A Multi-center, Open, Randomized, 18-month, Parallel-group, Superiority Study to Compare the Effect of Proactive Therapeutic Drug Monitoring Versus Standard of Care With Regards to Maintenance of Sustained Disease Control Without Flare in Adults With Rheumatoid Arthritis Treated With a Subcutaneous Tumor Necrosis Factor Inhibitor
Phase: PHASE4
Conditions: Rheumatoid Arthritis
Sponsor: Diakonhjemmet Hospital

 
Protocol ver. 1.0 19.04.2024  
 
 
 
 
 
 
 
 
 
Protocol Title:  
A multi-center, open, randomized, 18-month, parallel-group, superiority study to 
compare the effect of proactive therapeutic drug monitoring versus standard of 
care with regards to maintenance of sustained disease control without flare in 
adults with rheumatoid arthritis treated with a subcutaneous tumor necrosis factor 
inhibitor 
 
Protocol Version No. 1.0 
Amendment No.  
Date 19.04.2024 
Brief Title: 
Effect of proactive therapeutic drug monitoring on maintenance of sustained disease control 
in adults with rheumatoid arthritis on a subcutaneous TNF inhibitor: 
The Rheumatoid Arthritis therapeutic DRUg Monitoring trial (RA-DRUM)  
Study Phase: 4 
Acronym: RA-DRUM 
Sponsor name: Diakonhjemmet Hospital AS 
Contact person: Professor Espen A. Haavardsholm, MD PhD 
Legal Registered Address: 
Box 23 Vinderen, 0319 Oslo, Norway 
Telephone: 22 45 15 00 
E-mail: espen.haavardsholm@diakonsyk.no 
Regulatory Agency Identifier Number(s): 
EU CT No:  2023-510184-35-00 
Approval Date: NA 
 
 

 
Protocol ver. 1.0 19.04.2024  
 
 
 
 
 
 
 
 
I am responsible for ensuring that this protocol includes all essential information to be able to 
conduct this trial. I will submit the protocol and all other important trial-related information to 
the responsible investigator(s) so that they can conduct the trial correctly. I am aware that it is 
my responsibility to hold the staff members who work with this trial informed and trained. 
 
Sponsor Signatory: 
 
 
Professor Espen A. Haavardsholm, MD PhD 
Head of Research and Innovation, Division of 
Rheumatology and Research, Diakonhjemmet 
Hospital, Oslo, Norway 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Protocol ver. 1.0 19.04.2024  
 
 
 
 
 
 
 
Table of Contents  
 
Table of Contents ................................................................................. 3 
List of Abbreviations ............................................................................ 6 
1. 
Protocol Summary ................................................................ 7 
1.1. 
Synopsis .................................................................................. 7 
1.2. 
Schema .................................................................................... 9 
1.3. 
Schedule of Activities (SoA) ................................................ 10 
2. 
Introduction ......................................................................... 13 
2.1. 
Study Rationale ..................................................................... 13 
2.2. 
Background ........................................................................... 13 
2.2.1. 
Treatment of RA .................................................................... 13 
2.2.2. 
Serum Dug Levels and ADAb .............................................. 14 
2.2.3. 
Therapeutic Drug Monitoring ............................................... 14 
2.3. 
Benefit/Risk Assessment ....................................................... 15 
2.3.1. 
Risk Assessment .................................................................... 15 
2.3.2. 
Benefit Assessment ............................................................... 16 
2.3.3. 
Overall Benefit Risk Conclusion ........................................... 16 
3. 
Objectives and Endpoints ................................................... 17 
4. 
Study Design ........................................................................ 21 
4.1. 
Overall Design ...................................................................... 21 
4.2. 
Scientific Rationale for Study Design ................................... 22 
4.2.1. 
Patient Input into Design ....................................................... 22 
4.3. 
Justification for the Choice of Study Drug and the TDM 
Strategy ................................................................................. 22 
4.4. 
End-of-Study Definition ........................................................ 23 
5. 
Study Population ................................................................. 24 
5.1. 
Inclusion Criteria ................................................................... 24 
5.2. 
Exclusion Criteria .................................................................. 24 
5.3. 
Lifestyle Considerations ........................................................ 24 
5.4. 
Screen Failures ...................................................................... 24 
5.5. 
Criteria for Temporarily Delaying ........................................ 25 
6. 
Study Intervention and Concomitant Therapy ................ 26 
6.1. 
Study Intervention Administered .......................................... 26 
6.1.1. 
The TDM Group .................................................................... 26 
6.1.2. 
The Standard of Care Group ................................................. 27 
6.1.3. 
Both Groups .......................................................................... 27 
6.2. 
Preparation, Handling, Storage, and Accountability ............. 28 
6.3. 
Assignment to Study Intervention ......................................... 28 
6.4. 
Masking ................................................................................. 28 
6.5. 
Study Intervention Compliance............................................. 28 
6.6. 
Other Dose and Schedule Modification ................................ 29 
6.7. 
Continued Access to Study Intervention after the End of the 
Study ..................................................................................... 29 
6.8. 
Treatment of Overdose .......................................................... 29 
6.9. 
Prior and Concomitant Therapy ............................................ 29 

 
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6.9.1. 
Prior Therapy ......................................................................... 29 
6.9.2. 
Concomitant Medication ....................................................... 29 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal .............................................. 31 
7.1. 
Discontinuation of Study Intervention .................................. 31 
7.2. 
Participant Discontinuation/Withdrawal from the Study ...... 31 
7.3. 
Lost to Follow-up .................................................................. 31 
8. 
Study Assessments and Procedures ................................... 33 
8.1. 
Administrative General, Biobank and Baseline Procedures . 33 
8.1.1. 
Baseline Procedures .............................................................. 33 
8.1.2. 
Biobank Samples ................................................................... 34 
8.2. 
Efficacy Assessments ............................................................ 34 
8.2.1. 
Assessment of Disease Activity ............................................ 34 
8.2.2. 
Definition of Flare ................................................................. 36 
8.3. 
Safety Assessment ................................................................. 36 
8.3.1. 
Routine Laboratory Tests ...................................................... 37 
8.4. 
Adverse Events (AEs) Serious Adverse Events (SAEs), and 
Other Safety Reporting ......................................................... 37 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ............................................................................ 38 
8.4.2. 
Method of Detecting AEs and SAEs ..................................... 38 
8.4.3. 
Follow-up of AEs and SAEs ................................................. 38 
8.4.4. 
Regulatory Reporting Requirements for SAEs ..................... 38 
8.4.5. 
Pregnancy .............................................................................. 39 
8.5. 
ADAb and Serum Drug Level Assessments ......................... 39 
8.6. 
Genetics ................................................................................. 39 
8.7. 
Biomarkers ............................................................................ 40 
8.8. 
Health Economics ................................................................. 40 
9. 
Statistical Considerations ................................................... 41 
9.1. 
Statistical Hypotheses ........................................................... 41 
9.1.1. 
Multiplicity Adjustment ........................................................ 41 
9.2. 
Analysis Sets ......................................................................... 41 
9.3. 
Statistical Analyses ............................................................... 42 
9.3.1. 
General Considerations ......................................................... 42 
9.3.2. 
Primary Endpoint Analysis ................................................... 42 
9.3.3. 
Secondary Endpoint Analyses ............................................... 43 
9.4. 
Interim Analysis .................................................................... 43 
9.5. 
Sample Size Determination ................................................... 43 
10. 
Supporting Documentation and Operational 
Considerations ..................................................................... 45 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ....................................................................... 45 
10.1.1. Regulatory and Ethical Considerations ................................. 45 
10.1.2. Financial Disclosure .............................................................. 45 
10.1.3. Informed Consent Process ..................................................... 46 
10.1.4. Recruitment strategy ............................................................. 46 
10.1.5. Data Protection ...................................................................... 46 
10.1.6. Committees Structure ............................................................ 47 

 
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10.1.7. Dissemination of Clinical Study Data ................................... 47 
10.1.8. Data Quality Assurance ......................................................... 47 
10.1.9. Source Documents ................................................................. 48 
10.1.10. Study and Site Start and Closure ........................................... 48 
10.1.11. Publication Policy ................................................................. 49 
10.1.12. Funding .................................................................................. 49 
10.2. 
Appendix 2: Clinical Laboratory Tests ................................. 50 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ............... 51 
10.3.1. Definition of AE .................................................................... 51 
10.3.2. Definition of SAE .................................................................. 52 
10.3.3. Definition of suspected unexpected serious adverse reaction 
(SUSAR) ............................................................................... 53 
10.3.4. Recording and Follow-Up of AE and/or SAE ...................... 53 
10.3.5. Reporting of SAEs ................................................................ 54 
10.3.6. Reporting of SUSAR ............................................................. 55 
10.3.7. Annual safety reporting ......................................................... 55 
10.4. 
Appendix 4: Genetics ............................................................ 56 
10.5. 
Appendix 5: Patient Global Assessment of Disease Activity 
(PGA) .................................................................................... 57 
10.6. 
Appendix 6: Evaluator Global Assessment of Disease 
Activity (EGA) ...................................................................... 58 
10.7. 
Appendix 7: Disease Activity Score using 28 joints – C-
reactive protein (DAS28-CRP) ............................................. 59 
10.8. 
Appendix 8: 44 joint count .................................................... 60 
10.9. 
Appendix 9: Simple Disease Activity Index (SDAI) ............ 61 
10.10. 
Appendix 10: Clinical Disease Activity Index (CDAI) ........ 62 
10.11. 
Appendix 11: Rheumatoid Arthritis Flare Questionnaire (RA-
FQ) ........................................................................................ 63 
10.12. 
Appendix 12: Rheumatoid Arthritis Impact of Disease 
(RAID) .................................................................................. 64 
10.13. 
Appendix 13: Modified Heath Assessment Questionnaire 
(MHAQ) ................................................................................ 65 
10.14. 
Appendix 14: The 36-Item Short-form Health Survey (SF-36)
 ............................................................................................... 66 
10.15. 
Appendix 15: European Quality of Life 5 Dimensions (EQ-
5D)......................................................................................... 67 
10.16. 
Appendix 16: Work Productivity and Activity Impairment 
Questionnaire: Rheumatoid Arthritis (WPAI:RA)................ 68 
10.17. 
Appendix 17: Compliance Assessment ................................. 69 
10.18. 
Appendix 18: Contact Details ............................................... 70 
11. 
References ............................................................................ 72 
 
 
 

 
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List of Abbreviations  
ADAb 
Anti-drug antibodies 
AE 
Adverse Event  
ALT 
Alanine aminotransferase 
bDMARD 
Biological Disease-Modifying Anti-Rheumatic Drug 
CDAI 
Clinical Disease Activity Index 
CIOMS 
Council for International Organizations of Medical Sciences 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
DAS28-CRP 
Disease Activity Score using 28 joints C-reactive protein 
DMARD 
Disease-Modifying Anti-Rheumatic Drug 
eCRF 
electronic Case Report Form 
EGA 
Evaluators Global Assessment of Disease Activity 
ESR 
Erythrocyte Sedimentation Rate  
EULAR 
European Alliance of Associations for Rheumatology 
GCP 
Good Clinical Practice 
EQ-5D 
European Quality of Life 5 Dimensions 
HRQOL 
Health Related Quality Of Life 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
MHAQ 
Modified Health Assessment Questionnaire  
NRS 
Numeric Rating Scale 
NSAID 
Non-steroidal anti-inflammatory drug 
NYHA 
New York Hart Association 
PGA 
Patient Global Assessment of Disease Activity 
PROMs 
Patient reported outcome Measures 
RA 
Rheumatoid arthritis  
RA-FQ 
Rheumatoid Arthritis Flare Questionnaire 
RAID 
Rheumatoid Arthritis Impact of Disease 
SAE 
Serious Adverse Event   
SAP 
Statistical analysis plan 
SoA 
Schedule of Activities 
SDAI 
Simple Disease Activity Index 
csDMARD 
Conventional Synthetic Disease-Modifying Anti-Rheumatic Drug 
SF-36 
36-Item Short-form Health Survey 
SmPC 
Summary of Product Characteristics 
SC 
Subcutaneous 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TDM 
Therapeutic drug monitoring 
TNFi 
Tumor necrosis factor inhibitor  
tsDMARD 
Targeted synthetic Disease-Modifying Anti-Rheumatic Drug 
VAS 
Visual Analogue Scale 
WPAI:RA 
Work Productivity and Activity Impairment Questionnaire: 
Rheumatoid Arthritis 
 
 

 
Protocol ver. 1.0 19.04.2024  
 
 
 
 
 
 
 
1. 
Protocol Summary 
1.1. 
Synopsis 
 
The Rheumatoid Arthritis therapeutic DRUg Monitoring trial  
RA-DRUM 
 
Protocol Title  
 
A multi-center, open, randomized, 18-month, parallel-group, superiority study to 
compare the effect of proactive therapeutic drug monitoring versus standard of 
care with regards to maintenance of sustained disease control without flares in 
adults with rheumatoid arthritis treated with a subcutaneous tumor necrosis factor 
inhibitor 
Brief Title 
 
Effect of proactive therapeutic drug monitoring on maintenance of sustained disease 
control in adults with rheumatoid arthritis on a subcutaneous TNF inhibitor: 
The Rheumatoid Arthritis therapeutic DRUg Monitoring trial (RA-DRUM)  
Rationale  
There is a considerable variation in serum drug levels among rheumatoid arthritis (RA) 
patients on tumor necrosis factor inhibitors (TNFi), and a high number develop 
neutralizing anti-drug antibodies (ADAb). Sub-therapeutic drug levels and ADAb 
formation are major contributors to TNFi treatment failure and disease flare. Proactive 
therapeutic drug monitoring (TDM), i.e., individualized drug dosing based on regular 
assessments of serum drug levels and ADAb, has the potential to optimize the efficacy 
and safety of TNFi treatment. The Norwegian Drug Monitoring (NOR-DRUM) B 
study (JAMA 2021) showed that proactive TDM reduced the occurrence of flares in 
patients with immune-mediated inflammatory disease using infliximab, an 
intravenously administrated TNFi. Different administration routes and molecular 
structures limit the opportunity to extrapolate results from TDM of infliximab therapy 
to treatment with subcutaneous (SC) TNFi, and there is a need for trials investigating 
the efficacy of proactive TDM for SC TNFi.  
Objectives 
Primary objective: 
To assess whether TDM is superior to standard of care in order to maintain sustained 
disease control without flares in patients with RA treated with SC TNFi. 
 
Secondary objectives: 
• To compare effectiveness of proactive TDM to standard of care applying 
different outcome measures 
• To assess safety of proactive TDM 
• To assess whether proactive TDM influences drug survival, drug consumption, 
occurrence of ADAb and serum drug levels 
Endpoints 
Primary endpoint: 
Sustained disease control over the follow-up period of 18 months without flare, with 
flare defined as either of the following: 
• A combination of an increase in Disease Activity Score using 28 joints C-
reactive protein (DAS28-CRP) > 1.2, or > 0.6 if DAS28-CRP ≥ 3.2, AND  2 
swollen joints on examination of 44 joints 
 

 
Protocol ver. 1.0 19.04.2024  
 
 
 
 
 
 
 
• Consensus between patient and physician that a disease flare has occurred, 
leading to a major change in treatment 
If more than one TNFi type are included, subgroup analyses according to each TNFi 
type used will be performed.  
Secondary endpoints: 
• Disease activity at 4, 8, 12, and 18 months assessed by DAS28-CRP, Evaluators 
Global Assessment of Disease Activity (EGA), Clinical Disease Activity Index 
(CDAI), Simple Disease Activity Index (SDAI), American College of 
Rheumatology (ACR)/European Alliance of Associations for Rheumatology 
(EULAR) remission criteria, Rheumatoid Arthritis Impact of Disease (RAID), 
Modified Health Assessment Questionnaire (MHAQ), biochemical parameters 
• Time to disease flare  
• Number and type of adverse events (AEs) 
• Drug survival, drug consumption, occurrence of ADAb, serum drug levels 
Overall Design 
A multicenter, randomized, two-arm, parallel-group, open, superiority trial where adult 
participants with RA in DAS28-CRP remission or low disease activity (DAS28-CRP < 
3.2) on therapy with standard dose of a SC TNFi (adalimumab) for 3-24 months with 
indication for continuation of treatment according to the treating physician are stratified 
by country and allocated 1:1 to:  
• Administration of TNFi based on proactive TDM (TDM group) 
• Administration of TNFi based on standard of care without knowledge of serum 
drug levels or ADAb status (Standard of care group) 
The protocol has been developed with the aim of including RA patients on therapy with 
adalimumab. If sufficient evidence emerges regarding therapeutic ranges of other SC 
TNFi during the study period, it will be considered to amend the protocol to include 
RA patients on other SC TNFi. 
Visit Frequency 
Onsite visits will be conducted at 0, 4, 8, 12, and 18 months following randomization, 
with additional digital visits and blood sampling at 2, 6, 10, 14, and 16 months.    
Study Duration 
18 months 
Number of 
Participants 
A minimum of 350 patients will be enrolled. 

 
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1.2. 
Schema 
 
Created with BioRender 
DAS28-CRP = Disease Activity using 28 joints C-reactive protein; RA = rheumatoid arthritis; SC = subcutaneous; TNFi = Tumor Necrosis Factor Inhibitors 
 
 

 
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1.3. 
Schedule of Activities (SoA) 

 
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Procedure 
 
 
 
 
 
Screening 
Intervention Period (visit month/visit no)  
Targeted visit window: ±14days  
 
 
 
 
 
E/D 
 
 
 
Extra 
Visit 
 
 
 
 
Notes 
Baseline* 
 
Visit 1  
2 
 
Visit 2 
4* 
 
Visit 3 
6 
 
Visit 4 
8* 
 
Visit 5 
10 
 
Visit 6 
12* 
 
Visit 7 
14 
 
Visit 8 
16 
 
Visit 9 
18* 
 
Visit 10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
See Sections 5.1 and 5.2 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
See Sections 6.3 and 9.3.1 
Demography 
 
X 
 
 
 
 
 
 
 
 
 
 
 
See Section 8.1.1 
Height and weight 
 
X 
 
 
 
 
 
 
 
 
 
 
 
See Section 8.1.1 
Medical history including tobacco 
use 
 
X 
 
 
 
 
 
 
 
 
 
 
 
See Section 8.1.1 
Current medical conditions   
 
X 
 
 
 
 
 
 
 
 
 
 
 
See Section 8.1.1 
Routine laboratory tests 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
Hemoglobin, platelet count, white 
blood cells with differentials, ALT, 
creatinine, CRP, ESR.  
See Section 8.3.1 
Biobank full blood 
 
X 
 
 
 
 
 
 
 
 
 
 
 
All sites 
See Section 8.1.2 
Biobank** 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
Full blood, plasma and serum 
See Section 8.1.2 
Assessment of disease activity 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
DAS28-CRP, EGA, 44 joint count, 
CDAI, SDAI  
See Section 8.2.1 
Assessment of drug levels and 
ADAb*** 
 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Section 8.5 

 
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 RA-FQ, EQ-5D, WPAI:RA 
 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Sections 8.2.1 and 8.8 
SF-36, MHAQ, RAID 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
See Sections 8.2.1 and 8.8 
Record of concomitant medication 
for RA 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
See Section 6.9.2 
AE registration 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
See Section 10.3 
Adherence 
 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
By questionnaires and digital 
calendar 
See Section 6.5 
 
*Onsite hospital visits 
** Participants at Diakonhjemmet Hospital only 
***In all participants 
AE = Adverse Events; ALT=Alanine Transaminase; E/D = Early Discontinuation; EGA = Evaluators Global assessment of disease activity; ESR= Erythrocyte sedimentation rate; EQ-5D = 
European Quality of Life 5 Dimensions; Ex visits = Extra visit if flare; CDAI = Clinical disease activity index; CRP= C-reactive protein; DAS28-CRP = Disease Activity Score using 28 joints 
C-reactive protein; MHAQ = Modified Health Assessment Questionnaire; PGA = Patient Global assessment of disease activity; RAID = Rheumatoid Arthritis Impact of Disease; RA-FQ = 
Rheumatoid Arthritis Flare Questionnaire; SDAI = Simple disease activity index; SF-36= 36-Item Short-form health survey; WPAI:RA = Work Productivity and Activity Impairment 
Questionnaire: Rheumatoid Arthritis 

 
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2. 
Introduction 
This protocol outlines the RA-DRUM (Rheumatoid Arthritis therapeutic DRUg Monitoring) 
trial, a randomized controlled trial that aims to optimize therapy for patients with RA using 
SC TNFi. RA imposes a significant burden on patients, healthcare systems, and society (1). 
The proposed study will assess if individualizing treatment by TDM can improve the 
effectiveness of SC TNFi in maintaining disease control for patients with RA.  
2.1. 
Study Rationale 
TNFi are used worldwide, with adalimumab as one of the most used medical compounds 
overall in 2022 (2). TNFi, including adalimumab, have revolutionized the treatment of 
prevalent chronic immune-mediated inflammatory diseases, including RA (2-4). However, a 
significant proportion of RA patients either do not respond adequately to initiated therapy or 
lose treatment effect over time (5, 6). Disease flares can negatively impact quality of life and 
can lead to irreversible joint damage, prevention of flares is thus important in management of 
RA (1). Observational data have shown extensive individual variation in serum drug levels 
among patients on standard doses of adalimumab and other SC TNFi, suggesting both under- 
and overtreatment of a substantial proportion of patients (7-9). Additionally, TNFi and other 
therapeutic antibodies can elicit an immune response in the patient. Many patients develop 
anti-drug antibodies (ADAb) during therapy, contributing to reduced drug levels and 
increasing the risk of drug reactions (10). By individualizing therapy, i.e., reducing under-and 
over treatment and in guiding treatment decisions, TDM is a tool that can be used to optimize 
the effectiveness of TNFi treatment, making it a topic of great interest to clinicians nationally 
and internationally (11). 
The RA-DRUM study is the first trial to evaluate the effect of TDM in patients with RA 
treated with SC TNFi. It will provide important insights, aiming to contribute to the 
realization of a personalized medicine approach for TNFi therapy. The results of this study 
could also impact healthcare economics, as the high costs of TNFi restrict their use (12). 
Moreover, RA-DRUM presents unique opportunities for translational research on the poorly 
understood area of genetic and immunological mechanisms underlying drug immunogenicity 
(10). Further identification of predisposing genetic markers that could serve as predictors of 
loss of response is highly relevant to individualize treatment with biological drugs (13). 
While a personalized medicine approach to SC TNFi by TDM seems reasonable, the 
effectiveness of such a treatment strategy in the management of RA with regard to sustained 
disease control remains to be shown in a randomized controlled trial like the RA-DRUM trial. 
2.2. 
Background 
2.2.1. Treatment of RA  
RA is characterized by symmetric inflammation of the peripheral joints (14). The high burden 
of disease in RA is related both to symptoms of active inflammation and to the subsequent 
development of irreversible  joint damage (15). The overarching treatment goal is early and 
aggressive suppression of inflammation, and maintenance of remission or low disease activity 
to prevent structural damage and disability (16). TNFi are widely used antibody-based drugs 

 
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targeting TNF and are usually added if the treatment target is not achieved with a csDMARD, 
such as methotrexate (16). The introduction of TNFi around year 2000 played a significant 
role in making remission an achievable treatment goal in RA (3). However, more than half of 
patients lose efficacy over time (17, 18). A failure to maintain disease control has a major 
negative impact on patients’ quality of life and puts the individual at risk of developing 
serious organ damage and disability (19, 20). Loss of treatment effect can be due to 
underexposure to the drug (21).  
2.2.2. Serum Dug Levels and ADAb 
Therapy with SC TNFi and other biological drugs are not currently personalized, but 
prescribed in a uniform manner to all patients. Observational studies have shown associations 
between serum drug levels and effectiveness and also revealed considerable inter-individual 
variation in serum drug levels for TNFi, indicating both under- and overexposure (7-9, 22, 
23). Therapeutic ranges, i.e., serum levels expected to achieve the desired therapeutic effects, 
have been identified for adalimumab and other TNFi (7, 22-24). A considerable proportion of 
patients on standard dose have serum levels above or below the therapeutic range, indicating a 
potential for dose-optimization. One major reason for the large variation in serum drug levels 
is the development of ADAb which are formed as part of immune responses to TNFi and 
other biological drugs, which are large, complex and allogenic proteins (10). ADAb 
influences the pharmacokinetics of the drug either by direct binding to the target binding site 
of the therapeutic antibody (neutralizing ADAb) or by forming immune complexes with the 
drug resulting in altered clearance (non-neutralizing ADAb). ADAb production has proved to 
be a significant clinical problem. Low levels of ADAb might be transient, but high levels of 
ADAb reduce the effect of the drug and decrease serum drug levels (25, 26). Drug holidays or 
low-dose regimens have been shown to predispose to ADAb formation (27). Patients with RA 
may be more prone to ADAb formation than patients with other immune-mediated 
inflammatory diseases (27). Immunosuppressive co-medication, in particular methotrexate, is 
protective with a reduction of ADAb formation by up to 40% (25, 26, 28, 29). Whereas the 
precise immunological mechanisms leading to ADAb formation remains unknown, 
knowledge regarding predisposing genetic factors including HLA are increasing (13, 21, 30).   
2.2.3. Therapeutic Drug Monitoring 
Proactive TDM, a personalized treatment strategy based on regular assessments of serum drug 
levels and ADAb and adjustments in drug dose to keep serum drug levels within the defined 
therapeutic range, has been proposed as a clinical tool to optimize efficacy, patient safety and 
cost-effectiveness of TNFi treatment (11). A treatment strategy based on proactive TDM may 
improve TNFi therapy by: 
i) 
Minimizing drug underexposure, which might lead to loss of response 
ii) 
Reducing drug overexposure, which predispose patients to side effects and 
increases costs 
iii) 
Allowing for timely identification of ADAb development, with the possibility to 
prevent treatment failures prior to a clinical flare 
Methods for assessment of serum drug levels and ADAb are available for use in clinical 
practice (21). Guidelines and recommendations for implementation of TDM in standard care 
of patients on treatment with biological drugs are needed as the use of therapeutic monoclonal 

 
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antibodies are rapidly increasing (16, 31). However, due to limited high-grade evidence with 
regard to clinical utility and cost-effectiveness of TDM, treatment recommendations are 
inconclusive, and TDM has yet to gain widespread use within rheumatology. The need for 
prospective studies comparing TDM with usual care, is also highlighted in the research 
agenda of the recent EULAR points to consider for TDM in rheumatology (31).  
The NORwegian DRUg Monitoring (NOR-DRUM) trials, two randomized controlled trials 
across a range of IMIDs, demonstrated that TDM improved efficacy during maintenance-, but 
not during induction therapy with one TNFi, infliximab (32, 33). In these trials, proactive 
TDM resulted in a nearly 20% reduction in flare without increased infliximab consumption 
compared to usual care during maintenance therapy. Showing proof of principle of 
effectiveness of a TDM-based treatment strategy for infliximab, easily assessed due to its 
intravenous administration, was very important. Having established the benefit of TDM in 
principle, we now aim to determine if proactive TDM also is a viable, practical tool across the 
other TNFis, which are administered SC. 
Proving a benefit of TDM for SC TNFi will be a strong point in favor of TDM 
implementation into treatment guidelines, and can be expected to have a particularly strong 
impact on the medical community treating RA patients.  
As adalimumab is currently by far the most used SC TNFi and since knowledge of the 
therapeutic ranges is at this time most robust for adalimumab, this protocol has been 
developed with the aim of including RA patients on therapy with adalimumab. Should 
evidence regarding therapeutic ranges emerge and the clinical use of other SC TNFi increase 
during the study period, RA patients on other SC TNFi will be considered for inclusion 
following a protocol amendment.   
 
2.3. 
Benefit/Risk Assessment 
Participants are already on prescribed therapy with the investigational medicinal product 
(IMP) adalimumab, and the drug is continued in both groups. More detailed information about 
the known and expected benefits and risks and reasonably expected AEs of adalimumab can 
be found in the Summary of Product Characteristics (SmPC). 
2.3.1. Risk Assessment 
Investigational intervention: Patients are already on therapy with the IMP, no patients will 
start with a new drug as a consequence of study inclusion. During the conduct of the trial, 
some patients might change therapy due to findings of ADAb, but this we expect to be 
beneficial to the patient in that they may avoid a possible clinical flare (34). The IMP is used 
for an approved indication. The investigational intervention is not expected to increase the 
risk of AEs from the medication during the study. This includes participants with a dose 
decrease or increase due to the TDM strategy as treatment effectiveness and AEs are expected 
to be related to drug levels, i.e., the amount of pharmacologically active drug in the 
circulation, and not the dose. 
Study design: Participants in both groups will use slightly more time at each clinical visit 
compared to usual clinical care due to clinical evaluation by the blinded joint assessor. They 

 
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will have to fill inn PROs every second month. Except for blood sampling, which is also 
performed regularly in usual clinical care, there are no invasive procedures in this study.  
Mitigation Strategy 
Study personnel will receive adequate training. User representatives have participated in the 
protocol development and will be involved in the preparations for the practical conduct of the 
study, to ensure the participants' interests and preferences are adequately considered. 
Participants will receive close follow-up from a physician and study nurse in the study and 
will be given the opportunity for a rapid extra assessment if a suspected disease flare occurs. 
If the participant does not respond to the treatment, the investigator can switch treatment 
regardless of study arm and without consequence for further study participation. Patients can 
withdraw from the study at any time. 
2.3.2. Benefit Assessment 
For the individual participant 
Each participant will receive close follow-up. The follow-up will ensure careful and 
standardized assessment of treatment effects and AEs. In case of suspected disease flare, 
regardless of treatment group, the participant will be offered an extra assessment and 
necessary adjustment of treatment within a short time. The participant will contribute to 
knowledge within a clinically important field with current knowledge gaps.  
For the group of participants 
The results of RA-DRUM are expected to have significant implications for the use of 
adalimumab and other SC TNFi. Inadequate treatment effect and loss of effect over time is a 
major problem in the treatment of patients with a range of chronic immune-mediated 
inflammatory diseases such as RA. If RA-DRUM shows that individualized therapy based on 
TDM can improve treatment and/or result in fewer side effects, this study could contribute to 
more optimal drug treatment. This will have significant implications for patients with a range 
of immune-mediated inflammatory diseases. 
For society 
The economic burden of biological treatment is formidable. If it is possible to improve cost-
effectiveness, these expensive drugs could become available to more patients. If the drugs are 
used more effectively, the climate footprint may also be reduced. 
For science 
The genetic and immunological mechanisms underlying the development of ADAb are not 
known but are believed to be linked to certain hereditary factors (HLA). This large, well-
characterized cohort of patients will be able to contribute to translational research and 
generate new knowledge within this important area. 
2.3.3. Overall Benefit Risk Conclusion 
Considering the measures taken to minimize risk to the participants in this study, the potential 
risks identified in association with proactive TDM are justified by the anticipated benefits that 
may be afforded to patients with RA.  

 
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3. 
Objectives and Endpoints  
Objectives 
Endpoints 
Assessments 
Primary 
 
To assess whether proactive TDM 
is superior to standard of care in 
order to maintain sustained 
disease control without flares in 
patients with RA treated with SC 
TNFi. 
Sustained disease control over the follow-up period of 18 
months without flare, with flare defined as either of the 
following: 
A combination of an increase in Disease Activity Score using 
28 joints- C-reactive protein (DAS28-CRP) > 1.2, or > 0.6 if 
DAS28-CRP ≥ 3.2, AND  2 swollen joints on examination of 
44 joints 
Consensus between participant and physician that disease flare 
has occurred, leading to a major change in treatment* 
*A major change in treatment includes switching to another 
biological disease-modifying anti-rheumatic drug (bDMARD) or 
targeted synthetic disease-modifying anti-rheumatic drug 
(tsDMARD), adding a conventional synthetic disease-modifying 
anti-rheumatic drug (csDMARD), increasing the dose of a 
concomitant csDMARD, i.e., methotrexate increased by ≥ 5 
mg/week, adding or increasing systemic glucocorticoids (per orally, 
intravenous, or intramuscular), and receiving more than one intra 
articular glucocorticoid injection at one visit. If the dose of TNFi is 
increased for clinical reasons (Standard of care group), this should 
also be regarded as a major change in treatment. 
• DAS28-CRP  
• Joint count of 44 joints 
 

 
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Subgroup analyses of the primary endpoint according to each 
TNFi type (if more than one TNFi type will be included)  
Secondary  
 
To compare effectiveness of 
proactive TDM to standard of care 
on different outcome measures  
Disease activity at 4, 8, 12, and 18 months  
Time to disease flare (as defined above) 
 
• DAS28-CRP 
• Joint count of 44 joints  
• Patient Global assessment of disease 
activity (PGA) 
• Evaluator Global assessment of disease 
activity (EGA) 
• Clinical Disease Activity Index (CDAI)  
• Simple Disease Activity Index (SDAI)  
• Rheumatoid Arthritis Impact of disease 
(RAID) 
• Modified Health Assessment 
Questionnaire (MHAQ) 
• ACR/EULAR remission criteria 
• Biochemical parameters (C-reactive 
protein (CRP) and erythrocyte 
sedimentation rate (ESR)) 
Safety  
Number and type of adverse events (AE)  
• Assessments of AE 
To assess whether proactive TDM 
influences drug survival, drug 
consumption, occurrence of 
ADAb, and serum drug levels 
Drug survival, drug consumption, occurrence of ADAb, serum 
drug levels 
 
 
• Assessments of drug consumption  
• Drug survival 
• Assessments of serum drug levels and 
ADAb 

 
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Explorative/Other Objectives 
 
• To assess cost effectiveness, utility, and impact on quality of life of proactive TDM 
compared to standard of care  
• To assess whether biomarkers (including genetic markers) and other factors can predict 
development of ADAb in participants on SC TNFi 
• To study how serum drug levels and ADAb are associated with drug efficacy and safety  
• To study predictors of flare and treatment response  
• To study differences in immunogenicity between different SC TNFi  
• To characterize anti-drug immune responses, including ADAb isotypes, epitopes, and 
association to genetic markers (e.g., HLA) 
• To assess how TDM influences treatment with respect to serum drug/ADAb levels and 
disease activity 
• To assess efficacy of TDM in the subgroup of participants with ADAb 
• To study feasibility of TDM and compliance to the treatment algorithm  
• To study the performance of the treatment strategy within the group of participants affected 
by the algorithm  
• To study the effect of dose escalation/decrease on serum drug levels and clinical outcomes 
• To study the value of TDM in the setting of switching of drug to a different bDMARD 
• To study effectiveness of TDM in subgroups of participants where TDM is assumed to be 
particularly valuable, including participants with high disease activity at baseline, 
participants not on immunosuppressive co-medication, and participants with previous 
secondary loss of effect of TNFi  
• To study adherence  
• To study corticosteroid consumption  
• To study different measures for assessing flares   
• European Quality of Life 5 Dimensions 
(EQ-5D,  
36-Item Short-form health survey (SF-36), 
Work Productivity and Activity 
Impairment Questionnaire: Rheumatoid 
Arthritis (WPAI-GH) 
• Genetic markers and biomarkers 
• Assessments of serum drug levels and 
ADAb 
• Assessments of AE 
• DAS28-CRP, Joint count of 44 joints, 
PGA, EGA, CDAI, SDAI, RAID, MHAQ, 
ACR/EULAR remission criteria 
• Biochemical parameters (including CRP 
and ESR) 
• Drug survival 
• Adherence questionnaire  
• Drug calendar  
• Co-medication assessment 
• Rheumatoid arthritis flare questionnaire 
(RA-FQ 
 

 
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4. 
Study Design 
 
4.1. 
Overall Design 
 
• A multi-center, randomized, open (with partial blinding for outcome assessments), 
parallel-group, superiority study.  
• Study intervention assignment: 1:1 by central computer randomization at the time 
of inclusion, stratified by country.  
• Treatment strategies compared:  
o Administration of TNFi based on proactive TDM (TDM group) 
o Administration of TNFi according to standard of care without knowledge 
of serum drug levels or ADAb status (Standard of care group) 
• Population: Adult patients with RA in DAS28-CRP remission or low disease 
activity (DAS28-CRP < 3.2) on therapy with a SC TNFi (adalimumab) in standard 
dose for 3–24 months and an indication for continuation of treatment according to 
the treating physician. 
• Algorithm for dose adjustments: In the TDM group, adjustments of the dosing 
interval of the TNFi are made according to a predefined algorithm, with the aim of 
reaching and maintaining a serum drug level within the therapeutic range. 
• Duration of study: The randomized treatment strategy will be continued for the 
duration of the follow-up period (18 months). 
• Study visits: Onsite visits 0, 4, 8, 12, and 18 months. Additional digital visits and 
onsite blood sampling at 2, 6, 10, 14, and 16 months.    
• Primary endpoint: sustained disease control without disease flare during the 
follow-up period of 18 months. 
o In order to identify the primary endpoint, each study center will have a 
phone number for participants to call in case of increased disease activity. 
If a participant is experiencing a potential flare, a visit will be arranged 
within one week after contacting the study center to allow for a thorough 
examination and documentation of disease status. 
• Participants experiencing a flare (primary endpoint) will be followed according to 
the visit scheme. Further therapy will be at the discretion of the treating physician, 
but for participants in the TDM group, an increase in dose will be recommended if 
the drug level is low (according to the TDM algorithm). 
• Participants who are switched to another treatment during the study will still be 
followed according to the visit scheme but without TDM. 
• Biosimilars: Switching between biosimilar drugs is allowed at any time during the 
study. 

 
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4.2. 
Scientific Rationale for Study Design 
Study design: A randomized superiority trial is the preferred study design to assess an 
intervention suggested to improve clinical outcomes. 
Masking: Due to the need for communication between study personnel and participants 
regarding dose changes in the TDM group, blinding of study personnel and participants is not 
feasible. To mitigate the risk of expectation bias, joint count assessor (component of the 
primary outcome) will be blinded. 
Primary endpoint: To maintain sustained disease control is the treatment target in RA care (3). 
Preventing flares may improve quality of life, delay disease progression, and avoid 
irreversible organ damage, which can make a great difference to a large number of patients 
with RA (19, 20, 35, 36). There is no consensus on the definition of flare in RA. The 
definition of a flare used in the present study is based on work conducted within Outcome 
Measures in Rheumatology (OMERACT) on the minimally clinically important difference 
and minimally detectable difference of DAS28-CRP, and definitions used in prior randomized 
controlled trials (RCTs) within this field (33, 37-40).  
Eligibility: Inclusion criteria are wide in order to improve external validity. 
4.2.1. Patient Input into Design 
Three user representatives with RA were consulted in an early phase of planning this study 
and during protocol development. They gave input on the interventions, study outcomes, and 
study duration. Additionally, they gave specific input to the informed consent form and the 
patient information letter. The user representatives will continue their involvement during the 
continuation of the study. 
 
4.3. 
Justification for the Choice of Study Drug and the TDM Strategy  
As knowledge of the therapeutic ranges at this point is most robust for adalimumab, and since 
adalimumab is currently by far the most used SC TNFi, the study protocol has been developed 
with the aim of including RA patients on therapy with adalimumab. In case of evidence 
regarding therapeutic ranges for other SC TNFi emerge and their clinical use increase during 
the study period, RA patients on other SC TNFi will be considered for inclusion following a 
protocol amendment. 
The treatment algorithm in the TDM group is based on an extensive literature review, 
assessment of new unpublished data, and expert opinions. It has been developed through a 
series of meetings in the project group including international leading experts in this field 
(both clinicians experienced with TDM and laboratory physicians). 
There are strong indications that the lower limit of the therapeutic range of adalimumab in RA 
is close to 5 mg/L (7, 23, 41-44), and data indicate that an upper limit is around 12 mg/L (7, 
23, 42). 
The dose alterations recommended by the algorithm were based on literature review and on 
considerations of feasibility and expert opinion (44-47). The cut-off for ADAb leading to 

 
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change of therapy is based on clinical experience and is the same as the cut-off used in an 
equivalent assay for the TNFi infliximab in the previous NOR-DRUM trials (32, 33). 
4.4. 
End-of-Study Definition 
A participant is considered to have completed the study when the participant has completed the 
visit at 18 months. The end of the study is defined as the date of the last visit of the last 
participant in the study. 

 
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5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. A clinical diagnosis of RA  
2. ≥ 18 and < 75 years of age at screening 
3. On stable therapy with standard dose of a SC TNFi (adalimumab) for a minimum of 3 
months and a maximum of 24 months   
4. In low disease activity or remission (DAS28-CRP < 3.2) and indication for continuation 
of treatment according to the treating physician 
5. Subject capable of understanding and signing an informed consent form  
 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Major comorbidities, such as previous malignancies within the last 5 years, uncontrolled 
diabetes mellitus, severe infections (including HIV), uncontrollable hypertension, severe 
cardiovascular disease (NYHA class 3 or 4), severe respiratory diseases, demyelinating 
disease, significant chronic widespread pain syndrome, significant renal or hepatic 
disease, and/or other diseases or conditions which either contraindicate treatment with SC 
TNFi or make adherence to the protocol difficult 
2. Hypersensitivity to SC TNFi (adalimumab) 
3. Pregnancy, or subject considering becoming pregnant during the study period 
4. Psychiatric or mental disorders, alcohol abuse or other substance abuse, language barriers, 
or other factors that makes adherence to the study protocol difficult   
5. Changes in csDMARD co-medication, including dose changes of csDMARD or changes 
in the dose of corticosteroids within the last 2 months 
6. Co-medication with bDMARD, tsDMARD, or other immunosuppressive drugs (excluding 
csDMARD and corticosteroids ≤ 7.5 mg prednisolone (or equivalent) once daily).  
7. Active participation in any other interventional study 
8. In need of live vaccines during the study period 
 
5.3. 
Lifestyle Considerations  
 Not applicable.  
 
 
5.4. 
Screen Failures 
A screen failure occurs when a participant who has consented to participate in the clinical 
study is not subsequently entered in the study. A minimal set of screen failure information is 

 
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required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trails (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details 
and eligibility criteria.  
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened (maximally two times) under a new participant number for every 
screening/rescreening event. 
A list of pre-screened patients not eligible for screening will be kept with the patient 
identification list and will describe age, gender and reason for not eligible for screening.  
5.5. 
Criteria for Temporarily Delaying  
Not applicable.  

 
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6. 
Study Intervention and Concomitant Therapy 
Study interventions are all pre-specified investigational and non-investigational medicinal 
products, medical devices, and other interventions (e.g., surgical and behavioral interventions) 
intended to be administered to the study participants during the study conduct. 
Participants enrolled in the RA-DRUM trial are on therapy with SC TNFi. 
They are randomized 1:1 to either:  
o Administration of SC TNFi based on proactive TDM (TDM group) 
o Administration of SC TNFi according to standard of care without knowledge 
of serum drug levels or ADAb status (Standard of care group) 
If the participants are using prednisolone (≤ 7.5 mg prednisolone oral dose or equivalent) or 
concomitant csDMARD including methotrexate, sulfasalazine, hydroxychloroquine, or 
leflunomide in any dose this will be continued in an unchanged dose.  
 
6.1. 
Study Intervention Administered 
6.1.1. The TDM Group   
In the TDM, the SC TNFi dose will be adjusted according to the algorithms outlined in Table 
1 in order to keep the drug level within the therapeutic range.  
Prior to a dose change, the study personnel must check by a phone call to the participant if the 
drug has been administered according to the treatment algorithm (as defined in Table 1) or if 
injections have been postponed or dropped due to medical or other reasons.  
The following exceptions from the algorithm in Table 1 are recommended if the drug has not 
been administered according to the treatment algorithm during the last month: 
• If the drug level is low with no or low ADAb and there has been a pause in medication 
of more than 1 week for the last month prior to the blood sampling the dose should be 
kept stable 
• If the drug level is high and the participant has taken the injection in a higher dose or 
more frequent than prescribed, the dose should be kept stable. 
The reason for pause in therapy should be recorded in the eCRF.  
In the TDM group, results for drug levels and ADAb will be reported to the investigators via 
the eCRF within 10 days after receiving the sample. Results in the standard care group will be 
recorded in the eCRF but not accessible to study personnel, and transferred to the PI upon 
conclusion of the clinical trial.  
 
 

 
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Table 1.  Study Intervention 
 
Adalimumab  
x 
y 
z 
Trade name(s) 
Originator and all approved adalimumab 
biosimilars* 
 
 
 
Type 
Biologic drug 
 
 
 
Dose Formulation   
Subcutaneous (SC) injection 
 
 
 
Recommended Dose**  
40 mg SC every 14 days, if necessary 40 mg 
SC every 7 days or 80 mg SC every 14 days 
 
 
 
IMP and NIMP 
IMP 
 
 
 
Drug target range  
5.0-12.0 mg/L 
 
 
 
Cut-off ADAb high levels 
> 50 µg/L 
 
 
 
TDM strategy 
• 
Within target range 
Keep dose 
 
 
 
• 
Low drug levels, ADAb undetectable 
or low levels 
Decrease dosing interval by one week to a 
maximum of 40 mg/week 
 
 
 
• 
Low drug levels, ADAb high levels 
Switch to another therapy 
 
 
 
• 
High drug levels  
Increase dosing interval by one week up to a 
maximum of 6 weeks 
 
 
 
* All adalimumab biosimilars approved by the European Medicines Agency  
**According to the Summary of Product Characteristics (SmPC) 
ADAb = anti-drug antibodies; TDM = Therapeutic drug monitoring 
X,y,z: The protocol has been developed with the aim of including RA patients on therapy with adalimumab. If sufficient 
evidence emerges regarding therapeutic ranges of other SC TNFi during the study period, it will be considered to amend 
the protocol to include RA patients on other SC TNFi. 
 
6.1.2. The Standard of Care Group 
In participants randomized to the Standard of care group, the SC TNFi will be administered 
according to standard of care without knowledge of serum drug levels or ADAb at all visits 
throughout the study. Results of serum drug levels and ADAb testing in the Standard of care 
group will be kept hidden from the investigators.   
6.1.3. Both Groups 
In order to identify the primary endpoint, each study center will have a phone number for 
participants to call in case of increased disease activity. If a participant is experiencing a 
potential flare, a visit will be arranged within one week after contacting the study center to 
allow for a clinical examination and documentation of disease status.  
Participants with a flare (primary endpoint) will be followed according to the visit scheme. 
Further therapy will be at the discretion of the treating physician, but for participants in the 
TDM group, an increase in dose will be recommended if the drug level is low (according to 
the TDM algorithm). 
If SC TNFi is terminated due to any reason, the participant will still be included in the study 
and followed with study visits according to the planned visit schedule. The reason for 
termination of therapy should be recorded in the eCRF. If SC TNFi is terminated due to AE, 
the choice of treatment should be at the discretion of the investigator. Participants who are 

 
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switched to another treatment during the study will still be followed according to the visit 
scheme. Switching between biosimilar drugs is allowed at any time during the study. 
 
6.2. 
Preparation, Handling, Storage, and Accountability 
Participants will be prescribed the TNFi and receive it from the pharmacy as per usual routine 
use. Participants will handle, store, and administer the drug according to the SmPC. This 
includes following the expiry date on the packaging and keeping the drug cool during storage. 
The IMP has already been placed on the market as an authorized medicinal product in 
accordance with Directive 2001/83/EC and Regulation (EC) No 726/2004 of the European 
Parliament and of the Council, and there is no blinding of the IMP. Therefore, no additional 
labelling will be applied.  
 
6.3. 
Assignment to Study Intervention 
On the day of enrolment, participants will be assigned a unique randomization number in 
ascending numerical order at each study site. The randomization number encodes the 
participant’s assignment to one of the two treatment groups of the study according to the 
randomization schedule. Once a randomization number has been assigned, it may not be 
reassigned.  
Eligible participants will be allocated in a 1:1 ratio between TDM and Standard of care using 
a permuted block randomization procedure stratified by country (N=3), using random block 
sizes. Details of block size and allocation sequence generation will be kept in a separate 
document unavailable to those who enroll participants or assign treatment. 
The computer-generated allocation sequence will be incorporated into the eCRF system and 
made available to site personnel. The allocation will not be available until the participant has 
signed the informed consent form and deemed eligible to participate in the study. That is, 
study personnel will only know the treatment allocation of included participants, but not of 
future participants.  
6.4. 
Masking  
This is an open-label study; potential bias will be reduced by the following step:  
Blinded assessment of part of the primary outcome (joint count).   
6.5. 
Study Intervention Compliance 
Compliance with study intervention will be assessed at each visit including the digital visits. 
• At inclusion, the participant will be instructed to keep a drug-diary, either on a paper-form 
provided by study personnel or optionally electronically in their own calendar or with the 
RheumaBuddy® app. 
• At each visit (every two months), the participant will fill in the dates of the drug injections 
since the last visit in a calendar and fill out a questionnaire assessing compliance in into 
the eCRF. See Appendix 17 for wording of the questions. The questionnaire will be 
provided in the primary language of each country. 

 
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• Before adjusting the dosage according to the trial protocol, study personnel will call the 
participant and ask if they have taken the drug as prescribed the last four weeks. 
Deviations from the prescribed dosage regimen will be recorded in the eCRF, including 
the reason for deviation.  
6.6. 
Other Dose and Schedule Modification  
Modification of dosing regimens related to abnormal blood values and/or AEs should be 
performed based on the SmPC, clinical judgment and if necessary, contact with the study 
lead. If a TNFi dose is delayed due to non-RA related factors such as infections, surgery, 
vacation, subject non-compliance etc. this should be recorded and the reason given in the 
eCRF.  
6.7. 
Continued Access to Study Intervention after the End of the Study 
Participants will return to standard of care.  
6.8. 
Treatment of Overdose 
Not applicable.  
6.9. 
Prior and Concomitant Therapy 
6.9.1. Prior Therapy 
All prior use of disease-modifying drugs/immunosuppressive therapy (excluding 
corticosteroids and NSAIDs) will be recorded in the eCRF with specification of both the time 
(month and year) of treatment start and time of termination (month and year) of biological 
drugs. If known, the reason for termination of prior biological therapy (i.e., lack of efficacy, 
loss of efficacy, side effects, development of ADAb, or other) will be recorded. 
6.9.2. Concomitant Medication  
All concomitant medications for any conditions and changes in concomitant medications and 
dosages for RA will be documented in the eCRF. Participants should continue with the same 
concomitant medication as prior to randomization. Any co-medication with a csDMARD 
should be kept stable throughout the study, but tapering and termination due to AE is 
permitted. Flares leading to major changes in the concomitant treatment as defined in Section 
3 will lead to classification as a disease flare (primary endpoint of the study). Short courses of 
corticosteroids for acute medical conditions other than RA (for example asthma and allergy) 
are permitted and will be recorded. Participants can receive intra-articular injections in one 
swollen joint at each visit; more than one injection at one visit will be regarded as a major 
change in medication and lead to classification as flare (primary endpoint). NSAIDs are 
permitted for use at any time during the study. NSAID doses may be increased or tapered 
according to clinical response. The choice and dosage of NSAIDs will be at the discretion of 
the treating rheumatologist and should be recorded in the eCRF. Participants who experience 
a flare can receive concomitant medication or switch therapy as needed.  
The following concomitant medications are prohibited: 

 
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• bDMARD such as other TNFi, interleukin inhibitors, B- or T cell inhibitors 
• tsDMARD such as Janus Kinase Inhibitors 
• Other immunosuppressants than corticosteroids including but not limited to 
calcineurin inhibitors, cyclophosphamide, mycophenolate mofetil  
 

 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant should, if at all 
possible, remain in the study to be evaluated for the primary outcome.  
7.2. 
Participant Discontinuation/Withdrawal from the Study 
 
• A participant may withdraw from the study at any time at the participant’s own request for 
any reason (or without providing any reason). 
• A participant may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, or compliance reasons.  
• At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA. See SoA for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be 
completed. 
• The participant will be permanently discontinued from the study intervention and the 
study at that time. 
• If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, the participant may request destruction of any 
samples taken and not tested, if in accordance with local requirements and the investigator 
must document this in the site study records. 
7.3. 
Lost to Follow-up 
 
A participant will be considered lost to follow-up if the participant repeatedly fails to return 
for scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible, counsel the participant on the importance of maintaining the assigned visit 
schedule, and ascertain whether the participant wishes to and/or should continue in the 
study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must try 
to regain contact with the participant (where possible, telephone calls (maximum 2)), 
and if necessary, a certified letter to the participant’s last known mailing address or 
local equivalent methods. These contact attempts should be documented in the 
participant’s medical record. 

 
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• Should the participant continue to be unreachable, the participant will be considered to 
have withdrawn from the study.  

 
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8. 
Study Assessments and Procedures 
 
• Study procedures and their timing are summarized in the SoA.  
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the participant’s routine clinical management and 
obtained before signing of the ICF may be utilized for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the 
timeframe defined in the SoA. 
• In the event of a significant study-continuity issue (e.g., caused by a pandemic), alternate 
strategies for participant visits, assessments, medication distribution and monitoring may 
be implemented by the sponsor or the investigator, as per local health authority/ethics 
requirements.   
8.1. 
Administrative General, Biobank and Baseline Procedures  
A screening evaluation should be performed prior to or at the same day as the inclusion visit.  
The following procedures have to be completed before inclusion: 
• Signing the informed consent form  
• A formal assessment of the eligibility criteria 
8.1.1. Baseline Procedures 
Informed written consent must have been given voluntarily by each participant before any 
study specific procedures are initiated. In addition to the assessments and procedures 
performed at a regular visit described in the SoA (Section 1.3), the following assessments will 
be performed at baseline:  
Study nurse/investigator assessments: 
• Demographics (sex, birth date, and ethnic origin) 
• Tobacco use  
• Medical history (diagnosis, disease related previous therapy including both 
biological and non- biological disease modifying treatment with time for initiation 
and termination and reasons for discontinuation if known to the participant, 
duration of SC TNFi use, non-RA related medical and surgical history) 
• Height and weight  

 
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8.1.2. Biobank Samples  
Full blood samples (one 4 ml test tube) will be collected from all participants at the baseline 
visit and sent to the Department of Medical Biochemistry at Oslo University Hospital 
Radiumhospitalet, Norway, for biobanking. At the end of the inclusion period the samples 
will be transferred to a study specific biobank at Diakonhjemmet Hospital. Optionally, 
samples can be stored locally at the participating centers.  
 
Participants at Diakonhjemmet Hospital only, will additionally donate samples (full blood, 
serum and plasma) to a study specific biobank at all onsite visits (baseline, 4, 8, 12, 18 
months, early discontinuation visits and extra visits). The estimated total volume for biobank 
samples at each visit for these patients is 22 ml. All samples will be stored in suitable tubes 
and boxes designed to endure long-term storage and in a certified biobank below -70 °C. The 
samples will be stored until 31.12.2037 and remaining samples will thereafter be destroyed. 
The samples from the biobank will be used for research purposes only. Some analyses might 
take place in other countries than Norway including but not limited to the Netherlands, 
Sweden, Austria, Great Britain, Iceland, and the United States of America. These samples will 
be handled pseudonymised, the sample will be marked with the study ID. The laboratory 
receiving the samples will only have access to the study ID. The patient identification list will 
be stored locally at each study center. 
Genetic assessments are described in Section 8.6. 
 
8.2. 
Efficacy Assessments 
Planned time points for all efficacy assessments are provided in the SoA (Section 1.3). 
8.2.1. Assessment of Disease Activity  
 
Patient Global Assessment of Disease Activity (PGA) (48) 
PGA is measured on a 100 mm VAS according to the question: “Considering all the ways 
your arthritis affects you, rate how well you are doing on the following scale”, with 0 = best 
and 100 = worst (48-50). See Appendix 5. Approved versions in the primary language of each 
country will be used.    
 
Evaluator Global Assessment of Disease Activity (EGA) 
EGA is measured on a NRS according to the question “Please rate the patient’s overall 
(global) disease activity”, with 0 = best and 10 = worst (49). See Appendix 6. Approved 
versions in the primary language of each country will be used.    
 
Inflammation assessment by biochemical parameters 
Inflammation is measured by CRP and ESR will be recorded at all onsite visits. These tests 
will be analyzed at the local laboratory according to hospital procedures.  
 

 
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Disease Activity Score using 28 joints C-reactive protein (DAS28-CRP)  
The DAS28-CRP composite score includes the 28 tender and swollen joint counts, CRP and a 
PGA (on a 0-100mm VAS). The DAS28-CRP is calculated as follows: 
DAS28-CRP = 0.56*√ (tender joints 28) + 0.28*√ (swollen joints 28) + 0.36*ln(CRP 
(mg/L)+1) + 0.014*PGA + 0.96 
High disease activity is defined as a DAS28-CRP value > 5.1, moderate disease activity as 
DAS28-CRP > 3.2 – 5.1, low disease activity as a DAS28-CRP-value of 2.6 – 3.2, and 
remission as DAS28-CRP < 2.6 (50). See Appendix 7. 
 
44 joint count 
44 joint count are included in the original DAS and in addition to the joints included in 
DAS28 it includes the MTP joints and the sternoclavicular joints for a more comprehensive 
valuation of the participants’ joints (51). See Appendix 8. 
 
ACR/EULAR remission criteria  
The ACR/EULAR remission criteria defines a patient in remission when either a) the patient 
is in Boolean 2.0 remission with each of the variables TJC, SJC and CRP having a value of ≤1 
and PGA having a value ≤ 2 (PGA on a VAS scale 100mm/10, CRP in mg/dl) OR b) the 
SDAI score is ≤ 3.3 (52).  
 
Simple disease activity index (SDAI) and Clinical disease activity index (CDAI)  
The SDAI and CDAI have been developed to provide physicians and patients with simple and 
more comprehensible instruments for assessment of disease activity in RA. CDAI is the only 
composite index that does not incorporate an acute phase response and can therefore be used 
to conduct a disease activity evaluation essentially anytime and anywhere (49).  
The formula for SDAI is: swollen joints 28 + tender joints 28 + (PGA(VAS 0-100)/10) + 
EGA(NRS 0-10) + (CRP (mg/dL)/10).  
The formula for CDAI is: swollen joints 28 + tender joints 28 + (PGA (VAS 0-100)/10) + 
EGA (NRS 0-10).  
See Appendix 9 and 10. Approved versions in the primary language of each country will be 
used.    
 
Patient Reported Outcome Measures (PROMs) 
All PROMS will be collected by the eCRF module ViedocMe. If the patients do not respond 
to the questionnaires, two reminders will be sent out. Approved versions of the questionnaires 
in the primary language of each country will be used.    
 
Rheumatoid Arthritis Flare Questionnaire (RA-FQ) 
The RA-FQ was developed by the Omeract group to identify and measure flares in patients 
with RA. It encompasses pain, physical impairment, fatigue, stiffness, and participation, and 

 
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the score is calculated as the sum of responses for the 5 items (maximum 50) (39, 53). See 
Appendix 11. 
 
Rheumatoid Arthritis Impact of Disease (RAID) score 
The RAID questionnaire was developed by EULAR as a patient-derived composite score. It 
includes seven domains with the following relative weights: pain (0.21), functional disability 
(0.16), fatigue (0.15), emotional well-being (0.12), sleep (0.12), coping (0.12) and physical 
well-being (0.12) each rated on an NRS (0-10). The rates of each domain are weighted and 
summed to form a score in the range of 0-10 (54). See Appendix 12. 
 
Modified Heath Assessment Questionnaire (MHAQ) 
The Stanford Health Assessment Questionnaire (HAQ) was introduced in the 1980s and is 
now widely used in evaluation of physical function in patients with inflammatory joint 
diseases (IJD). A shortened version of the HAQ, the MHAQ reduced the number of items 
from 20 in the original HAQ to eight, and improved the feasibility in clinical practice. Each 
item is scored on a categorical 0-3 scale and the sum score is divided by 8 to form the MHAQ 
score 0.0 to 3.0 (55). See Appendix 13. 
 
8.2.2. Definition of Flare 
A flare is defined as a combination of an increase in DAS28-CRP of 1.2 units, or 0.6 if 
DAS28-CRP ≥ 3.2, AND at least 2 swollen joints on examination of 44 joints (39, 40, 53). 
If a participant does not fulfil the formal definition, but experiences a clinically significant 
worsening, according to both the investigator and participant, that leads to a major change* in 
treatment, this should be considered as a flare but be recorded separately in the eCRF.  
 
*A major change in treatment includes:  
• 
Switching to another bDMARD or a tsDMARD 
• 
Adding a csDMARD 
• 
Increasing the dose of a concomitant csDMARD 
• 
Adding or increasing systemic glucocorticoids (per orally, intravenous or 
intramuscular)  
• 
Receiving more than one intra-articular glucocorticoid injection at one visit 
• 
Shortening the interval of the SC TNFi for clinical reasons (Standard of care group) 
8.3. 
Safety Assessment  
Safety will be monitored by laboratory tests (Section 8.3.1) and the collection of AEs at every 
onsite visit. Significant findings that are present prior to the signing of informed consent must 
be included in the relevant medical history/current medical condition page of the eCRF. For 
details on AE collection and reporting, see Appendix 3.  
Any AE encountered during the clinical study will be reported in the eCRF (see Appendix 3 
for definitions). AE will be followed up as clinically indicated until they have returned to 

 
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baseline status or are stabilized. Events which are definitely due to disease progression will 
not be reported as an AE/SAE.  
• See Appendix 2 for the list of clinical laboratory tests to be performed and the SoA 
(Section 1.3) for the timing and frequency. 
• The investigator must review the laboratory results, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory results 
must be retained with source documents.  
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 8 weeks after the last dose of study intervention should 
be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor. 
o If clinically significant values do not return to normal/baseline within a period 
of time judged reasonable by the investigator, the etiology should be identified, 
and the sponsor notified. 
o All protocol-required laboratory tests, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3). 
o If laboratory values from non-protocol-specified laboratory tests performed at 
the institution’s local laboratory require a change in participant management or 
are considered clinically significant by the investigator (e.g., SAE or AE or 
dose modification), then the results must be recorded. 
8.3.1. Routine Laboratory Tests 
The following laboratory tests will be recorded at all visits. These tests will be analyzed at the 
local laboratory according to hospital procedures. If any requested testes are not available 
locally, samples will be referred to other laboratories according to local practice.  
• Hematology: Hemoglobin, white blood cells with differentials and platelet count 
• Blood chemistry: ALT, creatinine, ESR, CRP 
 
8.4. 
Adverse Events (AEs) Serious Adverse Events (SAEs), and Other 
Safety Reporting 
The definitions of AEs and SAEs can be found in Appendix 3. 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or study 
procedures, or that caused the participant to discontinue the study intervention (see Section 7). 
This includes events reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 

 
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8.4.1. Time Period and Frequency for Collecting AE and SAE Information 
All AE and SAEs will be collected from the start to stop of study intervention. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours after the investigator is made aware of the SAE, as 
indicated in Appendix 3. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion 
of the study participation. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the sponsor. 
8.4.2. Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
8.4.3. Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is provided in Appendix 
3. 
8.4.4. Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, institutional review boards 
(IRBs)/independent ethics committees (IECs), and investigators. 
• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the SmPC and will notify the IRB/IEC, if appropriate 
according to local requirements.  
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 

 
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8.4.5. Pregnancy 
• If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the 
pregnancy. 
• In case of pregnancy, the participant will exit the study. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy for medical reasons will be reported as an AE or 
SAE. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, and ectopic pregnancy) are considered SAEs and will be reported as 
such. 
8.5. 
ADAb and Serum Drug Level Assessments 
Serum samples will be drawn from all participants at all visits. The samples will be sent to the 
Department of Medical Biochemistry at Oslo University Hospital Radiumhospitalet, Norway, 
by regular mail or currier with the aim of reaching the laboratory within seven days after the 
sampling date. Serum TNFi levels and ADAb will be measured using validated automated 
fluorescence assays. These assays are currently used to assess samples for clinical practice 
from hospitals throughout Norway and have been used in prior clinical trials (32, 33, 56).  
Serum drug levels of SC TNFi are measured using recombinant TNF on the solid phase. As a 
result, only active TNFi (with the ability to bind TNF) will be measured. The assay for 
antibodies to TNFi only detects neutralizing antibodies, i.e., antibodies that block the TNF-
binding capacity of the TNFi. All assays are fully automated (including dilutions) on the 
AutoDELFIA platform (PerkinElmer). 
8.6. 
Genetics 
A 4 ml blood sample for DNA isolation will be collected from participants who have 
consented to participate in the study. Analyses using DNA/RNA will assess possible 
associations between genes and gene expressions and response/immunogenicity. Analyses 
will only be conducted at a group level and participants will not receive individual 
feedback/genetic counseling.  
Genetic analyses might take place in other countries than Norway including but not limited to 
the Netherlands, Sweden, Austria, Great Britain, Iceland, and the United States of America. 
These samples will be handled pseudonymised, the sample will be marked with a study ID. 
The laboratory receiving the samples will only have access to the study ID. The patient 
identification list will be stored locally at each site. 
Biobank samples will be stored until 31.12.2037 and remaining samples will thereafter be 
destroyed. 
See Appendix 4 for more information regarding genetic research. 
 

 
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8.7. 
Biomarkers 
Biomarker analyses as appropriate to investigate exploratory objectives may be performed.   
8.8. 
Health Economics  
For all participants throughout the study, the investigator and study site personnel will collect 
data about health care resource utilization associated with medical encounters. 
The data collected will 
• Include the reasons and duration of hospitalizations and emergency room visits and  
• Exclude procedures, tests, and encounters mandated by the protocol. 
The sponsor may use the collected data to conduct economic analyses.   
All participants will be asked to fill in the three standard instruments (questionnaires) to 
capture work productivity and health related quality of life: SF-36, EQ-5D and WPAI:RA. All 
questionnaires will be collected by the eCRF module ViedocMe. If the patients do not 
respond to the questionnaires, two reminders will be sent out. Approved versions of the 
questionnaires in the primary language of each country will be used.  
 
36-Item Short-form health survey (SF-36) 
The SF-36 is a multi-purpose, short-form health survey with 36 questions (57). It yields an 8-
scale profile of functional health and well-being scores as well as psychometrically-based 
physical and mental health summary measures and a preference-based health utility index 
(SF-6D) (58). It is a generic measure, as opposed to one that targets a specific age, disease, or 
treatment group. Accordingly, the SF-36 has proven useful in surveys of general and specific 
populations, comparing the relative burden of diseases, and in differentiating the health 
benefits produced by a wide range of different treatments (57). See Appendix 14. 
 
European Quality of Life 5 Dimensions (EQ-5D)  
The EQ-5D is a utility instrument for measurement of health-related quality of life. 
Applicable to a wide range of health conditions and treatments, it provides a simple 
descriptive profile and a single index value for health status (59, 60). See Appendix 15. 
 
Work Productivity and Activity Impairment Questionnaire: Rheumatoid Arthritis (WPAI:RA) 
The Work Productivity and Activity Impairment (WPAI) questionnaire is a tool that assesses 
impairments in both work and daily activities. It consists of six items that determine 
employment status and measure absenteeism caused by health issues, presenteeism, and 
overall health-related impairment in both paid work and regular activities over the preceding 7 
days. The questionnaire yields four outcomes: i) the percentage of work time missed due to 
health; ii) the percentage of impairment experienced while working due to health in the past 7 
days; iii) the percentage of overall work impairment; iv) activity impairment resulting from 
health issues. Participants will be asked to answer the Work Productivity and Activity 
Impairment Questionnaire: Rheumatoid Arthritis V2.0 (WPAI:RA) (61, 62). See Appendix 
16. 

 
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9. 
Statistical Considerations 
The statistical analyses are planned to be carried out when: 
• The planned number of participants have been included  
• Each included participant has completed their end-of-study visit, withdrawn, or been 
withdrawn according to protocol procedures 
• All data from the study period have been entered, verified, and validated according to 
the data management plan 
Prior to the statistical analysis, the data will be locked from further entering or editing. A SAP 
will be finalized prior to any analysis of treatment effects. The SAP will include a more 
technical and detailed description of the statistical analyses described in this section. This 
section gives a summary of the planned statistical analyses of the most important endpoints, 
including the primary endpoint and some key secondary endpoints. The SAP will be finalized, 
signed, and dated prior to database lock. Any deviation from the original statistical plan will 
be described and justified in the CSR. 
9.1. 
Statistical Hypotheses 
The primary objective is to study whether TDM is superior to standard of care in sustaining 
disease control during the 18-month follow-up period. To this end, we define the following 
hypotheses:  
• Null hypothesis: The probability of sustained disease control over 18 months in the TDM 
group equals that in the control group  
• Alternative hypothesis: The probability of sustained disease control over 18 months in the 
TDM group differs from that in the control group. 
The null hypothesis will be tested against the alternative hypothesis. Superiority of TDM over 
standard of care will be claimed if the primary null hypothesis is rejected by a two-sided test 
using a significance level of 5% and the treatment difference is in favor of the TDM group. 
9.1.1. 
Multiplicity Adjustment 
Only a single hypothesis test will be carried out, and only the p value associated with this 
comparison will be reported. No other hypothesis test will be carried out or p values reported, 
hence adjustment for multiplicity is not needed. All other comparisons will be descriptive and, 
where appropriate, accompanied by confidence intervals (unadjusted for multiplicity). 
9.2. 
Analysis Sets 
For the purposes of analysis, the following analysis sets are defined: 
All efficacy and safety analyses will be carried out in the full analysis set, defined as all 
randomized participants who have received at least one SC TNFi injection following 
randomization.  
 
 

 
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For both efficacy and safety analyses, participants will be included in the analyses according 
to their randomization group.  
9.3. 
Statistical Analyses 
9.3.1. 
General Considerations 
Randomization 
Allocation Sequence Generation 
Eligible patients will be allocated in a 1:1 ratio between TDM and standard of care using a 
computer randomization procedure stratified by country. Permuted block randomization, with 
random block sizes of 2, 4, and 6, will be used within each stratum. Details of the allocation 
sequence generation will be kept in a document unavailable to those who enroll patients or 
assign treatment. 
Allocation Procedure to Randomize Patients 
The computer-generated allocation sequence will be imported into the eCRF system and made 
available as patients are enrolled. A particular allocation will not be unveiled until the patient 
has been deemed eligible to participate and signed the informed consent form. 
9.3.2. 
Primary Endpoint Analysis 
9.3.2.1. Primary Analysis 
The primary endpoint is sustained disease control during follow-up. This is a binary variable, 
assuming the value 1 for a participant free of flare during follow-up and the value 0 for a 
participant experiencing one or more flares. 
The hypothesis test described in Section 9.1 will be carried using logistic regression. Beyond 
treatment group, the analysis will be adjusted for the stratification factor used in the 
randomization (country). The outcome of the hypothesis test will be decided upon by the p 
value associated with the treatment group variable. Superiority of TDM over standard of care 
is claimed if the primary null hypothesis is rejected by a two-sided using significance level of 
5% and the treatment difference is in favor of the TDM group.  
Missing values of the primary endpoint will be handled using multiple imputation, accounting 
for both partial missingness on visits as well as visits missed completely.   
Adjusted estimates of the probability of sustained disease control within randomization group 
and their between-group difference will be formed using average risk and risk difference 
estimators and presented with associated 95% confidence intervals. 
9.3.2.2. Sensitivity Analysis 
Sensitivity analyses will include additional approaches to dealing with missing values of the 
primary endpoint, possibly including, but not limited to, complete-case analysis, last-
observation carried forward imputation, and worst-case imputation (i.e., imputing missing 
values as flare). Additional analyses may include adjustment for unbalanced baseline 
covariates such as age, sex, and co-medication.  

 
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9.3.2.3. Supplementary Analysis 
The primary outcome will also be analyzed using Cox proportional-hazards regression. The 
time of first flare will serve as the event time, which for participants that are free of flare 
during follow-up will be censored at the last visit date. For this analysis, an assumption of 
independent censoring will be used, and adjustment for stratification factors used in the 
randomization will be made. 
9.3.2.4. Subgroup Analyses 
Subgroup analyses of the primary endpoint according to each TNFi type (if more than one 
TNFi type is included) will be carried out. 
9.3.3. 
Secondary Endpoint Analyses  
The between-group comparisons for secondary variables will be carried out in a manner 
similar to the primary endpoint where applicable and analyses will be performed based on the 
following methods (but not limited to): 
• Continuous secondary variables will be analyzed by linear regression, using mixed effects 
for repeated measures, or appropriate non-parametric alternatives  
• Binary response variables will be analyzed using logistic regression (possibly adjusting 
for within-subject dependencies by mixed model approaches)  
• Time-to-event variables will be analyzed using the Kaplan-Meier method, Cox regression 
analysis, and/or appropriate parametric models such as the Weibull model. 
9.4. 
Interim Analysis 
No interim analysis is planned. 
9.5. 
Sample Size Determination 
A minimum of 350 participants will be randomized.  
The sample size calculation is based on the primary outcome, sustained disease control 
throughout 18 months of follow-up, and an assumption that TDM will increase the probability 
of sustained control by 12.5 percentage points: from an assumed 72.5% for patients treated 
according to Standard of care to 85% for those whose treatment includes TDM. Requiring 
80% power to reject the primary null hypothesis, this implies that at least 350 participants are 
needed, assuming a 10-15% drop-out rate. However, if the inclusion rate is sufficiently high, 
the trial steering committee could decide to increase the sample size to a maximum of 450 
patients to achieve a higher power of 90% (Table 2). Sample sizes corresponding different 
combinations of power and effects of TDM (assuming the same 72.5% sustained remission 
rate in the Standard of care group, but without allowance for drop-out) are given in Table 2. 
Table 2. Power Calculations 
Power 
Difference in 
sustained disease 
control 10% 
Difference in 
sustained disease 
control 12.5% 
Difference in 
sustained disease 
control 15% 

 
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80% 
540 
330 
216 
90% 
724 
440 
290 
 
The assumed rates are based on data from two prior studies, the NOR-DRUM B and ARCTIC 
Rewind trials (33, 38, 63). Regarding the effect of TDM versus standard of care, the first of 
these estimated that the hazard rate of disease flare in patients on maintenance infliximab 
treatment without TDM was about twice that of those whose treatment included TDM. 
Regarding the flare rate associated with standard care, in the NOR-DRUM B trial 22 of 40 
(55%) RA patients in the standard of care group did not experience a disease flare during 12 
months of follow-up, whereas in the ARCTIC Rewind trial, which also had a 12-month 
follow-up period, the numbers were 41 of 45 patients (91%). The disease flare definition used 
in the current study is similar to the one employed in the ARCTIC Rewind trial, while the one 
in NOR-DRUM B was more liberal. However, the present inclusion requirement of a 
remission duration of at least 3 months is less stringent than in the ARCTIC Rewind trial (12 
months), but more so than in the NOR-DRUM B trial (none). Based on this, it seems 
reasonable to expect that approximately 80% of those in the standard of care group will be 
free of disease flare during the first 12 months of follow-up.  
Assuming constant hazards (i.e., exponential survival times), this implies a daily hazard rate 
of flare around 0.0006 in the Standard of care group (since exp(-0.0006*365) = 0.80) and, 
assuming a similar hazard ratio as in the NOR-DRUM B trial, 3.0e-4 in the TDM group. With 
these assumptions, it follows that 72.5% in the Standard of care group are expected to be 
flare-free during the 18 months of follow-up compared to an expected 85% in the TDM 
group(*). 
(*) Since, = exp(-0.0006*365*1.5) = 72.5%  and  exp(-0.0003*365*1.5)= 85%.     
 

 
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10. 
Supporting Documentation and Operational 
Considerations 
 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) international ethical guidelines 
o Applicable ICH Good Clinical Practice (GCP) guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, ICF, SmPC, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the sponsor or investigator as 
applicable and reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard 
to study participants. 
• The investigator will be responsible for the following, as applicable: 
o Providing written summaries of the status of the study to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies, European Medical Device Regulation 2017/745 
for clinical device research, and all other applicable local regulations 
10.1.2. Financial Disclosure 
Investigators will provide the sponsor with sufficient, accurate financial information as 
requested to allow the sponsor to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities. Investigators are responsible 
for providing information on financial interests during the course of the study and for 1 year 
after completion of the study. 

 
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10.1.3. Informed Consent Process 
• The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the potential participant and answer all questions 
regarding the study. 
• Potential participants must be informed that their participation is voluntary. They will be 
required to sign a statement of informed consent that meets the requirements of local 
regulations, ICH guidelines, privacy and data protection requirements, where applicable, 
and the IRB/IEC or study center. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study, if relevant. 
• A copy of the ICF(s) must be provided to the participant. 
• The informed consent will be obtained by study investigators (physicians or study nurses), 
not actively responsible for treatment of the patient at the time of the consent.  
10.1.4. Recruitment strategy 
Potential study participants with a documented diagnosis of RA on therapy with a SC TNFi 
(adalimumab) will be identified from the patient lists at the rheumatology outpatient clinic at 
each participating site either by health personnel during a clinical visit or by patient 
administrative tools and the electronic medical record system between planned visits. 
Personnel with legal access to the patient records and patient administrative tools can identify 
potentially eligible subjects. Names of potential participants will be forwarded to the study 
team (investigators and study-nurses) to be contacted for screening. In addition, participants 
may be identified from referral letters from other clinics or if a possible participant contact the 
clinic directly.  
Dedicated study personnel will be used for recruiting patients. Potential participants identified 
as described above will receive information about the trial from study personnel not actively 
responsible for treatment of the patient at the time. The information will be given verbally and 
the informed consent form will be handed out for the patient to read.  Potential participants 
will be offered sufficient time to meet a decision and if needed offered an additional phone 
consultation to discuss any further question they might have after reading the informed 
consent form and processed all the information given regarding the trial. 
10.1.5. Data Protection 
• Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• The participant must be informed that their personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 

 
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explained to the participant who will be required to give consent for their data to be used 
as described in the informed consent  
• The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• The contract between sponsor and study sites specifies responsibilities of the parties 
related data protection, including handling of data security breaches and respective 
communication and cooperation of the parties. 
• Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access. 
• In case personal data needs to be sent for analysis outside the European Union (EU) or the 
European Economic Area (EEA), appropriate measures to guarantee the protection of the 
data will be taken. Such transfer will be in accordance with the informed consent form and 
will follow the measures of the General Data Protection Regulation (EU) 2016/679 
(GDPR). Measures will include setting up standard contractual clauses for data transfers 
between EU/EEA and non-EU/EEA countries. 
• In case the data security has been breached for any of the participants, the sponsor must 
promptly but no later than 24 hours after becoming aware of the breach be notified. 
Prompt action to investigate the cause of the data breach must be made, and assistance to 
the sponsor in complying with Articles 32 to 36 of the GDPR. 
• Personal data will be stored for 25 years after end of study to comply with the 
requirements in Regulation (EU) No 536/2014 (Clinical Trials Regulation) 
10.1.6. Committees Structure 
The administrative structure of the study includes the steering committee and the study group 
(local advisory board, SQUEEZE team, user representatives and all local PIs) as listed in 
Appendix 18. The steering committee and study group will meet regularly as needed. The 
Medical Monitor will oversee study safety data and evaluate AEs and SAEs, as described in 
Appendix 3.   
10.1.7. Dissemination of Clinical Study Data 
The clinical trial results will be uploaded in CTIS within 1 year after study end. 
10.1.8. Data Quality Assurance 
• All participant data relating to the study will be recorded in an eCRFs. The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF. 
• Guidance on completion of eCRFs will be provided.  
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents. 

 
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• Monitoring details describing strategy, including definition of study critical data items 
and processes (e.g., risk-based initiatives in operations and quality such as risk 
management and mitigation strategies and analytical risk-based monitoring), methods, 
responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the 
monitoring plan.  
• The sponsor or designee is responsible for the data management of this study, 
including quality checking of the data. 
• The sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 25 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written notification 
to the sponsor. 
10.1.9. Source Documents 
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
• Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available. 
• Definition of what constitutes source data and its origin can be found in the source data 
list. 
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• The sponsor or designee will perform monitoring to confirm that data entered into the 
eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study 
is being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.10. 
Study and Site Start and Closure 
Study Start 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
Study/Site Termination 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 

 
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completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
• Occurrence of AEs unknown to date in respect of their nature, severity and duration 
• Medical or ethical reasons affecting the continued performance of the trial 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor’s procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants 
by the investigator 
• Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organizations used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The investigator shall promptly inform the participant and 
should assure appropriate participant therapy and/or follow-up 
10.1.11. 
Publication Policy 
• Upon study completion and finalization of the study report, the results of this study will be 
submitted for publication and posted in a publicly assessable database of clinical study 
results, CTIS. 
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data.  
• All personnel who have contributed significantly with the planning and performance of 
the study (Vancouver convention 1988) may be included in the list of authors. Authorship 
will be based on scientific contribution and enrolment and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.1.12. 
Funding 
This trial is performed under the SQUEEZE project. This project is fully funded from 
the European Union’s Horizon Europe research and innovation program 
under grant agreement No 101095052. Additional funding may be provided by the sponsor or 
co-sponsor. 
 

 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
 
• The tests detailed in SoA (Section 1.3) and Table 3 will be performed by the local 
laboratory. 
• Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
• Investigators must document their review of each laboratory safety report. 
 
Table 3: Protocol-required Safety Laboratory Tests 
Laboratory Tests 
Parameters 
Hematology 
• 
Platelet count 
• 
Hemoglobin 
• 
White blood cell (WBC) count with 
differential: 
− 
Neutrophils 
− 
Lymphocytes 
− 
Monocytes 
− 
Eosinophils 
− 
Basophils 
Clinical chemistry • 
C-reactive protein (CRP) 
• 
Erythrocyte sedimentation rate (ESR) 
• 
Creatinine 
• 
Alanine aminotransferase (ALT)  
 
 
 

 
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10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. Definition of AE 
• An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator (i.e., not related to progression of underlying 
disease, or more severe than expected for the participant’s condition) 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition 
• New condition detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
 
Events not Meeting the AE Definition 
• Any abnormal laboratory findings or other abnormal safety assessments that are 
associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the participant’s condition 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads 
to the procedure is the AE 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 

 
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• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen 
10.3.2. Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more 
of the criteria listed: 
a. Results in death 
b. Is life threatening 
The term life threatening in the definition of serious refers to an event in which the participant 
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. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfils any other serious criteria, the event is 
serious. When in doubt as to whether hospitalization occurred or was necessary, the AE 
should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g., sprained ankle) that may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as important medical events 
that that may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually be 
considered serious. 
o Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, convulsions not resulting in hospitalization, or development of 
intervention dependency or intervention abuse. 

 
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10.3.3. 
Definition of suspected unexpected serious adverse reaction 
(SUSAR) 
If an event is not an SAE per definition above, then it cannot be a SUSAR 
SUSAR Definition 
Adverse Reaction: all unwanted and unintended responses to an investigational medicinal 
product related to any dose administered.  
Unexpected Adverse Reaction: an adverse reaction, the nature or severity of which is not 
consistent with the applicable product information.  
Suspected Unexpected Serious Adverse Reaction: Unexpected Adverse Reaction that: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital abnormality or birth defect 
Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above. 
10.3.4. Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the sponsor in lieu of completion of the required form. 
• There may be instances when copies of medical records for certain cases are requested by 
the sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission. 
• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will assess intensity for each AE and SAE reported during the study and 
assign it to one of the following categories:  
• Mild: 
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual activities of 
daily living. 

 
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• Moderate:  
A type of AE that is usually alleviated with additional specific therapeutic 
intervention.  The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
• Severe:  
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.   
Assessment of Causality 
• The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgment to determine 
the relationship. 
• A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated. 
• For causality assessment, the investigator will also consult the IB and/or product 
information, for marketed products. 
• The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes There may be situations in which an SAE has 
occurred and the investigator has minimal information to include in the initial report to the 
sponsor. However, it is very important that the investigator always assess causality for 
every event before the initial transmission of the SAE data to the sponsor.  
• The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• New or updated information will be recorded in the originally submitted documents. 
• The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information. 
10.3.5. Reporting of SAEs 
SAE Reporting to the sponsor via an Electronic Data Collection Tool 

 
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• The primary mechanism for reporting an SAE to the sponsor will be the electronic data 
collection tool. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be 
taken offline to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
offline, then the site can report this information on a paper SAE form (see next section) or 
to the sponsor by telephone. 
• Contacts for SAE reporting is listed in Appendix 18.  
10.3.6. Reporting of SUSAR 
The investigator will report SAE to the medical monitor. The medical monitor will evaluate if 
the SAE also is a SUSAR, if so, the medical monitor will report the SUSAR to the Competent 
Authority through Eudravigilance (EV). 
Sponsor will ensure that all relevant information about SUSARs that are fatal or life-
threatening is recorded and reported as soon as possible and in no case later than seven (7) 
days after knowledge by the sponsor of such a case, and that relevant follow-up information is 
subsequently communicated within an additional eight (8) days. 
Other SUSARs will be reported no later than 15 days after the incident. 
10.3.7. 
Annual safety reporting 
The sponsor is responsible for writing and submitting the annual safety report (ASR) for the 
clinical trial according to local regulations. 
 
 
 
 

 
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10.4. 
Appendix 4: Genetics 
Analysis of DNA 
• Genetic variation may impact a participant’s response to study intervention (i.e.the 
risk of disease flare) and susceptibility to, and severity and progression of disease. 
Variable response to study intervention may be due to genetic determinants that 
impact drug absorption, distribution, metabolism (including ADAb formation), and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis from consenting 
participants.  
• DNA analyses will only be done to answer trial specific explorative 
objectives/endpoints as described in section 3 related  research related to study 
intervention or immunogenicity related to the IMP. Genetic research may consist of 
the analysis of one or more candidate genes or the analysis of genetic markers 
throughout the genome or analysis of the entire genome (as appropriate). 
• The samples may be analyzed as part of a multi-study assessment of genetic factors 
related to study specific endpoints i.e.  response to study intervention or 
immunogenicity. . 
• The results of genetic analyses may be reported in the CSR or in a separate study 
summary. 
• The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
• The samples will be retained while research on study intervention or study 
interventions of this class or indication continues but no longer than 10 years or other 
period as per local requirements. 
 
 

 
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10.5. 
Appendix 5: Patient Global Assessment of Disease Activity (PGA) 
 
Provided in the “Not for publication” Protocol only 
 
 
 
 

 
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10.6. 
Appendix 6: Evaluator Global Assessment of Disease Activity 
(EGA) 
 
Provided in the “Not for publication” Protocol only 
 
 
 

 
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10.7. 
Appendix 7: Disease Activity Score using 28 joints – C-reactive 
protein (DAS28-CRP) 
 
Provided in the “Not for publication” Protocol only 
 
 
 

 
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10.8. 
Appendix 8: 44 joint count 
 
Provided in the “Not for publication” Protocol only 
 
 
 

 
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10.9. 
Appendix 9: Simple Disease Activity Index (SDAI) 
 
Provided in the “Not for publication” Protocol only 
 
 

 
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10.10. Appendix 10: Clinical Disease Activity Index (CDAI) 
 
Provided in the “Not for publication” Protocol only 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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10.11. Appendix 11: Rheumatoid Arthritis Flare Questionnaire (RA-FQ) 
 
Provided in the “Not for publication” Protocol only 
 

 
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10.12. Appendix 12: Rheumatoid Arthritis Impact of Disease (RAID) 
 
Provided in the “Not for publication” Protocol only 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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10.13. Appendix 13: Modified Heath Assessment Questionnaire (MHAQ) 
 
Provided in the “Not for publication” Protocol only 
 
 

 
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10.14. Appendix 14: The 36-Item Short-form Health Survey (SF-36) 
 
Provided in the “Not for publication” Protocol only 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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10.15. Appendix 15: European Quality of Life 5 Dimensions (EQ-5D)  
 
Provided in the “Not for publication” Protocol only 
 
 
 
 

 
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10.16. Appendix 16: Work Productivity and Activity Impairment 
Questionnaire: Rheumatoid Arthritis (WPAI:RA) 
 
Provided in the “Not for publication” Protocol only 
 
 
 

 
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10.17. Appendix 17: Compliance Assessment 
 
Provided in the “Not for publication” Protocol only 
 
 
 

 
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10.18. 
Appendix 18: Contact Details 
 
Provided in the “Not for publication” Protocol only 
STEERING COMMITTEE 
 
Coordinating 
Investigator 
 
 
Squeeze WP6 Lead 
and Sponsor 
Representative 
 
National Coordinating 
Investigator  
 
Laboratory 
Coordinating 
Investigator 
 
Trial Statistician   
 
 
 
Clinical Trial 
Methodologist 
 
Medical Lead  
 
Laboratory Lead 
 
 
Study Coordinator  
 
LOCAL ADVISORY 
BOARD   
 
SQUEEZE LEAD 
 
 
USER 
REPRESENTATIVES 
 

 
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STUDY GROUP 
Steering committee 
Local advisory board 
SQUEEZE lead 
PIs at participating study centers   
User representatives 
 
 
PARTICIPATING STUDY CENTERS  
 
 
MEDICAL MONITOR 
 
 

 
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11. 
References 
1. 
Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. The Lancet. 2016;388(10055):2023-
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3. 
Smolen JS, Landewe RBM, Bergstra SA, Kerschbaumer A, Sepriano A, Aletaha D, et al. 
EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological 
disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis. 2023;82(1):3-18. 
4. 
Jang DI, Lee AH, Shin HY, Song HR, Park JH, Kang TB, et al. The Role of Tumor Necrosis 
Factor Alpha (TNF-α) in Autoimmune Disease and Current TNF-α Inhibitors in Therapeutics. Int J Mol 
Sci. 2021;22(5). 
5. 
Mehta P, Manson JJ. What Is the Clinical Relevance of TNF Inhibitor Immunogenicity in the 
Management of Patients With Rheumatoid Arthritis? Front Immunol. 2020;11:589. 
6. 
Bartelds GM, Krieckaert CL, Nurmohamed MT, van Schouwenburg PA, Lems WF, Twisk JW, 
et al. Development of antidrug antibodies against adalimumab and association with disease activity 
and treatment failure during long-term follow-up. Jama. 2011;305(14):1460-8. 
7. 
Jyssum I, Gehin JE, Sexton J, Kristianslund EK, Hu Y, Warren DJ, et al. Adalimumab serum 
levels and anti-drug antibodies: associations to treatment response and drug survival in inflammatory 
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8. 
Gehin JE, Warren DJ, Syversen SW, Lie E, Sexton J, Loli L, et al. Serum golimumab 
concentration and anti-drug antibodies are associated with treatment response and drug survival in 
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Gehin JE, Goll GL, Warren DJ, Syversen SW, Sexton J, Strand EK, et al. Associations 
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Gehin JE, Goll GL, Brun MK, Jani M, Bolstad N, Syversen SW. Assessing Immunogenicity of 
Biologic Drugs in Inflammatory Joint Diseases: Progress Towards Personalized Medicine. BioDrugs. 
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Syversen SW, Gehin JE, Goll GL, Bolstad N, Haavardsholm EA, Lillegraven S. Therapeutic 
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Bonafede M, Johnson BH, Princic N, Shah N, Harrison DJ. Cost per patient-year in response 
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Brun MK, Bjørlykke KH, Viken MK, Stenvik GE, Klaasen RA, Gehin JE, et al. HLA-DQ2 is 
associated with anti-drug antibody formation to infliximab in patients with immune-mediated 
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Gravallese EM, Firestein GS. Rheumatoid Arthritis - Common Origins, Divergent Mechanisms. 
The New England journal of medicine. 2023;388(6):529-42. 
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Lillegraven S, van der Heijde D, Uhlig T, Kvien TK, Haavardsholm EA. What is the clinical 
relevance of erosions and joint space narrowing in RA? Nat Rev Rheumatol. 2012;8(2):117-20. 
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Smolen JS, Landewé RBM, Bijlsma JWJ, Burmester GR, Dougados M, Kerschbaumer A, et 
al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological 
disease-modifying antirheumatic drugs: 2019 update. Annals of the rheumatic diseases. 
2020;79(6):685-99. 

 
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17. 
Movahedi M, Hepworth E, Mirza R, Cesta A, Larche M, Bombardier C. Discontinuation of 
biologic therapy due to lack/loss of response and adverse events is similar between TNFi and non-
TNFi class: Results from a real-world rheumatoid arthritis cohort. Semin Arthritis Rheum. 
2020;50(5):915-22. 
18. 
Arora A, Mahajan A, Spurden D, Boyd H, Porter D. Long-Term Drug Survival of TNF Inhibitor 
Therapy in RA Patients: A Systematic Review of European National Drug Registers. Int J Rheumatol. 
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19. 
Markusse IM, Dirven L, Gerards AH, van Groenendael JH, Ronday HK, Kerstens PJ, et al. 
Disease flares in rheumatoid arthritis are associated with joint damage progression and disability: 10-
year results from the BeSt study. Arthritis Res Ther. 2015;17(1):232. 
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