 
CRF and an email will be sent to the investigator of the site and the project manager of 
the trial. The investigator will be able to randomize the subject in the same web platform 
via the integrated IWRS. This should help the investigator to efficiently randomize the 
subject and to avoid errors or forgetfulness. 
Follow-up after Treatment Discontinuation: 
 When study treatment is discontinued, every effort will be made continue the follow up 
of the patients with their consent for collection of data on alternative treatments and 
outcomes. This will preserve the ability to analyze end points for all participants who 
underwent randomization. It also allows exploration of whether the assigned therapy 
affected the use and efficacy of subsequent therapies and provides the ability to monitor 
side effects that might occur or persist after the discontinuation of treatment. (Little et 
al, 2012). 
 When a patient withdraws or is withdrawn from the study, regardless of the reason, the 
date of withdrawal and the reason for termination will be documented on a 
withdrawal/trial completion page.  
 Every effort should be made to determine the reason why patients fail to return for the 
necessary visits or withdraw from the study. 
 
 


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Other statistical considerations. 
We will focus on effect sizes and confidence intervals in the statistical analysis of this trial. 
Only for the analysis of the primary endpoint and the main secondary endpoint statistical 
significance at the 5% alpha level will be determined. 
 
No deviations from the current statistical plan are foreseen and in case this would be needed at 
a later stage, an amendment to the protocol will be submitted 
Economic evaluation 
Depending on the clinical results of the trial, a health economic analysis may be justified. This 
could be part of a health technology assessment project at KCE. Quality of life (EQ5D) data, 
information on professional and vocational participation (Work Productivity and Activity 
Impairment (WPAI) questionnaire) as well as the national number of the participating patients 
are collected in this trial to facilitate a possible economic analysis. 
11 Data handling 
Data collection tools and source document identification 
Source data will be collected and recorded in the study participants’ files/medical records. They 
will be kept on a secured location at all times. The collection and processing of source data 
(from subjects enrolled in this study) will be limited to those data that are necessary to fulfill 
the objectives of the study. These data will be collected and processed with adequate 
precautions to ensure confidentiality and compliance with applicable data privacy protection 
laws and regulations. Appropriate technical and organizational measures to protect the data 
against unauthorized disclosures or access, accidental or unlawful destruction, or accidental 
loss or alteration will be put in place. Personnel whose responsibilities require access to 
personal data agree to keep the data confidential. 
Documentation of source data is necessary for the evaluation and validation of clinical findings, 
observations and other activities during a clinical study. Source documentation serves to 
substantiate the integrity of study data, confirms observations that are recorded and confirms 
the existence of study participants. Furthermore source documentation will be available for the 
following to confirm data collected in the e-CRF: subject identification, eligibility, and study 
identification; study discussion and date of informed consent; dates of visits; results of safety 
and efficacy parameters as required by the protocol; record of relevant adverse events and 
follow-up of adverse events as required by the protocol; intake of medication as prescribed for 
the study and relevant concomitant medication will be documented in the source data; and date 
of study completion and reason for early discontinuation of study drug or withdrawal from the 
study, if applicable. Data collection is the responsibility of the clinical study staff at the site 
under the supervision of the investigator. The investigator will maintain complete and accurate 
documentation for the study. All source documents will be reviewed by the clinical team to 
ensure that they are accurate and complete. 
As defined in section 1.52 of the ICH Guideline for Good Clinical Practice (ICH E6) source 
documents may include: original documents, data and records (e.g., hospital records, clinical 
and office charts, laboratory notes….) 
 PROs will be entered electronically by the patients into the e-CRF system. 
Case report forms 
CRFs are provided for each subject in electronic format. The study data will be transcribed on 
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anonymized manner, and transmitted in a secure manner to the Chief Investigator within the 
timeframe agreed upon between Chief Investigator and the sites.  
Worksheets may be used for the capture of some data to facilitate completion of the e-CRF. 
Any such worksheets (including but not limited to copies of the e-CRF) will become part of the 
study participant's source documentation. All data relating to the study must be recorded in e-
CRFs prepared by the investigator. Data must be entered into e-CRFs in English. Designated 
site personnel must complete the e-CRF as soon as possible after a subject visit, and the forms 
should be available for review at the next scheduled monitoring visit. 
The investigator will ensure that data are recorded on the e-CRFs as specified in the study 
protocol and in accordance with the instructions provided. 
All e-CRF entries, corrections, and alterations must be made by the investigator or other 
authorized study-site personnel. Proper audit trails are available to demonstrate the validity of 
the trial data. A copy of the completed e-CRFs will be archived at the study site. 
Data handling and record keeping 
The investigator will maintain a certified copy of e-CRFs and all source documents that support 
the data collected from each study participant, as well as all study documents as specified in 
ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical Trial, and all study 
documents as specified by the applicable regulatory requirement(s). The investigator will take 
measures to prevent accidental or premature destruction of these documents. 
If data need to be transferred, this will be performed via a secured method of transfer taking 
into account all applicable security arrangements and regulations (such as the Belgian Privacy 
Act of 8 December 1992 on the protection of privacy in relation to the processing of personal 
data and the European Data Protection Act). Receiving party will agree to keep the transferred 
data confidential at all times. Data will not be transferred outside of the EEA.  
12 Study monitoring, audit and inspection 
Prior to the initiation of treatment in any patient, a monitoring plan will be written according to 
the amended ICH-GCP 5.18.7. The monitor/CRA shall ensure that the investigator understands 
all requirements of the protocol and his/her regulatory responsibilities as an investigator.  The 
monitor will visit each clinical study site as described in the monitoring plan to ensure 
compliance with the protocol, to verify accuracy, completeness and correctness of data. 
The investigator will permit trial-related monitoring, audits, IEC review and regulatory 
inspection, providing direct access to all related source data / documents. 
E-CRF’s and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. EMA, FDA). The accuracy of the 
data will be verified by review of the source documents. 
 
In case of restrictions in the usual outpatient care organization at the participating rheumatology 
centers due to governmental or local regulations (e.g. related to the outbreak of an epidemic), 
monitoring at site will be suspended as long as needed. Remote e-CRF checks will be done by 
the monitor and data management to continuously follow-up on the trial. Findings of this remote 
check will be communicated with the sites. 
 
13 Archiving of Documentation 
The Sponsor is responsible for archiving study specific documentation (such as but not limited 
to protocol, potential amendments, final report and database) according to ICH-GCP. Source 


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data and Site-specific study documents (such as, but not limited to, ICF) will be archived locally 
on site according to local practice and guidelines for at least 20 years. Archived data may be 
held on electronic record, provided that a backup exists and that hard copies can be obtained, if 
required. Destruction of essential documents will require authorization from the Sponsor. 
Archiving at the end of the trial will be organized by the sponsor and done centrally. 
 
 


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14 Confidentiality 
The study protocol and other written materials provided by the Department of Rheumatology 
of the University Hospitals of Leuven and documentation, data and other information generated 
as part of this study will be held in strict confidence by the investigator and site staff. No 
information concerning the study or the data will be released to any unauthorized third party 
without prior written approval of the Department of Rheumatology of the University Hospitals 
of Leuven. 
15 Ethical and regulatory considerations 
Independent Ethics Committee (IEC) review& reports 
The study will be conducted in compliance with the principles of the Declaration of Helsinki 
(current version), the principles of GCP and in accordance with all applicable regulatory 
requirements. Before the start of the study, this protocol, the informed consent forms and other 
related documents e.g. advertisements and GP information letters, will be submitted for review 
to the IEC and to the Federal Agency for Medicines and Health Products (FAMHP) for Clinical 
Authorization (the below mentioned obligations shall only apply to the extent applicable). The 
study shall not commence until such approvals have been obtained. 
Any subsequent protocol amendments will be submitted to the IEC and Regulatory Authorities 
for approval. No substantial amendments that require review by IEC will be implemented until 
the IEC grants a favorable opinion for the study. The Chief Investigator acknowledges that 
amendments may also need to be reviewed and accepted by the FAMHP before they can be 
implemented in practice at sites. 
The study can and will be conducted only on the basis of prior informed consent by the study 
participants, or their legal representatives, to participate in the study. Extensive discussion of 
risks and possible benefits of participation will be provided to the patients and/or their families. 
The participating site shall obtain a signed informed consent form (ICF) for all study 
participants prior to their enrolment and participation in the study in compliance with all 
applicable laws, regulations and the approval of the (local) Ethics Committee, if required. The 
participating site shall retain such ICFs in accordance with the requirements of all applicable 
regulatory agencies and laws. 
All correspondence with the IEC/FAMHP shall be retained in the Trial Master File/Investigator 
Site File. 
The Chief Investigator acknowledges that it is his responsibility to produce annual progress 
reports (APR) and he will do so by submitting to the IEC/FAMHP within 30 days of the 
anniversary date on which the favorable opinion was given, and annually until the study is 
declared ended. 
The Chief Investigator shall notify the IEC/FAMHP of the end of the Study. Should the study 
be ended prematurely, the Chief Investigator will notify the IEC/FAMHP and include the 
reasons for the premature termination. The Chief Investigator will submit a final report with the 
results, including any publications/abstracts, to the IEC/FAMHP. 
Peer review 
This study protocol was peer reviewed by independent experts from the KCE Trials Board. Peer 
review was conducted by expert referees to the professional and scientific standards expected 
for clinical studies. 
 
 


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Public and Patient Involvement 
During protocol development, feedback from patient representatives/researchers (ReumaNet 
vzw) was included. 
Furthermore, we are planning to engage patient researchers as scientific collaborators in the 
TSC, participating to the further development of the protocol, the supervision of the trial, data 
analyses and preparation of the study report. Patient partners were involved in the development 
of the informed consent form and all other information leaflets that were developed for this 
trial. Moreover, the study design and important endpoints of the CareRA2020 trial are inspired 
by the results of previous research from our group that was looking into patient priorities 
concerning the management and treatment outcomes of RA.  
Every effort will be made to distribute the results of this trial to the general public. 
16 Regulatory Compliance  
Before the start of the study, this protocol and other related documents will be submitted for 
review to the Federal Agency for Medicines and Health Products for Clinical Trial 
Authorization (FAMHP). The study shall not commence until such approvals have been 
obtained. 
 
This study protocol and the conduct of the study in general is in compliance with applicable 
law, including but not limited to the Belgian law of May 7th 2004 regarding experiments on the 
human person and any relevant amendments. 
Protocol compliance  
The Chief Investigator is responsible for ensuring that the clinical study is performed in 
accordance with the protocol, current ICH guidelines on GCP, and applicable regulatory and 
country-specific requirements. GCP is an international ethical and scientific quality standard 
for designing, conducting, recording, and reporting studies that involve the participation of 
human subjects. Compliance with this standard provides public assurance that the rights, safety, 
and well-being of study participants are protected, consistent with the principles that originated 
in the Declaration of Helsinki, and that the clinical study data are credible. 
It is acknowledged and agreed that prospective, planned deviations or waivers to the protocol 
are not allowed under applicable regulations on clinical studies and must not be used. However, 
should there be an accidental protocol deviation, such deviation shall be adequately documented 
on the source documents and on the relevant forms and reported to the Chief Investigator and 
Sponsor immediately. Protocol deviations that are found to frequently recur will require 
immediate action. Chief Investigator acknowledges that such recurring protocol breaches could 
be potentially classified as a serious violation. 
Notification of Serious Violation to GCP and/or the protocol  
It is understood that “a serious violation” is likely to affect to a significant degree 
 the safety or physical or mental integrity of the participants of the study; or 
 the scientific value of the study 
The Sponsor shall be notified immediately upon becoming aware of a serious violation during 
the study conduct phase. The Sponsor shall notify the licensing authority in writing of any 
serious violation of the conditions and principles of GCP in connection with that study; or the 
protocol relating to that study, as amended from time to time, within 7 days of becoming aware 
of that violation. 
 
 


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Data protection and patient confidentiality  
The study will be conducted in compliance with the requirements of the Belgian Privacy Act 
of 8 December 1992 on the protection of privacy in relation to the processing of personal data 
and the European Data Protection Act. Any collection, processing and disclosure of personal 
data, such as patient health and medical information is subject to compliance with the 
aforementioned personal data protection laws. 
Any personal data shall be treated as confidential at all times including during collection, 
handling and use, and that the personal data (including in any electronic format) shall be stored 
securely at all times and with all technical and organizational security measures that would be 
necessary for compliance with data protection legislation. The Sponsor shall take appropriate 
measures to ensure the security of all personal data and guard against unauthorized access to or 
disclosure of or loss or destruction while in its custody. 
The personal data of study participants will be encoded, which means that they can only be 
related to an identifiable person by means of a unique code. The unique code will only be in the 
possession of the members of the study team who are in direct contact with the study 
participants. In no event will the coded personal data include personal identifiers, including any 
Study participant’s initials. Such coded personal data can only be traced or linked back by said 
study team members, and said study team members shall treat these codes as strictly 
confidential. 
Only anonymized personal data will be disclosed to KCE or, where specifically requested by 
KCE, coded personal data. In no event shall any of the reports, documents, information 
disclosed to KCE include data that may be linked to the specific identity of a study participant. 
The Sponsor shall make sure that the key to personal identities of all persons to whom the data 
relates is kept in a separate and secure place in compliance with applicable data privacy 
legislation and shall not be disclosed to KCE or unauthorized persons.  
All study related data and documents will be stored for twenty (20) years, in accordance with 
Belgian legislation. 
The collection of the national number and study code of all participating patients in a trusted 
third party database (TARDIS) under the governance of healthdata.be will allow for a later 
possible coupling of clinical data collected in the trial with billing data. This coupling could be 
of use in the context of a later health economic analysis. 
 
Financial and other competing interests for the Chief Investigator, PIs at each site and 
committee members for the overall trial management  
The Chief Investigator will be required to disclose any financial arrangement whereby the value 
of the compensation for conducting the study could be influenced by the outcome of the study; 
any significant payments of other sorts from the Sponsor, such as a grant to fund ongoing 
research, compensation in the form of equipment, retainer for ongoing consultation, honoraria, 
ownership interest that may be related to products, services or interventions considered for use 
in the study, or that may be significantly affected by the study, commercial ties with any 
pharmaceutical, behavior modification, and/or technology company, or any non-commercial 
potential conflicts e.g. professional collaborations that may impact on academic promotion. 
In consideration of participation in the study, the nominated payee will receive the sums set out 
in the payment schedule attached to the clinical trial agreement.  
Indemnity 
The Sponsor shall throughout the duration of the study effect and maintain with a reputable 
insurance company a policy or policies of insurance providing an adequate level of cover in 


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respect of all risks which may be incurred by the Sponsor arising out of the Sponsor's 
performance of the study, including the insurance that is required to be taken out as sponsor of 
the study as set out in the Law of 2004.  
The terms or the amount of cover of any insurance shall not relieve the Sponsor of any liabilities 
under the clinical trial agreement.  
Amendments  
In accordance with the Belgian law of May 7th 2004 regarding experiments on the human 
person, the Sponsor may make a non-substantial amendment at any time during a study. If the 
Sponsor wishes to make a substantial amendment to the cta or the documents that supported the 
original application for the cta, the Sponsor must submit a valid notice of amendment to the 
licensing authority (FAMHP; if applicable) for consideration. If the Sponsor wishes to make a 
substantial amendment to the IEC application or the supporting documents, the Sponsor must 
submit a valid notice of amendment to the IEC for consideration. The FAMHP and/or the IEC 
will provide a response regarding the amendment within 28 days of receipt of the notice. It is 
the Sponsor’s responsibility to decide whether an amendment is substantial or non-substantial 
for the purposes of submission to the FAMHP and/or IEC. 
Post-trial care 
Not applicable for this trial. From baseline onwards, patients receive optimal treatment, which 
will be continued at the end of the trial.  
Access to the final trial dataset 
The party who generates the study results will own them. Sponsor will have access to the study 
data. At the end of the study, KCE will receive from Sponsor specific study data. This will only 
be anonymous study data or, where requested by KCE, coded personal data are made available 
to KCE. The study data shall not be provided to a third party without the prior written approval 
of KCE, which approval KCE shall not unreasonably withhold or delay and which KCE may 
subject to specific conditions in order to ensure that the provision of said study data does not 
have a negative impact on the further performance of the study, the rights granted to KCE under 
the research agreement and/or the benefit of the Study for the patients and/or the public payers. 
17 Dissemination policy 
Dissemination policy 
The results of the study shall be owned by the party who generates them.  
 
The results of the study owned by Sponsor and/or (where applicable) any collaborator shall be 
disseminated as soon as possible, by disclosing them to the public by appropriate means, 
including in scientific publications (in any medium). Sponsor shall inform and discuss its 
dissemination strategy with KCE in advance.  
 
The final Study report should be made available for review by KCE before the results are 
disseminated. KCE shall be notified prior to any dissemination (including publication) (whether 
in oral, written or other form) of the foreground IP or results or study data or of matters arising 
from the study. The Chief Investigator shall send one draft copy of the proposed dissemination 
to KCE, at least ten (10) days for an abstract and thirty (30) days for a manuscript, before the 
date intended for dissemination. For the avoidance of doubt, this obligation continues after the 
end of the study. KCE may object within thirty (30) days of receiving notification, if, in its 
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the event Chief Investigator or (where applicable) any collaborator intends not to protect the 
results of the study it needs to formally notify KCE thereof before the dissemination takes place, 
Sponsor shall ensure that any dissemination is scientifically correct, objective and unbiased 
(taking into consideration the primary endpoint(s)).  
 
In the event of a multicenter study, Sponsor nor its collaborators shall independently publish or 
otherwise disclose any findings resulting from the study before publication of the main 
multicenter publication.  
 
Any dissemination shall acknowledge KCE’s financial support and carry a disclaimer as KCE 
may require in accordance with the clinical trial agreement.  
 
Open access will be ensured (free of charge, online access for any user) to all peer-reviewed 
scientific publications relating to the results of the study owned by it and/or the collaborators. 
In particular, Sponsor shall: (i) As soon as possible and at the latest on publication, deposit a 
machine readable electronic copy of the published version or final peer-reviewed manuscript 
accepted for publication in a repository for scientific publications; moreover Sponsor must aim 
to deposit at the same time the research data needed to validate the results of the study presented 
in the deposited scientific publications; and; (ii) Ensure open access to the deposited 
publication, via the repository at the latest on publication (if an electronic version is available 
for free via the publisher) or, within six (6) months of publication in any other case.  
Authorship eligibility guidelines and any intended use of professional writers 
The results of the main study will be submitted for publication in a peer reviewed rheumatology 
journal. All centers will be entitled to one authorship for the publication of the primary outcome 
data, depending on the requirements and regulations of the journal. Authorships for all other 
publications will be depending on the contribution of an investigator to the manuscript and to 
the inclusion of patients. All investigators will be mentioned as members of the CareRA2020 
study group. Additional publications concerning study data will have to be approved by the 
Chief Investigator and the local study team. 
 
 


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18 Reference List 
 
Verschueren P, Westhovens R. Optimal care for early RA patients: the challenge of translating 
scientific data into clinical practice. Rheumatology. 2011;50(7):1194-200. 
Westhovens R, Verschueren P. Rheumatoid arthritis: defining remission in patients with RA in 
clinical practice. Nature reviews Rheumatology. 2012;8(8):445-7. 
van Nies JA, Krabben A, Schoones JW, Huizinga TW, Kloppenburg M, van der Helm-van Mil 
AH. What is the evidence for the presence of a therapeutic window of opportunity in rheumatoid 
arthritis? A systematic literature review. Ann Rheum Dis. 2014;73(5):861-70. 
Deighton C, O'Mahony R, Tosh J, Turner C, Rudolf M. Management of rheumatoid arthritis: 
summary of NICE guidance. BMJ. 2009;338:b702. 
Smolen JS, Landewe R, Breedveld FC, Buch M, Burmester G, Dougados M, et al. EULAR 
recommendations for the management of rheumatoid arthritis with synthetic and biological 
disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73(3):492-509. 
Singh JA, Saag KG, Bridges SL, Jr., Akl EA, Bannuru RR, Sullivan MC, et al. 2015 American 
College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis 
Rheumatol. 2016;68(1):1-26. 
Gorter SL, Bijlsma JW, Cutolo M, Gomez-Reino J, Kouloumas M, Smolen JS, et al. Current 
evidence for the management of rheumatoid arthritis with glucocorticoids: a systematic 
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etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for the 
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19 Appendices 
Risk 
As the IMP(s) used in this trial, are used within the license, this trial can be categorized as a 
low intervention trial and so no risk/benefit analysis is required 
Study management / responsibilities  
Patient registration/randomisation procedure  
Registration and randomization of the patients will be done within the e-CRF.  The study site 
representatives will do the registration on the day of inclusion. Randomization will be done at 
the specified time points in the protocol if randomization criteria are met. 
Data management  
As described above in the protocol a monitoring plan will be developed as well as timelines for 
CRF entry. 
Data management will be done within the Department of Rheumatology of University Hospitals 
Leuven with support for data monitoring and query management of the CTC University 
Hospitals Leuven. 
Preparation and submission of amendments  
Preparation and submission of the protocol and amendments is the responsibility of the CI and 
PM.  
Data protection/confidentiality  
As described above all data collected within this protocol will be handled in a confidential 
manner.  Patients will be assigned a unique patient number, which will be used to store the data 
in the database.  
The database will be stored on an approved and secured data server, hosted by the vendor of 
the e-CRF. 
Approval for the set-up of the database will be obtained from the privacy commission. 
To obtain etanercept for randomized patients, some data need to be entered in the TARDIS 
system, which will be used for the reimbursement procedure as in standard of care. 
Also, baseline data for all patients will be entered into the TARDIS system, together with their 
unique study number. The collection of the national number and study code of all participating 
patients in a trusted third party database (TARDIS) under the governance of healthdata.be will 
allow for a later possible coupling of clinical data collected in the trial with billing data. This 
coupling could be of use in the context of a later health economic analysis.  
Also in the last case confidentiality of study subjects will be maintained as coupling of data 
bases will only be done by healthdata.be (TARDIS) as a third trusted party. 
Trial documentation and archiving  
Trial documentation will be provided electronically except for the site-specific logs (patient 
log, DoA, signature pages and signed ICF’s). Source data are part of the patient medical file. 
Documentation will be kept for at least 20 years. Archiving at the end of the trial will be 
organized by the sponsor and done centrally.  
Authorisation of participating sites  
Centers will be selected and authorized based on a formal feasibility visit performed by the 
sponsor, CI and a representative of the CRO appointed by KCE (Harmony). 


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Required documentation  
All the local documentation required prior to initiating a participating site should be collected 
in an Investigator Site File.  
The Investigator Site File contains all essential documents held by Investigator(s) conducting a 
study, which individually and collectively permit the evaluation of the conduct of a study and 
the quality of the data produced.  
For a list of all essential documents for the conduct of a clinical study, see ICH-GCP section 8. 
In this trial all documentation is kept on the e-platform except for the DoA, the patients 
identification list and the signed ICF’s.  These last documents will be kept separate in a binder 
on site. 
Procedure for initiating/opening a new site  
Pre-Trial Visit 
After IEC approval of a study, before the start of recruitment, monitoring starts with a 
preliminary meeting with the PI and /or the sub investigator(s). The study team is informed 
about all aspects related to the organization of the study (Investigator Site File (ISF), CRF, 
facilities, study medication.) in accordance with GCP. Information on how to organize an ISF 
as well as template log forms covering items like adverse event reporting, drug accountability, 
patient screening and identification, etc.…are provided  
Site Initiation Visit 
During the Site Initiating Visit (SIV), a first detailed review of all available documents in the 
ISF, essential to conduct a clinical study, will take place and study team is informed about all 
aspects related to the organization of the study. 
Principal Investigator responsibilities  
The local investigator is responsible to implement and conduct the trial in compliance with the 
approved protocol and will adhere to the principles outlined in the requirements for the conduct 
of clinical trials in the EU as provided for in " Directive 2001/20/EC” and any subsequent 
amendments, GCP guidelines, the Belgian law of May 7th 2004 regarding experiments on the 
human person, the Sponsor’s SOPs, and other regulatory requirements as amended. 
The local investigator is bound to confidentiality and will ensure that the confidential 
information contained in this document will not be used for any other purpose other than the 
evaluation or conduct of the clinical investigation. 
Except where the investigator’s signature is specifically required, it is understood that the term 
“investigator” as used in this protocol and protocol related documents refers to the investigators 
and/or appropriate study personnel that the investigators designates to perform a certain duty. 
The investigator is ultimately responsible for the conduct of all aspects of the study. 
The organizing center, Department of Rheumatology of the University Hospitals Leuven, will 
provide notification to the investigators of protocol and amendment approvals by regulatory 
authorities, if applicable. 
 


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Schedule of Procedures 
 
Flowchart
Screen
BL
W4
W8
w12
W16
w20
w24
w28
w32
w36
W40
w44
w48
W52
w56
w60
w64
Randomized at W8
X
X
X
X
X
X
X
X
X
X
X
X
Randomized at W16
X
X
X
X
X
X
X
X
X
X
X
X
Randomized at W24
X
X
X
X
X
X
X
X
X
X
X
X
Randomized at W32
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Not randomized
X
X
X
X
X
X
X
X
X
X
General mandatory visit
R+28w
General optional visit
R+24w
R+16w
R+8w
randomized patients
Mandatory visits for


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Safety Reporting Flow Chart  
To be developed based on the final protocol and what is described previously. 
Amendment History 
Amendment 
No. 
Protocol 
version no. 
Date 
issued 
Author(s) 
of changes 
Details of changes made 
0 
0.1 
17/12/2016 
JJ 
First draft 
0 
0.2 
02/01/2017 
JJ 
Second draft with 
implementation of remarks 
KCE and CTC 
0 
0.3 
05/01/2017 
JJ 
Draft after internal discussion 
RW, JJ and SP 
0 
0.4 
11/01/2017 
JJ 
Draft after remarks with PV VS 
SP JJ and AH (CTC) 
0 
0.5 
13/01/2017 
JJ 
Incorporating remarks PV, VS, 
PS and JJ 
0 
0.6 
19/01/2017 
JJ 
update 
0 
0.7 
27/01/2017 
JJ 
Pre Final draft 
0 
0.8 
31/01/2017 
JJ 
Final Draft 
0 
0.9 
04/04/2017 
JJ 
Implementations of remarks 
KCE, statistical plan included 
(PV, VS, SP) 
0 
1.0 
05/05/2017 
SP, VS, JJ, 
PV, BVC 
Further implementations of 
remarks KCE, statistical plan 
included (PV, VS, SP, BVC) 
0 
1.1 
31/07/2017 
JJ, SP, VS, 
KVE, PV 
Implementation of remarks 
KCE 
0 
1.2 
31/07/2017 
JJ, SP, VS, 
KVE, PV 
Internal revision Rheumatology 
0 
1.3 
04/09/2017 
JJ, PV, KCE Implementation of remarks 
KCE 
0 
1.4 
22/09/2017 
JJ 
Pre-final 
0 
1.5 
30/10/2017 
JJ, PV 
Revision of the UZ Leuven 
team 
0 
1.6 
20/11/2017 
JJ, PV 
Implementation of remarks 
KCE 
0 
1.7 
14/12/2017 
JJ, PV, CTC Implementation of remarks on 
Pharmacovigilance (CTC) and 
economic evaluation 
0 
1.8 
19/12/2017 
JJ, PV, CTC Review 
0 
1.9 
02/01/2018 
JJ 
 
0 
2.0 
09/01/2018 
JJ, PV 
Pre final review 
0 
2.1 
11/01/2018 
JJ, PV 
Final review 
0 
2.2 
25/01/2018 
RW, JJ, PV 
Final protocol 
0 
2.3 
06/02/2018 
JJ 
Correction of typo’s 


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0 
2.4 
26/04/2018 
JJ 
Information added on request of 
FAGG/EC 
SM001 
2.4 
26/04/2018 
NA 
Addition of 5 sites, no 
adaptations made to the 
protocol. 
SM002 
2.4 
26/04/2018 
NA 
Addition of 5 sites, no 
adaptations made to the 
protocol. 
SM003 
2.4 
26/04/2018 
NA 
Addition of 1 site, no adaptation 
made to the protocol. 
Non-SM1 
3.0 
16/07/2019 
DB, JJ, PV 
Non substantial amendment: 
Clarifications on the protocol  
and correction of typo’s 
SM004 
4.0 
18/03/2020 
JJ, DB, PV, 
CL 
Addition of procedures to be 
used in case of restrictions of 
regular outpatient visits due to 
governmental/local regulations 
(e.g. COVID-19 pandemic) 
Non-SM2 
4.1 
29/04/2020 
JJ 
Clarifications on the protocol 
and correction of typo’s 
 
Reason for non-substantial amendment 1 (non-SM1) protocol version 3.0 16/07/2019. 
 
The amendment is used to correct some typo’s and for implementing clarifications on: 
 
- 
The use of non-oral GC’s before baseline: besides IA corticosteroids also IM and IV 
corticosteroids are not allowed within 4 weeks prior to baseline. 
- 
The interpretation of the treat to target principle after w32 
- 
The start-up schedule of Methotrexate 
- 
Mandatory and optional visits 
- 
Relevant medication 
- 
Reportable (S)AE’s 
 
This protocol amendment does not change any procedure nor raise any possible new safety 
issues to patients and so only consists of clarifications to the protocol. 
After discussion with our TSMC, this protocol amendment is considered as non-substantial. 
 
Reason for substantial amendment 4 (SM004) protocol version 4.0 18/03/2020. 
 
The amendment is used to add procedures to be used during the course of the COVID-19 
outbreak, as government and hospital guidelines are limiting patient contacts when not assessed 
as essential. 
 
This protocol amendment does meet the criteria to be substantial. 
 
Reason for non-substantial amendment 2 (non-SM2) protocol version 4.1 dd 29/04/2020. 
 
The amendment is used to correct some typo’s and to add the restart of the screening of which 
a notification is sent to the FAGG/EC. 
 
This protocol amendment is considered as non-substantial.