Conditions: Rheumatoid Arthritis
Keywords: Methotrexate inadequate responders
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 599
Healthy volunteers: no

Brief summary:
Participants suffering from active rheumatoid arthritis despite continued treatment with methotrexate were evaluated for improvement of disease activity (efficacy) when taking GLPG0634 (3 different doses - 50 milligram \[mg\], 100 mg and 200 mg daily -, each evaluated as once daily \[QD\] and twice daily \[BID\] regimen) or matching placebo for 24 weeks.

•During the course of the study, patients were also examined for any side effects that could occur (safety and tolerability), and the amount of GLPG0634 present in the blood (Pharmacokinetics) as well as the effects of GLPG0634 on disease- and mechanism of action-related parameters in the blood (Pharmacodynamics) were determined. Also, the effects of different doses and dose regiments of GLPG0634 administration on participants' disability, fatigue, and quality of life were evaluated.

Detailed description:
* Treatment duration was 24 weeks in total.
* However, at Week 12, participants on placebo who did not achieve a 20% improvement in swollen joint count(SJC66) and tender joint count (TJC68) were re-randomized (automatically via interactive voice/web response \[IXRS\]) to treatment to receive GLPG0634 100 mg QD or 50 mg BID doses in a blinded fashion, participants on 50 mg QD who had not achieved a 20% improvement in SJC66 and TJC68 were assigned to 100 mg QD and participants on 25 mg BID. who did not achieve a 20% improvement in SJC66 and TJC68 were assigned to 50 mg BID. All continued the study until Week 24.
* Participants in the other groups maintained their randomized treatment until Week 24.

Arms:
arm 1: Participants received GLPG0634 matching placebo capsules, orally, twice daily (BID) during Weeks 1 to 12. Participants who were responders (having at least 20 percent \[%\] improvement on TJC68 and SJC66) remained on placebo while nonresponders were re-randomized to GLPG0634 100 milligram (mg) once daily (QD) or 50 mg BID during Weeks 13 to 24. arm 2: Participants received GLPG0634 50 mg capsules, orally, QD during Weeks 1 to 12. Participants who were responders (having at least 20% improvement on TJC68 and SJC66) remained on 50 mg QD while nonresponders were re-randomized to 100 mg QD during Weeks 13 to 24. arm 3: Participants received GLPG0634 100 mg capsules, orally, QD during Weeks 1 to 24. arm 4: Participants received GLPG0634 200 mg capsules, orally, QD during Weeks 1 to 24. arm 5: Participants received GLPG0634 25 mg capsules, orally, BID during Weeks 1 to 12. Participants who were responders (having at least 20% improvement on TJC68 and SJC66) remained on 25 mg BID while nonresponders were re-randomized to 50 mg BID during Weeks 13 to 24. arm 6: Participants received GLPG0634 50 mg capsules, orally, BID during Weeks 1 to 24. arm 7: Participants received GLPG0634 100 mg capsules, orally, BID during Weeks 1 to 24.

Interventions: intervention 1: GLPG0634 intervention 2: Placebo
Intervention descriptions: intervention 1: GLPG0634 capsules. intervention 2: Placebo capsules.

Protocol document:
Prot_000.pdf: 
 
 
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. 












 
 
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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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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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27 May 2014
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Protocol Amendment 5 – US Version 1 Final 
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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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Protocol Amendment 5 – US Version 1 Final 
Page 64 of 88
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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Page 65 of 88
• 
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 
 
 
 


 
 
CONFIDENTIAL 
Galapagos NV 
 
27 May 2014
GLPG0634-CL-203 
Protocol Amendment 5 – US Version 1 Final 
Page 76 of 88
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 
 


 
 
CONFIDENTIAL 
Galapagos NV 
 
27 May 2014
GLPG0634-CL-203 
Protocol Amendment 5 – US Version 1 Final 
Page 77 of 88
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 
Page 78 of 88
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) 
 
 


 
 
CONFIDENTIAL 
Galapagos NV 
 
27 May 2014
GLPG0634-CL-203 
Protocol Amendment 5 – US Version 1 Final 
Page 80 of 88
 
 


 
 
CONFIDENTIAL 
Galapagos NV 
 
27 May 2014
GLPG0634-CL-203 
Protocol Amendment 5 – US Version 1 Final 
Page 81 of 88
 
13.6 FACIT Fatigue Scale 
 
 


 
 
CONFIDENTIAL 
Galapagos NV 
 
27 May 2014
GLPG0634-CL-203 
Protocol Amendment 5 – US Version 1 Final 
Page 82 of 88
13.7 36-Item Short-Form Health Survey (SF-36) 


 
 
CONFIDENTIAL 
Galapagos NV 
 
27 May 2014
GLPG0634-CL-203 
Protocol Amendment 5 – US Version 1 Final 
Page 83 of 88
 


 
 
CONFIDENTIAL 
Galapagos NV 
 
27 May 2014
GLPG0634-CL-203 
Protocol Amendment 5 – US Version 1 Final 
Page 84 of 88


 
 
CONFIDENTIAL 
Galapagos NV 
 
27 May 2014
GLPG0634-CL-203 
Protocol Amendment 5 – US Version 1 Final 
Page 85 of 88


 
 
CONFIDENTIAL 
Galapagos NV 
 
27 May 2014
GLPG0634-CL-203 
Protocol Amendment 5 – US Version 1 Final 
Page 86 of 88


 
 
CONFIDENTIAL 
Galapagos NV 
 
27 May 2014
GLPG0634-CL-203 
Protocol Amendment 5 – US Version 1 Final 
Page 87 of 88


 
 
CONFIDENTIAL 
Galapagos NV 
 
27 May 2014
GLPG0634-CL-203 
Protocol Amendment 5 – US Version 1 Final 
Page 88 of 88
 

SAP_001.pdf: 


Statistical Analysis Plan GLPG0634-CL-203 (DARWIN1)
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TABLE OF CONTENTS
List of Tables ........................................................................................................................7
List of Figures.....................................................................................................................17
List of Listings ....................................................................................................................18
1. Study Design..................................................................................................................20
1.1.
Study Objectives...................................................................................................20
1.1.1.
Primary Objective ....................................................................................20
1.1.2.
Secondary Objectives ...............................................................................20
1.2.
Study Design.........................................................................................................20
1.3.
Protocol and Protocol Amendments ......................................................................21
1.4.
Flowchart..............................................................................................................22
2. Analysis Populations and treatment groups ................................................................24
2.1.
Analysis chapters ..................................................................................................24
2.1.1.
Efficacy data ............................................................................................24
2.1.2.
Safety data................................................................................................26
2.2.
Further Analysis populations.................................................................................28
2.2.1.
All Screened Subjects Population.............................................................28
2.2.2.
All Randomized Population......................................................................28
2.3.
Handling of unblinded subjects .............................................................................28
2.3.1.
Safety population .....................................................................................28
2.3.2.
Intent to Treat Population.........................................................................28
2.3.3.
Per Protocol Population............................................................................28
2.4.
Treatment Groups .................................................................................................28
2.4.1.
Randomized versus Actual Treatment ......................................................28
2.4.2.
Totals across Groups ................................................................................29
3. Analysis Periods and Analysis Time Points .................................................................29
3.1.
Relative Number of Days......................................................................................29
3.2.
Analysis Periods for Non-visit Data ......................................................................29
3.3.
Algorithm of Allocating Visits to Time Windows .................................................30
3.4.
Selection of Visits.................................................................................................31
4. Handling of Data...........................................................................................................31
4.1.
Calculation of Descriptive Statistics......................................................................31
4.2.
Calculation of Percentages ....................................................................................32
4.3.
Handling of Values below (or above) a Threshold.................................................32
4.3.1.
Safety Data...............................................................................................32
4.3.2.
PK Data....................................................................................................32
4.3.3.
PD Data....................................................................................................32
4.4.
Handling Missing Data .........................................................................................32
4.4.1.
Handling of Missing Date (Time) or Partially Known Date (Time)...........32
4.4.2.
Handling of missing values in scales or summary parameters ...................32
4.4.3.
Handling of missing values and early dropouts in the efficacy analyses 
during the first study period (up to Week 12)............................................32
4.4.4.
Handling of missing values and early dropouts in the efficacy analyses 
during the study period as a whole (full 24 weeks) ...................................33
4.4.5.
Handling of missing values and early dropouts in the efficacy analyses 
during the second study period (after Week 12)........................................33


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4.4.6.
Handling of missing values and early dropouts in the safety analysis........34
4.5.
Handling treatment switches at Week 12 in the efficacy and safety analysis..........34
4.5.1.
In the efficacy analysis of the full study as a whole (full 24 weeks) ..........34
4.5.2.
In the safety analysis of the full study as a whole (full 24 weeks)..............34
4.5.3.
In the efficacy and safety analysis of the second study period...................34
4.6.
Handling of Outliers..............................................................................................35
4.7.
Handling of seconds in datetime fields..................................................................35
4.8.
Stratification factors..............................................................................................35
5. Software and Procedures..............................................................................................35
5.1.
Software................................................................................................................35
5.2.
Procedures ............................................................................................................35
5.3.
Formats.................................................................................................................36
6. Statistical Methods........................................................................................................36
6.1.
Planned Analyses, Protocol Amendments Included ...............................................36
6.1.1.
Demographic and other baseline characteristics........................................36
6.1.2.
Efficacy Variables....................................................................................37
6.1.3.
Safety Variables .......................................................................................41
6.1.4.
Pharmacokinetic Analyses........................................................................41
6.1.5.
Pharmacodynamic Analyses.....................................................................41
6.1.6.
Pharmacokinetic, Efficacy, Safety and Pharmacodynamic Correlations....41
6.2.
Interim Analysis....................................................................................................41
6.3.
Changes to the Planned Analyses, Not Covered by Protocol Amendments ............43
6.3.1.
Changes before Interim Database Lock ....................................................43
6.3.2.
Changes after Interim Database Lock but before Final Database Lock......43
6.3.3.
Changes after Final Database Lock...........................................................44
7. Definitions of General Tables, Listings and Figures....................................................44
7.1.
Subject Disposition ...............................................................................................44
7.2.
Protocol Deviations and Eligibility........................................................................47
7.3.
Subjects Excluded from Analysis..........................................................................47
7.4.
Demographics and Baseline Disease Characteristics..............................................48
7.4.1.
Parameters................................................................................................48
7.4.2.
Analysis ...................................................................................................48
7.5.
Baseline disease characteristics .............................................................................50
7.5.1.
Parameters................................................................................................50
7.5.2.
Analysis ...................................................................................................51
7.6.
Medical History and Concurrent Diseases .............................................................53
7.7.
Prior and Concomitant Therapies ..........................................................................53
7.7.1.
Classification of Therapies .......................................................................53
7.7.2.
Coding of Therapies.................................................................................55
7.7.3.
Analysis ...................................................................................................55
7.8.
Exposure to Study Medication and Compliance ....................................................56
7.8.1.
Derivations for placebo/GLPG0634..........................................................56
7.8.2.
Tables up to Week 12...............................................................................56
7.8.3.
Tables for the whole 24 weeks period.......................................................57
7.8.4.
Listings ....................................................................................................57
7.9.
Exposure to methotrexate and Compliance............................................................58
7.9.1.
Derivations for methotrexate ....................................................................58
7.9.2.
Tables up to Week 12...............................................................................58


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7.9.3.
Tables for the whole 24 weeks period.......................................................59
7.9.4.
Listings ....................................................................................................59
8. Definitions of Efficacy Tables, Listings and Figures ...................................................59
8.1.
ACR20, ACR50, ACR70 and ACR-N...................................................................60
8.1.1.
Parameters................................................................................................60
8.1.2.
Tables over the whole 24 weeks period ....................................................61
8.1.3.
Figures over the whole 24 weeks period ...................................................70
8.1.4.
Tables after Week 12................................................................................71
8.1.5.
Figures after Week 12 ..............................................................................72
8.1.6.
Listings ....................................................................................................73
8.2.
EULAR remission.................................................................................................73
8.2.1.
Parameters................................................................................................73
8.2.2.
Tables over the whole 24 weeks ...............................................................73
8.2.3.
Figures over the whole 24 weeks period ...................................................73
8.2.4.
Tables after Week 12................................................................................74
8.2.5.
Figures after Week 12 ..............................................................................74
8.2.6.
Listings ....................................................................................................74
8.3.
SDAI and CDAI scores.........................................................................................74
8.3.1.
Parameters................................................................................................74
8.3.2.
Tables over the whole 24 weeks period ....................................................75
8.3.3.
Figures over the whole 24 weeks period ...................................................78
8.3.4.
Tables after Week 12................................................................................78
8.3.5.
Figures after Week 12 ..............................................................................78
8.3.6.
Listings ....................................................................................................79
8.4.
DAS28(CRP)........................................................................................................79
8.4.1.
Parameters................................................................................................79
8.4.2.
Tables over the whole 24 weeks period ....................................................80
8.4.3.
Figures over the whole 24 weeks period ...................................................84
8.4.4.
Tables after Week 12................................................................................84
8.4.5.
Figures after Week 12 ..............................................................................84
8.4.6.
Listings ....................................................................................................84
8.5.
ACR component: Tender and swollen joint counts................................................85
8.5.1.
Parameters................................................................................................85
8.5.2.
Tables over the whole 24 weeks period ....................................................85
8.5.3.
Figures over the whole 24 weeks period ...................................................86
8.5.4.
Tables after Week 12................................................................................86
8.5.5.
Figures after Week 12 ..............................................................................86
8.5.6.
Listings ....................................................................................................86
8.6.
ACR component: VAS scales................................................................................87
8.6.1.
Parameters................................................................................................87
8.6.2.
Tables over the whole 24 weeks period ....................................................87
8.6.3.
Figures over the whole 24 weeks study period..........................................88
8.6.4.
Tables after Week 12................................................................................88
8.6.5.
Figures after Week 12 ..............................................................................88
8.6.6.
Listings ....................................................................................................88
8.7.
ACR component: HAQ-DI....................................................................................89
8.7.1.
Parameters................................................................................................89
8.7.2.
Tables over the whole 24 weeks period ....................................................89
8.7.3.
Figures over the whole 24 weeks period ...................................................90


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8.7.4.
Tables after Week 12................................................................................91
8.7.5.
Figures after Week 12 ..............................................................................91
8.7.6.
Listings ....................................................................................................91
8.8.
ACR component: Serum CRP ...............................................................................91
8.8.1.
Parameters................................................................................................91
8.8.2.
Tables over the whole 24 weeks period ....................................................92
8.8.3.
Figures over the whole 24 weeks period ...................................................93
8.8.4.
Tables after Week 12................................................................................93
8.8.5.
Figures after Week 12 ..............................................................................93
8.8.6.
Listings ....................................................................................................93
8.9.
Quality of life: FACIT fatigue scale ......................................................................94
8.9.1.
Parameters................................................................................................94
8.9.2.
Tables over the whole 24 weeks period ....................................................94
8.9.3.
Figures over the whole 24 weeks period ...................................................95
8.9.4.
Tables after Week 12................................................................................95
8.9.5.
Figures after Week 12 ..............................................................................95
8.9.6.
Listings ....................................................................................................95
8.10. Quality of life: SF-36 ............................................................................................96
8.10.1. Parameters................................................................................................96
8.10.2. Tables over the whole 24 weeks period ..................................................101
8.10.3. Figures over the whole 24 weeks period .................................................102
8.10.4. Tables after Week 12..............................................................................102
8.10.5. Figures after Week 12 ............................................................................102
8.10.6. Listings ..................................................................................................102
9. Definitions of Pharmacokinetics Tables, Listings and Figures..................................103
10. Definitions of Pharmacodynamics Tables, Listings and Figures...............................103
10.1. Parameters ..........................................................................................................103
10.2. Tables .................................................................................................................103
10.3. Figures................................................................................................................104
10.4. Listings...............................................................................................................105
11. Definitions of PK/PD Tables, Listings and Figures ...................................................105
12. Definitions of safety Tables, Listings and Figures .....................................................105
12.1. Adverse Events ...................................................................................................105
12.1.1. Treatment-Emergent Principle................................................................105
12.1.2. Treatment Relatedness............................................................................106
12.1.3. Worst-Case Principle..............................................................................106
12.1.4. Adverse Event Onset Day and Duration..................................................106
12.1.5. Calculation of Percentages .....................................................................107
12.1.6. Tables up to Week 12.............................................................................107
12.1.7. Tables over the whole 24 weeks period ..................................................110
12.1.8. Listings ..................................................................................................111
12.2. Laboratory Safety................................................................................................113
12.2.1. Laboratory Units ....................................................................................113
12.2.2. Derived lab tests.....................................................................................113
12.2.3. Number of Significant Digits..................................................................114
12.2.4. Baseline and Change from Baseline........................................................114
12.2.5. Scoring of Laboratory Values.................................................................114
12.2.6. Handling of Urinalysis Results ...............................................................116


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12.2.7. Last on-treatment result..........................................................................116
12.2.8. Worst-Case Abnormality........................................................................117
12.2.9. Tables up to Week 12.............................................................................118
12.2.10.Figures up to Week 12............................................................................121
12.2.11.Tables over the whole 24 weeks period ..................................................122
12.2.12.Figures over the whole 24 weeks period .................................................123
12.2.13.Listings ..................................................................................................123
12.3. ECG....................................................................................................................124
12.3.1. Available Data........................................................................................124
12.3.2. Calculated Parameters ............................................................................124
12.3.3. Baseline and Change from Baseline........................................................124
12.3.4. Visits for analysis...................................................................................124
12.3.5. Normal Ranges.......................................................................................125
12.3.6. Analysis tables at Week 12.....................................................................125
12.3.7. Analysis tables for the whole 24 weeks period........................................126
12.3.8. Figures ...................................................................................................127
12.3.9. Listings ..................................................................................................127
12.4. Vital Signs ..........................................................................................................127
12.4.1. Available Data........................................................................................127
12.4.2. Baseline and Change from Baseline........................................................127
12.4.3. Normal Ranges.......................................................................................127
12.4.4. Last on-treatment result..........................................................................128
12.4.5. Worst-Case Abnormality........................................................................128
12.4.6. Tables up to Week 12.............................................................................128
12.4.7. Tables over the whole 24 weeks period ..................................................129
12.4.8. Figures ...................................................................................................130
12.4.9. Listings ..................................................................................................130
12.5. Physical Examinations ........................................................................................130
13. References ...................................................................................................................130


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LIST OF TABLES
Table 14.1.1.1: 
Subject disposition: Tabulation by region, country and investigator.........44
Table 14.1.1.2: 
Subject disposition: Analysis populations................................................45
Table 14.1.1.3: 
Subject disposition: No-treatment subjects: Tabulation of the 
reasons ....................................................................................................45
Table 14.1.1.4: 
Subject disposition up to Week 12: Tabulation of the number of 
subject at each time interval.....................................................................45
Table 14.1.1.5: 
Subject disposition up to study end: Tabulation of the number of 
subject at each time interval.....................................................................45
Table 14.1.1.6: 
Subject disposition: First and last date in the study ..................................46
Table 14.1.1.7: 
Subject disposition up to Week 12: Tabulation of the trial 
termination reasons..................................................................................46
Table 14.1.1.8: 
Subject disposition up to study end: Tabulation of the trial 
termination reasons..................................................................................46
Table 14.1.2.1: 
Major protocol deviations........................................................................47
Table 14.1.3.1: 
Demographic data ...................................................................................48
Table 14.1.3.2:
Demographic data for ACR20 responders versus non-responders at 
Week 12..................................................................................................49
Table 14.1.3.3: 
Baseline laboratory data: Tabulation of abnormalities..............................49
Table 14.1.3.4: 
Baseline ECG data: Tabulation of abnormalities......................................49
Table 14.1.3.5: 
Baseline vital signs data: Tabulation of abnormalities..............................49
Table 14.1.3.6: 
Baseline physical examination: Tabulation..............................................49
Table 14.1.3.7:
Screening and baseline disease characteristics .........................................51
Table 14.1.3.8:
Screening and baseline disease characteristics by region..........................51
Table 14.1.3.9:
Screening and baseline disease characteristics for ACR20 
responders versus non-responders at Week 12 .........................................52
Table 14.1.3.10:
Affected joints: Tabulation ......................................................................52
Table 14.1.3.11:
Prior RA medication................................................................................52
Table 14.1.3.12:
Prior RA medication for ACR20 responders versus non-responders 
at Week 12 ..............................................................................................52
Table 14.1.3.13:
Prior methotrexate: Descriptive statistics.................................................52
Table 14.1.3.14:
Prior steroid dose at the start of the study: Descriptive statistics...............52
Table 14.1.3.15: Medical history: Tabulation.....................................................................53
Table 14.1.3.16: Concurrent diseases: Tabulation ..............................................................53
Table 14.1.3.17: Prior therapies: Frequency table...............................................................55
Table 14.1.3.18: Concomitant therapies up to Week 12: Frequency table...........................55
Table 14.1.3.19: Concomitant therapies over the whole study period: Frequency table ......55
Table 14.1.3.20: Post-treatment therapies: Frequency table................................................55
Table 14.1.4.1: 
Use of study medication up to Week 12: Descriptive statistics.................56
Table 14.1.4.2: 
Use of study medication over the whole study period: Descriptive 
statistics...................................................................................................57
Table 14.1.4.3: 
Changes in methotrexate up to Week 12: tabulation.................................58


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Table 14.1.4.4: 
Use of methotrexate up to Week 12: Descriptive statistics of the 
average weekly dose................................................................................58
Table 14.1.4.5: 
Changes in methotrexate over the whole study period: tabulation ............59
Table 14.1.4.6: 
Use of methotrexate over the whole study period: Descriptive 
statistics of the average weekly dose........................................................59
Table 14.2.1.1.1: ACR20: Summary with overall p-value and pairwise comparisons 
versus placebo.........................................................................................61
Table 14.2.1.1.2: ACR20: Exploratory pairwise comparisons among the dose groups 
within each regimen ................................................................................62
Table 14.2.1.1.3: ACR20: Exploratory pairwise comparisons between regimens 
within each daily dose level.....................................................................62
Table 14.2.1.1.4: ACR50: Summary with overall p-value and pairwise comparisons 
versus placebo.........................................................................................63
Table 14.2.1.1.5: ACR50: Exploratory pairwise comparisons among the dose groups 
within each regimen ................................................................................63
Table 14.2.1.1.6: ACR50: Exploratory pairwise comparisons between regimens 
within each daily dose level.....................................................................64
Table 14.2.1.1.7: ACR70: Summary with overall p-value and pairwise comparisons 
versus placebo.........................................................................................64
Table 14.2.1.1.8: ACR70: Exploratory pairwise comparisons among the dose groups 
within each regimen ................................................................................64
Table 14.2.1.1.9: ACR70: Exploratory pairwise comparisons between regimens 
within each daily dose level.....................................................................64
Table 14.2.1.1.10: ACR20 at Week 12: Tabulation versus baseline characteristics................65
Table 14.2.1.1.11: ACR20 at Week 12: Exploratory logistic regression model 
containing baseline characteristics...........................................................66
Table 14.2.1.1.12: ACR-N: Summary with overall p-value and pairwise comparisons 
versus placebo.........................................................................................67
Table 14.2.1.1.13: ACR-N: Exploratory pairwise comparisons among the dose groups 
within each regimen ................................................................................67
Table 14.2.1.1.14: ACR-N: Exploratory pairwise comparisons between regimens 
within each daily dose level.....................................................................68
Table 14.2.1.1.15: Time to ACR20 response: Summary with overall p-value and 
pairwise comparisons versus placebo.......................................................68
Table 14.2.1.1.16: Time to ACR20 response: Exploratory pairwise comparisons 
among the dose groups within each regimen............................................69
Table 14.2.1.1.17: Time to ACR20 response: Exploratory pairwise comparisons 
between regimens within each daily dose level........................................69
Table 14.2.1.1.18: Time to ACR50 response: Summary with overall p-value and 
pairwise comparisons versus placebo.......................................................69
Table 14.2.1.1.19: Time to ACR50 response: Exploratory pairwise comparisons 
among the dose groups within each regimen............................................70


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Table 14.2.1.1.20: Time to ACR50 response: Exploratory pairwise comparisons 
between regimens within each daily dose level........................................70
Table 14.2.1.1.21: Time to ACR70 response: Summary with overall p-value and 
pairwise comparisons versus placebo.......................................................70
Table 14.2.1.1.22: Time to ACR70 response: Exploratory pairwise comparisons 
among the dose groups within each regimen............................................70
Table 14.2.1.1.23: Time to ACR70 response: Exploratory pairwise comparisons 
between regimens within each daily dose level........................................70
Table 14.2.1.1.24: ACR20 after Week 12: Frequency table...................................................71
Table 14.2.1.1.25: ACR50 after Week 12: Frequency table...................................................72
Table 14.2.1.1.26: ACR70 after Week 12: Frequency table...................................................72
Table 14.2.1.1.27: ACR-N after Week 12: Descriptive statistics ...........................................72
Table 14.2.1.2.1: EULAR remission: Summary with overall p-value and pairwise 
comparisons versus placebo.....................................................................73
Table 14.2.1.2.2: EULAR remission: Exploratory pairwise comparisons among the 
dose groups within each regimen.............................................................73
Table 14.2.1.2.3: EULAR remission: Exploratory pairwise comparisons between 
regimens within each daily dose level......................................................73
Table 14.2.1.2.4: EULAR remission after Week 12: Frequency table..................................74
Table 14.2.1.3.1: SDAI and CDAI: Descriptive statistics of the actual values .....................75
Table 14.2.1.3.2: SDAI and CDAI: Descriptive statistics of the change from baseline ........75
Table 14.2.1.3.3: SDAI and CDAI: Descriptive statistics of the percent change from 
baseline ...................................................................................................75
Table 14.2.1.3.4: SDAI and CDAI: Summary with overall p-value and pairwise 
comparisons versus placebo.....................................................................76
Table 14.2.1.3.5: SDAI and CDAI: Exploratory pairwise comparisons among the 
dose groups within each regimen.............................................................76
Table 14.2.1.3.6: SDAI and CDAI: Exploratory pairwise comparisons between 
regimens within each daily dose level......................................................77
Table 14.2.1.3.7: SDAI and CDAI remission: Summary with overall p-value and 
pairwise comparisons versus placebo.......................................................77
Table 14.2.1.3.8: SDAI and CDAI remission: Exploratory pairwise comparisons 
among the dose groups within each regimen............................................78
Table 14.2.1.3.9: SDAI and CDAI remission: Exploratory pairwise comparisons 
between regimens within each daily dose level........................................78
Table 14.2.1.3.10: SDAI and CDAI after Week 12: Descriptive statistics of the actual 
values......................................................................................................78
Table 14.2.1.3.11: SDAI and CDAI after Week 12: Descriptive statistics of the change 
from baseline...........................................................................................78
Table 14.2.1.3.12: SDAI and CDAI after Week 12: Descriptive statistics of the percent 
change from baseline...............................................................................78
Table 14.2.1.4.1: DAS28(CRP): Descriptive statistics of the actual values..........................80
Table 14.2.1.4.2: DAS28(CRP): Descriptive statistics of the change from baseline.............80


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Table 14.2.1.4.3: DAS28(CRP): Descriptive statistics of the percent change from 
baseline ...................................................................................................80
Table 14.2.1.4.4: DAS28(CRP): Summary with overall p-value and pairwise 
comparisons versus placebo.....................................................................80
Table 14.2.1.4.5: DAS28(CRP): Exploratory pairwise comparisons among the dose 
groups within each regimen.....................................................................80
Table 14.2.1.4.6: DAS28(CRP): Exploratory pairwise comparisons between regimens 
within each daily dose level.....................................................................81
Table 14.2.1.4.7: DAS28(CRP) change from baseline at Week 12: Tabulation versus 
baseline characteristics ............................................................................81
Table 14.2.1.4.8: DAS28(CRP) change from baseline at Week 12: Exploratory 
ANCOVA model containing baseline characteristics...............................82
Table 14.2.1.4.9: DAS28(CRP) remission: Summary with overall p-value and 
pairwise comparisons versus placebo.......................................................83
Table 14.2.1.4.10: DAS28(CRP) remission: Exploratory pairwise comparisons among 
the dose groups within each regimen .......................................................83
Table 14.2.1.4.11: DAS28(CRP) remission: Exploratory pairwise comparisons 
between regimens within each daily dose level........................................83
Table 14.2.1.4.12: DAS28(CRP) remission and low disease activity: Summary with 
overall p-value and pairwise comparisons versus placebo........................83
Table 14.2.1.4.13: DAS28(CRP) remission and low disease activity: Exploratory 
pairwise comparisons among the dose groups within each regimen .........83
Table 14.2.1.4.14: DAS28(CRP) remission and low disease activity: Exploratory 
pairwise comparisons between regimens within each daily dose 
level ........................................................................................................83
Table 14.2.1.4.15: DAS28(CRP) EULAR response: Frequency table....................................83
Table 14.2.1.4.16: DAS28(CRP) EULAR response: Exploratory pairwise comparisons 
among the dose groups within each regimen............................................84
Table 14.2.1.4.17: DAS28(CRP) EULAR response: Exploratory pairwise comparisons 
between regimens within each daily dose level........................................84
Table 14.2.1.4.18: DAS28(CRP) after Week 12: Descriptive statistics of the actual 
values......................................................................................................84
Table 14.2.1.4.19: DAS28(CRP) after Week 12: Descriptive statistics of the change 
from baseline...........................................................................................84
Table 14.2.1.4.20: DAS28(CRP) after Week 12: Descriptive statistics of the percent 
change from baseline...............................................................................84
Table 14.2.1.4.21: DAS28(CRP) EULAR response after Week 12: Frequency table.............84
Table 14.2.1.5.1: Joint counts: Descriptive statistics of the actual values.............................85
Table 14.2.1.5.2: Joint counts: Descriptive statistics of the change from baseline................85
Table 14.2.1.5.3: Joint counts: Descriptive statistics of the percent change from 
baseline ...................................................................................................85
Table 14.2.1.5.4: Joint counts: Summary with overall p-value and pairwise 
comparisons versus placebo.....................................................................86


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Table 14.2.1.5.5: Joint counts: Exploratory pairwise comparisons among the dose 
groups within each regimen.....................................................................86
Table 14.2.1.5.6: Joint counts: Exploratory pairwise comparisons between regimens 
within each daily dose level.....................................................................86
Table 14.2.1.5.7: Joint counts after Week 12: Descriptive statistics of the actual 
values......................................................................................................86
Table 14.2.1.5.8: Joint counts after Week 12: Descriptive statistics of the change from 
baseline ...................................................................................................86
Table 14.2.1.5.9: Joint counts after Week 12: Descriptive statistics of the percent 
change from baseline...............................................................................86
Table 14.2.1.6.1: VAS scores: Descriptive statistics of the actual values.............................87
Table 14.2.1.6.2: VAS scores: Descriptive statistics of the change from baseline................87
Table 14.2.1.6.3: VAS scores: Descriptive statistics of the percent change from 
baseline ...................................................................................................87
Table 14.2.1.6.4: VAS scores: Summary with overall p-value and pairwise 
comparisons versus placebo.....................................................................87
Table 14.2.1.6.5: VAS scores: Exploratory pairwise comparisons among the dose 
groups within each regimen.....................................................................88
Table 14.2.1.6.6: VAS scores: Exploratory pairwise comparisons between regimens 
within each daily dose level.....................................................................88
Table 14.2.1.6.7: VAS scores after Week 12: Descriptive statistics of the actual 
values......................................................................................................88
Table 14.2.1.6.8: VAS scores after Week 12: Descriptive statistics of the change from 
baseline ...................................................................................................88
Table 14.2.1.6.9: VAS scores after Week 12: Descriptive statistics of the percent 
change from baseline...............................................................................88
Table 14.2.1.7.1: HAQ-DI total and domain scores: Descriptive statistics of the actual 
values......................................................................................................89
Table 14.2.1.7.2: HAQ-DI total and domain scores: Descriptive statistics of the 
change from baseline...............................................................................90
Table 14.2.1.7.3: HAQ-DI total and domain scores: Descriptive statistics of the 
percent change from baseline...................................................................90
Table 14.2.1.7.4: HAQ-DI total and domain scores: Summary with overall p-value 
and pairwise comparisons versus placebo ................................................90
Table 14.2.1.7.5: HAQ-DI total and domain scores: Exploratory pairwise 
comparisons among the dose groups within each regimen .......................90
Table 14.2.1.7.6: HAQ-DI total and domain scores: Exploratory pairwise 
comparisons between regimens within each daily dose level....................90
Table 14.2.1.7.7: HAQ-DI total and domain scores after Week 12: Descriptive 
statistics of the actual values....................................................................91
Table 14.2.1.7.8: HAQ-DI total and domain scores after Week 12: Descriptive 
statistics of the change from baseline.......................................................91


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Table 14.2.1.7.9: HAQ-DI total and domain scores after Week 12: Descriptive 
statistics of the percent change from baseline...........................................91
Table 14.2.1.8.1: Serum CRP (mg/L): Descriptive statistics of the actual values.................92
Table 14.2.1.8.2: Serum CRP (mg/L): Descriptive statistics of the change from 
baseline ...................................................................................................92
Table 14.2.1.8.3: Serum CRP (mg/L): Descriptive statistics of the percent change 
from baseline...........................................................................................92
Table 14.2.1.8.4: Serum CRP (mg/L): Shift table versus baseline .......................................92
Table 14.2.1.8.5: Serum CRP (mg/L): Treatment-emergent normalizations per time 
point........................................................................................................92
Table 14.2.1.8.6: Serum CRP (mg/L): Summary with overall p-value and pairwise 
comparisons versus placebo.....................................................................92
Table 14.2.1.8.7: Serum CRP (mg/L): Exploratory pairwise comparisons among the 
dose groups within each regimen.............................................................92
Table 14.2.1.8.8: Serum CRP (mg/L): Exploratory pairwise comparisons between 
regimens within each daily dose level......................................................93
Table 14.2.1.8.9: Serum CRP (mg/L) after Week 12: Descriptive statistics of the 
actual values............................................................................................93
Table 14.2.1.8.10: Serum CRP (mg/L) after Week 12: Descriptive statistics of the 
change from baseline...............................................................................93
Table 14.2.1.8.11: Serum CRP (mg/L) after Week 12: Descriptive statistics of the 
percent change from baseline...................................................................93
Table 14.2.1.8.12: Serum CRP (mg/L) after Week 12: Shift table versus baseline.................93
Table 14.2.1.8.13: Serum CRP (mg/L) after Week 12: Treatment-emergent 
normalizations per time point ..................................................................93
Table 14.2.1.9.1: FACIT fatigue score: Descriptive statistics of the actual values ...............94
Table 14.2.1.9.2: FACIT fatigue score: Descriptive statistics of the change from 
baseline ...................................................................................................94
Table 14.2.1.9.3: FACIT fatigue score: Descriptive statistics of the percent change 
from baseline...........................................................................................95
Table 14.2.1.9.4: FACIT fatigue score: Summary with overall p-value and pairwise 
comparisons versus placebo.....................................................................95
Table 14.2.1.9.5: FACIT fatigue score: Exploratory pairwise comparisons among the 
dose groups within each regimen.............................................................95
Table 14.2.1.9.6: FACIT fatigue score: Exploratory pairwise comparisons between 
regimens within each daily dose level......................................................95
Table 14.2.1.9.7: FACIT fatigue score after Week 12: Descriptive statistics of the 
actual values............................................................................................95
Table 14.2.1.9.8: FACIT fatigue score after Week 12: Descriptive statistics of the 
change from baseline...............................................................................95
Table 14.2.1.9.9: FACIT fatigue score after Week 12: Descriptive statistics of the 
percent change from baseline...................................................................95
Table 14.2.1.10.1: SF-36: Descriptive statistics of the actual values....................................101


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Table 14.2.1.10.2: SF-36: Descriptive statistics of the change from baseline.......................101
Table 14.2.1.10.3: SF-36: Descriptive statistics of the percent change from baseline ..........101
Table 14.2.1.10.4: SF-36: Summary with overall p-value and pairwise comparisons 
versus placebo.......................................................................................101
Table 14.2.1.10.5: SF-36: Exploratory pairwise comparisons among the dose groups 
within each regimen ..............................................................................102
Table 14.2.1.10.6: SF-36: Exploratory pairwise comparisons between regimens within 
each daily dose level..............................................................................102
Table 14.2.1.10.7: SF-36 after Week 12: Descriptive statistics of the actual values.............102
Table 14.2.1.10.8: SF-36 after Week 12: Descriptive statistics of the change from 
baseline .................................................................................................102
Table 14.2.1.10.9: SF-36 after Week 12: Descriptive statistics of the percent change 
from baseline.........................................................................................102
Table 14.2.3.1:
Pharmacodynamics: YKL-40: Descriptive statistics...............................103
Table 14.2.3.2:
Pharmacodynamics: YKL-40: Summary with overall p-value and 
pairwise comparisons versus placebo.....................................................103
Table 14.2.3.3:
Pharmacodynamics: YKL-40: Exploratory pairwise comparisons 
among the dose groups within each regimen..........................................103
Table 14.2.3.4:
Pharmacodynamics: YKL-40: Exploratory pairwise comparisons 
between regimens within each daily dose level......................................104
Table 14.2.3.5:
Pharmacodynamics: YKL-40: Descriptive statistics for Week 12 
ACR20 responders versus non-responders.............................................104
Table 14.2.3.6:
Pharmacodynamics: YKL-40: Descriptive statistics for Week 12 
ACR50 responders versus non-responders.............................................104
Table 14.2.3.7:
Pharmacodynamics: YKL-40: Descriptive statistics for Week 12 
ACR70 responders versus non-responders.............................................104
Table 14.2.3.8:
Pharmacodynamics: YKL-40: Correlation with ACR20/50/70...............104
Table 14.2.3.9:
Pharmacodynamics: YKL-40: Correlation with continuous efficacy 
parameters.............................................................................................104
Table 14.3.1.1: 
Treatment-emergent adverse events up to Week 12: Summary table......107
Table 14.3.1.2: 
Treatment-emergent adverse events up to Week 12: Summary table 
by region ...............................................................................................107
Table 14.3.1.3: 
Treatment-emergent adverse events up to Week 12: Tabulation of 
all adverse events ..................................................................................107
Table 14.3.1.4: 
Treatment-emergent adverse events up to Week 12: Tabulation of 
all adverse events by region...................................................................108
Table 14.3.1.5: 
Treatment-emergent adverse events up to Week 12: Tabulation of 
all adverse events by gender ..................................................................108
Table 14.3.1.6: 
Treatment-emergent adverse events up to Week 12: Tabulation of 
all adverse events by age category.........................................................108
Table 14.3.1.7: 
Treatment-emergent adverse events up to Week 12: Tabulation per 
intensity.................................................................................................108


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Table 14.3.1.8: 
Treatment-emergent adverse events up to Week 12: Tabulation of 
all treatment-related events....................................................................108
Table 14.3.1.9: 
Treatment-emergent adverse events up to Week 12: Tabulation of 
all treatment-related events by gender....................................................108
Table 14.3.1.10: Treatment-emergent adverse events up to Week 12: Tabulation of 
all treatment-related events by age category...........................................108
Table 14.3.1.11: Treatment-emergent adverse events up to Week 12: Tabulation of 
the intensity of treatment-related events.................................................109
Table 14.3.1.12:
Treatment-emergent adverse events up to Week 12: Tabulation of 
the drug-relatedness of serious events....................................................109
Table 14.3.1.13: Treatment-emergent adverse events up to Week 12: Tabulation of 
the drug-relatedness of events leading to discontinuation.......................109
Table 14.3.1.14: Treatment-emergent adverse events up to Week 12: Tabulation of 
the drug-relatedness of events leading to a temporary stop.....................109
Table 14.3.1.15: Treatment-emergent adverse events up to Week 12: Tabulation of 
the drug-relatedness of individual stopping rules ...................................109
Table 14.3.1.16: Treatment-emergent adverse events over the whole study: Summary 
table ......................................................................................................110
Table 14.3.1.17: Treatment-emergent adverse events over the whole study: Summary 
table by region.......................................................................................110
Table 14.3.1.18: Treatment-emergent adverse events over the whole study: 
Tabulation of all adverse events.............................................................110
Table 14.3.1.19: Treatment-emergent adverse events over the whole study: 
Tabulation of all adverse events by region.............................................110
Table 14.3.1.20: Treatment-emergent adverse events over the whole study: 
Tabulation of all adverse events by gender ............................................110
Table 14.3.1.21: Treatment-emergent adverse events over the whole study: 
Tabulation of all adverse events by age category ...................................111
Table 14.3.1.22: Treatment-emergent adverse events over the whole study: 
Tabulation per intensity.........................................................................111
Table 14.3.1.23: Treatment-emergent adverse events over the whole study: 
Tabulation of all treatment-related events..............................................111
Table 14.3.1.24: Treatment-emergent adverse events over the whole study: 
Tabulation of all treatment-related events by gender..............................111
Table 14.3.1.25: Treatment-emergent adverse events over the whole study: 
Tabulation of all treatment-related events by age category.....................111
Table 14.3.1.26: Treatment-emergent adverse events over the whole study: 
Tabulation of the intensity of treatment-related events...........................111
Table 14.3.1.27:
Treatment-emergent adverse events over the whole study: 
Tabulation of the drug-relatedness of serious events..............................111
Table 14.3.1.28: Treatment-emergent adverse events over the whole study: 
Tabulation of the drug-relatedness of events leading to 
discontinuation......................................................................................111


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Table 14.3.1.29: Treatment-emergent adverse events over the whole study: 
Tabulation of the drug-relatedness of events leading to a temporary 
stop .......................................................................................................111
Table 14.3.1.30: Treatment-emergent adverse events over the whole study: 
Tabulation of the drug-relatedness of individual stopping rules..............111
Table 14.3.2.1: 
Laboratory data up to Week 12: Descriptive statistics of the actual 
values per time point .............................................................................118
Table 14.3.2.2: 
Laboratory data up to Week 12: Descriptive statistics of the changes 
from baseline per time point ..................................................................118
Table 14.3.2.3: 
Laboratory data up to Week 12: Descriptive statistics of the percent 
changes from baseline per time point.....................................................118
Table 14.3.2.4: 
Laboratory data up to Week 12: Shift table of the lab abnormalities 
per time point ........................................................................................119
Table 14.3.2.5: 
Laboratory data up to Week 12: Treatment-emergent lab 
abnormalities per time point ..................................................................119
Table 14.3.2.6: 
Laboratory data up to Week 12: Frequency table of the CTCAE 
toxicity grades per time point ................................................................119
Table 14.3.2.7: 
Laboratory data up to Week 12: Shift table of the CTCAE toxicity 
grades per time point .............................................................................119
Table 14.3.2.8:
Laboratory data up to Week 12: Treatment-emergent CTCAE 
toxicity grades per time point ................................................................119
Table 14.3.2.9: 
Laboratory data up to Week 12: Frequency table of the ATP III 
classes per time point.............................................................................120
Table 14.3.2.10: Laboratory data up to Week 12: Shift table of the ATP III classes 
per time point ........................................................................................120
Table 14.3.2.11:
Laboratory data up to Week 12: Treatment-emergent ATP III 
classes per time point.............................................................................120
Table 14.3.2.12:
Laboratory data up to Week 12: Frequency table of percent changes 
from baseline per time point in inhibin B and testosterone.....................120
Table 14.3.2.13: Laboratory data up to Week 12: Shift table of the categorical lab 
data per time point.................................................................................121
Table 14.3.2.14: Laboratory data over the whole study: Descriptive statistics of the 
actual values per time point ...................................................................122
Table 14.3.2.15: Laboratory data over the whole study: Descriptive statistics of the 
changes from baseline per time point.....................................................122
Table 14.3.2.16: Laboratory data over the whole study: Descriptive statistics of the 
percent changes from baseline per time point.........................................122
Table 14.3.2.17: Laboratory data over the whole study: Shift table of the lab 
abnormalities per time point ..................................................................122
Table 14.3.2.18: Laboratory data over the whole study: Treatment-emergent lab 
abnormalities per time point ..................................................................122
Table 14.3.2.19: Laboratory data over the whole study: Frequency table of the 
CTCAE toxicity grades per time point...................................................122


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Table 14.3.2.20: Laboratory data over the whole study: Shift table of the CTCAE 
toxicity grades per time point ................................................................122
Table 14.3.2.21:
Laboratory data over the whole study: Treatment-emergent CTCAE 
toxicity grades per time point ................................................................122
Table 14.3.2.22: Laboratory data over the whole study: Frequency table of the ATP 
III classes per time point........................................................................122
Table 14.3.2.23: Laboratory data over the whole study: Shift table of the ATP III 
classes per time point.............................................................................122
Table 14.3.2.24:
Laboratory data over the whole study: Treatment-emergent ATP III 
classes per time point.............................................................................122
Table 14.3.2.25:
Laboratory data over the whole study: Frequency table of percent 
changes from baseline per time point in inhibin B and testosterone........122
Table 14.3.2.26: Laboratory data over the whole study: Shift table of the categorical 
lab data per time point ...........................................................................122
Table 14.3.3.1:
ECG up to Week 12: Descriptive statistics of the actual values per 
time point ..............................................................................................125
Table 14.3.3.2:
ECG at Week 12: Descriptive statistics of the changes from baseline ....125
Table 14.3.3.3: 
ECG at Week 12: Shift table of the QT abnormalities............................125
Table 14.3.3.4:
ECG at Week 12: Treatment-emergent QT abnormalities ......................126
Table 14.3.3.5:
ECG at Week 12: Treatment-emergent abnormal change in QT.............126
Table 14.3.3.6:
ECG up to Week 12: Frequency table of the eCRF ECG 
interpretation per time point...................................................................126
Table 14.3.3.7:
ECG over the whole study: Descriptive statistics of the actual 
values per time point .............................................................................126
Table 14.3.3.8:
ECG over the whole study: Descriptive statistics of the changes 
from baseline.........................................................................................126
Table 14.3.3.9: 
ECG over the whole study: Shift table of the QT abnormalities .............126
Table 14.3.3.10:
ECG over the whole study: Treatment-emergent QT abnormalities........126
Table 14.3.3.11:
ECG over the whole study: Treatment-emergent abnormal change 
in QT.....................................................................................................126
Table 14.3.3.12:
ECG over the whole study: Frequency table of the eCRF ECG 
interpretation per time point...................................................................126
Table 14.3.4.1: 
Vital signs up to Week 12: Descriptive statistics of the actual values.....129
Table 14.3.4.2: 
Vital signs up to Week 12: Descriptive statistics of the changes 
from baseline.........................................................................................129
Table 14.3.4.3: 
Vital signs up to Week 12: Summary table of means .............................129
Table 14.3.4.4: 
Vital signs up to Week 12: Shift table of the abnormalities per time 
point......................................................................................................129
Table 14.3.4.5: 
Vital signs up to Week 12: Treatment-emergent abnormalities per 
time point ..............................................................................................129
Table 14.3.4.6: 
Vital signs over the whole study: Descriptive statistics of the actual 
values....................................................................................................130


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Table 14.3.4.7: 
Vital signs over the whole study: Descriptive statistics of the 
changes from baseline ...........................................................................130
Table 14.3.4.8: 
Vital signs over the whole study: Summary table of means....................130
Table 14.3.4.9: 
Vital signs over the whole study: Shift table of the abnormalities per 
time point ..............................................................................................130
Table 14.3.4.10: Vital signs over the whole study: Treatment-emergent abnormalities 
per time point ........................................................................................130
LIST OF FIGURES
Figure 14.2.1.1.1: ACR20/50/70: Plot per week...................................................................70
Figure 14.2.1.1.2: ACR20: Plot over time ............................................................................70
Figure 14.2.1.1.3: ACR50: Plot over time ............................................................................71
Figure 14.2.1.1.4: ACR70: Plot over time ............................................................................71
Figure 14.2.1.1.5: ACR-N: Plot over time............................................................................71
Figure 14.2.1.1.6: Time to ACR20 response: Kaplan-Meier plot..........................................71
Figure 14.2.1.1.7: Time to ACR50 response: Kaplan-Meier plot..........................................71
Figure 14.2.1.1.8: Time to ACR70 response: Kaplan-Meier plot..........................................71
Figure 14.2.1.2.1: EULAR remission: Plot per week............................................................73
Figure 14.2.1.2.2: EULAR remission: Plot over time ...........................................................73
Figure 14.2.1.3.1: SDAI and CDAI: Plot of the actual values over time ...............................78
Figure 14.2.1.3.2: SDAI and CDAI: Plot of the changes from baseline over time.................78
Figure 14.2.1.3.3: SDAI and CDAI: Plot of the percent changes from baseline over 
time.........................................................................................................78
Figure 14.2.1.4.1: DAS28(CRP): Plot of the actual values over time....................................84
Figure 14.2.1.4.2: DAS28(CRP): Plot of the changes from baseline over time .....................84
Figure 14.2.1.4.3: DAS28(CRP): Plot of the percent changes from baseline over time .........84
Figure 14.2.1.5.1: Joint counts: Plot of the actual values over time.......................................86
Figure 14.2.1.5.2: Joint counts: Plot of the changes from baseline over time ........................86
Figure 14.2.1.5.3: Joint counts: Plot of the percent changes from baseline over time............86
Figure 14.2.1.6.1: VAS scores: Plot of the actual values over time.......................................88
Figure 14.2.1.6.2: VAS scores: Plot of the changes from baseline over time.........................88
Figure 14.2.1.6.3: VAS scores: Plot of the percent changes from baseline over time ............88
Figure 14.2.1.7.1: HAQ-DI total and domain scores: Plot of the actual values over 
time.........................................................................................................90
Figure 14.2.1.7.2: HAQ-DI total and domain scores: Plot of the changes from baseline 
over time .................................................................................................90
Figure 14.2.1.7.3: HAQ-DI total and domain scores: Plot of the percent changes from 
baseline over time....................................................................................90
Figure 14.2.1.8.1: Serum CRP (mg/L): Plot of the actual values over time ...........................93
Figure 14.2.1.8.2: Serum CRP (mg/L): Plot of the changes from baseline over time.............93


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Figure 14.2.1.8.3: Serum CRP (mg/L): Plot of the percent changes from baseline over 
time.........................................................................................................93
Figure 14.2.1.9.1: FACIT fatigue score: Plot of the actual values over time .........................95
Figure 14.2.1.9.2: FACIT fatigue score: Plot of the changes from baseline over time...........95
Figure 14.2.1.9.3: FACIT fatigue score: Plot of the percent changes from baseline over 
time.........................................................................................................95
Figure 14.2.1.10.1: SF-36: Plot of the actual values over time.............................................102
Figure 14.2.1.10.2: SF-36: Plot of the changes from baseline over time ..............................102
Figure 14.2.1.10.3: SF-36: Plot of the percent changes from baseline over time..................102
Figure 14.2.3.1:
Pharmacodynamics: YKL-40: Mean plot over time ...............................104
Figure 14.2.3.2:
Pharmacodynamics: YKL-40: Correlation plots versus efficacy ............104
Figure 14.3.2.1: 
Laboratory data up to Week 12: Mean plots of the actual values 
over time ...............................................................................................121
Figure 14.3.2.2: 
Laboratory data up to Week 12: Mean plots of the changes from 
baseline over time..................................................................................121
Figure 14.3.2.3: 
Laboratory data up to Week 12: Mean plots of the percent changes 
from baseline over time .........................................................................121
Figure 14.3.2.4: 
Laboratory data over the whole study: Subject profile plots over 
time – subjects with a treatment-emergent abnormality..........................123
Figure 14.3.2.5:
Laboratory data over the whole study: Mean plots of the actual 
values over time ....................................................................................123
Figure 14.3.2.6: 
Laboratory data over the whole study: Mean plots of the changes 
from baseline over time .........................................................................123
Figure 14.3.2.7: 
Laboratory data over the whole study: Mean plots of the percent 
changes from baseline over time............................................................123
LIST OF LISTINGS
Listing 16.2.1.1: Subject disposition: Randomization.........................................................44
Listing 16.2.1.2:
Subject disposition: Region, country and site identification .....................44
Listing 16.2.1.3: Subject disposition: Number of days in study ..........................................45
Listing 16.2.1.4: Subject disposition: Trial termination ......................................................46
Listing 16.2.1.5: Subject disposition: Study analysis periods..............................................46
Listing 16.2.2.1: Protocol deviations..................................................................................47
Listing 16.2.2.2: Eligibility criteria: Violations ..................................................................47
Listing 16.2.2.3: Final eligibility statements.......................................................................47
Listing 16.2.3.1: Subjects excluded from the safety analysis ..............................................47
Listing 16.2.3.2: Subjects excluded from the efficacy ITT analysis ....................................47
Listing 16.2.3.3: Subjects excluded from the efficacy per-protocol analysis .......................48
Listing 16.2.4.1: Demographic data ...................................................................................49
Listing 16.2.4.2: Prior RA medication................................................................................53
Listing 16.2.4.3: Medical history........................................................................................53


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Listing 16.2.4.4: Concomitant diseases ..............................................................................53
Listing 16.2.4.5: Prior and concomitant therapies...............................................................55
Listing 16.2.5.1: Exposure to study medication: eCRF data................................................57
Listing 16.2.5.2: Exposure to study medication: Derived data ............................................57
Listing 16.2.5.3: Dispensed kit numbers.............................................................................57
Listing 16.2.5.4: Exposure to methotrexate: eCRF data......................................................59
Listing 16.2.5.5: Exposure to methotrexate: Derived data ..................................................59
Listing 16.2.6.1:
ACR20, ACR50, ACR70 and ACR-N .....................................................73
Listing 16.2.6.2:
EULAR remission...................................................................................74
Listing 16.2.6.3:
SDAI and CDAI......................................................................................79
Listing 16.2.6.4:
DAS28(CRP): Original data ....................................................................84
Listing 16.2.6.5.1: Joint counts: Identification of unassessable joints ....................................86
Listing 16.2.6.5.2: Joint counts: Derived data........................................................................87
Listing 16.2.6.6:
VAS scores..............................................................................................88
Listing 16.2.6.7:
HAQ-DI: Derived summary scores..........................................................91
Listing 16.2.6.8:
Serum CRP (mg/L)..................................................................................93
Listing 16.2.6.9:
Total FACIT fatigue score.......................................................................95
Listing 16.2.6.10: SF-36: Derived summary scores.............................................................102
Listing 16.2.8:
Pharmacodynamics: YKL-40.................................................................105
Listing 16.2.10.1: Treatment-emergent adverse events: Summary listing ...........................111
Listing 16.2.10.2: Pre-treatment adverse events: Summary listing......................................112
Listing 16.2.10.3: Adverse events: Full listing of the serious adverse events ......................112
Listing 16.2.10.4: Treatment-emergent adverse events: Full listing of the events 
leading to discontinuation......................................................................112
Listing 16.2.10.5: Treatment-emergent adverse events: Full listing of the events 
leading to a temporary stop....................................................................112
Listing 16.2.10.6: Adverse events: Coding information......................................................113
Listing 16.2.10.7: Adverse events: Listing of subjects for whom a narrative is required .....113
Listing 16.2.11.1: Laboratory data: Full listing...................................................................123
Listing 16.2.11.2: Laboratory data: Abnormalities listing...................................................123
Listing 16.2.11.3: Laboratory data: Clinically significant abnormalities.............................123
Listing 16.2.11.4: Laboratory data: Urinalysis results ........................................................123
Listing 16.2.11.5: Laboratory data: Positive pregnancy tests..............................................124
Listing 16.2.12.1: ECG: Full listing ...................................................................................127
Listing 16.2.12.2: ECG: Abnormalities listing ...................................................................127
Listing 16.2.13.1: Vital signs: Full listing ..........................................................................130
Listing 16.2.13.2: Vital signs: Abnormalities listing...........................................................130
Listing 16.2.14:
Physical examinations: Abnormal findings ............................................130


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1.
STUDY DESIGN
1.1.
STUDY OBJECTIVES
1.1.1. 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.
1.1.2. 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 regimens of GLPG0634 administration 
on subjects’ disability, fatigue, and quality of life.
1.2.
STUDY DESIGN
This is a multicenter, phase IIb, double-blind, placebo-controlled add on study in subjects 
with moderately to severely active RA who have an inadequate response to MTX. A total of 
595 subjects will be randomized to one of 6 dose regimens of GLPG0634 or to placebo, on 
top of their stable dose of MTX. Treatment duration will be 24 weeks. At Week 12, subjects 
on placebo who have not achieved a 20% improvement in swollen joint count (SJC66) and 
tender joint count (TJC68) will be re-randomized (automatically via interactive voice/web 
response [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 treatment groups will maintain their 
randomized treatment until Week 24.
Upon qualification for the study, subjects will be randomized to placebo or one of 6 dosing 
regimens in a 1:1:1:1:1:1:1 ratio (N=85 for each treatment group; total N=595), stratified by 
geographic region and previous use of a biological DMARD during a single clinical study 
setting.
Subjects participating in the study will be requested to attend a maximum of 11 visits 
throughout the study: Screening visit (up to 28 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 potentially a follow-up visit). At completion of the 24-week 




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1.4.
FLOWCHART
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 protocol Section 9.7.1.4.2..
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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2.
ANALYSIS POPULATIONS AND TREATMENT GROUPS
2.1.
ANALYSIS CHAPTERS
Each part of the analysis will consist of 2 or 3 main chapters:
1.
Chapter 1: Period 1 of the study (up to and including Week 12): safety 
2.
Chapter 2: The study as a whole (periods 1 and 2 together, spanning the entire 24 weeks): safety and efficacy
3.
Chapter 3: Period 2 of the study (from Week 12 until the end of the study): only for efficacy and adverse events.
Each analysis chapter will use its own set of “treatment groups” and imputation methods. Later in this document, when all parameters are 
analyzed separately, will be mentioned which is the primary.
2.1.1. Efficacy data
Study 
period
Treatment groups
Analysis populations
Imputation method
“Chapter 2”: 
Periods 1+2 
together (full 
24 weeks 
period)
The 7 original groups:

Placebo

GLPG0634 q.d. dosing groups:

50 mg q.d.

100 mg q.d.

200 mg q.d.

GLPG0634 b.i.d. dosing groups:

25 mg b.i.d.

50 mg b.i.d.

100 mg b.i.d.
For the subjects in the placebo and low dose groups who switched to 100 mg/day 
during the second study period: they will be handled as if they discontinued at Week 
12, and will be imputed from Week 12 onwards in the second study period. 
(Details: see further in the SAP)
ITT: all subjects 
randomized, exposed at 
least once, and with post-
baseline data for at least 
one efficacy parameter.
Per-protocol: subpopulation 
of ITT, excluding all 
critical (=major) protocol 
deviations. This is decided 
during the blind review 
meeting before final 
database lock. 
Observed case, non-
responder imputation 
(NRI), last 
observation carried 
forward (LOCF): 
depending on the 
parameter; is 
specified later when 
all parameters are 
discussed.


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Study 
period
Treatment groups
Analysis populations
Imputation method
“Chapter 3”: 
Period 2, as 
of Week 12
The Week 12 responders, remaining on the same treatment during the second study 
period: 7 treatment arms:

Continued placebo

Continued GLPG0634 50 mg q.d.

Continued GLPG0634 100 mg q.d.

Continued GLPG0634 200 mg q.d.

Continued GLPG0634 25 mg b.i.d.

Continued GLPG0634 50 mg b.i.d.

Continued GLPG0634 100 mg b.i.d.
This analysis will show whether Week 12 responders remain responders when 
treatment is continued unchanged.
The Week 12 non-responders, either “switching” to 100 mg/day or continuing the 
same mid/high dose during the second study period:

Placebo non-responders switched to GLPG0634 100 mg q.d.

GLPG0634 50 mg q.d. non-responders switched to GLPG0634 100 mg q.d.

Continued GLPG0634 100 mg q.d.

Continued GLPG0634 200 mg q.d.

Placebo non-responders switched to GLPG0634 50 mg b.i.d.

GLPG0634 25 mg b.i.d. non-responders switched to GLPG0634 50 mg b.i.d.

Continued GLPG0634 50 mg b.i.d.

Continued GLPG0634 100 mg b.i.d.
This analysis will show whether Week 12 non-responders start to respond when either 
treated for a longer period with the same mid/high dose, or have a dose increase to 100 
mg/day.
ITT: all subjects 
randomized, exposed at 
least once, and with post-
Week 12 data for at least 
one efficacy parameter.
Subjects who discontinued 
prior the Week 12 visit will 
be excluded from this 
analysis.
Observed case, non-
responder imputation 
(NRI), last 
observation carried 
forward (LOCF): 
depending on the 
parameter; is 
specified later when 
all parameters are 
discussed.


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2.1.2. Safety data
Study 
period
Treatment groups
Analysis populations
Imputation method
“Chapter 1”: 
Period 1, up 
to Week 12
The 7 original groups:

Placebo

GLPG0634 q.d. dosing groups:

50 mg q.d.

100 mg q.d.

200 mg q.d.

GLPG0634 b.i.d. dosing groups:

25 mg b.i.d.

50 mg b.i.d.

100 mg b.i.d.
Safety: all subjects 
randomized and exposed 
at least once.
Observed-case only 
(no imputation)


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Study 
period
Treatment groups
Analysis populations
Imputation method
“Chapter 2”: 
Periods 1+2 
together (full 
24 weeks 
period)
The 11 groups of the second study period, taking into account treatment switches:

Subjects starting on placebo

Continued placebo

Switched to 100 mg q.d.

Switched to 50 mg b.i.d.

GLPG0634 continued dosing in responders

50 mg q.d.

25 mg b.i.d.

GLPG0634 continued dosing in non-responders

50 mg q.d. increased to 100 mg q.d.

25 mg b.i.d. increased to 50 mg b.i.d.

GLPG0634 continued q.d. dosing groups

100 mg q.d.

50 mg b.i.d.

GLPG0634 continued b.i.d. dosing groups

200 mg q.d.

100 mg b.i.d.
For the subjects in the placebo and low dose groups who discontinued prior to Week 12: 
they will be included in the “continued placebo”, “continued 25 mg b.i.d.” and 
“continued 50 q.d.” groups.
Note that AEs will be presented overall, but also split up in the two study periods.
Safety: all subjects 
randomized and exposed 
at least once during the 
study.
Observed-case only 
(no imputation)


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2.2.
FURTHER ANALYSIS POPULATIONS
2.2.1. All Screened Subjects Population
All subjects who signed an informed consent form.
2.2.2. All Randomized Population
All subjects randomized into the study.
2.3.
HANDLING OF UNBLINDED SUBJECTS
2.3.1. Safety population
In case a particular subject would be unblinded (e.g., in case of an SAE), all safety data of this 
subject recorded in the database will still be included in the safety analysis.
2.3.2. Intent to Treat Population
In case a particular subject would be unblinded (e.g., in case of an SAE), all efficacy data of 
this subject up to the point of unblinding will still be included in the ITT efficacy analysis. 
Recorded efficacy data from the moment of unblinding onwards will be disqualified from the 
analysis. Such data will still be part of the listings, but will be labeled as use=no. Missing data 
after the moment of unblinding will be imputed using the same rules as used for other 
subjects.
2.3.3. Per Protocol Population
In case a particular subject would be unblinded (e.g., in case of an SAE), all efficacy data of 
this subject up to the point of unblinding will still qualify for the per-protocol efficacy 
analysis selection according to the above rule of excluding critical protocol deviations. 
Recorded efficacy data from the moment of unblinding onwards will be disqualified from the 
analysis. Such data will still be part of the listings, but will be labeled as use=no. Missing data 
after the moment of unblinding will be imputed using the same rules as used for other 
subjects.
2.4.
TREATMENT GROUPS
2.4.1. Randomized versus Actual Treatment
For efficacy parameters, the treatment group as assigned by the randomization will be used in 
the analysis (i.e., as-randomized analysis, considered closest to a worst-case intention-to-treat 
principle).
For safety parameters, the treatment that was actually used by the subject will be applied in 
the analysis (i.e., as-treated analysis, considered the fairest worst-case method to allocate 
potential safety problems to the treatment that was actually used). Such an as-treated analysis 
will only be done in case more than 20% of the actually used study drug was different than 
planned and is in a higher dose than planned. If the subject uses less than 20% of incorrect 
kits or the incorrect kit is a lower dose, then an as-randomized analysis will be applied. The 


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“20%” mentioned here is over the related study period: period 1 only, or full periods 1+2 
combined, or period 2 only (for AE), depending on the analysis chapter.
During the second part of the study: if the subject passed the re-randomization visit (Week 12) 
but it is unknown whether the subject actually used any study drug during the second part of 
the study, then it is assumed that the subject used at least one dose of study drug during the 
second part. If the subject passed the re-randomization visit and it is known that the subject 
did not take any study drug during the second part of the study, then the re-randomization will 
be ignored and the subject will only have a study part 1 in the analysis.
Differences between as-treated and as-randomized will be flagged in the listing on subject 
allocation.
2.4.2. Totals across Groups
A total across all groups will be presented for the General (subject disposition, demographics, 
etc) part of the analysis. For the Safety parts of the analysis, a total across all GLPG0634 
groups will be presented for data up to and including Week 12, and for data after Week 12 or 
data across the entire 24 weeks of the study a total across all groups will be presented. No
totals will be presented for PD or Efficacy. Totals will only be shown on tables, but not on 
listings or figures.
3.
ANALYSIS PERIODS AND ANALYSIS TIME POINTS
3.1.
RELATIVE NUMBER OF DAYS
The relative day (DY) is calculated as follows: 
= Visit date – reference date + 1 day, when the visit date is on or after the reference date
= Visit date – reference date, when the visit date is before the reference date.
The reference date in the study is the first study medication intake date, which by definition 
has DY=1. There is no DY=0.
3.2.
ANALYSIS PERIODS FOR NON-VISIT DATA
These analysis periods are to be used for allocation of adverse events and concomitant 
medications into periods.


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Analysis period
Period start date
Period end date
Screening
Date of signing the initial 
ICF.
First study drug 
administration date – 1 day.
First 12 weeks
First study drug 
administration date.
Date of the W12 visit.
Second 12 weeks
Date of the W12 visit + 1 
day.
Max ( trial termination date ;
date of last dose + 30 days ).
Full 24 weeks
First study drug 
administration date.
Max ( trial termination date ;
date of last dose + 30 days ).
The trial termination date is the date of last contact with the subject, as recorded in the eCRF.
Note that the last analysis period in case of early termination will always be ended by:
Maximum ( trial termination date ; date of last dose + 30 days). In case the subject rolls over 
to DARWIN3, the trial termination date will be used (no 30 days will be added since that 
would be during DARWIN3).
3.3.
ALGORITHM OF ALLOCATING VISITS TO TIME WINDOWS
All visits (including early discontinuation visits and unscheduled visits but excluding visits 
without data) will be placed into time windows according to their relative day (DY) in the 
study, according to the following allocation table:
Time point 
label
Target day
Interval lower bound
Interval upper bound
Screening (3)
NA
NA
NA
Baseline (1)
NA
NA
NA
Week 1
8
2
11
Week 2
15
12
21
Week 4
29
22
42
Week 8
57
43
70
Week 12
85
71
98
Week 16
113
99
126
Week 20
141
127
154
Week 24
169
155
182
>Week 24 (2)
NA
183
+∞
Follow-up (3)
7-10 days after last 
visit
NA
NA
(NA = not applicable).
Notes:
(1)
The actual baseline reference value will be determined per parameter as the last available pre-dosing data point, so might differ 
from this “baseline” visit interval. There will be only one baseline time point in this study: the last nonmissing value prior to first 
dosing of study drug.
(2)
Visits falling really late in the study (relative day > 182; excluding the follow-up visit) will be allocated to a “>Week 24” interval, 
and will not be shown in tables nor figures, but will only be listed.
(3)
For the screening and follow-up visits, no time window is defined. The visit as recorded in the eCRF will be used. Follow-up 
visits of subjects who discontinue the study prior to the Week 12 re-randomization will be shown separately as well in the tables 
that present the first part of the study only. For tables that present the study as a whole, all follow-up visits will be shown.
Tables, figures and listings will present the time points, not the visits.


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For ECGs, a different method will be used. See section 12.3 for the details.
3.4.
SELECTION OF VISITS
It is possible that more than one visit gets allocated into the same time window. In that case, 
only one visit will be selected for Tables and figures. The nonselected visit(s) will only be 
listed and flagged as use=no.
The visit with a relative day (DY) closest to the target day will be selected. If there are 
multiple visits at the same distance of the scheduled visit day (meaning: equal ABS(DY –
target day)), then the one latest in time is selected.
In case of an additional screening result, the last pre-baseline measurement is selected as 
screening value for analysis. This value (not the original screening value) was also used in the 
clinical center to include the subject in the study.
In case more than one parameter is measured per time point (e.g. for lab), the selection is 
performed per parameter and per time point, not per “sample” and per time point. Missing 
values are removed before the selection is made.
A missing baseline value will be imputed with the last nonmissing value of a preceding visit. 
This can be a screening visit or an unscheduled visit prior to the first dose of study 
medication; whichever comes latest. If there is no nonmissing result at such screening or 
unscheduled visits, then the missing baseline value remains missing.
In case the screening visit is used to impute the baseline, the visit will be duplicated in the 
derived dataset. The original screening visit as well as the imputed baseline will be presented 
in the tables. In the listings, only original screening data will be shown: the original screening 
visit will be shown and flagged as “reference” visit. The imputed baseline will not be shown.
In case an unscheduled visit is used to impute the baseline, the visit will be renamed to 
“baseline” in the derived dataset. The imputed baseline will be presented in the tables. In the 
listings, the original unscheduled data will be shown and flagged as “reference” visit.
4.
HANDLING OF DATA
4.1.
CALCULATION OF DESCRIPTIVE STATISTICS
For continuous parameters, descriptive statistics will be presented when N≥2. When N=1, the 
observation will not be shown in the table but only in the listing.
Descriptive statistics will include at least the following: 


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
the number of nonmissing data points (N) 

the arithmetic mean

the standard error (SE)

the median, minimum and maximum

95% confidence interval of the mean (only when requested).
4.2.
CALCULATION OF PERCENTAGES
Missing values will not be included in the denominator count when computing percentages.
Imputed missing values are no longer considered to be missing values.
4.3.
HANDLING OF VALUES BELOW (OR ABOVE) A THRESHOLD
4.3.1. Safety Data
Values below (above) the detection limit will be imputed by the value of the detection limit 
itself. Listings will always present the original value.
Example: if the database contains values like “<0.04”, then for the descriptive statistics the 
value of the detection limit (0.04) shall be used. A value like “>1000” will be imputed by 
“1000”.
4.3.2. PK Data
Values below the detection limit will be imputed by a zero. 
4.3.3. PD Data
Values below the detection limit will be imputed by half of the value of the detection limit 
itself. Listings will always present the original value.
4.4.
HANDLING MISSING DATA
4.4.1. Handling of Missing Date (Time) or Partially Known Date (Time)
No imputation will be done of missing date (time) fields, nor of the missing parts of partially 
known date (time) fields. When needed, a worst-case selection will be made. Such worst-case 
selection rules are elaborated in the specific sections (e.g., AE). 
4.4.2. Handling of missing values in scales or summary parameters
Missing items in scales or summary parameters will be imputed to allow for the derivation of 
the total scale/parameter score. The appropriate imputation rules will be described in the 
sections where the total scores are defined.
4.4.3. Handling of missing values and early dropouts in the efficacy 
analyses during the first study period (up to Week 12)
This is for the “efficacy chapter 2” analysis.


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For binary data (e.g., ACR20), two different imputations will be done for missing visits as 
well as early dropouts: non-responder imputation (NRI) and LOCF, up to and including Week 
12. The NRI imputation will be primary, and LOCF will be secondary. 
For other data (ordinal or continuous), missing visits as well as early dropouts will be imputed 
using the last observation carried forward (LOCF) algorithm, up to and including Week 12.
Definitions of the imputation methods:

LOCF (all types of parameters, from binary to continuous): to impute a missing value, the 
last preceding nonmissing value will be used (which could even be a baseline value).

NRI (binary response parameters only): to impute a missing response, the subject will be 
assumed to be a non-responder.
For all parameters, an observed-case analysis will also be performed (i.e., without any 
imputation). The observed-case analysis will serve as a sensitivity analysis (to ascertain the 
impact of early dropouts on the results) and will basically be limited to:

ACR20/50/70/N: descriptive at W12+W24 and inferential at W12

EULAR remission: descriptive at W12+W24

SDAI/CDAI: descriptive at BSL+W12+W24

DAS28: descriptive at BSL+W12+W24 and inferential at W12

All ACR components (VAS, joint counts, CRP, HAQ-DI): descriptive at 
BSL+W12+W24

QoL (FACIT,SF-36): descriptive at BSL+W12+W24.
4.4.4. Handling of missing values and early dropouts in the efficacy 
analyses during the study period as a whole (full 24 weeks)
This is for the “efficacy chapter 2” analysis.
For binary data (e.g., ACR20), two different imputations will be done for missing visits as 
well as early dropouts: non-responder imputation (NRI) and LOCF, up to and including Week 
24. The NRI imputation will be primary, and LOCF will be secondary. 
For other data (ordinal or continuous), missing visits as well as early dropouts will be imputed 
using the last observation carried forward (LOCF) algorithm, up to and including Week 24.
For all parameters, an observed-case analysis will also be performed (i.e., without any 
imputation). This observed-case will not be shown for subjects who switched treatment. See 
previous section for the parts where the observed-case analysis will be presented.
4.4.5. Handling of missing values and early dropouts in the efficacy 
analyses during the second study period (after Week 12)
This is for the “efficacy chapter 3” analysis.
Subjects in this analysis must have data after the Week 12 potential switch in dosing. Subjects 
who discontinued the study during the first period of the study will not be included in this 
analysis and will therefore also not be imputed.


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For binary data (e.g., ACR20), two different imputations will be done for missing visits as 
well as early dropouts during period 2: non-responder imputation (NRI) and LOCF, up to and 
including Week 24. The NRI imputation will be primary, and LOCF will be secondary. 
For other data (ordinal or continuous), missing visits as well as early dropouts during period 2
will be imputed using the last observation carried forward (LOCF) algorithm, up to and 
including Week 24.
Note that no Period 1 efficacy data will be carried forward into this chapter 3 analysis. 
For all parameters, an observed-case analysis will also be performed (i.e., without any 
imputation).
4.4.6. Handling of missing values and early dropouts in the safety analysis
No imputation is done of missing values or missing visits. The analysis will be observed-case 
only.
4.5.
HANDLING TREATMENT SWITCHES AT WEEK 12 IN THE 
EFFICACY AND SAFETY ANALYSIS
This section only applies to the Week 12 non-responders in the placebo and low dose groups, 
where there is a dose increase for the remaining 12 weeks until the end of the study, and also 
to the Week 12 responders in the placebo and low dose groups, who remain on the same 
treatment for the remaining 12 weeks until the end of the study.
4.5.1. In the efficacy analysis of the full study as a whole (full 24 weeks)
The efficacy analysis will apply the original 7 treatment groups (original randomization at 
baseline). Subjects who switch treatment at Week 12 will be regarded as having discontinued 
treatment at Week 12: their data after Week 12 will not be used in this analysis. Their efficacy 
data will be handled for the remainder of the study as described above in section 4.4.4. The
placebo, 50 mg q.d. and 25 mg b.i.d. groups will thus contain both data under this treatment 
(continued treatment groups), as well as Week 12 imputed information from non-responders 
who switch to a higher dose of GLPG0634. It is recognized that these 3 groups (placebo, 50 
mg q.d. and 25 mg b.i.d.) will only be an approximation, so the formal comparisons between 
all groups after Week 12 should be interpreted with care. LOCF, NRI and observed-case will 
be produced.
4.5.2. In the safety analysis of the full study as a whole (full 24 weeks)
The treatment groups that will be presented in the tables will distinguish treatment switches at 
Week 12 as separate arms: the period 1 & 2 treatment sequence will be used.
4.5.3. In the efficacy and safety analysis of the second study period
The treatment arms will be presented descriptively only, as separate columns.


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In the safety analysis, this only applies to the adverse events where the treatment-emergent 
AEs that emerge during the second part of the study will be presented separately. The lab 
data, ECG and vital signs are already presented in chapter 2 of the analysis.
4.6.
HANDLING OF OUTLIERS
All measured values will be included in the analyses.
4.7.
HANDLING OF SECONDS IN DATETIME FIELDS
If a datetime field contains seconds, these will be cut off (i.e., rounded down to the minute) 
prior to data analysis. The analysis will only use the date and time up to the minute.
4.8.
STRATIFICATION FACTORS
In case there is a discrepancy in randomization stratification stratum between IWRS and the 
actual eCRF data, then:
1.
The actual eCRF stratum will be used in analyses and analysis models, and
2.
Any such discrepancy will be flagged in the listing on randomizations (listing 16.2.1.1).
5.
SOFTWARE AND PROCEDURES
5.1.
SOFTWARE
SAS version 9.3 (or higher) will be used for programming.
5.2.
PROCEDURES
Analyses will comply with ICH regulations, in particular: (ICH-E3) , (ICH-E6) and (ICH-E9).
The following Galapagos SOPs will be followed:

SOP-CLI-001: Developing Clinical Study Documents (version 1.0)

SOP-CLI-003: Managing Data Processing Activities (version 1.0)

SOP-CLI-004: Managing DSMB Activities (version 1.0)
The following 
STAT SOPs will be followed:


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Location
Document 
Type
Document 
Number
Effective Date
Document Title
Global
SOP
03.002.01
03-Feb-2014
Providing Statistical Input to CSRs and 
Clinical Summaries for Submission 
Dossiers
Global
SOP
03.003.00
06-Feb-2012
Generation of define.xml
Global
SOP
03.004.01
03-Feb-2014
Statistical Input to Clinical Trial 
Protocols
Global
SOP
03.005.00
29-Mar-2012
Planning and Conducting Interim 
Analyses
Global
SOP
03.007.01
01-Oct-2013
Development of a Statistical Analysis 
Plan
Global
SOP
03.009.01
01-Oct-2013
Quality Control of SAS® Programming
Global
SOP
03.010.01
01-Oct-2013
Development of SAS® Programs
Global
SOP
03.011.00
30-Apr-2012
Randomization and Unblinding
Global
SOP
03.012.02
02-Dec-2013
Biostatistics and Statistical Programming 
Directory Structure Creation and Setup
Global
SOP
03.013.01
01-Oct-2013
Development and Production of Analysis 
Datasets
Global
SOP
03.014.01
29-Apr-2014
Biostatistics and Statistical Programming 
Functional Lead Responsibilities
Global
SOP
03.015.01
29-Apr-2014
Performing Blind Review of Data
5.3.
FORMATS
Derived data will be following CDISC ADaM 2.1 (ADaMIG 1.0) format.
Tables, listings and figures will follow the Mock TLFs, as provided in a separate document. 
6.
STATISTICAL METHODS
6.1.
PLANNED ANALYSES, PROTOCOL AMENDMENTS 
INCLUDED
6.1.1. Demographic and other baseline characteristics
Subject disposition including the reasons for study termination will be tabulated.
Demographic characteristics will be listed. Demographic characteristics will be summarized 
using appropriate descriptive statistics, as applicable. 


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6.1.2. Efficacy Variables
6.1.2.1.
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 non-responder imputation 
(NRI) of the ACR20 will be the primary parameter, with observed-case and last observation 
carried forward (LOCF) imputation as secondary confirmatory analyses.
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
≥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/L.
6.1.2.2.
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-N 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. It is a number varying between 0 and 100.
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) ], cut off at 0 in case it would be a negative number.
ACR/EULAR Remission
A subject’s disease activity status can be defined as being in remission if:
when scores on the TJC28, SJC28, CRP (actual value in mg/dL) and Patient Global 
Assessment of Disease Activity (cm) are all ≤1.


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Simplified Disease Activity Index (SDAI)
The SDAI 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 CDAI is the SDAI modified to exclude CRP.
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 Based on CRP (DAS28[CRP])
The DAS28(CRP) 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 


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Categorization of the DAS28(CRP) scores:

High disease activity: > 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 table:
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
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.
6.1.2.3.
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. 
The analysis will present the results in 2 chapters:
1.
Chapter 2: Analysis of the full 24 weeks study period. 
2.
Chapter 3: Analysis of the second study period, from Week 12 onwards.
All chapters will use the original baseline visit as reference.
Handling of discontinued subjects during the 24 weeks treatment period:

Subjects who discontinue within the first week so that ACR20/50/70 responses cannot be 
determined will be classified as non-responders.

For all discontinued subjects, visits after their discontinuation will be imputed for a 
duration depending on the analysis chapter:

Chapter 2: subjects discontinuing during the first study period will have their 
remaining visits imputed up to and including Week 12.

Chapter 2: subjects discontinuing the study will be imputed up to and including 
Week 24, irrespective of whether they discontinued during the first or second study 
period.

Chapter 3: subjects discontinuing during the first study period will not be imputed 
during the second study period. Subjects discontinuing during the second study 
period will be imputed up to and including Week 24.
The method of imputation will depend on the parameter: NRI and LOCF for binary data; 
LOCF for ordinal or continuous data. Observed-case will always be presented as well.


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Non-responding subjects from the placebo and lowest dose groups who are re-randomized at 
Week 12 will be handled as follows, again depending on the analysis chapter: 

Chapter 2: their original treatment group of the first study period will be used. The Week 
12 value will be carried forward to all further time points (and between-group 
comparisons) after Week 12.

Chapter 3: their actual assessments on Weeks 16-20-24 will be analyzed descriptively
using the new treatment groups.

See also: overview table, section 2.1. 
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.). This model will not use 
the placebo data. Differences among the q.d. groups and among the b.i.d. groups will be 
described using the same model. No adjustment for multiplicity will be done for these 
exploratory differences.
Analysis methods per post-baseline time point:

Binary parameters (such as ACR20): logistic regression model with factors treatment, 
region and previous use of biologics.

Continuous parameters: both the changes from baseline and the percent changes from 
baseline will be described. Formal between-group comparisons will be performed on the 
changes from baseline only, using an analysis of (co)variance (AN[C]OVA) model with 
factors treatment, baseline value, region and previous use of biologics. Baseline will be 
the last nonmissing value prior to first dosing in the study.

Time to (first) 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. 
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 AN(C)OVA models on the changes from baseline with factors treatment, 
baseline value, region and previous use of biologics. 
A descriptive sensitivity analysis by baseline characteristic (such as country, geographic 
region, previous use of biological DMARDs etc) will be performed for the ACR20 response
and the change in DAS28(CRP). Additionally an exploratory regression model will be fitted 
using a stepwise selection algorithm on the ACR20 response and the change in DAS28(CRP) 
at Week 12, using treatment and baseline characteristics as explanatory factors to investigate 
which baseline factors have an influence on the response.
Graphical presentations are added to facilitate the overall interpretation of the study results.


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6.1.3. 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, changes and and percent changes from baseline (or from screening, 
depending on the parameter) 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. 
The analysis will present the results in 2 chapters:
1.
Chapter 1: Analysis of the first study period, up to and including the Week 12 visit.
2.
Chapter 2: Analysis of the full 24 weeks study period.
Non-responding subjects from the placebo and lowest dose groups who are re-randomized at 
Week 12: the actual treatments will be presented. (See also: overview table, section 2.1.)
6.1.4. Pharmacokinetic Analyses
This will be elaborated in a separate SAP by 
. 
6.1.5. Pharmacodynamic Analyses
Serum levels of YKL-40 will be described as actual values, changes from baseline and 
percent changes from baseline. Between-group comparisons will be performed using the same 
ANCOVA models as used for the efficacy data. To further explore the data, scatterplots of the 
percent change from baseline in YKL-40 values versus efficacy parameters will be created.
Further analyses may be done at a later time, but these will not be part of the CSR.
6.1.6. Pharmacokinetic, Efficacy, Safety and Pharmacodynamic 
Correlations
This will be elaborated in a separate SAP by 
. 
6.2.
INTERIM ANALYSIS
Note that a DSMB is installed to monitor unblinded safety data during the course of the study. 
This is described in a separate DSMB Charter and DSMB SAP.
An unblinded interim analysis will be performed when all subjects have reached Week 12 (or 
have discontinued before Week 12). Only data from this study period will be included in the 
interim analysis.
The analysis will not present everything, but only a selection of parameters:




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6.3.
CHANGES TO THE PLANNED ANALYSES, NOT COVERED BY 
PROTOCOL AMENDMENTS
6.3.1. Changes before Interim Database Lock
No changes to the protocol-specified analyses were made. The SAP provides further 
elaborations, clarifications and specifications on the protocol-specified analyses.
Version changes after 1.0: 
Change from 1.0 to 3.0 SAP and Mocks due to technical issues in Galapagos’ electronic 
document management system (Plaza) without any change to document contents.
Change from 3.0 to 4.0 SAP and Mocks: corrections of the actual contents of the interim 
analysis (inconsistencies within the SAP and with DARWIN2). Also solving inconsistencies 
between SAP and Mocks, and between DARWIN1 and DARWIN2, and providing more 
clarification on the expected observed-case analysis.
6.3.2. Changes after Interim Database Lock but before Final Database 
Lock
Changes from 4.0 to 5.0 SAP:
Corrections:

The analysis periods were updated from the interim SAP: the actual Week 12 visit date
day is now included in the first 12 weeks of the study period. In the interim SAP it was 
mistakenly excluded from the first 12 weeks of the study.

Randomization stratification factors: it is now more clearly specified that in case of 
discrepancies between IWRS and eCRF, the real underlying eCRF stratum will be used in 
the analyses and analysis models. This was already so in the interim analysis, but 
possibly not clear enough in this SAP.

For safety data, the overall total was replaced by a total across the GLPG0634 groups 
only. This will allow easier comparison of the overall GLPG0634 safety versus the 
placebo group.

Baseline HAQ-DI, Baseline SDAI and Baseline CDAI will be added in the table on 
baseline disease characteristics.

VAS plots on percent changes from baseline: from the interim analysis it seemed that the 
mean values were not so much influenced by the few outliers as initially anticipated. 
Therefore medians are no longer needed: plots will be mean plots just like all other 
efficacy parameters.

Scatterplots between PK plasma levels and safety (lab safety and ECG QTcF) were 
removed. Because PK plasma sampling can happen at any time relative to the last drug 
intake (‘sparse sampling’), the result is not always representing the subject’s exposure. 
Making a correlation between the PK finding and safety would then be misleading.
Additons:


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
Pharmacodynamic analyses were added and specified for the final analysis.

DAS28(CRP) remission and low disease activity, SDAI remission, CDAI remission: 
between-group inferential statistics were added, similar to the ACR20 analysis, to allow a 
more detailed interpretation of the results.
6.3.3. Changes after Final Database Lock
None.
7.
DEFINITIONS OF GENERAL TABLES, LISTINGS AND 
FIGURES
Mock tables, listings and figures are provided in a separate document. 
All analyses will be run on the Safety population, unless specified otherwise.
7.1.
SUBJECT DISPOSITION
Listing 16.2.1.1: Subject disposition: Randomization
Listing of subject numbers, randomization and re-randomization groups, population flags, any 
information on code breaking, stratification factors (region, previous use of biologics), 
country and site.
All discrepancies (as-randomized versus as-treated, or discrepancies in stratification factors) 
will be flagged.
Regions used in the central randomization in the DARWIN program are:
Region
Countries belonging to the region
1: Latin America
Argentina, Chile, Colombia, Guatemala, Mexico
2: Central and Eastern Europe, EU
Bulgaria, Hungary, Latvia, Poland
3: Central and Eastern Europe, non-EU
Russia, Ukraine, Moldova
4: West and Asia Pac
Australia, Austria, Belgium, Czech Republic, France, Germany, Israel, 
New Zealand, Spain, USA
Population: all randomized population.
Listing 16.2.1.2: Subject disposition: Region, country and site identification
Listing of region, country and site numeric codes used for the numbering of the subjects, and 
the meaning of these codes.
Population: all screened population.
Table 14.1.1.1: 
Subject disposition: Tabulation by region, country and investigator


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Tabulation per initial treatment group (and overall) of the number of subjects in each of the 
regions, countries and investigator sites. For the interim analysis, only regions and countries 
will be presented.
Population: all randomized.
Table to be created for the Week 12 interim analysis as well.
Table 14.1.1.2: 
Subject disposition: Analysis populations
Tabulation per initial treatment group (and overall) of the number of subjects in each of the 
analysis populations defined in section 3.1, separated per study period.
Population: all screened population.
Table 14.1.1.3: 
Subject disposition: No-treatment subjects: Tabulation of the reasons
Tabulation of discontinuations and the reasons for discontinuation.
Population: all screened population, minus the safety population (so selecting only subjects 
who were never exposed to the study medication: subjects either never randomized or 
randomized but not exposed).
Table 14.1.1.4: 
Subject disposition up to Week 12: Tabulation of the number of 
subject at each time interval
Tabulation per treatment group (and overall) and per time point (up to and including Week 
12).
Population: safety.
Table 14.1.1.5: 
Subject disposition up to study end: Tabulation of the number of 
subject at each time interval
Repeat table after Week 12 and follow-up.
Population: safety subjects who entered the second part of the study.
Listing 16.2.1.3: Subject disposition: Number of days in study 
Listing per initial treatment group, per subject and per time point the number of days in study 
at the time of the visit (derivation of these “days”: see section 3.1), with population flags.
Population: safety.


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Table 14.1.1.6: 
Subject disposition: First and last date in the study
List the following (overall, not per subject):

Date of the first signature on study ICF

Date of first and last screening visit

Screening period duration: last screening date – first screening date + 1 day

Date of first study drug administration (periods 1 and 2)

Last visit date (all visits; including unscheduled visits)

Last date of contact in the study with any subject.
Population: all screened population.
Table 14.1.1.7: 
Subject disposition up to Week 12: Tabulation of the trial termination 
reasons
Tabulation per treatment group (and overall) of completion/discontinuations during the first 
period of the study, with the reasons for discontinuation. Subjects who moved on past the 
Week 12 visit will be shown as “completed”.
Population: safety.
Table to be created for the Week 12 interim analysis as well.
Table 14.1.1.8: 
Subject disposition up to study end: Tabulation of the trial 
termination reasons
Repeat table for the second period of the study.
Population: safety subjects who entered the second part of the study.
Listing 16.2.1.4: Subject disposition: Trial termination 
Listing per treatment group and per subject of the reason for completion/discontinuation and 
the number of days since first study treatment administration at trial termination. In case the 
discontinuation was due to AE, the AE preferred term will be presented in this listing. If there 
is a (verbatim) explanation on the discontinuation reason, this will also be presented in this 
listing.
Population: safety.
Listing 16.2.1.5: Subject disposition: Study analysis periods 
Listing per treatment group and per subject of the analysis periods in the study, together with 
the start and end dates of each analysis period. With the date of first and last use of study 
medication in each study period, population flags, the ICF signature date and trial termination 
date. (Analysis periods: see section 3.2)
Population: safety.


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7.2.
PROTOCOL DEVIATIONS AND ELIGIBILITY
Protocol deviations are determined and recorded whilst the study is ongoing, and the list is 
finalized prior to final database lock (and unblinding). All deviations are classified as either 
“critical” or “non-critical”. Only the critical (=major) protocol deviations will be presented in 
the tables. For more details, please refer to the Protocol Deviation Plan.
Table 14.1.2.1: 
Major protocol deviations 
Tabulation per treatment group (and overall) of the number (and percentage) of subjects
having a major/minor protocol deviation, together with the detailed protocol deviation 
categories of the major deviations only.
Population: safety.
Listing 16.2.2.1: Protocol deviations 
Listing per treatment group and per subject of all protocol deviations, with indication 
critical/non-critical.
Population: safety.
Listing 16.2.2.2: Eligibility criteria: Violations 
Only violated in- and exclusion criteria will be listed per treatment group and per subject.
These are criteria as ticked by the investigator in the eCRF.
Population: safety.
Listing 16.2.2.3: Final eligibility statements 
Listing per treatment group and per subject of the final eligibility statements in the eCRF at 
screening and at baseline.
Population: safety.
7.3.
SUBJECTS EXCLUDED FROM ANALYSIS
Listing 16.2.3.1: Subjects excluded from the safety analysis 
Listing of all subjects that were randomized and/or not treated: the trial termination reason 
and/or the reason for being a no-treatment subject will be listed, whichever is available.
Population: all screened population, minus the Safety population.
Listing 16.2.3.2: Subjects excluded from the efficacy ITT analysis 
Listing of all subjects that were exposed but who were not included in the ITT population: the 
trial termination reason and the reason for being excluded will be listed.
Population: Safety, minus the ITT population.


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Listing 16.2.3.3: Subjects excluded from the efficacy per-protocol analysis 
Listing of all subjects that were in the ITT population but not in the per-protocol population: 
the trial termination reason and the reason for being excluded will be listed.
Population: ITT population, minus the Per-protocol population.
7.4.
DEMOGRAPHICS AND BASELINE DISEASE 
CHARACTERISTICS
7.4.1. Parameters

sex

age (years) as recorded in the eCRF

age categories: 
< 45 ; 
[45,65[ ; 
[65,75[ ; 
≥ 75 years

year of birth: only listed

race

ethnicity

height (cm)

weight (kg)

body mass index BMI = (weight in kg) / (height in m)² (kg/m²): the BMI will be 
recalculated and rounded to the nearest integer, even when already available in the 
database. The original BMI will not be used in that case.

BMI categories: 
≤18.5;
]18.5,25.0] ; 
]25.0,30.0[ ;
≥30.0 kg/m²
7.4.2. Analysis
Table 14.1.3.1: 
Demographic data
Continuous parameters: descriptive statistics per treatment group (and overall). Overall p-
value to compare all groups: 1-way ANOVA model with factor treatment.
Categorical parameters: frequency tabulation per treatment group (and overall). Overall p-
value to compare all groups: Cochran-Mantel-Haenszel test for general association.
Population: safety, ITT, per-protocol.
Table to be created for the Week 12 interim analysis as well, but only for Safety and ITT
populations.


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Table 14.1.3.2:
Demographic data for ACR20 responders versus non-responders at 
Week 12
Same descriptive table as above, but split up for ACR20 responders and non-responders at 
Week 12. See further on for the definition of ACR20.
Population: ITT.
Table to be created for the Week 12 interim analysis as well.
Listing 16.2.4.1: Demographic data
Listing per treatment group and per subject of all demographic parameters.
Population: safety.
Table 14.1.3.3: 
Baseline laboratory data: Tabulation of abnormalities
Frequency tabulation per lab test and per treatment group (and overall) of the baseline result, 
categorized as low/normal/high according to the normal ranges (see section 12.2.5). Exclude 
the CRP.
Population: safety.
Table 14.1.3.4: 
Baseline ECG data: Tabulation of abnormalities
Frequency tabulation per parameter (QT and QTcF) per treatment group (and overall) of the 
baseline result, categorized as (same as in section 12.3.5):
≤450 ms ; 
]450,480] ms ; 
]480,500] ms ; 
>500 ms. 
Population: safety.
Table 14.1.3.5: 
Baseline vital signs data: Tabulation of abnormalities
Frequency tabulation per parameter and per treatment group (and overall) of the baseline 
result, categorized as low/normal/high according to the normal ranges (see section 12.4.3).
Population: safety.
Table 14.1.3.6: 
Baseline physical examination: Tabulation
Frequency tabulation per CRF body system and per treatment group (and overall) of the 
baseline result, categorized as normal/abnormal.
Population: safety.


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7.5.
BASELINE DISEASE CHARACTERISTICS
7.5.1. Parameters
-
Duration of RA (years) = 
( 	
  	) – ( )  
.
, rounded to the 
nearest integer. If the date of initial diagnosis is incomplete, then the following rules 
will be applied: Missing day: use the first of the month. Missing month: use January.
-
Duration of RA, categorized: 
<0.5; 
[0.5,2[ ; 
[2,5[ ; 
[5,10[ ; 
[10,20[ ; 
≥20 years
-
Screening and baseline CRP
-
Screening and baseline CRP, categorized:
<0.7 x ULN; 
[0.7,1.0] x ULN; 
]1.0,1.2[ x ULN;
≥ 1.2 x ULN
-
Change in CRP (baseline – screening)
-
Screening and baseline TJC68 and SJC66
-
Change in TJC68 and SJC66 = baseline – screening
-
Screening and baseline DAS28(CRP) – see further sections for the definition of the 
DAS28(CRP) 
-
Change in DAS28(CRP) = baseline – screening
-
Screening and baseline patient’s global evaluation of disease activity (0-100 mm 
VAS)
-
Change in patient’s global evaluation of disease activity = baseline – screening
-
Baseline investigator’s global evaluation of disease activity (0-100 mm VAS)
-
Baseline patient’s pain score (0-100 mm VAS)
-
Baseline HAQ-DI
-
Baseline SDAI
-
Baseline CDAI
-
RF status, classified as positive/negative based on the upper limit of the normal range 
(ULN):
o
Positive: value > ULN
o
Negative:. < value ≤ ULN
o
Missing: value is missing for any reason.
-
Anti-CCP status, classified as positive/negative based on the upper limit of the normal 
range (ULN):
o
Positive: value > ULN
o
Negative:. < value ≤ ULN
o
Missing: value is missing for any reason.
-
Affected joints identification  
-
Prior RA medication: 


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o
Generic names, also classified as: biological (anti-TNF or other biological 
DMARD), anti-TNF, other biological DMARD, conventional DMARD, 
NSAID, steroid, analgesic, other RA medication.
o
MTX duration (study screening date – date of start of MTX + 1 day), 
expressed in years. If there were multiple dosing periods of MTX, then the 
“duration” will add up all such episodes.
o
MTX duration, categorized as:
<0.5; 
[0.5,2[ ; 
[2,5[ ; 
[5,10[ ; 
[10,20[ ; 
≥20 years
o
MTX dose at the start of the study, expressed in mg/week
o
MTX dose at the start of the study, categorized as: 
<10 ; 
[10,15] ; 
]15,20] ; 
>20 mg/week
o
Steroids (as prednisolone-equivalent): total daily dose at the start of the study
o
Steroids (as prednisolone-equivalent): total daily dose at the start of the study, 
categorized as: 
<5 ;
[5,10[ ;
[10,15[ ;
[15,20[ ;
≥20 mg/day.
7.5.2. Analysis
Table 14.1.3.7:
Screening and baseline disease characteristics
Continuous parameters: descriptive statistics per treatment group (and overall). Overall p-
value to compare all groups: ANOVA model with factor treatment.
Categorical parameters: frequency tabulation per treatment group (and overall). Overall p-
value to compare all groups: Cochran-Mantel-Haenszel test for general association.
Population: safety, ITT, per-protocol.
Table to be created for the Week 12 interim analysis as well, but only for Safety and ITT
populations.
Table 14.1.3.8:
Screening and baseline disease characteristics by region
Same descriptive table as above, but split up for the 4 geographical regions.
Population: ITT.


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Table to be created for the Week 12 interim analysis as well.
Table 14.1.3.9:
Screening and baseline disease characteristics for ACR20 responders 
versus non-responders at Week 12
Same descriptive table as above, but split up for ACR20 responders and non-responders at 
Week 12.
Population: ITT.
Table to be created for the Week 12 interim analysis as well.
Table 14.1.3.10: Affected joints: Tabulation
Frequency table of the detailed affected joints, separately for: tender / swollen. No formal 
comparisons of treatment groups.
Population: Safety.
Table 14.1.3.11: Prior RA medication
Tabulation of the number of prior RA medications (split up for anti-TNF biological DMARD, 
other biological DMARD, conventional DMARD, NSAID, steroid, analgesic, other RA 
medication) and the generic terms per treatment group and overall. No formal comparisons of 
treatment groups.
Population: safety.
Table 14.1.3.12: Prior RA medication for ACR20 responders versus non-responders at 
Week 12
Same descriptive table as above, but split up for ACR20 responders and non-responders at 
Week 12. No formal comparisons of treatment groups.
Population: ITT.
Table 14.1.3.13: Prior methotrexate: Descriptive statistics
Descriptive statistics per treatment group (and overall) of the total prior MTX duration (in 
years) and the MTX dose at the start of the study (mg/week).
Frequency per treatment group (and overall) of the total prior MTX duration (in years).
Frequency per treatment group (and overall) of the MTX dose at the start of the study 
(mg/week).
Population: Safety.
Table 14.1.3.14: Prior steroid dose at the start of the study: Descriptive statistics
Descriptive statistics per treatment group (and overall) of the prior steroid dose at the start of 
the study (mg/day prednisolone-equivalent).


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Frequency per treatment group (and overall) of the prior steroid dose at the start of the study.
Population: Safety.
Listing 16.2.4.2: Prior RA medication
Listing per treatment group and per subject of the prior RA medications.
Population: safety.
7.6.
MEDICAL HISTORY AND CONCURRENT DISEASES
Table 14.1.3.15: Medical history: Tabulation
Frequency tabulation per treatment group (and overall) of the system organ classes and 
preferred terms, selecting only the medical history findings (i.e., condition no longer present 
at the start of the study).
Population: safety.
Table 14.1.3.16: Concurrent diseases: Tabulation
Frequency tabulation per treatment group (and overall) of the system organ classes and 
preferred terms.
Population: safety.
Listing 16.2.4.3: Medical history
Listing per treatment group and per subject of the medical history data findings (i.e., condition 
no longer present at the start of the study): original terms as well as coded terms.
Population: safety.
Listing 16.2.4.4: Concomitant diseases
Listing per treatment group and per subject of the concomitant diseases data findings (i.e., 
condition still present or unknown): original terms as well as coded terms.
Population: safety.
7.7.
PRIOR AND CONCOMITANT THERAPIES
Note that prior RA medications are presented in the section on baseline disease 
characteristics. They are not repeated here. 
7.7.1. Classification of Therapies
All prior and concomitant therapies will be allocated into exactly one of the following 
categories (using the analysis periods as defined in section 3.2):


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
Prior only: the therapy ended before the first study treatment administration.

Concomitant only: the therapy started on or after the first study drug administration.

Post-treatment: the therapy started after the last study drug administration.

Prior and concomitant: the therapy started before the first study drug administration, and
ended on or after the first study drug administration.
When the start date is completely missing, the therapy is assumed to have started on the same 
day as the first administration of study medication.
When the end date is missing, the therapy is assumed to be still ongoing after the end of the 
study.
When the start date is only partially known, the missing parts will be imputed by the first day 
of the month/year, or the day of the first medication intake in case the nonmissing part 
matches.
When the end date is only partially known, the missing parts will be imputed by the last day 
of the month/year, or the day of the last medication intake in case the nonmissing part 
matches.
Imputation of start and end dates is only done for the classification into prior / concomitant /
prior + concomitant. The listing will present the original start and end dates, also when 
incomplete. Fields like start and stop days will not be derived from imputed incomplete dates.
The relative study day of therapy start and stop will be derived as follows (only listed):
Start day
= (Therapy start date) – (date of first study medication administration) + 1, when the start date 
of therapy is known and complete, and when the therapy start date is on or after the date of 
first study medication;
= (Therapy start date) – (date of first study medication administration), when the start date of 
therapy is known and complete, and when the therapy start date is before the date of first 
study medication;
= missing when the start date of therapy is unknown, missing, or incomplete.
Stop day
= (Therapy stop date) – (date of first study medication administration) + 1, when the end date 
of therapy is known and complete, and the end date of therapy is on or after the date of first 
study medication;
= (Therapy stop date) – (date of first study medication administration), when the end date of 
therapy is known and complete, and the end date of therapy is before the date of first study 
medication;
= (Trial termination date) – (date of first study medication administration) + 1, when the 
therapy is still ongoing when the subject leaves the study; in such cases the stop day will be 
presented as “>XX days” in the listing;


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= missing when the end date of therapy is unknown, missing or incomplete and the therapy 
isn’t ongoing after the subject left the study.
7.7.2. Coding of Therapies
All therapies are coded using WHO-DRUG. In the table(s), the generic term will be used. 
Multiple records of the same generic term for the same subject with the same categorization 
will be counted only once. The table will therefore present subjects, not occurrences.
7.7.3. Analysis
Table 14.1.3.17: Prior therapies: Frequency table 
Frequency tabulation per treatment group (and overall) of the ATC classes and generic terms, 
of “prior” and “prior+concomitant” therapies only.
These are all the therapies that were used before the first intake of study medication.
Population: safety.
Table 14.1.3.18: Concomitant therapies up to Week 12: Frequency table 
Frequency tabulation per treatment group (and overall) of the ATC classes and generic terms, 
selecting both “concomitant” (with a start date during the first study period, or a missing start 
date) and “prior+concomitant” (all of them) therapies.
These are all the therapies that were used during the first 12 weeks of the study, 
concomitantly to the study medication.
Population: safety.
Table 14.1.3.19: Concomitant therapies over the whole study period: Frequency table 
Frequency tabulation per treatment group (and overall) of the ATC classes and generic terms, 
selecting “concomitant” and “prior+concomitant” therapies only.
These are all the therapies that were used during the study, concomitantly to the study 
medication.
Population: safety.
Table 14.1.3.20: Post-treatment therapies: Frequency table 
Frequency tabulation per treatment group (and overall) of the ATC classes and generic terms, 
selecting “post-treatment” therapies only.
These are all the therapies that were used during the study, but started after the last dose of 
study medication.
Population: safety.
Listing 16.2.4.5: Prior and concomitant therapies


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Listing per treatment group and per subject of all data on prior and concomitant therapies. 
Flags for prior/concomitant/post-treatment will be added. In case the therapy was due to an 
AE, the AE preferred term will be mentioned in this listing.
Population: safety.
7.8.
EXPOSURE TO STUDY MEDICATION AND COMPLIANCE
7.8.1. Derivations for placebo/GLPG0634
For the first period of the study (baseline – Week 12):

Total treatment duration (days) = (last dose administration date – first dose administration 
date) + 1 day, where the last dose administration date is cut off on the day prior to the 
Week 12 visit. (“Prior to the Week 12 visit”, because at the Week 12 visit the re-
randomization takes place and it is not known when exactly on that day the new study 
drug is being taken.)

Total treatment duration, excluding days off drug (days): sum of all durations (last – first 
+1) in the drug log pages where there is a morning and/or evening dose >0 capsules, and 
where the last duration is cut off on the day prior to the Week 12 visit.

Percentage days with an intake = 100% x 
	  	,   	

 
	 	
!

Total compliant treatment duration (days): sum of all durations (last – first +1) in the drug 
log pages where there is a morning and/or evening dose with exactly 2 capsules, and 
where the last duration is cut off on the day prior to the Week 12 visit.

Percentage compliance = 100% x 
	 	"  	
	 	
!
The “total duration” used as denominator in the above formulae equals: (date of Week 12 
visit) – (date of first drug intake). This total duration is not including the Week 12 visit itself, 
just like the above derivations, because of the treatment switch happening at Week 12 making 
it uncertain which drug intakes actually happened at the day of the visit itself.
For the total 24 weeks study period:

Total treatment duration (days) = (last dose administration date – first dose administration 
date) + 1 day.

Total treatment duration, excluding days off drug (days): sum of all durations (last – first 
+1) in the drug log pages where there is a morning and/or evening dose >0 capsules.

Percentage days with an intake = 100% x 
	  	,   	

 
	 	
!

Total compliant treatment duration (days): sum of all durations (last – first +1) in the drug 
log pages where there is a morning and/or evening dose with exactly 2 capsules.

Percentage compliance = 100% x 
	 	"  	
	 	
!
7.8.2. Tables up to Week 12
Table 14.1.4.1: 
Use of study medication up to Week 12: Descriptive statistics


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Descriptive statistics per treatment group (and overall) of the total treatment duration (days) 
and the overall compliance (%).
Frequency tabulation per treatment group (and overall) of the two treatment duration 
parameters, categorized in weeks.
Frequency tabulation per treatment group (and overall) of the days with intake and 
compliance, categorized as: 
<80% ;
[80%,100%[ ;
100% ;
]100%,120%] ;
>120%.
Population: safety.
7.8.3. Tables for the whole 24 weeks period
Table 14.1.4.2: 
Use of study medication over the whole study period: Descriptive 
statistics
Similar to the preceding table, also using the 11 treatment sequences of Chapter 3.
7.8.4. Listings
Listing 16.2.5.1: Exposure to study medication: eCRF data
Listing per treatment group and per subject of all data related to the use of study medication
as recorded in the eCRF.
Population: safety.
Listing 16.2.5.2: Exposure to study medication: Derived data
Listing per treatment group and per subject of all derived parameters related to the use of 
study medication.
Population: safety.
Listing 16.2.5.3: Dispensed kit numbers
Listing per treatment group and per subject of all dispensed placebo/GLPG0634 kit numbers, 
flagging any mistakes in dispensing.
Population: safety.


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7.9.
EXPOSURE TO METHOTREXATE AND COMPLIANCE
7.9.1. Derivations for methotrexate
The average weekly dose (mg) of methotrexate (MTX) in each of the two study periods is 
derived from summing up the durations of loglines with a weekly dose >0. The eCRF collects 
the use of MTX in terms of total weekly doses rather than daily doses.
For the first period of the study (screening – Week 12):

MTX dose change: decrease / no change / increase: at any time during the entire period, 
versus the dose used at the start of the study.

Total dose, excluding days off drug (days): sum of all doses (last – first +1) x (weekly 
dose in that period) in the MTX drug log pages where there is a weekly dose >0 mg, and 
where the first duration starts with the screening date and the last duration is cut off on 
the day of the Week 12 visit.
Average weekly dose (mg) = 
	 	
( 	
 #$ % 	
 ) / '
For the whole 24 weeks study period:

MTX dose change: decrease / no change / increase: at any time during the entire period, 
versus the dose used at the start of the study.

Total dose, excluding days off drug (days): sum of all doses (last – first +1) x (weekly 
dose in that period) in the MTX drug log pages where there is a weekly dose >0 mg, and 
where the first duration starts with the screening date and the last duration is cut off on 
the day of the Week 24/FU/Early discontinuation visit (whichever applies).
Average weekly dose (mg) = 
	 	
( 	
 #$ (/)*/+  , %  	
 #$ ) / '
7.9.2. Tables up to Week 12
Table 14.1.4.3: 
Changes in methotrexate up to Week 12: tabulation
Tabulation per treatment group (and overall) of the change in MTX dose (decrease/no 
change/increase).
Population: safety.
Table 14.1.4.4: 
Use of methotrexate up to Week 12: Descriptive statistics of the 
average weekly dose
Descriptive statistics per treatment group (and overall) and per study period of the average 
weekly dose (mg/week).
Frequency tabulation per treatment group (and overall) of the average weekly dose, 
categorized as: 
<10 ;
[10,15] ;
]15,20] ;
>20 mg/week.


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Population: safety.
7.9.3. Tables for the whole 24 weeks period
Similar tables, using the 11 treatment arms of Chapter 3:
Table 14.1.4.5: 
Changes in methotrexate over the whole study period: tabulation
Table 14.1.4.6: 
Use of methotrexate over the whole study period: Descriptive statistics
of the average weekly dose
7.9.4. Listings
Listing 16.2.5.4: Exposure to methotrexate: eCRF data
Listing per treatment group and per subject of all data related to the use of methotrexate, as 
recorded in the eCRF.
Population: safety.
Listing 16.2.5.5: Exposure to methotrexate: Derived data
Listing per treatment group and per subject of all derived parameters related to the use of 
methotrexate.
Population: safety.
8.
DEFINITIONS OF EFFICACY TABLES, LISTINGS AND 
FIGURES
Mock tables, listings and figures are provided in a separate document. 
All analyses will be run on the ITT population, unless specified otherwise.
General comment on the efficacy data listings: listings will present the observed-case time 
points, with imputed data (for components) clearly flagged. The LOCF- or NRI-imputed time 
points will not be shown.
General comments on the observed-case analysis: 


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
Is done for efficacy tables and listings, but not for efficacy plots.

Is done for Baseline, Week 12 and Week 24 in the descriptive statistics.

Is done for Week 12 only in the inferential statistics.

Is done for ITT only; not for per-protocol.
8.1.
ACR20, ACR50, ACR70 AND ACR-N
8.1.1. Parameters
ACR20 response when:

≥ 20% improvement from baseline in SJC66, and

≥ 20% improvement from baseline in TJC68, and

≥ 20% improvement from baseline in at least 3 of the following 5 items:

Pain VAS (taken from the HAQ-DI)

Patient’s Global Assessment of Disease Activity VAS

Physician’s Global Assessment of Disease Activity VAS

Total HAQ-DI score

CRP.
Subjects who do not meet this criterion are non-responders.
If any of the 7 components of the ACR20 would be missing, then this missing component will 
be imputed using the value of the last preceding nonmissing visit. If all components are
missing, then the derived ACR20 will remain missing. Imputation of such cases for the tables 
will be done there using LOCF or NRI like any other missing value.
Subjects who discontinue within the first week so that ACR20/50/70 responses cannot be 
determined will be classified as non-responders.
The ACR50 and ACR70 responses are derived using the same algorithm, but with 50% and 
70% cutoffs respectively.
Note that the primary endpoint of the study is the ACR20 at Week 12 in the ITT 
population, using NRI imputation.
The ACR-N is derived using the following formula:
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) ]
So this is taking the smallest of the percentage increases in SJC66, TJC68, and the third of the 
remaining 5 parameters. In case the ACR-N is negative (i.e., the subject actually worsens 
instead of improves), then the ACR-N is replaced by a 0. The ACR-N is therefore a number 
between 0 and 100.
The ACR-N represents the percentage NN% according to which the subjects would have been 
an “ACRNN” responder.


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(See further sections on how to derive these components.)
The time to ACR20 response
= (date of first time ACR20 response is reached) – (date of first medication intake) + 1 day, if 
the subject achieved ACR20 response during the initial 12 weeks treatment period, or
= MIN (date of the Week 12 visit , date of trial termination) – (date of first medication intake) 
+ 1 day, in case the subject did not achieve ACR20 response at any time during the initial 12 
weeks treatment period. 
Next to this, the visit during which the ACR20 response was first recorded will be analyzed as 
well: 

Week 1

Week 2

Week 4

Week 8

Week 12

Never (i.e., subject did not achieve ACR20 response during the initial 12 weeks of 
treatment). 
The time to ACR50 response and the time to ACR70 response are defined in the same way.
Note that the study period 2 cannot be used for the time-to-event derivation, because of the 
predefined potential treatment shifts at Week 12. 
Note that if for a specific visit both the regular CRP as well as the high-sensitive CRP are 
available, the high-sensitive CRP will be used for the derivation of the percentage change 
from baseline and also for the ACR20/50/70/N.
Note that the percentage change from baseline remains missing if the baseline value itself 
equals zero.
8.1.2. Tables over the whole 24 weeks period
Tables will present Weeks 1-2-4-8-12-16-20-24, unless specified otherwise. Tables will 
present the imputed 7 treatment groups, as mentioned in section 2.1.1.
Table 14.2.1.1.1: ACR20: Summary with overall p-value and pairwise comparisons 
versus placebo
Logistic regression model at each time point, modeling the responders. Factors in the model 
are: treatment, region, and previous use of biologics.
Per time point, the table will present:


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
Overall type-III p-value for all explanatory factors in the model.

Per group: number and percentage of responders, difference in percentage responders 
versus the placebo group (GLPG0634 minus placebo), together with a 95% confidence 
interval of this difference (as provided by SAS PROC FREQ).

Per group: p-value for pairwise comparison versus the placebo group, derived from 
contrasts within the overall regression model. These p-values will be presented both as 
uncorrected p-values as well as corrected for multiplicity according to Hommel’s closed-
testing method (SAS PROC MULTTEST).
The “raw” SAS PROC output must be provided in a statistical appendix listing.
The table will show:

NRI in ITT and in per-protocol

LOCF in ITT and in per-protocol

observed-case in ITT (descriptive at Week 12 + 24; inferential statistics at Week 12 
only).
Table to be created for the Week 12 interim analysis as well, cut off at Week 12. ITT only.
Table 14.2.1.1.2: ACR20: Exploratory pairwise comparisons among the dose groups 
within each regimen 
Logistic regression model at each time point, modeling the responders. Factors in the model 
are: treatment, region, and previous use of biologics. Placebo won’t be used, so can be 
omitted from the overall model.
Per time point, the table will present:

Per group: difference in percentage responders versus the other GLPG0634 groups within 
the same regimen (q.d. or b.i.d.), together with a 95% confidence interval of this 
difference (as provided by SAS PROC FREQ).

Per group: p-value for pairwise comparison versus the other GLPG0634 groups. These p-
values will be presented both as uncorrected p-values, and are derived as contrasts within 
the overall logistic regression model. As this is a purely exploratory analysis, no 
adjustment for multiplicity will be performed.
The “raw” SAS PROC output must be provided in a statistical appendix listing.
The table will show:

NRI in ITT and in per-protocol

LOCF in ITT and in per-protocol

observed-case in ITT (inferential statistics at Week 12 only).
Table to be created for the Week 12 interim analysis as well, cut off at Week 12. ITT only.
Table 14.2.1.1.3: ACR20: Exploratory pairwise comparisons between regimens within 
each daily dose level 
Logistic regression model at each time point, modeling the responders. Factors in the model 
are: regimen, dose, regimen*dose interaction, region, and previous use of biologics. Placebo 


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subjects will not be used in this model (as there is no q.d./b.i.d. regimen available for 
placebo). The regimen*dose interaction will be removed from the final model when not 
significant at level 0.10 (two-sided type-III p-value). Regimen will have 2 categories: q.d. or 
b.i.d. Dose will have 3 categories, corresponding to the total daily dose: 50 mg/day, 100 
mg/day, or 200 mg/day.
Per time point, the table will present:

Per dose: difference in percentage responders of q.d. versus b.i.d. within the same dose 
level (50, 100 or 200 mg/day), together with a 95% confidence interval of this difference
(as provided by SAS PROC FREQ).

Per group: p-value for pairwise comparison of q.d. versus b.i.d. These p-values will be 
presented both as uncorrected p-values, and are derived as contrasts within the overall 
logistic regression model. As this is a purely exploratory analysis, no adjustment for 
multiplicity will be performed.
The “raw” SAS PROC output must be provided in a statistical appendix listing.
The table will show:

NRI in ITT and in per-protocol

LOCF in ITT and in per-protocol

observed-case in ITT (inferential statistics at Week 12 only).
Table to be created for the Week 12 interim analysis as well, cut off at Week 12. ITT only.
Table 14.2.1.1.4: ACR50: Summary with overall p-value and pairwise comparisons 
versus placebo 
Repeat table of the ACR20 table.
The table will show:

NRI in ITT 

LOCF in ITT 

observed-case in ITT (descriptive at Week 12 + 24; inferential statistics at Week 12 
only).
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.
Table 14.2.1.1.5: ACR50: Exploratory pairwise comparisons among the dose groups 
within each regimen 
Repeat table of the ACR20 table.
The table will show:

NRI in ITT 

LOCF in ITT 

observed-case in ITT (inferential statistics at Week 12 only).
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.


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Table 14.2.1.1.6: ACR50: Exploratory pairwise comparisons between regimens within 
each daily dose level 
Repeat table of the ACR20 table.
The table will show:

NRI in ITT 

LOCF in ITT 

observed-case in ITT (inferential statistics at Week 12 only).
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.
Table 14.2.1.1.7: ACR70: Summary with overall p-value and pairwise comparisons 
versus placebo 
Repeat table of the ACR20 table.
The table will show:

NRI in ITT 

LOCF in ITT 

observed-case in ITT (descriptive at Week 12 + 24; inferential statistics at Week 12 
only).
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.
Table 14.2.1.1.8: ACR70: Exploratory pairwise comparisons among the dose groups 
within each regimen 
Repeat table of the ACR20 table.
The table will show:

NRI in ITT 

LOCF in ITT 

observed-case in ITT (inferential statistics at Week 12 only).
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.
Table 14.2.1.1.9: ACR70: Exploratory pairwise comparisons between regimens within 
each daily dose level 
Repeat table of the ACR20 table.
The table will show:

NRI in ITT 

LOCF in ITT 

observed-case in ITT (inferential statistics at Week 12 only).
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.


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Table 14.2.1.1.10:ACR20 at Week 12: Tabulation versus baseline characteristics
The table will show two methods of imputing missing values: LOCF and NRI.
Frequency tabulation of the ACR20 response rate at Week 12 per treatment group, split up 
according to the following baseline categories:

Demographics:

Region (as used in the central randomization)

Country

Gender

Age categories: 
< 45 ; 
[45,65[ ; 
[65,75[ ; 
≥ 75 years 

BMI categories: 
≤ 18.5;
] 18.5 , 25.0 ] ; 
] 25 , 30 [, 
≥ 30 kg/m²

Baseline disease characteristics:

Duration of RA: 
< 1; 
[ 1 , 2 [ ; 
[ 2 , 5 [ ; 
[ 5 , 10 [ ; 
[ 10 , 20 [ ; 
≥ 20 years

Baseline CRP: 
<0.7 x ULN;
[0.7,1.0] x ULN;
]1.0,1.2[ x ULN;
≥1.2 x ULN

Baseline TJC68: < 20, ≥ 20

Baseline SJC66: < 20, ≥ 20

Baseline DAS28(CRP): high, moderate, low, remission (see further section on 
DAS28 for the definition of these categories)

RF status

Anti-CCP status

Previous use of:

Biological (anti-TNF or other biological DMARD) yes/no,

anti-TNF yes/no, 

other biological DMARD yes/no, 

conventional DMARD yes/no, 

NSAID yes/no, 

steroid yes/no, 


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
analgesic yes/no, 

other RA medication yes/no.
Population: ITT.
Table to be created for the Week 12 interim analysis as well.
Table 14.2.1.1.11:ACR20 at Week 12: Exploratory logistic regression model containing 
baseline characteristics
The table will show two methods of imputing missing values: LOCF and NRI.
Logistic regression model of the ACR20 response at Week 12, with the following exploratory 
factors:

Treatment group

Demographics:

Region

Country

Gender

Age as continuous variable

BMI as continuous variable

Baseline disease characteristics:

Duration of RA as continuous variable

Baseline CRP as continuous variable

Baseline TJC68 and SJC66 as continuous variables

Baseline DAS28(CRP) as continuous variable

RF status

anti-CCP status

Previous use of:

Biological (anti-TNF or other biological DMARD) yes/no,

anti-TNF yes/no, 

other biological DMARD yes/no, 

conventional DMARD yes/no, 

NSAID yes/no, 

steroid yes/no, 

analgesic yes/no, 

other RA medication yes/no.
All these factors will be tested using a stepwise selection approach. Significance level to enter 
the model: 0.10; significance level to stay in the model: 0.05. The treatment groups will 
always be kept in the model, even when not significant at level 0.05. The table will present 
only the final model with type-III p-value and odds ratio estimates. The “raw” SAS PROC 
output must be provided in a statistical appendix listing, and will contain all details on the 
model building steps.
Population: ITT.


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Table 14.2.1.1.12:ACR-N: Summary with overall p-value and pairwise comparisons 
versus placebo 
P-values are generated from an ANOVA model at each time point. Factors in the model are: 
treatment, region, and previous use of biologics.
Per time point, the table will present:

Per group: sample regular statistics.

Per group: difference in LS-means versus the placebo group (GLPG0634 minus placebo), 
together with a 95% confidence interval of this difference.

Overall type-III p-value for “treatment”.

Per group: p-value for pairwise comparison versus the placebo group, derived from 
contrasts within the overall model. These p-values will be presented both as uncorrected 
p-values as well as corrected for multiplicity according to Hommel’s closed-testing 
method (SAS PROC MULTTEST).
Frequency per time point (weeks 12 and 24 only), and per treatment group. ACR-N will be 
presented in the following categories: 
<10, 
[10,20[, 
[20,30[, 
[30,40[, 
[40,50[, 
[50,60[, 
[60,70[, 
[70,80[, 
[80,90[, 
[90,100].
The “raw” SAS PROC output must be provided in a statistical appendix listing.
The table will show:

LOCF in ITT 

observed-case in ITT (descriptive at Week 12 + 24; inferential statistics at Week 12 
only).
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.
Table 14.2.1.1.13:ACR-N: Exploratory pairwise comparisons among the dose groups 
within each regimen 
ANOVA model at each time point. Factors in the model are: treatment, region, and previous 
use of biologics. Placebo won’t be used, so can be omitted from the overall model.
Per time point, the table will present:

Per group: difference in LS-means versus the other GLPG0634 groups within the same 
regimen (q.d. or b.i.d.), together with a 95% confidence interval of this difference.

Per group: p-value for pairwise comparison versus the other GLPG0634 groups. These p-
values will be presented both as uncorrected p-values, and are derived as contrasts within


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the overall model. As this is a purely exploratory analysis, no adjustment for multiplicity 
will be performed.
The “raw” SAS PROC output must be provided in a statistical appendix listing.
The table will show:

LOCF in ITT 

observed-case in ITT (inferential statistics at Week 12 only).
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.
Table 14.2.1.1.14:ACR-N: Exploratory pairwise comparisons between regimens within 
each daily dose level 
ANCOVA model at each time point. Factors in the model are: regimen, dose, regimen*dose 
interaction, region, and previous use of biologics. Placebo subjects will not be used in this 
model (as there is no q.d./b.i.d. regimen available for placebo). The regimen*dose interaction 
will be removed from the final model when not significant at level 0.10 (two-sided type-III p-
value). Regimen will have 2 categories: q.d. or b.i.d. Dose will have 3 categories, 
corresponding to the total daily dose: 50 mg/day, 100 mg/day, or 200 mg/day.
Per time point, the table will present:

Per dose: difference in LS-means of q.d. versus b.i.d. within the same dose level (50, 100 
or 200 mg/day), together with a 95% confidence interval of this difference.

Per group: p-value for pairwise comparison of q.d. versus b.i.d. These p-values will be 
presented both as uncorrected p-values, and are derived as contrasts within the overall 
model. As this is a purely exploratory analysis, no adjustment for multiplicity will be 
performed.
The “raw” SAS PROC output must be provided in a statistical appendix listing.
The table will show:

LOCF in ITT 

observed-case in ITT (inferential statistics at Week 12 only).
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.
Table 14.2.1.1.15:Time to ACR20 response: Summary with overall p-value and pairwise 
comparisons versus placebo
Descriptive statistics per treatment group.
Between-group comparison (overall and all pairwise comparisons versus placebo
P-values are generated from a Cox proportional hazards regression model. Factors in the 
model are: treatment, region, and previous use of biologics.
The table will present:

Per group: N (number of events, number of censored, number in total), mean (SE), 
median, quartiles.


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
Overall type-III p-values for treatment, region and previous use of biologics.

Per group: p-value for pairwise comparison versus the placebo group. These p-values will 
be corrected for multiplicity according to Hommel’s closed-testing method as 
implemented in SAS PROC MULTTEST. The uncorrected p-values will also be 
presented.
A frequency table of the time-to-event in categories (Week 1, Week 2, Week 4, Week 8, 
Week 12, never) will also be presented.
The “raw” SAS PROC output must be provided in a statistical appendix listing.
Population: ITT.
Table 14.2.1.1.16:Time to ACR20 response: Exploratory pairwise comparisons among 
the dose groups within each regimen 
Cox proportional hazards regression model. Factors in the model are: treatment, region, and 
previous use of biologics. Placebo won’t be used, so can be omitted from the overall model.
The table will present per group: p-value for pairwise comparison versus the other GLPG0634 
groups. These p-values will be presented both as uncorrected p-values, and are derived as 
contrasts within the overall model. As this is a purely exploratory analysis, no adjustment for 
multiplicity will be performed.
The “raw” SAS PROC output must be provided in a statistical appendix listing.
Population: ITT.
Table 14.2.1.1.17:Time to ACR20 response: Exploratory pairwise comparisons between 
regimens within each daily dose level 
Cox proportional hazards regression model. Factors in the model are: regimen, dose, 
regimen*dose interaction, region, and previous use of biologics. Placebo subjects will not be 
used in this model (as there is no q.d./b.i.d. regimen available for placebo). The regimen*dose 
interaction will be removed from the final model when not significant at level 0.10 (two-sided 
type-III p-value). Regimen will have 2 categories: q.d. or b.i.d. Dose will have 3 categories, 
corresponding to the total daily dose: 50 mg/day, 100 mg/day, or 200 mg/day.
The table will present per group: p-value for pairwise comparison of q.d. versus b.i.d. These 
p-values will be presented both as uncorrected p-values, and are derived as contrasts within 
the overall model. As this is a purely exploratory analysis, no adjustment for multiplicity will 
be performed.
The “raw” SAS PROC output must be provided in a statistical appendix listing.
Population: ITT.
Table 14.2.1.1.18:Time to ACR50 response: Summary with overall p-value and pairwise 
comparisons versus placebo
Repeat table of the ACR20 table.


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Population: ITT.
Table 14.2.1.1.19:Time to ACR50 response: Exploratory pairwise comparisons among 
the dose groups within each regimen 
Repeat table of the ACR20 table.
Population: ITT.
Table 14.2.1.1.20:Time to ACR50 response: Exploratory pairwise comparisons between 
regimens within each daily dose level 
Repeat table of the ACR20 table.
Population: ITT.
Table 14.2.1.1.21:Time to ACR70 response: Summary with overall p-value and pairwise 
comparisons versus placebo
Repeat table of the ACR20 table.
Population: ITT.
Table 14.2.1.1.22:Time to ACR70 response: Exploratory pairwise comparisons among 
the dose groups within each regimen 
Repeat table of the ACR20 table.
Population: ITT.
Table 14.2.1.1.23:Time to ACR70 response: Exploratory pairwise comparisons between 
regimens within each daily dose level 
Repeat table of the ACR20 table.
Population: ITT.
8.1.3. Figures over the whole 24 weeks period
Figure 14.2.1.1.1:ACR20/50/70: Plot per week 
Vertical bar chart of the ACR20, ACR50 and ACR70 response rates for the 7 treatment 
groups. Separate plot per week.
The plot will show two methods of imputing missing values: LOCF and NRI.
Population: ITT.
Figure 14.2.1.1.2:ACR20: Plot over time 
Line plot of the ACR20 response rates, with a separate line for each of the 7 treatment groups.


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The plot will show two methods of imputing missing values: LOCF and NRI.
Population: ITT.
Figure 14.2.1.1.3:ACR50: Plot over time 
Same plot for the ACR50 response.
The plot will show two methods of imputing missing values: LOCF and NRI.
Population: ITT.
Figure 14.2.1.1.4:ACR70: Plot over time 
Same plot for the ACR70 response.
The plot will show two methods of imputing missing values: LOCF and NRI.
Population: ITT.
Figure 14.2.1.1.5:ACR-N: Plot over time
Mean (without SE) plot of the ACR-N, with a separate line for each of the 7 treatment groups.
LOCF only.
Population: ITT.
Figure 14.2.1.1.6:Time to ACR20 response: Kaplan-Meier plot
Ascending Kaplan-Meier plot per treatment group.
Population: ITT.
Figure 14.2.1.1.7:Time to ACR50 response: Kaplan-Meier plot
Ascending Kaplan-Meier plot per treatment group.
Population: ITT.
Figure 14.2.1.1.8:Time to ACR70 response: Kaplan-Meier plot
Ascending Kaplan-Meier plot per treatment group.
Population: ITT.
8.1.4. Tables after Week 12
Tables will present only Weeks 12-16-20-24, unless specified otherwise. Tables will show the 
15 arms of the “third efficacy analysis chapter”.”.
Table 14.2.1.1.24:ACR20 after Week 12: Frequency table 
Frequency table per time point, and per treatment group (15 arms). 


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The table will show:

NRI in ITT

LOCF in ITT 

observed-case in ITT (weeks 12 + 24)
Table 14.2.1.1.25:ACR50 after Week 12: Frequency table 
Repeat table of the ACR20 table.
The table will show:

NRI in ITT 

LOCF in ITT 

observed-case in ITT (weeks 12 + 24)
Table 14.2.1.1.26:ACR70 after Week 12: Frequency table 
Repeat table of the ACR20 table.
The table will show:

NRI in ITT 

LOCF in ITT 

observed-case in ITT (weeks 12 + 24)
Table 14.2.1.1.27:ACR-N after Week 12: Descriptive statistics 
Descriptive statistics per time point, and per treatment group (15 arms).
Frequency at Weeks 12 and 24: per treatment group (15 arms). ACR-N will be presented in 
the following categories: 
<10, 
[10,20[, 
[20,30[, 
[30,40[, 
[40,50[, 
[50,60[, 
[60,70[, 
[70,80[, 
[80,90[, 
[90,100].
The table will show:

LOCF in ITT 

observed-case in ITT (weeks 12 + 24)
8.1.5. Figures after Week 12
No figures planned.


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8.1.6. Listings
Listing 16.2.6.1: ACR20, ACR50, ACR70 and ACR-N
Listing per treatment group, per subject and per time point of the ACR20/50/70 and ACR-N 
and their components.
Population: ITT.
8.2.
EULAR REMISSION
8.2.1. Parameters
EULAR remission: 

“YES” when TJC28 ≤ 1 and SJC28 ≤ 1 and CRP ≤ 1 mg/dL and patient’s global 
assessment of disease activity VAS ≤ 1 cm (or 10 mm).

“NO” when at least 1 of the 4 components has a value > 1. Note: in case of missing 
components, it is still possible to qualify as “non remission” if at least 1 of the 
nonmissing components has a value > 1. 

“MISSING” in all remaining cases.
If any of the 4 components of the EULAR would be missing, then this missing component 
will be imputed using the value of the last preceding nonmissing visit.
8.2.2. Tables over the whole 24 weeks
Tables will present Baseline-Weeks 1-2-4-8-12-16-20-24. Similar analysis tables as for 
ACR20 will be made. Analysis population: ITT. NRI, LOCF and observed case (descriptive 
only at weeks 12 + 24).
Table 14.2.1.2.1: EULAR remission: Summary with overall p-value and pairwise 
comparisons versus placebo 
Table 14.2.1.2.2: EULAR remission: Exploratory pairwise comparisons among the dose 
groups within each regimen 
Table 14.2.1.2.3: EULAR remission: Exploratory pairwise comparisons between 
regimens within each daily dose level 
8.2.3. Figures over the whole 24 weeks period
The same bar chart and line plot as for the ACR20 will be made. Population: ITT. NRI and 
LOCF imputations only.
Figure 14.2.1.2.1:EULAR remission: Plot per week
Figure 14.2.1.2.2:EULAR remission: Plot over time 


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8.2.4. Tables after Week 12
Table 14.2.1.2.4: EULAR remission after Week 12: Frequency table 
Table will present Weeks 12-16-20-24 for the 15 arms of “efficacy chapter 3”. A similar 
descriptive analysis as for ACR20 will be performed. Analysis population: ITT. NRI, LOCF 
and observed case (weeks 12 + 24).
8.2.5. Figures after Week 12
No figures planned.
8.2.6. Listings
Listing 16.2.6.2: EULAR remission
Listing per treatment group, per subject and per time point of the EULAR remission category 
and its components.
Population: ITT.
8.3.
SDAI AND CDAI SCORES
8.3.1. Parameters
SDAI = TJC28 + SJC28 + patient’s disease activity VAS (in cm)+ investigator’s disease 
activity VAS (in cm) + CRP (in mg/dL).
CDAI = TJC28 + SJC28 + patient’s disease activity VAS (in cm)+ investigator’s disease 
activity VAS (in cm).
(TJC28 and SJC28 are the 28 joint counts for tenderness and swelling. See further sections on 
how to derive these components.)
CDAI and SDAI scores can only be derived when all components are nonmissing. If any of 
the components would be missing, then this missing component will be imputed using the 
value of the last preceding nonmissing visit.
Note that if for a specific visit both the regular CRP as well as the high-sensitive CRP are 
available, the high-sensitive CRP will be used for the derivation of the SDAI.
Apart from the actual scores, the changes from baseline and percent changes from baseline 
will be derived.
The SDAI is also categorized:


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
High disease activity: SDAI > 26

Moderate disease activity: SDAI in ] 11 , 26 ]

Low disease activity: SDAI in ] 3.3 , 11 ]

Remission: SDAI ≤ 3.3 
The CDAI is also categorized:

High disease activity: CDAI > 22

Moderate disease activity: CDAI in ] 10 , 22 ]

Mild disease activity: CDAI in ] 2.8 , 10 ]

Remission: CDAI ≤ 2.8
Note that the percentage change from baseline remains missing if the baseline value itself 
equals zero.
8.3.2. Tables over the whole 24 weeks period
Tables will present Baseline-Weeks 1-2-4-8-12-16-20-24, unless specified otherwise. 
Analysis population: ITT. LOCF and observed case (descriptive only at Baseline and Weeks 
12 + 24).
Table 14.2.1.3.1: SDAI and CDAI: Descriptive statistics of the actual values
Descriptive statistics of the actual values per time point, and per treatment group.
Frequency per time point (all time points), and per treatment group. SDAI and CDAI will be 
presented in the categories defined above (remission, low, moderate, high).
The table will show:

LOCF in ITT 

observed-case in ITT (Baseline, Week 12 and Week 24 only)
Table 14.2.1.3.2: SDAI and CDAI: Descriptive statistics of the change from baseline
Descriptive statistics of the changes from baseline per time point, and per treatment group.
The table will show:

LOCF in ITT 

observed-case in ITT (weeks 12 + 24 only)
Table 14.2.1.3.3: SDAI and CDAI: Descriptive statistics of the percent change from 
baseline
Descriptive statistics of the percent changes from baseline per time point, and per treatment 
group.
Frequency table at Weeks 12 and 24 with cumulative percentages of the percent change from 
baseline, categorized as:


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≥ 0,
[ -10 , 0 [,
[ -20 , -10 [,
[ -30 , -20 [,
[ -40 , -30 [,
[ -50 , -40 [,
[ -60 , -50 [,
[ -70 , -60 [,
[ -80 , -70 [,
[ -90 , -80 [,
[ -100 , -90 [.
The table will show:

LOCF in ITT 

observed-case in ITT (weeks 12 + 24 only)
Table 14.2.1.3.4: SDAI and CDAI: Summary with overall p-value and pairwise 
comparisons versus placebo 
ANCOVA model on the change from baseline at each time point. Factors in the model are: 
treatment, baseline value, region, and previous use of biologics.
Per time point, the table will present:

Overall type-III p-value for all explanatory factors in the model.

Per group: difference in LS-means versus the placebo group (GLPG0634 minus placebo), 
together with a 95% confidence interval of this difference.

Per group: p-value for pairwise comparison versus the placebo group, derived from 
contrasts within the overall model. These p-values will be presented both as uncorrected 
p-values as well as corrected for multiplicity according to Hommel’s closed-testing 
method (SAS PROC MULTTEST).
The “raw” SAS PROC output must be provided in a statistical appendix listing.
The table will show:

LOCF in ITT 
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.
Table 14.2.1.3.5: SDAI and CDAI: Exploratory pairwise comparisons among the dose 
groups within each regimen 
ANCOVA model on the changes from baseline at each time point. Factors in the model are: 
treatment, baseline value, region, and previous use of biologics. Placebo won’t be used, so can 
be omitted from the overall model.
Per time point, the table will present:


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
Per group: difference in LS-means versus the other GLPG0634 groups within the same 
regimen (q.d. or b.i.d.), together with a 95% confidence interval of this difference.

Per group: p-value for pairwise comparison versus the other GLPG0634 groups. These p-
values will be presented both as uncorrected p-values, and are derived as contrasts within 
the overall model. As this is a purely exploratory analysis, no adjustment for multiplicity 
will be performed.
The “raw” SAS PROC output must be provided in a statistical appendix listing.
The table will show:

LOCF in ITT 
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.
Table 14.2.1.3.6: SDAI and CDAI: Exploratory pairwise comparisons between 
regimens within each daily dose level 
ANCOVA model on the change from baseline at each time point. Factors in the model are: 
baseline value, regimen, dose, regimen*dose interaction, region, and previous use of 
biologics. Placebo subjects will not be used in this model (as there is no q.d./b.i.d. regimen 
available for placebo). The regimen*dose interaction will be removed from the final model 
when not significant at level 0.10 (two-sided type-III p-value). Regimen will have 2 
categories: q.d. or b.i.d. Dose will have 3 categories, corresponding to the total daily dose: 50 
mg/day, 100 mg/day, or 200 mg/day.
Per time point, the table will present:

Per dose: difference in LS-means of q.d. versus b.i.d. within the same dose level (50, 100 
or 200 mg/day), together with a 95% confidence interval of this difference.

Per group: p-value for pairwise comparison of q.d. versus b.i.d. These p-values will be 
presented both as uncorrected p-values, and are derived as contrasts within the overall 
model. As this is a purely exploratory analysis, no adjustment for multiplicity will be 
performed.
The “raw” SAS PROC output must be provided in a statistical appendix listing.
The table will show:

LOCF in ITT 
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.
Table 14.2.1.3.7: SDAI and CDAI remission: Summary with overall p-value and 
pairwise comparisons versus placebo 
Similar table as for ACR20, presenting the rates of SDAI remission and CDAI remission at 
Week 12 and Week 24.
The table will show: 

NRI in ITT

LOCF in ITT 


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
observed-case in ITT (descriptive at Week 12 + 24; inferential statistics at Week 12 
only).
Table 14.2.1.3.8: SDAI and CDAI remission: Exploratory pairwise comparisons among 
the dose groups within each regimen 
Table 14.2.1.3.9: SDAI and CDAI remission: Exploratory pairwise comparisons 
between regimens within each daily dose level 
8.3.3. Figures over the whole 24 weeks period
LOCF only. Population: ITT.
Figure 14.2.1.3.1:SDAI and CDAI: Plot of the actual values over time
Mean (without SE) plot of the actual values over time up to (and including) Week 24, with a 
separate line for each of the 7 treatment groups.
Population: ITT.
Figure 14.2.1.3.2:SDAI and CDAI: Plot of the changes from baseline over time 
Mean (without SE) plot of the changes from baseline over time up to (and including) Week 
24, with a separate line for each of the 7 treatment groups. With a horizontal reference line at 
0, indicating no change.
Population: ITT.
Figure 14.2.1.3.3:SDAI and CDAI: Plot of the percent changes from baseline over time 
Repeat plot for the percent change.
Population: ITT.
8.3.4. Tables after Week 12
Tables will present Weeks 12-16-20-24, unless specified otherwise, for the 15 arms of 
“efficacy chapter 3”. A similar descriptive analysis will be performed. Analysis population: 
ITT. LOCF and observed case (weeks 12 +24).
Table 14.2.1.3.10:SDAI and CDAI after Week 12: Descriptive statistics of the actual 
values
Table 14.2.1.3.11:SDAI and CDAI after Week 12: Descriptive statistics of the change 
from baseline
Table 14.2.1.3.12:SDAI and CDAI after Week 12: Descriptive statistics of the percent 
change from baseline
8.3.5. Figures after Week 12
No figures planned.


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8.3.6. Listings
Listing 16.2.6.3: SDAI and CDAI
Listing per treatment group, per subject and per time point of the SDAI and CDAI scores and 
their components. SDAI and CDAI: actual values, changes from baseline, percent changes 
from baseline, and the categorization.
Population: ITT.
8.4.
DAS28(CRP)
8.4.1. Parameters
DAS28(CRP) = 0.56 x -TJC28 + 0.28 x -SJC28 + 0.36 x Ln[1+CRP(in mg/L)] + 0.014 x 
patient’s disease activity VAS (in mm) + 0.96
(TJC28 and SJC28 are the 28 joint counts for tenderness and swelling. See further sections on 
how to derive these components. Ln = natural logarithm.)
DAS28(CRP scores can only be derived when all components are nonmissing. If any of the 
components of the DAS28(CRP) would be missing, then this missing component will be 
imputed using the value of the last preceding nonmissing visit.
Note that if for a specific visit both the regular CRP as well as the high-sensitive CRP are 
available, the high-sensitive CRP will be used for the derivation of the DAS28(CRP).
Note that the percentage change from baseline remains missing if the baseline value itself 
equals zero.
Next to the actual DAS28(CRP) value, also the changes and percent changes from baseline 
will be derived.
Categorization of the DAS28(CRP) scores:

High disease activity: > 5.1

Moderate disease activity: ] 3.2 , 5.1 ]

Low disease activity: [ 2.6 , 3.2 ]

Remission: < 2.6
A second categorization of the DAS28(CRP) into EULAR response categories (none, 
moderate, good) will be done according to the following:


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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
8.4.2. Tables over the whole 24 weeks period
Tables will present Baseline-Weeks 1-2-4-8-12-16-20-24, unless specified otherwise. A 
similar analysis as to SDAI and CDAI will be performed. Analysis population: ITT. LOCF 
and observed case (descriptive at Baseline, Week 12 and Week 24; inferential statistics only 
at Week 12).
Table 14.2.1.4.1: DAS28(CRP): Descriptive statistics of the actual values
(descriptive statistics, including a frequency table at all time points)
Analysis population: ITT and per-protocol.
Table to be created for the Week 12 interim analysis as well, cut off at Week 12. ITT only.
Table 14.2.1.4.2: DAS28(CRP): Descriptive statistics of the change from baseline
(descriptive statistics, including a shift table at all time points)
Analysis population: ITT and per-protocol.
Table to be created for the Week 12 interim analysis as well, cut off at Week 12. ITT only.
Table 14.2.1.4.3: DAS28(CRP): Descriptive statistics of the percent change from 
baseline
(descriptive statistics, including a frequency table at Weeks 12 + 24)
Analysis population: ITT and per-protocol.
Table to be created for the Week 12 interim analysis as well, cut off at Week 12. ITT only.
Table 14.2.1.4.4: DAS28(CRP): Summary with overall p-value and pairwise 
comparisons versus placebo 
Analysis population: ITT and per-protocol.
Table to be created for the Week 12 interim analysis as well, cut off at Week 12. ITT only.
Table 14.2.1.4.5: DAS28(CRP): Exploratory pairwise comparisons among the dose 
groups within each regimen 
Analysis population: ITT and per-protocol.


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Table to be created for the Week 12 interim analysis as well, cut off at Week 12. ITT only.
Table 14.2.1.4.6: DAS28(CRP): Exploratory pairwise comparisons between regimens 
within each daily dose level 
Analysis population: ITT and per-protocol.
Table to be created for the Week 12 interim analysis as well, cut off at Week 12. ITT only.
Table 14.2.1.4.7: DAS28(CRP) change from baseline at Week 12: Tabulation versus 
baseline characteristics
The table will show LOCF only.
Descriptive statistics of the DAS28(CRP) change from baseline at Week 12 per treatment 
group, split up according to the following baseline categories:

Demographics:

Region (as used in the central randomization)

Country

Gender

Age categories: 
< 45 ; 
[45,65[ ; 
[65,75[ ; 
≥ 75 years 

BMI categories: 
≤ 18.5;
] 18.5 , 25.0 ] ; 
] 25 , 30 [, 
≥ 30 kg/m²

Baseline disease characteristics:

Duration of RA: 
< 1; 
[ 1 , 2 [ ; 
[ 2 , 5 [ ; 
[ 5 , 10 [ ; 
[ 10 , 20 [ ; 
≥ 20 years

Baseline CRP: 
<0.7 x ULN;
[0.7,1.0] x ULN;
]1.0,1.2[ x ULN;
≥ 1.2 x ULN

Baseline TJC68: < 20, ≥ 20

Baseline SJC66: < 20, ≥ 20

Baseline DAS28(CRP): high, moderate, low, remission (see further section on 
DAS28 for the definition of these categories)

RF status


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
Anti-CCP status

Previous use of:

Biological (anti-TNF or other biological DMARD) yes/no 

anti-TNF yes/no, 

other biological DMARD yes/no, 

conventional DMARD yes/no, 

NSAID yes/no, 

steroid yes/no, 

analgesic yes/no, 

other RA medication yes/no.
Population: ITT.
Table to be created for the Week 12 interim analysis as well.
Table 14.2.1.4.8: DAS28(CRP) change from baseline at Week 12: Exploratory 
ANCOVA model containing baseline characteristics
The table will show LOCF only.
ANCOVA model of the DAS28(CRP) change from baseline at Week 12, with the following 
exploratory factors:

Treatment group

Demographics:

Region

Country

Gender

Age as continuous variable

BMI as continuous variable

Baseline disease characteristics:

Duration of RA as continuous variable

Baseline CRP as continuous variable

Baseline TJC68 and SJC66 as continuous variables

Baseline DAS28(CRP) as continuous variable

RF status

anti-CCP status

Previous use of:

Biological (anti-TNF or other biological DMARD) yes/no 

anti-TNF yes/no, 

other biological DMARD yes/no, 

conventional DMARD yes/no, 

NSAID yes/no, 

steroid yes/no, 

analgesic yes/no, 

other RA medication yes/no.


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All these factors will be tested using a stepwise selection approach. Significance level to enter 
the model: 0.10; significance level to stay in the model: 0.05. The treatment groups will 
always be kept in the model, even when not significant at level 0.05. The table will present 
only the final model with type-III p-value and LS-mean estimates. The “raw” SAS PROC 
output must be provided in a statistical appendix listing, and will contain all details on the 
model building steps.
Population: ITT.
Table 14.2.1.4.9: DAS28(CRP) remission: Summary with overall p-value and pairwise 
comparisons versus placebo 
Similar table as for ACR20, presenting the rates of DAS28(CRP) remission at Week 12 and 
Week 24.
The table will show: 

NRI in ITT

LOCF in ITT 

observed-case in ITT (descriptive at Week 12 + 24; inferential statistics at Week 12 
only).
Table 14.2.1.4.10:DAS28(CRP) remission: Exploratory pairwise comparisons among the 
dose groups within each regimen 
Table 14.2.1.4.11:DAS28(CRP) remission: Exploratory pairwise comparisons between 
regimens within each daily dose level 
Table 14.2.1.4.12:DAS28(CRP) remission and low disease activity: Summary with 
overall p-value and pairwise comparisons versus placebo 
Similar table as for the remission, but now combining “remission” and “low disease activity” 
into one percentage.
Table 14.2.1.4.13:DAS28(CRP) remission and low disease activity: Exploratory pairwise 
comparisons among the dose groups within each regimen 
Table 14.2.1.4.14:DAS28(CRP) remission and low disease activity: Exploratory pairwise 
comparisons between regimens within each daily dose level 
Table 14.2.1.4.15:DAS28(CRP) EULAR response: Frequency table
Frequency per time point, and per treatment group. EULAR response will be presented in the 
categories defined above (none, moderate, good).
Overall p-value and pairwise comparisons versus placebo: Cochran-Mantel-Haenszel test for 
row mean score differences, controlling for region and prior biologics. These p-values will be 
corrected for multiplicity according to Hommel’s closed-testing method as implemented in 
SAS PROC MULTTEST. The uncorrected p-values will also be presented.
Population: ITT and per-protocol.


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Table 14.2.1.4.16:DAS28(CRP) EULAR response: Exploratory pairwise comparisons 
among the dose groups within each regimen 
Analysis population: ITT and per-protocol.
Comparisons between the doses within each regimen: Cochran-Mantel-Haenszel test for row 
mean score differences, controlling for region and prior biologics. As this is purely 
exploratory, no correction for multiplicity will be done.
Table 14.2.1.4.17:DAS28(CRP) EULAR response: Exploratory pairwise comparisons 
between regimens within each daily dose level 
Analysis population: ITT and per-protocol.
Comparisons between the regimens within each daily dose level: Cochran-Mantel-Haenszel 
test for row mean score differences, controlling for region and prior biologics. The placebo 
subjects will not be used for this comparison. As this is purely exploratory, no correction for 
multiplicity will be done.
8.4.3. Figures over the whole 24 weeks period
Same type of mean line plots as for the SDAI and CDAI. Population: ITT. LOCF only.
Figure 14.2.1.4.1:DAS28(CRP): Plot of the actual values over time 
Figure 14.2.1.4.2:DAS28(CRP): Plot of the changes from baseline over time 
Figure 14.2.1.4.3:DAS28(CRP): Plot of the percent changes from baseline over time 
8.4.4. Tables after Week 12
Tables will present Weeks 12-16-20-24, unless specified otherwise, for the 15 arms of 
“efficacy chapter 3”. A similar descriptive analysis as to SDAI and CDAI will be performed. 
Analysis population: ITT. LOCF and observed case (weeks 12 + 24).
Table 14.2.1.4.18:DAS28(CRP) after Week 12: Descriptive statistics of the actual values
Table 14.2.1.4.19:DAS28(CRP) after Week 12: Descriptive statistics of the change from 
baseline
Table 14.2.1.4.20:DAS28(CRP) after Week 12: Descriptive statistics of the percent 
change from baseline
Table 14.2.1.4.21:DAS28(CRP) EULAR response after Week 12: Frequency table
8.4.5. Figures after Week 12
No figures planned.
8.4.6. Listings
Listing 16.2.6.4: DAS28(CRP): Original data


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Listing per treatment group, per subject and per time point of the DAS28(CRP) score (actual 
values, changes from baseline, percent changes from baseline, and the two categorizations) , 
as well as the DAS28 components.
Population: ITT.
8.5.
ACR COMPONENT: TENDER AND SWOLLEN JOINT COUNTS
8.5.1. Parameters
TJC68 = (total number of tender joints) x 
D
E	 F 	
  G	!
SJC66 = (total number of swollen joints) x 

E	 F 	
  G	!
TJC28 and SJC28 will be calculated using the same formula but only selecting the 28 
relevant1 joints:
TJC28 = (total number of tender joints) x 
D
E	 F 	
  G	!
SJC28 = (total number of swollen joints) x 
D
E	 F 	
  G	!
For all 4 parameters, the actual values, changes from baseline and percent changes from 
baseline will be derived and analyzed.
The above formulae already deal with any potential missing values. If more than 50% of the 
joints is scored temporarily or permanently unassessable or simply missing, then the total 
joint count will be set to “missing”.
Note that the percentage change from baseline remains missing if the baseline value itself 
equals zero.
8.5.2. Tables over the whole 24 weeks period
Tables will present Screening-Baseline-Weeks 1-2-4-8-12-16-20-24, unless specified 
otherwise. The same analysis tables as DAS28(CRP) will be made. Analysis population: ITT. 
LOCF and observed case (descriptive only; baseline and weeks 12 + 24 only).
Table 14.2.1.5.1: Joint counts: Descriptive statistics of the actual values
Table 14.2.1.5.2: Joint counts: Descriptive statistics of the change from baseline
Table 14.2.1.5.3: Joint counts: Descriptive statistics of the percent change from baseline
                                                            
1 Relevant 28 joints are: shoulder, elbow, wrist, metacarpophalangeal and proximal 
interphalangeal; knee.


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(descriptive statistics, and a frequency table at weeks 12 + 24)
Table 14.2.1.5.4: Joint counts: Summary with overall p-value and pairwise comparisons 
versus placebo 
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.
Table 14.2.1.5.5: Joint counts: Exploratory pairwise comparisons among the dose 
groups within each regimen 
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.
Table 14.2.1.5.6: Joint counts: Exploratory pairwise comparisons between regimens 
within each daily dose level 
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.
8.5.3. Figures over the whole 24 weeks period
Same analysis as for the DAS28(CRP). Population: ITT. LOCF only.
Figure 14.2.1.5.1:Joint counts: Plot of the actual values over time 
Figure 14.2.1.5.2:Joint counts: Plot of the changes from baseline over time 
Figure 14.2.1.5.3:Joint counts: Plot of the percent changes from baseline over time 
8.5.4. Tables after Week 12
Tables will present Weeks 12-16-20-24, unless specified otherwise, for the 15 arms of 
“efficacy analysis chapter 3”. The same descriptive analysis as DAS28(CRP) will be 
performed. Analysis population: ITT. LOCF and observed case (weeks 12 + 24).
Table 14.2.1.5.7: Joint counts after Week 12: Descriptive statistics of the actual values
Table 14.2.1.5.8: Joint counts after Week 12: Descriptive statistics of the change from 
baseline
Table 14.2.1.5.9: Joint counts after Week 12: Descriptive statistics of the percent change 
from baseline
8.5.5. Figures after Week 12
No figures planned.
8.5.6. Listings
Listing 16.2.6.5.1:
Joint counts: Identification of unassessable joints
Listing per treatment group, per subject and per time point of the original 68/66 joints, 
selecting only the temporarily or permanently unassessable joints. There will be no listing of 
all assessed joints.


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Population: ITT.
Listing 16.2.6.5.2:
Joint counts: Derived data
Listing per treatment group, per subject and per time point of the TJC68, SJC66, TJC28 and 
SJC28: actual values, changes from baseline and percent changes from baseline.
Population: ITT.
8.6.
ACR COMPONENT: VAS SCALES
8.6.1. Parameters
Assessments (each in mm, ranging from 0 to 100 with smaller scores indicating a better health 
condition):

Patient’s pain VAS

Patient’s global assessment of disease activity VAS

Investigator’s global assessment of disease activity VAS
For all 3 parameters, the actual values, changes from baseline and percent changes from 
baseline will be derived and analyzed.
Note that the percentage change from baseline remains missing if the baseline value itself 
equals zero.
Blinded data prior to database lock has revealed extreme values in the %changes from 
baseline for subjects with a very low baseline value (0, 1, 2 …). No data will be excluded 
from the analysis; the data will go into the analysis as they are.
8.6.2. Tables over the whole 24 weeks period
Tables will present Baseline-Weeks 1-2-4-8-12-16-20-24, unless specified otherwise. The 
screening visit will only be listed (is already analyzed in the baseline disease characteristics 
tables). The same analysis tables as DAS28(CRP) will be made. Analysis population: ITT. 
LOCF and observed case (descriptive only at Baseline and Weeks 12 + 24).
Table 14.2.1.6.1: VAS scores: Descriptive statistics of the actual values
Table 14.2.1.6.2: VAS scores: Descriptive statistics of the change from baseline
Table 14.2.1.6.3: VAS scores: Descriptive statistics of the percent change from baseline
(descriptive statistics, and a frequency table at weeks 12 + 24)
Table 14.2.1.6.4: VAS scores: Summary with overall p-value and pairwise comparisons 
versus placebo 
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.


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Table 14.2.1.6.5: VAS scores: Exploratory pairwise comparisons among the dose groups 
within each regimen 
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.
Table 14.2.1.6.6: VAS scores: Exploratory pairwise comparisons between regimens 
within each daily dose level 
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.
8.6.3. Figures over the whole 24 weeks study period
Same analysis as for the DAS28(CRP). Population: ITT. LOCF only.
Figure 14.2.1.6.1:VAS scores: Plot of the actual values over time 
Figure 14.2.1.6.2:VAS scores: Plot of the changes from baseline over time 
Figure 14.2.1.6.3:VAS scores: Plot of the percent changes from baseline over time 
8.6.4. Tables after Week 12
Tables will present Weeks 12-16-20-24, unless specified otherwise, for the 15 arms of 
“efficacy chapter 3”. The same descriptive analysis as DAS28(CRP) will be performed. 
Analysis population: ITT. LOCF and observed case (weeks 12 + 24).
Table 14.2.1.6.7: VAS scores after Week 12: Descriptive statistics of the actual values
Table 14.2.1.6.8: VAS scores after Week 12: Descriptive statistics of the change from 
baseline
Table 14.2.1.6.9: VAS scores after Week 12: Descriptive statistics of the percent change 
from baseline
8.6.5. Figures after Week 12
No figures planned.
8.6.6. Listings
Listing 16.2.6.6: VAS scores
Listing per treatment group, per subject and per time point of the 3 VAS scores: actual values, 
changes from baseline and percent changes from baseline.
Population: ITT.


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8.7.
ACR COMPONENT: HAQ-DI
8.7.1. Parameters
The HAQ-DI consists of 20 individual items. 
The pain VAS of the HAQ-DI is analyzed separately as component of the ACR20/50/70, not 
in this chapter on HAQ-DI.
The HAQ-DI total scores are:

8 domain subscales: dressing, arising, eating, hygiene, walking, reaching, grip, activities

Overall total score
Derivation of these summary scores:

There are four response options ranging from “Without any difficulty” to “Unable to do”, 
scored from 0 to 3.

Step 1: Derive the 8 category scores by using the highest sub-category score from each 
domain.

Step 2: Adjust for use of aids/devices and/or help from another person when indicated:

Adjust the score for a domain by increasing a 0 or a 1 to a 2.

If a patient's highest score for that sub-category is a 2 it remains a 2, and if a 3, it 
remains a 3.

Step 3: Divide the summed domain scores by the number of domains answered to obtain 
a HAQ-DI score of 0-3 (3=worst functioning). There must be a nonmissing score for at 
least six of the eight domains. Otherwise a HAQ-DI score cannot be computed.
If any of the 20 items would be missing, then this missing component will be imputed using 
the value of the last preceding nonmissing visit.
The analysis will present the actual values, changes from baseline and percent changes from 
baseline.
The analysis will present the subscores only at baseline, Week 12 and Week 24. Not at 
intermediate time points. (Except in the mean plots, where all time points will be presented.)
Note that the percentage change from baseline remains missing if the baseline value itself 
equals zero.
8.7.2. Tables over the whole 24 weeks period
Tables will present Baseline-Weeks 1-2-4-8-12-16-20-24, unless specified otherwise. The 
same analysis tables as DAS28(CRP) will be made. Analysis population: ITT. LOCF and 
observed case (descriptive only at baseline and weeks 12 + 24).
Table 14.2.1.7.1: HAQ-DI total and domain scores: Descriptive statistics of the actual 
values


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Descriptive statistics at all time points. Frequency table at all time points of values ≤ or > 0.5
in the total HAQ-DI score. Subjects with a score below 0.5 are considered to have normal 
physical function.
Table 14.2.1.7.2: HAQ-DI total and domain scores: Descriptive statistics of the change 
from baseline
Descriptive statistics at all time points. Fequency table at all time points of the changes in 
total HAQ-DI score:
≤ -0.8
]-0.8 , -0.5]
]-0.5 , -0.3]
]-0.3 , -0.22]
> -0.22
Table 14.2.1.7.3: HAQ-DI total and domain scores: Descriptive statistics of the percent 
change from baseline
Descriptive statistics, and a frequency table (weeks 12 + 24).
Table 14.2.1.7.4: HAQ-DI total and domain scores: Summary with overall p-value and 
pairwise comparisons versus placebo 
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.
Table 14.2.1.7.5: HAQ-DI total and domain scores: Exploratory pairwise comparisons 
among the dose groups within each regimen 
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.
Table 14.2.1.7.6: HAQ-DI total and domain scores: Exploratory pairwise comparisons 
between regimens within each daily dose level 
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.
8.7.3. Figures over the whole 24 weeks period
Same analysis as for the DAS28(CRP). Population: ITT. LOCF only.
Figure 14.2.1.7.1:HAQ-DI total and domain scores: Plot of the actual values over time
Figure 14.2.1.7.2:HAQ-DI total and domain scores: Plot of the changes from baseline 
over time 
Figure 14.2.1.7.3:HAQ-DI total and domain scores: Plot of the percent changes from 
baseline over time 


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8.7.4. Tables after Week 12
Tables will present Weeks 12-16-20-24, unless specified otherwise, for the 15 arms of 
“efficacy chapter 3”. The same descriptive analysis as DAS28(CRP) will be performed. 
Analysis population: ITT. LOCF and observed case (weeks 12 + 24).
Table 14.2.1.7.7: HAQ-DI total and domain scores after Week 12: Descriptive statistics 
of the actual values
Table 14.2.1.7.8: HAQ-DI total and domain scores after Week 12: Descriptive statistics 
of the change from baseline
Table 14.2.1.7.9: HAQ-DI total and domain scores after Week 12: Descriptive statistics 
of the percent change from baseline
8.7.5. Figures after Week 12
No figures planned.
8.7.6. Listings
Listing 16.2.6.7: HAQ-DI: Derived summary scores
Listing per treatment group, per subject and per time point of all derived summary scores (the 
overall score and the 8 domain scores): actual values, changes from baseline and percent 
changes from baseline. Total HAQ-DI values of ≤ 0.5 as well as changes from baseline in 
total HAQ-DI of ≤ -0.22 will be flagged in the listing. Note that the pain VAS is already listed 
elsewhere so will be omitted from the HAQ-DI listing.
Population: ITT.
8.8.
ACR COMPONENT: SERUM CRP
8.8.1. Parameters
Serum CRP (mg/L) will be analyzed as raw values, change from baseline and percent change 
from baseline. 
Note that if for a specific visit both the regular CRP as well as the high-sensitive CRP are 
available, the high-sensitive CRP will be used in the analysis tables and figures. The regular 
CRP will then only be listed.
CRP and hsCRP values will also be categorized according to the lab’s normal ranges: normal 
(value ≤ ULN) or high (value > ULN), where ULN = upper limit of the normal range as 
provided by the central lab. Note that the same ULN (8.999) will be applied to both CRP and 
hsCRP.
Note that CRP and hsCRP will be excluded from the lab safety analysis.


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Note that the percentage change from baseline remains missing if the baseline value itself 
equals zero.
8.8.2. Tables over the whole 24 weeks period
Tables will present Screening-Baseline-Weeks 1-2-4-8-12-16-20-24, unless specified 
otherwise. The same analysis tables as DAS28(CRP) will be made. Analysis population: ITT. 
LOCF and observed case (descriptive only at baseline and weeks 12 + 24).
Table 14.2.1.8.1: Serum CRP (mg/L): Descriptive statistics of the actual values
Table 14.2.1.8.2: Serum CRP (mg/L): Descriptive statistics of the change from baseline
Table 14.2.1.8.3: Serum CRP (mg/L): Descriptive statistics of the percent change from 
baseline
(descriptive statistics at all time points; frequency table at weeks 12 + 24)
Overall as well as split up for subjects with a baseline CRP > ULN versus ≤ ULN.
Table 14.2.1.8.4: Serum CRP (mg/L): Shift table versus baseline
Shift table per treatment group and time point. The table will present the shift in category 
(normal/high/missing) at each post-baseline time point versus the baseline Day 1 category 
(normal/high/missing). 
Population: ITT population.
Table 14.2.1.8.5: Serum CRP (mg/L): Treatment-emergent normalizations per time 
point
Frequency table of the treatment-emergent CRP normalizations (i.e., a value shifting from an 
abnormally high baseline to a normal value a post-baseline time point) per treatment group 
and time point. Subjects with a missing or normal baseline CRP will not be used. Time points 
with a missing post-baseline result will not be used either. No formal between-group 
comparisons.
Note: normal/abnormal is derived according to the central lab’s upper limit of normal.
Population: ITT population.
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.
Table 14.2.1.8.6: Serum CRP (mg/L): Summary with overall p-value and pairwise 
comparisons versus placebo 
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.
Table 14.2.1.8.7: Serum CRP (mg/L): Exploratory pairwise comparisons among the 
dose groups within each regimen 
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.


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Table 14.2.1.8.8: Serum CRP (mg/L): Exploratory pairwise comparisons between 
regimens within each daily dose level 
Table to be created for the Week 12 interim analysis as well, cut off at Week 12.
8.8.3. Figures over the whole 24 weeks period
Same analysis as for the DAS28(CRP). Population: ITT. LOCF only.
Figure 14.2.1.8.1:Serum CRP (mg/L): Plot of the actual values over time 
Figure 14.2.1.8.2:Serum CRP (mg/L): Plot of the changes from baseline over time 
Figure 14.2.1.8.3:Serum CRP (mg/L): Plot of the percent changes from baseline over 
time 
8.8.4. Tables after Week 12
Tables will present Weeks 12-16-20-24, unless specified otherwise, for the 15 arms of 
“efficacy chapter 3”. The same descriptive analysis as DAS28(CRP) will be performed. 
Analysis population: ITT. LOCF and observed case (weeks 12 + 24).
Table 14.2.1.8.9: Serum CRP (mg/L) after Week 12: Descriptive statistics of the actual 
values
Table 14.2.1.8.10:Serum CRP (mg/L) after Week 12: Descriptive statistics of the change 
from baseline
Table 14.2.1.8.11:Serum CRP (mg/L) after Week 12: Descriptive statistics of the percent 
change from baseline
Table 14.2.1.8.12:Serum CRP (mg/L) after Week 12: Shift table versus baseline
Table 14.2.1.8.13:Serum CRP (mg/L) after Week 12: Treatment-emergent 
normalizations per time point
8.8.5. Figures after Week 12
No figures planned.
8.8.6. Listings
Listing 16.2.6.8: Serum CRP (mg/L)
Listing per treatment group, per subject and per time point of the raw CRP and hsCRP values, 
changes from baseline and percent changes from baseline. A flag “H” will be added for values 
above the upper limit of normal.
Population: ITT.


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8.9.
QUALITY OF LIFE: FACIT FATIGUE SCALE
8.9.1. Parameters
The scale (version 4) consists of 13 items: 
1.
I feel fatigued
2.
I feel weak all over
3.
I feel listless (“washed out”)
4.
I feel tired
5.
I have trouble starting things because I am tired
6.
I have trouble finishing things because I am tired
7.
I have energy
8.
I am able to do my usual activities
9.
I need to sleep during the day
10. I am too tired to eat
11. I need help doing my usual activities
12. I am frustrated by being too tired to do the things I want to do
13. I have to limit my social activity because I am tired
Each item is scored on an ordinal 5-point scale: Not At All; A Little Bit; Somewhat; Quite A 
Bit; Very Much.
The items must be scored as follows: 4=Not At All; 3=A Little Bit; 2=Somewhat; 1=Quite A 
Bit; 0=Very Much. Items 7 and 8 which are scored reversely. 
The total FACIT fatigue score is then derived, and ranges from 0 to 52 with a higher score 
indicating a better quality of life:
FACIT fatigue score = (Sum of all the scores) x 

IF 	
   J!
The FACIT fatigue score will only be derived when at least 7 of the 13 items are available, 
and will remain missing when 6 or less of the 13 items are available.
The analysis will use actual values, changes from baseline and percent changes from baseline.
Note that the percentage change from baseline remains missing if the baseline value itself 
equals zero.
8.9.2. Tables over the whole 24 weeks period
Tables will present Weeks 4, 12 and 24, unless specified otherwise. The same analysis as 
DAS28(CRP) will be performed. Analysis population: ITT. LOCF and observed case
(descriptive only at baseline, week 12 and week 24).
Table 14.2.1.9.1: FACIT fatigue score: Descriptive statistics of the actual values
Table 14.2.1.9.2: FACIT fatigue score: Descriptive statistics of the change from baseline


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Table 14.2.1.9.3: FACIT fatigue score: Descriptive statistics of the percent change from 
baseline
(descriptive statistics at all time points; frequency table at weeks 12 + 24)
Table 14.2.1.9.4: FACIT fatigue score: Summary with overall p-value and pairwise 
comparisons versus placebo 
Table 14.2.1.9.5: FACIT fatigue score: Exploratory pairwise comparisons among the 
dose groups within each regimen 
Table 14.2.1.9.6: FACIT fatigue score: Exploratory pairwise comparisons between 
regimens within each daily dose level 
8.9.3. Figures over the whole 24 weeks period
Line plots showing baseline, Week 4, 12 and 24. Same analysis as for the DAS28(CRP). 
Population: ITT. LOCF only.
Figure 14.2.1.9.1:FACIT fatigue score: Plot of the actual values over time
Figure 14.2.1.9.2:FACIT fatigue score: Plot of the changes from baseline over time 
Figure 14.2.1.9.3:FACIT fatigue score: Plot of the percent changes from baseline over 
time 
8.9.4. Tables after Week 12
Tables will present Weeks 4, 12 and 24, unless specified otherwise, for the 15 arms of 
“efficacy chapter 3”. The same descriptive analysis as DAS28(CRP) will be performed. 
Analysis population: ITT. LOCF and observed case (weeks 12 + 24).
Table 14.2.1.9.7: FACIT fatigue score after Week 12: Descriptive statistics of the actual 
values
Table 14.2.1.9.8: FACIT fatigue score after Week 12: Descriptive statistics of the 
change from baseline
Table 14.2.1.9.9: FACIT fatigue score after Week 12: Descriptive statistics of the 
percent change from baseline
8.9.5. Figures after Week 12
No figures planned.
8.9.6. Listings
Listing 16.2.6.9: Total FACIT fatigue score


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Listing per treatment group, per subject and per time point of the total score: actual values, 
changes from baseline and percent changes from baseline. The original 13 items will not be 
listed.
Population: ITT.
8.10.
QUALITY OF LIFE: SF-36
8.10.1. Parameters
The SF-36 (version 2) consists of 36 items. 
The 36 questions:

1:In general, would you say your health is

2:Compared to one year ago, how would you rate your health in general now

3A:Vigorous activities, such as running, lifting heavy objects, participating in strenuous
sports

3B:Moderate activities, such as moving a table, pushing a vacuum cleaner, bowling, or 
playing golf

3C:Lifting or carrying groceries

3D:Climbing several flights of stairs

3E:Climbing one flight of stairs

3F:Bending, kneeling, or stooping

3G:Walking more than a mile

3H:Walking several hundred yards

3I:Walking one hundred yards

3J:Bathing or dressing yourself

4A:As a result of your physical health, cut down on the amount of time you spent on work 
or other activities

4B:As a result of your physical health, accomplished less than you would like

4C:As a result of your physical health, were limited in the kind of work or other activities

4D:As a result of your physical health, had difficulty performing the work or other 
activities (for example, it took extra effort)

5A:As a result of any emotional problems, cut down the amount of time you spent on 
work or other activities

5B:As a result of any emotional problems, accomplished less than you would like

5C:As a result of any emotional problems, did work or other activities less carefully than 
usual

6:During the past 4 weeks, to what extent has your physical health or emotional problems 
interfered with your normal social activities with family, friends, neighbors, or groups

7:How much bodily pain have you had during the past 4 weeks

8:During the past 4 weeks how much did pain interfere with your normal work (including 
both work outside the home and housework)

9A:How much of the time during the past 4 weeks: did you feel full of life


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
9B:How much of the time during the past 4 weeks: have you been very nervous

9C:How much of the time during the past 4 weeks: have you felt so down in the dumps 
that nothing could cheer you up

9D:How much of the time during the past 4 weeks: have you felt calm and peaceful

9E:How much of the time during the past 4 weeks: did you have a lot of energy

9F:How much of the time during the past 4 weeks: have you felt downhearted and 
depressed

9G:How much of the time during the past 4 weeks: did you feel worn out

9H:How much of the time during the past 4 weeks: have you been happy

9I:How much of the time during the past 4 weeks: did you feel tired

10:During the past 4 weeks, how much of the time has your physical health or emotional 
problems interfered with your social activities (like visiting your friends, relatives, etc.)

11A:I seem to get sick a little easier than other people

11B:I am as healthy as anybody I know

11C:I expect my health to get worse

11D:My health is excellent
General comments: The coding and scoring for each component (PCS, MCS) is done 
according to the tables below.
Coding and Scoring for the 8 SF-36 (Version 2) Scales
Scale
Item
Coding (makes use of 
QSRCCD)
Range of raw 
score
Normalization*
Physical 
functioning
Items 3a to 3j
Yes, limited a lot=1
Yes, limited a little=2
No, not limited=3
10-30
(S-10)/20x100
Role-physical 
Items 4a to 4d
All of the time = 1
Most of the time = 2
Some of the time = 3
A little of the time = 4
None of the time = 5
4-20
(S-4)/16x100
Bodily pain
Item 7
None=6
Very mild=5.4
Mild=4.2
Moderate=3.1
Severe=2.2
Very severe=1
2-12
(S-2)/10x100
Item 8 if both 
items 7 and 8 
are answered
Not at all and item7 eq 
'None' = 6
Not at all and item7 not 
equal 'None' = 5


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Scale
Item
Coding (makes use of 
QSRCCD)
Range of raw 
score
Normalization*
A little bit = 4
Moderately = 3
Quite a bit = 2
Extremely = 1
Item 8 if item 
7 is not 
answered
Not at all =6
A little bit = 4.75
Moderately =3.5
Quite a bit = 2.25
Extremely = 1
General health 
Item 1
Excellent = 5
Very good = 4.4
Good = 3.4
Fair = 2
Poor = 1
5-25
(S-5)/20x100
Items 11a and 
11c
Definitely true = 1
Mostly true = 2
Don't know = 3
Mostly false = 4
Definitely false = 5
Items 11b and 
11d
Definitely true = 5
Mostly true = 4
Don't know = 3
Mostly false = 2
Definitely false = 1
Vitality
Items 9a and 
9e
All of the time = 5
Most of the time = 4
Some of the time = 3
A little of the time = 2
None of the time = 1
4-20
(S-4)/16x100
Items 9g and 
9i
All of the time = 1
Most of the time = 2
Some of the time = 3
A little of the time = 4
None of the time = 5
Social 
functioning
Item 6
Not at all = 5
Slightly = 4
Moderately = 3
Quite a bit = 2
2-10
(S-2)/8x100


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Scale
Item
Coding (makes use of 
QSRCCD)
Range of raw 
score
Normalization*
Extremely = 1
Item 10
All of the time = 1
Most of the time = 2
Some of the time = 3
A little of the time = 4
None of the time = 5
Role-emotional 
Items 5a to 5c
All of the time = 1
Most of the time = 2
Some of the time = 3
A little of the time = 4
None of the time = 5
3-15
(S-3)/12x100
Mental health
Items 9b, 9c 
and 9f
All of the time = 1
Most of the time = 2
Some of the time = 3
A little of the time = 4
None of the time = 5
5-25
(S-5)/20x100
Items 9d and 
9h
All of the time = 5
Most of the time = 4
Some of the time = 3
A little of the time = 2
None of the time = 1
*S = raw score = sum of item scores after coding
For the 8 raw scale scores calculations, if at least 50% of the items comprising a scale have 
non-missing responses, impute the average score calculated for the non-missing scale items 
for the missing items of the same scale. If more than 50% of scale items comprising a scale 
are missing a response, set the scale to missing.
Then each scale score needs to be standardized (z-score) as below:


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Standardization of the SF-36 (Version 2) Scale Scores
Item
Standardization (Z-score)
Physical functioning
PF_Z = (PF-83.29094)/23.75883
Role-physical
RP_Z = (RP-82.50964)/25.52028
Bodily pain
BP_Z = (BP-71.32527)/23.66224
General health
GH_Z = (GH-70.84570/20.97821
Vitality
VT_Z = (VT-58.31411)/20.01923
Social functioning
SF_Z = (SF-84.30250)/22.91921
Role-emotional
RE_Z = (RE-87.39733)/21.43778
Mental heath
MH_Z = (MH-74.98685)/17.75604
Note: Based on the 1998 general United States population.
Finally, the SF-36 physical and mental component transformed scores are calculated using the 
below conventions.
SF-36 Aggregate Component and Transformed Scores
Score
Calculation
Aggregate Standardized Score
Physical component
AGG_PHYS = (PF_Z * 0.42402) + (RP_Z * 0.35119) + 
(BP_Z * 0.31754) + (GH_Z * 0.24954) + (VT_Z * 0.02877) +
(SF_Z * -0.00753) + (RE_Z * -0.19206) +(MH_Z * -0.22069)
Mental component
AGG_MENT = (PF_Z * -0.22999) + (RP_Z * -0.12329) +
(BP_Z * -0.09731) + (GH_Z * -0.01571) + (VT_Z * 0.23534) +
(SF_Z * 0.26876) + (RE_Z * 0.43407) + (MH_Z * 0.48581)
Transformed Summary
Transformed physical
PCS = 50 + (AGG_PHYS * 10)
Transformed mental
MCS = 50 + (AGG_MENT * 10)
In addition, the 8 scale scores will be reported in norm-based transformation. Norm-based 
transformation will be achieved by multiplying each z-score by 10 and adding 50 to it:


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Item
Norm-based transformation of the z-scores
Physical functioning
Norm-based PF = 50 + (PF_Z*10)
Role-physical
Norm-based RP = 50 + (RP_Z*10)
Bodily pain
Norm-based BP = 50 + (BP_Z*10) 
General health
Norm-based GH = 50 + (GH_Z*10)
Vitality
Norm-based VT = 50 + (VT_Z*10)
Social functioning
Norm-based SF = 50 + (SF_Z*10)
Role-emotional
Norm-based RE = 50 + (RE_Z*10)
Mental heath
Norm-based MH = 50 + (MH_Z*10)
Derivation of these summary scores, including appropriate handling of missing items, will be 
done using the scoring software provided by the owner of the scale (QualityMetrics). 
Please refer to the SF-36 v2 manual for additional information.
The analysis will present the 2 summary component measures and the 8 domains:

Transformed physical component scale PCS and mental component scale MCS

Norm-based physical functioning (PF), role physical (RF), bodily pain (BP), general 
health (GH), vitality (VT), social functioning (SF), role emotional (RE) and mental health 
(MH)
The analysis will present actual values, changes from baseline and percent changes from 
baseline in the above-mentioned scores.
Note that the percentage change from baseline remains missing if the baseline value itself 
equals zero.
8.10.2. Tables over the whole 24 weeks period
Same analysis as for the DAS28(CRP). Population: ITT. Note that the SF-36 is only scored at 
baseline, Week 4, Week 12, and Week 24/EDV. LOCF and observed case (descriptive only at 
baseline and weeks 12 + 24). Tables will present the 8 domain scores and the 2 main scores.
Table 14.2.1.10.1:SF-36: Descriptive statistics of the actual values
Table 14.2.1.10.2:SF-36: Descriptive statistics of the change from baseline
Table 14.2.1.10.3:SF-36: Descriptive statistics of the percent change from baseline
(descriptive statistics at each time point; frequency table at weeks 12 + 24)
Table 14.2.1.10.4:SF-36: Summary with overall p-value and pairwise comparisons 
versus placebo 


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Table 14.2.1.10.5:SF-36: Exploratory pairwise comparisons among the dose groups 
within each regimen 
Table 14.2.1.10.6:SF-36: Exploratory pairwise comparisons between regimens within 
each daily dose level 
8.10.3. Figures over the whole 24 weeks period
Line plots showing baseline, Week 4, 12 and 24. Same analysis as for the DAS28(CRP). 
Population: ITT. LOCF only. Both main scores as well as the 8 subdomains will be presented.
Figure 14.2.1.10.1: SF-36: Plot of the actual values over time
Figure 14.2.1.10.2: SF-36: Plot of the changes from baseline over time 
Figure 14.2.1.10.3: SF-36: Plot of the percent changes from baseline over time 
8.10.4. Tables after Week 12
Tables will present Weeks 4, 12 and 24, unless specified otherwise, for the 15 arms of 
“efficacy chapter 3”. The same descriptive analysis as DAS28(CRP) will be performed. 
Analysis population: ITT. LOCF and observed case (weeks 12 + 24). Tables will present the 8 
domain scores and the 2 main scores.
Table 14.2.1.10.7: SF-36 after Week 12: Descriptive statistics of the actual values
Table 14.2.1.10.8: SF-36 after Week 12: Descriptive statistics of the change from 
baseline
Table 14.2.1.10.9: SF-36 after Week 12: Descriptive statistics of the percent change from 
baseline
8.10.5. Figures after Week 12
No figures planned.
8.10.6. Listings
Listing 16.2.6.10: SF-36: Derived summary scores
Listing per treatment group, per subject and per time point of all derived summary scores (the 
2 component scores and the 8 domain scores): actual values, changes from baseline and 
percent changes from baseline. The original 36 items will not be listed.
Population: ITT.


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9.
DEFINITIONS OF PHARMACOKINETICS TABLES, 
LISTINGS AND FIGURES
These analyses will be described in a separate SAP. A separate report will be written based on 
the analysis performed by
10.
DEFINITIONS OF PHARMACODYNAMICS TABLES, 
LISTINGS AND FIGURES
Mock tables, listings and figures are provided in a separate document. 
All analyses will be run on the ITT population, unless specified otherwise.
10.1.
PARAMETERS
Assessment: marker YKL-40 (also known as Chitinase 3 L 1, CHI3L1) in serum.
Visits to present:

Baseline

Week 12: this is either the Week 12 visit itself, OR the EDV visit in case the subject 
dropped out of the study prior to Week 12, OR the last post-baseline visit prior to Week 
12.
The actual values, changes from baseline and percent changes from baseline will be derived 
and analyzed.
Note that the percentage change from baseline remains missing if the baseline value itself 
equals zero.
10.2.
TABLES
Tables will present Baseline and Week 12, unless specified otherwise. Tables will present the 
7 treatment groups.
Analysis population: ITT. 
Table 14.2.3.1:
Pharmacodynamics: YKL-40: Descriptive statistics
Descriptive statistics of actual values, changes from baseline and percent changes from 
baseline.
Table 14.2.3.2:
Pharmacodynamics: YKL-40: Summary with overall p-value and 
pairwise comparisons versus placebo 
Analysis model is similar to DAS28(CRP). Only one time point: Week 12.
Table 14.2.3.3:
Pharmacodynamics: YKL-40: Exploratory pairwise comparisons 
among the dose groups within each regimen 


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Table 14.2.3.4:
Pharmacodynamics: YKL-40: Exploratory pairwise comparisons 
between regimens within each daily dose level 
Table 14.2.3.5:
Pharmacodynamics: YKL-40: Descriptive statistics for Week 12 
ACR20 responders versus non-responders
Same as previous table, but split up for Week 12 ACR20 responders and non-responders.
Table 14.2.3.6:
Pharmacodynamics: YKL-40: Descriptive statistics for Week 12 
ACR50 responders versus non-responders
Table 14.2.3.7:
Pharmacodynamics: YKL-40: Descriptive statistics for Week 12 
ACR70 responders versus non-responders
Table 14.2.3.8:
Pharmacodynamics: YKL-40: Correlation with ACR20/50/70
Relationship between the change from baseline in PD marker and ACR20 will be investigated 
via a logistic regression model on the ACR20 responses, with the following factors in the 
model: treatment groups, baseline YKL-40, change from baseline in YKL-40. ACR20 and 
YKL-40 will be taken from the same visit.
Same for the ACR50 and ACR70.
Table 14.2.3.9:
Pharmacodynamics: YKL-40: Correlation with continuous efficacy 
parameters
Relationship between the change from baseline in PD marker and the change from baseline in 
efficacy parameters will be investigated via Pearson’s correlation coefficient as provided by 
SAS PROC CORR. Efficacy parameters and YKL-40 will all be taken from the same visit. 
The following efficacy parameters will be tested:

ACR20 components: TJC68, SJC66,  the 3 VAS scores, CRP and HAQ-DI.

Summary scores: DAS28(CRP), CDAI and SDAI.
10.3.
FIGURES
Figure 14.2.3.1:
Pharmacodynamics: YKL-40: Mean plot over time
Line plot baseline-W12, like for the efficacy parameters. Plot will contain the 7 groups.
Analysis population: ITT. 
Figure 14.2.3.2:
Pharmacodynamics: YKL-40: Correlation plots versus efficacy 
Correlation scatterplots of the percent changes from baseline in YKL-40 versus:

Percent change from baseline in: TJC68, SJC66, the 3 VAS scores, CRP and HAQ-DI

Percent change from baseline in DAS28(CRP), CDAI and SDAI
Efficacy parameters and YKL-40 will all be taken from the same visit. Each plot on a new 
page, using different plot symbols per group. Because of the large number of groups, put the 
placebo with the qd dose groups on one plot, and the placebo with the bid dose groups on a 
second plot.


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Analysis population: ITT. 
10.4.
LISTINGS
Listing 16.2.8:
Pharmacodynamics: YKL-40
Listing per treatment group, per subject and per time point of the YKL-40 results: actual 
values, changes from baseline and percent changes from baseline.
Population: ITT.
11.
DEFINITIONS OF PK/PD TABLES, LISTINGS AND 
FIGURES
These analyses will be described in a separate SAP. A separate report will be written based on 
the analysis performed by 
.
12.
DEFINITIONS OF SAFETY TABLES, LISTINGS AND 
FIGURES
Mock tables, listings and figures are provided in a separate document. 
All analyses will be run on the Safety population, unless specified otherwise.
12.1.
ADVERSE EVENTS
12.1.1. Treatment-Emergent Principle
All adverse events with onset on or after first dosing are considered treatment-emergent 
adverse events (TEAE).
Adverse events will be placed into analysis periods according to their start date. Analysis 
periods: see section 3.2. The AE will only be presented in the analysis period during which it 
started. Rule: period start date ≤ AE start date ≤ period stop date. 
In case the AE start date is incomplete, a worst-case allocation will be done according to the 
available parts of the AE start date. When too much of the AE start date is missing to apply 
the above rules, the AE will be allocated to:

the first treatment period, in case the doubt is between the screening and first treatment 
analysis period;

both treatment periods, in case the doubt is between both treatment periods.
All adverse events emerging during the screening period will only be listed, not presented in 
any of the tables. These events are not TEAEs. All tables will present TEAEs only.


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12.1.2. Treatment Relatedness
Following (ICH-E3), the investigator’s assessment of drug relatedness will be dichotomized 
as follows:
Drug related: at least possibly drug related, OR with missing drug relatedness (= worst-case)
Not drug related: less than possibly drug related.
In tabulations this dichotomized parameter will be used, but in the listings the original 
parameter will be presented. Note that there is only the drug-relatedness assessment by the 
investigator.
12.1.3. Worst-Case Principle
When cross-tabulating AE preferred terms versus an AE attribute (e.g., intensity), the worst-
case is always applied within each analysis period. I.e., when a subject has two times the same 
AE preferred term in the same analysis period, then the subject is reported only once: only 
with the worst intensity. If this happens in two different analysis periods, the AE is reported 
twice: once in each analysis period.
12.1.4. Adverse Event Onset Day and Duration
AE onset day in the study
= (AE start date) – (date of first study drug administration) + 1, when the AE start date is 
completely known;
= missing when the AE start date is incomplete or unknown.
AE onset day in the period
= (AE start date) – (start date of the period into which the AE was allocated) + 1, when the 
AE start date is completely known;
= missing when the AE start date is incomplete or unknown.
AE duration 
= (AE stop date) – (AE start date) + 1, when both dates are completely known;
= (trial termination date) – (AE start date) + 1, when the AE start date is fully known but the 
AE is not resolved at the end of the study; in this case the duration will be presented as “>x 
days” in the listing to identify it as a censored result;
= missing when the AE start date is incomplete or unknown, or when the AE has resolved but 
with an incomplete or unknown end date.


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12.1.5. Calculation of Percentages
All percentages will be calculated against the total number of subjects that are still in the 
study in that particular analysis period.
12.1.6. Tables up to Week 12
No formal inferential statistics (p-values) will be derived.
An as-treated analysis will be performed. All tabulations and listings will present treatments 
rather than analysis periods.
Table 14.3.1.1: 
Treatment-emergent adverse events up to Week 12: Summary table
Tabulation per treatment of the number and percentage of subjects with the following:

Subjects with at least one treatment-emergent adverse event (TEAE)

Subjects with at least one serious TEAE

Subjects who died (treatment-emergent)

Subjects with at least one mild TEAE as worst intensity

Subjects with at least one moderate TEAE as worst intensity

Subjects with at least one severe TEAE

Subjects with at least one TEAE that was considered treatment-related

Subjects with at least one treatment-emergent SAE that was considered treatment-related

Subjects with at least one TEAE for which the study treatment was temporarily stopped

Subjects with at least one TEAE for which the study treatment was permanently stopped

Subjects with at least one TEAE flagged as an individual stopping criterion by the 
investigator.
Population: safety.
Table to be created for the Week 12 interim analysis as well.
Table 14.3.1.2: 
Treatment-emergent adverse events up to Week 12: Summary table by 
region
Same table as the preceding one, but by geographical region.
Population: safety.
Table 14.3.1.3: 
Treatment-emergent adverse events up to Week 12: Tabulation of all 
adverse events
Tabulation of TEAE preferred terms per body class, per treatment group.
Population: safety.
Table to be created for the Week 12 interim analysis as well.


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Table 14.3.1.4: 
Treatment-emergent adverse events up to Week 12: Tabulation of all 
adverse events by region
Same as previous table, but split up by geographical region.
Population: safety.
Table 14.3.1.5: 
Treatment-emergent adverse events up to Week 12: Tabulation of all 
adverse events by gender
Same as previous table, but split up for males and females.
Population: safety.
Table 14.3.1.6: 
Treatment-emergent adverse events up to Week 12: Tabulation of all 
adverse events by age category
Same as previous table, but split up for age categories: 
< 45 ; 
[45,65[ ; 
[65,75[ ;
≥ 75 years.
Population: safety.
Table 14.3.1.7: 
Treatment-emergent adverse events up to Week 12: Tabulation per 
intensity
Cross-tabulation of TEAE preferred terms versus their intensity. Use the worst-case intensity 
per TEAE per subject. Per treatment group.
Population: safety.
Table to be created for the Week 12 interim analysis as well.
Table 14.3.1.8: 
Treatment-emergent adverse events up to Week 12: Tabulation of all 
treatment-related events
Tabulation of TEAE preferred terms per body class, per treatment group. Selecting only the 
TEAEs that were treatment-related (see section 12.1.2).
Population: safety.
Table to be created for the Week 12 interim analysis as well.
Table 14.3.1.9: 
Treatment-emergent adverse events up to Week 12: Tabulation of all 
treatment-related events by gender
Table 14.3.1.10: Treatment-emergent adverse events up to Week 12: Tabulation of all 
treatment-related events by age category


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Table 14.3.1.11: Treatment-emergent adverse events up to Week 12: Tabulation of the 
intensity of treatment-related events
Cross-tabulation of TEAE preferred terms versus their intensity; per body class and per 
treatment group. Use the worst-case intensity per TEAE per subject, selecting only the TEAEs 
that were treatment-related (see section 12.1.2).
Population: safety.
Table to be created for the Week 12 interim analysis as well.
Table 14.3.1.12: Treatment-emergent adverse events up to Week 12: Tabulation of the 
drug-relatedness of serious events
Cross-tabulation of TEAE preferred terms versus their drug-relatedness; per body class and 
per treatment group. Selecting only the treatment-emergent serious adverse events.
Population: safety.
Table to be created for the Week 12 interim analysis as well.
Table 14.3.1.13: Treatment-emergent adverse events up to Week 12: Tabulation of the 
drug-relatedness of events leading to discontinuation
Cross-tabulation of TEAE preferred terms versus their drug-relatedness; per body class and 
per treatment group. Selecting only the TEAEs for which the study treatment was 
permanently discontinued (AE page), or for which the study was discontinued (trial 
termination page).
Population: safety.
Table to be created for the Week 12 interim analysis as well.
Table 14.3.1.14: Treatment-emergent adverse events up to Week 12: Tabulation of the 
drug-relatedness of events leading to a temporary stop
Cross-tabulation of TEAE preferred terms versus their drug-relatedness; per body class and 
per treatment group. Selecting only the TEAEs for which the study treatment was temporarily 
stopped (AE page).
Population: safety.
Table 14.3.1.15: Treatment-emergent adverse events up to Week 12: Tabulation of the 
drug-relatedness of individual stopping rules
Cross-tabulation of TEAE preferred terms versus their drug-relatedness; per body class and 
per treatment group. Selecting only the TEAEs that were flagged as “stopping criterion” in the 
eCRF by the investigator.
Population: safety.


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12.1.7. Tables over the whole 24 weeks period
The same tables will be created for the full 24 weeks period of the study, using the 11 groups
as specified in section 2.4. 
All tables will be created for 3 analysis periods: “first 12 weeks”, “second 12 weeks”, and 
“full 24 weeks” as defined in section 3.2.
Population: Safety.
Table 14.3.1.16: Treatment-emergent adverse events over the whole study: Summary 
table
Tabulation per treatment of the number and percentage of subjects with the following:

Subjects with at least one treatment-emergent adverse event (TEAE)

Subjects with at least one serious TEAE

Subjects who died (treatment-emergent)

Subjects with at least one mild TEAE as worst intensity

Subjects with at least one moderate TEAE as worst intensity

Subjects with at least one severe TEAE

Subjects with at least one TEAE that was considered treatment-related

Subjects with at least one treatment-emergent SAE that was considered treatment-related

Subjects with at least one TEAE for which the study treatment was temporarily stopped

Subjects with at least one TEAE for which the study treatment was permanently stopped

Subjects with at least one TEAE flagged as an individual stopping criterion by the 
investigator

Subjects with at least one TEAE that has not resolved.
Population: safety.
Table 14.3.1.17: Treatment-emergent adverse events over the whole study: Summary 
table by region
(only for the “full 24 weeks”, not for the two periods separately)
Table 14.3.1.18: Treatment-emergent adverse events over the whole study: Tabulation 
of all adverse events
Table 14.3.1.19: Treatment-emergent adverse events over the whole study: Tabulation 
of all adverse events by region
(only for the “full 24 weeks”, not for the two periods separately)
Table 14.3.1.20: Treatment-emergent adverse events over the whole study: Tabulation 
of all adverse events by gender
(only for the “full 24 weeks”, not for the two periods separately)


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Table 14.3.1.21: Treatment-emergent adverse events over the whole study: Tabulation 
of all adverse events by age category
(only for the “full 24 weeks”, not for the two periods separately)
Table 14.3.1.22: Treatment-emergent adverse events over the whole study: Tabulation 
per intensity
Table 14.3.1.23: Treatment-emergent adverse events over the whole study: Tabulation 
of all treatment-related events
Table 14.3.1.24: Treatment-emergent adverse events over the whole study: Tabulation 
of all treatment-related events by gender
(only for the “full 24 weeks”, not for the two periods separately)
Table 14.3.1.25: Treatment-emergent adverse events over the whole study: Tabulation 
of all treatment-related events by age category
(only for the “full 24 weeks”, not for the two periods separately)
Table 14.3.1.26: Treatment-emergent adverse events over the whole study: Tabulation 
of the intensity of treatment-related events
Table 14.3.1.27: Treatment-emergent adverse events over the whole study: Tabulation 
of the drug-relatedness of serious events
Table 14.3.1.28: Treatment-emergent adverse events over the whole study: Tabulation 
of the drug-relatedness of events leading to discontinuation
Table 14.3.1.29: Treatment-emergent adverse events over the whole study: Tabulation 
of the drug-relatedness of events leading to a temporary stop
Table 14.3.1.30: Treatment-emergent adverse events over the whole study: Tabulation 
of the drug-relatedness of individual stopping rules
12.1.8. Listings
Listing 16.2.10.1: Treatment-emergent adverse events: Summary listing
Listing per treatment group, per subject and per analysis period (excluding screening) of the 
following:


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
Period start and end date

AE preferred term (flagging serious TEAEs with an asterisk *)

AE start and end date

AE onset day in study

AE onset day in period

AE duration

AE intensity

AE drug relatedness

AE outcome

AE action taken

Concomitant therapy started (yes/no)

Individual stopping criterion (yes/no)
In such a way that all information fits on one line for each AE.
Periods without an AE will be included as “no AE” records.
Population: safety.
Listing 16.2.10.2: Pre-treatment adverse events: Summary listing
Listing per treatment group and per subject of the screening analysis period of all AE details, 
like in the previous listing. Subjects without an AE can be omitted from this listing.
Population: safety.
Listing 16.2.10.3: Adverse events: Full listing of the serious adverse events
Listing per treatment group, per subject and per analysis period (excluding screening) of all 
AE details, including MedDRA coding. Only actual serious adverse events will be presented 
here (irrespective their treatment-emergence, so also showing any SAEs during the screening 
analysis period).
Population: safety.
Listing 16.2.10.4: Treatment-emergent adverse events: Full listing of the events leading 
to discontinuation
Same as the previous listing, but only selecting TEAEs that lead to a permanent stop of study 
medication, or of the study itself. This is including the “stopping rules”.
Population: safety.
Listing 16.2.10.5: Treatment-emergent adverse events: Full listing of the events leading 
to a temporary stop
Same as the previous listing, but only selecting TEAEs that lead to a temporary stop of study 
medication.
Population: safety.


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Listing 16.2.10.6: Adverse events: Coding information
Listing of all available coding steps between AE verbatim and AE system organ class, 
mentioning also the subjects who had this AE. 
Population: safety.
Listing 16.2.10.7: Adverse events: Listing of subjects for whom a narrative is required
Listing and flagging subjects who:

Died

Had an SAE

Had an AE leading to study discontinuation

Had an AE leading to a permanent stop of study drug

Had an AE flagged as stopping criterion by the investigator in the eCRF.
Population: all screened subjects.
The clinical study report will add subject case narratives in the body of the report and/or in 
section 14.3.1. No standard programming is planned for this.
12.2.
LABORATORY SAFETY
12.2.1. Laboratory Units
The statistical analysis will only present results in Standard International (SI) units. Other 
units will not be presented.
Lab tests with only a very low sample size (N<3 in the study total column) will not be 
presented in the tables, but only in the listings. Lab tests that are not part of the planned test 
panels according to the protocol will only be listed.
Endocrine tests will only be presented for male subjects. If any results would be available for 
females (not planned in the protocol), then these will be left out of the tables but still 
presented in the listings.
Urinalysis tests will be presented as part of the descriptive statistics and/or shift tables.
The serum CRP will not be presented in this section (is considered an efficacy parameter).
12.2.2. Derived lab tests
The following two “tests” will be derived from the data provided by the central lab: the ratios 
TC/HDL and LDL/HDL, where TC=total cholesterol, and the ratio between the CD4 and 
CD8 absolute counts (CD4/CD8).
Note that if the denominator is zero, the ratios will not be calculated.


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The following “normal range” will be applied:
Lab test label in analysis
Normal range, males
Normal range, females
Derived TC/HDL ratio
0.0 - 5.0
0.0 - 4.5
Derived LDL/HDL ratio
0.0 - 3.5
0.0 - 3.0
No normal range is defined for the CD4/CD8 ratio.
These derived “tests” will be analyzed together with the tests provided by the lab. 
12.2.3. Number of Significant Digits
The original results and normal limits will be rounded to present only a relevant number of 
digits. The Mock TLFs contains a table on the expected number of significant digits per lab 
test. This rounding will be done prior to any parameter derivation. Note that this table also 
contains the classification of lab tests into categories.
12.2.4. Baseline and Change from Baseline
The baseline is defined as the last sample prior to first dosing, so should normally be from the 
Day -1 visit. Baseline will be determined per lab test individually. It is recognized that 
baseline tests may thus come from more than one lab sample and not just from the “baseline 
visit” sample. 
The change from baseline will be calculated for all post-baseline time points as:
Change from baseline at time point t = value at time point t – baseline value.
The percentage change from baseline will be calculated for all post-baseline time points as:
Percent change from baseline at time point t = 100 x (change from baseline at time point t / 
baseline value).
Note that the percent change from baseline will be left missing in case the baseline value is 
zero.
12.2.5. Scoring of Laboratory Values
12.2.5.1.
Scoring according to normal ranges
All values will be compared to their matching normal ranges. The normal ranges provided by 
the laboratory will be used for this, as available in the database. Values will be scored as 
abnormally low (L), normal (N) or abnormally high (H). 
A value is classified as abnormally low (L) when the value < lower limit of the normal range. 
A value is classified as abnormally high (H) when the value > upper limit of the normal range.
Values equal to the boundaries are still considered normal (N).
An original value like “<X” where X equals the lower limit of the normal range will be 
classified as abnormally low (L). An original value like “>X” where X equals the upper limit 
of the normal range will be classified as abnormally high (H). 


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A normal range of “<10” will be interpreted as: lower limit = 0; upper limit = 10.
A normal range of “>10” will be interpreted as: lower limit = 10; upper limit = +INF.
Tests without normal ranges will not be scored. 
Any already existing low/normal/high flags in the raw database will be ignored. The newly 
derived flag will be used for the analysis TLFs. Any clinical significance flags will be used in 
the listings.
12.2.5.2.
CTCAE V3.0 gradings for biochemistry tests
CTCAE version 3.0 classification is only for the below tests. For other tests, only the 
classification according to normal ranges will be done.
Lab test
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Albumin (g/L)
≥ LLN
[30,LLN[
[20,30[
<20
(NAP)
ALT, AST, 
alkaline 
phosphatase and 
γGT
≤ ULN
]1.0,2.5] 
x ULN
]2.5,5.0] 
x ULN
]5.0,20.0] 
x ULN
> 20.0 
x ULN
Amylase and 
lipase 
≤ ULN
]1.0,1.5] 
x ULN
]1.5,2.0] 
x ULN
]2.0,5.0] 
x ULN
> 5.0 
x ULN
Total bilirubin
≤ ULN
]1.0,1.5] 
x ULN
]1.5,3.0] 
x ULN
]3.0,10.0] 
x ULN
> 10.0 
x ULN
Calcium low 
(mmol/L)
≥ LLN
[2.00,LLN[
[1.75,2.00[
[1.50,1.75[
<1.50
Calcium high 
(mmol/L)
≤ ULN
]ULN,2.9]
]2.9,3.1]
]3.1,3.4]
>3.4
Total 
cholesterol 
(mmol/L)
≤ ULN
]ULN,7.75]
]7.75,10.34]
]10.34,12.92]
>12.92
Creatinine
≤ ULN
]1.0,1.5] 
x ULN
]1.5,3.0] 
x ULN
]3.0,6.0] 
x ULN
> 6.0 
x ULN
Glucose low 
(mmol/L)
≥ LLN
[3.0,LLN[
[2.2,3.0[
[1.7,2.2[
<1.7
Glucose high 
(mmol/L)
≤ ULN
]ULN,8.9]
]8.9,13.9]
]13.9,27.8]
>27.8
Phosphate 
(mmol/L)
≥ LLN
[0.8,LLN[
[0.6,0.8[
[0.3,0.6[
<0.3
Potassium low 
(mmol/L)
≥ LLN
[3.0,LLN[
(NAP)
[2.5,3.0[
<2.5
Potassium high 
(mmol/L)
≤ ULN
]ULN,5.5]
]5.5,6.0]
]6.0,7.0]
>7.0
Sodium low 
(mmol/L)
≥ LLN
[130,LLN[
(NAP)
[120,130[
<120
Sodium high 
(mmol/L)
≤ ULN
]ULN,150]
]150,155]
]155,160]
>160
Triglycerides 
≤ ULN
]1.0,2.5] 
x ULN
]2.5,5.0] 
x ULN
]5.0,10.0] 
x ULN
> 10.0 
x ULN
Note: 

LLN = lower normal limit


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
ULN = upper normal limit

(NAP) = grade does not exist.
12.2.5.3.CTCAE v3.0 gradings for hematology tests
CTCAE version 3.0 classification is only for the below tests. For other tests, only the 
classification according to normal ranges will be done.
Lab test
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin 
(g/L)
≥ LLN
[100,LLN[
[80,100[
[65,80[
< 65
WBC (giga/L)
≥ LLN
[3.0,LLN[
[2.0,3.0[
[1.0,2.0[
<1.0
Lymphocytes 
(giga/L)
≥ LLN
[0.8,LLN[
[0.5,0.8[
[0.2,0.5[
< 0.2
Neutrophils 
(giga/L)
≥ LLN
[1.5,LLN[
[1.0,1.5[
[0.5,1.0[
< 0.5
Platelet count 
(giga/L)
≥ LLN
[75,LLN[
[50,75[
[25,50[
< 25
INR and partial 
thromboplastin 
time
≤ ULN
]1.0,1.5] 
x ULN
]1.5,2.0] 
x ULN
>2.0 x ULN
(NAP)
Note: 

LLN = lower normal limit

ULN = upper normal limit

(NAP) = grade does not exist.
12.2.5.4.ATP III classifications
Lab test
Categories
LDL (mg/dL)
< 100
[100,130[
[130,160[
[160,190[
≥ 190
HDL (mg/dL)
< 40
[40,60[
≥ 60
Total cholesterol (mg/dL)
< 200
[200,240[
≥ 240
Triglycerides (mg/dL)
< 150
[150,200[
[200,500[
≥ 500
12.2.6. Handling of Urinalysis Results
Urinalysis tests for which a normal range is available will also be categorized as L, N, or H. If 
there is doubt on whether the result is within normal range or not, the worst-case will be 
taken. E.g., when the test result equals “4 to 6” and the normal range is 0-5, then the test result 
will be classified as abnormally high (H) of it is a post-baseline visit, and will be classified as 
normal (N) if it is a screening or baseline visit. The original urinalysis test result will not be 
used for the tables, but will only be listed.
Urinalysis tests for which no normal range is available will be listed only.
12.2.7. Last on-treatment result
Derived per parameter separately, for values as well as abnormalities.
Three last on-treatment determinations will be done, depending on the chapter of analysis:


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1.
Including all nonmissing post-baseline values, including “use=No” and unscheduled 
measurements, up to and including the Week 12 value.
2.
Including all nonmissing post-Week 12 values, including “use=No” and unscheduled 
measurements, up to and including the Week 24 value.
3.
Including all nonmissing post-baseline values, including “use=No” and unscheduled 
measurements, up to and including the Week 24 value.
Early discontinuation visits are considered as on-treatment visits as well.
12.2.8. Worst-Case Abnormality
Derived per parameter separately, for abnormalities only.
Three worst-case determinations will be done, depending on the chapter of analysis:
1.
Including all nonmissing post-baseline values, including “use=No” and unscheduled 
measurements, up to and including the Week 12 value. Also including the follow-up 
value in case the subject did not participate in the second period of the study. If the 
subject participated in the second period of the study, then the follow-up value will be 
included in the worst-case of the second period of the study, not of the first period.
2.
Including all nonmissing post-Week 12 values, including “use=No” and unscheduled 
measurements, up to and including the follow-up value.
3.
Including all nonmissing post-baseline values, including “use=No” and unscheduled 
measurements, up to and including the follow-up value.
12.2.8.1.
According to normal ranges
Possible categories:

H = abnormally high: at least one postdose measurement is above the normal range, and 
there are no values below the normal range.

L = abnormally low: at least one postdose measurement is below the normal range, and 
there are no values above the normal range.

H+L = abnormally high and low: at least one postdose measurement is above the normal 
range, and at least one other postdose measurement is below the normal range.

N = normal: all postdose measurements are within normal limits.
12.2.8.2.
According to CTCAE tox grades
The worst-case is the highest post-baseline tox grade. 
12.2.8.3.
According to the ATP III classifications
The worst-case is the highest post-baseline class for LDL, total cholesterol and triglycerides. 
The worst-case is the lowest post-baseline class for HDL.


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12.2.9. Tables up to Week 12
No formal inferential statistics (p-values) will be derived. Time points to present: screening, 
baseline, Weeks 1-2-4-8-12, last on-treatment, worst case.
If the subject did not participate in the second period of the study, then the follow-up visit will 
be presented in the table of the first period of the study. If the subject participated in the 
second period of the study, then the follow-up value will be presented in the table of the 
second period of the study, not of the first period.
Table 14.3.2.1: 
Laboratory data up to Week 12: Descriptive statistics of the actual 
values per time point
Descriptive statistics of actual values per lab test category (hematology, biochemistry, 
endocrine, urinalysis), lab test and unit, treatment group and time point. 
Population: safety.
Population: safety, selecting subjects with a baseline value within normal range (for endocrine 
tests only).
Table to be created for the Week 12 interim analysis as well.
Table 14.3.2.2: 
Laboratory data up to Week 12: Descriptive statistics of the changes 
from baseline per time point
Descriptive statistics of changes from baseline per lab test category (hematology, 
biochemistry, endocrine, urinalysis), lab test and unit, treatment group and time point. The 
actual value at baseline will also be presented in this table.
Population: safety.
Population: safety, selecting subjects with a baseline value within normal range (for endocrine 
tests only).
Table to be created for the Week 12 interim analysis as well.
Table 14.3.2.3: 
Laboratory data up to Week 12: Descriptive statistics of the percent 
changes from baseline per time point
Descriptive statistics of percent changes from baseline per lab test category (hematology, 
biochemistry, endocrine, urinalysis), lab test and unit, treatment group and time point. The 
actual value at baseline will also be presented in this table.
Population: safety.
Population: safety, selecting subjects with a baseline value within normal range (for endocrine 
tests only).
Table to be created for the Week 12 interim analysis as well.


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Table 14.3.2.4: 
Laboratory data up to Week 12: Shift table of the lab abnormalities 
per time point
Shift table per lab test category (hematology, biochemistry, endocrine, urinalysis), lab test, 
treatment group and time point. The table will present the shift in abnormality (L/N/…) at 
worst-case and last on-treatment (other time points: not needed) versus the baseline 
abnormality (L/N/H). Tests without normal ranges will not be presented in this table.
Population: safety.
Table 14.3.2.5: 
Laboratory data up to Week 12: Treatment-emergent lab 
abnormalities per time point
Frequency table of the treatment-emergent lab abnormalities per lab test category 
(hematology, biochemistry, endocrine, urinalysis), lab test, treatment group and time point 
(including the worst-case). A post-baseline abnormality is considered treatment-emergent if it 
differs from the baseline result. Tests without normal ranges will not be presented in this 
table.
Population: safety.
Table to be created for the Week 12 interim analysis as well.
Table 14.3.2.6: 
Laboratory data up to Week 12: Frequency table of the CTCAE 
toxicity grades per time point
Frequency table (with cumulative percentages) per lab test category (hematology, 
biochemistry, endocrine, urinalysis), lab test, treatment group and time point. 
Table for selected tests only.
Population: safety.
Table to be created for the Week 12 interim analysis as well.
Table 14.3.2.7: 
Laboratory data up to Week 12: Shift table of the CTCAE toxicity 
grades per time point
Shift table per lab test category (hematology, biochemistry, endocrine, urinalysis), lab test, 
treatment group and time point. The table will present the shift in CTCAE tox grade 
(0/1/2/3/4) at worst-case and last on-treatment (other time points: not needed) versus the 
baseline grade (0/1/2/3/4).
Table for selected tests only.
Population: safety.
Table 14.3.2.8:
Laboratory data up to Week 12: Treatment-emergent CTCAE toxicity 
grades per time point
Frequency table of the treatment-emergent lab CTCAE tox grades per lab test category 
(hematology, biochemistry), lab test, treatment group and time point (including worst-case). A 


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post-baseline grade is considered treatment-emergent if it is higher than the baseline tox 
grade. 
Table for selected tests only.
Population: safety.
Table to be created for the Week 12 interim analysis as well.
Table 14.3.2.9: 
Laboratory data up to Week 12: Frequency table of the ATP III 
classes per time point
Frequency table (with cumulative percentages) per lab test category (hematology,
biochemistry, endocrine, urinalysis), lab test, treatment group and time point.
Table for selected tests only.
Population: safety.
Table to be created for the Week 12 interim analysis as well.
Table 14.3.2.10: Laboratory data up to Week 12: Shift table of the ATP III classes per 
time point
Shift table per lab test category (hematology, biochemistry, endocrine, urinalysis), lab test, 
treatment group and time point. The table will present the shift in ATP III class at worst-case 
and last on-treatment (other time points: not needed) versus the baseline class.
Table for selected tests only.
Population: safety.
Table 14.3.2.11: Laboratory data up to Week 12: Treatment-emergent ATP III classes 
per time point
Frequency table of the treatment-emergent lab ATP III classes per lab test category 
(hematology, biochemistry), lab test, treatment group and time point (including worst-case). A 
post-baseline class is considered treatment-emergent if it differs from the baseline result and 
is of higher category. 
Table for selected tests only.
Population: safety.
Table to be created for the Week 12 interim analysis as well.
Table 14.3.2.12: Laboratory data up to Week 12: Frequency table of percent changes 
from baseline per time point in inhibin B and testosterone
Frequency table of the percent changes from baseline per lab test category (endocrine), lab 
test, treatment group and time point. The percent changes from baseline will be categorized 


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as: <-50%, [-50%,+50%], >+50%. A worst-case will also be shown selected as the lowest 
post-baseline value.
Table only for inhibin B, free testosterone, total testosterone.
Population: safety – males.
Population: safety, selecting male subjects with a baseline value within normal range.
Table to be created for the Week 12 interim analysis as well.
Table 14.3.2.13: Laboratory data up to Week 12: Shift table of the categorical lab data 
per time point
Shift table per lab test category (hematology, biochemistry, endocrine, urinalysis), lab test, 
treatment group and time point. Selecting only the tests with categorical data. The table will 
present the shift in value at each post-baseline time point versus the baseline value.
Population: safety.
12.2.10.
Figures up to Week 12
Figure 14.3.2.1: Laboratory data up to Week 12: Mean plots of the actual values over 
time
Mean plots of the actual values over time, with each lab test on a new page but with all 
treatment groups on the same plot using different plot symbols. Unscheduled or follow-up 
results will not be part of this plot.
Population: safety.
Figure to be created for the Week 12 interim analysis as well.
Figure 14.3.2.2: Laboratory data up to Week 12: Mean plots of the changes from 
baseline over time
Mean plots of the changes from baseline over time, with each lab test on a new page but with
all treatment groups on the same plot using different plot symbols. Unscheduled or follow-up 
results will not be part of this plot. With a horizontal reference line at zero, indicating no 
change. Plots will start with a zero mean at baseline.
Population: safety.
Figure to be created for the Week 12 interim analysis as well.
Figure 14.3.2.3: Laboratory data up to Week 12: Mean plots of the percent changes 
from baseline over time
Mean plots of the percent changes from baseline over time, with each lab test on a new page 
but with all treatment groups on the same plot using different plot symbols. Unscheduled or 
follow-up results will not be part of this plot. With a horizontal reference line at zero, 
indicating no change. Plots will start with a zero mean at baseline.


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Population: safety.
Figure to be created for the Week 12 interim analysis as well.
12.2.11.
Tables over the whole 24 weeks period
The same tables will be made as for the first period of the study, but with the 11 adapted 
treatment groups. Time points to present: screening, baseline, Week 1-2-4-8-12, last on-
treatment during period 1, worst case during period 1, Weeks 16-20-24, last on-treatment 
during period 2, follow-up (all follow-up visits in the study), worst case during period 2, last 
on-treatment during the whole study, worst case during the whole study. Population: Safety.
Table 14.3.2.14: Laboratory data over the whole study: Descriptive statistics of the 
actual values per time point
Table 14.3.2.15: Laboratory data over the whole study: Descriptive statistics of the 
changes from baseline per time point
Table 14.3.2.16: Laboratory data over the whole study: Descriptive statistics of the 
percent changes from baseline per time point
Table 14.3.2.17: Laboratory data over the whole study: Shift table of the lab 
abnormalities per time point
Table 14.3.2.18: Laboratory data over the whole study: Treatment-emergent lab 
abnormalities per time point
Table 14.3.2.19: Laboratory data over the whole study: Frequency table of the CTCAE 
toxicity grades per time point
Table 14.3.2.20: Laboratory data over the whole study: Shift table of the CTCAE 
toxicity grades per time point
Table 14.3.2.21: Laboratory data over the whole study: Treatment-emergent CTCAE 
toxicity grades per time point
Table 14.3.2.22: Laboratory data over the whole study: Frequency table of the ATP III 
classes per time point
Table 14.3.2.23: Laboratory data over the whole study: Shift table of the ATP III 
classes per time point
Table 14.3.2.24: Laboratory data over the whole study: Treatment-emergent ATP III 
classes per time point
Table 14.3.2.25: Laboratory data over the whole study: Frequency table of percent 
changes from baseline per time point in inhibin B and testosterone
Table 14.3.2.26: Laboratory data over the whole study: Shift table of the categorical 
lab data per time point


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12.2.12.
Figures over the whole 24 weeks period
The follow-up visit will not be shown on the mean plots because it is expected that it will 
happen only for a limited number of subjects, as a large number will roll over into study 205 
without a follow-up visit.
The same plots again, but with the 11 adapted treatment groups. Plots will show data from 
screening up to the end of the study.
Figure 14.3.2.4: Laboratory data over the whole study: Subject profile plots over time 
– subjects with a treatment-emergent abnormality
Figure 14.3.2.5:
Laboratory data over the whole study: Mean plots of the actual values 
over time
Figure 14.3.2.6: Laboratory data over the whole study: Mean plots of the changes from 
baseline over time
Figure 14.3.2.7: Laboratory data over the whole study: Mean plots of the percent 
changes from baseline over time
12.2.13.
Listings
All listings will contain next to the actual data (raw and changes) the following parameters:

a fasted Y/N flag

an abnormality L/H flag

CTCAE toxicity grade, ATP III classification

the test’s normal range

a clinical relevance flag
Listing 16.2.11.1: Laboratory data: Full listing
Listing per treatment group, per subject and per time point of all recorded data.
Population: safety.
Listing 16.2.11.2: Laboratory data: Abnormalities listing
Listing per treatment group, per subject and per time point of all post-baseline data scored as 
out-of-normal-range, plus also the baseline reference time point.
Population: safety.
Listing 16.2.11.3: Laboratory data: Clinically significant abnormalities
Listing per treatment group, per subject and per time point of the eCRF’s verbatim text field 
on clinically significant abnormalities.
Population: safety.
Listing 16.2.11.4: Laboratory data: Urinalysis results


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Listing per treatment group, per subject and per time point of the abnormal urinalysis results
only (including the baseline result as reference).
Population: safety.
Listing 16.2.11.5: Laboratory data: Positive pregnancy tests
Listing per treatment group, per subject and per time point of all pregnancy test results (urine 
and serum) for female subjects who had a positive test at some point.
Population: safety.
12.3.
ECG
12.3.1. Available Data
Available parameters: HR, QRS, QT, and an interpretation. The RR interval, when available, 
will only be listed.
12.3.2. Calculated Parameters
The QTc will always be derived during the statistical analysis, even when already available in 
the database. The value in the database will not be used in the analysis.
The QTc will be calculated using the following formula: Fridericia’s cube-root corrected QT 
(Fridericia, 1920):
QTcF (ms) = QT (ms) x K
LM(NOP)
Q
R
The QTcF will be rounded up to the nearest integer prior to the derivation of changes and 
categorizations.
12.3.3. Baseline and Change from Baseline
The baseline is defined as the last nonmissing value prior to dosing. Baseline will be 
determined per ECG parameter individually. It is recognized that baseline parameters may 
thus come from more than one ECG reading and not just from the “baseline visit” reading. 
The change from baseline will be calculated for all post-baseline time points as:
Change from baseline at time point t = value at time point t – baseline value.
12.3.4. Visits for analysis
An ECG is only taken at Screening (baseline), Week 12, Week 24/EDV and Follow-up. 
Therefore the analysis will not use any time windowing, but will just present the visits as they 
are: Baseline, Week 12 and Week 24, and Follow-up. See also mocks.


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In case the subject prematurely discontinues the study during the first period of the study, the 
EDV ECG will be used as “Week 12”. In case the subject prematurely discontinues the study 
during the second period of the study, the EDV ECG will be used as “Week 24”.
Because of this, there will not be a “last on-treatment” nor a “worst-case”.
12.3.5. Normal Ranges
For the QT and QTcF parameters, the following categorizations will be done:

of the actual values: 

<= 450 ms, 

]450,480] ms, 

]480,500] ms, 

>500 ms;

of the changes from baseline: 

<= 30 ms (including all decreases in QT), 

]30,60] ms, 

>60 ms.
12.3.6. Analysis tables at Week 12
No formal inferential statistics (p-values) are planned in this SAP.
If the subject did not participate in the second period of the study, then the follow-up visit will 
be presented in the table of the first period of the study. If the subject participated in the 
second period of the study, then the follow-up value will be presented in the table of the 
second period of the study, not of the first period.
Table 14.3.3.1:
ECG up to Week 12: Descriptive statistics of the actual values per time 
point
Descriptive statistics of the actual values per test and unit, and per treatment group.
Population: safety.
Table 14.3.3.2:
ECG at Week 12: Descriptive statistics of the changes from baseline
Descriptive statistics of the changes from baseline per test and unit, and per treatment group. 
The actual value at baseline will also be presented in this table.
Population: safety.
Table 14.3.3.3: 
ECG at Week 12: Shift table of the QT abnormalities
Shift table per test, treatment group and time point. The table will present the shift in 
abnormality at each post-baseline time point (including the worst-case) versus the baseline 
abnormality. Parameters: QT and QTcF.
Population: safety.


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Table 14.3.3.4:
ECG at Week 12: Treatment-emergent QT abnormalities
Frequency table of the treatment-emergent abnormalities per parameter and treatment group. 
A post-baseline abnormality is considered treatment-emergent if it is higher than the baseline 
result. Parameters: QT and QTcF.
Population: safety.
Table 14.3.3.5:
ECG at Week 12: Treatment-emergent abnormal change in QT
Frequency table per test and treatment group. The table will present the abnormality of the 
changes. Parameters: QT and QTcF.
Population: safety.
Table 14.3.3.6:
ECG up to Week 12: Frequency table of the eCRF ECG interpretation 
per time point
Frequency table per treatment group of the ECG interpretation scores as recorded in the 
eCRF. Interpretation scores are:

Normal ECG in sinus rhythm:

Cardiac conduction disorders;

Rate and rhythm disorders;

Supraventricular arrhythmias;

Ventricular arrhythmias.
Note that more than one of these items can be ticked.
Population: safety.
12.3.7. Analysis tables for the whole 24 weeks period
Repeat tables, population=safety, with the adapted treatment groups focusing on subjects who 
used GLPG0634 during both study periods:
Table 14.3.3.7:
ECG over the whole study: Descriptive statistics of the actual values 
per time point
Table 14.3.3.8:
ECG over the whole study: Descriptive statistics of the changes from 
baseline
Table 14.3.3.9: 
ECG over the whole study: Shift table of the QT abnormalities
Table 14.3.3.10: ECG over the whole study: Treatment-emergent QT abnormalities 
Table 14.3.3.11: ECG over the whole study: Treatment-emergent abnormal change in 
QT 
Table 14.3.3.12: ECG over the whole study: Frequency table of the eCRF ECG 
interpretation per time point


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12.3.8. Figures
No figures planned.
12.3.9. Listings
Listing 16.2.12.1: ECG: Full listing
Listing per treatment group, per subject and per time point of the ECG parameters (raw values 
as well as changes from baseline), flagging abnormal results. Includes the ECG interpretation 
and morphology findings.
Population: safety.
Listing 16.2.12.2: ECG: Abnormalities listing
Listing per treatment group, per subject and per time point of all post-baseline data scored as 
out-of-normal-range or clinically significant, plus also the baseline reference time point. 
Population: safety.
12.4.
VITAL SIGNS
12.4.1. Available Data
Available parameters: pulse rate, diastolic and systolic blood pressure, temperature.
12.4.2. Baseline and Change from Baseline
The baseline value will be the last nonmissing value prior to first dosing. Baseline will be 
determined per vital signs parameter individually. It is recognized that baseline parameters 
may thus come from more than one vital signs reading and not just from the “baseline visit” 
reading.
The change from baseline will be calculated for all post-baseline time points as:
Change from baseline at time point t = value at time point t – baseline value.
12.4.3. Normal Ranges
Parameter, unit
Normal range
Lower limit
Upper limit
Pulse, bpm
40
100
DBP, mmHg
45
90
SBP, mmHg
90
140
Temperature, °C
35.5
37.5


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Values equal to the boundaries are still considered normal (N). A value is classified as 
abnormally low (L) when the value < lower limit of the normal range. A value is classified as 
abnormally high (H) when the value > upper limit of the normal range.
12.4.4. Last on-treatment result
Derived per parameter separately, for values as well as abnormalities.
Three last on-treatment determinations will be done, depending on the chapter of analysis:
1.
Including all nonmissing post-baseline values, including “use=No” and unscheduled 
measurements, up to and including the Week 12 value.
2.
Including all nonmissing post-Week 12 values, including “use=No” and unscheduled 
measurements, up to and including the Week 24 value.
3.
Including all nonmissing post-baseline values, including “use=No” and unscheduled 
measurements, up to and including the Week 24 value.
Early discontinuation visits are considered as on-treatment visits as well.
12.4.5. Worst-Case Abnormality
Derived per parameter separately, for abnormalities only.
Three worst-case determinations will be done, depending on the chapter of analysis:
1.
Including all nonmissing post-baseline values, including “use=No” and unscheduled 
measurements, up to and including the Week 12 value. Also including the follow-up 
value in case the subject did not participate in the second period of the study. If the 
subject participated in the second period of the study, then the follow-up value will be 
included in the worst-case of the second period of the study, not of the first period.
2.
Including all nonmissing post-Week 12 values, including “use=No” and unscheduled 
measurements, up to and including the follow-up value.
3.
Including all nonmissing post-baseline values, including “use=No” and unscheduled 
measurements, up to and including the follow-up value.
Possible categories:

H = abnormally high: at least one postdose measurement is above the normal range, and 
there are no values below the normal range.

L = abnormally low: at least one postdose measurement is below the normal range, and 
there are no values above the normal range.

H+L = abnormally high and low: at least one postdose measurement is above the normal 
range, and at least one other postdose measurement is below the normal range.

N = normal: all postdose measurements are within normal limits.
12.4.6. Tables up to Week 12
No formal inferential statistics (p-values) will be derived. Time points to present: screening, 
baseline, Weeks 1-2-4-8-12, last on-treatment, worst case.
If the subject did not participate in the second period of the study, then the follow-up visit will 
be presented in the table of the first period of the study. If the subject participated in the 


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second period of the study, then the follow-up value will be presented in the table of the 
second period of the study, not of the first period.
Table 14.3.4.1: 
Vital signs up to Week 12: Descriptive statistics of the actual values
Descriptive statistics of the actual values per test and unit, treatment group and time point. 
Population: safety.
Table 14.3.4.2: 
Vital signs up to Week 12: Descriptive statistics of the changes from 
baseline
Descriptive statistics of the changes from baseline per test and unit, treatment group and time 
point. The actual value at baseline will also be presented in this table.
Population: safety.
Table 14.3.4.3: 
Vital signs up to Week 12: Summary table of means
Summary table per test and unit, treatment group and time point, showing only the mean 
value of actual values and changes from baseline.
Population: safety.
Table to be created for the Week 12 interim analysis as well.
Table 14.3.4.4: 
Vital signs up to Week 12: Shift table of the abnormalities per time 
point
Shift table per test, treatment group and time point. The table will present the shift in 
abnormality (L/N/…) for “last” and “worst-case” versus the baseline abnormality (L/N/H).
Population: safety.
Table 14.3.4.5: 
Vital signs up to Week 12: Treatment-emergent abnormalities per 
time point
Frequency table of the treatment-emergent abnormalities per parameter, treatment group and 
time point (including the worst-case). A post-baseline abnormality is considered treatment-
emergent if it is different from the baseline result. 
Population: safety.
12.4.7. Tables over the whole 24 weeks period
The same tables again, but with adapted treatment groups focusing on the subjects who used 
GLPG0634 during both study periods. Time points to present: screening, baseline, Week 1-2-
4-8-12, last on-treatment during period 1, worst case during period 1, Weeks 16-20-24, last 
on-treatment during period 2, last on-treatment during the whole study, follow-up (all follow-
up visits in the study), worst case during period 2, worst case during the whole study. 
Population: Safety.


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Table 14.3.4.6: 
Vital signs over the whole study: Descriptive statistics of the actual 
values
Table 14.3.4.7: 
Vital signs over the whole study: Descriptive statistics of the changes 
from baseline
Table 14.3.4.8: 
Vital signs over the whole study: Summary table of means
Table 14.3.4.9: 
Vital signs over the whole study: Shift table of the abnormalities per 
time point
Table 14.3.4.10: Vital signs over the whole study: Treatment-emergent abnormalities 
per time point
12.4.8. Figures
No figures are planned.
12.4.9. Listings
Listing 16.2.13.1: Vital signs: Full listing
Listing per treatment, per subject and per time point of all parameters: raw values, changes 
from baseline, and flagging abnormal results.
Population: safety.
Listing 16.2.13.2: Vital signs: Abnormalities listing
Listing per treatment group, per subject and per time point of all post-baseline data scored as 
out-of-normal-range or clinically significant, plus also the baseline reference time point. 
Population: safety.
12.5.
PHYSICAL EXAMINATIONS
Listing 16.2.14:
Physical examinations: Abnormal findings
Listing per treatment group, per subject and per time point of the selection of all abnormal 
findings (i.e., “abnormal” or “changed”).
Population: safety.
13.
REFERENCES
Fridericia, L. (1920). Die systolendauer im elektrokardiogramm bei normalen menschen und bei 
herzkranken. Acta Med Scand, 53:469-486.
ICH-E3. (December 1995). Structure and content of clinical study reports. Step 4 Guideline.


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ICH-E6. (17 July 1996). Guideline for good clinical practice. Step 5 Guideline.
ICH-E9. (5 February 1998). Statistical principles for clincal trials. Step 4 guideline.




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STATISTICAL ANALYSIS PLAN HISTORY
SAP / Amendment #
Date
Version
Statistical Analysis Plan-Addendum
13-Jun-2016
Version 1.0
Statistical Analysis Plan-Addendum 
v2.0
20-Jul-2016
Version 2.0:
In section “Step 3: Correlation of each 
individual biomarker versus week 12 
efficacy and safety”, supporting tables 
were added to the plots to display the 
Pearson or point-biserial correlation 
coefficients.
In section “Step 4: Biomarkers 
predicting the Week 12 Efficacy and 
Safety”, baseline value of the efficacy 
or safety parameters will be added as 
covariate in the ANCOVA model 
expect for ACR-N parameters.


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TABLE OF CONTENTS
List of Tables ........................................................................................................................4
List of Figures.......................................................................................................................4
List of Listings ......................................................................................................................5
1. Introduction ....................................................................................................................6
2. PD Populations................................................................................................................6
3. Treatment Groups...........................................................................................................6
3.1.
Randomized versus Actual Treatment .....................................................................6
3.2.
Treatment Group Labels..........................................................................................6
4. Analysis Periods and Analysis Time Points ...................................................................6
4.1.
Relative Number of Days........................................................................................6
4.2.
Algorithm of Allocating Visits to Time Windows ...................................................7
4.3.
Selection of Visits...................................................................................................7
5. Handling of Data.............................................................................................................8
5.1.
Calculation of Descriptive Statistics........................................................................8
5.2.
Calculation of Percentages ......................................................................................8
5.3.
Handling of Values below (or above) a Threshold...................................................8
5.4.
Handling of Missing Data .......................................................................................8
5.4.1.
Observed Cases (OC) .................................................................................8
5.4.1.
Last Observation Carried Forward (LOCF) ................................................8
5.4.2.
Handling of Missing Date(Time) or Partially Known Date(Time)...............9
5.5.
Handling of Outliers................................................................................................9
5.6.
Stratification factors................................................................................................9
6. Software and Procedures................................................................................................9
6.1.
Software..................................................................................................................9
6.2.
Procedures ..............................................................................................................9
6.3.
Formats.................................................................................................................10
7. Statistical Methods........................................................................................................10
7.1.
Planned Analyses, Protocol Amendments Included ...............................................10
7.2.
Changes to the Planned Analyses, Not Covered by Protocol Amendments ............10
8. Definitions of Pharmacodynamics Analysis Tables, Listings and Figures..................10
8.1.
PD Parameters ......................................................................................................11
8.2.
Step 1: Overall analysis of the biomarkers.............................................................11
8.3.
Step 2: Analysis of the biomarkers, split up for W12 responders and non-
responders.............................................................................................................15
8.4.
Step 3: Correlation of each individual biomarker versus Week 12 efficacy 
and safety..............................................................................................................16
8.5.
Step 4: Biomarkers predicting the Week 12 Efficacy and Safety ...........................17
9. References .....................................................................................................................20


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LIST OF TABLES
Table PD 1: 
Descriptive statistics of the actual values ...............................................11
Table PD 2: 
Descriptive statistics of the changes from baseline.................................11
Table PD 3: 
Descriptive statistics of the percent changes from baseline.....................12
Table PD 4: 
Summary with overall p-value and pairwise comparisons versus 
placebo..................................................................................................12
Table PD 5: 
Exploratory pairwise comparisons between regimens within each 
daily dose level......................................................................................13
Table PD 6: 
Descriptive statistics of the actual values, split up for Week 12 
responders vs non-responders ................................................................15
Table PD 7: 
Descriptive statistics of the changes from baseline, split up for 
Week 12 responders vs non-responders .................................................16
Table PD 8: 
Descriptive statistics of the percent changes from baseline, split up 
for Week 12 responders vs non-responders............................................16
Table PD 9: 
Summary on changes from baseline with overall p-value and p-
value for Week 12 response/non-response .............................................16
Table PD 10: 
Exploratory model to assess the relation between baseline PD 
markers and Week 12 response..............................................................17
Table PD 11: 
Exploratory model to assess the relation between the Week 4 
change from baseline in PD markers and Week 12 response ..................18
Table PD 12: 
Exploratory model to assess the relation between the Week 4 
%change from baseline in PD markers and Week 12 response...............18
Table PD 13: 
Exploratory model to assess the relation between baseline PD 
markers and Week 12 changes from baseline in efficacy........................18
Table PD 14: 
Exploratory model to assess the relation between the Week 4 
change from baseline in PD markers and Week 12 changes from 
baseline in efficacy................................................................................18
Table PD 15: 
Exploratory model to assess the relation between the Week 4 
percent change from baseline in PD markers and Week 12 changes 
from baseline in efficacy........................................................................18
Table PD 16: 
Exploratory model to assess the relation between baseline PD 
markers and Week 12 changes from baseline in safety...........................19
Table PD 17: 
Exploratory model to assess the relation between the Week 4 
change from baseline in PD markers and Week 12 changes from 
baseline in safety ...................................................................................19
Table PD 18: 
Exploratory model to assess the relation between the Week 4 
percent change from baseline in PD markers and Week 12 changes 
from baseline in safety...........................................................................19
LIST OF FIGURES
Figure PD 1: 
Mean(SE) plot of the actual values ........................................................14


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Figure PD 2: 
Mean(SE) plot of the changes from baseline..........................................15
Figure PD 3: 
Mean(SE) plot of the percent changes from baseline..............................15
Figure PD 4: 
Box plot of the actual values..................................................................15
Figure PD 5: 
Box plot of the changes from baseline ...................................................15
Figure PD 6: 
Box plot of the percent changes from baseline .......................................15
Figure PD 7: 
Scatterplots of the PD markers...............................................................15
Figure PD 8: 
Mean(SE) plot of the actual values: Week 12 responders vs non-
responders .............................................................................................16
Figure PD 9: 
Mean(SE) plot of the changes from baseline: Week 12 responders 
vs non-responders..................................................................................16
Figure PD 10: 
Mean(SE) plot of the percent changes from baseline: Week 12 
responders vs non-responders ................................................................16
Figure PD 11: 
Box plot of the actual values: Week 12 responders vs non-
responders .............................................................................................16
Figure PD 12: 
Box plot of the changes from baseline: Week 12 responders vs 
non-responders ......................................................................................16
Figure PD 13: 
Box plot of the percent changes from baseline: Week 12  
responders vs non-responders ................................................................16
Figure PD 14: 
Scatterplots of PD markers versus efficacy ............................................16
Figure PD 15: 
Scatterplots of PD markers versus safety ...............................................17
Figure PD 16: 
Scatterplots of baseline PD markers versus efficacy...............................18
Figure PD 17: 
Scatterplots of Week 4 change from baseline PD markers versus 
efficacy..................................................................................................18
Figure PD 18: 
Scatterplots of Week 4 %change from baseline PD markers versus 
efficacy..................................................................................................19
Figure PD 19: 
Scatterplots of baseline PD markers versus safety..................................19
Figure PD 20: 
Scatterplots of Week 4 change from baseline PD markers versus 
safety.....................................................................................................19
Figure PD 21: 
Scatterplots of Week 4 percent change from baseline PD markers 
versus safety..........................................................................................19
LIST OF LISTINGS
No listings planned. 


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1.
INTRODUCTION
This document is an addendum to the main study SAP version 5.00. It is intended to define 
the statistical analysis of the additional pharmacodynamics measurements.
This Addendum to the final SAP was written after database unblinding and after viewing the 
main study results.
2.
PD POPULATIONS
The PD population will be a subpopulation of the ITT from the main study analysis:

All randomized subjects who received at least one dose of study medication and have at 
least one post-Baseline efficacy assessment. This is the ITT population in the main study 
analysis, available in ADaM.ADSL variable ITTFL.

The 50 mg/day dose groups will be excluded (no PD samples analyzed for these groups; 
and still excluded from PD population if by accident there would be a result from a 50 
mg/day subject).

Also subjects who have no PD results (eg not allowed to analyze as per subject ICF 
version) will be excluded from this analysis.
The analysis population will always be indicated in a subtitle in the table, listing or figure.
3.
TREATMENT GROUPS
3.1.
RANDOMIZED VERSUS ACTUAL TREATMENT
For efficacy and PD parameters, the treatment group as assigned by the randomization will be 
used in the analysis (i.e., as-randomized analysis).
3.2.
TREATMENT GROUP LABELS
The following treatment group labels will be used in the tables, listings and figures:

Placebo

GLPG0634 100 mg q.d.

GLPG0634 200 mg q.d.

GLPG0634 50 mg b.i.d.

GLPG0634 100 mg b.i.d.
The 50 mg q.d. and 25 mg b.i.d. groups will not be used (because PD samples are not 
analysed).
4.
ANALYSIS PERIODS AND ANALYSIS TIME POINTS
4.1.
RELATIVE NUMBER OF DAYS
The relative day (DY) is calculated as follows: 
= Visit date – reference date + 1 day, when the visit date is on or after the reference date


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= Visit date – reference date, when the visit date is before the reference date.
The reference date in the study is the first study medication intake date, which by definition 
has DY=1. There is no DY=0.
4.2.
ALGORITHM OF ALLOCATING VISITS TO TIME WINDOWS
The main study analysis used the following time windows:
All visits (including early discontinuation visits and unscheduled visits but excluding visits 
without data) will be placed into time windows according to their relative day (DY) in the 
study, according to the following allocation table:
Time point 
label
Target day
Interval lower bound
Interval upper bound
Screening (3)
NA
NA
NA
Baseline (1)
NA
NA
NA
Week 1
8
2
11
Week 2
15
12
21
Week 4
29
22
42
Week 8
57
43
70
Week 12
85
71
98
Week 16
113
99
126
Week 20
141
127
154
Week 24
169
155
182
>Week 24 (2)
NA
183
+∞
Follow-up (3)
7-10 days after last 
visit
NA
NA
(NA = not applicable).
Notes:
(1)
The actual baseline reference value will be determined per parameter as the last available pre-dosing data point, so might differ 
from this “baseline” visit interval. There will be only one baseline time point in this study: the last non-missing value prior to first 
dosing of study drug.
(2)
Visits falling really late in the study (relative day > 182; excluding the follow-up visit) will be allocated to a “>Week 24” interval, 
and will not be shown in tables nor figures, but will only be listed.
(3)
For the screening and follow-up visits, no time window is defined. The visit as recorded in the eCRF will be used. Follow-up 
visits of subjects who discontinue the study prior to the Week 12 re-randomization will be shown separately as well in the tables 
that present the first part of the study only. For tables that present the study as a whole, all follow-up visits will be shown.
Tables, figures and listings will present the time points, not the visits.
For this additional PD analysis, only Baseline, Week 4 and Week 12 samples will be 
analyzed. These will be placed into the above time windows to allow a matching with the 
main analysis. If a PD result ends up in an analysis visit different from “baseline”, “week 4” 
and “week 12”, then it will not be used in the tables and figures. 
4.3.
SELECTION OF VISITS
It is possible that more than one visit gets allocated into the same time window. In that case, 
only one visit will be selected for tables and figures. The non-selected visit(s) will only be 
listed and flagged as use=no.


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The visit with a relative day (DY) closest to the target day will be selected. If there are 
multiple visits at the same distance of the scheduled visit day (meaning: equal ABS(DY –
target day)), then the one latest in time is selected.
In case more than one parameter is measured per time point , the selection is performed per 
parameter and per time point, not per “sample” and per time point. Missing values are 
removed before the selection is made.
5.
HANDLING OF DATA
5.1.
CALCULATION OF DESCRIPTIVE STATISTICS
For continuous parameters, descriptive statistics will be presented when N≥2. When N=1, the 
observation will not be shown in the table but only in the listing.
Descriptive statistics will include at least the following: 

the number of non-missing data points (N) 

the number of values above the lower limit of quantification and below the upper limit of 
quantification (only applicable to tables of actual values)

the arithmetic mean

the geometric mean (only applicable to tables of actual values)

the standard error (SE) and the standard deviation (SD)

the median, minimum and maximum

95% confidence interval of the mean (only when requested).
5.2.
CALCULATION OF PERCENTAGES
Missing values will not be included in the denominator count when computing percentages.
5.3.
HANDLING OF VALUES BELOW (OR ABOVE) A THRESHOLD
Values below the detection limit (“BLQ”, “<x” or “OOR <”) will be imputed by a value of 
“0.1”. Note that the central lab was unable to provide a value for the LLOQ.
Values flagged as extrapolated (ie, a result flagged with an asterisk) in the transfer from the 
bioanalysis lab will be handled as if they are BLQ, and will be imputed by “0.1” as well.
5.4.
HANDLING OF MISSING DATA
5.4.1. Observed Cases (OC)
No imputation is done of missing values.
5.4.1. Last Observation Carried Forward (LOCF)
A missing W4 analysis visit will be imputed by the last preceding non-missing data point. 
This can be a baseline value.


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A missing W12 analysis visit will be imputed by the last preceding non-missing data point. 
Again this could be a baseline value. This will only be done for the main descriptive statistics 
and comparisons vs placebo. Correlation analyses will be performed on OC only.
5.4.2. Handling of Missing Date(Time) or Partially Known Date(Time)
No imputation will be done of missing date(time) fields, nor of the missing parts of partially 
known date(time) fields. When needed, a worst-case selection will be made.
5.5.
HANDLING OF OUTLIERS
All measured values will be included in the analyses. However, analyses may be repeated 
after exclusion of outliers.
5.6.
STRATIFICATION FACTORS
In case there is a discrepancy in randomization stratification stratum between IWRS and the 
actual eCRF data, then the actual eCRF stratum will be used in analyses and analysis models.
These are available in the final ADaM.ADSL dataset: region and previous use of biologics. 
6.
SOFTWARE AND PROCEDURES
6.1.
SOFTWARE
SAS version 9.2 will be used for programming.
Each TLF will be presented in a separate PDF file. Image files (e.g. PNG or in Excel) should 
be available for plots.
SAS line size and page size:

SAS LSIZE = 144 

SAS PSIZE = 48
Page layout:

landscape

paper size: A4

margins in MS Word:

top, bottom, left, right: 2.5 cm

gutter: 0 cm

header, footer, from edge: 1.3 cm
6.2.
PROCEDURES
Analyses will comply with ICH regulations, in particular: (ICH-E3) , (ICH-E6) and (ICH-E9).
The following Galapagos SOPs will be followed:


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
SOP-CLI-001: Developing Clinical Study Documents (version 1.0)

SOP-CLI-003: Managing Data Processing Activities (version 1.0)
The following 
STAT SOPs will be followed:

-SOP-ST-003_1_0: Statistical Analysis (Date effective: 30 September 2015)

-SOP-ST-004_1_0: SAS Programming for Statistical Analysis (Date effective: 30 
September 2015)
6.3.
FORMATS
Derived data will be following CDISC ADaM 2.1  format. Since this extra analysis only 
contains PD, only one derived ADaM dataset ADPD2 will be created, containing the new PD 
parameters. A “DEFINE” file is not needed.
7.
STATISTICAL METHODS
7.1.
PLANNED ANALYSES, PROTOCOL AMENDMENTS 
INCLUDED
A descriptive analysis will present the actual values, changes from baseline and percent 
changes from baseline.
Treatment arms will be compared (similarly to efficacy) via an ANCOVA model on the 
changes from baseline, with explanatory factors: treatment, baseline value, stratification 
factors (geographical region, previous use of biologics). Pairwise comparisons versus placebo 
will be presented, corrected for multiplicity using Hommel’s method. Exploratory 
comparisons between the two regimens within each dose level will be presented as well.
Correlations versus efficacy and safety parameters will be investigated via logistic regression 
or ANCOVA models.
Figures will be added to depict the data. 
Early dropouts and missing analysis visits will be imputed via the LOCF algorithm for the 
descriptive analysis and comparisons vs placebo. Correlation analyses will be performed on 
OC only.
7.2.
CHANGES TO THE PLANNED ANALYSES, NOT COVERED BY 
PROTOCOL AMENDMENTS
Not applicable – all these analyses are post-lock.
8.
DEFINITIONS OF PHARMACODYNAMICS ANALYSIS
TABLES, LISTINGS AND FIGURES
All analyses will be run on the PD population, unless specified otherwise.


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8.1.
PD PARAMETERS
The raw PD markers will be provided by the bioanalysis lab: GM-CSF, IFNγ, IL-1β, IL-2,
IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17A, IL-21, IL-23, MIP-1α, MIP-
1β and TNF-α. All results are expressed in pg/mL. The raw values (with their unit) will be 
used in the analysis without any transformation or manipulation (except for the imputation of 
values BLOQ or missing values). 
Analysis will show actual values, changes from baseline and percent changes from baseline.
%change from baseline = 100 x (change from baseline) / baseline, and is only defined when 
the baseline ≠ 0.
8.2.
STEP 1: OVERALL ANALYSIS OF THE BIOMARKERS
Table PD 1: 
Descriptive statistics of the actual values
Descriptive statistics of the actual values per time point, and per treatment group.
The table will show:

LOCF

observed-case
Mock:
Note that this table contains geometric means, but none of the other tables need to.
Table PD 2: 
Descriptive statistics of the changes from baseline
Descriptive statistics of the changes from baseline per time point, and per treatment group.


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The table will show:

LOCF

observed-case
Mock:
Table PD 3: 
Descriptive statistics of the percent changes from baseline
Repeat table for the percent changes from baseline.
Table PD 4: 
Summary with overall p-value and pairwise comparisons versus 
placebo
ANCOVA model on the LOCF change from baseline biomarker at each time point. Factors in 
the model are: treatment, baseline value of the PD marker, region, and previous use of 
biologics.
Per time point, the table will present:

Overall type-III p-value for all explanatory factors in the model.

Per group: difference in LS-means versus the placebo group (GLPG0634 minus placebo), 
together with a 95% confidence interval of this difference.

Per group: p-value for pairwise comparison versus the placebo group, derived from 
contrasts within the overall model. These p-values will be presented both as uncorrected 
p-values as well as corrected for multiplicity according to Hommel’s closed-testing 
method (SAS PROC MULTTEST).
Mock:


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The table will show:

LOCF

observed-case
Table PD 5: 
Exploratory pairwise comparisons between regimens within each 
daily dose level
ANCOVA model on the change from baseline at each time point. Factors in the model are: 
baseline value, regimen, dose, regimen*dose interaction, region, and previous use of 
biologics. Placebo subjects will not be used in this model (as there is no q.d./b.i.d. regimen 
available for placebo). The regimen*dose interaction will be removed from the final model 
when not significant at level 0.10 (two-sided type-III p-value). Regimen will have 2 
categories: q.d. or b.i.d. Dose will have 2 categories, corresponding to the total daily dose: 
100 mg/day or 200 mg/day.
Per time point, the table will present:

Per dose: difference in LS-means of q.d. versus b.i.d. within the same dose level (100 or 
200 mg/day), together with a 95% confidence interval of this difference.

Per group: p-value for pairwise comparison of q.d. versus b.i.d. These p-values will be 
presented both as uncorrected p-values, and are derived as contrasts within the overall 
model. As this is a purely exploratory analysis, no adjustment for multiplicity will be 
performed.
Mock:


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The table will show:

LOCF

observed-case
Figure PD 1: 
Mean(SE) plot of the actual values
Mean(SE) plot over time of the actual values. Use a time-proportional horizontal axis.
Mock:
The plot will show:


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
LOCF

observed-case
Note that this is a generic mock plot. The “normal range” line does not apply to this PD 
analysis. 
The following standardized colors, line types and plot symbols will be used consistently 
throughout the entire analysis:
Treatment group label
plot symbol
line type
color
Placebo
Dot
Full line
Black
GLPG0634 100 mg q.d.
Square
Full line
Blue
GLPG0634 200 mg q.d.
Diamond
Dotted line
Green
GLPG0634 50 mg b.i.d.
Star 
Full line
Red
GLPG0634 100 mg b.i.d.
Plus
Dotted line
Orange
Figure PD 2: 
Mean(SE) plot of the changes from baseline
Figure PD 3: 
Mean(SE) plot of the percent changes from baseline
Figure PD 4: 
Box plot of the actual values
Figure PD 5: 
Box plot of the changes from baseline
Figure PD 6: 
Box plot of the percent changes from baseline
Figure PD 7: 
Scatterplots of the PD markers
Individual scatterplots for each PD marker versus the others. A separate plot per time point.
A) Actual values
B) Change from baseline
C) %change from baseline
8.3.
STEP 2: ANALYSIS OF THE BIOMARKERS, SPLIT UP FOR 
W12 RESPONDERS AND NON-RESPONDERS
All parameters shown are OC only.
Table PD 6: 
Descriptive statistics of the actual values, split up for Week 12 
responders vs non-responders
Repeats of the analysis of previous section, splitting up each page for Week 12 responders 
and non-responders on a separate page:
A) Subjects who had ACR20 response at W12
B) Subjects who did not have ACR20 response at W12
C) Subjects who had ACR50 response at W12
D) Subjects who did not have ACR50 response at W12
E)
Subjects who had DAS28 remission at W12
F)
Subjects who did not have DAS28 remission at W12
G) Subjects who had DAS28 remission or low disease activity at W12 


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H) Subjects who did not have DAS28 remission or low disease activity at W12.
Table PD 7: 
Descriptive statistics of the changes from baseline, split up for Week 
12 responders vs non-responders
Table PD 8: 
Descriptive statistics of the percent changes from baseline, split up 
for Week 12 responders vs non-responders
Table PD 9: 
Summary on changes from baseline with overall p-value and p-value 
for Week 12 response/non-response
ANCOVA model on the change from baseline in biomarker at each time point. Factors in the 
model are: treatment, baseline value of the PD marker, the response (W12 OC yes/no result), 
region, and previous use of biologics.
The p-value for the “response” parameter will indicate whether the average change in 
biomarker is different for responders vs non-responders.
Plain unformatted SAS output is acceptable.
For each of the responder/non-responder combinations of above tables.
Figure PD 8: 
Mean(SE) plot of the actual values: Week 12 responders vs non-
responders
Mean(SE) plots over time of the actual values like the above, eg split over 2 panels: subjects 
who reached response at W12 vs subjects who did not reach response at W12 (OC). For each 
of the responder/non-responder combinations of above tables.
Figure PD 9: 
Mean(SE) plot of the changes from baseline: Week 12 responders vs 
non-responders
Figure PD 10: 
Mean(SE) plot of the percent changes from baseline: Week 12
responders vs non-responders
Figure PD 11: 
Box plot of the actual values: Week 12 responders vs non-responders
Figure PD 12: 
Box plot of the changes from baseline: Week 12 responders vs non-
responders
Figure PD 13: 
Box plot of the percent changes from baseline: Week 12 responders 
vs non-responders
8.4.
STEP 3: CORRELATION OF EACH INDIVIDUAL BIOMARKER 
VERSUS WEEK 12 EFFICACY AND SAFETY
All parameters are analyzed as OC only.
Figure PD 14: 
Scatterplots of PD markers versus efficacy
Scatterplots of each PD marker vs the efficacy variables. Separate plot per time point.


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To depict the correlation numerically, a supporting table will be added to show the Pearson 
correlation coefficient at each time point and for each group. Versus binary responses 
(ACR20/50 and DAS28(CRP) remission and remission/LDA), a point-biserial correlation 
coefficient will be presented. Correlations will be flagged as: strong (>0.7 in absolute value), 
moderate (>0.5 in absolute value), or weak (>0.3 in absolute value).
Efficacy variables: ACR-N, DAS28(CRP), TJC68, SJC66, TJC28, SJC28, HAQ-DI, Pain 
VAS, Investigator’s global disease activity VAS, Subject’s global disease activity VAS, 
FACIT-F and CRP.
A) Actual values
B) Change from baseline
C) Percent changes from baseline.
Figure PD 15: 
Scatterplots of PD markers versus safety
Scatterplots of each PD marker vs the safety variables. Separate plot per time point.
To depict the correlation numerically, a supporting table will be added to show the Pearson 
correlation coefficient at each time point and for each group. Correlations will be flagged as: 
strong (>0.7 in absolute value), moderate (>0.5 in absolute value), or weak (>0.3 in absolute 
value).
Safety variables: hemoglobin, lymphocyte absolute count and subsets (CD3, CD4, CD8, 
CD4/CD8 ratio, CD16 CD56, CD19), neutrophils absolute count, and platelet count.
A) Actual values
B) Change from baseline
C) Percent changes from baseline.
8.5.
STEP 4: BIOMARKERS PREDICTING THE WEEK 12 
EFFICACY AND SAFETY
All parameters are analyzed as OC only.
Table PD 10: 
Exploratory model to assess the relation between baseline PD 
markers and Week 12 response
Logistic regression model, modeling the responders. 
Factors in the model are: treatment, region, previous use of biologics, and the baseline values 
of all the PD markers. Apply a backwards elimination process to retain only relevant 
parameters (significance level 0.05). Treatment must always be kept in the model.
Plain SAS procedure output is acceptable. Only the final model will be shown.
For responses:
A) ACR20
B) ACR50
C) DAS28(CRP) remission
D) DAS28(CRP) remission and low disease activity


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Table PD 11: 
Exploratory model to assess the relation between the Week 4 change 
from baseline in PD markers and Week 12 response
Table PD 12: 
Exploratory model to assess the relation between the Week 4 
%change from baseline in PD markers and Week 12 response
Table PD 13: 
Exploratory model to assess the relation between baseline PD 
markers and Week 12 changes from baseline in efficacy
ANCOVA model, modeling: the change from baseline in efficacy at W12.
Factors in the model are: treatment, region, previous use of biologics, baseline value (except 
for ACR-N parameter), and the baseline values of all the PD markers. Apply a backwards 
elimination process (significance level 0.05). Treatment must always be kept in the model.
Plain SAS procedure output is acceptable. Only the final model will be shown.
For efficacy parameters (Week 12 OC):
A) ACR-N
B) DAS28(CRP)
C) TJC68
D) SJC66
E) TJC28
F) SJC28
G) HAQ-DI
H) Pain VAS
I)
Investigator’s global disease activity VAS
J) Subject’s global disease activity VAS
K) FACIT-F
L) CRP
Table PD 14: 
Exploratory model to assess the relation between the Week 4 change 
from baseline in PD markers and Week 12 changes from baseline in 
efficacy
Table PD 15: 
Exploratory model to assess the relation between the Week 4 percent 
change from baseline in PD markers and Week 12 changes from 
baseline in efficacy
Figure PD 16: 
Scatterplots of baseline PD markers versus efficacy
Scatterplots of each PD marker (baseline value) vs the efficacy variables (W12 change from 
baseline).
Efficacy variables: ACR-N, DAS28(CRP), TJC68, SJC66, TJC28, SJC28, HAQ-DI, Pain 
VAS, Investigator’s global disease activity VAS, Subject’s global disease activity VAS, 
FACIT-F and CRP.
Figure PD 17: 
Scatterplots of Week 4 change from baseline PD markers versus 
efficacy


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Figure PD 18: 
Scatterplots of Week 4 %change from baseline PD markers versus 
efficacy
Table PD 16: 
Exploratory model to assess the relation between baseline PD 
markers and Week 12 changes from baseline in safety
ANCOVA model, modeling: the change from baseline in efficacy at W12.
Factors in the model are: treatment, region, previous use of biologics, baseline value, and the 
baseline values of all the PD markers. Apply a backwards elimination process (significance 
level 0.05). Treatment must always be kept in the model.
Plain SAS procedure output is acceptable. Only the final model will be shown.
For safety parameters (Week 12 OC):
A) Hemoglobin
B) Lymphocyte absolute count
C) CD3 absolute count
D) CD4 absolute count
E)
CD8 absolute count
F)
CD4/CD8 ratio
G) CD16 CD56 absolute count
H) CD19 absolute count
I)
Neutrophils absolute count
J)
Platelet count
Table PD 17: 
Exploratory model to assess the relation between the Week 4 change 
from baseline in PD markers and Week 12 changes from baseline in 
safety
Table PD 18: 
Exploratory model to assess the relation between the Week 4 percent 
change from baseline in PD markers and Week 12 changes from 
baseline in safety
Figure PD 19: 
Scatterplots of baseline PD markers versus safety
Scatterplots of each PD marker (baseline value) vs the safety variables (W12 change from 
baseline). 
Safety variables: hemoglobin, lymphocyte absolute count, neutrophils absolute count, and 
platelet count.
Figure PD 20: 
Scatterplots of Week 4 change from baseline PD markers versus 
safety
Figure PD 21: 
Scatterplots of Week 4 percent change from baseline PD markers 
versus safety


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9.
REFERENCES
ICH-E3. (December 1995). Structure and content of clinical study reports. Step 4 Guideline.
ICH-E6. (17 July 1996). Guideline for good clinical practice. Step 5 Guideline.
ICH-E9. (5 February 1998). Statistical principles for clincal trials. Step 4 guideline.