Clinical trial NCT04577781
Conditions: Rheumatoid Arthritis
Keywords: Arthritis Rheumatic Diseases Moderately active rheumatoid arthritis Severely active rheumatoid arthritis Joint Diseases Autoimmune Diseases Musculoskeletal Diseases Musculoskeletal and connective tissue disorders
Sponsor: Galapagos NV
Start date: 2020-10-12; Completion date: 2021-04-07
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study was to evaluate the effect of GLPG3970 compared to placebo on the signs and symptoms of Rheumatoid Arthritis (RA) in participants with moderately to severely active RA and an inadequate response to methotrexate (MTX).

Detailed description:

Arms: arm 1: Participants received 400 milligrams (mg) GLPG3970 oral solution, once daily (QD) for a period of 6 weeks. arm 2: Participants received GLPG3970 matching placebo oral solution, QD for a period of 6 weeks.
Interventions: intervention 1: GLPG3970 intervention 2: Placebo
Intervention descriptions: intervention 1: GLPG3970 powder and solvent for oral solution to be reconstituted prior to use. intervention 2: Placebo powder and solvent for oral solution to be reconstituted prior to use.

Protocol documents:
Prot_000.pdf: 
-1- 
 
 
Confidentiality Statement 
The information contained in this document is privileged and confidential. It is the property of Galapagos NV and 
may not be used, disclosed, reproduced or otherwise disseminated within your organization or communicated to any 
third parties without the express written authorization of Galapagos NV. 
 
CLINICAL STUDY PROTOCOL 
Project Number: 
GLPG3970 
 
 
Study Number: 
GLPG3970-CL-209 
 
 
Study Title: 
A randomized, double-blind, placebo-controlled, multicenter study to evaluate 
the safety, tolerability, efficacy and pharmacokinetics of GLPG3970, 
administered orally for 6 weeks in adult subjects with moderately to severely 
active rheumatoid arthritis and an inadequate response to methotrexate  
Short Study Title: 
A study evaluating the effects of GLPG3970 given as an oral treatment for 6 
weeks in adults with moderately to severely active rheumatoid arthritis and 
an inadequate response to methotrexate 
Clinical Study 
Phase: 
2 
Protocol Version:  
1.0 
Date: 
29-May-2020 
Status: 
Final 
 
 
EudraCT No: 
2020-000658-83 
CT.gov No: 
to be confirmed 
IND No: 
not applicable 
Sponsor: 
Galapagos NV, Generaal De Wittelaan L11 A3, 2800 Mechelen, Belgium 
Clinical Scientist: 
 
Translational 
Medicine Leader: 
 
 
General Protocol 
 




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TABLE OF CONTENTS 
EMERGENCY CONTACT INFORMATION ........................................................................... 2 
TABLE OF CONTENTS ........................................................................................................ 3 
CLINICAL STUDY PROTOCOL HISTORY ............................................................................ 7 
SUMMARY OF CHANGES ................................................................................................... 8 
LIST OF TABLES .................................................................................................................. 9 
LIST OF FIGURES ................................................................................................................ 9 
LIST OF APPENDICES ......................................................................................................... 9 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................10 
1. 
CLINICAL STUDY PROTOCOL SYNOPSIS .................................................................17 
2. 
INTRODUCTION ...........................................................................................................22 
2.1. 
Background - Nonclinical Studies .......................................................................23 
2.1.1. 
Nonclinical Pharmacokinetics .............................................................23 
2.1.2. 
Safety Pharmacology ..........................................................................23 
2.1.3. 
General Toxicology .............................................................................23 
2.1.4. 
Genotoxicity ........................................................................................24 
2.1.5. 
Embryo-fetal Development Toxicity .....................................................24 
2.1.6. 
Phototoxicity .......................................................................................24 
2.2. 
Background - Clinical Studies ............................................................................24 
3. 
CLINICAL STUDY OBJECTIVES ..................................................................................25 
3.1. 
Primary Objectives .............................................................................................25 
3.2. 
Secondary Objective ..........................................................................................25 
3.3. 
Other Objectives ................................................................................................25 
4. 
ENDPOINTS .................................................................................................................25 
4.1. 
Primary Endpoints..............................................................................................25 
4.2. 
Secondary Endpoints .........................................................................................25 
4.3. 
Other Endpoints .................................................................................................26 
5. 
INVESTIGATIONAL PLAN ............................................................................................26 
5.1. 
Clinical Study Design .........................................................................................26 
5.2. 
Start and End of Study Definition .......................................................................27 
5.3. 
Clinical Study Rationale .....................................................................................27 
5.4. 
Dosing Rationale ...............................................................................................28 
5.5. 
Potential Risks and Benefits ..............................................................................28 
6. 
CLINICAL STUDY POPULATION .................................................................................30 
6.1. 
Inclusion Criteria ................................................................................................30 




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9. 
STATISTICAL METHODS .............................................................................................57 
9.1. 
Determination of Sample Size ............................................................................57 
9.2. 
Population for Analyses .....................................................................................57 
9.2.1. 
All Screened Subjects .........................................................................57 
9.2.2. 
All Randomized Subjects ....................................................................58 
9.2.3. 
Full Analysis Set .................................................................................58 
9.2.4. 
Safety Analysis Set .............................................................................58 
9.3. 
Statistical Analyses ............................................................................................58 
9.3.1. 
General Statistical Considerations ......................................................58 
9.3.2. 
Interim Analysis ..................................................................................58 
9.3.3. 
Analyses of Demographics and Baseline Characteristics ....................59 
9.3.4. 
Analyses of Efficacy Parameters .........................................................59 
9.3.4.1. 
Analysis for Primary Efficacy Endpoint...............................59 
9.3.4.2. 
Analyses for Other Efficacy Endpoints ...............................59 
9.3.5. 
Analyses of Safety Data ......................................................................59 
9.3.5.1. 
Extent of Exposure ............................................................60 
9.3.5.2. 
Adverse Events .................................................................60 
9.3.5.3. 
Clinical Laboratory Evaluations ..........................................60 
9.3.5.4. 
Physical Examinations .......................................................60 
9.3.5.5. 
Vital Signs .........................................................................60 
9.3.5.6. 
12-Lead Electrocardiogram ................................................61 
9.3.6. 
Pharmacokinetic Analyses ..................................................................61 
 
 
9.3.8. 
Additional Statistical Considerations ...................................................61 
10. DATA MONITORING .....................................................................................................61 
10.1. 
Data Safety Monitoring Committee ....................................................................61 
11. SAFETY REPORTING ..................................................................................................62 
11.1. 
Definitions of Adverse Events, Serious Adverse Events and Special 
Situations ...........................................................................................................62 
11.1.1. 
Adverse Events ...................................................................................62 
11.1.2. 
Serious Adverse Events ......................................................................62 
11.1.3. 
Unlisted (Unexpected) Adverse Events/ Reference Safety 
Information ..........................................................................................63 
11.1.4. 
Adverse Events of Special Interest .....................................................63 
11.1.5. 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as Adverse Events or Serious Adverse Events .............63 
11.1.6. 
Special Situations ...............................................................................63 
11.2. 
Assessment of Adverse Events and Serious Adverse Events ............................64 
11.2.1. 
Assessment of Causality .....................................................................64 
11.2.2. 
Assessment of Severity ......................................................................65 
11.2.3. 
Action Taken Regarding Investigational Product .................................66 
11.2.4. 
Outcome .............................................................................................66 
11.3. 
Investigator Requirements and Instructions for Reporting Adverse Events, 
Serious Adverse Events, Pregnancies, and Other Special Situations to the 
Sponsor .............................................................................................................66 


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11.3.1. 
Adverse Events ...................................................................................66 
11.3.2. 
Serious Adverse Events ......................................................................67 
11.3.3. 
Pregnancy ..........................................................................................67 
11.3.4. 
Reporting of Special Situations (Other Than Pregnancy) and 
Associated Adverse Events ................................................................68 
11.4. 
Sponsor Reporting Requirements ......................................................................68 
12. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES .........................................68 
12.1. 
Sponsor’s Responsibilities .................................................................................69 
12.1.1. 
Regulatory Authority Approval ............................................................69 
12.1.2. 
Clinical Study Closure Considerations ................................................69 
12.1.3. 
Indemnification ....................................................................................69 
12.1.4. 
Insurance ............................................................................................70 
12.1.5. 
Archiving .............................................................................................70 
12.1.6. 
Reporting ............................................................................................70 
12.1.7. 
Publication ..........................................................................................70 
12.2. 
Investigator’s Responsibilities ............................................................................71 
12.2.1. 
Source Data and Data Capture ...........................................................71 
12.2.2. 
Archiving .............................................................................................71 
12.2.3. 
Participation Cards ..............................................................................71 
12.3. 
Confidentiality ....................................................................................................71 
12.4. 
Ethical Considerations .......................................................................................72 
12.4.1. 
Independent Ethics Committee / Institutional Review Board ...............72 
12.4.2. 
Informed Consent ...............................................................................73 
12.5. 
Data Quality Control/Assurance .........................................................................74 
12.5.1. 
Monitoring ...........................................................................................74 
12.5.2. 
Audit and Inspection ...........................................................................74 
13. REFERENCES ..............................................................................................................75 
14. APPENDICES ...............................................................................................................77 
SIGNATURE PAGE – SPONSOR ........................................................................................88 
SIGNATURE PAGE – INVESTIGATOR ...............................................................................89 
 
 


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CLINICAL STUDY PROTOCOL HISTORY 
Clinical Study Protocol (CSP) / 
Amendment # 
Date 
Main Rationale 
General / Country-Specific 
CSP Version 1.0 
29-May-2020 
Initial CSP Version 
General  
 
 


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SUMMARY OF CHANGES 
Not applicable because this is the initial clinical study protocol (CSP). 
 
 
 




 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations 
 
 
ACR 
American College of Rheumatology 
ADL 
Activities of Daily Living 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
BCRP 
Breast cancer resistance protein 
bDMARD 
biologic disease-modifying anti-rheumatic drug 
bpm 
beats per minute 
BMI 
body mass index 
 
 
CI 
confidence interval 
CIA 
collagen-induced arthritis 
CL 
clearance 
CLCr 
creatinine clearance 
CL/F 
apparent total clearance 
Cmax 
maximum observed plasma concentration 
CRF 
case report form 
CRP 
C-reactive protein 
CRO 
contract research organization 




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HDL 
high-density lipoprotein 
hERG 
human ether-a-go-go related gene 
HIV 
human immunodeficiency virus 
HOMA-IR 
Homeostatic model assessment of insulin resistance 
hsCRP 
high sensitivity C-reactive protein 
IB 
investigator’s brochure 
IC50 
half maximum inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
IL 
interleukin 
IP 
investigational product 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IXRS 
interactive voice/web response system 
JAK 
Janus kinase 
LDL 
low-density lipoprotein 
LFT 
liver function test 
LPS 
lipopolysaccharide 
LRV 
lower reference value 
MMRM 
mixed models for repeated measures 
mRNA 
messenger ribonucleic acid 
MTX 
methotrexate 


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NOAEL 
no-observed-adverse-effect level 
NSAID 
non-steroidal anti-inflammatory drug 
P1NP 
serum N terminal propeptide type I collagen 
PBMC 
peripheral blood mononuclear cells 
 
 
PK 
pharmacokinetic 
pop-PK 
population pharmacokinetics 
q.d. 
once daily 
QTcF 
QT interval corrected for the heart rate using Fridericia’s formula 
QTv 
QT interval corrected by heart rate using the van de Water formula 
RA 
rheumatoid arthritis 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
 
 
SIK 
salt-inducible kinase 
SJC66 
swollen joint count evaluated in 66 joints 
SOC 
System Organ Class 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
elimination half-life 
TB 
tuberculosis 
TEAE 
treatment-emergent adverse event 
TJC68 
tender joint count evaluated in 68 joints 


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TNF 
tumor necrosis factor 
TNFi 
tumor necrosis factor inhibitor 
TV 
target value 
ULN 
upper limit of normal 
VAS 
visual analog scale 
Vss 
volume of distribution at steady state 
WOCBP 
women of childbearing potential 
 
 






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1. 
CLINICAL STUDY PROTOCOL SYNOPSIS 
Title of Study 
A randomized, double-blind, placebo-controlled, multicenter study to evaluate the safety, 
tolerability, efficacy and pharmacokinetics of GLPG3970, administered orally for 6 weeks in 
adult subjects with moderately to severely active rheumatoid arthritis and an inadequate 
response to methotrexate 
Short Title of Study 
A study evaluating the effects of GLPG3970 given as an oral treatment for 6 weeks in adults 
with moderately to severely active rheumatoid arthritis and an inadequate response to 
methotrexate 
Phase of Development: Phase 2 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary  
 
To evaluate the effect of GLPG3970 compared to 
placebo on the signs and symptoms of rheumatoid 
arthritis (RA) in subjects with moderately to 
severely active RA and an inadequate response to 
methotrexate (MTX). 
Change from baseline in DAS28 (C-reactive protein 
[CRP]) at Week 6. 
Secondary 
 
To evaluate the safety and tolerability of 
GLPG3970 compared to placebo in subjects with 
moderately to severely active RA and an inadequate 
response to MTX. 
Number, incidence and severity of treatment-
emergent adverse events (TEAEs). 
To characterize the pharmacokinetics (PK) of 
GLPG3970 in subjects with moderately to severely 
active RA and an inadequate response to MTX. 
Observed GLPG3970 plasma trough concentrations 
(Ctrough). 


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The study is planned to randomize 25 subjects in a 3:2 ratio (15 subjects planned to receive 
GLPG3970 and 10 subjects planned to receive placebo). 
Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter parallel-group 
study evaluating GLPG3970 in adult subjects with moderately to severely active RA and an 
inadequate response to MTX. In this study, subjects will receive 1 dose level of GLPG3970 
(400 mg once daily [q.d.]) or placebo on top of their stable dose and dosing regimen of MTX. 
The study will consist of 3 study periods: 
− 
Screening period: up to 3 weeks with 1 study visit.  
− 
Double-blind treatment period: 6 weeks with 4 study site visits (Days 1, 15, 29, and 43) 
and 1 telephone call (Day 8). 
− 
Follow-up (FU) period: 2 weeks with 1 study visit. 
A schematic diagram of clinical study design, procedures, and stages is provided below. 
Study Duration 
Subjects will participate in the study for a maximum of 11 weeks (screening to FU) and will 
receive oral GLPG3970 or placebo, as a reconstituted oral solution, q.d. for 6 weeks. 


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Main Criteria for Inclusion and Exclusion 
Main Inclusion Criteria 
1. Male or female subject ≥18 and <65 years of age, on the date of signing the informed 
consent form (ICF). 
2. A body mass index (BMI) between 18–32 kg/m2, inclusive. 
3. Diagnosis of RA ≥6 months prior to screening AND meeting the 2010 ACR/ EULAR 
criteria of RA AND ACR functional class I-III. 
4. Have ≥6 swollen joints (from a SJC66) AND ≥8 tender joints (from a TJC68) at screening 
and at the baseline visit (Visit 1) prior to the first IP dosing. 
5. DAS28 (CRP) >3.2 (moderate disease) at screening. 
6. Screening serum high sensitivity CRP (hsCRP) > upper limit of normal (ULN, central 
laboratory reference: ≤ 5.0 mg/L). 
7. Inadequate response to MTX, i.e. treatment-experienced subjects who demonstrated 
inadequate clinical response during treatment with MTX. 
8. Have received MTX for ≥6 months and on stable dose (10 to 20 mg/week) of MTX for at 
least 4 weeks prior to screening and willing to continue on their current stable dose and 
dosing regimen for the duration of the study. 
9. If taking systemic steroids, prednisone equivalent at a dose of ≤10 mg/day and stable for 
at least 4 weeks prior to the first IP dosing. 
Main Exclusion Criteria 
1. Current therapy with any conventional disease-modifying anti-rheumatic drug (DMARD) 
other than MTX, including 
a. 
 oral or injectable gold, sulfasalazine, antimalarials, azathioprine, or D-penicillamine 
within 4 weeks prior to screening,  
b. cyclosporine within 8 weeks prior to screening, and  
c. 
leflunomide within 3 months prior to screening or a minimum 4 weeks prior to 
screening if after 11 days of standard cholestyramine therapy. 
2. Current or previous treatment with a biologic DMARD (bDMARD). Except for subjects 
who received bDMARDs only in a single clinical study setting: 
a. 
For whom the last dose of bDMARD ≥6 months prior to screening (12 months for 
rituximab or other lymphocyte depleting agents), AND; 
b. For whom the bDMARD was effective, without being discontinued due to lack of 
efficacy. 
3. Subjects who received an intra-articular or parenteral corticosteroid injection within 4 
weeks prior to screening. 
4. Subjects who received a prior surgical intervention within 12 weeks prior to screening or 
likely requirement for surgery during the study. 
5. Subject has a history of tuberculosis (TB) diagnosis or evidence of active or latent 
infection with Mycobacterium tuberculosis as defined by one of the following 
assessments: 
a. 
Positive QuantiFERON-TB Gold test result at screening, OR 


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b. Chest radiograph (posterior anterior view) taken within 12 weeks prior to screening, 
read by a qualified radiologist or pulmonologist, with evidence of current active TB 
or old inactive TB. 
6. Subject has any active systemic infection within the last 2 weeks prior to first IP dosing, 
or poorly controlled chronic cardiac, pulmonary, or renal disease. 
7. Subject has a known or suspected history of or a current immunosuppressive condition, or 
a history of invasive opportunistic infections (e.g. human immunodeficiency virus [HIV] 
infection, histoplasmosis, listeriosis, coccidiodmycosis, pneumocystosis, aspergillosis). 
8. Subject has a chronic hepatitis B virus (HBV) infection, as defined by persistent HBV 
surface antigen (HBsAg) positivity. Subject has hepatitis C virus (HCV) infection, as 
defined by positive HCV antibody at screening and detectable HCV viremia. Subjects 
with positive HCV antibody must undergo reflex HCV RNA testing, and subjects with 
HCV RNA positivity will be excluded. Subjects with positive HCV antibody and negative 
HCV RNA are eligible. 
9. Subject testing positive at screening for SARS-CoV-2 infection as detected by real time 
polymerase chain reaction (RT-PCR), subjects presenting any signs or symptoms as 
detected at baseline following careful physical examination (e.g. cough, fever, headaches, 
fatigue, dyspnea, myalgia, anosmia, dysgeusia, anorexia, sore throat, others) or reporting 
any signs and symptoms for the 2 preceding weeks, or subjects who have been exposed to 
individuals with confirmed or suspected diagnosis of SARS-CoV-2 within 2 weeks prior 
to baseline. In addition, any other locally applicable standard diagnostic criteria may also 
apply to rule out SARS-CoV-2 infection. 
Treatment and Treatment Schedule 
 
Investigational Medicinal Product, Dosage, and Mode of Administration 
GLPG3970 will be provided as a powder and solvent for oral solution, to be reconstituted 
prior to use. The final dosage form for administration is an oral solution containing 400 mg of 
the active pharmaceutical ingredient G1567970 (G1567970 is the compound code for 
Key selection criteria
• Inadequate response to
MTX
• Age ≥18 and <65 years
• RA diagnosis by ACR/EULAR 
criteria 
• ≥6 swollen joints from 
SJC66 and ≥8 tender joints 
from TJC68, CRP > ULN, 
DAS28 (CRP) > 3.2
Double-blind Treatment Period
Day 1 (Baseline) to Week 6
Follow-up Period
2 Weeks following  
end of Treatment
Screening
Up to 3 weeks
3:2 RANDOMIZATION
Group B (Placebo, n=10)
Group A (GLPG3970 400 mg q.d., n=15)
Key Outcome Measures
• Rate and severity TEAEs
• DAS28 (CRP)
• PK
•




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2. 
INTRODUCTION 
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory and joint degenerative disease 
that affects almost 1% of the adult population worldwide. The onset of RA classically occurs 
around 40 years of age (Oton & Carmona, 2020) and RA has a higher prevalence in women. The 
disease is characterized by pain, stiffness, and restricted mobility due to a persistent symmetrical 
inflammation of the synovial membrane of multiple joints that ultimately results in irreversible 
damage of the joint cartilage and bone (Smolen, Aletaha, Koeller, Weisman, & Emery, 2007). 
The treatment of RA aims to reduce synovial inflammation, relieve pain, prevent joint damage 
and deterioration of physical function and the final goal is to achieve remission or at least low 
disease activity for all patients. To date, monotherapy with methotrexate (MTX), a disease-
modifying anti-rheumatoid drug (DMARD), is the recommended first-line treatment for patients 
with RA. Many patients fail to respond or don’t achieve disease remission with MTX 
(Chatzidionysiou & Sfikakis, 2019; Köhler, Günther, & Kaudewitz, 2019). In clinical trials, 
remission rates with MTX (with or without corticosteroids) range from 15% to 50.8% in subjects 
with early RA (disease duration <1 year) and from 7.6% to 28% in subjects with RA disease 
duration >1 year (Chatzidionysiou & Sfikakis, 2019). For patients with moderate or high disease 
activity despite DMARD therapy, it is recommended to use a combination of DMARDs with a 
tumor necrosis factor inhibitor (TNFi), or a non-TNF biologic and, in the case of established RA, 
a Janus kinase (JAK) inhibitor can be used (Smolen, et al., 2020). Glucocorticoids are often used 
in combination during acute disease flares to relieve pain and swelling fast and to gain control of 
the inflammation. A number of pro-inflammatory cytokines including TNF and interleukin-6 (IL-
6) are involved in the pathophysiology of RA and thus, biologic DMARDs (bDMARDs), 
targeting those cytokines and cells of the immune system have been approved for the treatment of 
RA (such as adalimumab, etanercept, infliximab, abatacept, rituximab, tocilizumab etc.). Due to 
the inconvenience of parenteral administration, safety, and tolerability issues (e.g. increased risk 
for infection and potential immunogenicity), and failure or only partial response to biologicals, 
there is still a need for safer, better tolerable, and orally active drugs with a different mechanism 
of action that can effectively modify the disease course. Oral, small-molecule inhibitors of 
intracellular kinases might bring therapeutic benefit in a wide range of inflammatory diseases and 
could address this need. More recently, JAK inhibitors demonstrated good efficacy in patients 
with RA. Even though many efficient drugs are currently available for the treatment for RA, 
many patients still suffer from ongoing symptoms and don’t achieve the final goal which is 
sustained disease remission and drug-free remission (Ajeqanova & Huizinga, 2017). Thus, there 
is still unmet medical need for patients with RA. 
GLPG3970 has a dual mechanism of action with the potential to improve upon the currently 
available treatments, via the induction of immunoregulatory mechanisms in addition to its anti-
inflammatory properties. GLPG3970 is an oral, selective, small-molecule serine/threonine salt-
inducible kinase (SIK) 2 and 3 inhibitor. These kinases provide a molecular switch in the control 
of pro- and anti-inflammatory cytokine production. Inhibition of these targets blocks the 
production of pro-inflammatory cytokines (TNFα, IL-12) and increases IL-10 levels, which has a 
tolerogenic effect, by activated macrophages and dendritic cells, thereby, converting the 
inflammatory state of these cells toward regulatory and tolerogenic phenotypes. In a mouse 
model of RA, treatment with GLPG3970 reduced disease activity. 










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Refer to the Schedule of Activities (Section 8.11) for further details.  
A schematic diagram of clinical study design, procedures and stages is provided in Figure 1. 
 
Figure 1 
Schematic Diagram 
For detailed information regarding dosage form, packaging and labeling of the investigational 
product (IP) refer to Section 7.2, “Dosage and Administration” and Section 7.3, “Packaging, 
Labeling and Distribution”. 
5.2. 
Start and End of Study Definition 
The study start is defined when the first informed consent form (ICF) is signed. The end of the 
study is reached when the last FU visit, as planned according to the Schedule of Activities 
(Section 8.11), for the last subject is performed. 
5.3. 
Clinical Study Rationale 
Published data showed that RA results from a breakdown of immune tolerance (Smolen, Aletaha, 
Koeller, Weisman, & Emery, 2007). GLPG3970 displays a unique dual mode of action with an 
anti-inflammatory component (reduction of pro-inflammatory cytokines by activated monocytes, 
macrophages, dendritic cells and T cells) coupled with a robust induction of immunoregulatory 
mechanisms (induced production of IL-10) in activated monocytes, macrophages and dendritic 
cells. The mouse collagen-induced arthritis (CIA) model is one of the most widely used models 
for the study of new therapeutic treatment options in RA and mimics the characteristics of human 
RA. GLPG3970 has demonstrated therapeutic potential in this model at the highest dose of 
60 mg/kg b.i.d. tested, similar to anti-TNFα treatment used as active comparator in the model. 
Treatment with GLPG3970 showed a significant effect on protection against bone erosion 
(Larsen score) and significantly reduced the production of total immunoglobulin G (IgG) levels, 
quantified in plasma as a measure of the autoreactive B cell state in the arthritic CIA model. 
These data provide strong rationale for the evaluation of GLPG3970 in subjects with RA. 
The double-blind, placebo-controlled, randomized, parallel-group design is a standard design for 
a first study of GLPG3970 in subjects with RA. 
Key selection criteria
• Inadequate response to
MTX
• Age ≥18 and <65 years
• RA diagnosis by ACR/EULAR 
criteria 
• ≥6 swollen joints from 
SJC66 and ≥8 tender joints 
from TJC68, CRP > ULN, 
DAS28 (CRP) > 3.2
Double-blind Treatment Period
Day 1 (Baseline) to Week 6
Follow-up Period
2 Weeks following  
end of Treatment
Screening
Up to 3 weeks
3:2 RANDOMIZATION
Group B (Placebo, n=10)
Group A (GLPG3970 400 mg q.d., n=15)
Key Outcome Measures
• Rate and severity TEAEs
• DAS28 (CRP)
• PK
•






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may be performed during a SARS-CoV-2 pandemic, the age limit of participants was set to 65 
years of age and appropriate measures should be taken to minimize the risk of SARS-CoV-2 
infection for subjects participating in the study as well as study site personnel. Local guidelines to 
prevent SARS-CoV-2 infection should be adhered to and a leaflet should be made available for 
all subjects detailing the SARS-CoV-2 safety measures to be taken.  
In case a randomized subject is not available to attend a scheduled study visit on site due to 
SARS-CoV-2 travel restrictions, a phone call or a televisit may be conducted instead. It is 
strongly recommended to conduct planned study assessments for the applicable visit as per 
protocol as much as possible. If possible and if local regulations allow and the subject agrees, 
trained study staff or trained personnel are encouraged to collect study assessments at the study 
subjects’ home or a local facility if social distancing and hygiene rules can be applied.  
Only staff trained in conducting the protocol planned assessments are authorized to perform 
home or local facility visit assessments and the alternative arrangements need to be adequately 
documented. Direct to patient (DTP) shipments are possible if needed. Subjects presenting with 
signs and symptoms of infection, including SARS-CoV-2 infection should immediately contact 
the site investigator, who should inform the sponsor’s medical responsible as soon as possible, 
and SARS-CoV-2 testing should be performed. 
6. 
CLINICAL STUDY POPULATION 
6.1. 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study: 
1. Male or female subject ≥18 and <65 years of age, on the date of signing the ICF. 
2. A body mass index (BMI) between 18–32 kg/m2, inclusive. 
3. Diagnosis of RA ≥6 months prior to screening AND meeting the 2010 ACR/EULAR criteria 
of RA AND ACR functional class I-III. 
4. Have ≥6 swollen joints (from a SJC66) AND ≥8 tender joints (from a TJC68) at screening 
and at the baseline visit (Visit 1) prior to the first IP dosing. 
5. DAS28 (CRP) >3.2 (moderate disease) at screening. 
6. Screening serum high sensitivity CRP (hsCRP) > upper limit of normal (ULN, central 
laboratory reference: ≤ 5.0 mg/L). 
7. Inadequate response to MTX, i.e. treatment-experienced subjects who demonstrated 
inadequate clinical response during treatment with MTX. 
8. Have received MTX for ≥6 months and on stable dose (10 to 20 mg/week) of MTX for at 
least 4 weeks prior to screening and willing to continue on their current stable dose and 
dosing regimen for the duration of the study.  
9. If taking systemic steroids, prednisone equivalent at a dose of ≤10 mg/day and stable for at 
least 4 weeks prior to the first IP dosing. 
10. If taking non-steroidal anti-inflammatory drugs (NSAIDs), these must be at a stable dose for 
at least 2 weeks prior to first IP dosing. 
11. Female subjects of childbearing potential must have a negative highly sensitive (serum beta 
human chorionic gonadotropin) pregnancy test at screening. Female subjects of non-


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childbearing potential must have a negative FSH test at screening or must be at least 6 
months permanently surgically sterile (bilateral oophorectomy, i.e. surgical removal of 
ovaries, bilateral salpingectomy or hysterectomy, i.e. surgical removal of uterus).  
12. Female subject of child bearing potential or male subject must agree to use highly effective 
contraception/preventive exposure measures (as described in Section 6.3.1).  
13. Able and willing to comply with the CSP requirements (e.g. opening and reconstituting the 
IP formulation) and must sign and date the ICF as approved by the Independent Ethics 
Committee (IEC) / Institutional Review Board (IRB), prior to any screening evaluations. 
14. Able and willing to comply with restrictions on prior and concomitant medication as 
described in Section 6.3.2. 
6.2. 
Exclusion Criteria 
Subjects meeting one or more of the following criteria cannot be enrolled in this clinical study: 
1. Current therapy with any conventional DMARD other than MTX, including 
a. 
Oral or injectable gold, sulfasalazine, antimalarials, azathioprine, or D-penicillamine 
within 4 weeks prior to screening,  
b. Cyclosporine within 8 weeks prior to screening, and  
c. 
Leflunomide within 3 months prior to screening or a minimum 4 weeks prior to 
screening if after 11 days of standard cholestyramine therapy. 
2. Current or previous treatment with a bDMARD. Except for subjects who received 
bDMARDs only in a single clinical study setting: 
a. 
For whom the last dose of bDMARD ≥6 months prior to screening (12 months for 
rituximab or other lymphocyte depleting agents), AND; 
b. For whom the bDMARD was effective, without being discontinued due to lack of 
efficacy. 
3. Subjects who received an intra-articular or parenteral corticosteroid injection within 4 weeks 
prior to screening. 
4. Subjects who received a prior surgical intervention within 12 weeks prior to screening or 
likely requirement for surgery during the study. 
5. Subject has a history of tuberculosis (TB) diagnosis or evidence of active or latent infection 
with Mycobacterium tuberculosis as defined by one of the following assessments: 
a. 
Positive QuantiFERON-TB Gold test result at screening, OR 
b. Chest radiograph (posterior anterior view) taken within 12 weeks prior to screening, read 
by a qualified radiologist or pulmonologist, with evidence of current active TB or old 
inactive TB. 
6. Subject has any active systemic infection within 2 weeks prior to first IP dosing, or poorly 
controlled chronic cardiac, pulmonary, or renal disease. 
7. Subject has a known or suspected history of or a current immunosuppressive condition, or a 
history of invasive opportunistic infections (e.g. HIV infection, histoplasmosis, listeriosis, 
coccidiodmycosis, pneumocystosis, aspergillosis). 
8. Subject has a chronic hepatitis B virus (HBV) infection, as defined by persistent HBV 
surface antigen (HBsAg) positivity. Subject has hepatitis C virus (HCV) infection, as defined 


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by positive HCV antibody at screening and detectable HCV viremia. Subjects with positive 
HCV antibody must undergo reflex HCV RNA testing, and subjects with HCV RNA 
positivity will be excluded. Subjects with positive HCV antibody and negative HCV RNA 
are eligible. 
9. Subject testing positive at screening for SARS-CoV-2 infection as detected by real time 
polymerase chain reaction (RT-PCR), subjects presenting any signs or symptoms as detected 
at baseline following careful physical examination (e.g. cough, fever, headaches, fatigue, 
dyspnea, myalgia, anosmia, dysgeusia, anorexia, sore throat, others) or reporting any signs 
and symptoms for the 2 preceding weeks, or subjects who have been exposed to individuals 
with confirmed or suspected diagnosis of SARS-CoV-2 within 2 weeks prior to baseline 
(BMJ, 2020) (BMJ, 2020). In addition, any other locally applicable standard diagnostic 
criteria may also apply to rule out SARS-CoV-2 infection. 
10. Investigator or other study staff or relative thereof who is directly involved in the conduct of 
the study. 
11. Subject has any condition or circumstances that, in the opinion of the investigator, may make 
a subject unlikely or unable to complete the study or comply with study procedures and 
requirements. 
12. Subject has a known hypersensitivity to IP ingredients or history of a significant allergic 
reaction to IP ingredients as determined by the investigator. 
13. Subject has any illness, judged by the investigator as relevant for participation in the study, 
in the 3 months prior to the first dose of the IP. 
14. Subject has presence or sequelae of gastrointestinal, liver, kidney (creatinine clearance 
[ClCr] ≤90 mL/minute, for elderly ≤60 mL/minute, using the Cockcroft-Gault formula: if 
calculated result is ≤90 mL/minute, for elderly ≤60 mL/minute, if applicable, a 24-hour urine 
collection can be used) or other conditions known to interfere with the absorption, 
distribution, metabolism, or excretion of drugs. 
15. Subject has a history of malignancy within the past 5 years prior to screening with the 
exception of excised and curatively treated non-metastatic basal cell carcinoma or squamous 
cell carcinoma of the skin or carcinoma in situ cervix which is considered cured with 
minimal risk of recurrence. 
16. Subject concurrently participates or participated in a drug, drug/device or biologic 
investigational research study within 3 months or 5 half-lives of the IP, whichever is longer, 
prior to screening. 
17. Subject has a history or presence of clinically significant abnormalities detected on 12-lead 
ECG of either rhythm or conduction e.g. known long QT syndrome or a QTcF >450 ms 
(male), >460 ms (female) detected on the 12-lead ECG. A first-degree atrioventricular block 
will not be considered as a significant abnormality. 
18. Female subject is breast feeding or intending to become pregnant or breastfeed during the 
study. 
19. Subject was vaccinated with a live vaccine within 60 days prior to screening. 


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6.3. 
Prohibition and Restrictions 
6.3.1. 
Precautions for Sexual Intercourse 
Highly effective contraceptive measures for both males and females of childbearing potential 
must be documented in the source documents. 
6.3.1.1. 
Female Subjects 
Female subjects are considered of non-childbearing potential if they meet one of the following 
criteria: 
− 
No menses for 12 or more months without an alternative medical cause. A high follicle 
stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal replacement 
therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient. 
− 
Permanently surgically sterile (bilateral oophorectomy, i.e. surgical removal of ovaries, 
bilateral salpingectomy or hysterectomy, i.e. surgical removal of uterus). 
All other female subjects are considered to be of childbearing potential (WOCBP) and must use 
one of the following highly effective methods of birth control prior to the first dose of IP, during 
the clinical study and for at least 35 days after the last dose of IP: 
− 
Combined (estrogen and progesterone containing) (oral, intravaginal, transdermal) hormonal 
contraception associated with inhibition of ovulation plus a barrier method. 
− 
Progesterone-only hormonal (oral, injectable, implantable) contraception associated with 
inhibition of ovulation plus a barrier method. 
− 
Intrauterine device. 
− 
Intrauterine hormone-releasing system plus a barrier method. 
− 
Bilateral tubal occlusion. 
− 
Sexual abstinence defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments. The reliability of sexual abstinence needs 
to be evaluated in relation to the duration of the clinical study and the preferred and usual 
lifestyle of the subject. 
Periodic abstinence (e.g. calendar, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of a clinical study, withdrawal, spermicides only, and lactational 
amenorrhea method are not acceptable as methods of contraception. 
In case a WOCBP has a vasectomized partner, provided that partner is the sole sexual partner of 
the WOCBP clinical study participant and that the vasectomized partner has received medical 
assessment of the surgical success, then she is not required to use an additional form of 
contraception. 


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Within these limits, the specific forms of contraception employed are left to the discretion of the 
subject, the investigator, and/or the subject’s physician. 
The safety of GLPG3970 during breastfeeding is unknown. Nursing women are not allowed to 
take part in this clinical study. 
6.3.1.2. 
Male Subjects 
Non-vasectomized male subjects with female partners of childbearing potential must be willing 
to use a condom from the time of the first dose of IP, during the clinical study and for at least 
7 days after the last dose of IP, in addition to having their female partner use one of the following 
forms of contraception: 
− 
Combined (estrogen and progesterone containing) (oral, intravaginal, transdermal) hormonal 
contraception associated with inhibition of ovulation. 
− 
Progesterone-only hormonal (oral, injectable, implantable) contraception associated with 
inhibition of ovulation. 
− 
Intrauterine device. 
− 
Intrauterine hormone-releasing system. 
 
Sexual abstinence defined as refraining from heterosexual intercourse is considered a highly 
effective contraceptive measure only if it is the preferred and usual lifestyle of the subject. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical 
study. 
Periodic abstinence (e.g. calendar, symptothermal and post-ovulation methods), declaration of 
abstinence for the duration of a clinical study, withdrawal, spermicides only and lactational 
amenorrhea method are not acceptable methods of contraception. 
In a case where the female partner of a male subject has undergone documented surgical 
sterilization that was performed more than one year before screening, then the subject is not 
required to use an additional form of contraception. 
Vasectomized male subjects with female partners of childbearing potential are not required to use 
an additional form of contraception providing that surgical sterilization has been successful 
(documented azoospermia by semen analysis). 
No sperm donation is allowed from the first dose of IP during the clinical study until 7 days after 
the last dose of IP. 
6.3.2. 
Prior and Concomitant Medications 
Prior and concomitant therapies taken for long term treatment of pre-existing conditions are 
allowed, provided they are in accordance with the inclusion and exclusion criteria (see 
Section 6.1 and Section 6.2, respectively) and with the prohibitions and restrictions listed below. 


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Information on previous inadequate response on MTX therapy for RA within 2 years prior to 
screening should be recorded with approximate dates of use (year, duration in months) and dose. 
In case additional concomitant medications need to be administered or dose adjustments for pre-
existing conditions (except for RA) are needed during the study, the risk/benefit to the subject 
should be carefully assessed by the study physician and consideration given to the timing of any 
necessary introduction of new medications. 
If during the study, the subject’s condition necessitates the use of prohibited medication, the use 
of IP may be interrupted, preferably after consultation with the sponsor’s medical responsible. 
Re-introduction of IP can be considered after the treatment course with the prohibited medication 
has been stopped and after consultation with the sponsor’s medical responsible.  
During the study, subjects will be instructed to record any change in concomitant medication in a 
diary (see Section 8.8.1). 
Permitted Medications 
Permitted medications at screening and during the study include: 
− 
NSAIDs, provided that the dose is stable for at least 2 weeks prior to first IP dosing and, if 
possible, is kept constant during the study. 
− 
Analgesics, other than NSAIDs, up to the maximum recommended doses may be used for 
pain as required.  
− 
Oral steroids, provided that the dose is stable, at a dose of ≤10 mg/day prednisone or 
equivalent (see Appendix 7 for prednisolone conversion table) for at least 4 weeks prior to 
first IP dosing, and is kept stable for the study duration.  
− 
Medications prescribed for the treatment of comorbidities and which are not described as 
prohibited medications. 
Prohibited Medications 
Prohibited medications during the study include any DMARDs, other than background MTX, 
including: 
− 
Oral or injectable gold, sulfasalazine, antimalarials, azathioprine, or D-penicillamine within 
4 weeks prior to screening, 
− 
cyclosporine within 8 weeks prior to screening, 
− 
leflunomide within 3 months prior to screening or within 4 weeks prior to screening if after 
11 days of standard cholestyramine therapy. 
Current or previous treatment with a bDMARD. Except for subjects who received bDMARDs in 
a single clinical study setting: 
− 
For whom the last dose of bDMARD ≥6 months prior to screening (12 months for rituximab 
or other lymphocyte depleting agents), AND; 
− 
For whom the bDMARD was effective, without being discontinued due to lack of efficacy. 






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documents, and the subject will be asked to complete the ED visit and FU visit for safety 
assessments. 
Treatment with IP should be discontinued by the investigator (who may consult the sponsor’s 
medical responsible) for any of the following conditions: 
− 
Life-threatening adverse event (AE) or a serious adverse event (SAE) that places the subject 
at immediate risk. 
− 
Serious infections deemed related to study treatment by the investigator, and requiring 
parenteral antimicrobial therapy and/or hospitalization. 
− 
Confirmed pregnancy or lactation. 
− 
Arrhythmia or conduction abnormality, including but not limited to prolonged QT interval 
corrected for the heart rate using Fridericia’s formula (QTcF), where the severity is 
categorized as Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 
higher (QTcF >500 ms on at least 2 separate ECGs) or clinically significant arrhythmia of 
any grade. 
− 
Liver enzyme increase (see also Appendix 8)  
• 
AST and/or ALT ≥8x the ULN. 
• 
AST and/or ALT elevations ≥3x ULN with signs of liver damage (i.e. with the 
appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash and/or eosinophilia [>5%], and/or total bilirubin ≥2.0x ULN or international 
normalized ration [INR] >1.5) 
• 
In addition, a dose interruption or reduction (if applicable) should be considered if AST 
and/or ALT ≥3x ULN and <5x ULN and dosing with IP should be interrupted if AST 
and/or ALT ≥5 and <8x ULN. 
− 
Subjects presenting with signs and symptoms of SARS-CoV-2 infection should immediately 
contact the site investigator, who should inform the sponsor’s medical responsible as soon as 
possible, and report an AE/SAE as applicable. In case of suspected SARS-CoV-2 infection 
RT-PCR and serology tests should be performed to confirm the infection. The investigator, 
preferably after consultation with the sponsor’s medical responsible, must discontinue the 
subject from the study. The subject could be tested for SARS-CoV-2 in facilities outside the 
study site and if so, the subject should be instructed to immediately inform the study 
investigator if the test is positive and test results should be shared with the investigator as 
soon as possible. 
 
For subjects having: 
• 
AST or ALT ≥8xULN 
• 
AST or ALT ≥3xULN with signs of liver damage (i.e. with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or 
eosinophilia [>5%], and/or total bilirubin ≥1.5xULN or INR >1.5) 
 
The following steps will need to be performed by the investigator: 
 


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• 
The site should immediately contact the subject and require the subject to discontinue IP 
immediately. The subject should be asked to return to the site within a 48-hour window 
from awareness of the result.  
• 
A full evaluation of various causes of hepatitis should be conducted (i.e. infectious, 
alcohol, medications, anatomical).  
• 
An assessment of other concomitant medications and standard of care should be made. 
The investigator should consider whether it is in the best interest of the subject to 
stop/interrupt concomitant medications and standard of care treatment.  
• 
A detailed history including relevant information on alcohol use, recreational drug use, 
supplement consumption, any herbal remedies, family history, sexual history, travel 
history, history of contact with a jaundiced subject, surgery, occupational history, blood 
transfusion, history of liver or allergic disease, and any other potential causes of 
attributable to a liver insult should be collected.  
• 
A detailed assessment of the subject’s clinical condition and repeat laboratory tests for 
liver function tests (LFT), including albumin, creatine kinase, total bilirubin (direct and 
indirect), gamma-glutamyl transferase (GGT), INR, and alkaline phosphatase should be 
done. 
• 
Further testing for hepatitis A, B, and C, and for autoimmune hepatitis should be done. 
Other causes of viral hepatitis (cytomegalovirus or Eppstein Barr virus etc) should be 
excluded. Liver imaging should be considered.  
• 
Referral to a hepatologist or gastroenterologist should be requested. 
• 
All these cases should be reported as SAEs. 
If during the study, the subject’s condition necessitates the use of prohibited medication, the use 
of IP may be interrupted, preferably after consultation with the sponsor’s medical responsible. 
Re-introduction of IP can be considered after the treatment course with the prohibited medication 
has been stopped and after consultation with the sponsor’s medical responsible.  
Every effort should be made to keep subjects in the study and on treatment. However, the 
investigator, who may consult the sponsor’s medical responsible, can consider stopping the study 
treatment in case of concerns about the subject’s safety, serious or severe AEs or worsening of 
the disease condition, which in the investigator’s opinion needs an alternative treatment approach 
not being covered in the clinical study (e.g. rescue medication). If IP treatment is interrupted due 
to an SAE, IP could be restarted, as per the investigator’s judgment and after consultation with 
the sponsor’s medical responsible.  
When study treatment is discontinued, the subject will be requested to complete the assessments 
for the ED visit and return for the FU visit. Reason for discontinuation must be documented in 
the case report form (CRF). 
Subjects will be informed prior to clinical study entry that they are allowed to withdraw from the 
clinical study. At any time and for any reason, a subject’s participation in the clinical study may 
terminate at his/her request without prejudice to his/her future medical care. The subject will be 
encouraged to share the reason(s) for withdrawal so this can be documented in the source 


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documents, and to complete the ED visit and FU visit for safety assessments, but will not be 
obliged to do so. 
Subjects who withdraw from the clinical study without contact with the site (lost-to-FU) should 
be contacted by the site so that their health status can be assessed and documented in the source 
documents. The site should make every effort to understand whether the subject is alive, 
including checking the medical records and contacting general practitioner or relatives, if 
necessary. All attempts must be documented in the source documents.  
The sponsor has the right to terminate the clinical study at any time and for any reason. In this 
event, the investigator(s) and relevant authorities will be informed of the reason for clinical study 
termination. 
6.5. 
Measures to Minimize Bias 
6.5.1. 
Randomization 
At screening, subjects will be assigned a subject identification number. When a subject is 
confirmed to be eligible for the clinical study, the subject will be randomized. Allocation of each 
subject to a given treatment will be done using a centralized electronic system (interactive 
voice/web response system [IXRS]). Subjects will be randomized in a 3:2 ratio to GLPG3970 or 
placebo. 
6.5.2. 
Blinding and Unblinding 
This is a randomized, double-blind clinical study. The subjects and the entire clinical study team, 
including the investigators, clinical study coordinators, and sponsor personnel are blinded to 
treatment assignment. 
Blinded and packaged medication will be provided to the site. All IP formulations will be 
identical in appearance, shape, smell and taste, and will be packaged in the proper proportion to 
assure desired dosages and maintenance of the blinding.  
The blind can be broken by the investigator for the safety of a subject. The investigator is 
encouraged to discuss considerations to break the blind with the sponsor’s medical responsible, 
whenever possible and where the situation allows. However, the responsibility to break the 
treatment code in emergency situations resides solely with the investigator. The investigator is 
not required to discuss unblinding beforehand if he or she feels rapid emergency unblinding is 
necessary, but is required to inform the sponsor within 24 hours after unblinding has occurred. 
The blind can be broken via IXRS by the investigator. 
If the blind is broken for any reason during the course of the clinical study, the moment on which 
the blind was broken and all other relevant information will be documented by the site. The 
reason for breaking the blind will be indicated and justified in the source documentation. 




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Subjects will receive powder and solvent to take home. The total content of the oral solution, 
reconstituted from the whole amount of powder and solvent, will need to be drunk. Detailed 
instructions for preparing and storing the applicable doses will be provided to the subject via 
on-site training on dummy kits and via a patient leaflet. 
If a subject misses a dose (e.g. because he/she forgot to take the medication), he/she should take 
the missed dose within 12 hours after the planned intake time. If IP is not taken within 12 hours 
after the planned time, the missed dose should be skipped. For each dose taken at home, the time 
and date should be recorded in the subject’s diary. 
7.3. 
Packaging, Labeling and Distribution 
IP packages will be labeled with clinical study-specific details, including storage conditions. 
All manufacturing, packaging and labeling operations will be performed according to Good 
Manufacturing Practice for Medicinal Products and the relevant regulatory requirements. 
Each medication kit will be identified with a unique kit number. Multiple kits can be provided to 
a subject at each visit, providing the subject with sufficient IP to cover the period until the next 
scheduled visit. 
The distribution of IP to the site will only occur after the required local documentation is 
obtained, including clinical study approval by Competent Authorities and the IECs/IRBs, 
documentation on which the assessment of the investigator’s qualifications was based (e.g. 
curriculum vitae), and the signed and dated study agreement and financial agreement. 
To ensure study subjects maintain dosing per protocol requirements during this study special 
delivery services through DTP shipments of IP from the investigational site to the subject can be 
implemented in case of SARS-CoV-2 restrictions. DTP should only be used in case of emergency 
where on-site IP dispensation is not possible, and if allowed per local regulations. Local 
guidelines must be followed and regulatory approval or notification of authorities may be 
required. Agreement of the subject to receive IP at home is required prior to the shipment of IP 
from the investigational site to the subject’s home. The DTP process used will be reviewed and 
approved by the sponsor, but the DTP shipments will be coordinated by the investigational site(s) 
in collaboration with the local CRO without the involvement of the sponsor to ensure clinical 
study integrity in case of SARS-CoV-2 restrictions. 
7.4. 
Storage 
Sites are to store IP supplies in a secure area until dispensed. Powder and solvent for oral solution 
at room temperature (below 30 °C), should not be refrigerated or frozen and protected from light 
and stored in the original packaging.  
Sites will be required to monitor the storage temperature by using at least a min-max 
temperature-recording device and to keep a minimum to maximum temperature log, which must 
be completed each working day in order to establish a record of compliance with these storage 
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The investigator will instruct subjects on how the IP should be stored at home. Storage conditions 
to be taken into account by the subject when taking IP home, are described in the patient leaflet. 
7.5. 
Treatment Compliance and Drug Accountability 
The investigator should discuss treatment compliance with the subject prior to the start of the 
study. Missed doses should be discussed to try to ascertain the reason(s). Every effort should be 
made to ensure the proper subject dose. Subjects with poor compliance will be retrained by the 
site. IP administration as indicated by the subject (amounts as well as periods) will be recorded 
on the CRF. 
The pharmacist or designated clinical study personnel will maintain a documentation of the total 
amount of IP received at site, amount dispensed to the subject, and the amount of IP returned by 
the subject to the site. IP supplies for each subject will be inventoried and accounted for 
throughout the clinical study. At the end of the treatment period, these records will be checked 
against the inventory by the study monitor. All clinical supplies will be stored in locked and 
access controlled facilities. Subjects will record IP administration at home in a subject diary. 
Subjects will return any unused IP and empty IP packages at each study visit and/or ED visit. 
Upon sponsor approval, all unused IP and empty IP packages are to be returned from the sites 
and/or any vendor involved in the clinical study supplies management activities to the agreed 
location (depot), if possible. All returns and destruction must be properly documented.  
8. 
CLINICAL STUDY ASSESSMENTS 
Every effort should be made to ensure that CSP-required tests and procedures are completed as 
described in the Schedule of Activities (see Section 8.11). To avoid inter-observer variability, 
every effort should be made to ensure that all safety and efficacy evaluations are completed by 
the same individual who made the initial baseline determinations. In case study assessments are 
not performed for reasons related to SARS-CoV-2 pandemic restrictions, this should be 
documented in the medical records and e-CRF.  
In case a randomized subject is not available to attend a scheduled study visit on site due to of 
SARS-CoV-2 travel restrictions, a phone call or a televisit may be conducted instead. It is 
strongly recommended to conduct planned study assessments for the applicable visit as per 
protocol as much as possible. If possible and if local regulations allow and the subject agrees, 
trained study staff or trained personnel are encouraged to collect study assessments at the study 
subjects’ home or a local facility if social distancing and hygiene rules can be applied.  
Only staff trained in conducting the protocol planned assessments are authorized to perform 
home or local facility visit assessments and the alternative arrangements need to be adequately 
documented. Direct to patient shipments are possible if needed. Subjects presenting with signs 
and symptoms of infection, including SARS-CoV-2 infection should immediately contact the site 
investigator, who should inform the sponsor’s medical responsible as soon as possible, and 
SARS-CoV-2 testing should be performed. 




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− 
For QuantiFERON –TB Gold test with indeterminate result (the subject is not eligible if 
retest result is indeterminate or positive).  
− 
During screening or later during the study, retesting (resampling) of clinical laboratory safety 
tests or SARS-CoV-2 RT-PCR tests is allowed once, only for technical or transport reasons 
(e.g. sample hemolyzed, out of stability, late arrival at laboratory impacting sample quality, 
loss, or destruction of the sample before analysis). 
8.1.2. 
Rescreening of Subjects 
If a subject is a screening failure, it is allowed to rescreen the subject once, if the reason for 
failure is temporary and expected to resolve, as judged by the investigator. When a subject is 
rescreened, the subject needs to be reconsented and all screening assessments need to be 
repeated. The subject will be assigned a new subject identification number. The time in between 
2 screening attempts could vary depending on the screening failure reason. 
The following data will be collected for screening failure subjects: ICF signed data, 
demographics, failed inclusion or exclusion criteria, and AEs. 
8.2. 
Unscheduled Visits 
Additional visits can be performed at other time points for any safety assessments, if clinically 
indicated. These unscheduled visits and outcomes of additional assessments need to be recorded 
in the source and, if performed before the subject’s last visit per CSP, also in the CRF. 
8.3. 
Initial Subject and Disease Characteristics 
Subjects will be asked to attend the study site for a screening assessment. After giving written 
informed consent, demographic data (year of birth, age, sex, ethnicity and race) will be collected 
and medical history will be taken, including RA disease history and treatment history. RA disease 
history will capture the duration of disease, clinical symptoms, and medication used to treat the 
disease. A physical examination will be performed, including measurement of weight and height. 
The subject’s diagnosis of RA will be confirmed based on 2010 ACR/EULAR criteria 
(documented diagnosis) and classified as ACR functional class I-III.  
Vital signs (systolic and diastolic blood pressure, pulse, oral/tympanic body temperature, the 
same method of measuring body temperature to be used throughout the study) will be measured 
and a 12-lead ECG will be recorded. Subjects should rest for at least 5 minutes in the supine 
position before the ECG recording, blood pressure and pulse measurement. 
The inclusion and exclusion criteria will be checked to assess eligibility for the study. All 
screening tests will be reviewed to confirm eligibility before randomization and the first IP dose. 
A serum pregnancy test will be done for all female subjects as well as an FSH test for 
postmenopausal female subjects.  








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presenting such symptoms at screening/baseline should not be included/randomized in the study 
(see Section 6.2). Developing such symptoms during the study, should be managed as per Section 
8.5.6. 
8.5.4. 
Vital Signs 
Vital signs (systolic and diastolic blood pressure taken at the same arm for each measurement, 
pulse  and oral/tympanic body temperature, the same method of measuring body temperature to 
be used throughout the study) will be recorded in a standardized manner (i.e. after the subject has 
rested in a supine position for at least 5 minutes) at visits specified in the Schedule of Activities 
in Section 8.11 (see also Section 8.1, “Timing of Assessments”). Clinically significant abnormal 
values should be recorded as AEs. 
8.5.5. 
12-lead Electrocardiogram 
At the time points specified in the Schedule of Activities (see Section 8.11 and also Section 8.1, 
“Timing of Assessments”), a triplicate 12-lead ECG will be recorded and results will be sent for 
central reading.  
12-lead ECG recordings will be performed before blood sampling and after subjects rested for at 
least 5 minutes in supine position. In case an indwelling catheter is used, ECGs may be recorded 
after blood sampling, provided that there is at least 30 minutes between catheter insertion and the 
ECG recording. When catheter insertion would fail, the 12-lead ECG needs to be taken before the 
venipuncture and at least 30 minutes after the failed attempt. Triplicate ECGs will be performed 
within a time span of 10 minutes, with an approximate 3-minute interval between ECGs.  
The following parameters need to be recorded: heart rate, RR interval, PR interval, QRS interval, 
uncorrected QT interval, morphology and rhythm analysis (QTcF will be derived). QTcF will be 
considered as normal if ≤450 ms (male) and ≤460 ms (female), while a prolongation of QTcF to 
>500 ms or an increase from baseline >60 ms will be considered a threshold of concern.  
Immediately after recording, the ECG will be reviewed by the investigator on clinical significant 
abnormalities. This immediate review during the visit needs to be documented in the subject’s 
source. After receipt of the central report, also all flagged ECG abnormalities need to be assessed 
by the investigator on clinical relevance. Clinically significant abnormal findings should be 
recorded as AEs. 
8.5.6. 
Other Safety Assessments 
SARS-CoV-2 infection will be assessed at screening by RT-PCR and at baseline through careful 
physical examination to exclude any potential signs and symptoms of infection, e.g. cough, fever, 
headaches, fatigue, dyspnea, myalgia, anosmia, dysgeusia, anorexia, sore throat, etc. 
Additional RT-PCR and serology testing will be repeated at baseline for documentation and 
throughout the study as needed. The subject could be tested for SARS-CoV-2 in facilities outside 
the study site and if so, the subject should be instructed to immediately inform the study 








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8.11. 
Schedule of Activities 
For detailed instructions on the clinical study procedures, please see referred sections and Section 8.1, “Timing of Assessments”. 
EVENT 
SCREENING 
PERIOD 
TREATMENT PERIOD1,2 
FOLLOW-UP 
PERIOD2 
Study visit 
S 
1 
2 
3 
4 
5 
ED3 
FU Visit 
Study Weeks  
 
Baseline 
1 
2 
4 
6 
 
 
Study Day (D) ± Days  
-21 to -1 
1 
8 ± 2 
15 ± 2 
29 ± 2 
43 ± 2 
Early treatment 
discontinuation 
57 ± 3  
On site visit 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
Telephone call 
 
 
✓ 
 
 
 
 
 
Informed consent  
✓ 
 
 
 
 
 
 
 
Inclusion/exclusion criteria  
✓ 
✓ 
 
 
 
 
 
 
Demographics  
✓ 
 
 
 
 
 
 
 
Medical history  
✓ 
 
 
 
 
 
 
 
FSH test (postmenopausal 
women) 
✓ 
 
 
 
 
 
 
 
                                                 
1 On dosing days, all assessments are to be performed within 3 hours pre-dose, unless otherwise specified. 
2 Subjects must come for the study visits 1, 3 and 5 in the morning in a fasting state (no food intake for at least 8 hours). For Visit 1 (predose measurements) and for 2 post 
dose visits (Visit 3, 4 or 5) all attempts should be made to plan the visit within 2 days following MTX intake. 
3 Subjects who discontinue treatment early will be requested to return for an early discontinuation (ED) visit to complete all Visit 5 assessments and to return for a follow-up 
(FU) visit 14 ± 3 days after last IP administration. 
 


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EVENT 
SCREENING 
PERIOD 
TREATMENT PERIOD1,2 
FOLLOW-UP 
PERIOD2 
Study visit 
S 
1 
2 
3 
4 
5 
ED3 
FU Visit 
Study Weeks  
 
Baseline 
1 
2 
4 
6 
 
 
Study Day (D) ± Days  
-21 to -1 
1 
8 ± 2 
15 ± 2 
29 ± 2 
43 ± 2 
Early treatment 
discontinuation 
57 ± 3  
Pregnancy test4  
✓ 
✓ 
 
 
✓ 
✓ 
✓ 
 
Physical examination  
✓ 
✓ 
 
 
 
✓ 
✓ 
✓ 
Vital signs  
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
Body weight and height 5 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
12-lead triplicate ECG  
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
Serology  
✓ 
 
 
 
 
 
 
 
QuantiFERON-TB Gold test  
✓ 
 
 
 
 
 
 
 
SARS-CoV-2 RT-PCR test6 
✓ 
✓ 
As needed 
SARS-CoV-2 serology test6 
 
✓ 
As needed 
Randomization  
 
✓ 
 
 
 
 
 
 
Clinical safety blood samples  
✓ 
✓7 
 
✓7 
✓ 
✓7 
✓ 
✓ 
                                                 
4 Serum beta human chorionic gonadotropin at screening, baseline (Visit 1), Visit 4 and Visit 5, or at the ED visit, if applicable (all female subjects). 
5 Height only to be measured at screening. 
6 RT-PCR from a nasal swab sample at screening and RT-PCR from a nasal swab sample and serology testing at baseline (Visit 1), and as needed when subject presents signs 
and symptoms of SARS-CoV-2 infection. 
7 Fasted glucose, fasted insuline and HOMA-IR only at Visit 1, 3 and 5 and the ED visit, if applicable. 
 






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9. 
STATISTICAL METHODS 
All statistical methods shall be detailed in a statistical analysis plan (SAP) that will be finalized 
prior to the database lock and unblinding. All relevant data collected in this clinical study will be 
documented using summary tables, figures, and subject data listings. 
Any deviations from the CSP are to be justified in the SAP. 
9.1. 
Determination of Sample Size 
The operating characteristics of the chosen decision framework at a sample size of 15 subjects 
(GLPG3970) + 10 subjects (placebo) are represented in the following graphical output and table, 
and were deemed acceptable. A common standard deviation (SD) of 1.3 for placebo and 
GLPG3970 was assumed based on previous experience with RA studies.  
Lower Reference Value and Target Value for the decision framework were determined based on 
the published studies and the therapies in development or on the market. They were identified by 
the project team as the lowest delta of possible interest and the best case scenario for efficacy 
outcome respectively. 
A dropout rate of 20% was taken into account to allow a minimum of 20 subjects to complete the 
study. In case of drop-outs due to SARS-CoV-2 infection, additional subjects may be randomized 
on top of the planned sample size. The number of additional subjects randomized will not exceed 
the number of subjects dropping out of the study in relation to SARS-CoV-2. Randomization of 
additional subjects will ultimately be decided by the sponsor before any study lock or related 
unblinding has occurred. 
 
Probability 
Reference 
value 
Outcome 
0.852 
-1.6 
Signal detected 
0.043 
-1.6 
No conclusion 
0.105 
-1.6 
No signal 
detected 
0.192 
-0.6 
Signal detected 
0.091 
-0.6 
No conclusion 
0.717 
-0.6 
No signal 
detected 
 
 
 
9.2. 
Population for Analyses 
9.2.1. 
All Screened Subjects 
All subjects who signed and dated an ICF. 






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received. Clinical safety will be addressed by assessing AEs, laboratory assessments, physical 
examinations, vital signs, and 12-lead ECGs. 
9.3.5.1. 
Extent of Exposure 
A subject’s extent of exposure to the IP will be generated from the IP administration page of the 
CRF. Exposure data will be summarized by treatment group. Duration of exposure to the IP will 
be expressed as the number of days between the first and last dose of IP, inclusive, regardless of 
temporary interruptions in IP administration and summarized by treatment group. 
9.3.5.2. 
Adverse Events 
Clinical and laboratory AEs will be coded using the latest version of the Medical Dictionary for 
Regulatory Activities. System Organ Class (SOC), High-Level Group Term, High-Level Term, 
Preferred Term, and Lower-Level Term will be attached to the clinical database. 
The following AEs will be considered as TEAEs: 
Any AE with an onset date on or after the IP start date and no later than 14 days after last dose of 
IP, or any worsening of any AE on or after the IP start date. Investigators are not obliged to 
actively seek SAEs after the CSP-defined FU period. However, if the investigator is informed 
about an SAE that occurs at any time after the subjects post-treatment FU visit and the event is 
deemed relevant to the use of IP, they should promptly document and report the event to the 
sponsor by using the SAE form. 
Summaries (number and percentage of subjects) of TEAEs per subject by SOC and Preferred 
Term will be provided by treatment group. TEAEs will also be summarized by causal 
relationship to the IP and severity. In addition, TEAEs leading to ED of the IP will be 
summarized and listed. Also, all SAEs, including the non-treatment-emergent SAEs, will be 
listed. 
9.3.5.3. 
Clinical Laboratory Evaluations 
Laboratory assessments will be analyzed descriptively. Changes from baseline and treatment-
emergent shifts, according to normal ranges as well as CTCAE version current at the time of the 
assessment, will be presented. Analyses will be done per treatment group.  
9.3.5.4. 
Physical Examinations 
Only abnormal post-baseline physical examination results will be listed, when available. 
9.3.5.5. 
Vital Signs 
Vital signs will be analyzed descriptively. Changes from baseline will be presented as well. 
Analyses will be done per treatment group. 




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experts (such as an expert in the field of RA and an infectious diseases expert) to support data 
interpretation. The Committee will review unblinded safety data and assess any potential safety 
issues arising during the conduct of the clinical study, including (but not limited to) any potential 
issues in the context of the SARS-CoV-2 pandemic. The process is described in a separate 
‘Internal Safety Monitoring Committee Charter’. 
11. 
SAFETY REPORTING 
11.1. 
Definitions of Adverse Events, Serious Adverse Events and 
Special Situations 
11.1.1. 
Adverse Events 
An AE is any untoward medical occurrence, new or worsening of any pre-existing condition, in a 
clinical study subject administered a medicinal product and which does not necessarily have to 
have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (e.g. an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related. AEs may also include pre- or post-treatment complications that occur 
as a result of CSP-specified procedures, worsening of the targeted disease, overdose, drug 
abuse/misuse reports, or occupational exposure. Pre-existing conditions that increase in severity 
or change in nature during or as a consequence of participation in the clinical study will also be 
considered AEs. 
11.1.2. 
Serious Adverse Events 
An SAE is defined as an AE that: 
− 
Results in death; 
− 
Is life-threatening (Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.); 
− 
Requires in-patient hospitalization or prolongation of existing hospitalization; 
− 
Results in persistent or significant disability/incapacity; 
− 
Is a congenital anomaly / birth defect; 
− 
Is medically significant (medical and scientific judgment should be exercised in deciding 
whether other situations should be considered serious such as important medical events that 
might not be immediately life-threatening or result in death or hospitalization but might 
jeopardize the subject or might require intervention to prevent one of the other outcomes 
listed in the definition above). 


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11.1.3. 
Unlisted (Unexpected) Adverse Events/ Reference Safety Information 
An AE is considered unlisted if the nature or intensity is not consistent with the applicable 
product reference safety information. For an IP, the expectedness of an AE will be determined by 
whether or not it is listed in the reference safety information part of the IB. 
11.1.4. 
Adverse Events of Special Interest 
Not applicable. 
11.1.5. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events 
Laboratory abnormalities without clinical significance based on the investigator’s judgment are 
not considered AEs or SAEs. However, laboratory abnormalities (e.g. clinical chemistry, 
hematology, and urinalysis) or other abnormal (clinical study-specific) assessments (e.g. ECG, 
radiography, vital signs) that require medical or surgical intervention, are associated with signs 
and/or symptoms, and/or lead to IP interruption, modification or discontinuation must be 
recorded as an AE or SAE if they meet the definition as described in Sections 11.1.1 and 11.1.2, 
respectively. If the laboratory abnormality is part of a syndrome, the syndrome or diagnosis is to 
be reported (e.g. anemia instead of decreased hemoglobin). 
The following liver enzyme elevations should be reported as SAEs: 
− 
AST or ALT ≥8xULN. 
− 
AST or ALT ≥3xULN with signs of liver damage (total bilirubin >2xULN OR international 
normalized ratio >1.5, and/or with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia [>5%]). 
11.1.6. 
Special Situations 
Special situations are situations that have a possible impact on the safe use of the IP. These 
situations might be or might not be associated with AEs. 
− 
Pregnancy 
− 
Abuse or misuse of IP 
Abuse of IP is defined as the persistent or sporadic, intentional excessive use of the IP, which 
is accompanied by harmful physical or psychological effects. 
Misuse of IP is defined as a situation where the IP is intentionally and inappropriately used 
not in accordance with the product information. 
− 
Drug interaction or food interaction with IP 
A drug interaction with IP is defined as a situation in which there is evidence or a suspicion 
that the IP interacts with another drug when both are administered together. 
A food interaction with IP is defined as a situation in which there is evidence or a suspicion 
that the IP interacts with a food when taken together. 
− 
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A medication error with IP is defined as an unintended failure in the drug treatment process 
that leads to, or has the potential to lead to, harm to the subject. 
− 
Occupational exposure to IP 
Occupational exposure to IP is defined as an exposure to the IP as a result of one’s 
professional or non-professional occupation. 
− 
Overdose with IP 
An overdose of IP is defined as the administration of a quantity of the IP given per 
administration or cumulatively, which is above the dose of IP given during this study. 
− 
Product complaint or quality defect of IP 
Product complaint or quality defect of IP is defined as complaints or defects of the IP arising 
from potential deviations in the manufacture, packaging, or distribution of the IP. 
11.2. 
Assessment of Adverse Events and Serious Adverse Events 
The investigator is responsible for assessing AEs and SAEs for causality and severity. This is the 
basis for the sponsor’s final review and confirmation of accuracy and completeness of event 
information and causality assessments. 
11.2.1. 
Assessment of Causality 
The investigator is responsible for assessing the causal relationship to IP(s) administration or 
study procedures (e.g. invasive procedures such as venipuncture) based on her/his clinical 
judgment. The following decision choice will be used by the investigator to describe the causality 
assessment between the reported event or laboratory test abnormality and the IP. 
− 
Unrelated: 
Time relationship to IP intake is improbable. Related to other etiologies such as concomitant 
medications or subject's clinical state. 
− 
Unlikely: 
Time relationship to IP intake is improbable (but not impossible). Concomitant disease or 
other drugs provide plausible explanations. 
− 
Possible: 
Time relationship to IP intake is reasonable. Event or laboratory test abnormality could also 
be explained by disease or other drugs. Information on IP withdrawal may be lacking or 
unclear. 
− 
Probable: 
Time relationship to IP intake is reasonable. Unlikely to be attributed to concurrent disease 
or other drugs. Response to withdrawal is clinically reasonable and rechallenge not required. 


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− 
Certain: 
Time relationship to IP intake is plausible. Cannot be explained by concomitant disease or 
other drugs. Response to withdrawal is plausible (pharmacologically, pathologically). Event 
definitive pharmacologically or phenomenologically (i.e. an objective and specific medical 
disorder or a recognized pharmacological phenomenon). Rechallenge satisfactory, if ethical 
and necessary. 
 
It should be emphasized that ineffective treatment (worsening of the disease) should not be 
considered as causally related in the context of AE reporting. 
11.2.2. 
Assessment of Severity 
The severity of AEs should be graded using the CTCAE version current at the time of 
assessment. If a CTCAE criterion does not exist, the investigator should use the grade or 
adjectives: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening) or 
Grade 5 (fatal) to describe the maximum intensity of the AE. For purposes of consistency with 
the CTCAE, these intensity grades are defined in the table below. 
Table 1 
Grading of AE Severity 
Grade  
Adjective  
Description  
Grade 1  
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated  
Grade 2  
Moderate 
Local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL*  
Grade 3  
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**  
Grade 4  
Life-threatening 
Urgent intervention indicated  
Grade 5  
Death 
Death-related AE  
* 
Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for groceries or clothes, using the 
 
telephone, managing money, etc. 
** 
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
 
bedridden. 
For AEs associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in agreement 
with the grading of the laboratory abnormality. This is upon the investigator’s assessment. 
If there is a change in intensity (worsening or improvement) of an AE, it must be recorded. 


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11.2.3. 
Action Taken Regarding Investigational Product 
The action taken must be described by choosing from: 
− 
Dose not changed: In case no action is taken regarding the IP. 
− 
IP permanently discontinued: In case a subject is permanently discontinued from treatment 
or withdrawn from the study by the investigator (who may consult the sponsor’s medical 
monitor). 
− 
IP temporarily discontinued: In case the IP is temporarily discontinued by the investigator 
(who may consult the sponsor’s medical monitor). 
− 
Not applicable: Other situations (e.g. in case an AE started after the last IP administration). 
11.2.4. 
Outcome 
Each AE must be rated by choosing among: 
− 
Recovered/resolved; 
− 
Recovered/resolved with sequelae; 
− 
Recovering/resolving; 
− 
Not recovered/not resolved; 
− 
Fatal; 
− 
Unknown. 
11.3. 
Investigator Requirements and Instructions for Reporting Adverse 
Events, Serious Adverse Events, Pregnancies, and Other Special 
Situations to the Sponsor 
11.3.1. 
Adverse Events 
The AE reporting period for safety surveillance begins when the subject signs the ICF and ends at 
the subject’s last FU visit (the last FU visit after the last dose of IP). In this period, all new AEs, 
regardless of cause or relationship, derived by spontaneous, unsolicited reports of subjects, by 
observation and by routine open questioning (such as “How do you feel?”) need to be recorded in 
the source and in the CRF. 
In case an AE is ongoing at the time of the last FU visit, the investigator needs to FU on the 
subject until AE resolution or reasonable stabilization and to document in the subject’s source 
documentation. No related updates or additional data on the AE should be reported in the CRF. 
If a subject is documented as lost-to-FU, ongoing/unknown outcome AEs will not be followed-
up. 
If the AE meets the criteria for seriousness, the SAE form must be completed and sent to the 
sponsor within 24 hours (see Section 11.3.2). 


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11.3.2. 
Serious Adverse Events 
Subjects experiencing an SAE or an emergency situation will be examined by a physician as soon 
as possible. The subject will remain under observation as long as medically indicated. 
Appropriate laboratory tests will be performed until all parameters return to normal or are 
otherwise explained or stable. 
All SAEs, whether or not deemed IP related, must be recorded in the CRF and on the SAE form. 
The investigator must report each SAE immediately, and under no circumstances should this 
exceed 24 hours following the knowledge of the SAE, as is indicated on page 2 under 
“Emergency Contact Information”. 
The SAE form should at least contain identifiers of the subject and the reporter, SAE term and 
statement of relatedness to the IP, and at a later stage if not yet available within 24 hours, the 
form needs to be completed with a clearly written narrative describing signs, symptoms, and 
treatment of the event, diagnostic procedures, as well as any relevant laboratory data and any 
sequelae. 
Follow-up and outcomes should be reported and documented in the source documents for all 
subjects that experience an SAE. It is important that the information provided on the SAE form 
matches the information recorded on the CRF for the same event. 
Copies of additional laboratory tests, consultation reports, post-mortem reports, hospital case 
reports, autopsy reports, and other documents should be sent when requested and available. Only 
subject identifiers (subject number) should appear on the copies, and all names and initials should 
be blackened and rendered illegible. Follow-up reports relative to the subject’s subsequent course 
must be submitted until the event has subsided or, in case of permanent impairment, until the 
condition stabilizes. 
Any SAEs that occur after the post-treatment FU visit but within 30 days of the last dose of IP(s), 
regardless of causality, should also be reported (Emergency Contact Information on page 2). 
Investigators are not obligated to actively seek SAEs after the CSP-defined FU period. However, 
if the investigator is informed about an SAE that occurs at any time after the subjects’ post-
treatment FU visit and the event is deemed relevant to the use of IP(s), he/she should promptly 
document and report the event to the sponsor by using the SAE form. 
11.3.3. 
Pregnancy 
All initial reports of pregnancy in female subjects and pregnancies in partners of male subjects 
included in the clinical study must be recorded and documented in the source documents and on 
the pregnancy form. The investigator must report each pregnancy immediately, and under no 
circumstances should this exceed 24 hours following the knowledge of the pregnancy, as is 
indicated on page 2 under “Emergency Contact Information”.  
All pregnancies should be followed-up until delivery or pregnancy interruption. The investigator 
will contact the subject or partner of the subject after giving consent, at the expected time of 
delivery for FU and for information regarding the outcome of the newborn. Abnormal pregnancy 


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and/or abnormal newborn outcomes are considered SAEs and must be reported using the SAE 
form. 
11.3.4. 
Reporting of Special Situations (Other Than Pregnancy) and Associated 
Adverse Events 
In case a special situation is not associated with an AE, the special situation should be reported 
within 24 hours by using the Special Situations form as is indicated on page 2 under “Emergency 
Contact Information”. 
In case a special situation is associated with an AE, the special situation should be reported 
within 24 hours by using the Special Situations form and the associated AE should be reported as 
specified in Section 11.3.1. 
In case a special situation is associated with an SAE, the special situation should be reported 
within 24 hours by using the SAE form (and not the Special Situations form) and the associated 
SAE should be reported as specified in Section 11.3.2. 
11.4. 
Sponsor Reporting Requirements 
Depending on relevant local legislation or regulations, including the applicable United States 
Federal Drug Administration Code of Federal Regulations, the EU Clinical Trials Directive 
(2001/20/EC) and relevant updates, and other country-specific legislation or regulations, the 
sponsor may be required to expedite reports of SAEs and serious adverse drug reactions or 
suspected unexpected serious adverse reactions (SUSARs) to worldwide regulatory authorities. 
The sponsor or a specified designee will notify worldwide regulatory authorities and the relevant 
IEC/IRB in concerned Member States of applicable SUSARs as outlined in current regulations. 
Assessment of expectedness for SAEs will be determined using the reference safety information 
section in the IB or relevant local label as applicable. 
All concerned investigators will receive a safety letter notifying them of relevant SUSAR reports 
associated with any IP(s). The investigator should notify the IEC/IRB of SUSAR reports as soon 
as is practical, where this is required by local regulatory agencies, and in accordance with the 
local institutional policy. 
12. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This clinical study is conducted in accordance with the current applicable regulations, ICH-GCP 
Guideline E6 and its updates, and local ethical and legal requirements. 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety and well-being of 
clinical study subjects are protected, consistent with the principles that have their origin in the 
Declaration of Helsinki, and that the clinical study data are credible. 


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The name and address of each third party vendor (e.g. CRO) used in this study and the sponsor’s 
study team members will be maintained in the investigator’s and sponsor’s files as appropriate. 
12.1. 
Sponsor’s Responsibilities 
12.1.1. 
Regulatory Authority Approval  
Prior to clinical study start, this CSP together with all relevant documentation needs to be 
submitted to the respective regulatory authorities for review and approval in compliance with 
current regulations before the study can start. 
12.1.2. 
Clinical Study Closure Considerations 
The sponsor reserves the right to close the investigational site or end the clinical study at any 
time for any reason. In case of an early termination of the clinical study or temporary halt by the 
sponsor, the IEC/IRB and health authority will be notified within 15 calendar days, unless 
otherwise specified by the sponsor, the IEC/IRB or health authority, including a detailed written 
explanation of the reasons for the termination/halt. 
Reasons for the closure of an investigational site may include, but are not limited to: 
− 
Successful completion of the clinical study at the center. 
− 
The overall required number of subjects for the clinical study has been recruited. 
− 
Failure of the investigator to comply with the CSP, ICH-GCP guidelines or local 
requirements. 
− 
Inadequate recruitment of subjects by the investigator. 
 
Reasons for early termination of a clinical study by the sponsor may include, but are not limited 
to: 
− 
Safety concerns. 
− 
Sufficient data suggesting lack of efficacy. 
 
The end of clinical study declaration will be submitted to the regulatory authorities and IEC/IRB 
after the complete clinical study has ended in all participating centers, in all countries. This 
notification will also be submitted according to local requirements of the end of the clinical study 
in a given country/member state. 
12.1.3. 
Indemnification 
Under the conditions of a contract concluded between investigator, site and sponsor or designee, 
which shall prevail, the sponsor shall, except in case of gross negligence or willful misconduct, 
indemnify and hold harmless the investigator and his/her medical staff from any claim arising 
from the clinical study activities carried out in compliance with the CSP, sponsor’s instructions 
and applicable local regulations. 


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The investigator must notify the sponsor immediately upon notice of any claims or lawsuits. 
12.1.4. 
Insurance 
The sponsor shall maintain insurance coverage that is sufficient to cover its obligations and that 
is consistent with human clinical study local regulations. Provided that the subject has been 
treated according to the CSP and sponsor’s instructions, any injury caused to a subject which is 
the direct result of his/her participation to the clinical study shall be covered by the sponsor’s 
insurance, except in case of gross negligence or willful misconduct by the investigator. 
12.1.5. 
Archiving 
The sponsor will archive the content of the Trial Master File (TMF) for at least 25 years after the 
end of the clinical study. 
12.1.6. 
Reporting 
Where required by IEC/IRB per local requirements, at least once a year the investigator will 
provide the IEC/IRB with a progress report to allow review of the clinical study (see 
Section 12.4.1). At the end of the clinical study, the results of the clinical study will be reported 
in a CSR. The pop-PK analysis data, disease and/or drug-related biomarker data and mRNA data 
may be reported separately from the main CSR. A summary or full report, depending on the 
requirements, will be provided to the investigators, to the applicable regulatory authorities, and 
IECs/IRBs (if required by the applicable regulatory requirements) within one year, or 6 months 
for pediatric studies, after the end of the clinical study. 
12.1.7. 
Publication 
It is understood by the investigator that the sponsor shall be free to use the compound-related 
information, which is generated during the clinical study and may disclose it to other clinical 
investigators and to regulatory agencies. As a consequence, the investigator agrees to provide all 
clinical study results and data generated during this clinical study to the sponsor. 
The investigator shall not be authorized to submit the results of this clinical study and any data 
for public disclosure (e.g. publication or presentation) without the prior written approval of the 
sponsor, which shall not be unreasonably withheld. 
However, it is understood and agreed by the investigators that their results and/or findings shall 
not be authorized for publication prior to sponsor’s publication of the overall clinical study 
results. The investigator agrees that prior to the publication of any results, he/she shall provide 
the sponsor with a draft copy of the intended publication. The sponsor shall have the right to 
review it and to make any comments. In accordance with generally accepted scientific 
collaboration principles, co-authorship with any staff member sponsor involved in the clinical 
study, will be discussed and mutually agreed upon before submission of any manuscript to a 
publisher. 


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12.2. 
Investigator’s Responsibilities 
12.2.1. 
Source Data and Data Capture 
The nature and location of all source documents need to be identified and documented to ensure 
that all sources of original data required to complete the CRF are known and are accessible for 
verification by the monitor. 
Source data may be directly captured from devices transferred from third partners (e.g. laboratory 
data) or entered manually into the CRF. The CRF completion guidelines will be provided to each 
investigational site. 
It is recommended that the author of an entry in the source documents should be identifiable. 
Following ICH-GCP guidelines, direct access to sponsor’s representatives to source documents 
must be granted for the purpose of verifying that the data recorded on the CRF are consistent 
with the original source data. 
12.2.2. 
Archiving 
Unless local legislation requires archiving for a longer period, the investigator shall archive the 
content of the clinical investigator site file (ISF) for at least 25 years after the end of the clinical 
study. However, the medical files of subjects shall be archived in accordance with national law. 
The investigator should take measures to prevent accidental or premature destruction of these 
documents. 
Under no circumstance shall the investigator relocate or dispose any clinical study documents 
before having obtained a written approval of the sponsor. 
If it becomes necessary for the sponsor or the appropriate Regulatory Authority to review any 
documentation relating to this clinical study, the investigator must permit access to such reports. 
The subject is granting access to his/her source data by signing the ICF. 
Any difficulty in storing original documents must be discussed with the monitor prior to the 
initiation of the clinical study. 
12.2.3. 
Participation Cards 
If the subjects are not under 24-hour supervision of the investigator or site staff, they must be 
provided with a subject participation card indicating the name of the IP, the clinical study 
number, the investigator's name, and the site’s 24-hour emergency contact number. The subject 
should be advised to keep the participation card in his/her wallet at all times. 
12.3. 
Confidentiality 
The subject will receive all information as required by the EU General Data Protection 
Regulation, namely the identity and contact details of the controller, the contact details of the data 
protection officer, the clinical research purposes, the legal basis for the processing, the recipients 


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of the personal data, the transfer of the personal data to third countries and respective safeguards, 
the retention periods, the fair processing of his data, and all his/her data subject’s rights. All 
details are listed in the ICF. 
All information concerning the product and the sponsor’s operations (such as patent applications, 
formulas, manufacturing processes, basic scientific data, or formulation information supplied to 
the investigator by the sponsor and not previously published) is considered confidential and 
should not be disclosed by the investigator to any third party without the sponsor’s prior written 
approval. The investigator agrees to use this information only in accomplishing the clinical study 
and will not use it for other purposes. 
In order to permit easy identification of the individual subject during and after the clinical study, 
the investigator is responsible for keeping an updated Subject Identification Code List. The 
monitor will review this document for completeness. However, the investigator must guarantee 
the subject’s anonymity will be maintained. Therefore, in order to ensure subject confidentiality, 
the Subject Identification Code List must remain at the center and no copy will be made. 
12.4. 
Ethical Considerations 
12.4.1. 
Independent Ethics Committee / Institutional Review Board  
This clinical study can only be undertaken after IEC/IRB approval of this CSP together with all 
relevant documentation. This approval document must be dated and clearly identify the clinical 
study and the related clinical study documents being approved, including the subject 
compensation programs, if applicable. 
During the course of the clinical study, at least the following documents will be submitted to the 
IEC/IRB, per local requirements: 
− 
Changes to the IB 
− 
Reports of AEs that are serious, unlisted, and associated with the IP (in compliance with 
IEC/IRB, per local requirements) 
− 
CSP amendments 
− 
ICF amendments 
 
After the subject has completed the study, the subject will receive a financial compensation, or 
depending on the country, the study physician may offer the option of a course of post-study 
medication approved for the treatment of RA, at no cost and for a duration of up to 6 months.  
Subjects will be eligible for compensation in case a subject received at least 1 dose of IP and 
completed the study, or discontinued early for e.g. safety reasons. In case a subject withdraws 
from the study early compensation will be pro rata, unless the reason for withdrawal from the 
study is noncompliance, then no compensation will be provided. Any form of compensation and 
conditions for compensation will require approval by an IEC and documented in the ICF.  
The IEC/IRB is responsible for continuous review of the clinical study. Where required by 
IEC/IRB, per local requirements, at least once a year the investigator will provide the IEC/IRB 


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with a progress report to allow review of the clinical study. Additional progress reports should be 
provided according to local legal requirements. These requests and (re-)approvals, if applicable, 
should be documented in writing. 
12.4.2. 
Informed Consent 
The investigator or designated personnel must explain the clinical study and the implications of 
participation (e.g. objectives, methods, anticipated benefits, possible risks) to potential subjects 
according to applicable regulations prior to any clinical study-related activity. Subjects will be 
informed that their participation is voluntary and that they may withdraw from the clinical study 
at any time. They will be informed that choosing not to participate or to withdraw from the 
clinical study will not have an impact on the care the subject will receive for the treatment of 
his/her disease. 
The subject will be given sufficient time to read the ICF and to ask additional questions. After 
this explanation and before entry in the clinical study, the subject’s consent should be 
appropriately recorded by means of the subject's personally dated signature and by the 
investigator’s dated signature. In case the subject is unable to read and/or write, oral consent in 
the presence of at least one impartial witness who was also included when the affected person 
was being informed, may be given. The witness may not be anyone working at the site nor a 
member of the investigating team. The orally given consent shall be documented in writing, dated 
and signed by the witness. After having obtained the consent, a copy of the signed and dated ICF 
must be given to the subject. 
If new information becomes available relevant to the subject’s willingness to participate in the 
clinical study, the subject will be informed in a timely manner by means of an amended ICF. This 
amended ICF will be signed and dated by the subject (or, if applicable, by an independent 
witness) and the investigator to document the willingness of the subject to continue with the 
clinical study. 
This signed and dated amended version will be filed together with the initial signed and dated 
ICF. 
A pregnant partner, who agrees that information will be gathered about her pregnancy and the 
birth, will be asked to sign a specific ICF to participate in the data collection. Data about the 
health of the baby will be collected if the parent(s)/legal guardian(s) agree with the data 
collection and sign a specific ICF. 
Subjects who agree to participate in the study and who have signed informed consent, will be 
given the option to provide additional (and optional) informed consent for the long term storage 
of left over samples and associated data, collected during the study, for future scientific research.  


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12.5. 
Data Quality Control/Assurance 
12.5.1. 
Monitoring 
Data quality will be assured through Risk-Based Monitoring, medical monitoring, and other 
relevant activities as described in the Data Management Plan or Medical Review Plan and 
monitoring plans available in the TMF. This clinical study will be monitored by sponsor 
representatives according to their current standard operating procedures.  
To guarantee adequate protection of the subjects and to guarantee the quality of the data, the 
sponsor will ensure oversight of any clinical study-related duties and functions carried out on its 
behalf, including clinical study-related duties and functions that are subcontracted to another 
party by the sponsor’s contracted CRO(s).  
A risk-based Quality Management Plan (QMP) is prepared for the study that evaluates potential 
risks in relation to rights, safety, and well-being of the study subjects as well as the data integrity. 
The QMP describes and evaluates all involved stakeholder interfaces having potential critical 
impact on the above. Risks are considered at both the system level (e.g. standard operating 
procedures, computerized systems, personnel, and vendors) and study level (e.g. IP, study design, 
data collection, informed consent process and recording). 
12.5.2. 
Audit and Inspection 
To ensure compliance with relevant regulations, an independent quality assurance representative, 
regulatory authorities and/or IECs/IRBs may review this clinical study. This implies that 
auditors/inspectors will have the right to inspect the clinical study center(s) at any time during 
and/or after completion of the clinical study and will have access to the data generated during the 
clinical study, source documents, and subject's files. By participating in this clinical study, 
investigators agree to this requirement. 
 


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13. 
REFERENCES 
Ajeqanova, S., & Huizinga, T. (2017). Sustained remission in rheumatoid arthritis: latest 
evidence and clinical considerations. Ther Adv Musculoskel Dis, 9(10):249-262. 
BMJ, B. M. (2020, May 13). British Medical Journal Best Practice. Retrieved from 
Coronavirus disease 2019 (COVID-19) Diagnostic guidelines: 
https://bestpractice.bmj.com/topics/en-gb/3000168/history-exam 
BMJ, B. M. (2020, May 13). British Medical Journal Best Practice. Retrieved from 
Coronavirus disease 2019 (COVID-19) History and exam: 
https://bestpractice.bmj.com/topics/en-gb/3000168/history-exam 
Chatzidionysiou, K., & Sfikakis, P. (2019). Low rates of remission with methotrexate 
monotherapy in rheumatoid arthritis: review of randomised controlled trials could point 
towards a paradigm shift. RMD Open, 5(2):e000993. 
 
Frewer, P., Mitchell, P., Watkins, C., & Matcham, J. (2016). Decision-making in early clinical 
drug development. Pharmaceut. Statist., 15:255-263. 
Köhler, B., Günther, J., & Kaudewitz, D. L. (2019). Current therapeutic options in the 
treatment of rheumatoid arthritis. pii: E938. doi: 10.3390/jcm8070938. J Clin Med, 
8(7), pii: E938. 
 
 
Oton, T., & Carmona, L. (2020). The epidemiology of established rheumatoid arthritis. Best 
Practice & Research Clinical Rheumatology, 
https://doi.org/10.1016/j.berh.2019.101477. 
Siegel, J. N., & Zhen, B. (2005). Use of the American College of Rheumatology N (ARC-N) 
Index of Improvement in Rheumatoid Arthritis. Arthritis & Rheumatism, 52(6):1637-
1641. 
Smolen, J. S., Aletaha, D., Koeller, M., Weisman, M., & Emery, P. (2007). New therapies for 
treatment of rheumatoid arthritis. Lancet, 370:1861-1874. 
 
 
 


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Steriod Conversion Calculator. (n.d.). Retrieved from https://www.mdcalc.com/steroid-
conversion-calculator, accessed 26 November 2019. 
 
 
 








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Appendix 7: Prednisolone Conversion Table 
Glucocorticoid Name 
Dose Equivalent to 5 mg Prednisolone 
Prednisone 
5 mg  
Betamethasone 
0.6 mg 
Cortisol (hydrocortisone) 
20 mg 
Cortisone 
25 mg 
Deflazacort 
7.5 mg 
Dexamethasone 
0.75 mg 
Methylprednisolone 
4 mg 
Methylprednisolone Acetate 
4 mg 
Methylprednisolone Sodium Succinate 
4 mg 
Paramethasone 
2 mg 
Prednisolone 
5 mg 
Triamcinolone 
4 mg 
Beclometasone Dipropionate 
1.25 mg 
Budesonide 
1.5 mg 
Hydrocortisone Sodium Succinate 
20 mg 
 (Steriod Conversion Calculator) 
 


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Appendix 8: Algorithm for Elevated Liver Function Tests 
 
AST or ALT increase to 
Value Range 
≥1.5x to 
3xULN 
≥3x to <5xULN 
≥5x to <8xULN 
≥3xULN with signs 
of liver damage1 
≥8xULN 
IP Action 
Continue as 
planned 
Reduce or 
interrupt IP for 
at least 2 weeks 
Close 
observation2  
Interrupt IP for 
at least 2 weeks 
Close 
observation2 
Discontinue IP2 
Discontinue IP2 
 
 
 
 
↙ ↘ 
 
After at least 
2 weeks 
AST and ALT <3xULN 
 
AST or ALT ≥3xULN 
  
Weekly LFTs for the first 2 weeks 
(biweekly for the following 
weeks, or more frequently at 
investigator’s discretion) 
 
Discontinue IP 
Report SAE and complete liver event page for any of 
abnormalities listed below3: 
- 
AST/ALT increase ≥8xULN 
- 
AST/ALT increase ≥3xULN with signs of liver 
damage1  
 
1 Signs of liver damage: 
 
total bilirubin ≥2.0xULN OR international normalized ratio >1.5, and/or 
 
symptoms: appearance of fatigue, nausea, vomiting, right upper abdominal quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%)  
2 Close observation recommendations:  
 
Monitor 2 to 3 times per week all of the following parameters: ALT, AST, ALP, total bilirubin, eosinophils, INR. If local regulations allow, 
home visits can be performed if subjects cannot come to the clinical study center. 
 
Frequency of retesting can be reduced to once a week or less if abnormalities stabilize or the IP has been discontinued; however, monitoring 
might still be needed more frequently taking into consideration the standard of care and/or changes to this. 
 
Based upon investigator’s discretion gastroenterology or hepatology consultations, additional serology testing, imaging, and pathology 
assessments may be required. 
 
Re-query history of symptoms, prior and concurrent diseases, concomitant medication and non-prescription medicines, herbal, dietary 
supplements, alcohol use, recreational drug use, special diets. 
 
Rule out all of the following: acute viral hepatitis, autoimmune hepatitis, alcoholic hepatitis, non-alcoholic fatty hepatitis, hypoxic/ischemic 
hepatitis, biliary tract disease, and cholestasis. 
 
Re-query exposure to environmental chemical agents. 
3 The following steps should be followed: 
 
The site should immediately contact the subject and require the subject to discontinue IP immediately. The subject should be asked to return 
to the site within a 48-hour window from awareness of the result.  
 
A full evaluation of various causes of hepatitis should be conducted (i.e. infectious, alcohol, medications, anatomical).  


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− 
An assessment of other concomitant medications and standard of care should be made. The investigator should consider to whether is in the 
best interest of the subject to stop/interrupt concomitant medications and SOC treatment.  
− 
A detailed history including relevant information on alcohol use, recreational drug use, supplement consumption, any herbal remedies, family 
history, sexual history, travel history, history of contact with a jaundiced subject, surgery, occupational history, blood transfusion, history of 
liver or allergic disease, and any other potential causes of attributable to a liver insult should be collected.  
− 
A detailed assessment of the subject’s clinical condition and repeat laboratory tests for LFT, including albumin, creatine kinase, total bilirubin 
(direct and indirect), GGT, INR, and ALP should be done. 
− 
Further testing for Hepatitis A, B, and C, and for autoimmune hepatitis should be done. Other causes of viral hepatitis (cytomegalovirus or 
Epstein-Barr virus etc) should be excluded. Liver imaging should be considered.  
− 
Referral to a hepatologist or gastroenterologist should be requested. 
− 
All these cases should be reported as SAEs. 
 
 
 


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Appendix 9: 66/68 Joint Count 
Joints Assessed (left and right) for Swelling (66 Joints) and/or Tenderness (68 joints) 
Temporomandibular 
Sternoclavicular 
Acromioclavicular 
Shoulder 
Elbow 
Wrist 
Metacarpophalangeal 
First 
Second 
Third 
Fourth 
Fifth 
Proximal interphalangeal 
First 
Second 
Third 
Fourth 
Fifth 
Distal interphalangeal 
Second 
Third 
Fourth 
Fifth 
Hip # 
Knee 
Ankle 
Tarsus 
Metatarsophalangeal 
First 
Second 
Third 
Fourth 
Fifth 
Proximal interphalangeal (toe) 
First 
Second 
Third 
Fourth 
Fifth 
#Assessed for tenderness only 
 






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SIGNATURE PAGE – SPONSOR 
Study Title: 
A randomized, double-blind, placebo-controlled, multicenter study to 
evaluate the safety, tolerability, efficacy and pharmacokinetics of 
GLPG3970, administered orally for 6 weeks in adult subjects with 
moderately to severely active rheumatoid arthritis and an inadequate 
response to methotrexate 
CSP Version: 
1.0 
Date: 
 
 
This clinical study protocol has been reviewed and approved by the sponsor to ensure compliance 
with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) guidelines for Good Clinical Practices (GCP) and applicable regulatory 
requirements. 
 
 
 
  
  
Scientific Leader 
 Signature 
 Date 
 
 
 


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SIGNATURE PAGE – INVESTIGATOR 
Study Title: 
A randomized, double-blind, placebo-controlled, multicenter study to 
evaluate the safety, tolerability, efficacy and pharmacokinetics of 
GLPG3970, administered orally for 6 weeks in adult subjects with 
moderately to severely active rheumatoid arthritis and an inadequate 
response to methotrexate  
CSP Version: 
1.0 
Date: 
 
 
I, the undersigned, have read this clinical study protocol and will conduct the study as described 
in compliance with the clinical study protocol, in accordance with International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines 
for Good Clinical Practices (GCP) and applicable regulatory requirements. 
 
 
 
  
  
Investigator Name 
 Signature 
 Date 
 



SAP_001.pdf: 
 
-1- 
 
 
 
 
Confidentiality Statement 
The information contained in this document is privileged and confidential. It is the property of Galapagos NV and 
may not be used, disclosed, reproduced or otherwise disseminated within your organization or communicated to any 
third parties without the express written authorization of Galapagos NV. 
 
STATISTICAL ANALYSIS PLAN  
Project Number: 
GLPG3970 
 
Study Number: 
GLPG3970-CL-209 
Study Title: 
A randomized, double-blind, placebo-controlled, multicenter study to 
evaluate the safety, tolerability, efficacy and pharmacokinetics of 
GLPG3970, administered orally for 6 weeks in adult subjects with 
moderately to severely active rheumatoid arthritis and an inadequate 
response to methotrexate 
Development Phase: 
2 
Status: 
Final 
Version: 
2.0 
Date: 
7-May-2021 
EudraCT: 
2020-000658-83 
IND: 
Not applicable 
Sponsor: 
Galapagos NV, Generaal De 
Wittelaan L11 A3, 2800 
Mechelen, Belgium 
 
Biostatistician: 
 
Clinical Scientist: 
 


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TABLE OF CONTENTS 
VERSION HISTORY .................................................................................................................................................. 6 
LIST OF ABBREVIATIONS ....................................................................................................................................... 14 
1. 
INTRODUCTION ........................................................................................................................................... 17 
2. 
STUDY DESIGN AND OBJECTIVES ................................................................................................................. 17 
2.1. 
STUDY OBJECTIVES ......................................................................................................................................... 17 
2.1.1. 
Primary Objective ................................................................................................................................. 17 
2.1.2. 
Secondary Objectives ........................................................................................................................... 17 
2.1.3. 
Other Objectives ................................................................................................................................... 17 
2.2. 
STUDY ENDPOINTS ......................................................................................................................................... 17 
2.2.1. 
Primary Endpoint .................................................................................................................................. 17 
2.2.2. 
Secondary Endpoints ............................................................................................................................ 17 
2.2.3. 
Other Endpoints.................................................................................................................................... 18 
2.3. 
STUDY DESIGN .............................................................................................................................................. 18 
2.4. 
CLINICAL STUDY PROTOCOL (CSP) AND CSP AMENDMENTS .................................................................................. 19 
2.5. 
SCHEDULED OF ASSESSMENTS .......................................................................................................................... 19 
2.6. 
SAMPLE SIZE JUSTIFICATION ............................................................................................................................. 24 
2.7. 
RANDOMIZATION AND BLINDING ...................................................................................................................... 24 
2.7.1. 
Randomization ..................................................................................................................................... 24 
2.7.2. 
Blinding and Unblinding ....................................................................................................................... 25 
3. 
STUDY ESTIMANDS ..................................................................................................................................... 25 
4. 
GENERAL METHODOLOGY ........................................................................................................................... 27 
4.1. 
ANALYSIS SETS .............................................................................................................................................. 27 
4.1.1. 
All Screened Analysis Set ...................................................................................................................... 27 
4.1.2. 
All Randomized Analysis Set ................................................................................................................. 27 
4.1.3. 
Safety Analysis Set ................................................................................................................................ 27 
4.1.4. 
Full Analysis Set .................................................................................................................................... 27 
4.1.5. 
Pharmacokinetic Analysis Set ............................................................................................................... 27 
 
 
 
 
4.2. 
RANDOMIZED VERSUS ACTUAL TREATMENT GROUP ............................................................................................. 28 
4.3. 
ANALYSIS PERIODS AND ANALYSIS TIME POINTS ................................................................................................... 28 
4.3.1. 
Relative Day.......................................................................................................................................... 28 
4.3.2. 
Analysis Periods .................................................................................................................................... 29 
4.3.3. 
Analysis Windows ................................................................................................................................. 29 
4.3.4. 
Definition of Baseline ........................................................................................................................... 33 
4.3.5. 
Selection and Use of Analysis Visits ...................................................................................................... 33 
4.3.6. 
Handling of Missing Data ..................................................................................................................... 34 
4.3.6.1. 
Handling of Missing Date-Time Data ........................................................................................................... 34 
4.3.6.2. 
Handling of Missing Result Data .................................................................................................................. 34 
4.3.6.3. 
Censoring of Time to Event Data ................................................................................................................. 34 
4.3.7. 
Handling of Values Below or Above a Threshold .................................................................................. 34 
4.3.8. 
Handling of Outliers ............................................................................................................................. 35 
4.3.9. 
Stratification Factors ............................................................................................................................ 35 
4.4. 
PRESENTATION OF RESULTS.............................................................................................................................. 35 


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4.4.1. 
Presentation of Treatment Groups ....................................................................................................... 35 
4.4.2. 
Calculation of Descriptive Statistics...................................................................................................... 35 
4.4.3. 
Calculation of Percentages ................................................................................................................... 36 
5. 
INTERIM ANALYSES AND INTERNAL DATA SAFETY MONITORING COMMITTEE ........................................... 37 
6. 
STATISTICAL ANALYSES ............................................................................................................................... 37 
6.1. 
SUBJECT INFORMATION ................................................................................................................................... 37 
6.1.1. 
Demographic and Baseline Disease Characteristics ............................................................................. 37 
6.1.2. 
Allocation and Randomization ............................................................................................................. 38 
6.1.3. 
Disposition Information ........................................................................................................................ 38 
6.1.4. 
Protocol Deviations and Eligibility ........................................................................................................ 39 
6.1.5. 
Medical History and Concomitant Diseases ......................................................................................... 39 
6.1.6. 
Rheumatoid Arthritis Disease History (RA) ........................................................................................... 39 
6.1.7. 
Prior and Concomitant Medications ..................................................................................................... 39 
6.1.7.1. 
Coding of Reported Terms ........................................................................................................................... 39 
6.1.7.2. 
Classification of Medications ....................................................................................................................... 40 
6.1.7.3. 
Calculation of Relative Days ........................................................................................................................ 40 
6.1.7.4. 
Presentation of Results ............................................................................................................................... 40 
6.1.8. 
Procedures ............................................................................................................................................ 40 
6.1.9. 
Exposure to IP and Compliance ............................................................................................................ 40 
6.1.9.1. 
Derivation Rules .......................................................................................................................................... 40 
6.1.9.2. 
Presentation of Results ............................................................................................................................... 41 
6.2. 
EFFICACY ANALYSES ........................................................................................................................................ 42 
6.2.1. 
Level of Significance ............................................................................................................................. 42 
6.2.2. 
Primary Efficacy Parameter .................................................................................................................. 42 
6.2.2.1. 
Derivation Rules .......................................................................................................................................... 42 
6.2.2.2. 
Analyses Methods ....................................................................................................................................... 43 
6.2.2.3. 
Decision Making Methodology .................................................................................................................... 43 
6.2.2.4. 
 
6.2.3. 
Secondary Efficacy Parameters ............................................................................................................ 45 
6.2.3.1. 
Disease Activity Score Based on 28 Joints (C-reactive Protein) [DAS28 (CRP)]: Binary/Ordinal 
Categorization .................................................................................................................................................................. 45 
6.2.3.1.1 
Derivation Rules .......................................................................................................................................... 45 
6.2.3.1.2 
Analysis Methods ........................................................................................................................................ 46 
 
 
6.2.3.2.1 
Derivation Rules .......................................................................................................................................... 47 
6.2.3.2.2 
Analysis Methods ........................................................................................................................................ 47 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2.3.12. 
Patient’s Assessment of Morning Joint Stiffness (VAS) ............................................................................... 54 
6.2.4. 
Exploratory Efficacy Parameter(s) ........................................................................................................ 54 


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6.2.5. 
Subgroup Analyses ............................................................................................................................... 54 
6.3. 
SAFETY ANALYSES .......................................................................................................................................... 54 
6.3.1. 
Adverse Events ..................................................................................................................................... 55 
6.3.1.1. 
Definition of Treatment-Emergent Adverse Events .................................................................................... 55 
6.3.1.2. 
Coding of Reported Terms ........................................................................................................................... 55 
6.3.1.3. 
Allocation of Adverse Events to Analysis Periods ........................................................................................ 55 
6.3.1.4. 
Treatment Relatedness ............................................................................................................................... 56 
6.3.1.5. 
Worst-Case Selections ................................................................................................................................. 56 
6.3.1.6. 
Calculation of Relative Days and Duration .................................................................................................. 56 
6.3.1.7. 
Events of Special Interest ............................................................................................................................ 56 
6.3.1.8. 
Presentation of Results ............................................................................................................................... 57 
6.3.1.9. 
EudraCT Adverse Events Reporting ............................................................................................................. 57 
6.3.2. 
Laboratory Safety ................................................................................................................................. 57 
6.3.2.1. 
Available Data.............................................................................................................................................. 57 
6.3.2.2. 
Derivation Rules .......................................................................................................................................... 58 
6.3.2.3. 
Definition of Toxicity Grades ....................................................................................................................... 58 
6.3.2.4. 
Definition of Non-Graded Abnormalities .................................................................................................... 58 
6.3.2.5. 
Urinalysis Tests with Categorical Results ..................................................................................................... 59 
6.3.2.6. 
Treatment-Emergent Principle .................................................................................................................... 59 
6.3.2.7. 
Worst-Case Principle ................................................................................................................................... 59 
6.3.2.8. 
Hepatotoxicity ............................................................................................................................................. 60 
6.3.2.9. 
Presentation of Results ............................................................................................................................... 60 
6.3.3. 
Electrocardiogram ................................................................................................................................ 62 
6.3.3.1. 
Available Data.............................................................................................................................................. 62 
6.3.3.2. 
Derivation Rules .......................................................................................................................................... 62 
6.3.3.3. 
Abnormalities .............................................................................................................................................. 62 
6.3.3.4. 
Presentation of Results ............................................................................................................................... 63 
6.3.4. 
Vital Signs ............................................................................................................................................. 63 
6.3.4.1. 
Available Data.............................................................................................................................................. 63 
6.3.4.2. 
Derivation Rules .......................................................................................................................................... 63 
6.3.4.3. 
Abnormalities .............................................................................................................................................. 64 
6.3.4.4. 
Treatment-Emergent Principle .................................................................................................................... 64 
6.3.4.5. 
Worst-Case Abnormality ............................................................................................................................. 64 
6.3.4.6. 
Presentation of Results ............................................................................................................................... 64 
6.3.5. 
Physical Examinations .......................................................................................................................... 64 
6.3.6. 
SARS-CoV-2 Infection ............................................................................................................................ 65 
6.3.7. 
Subgroup Analyses ............................................................................................................................... 65 
6.4. 
PHARMACOKINETIC ANALYSIS ........................................................................................................................... 65 
6.4.1. 
Available Data ...................................................................................................................................... 65 
6.4.2. 
Presentation of Results ......................................................................................................................... 65 
 
 
 
 
 
 
 
6.7. 
CHANGES TO THE PLANNED ANALYSES, NOT COVERED BY PROTOCOL AMENDMENTS .................................................. 67 
7. 
REFERENCES ................................................................................................................................................ 68 
APPENDIX............................................................................................................................................................. 69 
APPENDIX I: LABORATORY: TOXICITY GRADING ...................................................................................................... 69 
APPENDIX II: VITAL SIGNS AND ELECTROCARDIOGRAM GRADING ........................................................................................ 75 
APPENDIX III: 66/68 JOINT COUNT .............................................................................................................................. 77 


-5- 
 
APPENDIX IV: SAS CODE ............................................................................................................................................ 78 
 
 


-6- 
 
VERSION HISTORY 
SAP Amendment # 
Date 
Description of changes 
SAP Version 1.0 Final 13-Nov-2020 
Original Version 
SAP Version 2.0 Final 07-May-2021 
Derivation of duration of RA incorrect (dates need to be 
switched). Updated to [(date of first study drug 
administration) – (date of initial diagnosis)] / 365.25. 
SAP Section 6.2.2.2: 
Removal of waterfall plots. 
Rationale: Waterfall plots were not previously removed 
from the SAP text. 
SAP Section 6.3.2.6: 
Addition of a specification for the treatment-emergent 
definition for the toxicity grade, we went from this: 
‘A post-baseline toxicity grade 1, 2, 3 or 4 is defined as 
treatment-emergent when higher than the toxicity grade 
of the baseline result. If the baseline result is missing, a 
post-baseline toxicity grade 1, 2, 3 or 4 will be 
considered as treatment-emergent.’ 
To this: 
‘A post-baseline toxicity grade 1, 2, 3 or 4 is defined as 
treatment-emergent when higher than the toxicity grade 
of the baseline result or when there is a change in 
direction (from H to L or from L to H). If the baseline 
result is missing, a post-baseline toxicity grade 1, 2, 3 or 
4 will be considered as treatment-emergent 
SAP Section 6.3.3.3 / Treatment-Emergent 
Abnormalities for ECG: 
Addition of a specification for the treatment-emergent 
definition for the Abnormalities, we went from this: 
‘Actual value: An abnormal post-baseline abnormality is 
defined as treatment-emergent when the abnormality is 
worse compared to the abnormality at baseline. When 
the baseline value is missing, post-baseline abnormalities 
are considered as treatment-emergent.’ 
To this: 


-7- 
 
‘Actual value: An abnormal post-baseline abnormality is 
defined as treatment-emergent when the abnormality is 
worse compared to the abnormality at baseline or when 
there is a change in direction (from H to L or from L to 
H). When the baseline value is missing, post-baseline 
abnormalities are considered as treatment-emergent.’ 
SAP Section 6.3.2.7: 
Specification of the definition of worst-case post-
baseline toxicity grade, from: 
‘The worst-case toxicity grade is the highest toxicity 
grade scored for the laboratory test (and direction, 
increases and decreases).’ 
To: 
‘The worst-case toxicity grade is the highest toxicity 
grade corresponding to the highest laboratory test value 
(by direction, increases and decreases). In case of 
several equal highest post-baseline actual values, the 
earliest occurrence will be taken for the analyses and 
will be flagged in the listings.’ 
SAP Section 6.3.3.3 / Worst-Case Abnormality: 
Addition of a specification for the Worst-Case 
Abnormality definition, as here under in bold and 
underline: 
‘The worst-case categorized actual analysis value is the 
category corresponding to the highest post-baseline 
actual value. In case of several equal highest post-
baseline actual values, the earliest occurrence will be 
taken for the analyses and will be flagged in the 
listings. 
The worst-case change from baseline is the category 
corresponding to the largest increase (positive change) 
from baseline. In case of several equal largest increase 
from baseline, the earliest occurrence will be taken for 
the analyses and will be flagged in the listings.’ 
SAP Section 6.3.4.5: 


-8- 
 
Change of the entire section to be aligned with ECG for 
Worst-Case Abnormality definition. Changed in : 
‘The worst-case post-baseline categorized actual 
analysis value will be determined per subject, per 
parameter and for each analysis period, using all non-
missing post-baseline records (including unscheduled 
and FU visits). 
The worst-case categorized actual analysis value is the 
category corresponding to the highest post-baseline 
actual value. In case of several equal highest post-
baseline actual values, the earliest occurrence will be 
taken for the analyses and will be flagged in the listings.’ 
SAP Section 6.1.8.2. and Mock table MTSIEX04 - 
Summary of MTX Drug Administration: 
Specification that the dose, the route and the dose from to 
be summarized are the ones measured at baseline. 
Addition of the ‘Dose form at baseline’ in the Mock 
table. Removal of ‘Dose adjusted from planned’ in the 
mock table as it is not measure at baseline. 
SAP Section 4.4.1.2 Handling of Missing Result Data, 
change in the last paragraph here under in bold and 
underlined to specify the definition of the non-responder 
imputation (NRI): 
‘For some binary endpoints, missing data will be 
handled using both an OC approach and non-responder 
imputation (NRI) as specified in Section 6.2. NRI being 
the imputation of missing values by a non-
response/non-remission.’ 
SAP Section 4.3.4, baseline definition, addition of the 
sentence in bold and underlined, for the parameter for 
which the time was planned to be collected: 
Baseline is defined as the last available assessment prior 
to the first intake of IP. For the parameters for which 
the time of assessment was planned to be collected, if 
for their assessment on the day of first intake the time is 
missing, their assessment at time point “PRE-DOSE” 
(when applicable) will be considered as baseline, 
otherwise, previous days last available assessment will 


-9- 
 
be selected.  For the parameters for which the time of 
assessment was not planned to be collected, their 
assessment on the day of first intake of IP will be 
considered as baseline. If multiple values on the same 
day qualify as last available assessment, the average of 
these values will be used in the analysis. 
SAP section 4.3.5. Selection and Use of Analysis Visits, 
proposition to remove the mention that the pre-baseline 
data will be provided in the profile line plot as these plots 
will be provide only on CHG and %CHG from baseline, 
as per change here under in bold: 
Before first administration of IP, only Baseline will be 
used for the entire statistical analysis. Pre-baseline 
assessments will only be listed and presented in 
individual subject profile plots. 
SAP Section: 6.5.1:  
Updated the unit for fasting insulin as “mU/L”. 
Updated derivation for HOMA-IR is  
HOMA-IR = (fasting insulin [mU/L] x fasting glucose 
[mg/dL]) / 405 
Rationale: protocol contains a typo error 
 
 
         
 
          
 
    
 
 
 
 
 
SAP Section 6.3.2.1: 




-11- 
 
HbA1c) are known to deviate heavily from the normal 
distribution but follow the log-normal distribution well. 
For these parameters, the geometric mean (GeoMean), 
geometric standard deviation (GeoSD), and geometric 
standard error (GeoSE) will be also reported for the 
summaries by treatment group and visit. GeoMean, 
GeoSD and GeoSE are not applicable for the summaries 
of the changes from baseline, however GeoMean, GeoSD 
and GeoSE will be reported for the summaries of percent 
changes from baseline. This will be done by obtaining 
the mean, SD and SE of log(value) - log(baseline) and 
then transforming these statistics back to the 'percent 
change scale' as 100 X {exponential(statistic) - 1}.” 
Section 6.1.8: section added for additional listing 
“Procedure” 
SAP:  
Section 6.2.3.11.2: the paragraph starting from “The 
analysis of percent change from baseline…” updated as 
below 
“The analysis of percent change from baseline will be 
performed by analyzing the log(value) - log (baseline) 
and transforming statistics back to the 'percent change 
scale' as 100X{exponential(statistic)-1}. The analysis of 
percent change from baseline up to week 6 will use the 
same method as for analysis of the primary efficacy 
endpoint as detailed in section 6.2.2.2. The GeoMean (./÷ 
GeoSE) of the actual values and percent changes from 
baseline will be presented graphically over time.”  
SAP section 6.3.2.9: updated this section to include 
“Profile line plots by subject of all actual observed values 
using relative day (ADY) will be presented by treatment 
group” 
TLF Mock: MGSFLB01: Figure for lab parameters of 
actual values over time added' 
SAP section 6.3.3.4: updated this section to include 
“Profile line plots by subject of all actual observed values 
using relative day (ADY) will be presented by treatment 
group” 








-15- 
 
ICF 
informed consent form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IP 
investigational product 
INF 
infinity 
IXRS 
interactive voice/web response system 
L 
low, below the lower limit of the normal range 
LDL 
low-density lipoprotein 
LLN 
lower limit of the normal range 
LLOQ 
lower limit of quantification 
LRV 
lower reference value 
LS 
least squares 
LSM 
least square mean 
MedDRA 
medical dictionary for regulatory activities 
MMRM 
mixed models for repeated measures 
MTX 
methotrexate 
n 
number of non-missing data points 
N 
normal, with the limits of the normal range 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NRI 
non-responder imputation 
OC 
observed cases 
 
 
 
 
 
 
PK 
pharmacokinetic(s) 
pop-PK 
population PK 
PR 
pulse rate 
QTc 
corrected QT interval 
QTcF 
QT interval corrected for the heart rate using Fridericia’s formula 
RA 
rheumatoid arthritis 
Reg 
regular test 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 


-16- 
 
 
 
SDTM 
study data tabulation model 
SE 
standard error 
SJC66 
swollen joint count evaluated in 66 joints 
SI 
standard international 
SMC 
Safety Monitoring Committee 
TE 
Treatment-emergent 
TEAE 
treatment-emergent adverse event 
TJC68 
tender joint count evaluated in 68 joints 
TLF 
tables, listings and figures 
TV 
target value 
ULN 
upper limit of the normal range 
ULOQ 
upper limit of quantification 
VAS 
visual analog scale 
WHO 
World Health Organization 






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Refer to the Schedule of Assessments (Section 2.5) for further details.  
A schematic diagram of clinical study design, procedures and stages is provided in Figure 
1. 
Figure 1 
Schematic Diagram 
 
2.4. 
Clinical Study Protocol (CSP) and CSP Amendments 
This SAP is based on the protocol version 1.0, dated 29-May-2020. 
2.5. 
Scheduled of Assessments 
The study assessments will be undertaken at time points as specified in the Schedule of 
Assessments (Table 1). For detailed instructions on the clinical study procedures, please 
see the relevant CSP sections and CSP Section 8.1, “Timing of Assessments”. 
Key selection criteria
• Inadequate response to
MTX
• Age ≥18 and <65 years
• RA diagnosis by ACR/EULAR 
criteria 
• ≥6 swollen joints from 
SJC66 and ≥8 tender joints 
from TJC68, CRP > ULN, 
DAS28 (CRP) > 3.2
Double-blind Treatment Period
Day 1 (Baseline) to Week 6
Follow-up Period
2 Weeks following  
end of Treatment
Screening
Up to 3 weeks
3:2 RANDOMIZATION
Group B (Placebo, n=10)
Group A (GLPG3970 400 mg q.d., n=15)
Key Outcome Measures
• Rate and severity TEAEs
• DAS28 (CRP)
• PK
•


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Table 1 Schedule of Assessments 
EVENT 
SCREENING 
PERIOD 
TREATMENT PERIOD1,2 
FOLLOW-UP 
PERIOD2 
Study visit 
S 
1 
2 
3 
4 
5 
ED3 
FU Visit 
Study Weeks  
 
Baseline 
1 
2 
4 
6 
 
 
Study Day (D) ± Days  
-21 to -1 
1 
8 ± 2 
15 ± 2 
29 ± 2 
43 ± 2 
Early treatment 
discontinuation 
57 ± 3  
On site visit 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
Telephone call 
 
 
✓ 
 
 
 
 
 
Informed consent  
✓ 
 
 
 
 
 
 
 
Inclusion/exclusion criteria  
✓ 
✓ 
 
 
 
 
 
 
Demographics  
✓ 
 
 
 
 
 
 
 
Medical history  
✓ 
 
 
 
 
 
 
 
FSH test (postmenopausal 
women) 
✓ 
 
 
 
 
 
 
 
Pregnancy test4  
✓ 
✓ 
 
 
✓ 
✓ 
✓ 
 
Physical examination  
✓ 
✓ 
 
 
 
✓ 
✓ 
✓ 
                                                 
1 On dosing days, all assessments are to be performed within 3 hours pre-dose, unless otherwise specified. 
2 Subjects must come for the study visits 1, 3 and 5 in the morning in a fasting state (no food intake for at least 8 hours). For Visit 1 (predose measurements) and for 2 post 
dose visits (Visit 3, 4 or 5) all attempts should be made to plan the visit within 2 days following MTX intake. 
3 Subjects who discontinue treatment early will be requested to return for an early discontinuation (ED) visit to complete all Visit 5 assessments and to return for a follow-up 
(FU) visit 14 ± 3 days after last IP administration. 
4 Serum beta human chorionic gonadotropin at screening, baseline (Visit 1), Visit 4 and Visit 5, or at the ED visit, if applicable (all female subjects). 


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EVENT 
SCREENING 
PERIOD 
TREATMENT PERIOD1,2 
FOLLOW-UP 
PERIOD2 
Study visit 
S 
1 
2 
3 
4 
5 
ED3 
FU Visit 
Study Weeks  
 
Baseline 
1 
2 
4 
6 
 
 
Study Day (D) ± Days  
-21 to -1 
1 
8 ± 2 
15 ± 2 
29 ± 2 
43 ± 2 
Early treatment 
discontinuation 
57 ± 3  
Vital signs  
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
Body weight and height 5 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
12-lead triplicate ECG  
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
Serology  
✓ 
 
 
 
 
 
 
 
QuantiFERON-TB Gold test  
✓ 
 
 
 
 
 
 
 
SARS-CoV-2 RT-PCR test6 
✓ 
✓ 
As needed 
SARS-CoV-2 serology test6 
 
✓ 
As needed 
Randomization  
 
✓ 
 
 
 
 
 
 
Clinical safety blood samples  
✓ 
✓7 
 
✓7 
✓ 
✓7 
✓ 
✓ 
Clinical safety urine samples 8  
✓ 
✓9 
 
✓ 
✓ 
✓9 
✓ 
✓ 
                                                 
5 Height only to be measured at screening. 
6 RT-PCR from a nasal swab sample at screening and RT-PCR from a nasal swab sample and serology testing at baseline (Visit 1), and as needed when subject presents signs 
and symptoms of SARS-CoV-2 infection. 
7 Fasted glucose, fasted insuline and HOMA-IR only at Visit 1, 3 and 5 and the ED visit, if applicable. 
8 On dosing days, clinical safety urine samples will be taken predose, on the same visit day. 
9 Visit 1 and 5: predose and 2 hours postdose. Calcium and phosphate should only be evaluated at Visits 1 and 5. 






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2.6. 
Sample Size Justification 
The operating characteristics of the chosen decision framework at a sample size of 15 subjects 
(GLPG3970) + 10 subjects (placebo) are represented in the following graphical output and table, 
and were deemed acceptable. A common standard deviation (SD) of 1.3 for placebo and 
GLPG3970 was assumed based on previous experience with RA studies.  
Lower Reference Value (LRV) and Target Value (TV) for the decision framework were 
determined based on the published studies and the therapies in development or on the market. 
They were identified by the project team as the lowest delta of possible interest and the best case 
scenario for efficacy outcome respectively. 
A dropout rate of 20% was taken into account to allow a minimum of 20 subjects to complete the 
study. In case of drop-outs due to SARS-CoV-2 infection, additional subjects may be randomized 
on top of the planned sample size. The number of additional subjects randomized will not exceed 
the number of subjects dropping out of the study in relation to SARS-CoV-2. Randomization of 
additional subjects will ultimately be decided by the sponsor before any study lock or related 
unblinding has occurred. 
 
Probability 
Reference 
value 
Outcome 
0.852 
-1.6 
Signal detected 
0.043 
-1.6 
No conclusion 
0.105 
-1.6 
No signal 
detected 
0.192 
-0.6 
Signal detected 
0.091 
-0.6 
No conclusion 
0.717 
-0.6 
No signal 
detected 
 
 
 
2.7. 
Randomization and Blinding 
2.7.1. 
Randomization 
At screening, subjects will be assigned a subject identification number. When a subject is 
confirmed to be eligible for the clinical study, the subject will be randomized at visit 1. 
Allocation of each subject to a given treatment will be done using a centralized electronic system 
(interactive voice/web response system [IXRS]). Subjects will be randomized in a 3:2 ratio to 
GLPG3970 or placebo. 


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2.7.2. 
Blinding and Unblinding 
This is a randomized, double-blind clinical study. The subjects and the entire clinical study team, 
including the investigators, clinical study coordinators, and sponsor personnel are blinded to 
treatment assignment. 
Blinded and packaged medication will be provided to the site. All IP formulations will be 
identical in appearance, shape, smell and taste, and will be packaged in the proper proportion to 
assure desired dosages and maintenance of the blinding.  
The blind can be broken by the investigator for the safety of a subject. The investigator is 
encouraged to discuss considerations to break the blind with the sponsor’s medical responsible, 
whenever possible and where the situation allows. However, the responsibility to break the 
treatment code in emergency situations resides solely with the investigator. The investigator is 
not required to discuss unblinding beforehand if he or she feels rapid emergency unblinding is 
necessary, but is required to inform the sponsor within 24 hours after unblinding has occurred. 
The blind can be broken via IXRS by the investigator. 
If the blind is broken for any reason during the course of the clinical study, the moment on which 
the blind was broken and all other relevant information will be documented by the site. The 
reason for breaking the blind will be indicated and justified in the source documentation. 
If an adverse event (AE) leads to unblinding, the AE will be given as the reason for unblinding. 
All subjects who are unblinded should, where possible, complete the FU visit assessments 14±3 
days after unblinding. Any AEs will be followed until resolution. 
Code-breaking information (via IXRS vendor) will be provided to the bioanalytical laboratory 
responsible for plasma drug determination sample analysis, the person responsible for providing 
unblinded data to the internal Safety Monitoring Committee (SMC), the contract research 
organization (CRO) responsible for the population PK modeling, and to the sponsor 
pharmacovigilance vendor for serious adverse event (SAE) reporting purposes.  
3. 
STUDY ESTIMANDS 
Hypothetical and treatment policy estimand for primary efficacy endpoint: 
Attribute 
Details 
Treatments 
GLPG3970 (400 mg q.d.) vs. Placebo 
Population 
• Population target defined through the 
inclusion/exclusion criteria (see CSP).  
• Analysis Set: Full Analysis Set (FAS), 
defined as all randomized subjects 


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who have received at least 1 dose of 
IP. 
Endpoint 
Change from baseline in DAS28 (CRP) at 
Week 6. 
Population-level summary 
Difference (GLPG3970-Placebo) in least 
square mean (LSM).For further details see 
study SAP section 6.2.2.2. 
Intercurrent events and strategies to handle 
those 
• Early treatment discontinuation (for 
any reason) is handled using the  
hypothetical strategy 
• Other intercurrent events (e.g. major 
protocol violations, intake of 
prohibited medication, lack of 
compliance) are handled using the 
treatment policy strategy (i.e. they are 
ignored) 
 
Estimand for the secondary objective (safety) 
Attribute 
Details 
Treatments 
GLPG3970 (400 mg qd) vs. Placebo 
Population 
• Population target defined through the inclusion/exclusion 
criteria (see CSP).  
• Analysis Set: Safety Analysis Set, defined as all subjects 
who were administered IP at least once. 
Endpoint 
Presence of TEAE 
Population-level 
summary 
Percentage of subjects with TEAEs. 
Intercurrent events and 
strategies to handle 
these 
Intercurrent event: early treatment discontinuation (for any reason): 
handled using the while-on-treatment strategy. It is expected that no 
further data collection happens after treatment discontinuation, 
except of course the normal FU visit. All collected data up to (and 
including) the last contact FU visit is regarded as possibly 






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4.3.2. 
Analysis Periods 
For treated subjects, adverse events and assessments will be allocated to analysis periods 
according to  
Table 1. 
Table 1 
Analysis Periods 
Analysis Period 
Start Analysis Period 
End Analysis Period 
Screening 
Date of signing the ICF, with 
00:00 added as time part 
Date (time) of first IP 
administration - 1 minute 
Treatment 
Date (time) of first IP 
administration.  
Study termination date (i.e. 
date of last contact), with 
23:59 added as time part  
  
 
The last analysis period will always end on the date of last contact. 
For every subject, all assessments performed and all events occurring during the study are 
expected to have a (start) date (/time) between the date of informed consent (IC) signature and 
the last contact date. Obvious exemptions are historical records like medical history or 
concomitant therapies having started before the study. 
Assessments and events will be allocated to one of these analysis periods by incidence, meaning 
placing the record (start) date and time between the matching start and end dates and times of the 
subject’s own analysis periods, assuming completeness of all dates and times, or further 
determined by the presence of timing indicators such as tick boxes flagging AEs starting 
before/after first IP administration, or by worst-case considerations for AEs if needed. For the 
parameters for which the time of assessment was not planned to be collected, their assessment on 
the day of first IP administration will be considered as baseline and will be reported under the 
‘Screening’ analysis period with the exception of AEs. 
 
4.3.3. 
Analysis Windows 
For the efficacy, PK,
 and safety assessments, all data (including data obtained at unscheduled 
visits) will be placed into time windows based on the relative day (ADY) of the assessment 
(relative to the first dose of IP), according to the following allocation tables: 
For endpoints with multiple components, analysis windows will be derived separately for each 
component/parameter.


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Table 2: Analysis Visit Window for non-PK data 
 
Visit date and time 
Relative day 
(ADY) 
Assessment visit (VISIT) 
Time window 
(in ADY) 
Target day 
Analysis visit 
(AVISIT) 
On or before first study 
drug administration 
≤1 
Last assessment at any point in time before 
first study drug administration 
≤1 
1 
Baseline 
After first study drug 
administration  
>1 
Any scheduled (non follow-up), 
unscheduled, or early discontinuation visit 
 
2 to 12 
 
8 
 
Week 1 
13 to 22 
15 
Week 2 
23 to 36 
29 
Week 4 
37 to 49 
43 
Week 6 
Follow-up 
CRF collected 
follow-up visit 
 
Follow-up 
 
 
 
 


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Table 3: Analysis Visit Window for PK data 
Visit date and 
time 
Relative 
day 
(ADY) 
Assessment visit 
(VISIT) 
Time 
window 
(in 
ADY) 
Target 
day 
Analysis 
visit 
(AVISIT) 
Analysis time point (ATPT) 
Before first 
study drug 
administration 
<1 or 
pre-dose 
at 
ADY=1 
Last assessment at any 
point in time before first 
study drug administration 
<1 or 
pre-dose 
at 
ADY=1 
1 
Baseline 
Pre-dose (within 30 minutes prior 
to dosing) 
Same as or after 
first study drug 
administration  
≥ 1 
Any scheduled (non 
follow-up), unscheduled, 
or early discontinuation 
visit 
1 
1 
Day 1 
As indicated in the database: 
0.5-1.5, 2-2.5 hours post-dose 
13 to 22 
15 
Week 2 
As indicated in the database: 
Pre-dose (within 30 minutes prior 
to dosing) 
23 to 36 
29 
Week 4 
As indicated in the database: 
Pre-dose (within 30 minutes prior 
to dosing) 
37 to 49 
43 
Week 6 
As indicated in the database: 
Pre-dose (within 30 minutes prior 
to dosing) and within [4-6 hours 
post dose]. 


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Visit date and 
time 
Relative 
day 
(ADY) 
Assessment visit 
(VISIT) 
Time 
window 
(in 
ADY) 
Target 
day 
Analysis 
visit 
(AVISIT) 
Analysis time point (ATPT) 
Follow-up 
CRF 
collected 
follow-
up visit 
 
Follow-up 
 
 




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• Step 2: Within each visit window, select the data points for analysis. 
• Step 3: Combine these selected data points within each analysis visit window across the 
components 
4.3.6. 
Handling of Missing Data 
4.3.6.1. 
Handling of Missing Date-Time Data 
No imputations will be done in case of missing date (time) fields, nor for the missing parts of 
partially known date (time) fields. 
Assessments with missing date (time) will be omitted from the summaries by visit. 
Event-type data (e.g. AEs, concomitant medications) with missing date (time) will be allocated to 
analysis periods using a worst-case approach as explained in the respective sections. 
4.3.6.2. 
Handling of Missing Result Data 
No imputation will be done of missing result data unless otherwise specified. That is, an observed 
case (OC) analysis will be performed unless otherwise specified. Endpoints analyzed via mixed 
models for repeated measures (MMRM) handle missing data via the maximum-likelihood 
function. 
For some binary endpoints, missing data will be handled using both an OC approach and non-
responder imputation (NRI) as specified in Section 6.2. NRI being the imputation of missing 
values by a non-response/non-remission. 
4.3.6.3. 
Censoring of Time to Event Data 
Not applicable.  
4.3.7. 
Handling of Values Below or Above a Threshold 
Results of continuous parameters, as well as normal limits of these reported as below (or above) 
the detection limit will be imputed by the value one precision unit smaller (or larger) than the 
detection limit itself. In listings, the original value will be presented. 
Example: if the database contains the value “<0.04”, then for the descriptive statistics the value 
“0.03” will be used. The value “>1000” will be imputed by “1001”. 
For PK data, values below the limit of quantification will be imputed by 0 for the calculation of 
descriptive statistics presentation; except for the geometric mean and the geometric CV%, where 
it will be imputed as LLOQ/2. These values will be listed as “below lower limit of quantification 
(BLOQ)”. 
  




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− 
the median, minimum and maximum; 
− 
90% confidence interval (CI) of the mean (if indicated in the relevant section). 
− 
Some parameters namely hsCRP, cytokines (IL-10 and TNFα) and metabolic parameters 
(fasted insulin, HOMA-IR and HbA1c) are known to deviate heavily from the normal 
distribution but follow the log-normal distribution well. For these parameters, the geometric 
mean (GeoMean), geometric standard deviation (GeoSD), and geometric standard error 
(GeoSE) will be also reported for the summaries by treatment group and visit. GeoMean, 
GeoSD and GeoSE are not applicable for the summaries of the changes from baseline, 
however GeoM, GeoSD and GeoSE will be reported for the summaries of percent changes 
from baseline. This will be done by obtaining the mean, GeoSD and GeoSE of log(value) - 
log(baseline) and then transforming these statistics back to the 'percent change scale' as 100 
X {exponential(statistic) - 1}. 
 
For PK data, descriptive statistics will include: 
 
− 
the number of non-missing observations (n); 
− 
the number of data points above the LLOQ; 
− 
the arithmetic mean; 
− 
SE and SD; 
− 
the median, minimum and maximum; 
− 
the coefficient of variation (CV%); 
− 
the geometric mean and geometric CV%. 
 
If less than 50% of the subjects have quantifiable values, only the number of subjects with data, 
number of data points above the LLOQ, the arithmetic mean, median, minimum, and maximum 
will be presented with the original calculated value. The other descriptive statistics will be listed 
as “NC” (not calculated). 
If the calculated descriptive statistic is BLOQ, then it will be presented as “BLOQ”. 
Individual values and descriptive statistics of concentrations and PK parameters will be presented 
with 3 significant digits. 
4.4.3. 
Calculation of Percentages 
Frequencies and percentages will be generated for categorical parameters. 
For event-type data (e.g. AEs), the denominator will be all subjects in the analysis set and 
analysis period. For other data (e.g. worst-case analysis of assessments), the denominator will be 
all subjects with (post-baseline) data for the parameter, in the analysis set and analysis 
window/period. 


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5. 
INTERIM ANALYSES AND INTERNAL DATA SAFETY 
MONITORING COMMITTEE 
No formal interim analysis is planned for this clinical study.  
An internal SMC independent from the study will review unblinded safety data during the course 
of the study. This Committee may involve external medical experts (such as an expert in the field 
of RA and an infectious diseases expert) to support data interpretation. The Committee will 
review unblinded safety data and assess any potential safety issues arising during the conduct of 
the clinical study, including (but not limited to) any potential issues in the context of the SARS-
CoV-2 pandemic. The clinical study team will remain blinded to the allocation of subjects to 
treatments during the course of the study. The process is described in a separate ‘SMC Charter’. 
6. 
STATISTICAL ANALYSES 
6.1. 
Subject Information 
Subject information will be tabulated using the Safety Analysis Set, unless specified otherwise. 
No inferential testing will be performed, nor will p-values be provided. 
Subject information will be tabulated with descriptive statistics per planned treatment group, as 
well as overall. 
6.1.1. 
Demographic and Baseline Disease Characteristics 
The following parameters will be summarized: 
 
date of ICF signature (listed); 
 
sex; 
 
age at signing the ICF (years); 
 
age, categorized (years): 18 ≤ age < 65; 65 ≤ age < 85; age ≥85; 
 
race and ethnicity; 
 
height at baseline (cm); 
 
weight at baseline (kg); 
 
body mass index (BMI) at baseline (kg/m²) ൌ 
௪௘௜௚௛௧ ሺ௞௚ሻ
௛௘௜௚௛௧మ ሺ௠మሻ   
(BMI will not be recalculated if already available in the database); 
 
duration of RA (years)  
 ൌ
ሺௗ௔௧௘ ௢௙ ௙௜௥௦௧ ௦௧௨ௗ௬ ௗ௥௨௚ ௔ௗ௠௜௡௜௦௧௥௔௧௜௢௡ሻିሺௗ௔௧௘ ௢௙ ௜௡௜௧௜௔௟ ௗ௜௔௚௡௢௦௜௦ሻାଵ
ଷ଺ହ.ଶହ
 
If missing day: use 1st day of the month 
If missing both day and month: use 1st of January; 
 
Duration of RA, categorized (years): < 1; 1 ≤ duration < 5; 5 ≤ duration < 10; 10 ≤ 
duration < 15; 15 ≤ duration < 20; duration ≥ 20; 
 
hsCRP (mg/L) at baseline;  


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DAS28 (CRP) at baseline; 
− 
 
 
 
 
 
− 
TJC68 and SJC66 joint counts; 
− 
 
 
 
 
 
 
 
 
 
 
Demographic and baseline disease characteristics will be listed.  
6.1.2. 
Allocation and Randomization 
The number of subjects (and percent) per treatment group and overall will be tabulated per 
country and site. 
The following listings will be provided: 
− 
Listing per subject of the IP kit numbers, IP lot numbers dispensed/returned.  
− 
Randomization schemes and codes, with the treatment assigned to each subject. This listing 
includes a flag in case of discrepancies or errors between the assigned and the actual 
treatment taken, and should also include flags declaring any (potential) unblinding. 
6.1.3. 
Disposition Information 
The following tabulations will be provided, by treatment group and overall: 
− 
The number of subjects screened, not-randomized (including reasons), randomized (treated 
and not treated), and treated with GLPG3970 and Placebo. 
− 
 Number (percent) of subjects randomized per country and site. 
− 
The number (percent) of subjects in each analysis set as defined in Section 4.1. 
− 
The number (percent) of subjects per analysis window as defined in Section 4.3.3. 
− 
The number (percent) of subjects who completed/discontinued the IP administration 
schedule and the reasons for discontinuation. 
− 
The number (percent) of subjects who completed/discontinued the study and the reasons for 
discontinuation.  
 
Discontinuation related to SARS-CoV-2 will be flagged in the listing. 
 
Additionally, the following information will be provided in listings: 
 
− 
Subject identification and randomization (country, site number, investigator, subject 
number). 


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− 
Randomization number and date, planned and actual randomization group, with flags for any 
discrepancies. 
− 
Subjects excluded from the safety and full analysis sets, including reasons. 
− 
First and Last Key Dates in the Study will be listed 
 
6.1.4. 
Protocol Deviations and Eligibility 
Major protocol deviations are determined and recorded while the study is ongoing, and the list is 
finalized prior to database lock (and unblinding). For more details, please refer to the Protocol 
Deviations Plan. 
The number (percent) of subjects with major protocol deviations will be tabulated, overall and 
per class of deviation, by treatment group and overall. 
All available information concerning major protocol deviations, including COVID-19 related 
verbatim, violations on eligibility criteria and subjects not treated will be listed. Protocol 
deviations leading to the exclusion of subjects from any analysis set, as applicable, will be 
flagged. 
Minor protocol deviations will not be tabulated and will not be listed. 
6.1.5. 
Medical History and Concomitant Diseases 
Frequency tabulations, per treatment group and overall, per system organ class and preferred term 
will be provided for the medical history findings (i.e., conditions no longer present at the start of 
the study) as well as for the concomitant diseases (i.e. conditions present at the start of the study) 
using Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary. 
All medical history findings and concurrent diseases will be listed separately. 
6.1.6. 
Rheumatoid Arthritis Disease History (RA) 
Frequency tabulations, per treatment group and overall, per system organ class and preferred term 
will be provided for the RA disease history using MedDRA coding dictionary. 
All RA disease history will be listed. 
6.1.7. 
Prior and Concomitant Medications 
6.1.7.1. 
Coding of Reported Terms 
All prior and concomitant medication terms will be coded in the database using the World Health 
Organization (WHO) drug coding dictionary. 


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6.1.7.2. 
Classification of Medications 
All prior and concomitant medication records will be categorized as follows, considering their 
date and flags indicating the relative timing versus study (drug) start or end (before, after, 
ongoing): 
− 
Prior only: when the record ended before the first IP administration date. 
− 
Concomitant only: when the record started on or after the first IP administration date. 
− 
Prior and concomitant: when the record started before the date of first IP administration, and 
ended on or after this point, or continued. 
When the start or end date of the prior and concomitant medication records are incomplete (and 
no flags indicating relative timing are available), the date of first IP administration will be 
considered to the same level of information provided by these incomplete dates to categorize the 
timing of these records. This means that a record only having month and year will be categorized 
comparing only to the month and the year of the date of first IP administration. 
6.1.7.3. 
Calculation of Relative Days 
For both the start and the end dates of the concomitant medication records, their day relative to 
the day of first IP administration will be calculated as described in Section 4.3.1. 
6.1.7.4. 
Presentation of Results 
A frequency tabulation per planned treatment group and overall of the Anatomical Therapeutic 
Chemical (ATC) classification classes level 4 by therapeutic subgroup (ATC level 2) and generic 
term of the prior medication (defined as ‘prior only’ and ‘prior and concomitant’) will be 
provided as well as of the concomitant medication (defined as ‘concomitant only’ and ‘prior and 
concomitant’). 
A listings of prior and concomitant medications will be provided. Also, prior and concomitant 
corticosterioid listing will be provided separately (the list of the ATC codes to be selected in this 
listing will be provided by the Galapagos medical services). 
6.1.8. 
Procedures 
Procedures results will only be listed. 
6.1.9. 
Exposure to IP and Compliance 
6.1.9.1. 
Derivation Rules 
Derived Parameters: Extent of Exposure to IP 
− 
Total treatment duration (days) = last IP administration date – first IP administration date 
+ 1 day. 


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 
Total treatment duration, excluding days off IP: Sum of the number of days with any IP 
administration. 
 
Total treatment duration, full compliance (days): Number of days where the complete 
volume of IP has been administered. 
 
Derived Parameters: Compliance 
 
Overall compliance (%) ൌ100 ൈ 
௡௨௠௕௘௥ ௢௙ ௗ௢௦௘௦ ௔௖௧௨௔௟௟௬ ௧௔௞௘௡
௡௨௠௕௘௥ ௢௙ ௗ௢௦௘௦ ௧௛௔௧ ௦௛௢௨௟ௗ ௛௔௩௘ ௕௘௘௡ ௧௔௞௘௡ 
 
 
Percent days with any intake (%) ൌ100 ൈ 
௧௢௧௔௟ ௧௥௘௔௧௠௘௡௧ ௗ௨௥௔௧௜௢௡,௘௫௖௟௨ௗ௜௡௚ ௗ௔௬௦ ௢௙௙ ௗ௥௨௚
௧௢௧௔௟ ௧௥௘௔௧௠௘௡௧ ௗ௨௥௔௧௜௢௡
 
 
 
Percent days full compliance (%) ൌ100 ൈ 
௧௢௧௔௟ ௧௥௘௔௧௠௘௡௧ ௗ௨௥௔௧௜௢௡,௙௨௟௟௬ ௖௢௠௣௟௜௔௡௧
௧௢௧௔௟ ௧௥௘௔௧௠௘௡௧ ௗ௨௥௔௧௜௢௡
 
 
Derived Parameters: Extent of Exposure to MTX Drug 
 
Total treatment duration (days) = last MTX administration date – first MTX 
administration date + 1 day. 
 
Total treatment duration, excluding days off MTX: Sum of the number of days with any 
MTX administration. 
 
6.1.9.2. 
Presentation of Results 
Summary statistics per planned treatment group and overall will be provided for each compliance 
and extent of exposure parameter for IP administration. Frequency tables will be provided for the 
compliance parameters, using the following categories: <80%; 80% ≤ x < 100%; 100%; 100% < 
x ≤ 120%; > 120%. 
All original IP administration records will be listed per subject. The listing will include all 
deviations from IP schedules such as missed or reduced doses and GLPG3970/placebo switches 
and will also include food intake status at the time of IP administration. IP exposure and compliance 
data will be listed. 
For MTX administration, a table summarizing the number and percent of subjects taking MTX 
by planned treatment group and overall will be provided. In addition, the following parameters 
will be summarized: 
 
Dose at baseline (mg); 
 
Route at baseline; 
 
Dose form at baseline; 
 
Total treatment duration (days); 
 
Total treatment duration, excluding days off MTX 


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6.2. 
Efficacy Analyses 
Efficacy analyses will be performed on the FAS.  
Tabulations will be shown per planned treatment group. 
6.2.1. 
Level of Significance 
Statistical tests for efficacy analysis will be done at a 2-sided significance level of 10%. 
 
6.2.2. 
Primary Efficacy Parameter 
The primary endpoint for this study is the change from baseline in DAS28 (CRP) at Week 6. The 
DAS28 (CRP) is a derived measurement with differential weighting given to each component  
such as TJC28, SJC28, patient’s global assessment of disease activity (0–100-mm VAS), and 
serum CRP level. A DAS28-CRP below the value of 2.6 is interpreted as Remission.  
6.2.2.1. 
Derivation Rules 
The DAS assessment is a derived measurement with differential weighting given to each 
component. The DAS28 (CRP) will be calculated at each assessment time point.  
The components of the DAS28 arthritis assessment include:  
x Tender Joint Count 28 (TJC28) ranges from 0-28 
x Swollen Joint Count 28 (SJC28) ranges from 0-28 
x High sensitivity C-reactive protein (hsCRP) (in mg/L) 
x Patient’s disease activity VAS (in mm)  (ranges from 0 = best to 100 = worst) 
The DAS28 (CRP) score will be calculated using the below formula: 
DAS28 (CRP) = 0.56 x ඥTJC28 + 0.28 x ඥSJC28 + 0.36 x Ln[1+CRP(in mg/L)] + 0.014 x 
patient’s disease activity VAS (in mm) + 0.96 (Mack, Hsia, & Aletaha, 2017) 
where Ln is the natural logarithm 
A lower score is considered as better disease activity. If one of the component is missing at a 
specific analysis visit, DAS28 (CRP) will not be calculated for that assessment and will be set to 
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6.2.2.2. 
Analyses Methods 
DAS28 (CRP) data will be analyzed descriptively as actual (observed) values and changes from 
baseline. Percent change from baseline will not be calculated for the primary endpoint. 
A MMRM will be used on the DAS28 (CRP) changes from baseline to compare treatment 
groups, with a 90% CI of the treatment difference at Week 6. 
The following covariates will be used: treatment by visit interaction and baseline DAS28 by visit 
interaction. An unstructured variance-covariance matrix will be used to model the residuals. If the 
default Newton–Raphson algorithm used by SAS PROC MIXED fails to converge, the following 
will be tried to avoid lack of convergence while maintaining an unstructured variance: 
A. The Fisher scoring algorithm (via the SCORING=5 option of the PROC MIXED 
statement) will be used to obtain the initial values of covariance parameters.  
B. If the above fails, the no-diagonal factor analytic structure will be used which 
effectively performs the Cholesky decomposition via the TYPE=FA0(V) option of 
the REPEATED statement, where V is the total number of visits in the response 
vector (V = 3). 
C. If all the above fails, the variance-and-correlations parameterization will be 
attempted using TYPE =UNR 
In the rare case where all the above fails, the Toeplitz structure with the sandwich variance 
estimator (EMPIRICAL option) will be used. If this option also fails, the AR(1) + random 
intercept model will be tried with the sandwich variance estimator. 
The LSM, LSM difference between GLPG3970 and the placebo group (reference category), 
standard error, two-sided 90% CIs for the LSM and difference between treatment groups and p-
value for treatment differences will be presented. The number of subjects in the analysis population 
and number of subjects in the analysis will be provided by treatment group. 
Graphs of the mean (+- SE) actual values over time and of the mean (+- SE) change from 
baseline. In addition, profile line plots of the change from baseline will be provided by treatment 
group. 
6.2.2.3. 
Decision Making Methodology 
The decision making methodology described by Frewer et al (Frewer, Mitchell, Watkins, & 
Matcham, 2016) will be used to provide further insight into the treatment effect of GLPG3970 
over placebo, and will support scenario analyses. The posterior distribution of this treatment 
effect will be estimated, and from this distribution probabilities of reaching at least a certain 
effect (delta) will be derived, e.g. a range of plausible effect size values going from as high as P 
(delta ≤ -1.6) to as low as P (delta ≤ -0.6).  
The chosen framework parameters are as follows: 


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TV: -1.6 and LRV: -0.6 
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False stop risk: 10% and false go risk: 20% 
- 
Framework rules: 
o Signal detected if P10 < TV and P80 < LRV  
o No signal detected if P10 ≥ TV 
o No conclusion if P10 < TV  
More details about this analysis will be provided in a separate document. This output will be 
generated for decision making purposes and will not be part of the CSR. 
6.2.2.4. 
Area Under the Efficacy Curve (AUEC) 
To further explore the data in a slightly different fashion, the area under the efficacy curve 
(AUEC) based on the MMRM-derived LS-means will be derived for GLPG3970 and placebo. 
The AUEC will be calculated using the trapezoidal rule as illustrated in Figure 2. A 90% 
confidence interval and between-group p-value will be derived as well. All will be based on the 
MMRM model for the DAS28(CRP) change from baseline.  
Figure 2: Graphical illustration calculation AUEC 
 
 






















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6.3.1. 
Adverse Events 
All AEs and changes in attributes (worsening and improvement) of AEs are reported in the 
database. An identification number serves to link the records considered by the investigator as 
describing the evolution of one and the same event. 
6.3.1.1. 
Definition of Treatment-Emergent Adverse Events 
The analysis of AEs will be based on treatment-emergent events (TEAE).  
TEAEs are defined as  
− 
Any AE with an onset date on or after the IP start date and no later than 14 days after last 
dose of IP, or any worsening of any AE on or after the IP start date. 
− 
Improvement or no change of any ongoing AEs on or after the IP start date are not 
considered treatment-emergent. If an AE is ongoing at the time of first IP intake, if there is 
no change or an improvement in its toxicity grade or its seriousness status (reported in the 
‘Change in Adverse event details Entry’ CRF page), this AE will not be considered as 
treatment-emergent. 
 
6.3.1.2. 
Coding of Reported Terms 
All AE terms will be coded in the database using the latest version of MedDRA coding 
dictionary. AEs will be graded using the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE). 
All tables will show the AE preferred terms grouped into system organ class. Subject listings will 
also show the reported terms (verbatim). Any other coding levels will only be shown in a listing 
summarizing coding unless explicitly mentioned otherwise. 
6.3.1.3. 
Allocation of Adverse Events to Analysis Periods 
All AEs will be placed into analysis periods considering their start date, aiming to report the 
incidence of these events only in the analysis period during which they started. 
The general rule for allocation of AEs to analysis periods follows: 
Analysis period start date ≤ AE start date ≤ analysis period end date 
If the start date of an AE is missing or incomplete to a level preventing a clear allocation of the 
AE to one single analysis period and no flag indicating timing relative to study medication is 
available, a worst-case consideration (see below) will be done aiming to allocate the AE to one 
single analysis period, if possible. When a worst-case consideration is needed, the end date of the 
AE, if and as available, should also be considered; if such AEs clearly end on a given point, this 
will exclude the possibility to allocate the AE to an analysis period after that point. 


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− 
An AE which according to the available information of its start date could belong to the 
screening as well as to the treatment analysis period will only be placed in the treatment 
period. 
− 
An AE with a missing start date will be allocated to the treatment period unless the “Prior to 
First GLPG3970/Placebo Treatment= “Yes”. 
 
6.3.1.4. 
Treatment Relatedness 
Following the guideline ICH-E3 Structure and Content of Clinical Study Reports (Step 4 
Version), the originally reported relatedness to IP of an AE will be dichotomized as follows: 
− 
Not IP related: all non-missing weaker levels of relatedness than ‘possibly drug related’. 
− 
IP related: ‘possibly drug related’ and all stronger levels of relatedness (this class also 
includes any missing drug relatedness, as a worst-case consideration). 
 
Only this dichotomized relatedness will be used in tables and can apply to different IPs when 
relatedness has been collected separately per IP; relatedness as originally reported will only be 
listed. 
6.3.1.5. 
Worst-Case Selections 
When cross-tabulating AE preferred terms versus an AE attribute (like intensity), only the worst-
case within each same preferred term, same subject and same analysis period will be considered, 
i.e. when the same subject has more than once the same AE preferred term reported in the same 
treatment group, the subject will be counted only once and will be shown under the worst 
outcome (like the worst intensity for that AE in the concerned treatment period). 
The severity grade of events for which the investigator did not record severity will be categorized as 
“missing” for tabular summaries and data listings. The missing category will be presented last in summary 
presentation. 
6.3.1.6. 
Calculation of Relative Days and Duration 
For each newly reported event, and reported worsening or improvement of an existing event, the 
start day in the study (the day of the AE start date relative to the date of first IP administration), 
the start day in the analysis period, and the duration (in days) will be calculated. In addition, the 
relative day and duration will be derived for the entire event; that is, the full evolution of the 
event, including the initial reporting and all subsequent worsening and/or improvement. 
Relative days and durations will only be listed. 
See Section 4.3.1 for the calculation of relative days. 
6.3.1.7. 
Events of Special Interest 
Not applicable. 


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6.3.1.8. 
Presentation of Results 
The analysis will focus on AEs reported during the treatment period. AEs reported during the 
screening period will only be listed. 
All AEs tables will show the number of subjects with TEAEs. 
AEs which are not treatment-emergent will only be listed. 
A summary table will be provided, showing the number (percent) of subjects with at least one: 
− 
TEAE, 
− 
IP-related TEAE, 
− 
Serious TEAE, 
− 
TEAE leading to death, 
− 
TEAEs by worst intensity (CTCAE Toxicity Grade), 
− 
TEAE leading to IP discontinuation. 
 
The AE terms will be presented sorted in descending order of frequency, prioritizing the 
GLPG3970 treatment group and then for placebo, first by system organ class, then by preferred 
term, and then alphabetically. 
Frequency tabulations, by system organ class and preferred term, of the number (percent) of 
subjects with a TEAE will be presented. Similar tables will be provided by worst intensity, and 
for IP-related TEAEs, grade 3-4-5 TEAEs, serious TEAEs and TEAEs leading to IP 
discontinuation of IP. 
All AE data will also be listed, including separate lists for SAEs, AEs leading to death, and AEs 
leading to IP discontinuation. Listings will clearly indicate AEs to be treatment-emergent or not. 
In addition, AEs related to SARS-Cov-2 will be listed separately. 
6.3.1.9. 
EudraCT Adverse Events Reporting 
For the purpose of EudraCT reporting, the following tabulations will be created: 
Frequency tabulations, by system organ class and preferred term, of the number (percent) of 
subjects with non-serious TEAE will be presented. A similar table will be provided for all serious 
TEAEs, as well as a table for non-serious TEAEs reported in at least 2 subjects in any treatment 
group.   
6.3.2. 
Laboratory Safety 
6.3.2.1. 
Available Data 
Laboratory tests scheduled are described in the protocol section 8.5.2. In addition, the derived 
laboratory tests described in Section 6.3.2.2 will be added. 




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6.3.2.5. 
Urinalysis Tests with Categorical Results 
Results of urinalysis with qualitative results will be tabulated by time point. No toxicity grading 
or non-graded abnormalities will be derived for these tests. 
6.3.2.6. 
Treatment-Emergent Principle 
Toxicity Grades 
A post-baseline toxicity grade 1, 2, 3 or 4 is defined as treatment-emergent when higher than the 
toxicity grade of the baseline result or when there is a change in direction (from H to L or from L 
to H). If the baseline result is missing, a post-baseline toxicity grade 1, 2, 3 or 4 will be 
considered as treatment-emergent. 
Non-graded Abnormalities 
A post-baseline non-graded abnormality class L or H is defined as treatment-emergent when it 
differs from the abnormality class of the baseline result. If the baseline result is missing, a post-
baseline abnormality L or H will be considered as treatment-emergent. 
6.3.2.7. 
Worst-Case Principle 
Toxicity Grading 
The worst-case post-baseline toxicity grade 0, 1, 2, 3 or 4 will be determined per subject, per 
laboratory test (and direction, increases and decreases) and for each analysis period, using all 
non-missing post-baseline records (including unscheduled and FU visits). 
The worst-case toxicity grade is the highest toxicity grade corresponding to the highest laboratory 
test value (by direction, increases and decreases). In case of several equal highest post-baseline 
actual values, the earliest occurrence will be taken for the analyses and will be flagged in the 
listings.   
− 
Grade 0: all post-baseline toxicity grades are classified as 0 
− 
Grade 1: all post-baseline toxicity grades are classified as ≤1 
− 
Grade 2: all post-baseline toxicity grades are classified as ≤2 
− 
Grade 3: all post-baseline toxicity grades are classified as ≤3 
− 
Grade 4: all post-baseline toxicity grades are classified as ≤4 
 
If any record is missing, then the toxicity grade is considered as ‘missing’. 
Non-graded Abnormalities 
The following worst-case post-baseline abnormalities L, N or H will be determined per subject, 
per laboratory test and for each analysis period, using all non-missing post-baseline records 
(including unscheduled and FU visits): 


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− 
L = low: at least one post-baseline result is classified as L. 
− 
N = normal: all post-baseline results are classified as N. 
− 
H = high: at least one post-baseline result is classified as H. 
If, for a subject, both L and H are reported, the subject will be counted twice in the table: once 
with a worst-case L and once with a worst-case H. 
6.3.2.8. 
Hepatotoxicity 
Hepatotoxicity will be investigated by tabulating the aspartate aminotransferase (AST) and 
alanine aminotransferase (ALT) values categorized as >3, >5, >10 and >20 times their upper 
limit of normal (per analyte and over both analytes combined), ALP categorized as > 1.5 times 
the upper limit and total bilirubin as > 2 times the upper limit of normal. Elevations of AT (AST 
or ALT) > 3 times their upper limits accompanied by elevated total bilirubin (>1.5×ULN, 
>2×ULN) on the same day will also be tabulated. 
 
To assess the potential of the drug to cause severe liver damage, possible Hy’s Law cases will be 
identified. These subjects are defined as having any elevated AT (AST or ALT) of >3×ULN, 
ALP <2×ULN, and associated with an increase in total bilirubin >2×ULN on the same day.   
6.3.2.9. 
Presentation of Results 
No formal inferential statistics (p-values) will be derived. 
Continuous laboratory tests16 including glucose, cholesterol, triglycerides, low-density 
lipoprotein (LDL), high-density lipoprotein (HDL) and fasted glucose, will be summarized by 
means of descriptive statistics (including 90% CI of the mean change) by laboratory test, 
treatment group and analysis window. Actual values, changes from baseline and percent change 
from baseline will be tabulated separately. Continuous values for metabolic markers will be 
summarized in the pharmacodynamic analysis section. 
Profile line plots by subject of all actual observed values using relative day (ADY) will be 
presented by treatment group. Graphs of the mean (+- SE) actual values over time and of the 
mean (+- SE) change from baseline, and percent changes from baseline will be presented for all 
continuous laboratory parameters, with the exception of the metabolic markers. Also, line plots 
for subjects will be provided by treatment group.  
The analysis of abnormalities will focus on assessments reported during the treatment period. 
Results reported before baseline will only be listed.  
Non-graded abnormalities and toxicities grades of the actual values will be presented as shift 
tables of the worst-case abnormality/toxicity grade versus the baseline abnormality/toxicity 
                                                 
16 With the exception of the metabolic markers [fasted insulin, homeostatic model assessment of insulin resistance 
(HOMA-IR) and HbA1c] and inflammation marker hsCRP. 


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grade. The table will be created per laboratory test, treatment group and analysis period. The 
results of non-graded abnormalities and toxicities grades will be shown separately.  
A frequency table of the number (percent) of subjects with treatment-emergent worst-case 
abnormalities/toxicity grade per laboratory test, treatment group and analysis period will be 
presented. The results of non-graded abnormalities and toxicities grades will be shown 
separately. 
A frequency table of the number (percent) of subjects will be also provided for hepatotoxicity 
flags defined before. These abnormalities will be also flagged in the individual data laboratory 
listing. 
Listing will be provided for the laboratory test along with flag for abnormality results. In 
addition, pregnancy result will be listed separately. 
 
 


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6.3.3. 
Electrocardiogram 
6.3.3.1. 
Available Data 
The following ECG parameters will be analysed: heart rate (HR), RR interval, PR interval, QRS 
interval, uncorrected QT interval, QTcF (derived). 
6.3.3.2. 
Derivation Rules 
Derived Parameters 
The Fridericia’s cube-root corrected QT (QTcF) will be calculated using the following formula. 
Fridericia’s cube-root corrected QT (Fridericia, 1920): 
ܳܶܿܨ ሺ݉ݏሻൌܳܶ ሺ݉ݏሻൈට
ଵ଴଴଴
ோோ ሺ௠௦ሻ
య
 
If RR is missing, then it will be derived from HR using the formula RR(ms) = 60 × HR(bpm). 
Handling of ECGs Measured in Triplicate 
If ECG is collected in triplicates, the following approach will be taken. 
First, any derivation of ECG parameters will be done before handling ECG triplicates. Next, the 
mean of the triplicate ECG values will be calculated for each individual ECG parameter, without 
rounding the result. These calculated means will constitute the analysis values; any derivation 
(e.g. change from baseline, assignment of abnormalities) and statistic will be based on the mean 
value of the triplicates. 
The values of the original members of a triplicate will be listed. 
6.3.3.3. 
Abnormalities 
The actual analysis values and changes from baseline of the QT and QTcF parameters will be 
categorized into the abnormality classes as defined in the SAP Appendix II. 
Worst-Case Abnormality 
The worst-case post-baseline categorized actual analysis value and the worst-case categorized 
change from baseline for QT and QTcF will be determined per subject, per parameter, and for 
each analysis period, using all non-missing post-baseline records (including unscheduled and FU 
visits). 
The worst-case categorized actual analysis value is the category corresponding to the highest 
post-baseline actual value. In case of several equal highest post-baseline actual values, the earliest 
occurrence will be taken for the analyses and will be flagged in the listings.   
The worst-case change from baseline is the category corresponding to the largest increase 
(positive change) from baseline. In case of several equal largest increase from baseline, the 
earliest occurrence will be taken for the analyses and will be flagged in the listings.   


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Treatment-Emergent Abnormalities 
Actual value: An abnormal post-baseline abnormality is defined as treatment-emergent when the 
abnormality is worse compared to the abnormality at baseline or when there is a change in 
direction (from H to L or from L to H). When the baseline value is missing, post-baseline 
abnormalities are considered as treatment-emergent. 
An abnormal category for change from baseline is always treatment-emergent. 
6.3.3.4. 
Presentation of Results 
No formal inferential statistics (p-values) will be derived. 
Continuous parameters will be summarized by means of descriptive statistics (including 90% CI 
of the mean change) by parameter, treatment group and analysis window. Actual values, change 
from baseline and percent changes from baseline will be tabulated separately. 
Profile line plots by subject of all actual observed values using relative day (ADY) will be 
presented by treatment group. Graphs of the mean (+- SE) actual values over time and of the 
mean (+- SE) change from baseline and percent change from baseline will be presented. A line 
plot by subject of the change from baseline will also be provided by treatment group.  
The analysis of abnormalities will focus on assessments reported during the treatment period. 
Results reported during the screening or post-treatment (if defined) period will only be listed. 
Abnormalities of the actual values will be presented as shift tables of the worst-case abnormality 
versus the baseline abnormality. The table will be created per parameter, treatment group and 
analysis period. 
A frequency table of the number (percent) of subjects with treatment-emergent worst-case 
abnormalities and the worst change per parameter, treatment group and analysis period will be 
presented. 
A frequency table per treatment group and time point of the ECG interpretations as recorded in 
the case report form (CRF) will be provided. 
A Listing will be provided along with abnormality. 
6.3.4. 
Vital Signs 
6.3.4.1. 
Available Data 
The following vital signs parameters will be analyzed: weight (kg), BMI (kg/m2), diastolic and 
systolic blood pressure (mmHG), pulse rate (beats/min) and body temperature (C). 
6.3.4.2. 
Derivation Rules 
Not applicable. 


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6.3.4.3. 
Abnormalities 
Vital signs data will be categorized according to the cutoffs provided in the SAP Appendix II.  
6.3.4.4. 
Treatment-Emergent Principle 
A post-baseline abnormality class L or H is defined as treatment-emergent when it differs from 
the abnormality class at baseline. If the baseline result is missing, a post-baseline abnormality 
L or H will be considered as treatment-emergent. 
An abnormal category for change from baseline is always treatment-emergent. 
6.3.4.5. 
Worst-Case Abnormality 
The worst-case post-baseline categorized actual analysis value will be determined per subject, per 
parameter and for each analysis period, using all non-missing post-baseline records (including 
unscheduled and FU visits). 
The worst-case categorized actual analysis value is the category corresponding to the highest 
post-baseline actual value. In case of several equal highest post-baseline actual values, the earliest 
occurrence will be taken for the analyses and will be flagged in the listings.  
6.3.4.6. 
Presentation of Results 
No formal inferential statistics (p-values) will be derived. 
Continuous parameters will be summarized by means of descriptive statistics (including 90% CI 
of the mean change) by parameter, treatment group and analysis window. Actual values, change 
from baseline and percent change from baseline will be tabulated separately. 
Graphs of the mean (+- SE) actual values over time and of the mean (+- SE) change from 
baseline, and percent changes from baseline will be presented. 
The analysis of abnormalities will focus on assessments reported during the treatment period. 
Results reported during the screening or post-treatment (if defined) period will only be listed. 
Abnormalities of the actual values will be presented as shift tables of the worst-case abnormality 
versus the baseline abnormality. The table will be created per parameter (and position if 
applicable), treatment group and analysis period. 
A frequency table of the number (percent) of subjects with treatment-emergent worst-case 
abnormalities per parameter, treatment group and analysis period will be presented. 
A listing will be provided along with abnormality. 
6.3.5. 
Physical Examinations 
Physical examination results will only be listed. 


























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APPENDIX III: 66/68 Joint Count  
Joints Assessed (left and right) for Swelling (66 Joints) and/or Tenderness (68 joints) 
Temporomandibular 
Sternoclavicular 
Acromioclavicular 
Shoulder* 
Elbow* 
Wrist* 
Metacarpophalangeal* 
First 
Second 
Third 
Fourth 
Fifth 
Proximal interphalangeal*  
First 
Second 
Third 
Fourth 
Fifth 
Distal interphalangeal 
Second 
Third 
Fourth 
Fifth 
Hip # 
Knee* 
Ankle 
Tarsus 
Metatarsophalangeal 
First 
Second 
Third 
Fourth 
Fifth 
Proximal interphalangeal (toe) 
First 
Second 
Third 
Fourth 
Fifth 
#Assessed for tenderness only