Randomized, Double-blind, Placebo-controlled, Multicenter, Phase IIb Dose Finding Study of GLPG0634 Administered for 24 Weeks in Combination With Methotrexate to Subjects With Moderately to Severely Active Rheumatoid Arthritis Who Have an Inadequate Response to Methotrexate Alone
Phase: PHASE2
Conditions: Rheumatoid Arthritis
Sponsor: Galapagos NV

 
 
CLINICAL STUDY PROTOCOL 
AMENDMENT 5 – US ONLY 
Randomized, double-blind, placebo-controlled, multicenter, 
phase IIb dose finding study of GLPG0634 administered for 
24 weeks in combination with methotrexate to subjects with 
moderately to severely active rheumatoid arthritis who have an 
inadequate response to methotrexate alone 
Protocol Number: 
GLPG0634-CL-203 
EudraCT Number: 
2012-003635-31 
Country: 
United States of America 
 
 
Test Drug/Investigational Product: 
GLPG0634 
Phase: 
phase IIb 
Sponsor: 
Galapagos NV 
Generaal De Wittelaan L11A3  
2800 Mechelen 
Belgium 
Date of Original Protocol: 
Date of Amendment 1: 
Date of amendment 2: 
Date of Amendment 3: 
Date of Amendment 4 – US Only: 
Date of Amendment 4 – France Only: 
Date of Amendment 4: 
Date of Amendment 5: 
Date of Amendment 5 – US Only:  
14 March 2013 
11 April 2013 
17 April 2013 
02 August 2013 
11 November 2013 
20 November 2013 
20 November 2013 
20 May 2014 
27 May 2014 
CONFIDENTIAL 
This protocol may not be reproduced or communicated to a third party without 
the written permission of Galapagos NV. 

 
 
CONFIDENTIAL 
Galapagos NV 
 
27 May 2014
GLPG0634-CL-203 
Protocol Amendment 5 – US Only Final 
Page 7 of 88
• Treatment failure deemed by the investigator as lack of improvement or worsening of the 
disease symptoms or occurrence of intolerable AEs. 
Treatment with GLPG0634 will be discontinued and the patient withdrawn from this study for: 
• 
… 
• 
Two sequential Ddecreases from the baseline of inhibin B by 50% or Testosterone by 50% 
with concurrent increases in FSH or LH respectively.3 
After becoming aware of any of the above described abnormal laboratory changes occurring at any 
one time, an unscheduled visit (i.e. second sequential) must occur to retest within 3 to 5 days. The 
retesting for laboratory parameters should occur within 3 to 5 days.  
1 In each case, there is a need for additional investigations, such as review of ethanol, recreational drug and dietary supplement 
consumption; testing for acute hepatitis A, B or C infection and biliary tract imaging should be promptly discussed with the 
Study Medical Monitor. 
2 At the time of study completion or discontinuation, if a patient should exhibit elevations in serum creatinine ≥33% above the 
average of screening and baseline values, they should be re-tested every 1 to 2 weeks until the serum creatinine elevation is 
fully reversed to within 10% of the average of screening and baseline values. 
3 In each case, hormones in male subjects should be monitored monthly and if no positive dynamics is seen after 3 months 
from stopping GLPG0634, referral to an andrologist should be considered. 
Section 8.5.8 Prior and Concomitant Therapy 
Concomitant therapies taken for the long term treatment of preexisting conditions can continue during 
the study provided they are in accordance with the inclusion and exclusion criteria. It is preferred that 
these medications be stabilized prior to study entry and continued without variation of dose or 
regimen during the study. 
In case new therapies need to be administered during the study, the risk/benefit to the subject should 
be carefully assessed and consideration given to the timing of any necessary introduction of new 
medications. 
Permitted concomitant medications at Screening and during the study include:  
• 
Antimalarials, which must be at a stable dose for at least 12 weeks prior to 
ScreeningBaseline. 
• 
NSAIDs, provided that the dose is stable for at least 2 weeks prior to ScreeningBaseline and, 
if possible, is kept constant during the study;  
• 
Oral steroids, provided that the dose is stable, is ≤10 mg/day prednisone or equivalent for at 
least 4 weeks prior to ScreeningBaseline, and is kept stable for the study duration; and  
• 
Analgesics, other than NSAIDs, up to the maximum recommended doses may be used for 
pain as required. However, subjects must not take analgesics within 24 hours before a visit 
where clinical efficacy assessments are performed and recorded. 
… 
Female subjects of childbearing potential will use highly effective birth-control methods as outlined in 
the inclusion criteria and agree to continue their use during the study and for at least 12 weeks after 
the last dose of study medication. The use of hormonal contraceptives will be recorded in the 
Concomitant Therapy section of the eCRF. Applicable procedures and treatment guidance based on 
package inserts will be respected.  
… 
Previous use of JAK or SYK inhibitors is prohibited. 

 
 
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27 May 2014
GLPG0634-CL-203 
Protocol Amendment 5 – US Only Final 
Page 8 of 88
Section 8.5.9 Treatment Compliance and Drug Accountability 
For each dose taken, the date, the time of intake, and the number of capsules taken should be 
recorded on the subject diary card. 
The investigator or designated study personnel will maintain a log of all drug dispensed and returned. 
Drug supplies for each subject will be inventoried and accounted for throughout the study. 
Subjects with a poor compliance (<80% or >120%) will be retained by the study site. If study drug 
compliance remains <80% or >120% between study visits, or if the subject missed more than 2 visits, 
the subject will be evaluated for potential discontinuation. Any discontinuation should be done in 
consultation with the Medical Monitor. 
Section 8.6.1.1 Screening Period (Visit 1, Day -29 to Day -2) 
• Each subject will receive a patient number by using the IXRS system. 
 
Note 1: Retesting during the Screening period is only allowed once for abnormal lab values except 
for positive QuantiFERON-TB Gold, Hepatitis B, Hepatitis C, HIV or pregnancy test in a female of 
childbearing potential AND only in case it is still possible to randomize the patient within the per 
protocol defined Screening period of 28 calendar days. 
Note 2: Rescreening is only allowed in specific situations and after having obtained written sponsor 
approval. 
Section 8.6.2.8 Week 24 (Visit 10) or Early Discontinuation Visit (EDV) 
The Week 24 visit (Visit 10) will take place on Day 169 ± 2 calendar days relative to the start of study 
medication intake. If the subject discontinues from the study early, the following procedures will be 
performed. This visit needs to be entered in IXRS. 
Section 8.7.1.5 Flow chart 
IXRS call was added to the D169/W24 and EDV visits in the flow chart. 
Section 8.9.2 Monitoring. 
Data for each subject will be recorded on an eCRF. Data collection must be completed for each 
subject who signs an ICF and is administered study medication. 

 
 
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Galapagos NV 
 
27 May 2014
GLPG0634-CL-203 
Protocol Amendment 5 – US Only Final 
Page 10 of 88
2 Study Personnel 
Sponsor Personnel 
Project Manager  
Name: 
 
Title: 
Clinical Project Manager 
External consultant for the department of clinical operations 
Address: 
Galapagos NV 
Gen. De Wittelaan, L11A3 
2800 Mechelen 
Belgium 
Telephone No.: 
 
Medical Safety Officer  
Name: 
 
Title: 
Medical Safety Officer 
Address: 
Galapagos NV 
Gen. De Wittelaan, L11A3 
2800 Mechelen 
Belgium 
Telephone No.: 
 
Medical Monitor  
Name: 
 
Title: 
Medical Monitor 
Address: 
Galapagos NV 
Gen. De Wittelaan, L11A3 
2800 Mechelen 
Belgium 
Telephone No.: 
 
 

 
 
CONFIDENTIAL 
Galapagos NV 
 
27 May 2014
GLPG0634-CL-203 
Protocol Amendment 5 – US Only Final 
Page 12 of 88
3 Synopsis 
Protocol Number: 
GLPG0634-CL-203 
Title: 
Randomized, 
double-blind, 
placebo-controlled, 
multicenter, phase IIb dose finding study of GLPG0634 
administered 
for 
24 
weeks 
in 
combination 
with 
methotrexate to subjects with moderately to severely 
active rheumatoid arthritis who have an inadequate 
response to methotrexate alone 
Test Drug/Investigational 
Product: 
GLPG0634 
Number of Study Centers: International multicenter. Approximately 120 sites. 
Phase: 
IIb 
Objectives: 
The primary objective is to evaluate the efficacy in terms 
of the percentage of subjects achieving an American 
College of Rheumatology (ACR)20 response, of different 
doses and dose regimens of GLPG0634 compared to 
placebo at Week 12. 
The secondary objectives are to evaluate the efficacy in 
terms of the percentage of subjects achieving an ACR20, 
ACR50, ACR70, ACR-N, the disease activity score based 
on 28 joints (DAS28 [c-reactive protein {CRP}]), European 
League Against Rheumatism (EULAR) response and 
ACR/EULAR remission, clinical disease activity index 
(CDAI), and simplified disease activity index (SDAI) with 
different doses and dose regimens of GLPG0634 
compared to placebo at every visit; to evaluate the safety 
and tolerability of different doses and dose regimens of 
GLPG0634 in comparison with placebo; to characterize 
the 
population 
pharmacokinetics 
(PK) 
and 
pharmacodynamics (PD) of GLPG0634 and its metabolite 
(G254445) in subjects with rheumatoid arthritis (RA) and 
investigate the relationship between exposure and 
efficacy/safety/PD; and to evaluate the effects of different 
doses and dose regimens of GLPG0634 administration on 
subjects’ disability, fatigue, and quality of life. 
Study Design: 
This will be a double-blind, placebo-controlled add on 
study in subjects with moderately to severely active RA 
who have an inadequate response to methotrexate (MTX) 
(oral or parenteral). A total of 595 subjects will each be 
randomized to one of 6 dose regimens of GLPG0634 
(3 dose levels administered either once or twice daily) or 
placebo on top of each subject’s stable dose of MTX. 
Treatment duration will be 24 weeks.  
Number of Subjects:  
595 subjects to be randomized. 

 
 
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27 May 2014
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Study Population 
(continued): 
Main exclusion criteria:  
• 
current 
therapy 
with 
any 
disease-modifying 
anti-rheumatic drugs (DMARD) other than MTX, 
including oral or injectable gold, sulfasalazine, 
antimalarials, azathioprine, or D-penicillamine 
within 4 weeks prior to Baseline, cyclosporine 
within 8 weeks prior to Baseline, and leflunomide 
within 3 months prior to Baseline or a minimum 
4 weeks prior to Baseline if after 11 days of 
standard cholestyramine therapy,  
• 
current or previous RA treatment with a biologic 
DMARD, with the exception of biologic DMARDs 
administered in a single clinical study setting more 
than 6 months prior to Screening (12 months for 
rituximab or other B cell depleting agents), where 
the biologic DMARD was effective, and if 
discontinued, this should not be due to lack of 
efficacy,  
• 
previous treatment at any time with a cytotoxic 
agent, other than MTX, before Screening.  
Primary Endpoint: 
Percentage of subjects achieving an ACR20 response at 
Week 12 
Secondary Endpoints: 
Percentage of subjects achieving ACR20 response at 
Week 24, percentage of subjects achieving ACR50, 
ACR70, ACR-N, DAS28(CRP), EULAR response and 
ACR/EULAR remission, CDAI, SDAI response, the 
change in Baseline in Quality of Life (functional 
assessment of chronic illness therapy [FACIT] and short 
form-36 [SF-36]) scores at Weeks 1, 2, 4, 8, 12, and 24, 
as appropriate. 
Efficacy analysis: 
The efficacy analysis will be performed on all subjects 
who used the study medication at least once and have 
post-Baseline efficacy data. ACR20, ACR50, ACR70, 
ACR-N, 
EULAR 
response, 
DAS28(CRP) 
and 
ACR/EULAR remission, components of the ACR, and 
DAS28, CDAI and SDAI at each post-dosing visit will be 
analyzed descriptively. Between-group comparisons will 
also be done for each dose group versus the placebo 
group. The effects of different doses of GLPG0634 
administration on subject’s disability, fatigue, and quality 
of life will also be evaluated. Hommel’s closed-testing 
correction procedure will be applied to adjust for 
multiplicity. This study is not powered for any formal 
comparison among the dose groups, nor for comparisons 
between the q.d. and b.i.d. regimens. Differences 
between the q.d. and b.i.d. regimens will be calculated 
and 
presented 
with 
a 
95% 
confidence 
interval. 
Differences between the q.d. and b.i.d. regimens will also 
be tested exploratively via a model containing the total 
daily dose (50/100/200 mg) as well as the regimen 
(q.d./b.i.d.). 

 
 
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4 Table of Contents 
1 
Protocol Approval Signatures ...................................................................... 9 
2 
Study Personnel .......................................................................................... 10 
3 
Synopsis ...................................................................................................... 12 
4 
Table of Contents ........................................................................................ 16 
5 
List of Abbreviations and Definition of Terms .......................................... 19 
6 
Introduction ................................................................................................. 21 
6.1 
Rheumatoid Arthritis ................................................................................... 21 
6.2 
Background on GLPG0634 ......................................................................... 22 
6.3 
Background - Pre-clinical Studies .............................................................. 22 
6.3.1 
Physical, Chemical and Pharmaceutical Properties and 
Formulations ................................................................................. 22 
6.3.2 
Pharmacology ............................................................................... 22 
6.3.3 
Nonclinical Pharmacokinetics and Product Metabolism ................. 23 
6.3.4 
Toxicology ..................................................................................... 23 
6.4 
Background - Preliminary Clinical Data ..................................................... 27 
6.5 
Clinical Risks/Benefits ................................................................................ 28 
6.6 
Rationale for the Study ............................................................................... 30 
6.7 
Rationale of Choice of the Dose and Dosing Interval ............................... 31 
7 
Study Objectives ......................................................................................... 33 
7.1 
Primary Objective ........................................................................................ 33 
7.2 
Secondary Objectives ................................................................................. 33 
8 
Investigational Plan ..................................................................................... 34 
8.1 
Overall Study Design and Plan ................................................................... 34 
8.2 
Discussion of Study Design ....................................................................... 35 
8.3 
Selection of Study Population .................................................................... 35 
8.3.1 
Number of Planned Subjects ......................................................... 35 
8.3.2 
Inclusion Criteria ........................................................................... 35 
8.3.3 
Exclusion Criteria .......................................................................... 36 
8.3.4 
Removal of Subjects from Therapy or Assessments ..................... 38 
8.4 
Data Safety Monitoring Board .................................................................... 40 
8.5 
Investigational Products. ............................................................................ 40 
8.5.1 
Investigational Products Administered .......................................... 40 
8.5.2 
Identity of Investigational Products ................................................ 40 
8.5.3 
Packaging, Labelling and Distribution ........................................... 41 

 
 
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8.5.4 
Method of Assigning Subjects to Treatment Groups ..................... 41 
8.5.5 
Selection of Doses in the Study .................................................... 42 
8.5.6 
Selection and Timing of Dose for Each Subject ............................. 42 
8.5.7 
Blinding ......................................................................................... 42 
8.5.8 
Prior and Concomitant Therapy .................................................... 43 
8.5.9 
Treatment Compliance and Drug Accountability ............................ 44 
8.5.10 
Subject Diary Card ........................................................................ 44 
8.6 
Study Procedures ........................................................................................ 45 
8.6.1 
Pre-treatment ................................................................................ 45 
8.6.2 
Treatment Period .......................................................................... 46 
8.6.3 
Follow-up (Visit 11) ....................................................................... 50 
8.6.4 
Duration of Treatment ................................................................... 51 
8.7 
Efficacy, Pharmacokinetics, Pharmacodynamics and Safety Variables . 51 
8.7.1 
Efficacy, Pharmacokinetics, Pharmacodynamics and Safety 
Measurements Assessed and Flow Chart ..................................... 51 
8.7.2 
Appropriateness of Measurements ................................................ 61 
8.8 
Statistical Methods ...................................................................................... 61 
8.8.1 
Statistical and Analytical Plans ...................................................... 61 
8.8.2 
Determination of Sample Size ....................................................... 66 
8.9 
Quality Assurance and Quality Control ..................................................... 67 
8.9.1 
Audit and Inspection ..................................................................... 67 
8.9.2 
Monitoring ..................................................................................... 67 
8.9.3 
Data Management and Coding ..................................................... 67 
9 
Records and Supplies ................................................................................. 69 
9.1 
Drug Accountability .................................................................................... 69 
9.2 
Financing and Insurance ............................................................................ 69 
10 
Ethics ........................................................................................................... 70 
10.1 Independent Ethics Committee or Institutional Review Board ................ 70 
10.2 Regulatory Authorities ................................................................................ 70 
10.3 Ethical Conduct of the Study ...................................................................... 70 
10.4 Informed Consent ........................................................................................ 70 
10.5 Subject Confidentiality ................................................................................ 71 
11 
Reporting and Publication, Including Archiving ....................................... 72 
12 
References ................................................................................................... 73 
13 
Appendices .................................................................................................. 74 
13.1 Investigator Signature Page ....................................................................... 75 
13.2 66/68 Joint Count ........................................................................................ 76 
13.3 Patient’s Global Assessment of Disease Activity Questionnaire ............ 77 

 
 
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13.4 Physician’s Global Assessment of Disease Activity Questionnaire ........ 78 
13.5 Health Assessment Questionnaire - Disability Index (HAQ-DI) ................ 79 
13.6 FACIT Fatigue Scale .................................................................................... 81 
13.7 36-Item Short-Form Health Survey (SF-36) ................................................ 82 
 
 

 
 
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5 List of Abbreviations and Definition of Terms 
Abbreviations 
ACR 
= 
American College of Rheumatology 
AE 
= 
adverse event 
ALT 
= 
alanine aminotransferase 
AST 
= 
aspartate aminotransferase 
ATP 
= 
adenosine triphosphate 
AUC 
= 
area under the curve 
AUC0-24h 
= 
area under the the concentration-time curve from 0 to 24 hours 
b.i.d. 
= 
bis in die (twice daily) 
BUN 
= 
blood urea nitrogen 
CCP 
= 
cyclic citrullinated peptide 
CD 
= 
Crohn’s disease 
CDAI 
= 
Clinical Disease Activity Index 
CES 
= 
carboxylesterases 
CFR 
= 
Code of Federal Regulations 
CIA 
= 
collagen-induced arthritis 
CMV 
= 
cytomegalovirus 
CNS 
= 
central nervous system 
CRP 
= 
c-reactive protein 
CYP 
= 
cytochrome P450 
DAS28 
= 
disease activity score based on 28 joints 
DMARD 
= 
disease-modifying anti-rheumatic drug 
DSMB 
= 
Data Safety Monitoring Board 
ECG 
= 
electrocardiogram 
eCRF 
= 
electronic case report form  
EDC 
= 
electronic data capture 
EDV 
= 
early discontinuation visit 
EULAR 
= 
European League Against Rheumatism 
FACIT 
= 
functional assessment of chronic illness therapy 
FDA 
= 
Food and Drug Administration 
FSH 
= 
follicle stimulating hormone 
GCP 
= 
Good Clinical Practice 
GGT 
= 
gamma glutamyltransferase 
GH 
= 
general health 
GI 
= 
gastrointestinal 
HAQ-DI 
= 
Health Assessment Questionnaire – Disability Index 
HCl 
= 
hydrochloride 
HDL 
= 
high density lipoprotein 
hERG 
= 
human ether-a-go-go related gene 
HIV 
= 
human immunodeficiency virus 
HR 
= 
heart rate 
IB 
= 
investigator’s brochure 
ICF 
= 
informed consent form 
ICH 
= 
International Conference on Harmonisation 
IEC 
= 
Independent Ethics Committee 
IL 
= 
interleukin 
IRB 
= 
Institutional Review Board 
ITT 
= 
intent-to-treat 
IV 
= 
intravenous 

 
 
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IXRS 
= 
interactive voice/web response system 
JAK 
= 
janus kinase 
LDL 
= 
low density lipoprotein 
LH 
= 
luteinizing hormone 
Ln 
= 
natural logarithm 
miRNA 
= 
micro ribonucleic acid 
MTX 
= 
methotrexate 
NOAEL 
= 
no-observed-adverse-effect level 
NOEL 
= 
no-observed-effect-level 
NONMEM = 
nonlinear mixed-effects modeling 
NSAID 
= 
non-steroidal anti-inflammatory drug 
NYHA 
= 
New York Heart Association 
OATs 
= 
organic anion transporters 
PD 
= 
pharmacodynamic 
PK 
= 
pharmacokinetic 
PRL 
= 
prolactin 
q.d. 
= 
quaque die (once daily) 
RA 
= 
rheumatoid arthritis 
RBC 
= 
red blood cell 
RF 
= 
rheumatoid factor 
SAE 
= 
serious adverse event 
SDAI 
= 
Simplified Disease Activity Index 
SF-36 
= 
36-item short-form health survey 
SI 
= 
International System of Units 
SJC 
= 
swollen joint count 
SOP 
= 
Standard operating procedure 
SQRT 
= 
square root 
STAT 
= 
signal transducer and activation of transcription 
SYK 
= 
spleen tyrosine kinase 
t1/2 
= 
terminal elimination half-life 
TB 
= 
tuberculosis 
TJC 
= 
tender joint count 
tmax 
= 
time to maximum plasma concentration 
TNF 
= 
tumor necrosis factor 
TYK 
= 
tyrosine kinase 
ULN 
= 
upper limit of the normal (reference) laboratory range 
VAS 
= 
visual analog scale 
WBC 
= 
white blood cell 
 

 
 
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6 Introduction 
6.1 
Rheumatoid Arthritis 
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory and joint degenerative 
disease that affects almost 1% of the adult population worldwide, with onset classically 
between the ages of 30 and 50 and 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.1,2,3 
Development of the disease involves an inflammatory response of the synovial membrane 
that is accompanied by infiltration of a variety of immune cells which leads to the build-up 
and maintenance of a cytokine network. One of the cytokines central to this network is tumor 
necrosis factor α (TNF-α), as is clearly demonstrated by the clinical success of the TNF-α 
blockers in treating RA. TNF-α and other proinflammatory cytokines contribute to cartilage 
and bone erosion by inducing release of degradative enzymes such as the matrix 
metalloproteinases and stimulating the release of receptor activator for nuclear factor κ B 
ligand which triggers differentiation of hematopoietic cells into bone-resorbing osteoclasts. 
When left untreated, the disease leads to significant disability associated with high economic 
costs. 
In recent years, the therapeutic management of subjects with RA has seen a major 
revolution. Ten years ago, therapeutic approaches relied on disease-modifying antirheumatic 
drugs (DMARDs) such as methotrexate (MTX) and sulfasalazine that had only partial clinical 
benefit and were associated with significant toxicity. A considerable advance in the treatment 
of RA came from the introduction of the biological therapeutics like etanercept, infliximab, 
adalimumab or more recently, certolizumab pegol, which neutralize TNF-α. Spurred by their 
therapeutic success, more biologicals aimed at targeting other molecules involved in RA 
pathology are being developed. An anti-CD20 antibody (rituximab) directed at depleting B 
cells, a fusion protein targeting T-cell co-stimulation (abatacept), and tocilizumab, targeting 
the interleukin 6 receptor, have all recently been approved for the treatment of RA.4 
Due to the high production costs, inconvenience of parenteral administration, increased risk 
for infections, and potential immunogenicity of biologicals, there is still a need for less 
expensive and orally active drugs. Hence, various companies are pursuing the development 
of small-molecule inhibitors, targeting disease-relevant signal transduction pathways, e.g., 
janus kinase (JAK) inhibitors (tofacitinib, Pfizer; INCB28050, Incyte; VX 509, Vertex) or the 
spleen tyrosine kinase (SYK) inhibitor R788 (Rigel). 
In November 2012, tofacitinib (Xeljanz) became the first JAK inhibitor to receive Food and 
Drug Administration (FDA) approval for the treatment of adult patients with RA. Tofacitinib is 
a small molecule suitable for oral administration, has strong binding affinity for JAK1 and 
JAK3, and weaker affinity for JAK2. The extensive pre-clinical and phase I, II, and III clinical 
development programs demonstrated its mechanisms of action via antiinflammatory and 
immunosuppressive effects. The drug proved to be efficacious in treating the signs and 
symptoms of RA and was well tolerated. Overall, the side-effects and risk profiles of 
tofacitinib are similar to those of several conventional antirheumatic agents with cytopaenias, 
elevated levels of liver function enzymes, increased level of low-density lipoprotein (LDL), 
high-density lipoprotein (HDL) cholesterol5, and small increased risk for infections including 
serious and opportunistic infections seen during the studies. INCB28050, a molecule with 
strong binding affinity for JAK1 and 2, has been through extensive phase I and II testing and 

 
 
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currently undergoing large scale phase III studies. In phase II clinical studies, VX-509 
specifically targeted JAK3. Both these molecules have demonstrated efficacy roughly similar 
to tofacitinib with an equally manageable side-effect profile.  
6.2 
Background on GLPG0634  
Janus kinases are intracellular cytoplasmic tyrosine kinases (TYKs) that transduce cytokine 
signaling from membrane receptors to the nucleus of cells. JAK inhibitors block the signaling 
of various cytokines, growth factors and hormones, including the pro-inflammatory cytokine 
interleukin (IL)-6. Four different types of JAKs are known which (co-)interact with different 
sets of membrane receptors: JAK1, JAK2, JAK3 and TYK2. Inhibition of JAKs is a promising 
therapeutic option for a range of inflammatory conditions including RA and Crohn’s disease 
(CD). 
GLPG0634 is a potent and selective inhibitor of JAK1. The compound is currently in phase II 
development for RA and CD and has shown good preliminary efficacy in RA patients. No 
typical JAK2 side effects such as anemia were observed in clinical studies. The anticipated 
therapeutic daily dose range is 50 to 200 mg. 
GLPG0634 is metabolized to form one major active metabolite, G254445. Though the 
potency of this metabolite is lower than the parent molecule, the overall exposure and peak 
plasma concentration in humans is higher. As a consequence, dedicated pharmacology and 
toxicology studies have been performed with G254445. Results from pharmacodynamics 
(PD) testing in healthy volunteers suggest that the clinical activity of GLPG0634 could result 
from the combination of the parent molecule and the metabolite. 
More information on the study drug along with references to support the cited data are 
presented in the Investigator’s Brochure (IB).6 A summary is provided hereafter. 
6.3 
Background - Pre-clinical Studies 
6.3.1 Physical, Chemical and Pharmaceutical Properties and Formulations 
The chemical name of GLPG0634 is N-(5-(4-((1,1-dioxidothiomorpholin-4-yl)methyl)phenyl)-
[1,2,4]triazole[1,5-a]pyridin-2-yl)cyclopropanecarboxamide hydrochloride trihydrate. 
Two clinical formulations with various strengths are currently available: an oral capsule (10-
100 mg per capsule) filled with the hydrochloride (HCl) salt of GLPG0634; and a film-coated 
tablet (25-100 mg per tablet) of the HCl salt of GLPG0634. 
6.3.2 Pharmacology 
6.3.2.1 Primary and Secondary Pharmacology 
GLPG0634 is an adenosine triphosphate (ATP)-competitive inhibitor of JAK1. It is highly 
selective for inhibition of JAK1 among 451 unique kinase gene products tested in vitro. In 
cellular assays, it inhibits biological processes involving JAK1 from 179 nM onwards, with a 
30-fold selectivity over JAK2 in human whole blood. A high potency is observed in the rat 
collagen-induced arthritis (CIA) model. 
Metabolite G254445 exhibits a similar JAK1 selectivity profile while being approximately 10-
fold less potent as compared to parent GLPG0634, in vitro. In the rat CIA model, while being 

 
 
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different mechanism of action that can effectively modify the disease course and that are 
safe and well tolerated.   
GLPG0634 is a small molecule for oral daily administration that has shown promising results 
as a potentially safe and effective RA treatment. Study GLPG0634-CL-203 is a therapeutic 
phase IIb dose-finding study to compare 3 daily doses (50 mg, 100 mg and 200 mg) of 
GLPG0634 and 2 dose regimens (q.d. and b.i.d.) versus placebo to be administered daily for 
24 weeks in subjects with established RA, who have moderately to severely active disease 
despite MTX treatment. The aims of the current study are to evaluate the efficacy of varying 
doses and regimens of GLPG0634, to identify the minimally and optimally effective dose, 
and to assess the safety and tolerability, as well as to describe the PK and PD parameters of 
the compound in this subject population. 
MTX is the most commonly prescribed conventional DMARD in RA treatment. Subsequently, 
subjects with inadequate response to MTX who express signs of active disease at Screening 
are a commonly used subject population for clinical studies evaluating the efficacy of novel 
RA treatments in comparison with placebo. For JAK inhibitors, a 24-week treatment duration 
allows sufficient time for improvement in manifestations of active disease to be 
demonstrated and confirms that clinical benefit is sustained over time. Withholding subjects 
with sub-optimally treated disease from more effective treatments with a background MTX 
therapy for a maximum of 12 weeks is considered clinically and ethically acceptable. 
The ACR criteria for 20%, 50%, and 70% improvement in disease activity (ACR20, ACR50, 
and ACR70) responses and the Disease Activity Score based on 28 joints (DAS28) are 
considered reliable measures of response to treatment and disease activity, respectively. 
Comparison between the treatment arms of the proportions of subjects achieving an ACR20 
response at Week 12, which is the study’s primary efficacy endpoint, allows for 
straightforward interpretation of a positive clinically meaningful result and has been shown to 
achieve high discriminatory capacity, and it is therefore considered an adequate primary 
endpoint for dose-finding studies. The evaluation of ACR50 and ACR70 responses 
(secondary endpoints) further allows for a preliminary assessment of the study drug as a 
potentially effective treatment for RA and will provide useful information for planning and 
adequately sizing future confirmatory phase III clinical studies. 
Evaluation of continuous outcome measures of DAS28 and ACR-N as secondary endpoints 
enables the demonstration of improvement and magnitudes of benefit for study subjects. 
The European League Against Rheumatism (EULAR) response criteria classify subjects as 
non-, moderate-, or good responders dependent on the extent of change and the level of 
disease activity reached. These criteria are useful when describing clinically meaningful 
therapeutic targets. Clinical Diagnostic Activity Index (CDAI) and Simplified Diagnostic 
Activity Index (SDAI) are simple formulae that were primarily developed for use in clinical 
practice but have been widely used in clinical studies to demonstrate the impact of a study 
drug on controlling disease activity. Assessing quality of life (measured by the functional 
assessment of chronic illness therapy [FACIT] and 36-item short form health survey [SF-36]) 
at Baseline and during the course of study treatment provides further insight into the effects 
on modifying disease course and its impact on everyday life.   
6.7 
Rationale of Choice of the Dose and Dosing Interval 
For the current study, enrolled subjects will be randomized to receive 3 different treatment 
daily doses of GLPG0634 (50 mg, 100 mg, or 200 mg) or placebo as an add-on to their 
stable weekly dose of MTX. There are 2 dose regimens: the aforementioned daily doses will 

 
 
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7 Study Objectives 
7.1 
Primary Objective 
The primary objective of the study is to evaluate the efficacy in terms of the percentage of 
subjects achieving an ACR20 response, of different doses and dose regimens of GLPG0634 
compared to placebo at Week 12. 
7.2 
Secondary Objectives 
The secondary objectives of the study are: 
• 
To evaluate the efficacy in terms of the percentage of subjects achieving an ACR20, 
ACR50, ACR70, ACR-N, DAS28(CRP), EULAR response and ACR/EULAR 
remission, CDAI, and SDAI with different doses and dose regimens of GLPG0634 
compared to placebo at every visit. 
• 
To evaluate the safety and tolerability of different doses and dose regimens of 
GLPG0634 in comparison with placebo. 
• 
To characterize the population PK and PD of GLPG0634 and its metabolite 
(G254445) in subjects with rheumatoid arthritis and investigate the relationship 
between exposure and efficacy/safety/PD. 
• 
To evaluate the effects of different doses and dose regiments of GLPG0634 
administration on subjects’ disability, fatigue, and quality of life. 

 
 
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A diagram of the study design can be found below. 
Week 1 - 12  
Week 13 – 24   
Randomized to placebo 
Responders (i.e., having at least 20% improvement 
on TJC68 and SJC66) remain on placebo 
Nonresponders re-randomized to 100 mg q.d. 
Nonresponders re-randomized to 50 mg b.i.d. 
Randomized to 50 mg q.d. 
Responders remain on 50 mg q.d. 
Nonresponders assigned to 100 mg q.d. 
Randomized to 25 mg b.i.d. 
Responders remain on 25 mg b.i.d. 
Nonresponders assigned to 50 mg b.i.d. 
Randomized to 100 mg q.d. 
Remain on 100 mg q.d. 
Randomized to 50 mg b.i.d. 
Remain on 50 mg b.i.d. 
Randomized to 200 mg q.d.* 
Remain on 200 mg q.d.* 
Randomized to 100 mg b.id* 
Remain on 100 mg b.i.d.* 
*
 
8.2 
Discussion of Study Design 
The discussion of study design is presented in Section 6.7. 
8.3 
Selection of Study Population 
8.3.1 Number of Planned Subjects  
Sufficient subjects will be screened to ensure that 595 subjects will be randomized to one of 
the 6 treatment arms with GLPG0634 or to placebo. Details of the statistical considerations 
for the number of subjects are presented in Section 8.8.2. 
8.3.2 Inclusion Criteria 
To be eligible for study entry subjects must fulfil all of the following criteria: 
1. 
Male or female subjects who are ≥18 years of age, on the day of signing informed 
consent. 
2. 
Diagnosis of RA since at least 6 months prior to Screening and meeting the 2010 
ACR/EULAR criteria of RA and ACR functional class I-III. 
3. 
Have ≥6 swollen joints (from a 66-joint count) and ≥8 tender joints (from a 68-joint 
count) at Screening and Baseline, and a Screening serum CRP ≥0.7 x upper limit of 
the normal (reference) laboratory range (ULN). 
4. 
Have received MTX (oral or parenteral) for ≥6 months and have been on a stable dose 
(15 mg/week to 25 mg/week) of MTX for at least 4 weeks prior to Screening and willing 
to continue on this regimen for the duration of the study. Stable doses of MTX as low 
as 10 mg/week are allowed, when there is documented evidence of intolerance or 
safety issues at higher doses. 
5. 
If taking oral steroids, these should be at a dose ≤10 mg/day of prednisone or 
prednisone equivalent and stable for at least 4 weeks prior to Baseline. 
6. 
If taking non-steroidal anti-inflammatory drugs (NSAIDs), these must be at a stable 
dose for at least 2 weeks prior to Baseline. 
7. 
The results of the following laboratory tests performed at the central laboratory at 
Screening must be within the limits specified below: 

 
 
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Hemoglobin ≥10 g/dL (International System of Units [SI]: ≥100 g/L); 
a)
 
WBCs ≥3.0 x 103 cells/mm3 (SI: ≥3.0 x 109 cells/L); 
b)
 
Neutrophils ≥2.0 x 103 cells/mm3 (SI: ≥2.0 x 109 cells/L); 
c)
 
Lymphocytes ≥1.0 x 103 cells/mm3 (SI: ≥1.0 x 109 cells/L); 
d)
 
Platelets ≥100 x 103 cells/mm3 (SI: ≥100 x 109 cells/L); 
e)
 
Serum ALT and aspartate aminotransferase (AST) ≤1.5 x ULN; 
f)
 
Total bilirubin level ≤1.25 x ULN; 
g)
 
Alkaline phosphatase ≤1.5ULN; 
h)
 
Lipase ≤1.5 x ULN and amylase ≤1.5ULN; 
i)
 
Creatinine clearance >60 mL/min. Creatinine clearance will be calculated using 
j)
the Cockroft-Gault formula. 
8. 
Female subjects must have a negative pregnancy test unless they are surgically sterile 
or have been post-menopausal for at least one year (12 consecutive months without 
menses); in case of doubt a determination of serum FSH can be done with FSH levels 
above 35 mIU/mL being confirmative for menopause. 
9. 
Women of childbearing potential must use a highly effective method of birth control 
and agree to continue its use during the study and for at least 12 weeks after the last 
dose of study medication. Highly effective methods of birth control include implantable 
methods, intrauterine devices, tubal ligation (if performed more than one year before 
Screening), or double barrier contraception. In case an oral, patch, or injectable 
contraceptive method is used, this should be done together with a male partner using 
a condom (addition of spermicide jelly is advisable), Or in the case of a vasectomized 
male partner the procedure must have been performed at least 12 weeks prior to 
screening and an absence of sperm in the ejaculate have been recorded in the 
medical documentation prior to screening. Total sexual abstinence may be considered 
acceptable at the discretion of the investigator. 
10. 
Sexually active men must agree to use a highly effective method of contraception 
(double barrier) during the study and continue its use for at least 12 weeks after the 
last dose of study medication. Vasectomized males do not need to use additional 
forms of contraception providing that the procedure was performed at least 12 weeks 
prior to screening and an absence of sperm in the ejaculate has been documented 
prior to screening. Total sexual abstinence may be considered acceptable at the 
discretion of the investigator. 
11. 
Able and willing to sign the informed consent as approved by the Independent Ethics 
Committee (IEC)/Institutional Review Board (IRB), prior to Screening evaluations and 
agree to schedule of assessments. 
12. 
Judged to be in good health, except for their RA, as determined by the investigator 
based upon the results of medical history, laboratory profile, physical examination, 
chest X-ray, and a 12-lead ECG performed during Screening. 
8.3.3 Exclusion Criteria 
Subjects will be excluded from the study if one or more of the following statements are 
applicable: 
1. 
Current therapy with any DMARD other than MTX, including oral or injectable gold, 
sulfasalazine, antimalarials, azathioprine, or D-penicillamine within 4 weeks prior to 
Baseline, cyclosporine within 8 weeks prior to Baseline, and leflunomide within 3 
months prior to Baseline or a minimum 4 weeks prior to Baseline if after 11 days of 
standard cholestyramine therapy. 
2. 
Current or previous RA treatment with a biologic DMARD, with the exception of 
biologic DMARDs  

 
 
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• 
administered in a single clinical study setting, and;  
• 
more than 6 months prior to Screening (12 months for rituximab or other B 
cell depleting agents), and; 
• 
where the biologic DMARD was effective, and if discontinued, this should 
not be due to lack of efficacy. 
3. 
Previous treatment at any time with a cytotoxic agent, other than MTX, before 
Screening. 
These 
agents 
include, 
but 
are 
not 
limited 
to 
chlorambucil, 
cyclophosphamide, nitrogen mustard, or other alkylating agents. 
4. 
Previous use of JAK inhibitors. 
5. 
Receipt of an intra-articular or parenteral corticosteroid injection within 4 weeks prior to 
Screening. 
6. 
Known hypersensitivity to study medication ingredients or a significant allergic reaction 
to any drug as determined by the investigator, such as anaphylaxis requiring 
hospitalization. 
7. 
Positive serology for human HIV 1 or 2 or hepatitis B or C or any history of hepatitis 
from any cause with the exception of hepatitis A. 
8. 
Immunocompromised subjects who in the opinion of the investigator are at an 
unacceptable risk for participating in the study. 
9. 
Previous history of symptomatic herpes zoster or herpes simplex infection within 12 
weeks prior to Screening or have a history of disseminated/complicated herpes zoster 
infection (multi-dermatomal involvement, ophthalmic zoster CNS involvement or 
postherpetic neuralgia). 
10. 
Known active infection of any kind (excluding fungal infection of nail beds), or any 
major episode of infection requiring hospitalization or treatment with parenteral 
(intramuscular or IV) anti-infectives (antibiotics, antiviral, anti-fungals or anti-parasitic 
agents) within 4 weeks of the Screening Visit or completion of oral anti-infectives within 
2 weeks of the Screening Visit. 
11. 
Currently on any therapy for chronic infection (such as pneumocystis, cytomegalovirus 
(CMV), herpes simplex, herpes zoster and atypical mycobacteria). 
12. 
History of any inflammatory rheumatological disorder other than RA except secondary 
Sjögren´s Syndrome. 
13. 
Any surgical procedure, including bone/joint surgery/synovectomy (including joint 
fusion or replacement) within 24 weeks prior to the Screening Visit. 
14. 
History of moderate to severe congestive heart failure (New York Heart Association 
[NYHA] class III or IV), recent (within 24 weeks prior to study entry) cerebrovascular 
accident and any other condition which, in the opinion of the investigator, would put the 
subject at risk by participation in the study. 
15. 
History or current symptoms of GI tract ulceration and/or diverticulitis. 
16. 
History of malignancy within the past 5 years (except for basal cell carcinoma of the 
skin or cervical carcinoma in situ that has been treated with no evidence of 
recurrence). 
17. 
History of lymphoproliferative disease; or signs and symptoms suggestive of possible 
lymphoproliferative disease including lymphadenopathy or splenomegaly. 
18. 
History of active or latent tuberculosis (TB) infection as determined by either: 
a) 
positive QuantiFERON TB Gold test result OR 
b) 
chest radiograph (both posterior-anterior and lateral views), taken within 
3 months prior to Screening and read by a qualified radiologist, with evidence of 
current active TB or old inactive TB symptoms of clinically significant illness in 
the 3 months before the initial study medication administration. 
19. 
History of invasive infection (e.g., listeriosis and histoplasmosis). 
20. 
Treatment with any drug known to have a well-defined potential for toxicity to a major 
organ in the last 3 months preceding the initial study drug administration. 

 
 
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21. 
Administration of a live vaccine within 90 days or an attenuated vaccine within 30 days 
prior to the initial study medication administration. 
22. 
Participation in any investigational drug/device clinical study within 4 weeks prior to 
Screening. 
23. 
History within the previous 2 years or current evidence of drug or alcohol abuse. 
24. 
If applicable to national or local legislation: history of being admitted to an institution 
under an administrative or court order. 
25. 
Breastfeeding during the study. 
26. 
Any condition or circumstances which, in the opinion of the investigator, may make a 
subject unlikely or unable to complete the study or comply with study procedures and 
requirements. 
27. 
Significant blood loss (including blood donation [> 500 mL]) or a transfusion of any 
blood product within 12 weeks prior to the initial study medication administration. 
8.3.4 Removal of Subjects from Therapy or Assessments 
Subjects may stop study medication for any of the following reasons: 
• Subject request. 
• Use of non-permitted concurrent therapy. 
• Noncompliance with the study medication (see Section 8.5.9). 
• Noncompliance with the study procedures (see Section 8.5.9 and Section 8.6). 
• Lost to follow-up. 
• Occurrence of AEs not compatible with the continuation of subject participation in the 
study, in the investigator’s opinion. This also includes any clinically significant 
laboratory results, ECGs and vital signs. 
• Investigator request. 
• Sponsor request. 
• Treatment failure deemed by the investigator as lack of improvement or worsening of 
the disease symptoms or occurrence of intolerable AEs. 
Treatment with GLPG0634 will be discontinued and the subject withdrawn from this study 
for: 
• 
Serious infections (those requiring parenteral antimicrobial therapy or 
hospitalization). 
• 
Any opportunistic infections. 
• 
Complicated herpes zoster infection (multi-dermatomal, disseminated, ophthalmic or 
CNS involvement).  
• 
Two sequential total white cell counts <2000 cells/mm3 (SI: <2.0 x 109 cells/L). 
• 
Two sequential neutrophil counts <1000 neutrophils/mm3 (SI: <1.0 x 109 cells/L). 
• 
Two sequential lymphocyte counts <750 lymphocytes/mm3 (SI: <0.75 x 109 cells/L). 
• 
Two sequential hemoglobin <8.0 g/dL (SI: <80 g/L). 
• 
Two sequential platelet counts <75,000 platelets/mm3 (SI: <75.0 x 109 cells/L). 
• 
Two sequential AST or ALT elevations >3 times the upper limit of normal with at least 
one total Bilirubin value >2 times the upper limit of normal1. 
• 
Two sequential AST or ALT elevations >3 times the upper limit of normal 
accompanied by symptoms consistent with hepatic injury1. 

 
 
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• 
Two sequential AST or ALT elevations >3 times the upper limit of normal 
accompanied by elevated INR. 
• 
Two sequential AST or ALT elevations >5 times the upper limit of normal, regardless 
of total Bilirubin or accompanying symptoms1. 
• 
Two sequential increases in serum creatinine >50% over the average of screening 
and baseline values2. 
• 
Two sequential decreases from the baseline of inhibin B by 50% or testosterone by 
50% with concurrent increases in FSH or LH respectively.3 
 
After becoming aware of any of the above described abnormal laboratory changes occurring 
at any one time, an unscheduled visit (i.e. second sequential) must occur to retest within 3 to 
5 days. 1 In each case, there is a need for additional investigations, such as review of ethanol, recreational drug and dietary 
supplement consumption; testing for acute hepatitis A, B or C infection and biliary tract imaging should be promptly discussed 
with the Study Medical Monitor. 
2 At the time of study completion or discontinuation, if a subject should exhibit elevations in serum creatinine ≥33 % above the 
average of screening and baseline values, they should be re-tested every 1 to 2 weeks until the serum creatinine elevation is 
fully reversed to within 10% of the average of screening and baseline values. 
3 In each case, hormones in male subjects should be monitored monthly and if no positive dynamics is seen after 3 months 
from stopping GLPG0634, referral to an andrologist should be considered. 
Subjects who stop study medication for any reason will not be replaced. Subjects 
withdrawing from the study will be encouraged to complete the same final evaluations as 
subjects completing the study according to the protocol, particularly safety evaluations in the 
subject’s interest so that data can be recorded in the same way as for subjects who 
completed the study. Subjects are free to withdraw from the study at any time without 
providing reason(s) for withdrawal and without prejudice to further treatment. The reason(s) 
for withdrawal will be documented in the electronic case report form (eCRF). 
Reasonable efforts will be made to contact subjects who are lost to follow-up. These must be 
documented in the subject’s file.  
The sponsor has the right to terminate the study at any time in case of safety concerns or if 
special circumstances concerning the study medication or the company itself occur, making 
further treatment of subjects impossible. In this event, the investigator(s) and relevant 
authorities will be informed of the reason for study termination. 

 
 
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subjects on 25 mg b.i.d. who have not achieved a 20% improvement in SJC66 and TJC68 
will be assigned to 50 mg b.i.d. All will continue the study until Week 24. Subjects in the 
other groups will maintain their randomized treatment until Week 24. 
8.5.5 Selection of Doses in the Study 
Details of the selection of doses in the study are presented in Section 6.7. 
8.5.6 Selection and Timing of Dose for Each Subject 
The study medication will be administered with a glass of water daily in the morning and in 
the evening. 
Each subject’s dose will be selected by random allocation according to randomization 
procedures. 
If a subject misses a dose (e.g., because he/she forgot to take the medication), he/she 
should take the missed dose within 5 hours after the planned intake time. If the study 
medication is not taken within 5 hours after the planned time, the missed dose should be 
skipped. For each dose taken, the number of capsules taken should be recorded on the 
subject’s diary card. Additional to the number of capsules taken, the date and time of the 
very first intake, and for selected visits, the 2 most recent intakes prior to the visits will be 
recorded on the subject’s diary card. For the methotrexate, the date and time for the most 
recent intake prior to the selected visits will be captured on the subject’s diary card.  During 
each visit, the investigator will record a summary of the study medication intake data in the 
eCRF. 
Dose reduction during the study is not allowed. Instead, the subject should either temporarily 
stop all intake or permanently stop study medication. Every effort should be made to contact 
the medical monitor before stopping study medication (temporarily or permanently). 
8.5.7 Blinding 
This is a randomized, double-blind study. The subject, the investigator, the study 
coordinator, the sponsor and the entire study processing team will remain blinded to 
treatment assignment. The blind can be broken only if the investigator deems it necessary 
for the safe treatment of a subject, and whenever possible the medical monitor and sponsor 
should be consulted before breaking the blind. 
If the blind is broken for any reason during the course of the study, the moment on which the 
blind was broken and all other relevant information will be documented by the investigative 
site, 
, and other sponsor designees, as appropriate. The reason for breaking 
the blind will be indicated and justified in the source documentation and in the eCRF. The 
blind can be broken by the investigator via the IXRS system. 
All subjects who are unblinded while on the study will be withdrawn at the moment of 
unblinding, with the reason for unblinding given as the reason for discontinuation from the 
study. If an AE leads to unblinding, the AE should be given as the reason for unblinding and 
the AE should also be recorded in the eCRF. All subjects who are unblinded should, where 
possible, complete the early discontinuation visit (EDV). Any AEs should be followed until 
resolution. 

 
 
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8.5.8 Prior and Concomitant Therapy  
Concomitant therapies taken for the long term treatment of pre-existing conditions can 
continue during the study provided they are in accordance with the inclusion and exclusion 
criteria. It is preferred that these medications be stabilizedand continued without variation of 
dose or regimen during the study. 
In case new therapies need to be administered during the study, the risk/benefit to the 
subject should be carefully assessed and consideration given to the timing of any necessary 
introduction of new medications. 
Permitted concomitant medications at Screening and during the study include:  
• 
NSAIDs, provided that the dose is stable for at least 2 weeks prior to Baseline and, if 
possible, is kept constant during the study;  
• 
Oral steroids, provided that the dose is stable, is ≤10 mg/day prednisone or 
equivalent for at least 4 weeks prior to Baseline, and is kept stable for the study 
duration; and  
• 
Analgesics, other than NSAIDs, up to the maximum recommended doses may be 
used for pain as required. However, subjects must not take analgesics within 24 
hours before a visit where clinical efficacy assessments are performed and recorded. 
All local standard-of-care practices for the administration of methotrexate, including 
laboratory testing, follow-up care and contraindications should be performed according to 
local standards of care throughout the study. If subjects were taking folic acid at Screening 
as a preventive measure for MTX toxicity, this should be continued at a stable dose for the 
duration of the study.  
Female subjects of childbearing potential will use highly effective birth-control methods as 
outlined in the inclusion criteria and agree to continue their use during the study and for at 
least 12 weeks after the last dose of study medication. The use of hormonal contraceptives 
will be recorded in the Concomitant Therapy section of the eCRF. Applicable procedures 
and treatment guidance based on package inserts will be respected.  
Hormone replacement therapy will be allowed in post-menopausal women ifongoing at the 
time of Screening. The use of hormone replacement therapy will be recorded in the 
Concomitant Therapy section of the eCRF. Applicable procedures and treatment guidance 
based on package inserts will be respected. 
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 Baseline, cyclosporine within 8 weeks prior to Baseline, and 
leflunomide within 3 months prior to Baseline or a minimum 4 weeks prior to Baseline if after 
11 days of standard cholestyramine therapy. 
Current or previous RA treatment with a biologic DMARD is prohibited, with the exception of 
biologic DMARDs administered in a single clinical study setting more than 6 months prior to 
Screening (12 months for rituximab or other B-cell-depleting agents), where the biologic 
DMARD was effective, and if discontinued, this should not be due to lack of efficacy. 

 
 
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Previous treatment at any time with a cytotoxic agent, other than MTX, before screening is 
prohibited. These agents include, but are not limited to chlorambucil, cyclophosphamide, 
nitrogen mustard, and other alkylating agents. 
Previous use of JAK inhibitors is prohibited. 
Receipt of an intra-articular or parenteral corticosteroid injection within 4 weeks prior to 
Screening is prohibited. 
Vaccine Guidelines: 
Vaccination with live components is prohibited during the study and for 6 weeks after the last 
dose of study drug. Also routine household contact with persons vaccinated with live vaccine 
components should be avoided. These vaccines include varicella, oral polio and inhaled flu 
vaccine. General guidelines suggest that exposure should be avoided following vaccination 
with these vaccines for the stated time period: 
• 
Varicella or attenuated typhoid fever vaccination for 4 weeks following vaccination; 
• 
Oral polio vaccination for 6 weeks following vaccination; 
• 
Attenuated rotavirus vaccine for 10 days following vaccination; 
• 
Inhaled flu vaccine for 1 week following vaccination. 
When inactivated flu vaccines are to be used during the study, it should be borne in mind 
that vaccination responses have not been studied during the administration of GLPG0634. 
Currently, there are no available data on continuous use of GLPG0634 and its impact on 
immune responses following vaccination. 
8.5.9 Treatment Compliance and Drug Accountability 
For each dose taken, the date, time of intake, and number of capsules taken should be 
recorded on the subject diary card. 
The investigator or designated study personnel will maintain a log of all drug dispensed and 
returned. Drug supplies for each subject will be inventoried and accounted for throughout the 
study. 
Subjects with a poor compliance (<80% or >120%) will be retained by the study site. If study 
drug compliance remains <80% or >120% between study visits, or if the subject missed 
more than 2 visits, the subject will be evaluated for potential discontinuation. Any 
discontinuation should be done in consultation with the Medical Monitor. 
8.5.10 Subject Diary Card 
Subjects will record any changes in concomitant illnesses, new AEs and any change in 
concomitant medication in their diary cards. Adverse events and changes in concomitant 
medication will be transcribed into the eCRF by the investigator. Details of dosing with study 
medication will be recorded in the subject diary and summarized in the eCRF by the 
investigator.  

 
 
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The subject diary card will be considered source information. The data from the subject diary 
card will not be entered into the study database. 
8.6 
Study Procedures 
All planned study assessments are presented in the flow chart in Section 8.7.1.5. 
8.6.1 Pre-treatment 
Written informed consent will be obtained before any study-related procedures and/or 
assessments are performed. 
8.6.1.1 Screening Period (Visit 1, Day -29 to Day -2) 
• Each subject will receive a patient number by using the IXRS system. 
• Each subject will be assessed for eligibility against the inclusion and exclusion criteria. 
• The subject’s full medical history, including concomitant illnesses and diseases and 
concomitant medications will be documented. 
• Demographic data will be recorded. 
• Baseline disease characteristics will be recorded. 
• A physical examination will be performed, including body weight and height, and the 
results will be documented. 
• Vital signs (blood pressure, heart rate [HR], and oral temperature) will be measured. 
• TB test (QuantiFERON-TB Gold test) and chest X-ray will be performed (chest X-ray is 
to be performed only if not performed in the previous 3 months (results must be 
available at the site for any chest X-ray performed in the previous 3 months). 
• Serology (including hepatitis B and C, HIV 1 and 2, rheumatoid factor [RF] and 
anti-cyclic citrullinated peptide [CCP] tests) will be performed on a sample collected 
at this visit. 
• An ECG will be performed. 
• Hematology, clinical chemistry and urinalysis tests (dipstick and microscopy) will be 
performed on samples collected at this visit. A serum pregnancy test will be 
performed on women of childbearing potential. 
• Serum CRP will be measured. 
• SJC66 and TJC68 evaluations will be performed. 
• The subject will complete the Patient’s Global Assessment of Disease Activity. 
Note 1: Retesting during the Screening period is only allowed once for abnormal lab values 
except for positive QuantiFERON-TB Gold, Hepatitis B, Hepatitis C, HIV or pregnancy test in 
a female of childbearing potential AND only in case it is still possible to randomize the patient 
within the per protocol defined Screening period of 28 calendar days. 
 
Note 2: Rescreening is only allowed in specific situations and after having obtained written 
sponsor approval. 
 
8.6.1.2 Baseline Visit (Visit 2, Day -1) 
The Baseline visit (Visit 2) will take place from 1 to 28 calendar days after the Screening visit 
(Visit 1). 

 
 
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• Visit 2 will take place when the laboratory test results from the Screening period are 
available. 
• Each subject will be reassessed for eligibility against the inclusion and exclusion 
criteria. 
• Any changes in concomitant diseases and illnesses since signing the ICF will be 
documented as AEs. 
• Changes in concomitant medication will be documented and linked to AEs if relevant. 
• Vital signs will be measured. 
• A physical examination will be performed. 
• Hematology, clinical chemistry, and urinalysis (dipstick and microscopy) tests will be 
performed on samples collected at this visit. A urine pregnancy test will be performed 
on females of childbearing potential. 
• Blood samples for measurement of PD parameters will be collected. 
• Serum CRP will be measured. 
• SJC66 and TJC68 evaluations will be performed. 
• Physician’s and Patient’s Global Assessments of Disease Activity will be completed. 
• The subject will complete the Health Assessment Questionnaire – Disability Index 
(HAQ-DI). 
• The subject will complete the FACIT fatigue scale and the SF-36 questionnaire. 
• The subject will be randomly assigned to treatment (upon qualification for the study) 
using IXRS. 
• A subject diary card will be dispensed. 
When all the Baseline procedures have been performed and the investigator has confirmed 
the subject’s eligibility for the study, the study medication will be dispensed to the subject 
according to the information provided using the IXRS system. The subject will start taking 
the study medication on Day 1, the day after the Baseline visit (Day -1). 
8.6.2 Treatment Period 
8.6.2.1 Week 1 (Visit 3)  
The Week 1 visit (Visit 3) will take place on Day 8 ± 2 calendar days relative to the start of 
the study medication intake. 
• Any remaining study medication as well as empty study medication containers will be 
returned to the investigator, and an accountability check will be performed. 
• Any AEs that have occurred since signing the informed consent form (ICF) will be 
documented, and any changes in concomitant medication will be reported. 
• Vital signs will be measured. 
• Blood samples for measurement of PD parameters will be collected. 
• The subject diary card will be collected, a summary will be recorded in the eCRF, and 
a new subject diary card dispensed. 
• Serum CRP will be measured. 
• SJC66 and TJC68 evaluations will be performed 
• Physician’s and Patient’s Global Assessments of Disease Activity will be completed. 
• The subject will complete the HAQ-DI. 
• Hematology, clinical chemistry, and urinalysis (dipstick and microscopy) tests will be 
performed on samples collected at this visit. A urine pregnancy test will be performed 
on females of childbearing potential. 

 
 
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When all of these procedures have been performed, the study medication will be dispensed 
according to the information provided using IXRS and all subsequent visits will be 
scheduled. 
8.6.2.2 Week 2 (Visit 4)  
The Week 2 visit (Visit 4) will take place on Day 15 ± 2 calendar days relative to the start of 
study medication intake. 
• Any remaining study medication as well as empty study medication containers will be 
returned to the investigator, and an accountability check performed. 
• Any AEs that have occurred since signing the ICF will be documented, and any 
changes in concomitant medication will be reported. 
• Vital signs will be measured. 
• The subject diary card will be collected, a summary will be recorded in the eCRF, and 
a new subject diary card will be dispensed. 
• Serum CRP will be measured. 
• SJC66 and TJC68 evaluations will be performed. 
• Physician’s and Patient’s Global Assessments of Disease Activity will be completed. 
• The subject will complete the HAQ-DI. 
• Hematology, clinical chemistry, and urinalysis (dipstick and microscopy) tests will be 
performed on samples collected at this visit. A urine pregnancy test will be performed 
on females of childbearing potential. 
When all of these procedures have been performed, the study medication will be dispensed 
according to the information provided using IXRS and the date of the next visit will be 
confirmed. 
8.6.2.3 Week 4 (Visit 5)  
The Week 4 visit (Visit 5) will take place on Day 29 ± 2 calendar days relative to the start of 
study medication intake. 
• Any remaining study medication as well as empty study medication containers will be 
returned to the investigator, and an accountability check will be performed. 
• Any AEs that have occurred since signing the ICF will be documented, and any 
changes in concomitant medication will be reported. 
• Vital signs will be measured. 
• The subject diary card will be collected, a summary will be recorded in the eCRF, and 
a new subject diary card will be dispensed. 
• Blood samples for measurement of PK and PD parameters will be collected. 
• Serum CRP will be measured. 
• SJC66 and TJC68 evaluations will be performed. 
• Physician’s and Patient’s Global Assessments of Disease Activity will be completed. 
• The subject will complete the HAQ-DI. 
• The subject will complete the FACIT fatigue scale and the SF-36 questionnaire. 
• Hematology, clinical chemistry, and urinalysis (dipstick and microscopy) tests will be 
performed on samples collected at this visit. A urine pregnancy test will be performed 
on females of childbearing potential. 

 
 
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When all of these procedures have been performed, the study medication will be dispensed 
according to the information provided using IXRS and the date of the next visit will be 
confirmed. 
8.6.2.4 Week 8 (Visit 6) 
The Week 8 visit (Visit 6) will take place on Day 57 ± 2 calendar days relative to the start of 
study medication intake. 
• Any remaining study medication as well as empty study medication containers will be 
returned to the investigator and an accountability check will be performed. 
• Any AEs that have occurred since signing the ICF will be documented and any 
changes in concomitant medication will be reported. 
• Vital signs will be measured. 
• The subject diary card will be collected, a summary will be recorded in the eCRF, and 
a new subject diary card will be dispensed. 
• Serum CRP will be measured. 
• SJC66 and TJC68 evaluations will be performed. 
• Physician’s and Patient’s Global Assessments of Disease Activity will be completed. 
• The subject will complete the HAQ-DI. 
• Hematology, clinical chemistry, and urinalysis (dipstick and microscopy) tests will be 
performed on samples collected at this visit. A urine pregnancy test will be performed 
on females of childbearing potential. 
When all of these procedures have been performed, the study medication will be dispensed 
according to the information provided using IXRS and the date of the next visit will be 
confirmed. 
8.6.2.5 Week 12 (Visit 7)  
The Week 12 visit (Visit 7) will take place on Day 85 ± 2 calendar days relative to the start of 
study medication intake. 
• Any remaining study medication as well as empty study medication containers will be 
returned to the investigator and an accountability check will be performed. 
• Any AEs that have occurred since signing the ICF will be documented, and any 
changes in concomitant medication will be reported. 
• Vital signs will be measured. 
• A 12-lead ECG will be performed. 
• A physical examination will be performed. 
• The subject diary card will be collected, a summary will be recorded in the eCRF, and 
a new subject diary card will be dispensed. 
• Blood samples for measurement of PK and PD parameters will be collected. 
• Serum CRP will be measured. 
• SJC66 and TJC68 evaluations will be performed. 
• Physician’s and Patient’s Global Assessments of Disease Activity will be completed. 
• The subject will complete the HAQ-DI. 
• The subject will complete the FACIT fatigue scale and the SF-36 questionnaire. 
• Hematology, clinical chemistry, and urinalysis (dipstick and microscopy) tests will be 
performed on samples collected at this visit. A urine pregnancy test will be performed 
on females of childbearing potential. 

 
 
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At visit 7, subjects on placebo who have not achieved a 20% improvement in SJC66 and 
TJC68 will be re-randomized (automatically via IXRS) to treatment to receive GLPG0634 
100 mg q.d. or 50 mg b.i.d. doses in a blinded fashion, subjects on 50 mg q.d. who have not 
achieved a 20% improvement in SJC66 and TJC68 will be assigned to 100 mg q.d. and 
subjects on 25 mg b.i.d. who have not achieved a 20% improvement in SJC66 and TJC68 
will be assigned to 50 mg b.i.d. All will continue the study until Week 24. Subjects in the 
other groups will maintain their randomized treatment until Week 24. 
When all of these procedures have been performed, the study medication will be dispensed 
according to the information provided using IXRS and the date of the next visit confirmed. 
8.6.2.6 Week 16 (Visit 8) 
The Week 16 visit (Visit 8) will take place on Day 113 ± 2 calendar days relative to the start 
of study medication intake. 
• Any remaining study medication as well as empty study medication containers will be 
returned to the investigator, and an accountability check will be performed. 
• Any AEs that have occurred since signing the ICF will be documented, and any 
changes in concomitant medication will be reported. 
• Vital signs will be measured. 
• The subject diary card will be collected, a summary will be recorded in the eCRF, and 
a new subject diary card will be dispensed. 
• Serum CRP will be measured. 
• SJC66 and TJC68 evaluations will be performed. 
• Physician’s and Patient’s Global Assessments of Disease Activity will be completed. 
• The subject will complete the HAQ-DI. 
• Hematology, clinical chemistry, and urinalysis (dipstick and microscopy) tests will be 
performed on samples collected at this visit. A urine pregnancy test will be performed 
on females of childbearing potential. 
When all of these procedures have been performed, the study medication will be dispensed 
according to the information provided using IXRS and the date of the next visit will be 
confirmed. 
8.6.2.7 Week 20 (Visit 9) 
The Week 20 visit (Visit 9) will take place on Day 141 ± 2 calendar days relative to the start 
of study medication intake. 
• Any remaining study medication as well as empty study medication containers will be 
returned to the investigator, and an accountability check will be performed. 
• Any AEs that have occurred since signing the ICF will be documented, and any 
changes in concomitant medication will be reported. 
• Vital signs will be measured. 
• The subject diary card will be collected, a summary will be recorded in the eCRF, and 
a new subject diary card will be dispensed. 
• Serum CRP will be measured. 
• SJC66 and TJC68 evaluations will be performed. 
• Physician’s and Patient’s Global Assessments of Disease Activity will be completed. 
• The subject will complete the HAQ-DI. 

 
 
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• Hematology, clinical chemistry, and urinalysis (dipstick and microscopy) tests will be 
performed on samples collected at this visit. A urine pregnancy test will be performed 
on females of childbearing potential. 
When all of these procedures have been performed, the study medication will be dispensed 
according to the information provided using IXRS and the date of the next visit will be 
confirmed. 
8.6.2.8 Week 24 (Visit 10) or Early Discontinuation Visit (EDV) 
The Week 24 visit (Visit 10) will take place on Day 169 ± 2 calendar days relative to the start 
of study medication intake. If the subject discontinues from the study early, the following 
procedures will be performed. This visit needs to be entered in IXRS. 
• Any remaining study medication as well as empty study medication containers will be 
returned to the investigator, and an accountability check will be performed. 
• Any AEs that have occurred since signing the ICF will be documented, and any 
changes in concomitant medication will be reported. 
• Vital signs will be measured. 
• An ECG will be performed. 
• A physical examination will be performed and a summary will be recorded in the 
eCRF. 
• The subject diary card will be collected. 
• Blood samples for measurement of PK and PD parameters will be collected. 
• Serum CRP will be measured. 
• SJC66 and TJC68 evaluations will be performed. 
• Physician’s and Patient’s Global Assessments of Disease Activity will be completed. 
• The subject will complete the HAQ-DI. 
• The subject will complete the FACIT fatigue scale and the SF-36 questionnaire. 
• Hematology, clinical chemistry, and urinalysis (dipstick and microscopy) tests will be 
performed on samples collected at this visit. A serum pregnancy test will be 
performed on females of childbearing potential. 
8.6.3 Follow-up (Visit 11) 
A Follow-up visit (Visit 11) will be performed only for subjects discontinuing prematurely from 
the study and for subjects not entering the Long Term Follow-up Study GLPG0634-CL-205. 
This will take place 7 to 10 calendar days after either the EDV or the Week 24 visit. 
• Any AEs that have occurred since signing the ICF will be documented, and any 
changes in concomitant medication will be reported. 
• Vital signs will be measured. 
• A 12-lead ECG will be performed. 
• A physical examination will be performed. 
• Hematology, clinical chemistry, and urinalysis (dipstick and microscopy) tests will be 
performed on samples collected at this visit. A urine pregnancy test will be performed 
on females of childbearing potential. 

 
 
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8.6.4 Duration of Treatment 
Subjects participating in the study will be requested to attend a total of 11 visits throughout 
the study: Screening visit (up to 28 calendar days before Baseline visit), Baseline visit, Week 
1 visit, Week 2 visit, Week 4 visit, Week 8 visit, Week 12 visit, Week 16 visit, Week 20 visit, 
Week 24 visit, and for the subjects not entering the Long Term Follow-up study (GLPG0634-
CL-205), a Follow-up visit 7 to 10 days after end of study treatment. 
Consequently, each subject will remain in the study for a maximum of 29 weeks (from 
Screening visit to Follow-up visit). Treatment will last for 24 weeks. 
8.7 
Efficacy, Pharmacokinetics, Pharmacodynamics and Safety Variables  
The flow chart in Section 8.7.1.5 shows the planned study assessments. 
8.7.1 Efficacy, Pharmacokinetics, Pharmacodynamics and Safety Measurements 
Assessed and Flow Chart  
8.7.1.1 Efficacy Assessments 
8.7.1.1.1 Evaluation of Disease Activity 
Efficacy assessments will be carried out at Screening (joint counts and Patient’s Global 
Assessment of Disease Activity only); Baseline (Day -1); at Weeks 1, 2, 4, 8, 12, 16, 20, and 
24; and at the EDV (if applicable).  
Each of 68 joints will be evaluated for tenderness, and each of 66 joints will be evaluated for 
swelling (Appendix 13.2).  
A joint assessor with adequate training and experience in performing joint assessments will 
be designated at each study site to perform all joint assessments. The joint assessor should 
preferably be a rheumatologist, however, if a rheumatologist is not available, it should be a 
health care worker with at least one year’s experience in performing joint assessments. The 
assessor should remain the same throughout the study per subject, as much as possible. It 
is required that the designated joint assessor identify an appropriate back-up assessor to 
provide coverage if the designated joint assessor is absent. 
8.7.1.1.2 Patient’s Global Assessment of Disease Activity 
The Patient’s Global Assessment of Disease Activity will be recorded on a 0 to 100 visual 
analog scale (VAS), with 0 indicating “very well” and 100 indicating “very poor” to the 
question “Considering all the ways arthritis affects you, how well are you doing today?” 
(Appendix 13.3). 
8.7.1.1.3 Physician’s Global Assessment of Disease Activity 
The Physician’s Global Assessment of Disease Activity will be recorded on a 0 to 100 mm 
VAS, with 0 indicating “no disease activity” and 100 indicating “extreme disease activity”. 
The evaluating physician and the subject must complete the global assessments 
independently of each other (Appendix 13.4). 

 
 
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8.7.1.1.4 Health Assessment Questionnaire – Disability Index (HAQ-DI) 
The functional status of the subject will be assessed using the HAQ-DI. This 20-question 
instrument assesses the degree of difficulty a person has in accomplishing tasks in 8 
domains (dressing, arising, eating, walking, hygiene, reaching, gripping and errands/chores). 
Responses are scored on a 4-point Likert scale from 0, indicating no difficulty, to 3, 
indicating inability to perform a task in that area. The need for aids/devices or help from 
another person will also be recorded. The HAQ-DI total score ranges from 0 to 3 with higher 
scores indicating greater dysfunction (Appendix 13.5). 
As part of the HAQ-DI, subjects will be asked to assess their average pain during the last 
week on a 0 to 100 mm VAS, with 0 indicating “no pain” and 100 indicating “severe pain”. 
This assessment should be completed before the joint examination. This pain score will be 
used to drive the ACR20/50/70. 
8.7.1.1.5 FACIT Fatigue Scale 
The FACIT fatigue scale (version 4) measures an individual’s level of fatigue during their 
usual daily activities over the past week. It consists of 13 questions with a 7-day recall period 
on a 5-point Likert scale, with 0 indicating “not at all” and 4 indicating “very much”. The total 
score ranges from 0 to 52. The higher the score, the better the quality of life (Appendix 13.6). 
8.7.1.1.6 36-Item Short-form Health Survey (SF-36) 
The health-related quality of life of the subject will be assessed using the SF-36 (version 2) 
with a 4-week recall period. This consists of 36 questions belonging to 8 domains in 2 
components: 
• 
Physical well-being: 4 domains: physical functioning (10 items), role physical 
(4 items), bodily pain (2 items), and general health perceptions (5 items). 
• 
Mental well-being: 4 domains: vitality (4 items), social functioning (2 items), role 
emotional (3 items), and mental health (5 items). 
The remaining item (health transition) is not part of the above domains but is kept separately 
(Appendix 13.7). 
These scales will be rescaled from 0 to 100 (converting the lowest possible score to 0 and 
the highest possible score to 100), with higher scores indicating a better quality of life. 
8.7.1.2 Pharmacokinetic Assessments 
One blood sample (2 mL) for analysis of GLPG0634 and its metabolite (G254445) in plasma 
will be collected at Weeks 4, 12, and 24 (or the EDV, if applicable) by venipuncture (or 
indwelling cannula) in the forearm into tubes containing lithium heparin and will be 
immediately chilled (ice bath), processed and frozen as plasma at -20oC (-4oF). Additional 
analyses (e.g. for MTX and its metabolite) might be performed using the same blood 
samples. 
 

 
 
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8.7.1.3 Pharmacodynamic Assessments 
Blood samples for PD assessments will be collected in all subjects at Baseline (Day -1), 
Week 1, Week 4, Week 12, and Week 24 or the EDV. 
Two blood samples of 2.5 mL each will be collected in 2 PAXgene tubes. Immediately after 
collection, the tubes will be gently inverted 8 to 10 times and stored at room temperature for 
a minimum of 2 hours and a maximum of 72 hours before freezing at -20°C (-4°F) for 
storage until further analysis (gene expression in circulating leukocytes; messenger 
ribonucleic acid as well as micro ribonucleic acid [miRNA] profiling). 
Additionally, 1 blood sample of 8.5 ml will be collected in a SST tube. The sample will be 
allowed to clot in the tube for 30 minutes at room temperature, after which the tube will be 
centrifuged. Serum will be extracted, divided over 4 aliquots and frozen at -80°C (-112°F) 
until further analysis (analytes and miRNA profiling). 
8.7.1.4 Safety Assessments 
8.7.1.4.1 Adverse Event Definitions and Reporting 
8.7.1.4.1.1 Definitions 
International Conference on Harmonization (ICH) and European guidance will be followed 
for AE reporting. 
Adverse Event 
An AE is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or noninvestigational) product. An AE does not necessarily have a 
causal relationship with the treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or noninvestigational) product, whether or not 
related to that medicinal (investigational or noninvestigational) product. 
This includes any occurrence that is new in onset or aggravated in intensity or frequency 
from the baseline condition (signing the ICF) or abnormal results of diagnostic procedures, 
including laboratory test abnormalities. 
Serious Adverse Event 
A SAE is any untoward medical occurrence that at any dose meets any of the following 
conditions: 
• 
results in death. 
• 
is life-threatening: the subject is at risk of death at the time of the event. It does not 
refer to an event that hypothetically might cause death if it were more severe. 
• 
requires inpatient hospitalization or prolongation of existing hospitalization. 
• 
results in persistent or significant disability or incapacity. 
• 
is a congenital anomaly or birth defect. 
• 
is a medically significant event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the subject or may require intervention 
to prevent one of the other outcomes listed in the definitions above. 

 
 
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Unexpected Adverse Event/Reference Safety Information 
An AE is considered unexpected if the nature or intensity is not consistent with the 
applicable product reference safety information. For an investigational product, the 
expectedness of an AE will be determined by whether or not it is listed in the IB. For a non-
sponsor investigational medicinal product (e.g., a comparator product) with a marketing 
authorization, the expectedness of an adverse event will be determined by whether or not it 
is listed in the manufacturer’s prescribing information. 
Intensity of an Adverse Event 
Each AE must be rated on a 3-point scale of increasing intensity: 
• 
Mild: Transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required. 
• 
Moderate: Mild to moderate limitation in activity; some assistance may be needed; no 
or minimal medical intervention/therapy required. 
• 
Severe: Marked limitation in activity; some assistance usually required; medical 
intervention/therapy required, hospitalization possible. 
If there is a change in intensity of an ongoing AE, it must be recorded as a separate event. 
Causality Assessment 
The following decision choice will be used by the investigator to describe the causality 
assessment between the reported event and the investigational medicinal product.  
• 
Unrelated: No relationship between the AE and the administration of investigational 
product; related to other etiologies such as concomitant medications or subject’s 
clinical state. 
• 
Unlikely: Event or laboratory test abnormality with a time to study medication intake 
that makes a relationship improbable (but not impossible). Disease or other drugs 
provide plausible explanations. 
• 
Possible: Event or laboratory test abnormality with reasonable time relationship to 
study medication intake that could also be explained by disease or other drugs. 
Information on drug withdrawal may be lacking or unclear. 
• 
Probable: Event or laboratory test abnormality, with reasonable time relationship to 
study medication intake. Event unlikely to be attributed to disease or other drugs. 
Response to withdrawal is clinically reasonable and rechallenge not required. 
• 
Certain: Event or laboratory test abnormality, with plausible time relationship to study 
medication intake which cannot be explained by 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 
necessary. 
Action Taken Regarding Investigational Product 
The action taken must be described by choosing among: 
• 
Dose not changed: No action is taken regarding the study medication. 

 
 
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subjects who have participated in it, will be reported by the sponsor/
 as soon 
as possible to the competent authority(ies) concerned together with proposed actions. 
8.7.1.4.2 Clinical Laboratory Evaluation 
The hematology and clinical chemistry laboratory analyses will be performed at a central 
laboratory (
). Reference ranges will be supplied by the central laboratory 
and used by the investigator to assess the laboratory data for clinical significance and 
pathological changes. 
The total amount of blood to be taken during the study will not exceed 600 mL. 
The following laboratory safety tests will be performed at every visit: 
Hematology 
Hemoglobin, hematocrit, WBC count (total and differential), RBC count, differential 
lymphocyte count (by flow cytometry: CD3, CD19, CD4, CD8, CD3-/CD16+, and CD56+), 
platelet count, activated partial thromboplastin time, and prothrombin time. 
Clinical Chemistry 
Creatinine, blood urea nitrogen (BUN), AST, ALT, gamma glutamyltransferase (GGT), 
alkaline phosphatase, total bilirubin, amylase, lipase, albumin, total protein, sodium, 
potassium, chloride, glucose, uric acid, total cholesterol, HDL and LDL, triglycerides, 
calcium, phosphorus, and CRP. 
Serum pregnancy test for females of childbearing potential at Screening and Week 24 
only/EDV only. 
Hormone tests (for male subjects only) 
Testosterone (total and free), LH, FSH, prolactin, and inhibin B. 
Urinalysis 
pH, glucose, ketone bodies, indicators of blood and WBC, and protein (quantitative). 
Urine pregnancy test for females of childbearing potential at all visits, excluding Screening 
and Week 24/EDV. 
8.7.1.4.3 Other Laboratory Variables 
Serology 
Hepatitis B and C, HIV 1 and 2, RF and anti-CCP at Screening only. 
Other 
TB (QuantiFERON-TB Gold) test at Screening only. 

 
 
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8.7.1.4.4 Vital Signs 
Vital signs (blood pressure, HR and oral temperature) will be recorded as described in the 
schedule of observations in a standardized manner, i.e. after the subject has rested in the 
sitting position for 5 minutes.  
8.7.1.4.5 Physical Examination 
A physical examination will be performed at times as described in the schedule of 
observations. Any changes from the Baseline assessment will be recorded. Height and 
weight will be measured at Screening only. 
8.7.1.4.6 Other Safety Assessments  
12-lead ECG 
A resting 12-lead ECG will be performed at times presented in the schedule of observations. 
Subjects should rest for at least 5 minutes in the supine position before ECG evaluation. 
Parameters to be recorded in the eCRF include: HR, RR, QRS, uncorrected QT, 
morphology, and rhythm analysis. QTcF will be derived during the statistical analysis. ECGs 
will be interpreted by the investigator for clinical significance and results will be entered into 
the eCRF. 
Chest X-ray 
A chest X-ray (both anterior-posterior and lateral views) will be taken during the Screening 
period and reviewed by a qualified radiologist. If chest radiographs have been taken within 
12 weeks of the Screening visit (documented evidence is needed) then the chest 
radiographs do not need to be repeated (as long as they demonstrate no clinically significant 
abnormality, and no signs or symptoms suggestive of lung disease including current active 
or latent TB, which would exclude the subject from the study). The results must be entered 
into the eCRF. 
 

 
 
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8.7.1.5 Flow Chart 
Event 
Screening Baseline1 
Treatment period2 
FU visit3 
Study days (D) 
/weeks (W) 
D-29 to 
D-2 
D -1 
D8/ 
W1 
D15/ 
W2 
D29/ 
W4 
D57/ 
W8 
D85/ 
W12 
D113/ 
W16 
D141/ 
W20 
D169/ 
W24 
EDV4 
W24 or 
EDV +  
7-10 
days 
Informed 
consent 
Written informed consent will be obtained before any study-related procedures and/or assessments 
are performed. 
Inclusion/ 
exclusion criteria 
X 
X5 
 
 
 
 
 
 
 
 
 
 
Demographic 
data and 
baseline disease 
characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history/ 
concomitant 
illnesses 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
X6 
X 
 
 
 
 
X 
 
 
X 
X 
X 
Serology7 
X 
 
 
 
 
 
 
 
 
 
 
 
TB test and 
chest X-ray8 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
Vital signs10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical 
laboratory tests11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK 
blood 
samples12 
 
 
 
 
X 
 
X 
 
 
X 
X 
 
PD 
blood 
samples13 
 
X 
X 
 
X 
 
X 
 
 
X 
X 
 
 
1 Subjects will begin to take their treatment on the next morning (Day 1) following randomization. 
2 During the treatment period, a visit time window of ± 2 calendar days is allowed. 
3 Follow-up visit will be performed only for subjects discontinuing prematurely from the study and for subjects not 
entering the Long Term Follow-up study GLPG0634-CL-205. 
4 Early discontinuation visit. 
5 Eligibility criteria check based on the laboratory results from the Screening visit. 
6 At Screening, includes height and weight. 
7 Includes Hepatitis B and C, HIV 1 and 2, RF, and anti-CCP. 
8 X-ray should be performed if results from an X-ray performed in the previous 3 months are not available at the site. 
9 For female subjects only. To be performed on serum at Screening and Week 24/EDV and on urine for other visits. 
10 Vital signs are defined as blood pressure (systolic and diastolic), HR, and oral temperature. 
11 Refer to Section 8.7.1.4.2. 
12 PK samples: 1 blood sample (2 mL) for analysis of GLPG0634 and its main metabolite (G254445) in plasma. 
13 PD samples: 4 blood samples (2x4 mL for serum preparation and 2x2.5 mL in PAXgene tubes) will be collected for 
analysis of serum (analytes and miRNA profiling) and whole blood (gene expression in circulating leukocytes, mRNA 
and miRNA profiling). 

 
 
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Event 
Screening Baseline14 
Treatment period15 
FU 
visit16 
Study days (D) 
/weeks (W) 
D-29 to 
D-2 
D -1 
D8/ 
W1 
D15/ 
W2 
D29/ 
W4 
D57/ 
W8 
D85/ 
W12 
D113/ 
W16 
D141/ 
W20 
D169/ 
W24 
EDV17 W24 or 
EDV +  
7-10 
days 
Randomization 
 
X18 
 
 
 
 
X19 
 
 
 
 
 
IXRS call 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense study 
medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Subject diary 
card 
dispensation20 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Subject diary 
card collection 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Drug 
accountability 
check 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study medication 
dosing 
 
 
 
 
 
 
 
 
 
 
 
 
Serum CRP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
SJC66 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
TJC68 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physician’s 
Global 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient’s Global 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HAQ-DI 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
FACIT fatigue 
scale 
 
X 
 
 
X 
 
X 
 
 
X 
X 
 
SF-36 
questionnaire 
 
X 
 
 
X 
 
X 
 
 
X 
X 
 
AE assessment 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
 
 
 
 
 
 
 
 
 
 
 
 
14 Subjects will begin to take their treatment on the next morning (Day 1) following randomization. 
15 During the treatment period, a visit time window of ± 2 calendar days is allowed. 
16 Follow-up visit will be performed only for subjects discontinuing prematurely from the study and for subjects not 
entering the Long Term Follow-up study GLPG0634-CL-205. 
17 Early discontinuation visit. 
18 Upon qualification for the study. 
19 At Week 12, subjects on placebo who have not achieved a 20% improvement in SJC66 and TJC68 will be re 
randomized (automatically via IXRS) to treatment to receive GLPG0634 100 mg q.d. or 50 mg b.i.d. doses in a 
blinded fashion, subjects on 50 mg q.d. who have not achieved a 20% improvement in SJC66 and TJC68 will be 
assigned to 100 mg q.d. and subjects on 25 mg b.i.d. who have not achieved a 20% improvement in SJC66 and 
TJC68 will be assigned to 50 mg b.i.d. All will continue in the study until Week 24. Subjects in the other groups will 
maintain their randomized treatment until Week 24. 
20 Subject diary card will be dispensed to subjects on D -1 and at every following visit; subjects should be instructed to 
bring their diary card along with them to all visits. 
 

 
 
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8.7.2 Appropriateness of Measurements 
The efficacy and safety assessments are widely used and generally recognized as reliable, 
accurate, and relevant to the disease condition. 
8.8 
Statistical Methods 
8.8.1 Statistical and Analytical Plans 
A detailed statistical analysis plan will be created and finalized prior to the interim database 
lock and final database lock. 
8.8.1.1 Datasets or Populations Analyzed 
All randomized subjects who received at least one dose of study medication and have at 
least one post-Baseline efficacy assessment will be included in the efficacy analysis (intent-
to-treat [ITT]). 
A secondary per-protocol analysis will be performed to confirm the ITT analysis, excluding 
subjects with major protocol deviations (such as Baseline CRP within normal range, 
Baseline TJC68 <8, Baseline SJC66 <6, <80% study medication compliance, or use of 
forbidden concomitant medications). Full details of the major protocol deviations will be 
described in the statistical analysis plan, with adherence to analysis sets agreed upon prior 
to database lock and unblinding. 
All randomized subjects who received at least one dose of study medication will be included 
in the safety analysis. 
All randomized subjects who received at least one dose of GLPG0634 and who have at least 
one PK measurement will be included in the PK analysis. 
Reasons for study termination will be tabulated. 
8.8.1.2 Demographic and Other Baseline Characteristics 
Demographic characteristics will be listed. Demographic characteristics will be summarized 
using appropriate descriptive statistics, as applicable. Details of the summaries to be 
produced will be included in the statistical analysis plan. 
8.8.1.3 Efficacy Variables 
Definition of Primary Efficacy Endpoint - ACR20 at Week 12 
The primary endpoint is the percentage of subjects achieving an ACR20 response at Week 
12. Other time points will be regarded as secondary endpoints. 
The ACR response is a measurement of improvement in multiple disease assessment 
criteria. The ACR20 response is defined as: 
≥20% improvement from Baseline in SJC66 (66 joints) and TJC68 (68 joints) 
AND 

 
 
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≥20% improvement from Baseline in at least 3 of the following 5 assessments 
• 
Pain (VAS) in cm (from HAQ-DI). 
• 
Patient’s Global Assessment of Disease Activity (VAS) in cm. 
• 
Physician’s Global Assessment of Disease Activity (VAS) in cm. 
• 
Patient’s Assessment of Physical Function as measured by HAQ-DI. 
• 
CRP in mg/dL or mg/L. 
Definition of Secondary Efficacy Endpoints 
ACR50 and ACR70 
ACR50 and ACR70 are similarly defined as ACR20, except the improvement threshold from 
Baseline is 50% and 70%, respectively.  
ACR-N 
The ACR-N7 is the smallest percentage improvement in swollen and tender joints and the 
median of the remaining 5 core parameters, and is expected to be more sensitive to change 
than the ACR20, ACR50 or ACR70. 
ACR-N = MIN [%improvement in TJC68,  
%improvement in SJC66,  
MED %improvement in (patient’s global assessment, physician’s 
global assessment, patient’s assessment of pain, HAQ-DI, CRP)] 
ACR/EULAR Remission 
A subject’s disease activity status can be defined as being in remission: 
when scores on the TJC28, SJC28, CRP (actual value in mg/dL) and Patient Global 
Assessment of Disease Activity (cm) are all ≤1. 
Simplified Disease Activity Index (SDAI) 
The SDAI8 is the numerical sum of 5 outcome parameters: TJC28, SJC28, Patient Global 
Assessment of Disease Activity (in cm), Physician’s Global Assessment of Disease Activity 
(in cm), and CRP (mg/dL). 
SDAI = TJC28 + SJC28 + Patient’s Global Assessment of Disease Activity (VAS in cm) + 
Physician’s Global Assessment of Disease Activity (VAS in cm) + CRP (mg/dL) 
The SDAI can be categorized: 
• 
High disease activity: SDAI >26 
• 
Moderate disease activity: [11,26] 
• 
Low disease activity: [3.3,11] 
• 
Remission: ≤3.3  
Clinical Disease Activity Index (CDAI) 
The CDAI9 is the SDAI modified to exclude CRP. 

 
 
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CDAI = TJC28 + SJC28 + Patient’s Global Assessment of Disease Activity (VAS in cm) + 
Physician’s Global Assessment of Disease Activity (VAS in cm) 
The CDAI can also be categorized: 
• 
High disease activity: >22 
• 
Moderate disease activity: [10,22] 
• 
Mild disease activity: [2.8,10] 
• 
Remission: ≤2.8 
Disease Activity Score 28 Joints Corrected for CRP (DAS28[CRP]) 
The DAS28(CRP)10 is a statistically derived index combining tender joints (28 joints), swollen 
joints (28 joints), CRP and Patient’s Global Assessment of Disease Activity (general health, 
GH). DAS28(CRP) is defined as follows: 
DAS28(CRP) = 0.56 x SQRT(TJC28) + 0.28 x SQRT(SJC28) + 0.36 x Ln(CRP+1) + 0.014 x 
GH + 0.96, 
Where: 
TJC28 is 28 joint count for tenderness 
SJC28 is 28 joint count for swelling.  
Ln(CRP1+1) is the natural logarithm of (CRP value [mg/L] + 1) 
SQRT is square root 
GH is the Patient’s Global Assessment of Disease Activity on a 100 mm VAS  
 
Categorization of the DAS28(CRP) scores: 
High disease activitiy: >5.1 
Moderate disease activity: [3.2,5.1] 
Low disease activity: [2.6,3.2] 
Remission: <2.6 
EULAR Response 
A second categorization of the DAS28(CRP) will be done according to the following table11: 
Actual 
DAS28(CRP) 
Improvement in DAS28(CRP) from Baseline: 
> 1.2 
> 0.6, ≤ 1.2] 
≤ 0.6 
≤ 3.2 
Good 
Moderate 
None 
> 3.2, ≤ 5.1] 
Moderate 
Moderate 
None 
> 5.1 
Moderate 
None 
None 
 

 
 
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Quality of Life - FACIT Fatigue Scale and SF-36 
Quality of life will be assessed using the FACIT fatigue scale and the SF-36 questionnaire. 
The appropriate (sub)totals will be derived according to the scale’s scoring algorithm. 
Methods of Analysis 
Efficacy data (ACR20, ACR50, ACR70, ACR-N, DAS28(CRP), EULAR response, and 
ACR/EULAR remission, and components of the ACR, CDAI and SDAI at each post-dosing 
visit) will be analyzed descriptively.  
Between-group comparisons will be done for each dose group versus the placebo group. 
Hommel’s closed-testing correction procedure (as implemented in SAS PROC MULTTEST) 
will be applied to adjust for multiplicity.  
This study is not powered for any formal comparison among the dose groups, nor for 
comparisons between q.d. and b.i.d. regimens. However, differences between q.d. and b.i.d. 
regimens will be calculated and presented with a 95% confidence interval.  Differences 
between q.d. and b.i.d. regimens will also be tested exploratively via a model containing the 
total daily dose (50/100/200 mg) as well as the regimen (q.d./b.i.d.). Differences among the 
q.d. groups and among the b.i.d. groups will be described in the same way. No adjustment 
for multiplicity will be done for these exploratory differences. 
Nonresponding subjects from the placebo and lowest dose groups who are re-randomized at 
Week 12 will be handled as follows:  
• 
Their Week 12 value will be carried forward in the original treatment group to all 
further time points (and between-group comparisons) after Week 12.  
• 
Their actual assessments on Weeks 16, 20 and 24 will be analyzed descriptively as 
these represent their response after 12 weeks of GLPG0634 exposure after first 
having failed on placebo or a low dose. 
Analysis methods per post-Baseline time point: 
• 
Binary parameters: logistic regression model with factors treatment, region and 
previous use of biologics. 
• 
Continuous parameters: changes from Baseline and percent changes from Baseline: 
using an analysis of (co)variance model with factors treatment, baseline value, region 
and previous use of biologics. 
• 
Time to response (ACR20/50/70) will be analyzed using Kaplan-Meier survival 
techniques, and groups will be compared against placebo using a Cox proportional 
hazards regression model with factors treatment, region and previous use of 
biologics.  
Other applicable factors, if any, will also be included in the models. Quality of Life data 
(FACIT fatigue scale and SF-36 questionnaire) will be analyzed descriptively. Exploratory 
between-group comparisons will also be done at each post-Baseline time point using 
analysis of (co)variance models on the changes from Baseline with factors treatment, 
Baseline value, region and previous use of biologics.  
Handling of discontinued subjects during the 24-week treatment period: 

 
 
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• 
Subjects who discontinue within the first week so that ACR20/50/70 responses 
cannot be determined will be classified as nonresponders. 
• 
For all discontinued subjects, their last observed nonmissing result will be used in the 
subsequent visits (last observation carried forward algorithm). Also for the 
ACR20/50/70 responses as part of the secondary/supportive analyses. 
A descriptive sensitivity analysis by country, geographic region and previous use of biologics 
will be performed for the ACR criteria response rates. 
Further exploratory analyses may be added when deemed useful to understand the data. 
Graphical presentations may be added to facilitate the overall interpretation of the study 
results. 
8.8.1.4 Safety Variables 
Clinical safety will be evaluated by assessing treatment-emergent AEs, physical 
examinations, laboratory assessments, ECG, and vital signs results in a descriptive manner. 
Original results and changes from Baseline or from Screening, for the ECG, will be 
summarized for the laboratory data, vital signs, and ECG values. Values will be categorized 
as low/normal/high according to normal ranges, and shift tables versus baseline will be 
created to determine treatment-emergent abnormalities.  
8.8.1.5 Interim Analyses 
A fully unblinded interim analysis will be performed when all subjects have reached Week 
12. The statistical analysis of the unblinded data will be handled by a statistician who is 
independent from the regular study team. The lead statistician and corresponding biometrics 
team will remain blinded and will not be involved in the interim analyses in order to preserve 
blinding when assessing the final results at Week 24. 
This interim analysis output will comprise summary tables and plots, but no listings. These 
summary results will be viewed by the sponsor, but no individual subject data (such as 
listings or datasets) will be exchanged. The analysis will summarize demographics, reason 
for early discontinuation from the study, efficacy (i.e., ACR20, ACR50, ACR70, ACR-N, 
DAS28[CRP] with low disease activity, CDAI/SDAI with low disease activity, CRP, and HAQ-
DI) and safety (i.e., AE, SAE, and selected laboratory tests).  
The interim analysis is intended to support preliminary dose-selection for the GLPG0634 
phase III program. Because this efficacy analysis matches the full Week 12 primary analysis, 
there is no inflation of the type-I error rate, and therefore no statistical correction is applied. 

 
 
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8.9 
Quality Assurance and Quality Control  
8.9.1 Audit and Inspection 
Study centers and study documentation may be subject to Quality Assurance audit during 
the course of the study by 
, the sponsor or its nominated representative. In 
addition, inspections may be conducted by regulatory authorities at their discretion. 
8.9.2 Monitoring 
Data for each subject will be recorded on an eCRF. Data collection must be completed for 
each subject who signs an ICF. 
In accordance with cGCP and ICH guidelines, the study monitor will carry out source 
document verification at regular intervals to ensure that the data collected in the eCRF are 
accurate and reliable. The frequency of monitoring visits will be determined by the rate of 
subject recruitment.  
The following will be reviewed at these visits: 
• Compliance with the protocol. 
• Consent procedure. 
• Source documents. 
• AE procedures. 
• Storage and accountability of materials. 
The monitoring visits also provide the sponsor with the opportunity to ensure the 
investigator’s obligations and all applicable ICH or health authority regulation requirements 
are being fulfilled. 
The investigator must permit the monitor, the IEC/IRB, the sponsor’s internal auditors and 
representatives from regulatory authorities direct access to all study-related documents and 
pertinent hospital or medical records for confirmation of data contained within the eCRFs. 
Subject confidentiality will be protected at all times. 
8.9.3 Data Management and Coding 
 will be responsible for activities associated with the data management of this 
study. This will include setting up a relevant database and data transfer mechanisms, along 
with appropriate validation of data and resolution of queries. Data generated within this 
clinical study will be handled according to the relevant standard operating procedures 
(SOPs) of the data management and biostatistics departments of 
 
Study centers will enter data directly into the electronic data capture (EDC) system by 
completing the eCRF via a secure internet connection. Data entered into the eCRF must be 
verifiable against source documents at the study center. Data to be recorded directly on the 
eCRF (without prior written or electronic record) will be identified and the eCRF will be 
considered the source document. Any changes to the data entered into the EDC system will 
be recorded in the audit trail and will be FDA Code of Federal Regulations (CFR) 21 Part 11 
compliant. 

 
 
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Data entered into the eCRF will be validated as defined in the data validation plan. External 
data checks will be programmed where appropriate (e.g., for laboratory data, ECGs) as well 
as for cross table checking between eCRFs (e.g., AE and concomitant medication forms).  
Medical coding will use the Medical Dictionary for Regulatory Activities for concomitant 
diseases and AEs and World Health Organization Drug for medications. 
Missing or inconsistent data will be queried in writing to the investigator for clarification. 
Subsequent modifications to the database will be documented. 

 
 
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9 Records and Supplies 
9.1 
Drug Accountability 
On receipt of the study medication, the investigator (or deputy) will conduct an inventory of 
the supplies and verify that study medication supplies are received intact and in the correct 
amounts before completing a supplies receipt. The investigator will retain a copy of this 
receipt at the study center and return the original receipt to the study monitor. The inventory 
of supplies at each study center may be checked at any time during the study by the 
monitor. 
It is the responsibility of the study monitor to ensure that the investigator (or deputy) has 
correctly documented the amount received, dispensed and returned of the study medication 
on the dispensing log that will be provided. A full drug accountability log will be maintained at 
the study center at all times. The study monitor will arrange collection/destruction of unused 
study medication returned by the subject. The study monitor will also perform an inventory of 
study medication at the close-out visit to the study center. All discrepancies must be 
accounted for and documented. 
9.2 
Financing and Insurance 
Financing and insurance of this study will be outlined in a separate agreement between 
 
and the sponsor. 

 
 
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10 Ethics 
10.1 Independent Ethics Committee or Institutional Review Board 
Before initiation of the study at each study center, the protocol, the ICF, other written 
material given to the subjects, and any other relevant study documentation will be submitted 
to the appropriate IEC/IRB. Written approval of the study and all relevant study information 
must be obtained before the study center can be initiated or the study medication is released 
to the investigator. Any necessary extensions or renewals of IEC/IRB approval must be 
obtained for changes to the study such as modification of the protocol, the ICF or other study 
documentation. The written approval of the IEC/IRB together with the approved ICF must be 
filed in the study files. 
The investigator will report promptly to the IEC/IRB any new information that may adversely 
affect the safety of the subjects or the conduct of the study. The investigator will submit 
written summaries of the study status to the IEC/IRB as required. On completion of the 
study, the IEC/IRB will be notified that the study has ended. 
10.2 Regulatory Authorities 
The protocol, name, and study center of the investigators, the votes of the IEC(s)/IRB(s), as 
well as other relevant study documentation will be submitted to the Regulatory Authorities of 
the participating countries, according to local/national requirements, for review and approval 
before the beginning of the study. On completion of the study, the Regulatory Authorities will 
be notified that the study has ended. 
10.3 Ethical Conduct of the Study 
The investigator(s) and all parties involved in this study should conduct the study in 
adherence to the ethical principles based on the Declaration of Helsinki, GCP, ICH 
guidelines, and the applicable national and local laws and regulatory requirements. 
10.4 Informed Consent 
The process of obtaining informed consent must be in accordance with applicable regulatory 
requirement(s), and must adhere to GCP.  
The investigator is responsible for ensuring that no subject undergoes any study related 
examination or activity before that subject has given written informed consent to participate 
in the study.  
The investigator or designated personnel will inform the subject of the objectives, methods, 
anticipated benefits and potential risks and inconveniences of the study. The subject should 
be given every opportunity to ask for clarification of any points he does not understand and, 
if necessary, ask for more information. At the end of the interview, the subject will be given 
ample time to consider the study. Subjects will be required to sign and date the ICF. After 
signatures are obtained, the ICF will be kept and archived by the investigator in the 
investigator’s study file. A signed and dated copy of the subject ICF will be provided to the 
subject or their authorized representative. 
It should be emphasized to the subject that he or she is at liberty to refuse to enter the study 
or to withdraw from the study at any time, without consequences for their further care or 

 
 
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penalty or loss of benefits to which the subject is otherwise entitled. Subjects who refuse to 
give or who withdraw written informed consent should not be included or continue in the 
study. 
If new information becomes available that may be relevant to the subject’s willingness to 
continue participation in the study, a new ICF will be approved by the IEC(s)/IRB(s) (and 
Regulatory Authorities if required). The study subjects will be informed about this new 
information and re consent will be obtained. 
10.5 Subject Confidentiality 
Monitors, auditors, and other authorized agents of the sponsor and/or its designee, the 
IEC(s)/IRB(s) approving this research, and the United States FDA, as well as that of any 
other applicable agency(ies) in other countries, will be granted direct access to the study 
subjects’ original medical records for verification of clinical study procedures and/or data, 
without violating the confidentiality of the subjects to the extent permitted by the law and 
regulations. In any presentations of the results of this study or in publications, the subjects’ 
identity will remain confidential. 
 

 
 
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11 Reporting and Publication, Including Archiving 
The name of the coordinating investigator will be documented separately. During the study, 
the sponsor will contact some of the participating investigators and assess their interest in 
taking up the role of the coordinating investigator. Once selected the coordinating 
investigator will help review and sign-off the final clinical study report. 
Essential documents are those documents that individually and collectively permit evaluation 
of the study and quality of the data produced. After completion of the study, all documents 
and data relating to the study will be kept in an orderly manner by the investigator in a 
secure study file. This file will be available for inspection by the sponsor or its 
representatives. Essential documents should be retained for 2 years after the final marketing 
approval in an ICH region or for at least 2 years since the discontinuation of clinical 
development of the test drug/investigational product or according to local regulation if they 
state otherwise. It is the responsibility of the sponsor to inform the study center of when 
these documents no longer need to be retained. The investigator must contact the sponsor 
before destroying any study related documentation. In addition, all subject medical records 
and other source documentation will be kept for the maximum time permitted by the hospital, 
institution, or medical practice. 
The sponsor must review and approve any results of the study or abstracts for professional 
meetings prepared by the investigator(s). Published data must not compromise the 
objectives of the study. Data from individual study centers in multicenter studies must not be 
published separately. 

 
 
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12 References 
 
Smolen JS, Steiner G, Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug 
1.
Discov. 2003;2:473-488. 
 
Smolen JS et al., New therapies for treatment of rheumatoid arthritis. Lancet. 
2.
2007;370:1861-1874. 
 
Firestein GS, Evolving concepts of rheumatoid arthritis. Nature. 2003;15;423:356 361. 
3.
 
EMEA website: http://www.emea.europa.eu/htms/human/epar/a.htm. 
4.
 
Nature Biotechnology, 2011, Volume 29, 467-468. 
5.
 
Investigator Brochure of GLPG0634. Version 7, 21 Feb 2014 
6.
 
Jeffrey N. Siegel, Bo-Guang Zhen, Arthritis & Rheumatism. 2005 Jun. 52; 6:1637–
7.
1641. 
 
American 
College 
of 
Rheumatology/European 
League 
Against 
Rheumatism 
8.
Provisional Definition of Remission in Rheumatoid Arthritis for Clinical Trials David T. 
Felson, Josef S. Smolen, George Wells, et al. Arthritis & Rheumatism. 2011 Mar. 63; 
3:573–586. 
 
The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index 
9.
(CDAI): A review of their usefulness and validity in rheumatoid arthritis D. Aletaha, J. 
Smolen. Clin Exp Rheumatol. 2005; 23 (Suppl. 39):S100-S108. 
 
Modified disease activity scores that include twenty-eight-joint counts. Development 
10.
and validation in a prospective longitudinal study of patients with rheumatoid arthritis. 
Prevoo ML, van 't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. 
Arthritis Rheum. 1995 Jan;38(1):44-8. 
 
The Disease Activity Score and the EULAR response criteria. J. Fransen, P.L.C.M. 
11.
van Riel. Clin Exp Rheumatol 2005; 23 (Suppl. 39):S93-S99. 

 
 
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13 Appendices 

 
 
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13.1 Investigator Signature Page 
Protocol Title: 
Randomized, 
double-blind, 
placebo-controlled, 
multicenter, 
phase IIb dose finding study of GLPG0634 administered for 24 
weeks in combination with methotrexate to subjects with 
moderately to severely active rheumatoid arthritis who have an 
inadequate response to methotrexate alone 
Protocol Number: 
GLPG0634-CL-203 
Confidentiality and GCP Compliance Statement 
I, the undersigned, have reviewed this protocol, including appendices, and I will conduct the 
study as described in compliance with this protocol, GCP, and relevant ICH guidelines. 
Once the protocol has been approved by the IEC/IRB, I will not modify this protocol without 
obtaining prior approval of Galapagos NV and of the IEC/IRB. I will submit the protocol 
modifications and/or any ICF modifications to Galapagos NV and IEC/IRB, and approval will 
be obtained before any modifications are implemented. 
I understand that all information obtained during the conduct of the study with regard to the 
subjects’ state of health will be regarded as confidential. No subjects’ names will be 
disclosed. All subjects will be identified by assigned numbers on all eCRFs, laboratory 
samples or source documents forwarded to the sponsor. Clinical information may be 
reviewed by the sponsor or its agents or regulatory agencies. Agreement must be obtained 
from the subject before disclosure of subject information to a third party. 
Information developed in this clinical study may be disclosed by Galapagos NV to other 
clinical investigators, regulatory agencies, or other health authority or government agencies 
as required. 
Investigator Signature 
Date 
Printed Name 
Institution 
 
 
 

 
 
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13.2 66/68 Joint Count 
Joints Assessed (left and right) 
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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Galapagos NV 
 
27 May 2014
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Protocol Amendment 5 – US Version 1 Final 
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13.3 Patient’s Global Assessment of Disease Activity Questionnaire 
Instructions: 
 
Considering all the ways arthritis affects you, how well are you doing today?  Please indicate 
by making a vertical line (I) through the line below. 
 
 
 
 
Very Well  
 
 
 
Very Poor 
 
Note: The VAS Scale must be 100 mm long. 

 
 
CONFIDENTIAL 
Galapagos NV 
 
27 May 2014
GLPG0634-CL-203 
Protocol Amendment 5 – US Version 1 Final 
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13.4 Physician’s Global Assessment of Disease Activity Questionnaire 
Instructions: 
Please indicate your assessment of the subject’s overall disease activity by marking a 
vertical line (I) through the line below. 
 
 
 
 
No Disease Activity  
 
 
Extreme Disease Activity 
 
Note: The VAS Scale must be 100 mm long. 

 
 
CONFIDENTIAL 
Galapagos NV 
 
27 May 2014
GLPG0634-CL-203 
Protocol Amendment 5 – US Version 1 Final 
Page 79 of 88
13.5 Health Assessment Questionnaire - Disability Index (HAQ-DI) 
 
 

 
 
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13.6 FACIT Fatigue Scale 
 
 

 
 
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Galapagos NV 
 
27 May 2014
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Protocol Amendment 5 – US Version 1 Final 
Page 82 of 88
13.7 36-Item Short-Form Health Survey (SF-36) 

 
 
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27 May 2014
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Protocol Amendment 5 – US Version 1 Final 
Page 88 of 88