SPondyloArthritis: Inducing Drug-free Remission by Early TNF-Alpha bloCkade Under Guidance of Single Cell RNA Sequencing and Epigenetic Profiling. (The SPARTACUS Trial)
Phase: PHASE3
Conditions: Peripheral Spondyloarthritis
Sponsor: University Hospital, Ghent

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Protocol “SPARTACUS”, versie 5.1, dd 04/06/2025 
 
SPondyloArthritis: inducing drug-free Remission by 
early TNF-Alpha bloCkade Under guidance of Single cell 
RNA sequencing and epigenetic profiling.  
 
 
 
 
Short title 
 
 
The SPARTACUS trial 
Protocol version and date 
 
v 5.1 – 04/06/2025 
EU reference number 
 
2023-510085-27-00 
 
Local reference number 
BC-6226 
 
Sponsor 
 
Ghent University Hospital 
Department of Rheumatology  
Corneel Heymanslaan 10,  
9000 Ghent 
Belgium 
 
Coordinating Investigators 
 
Prof. Dr. Dirk Elewaut 
Prof. Dr. Filip Van den Bosch 
Prof. Dr. Philippe Carron 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol “SPARTACUS”, versie 5.1, dd 04/06/2025 
Protocol modification history 
 
Version 
Date 
Description of modification 
1.3 
2020-07-30 
First approved version 
2.1 
2021-02-09 
- Rename Producer to Manufacturer in 6.2.2 
- Update in section 6.2.5 
- Addition of Site ZNA Jan Palfijn in 6.3.1 
- Addition of exclusion criteria in 6.3.3 
- Addition of location clarification and research 
samples in ‘Procedures’, Phase A (7.1.1) 
- Update footnote ‘g’ in flowchart Phase A 
- Update footnote ‘e’ in flowchart Phase B 
- Addition of a note to Addendum 7i at question 
1, 2 and 3  
- Addition of a note to Addendum 7j at question 1 
and 2  
2.2 
2021-04-06 
- Update in ‘Prior and concomitant use of 
DMARDs, NSAIDs and glucocorticoids’ Table 
1, section 9 
- Addition of comment to Addendum 6b 
3.0 
2022-10-06 
- Addition of clarification to Section 3 that the 
SPARTACUS trial is part of a bigger 
SPARTACUS project of the VIB Grand 
Challenges Program 
- Clarification in Section 3 that the Uncertainty 
analysis will be performed by Maastricht 
University 
- Section 4.3: replace VIB Research unit with KU 
Leuven Research Unit 
- Correction of wording in Section 5: Trial 
replaced with project 
- Section 7: Update of Visit time window Phase 
A, Visit 1A and Visit 1B + clarification about 
TB, Hep B, Hep C, HIV and CLV IgG 
Screening + clarification of what test results 
are allowed from previous testing + 
clarification about research samples at Visit 5 
and Visit 8 
- Addition of Phase A – Unscheduled visit 
(Section 7.1.1, Flowchart Phase A) 
- Update footnote ‘b,e,g a,d i’ in Flowchart Phase 
A 
- Addition of ‘Physician Global NRQ at Week 12 
and update of footnote ‘e’ in Phase B 
Flowchart 
- Updated DSUR wording in Section 11 

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- Addition of clarification about ‘analysis of the 
samples’ in Section 12.2 
- Update in Section 12.3, Statistical analysis 
- Addendum 7k: update possible responses for 
Q13 
3.1 
2023-08-03 
- Update of references to Global Safety Intake 
Form  
- Addition of Section 19 to include the addenda 
- Update of Addendum 10 and 11 (CIOMS form 
and Adverse Event Reporting Form) 
3.2 
2024-01-30 
- Addition of Table of Content 
- Signature page:  Name  UZ Ghent investigators 
removed 
3.3 
2024-05-01 
- AST test is no longer required 
4.0 
 
03/02/2025 
- Use of new protocol template to ensure all 
needed sections are included. 
- make the document CTR compliant 
- Update contact information manufacturer 
blinded methotrexate 
- define MSD/Merck as distributor of Golimumab 
up until 30th of September 2024. 
- Update of Addendum 10 and 11 (CIOMS form 
and Adverse Event Reporting Form) 
- Removed stratification into groups of <3 
months symptom duration and ≥3 month and 
<12 months symptom duration which has an 
impact on the sample size calculation. A 
sample size of at least 45 patients in each 
group is sufficient to obtain 80% power or 
more to detect a difference in proportions of 
30% (20% versus 50%) at the alpha level of 
5% using a Fisher's exact test.  
5.0 
03/04/2025 
- Reference to the investigators brochure was 
removed.  
- Storage period biological samples is 10 years 
- Contraceptives must be used up until 6 months 
after last dose.  
- Donation of eggs (ova, oocytes) or sperm is not 
allowed during the study and for 6 months 
after the last dose of the study drug. 
5.1 
04/06/2025 
- Administrative correction  

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Protocol “SPARTACUS”, versie 5.1, dd 04/06/2025 
Table of contents 
Inhoud 
Protocol modification history ............................................................................................................... 2 
Table of contents .................................................................................................................................. 4 
List of abbreviations ............................................................................................................................. 7 
Part I: Trial-related part of the protocol ............................................................................................... 9 
1 
Title of the trial ............................................................................................................................. 9 
2 
Trial number ................................................................................................................................. 9 
3 
General information ..................................................................................................................... 9 
3.1 
National Coordinating Investigator(s) ................................................................................... 9 
3.2 
Sponsor .................................................................................................................................. 9 
3.3 
Departments/laboratories involved in the study .................................................................. 10 
4 
Introduction ................................................................................................................................ 10 
4.1 
Rationale + Background ...................................................................................................... 10 
4.2 
Risk/Benefit assessment ...................................................................................................... 11 
4.3 
Patient participation in trial design ...................................................................................... 12 
5 
Objective(s) of the study ............................................................................................................ 12 
5.1 
Main objectives .................................................................................................................... 12 
5.2 
Secondary objectives ........................................................................................................... 13 
6 
End points ................................................................................................................................... 15 
6.1 
Primary end points ............................................................................................................... 15 
6.2 
Secondary end points ........................................................................................................... 15 
7 
Trial Design - The present study ................................................................................................ 17 
7.1 
Study design description ...................................................................................................... 17 
7.2 
Start of the trial .................................................................................................................... 22 
7.3 
End of the trial ..................................................................................................................... 22 
7.3.1 
For an individual subject .............................................................................................. 22 
7.3.2 
For the whole trial ........................................................................................................ 22 
7.4 
Trial duration ....................................................................................................................... 22 
7.4.1 
For an individual subject .............................................................................................. 23 
7.4.2 
For the whole trial ........................................................................................................ 23 
8 
Trial Population .......................................................................................................................... 23 
8.1 
Number of subjects and planned recruitment rate ............................................................... 23 
8.2 
Inclusion and exclusion criteria ........................................................................................... 23 
8.2.1 
Inclusion criteria ........................................................................................................... 23 
8.2.2 
Exclusion criteria .......................................................................................................... 24 
8.2.3 
Justification of in- and exclusion criteria ..................................................................... 25 
8.3 
Withdrawal and replacement of subjects ............................................................................. 25 
8.3.1 
Withdrawal of subjects ................................................................................................. 25 
8.3.2 
Replacement of subjects ............................................................................................... 26 
8.3.3 
Follow-up of withdrawn subjects ................................................................................. 26 
8.4 
Method of recruitment and compensation for subjects ....................................................... 26 
8.5 
Subject eligibility screening ................................................................................................ 27 
8.6 
Subject follow-up after trial participation ........................................................................... 27 
8.7 
Restrictions and prohibitions for the subjects ...................................................................... 27 
9 
Investigational Medicinal Product (IMP) ................................................................................... 28 
9.1 
General information ............................................................................................................. 28 
9.1.1 
Reporting requirements for investigational product complaints .................................. 28 

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9.1.2 
Treatment compliance .................................................................................................. 29 
9.1.3 
Drug Accountability ..................................................................................................... 29 
9.1.4 
Storage conditions ........................................................................................................ 29 
9.2 
Golimumab (blinded) .......................................................................................................... 30 
9.2.1 
General information ..................................................................................................... 30 
9.2.2 
IMP rationale ................................................................................................................ 30 
9.2.3 
Preparation, administration, dosage and dose frequency of the IMP ........................... 30 
9.2.4 
Permitted dose adjustments and interruption of treatment ........................................... 31 
9.2.5 
Duration of treatment ................................................................................................... 31 
9.2.6 
Packaging and labeling of the IMP .............................................................................. 31 
9.2.7 
Traceability, storage, return and destruction of the IMP .............................................. 31 
9.2.8 
Known side effects of the medication .......................................................................... 31 
9.3 
Simponi® (open-label) ......................................................................................................... 32 
9.3.1 
General information ..................................................................................................... 32 
9.3.2 
IMP rationale ................................................................................................................ 33 
9.3.3 
Preparation, administration, dosage and dose frequency of the IMP ........................... 33 
9.3.4 
Permitted dose adjustments and interruption of treatment ........................................... 33 
9.3.5 
Duration of treatment ................................................................................................... 33 
9.3.6 
Packaging and labeling of the IMP .............................................................................. 33 
9.3.7 
Traceability, storage, return and destruction of the IMP .............................................. 34 
9.3.8 
Known side effects of the medication .......................................................................... 34 
9.4 
Placebo Golimumab ............................................................................................................ 34 
9.4.1 
General information ..................................................................................................... 34 
9.4.2 
IMP rationale ................................................................................................................ 34 
9.4.3 
Preparation of the IMP, administration, dosage and dose frequency of the IMP ........ 34 
9.4.4 
Permitted dose adjustments and interruption of treatment ........................................... 35 
9.4.5 
Duration of treatment ................................................................................................... 35 
9.4.6 
Packaging and labeling of the IMP .............................................................................. 35 
9.4.7 
Traceability, storage, return and destruction of the IMP .............................................. 35 
9.5 
Ledertrexate ......................................................................................................................... 35 
9.5.1 
General information ..................................................................................................... 35 
9.5.2 
IMP rationale ................................................................................................................ 36 
9.5.3 
Preparation of the IMP, administration, dosage and dose frequency of the IMP ........ 36 
9.5.4 
Permitted dose adjustments and interruption of treatment ........................................... 36 
9.5.5 
Duration of treatment ................................................................................................... 37 
9.5.6 
Packaging and labeling of the IMP .............................................................................. 37 
9.5.7 
Traceability, storage, return and destruction of the IMP .............................................. 37 
9.5.8 
Known side effects of the medication .......................................................................... 37 
9.6 
Placebo Ledertrexate ........................................................................................................... 38 
9.6.1 
General information ..................................................................................................... 38 
9.6.2 
IMP rationale ................................................................................................................ 38 
9.6.3 
Preparation of the IMP, administration, dosage and dose frequency of the IMP ........ 38 
9.6.4 
Permitted dose adjustments and interruption of treatment ........................................... 39 
9.6.5 
Duration of treatment ................................................................................................... 39 
9.6.6 
Packaging and labeling of the IMP .............................................................................. 39 
9.6.7 
Traceability, storage, return and destruction of the IMP .............................................. 39 
9.7 
Management of pSpA .......................................................................................................... 39 
10 Concomitant medication and treatment ...................................................................................... 39 
Rescue therapy ............................................................................................................................... 41 
11 Procedures and Study Flow-Chart .............................................................................................. 41 

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11.1 
Eligibility screening process ............................................................................................ 41 
11.2 
Informed consent ............................................................................................................. 42 
11.3 
Measures taken to minimise bias ..................................................................................... 42 
11.3.1 Randomisation/Blinding/Deblinding ........................................................................... 42 
11.4 
Study specific Procedures and Interventions ................................................................... 43 
11.4.1 ‘SPARTACUS Phase A’ .............................................................................................. 43 
11.4.2 ‘SPARTACUS Phase B’ .............................................................................................. 53 
12 Biological samples ..................................................................................................................... 59 
13 Statistical considerations ............................................................................................................ 60 
13.1 
Sample size calculation, power calculation, significance level ....................................... 60 
13.2 
Type of statistical methods and team ............................................................................... 60 
14 Data handling ............................................................................................................................. 61 
14.1 
Method of data collection ................................................................................................ 61 
14.1.1 Case Report Form (CRF) ............................................................................................. 62 
14.1.2 Data directly collected in the eCRF (no source available) ........................................... 62 
14.2 
Data storage ..................................................................................................................... 62 
14.3 
Archiving of data ............................................................................................................. 62 
14.4 
Access to data .................................................................................................................. 63 
15 Safety .......................................................................................................................................... 64 
15.1 
Definitions ........................................................................................................................ 64 
15.2 
Reporting requirements .................................................................................................... 65 
15.2.1 AE reporting ................................................................................................................. 65 
15.2.2 SAE reporting ............................................................................................................... 66 
15.2.3 SUSAR reporting ......................................................................................................... 66 
15.2.4 Other reporting requirements ....................................................................................... 67 
15.3 
List of contact details for safety reporting ....................................................................... 67 
15.4 
Flowchart reporting .......................................................................................................... 68 
15.5 
Events excluded from reporting ....................................................................................... 68 
15.6 
Data Safety Monitoring Board (DSMB) .......................................................................... 68 
15.7 
Annual Safety Report (ASR) ........................................................................................... 68 
15.8 
Follow-up after an adverse reaction ................................................................................. 69 
16 Monitoring, audits and inspections ............................................................................................ 69 
16.1 
Monitoring ....................................................................................................................... 69 
16.1.1 General ......................................................................................................................... 69 
16.1.2 Monitoring team ........................................................................................................... 69 
16.1.3 Scope ............................................................................................................................ 69 
16.2 
Inspection ......................................................................................................................... 70 
16.3 
Deviation policy ............................................................................................................... 70 
16.4 
Serious breach to GCP and/or the protocol ...................................................................... 70 
16.5 
Early termination ............................................................................................................. 71 
17 Ethical and legal aspects ............................................................................................................ 71 
17.1 
Good Clinical Practice ..................................................................................................... 71 
17.2 
Informed consent ............................................................................................................. 71 
17.3 
Approval of the study protocol ........................................................................................ 72 
17.3.1 General ......................................................................................................................... 72 
17.3.2 Protocol modifications and urgent safety measures ..................................................... 72 
17.4 
Confidentiality and data protection .................................................................................. 72 
17.5 
Liability and insurance ..................................................................................................... 73 
18 Publication policy ....................................................................................................................... 73 
Signature page .................................................................................................................................... 75 

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19 Addenda ..................................................................................................................................... 76 
 
 
List of abbreviations 
AE 
 
= 
Adverse Event 
ASR 
 
= 
Annual Safety Report 
CA 
 
=  
Competent Authority  
CI 
 
= 
Co-ordinating Investigator 
CT 
 
= 
Clinical Trial Unit 
CTD 
 
=  
Clinical Trial Directive 
CTIS  
= 
Clinical Trials Information System 
CTR 
 
=  
Clinical Trial Regulation 
DLP 
 
=  
Data Lock Point 
DSMB  
= 
Data Safety Monitoring Board 
DSUR  
= 
Development Safety Update Report 
EC 
 
= 
Ethics Committee 
eCRF  
= 
electronic Case Report Form 
EDC 
 
= 
Electronic Data Capture 
EMA  
= 
European Medicines Agency 
EPD 
 
= 
Electronic Patient Dossier 
EU 
 
= 
European Union 
EV 
 
=  
Eudravigilance 
FAMHP 
= 
Federal Agency for Medicines and Health Products 
GCP  
= 
Good Clinical Practice 
GDPR  
= 
General Data Protection Regulation 
GMP  
= 
Good Manufacturing Practice 
HIRUZ  
= 
Health, Innovation and Research Institute UZ Ghent 
IB 
 
= 
Investigator’s Brochure 
ICF 
 
= 
Informed Consent Form 
IEC  
 
=  
Independent Ethics Committee  
IMP 
 
= 
Investigational Medicinal Product 
PI 
 
= 
Principal Investigator 
RA  
 
=  
Regulatory Authority 
RSI 
 
= 
Reference Safety Information 
SAE 
 
= 
Serious Adverse Event 
SmPC  
= 
Summary of Product Characteristics 

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SOP 
 
= 
Standard Operating Procedure 
SUSAR 
= 
Suspected Unexpected Serious Adverse Reaction 
 

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Part I: Trial-related part of the protocol 
 
1 Title of the trial 
 
SPondyloArthritis: inducing drug-free Remission by early TNF-Alpha 
bloCkade Under guidance of Single cell RNA sequencing and epigenetic 
profiling. “The SPARTACUS trial” 
 
2 Trial number 
 
Protocol: BC-6226 
 
EU Reference number: 2023-510085-27-00  
3 General information 
 
3.1 National Coordinating Investigator(s) 
 
Prof. Dr. Filip Van den Bosch 
Prof. Dr. Dirk Elewaut 
Dr. Philippe Carron 
 
Ghent University Hospital (UZ Ghent), Department of Rheumatology 
C. Heymanslaan 10 
B-9000 Ghent 
Tel: +32 (0)9 332 2520 
Fax: +32 (0)9 332 4787 
 
E-mail: 
filip.vandenbosch@ugent.be,  
dirk.elewaut@ugent.be 
philippe.carron@ugent.be 
 
3.2 Sponsor 
 
UZ Ghent 
C. Heymanslaan 10 
9000 Ghent 
 

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3.3 Departments/laboratories involved in the study 
 
Be-GIANT Consortium: Department of Rheumatology in different hospitals 
 
VIB Inflammation Research Center Ghent – Single Cell Platform: 
- 
Research Unit: Dirk Elewaut and Koen Venken 
- 
Martin Guilliams 
 
KU Leuven: 
- 
Research Unit: Frederik de Smet and Rik Lories 
 
Maastricht University Medical Center: 
- 
Health Economics Research Unit: Annelies Boonen. 
 
4 Introduction 
 
4.1 Rationale + Background 
Treatment of immune-mediated inflammatory diseases, such as SpA, with cytokine-
directed bDMARDs, such as TNFi, has led to a revolution in the short and long-term 
control of symptoms, the improvement of quality of life and the prevention of irreversible 
structural damage.  However, when started in the chronic phase of the disease (usually 
after failure of csDMARDs), these drugs need to be administered continuously, which in 
turn is associated with a major cost in healthcare expenditure (not only because of chronic 
treatment costs, but also as a consequence of the management of potential long-term side 
effects).  The results of the proof-of-concept CRESPA trial suggest that by treating patients 
earlier, we can reach a state of sustained remission in which no long-term continuation of 
expensive drugs with potentially severe side effects is needed. 
The SPARTACUS project aims to compare (cost-)effectiveness of inducing clinical 
remission in early forms of pSpA with a TNFi versus the current treatment paradigm with 
csDMARDs.  Based on the preliminary CRESPA-trial-evidence, that intensive treatment in 
early phases of pSpA, is able to induce remission, we will also discontinue (biological) 
treatment in the second phase of this randomized, controlled clinical trial, once patients 
have achieved a status of sustained clinical remission; this will allow us to evaluate the 
possibility of drug-free remission.  The time frame by which induction of drug-free 
remission is achievable is currently unclear.  Therefore, we will analyse treatment 
responses in function of symptom duration (effect of symptom duration as a continuous 
variable, comparison between <3 months versus between 3 and 12 months).  An 
additional unique feature of SPARTACUS project is the search of new biomarkers using 
state-of-the-art technologies both in synovial tissue and/or peripheral blood.  Their ability to 
predict drug-free remission will be assessed in order to identify patients that may benefit 
from such an early induction therapy.  The effect of improved patient selection and the 
potential better cost-effectiveness of intensive management of early pSpA will be 
estimated.  Collectively, SPARTACUS should pave the path towards converting chronic 
lifelong therapy into a temporary intervention, which would result in a major societal impact 
on health and wealth. 
 

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References: 
 
1. Rudwaleit M, et al.  The Assessment of SpondyloArthritis international Society 
classification criteria for peripheral spondyloarthritis and for spondyloarthritis in 
general.  Ann Rheum Dis 2011;70:25-31. 
2. Mease P, et al.  Randomized controlled trial of adalimumab in patients with 
nonpsoriatic peripheral spondyloarthritis.  Arthritis Rheumatology 2015;67(4):914-
23. 
3. Van den Bosch F, et al.  Long-term efficacy and predictors of remission following 
adalimumab treatment in peripheral spondyloarthritis: 3-year results from Ability-2.  
RMD Open 2018;4:e000566. 
4. Carron P, et al.  Anti-TNF-induced remission in very early peripheral 
spondyloarthritis: the CRESPA study.  Ann Rheum Dis 2017;76:1389-95. 
5. Carron P, et al.  High rate of drug-free remission after induction therapy with 
golimumab in early peripheral spondyloarthritis.  Arthritis Rheumatology 
2018;70:1769-77. 
 
 
4.2 Risk/Benefit assessment 
Traditionally, management recommendations for rheumatic diseases (and reimbursement 
criteria in Belgium) follow a step-up strategy, starting with non-steroidal anti-inflammatory 
drugs (NSAIDs) and/or conventional synthetic disease modifying anti-rheumatic drugs 
(csDMARDs) as first line treatment options. Biologic DMARDs (bDMARDs), including 
TNFi, are recommended as second line treatment in patients with refractory disease.  
While treatment in these cases is still very effective, there is a significant percentage of 
patients that does not achieve a relevant improvement and in most cases prolonged (life-
long) treatment will be necessary. 
We hypothesized that by first line use of bDMARDs in an early disease stage, the clinical 
response would not only be better, but that early induction of remission could also permit 
the temporary use of a bDMARD (allowing the patient to reach a status of “drug-free 
remission”).  We have tested this hypothesis in a proof of concept study, the CRESPA trial 
(Clinical Remission in very Early SPondyloArthritis), in which patients with peripheral SpA 
and less than 3 months of symptom duration, were randomized to TNF inhibition (TNFi) 
with golimumab versus placebo (Carron P, et al. Ann Rheum Dis. 2017; Carron P, et al. 
Arthritis Rheumatol. 2018).  In this pilot trial we were able to demonstrate that 82% of all 
included patients achieved complete resolution of symptoms (arthritis, enthesitis, 
dactylitis), after which treatment with golimumab was discontinued. Intriguingly, over 50% 
of patients were staying in drug-free remission (with currently a follow-up of >2 years).  
Hence, the CRESPA trial pointed for the first time to the possibility of inducing drug-free 
remission in a significant proportion of patients suffering from a disease that had been 
previously considered to require lifelong medication. 
There were some challenges and limitations with regard to the CRESPA trial: 
- 
The main challenge was the fact that patients could not have signs or symptoms of 
arthritis/enthesitis/dactylitis for >3 months.  This required an extensive referral 
network with fast-track consultations to check eligibility for trial inclusion.  As a 
consequence, the CRESPA trial consisted of a very specific pSpA population with 
extremely short symptom duration.  We do not know if the results (high rates of 
clinical remission with TNFi-treatment; significant percentage of patients in drug-

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free remission after TNFi-withdrawal) can be extrapolated to a pSpA population with 
longer symptom duration. 
- 
The main limitation of the CRESPA trial was the fact that the control group 
consisted of placebo.  This was done in order to be able to estimate the rate of 
spontaneous clinical remission in this population (which was remarkably low), but 
one could argue that in daily practice such patients would have been treated with 
csDMARDs. 
 
The current SPARTACUS trial will address both issues: 
- 
Peripheral SpA patients with a symptom duration up to 1 year at screening will be 
eligible for inclusion.  This will allow us to evaluate if there is a specific window of 
opportunity timeframe when the disease is more susceptible to effective treatment. 
- 
In SPARTACUS, we will not compare the “TNFi-Induction” group with placebo, but 
with a more daily practice “csDMARD-Step-up” treatment strategy. 
 
The obvious advantages for the patients participating in this trial will be the early access to 
bDMARD therapy (at a stage where Belgian reimbursement would not allow this effective 
therapy) and the fact that (compared to the CRESPA trial) there is no risk of placebo-
treatment.  While it could be considered that TNFi treatment can be associated with side 
effects, these drugs are currently indicated and reimbursed for multiple diseases in the 
SpA-concept, albeit in the more longstanding phases of the disease when there is already 
definitive structural damage. 
 
4.3 Patient participation in trial design 
Not applicable 
 
5 Objective(s) of the study 
5.1 Main objectives 
The SPARTACUS study will explore the therapeutic efficacy of 2 different treatment 
strategies for patients suffering from peripheral Spondyloarthritis (pSpA), classified 
according to the “Assessment in SpondyloArthritis international Society” (ASAS) 
classification criteria (1) (see Addendum 1); it will be set up as a 48-week, prospective, 
randomized, active-comparator controlled, double-blind, double-dummy, clinical trial with a 
two-fold clinical objective: 
- To compare a standard step-up approach using conventional synthetic Disease-
Modifying 
Anti-Rheumatic 
Drugs 
(csDMARDs), 
such 
as 
methotrexate 
and/or 
sulphasalazine (the “csDMARD Step-Up”-strategy), with an early remission-induction 
treatment strategy that immediately introduces biological DMARDs (bDMARDs) as the first 
step in the treatment algorithm; in this group the Tumor Necrosis Factor inhibitor (TNFi) 
golimumab will be utilised (the “TNFi Induction”-strategy). 
 
The double-blind phase of the study will compare the 2 treatment strategies with regard to 
the proportion of patients that achieve a status of (sustained) clinical remission.   
 

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In patients that reach sustained clinical remission, all study treatments (both in the 
“csDMARD Step-up”-group and the “TNFi Induction”-group) will be stopped, and long-
term, clinical follow-up of these patients will allow to explore the possibility of “drug-free 
remission”; also with regard to this objective, the difference in symptom duration will be 
evaluated. 
 
5.2 Secondary objectives 
To try to define the window of opportunity within which temporary treatment with 
bDMARDs might be more effective, by analysing patients according to symptom duration, 
either as a continuous variable, or by comparing patients with shorter symptom duration 
(<3 months) versus those with more longstanding disease (between 3-12 months of 
symptom duration). 
 
 
 
SPARTACUS trial is part of a bigger SPARTACUS project of the VIB Grand Challenges 
Program and will have several achievable goals: 
 
1. To show superiority of early treatment of pSpA patients with bDMARDs as 
compared to standard of care. 
In current practice, TNFi, the predominant bDMARDs in SpA, are only reimbursed in a 
restricted number of indications: they can be prescribed for axial spondyloarthritis (axSpA) 
and for the specific pSpA-entity, psoriatic arthritis (PsA); however, even in PsA, they are 
only reimbursed for longstanding, erosive disease, when patients have already failed 
(multiple) csDMARD(s).  In patients with pSpA without psoriasis, rheumatologists can only 
prescribe csDMARDs, because TNFi are still off-label despite the overall good efficacy 
observed in several proof-of-concept studies, incl. one phase 3 trial (Ability-2) (2). For this 
subgroup of patients, the unmet need is therefore still unacceptably high.  Moreover, the 
patients included in Ability-2 reflected the current step-up treatment paradigm: patients 
already had longstanding disease (symptom duration of approx. 7 years) and had used 
(and failed) conventional treatment options before trial entry (99% prior use of Non-
Steroidal Anti-Inflammatory Drugs (NSAIDs), 69% prior csDMARD use).  In this 
population, a statistically significant difference between adalimumab and placebo was 
observed, but clinical remission rates remained somehow disappointing with only 33% of 
patients reaching the predefined remission outcome after 3 years of continuous 
adalimumab use (3). 
Until recently, no data were available regarding the treatment of early pSpA with 
bDMARDs.  To address this knowledge gap, we designed a proof-of concept study to 
explore the therapeutic potential of TNFi in patients with pSpA with very short symptom 
duration, the CRESPA-trial (4).  In this study, all patients had a symptom duration of less 
than 12 weeks: they were randomized to receive either immediate TNFi therapy 
(golimumab) or placebo.  In summary, the results of this trial demonstrated that after 24 
weeks of treatment, complete clinical remission could be achieved in 75% of golimumab-
treated patients versus only 20% in patients treated with placebo (thus refuting the 
perception that a large majority of pSpA patients would go in spontaneous clinical 
remission).  Due to the placebo-controlled design, the CRESPA trial did not provide any 
data on the percentage of patients that would have achieved clinical remission while on 
standard-of-care “csDMARD Step-up” treatment.  The design of the SPARTACUS head-
to-head trial will allow us to evaluate superiority of the new approach to current practice. 

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2. To delineate the window of opportunity for intensive treatment of pSpA: a 
transient time frame in which a disease is more susceptible to treatment.  
In the proof-of-concept CRESPA trial, all included patients had a symptom duration of less 
than 12 weeks.  In these patients very high clinical remission rates were observed when 
patients were immediately treated with a TNFi.  Interestingly, when the bDMARD treatment 
was interrupted after reaching sustained remission, 53% of patients remained in drug-free 
remission at long-term follow-up (5), providing preliminary evidence for the “window of 
opportunity” hypothesis: by effectively tackling pSpA (with bDMARDs) in a very early 
phase of the disease, drug-free remission might be an achievable goal in a significant 
number of patients.  However, the CRESPA-trial does not allow to generalize the findings 
to pSpA patients with longer symptom duration.  Moreover, the above-mentioned 
extension of the Ability-2 study would suggest that patients with a symptom duration of 
multiple years would have lower remission rates and would need chronic, life-long 
bDMARD treatment.  The SPARTACUS trial will still focus on early treatment of pSpA 
(symptom duration <12 months), and will analyse the effect of symptom duration on 
reaching the different outcomes. The goal is to demonstrate that drug-free remission is a 
feasible outcome when an early intensive treatment strategy is adopted and to delineate 
the window of opportunity (in terms of symptom duration) in which such a remission-
induction strategy is successful, leading to significant health economic benefits (goals 4 
and 5). 
 
3. To unravel new biomarkers of therapy response using cutting-edge single cell 
technology. 
In the CRESPA trial, we observed that despite the fact that 53% of patients were able to 
achieve drug-free remission, a significant proportion nevertheless relapsed.  In this small 
proof-of-concept study, we were not able to detect significant predictors or remission or 
relapse.  Also, 18% of patients did not achieve sustained clinical remission, but 
nevertheless experienced a significant improvement of signs and symptoms; in these 
patients long-term treatment was necessary. These results indicate that clinical response 
to TNFi is heterogeneous and underscores the need for biomarkers that can identify at 
baseline different pathogenic subsets that are associated with the (lack of) response to a 
TNFi. The recent introduction of new procedures such as ultrasound-guided synovial 
biopsy sampling in our early arthritis clinic has permitted to access synovial samples of 
virtually all peripheral joints (incl. wrists and small finger joints).  By using innovative and 
unbiased tools recently developed in the area of single-cell analyses (RNA-sequencing 
and epigenetic profiling) by VIB and KU Leuven, we will obtain profound insights into the 
cellular heterogeneity of these unique patient samples. 
 
4. To determine health-economic and societal impact of early, intensive bDMARD 
treatment of patients with recent-onset pSpA (compared to the currently reimbursed 
csDMARD Step-up strategy). 
A unique feature of SPARTACUS is that clinical trial and biomarker discovery will be 
coupled to calculation of the health-economic benefits of such an approach.  We aim to 
determine from a healthcare and a societal perspective, the 2 years´ cost-utility, as well as 
a model-based lifelong incremental cost-utility of the innovative strategy compared to usual 
care.  Uncertainty analyses will be performed and budget impact for the Belgian healthcare 
and social security (work disability) system will be calculated by Maastricht University.  
Consistent with the increased call for transparency in health economic modelling, we aim 
to make our model available as a semi-open source model. 

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5. To increase awareness among referring physicians (general practitioners, other 
specialties that may evaluate patients with early SpA) and patient-advocacy groups 
about the value of early recognition and treatment in rheumatology. 
It is still a great challenge to diagnose patients in an early stage of their disease.  The 
delay between symptoms and diagnosis in SpA is still several years.  As discussed above, 
it has been shown that in later stages of the disease, the treatment effect (even with 
bDMARDs) may be less impressive and chronic therapy is needed without possibility of 
drug withdrawal (leading to a high socioeconomic burden). The broad set-up of 
SPARTACUS across health institutes in Flanders will greatly facilitate the awareness and 
direct implementation of early arthritis strategies among physicians.  Finally, results from 
SPARTACUS will provide evidence that will facilitate discussions with patients about 
treatment choices and ensure realistic treatment expectations and optimal health 
behaviour in patients with early pSpA. 
6 End points 
 
6.1 Primary end points 
The primary endpoint of the study will be the comparison between the 2 treatment 
strategies at week 24 with regard to achievement of clinical remission (defined as 
complete absence of arthritis, dactylitis or enthesitis on clinical examination).  At the week 
24 timepoint, there are 3 possible scenario’s (figure 3): 
 
1. In patients that do not reach a state of clinical remission at week 24, blinded study 
medication will be interrupted and all patients will start open-label SC golimumab for 
an additional 36 weeks (up to max. week 60). 
2. In patients that achieve sustained clinical remission at week 24, defined as absence 
of clinical arthritis, enthesitis and dactylitis at both week 12 and week 24, all study 
medication will be discontinued and prospective follow-up will be planned in 
SPARTACUS Phase B. 
3. In patients that reach a state of clinical remission at week 24, but that did not yet 
reach this status at week 12, blinded study medication will be continued without any 
change in the treatment schedule for another 12 weeks. 
 
6.2 Secondary end points 
In addition to this, several secondary endpoints will be evaluated: 
 
- 
Comparison between the “TNFi induction” group and the “csDMARD Step-up” 
group regarding: 
o Achievement of “sustained clinical remission” at week 24 (and week 36 for 
the patients remaining on blinded study medication). 
o Improvement from baseline to week 12 and 24 in individual clinical 
assessments (78-Tender Joint Count, 76-Swollen Joint Count, Dactylitis 
Count, SPARCC Enthesitis Score) and composite scores (ASDAS: Axial 
Spondyloarthritis Disease Activity Score). 

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o Improvement from baseline to week 12 and 24 in patient-reported outcomes 
(Patient global assessment of disease activity and pain, BASDAI, BASFI, 
ASAS Health Index. 
o Improvement from baseline to week 12 and 24 in inflammatory parameters 
(ESR, CRP). 
o Changes in concomitant NSAID intake (NSAID-index) and “escape” intra-
articular glucocorticoid injections between baseline and week 24 
- 
Difference in occurrence of (serious) adverse events (AEs) and AEs of specific 
interest between the 2 treatment strategies from baseline to week 24 (and week 36 
for patients remaining on blinded study medication).  Descriptive analysis of the 
number and type of adverse events between both strategies 
- 
Percentage of patients achieving (sustained) clinical remission with open-label 
golimumab treatment after failure of the initial randomized, blinded treatment 
strategy. 
- 
Exploration of difference in percentage of patients that reach (sustained) clinical 
remission according to symptom duration (<3 months versus ≥3 month and <12 
months). The interaction between treatment group and symptom duration as a 
continuous predictor will also be analyzed to investigate the effect of symptom 
duration with regard to reaching the specified primary and secondary outcomes. 
- 
For patients in SPARTACUS Phase B (drug-free remission period): 
o Exploration of the duration of drug-free remission. 
o Time to (documented) pSpA disease flare. 
o Time to restart of “standard-of-care” pSpA treatment. 
o Exploration of clinical parameters that could be predictive for reaching 
(sustained) clinical remission and/or flare. 
- 
Correlation between the “Patient Acceptable Signs & Symptoms Improvement” 
(“PASSI”) and different clinical assessments, laboratory values and patient-reported 
outcomes (or combinations thereof). 
 
 
 

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7 Trial Design - The present study  
 
7.1 Study design description 
 
The SPARTACUS clinical trial is a prospective, randomized, active-comparator controlled, 
double-blind, double-dummy, phase III, national multicentric clinical trial which consists of 
2 phases (duration phase A is up to 60 weeks, phase B up to 3 years): 
 
SPARTACUS Phase A: “Remission-Induction Phase”: 
(Baseline to (maximum) week 60: for a global overview see Addendum 2) 
All patients (n=90) will be randomized (1:1) to either immediately receiving TNFi 
(golimumab) monotherapy (“TNFi Induction”-group) (n=45), or to the step-up regimen with 
csDMARDs (“csDMARD Step-up”-group) (n=45) (figure 1).  
Synovial biopsies will be harvested during the screening period by ultrasound (US) guided 
biopsy for small joints (Metacarpophalangeal- (MCP) and proximal interphalangeal- joints 
(PIP) of the hands, metatarsophalangeal joints (MTP) of the feet) or certain large joints 
(elbow, wrist, knee, ankle). In case of multiple small joint involvement, a joint with a score 
of 2 or more on Grey Scale/Power Doppler US assessment will be chosen to sample. 
 
The patients in the TNFi-induction group will receive golimumab at a standard dose of 50 
mg subcutaneously (SC) every 4 weeks (with matching methotrexate (MTX)-placebo) 
(figure 1). In case of potential intolerance or toxicity to MTX-placebo (see paragraph 9.5.8 
for known side effects of MTX) , the dose will be gradually tapered to a minimum of 7.5 mg 
per week. When there are no tolerability/toxicity issues, the weekly dose of MTX-placebo 
will be increased to 20 mg at week 4. 
 

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The patients in the csDMARD-Step-up group (figure 1) will start with oral methotrexate 
(MTX) at a weekly dose of 15 mg for 4 weeks (with matching TNFi-placebo injections). In 
case of potential intolerance or toxicity to MTX (see paragraph 9.5.8 for known side effects 
of MTX), the dose will be gradually tapered to a minimum of 7.5 mg per week. When there 
are no tolerability/toxicity issues, the weekly dose of MTX will be increased to 20 mg at 
week 4. At week 12, a “Patient Acceptable Signs & Symptoms Improvement” (‘PASSI’) will 
be assessed by asking the question “Taking into account both efficacy and side effects, 
did you experience over the past 12 weeks enough improvement in signs and symptoms 
of your’ arthritis-enthesitis-dactylitis to consider continuation of the same treatment 
schedule for the next 12 weeks?” (see Addendum 3). If yes, all study medication will be 
kept stable until week 24; if no, oral sulphasalazine at a dose of 2 g per day will be started 
(escape medication) (figure 2). 
 
 
 
The need for concomitant intake of NSAIDs will be recorded (by calculating the NSAID-
index); in case of persistent severe arthritis, a maximum of 2 intra-articular corticosteroid 
injections will be allowed (starting at week 12 after the clinical evaluations, but before the 
week 20 assessment). Both NSAID-index and number of corticosteroid injections will be 
considered as surrogate (in)efficacy markers. From week 20, all concomitant medication 
(see section 9) should be kept stable until the assessment of the primary endpoint at week 
24. 
 
The primary endpoint of the study will be the comparison between the 2 treatment 
strategies at week 24 with regard to achievement of clinical remission (defined as 
complete absence of arthritis, dactylitis or enthesitis on clinical examination).  At the week 
24 timepoint, there are 3 possible scenario’s (figure 3): 
 
1. In patients that do not reach a state of clinical remission at week 24, blinded study 
medication will be interrupted and all patients will start open-label SC golimumab for 
an additional 36 weeks (up to max. week 60). 

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2. In patients that achieve sustained clinical remission at week 24, defined as absence 
of clinical arthritis, enthesitis and dactylitis at both week 12 and week 24, all study 
medication will be discontinued and prospective follow-up will be planned in 
SPARTACUS Phase B. 
3. In patients that reach a state of clinical remission at week 24, but that did not yet 
reach this status at week 12, blinded study medication will be continued without any 
change in the treatment schedule for another 12 weeks. 
 
 
At week 36 (figure 4), patients that have continued the blinded study medication, will be re-
assessed regarding sustained clinical remission (at week 24 and 36): if yes, all study 
medication will again be discontinued and prospective follow-up will be planned in 
SPARTACUS Phase B.  If no, these patients will start open-label SC golimumab for an 
additional 24 weeks (up to max. week 60). 
If patients were in the “open-label golimumab treatment arm”, effectiveness of the 
treatment will be assessed by using the “PASSI”-question.  Inadequate responders will be 
discontinued from the study and will be treated with standard-of-care medication at the 
discretion of their treating rheumatologist, whereas patients with an acceptable 
improvement in signs and symptoms will continue with the same (open-label) medication 
schedule. 
 

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At week 48 (figure 5), all patients still remaining in SPARTACUS Phase A will have been 
treated with open-label golimumab (for a minimum of 12 weeks, but potentially up to 48 
weeks).  In patients reaching at this timepoint sustained clinical remission (at week 36 and 
48), golimumab will be discontinued and prospective follow-up will be planned in 
SPARTACUS Phase B.  For the other patients there are 3 possible scenarios: 
 
1. Patients reaching clinical remission for the first time at week 48 will continue without 
any change in the treatment schedule for another 12 weeks. 
2. Patients with an inadequate response (based on the “PASSI”-question), will be 
discontinued from the study and will be treated with standard-of-care medication at 
the discretion of their treating rheumatologist. 
3. Patient with an acceptable improvement (but no clinical remission) will continue 
open-label golimumab treatment for an additional 12 weeks, but in these patients 
open-label methotrexate will be associated (unless contra-indicated) to fulfil Belgian 
reimbursement criteria for TNFi. 
 
 

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At week 60 (final study visit of SPARTACUS Phase A) (figure 6), patients reaching 
sustained clinical remission (at week 48 and 60), will roll-over into SPARTACUS Phase B.  
All other patients will be discontinued and will be treated with standard-of-care medication 
(including TNFi, if in accordance with Belgian reimbursement criteria). 
 
 
 
SPARTACUS Phase B: “Drug-Free Remission Phase”: cessation of therapy and 
exploration of drug-free remission in patients that achieve sustained clinical 
remission while on therapy in phase A: 
(Duration: max. 3 years) 
After reaching ‘sustained clinical remission’, as defined above, all medication will be 
discontinued (possible timepoints for entering phase B would be week 24, 36, 48 and 60 of 

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phase A); the last study visit of Phase A will become visit 1 in Phase B.  In this prospective 
study, all patients will be systematically followed and data about disease activity will be 
collected at predefined timepoints (every 12 weeks in the first year; thereafter every 24 
weeks).  This will allow us to explore the possibility of maintaining drug-free remission. If a 
flare occurs within 144 weeks after medication withdrawal, standard-of-care treatment will 
be started at the discretion of the treating rheumatologist; at that time, phase B will end. 
Patients who are still in drug-free remission and reach the Phase B final study visit at week 
144 will be prospectively followed in the Be-GIANT cohort allowing further long-term 
follow-up. 
 
7.2 Start of the trial 
 
The trial is considered started upon the first act of recruitment of a potential subject. For 
this trial this is considered as the first patient being informed about the study by his/her 
treating physician. 
The start of the trial shall be notified to the RA within 15 calendar days. 
The first visit of the first subject (i.e. when the first subject or his/her legally designated 
representative signs his/her first informed consent to participate in the trial) (FVFS) will 
also be notified to the RA within 15 calendar days. 
 
7.3 End of the trial 
7.3.1 For an individual subject 
 
The subject has completed the trial when he or she has completed all phases of the study, 
including the last visit or the last scheduled procedures, as described in this protocol. 
 
 
7.3.2 For the whole trial 
 
The end of the recruitment of subjects shall be notified to the RA within 15 calendar days. 
Overall, the end of the trial is reached 30 days after the last study procedure for the last 
subject has occurred (the last visit of the last subject, LVLS). 
As soon as the whole trial has ended (cfr. the definition above), the RA shall be notified 
within 15 calendar days. 
A summary of the results of the trial will be submitted to the RA within 1 year from the end 
of the trial, irrespective of the outcome of the trial. 
 
 
7.4 Trial duration 
 

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7.4.1 For an individual subject 
The on-study estimated total duration of the study, from the time the informed consent 
document is signed until the last visit or the last scheduled procedures is up to 60 week for 
phase A and up to 3 years for phase B. 
7.4.2 For the whole trial 
 
We estimate to recruit subjects for a period of 56 months, last subject last visit (LSLV) will 
be reached 51 months later. The total duration of the study will thus be 107 months.   
 
8 Trial Population 
8.1 Number of subjects and planned recruitment rate 
 
In total it is expected to recruit 110 patients, of which 90 patients will be randomized in this 
trial and reach the primary endpoint timepoint (taking into account screen failures and drop 
outs) They will be recruited in  rheumatology departments of different hospitals.  At the UZ 
Ghent, the UZ Leuven and ZNA Jan Palfijn sites synovial biopsy sampling units are 
operational. The inclusion of patients is competitive, meaning that there are no minimum or 
maximum quota for inclusions per center. 
 
8.2 Inclusion and exclusion criteria 
8.2.1 Inclusion criteria 
8.2.1.1 SPARTACUS Phase A: “Remission-Induction Phase” 
A subject will be eligible for study participation if all of the following criteria are met:  
- 
Subjects must be able and willing to provide written informed consent and comply 
with the requirements of this study protocol. 
- 
Subjects must be between 18 and 65 years of age. 
- 
Subjects must have been diagnosed with peripheral spondyloarthritis by the treating 
rheumatologist. 
- 
Subjects must meet the ASAS classification criteria for peripheral spondyloarthritis 
(see addendum 1): subjects must have current arthritis (asymmetric or 
predominantly in the lower limbs) or current enthesitis (except for enthesitis only 
along the spine, sacroiliac joints and/or chest wall) or current dactylitis plus at least 
1 of the following SpA features: 
• 
Anterior uveitis confirmed by an ophthalmologist (past or present) 
• 
Crohn’s disease or ulcerative colitis diagnosed by a gastroenterologist (past or 
present). 
• 
Evidence of preceding infection (acute diarrhea or non-gonococcal urethritis or 
cervicitis 1 month before arthritis). 
• 
Psoriasis diagnosed by a dermatologist (past or present). 
• 
HLA B27 positivity 
• 
Sacroiliitis by imaging defined as bilateral grade 2–4 or unilateral grade 3–4 
sacroiliitis on plain radiographs, according to the modified New York criteria or 

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active sacroiliitis on MRI according to the ASAS consensus definition (ref of 
addendum). 
- 
Subjects must have had onset of peripheral SpA symptoms ≤12 months prior to the 
screening visit. 
- 
Subjects must have active disease at screening defined by Patient Global 
Assessment of Disease Activity Numerical Rating Scale (NRS) ≥ 4 and Patient 
Global Assessment of Pain NRS ≥ 4.  At the baseline visit patients will be clinically 
evaluated to exclude spontaneous clinical remission. 
- 
In subjects with concurrent axial SpA symptoms, the peripheral SpA symptoms 
must be the predominant symptoms at study entry based on the Investigator’s 
clinical judgment. 
- 
Subjects must have a negative PPD test (or equivalent) and chest radiography 
(anteroposterior and lateral view) at screening. If the subject has a positive PPD 
test (or equivalent), has had a past ulcerative reaction following PPD placement 
and/or a chest radiography consistent with prior TB exposure, the subject must 
initiate, or have documented completion of a course of anti-TB therapy. 
- 
Women of childbearing potential or men capable of fathering children must be using 
adequate birth control measures during the study and for 6 months after receiving 
the last administration of study agent (cfr. section 8.7). 
- 
Subject is judged to be in good health as determined by the principal investigator 
based upon the results of medical history, physical examination, laboratory profile, 
and chest x-ray (CXR) performed during screening. 
- 
Subjects must be able and willing to self-administer SC injections or have a 
qualified person available to administer SC injections. 
 
8.2.1.2 SPARTACUS Phase B: “Drug-Free Remission Phase” 
A subject will be eligible for phase B of the study if all of the following criteria are met:  
- 
Subjects must have participated in SPARTACUS Phase A. 
- 
Subjects must have reached a status of sustained clinical remission (defined as 
absence of clinical arthritis, enthesitis and dactylitis at 2 consecutive ‘major’ visits 
with an interval of 12 weeks). 
8.2.2 Exclusion criteria 
 
• Medical history of inflammatory arthritis of a different etiology than peripheral 
spondyloarthritis (e.g. rheumatoid arthritis, systemic lupus erythematosus, gout, …). 
• Prior adequate treatment with methotrexate and/or sulphasalazine. 
• Prior exposure to any biologic therapy with a potential therapeutic impact on SpA. 
• Treatment with any investigational drug of chemical or biological nature within a 
minimum of 30 days or 5 half-lives of the drug (whichever is longer) prior to the 
Baseline Visit. 
• Subject is taking or has taken prohibited medications as outlined in Table 1 without 
meeting the mandatory washout period(s) relative to the baseline visit. 
• Infection(s) requiring treatment with intravenous (iv) anti-infective agents within 30 
days prior to the Baseline visit or oral anti-infectives within 14 days prior to the 
baseline Visit. 

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• Have a known hypersensitivity to human immunoglobulin proteins or other 
components of golimumab. 
• History of central nervous system (CNS) demyelinating disease or neurologic 
symptoms suggestive of CNS demyelinating disease. 
• History of listeriosis, histoplasmosis, chronic or active Hepatitis B infection, Hepatitis 
C infection, human immunodeficiency virus (HIV) infection, immunodeficiency 
syndrome, chronic recurring infections or active TB. 
• (History of) 
chronic heart 
failure 
(CHF), 
including 
medically 
controlled, 
asymptomatic CHF. 
• History of malignancy (including lymphoma and leukemia) other than a successfully 
treated non-metastatic cutaneous squamous cell or basal cell carcinoma or 
localized carcinoma in situ of the cervix. 
• Have received any live virus or bacterial vaccination within 3 months prior to the first 
administration of study agent; patients who are expected to receive such 
vaccinations during the trial, or within 3 months after the last administration of study 
agent. 
• Positive serum pregnancy test at screening. 
• Female subjects who are breast-feeding. 
• Clinically significant abnormal screening laboratory results as evaluated by the 
Investigator. 
• Positive anti-cyclic citrullinated peptide (anti-CCP) antibody at screening if the titers 
are crossing 3 times the upper limit of normal. 
• Subject is considered by the investigator, for any reason, to be an unsuitable 
candidate for the study. 
• Subject with current symptoms of fibromyalgia that would confound evaluation of 
the patient. 
 
8.2.3 Justification of in- and exclusion criteria 
Not applicable 
 
8.3 Withdrawal and replacement of subjects 
 
8.3.1 Withdrawal of subjects 
 
Subjects are free to withdraw from participation in the trial at any time. A subject must be 
discontinued from the trial if the subject withdraws consent. The reason why a subject 
withdraws consent, if given, must be recorded in detail in the electronic Case Report Form 
(eCRF) and in the subject’s medical records. The already gathered subject data should 
remain in the trial database. 
However, subjects can choose to discontinue trial treatment or interventions, but remain in 
the trial for other assessments or data collection, if applicable. The reasons for a subject to 
withdraw from trial treatment, if given, must be recorded in detail in the electronic Case 
Report Form (eCRF) and in the subject’s medical records. The subject data should be 
collected in the eCRF. 
An investigator may discontinue trial treatment for a subject for the following reasons: 
• 
Pregnancy; 

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• 
Significant trial intervention non-compliance; 
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the trial would not be in the best 
interest of the subject; 
• 
Disease progression which requires discontinuation of the trial intervention; 
• 
If the subject meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further trial participation; 
• 
Subject unable to receive study intervention for a duration of at least 3 months  
The reasons for withdrawing a subject from study treatment must be recorded in detail in 
the electronic Case Report Form (eCRF) and in the subject’s medical records. However, 
even if trial treatment is discontinued, the subject will remain in the trial and other 
assessments or data collection should be done, if applicable. The subject data should be 
collected in the eCRF. 
A subject will be considered lost to follow-up if he or she fails to return for 2 consecutive 
scheduled visits and is unable to be contacted by the trial site staff. 
The following actions must be taken if a subject fails to return for a required trial visit: 
• 
The site will attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain if the subject wishes to and/or should continue in the trial; 
• 
Before a subject is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the subject (when possible, three telephone calls and if 
necessary a certified letter to the subject’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject’s medical record or 
study file; 
• 
Should the subject continue to be unreachable, he or she will be considered to have 
withdrawn from the trial with a primary reason of lost to follow-up. 
 
 
8.3.2 Replacement of subjects 
Drop-out subjects that were randomized and have received at least one dose of study 
drug, will not be replaced. 
 
8.3.3 Follow-up of withdrawn subjects 
 
Regardless of the reason for withdrawal, the Principal Investigator (PI) must consider the 
following: 
• 
Procedures for safe discontinuation of treatment; 
• 
Retention and use of the data already collected. 
• 
In case of withdrawing from study treatment, continue other assessments or data collection, 
if applicable. 
 
 
8.4 Method of recruitment and compensation for subjects 
 

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Subjects are transferred by their rheumatologist or physician. An investigator trained on 
the study protocol will inform possible eligible subjects about the study. If a subject shows 
interest in participation the ICF is provided and subjects are given time to read the 
document, ask questions, and discuss participation with others as desired. 
Based on the subjects history during anamnesis conducted by a staff member of the 
Department of Reumatology, subjects will be included in the study when they sign the 
study specific ICF and meet all the in- and exclusion criteria. 
There will be no compensation for study participation. 
 
8.5 Subject eligibility screening 
 
Screen failures are subjects who consent to participate in the trial but do not meet one or 
more criteria required for participation in the trial during the screening procedures. Screen 
failures will not be enrolled in the trial. A minimal set of screen failure information will be 
kept to ensure transparent reporting of screen failure subjects. 
Screen failures may be rescreened. 
 
8.6 Subject follow-up after trial participation 
 
No special care is needed after discontinuation of the trial. All patients that did not reach 
‘sustained clinical remission’ will be treated with standard-of-care medication by their 
treating rheumatologist. After giving consent, all patients that leave the trial, regardless of 
outcome, can be prospectively followed in the Be-GIANT cohort allowing further long-term 
follow-up. 
 
 
8.7 Restrictions and prohibitions for the subjects 
 
- 
Patients should not donate blood at any time during the study or for 3 months after 
last dose of study drug. 
- 
Adequate contraception* should be used during the study and for 6 months after the 
last dose by  
o Included women of childbearing potential and  
o Included men capable of fathering children and their fertile partners  
- 
Female subjects must not donate eggs (ova, oocytes) during the study and for 6 
months after the last dose of study drug.  
- 
Male subjects must agree to no donate sperm while in the study and for 6 months 
after the last dose of study drug.  
- 
There are no other restrictions except those specified in the exclusion criteria and 
the restrictions regarding the use of concomitant medications (see chapter 9). 
 
* Adequate contraceptive methods are: 
(1) Oral, injectable or implanted hormonal methods of contraception.  Hormonal 
contraception exists in the form of (1) pills (which must be taken every day), (2) injections 
(which work for about 3 months) and (3) implanted devices that are inserted into the uterus 
and allowed to remain there for several years. 

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(2) Placement of an intrauterine device (IUD) or an intrauterine system (IUS) or 
(3) Total abstinence (no sex/concourse) or 
(4) Prior vasectomy or removal of the ovaries / ligature of the fallopian tubes (male/female 
sterilization) 
 
 
 
9 Investigational Medicinal Product (IMP) 
9.1 General information 
 
CTU-1 of the University Hospital Ghent is responsible for the randomisation of the blinded 
study medication (secondary packaging). 
In this study, the patients may also take NSAIDs and/or sulphasalazine which are 
registered drugs for the management of pSpA. All patients also take oral folic acid 
supplementation according to standard clinical practice. 
 
9.1.1 Reporting requirements for investigational product complaints 
The following could be considered potential product complaints that need to be reported to 
the sponsor. Should any such concerns or irregularities occur, the IMP will not be used 
and shall be kept in quarantine until confirms that it is permissible to use was received.  
 
Examples of Product Complaints: 
• Packaging: for example, broken container or cracked container 
• Usage: for example, subject or healthcare provider cannot appropriately use the product 
• Labeling: for example, missing labels, illegible labels, incorrect labels, and/or suspect 
labels 
• Change in IMP appearance: for example color change or presence of foreign material 
• Unexpected quantity in bottle: for example number of tablets or amount of fluid 
• Evidence of tampering or stolen material 
 
The report of a product complaint may be made by telephone, e-mail or facsimile (FAX).  
 
Contact details of the National Coordinating Investigator: 
e-mail: dirk.elewaut@ugent.be or filip.vandenbosch@ugent.be 
tel.: 09/332 2240 or 09/332 2863 
fax: 09/332 4787 
 
Contact details of the producer of blinded methotrexate: 
e-mail : erik.lagae@ardena.com  
Kleimoer 4 
9030 Mariakerke 
tel.: 09/267 65 00 
 
Contact details of the MAH/producer of methotrexate matching placebo: 
 
e-mail : pharmacy.clinicaltrials@UZGENT.be 
 
tel : 09/332 29 73 
 
fax: 09/332 3869 

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Contact details of MAH/producer of Golimumab and matching placebo :  
Up 
until 
30-Sep-2024, 
Merck 
Global 
should 
be 
informed 
by 
e-mail: 
dpoc_belux@merck.com. 
 
9.1.2 Treatment compliance 
The 
investigator 
or 
his/her 
designated 
and 
qualified 
representatives 
will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol. 
 
Subject dosing will be recorded on a subject diary.  Subjects will be instructed to return all 
drug containers (even if empty) to the study site personnel at each clinic visit.  The study 
site personnel will document compliance in the study source documents and in the 
electronic CRF (eCRF). 
 
9.1.3 Drug Accountability 
 
The arrival of the study medication at the hospital pharmacy and the delivery to the 
study site will be documented.  
 
The investigator or his/her representative will verify that study drug supplies are received 
intact and in correct amounts.  To maintain transparency, the drug accountability will be 
documented in the eCRF REDCap with the description of the batch number, expiration 
date, date dispensed and subject number.  Subjects will record the date of administration 
and the amount that is administered in a subject dosing diary. The dosing diary will be kept 
in de subject binder. 
 
All empty/used study drug packaging will be inventoried by the site. Empty/used study 
drug packaging should be returned by the subject at each visit for accountability and 
compliance purposes and new packaging issued as necessary.  
 
After drug accountability has been completed by the site, empty used packaging may be 
discarded with any subject identifiers removed. 
 
Unused study drug and used packaging with remaining study drug will be destroyed on 
site according to local procedures or regulations.  The destruction must be documented on 
the drug accountability log with the amount that was discarded and date of destruction. 
 
9.1.4 Storage conditions 
At the time of randomization and in alignment with the protocol, patient-specific study drug 
packages (containing golimumab/placebo and methotrexate/placebo) will be shipped from 
the pharmacy of the Ghent university hospital to the local study site under the respective 
temperature-controlled conditions described above conform good manufacturing practices  
(GMP). 
The patient-specific packages will again be stored at the local study site under the same 
temperature-controlled conditions. 

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9.2 Golimumab (blinded) 
9.2.1 General information 
 
Also refer to 
SmPC + IMPD  
Name of the IMP 
Blinded Golimumab 
Qualitative and 
quantitative composition 
Each pre-filled syringe of 1 mL contains 50 mg golimumab 
The substance has been registered with the EMA as = 
SUB25638 
Pharmaceutical form 
Solution for injection in pre-filled syringe (blinded) 
Method of 
administration 
Subcutaneous use 
Authorised in the EU 
Yes 
Used within scope 
No (blinded) 
Marketing authorisation 
holder 
Janssen Biologics B.V. 
Marketing authorisation 
number(s) 
Syringe: EU/1/09/546/003 
Manufacturer 
Janssen Biologics B.V., Einsteinweg 101, 2333 CB Leiden, 
Nederland 
Distributor 
Up until 30-Sep-2024:MSD Belgium, Lynx Binnenhof 5, B 
1200 Brussel 
Responsible for batch 
release 
Janssen Biologics B.V., Einsteinweg 101, 2333 CB Leiden, 
Nederland 
 
9.2.2 IMP rationale 
 
Refer to Section 5, Objectives of the study 
 
9.2.3 Preparation, administration, dosage and dose frequency of the IMP 
 
Golimumab, which will be immediately used by patients randomized in the “TNFi-
induction”-group, is a human monoclonal antibody (mab) with an IgG1 heavy chain isotype 
and a kappa light chain isotype that binds TNF-alfa with high affinity and specificity. The 
molecule is produced by a stable, recombinant murine cell line transfected with DNA 
coding for the heavy and light chains of the mab. Golimumab is supplied as a liquid in a 
prefilled syringe (PFS) for subcutaneous administration. Each prefilled syringe contains 50 
mg (0.5 mL fill of liquid) golimumab, histidine, sorbitol and polysorbate 80 at pH 5.5. No 
preservatives are present. The prefilled syringe with golimumab will be administrated 
subcutaneously every 4 weeks. This is the standard dose/regimen recommended (and 
reimbursed in Belgium) for the indications psoriatic arthritis, ankylosing spondylitis and 
rheumatoid arthritis. 
 

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Protocol “SPARTACUS”, versie 5.1, dd 04/06/2025 
9.2.4 Permitted dose adjustments and interruption of treatment 
 
[Fill in] The prefilled syringe with golimumab will be administrated subcutaneously every 4 
weeks. In accordance with the visiting schedule, mentioned in section 11.4, there is a 
window of +/- 7 days.  
In case of AE’s the investigator can decide to interrupt or postpone the treatment.  
 
9.2.5 Duration of treatment 
 
Refer to Section 7, Study design to find detailed information about the Phase A and B 
treatment duration. 
 
9.2.6 Packaging and labeling of the IMP 
 
All blinded golimumab will be supplied as a sterile liquid in a 0.5 mL single-use prefilled 
syringe for subcutaneous administration. 
 
Up until 30-Sep-2024, the prefilled syringes with blinded golimumab will be labelled by 
MSD. 
 
9.2.7 Traceability, storage, return and destruction of the IMP 
 
The UZ Ghent Pharmacy will store the prefilled syringes with golimumab until time of 
randomization in a locked refrigerator, which will be temperature-controlled by using a 
temperature logger (between 2°C and 8°C).  The prefilled syringes will be protected from 
light. 
 
9.2.8 Known side effects of the medication 
Golimumab (SIMPONI®) is a prescription medicine. Common side effects of golimumab 
include: upper respiratory tract infection, viral infections such as flu, and reactions at site of 
injection. 
 
SERIOUS INFECTIONS 
Golimumab can lower the ability to fight infections. There are reports of serious infections 
caused by bacteria, fungi, or viruses that have spread throughout the body, including 
tuberculosis (TB) and histoplasmosis. Some of these infections have been fatal. TB should 
be tested before starting golimumab and signs of TB will be monitored during treatment. 
 
CANCER 
Some people treated with golimumab have developed certain kinds of (skin) cancer. 
 
USE WITH OTHER DRUGS 
People taking golimumab should not receive live vaccines or treatment with weakened 
bacteria (such as Bacillus Calmette-Guerin for bladder cancer). 
 

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HEPATITIS B INFECTION 
Reactivation of hepatitis B virus has been reported in patients who are carriers of this virus 
and are taking TNF-blocker medicines, such as golimumab. Some of these cases have 
been fatal. Patients will be screened for hepatitis B infection prior to randomization. 
 
HEART FAILURE 
Heart failure can occur or get worse in people who use TNF blockers, including 
golimumab. 
 
NERVOUS SYSTEM PROBLEMS 
Rarely, people using TNF blockers, including golimumab, can have nervous system 
problems such as multiple sclerosis or Guillain-Barré syndrome. 
 
IMMUNE SYSTEM PROBLEMS 
Rarely, people using TNF blockers have developed lupus-like symptoms. 
 
LIVER PROBLEMS 
Serious liver problems can happen in people using TNF blockers, including golimumab. 
 
BLOOD PROBLEMS 
Low blood counts have been observed with people using TNF blockers, including 
golimumab. 
 
ALLERGIC REACTIONS 
Allergic reactions can happen in people who use TNF-blocker medicines, including 
golimumab. Some reactions can be serious and life-threatening. 
 
9.3 Simponi® (open-label) 
9.3.1 General information 
 
Also refer to 
SmPC 
Name of the IMP 
Simponi, active substance Golimumab 
Qualitative and 
quantitative composition 
Each pre-filled syringe of 1 mL contains 50 mg golimumab  
The substance has been registered with the EMA as = 
SUB25638 
Pharmaceutical form 
Solution for injection in pre-filled injector (open-label) 
Method of 
administration 
Subcutaneous use 
Authorised in the EU 
Yes 
Used within scope 
Yes 
Marketing authorisation 
holder 
Janssen Biologics B.V. 
Marketing authorisation 
number(s) 
Injector: EU/1/09/546/001 
Syringe: EU/1/09/546/003 
Manufacturer 
Up until 30-Sep-2024, for open-label golimumab Simponi® 
SmartjectTM: MSD Belgium, Lynx Binnenhof 5, B 1200 
Brussel 
Distributor 
Up until 30-Sep-2024: MSD Belgium, Lynx Binnenhof 5, B 

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1200 Brussel 
Responsible for batch 
release 
Janssen Biologics B.V., Einsteinweg 101, 2333 CB Leiden, 
Nederland 
 
9.3.2 IMP rationale 
 
Refer to Section 5, Objectives of the study 
 
9.3.3 Preparation, administration, dosage and dose frequency of the IMP 
 
Golimumab, which will be immediately used by patients randomized in the “TNFi-
induction”-group, is a human monoclonal antibody (mab) with an IgG1 heavy chain isotype 
and a kappa light chain isotype that binds TNF-alfa with high affinity and specificity. The 
molecule is produced by a stable, recombinant murine cell line transfected with DNA 
coding for the heavy and light chains of the mab. Golimumab is supplied as a liquid in a 
prefilled syringe (PFS) for subcutaneous administration. Each prefilled syringe contains 50 
mg (0.5 mL fill of liquid) golimumab, histidine, sorbitol and polysorbate 80 at pH 5.5. No 
preservatives are present. The prefilled syringe with golimumab will be administrated 
subcutaneously every 4 weeks. This is the standard dose/regimen recommended (and 
reimbursed in Belgium) for the indications psoriatic arthritis, ankylosing spondylitis and 
rheumatoid arthritis. 
 
9.3.4 Permitted dose adjustments and interruption of treatment 
 
[Fill in]  The prefilled syringe with golimumab will be administrated subcutaneously every 4 
weeks. In accordance with the visiting schedule, mentioned in section 11.4, there is a 
window of +/- 7 days.  
In case of AE’s the investigator can decide to interrupt or postpone the treatment.  
 
 
9.3.5 Duration of treatment 
 
Refer to Section 7, Study design to find detailed information about the Phase A and B 
treatment duration. 
 
9.3.6 Packaging and labeling of the IMP 
 
The open-label golimumab (Simponi®) will be supplied as a sterile liquid in a 0.5 mL single-
use prefilled SmartJect autoinjector device or prefilled syringe for subcutaneous 
administration. 
 
Simponi® that is already on site will be relabeled at the local hospital pharmacy. Open-
label golimumab that will be supplied and distributed by UZ Gent pharmacy will also be 
labeled by the UZ Gent pharmacy. 

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Protocol “SPARTACUS”, versie 5.1, dd 04/06/2025 
9.3.7 Traceability, storage, return and destruction of the IMP 
 
The Simponi® Smartject autoinjectors and syringes will be stored in a locked refrigerator at 
the participating centers, which will be temperature-controlled by using a temperature 
logger (between 2°C and 8°C) and protected from light. 
 
 
9.3.8 Known side effects of the medication 
Refer to Section 9.2.8. 
 
9.4 Placebo Golimumab 
9.4.1 General information 
 
Also refer to 
IMPD 
Name of the IMP 
Placebo  
Qualitative and quantitative 
composition 
/ 
Pharmaceutical form 
Solution for injection in pre-filled syringe 
Method of administration 
Subcutaneous use 
Authorised in the EU 
NA 
Used within scope 
NA 
Marketing authorisation 
holder 
NA 
Marketing authorisation 
number(s) 
NA 
Manufacturer 
Janssen Biologics B.V., Einsteinweg 101, 2333 CB 
Leiden, Nederland 
Distributor 
Up until 30-Sep-2024: MSD Belgium, Lynx Binnenhof 
5, B 1200 Brussel 
Responsible for batch 
release 
Janssen Biologics B.V., Einsteinweg 101, 2333 CB 
Leiden, Nederland 
 
9.4.2 IMP rationale 
 
Refer to Section 5, Objectives of the study. 
9.4.3 Preparation of the IMP, administration, dosage and dose frequency of 
the IMP 
 
For patients in the “csDMARD-Step-up”-group, placebo Golimumab injections will be 
administered, consisting of an aqueous medium of histidine, sorbitol, and polysorbate 80 
at pH 5.5; this will be supplied as a sterile liquid for SC injection at a volume of 0.5 mL in 
single-use prefilled syringes. 
 

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The prefilled syringe with placebo golimumab  will be administrated subcutaneously every 
4 weeks. 
 
9.4.4 Permitted dose adjustments and interruption of treatment 
 
[Fill in] The prefilled syringe with golimumab will be administrated subcutaneously every 4 
weeks. In accordance with the visiting schedule, mentioned in section 11.4, there is a 
window of +/- 7 days.  
In case of AE’s the investigator can decide to interrupt or postpone the treatment.  
 
 
9.4.5 Duration of treatment 
 
Refer to Section 7, Study design to find detailed information about the Phase A and B 
treatment duration. 
 
9.4.6 Packaging and labeling of the IMP 
 
Placebo Golimumab will be supplied as a sterile liquid in a 0.5 mL single-use prefilled 
syringe for subcutaneous administration. 
Up until 30-Sep-2024, the prefilled syringes with placebo golimumab will be labelled by 
MSD. 
 
9.4.7 Traceability, storage, return and destruction of the IMP 
 
The UZ Ghent Pharmacy will store the prefilled syringes with placebo golimumab until time 
of randomization in a locked refrigerator, which will be temperature-controlled by using a 
temperature logger (between 2°C and 8°C).  The prefilled syringes will be protected from 
light. 
 
9.5 Ledertrexate 
9.5.1 General information 
 
Also refer to 
Investigational Medicinal Product Dossier (IMPD) 
Name of the IMP 
Ledertrexate, active substance = Methotrexate 
Qualitative and quantitative 
composition 
Each tablet contains methotrexate sodium equivalent 
to 2.5 mg of methotrexate. 
The substance has been registered with the EMA as = 
SUB08856MIG 
Pharmaceutical form 
Capsule 
Method of administration 
Oral use 
Authorised in the EU 
Yes 
Used within scope 
Yes 

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Marketing authorisation 
holder 
Pfizer NV/SA 
Marketing authorisation 
number(s) 
Pfizer: BE003446 
Manufacturer 
For blinded methotrexate: Ardena Drug Development 
& Manufacturing, Ardena Gent NV, Kleimoer 4, B 9030 
Mariakerke. 
 
Contact persons: 
Annelies 
Paridaens, 
Director 
Project 
Management. 
E-mail: Annelies.Paridaens@ardena.com 
 
Emily De Lombaerde, Project Manager 
E-mail: emily.delombaerde@ardena.com 
Telephone: +32 (0)9 267 65 00 
 
Distributor 
University Hospital Ghent pharmacy – clinical trials C. 
Heymanslaan 10, B 9000 Ghent 
 
Responsible for batch 
release 
University Hospital Ghent pharmacy 
 
9.5.2 IMP rationale 
 
Refer to Section 5, Objectives of the study. 
 
9.5.3 Preparation of the IMP, administration, dosage and dose frequency of 
the IMP 
 
In the “csDMARD-Step-up”-group, patients will start with oral methotrexate (MTX) 
capsules at a weekly dose of 15 mg for 4 weeks. In case of intolerance or toxicity to MTX, 
the weekly dose will be tapered to 10 mg at week 4 and if still problematic to 7,5 mg at 
week 8; in case of persisting intolerance/toxicity issues, MTX will be stopped at week 12. 
When there are no tolerability/toxicity issues, the weekly dose of MTX will be increased to 
20 mg at week 4 (with a possibility to taper down if intolerance/toxicity would occur at this 
higher dose). Methotrexate 2,5 mg capsules contain the following supplements: lactose 
monohydrate, pre-gelled corn starch, magnesium stearate, sodium hydroxide, black iron 
oxide, titanium dioxide, yellow iron oxide and hypromellose. 
 
The methotrexate capsules will be administered orally every week. The capsules should 
be swallowed whole and intact. They should not be opened or chewed or crushed. 
 
9.5.4 Permitted dose adjustments and interruption of treatment 
 
Patients will start with oral methotrexate (MTX) capsules at a weekly dose of 15 mg for 4 
weeks. In case of intolerance or toxicity to MTX or MTX placebo, the weekly dose of MTX 
or MTX placebo can be tapered to 10 mg at week 4, with a further possible reduction to 

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7,5 mg at week 8; in case of persistent intolerance/toxicity, MTX or MTX placebo will be 
stopped at week 12. For safety reasons, the dose reduction rate can be adapted at the 
discretion of the investigator.  
 
9.5.5 Duration of treatment 
 
Refer to Section 7, Study design to find detailed information about the Phase A and B 
treatment duration. 
 
9.5.6 Packaging and labeling of the IMP 
 
Methotrexate will be supplied as capsules of 2.5 mg for oral administration packed in 
HDPE (high density polyethylene) bottle, 40 capsules per bottle. 
CTU-1 of the University Hospital Ghent will label the bottles. 
9.5.7 Traceability, storage, return and destruction of the IMP 
 
The methotrexate capsules will be stored until time of randomization at the pharmacy of 
the Ghent university hospital; capsules will be stored in a locked room with a temperature 
logger (at a temperature between 15°C and 25°C).   
9.5.8 Known side effects of the medication 
Methotrexate (LEDERTREXATE®) is a prescription medicine. 
 
VERY COMMON SIDE EFFECTS (≥ 10%) 
Anorexia, nausea, vomiting, abdominal pain, ulcerations of the mucous membrane of 
mouth and throat (especially during the first 24 to 48 hours after administration), stomatitis, 
dyspepsia, increase in liver related enzymes (ALT, alkaline phosphatase, bilirubin, and 
LDH levels), decreased resistance to infection. 
 
COMMON SIDE EFFECTS (≥ 1%) 
Leukocytopenia, thrombocytopenia, anaemia, headache, pulmonary complications due to 
interstitial pneumonitis, diarrhoea, erythema, itching. 
 
UNCOMMON SIDE EFFECTS (≥ 0.1%) 
Severe anemia, allergic reactions, diabetes mellitus, depression, vertigo, confusion, 
convulsion, vasculitis, pulmonary fibrosis, gastro-intestinal bleeding and ulcers, 
development of liver fattening, liver fibrosis, exanthema, photosensitivity, poorly healing 
wounds, increase of rheumatic nodules, herpes zoster, skin ulcerations, arthralgia, 
myalgia, cystitis, haematuria. 
 
RARE SIDE EFFECTS (≥ 0.01%) 
Endocarditis, mood alterations, hypotension, thromboembolic events (e.g., arterial 
thrombosis, cerebral thrombosis, thrombophlebitis, deep vein thrombosis, retinal vein 
thrombosis, pulmonary embolism), sore throat, apnoea, discoloration or yellowing of the 
skin or the eyes indicating acute hepatitis, acne, gingival hyperplasia, renal failure, 
menstrual disorder, transient oligospermia. 
 

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9.6 Placebo Ledertrexate 
9.6.1 General information 
 
Also refer to 
Investigational Medicinal Product Dossier (IMPD) 
Name of the IMP 
Placebo Ledertrexate 
Qualitative and quantitative 
composition 
A capsule will be filled with 292 mg lactose 
monohydrate as excipient 
Pharmaceutical form 
Capsule 
Method of administration 
Oral use 
Authorised in the EU 
NA 
Used within scope 
NA 
Marketing authorisation 
holder 
NA 
Marketing authorisation 
number(s) 
NA 
Manufacturer 
University Hospital Ghent pharmacy – CTU-1, C. 
Heymanslaan 10, B 9000 Ghent 
Distributor 
University Hospital Ghent pharmacy – clinical trials C. 
Heymanslaan 10, B 9000 Ghent 
 
Responsible for batch 
release 
University Hospital Ghent pharmacy 
 
9.6.2 IMP rationale 
 
Refer to Section 5, Objectives of the study. 
 
9.6.3 Preparation of the IMP, administration, dosage and dose frequency of 
the IMP 
 
In the “csDMARD-Step-up”-group, patients will start with oral methotrexate (MTX) 
capsules at a weekly dose of 15 mg for 4 weeks. In case of intolerance or toxicity to MTX, 
the weekly dose will be tapered to 10 mg at week 4 and if still problematic to 7,5 mg at 
week 8; in case of persisting intolerance/toxicity issues, MTX will be stopped at week 12. 
When there are no tolerability/toxicity issues, the weekly dose of MTX will be increased to 
20 mg at week 4 (with a possibility to taper down if intolerance/toxicity would occur at this 
higher dose). Methotrexate 2,5 mg capsules contain the following supplements: lactose 
monohydrate, pre-gelled corn starch, magnesium stearate, sodium hydroxide, black iron 
oxide, titanium dioxide, yellow iron oxide and hypromellose. 
 
In the “TNFi-induction”-group, matching placebo pills will be used looking identical to the 
methotrexate pills without the methotrexate active ingredient. 
 
 
The methotrexate placebo capsules will be administered orally every week. The capsules 
should be swallowed whole and intact. They should not be opened or chewed or crushed. 

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9.6.4 Permitted dose adjustments and interruption of treatment 
 
Patients will start with oral methotrexate (MTX) capsules at a weekly dose of 15 mg for 4 
weeks. In case of intolerance or toxicity to MTX or MTX placebo, the weekly dose of MTX 
or MTX placebo can be tapered to 10 mg at week 4, with a further possible reduction to 
7,5 mg at week 8; in case of persistent intolerance/toxicity, MTX or MTX placebo will be 
stopped at week 12. For safety reasons, the dose reduction rate can be adapted at the 
discretion of the investigator.  
 
 
 
9.6.5 Duration of treatment 
 
Refer to Section 7, Study design to find detailed information about the Phase A and B 
treatment duration. 
 
9.6.6 Packaging and labeling of the IMP 
 
Methotrexate placebo  will be supplied as capsules of 2.5 mg for oral administration 
packed in HDPE (high density polyethylene) bottle, 40 capsules per bottle. 
 
CTU-1 of the University Hospital Ghent will label the bottles. 
9.6.7 Traceability, storage, return and destruction of the IMP 
 
The methotrexate placebo capsules will be stored until time of randomization at the 
pharmacy of the Ghent university hospital; capsules will be stored in a locked room with a 
temperature logger (at a temperature between 15°C and 25°C).   
9.7 Management of pSpA 
 
In this study, the patients may also take NSAIDs and/or sulphasalazine which are 
registered drugs for the management of pSpA. All patients should take oral folic acid 
supplementation according to standard clinical practice. 
 
10 Concomitant medication and treatment 
 
The use of DMARDs (conventional synthetic, targeted synthetic or biological), NSAIDs and 
glucocorticoids, allowed prior to entry in the trial and/or during the trial (up to 3 months 
after last study drug administration) is summarized in table 1. 
 
Table 1: Prior and concomitant use of DMARDs, NSAIDs and glucocorticoids. 
Drug 
Prior Exposure 
Concomitant use 
Adequate dose of methotrexate 
Not allowed 
(Study medication) 

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Adequate dose of sulphasalazine 
Not allowed 
(Escape medication) 
Other csDMARDs (e.g. hydroxychloroquine, …) 
Allowed 
Not allowed 
tsDMARDs (with therapeutic effect on SpA) 
Not allowed 
Not allowed 
bDMARDs (with therapeutic effect on SpA) 
Not allowed 
Not allowed, except 
golimumab (study drug) 
NSAIDs 
Stable ≤1 week 
before baseline 
Allowed (incl. dose 
adjustment & stop) 
Intra-articular glucocorticoid injection 
Prior corticoid 
infiltrations are 
allowed provided 
that the necessary 
wash out (≥ 6 
weeks) before 
biopsy is respected 
Max. 2 injections 
between week 12 and 20 
Short course oral glucocorticoids 
Not allowed <6 
weeks before 
baseline 
Not allowed 
Prolonged oral glucocorticoids 
Not allowed 
Not allowed 
Intravenous or intramuscular glucocorticoids 
Not allowed 
Not allowed 
Topical corticosteroid treatment for psoriasis 
Allowed 
Allowed 
Topical treatment for uveitis 
Allowed 
Allowed 
 
Non-steroidal anti-inflammatory drugs (NSAIDs) 
All patients are allowed to be treated with NSAIDs provided that the dose is stable and not 
exceeding the maximum recommended dose. NSAID treatment should be stable for 1 
week before the first study drug administration. 
During the trial, NSAID intake should not exceed the maximum recommended dose; the 
dose can be adapted or even stopped at the discretion of the treating rheumatologist.  The 
need for concomitant intake of NSAIDs, including changes in the dosing schedule, will be 
recorded (by calculating the NSAID-index). This index will be considered as a surrogate 
(in)efficacy marker. 
 
From week 20, all concomitant oral medication should be kept stable until the assessment 
of the primary endpoint at week 24. 
 
Intra-articular glucocorticoid injections 
- 
Treatment with intra-articular glucocorticoid injection(s) for peripheral SpA 
symptoms are allowed provided that the necessary wash out (≥ 6 weeks) before 
biopsy is respected. In. 
- 
In case of persistent severe arthritis, a maximum of 2 intra-articular glucocorticoid 
injections will be allowed (between week 12 (after the clinical evaluations) but 
before the week 20 assessment). The number of glucocorticoid injections will be 
considered as a surrogate (in)efficacy marker.  When patients have received intra-
articular injections, they will – by default – be considered as non-responders at 
week 24. 
 
Investigational drugs 

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Prior use of any investigational drug of chemical or biological nature within a period of 30 
days or 5 half-lives of the drug (whichever is longer) before the baseline visit is not 
allowed; concomitant use of these drugs is not allowed during the trial. 
 
Vaccines: 
Patient may not have received, or are expected to receive, any live virus or bacterial 
vaccination within 3 months prior to the first administration of study agent, during the trial, 
or within 3 months after the last administration of study agent. 
 
In line with international management recommendations investigators should ensure that 
the vaccination status of patients with inflammatory rheumatic diseases is up to date; this 
would include booster vaccinations for influenza and Covid-19. At present there is no 
convincing evidence that these vaccines would interfere or create safety hazards in 
combination with the treatment strategies applied in the Spartacus trial. 
 
All patients will receive oral folic acid according to standard clinical practice when using 
MTX. 
 
Rescue therapy 
 
There are essentially 3 types of “rescue therapy”: 
- 
At week 12, a “Patient Acceptable Signs & Symptoms Improvement”-question 
(“PASSI”) will be asked.  If the patient has not experienced an acceptable 
improvement of signs and symptoms, oral sulphasalazine at a dose of 2 g per day 
will be added to the blinded study medication. 
- 
Between week 12 (after efficacy evaluation) and week 24, there is a possibility to 
inject a persistently swollen joint with glucocorticoids.  This procedure can only be 
performed twice in this 12-week time-window. 
- 
At week 24, there is an option to treat patients, that did not reach clinical remission 
with the blinded study medication, with open-label golimumab at the standard dose 
of 50 mg SC every 4 weeks.  This option is also available at week 36 for patients 
that have remained on blinded study medication. 
 
The use of concomitant medication will be recorded from screening until the patient’s last 
study visit. During the screening visit all current medication will be recorded on the 
concomitant medication log: Medication name, indication, dosage, frequence, start- and 
stop date. During each trial visit, the change in medication use will be registered in  this 
log. Supplements are not considered as medication.  
 
 
11 Procedures and Study Flow-Chart 
 
11.1 Eligibility screening process 
Refer to section 8.5. 
 

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11.2  Informed consent 
Refer to section 17.2. 
 
11.3  Measures taken to minimise bias 
 
11.3.1 
Randomisation/Blinding/Deblinding 
 
All patients (n=97) will be randomized (1:1) to either immediately receiving golimumab 
monotherapy (n=48) (the “TNFi-induction”-group), or to the step-up regimen with 
csDMARDs (n=47) (“csDMARD-Step-up”-group) in a double-blind, double-dummy design. 
 
The “TNFi-induction”-group will receive the standard golimumab dose of 50 mg 
subcutaneously (SC) every 4 weeks (with matching csDMARD-placebo capsules). 
In the “csDMARD-Step-up” regimen, patients will start with oral methotrexate (MTX) 
capsules at a weekly dose of 15 mg for 4 weeks (with matching “golimumab”-placebo 
injections). In case of intolerance or toxicity to MTX or MTX placebo, the weekly dose of 
MTX or MTX placebo can be tapered to 10 mg at week 4, with a further possible reduction 
to 7,5 mg at week 8; in case of persistent intolerance/toxicity, MTX or MTX placebo will be 
stopped at week 12. When there are no tolerability/toxicity issues, the weekly dose of MTX 
or MTX placebo will be increased to 20 mg at week 4 (with an option to again reduce the 
dose in case of intolerance/toxicity). 
 
At week 12, “Patient Acceptable Signs & Symptoms Improvement” (“PASSI”) will be 
assessed (see Addendum 3) in order to determine the need for additional, open-label 
“escape” csDMARD treatment: in case of an acceptable improvement, blinded study 
medication will be continued until week 24; if there is no satisfactory response, oral 
sulphasalazine can be added to the blinded study medication at a dose of 2 g per day 
(escape medication). 
 
The randomization to either the “TNFi induction”-group or the “csDMARD Step-up”-group 
will be done at the UZ Ghent Pharmacy and the randomization list will be kept there.  If 
according to the data entered in the eCRF, the patient is eligible for randomization, the 
RedCap system will send a notification to the coordinating study team. Upon review of the 
screening visit data (including in- and exclusion criteria), the coordinating study team will 
approve randomization in the eCRF. This will trigger communication with the UZ Ghent 
pharmacy who will randomize the patient. The local site will be informed via an email and 
the eCRF system. The UZ Ghent Pharmacy will assemble patient-specific medication kits 
that will contain (according to the randomization list) the golimumab/placebo syringes for 
each individual patient.  When a new patient is to be randomized, the kits will be sent to 
the site containing: 
 
- 
7 golimumab/placebo syringes: 
o 6 syringes for administration at baseline and weeks 4, 8, 12, 16 and 20. 
o 1 spare syringe: 
▪ To be used in case of a problem with the first 6 syringes. 
▪ This syringe will be administered at week 24 in case the patient would 
need to continue at week 24 for another 12 weeks with blinded study 

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drug.  In that case 2 more golimumab/placebo syringes will be 
distributed for administration on weeks 28 and 32. 
 
At the time of randomisation of a first patient the site will receive a number of methotrexate 
and placebo bottles provided with a randomisation number. This medication is not patient-
specific and will be allocated per study visit. 
 
At the start of the study, the UZ Ghent Pharmacy will send the unblinding information, in a 
sealed envelope, to the national coordinating investigator conform the GMP regulation. If 
the local investigator would feel that unblinding of study medication has become 
necessary, the national coordinating investigator at UZ Ghent should be contacted to 
discuss the case (see contact information paragraph 15.3). If necessary, the coordinating 
investigator at UZ Ghent can unblind the patient in question and send  notification  thereof  
to HIRUZ and the UZ Ghent Pharmacy. 
The study code should only be broken for valid medical or safety reasons, e.g. in the case 
of a severe adverse event where it is necessary for the investigator or treating health care 
professional to know which treatment the subject is receiving before he or she can be 
treated. If possible, other study team members should remain blinded. 
The code breaks for the trial are kept in a separate study binder. The binder is located in a 
locked cupboard that only the study staff have access to.  In the event a code is required 
to be unblinded a formal request for unblinding will be made by the local PI to the 
Coordinating Investigator (CI). 
The CI/PI documents the breaking of the code and the reasons for doing so on the 
eCRF/study documents, in the site file and medical notes. It will also be documented at the 
end of the trial in any final study report and/or statistical report. 
The study team will notify the Sponsor in writing as soon as possible following the code 
break detailing the necessity of the code break. 
As the investigator is responsible for the medical care of the individual study subject 
(Declaration of Helsinki §3 and ICH 4.3) the coding system should include a mechanism 
that permits rapid unblinding (ICH GCP 5.13.4). The investigator cannot be required to 
discuss unblinding if he or she feels that emergent unblinding is necessary. 
 
 
Patients for whom the medication is unblinded will be discontinued from the clinical trial.   
 
 
 
11.4  Study specific Procedures and Interventions 
11.4.1 
 ‘SPARTACUS Phase A’ 
 
Phase A – Visit 1A: CLINICAL SCREENING (week -6 to -4 days) 
▪ Informed consent. 
▪ Check fulfilment of in- and exclusion criteria. 
▪ Demographic data, symptom duration, medical history, incl. past anti-rheumatic 
treatment, smoking/alcohol status, and family history. 
▪ Current medication (dose and duration). 

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▪ Latent Tuberculosis (TB) screening: chest X-ray (if not performed within the last 3 
months), TB test (Mantoux PPD-test or Quantiferon), TB questionnaire (see 
Addendum 4). 
▪ Patient reported outcomes: 
o Patient global assessment of disease activity (0-10 numerical rating scale). 
o Patient global assessment of pain (0-10 numerical rating scale). 
▪ Physical examination. 
▪ Vital signs (blood pressure, heart frequency). 
▪ Weight, length. 
▪ Rheumatological examination (see Addendum 5): 
o 78-Tender and 76-swollen joint count. 
o Dactylitis assessment. 
o Enthesitis assessment (SPARCC (SPondyloArthritis Research Consortium of Canada) 
Enthesitis Index). 
o Physician global assessment of disease activity (0-10 numerical rating 
scale). 
▪ Laboratory investigation: 
o Diagnosis: HLA B27 (if not known), anti-CCP antibodies (if not determined 
within the last 12 months). 
o Screening: peripheral blood count, serum creatinine, uric acid, liver function 
tests (ALT, gamma-GT, Alkaline Phosphatase, LDH), Creatine Kinase.  
(laboratory evaluations considered “standard-of-care” daily practice for SpA 
patients treated with csDMARDs and TNFi). (the results of tests performed 
within the last  month are allowed ). 
o  
o Serum pregnancy test. 
o Screening for Hepatitis B, Hepatitis C, HIV and CMV IgG. (if not determined 
within the last 3 months). 
 
o Disease activity: inflammatory parameters: erthrocyte sedimentation rate 
(ESR), C-reactive protein (CRP). 
 
Phase A – Visit 1B: SYNOVIAL BIOPSY SCREENING (week -6 to -4 days) 
Performed in one of the synovial biopsy sampling units 
▪ Ultrasound evaluation of clinically swollen joints identified at visit 1A. 
▪ Ultrasound-guided synovial tissue sampling of a representative swollen joint (see 
Addendum 6 for list of joints that can be sampled).  In case of multiple small joint 
involvement, a joint with a score of 2 or more on Grey Scale/Power Doppler 
ultrasound assessment will be chosen to sample. 
▪ Laboratory investigation: Research samples (4 x 8ml blood-CPT  (Cell Preparation 
Tube) and 10ml serum) 
▪ Check fulfilment of in- and exclusion criteria. 
▪ Post biopsy questionnaire (see Addendum 9) 
 
 
Phase A – Visit 2: BASELINE (week 0) 
▪ Check fulfilment of in- and exclusion criteria. 
▪ Current medication (dose and duration). 
▪ Patient reported outcomes (see Addendum 7): 

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o Patient global assessment of disease activity (0-10 numerical rating scale). 
o Patient global assessment of pain (0-10 numerical rating scale). 
o Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). 
o Bath Ankylosing Spondylitis Functional Index (BASFI). 
o Health Assessment Questionnaire (for SpA) (HAQ(-SpA)). 
o  Assessment of SpondyloArthritis international Society (ASAS) Health Index 
(ASAS-HI). 
o “Health Economic Evaluation”: EuroQoL 5 dimensions, co-morbidity Index 
(SCQ) and healthcare utilization and productivity (in the past 6 months), level 
of education 
▪ Targeted physical examination. 
▪ Follow-up upon the synovial biopsy if performed 
▪ Rheumatological examination (see Addendum 5): 
o 78-Tender and 76-swollen joint count. 
o Dactylitis assessment. 
o Enthesitis assessment (SPARCC Enthesitis Index). 
o Bath Ankylosing Spondylitis Metrology Index (BASMI), including tragus-to-
wall distance, lumbar flexion (Schöber index), lumbar lateroflexion, cervical 
rotation and intermalleolar distance; chest expansion. 
o Psoriasis skin evaluation (if applicable). 
▪ Laboratory investigation: 
o Research samples (if not taken at Visit 1B 4 x 8ml blood-CPT + 10ml serum 
if treated in a synovial biopsy sampling unit) 
▪ Assessment of adverse events after start of blinded study medication. 
▪ Dispensation of study drug and treatment schedule education/diary: 
o Administration of Golimumab/Placebo injection at study site. 
o Dispensation of Placebo/Methotrexate capsules for weekly intake at home. 
 
Phase A – Visit 3: WEEK 4 (+/- 1 week)  
▪ Assessment of adverse events. 
▪ Current medication (dose and duration). 
▪ Study drug accountability. 
▪ Patient reported outcomes (see Addendum 7): 
o Patient global assessment of disease activity (0-10 numerical rating scale). 
o Patient global assessment of pain (0-10 numerical rating scale). 
o Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). 
▪ Targeted physical examination. 
▪ Rheumatological examination (see Addendum 5): 
o 78-Tender and 76-swollen joint count. 
o Dactylitis assessment. 
o Enthesitis assessment (SPARCC Enthesitis Index). 
▪ Laboratory investigation: 
o Disease activity: ESR, CRP. 
o Safety: peripheral blood count, serum creatinine, liver function tests (ALT). 
▪ Dispensation of study drug: 
o Administration of Golimumab/Placebo injection at study site. 
o Dispensation of Placebo/Methotrexate capsules for weekly intake at home.  
Dose according to tolerance (see Addendum 8). 

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Phase A – Visit 4: WEEK 8 (+/- 1 week)  
▪ Assessment of adverse events. 
▪ Current medication (dose and duration). 
▪ Study drug accountability. 
▪ Patient reported outcomes (see Addendum 7): 
o Patient global assessment of disease activity (0-10 numerical rating scale). 
o Patient global assessment of pain (0-10 numerical rating scale). 
o Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). 
▪ Targeted physical examination. 
▪ Rheumatological examination (see Addendum 5): 
o 78-Tender and 76-swollen joint count. 
o Dactylitis assessment. 
o Enthesitis assessment (SPARCC Enthesitis Index). 
▪ Laboratory investigation: 
o Disease activity: ESR, CRP. 
o Safety: at the discretion of the treating rheumatologist. 
▪ Dispensation of study drug: 
o Administration of Golimumab/Placebo injection at study site. 
o Dispensation of Placebo/Methotrexate capsules for weekly intake at home.  
Dose according to tolerance (see Addendum 8). 
 
Phase A – Visit 5: WEEK 12 (+/- 1 week) 
▪ Assessment of adverse events. 
▪ Tuberculosis Questionnaire. 
▪ Current medication (dose and duration). 
▪ Study drug accountability. 
▪ Patient reported outcomes (see Addendum 7): 
o Patient global assessment of disease activity (0-10 numerical rating scale). 
o Patient global assessment of pain (0-10 numerical rating scale). 
o Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). 
o Bath Ankylosing Spondylitis Functional Index (BASFI). 
o Assessment of SpondyloArthritis international Society (ASAS) Health Index 
(ASAS-HI). 
o “Health Economic Evaluation”: EuroQoL 5 dimensions, co-morbidity Index 
(SCQ) and healthcare utilization and productivity (in the past 3 months) 
o Patient Acceptable Signs & Symptoms Improvement (“PASSI”) question 
(See Addendum 3). 
▪ Targeted physical examination. 
▪ Vital signs (blood pressure, heart frequency). 
▪ Weight. 
▪ Smoking/alcohol status 
▪ Rheumatological examination (see Addendum 5): 
o 78-Tender and 76-swollen joint count. 
o Dactylitis assessment. 
o Enthesitis assessment (SPARCC Enthesitis Index). 

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o Bath Ankylosing Spondylitis Metrology Index (BASMI), including tragus-to-
wall distance, lumbar flexion (Schöber index), lumbar lateroflexion, cervical 
rotation and intermalleolar distance; chest expansion. 
o Psoriasis skin evaluation (if applicable). 
o Physician global assessment of disease activity (0-10 numerical rating 
scale). 
▪ Laboratory investigation: 
o Disease activity: ESR, CRP. 
o Safety: peripheral blood count, serum creatinine, liver function tests (ALT). 
o Research samples (only 10ml serum if  treated in UZ Ghent or UZ Leuven) 
▪ Dispensation of study drug and treatment schedule education: 
o Administration of Golimumab/Placebo injection at study site. 
o Dispensation of Placebo/Methotrexate capsules for weekly intake at home.  
Dose according to tolerance (see Addendum 8). 
o Depending on the response to the “PASSI”-question: 
▪ “PASSI”-Yes: continuation of blinded study medication 
▪ “PASSI”-No: prescription of Sulphasalazine open-label escape 
treatment. 
 
Phase A – Visit 6: WEEK 16 (+/- 1 week) 
▪ Assessment of adverse events. 
▪ Current medication (dose and duration). 
▪ Study drug accountability. 
▪ Patient reported outcomes (see Addendum 7): 
o Patient global assessment of disease activity (0-10 numerical rating scale). 
o Patient global assessment of pain (0-10 numerical rating scale). 
o Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). 
▪ Targeted physical examination. 
▪ Rheumatological examination (see Addendum 5): 
o 78-Tender and 76-swollen joint count. 
o Dactylitis assessment. 
o Enthesitis assessment (SPARCC Enthesitis Index). 
▪ Laboratory investigation: 
o Disease activity: ESR, CRP. 
o Safety: at the discretion of the treating rheumatologist (depending on the use 
of e.g. sulphasalazine escape medication). 
▪ Dispensation of study drug: 
o Administration of Golimumab/Placebo injection at study site. 
o Dispensation of Placebo/Methotrexate capsules for weekly intake at home.  
Dose according to tolerance (see Addendum 8). 
 
Phase A – Visit 7: WEEK 20 (+/- 1 week) 
▪ Assessment of adverse events. 
▪ Current medication (dose and duration). 
▪ Study drug accountability. 
▪ Patient reported outcomes (see Addendum 7): 

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o Patient global assessment of disease activity (0-10 numerical rating scale). 
o Patient global assessment of pain (0-10 numerical rating scale). 
o Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). 
▪ Targeted physical examination. 
▪ Rheumatological examination (see Addendum 5): 
o 78-Tender and 76-swollen joint count. 
o Dactylitis assessment. 
o Enthesitis assessment (SPARCC Enthesitis Index). 
▪ Laboratory investigation: 
o Disease activity: ESR, CRP. 
o Safety: at the discretion of the treating rheumatologist (depending on the use 
of e.g. sulphasalazine escape medication). 
▪ Dispensation of study drug: 
o Administration of Golimumab/Placebo injection at study site. 
o Dispensation of Placebo/Methotrexate capsules for weekly intake at home.  
Dose according to tolerance (see Addendum8). 
 
Phase A – Visit 8: WEEK 24 (+/- 1 week) 
▪ Assessment of adverse events. 
▪ Tuberculosis Questionnaire. 
▪ Current medication (dose and duration). 
▪ Study drug accountability. 
▪ Patient reported outcomes (see Addendum 7): 
o Patient global assessment of disease activity (0-10 numerical rating scale). 
o Patient global assessment of pain (0-10 numerical rating scale). 
o Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). 
o Bath Ankylosing Spondylitis Functional Index (BASFI). 
o Health Assessment Questionnaire (for SpA) (HAQ(-SpA)). 
o  Assessment of SpondyloArthritis international Society (ASAS) Health Index 
(ASAS-HI). 
o “Health Economic Evaluation”: EuroQoL 5 dimensions, co-morbidity Index 
(SCQ) and healthcare utilization and productivity (in the past 3 months) 
▪ Targeted physical examination. 
▪ Vital signs (blood pressure, heart frequency). 
▪ Weight. 
▪ Smoking/alcohol status 
▪ Rheumatological examination (see Addendum 5): 
o 78-Tender and 76-swollen joint count. 
o Dactylitis assessment. 
o Enthesitis assessment (SPARCC Enthesitis Index). 
o Bath Ankylosing Spondylitis Metrology Index (BASMI), including tragus-to-
wall distance, lumbar flexion (Schöber index), lumbar lateroflexion, cervical 
rotation and intermalleolar distance; chest expansion. 
o Psoriasis skin evaluation (if applicable). 
o Physician global assessment of disease activity (0-10 numerical rating 
scale). 
▪ Laboratory investigation: 
o Disease activity: ESR, CRP. 

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o Safety: peripheral blood count, serum creatinine, uric acid, liver function tests 
(ALT, gamma-GT, Alkaline Phosphatase, LDH), Creatine Kinase. 
▪ Research samples (4 x 8ml blood-CPT and 10ml serum if treated in UZ Ghent or 
UZ Leuven) 
▪ Trial continuation evaluation based on clinical remission (yes/no) at week 24 and 
potential sustained clinical remission (at week 12 and 24): 
o No clinical remission: stop blinded study medication; start open-label 
golimumab 50 mg SC every 4 weeks. 
o Clinical remission (but not sustained remission): continuation of the same 
blinded study medication. 
o Sustained clinical remission: stop blinded study medication; roll-over into 
SPARTACUS Phase B – visit 1. 
▪ For patients continuing in SPARTACUS Phase A: dispensation of study drug and 
treatment schedule education: 
o Blinded continuation group: 
▪ Administration of Golimumab/Placebo injection at study site. 
▪ Dispensation of Placebo/Methotrexate capsules for weekly intake at 
home.  Dose according to tolerance (see Addendum 8). 
o Open-label golimumab group: 
▪ Administration of Golimumab injection at study site. 
 
Phase A – Visit 9: WEEK 28 (+/- 1 week) 
▪ Assessment of adverse events. 
▪ Current medication (dose and duration). 
▪ Study drug accountability. 
▪ Patient reported outcomes (see Addendum 7): 
o Patient global assessment of disease activity (0-10 numerical rating scale). 
o Patient global assessment of pain (0-10 numerical rating scale). 
o Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). 
▪ Targeted physical examination. 
▪ Rheumatological examination (see Addendum 5): 
o 78-Tender and 76-swollen joint count. 
o Dactylitis assessment. 
o Enthesitis assessment (SPARCC Enthesitis Index). 
▪ Laboratory investigation: 
o Disease activity: ESR, CRP. 
o Safety: peripheral blood count, serum creatinine, liver function tests (ALT). 
▪ Dispensation of study drug: 
o Blinded continuation group: 
▪ Administration of Golimumab/Placebo injection at study site. 
▪ Dispensation of Golimumab/Placebo injection for week 32 
administration at home.  Education regarding self-injection. 
▪ Dispensation of Placebo/Methotrexate capsules for weekly intake at 
home.  Dose according to tolerance (see Addendum 8). 

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o Open-label golimumab group: 
▪ Administration of Golimumab injection at study site. 
▪ Dispensation of Golimumab injection for week 32 administration at 
home.  Education regarding self-injection. 
 
Phase A – Visit 10: WEEK 36 (+/- 1 week) 
▪ Assessment of adverse events. 
▪ Tuberculosis Questionnaire. 
▪ Current medication (dose and duration). 
▪ Study drug accountability. 
▪ Patient reported outcomes (see Addendum 7): 
o Patient global assessment of disease activity (0-10 numerical rating scale). 
o Patient global assessment of pain (0-10 numerical rating scale). 
o Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). 
o Bath Ankylosing Spondylitis Functional Index (BASFI). 
o Assessment of SpondyloArthritis international Society (ASAS) Health Index 
(ASAS-HI). 
o “Health Economic Evaluation”: EuroQoL 5 dimensions, co-morbidity Index 
(SCQ) and healthcare utilization and productivity (in the past 3 months) 
o Patient Acceptable Signs & Symptoms Improvement (“PASSI”) question (see 
Addendum 3). 
▪ Targeted physical examination. 
▪ Vital signs (blood pressure, heart frequency). 
▪ Weight. 
▪ Smoking/alcohol status 
▪ Rheumatological examination (see Addendum 5): 
o 78-Tender and 76-swollen joint count. 
o Dactylitis assessment. 
o Enthesitis assessment (SPARCC Enthesitis Index). 
o Bath Ankylosing Spondylitis Metrology Index (BASMI), including tragus-to-
wall distance, lumbar flexion (Schöber index), lumbar lateroflexion, cervical 
rotation and intermalleolar distance; chest expansion. 
o Psoriasis skin evaluation (if applicable). 
o Physician global assessment of disease activity (0-10 numerical rating 
scale). 
▪ Laboratory investigation: 
o Disease activity: ESR, CRP. 
o Safety: peripheral blood count, serum creatinine, uric acid, liver function tests 
(ALT, gamma-GT, Alkaline Phosphatase, LDH), Creatine Kinase. 
▪ Trial continuation evaluation based on clinical remission (yes/no) at week 36 and 
potential sustained clinical remission (at week 24 and 36): 
o Blinded continuation group: 
▪ No clinical remission: stop blinded study medication; start open-label 
golimumab 50 mg SC every 4 weeks. 
▪ Sustained clinical remission: stop blinded study medication; roll-over 
into SPARTACUS Phase B – visit 1. 

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o Open-label golimumab group: additional decision based upon “PASSI”-
question (yes/no) 
▪ Clinical remission: continuation of open-label golimumab 50 mg SC 
every 4 weeks. 
▪ No clinical remission and “PASSI”-yes: continuation of open-label 
golimumab 50 mg SC every 4 weeks. 
▪ No clinical remission and “PASSI”-no: study discontinuation, further 
(standard-of-care) treatment at the discretion of the treating 
rheumatologist. 
▪ For patients continuing in SPARTACUS Phase A: dispensation of study drug: 
o Administration of Golimumab injection at study site. 
o Dispensation of Golimumab injections for week 40 and week 44 
administration at home. Education regarding self-injection. 
 
Phase A – Visits 11: WEEK 48 (+/- 1 week) 
▪ Assessment of adverse events. 
▪ Tuberculosis Questionnaire. 
▪ Current medication (dose and duration). 
▪ Study drug accountability. 
▪ Patient reported outcomes (see Addendum 7): 
o Patient global assessment of disease activity (0-10 numerical rating scale). 
o Patient global assessment of pain (0-10 numerical rating scale). 
o Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). 
o Bath Ankylosing Spondylitis Functional Index (BASFI). 
o Health Assessment Questionnaire (for SpA) (HAQ(-SpA)). 
o  Assessment of SpondyloArthritis international Society (ASAS) Health Index 
(ASAS-HI). 
o “Health Economic Evaluation”: EuroQoL 5 dimensions, co-morbidity Index 
(SCQ) and healthcare utilization and productivity (in the past 3 months) 
o Patient Acceptable Signs & Symptoms Improvement (“PASSI”) question (see 
Addendum 3). 
▪ Targeted physical examination. 
▪ Vital signs (blood pressure, heart frequency). 
▪ Weight. 
▪ Smoking/alcohol status 
▪ Rheumatological examination (see Addendum 5): 
o 78-Tender and 76-swollen joint count. 
o Dactylitis assessment. 
o Enthesitis assessment (SPARCC Enthesitis Index). 
o Bath Ankylosing Spondylitis Metrology Index (BASMI), including tragus-to-
wall distance, lumbar flexion (Schöber index), lumbar lateroflexion, cervical 
rotation and intermalleolar distance; chest expansion. 
o Psoriasis skin evaluation (if applicable). 
o Physician global assessment of disease activity (0-10 numerical rating 
scale). 
▪ Laboratory investigation: 
o Disease activity: ESR, CRP. 

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o Safety: peripheral blood count, serum creatinine, uric acid, liver function tests 
(ALT, gamma-GT, Alkaline Phosphatase, LDH), Creatine Kinase. 
▪ Trial continuation evaluation based on clinical remission (yes/no) at week 48 and 
potential sustained clinical remission (at week 36 and 48): 
o Sustained clinical remission: stop open-label golimumab, roll-over into 
SPARTACUS Phase B – Visit 1 
o Clinical remission (but not yet sustained): continuation of open-label 
golimumab 50 mg SC every 4 weeks. 
o No clinical remission and “PASSI”-yes: continuation of open-label golimumab 
50 mg SC every 4 weeks with the addition of “commercial methotrexate” 
(reimbursed, standard-of-care). 
o No clinical remission and “PASSI”-no: study discontinuation, further 
(standard-of-care) treatment at the discretion of the treating rheumatologist. 
▪ For patients continuing in SPARTACUS Phase A: dispensation of study drug: 
o Administration of Golimumab injection at study site. 
o Dispensation of Golimumab injections for week 52 and week 56 
administration at home.  Education regarding self-injection. 
o Prescription of “commercial methotrexate” (dose at the discretion of the 
treating rheumatologist). 
 
Phase A – Visits 12: WEEK 60 – END OF PHASE A VISIT or EARLY 
DISCONTINUATION VISIT (+/- 1 week) 
▪ Assessment of adverse events. 
▪ Tuberculosis Questionnaire. 
▪ Current medication (dose and duration). 
▪ Study drug accountability. 
▪ Patient reported outcomes (see Addendum 7): 
o Patient global assessment of disease activity (0-10 numerical rating scale). 
o Patient global assessment of pain (0-10 numerical rating scale). 
o Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). 
o Bath Ankylosing Spondylitis Functional Index (BASFI). 
o Assessment of SpondyloArthritis international Society (ASAS) Health Index 
(ASAS-HI). 
o “Health Economic Evaluation”: EuroQoL 5 dimensions, co-morbidity Index 
(SCQ) and healthcare utilization and productivity (in the past 3 months) 
▪ Targeted physical examination. 
▪ Vital signs (blood pressure, heart frequency). 
▪ Weight. 
▪ Smoking/alcohol status 
▪ Rheumatological examination (see Addendum 5): 
o 78-Tender and 76-swollen joint count. 
o Dactylitis assessment. 
o Enthesitis assessment (SPARCC Enthesitis Index). 
o Bath Ankylosing Spondylitis Metrology Index (BASMI), including tragus-to-
wall distance, lumbar flexion (Schöber index), lumbar lateroflexion, cervical 
rotation and intermalleolar distance; chest expansion. 

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o Psoriasis skin evaluation (if applicable). 
o Physician global assessment of disease activity (0-10 numerical rating 
scale). 
▪ Laboratory investigation: 
o Disease activity: ESR, CRP. 
o Safety: peripheral blood count, serum creatinine, uric acid, liver function tests 
(ALT, gamma-GT, Alkaline Phosphatase, LDH), Creatine Kinase. 
▪ Trial continuation evaluation: 
o Open-label golimumab monotherapy group (decision based on sustained 
clinical remission at week 48 and 60: 
▪ Sustained clinical remission: stop open-label golimumab, roll-over into 
SPARTACUS Phase B – Visit 1 
▪ No sustained clinical remission: study discontinuation, further 
(standard-of-care) treatment at the discretion of the treating 
rheumatologist. 
o Open-label golimumab with “commercial methotrexate” group: study 
discontinuation, further (standard-of-care) treatment at the discretion of the 
treating rheumatologist. 
 
Phase A – UNSCHEDULED VISIT 
▪ Assessment of adverse events. 
▪ Current medication (dose and duration). 
▪ Patient reported outcomes (see Addendum 7): 
o Patient global assessment of disease activity (0-10 numerical rating scale). 
o Patient global assessment of pain (0-10 numerical rating scale). 
o Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). 
▪ Targeted physical examination. 
▪ Rheumatological examination (see Addendum 5) at the discretion of the 
investigator: 
o 78-Tender and 76-swollen joint count. 
o Dactylitis assessment. 
o Enthesitis assessment (SPARCC Enthesitis Index). 
o Bath Ankylosing Spondylitis Metrology Index (BASMI), including tragus-to-
wall distance, lumbar flexion (Schöber index), lumbar lateroflexion, cervical 
rotation and intermalleolar distance; chest expansion. 
o Psoriasis skin evaluation (if applicable). 
▪ Laboratory investigation at the discretion of the investigator 
 
11.4.2 ‘SPARTACUS Phase B’ 
 
Systematic Follow-Up Visits 
 
 
Visit 
Week 
Window 
Description 
Phase B 
1 
0 
- 
Phase A “Roll-over” visite 
Phase B 
2 
12 
±1 week 
Follow-Up Phase A adverse events 
Phase B 
3 
24 
±1 week 
 
Phase B 
4 
36 
±1 week 
 

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Phase B 
5 
48 
±1 week 
 
Phase B 
6 
72 
±2 weeks 
 
Phase B 
7 
96 
±2 weeks 
 
Phase B 
8 
120 
±2 weeks 
 
Phase B 
9 
144 
±2 weeks 
Final study visit 
 
▪ Assessment of significant adverse events, extra-articular manifestations and / or 
relevant comorbidities. 
▪ Current medication (dose and duration). 
▪ Patient reported outcomes (See Addendum 7): 
o Patient global assessment of disease activity (0-10 numerical rating scale). 
o Patient global assessment of pain (0-10 numerical rating scale). 
o Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). 
o Bath Ankylosing Spondylitis Functional Index (BASFI). 
o Health Assessment Questionnaire (for SpA) (HAQ(-SpA)). 
o Assessment of SpondyloArthritis international Society (ASAS) Health Index 
(ASAS-HI). 
o “Health Economic Evaluation”: co-morbidity Index (SCQ), EuroQoL 5 
dimensions and validated cost questionnaires (healthcare utilization in the 
past 6 months) 
▪ Targeted physical examination. 
▪ Weight. 
▪ Smoking/alcohol status 
▪ Rheumatological examination (see Addendum 5): 
o 78-Tender and 76-swollen joint count. 
o Dactylitis assessment. 
o Enthesitis assessment (SPARCC Enthesitis Index). 
o Bath Ankylosing Spondylitis Metrology Index (BASMI), including tragus-to-
wall distance, lumbar flexion (Schöber index), lumbar lateroflexion, cervical 
rotation and intermalleolar distance; chest expansion. 
o Psoriasis skin evaluation (if applicable). 
o Physician global assessment of disease activity (0-10 numerical rating 
scale). 
▪ Laboratory investigation: 
o Disease activity: ESR, CRP. 
o Safety (only at the Phase B – Visit 2 – Week 12 visit): peripheral blood count, 
serum 
creatinine, 
liver 
function 
tests 
(ALT, 
Gamma-GT, 
Alkaline 
Phosphatase, LDH), creatine kinase. 
o Research samples (Visit 1 and Visit 2) 
▪ Flare vs. (sustained) drug-free remission evaluation: 
o Remission: continuation in SPARTACUS Phase B 
o Flare: discontinuation from SPARTACUS Phase B; start of (standard-of-care) 
treatment at the discretion of the treating rheumatologist. 
 
Unscheduled Flare Identification Visit(s) 
▪ Assessment of significant adverse events, extra-articular manifestations and / or 
relevant comorbidities. 
▪ Current medication (dose and duration). 
▪ Patient reported outcomes  (see Addendum 7): 

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o Patient global assessment of disease activity (0-10 numerical rating scale). 
o Patient global assessment of pain (0-10 numerical rating scale). 
o Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). 
o Bath Ankylosing Spondylitis Functional Index (BASFI). 
o Health Assessment Questionnaire (for SpA) (HAQ(-SpA)). 
o  Assessment of SpondyloArthritis international Society (ASAS) Health Index 
(ASAS-HI). 
o “Health Economic Evaluation”: EuroQoL 5 dimensions, co-morbidity Index 
(SCQ) and healthcare utilization in the past 6 months 
▪ Targeted physical examination. 
▪ Weight. 
▪ Rheumatological examination (see Addendum 5): 
o 78-Tender and 76-swollen joint count. 
o Dactylitis assessment. 
o Enthesitis assessment (SPARCC Enthesitis Index). 
o Bath Ankylosing Spondylitis Metrology Index (BASMI), including tragus-to-
wall distance, lumbar flexion (Schöber index), lumbar lateroflexion, cervical 
rotation and intermalleolar distance; chest expansion. 
o Psoriasis skin evaluation (if applicable). 
o Physician global assessment of disease activity (0-10 numerical rating 
scale). 
▪ Laboratory investigation: 
o Disease activity: ESR, CRP. 
o Safety: peripheral blood count, serum creatinine, liver function tests (ALT, 
Gamma-GT, Alkaline Phosphatase, LDH), creatine kinase. 
▪ Flare vs. (sustained) drug-free remission evaluation: 
o Remission: continuation in SPARTACUS Phase B 
o Flare: discontinuation from SPARTACUS Phase B; start of (standard-of-care) 
treatment at the discretion of the treating rheumatologist. 
 
 
Flare Follow-Up Visit/phone call (3 months after Flare ID visit  +/-1 month)     
▪ Current medication (dose and duration).

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Protocol “SPARTACUS”, versie 5.1, dd 04/06/2025 
Flowchart 
Schedule of planned study activities per visit for SPARTACUS Phase A 
Protocol Activity 
V1A 
V1B 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
UNS 
scr 
Biopt 
W0 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W36 
W48 
W60 
 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion crit 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
synovial biopsy & Ultrasound 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Anamnesisa 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Current Medication 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
Adverse Events 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
Latent TB screeningb 
x 
 
 
 
 
x 
 
 
x 
 
x 
x 
x 
 
Patient disease activity & pain NRS 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
BASDAI 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
BASFI, ASAS-HI, Health economic evaluations 
 
 
x 
 
 
x 
 
 
x 
 
x 
x 
x 
 
HAQ-SpA 
 
 
x 
 
 
 
 
 
x 
 
 
x 
 
 
Post biopsy questionnaire 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
(Targeted) Physical examinationf 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
Vital Signs 
x 
 
 
 
 
x 
 
 
x 
 
x 
x 
x 
 
Length (only at screening), weight 
x 
 
 
 
 
x 
 
 
x 
 
x 
x 
x 
 
Smoking/alcohol status 
x 
 
 
 
 
x 
 
 
x 
 
x 
x 
x 
 
76SJC/78TJC, dactylitis, enthesitis (SPARCC) 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
BASMI, chest expansion, Psoriasis assessment 
 
 
x 
 
 
x 
 
 
x 
 
x 
x 
x 
X 
Physician global NRS 
x 
 
 
 
 
x 
 
 
x 
 
x 
x 
x 
 
HLA B27c, anti-CCP ABd, HBVi, HCVi, HIVi, CMV IgGi 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Lab testse 
xe 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
ESR, CRP 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
Serum Pregnancy Testing 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research samplesg 
 
x 
xh 
 
 
x 
 
 
x 
 
 
 
 
 
PASSI 
 
 
 
 
 
x 
 
 
 
 
x 
x 
 
 
Assessment of clinical remission status 
 
 
 
 
 
x 
 
 
x 
 
x 
x 
x 
 
Study drug admin/dispensation 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Study drug accountability 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 

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Protocol “SPARTACUS”, versie 5.1, dd 04/06/2025 
a Demographic data, symptom duration, medical history, past anti-rheumatic treatment, family history 
b  v1A: chest X-ray (if not performed within the last 3 months), TB test (Mantoux PPD-test or Quantiferon), TB questionnaire; other visits: only TB questionnaire 
c  If not known 
d if not determined within the last 12 months 
e At v1A (for visit 1A: results of tests performed within the last month are allowed), week 24, week 36, week 48, week 60: peripheral blood count, serum creatinine, uric 
acid, liver function tests (ALT, GGT, AP, LDH), CK 
 At week 4, week 12, week 28: peripheral blood count, serum creatinine, ALT 
 At week 8, week 16, week 20: at the discretion of the treating rheumatologist 
At the unscheduled visit: at the discretion of the treating rheumatologist 
f Full physical exam at screening, targeted physical exam at the other visits 
g 4 x 8ml blood-CPT  (the synovial biopsy sampling units will also collect 10ml serum; at week 12: only 10ml serum; ZNA Jan Palfijn will only collect serum at BL) 
h Only if no samples taken at visit 1B 
i if not determined within the last 3 months 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol “SPARTACUS”, versie 5.1, dd 04/06/2025 
Schedule of planned study activities per visit for SPARTACUS Phase B 
Protocol Activity 
V1a 
V2 
V3-9 
Unscheduled flare identification visit Flare follow-up visit (phone call) 
Week 0  
Week 
12 
Every 12/24 weeksd 
Inclusion/Exclusion 
x 
 
 
 
 
Current Medication 
 
x 
x 
x 
x 
Adverse Events 
 
x 
x 
x 
 
Patient Reported Outcomesb 
 
x 
x 
x 
 
Targeted physical exam 
 
x 
x 
x 
 
Weight 
 
x 
x 
x 
 
Smoking/alcohol status 
 
x 
x 
 
 
76SJC/78TJC 
 
x 
x 
x 
 
Dactylitis 
 
x 
x 
x 
 
Enthesitis (SPARCC) 
 
x 
x 
x 
 
BASMI, chest expansion 
 
x 
x 
x 
 
Psoriatic skin evaluation (if applicable) 
 
x 
x 
x 
 
Physician global NRS 
 
x 
x 
x 
 
Lab tests: ESR, CRP 
 
x 
x 
x 
 
Safety Lab testsc 
 
x 
 
x 
 
Research samplese 
x 
x 
 
 
 
Determination of Flare versus remission status 
 
x 
x 
x 
 
a V1 = phase A ‘Roll-over’ visit, combined with the phase A visit in which sustained remission was obtained 
b Patient global assessment of disease activity NRS, patient global assessment of pain NRS, BASDAI, BASFI, HAQ-SpA, ASAS-HI, Health economic evaluations 
c peripheral blood count, serum creatinine, liver function tests (ALT, GGT, AP, LDH), creatinine kinase 
d at year 1 every 12 weeks: week 24, week 36, week 48 
 at years 2-3 every 24 weeks: week 72, week 96, week 120, week 144 
e 4 x 8ml blood-CPT (UZ Ghent and UZ Leuven also collect 10ml serum) 
 
 
 

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12 Biological samples 
 
Laboratory tests as indicated in the trial protocol will be performed by the local 
laboratory of the trial site.  As patients will be treated with active medication in both trial 
arms during SPARTACUS Phase A, all efficacy and safety laboratory samples are 
considered to be standard-of-care (from screening until 12 weeks after last study 
administration); they will be performed according to (inter)national clinical practice 
guidelines.  At SPARTACUS Phase A – Visit 1 (screening), there will also be a 
standard-of-care analysis of HLA B27 (if not known), anti-CCP antibodies (if not 
determined in the last 12 months), and if not determined in the last 3 months: Hepatitis 
B, Hepatitis C,HIV and CMV IgG. 
 
During SPARTACUS Phase B (“drug-free remission period”) efficacy laboratory 
samples will be collected at the designated timepoints; they will also be analysed at the 
local laboratory. 
 
During the Spartacus trial, research samples (i.e. synovial tissue samples, blood-CPT 
and serum samples) will be collected, pseudonimized and stored in the “SPARTACUS 
Biobank”.  
 
The synovial tissue samples taken at UZ Ghent and UZ Leuven will be processed and 
stored at MRB Ghent and the Translational Cell & Tissue Research Lab KU Leuven 
respectively according to the Spartacus LAB SOP: ‘Synovial biopsy tissue Freezing’ and 
the Spartacus LAB SOP: ‘Synovial tissue_FFPE’. The synovial tissue samples taken at 
the ZNA Jan Palfijn Hospital will be sent immediately to MRB Ghent to be processed 
and stored according to the above-mentioned SOPs. Afterwards the synovial tissue 
samples will be shipped in batch to the VIB Inflammation Research Center Ghent for 
further downstream analysis. 
 
The blood-CPT samples taken at UZ Ghent and UZ Leuven will be processed in MRB 
Ghent and the Translational Cell & Tissue Research Lab KU Leuven respectively, 
according to the Spartacus LAB SOP: ‘CPT Protocol for isolation of PBMC’ and 
afterwards prepared for storage according to the Spartacus LAB SOP: ‘PBMC 
Freezing’. These samples will then be stored at MRB Ghent and the Translational Cell & 
Tissue Research Lab KU Leuven respectively. The blood-CPT samples taken at the 
other participating centers will be processed at the local lab according to the Spartacus 
LAB SOP: ‘Preparing CPT blood tubes for shipping’ and shipped to MRB Ghent. They 
will be further processed in MRB Ghent according to the Spartacus LAB SOP: ‘CPT 
Protocol for isolation of PBMC’ and afterwards prepared for storage according to the 
Spartacus LAB SOP: ‘PBMC Freezing’. For the further downstream analysis, the 
required fraction will be shipped in batch from MRB Ghent to the VIB center in Ghent 
and Translational Cell & Tissue Research Lab KU Leuven. The remainder of the 
PBMCs (i.e., the fraction that is left after analysis in the Translational Cell & Tissue 
Research Lab KU Leuven and VIB) will be shipped (back) to MRB Ghent. 
 
The blood serum samples taken at UZ Ghent and UZ Leuven will be processed in MRB 
Ghent and the Translational Cell & Tissue Research Lab KU Leuven respectively 
according to the Spartacus LAB SOP: ‘Serum collection and storage’. Afterwards these 
samples will be shipped in batch to the MRB Ghent for further downstream analysis by 

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VIB. For the patients that undergo a synovial biopsy at the ZNA Jan Palfijn Hospital, 
blood serum samples will also be taken during this biopsy visit and shipped to MRB 
Ghent for further processing and downstream analysis by VIB as described above. 
 
Samples will be stored for max. 10 years upon collection of each individual sample until 
downstream analyses (as defined  in the protocol) are performed. 
 
Unused, leftover material will be transferred to the “Biobank van menselijk 
lichaamsmateriaal 
van 
patiënten 
met 
reumatische 
en/of 
musculoskeletale 
aandoeningen en gezonde controles” (under supervision of Prof. Dr. Dirk Elewaut) upon 
appropriate written informed consent. 
 
13 Statistical considerations 
13.1 Sample size calculation, power calculation, significance level 
 
The primary end point of SPARTACUS is the percentage of patients going into 
remission.  
The sample size for SPARTACUS was calculated based on the percentage of patients 
that went into clinical remission (TNFi versus placebo) in the CRESPA trial: 75% in 
the TNFi group versus 20% in the placebo group. Currently, there are no data in 
peripheral Spondyloarthritis regarding the percentage of patients going into clinical 
remission under a treatment with Methotrexate. There are also no data regarding 
differences in treatment effect regarding symptom duration: <3 months versus >3 
months.  Therefore, we estimated an expected 30% difference in percentage of patients 
going into clinical remission between both groups (MTX versus TNFi): 20% versus 50%. 
A sample size of at least 45 patients in each group is sufficient to obtain 80% power or 
more to detect a difference in proportions of 30% (20% versus 50%) at the alpha level 
of 5% using a Fisher's exact test.  
 
 
13.2 Type of statistical methods and team 
 
The primary endpoint of SPARTACUS is to compare the proportion of patients 
achieving clinical remission, defined as absence of arthritis, enthesitis and dactylitis at 
week 24, in the “TNFi induction”-group versus the “csDMARD Step-up” group. This will 
be done using appropriate statistical methods. Statistical tests and evaluations will be 
performed by Philippe Carron and Filip Van den Bosch (Ghent University Hospital, 
Department of Rheumatology); where appropriate, expert statistical advice will be 
sought (Roos Colman, Ghent University Hospital, Department of Medical Statistics). 
 
In addition to this, several secondary endpoints will be evaluated: 
 
- 
Comparison between the “TNFi induction” group and the “csDMARD Step-up” 
group regarding: 

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o Achievement of “sustained clinical remission” at week 24 (and week 36 for 
the patients remaining on blinded study medication). 
o Improvement from baseline to week 12 and 24 in individual clinical 
assessments (78-Tender Joint Count, 76-Swollen Joint Count, Dactylitis 
Count, SPARCC Enthesitis Score) and composite scores (ASDAS: Axial 
Spondyloarthritis Disease Activity Score). 
o Improvement from baseline to week 12 and 24 in patient-reported 
outcomes (Patient global assessment of disease activity and pain, 
BASDAI, BASFI, ASAS Health Index. 
o Improvement from baseline to week 12 and 24 in inflammatory parameters 
(ESR, CRP). 
o Changes in concomitant NSAID intake (NSAID-index) and “escape” intra-
articular glucocorticoid injections between baseline and week 24 
- 
Difference in occurrence of (serious) adverse events (AEs) and AEs of specific 
interest between the 2 treatment strategies from baseline to week 24 (and week 
36 for patients remaining on blinded study medication).  Descriptive analysis of 
the number and type of adverse events between both strategies 
- 
Percentage of patients achieving (sustained) clinical remission with open-label 
golimumab treatment after failure of the initial randomized, blinded treatment 
strategy. 
- 
Exploration of difference in percentage of patients that reach (sustained) clinical 
remission according to symptom duration (<3 months versus ≥3 month and <12 
months). The interaction between treatment group and symptom duration as a 
continuous predictor will also be analyzed to investigate the effect of symptom 
duration with regard to reaching the specified primary and secondary outcomes. 
- 
For patients in SPARTACUS Phase B (drug-free remission period): 
o Exploration of the duration of drug-free remission. 
o Time to (documented) pSpA disease flare. 
o Time to restart of “standard-of-care” pSpA treatment. 
o Exploration of clinical parameters that could be predictive for reaching 
(sustained) clinical remission and/or flare. 
- 
Correlation between the “Patient Acceptable Signs & Symptoms Improvement” 
(“PASSI”) and different clinical assessments, laboratory values and patient-
reported outcomes (or combinations thereof). 
 
 
14 Data handling 
 
14.1 Method of data collection 
 
An electronic data capture (EDC) system, i.e. REDCap, will be used for data collection. 
REDCap is provided and maintained by Vanderbilt University; a license for use was 
granted to the Health, Innovation and Research Institute (HIRUZ). REDCap is a web-
based system. 
 

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14.1.1 Case Report Form (CRF) 
 
Only the data required by the protocol are captured in the eCRF. The eCRFs and the 
database will be developed, based on the protocol. The final eCRF design will be 
approved by the CI. 
The study site staff is responsible for data entry in REDCap. 
Subjects that are included in the trial, will be assigned a unique study number upon their 
registration in REDCap. On all documents submitted to the sponsor or CI, subjects will 
pseudonomised. REDCap has built-in options for univariate alerts, such as valid-value, 
valid-range, and missing-value alerts. 
Data reported on each eCRF should be consistent with the source data. If information is 
not known, this must be clearly indicated on the eCRF. All missing and ambiguous data 
will be clarified. 
All data entries and corrections will only be performed by study site staff, authorised by 
the Investigator. Data will be reviewed by trained personnel (monitor, data manager) 
and any errors or inconsistencies will be clarified. 
 
14.1.2 Data directly collected in the eCRF (no source available) 
 
For this trial, we use ePRO’s where the participants complete surveys in the hospital on 
a tablet of the hospital and connected to a secured hospital network. The ePRO can be 
opened by using a survey link that is unique per participant and per visit. 
The participant will need to log in to the survey before he/she can complete the survey.  
 
14.2 Data storage 
 
The data is accessed through a web browser directly on the secure REDCap server. 
The server is hosted within the Ghent University Hospital campus and meets hospital 
level security and back-up requirements. 
 
Privacy and data integrity between the user’s browser and the server is provided by 
mandatory use of Transport Layer Security (TLS), and a server certificate issued by 
TERENA (Trans-European Research and Education Networking Association). All trial 
sites will have access to REDCap. Site access is controlled with IP restriction. 
 
14.3 Archiving of data 
 
The investigator and sponsor specific essential documents will be retained for at least 
25 years. At that moment, it will be judged whether it is necessary to retain them for a 
longer period, according to applicable regulatory or other requirements. 
 
Once all subjects have completed the study visits and the study was closed the study 
documents will be archived. Documents will be stored at MERAK N.V. BELGIE 
Steenhoevestraat 6 - 2800 Mechelen - tel. +32 (0)15 28 40 60 

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14.4 Access to data 
 
The investigators and institutions involved in the trial will permit clinical trial-related monitoring, 
audits and regulatory inspections (including provision of direct access to source data and 
documents). 
Login in REDCap is password controlled. Each user will receive a personal login name and 
password and will have a specific role which has predefined restrictions on what is allowed in 
REDCap. Furthermore, users will only be able to see data of subjects of their own site. Any 
activity in the software is traced and transparent via the audit trail. 
 

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15 Safety 
15.1 Definitions 
 
 
Adverse Events and Adverse Reactions 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a subject to whom a 
medicinal product is administered and which does not 
necessarily have a causal relationship with this treatment. 
Unexpected Adverse 
Event 
An adverse event of which the nature or severity is not 
consistent with the Reference Safety Information (RSI) of 
the product (i.e. the applicable information in the 
Investigator’s 
Brochure 
(IB) 
for 
an 
investigational 
medicinal product which is not authorised or in the 
Summary of Product Characteristics (SmPC) for an 
authorised investigational medicinal product). 
Adverse Reaction 
(AR) 
An untoward and unintended response in a subject to an 
investigational medicinal product which is related to any 
dose administered to that subject. The phrase “response 
to an investigational medicinal product” means that a 
causal relationship between a study 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 study medication qualify as adverse reactions. 
Serious Adverse 
Event (SAE) 
Any untoward medical occurrence that: 
• 
requires inpatient hospitalisation or prolongation of 
existing hospitalisation; 
• 
results in persistent or significant disability/incapacity; 
• 
results in a congenital anomaly or birth defect; 
• 
is life-threatening; or 
• 
results in death. 
Other important medical events may also be considered 
serious if they jeopardise the subject or require an 
intervention to prevent one of the above consequences. 
NOTE: The term “life-threatening” in the definition of 
“serious” refers to an event in which the subject was at 
risk of death at the time of the event; it does not refer to 
an event which hypothetically might have caused death if 
it were more severe. 
Suspected 
Unexpected Serious 
Adverse Reaction 
(SUSAR) 
A serious adverse reaction, the nature, severity or 
outcome of which is not consistent with the Reference 
Safety Information (RSI). 

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NB: to avoid confusion or misunderstanding of the difference between the terms 
“serious” and “severe”, the following note of clarification is provided: “Severe” is often 
used to describe intensity of a specific event, which may be of relatively minor medical 
significance. “Seriousness” is the regulatory definition supplied above. 
 
Attributions 
Term 
Definition 
Not related 
An adverse event which is not related to the use of the 
drug. 
Unlikely related 
An adverse event for which an alternative explanation is 
more likely - e.g. concomitant drug(s), concomitant 
disease(s), and/or the relationship in time suggests that a 
causal relationship is unlikely. 
Possibly related 
An adverse event which might be due to the use of the 
drug. An alternative explanation - e.g. concomitant 
drug(s) or concomitant disease(s) - is inconclusive. The 
relationship in time is reasonable; therefore the causal 
relationship cannot be excluded. 
Probably related 
An adverse event which might be due to the use of the 
drug. The relationship in time is suggestive (e.g. 
confirmed by dechallenge). An alternative explanation is 
less likely - e.g. concomitant drug(s) or concomitant 
disease(s). 
Definitely related 
An adverse event which is listed as a possible adverse 
reaction and cannot be reasonably explained by an 
alternative explanation - e.g. concomitant drug(s) or 
concomitant disease(s). The relationship in time is very 
suggestive (e.g. it is confirmed by dechallenge and 
rechallenge). 
 
An adverse event is considered associated with the use of the drug if the attribution is 
‘possibly’, ‘probably’ or ‘definitely related’. 
 
15.2 Reporting requirements 
 
List of abbreviations 
AE 
 
Adverse Event 
CA 
 
Competent Authority 
EC 
 
Ethics Committee 
RA 
 
Regulatory authorities 
SAE  
Serious Adverse Event 
SSAR  
Suspected Serious Adverse Reaction 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
 
15.2.1 
AE reporting 
 
Adverse events (AE) 
The following information will be recorded: 

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• 
nature of adverse event 
• 
date and time of occurrence and disappearance 
• 
intensity: mild, moderate or severe 
• 
frequency: once, continuous or intermittent 
• 
decision regarding study: continuation or withdrawal 
• 
relation to the study medication (see below) 
 
AE’s will be recorded from the first drug administration until the patient’s last study visit. 
Special attention will be given to those subjects who have discontinued the trial for an 
AE, or who experienced a severe or a serious AE. 
 
15.2.2 
SAE reporting 
 
 
Medical events that occur between signing of the Informed Consent and the first intake 
of trial medication will be documented on the medical and surgical history section and 
concomitant diseases page of the eCRF. 
SAE’s occurring within a period of 30 days following the last intake of trial medication 
will also be handled as such if spontaneously reported to the investigator. 
 
All serious adverse events (SAE) (initial and follow up information – except for those, 
described in 15.5 and events, described in section 15.2.4, and pregnancies occurring 
during clinical trial must be reported by the local Principal Investigator within 24 hours 
after becoming aware of the SAE to: 
- 
The national coordinating Investigator 
- 
HIRUZ of the University Hospital Ghent who report to the central EC 
- 
The designated contact person of the Marketing Authorisation Holder (MAH) or 
producer of the medicinal (investigational) product 
This reporting is done by using the appropriate SAE form. For the contact details, see 
below. 
 
It is the responsibility of the local Principal Investigator to report the local SAE’s to the 
local EC. 
 
15.2.3 
SUSAR reporting 
 
In case the Coordinating Investigator/sponsor, in consultation with HIRUZ CTU, decides 
the SAE is a SUSAR (considering the seriousness, probability of harmfulness and 
unexpectedness), HIRUZ CTU will report the SUSAR to the EMA, through the 
Eudravigilance (EV) database within the timelines as defined in European legislation. In 
case of a life-threatening SUSAR the sponsor should report at least the minimum 
information as soon as possible and in any case no later than 7 calendar days after 
being made aware of the case.  In case of a non-life-threatening SUSAR the reporting 
process must be completed within 15 calendar days. 
 
Coordinating Investigator informs local PIs of safety profile changes, not of individual 
SUSAR reports. For example, information derived from SUSAR reports could be 

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provided via investigators’ letters including both an updated benefit-risk evaluation and 
risk mitigation measures. 
 
15.2.4 
Other reporting requirements 
 
NA 
 
15.3 List of contact details for safety reporting 
The first report of a serious adverse event may be made by telephone, e-mail or 
facsimile (FAX).  
 
Contact details of HIRUZ: 
e-mail: hiruz.ctu@uzgent.be  
tel.: 09/332 05 00 
 
Contact details of the National Coordinating Investigator: 
e-mail: dirk.elewaut@ugent.be or filip.vandenbosch@ugent.be 
tel.: 09/332 2240 or 09/332 2863 
fax: 09/332 4787 
 
Contact details of the producer of blinded methotrexate: 
e-mail: erik.lagae@ardena.com 
Kleimoer 4 
9030 Mariakerke 
tel.: 09/267 65 00 
 
 
Contact details of the MAH/producer of methotrexate matching placebo: 
 
e-mail: pharmacy.clinicaltrials@UZGENT.be 
 
tel : 09/332 29 73 
 
fax: 09/332 3869 
 
Contact details of MAH/producer of open label and blinded Golimumab and matching 
placebo :  
• Up until 30-Sep-2024: Merck Global Safety should be informed by fax using the 
1301.10_IIS AE Fax Form and the Global Safety Intake Form 
 
fax:  02 332 13 79     email: dpoc_belux@merck.com 
 
 
The investigator must provide the minimal information: i.e. trial number, subject's initials 
and year of birth, medication code number, period of intake, nature of the adverse event 
and investigator's attribution. 
This report of a serious adverse event by telephone must always be confirmed by a 
written, more detailed report. For this purpose the appropriate SAE form will be used. 
Pregnancies occurring during clinical trials are considered immediately reportable 
events. They must be reported as soon as possible using the same SAE form. The 
outcome of the pregnancy must also be reported. 
 

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If the subjects are not under 24-hour supervision of the investigator or his/her 
staff (out-patients, volunteers), they (or their designee, if appropriate) must be 
provided with a "trial card" indicating the name of the investigational product, the 
trial number, the investigator's name and a 24-hour emergency contact number. 
15.4 Flowchart reporting 
 
Type of Adverse 
Event 
Action(s) be taken 
AE 
List all relevant AEs per subject in the patient’s file and 
add this information to the CRF. 
SAE 
• 
Notify to HIRUZ CTU and CI within 24 hours after 
becoming aware of the SAE; 
• 
Add the SAE to a list that will be reported yearly (see 
section 15.7); 
• 
Add the SAE in the CRF (please take into account section 
15.5). 
SUSAR 
• 
Notify to HIRUZ CTU and CI within 24 hours after 
becoming aware of the SAE; 
• 
The 
CI/sponsor 
will 
assess 
the 
causality 
and 
unexpectedness of the SAE to determine if it qualifies as a 
SUSAR. 
• 
HIRUZ CTU submits the SUSAR to the EMA (through EV 
database) after communication with the CI; 
• 
Study team of CI informs company that provides the IMP 
(as stipulated in the agreement). 
• 
Coordinating Investigator informs local PIs of safety profile 
changes. 
 
Reporting to the local ethics committee of SAEs and SUSARs remains the responsibility 
of the PI and should be done in accordance with the requirements of the local 
institution’s procedure. 
15.5 Events excluded from reporting 
NA 
15.6 Data Safety Monitoring Board (DSMB) 
 
All IMP is authorised and used in current practice. Considering the known safety profile 
of the IMP and trial design, a DSMB is not foreseen. 
 
15.7 Annual Safety Report (ASR) 
The Coordinating Investigator will provide an ASR once a year throughout the entire 
duration of the clinical study, or on request, to the EMA.. This ASR will include all SAEs 
and relevant safety information regarding all investigational medicinal products, used in 
this trial. 
 

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The report will be submitted no later than 60 calendar days after the ASR Data Lock 
Point (DLP). The first DLP is 1 year after the first date of the sponsor’s authorisation to 
conduct the clinical trial. Subsequently, the ASR will be submitted each year (+ 
maximum 60 days) until the trial is declared ended. 
The Coordinating Investigator provides the ASR to all local PIs. 
 
15.8 Follow-up after an adverse reaction 
After the initial AE/SAE report, the investigator must proactively follow each participant 
at subsequent visits/contacts. The investigator is obligated to perform or arrange for the 
conduct of supplemental measurements and/or evaluations as medically indicated or as 
requested to elucidate the nature  and/or causality of the AE or SAE as fully as possible. 
All SAEs as defined in Section 15.1, will be followed until resolution, stabilization, the 
event is otherwise explained, or the participant is lost for follow-up (defined in Section 
8.3)  
16 Monitoring, audits and inspections 
16.1 Monitoring 
 
16.1.1 
General 
 
Monitoring of the trial will be performed in compliance with GCP E6(R2) and the 
applicable regulatory requirements. The study team will be trained during an initiation 
visit by the monitor. A detailed description of the monitoring tasks can be found in the 
latest version of the (study-specific) ‘Clinical Trial Monitoring Plan’. 
 
16.1.2 
Monitoring team 
 
Monitoring services will be provided by HIRUZ CTU. All relevant contact details (e.g. 
primary contact person) can be found in the ‘Clinical Trial Monitoring Plan’. 
 
16.1.3 
Scope 
 
Monitoring services will consist of the following (non-exhaustive list): 
• 
review of informed consents and the followed process; 
• 
check on recruitment status; 
• 
checking for protocol deviations/violations; 
• 
checking GCP compatibility; 
• 
check on safety reporting compliance; 
• 
IMP handling and storage; 
• 
review of study data. 
More information can be found in the Clinical Trial Monitoring Plan. 
 

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16.2 Inspection 
 
This trial can be inspected at any time by regulatory agencies during or after completion 
of the trial. Therefore access to all study records, including source documents, must be 
accessible to the inspection representatives. Subject privacy must be respected at all 
times, in accordance to GDPR, GCP and all other applicable local regulations. 
The investigator/study team should immediately notify the sponsor if (s)he has been 
contacted by a regulatory agency concerning an upcoming inspection. 
 
16.3 Deviation policy 
 
Sponsor and all investigators agree to take any reasonable actions to correct protocol or 
other deviations/violations noted during monitoring/inspection, in consultation with the 
monitoring team. All deviations must be documented on the correct deviation log by the 
study team that is kept available at any time for monitoring/inspection purposes. Subject 
deviations must be reported in the eCRF. Site deviations and sponsor deviations must 
be reported on the paper Site Deviation Log and Sponsor Deviation Log, respectively, 
and each deviation has to be signed off. Under emergency circumstances, deviations 
from the protocol to protect the rights, safety or well-being of human subjects may take 
place without prior approval of the sponsor and the RA. 
 
16.4 Serious breach to GCP and/or the protocol 
 
A ‘serious breach’ means a breach likely to affect to a significant degree the safety and 
rights of a subject or the reliability and robustness of the data generated in the clinical 
trial.  
Any deviation of the approved protocol version or the CTR that is likely to affect subject 
safety, data integrity and/or study conduct should be clearly documented on the 
applicable deviation log and will be communicated with the Coordinating Investigator, 
HIRUZ CTU and possibly the RA. 
Please contact HIRUZ CTU immediately in case of a potential serious breach: 
hiruz.ctu@uzgent.be and/or +3293320500. 
The sponsor shall notify the RA about a serious breach of the CTR or of the version of 
the protocol applicable at the time of the breach through the EU portal without undue 
delay but not later than seven days of becoming aware of that breach. 
 
Early termination of the trial (in a specific center or overall) may be necessary in case of 
major non-compliance. 
 
The following items will be documented on the protocol deviation log: date of deviation, 
description of deviation, actions taken and classification of deviation. Deviations will be 
classified as minor or major.  A minor protocol deviation is a deviation that does not 
affect the safety, rights or well-being of subjects or the quality of their data. A major 
protocol deviation is a deviation that affects safety, rights or well-being of subjects or 
quality of their data.  
 

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Any deviation that potentially interferes with and/or affects the efficiency and/or quality 
conduct of the study will be discussed by the monitor with the PI and will be 
documented on the monitoring report including a proposed plan of action for resolution if 
applicable. 
 
16.5 Early termination 
 
Early termination or suspension of the study or an investigational site may be necessary 
in case of major non-compliance, critical safety issues or premature trial discontinuation.  
This can occur at any time by the sponsor, principal investigator of the local site, EC or 
regulatory authority.  In the event that the clinical investigation would be discontinued 
prematurely, all clinical investigation products will be retained, the terminating party 
shall justify its decision in writing and the sponsor will communicate (via Hiruz CTU) 
early termination, including the reason for early termination, to the EC and regulatory 
authority.  
 
 
17 Ethical and legal aspects 
17.1 Good Clinical Practice 
 
The trial will be conducted in accordance with the latest version of the ICH E6 (R2) GCP 
guidelines, creating a standard for the design, conduct, performance, monitoring, 
auditing, recording, analyses and reporting of clinical studies that provides assurance 
that the data and reported results are accurate and that the rights, integrity and 
confidentiality of study subjects are protected. 
 
17.2 Informed consent 
 
Eligible subjects may only be included in the trial after providing written (witnessed, if 
needed) IEC-approved informed consent, or, if incapable of doing so, after such 
consent has been provided by a legally acceptable representative(s) of the subject. 
Informed consent must be obtained before conducting any study-specific procedures 
(as described in this protocol). 
Prior to entry in the trial, the investigator must explain the trial and the implication(s) of 
participation to potential subjects and/or their legal representatives. Subjects will be 
informed that their participation is voluntary and that they may withdraw consent to 
participate at any time. Participating subjects will be told that their records may be 
accessed by competent authorities and by authorised persons without violating the 
confidentiality of the subject, to the extent permitted by the applicable law(s) and/or 
regulations. By signing the Informed Consent Form (ICF), the subjects or legally 
acceptable representatives are authorising such access. 
After this explanation and before entry to the trial, written, dated and signed informed 
consent should be obtained from the subject or legally acceptable representative. The 
ICF should be provided in a language sufficiently understood by the subject. Subjects 
must be given the opportunity to ask questions. 

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The subject or legally acceptable representative will be given sufficient time to read the 
ICF and to ask additional questions. After this explanation and before entry to the trial, 
consent should be appropriately recorded by means of either the subject’s or his/her 
legal representative’s dated signature or the signature of an independent witness who 
certifies the subject’s consent in writing. After having obtained the consent, a copy of 
the ICF must be given to the subject. 
 
In case the subject or legally acceptable representative is unable to read, an impartial 
witness must attest the informed consent. 
Subjects who are unable to comprehend the information provided can only be enrolled 
after consent of a legally acceptable representative. 
The following information should be added to the electronic patient dossier (EPD): 
• 
which version of the ICF was obtained; 
• 
who signed the ICF; 
• 
if sufficient time has been given to consider participation into the trial; 
• 
which investigator obtained ICF with the date of signature; 
• 
if a copy was provided to the subject; 
• 
start and end of participation in the trial. 
 
 
17.3 Approval of the study protocol 
 
17.3.1 
General 
 
The protocol has been reviewed and approved by the RA. This trial cannot start before 
their approval has been obtained, a site initiation visit has been performed by the 
monitor and, if applicable, all necessary agreements are finalized. 
 
17.3.2 
Protocol modifications and urgent safety measures 
 
Any substantial change or addition to the protocol can only be made in a written 
protocol modification that must be approved by the RA. 
Only modifications that are intended to eliminate an apparent immediate safety threat to 
the participants may be implemented immediately. 
Notwithstanding the need for approval of formal protocol modifications, the investigators 
are expected to take any immediate action, required for the safety of any subject 
included in this trial, even if this action represents a deviation from the protocol. These 
actions should always be notified to the sponsor without undue delay, in order for the 
sponsor to notify the RA. 
 
17.4 Confidentiality and data protection 
 
All study data will be handled in accordance with the law on General Data Protection 
Regulation (GDPR) and institutional rules (i.e. in accordance with the Belgian laws 
dated on 30-JUL-2018 and 22-AUG-2002). 

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The collection and processing of personal data from subjects enrolled in this trial will be 
limited to those data that are necessary to fulfill the objectives of the trial. These data 
must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. 
Appropriate technical and organisational measures to protect the personal data against 
unauthorised disclosures or access, accidental or unlawful destruction, or accidental 
loss or alteration must be put in place. Sponsor and site personnel whose 
responsibilities require access to personal data agree to keep the identity of subjects 
confidential. In case of data security breach, local institution’s procedures will be 
followed. 
Site personnel informs the subject about the the processing of personal data and direct 
access for the investigator/institution to his or her original medical records (source 
data/documents) for trial-related monitoring, audit, Ethics Committee review and 
regulatory inspection. The subject is also informed about the data to other entities, if 
applicable. 
 
All data will be Pseudonymised. Pseudonymisation is the responsibility of the PI. 
Pseudonymisation can be done by the PI or any other medical practitioner–investigator 
appointed by the PI and legally authorised to do so (therapeutic relationship with the 
participant). The key for encryption and decryption of pseudonymised data is kept by 
the PI and other investigators authorised by the PI. Data is processed in an electronic, 
secure database (REDCap), in accordance with the technical and organisational 
security measures of the Ghent University Hospital. 
 
Privacy and confidentiality of data generated in the future on stored samples will be 
protected by the same standards applicable to all other clinical data. 
Stored samples will be [Choose from the list] throughout the sample storage and 
analysis process and will not be labeled with personal identifiers. 
 
17.5 Liability and insurance 
 
 
This study protocol is without prejudice to national and European Union law on the civil 
and criminal liability of the Sponsor, Coordinating Investigator, Principal Investigator(s) 
and other parties concerned. 
The sponsor has entered into a no-fault insurance policy for this trial, in accordance with 
the relevant legislation (article 12 of the Belgian Law of 7 May 2017 and article 76 of the 
EU Regulation 536/2014). 
 
 
18 Publication policy 
 
The results of this study will be reported and published at conferences and in peer-
reviewed clinical journals.  The privacy of the subjects will be respected at all times.  
Authorship publications will follow the Uniform Requirement for Manuscripts Submitted 
to Biomedical Journals (International Committee of Medical Journal Editors, 2009), 
which states: 

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“Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the article 
or revising it critically for important intellectual content; (3) final approval of the version 
to be published and (4) Agreement to be accountable for all aspects of the work in 
ensuring that questions related to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved.  Authors should meet conditions 1, 2, 3 and 4.” 
 
For further details , see http://www.icmje.org/recommendations/browse/roles-and-
responsibilities/defining-the-role-of-authors-and-contributors.html. 
 
For the SPARTACUS-trial the following additional criteria will be applicable with regard 
to publications concerning the clinical outcomes of the study: 
- 
An investigator from a trial site that has included at least 1 (randomized) patient 
will be listed under the ”SPARTACUS-consortium” and in the acknowledgment 
section of the publication: their name will appear upon searching for publications 
in “Pubmed”. 
- 
An investigator from a trial site that has included at least 5 (randomized) patients 
will be mentioned as co-author on the publications. 
- 
A trial site that has included more than 10 (randomized) patients will be allowed 
to have 2 co-authors on the main publication. 
Concerning the publication of the translational / basic science results, trial sites that 
have included more than 10 (randomized) patients will have 1 co-author on these 
publications. 
 
A publication steering committee will be formed, consisting of Prof. Dr. Dirk Elewaut 
(VIB Ghent), Prof. Dr. Rik Lories (KU Leuven), Dr. Philippe Carron and Prof. Dr. Filip 
Van den Bosch (Ghent University hospital – coordinating clinical trial center). The 
steering committee will be in charge of the global publication strategy. After publication 
of the main study results, investigators from the different participating centers that have 
included at least 1 (randomized) patient will have the opportunity to submit proposals to 
the steering committee for ancillary analyses; this will be done via the standardized form 
in addendum 12.  Ancillary analysis requests will be reviewed by the steering 
committee, which may ask for additional information or suggest alternative analyses.  
For specific research questions, the steering committee may decide to ask an additional 
review by external referees (e.g. for health economic analyses, …). 
 

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Signature page 
 
SPondyloArthritis: inducing drug-free Remission by 
early TNF-Alpha bloCkade Under guidance of Single 
cell RNA sequencing and epigenetic profiling.  
 
I certify that I will conduct the trial in compliance with the protocol, any modifications, 
GCP and the declaration of Helsinki, the CTR and all other applicable regulatory 
requirements. 
 
 
Investigator: 
 
Name:  
 
 
Title:  
 
 
Signature: 
 
Date:  
________________________________________________ 
 
 
Investigator: 
 
Name:  
 
 
Title:  
 
 
Signature: 
 
 
Date:  
________________________________________________ 
 
 
Investigator: 
 
Name:  
 
 
Title:  
 
 
Signature: 
 
 
Date:  
________________________________________________ 

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19 Addenda 
Addendum 1: 
ASAS (Assessment in SpondyloArthritis international 
Society) Classification Criteria 
 
 
For SPARTACUS inclusion-purposes, classification of peripheral SpA patients will be 
done using the “left arm” of the criteria, requiring “arthritis or enthesitis or dactylitis” plus 
≥1 specific SpA feature. 
 
Patients only fulfilling the “right arm” of the criteria can be discussed with a coordinating 
investigator of UZ Ghent on an individual basis. 
 
 

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Addendum 2: 
SPARTACUS Phase A (Remission Induction) Study Design 

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Addendum 3: 
Patient Acceptable Signs & Symptoms Improvement 
(“PASSI”) Questionnaire 
 
- 
Taking into account both efficacy and side effects, did you experience over the 
past 12 weeks enough improvement in signs and symptoms of your arthritis-
enthesitis-dactylitis to consider continuation of the same treatment schedule for 
the next 12 weeks?” 
 
 
- 
“Als u rekening houdt met zowel het effect als de bijwerkingen van het 
behandelingsschema dat u de voorbije 12 weken heeft gekregen, hebt u dan 
voldoende verbetering ervaren in de symptomen van uw artritis-enthesitis-
dactylitis om de volgende 12 weken hetzelfde behandelingsschema aan te 
houden?” 
 

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Addendum 4: 
Tuberculosis Questionnaire 
 
1. Have you or an immediate family member or other close contact ever been 
diagnosed or treated for tuberculosis?   □ No    □ Yes 
2. Have you lived in or had prolonged travels to countries in the following regions: 
 □ No    □ Yes 
  
    - Africa 
    - Eastern Europe 
    - Asia 
    - Russia 
    - Latin America 
    - Caribbean Islands 
3. Have you lived or worked in a prison, refugee camp, homeless shelter, immigration 
center, or nursing home?   □ No    □ Yes 
4. Have you, or an immediate family member, had any of the following problems for 
the past 3 weeks or longer:   □ No    □ Yes 
 
    - Chronic Cough 
    - Production of Sputum 
    - Blood-Streaked Sputum 
    - Unexpected Weight Loss 
    - Fever 
    - Fatigue/Tiredness 
    - Night Sweats 
    - Shortness of Breath 
 

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Addendum 5a: 
Rheumatological Examinations 
78-Tender and 76-Swollen Joint Count 
 
Joint Count : Worksheet (Tender & Swollen Joint Count) : 1 = present,0 = absent, ND/NA 
 
Right 
Left 
Joint 
Pain/tenderness 
Swelling 
Pain/tenderness 
Swelling 
Temporomandibular 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Sternoclavicular 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Acromio-clavicular 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Shoulder 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Elbow 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Wrist 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
CMC1 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Metacarpophalangeal 1 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Metacarpophalangeal 2 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Metacarpophalangeal 3 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Metacarpophalangeal 4 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Metacarpophalangeal 5 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Thumb Interphalangeal 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Prox. Interphalangeal 2 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Prox. Interphalangeal 3 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Prox. Interphalangeal 4 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Prox. Interphalangeal 5 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Dist. Interphalangeal 2 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Dist. Interphalangeal 3 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Dist. Interphalangeal 4 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Dist. Interphalangeal 5 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Hip 
0 
1 
NA 
 
 
 
0 
1 
NA 
 
 
 
Knee 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Ankle 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Tarsus 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Metatarsophalangeal 1 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Metatarsophalangeal 2 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Metatarsophalangeal 3 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Metatarsophalangeal 4 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Metatarsophalangeal 5 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Great Toe/Hallux 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Interphalangeal 2 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Interphalangeal 3 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Interphalangeal 4 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Interphalangeal 5 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
DIP 2 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
DIP 3 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Dip 4 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
Dip 5 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
0 
1 
NA 
 
 

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Addendum 5b: 
Rheumatological Examinations 
Dactylitis Count / Score 
 
DACTYLITIS  (Code: 0 = Absent, 1 = Present) 
 
Joint 
Right 
Left 
Finger 1 = thumb 
 
 
Finger 2 
 
 
Finger 3 
 
 
Finger 4 
 
 
Finger 5 
 
 
Toe 1 = big toe 
 
 
Toe 2 
 
 
Toe 3 
 
 
Toe 4 
 
 
Toe 5 
 
 
 

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Addendum 5c: 
Rheumatological Examinations 
SPondyloArthritis Research Consortium of Canada 
(SPARCC) Enthesitis Index 
 
 
 
 
 
 
Maksymowych WP et al. Ann Rheum Dis 2009;68:948-953 
 

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Addendum 5d: 
Rheumatological Examinations 
Bath Ankylosing Spondylitis Metrology Index (BASMI) 
 
 
 
 
 
 
 
 
 

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Addendum 5e: 
Rheumatological Examinations 
Skin Assessment 
 
Investigator Global Assessment for overall psoriatic disease 
 
Score 
Description 
□  Clear 
 
- 
No signs of psoriasis  
        (post-inflammatory hyperpigmentation may be present) 
□  Almost clear 
 
- 
Normal to pink coloration of lesions 
- 
No thickening 
- 
No to minimal focal scaling 
□  Mild disease 
 
- 
pink to light red coloration 
- 
Just detectable to mild thickening 
- 
Predominantly fine scaling 
□  Moderate disease 
 
- 
Dull bright red, clearly distinguishable erythema 
- 
Clearly distinguishable to moderate thickening 
- 
Moderate scaling 
□  Severe disease 
 
- 
Bright to deep dark red coloration 
- 
Severe thickening with hard edges 
- 
Severe / coarse scaling covering almost all or all lesions 
 
 
  
 

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Addendum 6a: 
Protocol:  Synovial biopsies 
 
 
Preparation phase:  
Depending on the joint to be examined and biopsied, the patient is positioned lying 
down or sitting. The highest comfort of the patient is pursued. The procedure is 
carried out under strict aseptic conditions (i.e., sterile) and the necessary 
precautions are taken for this (use of sterile drapes around the relevant joint, 
thorough disinfection, face mask, gloves, sterile covering of the ultrasound probe). 
A comprehensive ultrasound examination of the relevant joint is first conducted to 
identify the correct structures and locate the best site for tissue sampling. 
 
Actual procedure:  
The trajectory that the biopsy needle will follow from the external skin surface to 
the tissue to be biopsied will be anesthetized using an injection of lidocaine. This 
should take effect for 3 to 5 minutes before the actual tissue collection will occur. 
In the meantime, the researcher and the assisting personnel will prepare the 
biopsy material. The ultrasound probe is sterilely packaged and placed on the joint 
where the biopsy will take place. The researcher can form a clear image on the 
screen of where the biopsy will take place. The tip of the needle will first be 
inserted subcutaneously and this can be visualized by the researcher. This needle 
is then advanced along the trajectory until it reaches the tissue that one wants to 
biopsy. When the researcher is certain of the correct location in the joint, several 
biopsies (10-12) of the tissue will be taken while the needle remains in place. After 
sufficient tissue samples have been taken, excess fluid will be aspirated. 
 
Aftercare:  
The injection site is to be disinfected again and covered with a plaster or bandage. 
The patient must remain in the department for observation for up to 30 minutes 
after the biopsy. No specific monitoring is required. The patient is advised to 
contact the responsible or treating physician in case of pain, swelling, or redness 
of the biopsied joint within 5-7 days after the procedure. If desired, pain relievers 
(paracetamol, anti-inflammatories) can be taken, but this is not mandatory. Local 
ice application may also be done if the patient finds it necessary. 

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Addendum 6b: 
 
Joints accessible for synovial tissue sampling 
(Provided there has not been a steroid injection the last 6 weeks) 
 
 
• Wrist 
• Elbow 
• Metacarpophalangeal joints (MCP) 
• Proximal Interphalangeal joints (PIP) 
• Knee 
• Ankle 
• Metatarsophalangeal joints (MTP) 
 
 

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Addendum 7a – 7k: 
Patient-Reported Outcomes 
 
a) BASDAI 
b) BASFI 
c) PATIENT GLOBAL DISEASE-ACTIVITY 
d) PATIENT GLOBAL PAIN 
e) HAQ (Health Assessment Questionnaire) 
HAQ Spondyloarthropathie 
f) ASAS- Health Index 
g) EQ-5D 
h) Co-morbidity index 
i) CARE CONSUMPTION AND PRODUCTIVITY QUESTIONNAIRE (baseline) 
j) CARE CONSUMPTION AND PRODUCTIVITY QUESTIONNAIRE (Follow-up) 
k) EDUCATION AND WORKING STATUS  (Baseline) 
EDUCATION AND WORKING STATUS  (Follow-up) 
 
Questionnaires can be obtained upon request. 
 

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Addendum 8a: 
Medication Schedules: Methotrexate/Placebo 
 
Standard step-up schedule in case of good tolerance to Methotrexate/Placebo 
 
Week 
Dose 
Baseline 
15mg 
Week 4 
20mg 
Week 8 
20mg 
Week 12 until sustained remission 
20mg 
Sustained remission 
STOP 
 
Standard step-down schedule in case of immediate intolerance and / or toxicity to 
Methotrexate/Placebo  
 
Week 
Down titration  
Baseline 
15mg 
Week 4 
10mg 
Week 8 
7.5 mg 
Week 12 
STOP 
 
In case of intolerance and / or toxicity occurring at a certain dose of methotrexate / 
placebo at any time point during Phase A, the previous tolerated dose will be used. 
 

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Addendum 8b: 
Medication Schedules: NSAIDs 
 
 
 
 

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Questionnaire can be obtained upon request.
 
Addendum 9 
 
Post Biopsy Questionnaire 
 
 

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Addendum 10  
CIOMS FORM  
I. REACTION INFORMATION  
II. SUSPECT DRUG(S) INFORMATION  
III. CONCOMITANT DRUG(S) AND HISTORY  
IV. MANUFACTURER INFORMATION  
 
 
Applicable up until 30 September 2024. 
 
 
 
GCD-SOP-601.4 
Intake Form Instructio 

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Addendum 11 
 
Applicable up until 30 September 2024. 
 
 
 

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Addendum 12 
 
SPARTACUS Ancillary Research Project Proposal 
 
 
Title of the project: 
 
 
 
Date of submission: 
 
Investigator: 
Name: ……………………………………………………… First name: ……………………… 
e-mail address: ………………………………………………………………………………….. 
 
Rationale of this research proposal: 
 
 
 
 
 
Objectives: 
 
 
 
 
 
Statistical analysis plan: 
 
 
 
 
 
Time frame for this analysis :