Clinical trial NCT03798366
Conditions: Systemic Sclerosis
Sponsor: Galapagos NV
Start date: 2019-01-14; Completion date: 2020-06-22
Enrollment: 33 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of the study is to see if GLPG1690 helps (together with the standard of care treatment) in the treatment of the skin and other areas affected by systemic sclerosis.

Another aim is to find out how safe/well tolerated GLPG1690 will be and whether there are any side effects. The study will also look at other things, including whether the study drug affects disease progression and also if it changes any aspect of the quality of life.

Detailed description:

Arms: arm 1: Participants received GLPG1690 600 milligrams (mg), orally once daily for 24 weeks. arm 2: Participants received GLPG1690 matching placebo, orally once daily for 24 weeks.
Interventions: intervention 1: GLPG1690 intervention 2: Placebo
Intervention descriptions: intervention 1: Film-coated tablets of GLPG1690 for oral use. intervention 2: Film-coated tablets of GLPG1690 matching placebo for oral use.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIALITY STATEMENT 
The information contained in this document is privileged and confidential. It is the property of Galapagos NV and may not be 
used, disclosed, reproduced or otherwise disseminated within your organization or communicated to any third parties without 
the express written authorization of Galapagos NV. 
 
CLINICAL STUDY PROTOCOL (CSP) 
 
Project Number: 
GLPG1690 
 
Study Number: 
GLPG1690-CL-204 
Study Title: 
A Phase 2a randomized, double-blind, placebo-controlled, multi-
center study to evaluate the efficacy, safety, and tolerability of 
orally administered GLPG1690 for 24 weeks in subjects with 
systemic sclerosis 
 
Development Phase: 
2a 
Status: 
Final 
CSP Version: 
 
5.00 
Date: 
28-Apr-2020 
Amendment: 
3 
 
 
EudraCT No.: 
2018-001817-33 
CT.gov No.: 
NCT03798366 
IND No.: 
140691 
Sponsor: 
Galapagos NV, Generaal De Wittelaan L11 A3, 2800 Mechelen, 
Belgium 
Study Physician: 
 MD 
General Protocol 
 


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EMERGENCY CONTACT INFORMATION 
In case of a serious adverse event (SAE), a Special Situation (see Section 9.1.6), or in case 
of pregnancy during the clinical study, the investigator must report this immediately, and under 
no circumstances later than 24 hours following the knowledge of the SAE or pregnancy, as 
follows:  
 
Fax #: 
 
or 
E-mail: 
 
 
In case of medical questions during the course of the study, the investigator must contact the 
contract research organization (CRO) Medical Monitor. For urgent medical/safety questions, 
the investigator can contact the safety hotline.  
 
 
 
CRO Lead Medical Monitor: 
 
Contact Safety Hotline:  
EMEA: 
North America: 
 
 
 
 
Sponsor Contact Number: 
  


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TABLE OF CONTENTS 
Emergency Contact Information ............................................................................................ 2 
Table of Contents ..................................................................................................................... 3 
Clinical Study Protocol History .............................................................................................. 7 
Summary of Changes ............................................................................................................... 8 
List of Abbreviations and Definition of Terms .................................................................... 13 
1. Summary ........................................................................................................................... 17 
2. Introduction ...................................................................................................................... 19 
2.1. Background - Nonclinical Studies ............................................................................ 20 
2.1.1. Physical, Chemical, Pharmaceutical Properties, and Formulation .................. 20 
2.1.2. Pharmacology .................................................................................................. 20 
2.1.2.1. Primary and Secondary Pharmacology .............................................. 20 
2.1.2.2. Safety Pharmacology .......................................................................... 21 
2.1.3. Nonclinical Pharmacokinetics and Product Metabolism ................................. 21 
2.1.4. Toxicology ....................................................................................................... 22 
2.1.4.1. General Toxicology ............................................................................ 22 
2.2. Background - Clinical Studies .................................................................................. 23 
2.2.1. Clinical Safety ................................................................................................. 23 
2.2.2. Clinical Efficacy .............................................................................................. 23 
2.2.3. Clinical Pharmacokinetics ............................................................................... 24 
2.2.4. Clinical Pharmacodynamics ............................................................................ 24 
3. Clinical Study Objectives ................................................................................................. 25 
3.1. Primary Objective ..................................................................................................... 25 
3.2. Secondary Objective ................................................................................................. 25 
3.3. Other Objectives ........................................................................................................ 25 
4. Investigational Plan .......................................................................................................... 25 
4.1. Overall Clinical Study Design .................................................................................. 25 
4.2. Clinical Study Rationale ........................................................................................... 27 
4.2.1. Dose Rationale ................................................................................................. 28 
4.2.2. Clinical Study Design Rationale ...................................................................... 28 
4.3. Endpoints ................................................................................................................... 28 
4.3.1. Primary Endpoint ............................................................................................. 29 
4.3.2. Secondary Endpoint ......................................................................................... 29 
4.3.3. Other Endpoints ............................................................................................... 29 
4.4. Potential Risks and Benefits ...................................................................................... 29 
4.5. Clinical Study Population ......................................................................................... 31 
4.5.1. Inclusion Criteria ............................................................................................. 31 
4.5.2. Exclusion Criteria ............................................................................................ 32 
4.5.3. Prohibition and Restrictions ............................................................................ 33 
4.5.3.1. Precautions for Sexual Intercourse ..................................................... 33 
4.5.3.2. Prior and Concomitant Medications ................................................... 35 
4.5.3.3. Food and Beverage Restrictions ......................................................... 38 
4.5.3.4. Other Prohibitions and Restrictions .................................................... 38 
4.5.4. Treatment Discontinuation (Temporarily and Permanently), Subject 
Withdrawal, and Study Termination ................................................................ 38 
4.6. Measures to Minimize Bias ....................................................................................... 40 
4.6.1. Randomization ................................................................................................. 40 






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10.2.3. Archiving ....................................................................................................... 68 
10.2.4. Participation Cards ......................................................................................... 69 
10.3. Confidentiality ........................................................................................................... 69 
10.4. Ethical Considerations .............................................................................................. 69 
10.4.1. Independent Ethics Committee (IEC) / Institutional Review Board (IRB) ... 69 
10.4.2. Informed Consent .......................................................................................... 70 
10.5. Data Quality Control / Assurance ............................................................................. 71 
10.5.1. Monitoring ..................................................................................................... 71 
10.5.2. Audit and Inspection ...................................................................................... 71 
References ............................................................................................................................... 72 
Appendices .............................................................................................................................. 74 
Appendix 1: 
Known CYP2C8 Substrates ............................................................. 74 
Appendix 2: 
Known Strong CYP3A4 Inducers and Potent P-gp Inducers ...... 75 
Appendix 3: 
Known Strong CYP3A4 Inhibitors ................................................. 76 
Appendix 4: 
Known Potent P-gp Inhibitors ........................................................ 77 
Appendix 5: 
Medication Known to Prolong QT Interval ................................... 78 
Signature Page – Sponsor ...................................................................................................... 79 
Signature Page – Investigator ............................................................................................... 80 
 
 




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SUMMARY OF CHANGES 
Amendment 3 (28-Apr-2020) 
The overall reason for this amendment:  
To implement the urgent safety measures (USM) to mitigate the impact of the current COVID-19 pandemic 
for the participating systemic sclerosis patients. These were detailed in the USM letter dated 08 April 2020 
and sent to investigators, Competent Authorities, Ethics Committees, and Institutional Review Boards.  
 
The objective of these USMs is to reduce the risk of infections for the study subjects by increasing the 
flexibility of study visits and thereby avoid exposure risk during the pandemic. The measures apply 
specifically to subjects who are unable or unwilling to perform on-site study procedures due to the COVID-19 
pandemic. 
The changes made to CSP GLPG1690-CL-204 Version 4.00 (31 Jul 2019), are listed below, with a brief 
rationale of each change and the applicable sections. 
For any subjects who, due to any COVID-19-related reason, cannot attend the final visit in the treatment 
period, Visit 9 (24 weeks), within the time window of ±4 days, the window for the visit may be increased to 
±28 days. The subject should continue the intake of Investigational Medicinal Product (IMP) until Visit 9 
(ultimately until Week 28). 
For the rollover of a subject into the GLPG1690-CL-206 Open-Label Extension study, a complete, on-site 
rollover visit is required. If Visit 9 cannot be conducted on site within the extended window of Week 24 +28 
days, the subject will be given the opportunity to rollover into the Open-Label Extension study until Week 32. 
In this case, the subject will however be off study medication and not receive IMP between Week 28 to 32. 
The Visit 9/rollover assessments should be performed at this on-site visit, 
 
 
If the rollover visit cannot be scheduled before Week 32, the subject will continue in the follow-up period of 
GLPG1690-CL-204 with a first follow-up visit 4 weeks after last IMP administration.  
Applicable Sections:  
Section 4.1 Overall Clinical Study Design 
Section 6.1 Timing of assessments 
Section 6.11 Schedule of Activities 
If Visit 9 needs to be postponed until after Week 24, regular phone calls at Week 24 and every 14 days 
thereafter should be implemented to evaluate the subject’s safety until a visit can take place on site. 
In addition, if any of the follow-up visits cannot be performed on site, a phone call to evaluate the subject’s 
safety should be performed. 
The information to be collected during these phone calls is detailed in the USM letter and summarized in the 
protocol Section 6.6. 
Applicable Sections:  
Section 6.1 Timing of events 
Section 6.6 Safety assessments 
Section 6.11 Schedule of activities 
When Visit 9 needs to be postponed beyond Week 24, a Direct-to-Patient (DTP) shipment of one additional 
IMP kit may be implemented to cover the prolongation of treatment (by up to 28 days).  
Urine pregnancy tests to perform the monthly pregnancy test at home until follow-up visit 1 (if applicable) 
and treatment or follow-up diary cards should also be shipped to the subject to cover the longer period 
between on-site visits. 
Applicable Sections: 
Section 5.3 Packaging, labelling, and distribution 
Section 6.1 Timing of events 
Section 6.6 Safety assessments 
 
 




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The period of time prior to screening during which subjects’ medications should be stable has been 
clarified.  
Bosentan has been added to the list of excluded medications, and hydroxychloroquine to the list of 
medication known to prolong QT interval (to be used with caution). 
The prohibition of B-cell depleting agents has been broadened to “other monoclonal 
antibodies”. 
Applicable Sections:  
Section 4.5.3.2 Prior and Concomitant Medications 
Appendix 2 Known Strong CYP3A4 Inducers and Potent P-gp Inducers 
Appendix 5 Medication Known to Prolong QT interval 
The list of clinical laboratory tests has been revised  
 
Mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin 
concentration have been added to the hematology parameters. 
 
Creatine kinase has been added to the serum chemistry parameters. 
 
Ketone have been added to the urinalysis parameters 
Applicable Section: Section 6.6.2 Clinical laboratory evaluations 
The ECG parameter QTcB will not be derived. 
Applicable Section: Section 6.6.5 12-lead Electrocardiogram 
 
 
An interim analysis at Week 16 is no longer planned. The sponsor decided that an interim analysis 
is no longer required. 
A clarification has been added that the primary analysis of efficacy will be performed at Week 24, 
at the end of the double-blind treatment period. 
Applicable Sections:  
Section 4.6.2 Blinding and Unblinding 
Section 7 Statistical Methods 
New section – Section 7.3.2. Primary Analysis 
Renumbered section - Section 7.3.2 7.3.3 Interim Analysis 
 




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Minor edits and administrative updates throughout the protocol.  
Applicable Sections:  
Title Page 
Section 2.2.1 Clinical Safety 
Signature Page – Sponsor  
Appendix 2 
 
 
Amendment 1 (13-Nov-2018) 
The overall reason for this amendment: 
Subject exclusion criteria were revised to comply with the 
 Law and facilitate subject 
recruitment.  
The changes made to the CSP GLPG1690-CL-204 Version 2.00, {20-aug-2018}, are listed below, 
reflecting a brief rationale of each change and the applicable sections. 
Rationale: The protocol was updated to revise the definition of abnormal renal function in 
exclusion criterion 19. The initial exclusion criterion was too stringent for this patient population. 
The change is not expected to affect subjects’ safety. 
Applicable Sections: 4.5.2 Exclusion Criteria  
Rationale: The protocol was updated to add an exclusion criteria 30 to comply with the 
 
 
Applicable Sections: 4.5.2 Exclusion Criteria  
Rationale: The procedure for collection of informed consent of a patient unable to read and/or write 
was amended to comply with the 
 
 
Applicable Sections: 10.4.2 Informed Consent  
Rationale: The protocol was updated to delete Appendix 1 with normal ranges for vital signs and 
ECG parameters. The clinical significance of vital signs and ECG assessments is to be at the 
investigator’s discretion. 
Applicable Sections: Appendix 1 
 
 
 




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eGFR 
estimated glomerular filtration rate 
 
 
ENPP 
ectonucleotide pyrophosphatase/phosphodiesterase 
EoS 
end of the study 
ERS 
European Respiratory Society 
ET-1 
endothelin-1 
EU 
European Union 
EULAR 
European League Against Rheumatism 
FC 
fold change 
 
 
 
 
FSH 
follicle stimulating hormone 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice(s) 
GGT 
gamma glutamyl transferase 
GLP 
Good Laboratory Practice 
 
 
HIV 
human immunodeficiency virus 
HMA 
Heads of Medicines Agencies 
 
 
IB 
investigator’s brochure 
IC50 
50% inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IL-x 
interleukin x 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IPF 
idiopathic pulmonary fibrosis 
IRB 
Institutional Review Board 
IWRS 
interactive web response system 
JRS 
Japanese Respiratory Society 
LFT 
liver function test 
LPA 
lysophosphatidic acid 


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LPC 
Lysophosphatidylcholine 
LPD 
lysophospholipase D 
LS 
least square 
 
 
MATE 
multi drug and toxin extrusion transporter 
MCID 
Minimal Clinically Important Difference 
MMF 
mycophenolate mofetil 
MMRM 
mixed-effects model for repeated measures 
mRSS 
modified Rodnan skin score  
NOAEL 
no observed adverse effects level 
NOEL 
no observed effect level 
 
 
PDE 
Phosphodiesterase 
P-gp 
P-glycoprotein 
 
 
PLA 
phospholipase A 
PLC 
phospholipase C 
 
 
q.d. 
once daily 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
QTcV 
QT interval corrected for heart rate using Van de Water’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SCTC 
Scleroderma Clinical Trials Consortium 
 
 
SOC 
System Organ Class 
SUSAR 
suspected unexpected serious adverse reaction 
 
 
TEAE 
treatment-emergent adverse event 
TGFβ 
transforming growth factor β 
 
TNF 
tumor necrosis factor 
ULN 
upper limit of normal 
 
 


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WOCBP 
women of childbearing potential 
Definition of Terms 
BMI 
Weight (kg) / (height [m])2 
QTcF 
QTcF = QT / RR1/3 
 
 
 






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2. 
INTRODUCTION 
For more details refer to the investigator’s brochure (IB) for GLPG1690 (Edition 6, 28-Jun-
2019) and relevant updates/addenda. 
This clinical study will be conducted in accordance with the current International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use - Good 
Clinical Practice (ICH-GCP) Guideline E6 (see also Section 10). 
Systemic Sclerosis 
Systemic sclerosis (scleroderma) is a rare autoimmune disease of the connective tissue with the 
highest mortality rate of all rheumatic diseases. The disease has a female predominance (3:1) 
and a peak onset in the fourth decade of life. Systemic sclerosis has three major pathogenic 
components: (i) fibrosis with thickening of the skin and inner organs, (ii) inflammation, and 
(iii) vasculopathy. Major organs affected are the skin, the lung (pulmonary fibrosis and 
pulmonary arterial hypertension), the kidneys, the gastrointestinal tract, the musculoskeletal 
system, the retroperitoneal space, and the heart. Current treatment options for systemic sclerosis 
are limited and include topical skin treatments, non-steroidal anti-inflammatory drugs, steroids, 
and other immunosuppressants (methotrexate, mycophenolate mofetil [MMF], azathioprine, 
cyclophosphamide).  
At present, there are no approved drugs for the treatment of systemic sclerosis, indicating a 
high-level unmet medical need.  
The sponsor is currently pursuing the development of GLPG1690, a small-molecule autotaxin 
(ATX) inhibitor targeting disease-relevant signal transduction pathways, for the treatment of 
systemic sclerosis. 
Mode of Action  
GLPG1690 is a novel, potent, and selective small-molecule inhibitor of ATX. 
ATX, also known as ectonucleotide pyrophosphatase/phosphodiesterase (ENPP) 2 or 
lysophospholipase D (LPD), is a ~120 kDa protein that belongs to the ENPP enzyme family. 
ATX is the only ENPP enzyme with LPD activity and is responsible for the hydrolysis of 
lysophosphatidylcholine (LPC) to produce the bioactive lipid lysophosphatidic acid (LPA). The 
term LPA covers several chemical species able to activate LPA receptors depending on the 
nature of the fatty acid side chain on the glycerol backbone. The most abundant LPA species in 
human plasma is LPA C18:2 with a fatty acid side chain of 18 carbon atoms including 
two unsaturated bonds (Bandoh K. et al, 2000). Literature data have identified the ATX/LPC 
axis as the main source of LPA in blood (Tanaka M. et al., 2006; Tsuda S. et al., 2006).  
LPA acts through six different G-protein coupled receptors (LPA1-6) whereby mainly LPA1-3 
have been associated with the pathogenic (pro-inflammatory and pro-fibrotic) effects of LPA. 
Targeting the ATX pathway by antagonizing LPA1 in a previous Phase 2a study (SAR100842) 
in systemic sclerosis was well tolerated and resulted in clinical improvements of skin 
pathologies (modified Rodnan skin score [mRSS]) and skin biomarkers, suggesting that 




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2.1.2.2. 
Safety Pharmacology 
The safety pharmacology package conducted to investigate the potential effect of GLPG1690 
on cardiovascular, respiratory, and central nervous systems did not show any biologically 
relevant effects. 
2.1.3. Nonclinical Pharmacokinetics and Product Metabolism 
The absolute oral bioavailability was moderate in rodents (25% to 36%), low in 
monkeys (14%), and high in dogs (102%).  
GLPG1690 was highly bound to plasma proteins: 99.1% in human and 97.9-99.6% in rat, dog, 
mouse, rabbit, and monkey.  
Overall, GLPG1690 did not extensively distribute into tissues as shown by the low volume of 
distribution at steady state (Vss) ranging from 0.35 L/kg in the mouse to 0.55 L/kg in the 
monkey. In rat, [14C]-GLPG1690 was widely distributed throughout the body. Highest 
concentrations of radioactivity were observed in contents of the gastrointestinal (GI) tract, 
glandular tissues, liver, and uveal tract. Some affinity was observed of GLPG1690 and/or 
metabolites for melanin-containing tissues, like uveal tract and meninges. 
After oral administration, drug-related material is excreted mainly in feces in rat (about 90% or 
greater). In bile duct-cannulated rats, about 50% of orally administered radioactivity was 
recovered in bile. 
Upon repeated once daily (q.d.) oral dosing of GLPG1690, no significant accumulation was 
observed in plasma, except in male rats (20 mg/kg/day) and dogs (50/65 mg/kg/day at 
Week 39). Gender differences in PK profiles were observed in rats but not in dogs. 
The total plasma clearance of GLPG1690 was low in mice, rats, monkeys, and dogs, ranging 
between 3% and 23% of the hepatic blood flow. Therefore, GLPG1690 is expected to undergo 
a low first-pass effect after oral dosing.  
The primary cytochrome P450 (CYP) enzyme involved in GLPG1690 metabolism was 
CYP3A4. In vitro metabolism studies in hepatocytes revealed 26 potential metabolites. 
Metabolites formed in human hepatocytes were all present to a similar or higher extent in rat 
and/or dog hepatocytes, the animal species selected for toxicity studies.  
An in vitro study with GLPG1690 in human hepatocytes showed no clinically relevant 
induction of human CYP2B6 and CYP2C enzymes. Weak induction of CYP1A2 and CYP3A4, 
cannot be excluded at a GLPG1690 dose of 600 mg  in human, with a maximal decrease of 
around 30% in the exposure of a sensitive probe substrate for both CYP enzymes.  
An in vitro study with GLPG1690 in human liver microsomes indicated no clinically relevant 
inhibition of the majority of CYP enzymes. Weak competitive reversible inhibition of CYP2C8 
and CYP3A4/5 cannot be excluded at a GLPG1690 dose of 600 mg in human, with a maximal 
increase of approximately 1.7- and 1.5-fold, respectively in the exposure of a sensitive probe 
substrate. 
GLPG1690 demonstrated a strong time-dependent, irreversible inhibition potential against 
CYP2C8-mediated metabolism. This could likely lead to a pronounced interaction with a 


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sensitive CYP2C8 probe substrate (increased exposure) if co-administered with a GLPG1690 
dose of 600 mg in human. 
No interaction of GLPG1690 is expected with renal uptake transporters, organic cation 
transporter (OCT)2, organic anion transporter (OAT)1 and OAT3 and hepatic efflux 
transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). For the hepatic 
uptake transporters OATP1B1, OATP1B3, and OCT1, and the multi drug and toxin extrusion 
(MATE) efflux transporters MATE1 (hepatic/renal) and MATE2K (renal), a clinical interaction 
with GLPG1690 cannot be ruled out, however substantial interactions are not anticipated. For 
the intestinal efflux P-gp and BCRP transporters and the hepatic efflux bile salt export pump 
transporters an interaction cannot be ruled out.   
2.1.4. Toxicology 
2.1.4.1. 
General Toxicology 
A comprehensive toxicology program has been conducted with GLPG1690. This program 
includes Good Laboratory Practice (GLP) oral repeat-dose toxicity studies of up to 26 weeks in 
rats and 39 weeks in dogs, embryo fetal development studies in rats and rabbits, fertility studies 
in male and female rats, non-TgrasH2 mice preliminary studies, preliminary carcinogenicity 
studies, and i vivo and in vitro genotoxicity studies. Additional toxicology studies conducted 
include phototoxicity studies and dose range-finding studies in rats and dogs. 
In rats, no GLPG1690-related mortality was observed. The dose-limiting adverse effects 
consisted of reduced food consumption and markedly decreased body weight (BW) gain at 
1,000 mg/kg/day in the 4-week toxicity study, histopathological changes in the testes with 
reduced sperm parameters at ≥130 mg/kg/day in the 13- and 26-week GLP studies, and the 
presence of vacuolated alveolar macrophages, with alveolar amorphous material and 
perivascular inflammatory cell infiltration in the lungs of females in the 26-week GLP study. 
The no observed adverse effects level (NOAEL) values in rats were set at 40 and 130 mg/kg/day 
in males and females, respectively, in the 26-week GLP study.  
In repeat oral dose toxicity studies in dogs, the dose-limiting effects corresponded to decreased 
white blood cell count and food consumption, emesis and BW loss, associated with poor clinical 
conditions at doses ≥100 mg/kg/day in the 13- and 39-week GLP studies, respectively. QT 
prolongation (in 4-, 13-, and 39-week studies), which was considered non-adverse, were also 
observed in repeat oral dose toxicity studies in dogs. Additional adverse findings in dogs 
consisted of adverse altered sperm parameters and inflammatory cell infiltrates in the liver and 
minimal bile duct hyperplasia at 150/100 mg/kg/day (in the 13-week GLP toxicity study) and 
QT prolongation (in 4-, 13- and 39-week studies). The NOAEL value in dogs was set at 
50/65 mg/kg/day in the 39-week GLP study.  
Male and female fertility studies in rats showed that there were no effects of GLPG1690 on 
mating performance, fertility, or reproduction in either male or female rats at the different dose 
levels tested. As the effects on sperm and testis proved reversible and had no functional impact 
on animal fertility parameters, the risk of an impact on male fertility in adult subjects is 
considered low. In males, the no observed effect level (NOEL) for mating performance and 
fertility was set at 400 mg/kg/day and the NOAEL for sperm changes was determined at 
40 mg/kg/day; the latter is in line with previous studies (i.e.13 week rat study). In females, the 
NOEL for mating performance and fertility was considered to be 120 mg/kg/day. 


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In reproductive embryofetal development studies with GLPG1690 in rats and rabbits, major 
external, visceral, and skeletal abnormalities were seen in fetuses of both species as well as 
increased incidences of post-implantation losses. In rats, the maternal and developmental 
NOAELs were determined at 60 mg/kg/day and 10 mg/kg/day, respectively. In rabbits, the 
maternal and developmental NOAELs were determined at 15 mg/kg/day and 5 mg/kg/day, 
respectively. 
GLPG1690 showed no genotoxic effects in vitro or in vivo. 
GLPG1690 showed a phototoxic potential in vitro. However, this potential has not been 
confirmed in an in vivo study in female pigmented Long-Evans rats, investigating the 
phototoxic effects on the eyes and the skin. No evidence of cutaneous or ocular phototoxicity 
was noted at doses of 100 and 300 mg/kg.  
2.2. 
BACKGROUND - CLINICAL STUDIES 
2.2.1. Clinical Safety 
In clinical pharmacology studies, GLPG1690 has been administered to 85 healthy subjects as 
single doses (dose range: 20 to 1500 mg), to 96 healthy subjects in repeated doses (dose range: 
100 to 1000 mg for either 7 or 14 days).  
Administration of GLPG1690 in these Phase 1 studies was considered safe and well tolerated. 
No deaths, other serious treatment-emergent adverse events (TEAEs), TEAEs leading to IMP 
discontinuation, or clinically significant abnormalities related to laboratory parameters, 
electrocardiogram (ECG), vital signs, or physical examinations were reported during any of 
these Phase 1 studies. GLPG1690 was well tolerated and all TEAEs were at most moderate in 
severity.  
Administration of oral doses of GLPG1690 600 mg q.d. as a capsule for 12 weeks in 17 subjects 
with IPF was well tolerated (Phase 2a study GLPG1690-CL-202). No deaths were reported. 
Serious TEAEs were experienced by one subject in the GLPG1690 600 mg q.d. group 
(cholangiocarcinoma, led to permanent discontinuation) and by two subjects in the placebo 
group (atrioventricular block second degree in one subject, led to permanent discontinuation; 
and lower respiratory tract infection, urinary tract infection, and acute kidney injury in the other 
subject). 
None of these serious TEAEs were considered related to IMP. No notable differences were 
observed in the incidences of treatment-emergent abnormalities between subjects with IPF 
treated with GLPG1690 600 mg q.d. or placebo. The majority of TEAEs were mild to moderate 
in severity. No clinically significant abnormalities related to laboratory parameters, 
electrocardiogram (ECG), vital signs, or physical examinations were reported. 
2.2.2. Clinical Efficacy  
Following 12 weeks of treatment in subjects with IPF in study GLPG1690-CL-202, on-site 
forced vital capacity (FVC) spirometry performed at screening, baseline, Weeks 1, 2, 4, 8, 
and 12 (or at early discontinuation [ED], if applicable), and at follow-up (2 weeks after the last 
IMP intake) showed that FVC values remained stable in the majority of subjects taking 
GLPG1690 600 mg q.d. 


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2.2.3. Clinical Pharmacokinetics 
GLPG1690 formulated as a liquid suspension was rapidly absorbed with a median time to 
maximum observed plasma concentration (tmax) of 0.5 to 2 hours. Steady-state exposure of 
GLPG1690 increased approximately (slight over proportionality) in proportion with the dose 
between 300 to 1,000 mg total daily dose. Excretion of unchanged GLPG1690 in human urine 
was low (<1.8% in 24 hours) and rapid. There was no impact on the urinary 6-β-OH-
cortisol/cortisol ratio after repeated dosing suggesting a lack of CYP3A4 induction by 
GLPG1690.  
Given as tablet, food decreased the rate of absorption of GLPG1690 but there was no clinically 
relevant difference in the bioavailability of GLPG1690. A higher between-subject variability 
was observed in fasted state, with four subjects out of 12 having 5- to 10-fold lower exposure 
than the other subjects. The rate of elimination was not impacted by food. The overall mean 
terminal elimination half-life (t1/2) after a single dose as tablets was approximately 11 hours. 
GLPG1690 exposure is reduced up to 90% by the strong CYP3A4/potent P-gp inducer rifampin 
(by 6.0- and 9.3-fold for Cmax and area under the plasma concentration-time curve from time 0 
to 24 h [AUC0-24h], respectively). Exposure of GLPG1690, as measured by the area under the 
plasma concentration-time curve from time zero extrapolated to infinity (AUC0-∞), was 3- and 
4 fold greater when administered in combination with itraconazole (a strong CYP3A4 and 
potent P-gp inhibitor) and voriconazole (a strong CYP3A4 inhibitor, but non-P-gp inhibitor), 
respectively, than when as administered alone. Maximum exposure (Cmax) of GLPG1690 
increased slightly following administration of GLPG1690 in combination with itraconazole or 
voriconazole compared with administration of GLPG1690 only (Cmax values were 1.4-fold 
greater following administration in combination with itraconazole or voriconazole). This 
increase is unlikely to be clinically significant. GLPG1690 can therefore be classified as a 
moderately sensitive substrate of CYP3A4 as it demonstrated an increase in AUC of ≥2 to <5-
fold with strong index inhibitors. 
The PK of GLG1690 was similar between Caucasian and Japanese healthy male subjects. The 
PK of GLPG1690 in subjects with IPF was not markedly different from those observed in 
healthy subjects at the same dose level. 
2.2.4. Clinical Pharmacodynamics 
After a single administration of GLPG1690, a significant dose-dependent percentage reduction 
of LPA C18:2 was observed in plasma. This effect started from 0.5 hours after IMP intake, 
reached a plateau, and was sustained over time up to 24 hours after IMP intake. Multiple q.d. 
or b.i.d. ascending doses resulted in a similar effect on LPA C18:2. A strong reduction in LPA 
C18:2 levels was already observed at Day 14 before IMP intake, pointing to a sustained effect 
over 14 days.  
The sustained effect on LPA C18:2 was also confirmed by area under the effect-time curve 
(AUEC) for the percentage reduction from baseline and maximum effect (expressed as a 
percentage reduction from baseline) (Emax).GLPG1690 induced a fast and sustained reduction 
in plasma LPA C18:2 levels in subjects with IPF, indicative for target engagement. At the 
follow-up visit, the mean LPA C18:2 level was back to baseline levels, indicating that the 
inhibitory effect of GLPG1690 on the target is reversible. 




Cli nical St u d y Pr ot o c ol ( C S P) G L P G 1 6 9 0 -C L -2 0 4  
P a ge 2 6 /8 0  
 
 
 
V ersi o n 5 . 0 0, Fi nal, 2 8 -A pr -2 0 2 0  
C o nfi d e ntial I nf or mati o n  
 
 
Fi g ure  1 : 
Sc he m atic St u d y O ver vie w  
D = D a y, F U = F oll o w -u p, V = V isit, W = W ee k. 
* T his will be a p h o ne call t o assess safet y ( n o cli nical st u d y ce nter visit).  
 
F or t he i n - a n d e x cl usi o n criteria please refer t o Secti o n 4. 5. 1 , “I n cl usi o n Criteria” a n d 
Secti o n  4. 5. 2 , “E x cl usi o n Criteria ”.  
T he s u bjects will visit t he cli nical st u d y ce nter at scree ni n g/ Visit 1 ( Da y  -2 8 t o Da y  -1), 
Da y  1/ Visit 2 ( baseli ne), 
Da y  1 5 ( Wee k  2/ Visit 3), 
Da y  2 9 ( Wee k  4/ Visit 4), 
Da y  5 7 
( Wee k 8/ Visit 5), D a y  1 1 3 ( Wee k  1 6/ Visit 7 ), Da y 1 6 9 ( Wee k  2 4/ Visit 9 ), a n d, if a p plica ble, 
t he E D visit. At Wee ks 1 2 ( Visit 6) a n d 2 0 ( Visit 8), a p h o ne call will be ma de t o assess safet y. 
I n a d diti o n, a f oll o w-u p visit will be pla n ne d 4  wee ks after t he last a d mi nistrati o n of I M P 
( Da y 1 9 7 [ Wee k  2 8]) (i. e. F oll o w -u p Visit 1) a n d a sec o n d f oll o w -u p visit will be pla n ne d 
1 2  wee ks after t he last a d mi nistrati o n of I M P ( Da y  2 5 3 [ Wee k  3 6]) (i.e. F oll o w -u p Visit 2). 
A d diti o nal u nsc he d ule d visits are all o we d f or a n y s afet y assess me nts if cli nicall y i n dicate d (see 
Secti o n  6. 2 ).  
F or a n y s u bjects w h o , d u e t o a n y C O VI D-1 9 -rel ate d reas o n, ca n n ot perf or m Vi sit 9 (Wee k 2 4 ), 
wit hi n t he ti me wi n d o w of ± 4 da ys , t he wi n d o w f or t he visit ma y be i n crease d t o ± 2 8 da ys.  
Eac h s u bject will be i n t h e st u d y f or u p t o a p pr o xi matel y 4 0  wee ks ( u p t o 4  wee ks of scree ni n g, 
2 4  wee ks of treat me nt, a n d 1 2  wee ks of f oll o w -u p).  C o vi d -1 9 miti gati o n meas ures ma y 
i ncreas e t he ti me i n t he st u d y u p t o a p pr o xi matel y 4 4 wee ks. 
F or detaile d i nf o re gar di n g d osa ge f or m, pac ka gi n g , a n d la beli n g of t he I M P, please refer t o 
Secti o n 5. 2 , “D os a ge a n d A d mi nistrati o n ” a n d Secti o n  5. 3 , “Pac ka gi n g, La beli n g , a n d 
Distri b uti o n ”. 
T he e n d of t he st u d y ( E o S) is reac he d w he n t he last visit of t he last s u bject is perf or me d.  
O pe n -l a bel E xte nsi o n 
S u bjects w h o c o m plete d t he Wee k  2 4 visit will be offere d treat me nt wit h G L P G 1 6 9 0 i n a n 
o pti o nal o pe n -la bel e xte nsi o n, pr o vi de d re g ulat or y a n d I n d e pe n d e nt Et hics C o m mittee 
(I E C)/I nstit uti o nal Re vie w B o ar d (I R B) a p pr o vals f or s uc h a n e xte nsi o n is gra nte d. I n t his case, 
t he f oll o w-u p visits are n ot perf or me d f or t hese s u bjects. T his e xte nsi o n is descri be d i n a 
se parat e pr ot oc ol, St u d y G L P G 1 6 9 0-C L -2 0 6 . 
F or t he r oll o ver of a s u bject i nt o t he G L P G 1 6 9 0-C L -2 0 6 st u d y, a  c o m plet e r oll o ver visit , at 
Visit 9 of t his st u d y ( G L P G 1 6 9 0 -C L -2 0 4),  is re q uire d.   


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If Visit 9 cannot be conducted on site within the extended window of Week 24 +28 days, due 
to any COVID-19-related reason, the subject will be given the opportunity to complete an on-
site visit and rollover into the Open-Label Extension study until Week 32. The Visit 9/rollover 
assessments should be performed at this on-site visit, 
. The subject will however be off study medication and not receive 
IMP between Week 28 to 32. If the subject decides not to rollover to GLPG1690-CL-206, and 
the on-site visit can be conducted in the window Week 32 ±7 days after initial IMP start in 
GLPG1690-CL-204, the on-site visit should be considered to be Follow-up visit 1.  
If the rollover visit cannot be scheduled before Week 32, the subject will continue in the 
follow-up period of GLPG1690-CL-204 with a first follow-up visit 4 weeks after last IMP 
administration. 
4.2. 
CLINICAL STUDY RATIONALE 
Systemic sclerosis is a chronic and progressive disease with the highest morbidity and mortality 
among all autoimmune diseases without any approved drug, indicating a high unmet medical 
need for the development of novel disease-modifying therapies.   
In vitro and in vivo studies indicate an essential role for ATX, an enzyme with LPD activity 
responsible for the production of the pro-inflammatory/pro-fibrotic mediator LPA, in systemic 
sclerosis: ATX mRNA expression is significantly increased in systemic sclerosis skin biopsies 
compared to controls. In response to LPA, systemic sclerosis-derived dermal fibroblasts 
produce significant amounts of IL-6 that has been involved in systemic sclerosis pathogenesis. 
Two preclinical studies using independent skin fibrosis models (bleomycin and 
sclerodermatous cGvHD models) demonstrated a high level of target engagement and efficacy 
upon ATX inhibition. Moreover, GLPG1690 dose-dependently inhibited the production of the 
fibrogenic mediator CTGF by human dermal fibroblasts upon TGFβ-triggering. Overall, 
inhibition of ATX has the potential for a triple mechanism of action in systemic sclerosis: 
(i) inhibition of pro-fibrotic LPA, (ii) inhibition of pro-inflammatory IL-6 (ATX-IL-6 loop), 
and (iii) inhibition of angiogenic ET-1, thereby addressing all three major pathogenic 
components of systemic sclerosis (described in Section 2.1.2). 
GLPG1690 is currently in clinical development for the treatment of patients with IPF. This 
study will assess GLPG1690 as a potential first-in-class disease-modifying drug for systemic 
sclerosis. 
As described in Section 2.2, results from a GLPG1690 Phase 1 first-in-human study 
(GLPG1690-CL-101) generated promising PD results (target engagement, LPA reduction) and 
indicated that GLPG1690 was generally safe and well tolerated in a population of healthy 
subjects. Moreover, safety, PK, and PD properties were successfully evaluated in a Phase 2a 
study in subjects with IPF (GLPG1690-CL-202). In a previous Phase 2a study (SAR100842), 
targeting the ATX pathway in systemic sclerosis by antagonizing LPA1 was well tolerated and 
resulted in clinical improvements of skin pathologies (mRSS) and skin biomarkers, suggesting 
that targeting the ATX pathway is promising in modulating skin pathologies in systemic 
sclerosis (Allanore T. et al., 2018). 
When viewed in combination, these preclinical and clinical studies strongly suggest that 
interfering with ATX by GLPG1690 in systemic sclerosis is a promising novel disease-
modifying approach. 


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4.2.1. Dose Rationale 
A dose of GLPG1690 600 mg q.d. for oral administration has been selected to be evaluated in 
this Phase 2a study. 
This selection is based on the effective dose tested in a Phase 2a study in subjects with IPF 
(GLPG1690-CL-202) and on the observations made on efficacy, PD, PK, safety, and 
tolerability in the same study, where GLPG1690 was evaluated as monotherapy versus placebo, 
as well as on the Phase 1 results in the healthy-subject study (GLPG1690-CL-101). 
A population PK and PK/PD model was developed to describe the exposure-response 
relationships of GLPG1690 and LPA C18:2 as PD biomarker. Subsequent simulations suggest 
that the anticipated therapeutic dose of 600 mg leads to 88% (range: 86%-89%) LPA C18:2 
reduction at steady state. Predicted concentrations at a dose of 600 mg q.d. were above the LPA 
C18:2 IC50 for 100% of the dosing interval.  
4.2.2. Clinical Study Design Rationale 
This is a randomized, double-blind, parallel-group, placebo-controlled, multi-center, Phase 2a 
24-week study in subjects with systemic sclerosis. The randomized double-blind study design 
was chosen because it is the most rigorous method to generate high-quality scientific data and 
there is no approved alternative treatment available for comparison. A placebo-controlled study 
contains internal evidence of assay sensitivity (i.e. when a difference is demonstrated, it is 
interpretable without reference to external findings), measures absolute safety and efficacy (i.e. 
it measures the total pharmacologically mediated effect of treatment), is very efficient (i.e. can 
measure treatment effects with a smaller sample size compared with any other type of controlled 
study) and minimizes the effect of subject and investigator expectations (ICH E10, 2000). The 
2:1 randomization to GLPG1690 avoids unnecessary exposure of subjects to placebo and is 
typical for Phase 2a studies in systemic sclerosis. The subject eligibility criteria are typical for 
patient studies in early progressive diffuse cutaneous systemic sclerosis. Based on current 
European League Against Rheumatism (EULAR) and Scleroderma Clinical Trials Consortium 
(SCTC) recommendations, background treatment is allowed as defined in Section 4.5.3.2, 
“Prior and Concomitant Medications”. The study duration (24 weeks) was chosen based on 
experience with previous clinical studies in diffuse systemic sclerosis with a similar mode of 
action and similar clinical endpoints. The 12-week follow-up period was chosen based on 
experience with a previous clinical study targeting LPA1 in order to assess the occurrence of 
flares after IMP discontinuation in subjects with systemic sclerosis compared to placebo. 
4.3. 
ENDPOINTS 
Based on in-house and external preclinical data as well as regulatory experience from previous 
Phase 2 and Phase 3 studies in systemic sclerosis, mRSS is chosen as primary endpoint. mRSS 
is a validated outcome measure used in numerous clinical studies in systemic sclerosis and has 
a defined Minimal Clinically Important Difference (MCID). mRSS is valuable for the 
evaluation of new treatments for systemic sclerosis as it not only reflects the skin disease 
component but also inner organ fibrosis in a noninvasive manner.  




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(rabbits). No data have been generated in lactating women and on excretion in milk. In view of 
the teratogenic effects seen in animals and limited knowledge of the possible effects of 
GLPG1690 on lactation at this stage of development, GLPG1690 should not be given to 
pregnant or lactating women. In addition, highly effective contraceptive measures/preventive 
exposure measures should be taken by women of childbearing potential (WOCBP) and by men 
to prevent pregnancy and to avoid the risk of exposure of the embryo or fetus. Detailed 
information on contraceptive measures is given in Section 4.5.3.1. 
QT Interval Prolongation  
The potential effect of GLPG1690 on QT interval prolongation is not fully known. 
Consequently, subjects with long QT syndrome or QTcF >450 ms during screening will be 
excluded. The chronic use or initiation of medication known to prolong the QT interval needs 
to be evaluated on a case-by-case basis. Periodic ECG recording and monitoring with central 
reading will be implemented for the duration of the study. A list intended as guidance for the 
investigator is provided in Appendix 5. 
Drug-drug Interaction 
For potential concomitant medication interactions, specific monitoring and guidance will be 
implemented during the study (refer to Section 4.5.3.2).  
Clinical Studies 
GLPG1690 has been evaluated in several clinical pharmacology studies and in the GLPG1690-
CL-202 study with subjects with IPF. Administration of GLPG1690 was generally safe and 
well tolerated. In the GLPG1690-CL-202 study, FVC values remained stable in the majority of 
subjects on GLPG1690 600 mg q.d. (+8 mL mean change from baseline) when administered 
for 12 weeks (refer to Section 2.2).  
Special Populations 
As there is limited clinical experience with GLPG1690 so far, the IMP should not be 
administered to subjects with moderate to severe renal impairment or hepatic impairment. 
Refer to the IB for GLPG1690 (Edition 6, 28-Jun-2019) and relevant updates/addenda for 
additional information on the safety of the IMP. 


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4.5. 
CLINICAL STUDY POPULATION 
4.5.1. Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study. 
1. Able and willing to comply with the protocol requirements and to sign the informed consent 
form (ICF) as approved by the IEC/IRB, prior to any screening evaluations. 
2. Male and female subjects ≥18 years at the time of consent who meet the American College 
of Rheumatology (ACR)/EULAR 2013 diagnostic criteria (Van den Hoogen F. et al., 
2013) for systemic sclerosis with diffuse cutaneous involvement (according to LeRoy’s 
criteria) and ≤5 years since the onset of the first systemic sclerosis manifestation other than 
Raynaud's phenomenon. 
3. mRSS >10 at screening. 
4. Active disease at screening, as defined by: 
 
Worsening of skin thickening (≥2 mRSS points) as assessed by mRSS measured at 
screening versus a previous mRSS assessment made within 6 months prior to 
screening, or 
 
New areas of skin involvement within 6 months prior to screening as documented by 
physician note, or 
 
New-onset systemic sclerosis with symptoms or signs other than Raynaud’s 
phenomenon within 2 years prior to screening, or 
 
≥1 tendon friction rub (palpated in the finger flexors or extensors, wrist flexors or 
extensors, olecranon bursa, shoulders, knees, anterior or posterior ankles with active 
motion). 
5. Subject must be able and willing to comply with restrictions on prior and concomitant 
medication as described in Section 4.5.3.2. 
6. Criterion modified per amendment. 
6.1 
Female subjects of childbearing potential must have a negative serum 
pregnancy test at screening and a negative urine pregnancy test at the baseline visit. 
7. Female subjects of childbearing potential or male subjects with female partners of 
childbearing potential must be willing to comply with the contraceptive methods 
described in Section 4.5.3.1 prior to the first dose of the IMP, during the clinical study, 
and for at least 90 days after the last dose of the IMP for male subjects and 30 days after 
the last dose of the IMP for female subjects. 
8. A body mass index (BMI) between 18–35 kg/m2, inclusive, at screening. 
Criterion modified per amendment for 
 only. 
8.1 
A body mass index (BMI) between 18–30 kg/m2, inclusive, at screening. 
9. Judged to be in good health by the investigator based upon the results of a medical 
history, physical examination, vital signs, 12-lead ECG, and fasting clinical laboratory 
safety tests. Clinical laboratory safety test results must be within the reference ranges or 
test results that are outside the reference ranges need to be considered non-clinically 
significant in the opinion of the investigator.  


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4.5.2. Exclusion Criteria 
Subjects meeting one or more of the following criteria cannot be enrolled in this clinical 
study: 
1. 
Known hypersensitivity to IMP ingredients or history of a significant allergic reaction 
to any drug as determined by the investigator, such as anaphylaxis requiring 
hospitalization.  
2. 
Breastfeeding female or subject intending to become pregnant or breastfeed. 
3. 
History of or a current immunosuppressive condition (e.g. human immunodeficiency 
virus [HIV] infection, congenital, acquired). 
4. 
Criterion modified per amendment. 
4.1. 
Positive blood testing for hepatitis B surface antigen or hepatitis C virus 
(antibody, confirmed by hepatitis C virus RNA positivity). Note: Subjects with 
a resolved hepatitis A at least 3 months prior to screening can be screened. 
5. 
Criterion modified per amendment. 
5.1. 
History of malignancy within the past 5 years (except for carcinoma in situ of 
the uterine cervix, basal cell carcinoma of the skin that has been treated with 
no evidence of recurrence, prostate cancer medically managed through active 
surveillance or watchful waiting, and squamous cell carcinoma of the skin if 
fully resected and ductal carcinoma in situ). 
6. 
Criterion modified per amendment. 
6.1. 
Clinically significant abnormalities, in the opinion of the investigator, detected 
on ECG at screening of either rhythm or conduction, QTcF >450 ms, or a 
known long QT syndrome. 
7. 
Underwent major surgery within 3 months prior to the baseline visit or have major 
surgery planned during the study period. 
8. 
Criterion modified per amendment. 
8.1. 
Unstable cardiovascular, pulmonary, or other disease (other than systemic 
sclerosis-related), in the opinion of the investigator, within 6 months prior to 
the baseline visit (e.g. coronary heart disease, heart failure, stroke). 
9. 
Previous or planned hematopoietic stem cell transplantation. 
10. 
Subjects on phototherapy within 6 weeks prior to the baseline visit. 
11. 
Severe pulmonary disease with FVC ≤45% of predicted within 6 months prior to the 
baseline visit. 
12. 
Chronic or ongoing active infectious disease, including tuberculosis (requiring 
hospitalization or systemic treatment within 4 weeks prior to the baseline visit). 
13. 
Criterion modified per amendment. 
13.1. Taking medication known to be a substrate mainly metabolized by CYP2C8 
(Appendix 1) within 4 weeks or 5 half-lives of the drug (whatever is longer) 
prior to the baseline visit. 
14. 
Criterion modified per amendment. 
14.1. Taking medication known to be strong inducers of CYP3A4 and also including 
St. John’s Wort (Appendix 2) within 4 weeks or 5 half-lives of the drug 
(whatever is longer) prior to the baseline visit. 
15. 
Criterion modified per amendment. 
15.1. Taking medication known to be strong inhibitors of CYP3A4 (Appendix 3) 
within 4 weeks or 5 half-lives of the drug (whatever is longer) prior to the 
baseline visit. 


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16. 
Criterion modified per amendment. 
16.1. Taking medication known to be potent inducers of P-gp (Appendix 2) within 4 
weeks or 5 half-lives of the drug (whatever is longer) prior to the baseline visit. 
17. 
Criterion modified per amendment. 
17.1. Taking medication known to be potent inhibitors of P-gp (Appendix 4) within 
4 weeks or 5 half-lives of the drug (whatever is longer) prior to the baseline 
visit. 
18. 
Abnormal liver function test (LFT) at screening, defined as aspartate aminotransferase 
(AST), and/or alanine aminotransferase (ALT), and/or bilirubin, and/or alkaline 
phosphatase >2x upper limit of normal (ULN). Retesting is allowed once. 
19. 
Criterion modified per amendment. 
19.1. Abnormal renal function at screening, defined as estimated glomerular 
filtration rate (eGFR) <60 mL/min/1.73 m² using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation. Retesting is allowed once. 
20. 
Hemoglobin level <10 g/dL at screening. Retesting is allowed once. 
21. 
Concurrent participation or participation in a drug, drug/device, or biologic 
investigational research study within 5 half-lives of the IMP (or within 8 weeks when 
half-life is unknown) prior to the baseline visit, or prior participation in an 
investigational antibody study within 6 months prior to the baseline visit. 
22. 
Gastrointestinal involvement (e.g. unable to swallow) preventing oral administration 
of IMP. 
23. 
Subjects diagnosed with: 
 
Systemic sclerosis sine scleroderma, or 
 
Localized scleroderma, or 
 
Eosinophilic fasciitis, eosinophilia myalgia syndrome. 
24. 
Diagnosis of another connective tissue disorder by ACR criteria. 
25. 
History of diverticulosis requiring antibiotic treatment or any other gastrointestinal 
condition that might predispose to perforations. 
26. 
Investigator or other study staff or relative thereof who is directly involved in the 
conduct of the study. 
27. 
Significant blood loss (including blood donation [>450 mL]), or transfusion of any 
blood product within 12 weeks prior to the baseline visit. 
28. 
Active drug or alcohol abuse (more than 3 glasses of wine or beer or equivalent/day) 
within 2 years prior to first IMP intake. 
29. 
Any other clinical condition or circumstances that in the opinion of the investigator 
may make a subject unsuitable for inclusion or unable to complete the study or comply 
with study procedures and requirements. 
30. 
A history of being admitted to an institution under an administrative or court order, if 
applicable by local legislation. 
4.5.3. Prohibition and Restrictions 
4.5.3.1. 
Precautions for Sexual Intercourse 
Highly effective contraceptive measures for both males and females of childbearing potential 
must be documented in the source documents. 


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4.5.3.1.1. 
Female subjects 
In line with the Heads of Medicines Agencies (HMA)’s Clinical Trial Facilitation Group 
(CTFG) recommendation, female subjects are considered of non-childbearing potential if they 
meet one of the following criteria: 
 
No menses for 12 or more months without an alternative medical cause. A high follicle 
stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient. 
 
Permanently surgically sterile (bilateral oophorectomy [i.e. surgical removal of ovaries], 
bilateral salpingectomy, or hysterectomy [i.e. surgical removal of uterus]). 
All other female subjects are considered to be of childbearing potential (WOCBP) and must 
use one of the following highly effective methods of birth control prior to the first dose of 
IMP, during the clinical study and for at least 30 days after the last dose of IMP:  
 
Combined (estrogen and progesterone containing) (oral, intravaginal, transdermal) 
hormonal contraception associated with inhibition of ovulation plus a barrier method1. 
 
Progesterone-only hormonal (oral, injectable, implantable) contraception associated 
with inhibition of ovulation plus a barrier method1.  
 
Intrauterine device. 
 
Intrauterine hormone-releasing system. 
 
Bilateral tubal occlusion.  
 
Sexual abstinence defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the clinical study and the preferred 
and usual lifestyle of the subject.  
Periodic abstinence (e.g. calendar, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of a clinical study, withdrawal, spermicides only, and lactational 
amenorrhea method are not acceptable as methods of contraception. 
In case a WOCBP has a vasectomized partner, provided that partner is the sole sexual partner 
of the WOCBP clinical study participant and that the vasectomized partner has received 
medical assessment of the surgical success, then she is not required to use an additional form 
of contraception. 
Within these limits, the specific forms of contraception employed are left to the discretion of 
the subject, the investigator, and/or the subject’s physician.  
WOCBP will be requested to do a monthly urine pregnancy test during the treatment period, 
and a urine pregnancy test at the Follow-up Visit 1. The monthly pregnancy test for Weeks 12 
and 20 will be performed at home by the subject using home testing kits. The site will 
construct the subjects on how to use and read the pregnancy tests. The outcome must be 
documented on the subject diary card and the site will obtain the results during the phone call 
and record in the source and case report form (CRF). In case of a positive urine pregnancy test 
at home, the subject should immediately contact the clinical study center and the investigator 
                                                     
1 As there is no current data available regarding potential interactions between IMP and hormonal contraceptives, 
female subjects who use hormonal contraception should supplement this with a barrier method (preferably male 
condom). 


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must report this immediately, and under no circumstances later than 24 hours after being 
made aware.  
The safety of GLPG1690 during breastfeeding is unknown. Women who are nursing are not 
allowed to take part in this clinical study. 
4.5.3.1.2. 
Male subjects 
Men should be advised not to father a child while receiving treatment and must use effective 
contraception during and up to 90 days after treatment. Male subjects intending to father a 
child, should discontinue treatment with IMP and wait for at least 90 days before stopping the 
contraceptive measures detailed in this section. 
Non-vasectomized male subjects with female partners of childbearing potential must be 
willing to use a condom from the time of the first dose of IMP, during the clinical study, and 
for at least 90 days after the last dose of IMP, in addition to having their female partner use 
one of the following forms of contraception: 
 
Combined (estrogen and progesterone containing) (oral, intravaginal, transdermal) 
hormonal contraception associated with inhibition of ovulation.  
 
Progesterone-only hormonal (oral, injectable, implantable) contraception associated 
with inhibition of ovulation.  
 
Intrauterine device. 
 
Intrauterine hormone-releasing system. 
Sexual abstinence defined as refraining from heterosexual intercourse during the entire period 
of risk associated with the study treatments is considered a highly effective contraceptive 
measure. The reliability of sexual abstinence needs to be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the subject.  
Periodic abstinence (e.g. calendar, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of a clinical study, withdrawal, spermicides only, and lactational 
amenorrhea method are not acceptable methods of contraception.  
In a case where the female partner of a male participant has undergone documented surgical 
sterilization that was performed more than 1 year before screening, then the subject is not 
required to use an additional form of contraception.  
Vasectomized male subjects with female partners of childbearing potential are not required to 
use an additional form of contraception providing that surgical sterilization has been 
successful (documented azoospermia by semen analysis). 
No sperm donation is allowed from first dose of IMP, during the clinical study, and until 
90 days after the last dose of IMP. 
4.5.3.2. 
Prior and Concomitant Medications 
Prior Medication 
Prior medication taken up to 12 weeks prior to and during the screening period will be recorded 
after signing of the ICF, at Visit 1. 


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Concomitant Medication 
Should any treatment other than the IMP be used during the course of the study, the name of 
the medication, the dosage, the route, the reason for medication, and the start and stop dates of 
administration must be recorded in the CRF until Follow-up Visit 2.  
Concomitant medications taken for the long-term treatment of pre-existing conditions can 
continue during the study, provided they are in accordance with the in- and exclusion criteria 
(see Sections 4.5.1 and 4.5.2, respectively). It is required that these medications are stabilized 
prior to study entry (8 weeks prior to screening, or longer if t1/2 and/or time to reach steady state 
of the drug requires) and preferably continue without variation of dose or regimen during the 
study. 
In case additional concomitant medication needs to be administered or dose adjustments for 
pre-existing conditions need to be performed during the study, the benefit-risk to the subject 
should be carefully assessed and consideration given to the timing of any necessary introduction 
of new medications.  
The following medications are prohibited within 4 weeks prior to the baseline visit and during 
the treatment period: warfarin, antifibrotic agents (including colchicine, minocycline, tyrosine 
kinase inhibitors [nilotinib, imatinib, dasatinib, nintedanib], pirfenidone), bosentan or Type 1 
oral collagen. The following medications are prohibited within 3 months prior to the baseline 
visit and during the treatment period: steady dose of prednisone or its equivalent >10 mg/day, 
methotrexate >20 mg/week, azathioprine >150 mg/day, MMF >3 g/day, mycophenolic acid 
>2.16 g/day, leflunamide >20 mg/day. Cyclophosphamide is prohibited within 6 months prior 
to the baseline visit and during the treatment period, as well as the following biologics: 
tocilizumab or other drugs targeting IL-6/IL-6 receptor, abatacept, anti-tumor necrosis factor 
(TNF) drugs, rituximab, belimumab, or other monoclonal antibodies.  
If during the study, the subject’s condition necessitates the use of one of the abovementioned 
medications (excluding prednisone or its equivalent >10 mg/day), the use of IMP should be 
interrupted until resolution or stabilization of this condition, preferably after consultation with 
the contract research organization (CRO) medical monitor (as per study contact list) or 
sponsor’s study physician (if the former is not available).  
Precautions with concomitant medication known to prolong the QT interval 
The use of medication known to prolong QT interval during the study needs to be based on a 
benefit-risk evaluation by the investigator, e.g. in the case of atrial fibrillation. In certain other 
situations (e.g. the initiation of macrolides or fluoroquinolones in case of a lower respiratory 
tract infection), when the benefit-risk evaluation necessitates the administration of medication 
known to or potentially prolonging QT, IMP can be interrupted as evaluated by the investigator 
after clinical assessment of the subject’s profile, including the baseline QTcF and how this has 
changed over time for this specific subject. If the investigator elects to continue IMP, additional 
monitoring will be performed as per investigator’s judgment. A nonexhaustive list of 
medication known to prolong QT interval is provided in Appendix 5. Note: In case QT interval 
prolongation is reported in a subject while receiving one of these medications, the investigator 
should follow the labels and Risk Evaluation and Mitigation Strategies guidance.   


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Precautions with other concomitant medications 
At dose levels of 600 mg q.d., GLPG1690 has the potential to substantially influence the 
metabolism of CYP2C8 substrates and to potentially be influenced by known strong 
CYP3A4/potent P-gp inducers/inhibitors. 
 
GLPG1690 demonstrated a strong time-dependent inhibition potential against 
CYP2C8-mediated metabolism. Consequently, GLPG1690 should not be used 
concomitantly with medications primarily or solely metabolized via CYP2C8 
(see Appendix 1). For other medications involving part of their metabolism pathway via 
CYP2C8, caution should be applied on a case-by-case basis taking into consideration the 
benefit-risk ratio. Statins such as fluvastatin and pitavastatin are metabolized to some 
degree by CYP2C8, and need to be used with caution. Other statins such as simvastatin, 
lovastatin, and atorvastatin are theoretically less metabolized by CYP2C8. Monitoring of 
LFTs and creatine kinase is implemented during the study, and guidance to the subject 
aligned with guidance for statins in clinical practice is therefore strongly recommended. 
Loperamide is also a substrate of CYP2C8, and special caution should be applied in 
alignment with clinical practice. 
 
GLPG1690 is a substrate of CYP3A4 and P-gp, and could therefore be influenced by 
their respective inhibitors and inducers. GLPG1690 exposure is reduced up to 90% by the 
strong CYP3A4/potent P-gp inducer rifampin. As a consequence, strong inducers of 
CYP3A4 and/or P-gp are part of the exclusion criteria and should be avoided during the 
study to ensure proper exposure to GLPG1690 (see Appendix 2). For inhibition, strong 
CYP3A4 and dual strong 3A4 and potent P-gp inhibitors have shown that GLPG1690 
exposure increased by 3 to 4 fold when coadministered, therefore use of known strong 
CYP3A4 inhibitors and potent P-gp inhibitors is prohibited during the study (see 
Appendix 3 and Appendix 4). Antibiotics from the macrolide therapeutic class are 
excluded, unless they are used for the short-term treatment of a lower respiratory tract 
infection with interruption of IMP, which is restarted as soon as possible after the 
completion of the treatment with macrolides. 
It is highly recommended that the CRO medical monitor (as per study contact list) or sponsor’s 
study physician (if the former is not available) are consulted before the initiation of medication 
known to prolong QT interval, to be a CYP2C8 substrate, or to inhibit or induce P-gp/CYP3A4. 
In certain situations, when the benefit-risk evaluation necessitates the administration of 
medication excluded from use during the study, the use of IMP should be interrupted until 
resolution or stabilization of this condition, preferably after consultation with the CRO medical 
monitor (as per study contact list) or sponsor’s study physician (if the former is not available) 
and restarted as soon as possible.  
As a rule, inclusion of subjects with stable chronic illness on stable medications which are 
metabolized/transported by the abovementioned CYP/transporter enzymes should be decided 
on a case-by-case basis if not excluded or prohibited, taking into account the medical history, 
concomitant medication of the subject, the therapeutic index of the medication, and safety 
profile.  
As indicated in the study contact list, the CRO medical monitor should be contacted, or the 
sponsor’s study physician in case the former is not available (when deemed necessary by the 
investigator), specifically for medication with a narrow therapeutic index and/or a risk of 
(un)predictable AEs.  


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Rescue medication  
If the subject shows a worsening of his/her systemic sclerosis disease condition (e.g. acute 
exacerbation), all treatment options are allowed at the investigator’s discretion. The decision to 
continue the IMP should be taken on a case-by-case basis. 
4.5.3.3. 
Food and Beverage Restrictions 
The use of St. John’s Wort is prohibited during the study. 
Double-strength grapefruit juice is potentially a potent CYP3A4 inhibitor and therefore should 
be avoided during the study. 
4.5.3.4. 
Other Prohibitions and Restrictions  
Not applicable. 
4.5.4. Treatment Discontinuation (Temporarily and Permanently), Subject 
Withdrawal, and Study Termination  
A subject may be withdrawn from the clinical study at any time without the subject’s consent 
if the investigator or sponsor determines that it is not in the best interest of the subject to 
continue participation. In such case, the reason for withdrawal will be documented in the source 
documents, and the subject will complete the ED visit and follow-up visits for safety 
assessments. 
Treatment with IMP should be discontinued by the investigator (preferably after discussion 
with the CRO medical monitor, who may consult and must inform the sponsor’s study 
physician) for any of the following conditions: 
 
Life-threatening AE or an SAE that places the subject at immediate risk. 
 
Serious infections deemed related to study treatment by the investigator, and requiring 
parenteral antimicrobial therapy and/or hospitalization. 
 
Confirmed pregnancy: if a subject becomes pregnant during the study (to be confirmed 
by local serum pregnancy test; central measurement will also be performed), the IMP has 
to be stopped immediately and the subject has to be followed up until birth or otherwise 
termination of pregnancy. The subject needs to be unblinded immediately and repeat 
counseling on birth defect risk must be offered in case she was on active drug. 
 
Arrhythmia or conduction abnormality, including but not limited to prolonged QTcF, 
where the severity is categorized as Common Terminology Criteria for Adverse Events 
(CTCAE) Grade 3 or higher (QTcF >500 ms on at least two separate ECGs). 
 
An increase for QTcF with >60 ms change from baseline (Visit 2) or QTcF >500 ms at 
any ECG recording (triplicate mean or single) needs to be confirmed by an ECG recording 
as soon as possible from the original abnormal recording at the same visit. In case of an 
abnormal ECG on both of these two recordings, the investigator needs to send an 
immediate alert to the CRO medical monitor (as per study contact list) or sponsor’s study 
physician (if the former is not available). If the ECG abnormality is before IMP intake, 
IMP administration will be withheld until the central reader has reviewed the ECG 
registration. In case of confirmation of the ECG abnormality, IMP will be discontinued 
for this subject. 


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 
Increase in LFT: 
 
AST or ALT ≥8x ULN. 
 
AST or ALT ≥3x ULN with signs of severe liver damage (i.e. with the appearance of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or 
eosinophilia [>5%], and/or total bilirubin ≥1.5x ULN or international normalized 
ratio [INR] >1.5). 
 
AST or ALT ≥3x ULN for more than 2 weeks. 
 
Clinical laboratory test suggestive of cholestasis with total serum bile acid levels 
>3x ULN on a sample taken in fasted state (at least 8 hours fasted). If the routine random 
or postprandial total serum bile acid sample is >3x ULN, then the subject should have a 
fasted sample taken within 1 to 5 days. The results of this test will determine whether the 
subject should discontinue IMP or not. 
When test results need to be confirmed, the subject should return to the clinical study center 
and be evaluated as soon as possible, preferably within 48 hours from awareness of the 
abnormal results. This evaluation should include laboratory tests, detailed history, and physical 
assessment. In addition to repeating AST and ALT, laboratory tests should include albumin, 
creatine kinase, total bilirubin, direct and indirect bilirubin, gamma glutamyl transferase (GGT), 
INR, and alkaline phosphatase. A detailed history, including relevant information, such as 
review of ethanol, recreational drug and supplement consumption, family history, sexual 
history, travel history, history of contact with a jaundiced subject, surgery, blood transfusion, 
history of liver or allergic disease, and work exposure, should be collected. Further testing for 
acute hepatitis A, B, or C infection and liver imaging (e.g. biliary tract) may be warranted. All 
cases confirmed on repeat testing with no other cause for LFT abnormalities identified at the 
time should be considered potential Hy’s Law cases irrespective of availability of all the results 
of the investigations performed to determine etiology of the abnormal LFTs. Such potential 
Hy’s Law cases should be reported as SAEs. 
Every effort should be made to keep subjects in the study and on treatment. However, the 
investigator can consider stopping the treatment with GLPG1690 or placebo, preferably after 
consultation with the sponsor’s study physician, in case of concerns about the subject’s safety, 
major protocol noncompliance, serious or severe AEs or worsening of the disease condition, 
which in the investigator’s opinion needs an alternative treatment approach not being covered 
in the clinical study (e.g. rescue medication).  
When study treatment is discontinued, the subject will be requested to return for the ED visit 
and follow-up visits. 
Subjects will be informed prior to clinical study entry that they are allowed to withdraw from 
the clinical study. At any time and for any reason, a subject’s participation in the clinical study 
may terminate at his/her request without prejudice to his/her future medical care. The subject 
will be encouraged to share the reason(s) for withdrawal so this can be documented in the source 
documents, and to complete the ED visit and follow-up visits for safety assessments, but will 
not be obliged to do so. 
Subjects who withdraw from the clinical study without contact with the clinical study center 
(lost-to-follow-up) should be contacted by the clinical study center so that their health status 
can be assessed and documented in the source documents. The clinical study center should 
make every effort to understand whether the subject is alive, including checking the medical 


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records, contacting general practitioner or relatives, if necessary. All attempts must be 
documented in the source documents.  
Subjects who discontinue IMP or the study will not be replaced. 
The sponsor has the right to terminate the clinical study at any time in case of safety concerns 
or if special circumstances concerning the IMP 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 clinical study termination. 
4.6. 
MEASURES TO MINIMIZE BIAS 
4.6.1. Randomization 
At screening, subjects will be assigned a subject identification. When a subject is confirmed to 
be eligible for the clinical study, the subject will be randomized. Allocation of each subject to 
a given treatment will be done using a centralized electronic system (interactive web response 
system [IWRS]). Subjects will be randomized in a 2:1 ratio to receive GLPG1690 600 mg q.d. 
or matching placebo, respectively. 
For each subject at each clinical study center visit, the clinical study center will contact the 
IWRS for the appropriate treatment number to be assigned. The medication kit(s) will contain 
the relevant IMP for the period until the next clinical study center visit. 
Subjects and study personnel will be blinded to the treatment assigned to the subject. Additional 
details on blinding and unblinding are provided in Section 4.6.2. 
4.6.2. Blinding and Unblinding 
This is a randomized, double-blind clinical study. The subject and the entire clinical study team, 
including the investigators, clinical study coordinators, and sponsor personnel are blinded to 
treatment assignment. 
Blinded and packaged medication will be provided to the clinical center. The placebo 
formulation will match the active formulation in size, color, shape, and appearance. All IMP 
formulations (active and placebo) will be packaged in the proper proportion to assure desired 
dosages and maintenance of the blinding.  
The blind can be broken only if the investigator deems it necessary for the safety of a subject. 
The investigator is encouraged to discuss considerations to break the blind with the CRO 
medical monitor (as per study contact list) or the sponsor’s study physician (in case the former 
is not available), whenever possible and where the situation allows. However, the responsibility 
to break the treatment code in emergency situations resides solely with the investigator. The 
investigator is not required to discuss unblinding beforehand if he or she feels rapid emergency 
unblinding is necessary, but is required to inform the CRO medical monitor and the sponsor in 
a timely fashion after unblinding has occurred. 
The blind can be broken by the investigator via IWRS.  


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Code-break information (via IWRS vendor/randomization list) will be provided to the 
bioanalytical laboratory responsible for plasma drug determination sample analysis, and to the 
sponsor pharmacovigilance lead for SAE reporting purposes. 
5. 
INVESTIGATIONAL MEDICINAL PRODUCT 
5.1. 
IDENTITY OF THE INVESTIGATIONAL MEDICINAL 
PRODUCT 
The IMPs (GLPG1690 and placebo) will be supplied to the clinical study center, by and under 
the responsibility of the sponsor, who will also provide the investigator with European Union 
(EU) Qualified Person release documents. 
GLPG1690 will be provided as film-coated tablets for oral use, containing 200 mg G451990 
each (G451990 is the compound code for GLPG1690). The placebo will be provided as 
matching film-coated tablets for oral use.  
A full list of excipients used in the film-coated tablet formulation is available in the IB for 
GLPG1690 (Edition 6, 28-Jun-2019) and relevant updates/addenda.  
5.2. 
DOSAGE AND ADMINISTRATION 
The following dose will be used: 
 
600 mg GLPG1690 q.d. (as three GLPG1690 film-coated tablets of 200 mg). 
 
Placebo q.d. (as three placebo film-coated tablets). 
The IMP is to be taken q.d. around the same time every day with food (e.g. breakfast, small 
meal, or a snack) or after food intake; taking into account the timing of the planned visits, with 
a maximum of 2 hours between the food intake and IMP intake. Subjects will be instructed to 
swallow the tablets as a whole with a glass of water and to not chew the IMP prior to 
swallowing. On clinical study center visit days, the IMP will be administered at the clinical 
study center after predose assessments have been completed. 
If a subject misses a dose (e.g. because he/she forgot to take the medication), he/she should take 
the missed dose within 12 hours after the planned intake time and within 2 hours of food intake. 
If the IMP is not taken within 12 hours after the planned time, the missed dose should be 
skipped. 
5.3. 
PACKAGING, LABELING, AND DISTRIBUTION 
The film-coated tablet for oral use will be packaged in blisters. IMP packages will be labeled 
with clinical study-specific details. 
All manufacturing, packaging, and labeling operations will be performed according to Good 
Manufacturing Practice for Medicinal Products and the relevant regulatory requirements. 
Each medication kit will be identified with a unique kit number. A multiple of kits will be 
provided to the subject at each clinical study center visit, providing the subject with sufficient 
tablets to cover the period until the next scheduled clinical study center visit.  


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If subjects, due to any COVID-19-related reason, cannot attend Visit 9 (Week 24) within the 
time window of ±4 days, the window for the visit may be increased to ±28 days (Section 6.1). 
If Visit 9 is postponed beyond Week 24, a Direct-to-Patient (DTP) shipment of one additional 
IMP kit may be implemented to cover the treatment prolongation of up to 28 days.  
If Visit 9 is not conducted in the extended (±28 days) window, i.e. after Week 28, no further 
IMP will be provided to the subject, and the subject will not take any IMP after Visit 9 (i.e. 
ultimately Week 28).  
The distribution to the clinical study center will only occur after the required local 
documentation is obtained including clinical study approval by Competent Authorities and the 
IECs/IRBs, documentation on which the assessment of the investigator’s qualifications was 
based (e.g. curriculum vitae) and the signed and dated study agreement and financial agreement. 
5.4. 
STORAGE 
Clinical study centers are to store all drug supplies in a secure, locked area with limited access 
below 30°C, protected from light, until dispensed. Clinical study centers will be required to 
monitor the storage temperature by using at least a calibrated minimum-maximum temperature-
recording device and to keep a minimum to maximum temperature log which must be 
completed each working day in order to establish a record of compliance with these storage 
conditions. The investigator will instruct subjects on how the IMP should be stored at home. 
5.5. 
TREATMENT COMPLIANCE AND DRUG ACCOUNTABILITY 
For each dose taken at home, the date and number of tablets taken should be recorded on the 
subject diary card (see Section 6.4 for additional information). Any interruption or change in 
treatment (together with the reason for change) should be documented on the subject diary card. 
The pharmacist or designated clinical study personnel will maintain a log of the total amount 
of IMP received at the clinical study center, the amount dispensed to the subject, and the amount 
of IMP returned by the subject to the clinical study center. IMP supplies for each subject will 
be inventoried and accounted for throughout the clinical study. At the end of the treatment 
period, these records will be checked against the inventory by the study monitor. All clinical 
supplies will be stored in locked facilities. 
Subjects will return any unused IMP and empty IMP packages at each clinical study center 
visit. Missed doses should be discussed to try to ascertain the reason(s). Every effort should be 
made to ensure proper subject dosing. Subjects with poor compliance will be retrained by the 
clinical study center. Upon sponsor approval, all unused IMP and empty IMP packages will be 
destroyed at the clinical study center. If destruction by the clinical study center is not possible 
or the destruction process is found unacceptable by the sponsor, the IMP should be returned to 
the drug supplier/drug depot as appropriate.  
At each clinical study center visit, clinical study center staff will review treatment compliance 
by assessing the number of returned IMP.  
6. 
CLINICAL STUDY ASSESSMENTS 
Every effort should be made to ensure that clinical study protocol (CSP)-required tests and 
procedures are completed as described in the Schedule of Activities (see Section 6.11). To avoid 






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The inclusion and exclusion criteria will be checked to assess eligibility for the study. All 
screening tests will be reviewed to confirm eligibility before randomization and IMP intake. 
Retesting of individual screening assessment(s) that did not meet eligibility criteria is not 
permitted, with the following exceptions AND only in case it is still possible to randomize the 
subject within the per-protocol defined screening period of 28 days: 
 
Laboratory values for LFTs, eGFR, and hemoglobin can be retested once. 
 
Lost or invalid blood or urine samples.  
Rescreening: in case of screening failure, subjects are allowed to be rescreened maximum 
two times, after signing a new ICF. Rescreening can start at least 6 weeks after the initial 
laboratory testing of the previous screening.  
6.4. 
SUBJECT DIARY CARD 
Subjects will be given diary cards from Visit 2 until Follow-up Visit 1 to record the following: 
 
From Day 1 until the last visit of the treatment period, subjects will be asked to record the 
date of IMP intake, the number of tablets taken for each administration, any change in 
intake and reason for the change, and monthly urine pregnancy test outcome (only for 
WOCBP, see Section 4.5.3.1.1). 
 
From Day 1 until Follow-up Visit 2, subjects will be asked to record changes in 
concomitant medication regimen, including new medicines not captured in medication 
history, and any other concomitant medication used as well as any emerging AE.  
Subjects will be instructed to bring their diary cards and used/unused IMP to each clinical study 
center visit. At each clinical study center visit, review of compliance with the diary cards and 
subject re-training if needed, will be performed.  
6.5. 
EFFICACY ASSESSMENTS 
6.5.1. Modified Rodnan Skin Score 
mRSS is an established primary outcome measure in most therapeutic studies in systemic 
sclerosis, based on the evidence that skin thickness serves as a surrogate for overall disease 
activity, severity, and mortality in systemic sclerosis. mRSS scoring will be performed at Visit 1 
(screening), Visit 2 (baseline), Visits 4, 5, 7, and 9, ED (if applicable), and Follow-up Visit 1. 
mRSS will be assessed in a standardized manner according to published protocols by the SCTC 
and the World Scleroderma Foundation (Khanna D. et al., 2017) by the responsible study 
physician. Preferably, each subject will be assessed by the same study physician (or nurse 
practitioner, as acceptable according to local clinical study center setup and meeting the 
experience criterion defined outside the protocol) for the entire study. The 17-site mRSS will 
be used, with each site assessed on a scale of 0 to 3 with a maximum score of 51. For individual 
subjects, clinically meaningful changes in skin score (MCID) are 4.7 skin score units and/or at 
least 20% change in overall mRSS (Khanna D. et al., 2006). Regardless of experience, each 
assessor will need to undergo study-specific training and qualification to ensure consistency. In 
the event of a change of assessor, consistency of scoring between assessors should ideally be 
assessed and documented (i.e. new and previous assessor carry out scoring in parallel). 


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6.6. 
SAFETY ASSESSMENTS 
This section describes methods and timing for all safety assessments and recording. Additional 
assessments (e.g. unscheduled clinical laboratory tests or extra vital signs recordings) are 
allowed to ensure appropriate collection of safety data and to assess any perceived safety 
concerns. 
For subjects who, due to any COVID-19-related reason, cannot perform the study 
procedures. 
If Visit 9 needs to be postponed until after Week 24, regular phone calls at Week 24 and every 
14 days thereafter should be implemented to evaluate the subject’s safety until a visit can take 
place on-site. In addition, if any of the follow-up visits cannot be performed on site, a phone 
call to evaluate the subject’s safety should be performed. 
During these phone calls, the investigator should at least discuss the following items and collect 
the following information as much as possible: 
 
subject’s general condition and ongoing study medication intake 
 
information on any adverse events (changes of ongoing or new events) 
 
information on concomitant medication intake 
 
completion of subject diary cards and urine pregnancy test and result (monthly, if 
applicable) by the subject 
 
the possibility for local laboratory testing, vital signs, and ECG should be considered, and 
discussed. This local testing may occur either prior to the phone call, or as a consequence 
of the exchanged information, at the discretion of the investigator. 
All adverse events including those based on, or identified by local testing need to be reported 
in the eCRF, and any SAEs should be reported within 24 hours with the SAE form.  
Urine pregnancy tests to perform the monthly pregnancy test at home until follow-up visit 1 (if 
applicable) and treatment or follow-up diary cards will also be shipped to the patient to cover 
the longer period between on-site visits. 
6.6.1. Adverse Events 
The AEs reporting period for safety surveillance begins when the subject signs the ICF and 
ends at his/her last follow-up visit as defined in the Schedule of Activities (see Section 6.11). 
Detailed definitions, ratings, and reporting requirements for AEs and SAEs are found in Section 
9. 
6.6.2. Clinical Laboratory Evaluations 
The following clinical laboratory safety tests will be performed: 
 
Hematology: hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, hemoglobin, red blood cell count, white blood 
cell count, white blood cell differential count (absolute and relative), and platelets. 
 
Coagulation: INR, thromboplastin time, and partial thromboplastin time. 
 
Serum/plasma chemistry: random glucose, urea, creatinine, uric acid, sodium, potassium, 
calcium, chloride, phosphorus, AST, ALT, GGT, total bilirubin, alkaline phosphatase, 


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lactate dehydrogenase, total serum bile acid, albumin, total proteins, triglycerides, 
cholesterol (total, low density lipoprotein, and high density lipoprotein), creatine kinase, 
and C-reactive protein. 
 
Urinalysis:  
 
Dipstick: pH, glucose, proteins, blood, leucocytes, ketones. 
 
Microscopic examination of the sediment (cylinders, erythrocytes, leucocytes) if 
indicated. 
 
Serology: hepatitis B surface antigen, hepatitis C virus antibody, and HIV-1 and HIV-2 
antibodies (only at screening). Positive hepatitis and HIV results should be reported by 
the investigator as required by local law.  
 
FSH test for females at screening to confirm menopause if applicable. 
 
Pregnancy test for females: serum beta human chorionic gonadotropin at screening, urine 
pregnancy test on a monthly basis (only for WOCBP).  
The clinical laboratory evaluations will be performed at visits specified in the Schedule of 
Activities in Section 6.11 (see also Section 6.1, “Timing of Assessments”). Reference ranges 
will be supplied by the central laboratory. Clinical laboratory values outside the normal range 
will be flagged and clinical relevance will be assessed by the investigator. Only laboratory test 
abnormalities judged as clinically significant by the principal investigator should be recorded 
as AEs.  
The details of blood and urine sample handling and shipment instructions will be provided in a 
separate laboratory manual. 
6.6.3. Physical Examination 
Physical examinations will be conducted by a physician, trained physician’s assistant, or nurse 
practitioner (as acceptable according to local regulation) at visits specified in the Schedule of 
Activities in Section 6.11. The person conducting the physical examination will document this 
in the subject’s medical records. Clinically significant abnormal findings should be recorded as 
AEs. Height and weight will only be recorded at screening. 
6.6.4. Vital Signs 
Vital signs (SBP, DBP, heart rate, respiratory rate, and body temperature) will be recorded in a 
standardized manner (i.e. after the subject has rested in a supine position for 5 minutes) at visits 
specified in the Schedule of Activities in Section 6.11. Clinically significant abnormal values 
should be recorded as AEs. 
6.6.5. 12-lead Electrocardiogram 
At the time points specified in the Schedule of Activities (see Section 6.11) a 12-lead ECG will 
be recorded and results will be sent for central reading. Triplicate ECGs will be performed 
irrespective of IMP intake at Visit 1 (screening), within 30 minutes before IMP intake and 
between 2 to 3 hours after IMP intake at Visit 2 (baseline) and Visit 3. A single ECG will be 
performed within 30 minutes before IMP intake at Visits 7 and 9, and irrespective of IMP intake 
at ED (if applicable) and Follow-up Visit 1. The ECG must be taken after subjects rested for at 
least 5 minutes in the supine position. In case an indwelling catheter is used, ECGs may be 
recorded after blood sampling, provided that there is at least 30 minutes between catheter 
insertion and the ECG recording. When catheter insertion would fail, the 12-lead ECG needs to 










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6.11. SCHEDULE OF ACTIVITIES 
For detailed instructions on the clinical study procedures, please see referred Sections and Section 6.1, “Timing of Assessments”. 
EVENT 
SCREENING 
TREATMENT PERIOD 
FOLLOW-UP j 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
EDa 
FU1 
FU2 
Study Day (D) or Week (W)b ± days (d) 
D-28 to D-1 
D1 
W2 
±2d 
W4 
±2d 
W8 
±4d 
W12c 
±4d 
W16 
±4d 
W20c 
±4d 
W24i 
±4d 
 
W28 
±7d 
W36  
±7d 
Informed consent (Section 6.3) 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria (Section 6.3) 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics (Section 6.3) 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history/concurrent illnesses (Section 6.3) 
 
 
 
 
 
 
 
 
 
 
 
 
FSH test (Section 6.6.2) 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization (Section 4.6.1) 
 
 
 
 
 
 
 
 
 
 
 
 
Phone call 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test d (Section 6.6.2) 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination (Section 6.6.3) 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (Section 6.6.4) 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECGe (Section 6.6.5) 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (Section 6.6.2) 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests (Section 6.6.2) 
 
 
 
 
 
 
 
 
 
 
 
 






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7. 
STATISTICAL METHODS 
All statistical methods shall be detailed in a statistical analysis plan (SAP) that will be prepared 
before the Week 24 primary analysis. All relevant data collected in this clinical study will be 
documented using summary tables, figures, and subject data listings. 
Any deviations from the protocol are to be justified in the SAP. 
7.1. 
DETERMINATION OF SAMPLE SIZE 
Sample size was based on empirical considerations. The number of subjects (30) included in 
this study should give reasonable precision around the estimates derived for the efficacy 
evaluation. 
The primary endpoint of the study is the change from baseline in mRSS over 24 weeks. 
Considering 20 and 10 subjects in the GLPG1690 and placebo arm, respectively, and a common 
standard deviation of 5 on the change from baseline in mRSS, the MCID of 4.7, and taking into 
account a 10% dropout, the probability to observe a treatment effect of more than 4 points is 
63%.  
7.2. 
POPULATION FOR ANALYSES 
7.2.1. All Screened Subjects 
All subjects who signed and dated an ICF and underwent screening assessments to check 
whether or not they are eligible to participate in the clinical study. 
7.2.2. All Enrolled Subjects 
All subjects who were found eligible to participate in the clinical study and could be 
randomized. 
7.2.3. All Randomized Subjects 
All enrolled subjects who were randomized into the clinical study. 
7.2.4. Full Analysis Set 
All randomized subjects who have received/used at least 1 dose of IMP. 
7.2.5. Per-Protocol Set 
All Full Analysis Set subjects who did not have a major protocol deviation that impacts the 
efficacy results (as defined in a protocol deviation plan). The determination of the per-protocol 
population will be finalized and documented prior to database lock and unblinding. 






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7.3.6. Analyses of Safety Data 
All safety analyses will be performed using the Safety Analysis Set (Section 7.2.6). All safety 
data collected on or after the first dose of IMP administration up to the last contact after the last 
dose of IMP, unless specified otherwise, will be summarized by treatment group according to 
the IMP received. Clinical safety will be addressed by assessing AEs, laboratory assessments, 
physical examinations, vital signs, and 12-lead ECGs. 
7.3.6.1. 
Extent of Exposure 
A subject’s extent of exposure to IMP will be generated from the IMP administration page of 
the CRF. Exposure data will be summarized by treatment group. Duration of exposure to IMP 
will be expressed as the number of days between the first and last dose of IMP, inclusive, 
regardless of temporary interruptions in IMP administration and summarized by treatment 
group. 
7.3.6.2. 
Adverse Events 
Clinical and laboratory AEs will be coded using the latest version of the Medical Dictionary 
for Regulatory Activities. System Organ Class (SOC), High Level Group Term, High-Level 
Term, Preferred Term, and Lower-Level Term will be attached to the clinical database. 
The following AEs will be considered as treatment-emergent AEs (TEAEs):  
Any AE with an onset date on or after the start of IMP intake and no later than 30 days after 
last dose of IMP, or any worsening of any AE on or after the start of IMP intake.  
AEs reported before the start of IMP or later than 30 days after the last dose of IMP will be 
listed. 
In addition, summaries and/or listings will be provided for the suspected symptoms/AEs of flare 
with an onset date on or after the IMP start date until the EoS (including information from 
Follow-up Visit 2). 
Summaries (number and percentage of subjects) of TEAEs per subject by SOC and Preferred 
Term will be provided by treatment group. TEAEs will also be summarized by causal 
relationship to IMP and severity. In addition, TEAEs leading to premature discontinuation of 
IMP will be summarized and listed. Also, all SAEs, including the non-treatment-emergent 
SAEs, will be listed. 
7.3.6.3. 
Clinical Laboratory Evaluations 
Laboratory assessments will be analyzed descriptively. Changes from baseline (Day 1 before 
IMP intake) and shifts according to normal ranges will be presented as well. Analyses will be 
done per treatment group.  
7.3.6.4. 
Physical Examinations 
Only abnormal post-baseline physical examination results will be listed. 






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9.1.3. Unlisted (Unexpected) Adverse Event/Reference Safety Information 
An AE is considered unlisted if the nature or intensity is not consistent with the applicable 
product reference safety information. For an IMP, the expectedness of an AE will be determined 
by whether or not it is listed in the reference safety information part of the IB. 
9.1.4. Adverse Events of Special Interest 
Not applicable. 
9.1.5. Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as Adverse Events or Serious Adverse Events 
Laboratory abnormalities without clinical significance based on the investigator’s judgment, 
are not considered AEs or SAEs. However, laboratory abnormalities (e.g. clinical chemistry, 
hematology, and urinalysis) or other abnormal (clinical study-specific) assessments (e.g. ECG, 
radiography, vital signs) that require medical or surgical intervention, are associated with signs 
and/or symptoms, lead to IMP interruption, modification, or discontinuation must be recorded 
as an AE or SAE if they meet the definition as described in Sections 9.1.1 and 9.1.2, 
respectively. If the laboratory abnormality is part of a syndrome, the syndrome or diagnosis is 
to be reported (e.g. anemia instead of decreased hemoglobin). 
9.1.6. Special Situations 
Special situations are situations that have a possible impact on the safe use of the IMP. These 
situations might be or might not be associated with AEs. 
 Pregnancy  
 Abuse or misuse of study drug 
- 
Abuse of study drug is defined as the persistent or sporadic, intentional 
excessive use of the study drug, which is accompanied by harmful physical or 
psychological effects. 
- 
Misuse of study drug is defined as a situation where the study drug is 
intentionally and inappropriately used not in accordance with the product 
information. 
  Drug interaction or food interaction with study drug 
- 
A drug interaction with study drug is defined as a situation in which there is 
evidence or a suspicion that the study drug interacts with another drug when 
both are administered together. 
- 
A food interaction with study drug is defined as a situation in which there is 
evidence or a suspicion that the study drug interacts with a food when taken 
together. 
  Medication error with study drug 


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- 
A medication error with study drug is defined as an unintended failure in the 
drug treatment process that leads to, or has the potential to lead to, harm to the 
patient. 
  Occupational exposure to study drug 
- 
Occupational exposure with study drug is defined as an exposure to the study 
drug as a result of one’s professional or non-professional occupation. 
  Overdose with study drug 
- 
An overdose of study drug is defined as the administration of a quantity of the 
study drug given per administration or cumulatively, which is the intake of 
more than three tablets/day  
  Product complaint or quality defect of study drug 
- 
Product complaint or quality defect of study drug is defined as complaints or 
defects of the study drug arising from potential deviations in the manufacture, 
packaging, or distribution of the study drug. 
9.2. 
ASSESSMENT OF ADVERSE EVENTS AND SERIOUS 
ADVERSE EVENTS 
The investigator is responsible for assessing AEs and SAEs for causality and severity. This is 
the basis for the sponsor’s final review and confirmation of accuracy and completeness of event 
information and causality assessments. 
9.2.1. Assessment of Causality 
The investigator is responsible for assessing the causal relationship to IMP(s) administration or 
study procedures (e.g. invasive procedures such as venipuncture) based on her/his clinical 
judgment. The following decision choice will be used by the investigator to describe the 
causality assessment between the reported event or laboratory test abnormality and the IMP. 
 
Unrelated: 
Time relationship to IMP intake is improbable. Related to other etiologies such as 
concomitant medications or subject's clinical state.  
 
Unlikely: 
Time relationship to IMP intake is improbable (but not impossible). Concomitant disease 
or other drugs provide plausible explanations. 
 
Possible: 
Time relationship to IMP intake is reasonable. Event or laboratory test abnormality, 
could also be explained by disease or other drugs. Information on IMP withdrawal may 
be lacking or unclear. 
 
Probable: 
Time relationship to IMP intake is reasonable. Unlikely to be attributed to concurrent 
disease or other drugs. Response to withdrawal is clinically reasonable and rechallenge 
not required. 


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 
Certain: 
Time relationship to IMP intake is plausible. Cannot be explained by concomitant disease 
or other drugs. Response to withdrawal is plausible (pharmacologically, pathologically). 
Event definitive pharmacologically or phenomenologically (i.e. an objective and specific 
medical disorder or a recognized pharmacological phenomenon). Rechallenge 
satisfactory, if ethical and necessary. 
It should be emphasized that ineffective treatment (worsening of the disease) should not be 
considered as causally related in the context of AE reporting. 
9.2.2. Assessment of Severity 
The severity of AEs should be graded using the CTCAE version 5.0. If a CTCAE criterion does 
not exist, the investigator should use the grade or adjectives: Grade 1 (mild), Grade 2 
(moderate), Grade 3 (severe), Grade 4 (life-threatening) or Grade 5 (fatal) to describe the 
maximum intensity of the AE. For purposes of consistency with the CTCAE, these intensity 
grades are defined in the table below. 
Table 2 
Grading of Adverse Event Severity 
Grade  
Adjective  
Description  
Grade 1  
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated  
Grade 2  
Moderate 
Local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL*  
Grade 3  
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**  
Grade 4  
Life-threatening 
Urgent intervention indicated  
Grade 5  
Death 
Death-related AE  
* Activities of Daily Living (ADL) Instrumental ADL refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
** Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
For AEs associated with laboratory abnormalities, the event should be graded on the basis of 
the clinical severity in the context of the underlying conditions; this may or may not be in 
agreement with the grading of the laboratory abnormality. This is upon the investigator’s 
assessment. 
If there is a change in intensity (worsening or improvement) of an AE, it must be recorded. 
9.2.3. Outcome 
Each AE must be rated by choosing among: 
 
Recovered/resolved. 
 
Recovered/resolved with sequelae. 
 
Recovering/resolving. 
 
Not recovered/not resolved. 
 
Fatal. 
 
Unknown. 


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9.3. 
INVESTIGATOR REQUIREMENTS AND INSTRUCTIONS FOR 
REPORTING ADVERSE EVENTS, SERIOUS ADVERSE 
EVENTS, PREGNANCIES, AND OTHER SPECIAL 
SITUATIONS TO THE SPONSOR 
9.3.1. Adverse Events 
The AE reporting period for safety surveillance begins when the subject signs the ICF and ends 
at the subject’s last follow-up visit (the last follow-up visit after the last dose of IMP) as 
described in the Schedule of Activities (see Section 6.11). In this period, all new AEs, regardless 
of cause or relationship, derived by spontaneous, unsolicited reports of subjects, by observation 
and by routine open questioning (such as “How do you feel?”) need to be recorded in the source 
and in the CRF.  
In case an AE is ongoing at the time of the last follow-up visit, the investigator needs to follow 
on the subject until AE resolution or reasonable stabilization and to document in the subject’s 
source documentation. No related updates or additional data on the AE should be reported in 
the CRF.  
If a subject is documented as lost-to-follow-up, ongoing/unknown outcome AEs will not be 
followed up. 
If the AE meets the criteria for seriousness, the SAE form must be completed and sent to the 
sponsor within 24 hours (see Section 9.3.2). 
9.3.2. Serious Adverse Events 
Subjects experiencing an SAE or an emergency situation will be examined by a physician as 
soon as possible. The subject will remain under observation as long as medically indicated. 
Appropriate laboratory tests will be performed until all parameters return to normal or are 
otherwise explained or stable.  
All SAEs, whether or not deemed IMP-related, must be recorded in the CRF and on the SAE 
form. The investigator must report each SAE immediately, and under no circumstances should 
this exceed 24 hours following the knowledge of the SAE, as is indicated on page 2 under 
“Emergency Contact Information”. 
The SAE form should at least contain identifiers of the subject and the reporter, SAE term and 
statement of relatedness to the IMP, and at a later stage if not yet available within 24 hours, the 
form needs to be completed with a clearly written narrative describing signs, symptoms, and 
treatment of the event, diagnostic procedures, as well as any relevant laboratory data and any 
sequelae. 
Follow-up and outcomes should be reported and documented in the source documents for all 
subjects that experience an SAE. It is important that the information provided on the SAE form 
matches the information recorded on the CRF for the same event. 
Copies of additional laboratory tests, consultation reports, postmortem reports, hospital case 
reports, autopsy reports, and other documents should be sent when requested and available. 
Only subject identifiers (subject number) should appear on the copies, and all names and initials 


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should be blackened and rendered illegible. Follow-up reports relative to the subject’s 
subsequent course must be submitted until the event has subsided or, in case of permanent 
impairment, until the condition stabilizes.  
Any SAEs that occur after the post-treatment follow-up visit but within 30 days of the last dose 
of IMP(s), regardless of causality, should also be reported (Emergency Contact Information on 
page 2). Investigators are not obligated to actively seek SAEs after the CSP-defined follow-up 
period. However, if the investigator is informed about an SAE that occurs at any time after the 
subjects’ post-treatment follow-up visit and the event is deemed relevant to the use of IMP(s), 
he/she should promptly document and report the event to the sponsor by using the SAE form. 
9.3.3. Pregnancy 
All initial reports of pregnancy in female subjects and pregnancies in partners of male subjects 
included in the clinical study must be recorded and documented in the source documents and 
on the pregnancy form. The investigator must report each pregnancy immediately, and under 
no circumstances should this exceed 24 hours following the knowledge of the pregnancy, as is 
indicated on page 2 under “Emergency Contact Information”.  
All pregnancies should be followed up until delivery or pregnancy interruption. The 
investigator will contact the subject or partner of the subject after giving consent, at the expected 
time of delivery for follow-up and for information regarding the outcome of the newborn. 
Abnormal pregnancy and/or abnormal newborn outcomes are considered SAEs and must be 
reported using the SAE form. 
9.3.4. Reporting of Special Situations (Other Than Pregnancy) and 
Associated Adverse Events 
In case a special situation is not associated with an AE, the special situation should be reported 
within 24 hours by using the Special Situations form as is indicated on page 2 under 
“Emergency Contact Information”. 
In case a special situation is associated with an AE, the special situation should be reported 
within 24 hours by using the Special Situations form and the associated AE should be reported 
as specified in Section 9.3.1. 
In case a special situation is associated with an SAE, the special situation should be reported 
within 24 hours by using the SAE form (and not the Special Situations form) and the associated 
SAE should be reported as specified in Section 9.3.2. 
9.4. 
SPONSOR REPORTING REQUIREMENTS 
Depending on relevant local legislation or regulations, including the applicable United States 
Federal Drug Administration Code of Federal Regulations, the EU Clinical Trials Directive 
(2001/20/EC) and relevant updates, and other country specific legislation or regulations, the 
sponsor may be required to expedite to worldwide regulatory agencies reports of SAEs, serious 
adverse drug reactions, or suspected unexpected serious adverse reactions (SUSARs). The 
sponsor or a specified designee will notify worldwide regulatory agencies and the relevant 
IEC/IRB in concerned Member States of applicable SUSARs as outlined in current regulations. 


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Assessment of expectedness for SAEs will be determined using reference safety information 
section in the IB or relevant local label as applicable.  
All concerned investigators will receive a safety letter notifying them of relevant SUSAR 
reports associated with any IMP(s). The investigator should notify the IEC/IRB of SUSAR 
reports as soon as is practical, where this is required by local regulatory agencies, and in 
accordance with the local institutional policy. 
10. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This clinical study is conducted in accordance with the current applicable regulations, 
ICH-GCP Guideline E6, EU Directive 2001/20/EC and its updates, and local ethical and legal 
requirements. 
GCP is an international ethical and scientific quality standard for designing, conducting, 
recording and reporting studies that involve the participation of human subjects. Compliance 
with this standard provides public assurance that the rights, safety and well-being of clinical 
study subjects are protected, consistent with the principles that have their origin in the 
Declaration of Helsinki, and that the clinical study data are credible. 
The name and address of each third party vendor (e.g. CRO) used in this study and the sponsor’s 
study team members will be maintained in the investigator’s and sponsor’s files as appropriate. 
10.1. SPONSOR’S RESPONSIBILITIES 
10.1.1. Regulatory Approval / Notification 
Prior to clinical study start, this CSP together with all relevant documentation will be submitted 
to the local regulatory authorities for review and approval and/or notification in compliance 
with local requirements.   
10.1.2. Clinical Study Closure Considerations 
The sponsor reserves the right to close the investigational site or end the clinical study at any 
time for any reason. In case of an early termination of the clinical study or temporary halt by 
the sponsor, the IEC/IRB should be notified within 15 calendar days unless otherwise specified 
by the IEC/IRB, including a detailed written explanation of the reasons for the termination/halt. 
The end of clinical study declaration will be submitted to the regulatory authorities and IEC/IRB 
after the complete clinical study has ended in all participating centers, in all countries. This 
notification will also be submitted within 90 days of the end of the clinical study in a given 
country/member state or within the timelines required by the local regulations. 
Reasons for the closure of an investigational site include but are not limited to: 
 
Successful completion of the clinical study at the center. 
 
The overall required number of subjects for the clinical study has been recruited.  
 
Failure of the investigator to comply with the CSP, ICH-GCP Guidelines or local 
requirements. 
 
Inadequate recruitment of subjects by the investigator. 


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Reasons for early termination of a clinical study by the sponsor may include but are not limited 
to: 
 
Safety concerns. 
 
Sufficient data suggesting lack of efficacy. 
10.1.3. Indemnification 
Under the conditions of a contract concluded between investigator, site, and sponsor or 
designee, which shall prevail, sponsor shall, except in case of gross negligence or willful 
misconduct, indemnify and hold harmless the investigator and his/her medical staff from any 
claim arising from the clinical study activities carried out in compliance with the CSP, sponsor’s 
instructions, and applicable local regulations. 
The investigator must notify the sponsor immediately upon notice of any claims or lawsuits. 
10.1.4. Insurance 
Sponsor shall maintain insurance coverage that is sufficient to cover its obligations and that is 
consistent with human clinical study local regulations. Provided that the subject has been treated 
according to the CSP and sponsor’s instructions, any injury caused to a subject which is the 
direct result of his/her participation to the clinical study shall be covered by sponsor’s insurance, 
except in case of gross negligence or willful misconduct by the investigator. 
10.1.5. Reporting 
Where required by IEC/IRB per local requirements, at least once a year the investigator will 
provide the IEC/IRB with a progress report to allow review of the clinical study (see 
Section 10.4.1). At the end of the clinical study, the results of the clinical study will be reported 
in a clinical study report. A summary or full report, depending on the requirements, will be 
provided to the investigators, to the applicable regulatory authorities and IECs/IRBs if required 
by the applicable regulatory requirements within one year, or 6 months for pediatric studies, 
after the end of the clinical study. 
10.1.6. Publication 
It is understood by the investigator that the sponsor shall be free to use the compound-related 
information which is generated during the clinical study and may disclose it to other clinical 
investigators and to regulatory agencies. As a consequence, the investigator agrees to provide 
all clinical study results and data generated during this clinical study to the sponsor. 
The investigator shall not be authorized to submit the results of this clinical study and any data 
for public disclosure (e.g. publication or presentation) without the prior written approval of the 
sponsor which shall not be unreasonably withheld.  
However, it is understood and agreed by the investigators that their results and/or findings shall 
not be authorized for publication prior to sponsor’s publication of the overall clinical study 
results. The investigator agrees that prior to the publication of any results, he/she shall provide 
the sponsor with a draft copy of the intended publication. Sponsor shall have the right to review 
it and to make any comments. In accordance with generally accepted scientific collaboration 


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principles, co-authorship with any staff member sponsor involved in the clinical study, will be 
discussed and mutually agreed upon before submission of any manuscript to a publisher. 
10.2. INVESTIGATOR’S RESPONSIBILITIES 
10.2.1. Financial Disclosure 
The disclosed financial interest of the investigators must be collected before screening of the 
first subject, following clinical study completion at the investigator site, and 1 year following 
overall clinical study completion. The investigators should promptly update this information if 
any relevant changes occur during this period. Disclosable financial interests will be recorded 
on the Investigator Financial Disclosure Form. 
Any investigator(s) added as investigational staff must complete the Investigator Financial 
Disclosure Form at the beginning of their participation in the clinical study. For any 
investigator(s) leaving the site prior to clinical study completion, an Investigator Financial 
Disclosure Form should be obtained at the end of their contribution to the clinical study. 
10.2.2. Source Data and Data Capture 
The nature and location of all source documents need to be identified and documented to ensure 
that all sources of original data required to complete the CRF are known and are accessible for 
verification by the monitor.  
Source data may be directly captured from devices transferred from third partners 
(e.g. laboratory data) or entered manually into the CRF. The CRF completion guidelines will 
be provided to each investigational site. 
It is recommended that the author of an entry in the source documents should be identifiable. 
Following ICH-GCP Guidelines, direct access to sponsor’s representatives to source documents 
must be granted for the purpose of verifying that the data recorded on the CRF are consistent 
with the original source data. 
10.2.3. Archiving 
The investigator shall maintain the clinical study-specific documents as specified in Section 8 
“Essential Documents for the Conduct of a Clinical Study” of the ICH-GCP Guidelines and as 
required by the applicable regulatory requirement(s). The investigator should take measures to 
prevent accidental or premature destruction of these documents. 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the IMP. These documents should be retained for a 
longer period if required by the applicable regulatory requirements or by an agreement with the 
sponsor. 
Under no circumstance shall the investigator relocate or dispose any clinical study documents 
before having obtained a written approval of the sponsor. 


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If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this clinical study, the investigator must permit access to such reports. 
The subject is granting access to his/her source data by signing the ICF. 
Any difficulty in storing original documents must be discussed with the monitor prior to the 
initiation of the clinical study.  
10.2.4. Participation Cards 
If the subjects are not under 24-hour supervision of the investigator or site staff, they must be 
provided with a subject participation card indicating the name of the IMP, the clinical study 
number, the investigator's name and a 24-hour emergency contact number. The subject should 
be advised to keep the participation card in his/her wallet at all times. 
10.3. CONFIDENTIALITY 
All information concerning the product and the sponsor’s operations (such as patent 
applications, formulae, manufacturing processes, basic scientific data or formulation 
information supplied to the investigator by the sponsor and not previously published) is 
considered confidential and should not be disclosed by the investigator to any third party 
without the sponsor’s prior written approval. The investigator agrees to use this information 
only in accomplishing the clinical study and will not use it for other purposes. 
In order to permit easy identification of the individual subject during and after the clinical study, 
the investigator is responsible for keeping an updated Subject Identification Code List. The 
monitor will review this document for completeness. However, the investigator must guarantee 
the subject’s anonymity will be maintained. Therefore, in order to ensure subject 
confidentiality, the Subject Identification Code List must remain at the center and no copy will 
be made. 
The subject will receive all information as required by the EU General Data Protection 
Regulation and other data privacy regulations, namely the identity and contact details of the 
controller, the contact details of the data protection officer, the clinical research purposes, the 
legal basis for the processing, the recipients of the personal data, the transfer of the personal 
data to third countries and respective safeguards, the retention periods, the fair processing of 
his/her data, and all his/her data subject’s rights. All details are listed in the ICF.  
10.4. ETHICAL CONSIDERATIONS 
10.4.1. Independent Ethics Committee (IEC) / Institutional Review Board 
(IRB) 
This clinical study can only be undertaken after full approval of the CSP, ICF, any other written 
information given to subjects, and subject recruitment materials has been obtained from the 
IEC/IRB. This approval document must be dated and clearly identify the clinical study and the 
related clinical study documents being approved, including the subject compensation programs, 
if applicable. 


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Confidential Information 
 
During the course of the clinical study, at least the following documents will be submitted to 
the IEC/IRB per local requirements: 
 
Changes to the IB. 
 
Reports of AEs that are serious, unlisted and associated with the investigational drug (in 
compliance with IEC/IRB, per local requirements). 
 
CSP amendments. 
 
ICF amendments. 
CSP amendments and applicable ICF amendments must promptly be submitted to the IEC/IRB 
for review and approval prior to implementation of the change(s), except when necessary to 
eliminate an immediate hazard to the clinical study subjects, or according to local requirements. 
The IEC/IRB is responsible for continuous review of the clinical study. Where required by 
IEC/IRB per local requirements, at least once a year the investigator will provide the IEC/IRB 
with a progress report to allow review of the clinical study. Additional progress reports should 
be provided according to local legal requirements. These requests and (re) approvals, if 
applicable, should be documented in writing. 
10.4.2. Informed Consent 
The investigator or designated personnel must explain the clinical study and the implications 
of participation (e.g. objectives, methods, anticipated benefits, and possible risks) to potential 
subjects according to applicable regulations prior to any clinical study-related activity. Subjects 
will be informed that their participation is voluntary and that they may withdraw from the 
clinical study at any time. They will be informed that choosing not to participate or to withdraw 
from the clinical study will not have an impact on the care the subject will receive for the 
treatment of his/her disease.  
The subject will be given sufficient time to read the ICF and to ask additional questions. After 
this explanation and before entry in the clinical study, subject’s consent should be appropriately 
recorded by means of the subject's personally dated signature and by the investigator’s dated 
signature. In case the subject is unable to read and/or write, oral consent in the presence of at 
least one impartial witness, who was also included when the affected person was being 
informed, may be given. The witness may not be anyone working at the trial site nor a member 
of the investigating team. The orally given consent shall be documented in writing, dated and 
signed by the witness.. After having obtained the consent, a copy of the signed and dated ICF 
must be given to the subject.  
If new information becomes available relevant to the subject’s willingness to participate in the 
clinical study, the subject will be informed in a timely manner by means of an amended ICF. 
This amended ICF will be signed and dated by the subject (or, if applicable, by an independent 
witness) and the investigator to document the willingness of the subject to continue with the 
clinical study. 
This signed and dated amended version will be filed together with the initial signed and dated 
ICF. 
A pregnant partner who agrees that information will be gathered about her pregnancy and the 
birth and health of her baby, will sign a specific ICF to participate in the data collection.  


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10.5. DATA QUALITY CONTROL / ASSURANCE 
10.5.1. Monitoring 
This clinical study will be monitored by sponsor representatives according to their current 
Standard Operating Procedures for the monitoring of clinical studies as described in the 
monitoring plan. 
To guarantee adequate protection of the subjects and to guarantee the quality of the data, the 
sponsor will ensure oversight of any clinical study-related duties and functions carried out on 
its behalf, including clinical study-related duties and functions that are subcontracted to another 
party by the sponsor’s contracted CRO(s). 
10.5.2. Audit and Inspection 
To ensure compliance with relevant regulations, an independent quality assurance 
representative, regulatory authorities and/or IECs/IRBs may review this clinical study. This 
implies that auditors/inspectors will have the right to inspect the clinical study center(s) at any 
time during and/or after completion of the clinical study and will have access to the data 
generated during the clinical study, source documents, and subject's files. By participating in 
this clinical study, investigators agree to this requirement. 
 




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Confidential Information 
 
Tanaka, M., Okudaira, S., Kishi, Y., et al. (2006). Autotaxin stabilizes blood vessels and is 
required for embryonic vasculature by producing lysophosphatidic acid. J Biol Chem, 
281(35), 25822-25830.  
Tsuda, S., Okudaira, S., Moriya-Ito, K., et al. (2006). Cyclic phosphatidic acid is produced by 
autotaxin in blood. J Biol Chem, 281(36), 26081-26088. 
Van den Hoogen, F., Khanna, D., Fransen, J., et al. (2013). 2013 classification criteria for 
systemic sclerosis: an American College of Rheumatology/European League against 
Rheumatism collaborative initiative. Arthritis Rheum, 65(11), 2737-2747. 
Woosley, RL., Heise, CW., Romero, KA. (2018). QTdrugs List. Retrieved July 24, 2018, 
from www.CredibleMeds.org.  
 
 


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APPENDICES 
 
APPENDIX 1: KNOWN CYP2C8 SUBSTRATES 
Excluded medication: 
Amiodarone 
Buprenorphine 
Amiodaquine; Chloroquine 
Repaglinide 
Rosiglitazone, pioglitazone 
Verapamil 
Zopiclone 
This list is intended as a guidance for the investigator. 
 
 


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APPENDIX 2: KNOWN STRONG CYP3A4 INDUCERS AND 
POTENT P-GP INDUCERS 
Excluded medication: 
Barbiturates  
Carbamazepine 
Glucocorticoids: steady dose of  prednisone or equivalent >10 mg/day 
Modafinil 
Oxcarbazepine 
Phenobarbital 
Phenytoin 
Pioglitazone 
Rifabutin 
Rifampin 
Bosentan 
St. John’s Wort 
This list is intended as a guidance for the investigator. 
 
 


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APPENDIX 3: KNOWN STRONG CYP3A4 INHIBITORS 
Excluded medication: 
Clarithromycin 
Itraconazole 
Ketoconazole 
Nefazodone 
Suboxone® 
Telithromycin 
This list is intended as a guidance for the investigator. 
 
 


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APPENDIX 4: KNOWN POTENT P-GP INHIBITORS 
Excluded medication: 
Amiodarone 
Azelastine 
Azithromycin – Clarithromycin – Erythromycin – Roxithromycin – Telithromycin 
(unless used under the condition described in Section 4.5.3.2) 
Cyclosporine 
Itraconazole - Ketoconazole 
Tamoxifen 
Verapamil 
This list is intended as a guidance for the investigator. 
 
 


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APPENDIX 5: MEDICATION KNOWN TO PROLONG QT 
INTERVAL 
This is based on the CredibleMeds list of medication known to prolong QT interval/cause 
Torsade de Pointes (Woosley RL. et al., 2018).  
Medication to be used with caution: 
Disopyramide 
Dofetilide 
Flecainide 
Ibutilide 
Quinidine 
Sotalol 
Hydroxychloroquine 
This list is intended as a guidance for the investigator. 
 
 


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SIGNATURE PAGE – SPONSOR 
 
Study Title: 
A Phase 2a randomized, double-blind, placebo-controlled, multi-center study 
to evaluate the efficacy, safety, and tolerability of orally administered 
GLPG1690 for 24 weeks in subjects with systemic sclerosis 
CSP Version: 
5.00 
Date: 
28-Apr-2020 
 
This clinical study protocol has been reviewed and approved by the sponsor to ensure 
compliance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidelines for Good Clinical Practices (GCP) and 
applicable regulatory requirements. 
 
An electronic signature for the sponsor is provided at the end of the document. 
 
 MD 
  
  
Study Physician 
 Signature 
 Date 
 
 
 


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SIGNATURE PAGE – INVESTIGATOR 
 
Study Title: 
A Phase 2a randomized, double-blind, placebo-controlled, multi-center study 
to evaluate the efficacy, safety, and tolerability of orally administered 
GLPG1690 for 24 weeks in subjects with systemic sclerosis 
CSP Version: 
5.00 
Date: 
28-Apr-2020 
 
I, the undersigned, have read this clinical study protocol and will conduct the study as described 
in compliance with the clinical study protocol, in accordance with International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
guidelines for Good Clinical Practices (GCP) and applicable regulatory requirements. 
 
 
 
  
  
Investigator Name 
 Signature 
 Date 
 
 


Signature Page for glpg1690-cl-204-protocol 11151
Signature Page for glpg1690-cl-204-protocol 11151
Approval
al Director Phase I
Translational Medicine
28-Apr-2020 14:26:27 GMT+0000

SAP_001.pdf: 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document is privileged and confidential. It is the property of Galapagos 
NV or Galapagos SASU and may not be used, disclosed, reproduced or otherwise disseminated within your 
organization or communicated to any third parties without the express written authorization of Galapagos 
NV or Galapagos SASU. 
 
 
STATISTICAL ANALYSIS PLAN 
 
Project Number: 
GLPG1690 
 
Study Number: 
GLPG1690-CL-204 
Study Title: 
A Phase 2a randomized, double-blind, placebo-controlled, multi-
center study to evaluate the efficacy, safety, and tolerability of 
orally administered GLPG1690 for 24 weeks in subjects with 
systemic sclerosis 
 
Development Phase: 
IIa 
Status: 
Final 
Version: 
1.00 
Date: 5-Aug-2020 
EudraCT: 
2018-001817-33 
IND: 
140691 
Sponsor: 
Galapagos NV, Generaal De 
Wittelaan 
L11 
A3, 
2800 
Mechelen, Belgium 
 
Biostatistician: 
 
GLPG Biostatistician: 
 
Medical Lead: 
 
  




Statistical Analysis Plan GLPG1690-CL-204 
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5.2. 
Subject Information .................................................................................................. 21 
5.2.1. 
Demographic and Baseline Disease Characteristics ................................... 21 
5.2.2. 
Disposition Information .............................................................................. 22 
5.2.3. 
Protocol Deviations and Eligibility ............................................................. 22 
5.2.4. 
Inclusion and Exclusion Criteria ................................................................. 23 
5.2.5. 
Medical History and Concomitant Diseases ............................................... 23 
5.2.6. 
Prior and Concomitant Medications ........................................................... 23 
5.2.6.1. 
Coding of Reported Terms ....................................................... 23 
5.2.6.2. 
Classification of Medications ................................................... 23 
5.2.6.3. 
Calculation of Relative Days ................................................... 24 
5.2.6.4. 
Presentation of Results ............................................................. 24 
5.2.7. 
Prior and Concomitant Non-Drug Therapies .............................................. 24 
5.2.7.1. 
Coding of Reported Terms ....................................................... 24 
5.2.7.2. 
Classification of Non-Drug Therapies ..................................... 24 
5.2.7.3. 
Calculation of Relative Days ................................................... 24 
5.2.7.4. 
Presentation of Results ............................................................. 24 
5.2.8. 
Exposure to IMP and Compliance .............................................................. 25 
5.2.8.1. 
Derivation Rules....................................................................... 25 
5.2.8.2. 
Presentation of Results ............................................................. 25 
5.3. 
Efficacy Analyses ..................................................................................................... 25 
5.3.1. 
Level of Significance .................................................................................. 26 
5.3.2. 
Primary Efficacy Parameter ........................................................................ 26 
5.3.2.1. 
Definition ................................................................................. 26 
5.3.2.2. 
Derivation Rules....................................................................... 26 
5.3.2.3. 
Analysis Methods ..................................................................... 26 
5.3.3. 
Sensitivity of Primary Endpoint .................................................................. 27 
5.3.3.1. 
Derived mRSS .......................................................................... 27 
5.3.4. 
Other Efficacy Parameters .......................................................................... 27 
5.3.3.1.1. 
Definition ................................................................ 27 
5.3.3.1.2. 
Derivation Rules ..................................................... 27 
5.3.3.1.3. 
Analysis Methods .................................................... 27 






Statistical Analysis Plan GLPG1690-CL-204 
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VERSION HISTORY 
SAP Amendment # 
Date 
Description of changes 
 
 
 
 
 
 
 










Statistical Analysis Plan GLPG1690-CL-204 
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2.3. 
STUDY DESIGN 
This is a randomized, double-blind, parallel-group, placebo-controlled, multi-center, Phase 2a 
study designed to evaluate the efficacy, safety, and tolerability of a 600 mg once daily (q.d.) 
dose of orally administered GLPG1690 over 24 weeks in approximately 30 adult subjects with 
a confirmed diagnosis of systemic sclerosis.  
At Day 1/Visit 2 (baseline), subjects will be randomized in a 2:1 ratio to GLPG1690 600 mg 
q.d. taken as three film-coated tablets of 200 mg, or matching placebo q.d. administered for 24 
weeks in addition to background treatment as defined in the protocol. 
The subjects will visit the clinical study center at screening/Visit 1 (Day -28 to Day -1), Day 
1/Visit 2 (baseline), Day 15 (Week 2/Visit 3), Day 29 (Week 4/Visit 4), Day 57 (Week 8/Visit 
5), Day 113 (Week 16/Visit 7), Day 169 (Week 24/Visit 9), and, if applicable, the early 
discontinuation (ED) visit. At Weeks 12 (Visit 6) and 20 (Visit 8), a phone call will be made to 
assess safety. In addition, a follow-up visit will be planned 4 weeks after the last administration 
of IMP (Day 197 [Week 28]) (i.e. Follow-up Visit 1) and a second follow-up visit will be 
planned 12 weeks after the last administration of IMP (Day 253 [Week 36]) (i.e. Follow-up 
Visit 2). Additional unscheduled visits are allowed for any safety assessments if clinically 
indicated (see protocol Section 6.2). The end of the study (EoS) is reached when the last visit 
of the subject is performed. The assessments performed at each visit are detailed in the Schedule 
of Activities (see Appendix 1). 
A schematic diagram of the clinical study design, procedures, and stages is provided in Figure 
1 (section 2.5). 
Each subject will be in the study for up to approximately 40 weeks (up to 4 weeks of screening, 
24 weeks of treatment, and 12 weeks of follow-up). 
Open-label Extension 
Subjects who completed the Week 24 visit will be offered treatment with GLPG1690 in an 
optional open-label extension (OLE), provided regulatory and Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB) approvals for such an extension is granted. In this case, 
the follow-up visits as scheduled in protocol GLPG1690-CL-204, will not be performed for 
these subjects.  
The analysis methods of the OLE study is not presented in this SAP and will be described in a 
separate SAP.  


Statistical Analysis Plan GLPG1690-CL-204 
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2.4. 
CSP AND CSP AMENDMENTS 
Protocol Versions 
Date (ddMMMyyyy) 
Version 1 
31JUL2018 
Version 2 
20AUG2018 
Amendment 1: Version 3  
13NOV2018 
Amendment 2: Version 4 
31JUL2019 
Amendment 3: Version 5 
28APR2020 
 
 
Protocol Amendments 
Date (ddMMMyyyy) 
 Country Specific Amendment 
12MAR2019 
This SAP was based on the latest version of the protocol that was available at the time of its 
finalization. 
2.5. 
FLOW CHART 
A schematic diagram of the clinical study design, procedures, and stages is provided in Figure 
1. 
Figure 1: Schematic Study Overview 
 
D=Day, FU=Follow-up, V=Visit, W=Week. 
* This will be a phone call to assess safety (no clinical study center visit).  
2.6. 
SAMPLE SIZE JUSTIFICATION 
Sample size was based on empirical considerations. The number of subjects (30) included in 
this study should give reasonable precision around the estimates derived for the efficacy 
evaluation. 
The primary endpoint of the study is the change from baseline in mRSS over 24 weeks. 
Considering 20 and 10 subjects in the GLPG1690 and placebo arm, respectively, and a common 
standard deviation (SD) of 5 on the change from baseline in mRSS, the Minimal Clinically 
Important Difference (MCID) of 4.7, and taking into account a 10% dropout, the probability to 
observe a treatment effect of more than 4 points is 63%. 


Statistical Analysis Plan GLPG1690-CL-204 
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2.7. 
RANDOMIZATION AND BLINDING 
Randomization 
This is a randomized, double-blind clinical study. At screening, subjects will be assigned a 
subject identification. When a subject is confirmed to be eligible for the clinical study, the 
subject will be randomized. Allocation of each subject to a given treatment will be done using 
a centralized electronic system (interactive web response system [IWRS]). Subjects will be 
randomized in a 2:1 ratio to receive GLPG1690 600 mg q.d. or matching placebo, respectively. 
For each subject at each clinical study center visit, the clinical study center will contact the 
IWRS for the appropriate treatment number to be assigned. The medication kit(s) will contain 
the relevant IMP for the period until the next clinical study center visit. 
Subjects and the entire clinical study team, including the investigators, clinical study 
coordinators, 
 and sponsor personnel are blinded to treatment assignment.  
Blinding and Unblinding 
Blinded and packaged medication will be provided to the clinical center.  
The blind can be broken by the investigator via IWRS only if the investigator deems it necessary 
for the safety of a subject. Further details are included in section 4.6.2 of the protocol. 
Code-break information (via IWRS vendor/randomization list) will be provided to the 
bioanalytical laboratory responsible for plasma drug determination sample analysis, and to the 
sponsor pharmacovigilance lead for SAE reporting purposes. 
Biostatistics team will be unblinded at the time of the primary analysis which is scheduled when 
all patients completed the Week 24 visit and data is locked for the primary analysis. Only study 
team members included in the analyses and reporting activities will become unblinded at the 
time of the primary analysis in case it is different from the CL-204 study full analysis with 
regards to timing.  
3. 
GENERAL METHODOLOGY 
3.1. 
ANALYSIS SETS 
The analysis sets used in the statistical analyses are detailed in the following subsections. The 
analysis set will always be indicated in a subtitle in the TLF. 
3.1.1. All Screened Analysis Set 
All subjects who signed and dated an informed consent form (ICF) and underwent screening 
assessments to check whether or not they are eligible to participate in the clinical study. 
3.1.2. All Randomized Analysis Set 
All enrolled subjects who were randomized into the clinical study. Subjects will be analyzed 
according to the treatment arm to which they were randomized.   




Statistical A nal ysis Pla n  G L P G 1 6 9 0 -C L -2 0 4  
P a ge 1 5 /5 6  
 
 
 
 
 
 
 
 
3. 2.  
R A N D O MI Z E D V E R S U S A C T U A L T R E A T M E N T G R O U P  
F or all s u bject data , t he treat me nt gr o u p as assi g n e d b y t h e ra n d o mizati o n will be use d i n t he 
a nal ysis (i. e., as -ra n d o mi ze d a nal ysis). 
Differe nces b e t wee n t he ra n d o mize d a n d act ual tr eat m e nt gr o u p will be e x plai ne d i n t he C S R . 
3. 3.  
A N A L Y SI S P E RI O D S A N D  A N A L Y SI S TI M E P OI N T S  
3. 3. 1.  Rel ati ve D a y  
T he ti mi n g of a n assess m e nt or a n e ve nt relati ve  t o a refere n ce dat e will be calc ulate d as f oll o ws: 
𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝑑𝑎𝑦 (𝐷𝑌) 
= 𝑐𝑜𝑛𝑐𝑒𝑟𝑛𝑒𝑑 𝑑𝑎𝑡𝑒−𝑟𝑒𝑓𝑒𝑟𝑒𝑛𝑐𝑒 𝑑𝑎𝑡𝑒 + 1  𝑑𝑎𝑦,  w h e n c o nc er n e d  d at e   ≥  r ef er e nc e  d at e  
= 𝑐𝑜𝑛𝑐𝑒𝑟𝑛𝑒𝑑 𝑑𝑎𝑡𝑒−𝑟𝑒𝑓𝑒𝑟𝑒𝑛𝑐𝑒 𝑑𝑎𝑡𝑒, w h e n t h e c o nc er n e d  d at e <r ef er e nc e  d at e   
- 
T he refere n ce d ate is t he date of t he first I M P i nta ke, u nless s pecifie d ot h er wise. 
- 
T he c o ncer ne d d ate  c o ul d be t he meas ure me nt d at e of t he assess me nt, or t h e start o r e n d 
date of t he e v e nt.  
- 
D ate  i m plies a c o m plete date. If t he date is (partiall y) missi n g, t he relati ve da y will be 
missi n g.   
E x ce pti o n: if t he e n d date of a n e ve nt is f ull y missi n g at data bas e l oc k (i n case of a n i nteri m 
a nal ysis) or at t he s u bj ect’s st u d y ter mi nati o n, t he e ve nt will be c o nsi dere d as o n g oi n g. T h e e n d 
date will be i m p ute d b y t he data base c ut off date or t he date o f last visit f or cases w here s u bject 
ter mi nate d st u d y. I n listi n g, t he d urati o n will be pri nte d as “ > X da ys”. 
3. 3. 2.  D ur ati o n  
T he d urati o n of a n assess me nt or a n e ve nt will be calc ulate d as f oll o ws:  
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 (𝑑𝑎𝑦𝑠) = 𝑒𝑛𝑑 𝑑𝑎𝑡𝑒−𝑠𝑡𝑎𝑟𝑡 𝑑𝑎𝑡𝑒+ 1  𝑑𝑎𝑦 
- 
D ate  i m plies a c o m plete date. If t he date is (partiall y) missi n g, t he d urati o n  will be 
missi n g.   
E x ce pti o n: if t he e n d date of a n e ve nt is f ull y missi n g at data bas e l oc k (i n case of a n i nteri m 
a nal ysis) or at t he s u bj ect’s st u d y ter mi nati o n, t he e ve nt will be c o nsi dere d as o n g oi n g. T h e e n d 
date will be i m p ute d b y t he data base c ut off date or t he date of last visit f or cases w here s u bject 
ter mi nate d st u d y. I n listi n g, t he d urati o n will be pri nte d as “ > X da ys”. 
3. 3. 3.  A n al ysis P eri o ds  
All e ve nt -t y pe d ata (e. g., A Es ) a n d assess me nts will be all ocate d t o a nal ysis peri o ds acc or di n g 
t o Ta ble 1 . 


Statistical Analysis Plan GLPG1690-CL-204 
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Table 1: Analysis Periods 
Analysis Period 
Start Analysis Period 
End Analysis Period 
Screening 
Date of signing the ICF. 
Date of first IMP intake - 1 day 
Treatment 
Date of first IMP administration.  
For subjects not entering CL-206 
study: date of last intake of IMP + 
30 days. 
 
For subjects who entered the CL-
206 study: the date of last intake of 
IMP + 30 days or the date of first 
OLE 
IMP 
administration 
(excluded), whichever comes first. 
Post-Treatment 
End date of the treatment period + 
1 day. 
Date of last contact in CL-204 
study. For subjects who entered the 
CL-206 study this will be the date 
of first OLE IMP administration. 
ICF: informed consent form 
The last analysis period will always end on the date of last contact, collected on the Study 
Completion/Discontinuation of Study eCRF page, whichever is earliest. 
3.3.4. Analysis Windows 
All assessments including data collected on unscheduled visits, will be allocated to analysis 
visits (time windows) based on the relative day of the assessment (see section 3.3.1) and 
according to the algorithm in Table 2. TFLs will present the analysis visits when analysis is 
derived.  
Table 2: Analysis Windows  
Analysis 
Visit 
label 
Target Day 
Interval Lower Bound 
Interval Upper Bound 
Vital signs, Clinical Laboratory tests 
Baseline* 
1 
-INF 
1 
Week 2 
15 
2 
22 
Week 4 
29 
23 
43 
Week 8 
57 
44 
85 
Week 16 
113 
86 
141 
Week 24 
169 
142 
197 
Week 28 
198 
198 
+INF 
12-Lead ECG 
Baseline* 
1 
-INF 
1 
Day 1 
1 
1 
2 
Week 2 
15 
3 
64 
Week 16 
113 
65 
141 
Week 24 
169 
142 
197 
Week 28  
198 
198 
+INF 
mRSS 
Baseline* 
1 
-INF 
1 
Week 4 
29 
2 
43 
Week 8 
57 
44 
85 
Week 16 
113 
86 
141 
Week 24 
169 
142 
197 
Week 28  
198 
198 
+INF 




Statistical Analysis Plan GLPG1690-CL-204 
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IMP administration. If no triplicate (or duplicate) results are available before the first dose, the 
last value before first study drug administration will be used.  
Selection of Visits 
Per parameter, analysis visit and timepoint, the value closest to the target date will be used in 
analysis tables and figures. Other values will be listed only. If more than one value is located at 
the same distance from the target day, then the latest in time will be selected. If there are two 
values on the same day and no time indicating which one is last, the average of the two will be 
calculated. 
3.4. 
HANDLING OF DATA 
3.4.1. Handling of Missing Data 
3.4.1.1. 
Handling of Missing Date Time Data 
Generally no imputations will be done in case of missing date (time) fields, nor for the missing 
parts of partially known date (time) fields apart from partially missing initial diagnosis dates. 
When the date of initial diagnosis is partially missing, the following rules will be used in order 
to determine the duration of disease: 
• If the day of initial diagnosis is missing, then 01 will be assigned to the missing 
fields. 
• If the month of initial diagnosis is missing, then January will be assigned to the 
missing fields. 
• If date of initial diagnosis is completely missing, no imputation will be done. 
Assessments with completely missing date (time) will be omitted from the analysis.  
Event-type data (e.g. adverse events, concomitant medications) with missing date (time) will 
be allocated to analysis periods using a worst-case approach as explained in the respective 
sections. 
3.4.1.2. 
 Handling of Missing Result Data 
No imputation will be done of missing results unless specified otherwise in corresponding 
sections (i.e. observed cases (OC) analysis). 
3.4.2. Handling of Values Below or Above a Threshold 
Values below (above) the quantification limit will be imputed by the value one unit smaller 
(larger) than the quantification limit itself. In listings, the original value will be presented. 
Example: if the database contains the value “<0.04”, then for the descriptive statistics the value 
“0.03” will be used. The value “>1000” will be imputed by “1001”. 






Statistical A nal ysis Pla n  G L P G 1 6 9 0 -C L -2 0 4  
P a ge 2 1 /5 6  
 
 
 
 
 
 
 
 
 
5. 2.  
 S U B J E C T I N F O R M A TI O N  
S u bject i nf or mati o n will be ta b ulate d usi n g t he  F A S  u nless ot her wise s pecifie d . N o i nfere ntial 
testi n g will be perf or me d, n or will p -val ues  be pr o vi de d.   
S u bject i nf or mati o n will be ta b ulate d wit h des cri pti ve statistics per treat me nt gr o u p a n d o verall.  
5. 2. 1.  De m o gr a p hic a n d B aseli ne D ise ase C h ar acteristics  
T he f oll o wi n g p ara m eters will be s u m marize d:  
- 
Ge n der : Mal e; Fe m ale 
- 
A ge at si g ni n g t he I C F ( years)  
- 
A ge , cat e g ori ze d ( years): a ge ≤ 4 5 ; a ge >  4 5  
- 
Et h nicit y: N ot Re p orte d; His pa nic or Lati n o; N o n His pa nic or Lati n o; U n k n o w n  
- 
R ace: A merica n I n di a n or Alas kan  Nati ve; Asia n; Blac k or Africa n A meri ca n; Nati ve 
Ha waiia n or O t her Pacific Isla n der; a n d W hite 
- 
Is t he S u bject of J a pa nes e A ncestr y?: Yes; N o 
- 
Baseli ne H ei g ht (c m)  
- 
Baseli ne W ei g ht ( k g)  
- 
B o d y M ass In d e x B MI  ( k g/ m²)  
 
A ge, hei g ht,  wei g ht , a n d B MI will be s u m marize d usi n g d escri pti ve statistics.  T he n u m b er 
a n d perce nt a ge of s u bject s b y a ge cat e g or y, ge n der , et h nicit y, a n d race will als o be 
re p orte d.  
 
A s u m mar y of b aseli ne i nf or mati o n will be prese nte d a n d s u m marize t he f oll o wi n g 
para meters : 
- 
D urati o n of diseas e ( years) = 
(
 
 
 
 
)–  (
 
 
 
)
 
.
.  
- 
D urati o n of diseas e , cat e g orize d ( years): d urati o n  < 2 ; d urati o n  ≥ 2  
- 
Baseli ne  t otal m R S S sc ores 
S u bjects w it h/ wit h o ut l u n g diseas e at bas eli ne: prese nce of l u n g disease at baseli ne is defi ne d 
base d o n Scler o d er ma Cli nical Trials C o ns orti u m ( S C T C) criteria i de ntifie d base d o n me dical 
hist or y data. S u bjects wit h l u n g diseas e at baseli ne will be defi ne d as s u bjects wit h a n y 
me dical hist or y preferre d  ter m of ‘I nterstitial l u n g disease’ or ‘ S yste mic s cler osis p ul m o nar y’ 


Statistical Analysis Plan GLPG1690-CL-204 
Page 22/56 
 
 
 
 
 
 
 
 
that were active at baseline (i.e. start date is prior to first dose of study medication and end 
date is after first dose of study medication or ongoing). All other baseline efficacy and safety 
parameters will be presented together with post-baseline results by timepoint tables. 
For more details on the imputation of date of initial diagnosis, refer to section 3.4.1.1. 
5.2.2. Disposition Information 
The following tabulations will be provided: 
- 
The number of subjects screened, randomized and not-randomized, with the reason for 
not being randomized. For all subjects screened only. 
- 
Number (percent) of all randomized subjects per country and investigator by treatment 
and overall. 
- 
The number of subjects in screened analysis set and number (percent) of subjects in 
each analysis set (randomized, FAS, PP, 
 and safety sets), on the 
“All randomized Analysis Set” as defined in section 3.1 by treatment and overall. 
- 
The number (percent) of subjects per analysis window for mRSS as defined in section 
3.3.4 by treatment and overall. 
- 
The number (percent) of subjects who completed/discontinued the study treatment and 
the reasons for discontinuation by treatment and overall. 
- 
The number (percent) of subjects who completed the study, subjects who completed the 
treatment period and entered the OLE study, subjects who completed the treatment 
period and entered Follow-up phase (i.e. did not entered the OLE study), subjects who 
completed Follow-up phase and subjects who discontinued the study and the reasons 
for discontinuation. 
5.2.3.  Protocol Deviations and Eligibility 
Major protocol deviations are determined and recorded while the study is ongoing, and the list 
is finalized prior to unblinding for the Primary Analysis (although any possible protocol 
deviations collected between data cut for Primary Analysis and database lock for Final Analysis 
will continue to be reviewed). For more details, please refer to the Protocol Deviations Plan. 
The number (percent) of subjects with major protocol deviations will be tabulated, overall and 
per class of deviation, by treatment group and overall.  
All available information concerning major protocol deviations, deviations on eligibility criteria 
and subjects not treated will be listed. Protocol deviations leading to exclusion from any 
analysis set (see section 3.1.5) will be flagged. 


Statistical Analysis Plan GLPG1690-CL-204 
Page 23/56 
 
 
 
 
 
 
 
 
5.2.4. Inclusion and Exclusion Criteria 
All inclusion and exclusion criteria that subjects did not fulfil will be listed in detail on the All 
Screened Analysis Set. 
5.2.5. Medical History and Concomitant Diseases 
Medical history will be coded using the latest version of the medical dictionary for regulatory 
activities (MedDRA) as per the data validation manual (DVM). The number and percentage of 
subjects with any medical history will be summarized overall and for each predefined system 
organ class (SOC) and preferred term (PT). Frequency tabulations per SOC and PT will be 
provided for the medical history findings: (i.e., any event with a stop date prior to first IMP 
intake) as well as for the concomitant diseases (i.e., ongoing conditions or conditions with a 
stop date on or after first IMP intake). 
5.2.6. Prior and Concomitant Medications 
A prior medication is defined as any medication that is taken prior to the first dose of IMP. A 
concomitant medication is defined as any medication that has a stop date that is on or after the 
date of first dose of IMP or is ongoing. Medications that started prior to the first dose of IMP 
and have stop date on or after the first dose of IMP or is ongoing are defined as both prior and 
concomitant medications. 
5.2.6.1. 
Coding of Reported Terms 
All medications used within 12 weeks prior to and during the screening period will be collected 
on the electronic case report form (eCRF). All medications will be coded according to the latest 
World Health Organization Drug Dictionary (WHO-DD). 
5.2.6.2. 
Classification of Medications 
All prior and concomitant medication records will be categorized as follows, considering their 
date and flags indicating the relative timing versus study (IMP) start or end (before, after, 
ongoing…): 
- 
Prior only: when the record ended before first IMP administration date. 
- 
Concomitant only: when the record started on or after the first IMP administration date. 
- 
Prior and concomitant: when the record started before the date of first IMP 
administration, and ended on or after this point, or continued, or if end date is missing. 
When the start or end date of the prior and concomitant medication records are incomplete (and 
no flags indicating relative timing are available), the date of first IMP administration will be 
considered to the same level of information provided by these incomplete dates to categorize 
the timing of these records. This means that a record only having month and year will be 
categorized comparing only to the month and year of the date of first IMP administration. Worst 
case scenario will be used to categorize concomitant medications: if the same level of 
information provided by incomplete concomitant medication start date is identical first IMP 
administration, then the medication will be considered as both prior and concomitant, given end 


Statistical Analysis Plan GLPG1690-CL-204 
Page 24/56 
 
 
 
 
 
 
 
 
date is not prior to first IMP administration. If the same level of information provided by 
incomplete concomitant medication end date is identical first IMP administration, then the 
medication will be considered as both prior and concomitant, given start date is not after to first 
IMP administration. 
5.2.6.3. 
Calculation of Relative Days 
For both the start and the end dates of the concomitant medication records, their day relative to 
the day of first IMP administration will be calculated as described in section 3.3.1. 
5.2.6.4. 
Presentation of Results 
A frequency tabulation of the anatomical therapeutic chemical (ATC) classes Level 4 by 
therapeutic subgroup (ATC Level 2) and anatomical main group (ATC Level 1) of the prior 
medications (defined as ‘prior only’ and ‘prior and concomitant’) will be provided as well as 
of the concomitant medications (defined as ‘concomitant only’ and ‘prior and concomitant’).  
All medications will be listed in detail. 
5.2.7. Prior and Concomitant Non-Drug Therapies 
5.2.7.1. 
Coding of Reported Terms 
All non-drug therapies used within 12 weeks prior to and during the screening period will be 
collected on the electronic case report form (eCRF). All non-drug therapies will be coded 
according to the latest MedDRA Dictionary. 
A prior non-drug therapy is defined as any non-drug therapy that is taken prior to the first dose 
of IMP. A concomitant non-drug therapy is defined as any non-drug therapy that has a stop date 
that is on or after the date of first dose of IMP or is ongoing.  
5.2.7.2. 
Classification of Non-Drug Therapies 
All prior and concomitant non-drug therapy records will be categorized as specified in section 
5.2.6.2. 
5.2.7.3. 
Calculation of Relative Days 
For both the start and the end dates of the concomitant non-drug therapy records, their day 
relative to the day of first IMP administration will be calculated as described in section 3.3.1. 
5.2.7.4. 
Presentation of Results 
A frequency tabulation of the SOC and PT term of non-drug therapies of the prior therapies 
(defined as ‘prior only’ and ‘prior and concomitant’) will be provided. Similarly, a separate 
table will be provided for concomitant therapies (defined as ‘concomitant only’ and ‘prior and 
concomitant’). 
All non-drug therapies will be listed in detail. 


Statistical A nal ysis Pla n  G L P G 1 6 9 0 -C L -2 0 4  
P a ge 2 5 /5 6  
 
 
 
 
 
 
 
 
5. 2. 8.  E x p os ure t o  I M P a n d C o m pli a nce  
5. 2. 8. 1.  
Deri v ati o n R ules  
Deri ve d P ar a meters: E xte nt of E x p os ure t o  I M P 
- 
T ot al tre at me nt d ur ati o n ( d ays)  = l ast I M P a d mi nistrati o n date –  first I M P 
a d mi nistrati o n date + 1 d a y.  
- 
T ot al tre at me nt d ur ati o n, excl u di n g d a ys off st u dy I M P: N u m ber of da ys wit h a n y I M P 
a d mi nist rati o n.  
- 
T ot al  tre at me nt d ur ati o n, f ully c o m pli a nt ( d ays): 
N u m ber of da ys 
wit h I M P 
a d mi nistrati o n, as pla n ne d per C S P.  
Deri ve d P ar a meters: C o m pli a nce  
- 
Over all c o m pli a nce ( %)  = 1 0 0 x 
 
 
 
 
 
 
 
 
 
 
 
 
N u m ber of  ta blets t hat s h o ul d ha ve bee n us e d will be calc ul ate d as:  
T otal treat me nt d urati o n  * 3  
- 
Perce nt a ge d a ys wit h a n y i nt ake ( %) = 1 0 0 x 
 
 
,
 
 
 
 
 
 
- 
Perce nt a ge d a ys f ully c o m pli a n t ( %) = 1 0 0 x 
 
 
,
 
 
 
 
N u m ber of ta blets act uall y use d will be base d o n t he e x p os ure rec or ds  c ollecte d i n t he data base.  
5. 2. 8. 2.  
Prese nt ati o n of Res ults  
S u m mar y statistics will be pr o vi de d f or eac h c o m plia nce a n d e xte nt of e x p os ure para m eter  o n 
t he Safet y Set. 
Fre q u e nc y ta bl es will be pr o vi de d f or t he c o m plia nce para meters, usi n g t he f oll o wi n g 
cate g ories : < 8 0 %; 8 0 % ≤ x < 1 0 0 %; 1 0 0 %; 1 0 0 % < x ≤ 1 2 0 %; > 1 2 0 % . Perce nta ges will b e 
calc ulate d o ut of t h e n u m ber of s u bjects w h o were d ose d.  
5. 3.  
E F FI C A C Y A N A L Y S E S  
Efficac y a n al ys es will be perf or m e d o n t he F A S . T o i n vesti gate t he i m pact of n o n-c o m plia nce 
a n d pr ot oc ol vi olat ors , a Per-Pr ot oc ol a nal ysis will als o be perf or me d f or t h e pri mar y e n d p oi nt, 
if m ore t ha n 1 0% of t he s u bjects ha ve at least o ne  maj or  pr ot oc ol de viati o n lea di n g t o e x cl usi o n 
t o t he P P  A nal ysis Set . 
Ta b ulati o ns will be s h o w n per treat me nt gr o u p.  


Statistical Analysis Plan GLPG1690-CL-204 
Page 26/56 
 
 
 
 
 
 
 
 
5.3.1. Level of Significance 
All statistical tests will be 2-sided and performed at the 5% significance level, thereby providing 
95% (2-sided) CIs. However, given the exploratory nature of this proof-of-concept study, the 
success of the study will be based on the evaluation of all analysis results, including safety 
profile and descriptive analysis of all efficacy endpoints. 
5.3.2. Primary Efficacy Parameter 
5.3.2.1. 
Definition 
The primary endpoint of the study is the change from baseline in mRSS over 24 weeks. This is 
collected at the time points specified in the Schedule of Activities (see Appendix 1).  
For individual subjects, clinically meaningful changes in skin score (MCID) are 4.7 skin score 
units and/or at least 20% change in overall mRSS. Only decreases from baseline will be deemed 
clinically meaningful changes in skin score. 
5.3.2.2. 
Derivation Rules 
Total mRSS score will be analyzed as reported by the investigator, considering that all 
individual scores are completed, no imputation will be done on the primary efficacy endpoint. 
5.3.2.3. 
Analysis Methods 
The following analyses will be done on the FAS as the primary analysis, and repeated on the 
PP Analysis Set, if more than 10% of the subjects have at least one major protocol deviation, 
to confirm the results of the primary analysis: 
The mRSS and change from baseline in mRSS score (primary endpoint) will be summarized 
by descriptive statistics. Mean (±SE) plots over time (analysis visits based on time window) for 
both treatment groups, and similar mean (±SE) plots for the change from baseline will be 
presented. Additionally, spaghetti plot of change from baseline will be displayed with subjects 
presented by treatment.  
Change from baseline in mRSS will be analyzed using a mixed-effects model for repeated 
measures (MMRM). The model will include treatment and visit as fixed effects, baseline mRSS 
and country as covariates, and treatment-visit as interaction terms. Subject will be included in 
the model as a random effect. The likelihood-based MMRM will be performed using a SAS 
PROC MIXED procedure (see Appendix 3), and the Kenward-Roger method for degrees of 
freedom will be applied. The restricted maximum likelihood (REML) method will be used for 
estimation. The Least Square (LS) means along with the associated SE and 95% CIs, as well as 
the difference in LS means and associated 95% CIs will be displayed at each time point. For 
exploratory purpose only, p-values will also be displayed for testing the difference in LS means 
at each timepoint. The p-value derived for the overall difference between treatment groups will 
also be displayed, as well as all p-values for fixed effects included in the model. 
The variance-covariance matrix will be assumed to be unstructured. If the procedure does not 
converge then a compound symmetric variance-covariance matrix will be used instead.    
















Statistical Analysis Plan GLPG1690-CL-204 
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5.4.1. Adverse Events 
All adverse events (AEs) and changes in attributes (worsening and improvement) of AEs are 
reported in the database. An identification number serves to link the records considered by the 
investigator as describing the evolution of one and the same event. 
5.4.1.1. 
Definition of Treatment-Emergent Adverse Events 
The analysis of adverse events will be based on treatment-emergent events (TEAE). TEAEs are 
defined as  
- 
For subjects not entering the OLE study: AEs having a start date equal or after the date 
of the first IMP administration and up to the last dose date + 30 days.  
- 
For subjects who entered the OLE study: AEs having a start date equal or after the date 
of the first IMP administration and up to the date of last double-blinded  
IMP dose date + 30 days or the date of first OLE IMP administration (excluded), 
whichever comes first. 
- 
And is either a newly reported event, or a worsening* of an existing event. 
Improvements are not considered treatment-emergent. 
*Worsening is defined as worsening in at least one of the following attributes: seriousness, 
severity, relationship and/or action taken. 
5.4.1.2. 
Coding of Reported Terms 
All AE terms will be coded in the database using the MedDRA version 21.0 or higher coding 
dictionary. 
All tables in this section will show the AE terms coded into PT grouped into body SOC. Subject 
listings will also show the reported terms. Any other coding levels will only be shown in a 
listing summarizing coding or if explicitly mentioned.   
5.4.1.3. 
Allocation of Adverse Events to Analysis Periods 
All AEs records will be placed into analysis periods considering their start date, aiming to report 
the incidence of these events only in the analysis period during which they started. 
The general rule for allocation of AEs to analysis periods follows: 
Analysis period start date ≤ AE start date ≤ analysis period end date  
If the start date of an AE is missing or incomplete to a level preventing a clear allocation of the 
AE to one single analysis period and no flag indicating timing relative to study medication is 
available, a worst-case consideration (see below) will be done aiming to allocate the AE to one 
single analysis period, if possible. When a worst-case consideration is needed, the end date of 
the AE, if and as available, should also be considered; if such AEs clearly end on a given point, 
this will exclude the possibility to allocate the AE to an analysis period after that point. 


Statistical Analysis Plan GLPG1690-CL-204 
Page 35/56 
 
 
 
 
 
 
 
 
- 
An AE which according to the available information of its start date could belong to the 
screening as well as to the treatment period will only be placed in the treatment period. 
- 
An AE which according to the available information of its start date could belong to 
treatment period as well as to follow-up period will only be placed in the treatment 
period. 
- 
An AE with a missing start date will be allocated to treatment period. 
- 
If an AE can be allocated to both double-blind and open-label (i.e. CL-206 study) 
treatment period based on the above rules, then the event will be reported for CL-204 
double-blind treatment period during CL-204 study analyses.  
5.4.1.4. 
Treatment Relatedness 
Following ICH-E3 (ICH), the originally reported relatedness to IMP of an AE will be 
dichotomized as follows: 
- 
Not IMP related: all non-missing weaker levels of relatedness than ‘possibly IMP 
related’.  
- 
IMP related: ‘possibly IMP related’ and all stronger levels of relatedness (this class also 
includes any missing IMP relatedness, as a worst-case consideration). 
Only this dichotomized relatedness will be used in tables. Relatedness as originally reported 
will only be listed.  
5.4.1.5. 
Presentation of Adverse Events and of Event Episodes 
All AEs tables will only show TEAEs and will show counts of the number of subjects with 
TEAEs. The number of event episodes will be shown only in tables where explicitly mentioned. 
AEs starting before first IMP administration or later than 30 days after the last dose of IMP but 
before first OLE IMP administration (not TEAEs) will only be listed. AEs reported on or after 
the date of first OLE IMP administration will be included in the CSR produced after CL-206 
study has been completed.  
AEs leading to death will be presented in a separate listing.  
5.4.1.6. 
Worst-Case Selections 
When cross-tabulating AE preferred terms versus an AE attribute (like severity), only the worst-
case within each same preferred term, same subject and same analysis period will be considered, 
i.e., when a same subject has more than once the same AE preferred term reported in the same 
treatment group, the subject will be counted only once and will be shown under the worst 
outcome (like the worst severity for that AE in the concerned treatment period). 


Statistical Analysis Plan GLPG1690-CL-204 
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5.4.1.7. 
Calculation of Relative Days and Duration 
For each AE record, its start day in study (the day of the AE start date relative to the date of 
first IMP administration), its start day in the analysis period, and its duration (in days) will be 
calculated and shown only in listings.  
See sections 3.3.1 and 3.3.2 for the calculation of relative days and duration respectively. 
5.4.1.8. 
Presentation of Results 
A summary table will be provided, showing then number (percentage) of subjects with: 
- 
at least one TEAE, 
- 
at least one IMP-related TEAE,  
- 
any serious TEAE,  
- 
any TEAE leading to death,  
- 
any TEAEs by worst severity,  
- 
TEAE leading to IMP discontinuation. 
Frequency tabulations, by SOC and PT, of the number (percent) of subjects with a TEAE will 
be presented by treatment group. Similar tables will be provided for the following groups: 
Severity (‘Grade 1 -  Mild’, ‘Grade 2 – Moderate’, ‘Grade 3 – Severe’, ‘Grade 4 – Life 
Threatening’, and ‘Grade 5 – Death’) 
- 
Related TEAEs 
  
- 
Related TEAEs by severity 
- 
Serious TEAEs. 
Serious adverse events, AEs leading to death, AEs leading to IMP and trial discontinuation will 
be listed.  
5.4.1.9. 
EudraCT Adverse Events Reporting 
For the purpose of EudraCT reporting, the following tabulations will be added: 
Frequency tabulations, by SOC and PT, of the number (percent) of subjects with non-serious 
TEAE will be presented. A similar table will be provided for the all serious TEAEs (counting 
events), as well as a table for non-serious TEAEs reported in at least 5% of the subjects in any 
treatment group. 




Statistical Analysis Plan GLPG1690-CL-204 
Page 38/56 
 
 
 
 
 
 
 
 
Urinalysis tests will be presented as part of the descriptive statistics tables.  
Results of serology testing, pregnancy test, and FSH will only be listed. 
5.4.3.2. 
Derivation Rules 
Fasted and Non-Fasted Results 
Laboratory parameters that are sensitive to the fasting status: glucose, triglycerides. 
These parameters will be tabulated with descriptive statistics by fasting/non-fasting and toxicity 
grade. Laboratory results for which the fasting status is missing, will be considered as taken 
non-fasted. 
5.4.3.3. 
Definition of Toxicity Grades 
Toxicity grades will only be derived for laboratory tests for which toxicity gradings are 
available. 
For the analysis values of the following continuous laboratory parameters, toxicity grades will 
be determined as implemented in the next table (Common Terminology Criteria for Adverse 
Events (CTCAE), v5.0: November 27, 2017). Analysis results scoring below the lowest grade 
limits are defined to correspond to grade 0. 
Table 4: Laboratory Toxicity Grades 
Parameter 
Direction 
of 
abnormal 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Alanine amino 
transferase 
high 
>ULN-3 x ULN 
>3 x ULN -5 x 
ULN 
>5 x ULN - 8 x 
ULN 
>8 x ULN  
Albumin (g/L) 
low 
<LLN-30 
<30-20 
<20 
- 
Alkaline 
phosphatase 
high 
>ULN-2.5 x 
ULN 
>2.5 x ULN -5 x 
ULN 
>5 x ULN -20 x 
ULN 
>20 x ULN  
Aspartate amino 
transferase 
high 
>ULN-3 x ULN 
>3 x ULN -5 x 
ULN 
>5 x ULN -8 x 
ULN 
>8 x ULN  
Bilirubin [total] 
high 
>ULN-1.5 x 
ULN 
>1.5 x ULN -3 x 
ULN 
>3 x ULN -10 x 
ULN 
>10 x ULN  
Calcium, below 
(mmol/L) 
low 
<LLN-2.0 
<2.0-1.75 
<1.75-1.5 
<1.5 
Calcium, above 
(mmol/L) 
high 
>ULN-2.9 
>2.9-3.1 
>3.1-3.4 
>3.4 
Cholesterol 
(mmol/L) 
high 
>ULN-7.75 
>7.75-10.34 
>10.34-12.92 
>12.92 
Creatine kinase 
high 
>ULN-2.5 x ULN 
>2.5 x ULN -5 x 
ULN 
>5 x ULN -10 x 
ULN 
>10 x ULN 
Creatinine 
high 
>ULN-1.5 x ULN 
>1.5 x ULN -3 x 
ULN or 
>1.5 x baseline -3 
x baseline 
>3 x ULN -6 x 
ULN or >3 x 
baseline 
>6 x ULN 
eGFR/  
Creatinine 
clearance 
low 
<LLN-60 
<60-30 
<30-15 
<15 


Statistical Analysis Plan GLPG1690-CL-204 
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Parameter 
Direction 
of 
abnormal 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
(mL/min/1.73 
m2) 
Eosinophils 
absolute count 
high 
>ULN 
- 
- 
- 
Eosinophils 
relative count 
(%) 
high 
>7 
- 
- 
- 
Gamma-
glutamyl 
transferase 
high 
>ULN-2.5 x 
ULN 
>2.5 x ULN -5 x 
ULN 
>5 x ULN -20 x 
ULN 
>20 x ULN 
Glucose 
[fasting], below 
(mmol/L)  
low 
<LLN-3.0 
<3.0-2.2 
<2.2-1.7 
<1.7 
Hemoglobin, 
below (g/L) 
low 
<LLN-100 
<100-80 
<80 
- 
Hemoglobin, 
above (g/L) 
high 
Increase >0-20 
Increase >20-40 
Increase >40 
- 
Lymphocytes, 
below (10^9/L) 
low 
<LLN-0.8 
<0.8-0.5 
<0.5-0.2 
<0.2 
Lymphocytes, 
above (10^9/L) 
high 
- 
>4.0-20.0 
>20.0 
- 
Neutrophils, 
below (10^9/L) 
low 
<LLN-1.5 
<1.5-1.0 
<1.0-0.5 
<0.5 
Potassium, 
below (mmol/L) 
low 
<LLN-3.0 
- 
<3.0-2.5 
<2.5 
Potassium, 
above (mmol/L) 
high 
>ULN-5.5 
>5.5-6.0 
>6.0-7.0 
>7.0 
Sodium, below 
(mmol/L) 
low 
<LLN-130 
<130-125 
<125-120 
<120 
Sodium, above 
(mmol/L) 
high 
>ULN-150 
>150-155 
>155-160 
>160 
Triglycerides 
fasting and non-
fasting (mmol/L)  high 
>1.71-3.42 
>3.42-5.7 
>5.7-11.4 
>11.4 
Partial 
thromboplastin 
time [activated 
or not specified]  
high 
>ULN-1.5 x ULN 
>1.5 x ULN -2.5 
x ULN 
>2.5 x ULN 
- 
International 
normalized ratio 
high 
>1.2 x ULN -1.5 x 
ULN 
>1.5 x ULN -2.5 
x ULN 
>2.5 x ULN 
- 
Platelets 
(10^9/L) 
low 
<LLN-75 
<75-50 
<50-25 
<25 
White blood 
cells, below 
(10^9/L) 
low 
<LLN-3 
<3-2 
<2-1 
<1 
White blood 
cells, above 
(10^9/L) 
high 
- 
- 
>100 
- 
Legend: 
[Specifications].  
(Specific unit into which the defined grades apply). 
Baseline value is defined as abnormal if the value is not within the normal range. For directional toxicity of high an abnormal baseline 
will be a baseline value which is higher than the upper limit of the reference range. For directional toxicity of low, an abnormal baseline 
will be a baseline value which is lower than the lower limit of the reference range. 
x LLN / x ULN = times the lower / times the upper limit of the normal range. 
Below / above = differentiate grade definitions in the low / high sense for a same parameter.  


Statistical Analysis Plan GLPG1690-CL-204 
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The following parameters will be analyzed and categorized based on pre-defined criterion 
without using the above defined grading system: 
- Prothrombin time: >ULN-1.5 x ULN; >1.5 x ULN - 2.5 x ULN; >2.5 x ULN 
- Glucose [fasting] (mmol/L): >7.2 
- High density lipoprotein (mmol/L): <1.554 
- Low density lipoprotein (mmol/L): >4.144 
The analysis of these parameters will be performed in the same way as the analysis of the 
parameters with standard toxicity grade. 
5.4.3.4. 
Definition of Non-Graded Abnormalities 
Non-graded abnormalities will be determined only for the parameters having no definitions of 
toxicity grades (see section 5.3.3.3). 
For laboratory tests provided by the laboratory, the position of the actual analysis values versus 
their normal ranges will be determined directly by using the position indicator provided in the 
database as reported, expressing the classes for these analysis values as low (L), normal (N) or 
high (H). L, N and H are further referred to as non-graded abnormalities. 
5.4.3.5. 
Urinalysis Tests with Categorical Results  
Results of urinalysis with qualitative results will be tabulated by time point. No toxicity grading 
or non-graded abnormalities will be derived.  
5.4.3.6. 
Treatment Emergent Principle  
Toxicity Grades 
A post-baseline toxicity grade 1, 2, 3 or 4 is defined as treatment-emergent when higher than 
the toxicity grade of the baseline result. If the baseline result is missing, a post-baseline toxicity 
grade 1, 2, 3 or 4 will always be considered as treatment-emergent. 
For prothrombin time parameter a post-baseline value meeting the defined abnormality criteria 
is regarded as treatment-emergent if the post-baseline criteria meet a higher degree of 
abnormality than the baseline value (e.g. post-baseline value meeting >1.5-2.5 x ULN category 
while baseline meeting >ULN-1.5 x ULN category) or the baseline value is missing or does not 
meet any abnormality criteria. For glucose [fasting], high density lipoprotein and low density 
lipoprotein a post-baseline abnormal category will be regarded as treatment emergent, if the 
baseline value is missing or does not meet the defined abnormality criteria. 
Non-graded Abnormalities 
A post-baseline non-graded abnormality class L or H is defined as treatment-emergent when it 
differs from the abnormality class of the baseline result. If the baseline result is missing, a post-
baseline abnormality L or H will always be considered as treatment-emergent. 


Statistical Analysis Plan GLPG1690-CL-204 
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5.4.3.7. 
Worst-Case 
Toxicity Grading 
The worst-case post-baseline toxicity grade 0, 1, 2, 3 or 4 will be determined per subject, per 
parameter (and sense, if below and above) during the on-treatment analysis period, using all 
non-missing post-baseline records within that period (including unscheduled and follow-up 
visits). 
The worst-case toxicity grade is the highest toxicity grade scored for the parameter (in each 
sense, if below and above).  
Non-graded Abnormalities 
The following worst-case post-baseline abnormalities L, N or H will be determined per subject, 
per parameter and for the on-treatment analysis period, using all non-missing post-baseline 
records within that period (including unscheduled and follow-up visits): 
- 
L = low: at least one post-baseline result is classified as L. 
- 
N = normal: all post-baseline results are classified as N.  
- 
H = high: at least one post-baseline result is classified as H. 
If, for a subject, both L and H are reported, the subject will be counted twice in the table: once 
with a worst-case L and once with a worst-case H. 




Statistical Analysis Plan GLPG1690-CL-204 
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A frequency table of the number (percentage) of subjects with treatment-emergent worst-case 
abnormalities per parameter and treatment group for the on-treatment analysis period will be 
presented. The results of non-graded abnormalities and toxicities grades will be shown 
separately. 
Urinalysis tests for which no normal range is available will be tabulated separately as 
categorical data. 
Clinical laboratory values will also be listed including normal ranges and indicating if value is 
out of range. Separate listings will also be created to include all laboratory values of a subject 
who has had at least one value meeting CTCAE grading 3 or higher category. 
5.4.4. Electrocardiogram 
5.4.4.1. 
Available Data 
All subjects will have a standard 12-lead electrocardiogram (ECG) performed at the time points 
specified in the Schedule of Activities (see Appendix 1). The following ECG parameters will 
be analyzed: heart rate (bpm), PR interval, QRS interval, uncorrected QT interval (ms), 
morphology, QT interval corrected for the heart rate using Fridericia’s formula (QTcF) (ms). 
5.4.4.2. 
Derivation Rules 
Derived Parameters 
The ECG parameters will be provided in the clinical database, no imputation will be done. 
Handling of ECGs Measured in Triplicate 
If ECG is collected in triplicates (or duplicates), the following approach will be taken.  
The mean of the triplicate (or duplicate) ECG values will be calculated for each individual ECG 
parameter, without rounding the result. These calculated means will constitute the analysis 
values; any derivation (e.g. change from baseline, assignment of abnormalities) and statistic 
will be based on the mean value of the triplicates (or duplicates). 
When a single ECG is performed, the actual results of the single ECG will be summarized. 
The values of the individual triplicate (or duplicate) assessments will be listed, i.e. will not be 
summarized or graphically presented. 
 
 


Statistical Analysis Plan GLPG1690-CL-204 
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5.4.4.3. 
Abnormalities 
The actual analysis values and changes from baseline of the QT and QTcF parameters will be 
categorized into the abnormality classes as defined in ICH E14: 
Table 6: Abnormalities on ECG Parameters 
Parameter 
Abnormality 
Limits 
Abnormalities on actual values 
QT and QTcF (ms) 
QT* ≤ 450 
450 < QT* ≤ 480 
480 < QT* ≤ 500 
QT* > 500 
≤ 450 
450 < value ≤ 480 
480 < value ≤ 500 
> 500 
Abnormalities on change from Baseline 
QT and QTcF (ms) 
QT* change ≤ 30 
≤ 30 
 
30 < QT* change ≤ 60 
30 < value ≤ 60 
 
QT* change > 60 
> 60 
* Indicate which QT(c) parameter is analyzed in the label 
Worst-Case Abnormality 
The worst-case post-baseline categorized actual analysis value and the worst-case categorized 
change from baseline for QT and QTcF will be determined per subject, per parameter, using all 
non-missing post-baseline records (including unscheduled and follow-up visits) for the on-
treatment analysis period. 
The worst-case categorized actual analysis value is the category corresponding to the highest 
post-baseline actual value. 
The worst-case change from baseline is the category corresponding to the largest increase 
(positive change) from baseline. 
For the overall interpretation the worst-case post-baseline will be determined per subject, per 
parameter, and for on-treatment analysis period, using all non-missing post-baseline records 
(including unscheduled and follow-up visits) as follow: 
- 
Normal: if all the post-baseline results are normal 
- 
Abnormal: if at least one post-baseline result is abnormal. 
Treatment Emergent Abnormalities 
Actual value: An abnormal post-baseline abnormality is defined as treatment-emergent when 
the abnormality is worse compared to the abnormality at baseline. If the baseline result is 
missing, a post-baseline result outside of the normal range will always be considered as 
treatment-emergent. 
An abnormal category for change from baseline is always treatment-emergent. 


Statistical Analysis Plan GLPG1690-CL-204 
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5.4.4.4. 
Presentation of Results 
No formal inferential statistics (p-values) will be presented. 
Continuous parameters will be summarized by means of descriptive statistics (including 95% 
CI of the mean change from t-test) by parameter, treatment group and analysis visit. Actual 
values and changes from baseline will be tabulated separately.  
All ECG abnormalities after the first dose of study medication up to 30 days after the last dose, 
if the subject did not enroll in the OLE study, or the earliest between the last IMP intake + 30 
days during the double-blind study and the first dose of IMP in the OLE study (excluded), if 
the subject continues in OLE, will be included. 
Abnormalities of the actual values will be presented as shift tables of the worst-case abnormality 
versus the baseline abnormality. The table will be created per parameter, treatment group for 
the on-treatment analysis period. 
A frequency table of the number (percentage) of subjects with treatment-emergent worst-case 
abnormalities per parameter, treatment group for the on-treatment analysis period will be 
presented. Overall interpretation as assessed by the investigator will also be summarized. 
5.4.5. Vital Signs 
5.4.5.1. 
Available Data 
The following vital signs parameters will be analyzed: Systolic Blood Pressure (SBP) (mmHg), 
Diastolic Blood Pressure (DBP) (mmHg), heart rate (bpm), respiratory rate (breaths/minute), 
and body temperature (ᵒC). Vital signs will be analyzed regardless of assessment position. If 
there are more values available for a subject taken by different positions for a visit, then 
selection rules for the analyses will be applied as described in Section 3.3.4. No adjustment to 
the temperature will be made to account for the possible different method of collection. 
5.4.5.2. 
Abnormalities 
The relevant vital sign values at each visit will be classified based on the reference ranges found 
in Table 7 below.  
Table 7: Normal Ranges for Vital Signs 
Systolic blood 
pressure 
(mmHg) 
Diastolic blood 
pressure 
(mmHg) 
Heart rate 
(bpm) 
Tympanic 
temperature (°C) 
Respiratory rate 
(breaths per 
min) 
90≤ SBP ≤140 
45≤ DBP ≤90 
50≤ HR ≤100 
35.5≤ t° ≤37.5 
12≤ RR ≤20 


Statistical Analysis Plan GLPG1690-CL-204 
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5.4.5.3. 
Treatment Emergent Principle 
A post-baseline abnormality class L or H is defined as treatment-emergent when it differs from 
the abnormality class at baseline. If the baseline result is missing, a post-baseline abnormality 
L or H will always be considered as treatment-emergent. 
5.4.5.4. 
Worst-Case Abnormality 
The following worst-case post-baseline abnormalities low, below the lower limit of the normal 
range (L), normal, with the limits of the normal range (N) or high, above the upper limit of the 
normal range (H) will be determined per subject, per parameter and for the on-treatment 
analysis period, using all non-missing post-baseline records (including unscheduled and follow-
up visits):   
- 
L = low: at least one post-baseline result is classified as L. 
- 
N = normal: all post-baseline results are classified as N.  
- 
H = high: at least one post-baseline result is classified as H. 
If, for a subject, both L and H are reported, the subject will be counted twice in the table: once 
with a worst-case L and once with a worst-case H. 
5.4.5.5. 
Presentation of Results 
No formal inferential statistics (p-values) will be derived. 
Continuous parameters will be summarized by means of descriptive statistics (including 95% 
CI of the mean change from a t-test) for all vital sign parameters and analysis visits, by treatment 
group and overall for subjects in the applicable Safety Set. Actual values and changes from 
baseline will be tabulated separately.  
All abnormalities after the first dose of study medication up to 30 days after the last dose, if the 
subject did not enroll in the OLE study, or the earliest between the last IMP intake + 30 days 
during the double-blind study and the first dose of IMP in the OLE study (excluded), if the 
subject continues in OLE, will be included. 
Abnormalities of the actual values will be presented as shift tables of the worst-case abnormality 
versus the baseline abnormality. The table will be created per parameter and treatment group 
for the on-treatment analysis period. 
A frequency table of the number (percentage) of subjects with treatment-emergent worst-case 
abnormalities per parameter, treatment group for the on-treatment analysis period will be 
presented. 
Mean (± SE) plots over time for both treatment groups, with heart rate, respiratory rate, and 
blood pressure by position on a new page, will be displayed. 










Statistical Analysis Plan GLPG1690-CL-204 
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Statistical Analysis Plan GLPG1690-CL-204 
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APPENDIX 1 
EVENT 
SCREENING 
TREATMENT PERIOD 
FOLLOW-UPj 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
EDa 
FU1 
FU2 
Study Day (D) or Week (W)b ± days (d) 
D-28 to D-1 
D1 
W2 
±2d 
W4 
±2d 
W8 
±4d 
W12c 
±4d 
W16 
±4d 
W20c 
±4d 
W24i 
±4d 
 
W28 
±7d 
W36  
±7d 
Informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history/concurrent illnesses 
 
 
 
 
 
 
 
 
 
 
 
 
FSH test 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
Phone call 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testd 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECGe 
 
 
 
 
 
 
 
 
 
 
 
 
Serology 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests 
 
 
 
 
 
 
 
 
 
 
 
 
mRSS 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan GLPG1690-CL-204 
Page 53/56 
 
 
 
 
 
 
 
 
EVENT 
SCREENING 
TREATMENT PERIOD 
FOLLOW-UPj 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
EDa 
FU1 
FU2 
Study Day (D) or Week (W)b ± days (d) 
D-28 to D-1 
D1 
W2 
±2d 
W4 
±2d 
W8 
±4d 
W12c 
±4d 
W16 
±4d 
W20c 
±4d 
W24i 
±4d 
 
W28 
±7d 
W36  
±7d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
() 
() 
 
 
 
 
 
 
 
 
 
 
 
() 
() 
Dispense subject diary 
 
 
 
 
 
 
 
 
 
 
 
 
Collect subject diary 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense IMP 
 
 
 
 
 
 
 
 
 
 
 
 
Review IMP compliance 
 
 
 
 
 
 
 
 
 
 
 
 






Statistical Analysis Plan GLPG1690-CL-204 
Page 56/56 
 
 
 
 
 
 
 
 
 
APPENDIX 3 
The below SAS code represents the analysis model used for the primary efficacy variable 
analysis.  
The variance-covariance matrix will be assumed to be unstructured. If the procedure does not 
converge then a compound symmetric variance-covariance matrix will be used instead 
.