Clinical trial NCT04577794
Conditions: Ulcerative Colitis
Keywords: Colitis Ulcer Moderately active ulcerative colitis Chronic inflammatory bowel disease Inflammatory Bowel Diseases Digestive System Diseases
Sponsor: Galapagos NV
Start date: 2020-10-05; Completion date: 2021-05-31
Enrollment: 31 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study was to evaluate the effect of GLPG3970 compared to placebo on the signs and symptoms of Ulcerative Colitis (UC) in participants with moderately to severely active UC.

Detailed description:

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

Protocol documents:
Prot_000.pdf: 
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Confidentiality Statement 
The information contained in this document is privileged and confidential. It is the property of Galapagos NV and 
may not be used, disclosed, reproduced or otherwise disseminated within your organization or communicated to any 
third parties without the express written authorization of Galapagos NV. 
 
CLINICAL STUDY PROTOCOL 
Project Number: 
GLPG3970 
 
 
Study Number: 
GLPG3970-CL-210 
 
 
Study Title 
A randomized, double-blind, placebo-controlled, multicenter study to evaluate 
the safety, tolerability, efficacy, and pharmacokinetics of GLPG3970, 
administered orally for 6 weeks in adult subjects with moderately to severely 
active ulcerative colitis 
Short Study Title 
A study evaluating the effects of GLPG3970 given as an oral treatment for 6 
weeks in adults with ulcerative colitis 
Clinical Study 
Phase: 
2 
Protocol Version: 
1.0 
 
 
Date: 
2-Jul-2020 
 
 
Status 
Final 
 
 
EudraCT No: 
2020-000659-11 
CT.gov No: 
to be confirmed 
IND No: 
not applicable 
Sponsor: 
Galapagos NV, Generaal De Wittelaan L11 A3, 2800 Mechelen, Belgium 
Medical Leader: 
 
General Protocol 
 




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TABLE OF CONTENTS 
EMERGENCY CONTACT INFORMATION ........................................................................... 2 
TABLE OF CONTENTS ........................................................................................................ 3 
SUMMARY OF CHANGES ................................................................................................... 8 
LIST OF TABLES .................................................................................................................. 9 
LIST OF FIGURES ...............................................................................................................10 
LIST OF APPENDICES ........................................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................12 
1. 
CLINICAL STUDY PROTOCOL SYNOPSIS .................................................................19 
2. 
INTRODUCTION ...........................................................................................................24 
2.1. 
Background - Non-clinical Studies .....................................................................24 
2.1.1. 
Nonclinical Pharmacokinetics .............................................................24 
2.1.2. 
Safety pharmacology ..........................................................................25 
2.1.3. 
General toxicology ..............................................................................25 
2.1.4. 
Genotoxicity ........................................................................................25 
2.1.5. 
Embryo-fetal Development Toxicity .....................................................25 
2.1.6. 
Phototoxicity .......................................................................................26 
2.2. 
Background - Clinical Studies ............................................................................26 
3. 
CLINICAL STUDY OBJECTIVES ..................................................................................27 
3.1. 
Primary Objective...............................................................................................27 
3.2. 
Secondary Objective ..........................................................................................27 
3.3. 
Other Objective ..................................................................................................27 
4. 
ENDPOINTS .................................................................................................................27 
4.1. 
Primary Endpoint ...............................................................................................27 
4.2. 
Secondary Endpoints .........................................................................................27 
4.3. 
Other Endpoints .................................................................................................27 
5. 
INVESTIGATIONAL PLAN ............................................................................................28 
5.1. 
Clinical Study Design .........................................................................................28 
5.2. 
Start and End of Study Definitions .....................................................................29 
5.3. 
Clinical Study Design Rationale .........................................................................29 
5.4. 
Dosing Rationale ...............................................................................................30 
5.5. 
Potential Risks and Benefits ..............................................................................30 
6. 
CLINICAL STUDY POPULATION .................................................................................32 
6.1. 
Inclusion Criteria ................................................................................................32 
6.2. 
Exclusion Criteria ...............................................................................................34 
6.3. 
Prohibition and Restrictions ...............................................................................36 






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11.2.3. 
Assessment of Severity ......................................................................72 
11.2.4. 
Outcome .............................................................................................73 
11.3. 
Instructions for Reporting Adverse Events, Serious Adverse Events, 
Pregnancies, and Other Special Situations ........................................................73 
11.3.1. 
Adverse Events ...................................................................................73 
11.3.2. 
Serious Adverse Events ......................................................................73 
11.3.3. 
Pregnancy ..........................................................................................74 
11.3.4. 
Reporting of Special Situations (Other Than Pregnancy) With or 
Without Associated Adverse Events ...................................................75 
11.4. 
Sponsor Reporting Requirements ......................................................................75 
12. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES .........................................75 
12.1. 
Sponsor’s Responsibilities .................................................................................76 
12.1.1. 
Regulatory Authority Approval ............................................................76 
12.1.2. 
Clinical Study Closure Considerations ................................................76 
12.1.3. 
Indemnification ....................................................................................76 
12.1.4. 
Insurance ............................................................................................77 
12.1.5. 
Archiving .............................................................................................77 
12.2. 
Reporting ...........................................................................................................77 
12.3. 
Publication .........................................................................................................77 
12.4. 
Investigator’s Responsibilities ............................................................................78 
12.4.1. 
Source Data and Data Capture ...........................................................78 
12.4.2. 
Archiving .............................................................................................78 
12.4.3. 
Participation Cards ..............................................................................78 
12.5. 
Confidentiality ....................................................................................................78 
12.6. 
Ethical Considerations .......................................................................................79 
12.6.1. 
Independent Ethics Committee / Institutional Review Board ...............79 
12.6.2. 
Informed Consent ...............................................................................80 
12.7. 
Data Quality Control/Assurance .........................................................................81 
12.7.1. 
Monitoring ...........................................................................................81 
12.7.2. 
Audit and Inspection ...........................................................................81 
13. REFERENCES ..............................................................................................................82 
14. APPENDICES ...............................................................................................................85 
SIGNATURE PAGE – SPONSOR ...................................................................................... 112 
SIGNATURE PAGE – INVESTIGATOR ............................................................................. 113 


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


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


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LIST OF TABLES 
Table 1: Grading of AE Severity ...........................................................................................72 
 
 


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LIST OF FIGURES 
Figure 1: 
Schematic Diagram ..........................................................................................29 
 
 


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LIST OF APPENDICES 
Appendix 1: Prednisolone Conversion Table ........................................................................86 
Appendix 2: Vaccinations .....................................................................................................87 
 
 
 
 
 
 
Appendix 9: Algorithm for Elevated Liver Function Tests .....................................................91 
Appendix 10: Mayo Scoring System and 
93 
 
 
 
 
 
  


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase 
5-ASA 
5-aminosalicylate 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
BCRP 
breast cancer resistance protein 
BMI 
body mass index 
CI 
confidence interval 
Cl 
clearance 
ClCr 
creatinine clearance 
Cmax 
maximum observed plasma concentration 
CRF 
case report form 
CRO 
contract research organization 
CRP 
C-reactive protein 
CSP 
clinical study protocol 
CTCAE 
Common Terminology Criteria for Adverse Events 
Cthrough 
plasma trough concentration 
CYP 
cytochrome P450 
DTP 
Direct to Patient 
 
 
 
 
ECG 
electrocardiogram 


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ED 
early discontinuation 
ES 
endoscopy subscore 
ESP 
European Society of Pathology 
EU 
European Union 
F 
absolute oral bioavailability 
FIH 
first-in-human 
FSH 
follicle stimulating hormone 
GALT 
gut-associated lymphoid tissue 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
HbA1c 
glycosylated hemoglobin 
HBsAg 
hepatitis B virus surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
hERG 
human ether-a-go-go related gene 
HIV 
human immunodeficiency virus 
IB 
investigator’s brochure 
IBD 
inflammatory bowel disease 
 
 
 
  
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 


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IL 
interleukin 
IP 
investigational product 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
Institutional Review Board 
ISF 
investigator site file 
IXRS 
interactive voice/web response system 
JAK 
Janus kinase 
LFT 
liver function test 
LPS 
lipopolysaccharide 
LRV 
lower reference value 
MCS 
Mayo Clinic Score 
MMRM 
Mixed Models for Repeated Measure 
NAG 
N-acetyl-β-D-glucosaminidase 
NOAEL 
no-observed-adverse-effect level 
OATP 
organic anion transporter 
OCT 
organic cation transporter 
PBMC 
peripheral blood mononuclear cells 
 
 
PGA 
physician’s global assessment 
P-gp 
permeability-glycoprotein 
PK 
pharmacokinetic(s) 
q.d. 
once daily 
QMP 
Quality Management Plan 


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RB 
rectal bleeding 
 
 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SF 
stool frequency 
SI 
international system of units 
SIK 
salt-inducible kinase 
SoC 
standard-of-care 
spp 
species 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
half-life 
TB 
tuberculosis 
TEAE 
treatment-emergent adverse event 
Th 
helper T cell 
TMF 
Trial Master File 
TNF 
tumor necrosis factor alpha 
Treg 
regulatory T cell 
TV 
target value 
UC 
ulcerative colitis 
 
 
ULN 
upper limit of normal range 
 
 
Vss 
volume of distribution at steady state 
WBC 
white blood cell 


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WOCBP 
women of childbearing potential 
 
 




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QTcF 
QT interval corrected for heart rate using Fridericia’s formula: 
QTcF = QT/RR1/3 QT  
RR = the interval from the onset of one QRS complex to the onset 
of the next QRS complex 
QTv 
QT interval corrected by heart rate using the van de Water formula 


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1. 
CLINICAL STUDY PROTOCOL SYNOPSIS 
Title of Study 
A randomized, double-blind, placebo-controlled, multicenter study to evaluate the safety, 
tolerability, efficacy, and pharmacokinetics of GLPG3970 administered orally for 6 weeks, in 
adult subjects with moderately to severely active ulcerative colitis 
Short Title of Study 
A study evaluating the effects of GLPG3970 given as an oral treatment for 6 weeks in adults 
with ulcerative colitis 
Phase of Development: 2 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary  
 
To evaluate the effect of GLPG3970 compared to 
placebo on the signs and symptoms of ulcerative 
colitis (UC) in subjects with moderately to severely 
active UC. 
Change from baseline in total Mayo Clinic Score 
(MCS) at Week 6. 
Secondary 
 
To evaluate the safety and tolerability of 
GLPG3970 compared to placebo in subjects with 
moderately to severely active UC. 
Number, incidence, and severity of treatment-
emergent adverse events (TEAEs). 
To characterize the pharmacokinetics (PK) of 
GLPG3970 in subjects with moderately to severely 
active UC. 
Observed GLPG3970 plasma trough concentrations 
(Ctrough). 
 


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Planned Number of Subjects  
The study is planned to randomize 30 subjects in a 2:1 ration (20 subjects planned to receive 
GLPG3970 and 10 subjects planned to receive placebo). 
Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, multi-center parallel-group 
study evaluating GLPG3970 in adult subjects with moderately to severely active UC. In this 
study, subjects will receive 1 dose level of GLPG3970 (400 mg once daily [q.d.]). 
A schematic diagram of clinical study design, procedures and stages is provided below. 
Study Duration 
The subjects will be in the study for a duration of 13 weeks (screening to follow-up): up to 5 
weeks of screening, 6 weeks of treatment, and 2 weeks of follow-up. 


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Main Criteria for Inclusion and Exclusion 
 
Main Inclusion Criteria 
1. Subject must be able and willing to comply with the clinical study protocol (CSP) 
requirements and must sign and date the informed consent form (ICF) as approved by the 
Independent Ethics Committee (IEC) / Institutional Review Board (IRB), prior to any 
screening evaluations. 
2. Subjects must be ≥18 and <65 years of age, on the date of signing the ICF. 
3. Documented diagnosis of UC of ≥3 months. The criteria for documentation of UC diagnosis 
based on endoscopy will be medical record documentation, and/or a colonoscopy report 
dated ≥3 months before screening, which shows features consistent with UC. 
4. Treatment-experienced subjects with moderately to severely active disease, who have either 
previously demonstrated inadequate clinical response, loss of response, or intolerance to at 
least 1 course of standard-of-care (SoC) therapy for UC (i.e. steroids [oral or parenteral, 
including but not limited to prednisone, prednisolone, budesonide], 5-aminosalicylate [5-
ASA] derivatives [including but not limited to mesalamine, sulfasalazine], anti-metabolites 
[including but not limited to azathioprine, 6 mercaptopurine, methotrexate], anti-TNF 
agents, anti-integrins, Janus kinase [JAK] inhibitors), as confirmed by the investigator. 
5. Moderately to severely active UC as determined at screening by:  
a. Centrally-read endoscopic evidence of disease activity (MCS-ES ≥2 OR UCEIS ≥4) 
with a minimum disease extent of 15 cm from anal verge; AND 
b. MCS SF subscore ≥1; AND 
c. MCS RB subscore ≥1. 
6. Subjects currently receiving the following SoC therapies for UC are eligible providing they 
have been on a stable dose for the designated period of time and are anticipated to be stable 
throughout the study: 
a. oral corticosteroids (prednisone ≤20 mg/day or equivalent or budesonide ≤3 mg/day) 
stable dose for at least 2 weeks prior to first IP dosing. 
b. oral 5-ASA compounds (mesalamine ≤4 g/day or sulfasalazine ≤4 g/day) stable dose for 
at least 4 weeks prior to first IP dosing. 
c. oral thiopurines (azathioprine ≤2.5 mg/kg/day and 6-mercaptopurine 1.5 mg/kg/day) 
stable dose for at least 12 weeks prior to first IP dosing, or methotrexate ≤20 mg/week, 
stable dose for at least 12 weeks prior to first investigational product (IP) dosing. 
 
Main Exclusion Criteria 
1. Diagnosis of Crohn’s disease, indeterminate colitis, ischemic colitis, fulminant colitis, or 
toxic megacolon. 
2. Prior surgical intervention for UC (e.g. colectomy, partial colectomy, ileostomy or 
colostomy) or likely requirement for surgery for UC, during the study. 
3. History or evidence of incompletely resected colonic mucosal dysplasia. 
4. Exhibit acute severe UC per the following criteria: 
a. bloody diarrhea ≥6/day  
AND 






















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In case a randomized subject is not available to attend a scheduled study visit on site due to 
SARS-CoV-2 travel restrictions, a phone call or a televisit may be conducted instead. It is 
strongly recommended to conduct planned study assessments for the applicable visit as per 
protocol as much as possible. If possible and if local regulations allow and the subject agrees, 
trained study staff or trained personnel are encouraged to collect study assessments at the study 
subjects’ home or local facility if social distancing and hygiene rules can be applied.  
Only staff trained in conducting the protocol planned assessments are authorized to perform 
home or local facility visits assessments and the alternative arrangements need to be adequately 
documented. Direct to Patient (DTP) shipments are possible if needed. Subjects presenting with 
signs and symptoms of infection, including SARS-CoV-2 infection should immediately contact 
the site investigator, who should inform the sponsor’s medical responsible as soon as possible, 
and SARS-CoV-2 testing should be performed. 
6. 
CLINICAL STUDY POPULATION 
6.1. 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study: 
1. Subject must be able and willing to comply with the CSP requirements and must sign and 
date the ICF as approved by the Independent Ethics Committee (IEC) / Institutional Review 
Board (IRB), prior to any screening evaluations. 
2. Subjects must be ≥18 and <65 years of age, on the date of signing the ICF. 
3. Documented diagnosis of UC of ≥3 months. The criteria for documentation of UC diagnosis 
based on endoscopy will be medical record documentation, and/or a colonoscopy report 
dated ≥3 months before screening, which shows features consistent with UC. 
4. Treatment-experienced subjects with moderately to severely active disease, who have either 
previously demonstrated inadequate clinical response, loss of response, or intolerance to at 
least 1 course of standard-of-care (SoC) therapy for UC (i.e., steroids [oral or parenteral, 
including but not limited to prednisone, prednisolone, budesonide], 5-aminosalicylate [5-
ASA] derivatives [including but not limited to mesalamine, sulfasalazine], anti-metabolites 
[including but not limited to azathioprine, 6 mercaptopurine, methotrexate], anti-TNF agents, 
anti-integrins, Janus kinase [JAK] inhibitors), as confirmed by the investigator. 
5. Moderately to severely active UC as determined at screening by:  
a. 
Centrally-read endoscopic evidence of disease activity (MCS-ES ≥2 OR UCEIS ≥4) 
with a minimum disease extent of 15 cm from anal verge; AND 
b. MCS SF subscore ≥1; AND 
c. 
MCS RB subscore ≥1. 
6. Subject must be otherwise healthy on the basis of physical examination, medical history, 
vital signs, 12-lead electrocardiogram (ECG), and clinical laboratory tests performed during 


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screening. If there are abnormalities, they should be consistent with the underlying illness in 
the study population or considered not to be clinically significant in the opinion of the 
investigator.  
7. Female subject of child bearing potential must have a negative highly sensitive (serum beta 
human chorionic gonadotropin) pregnancy test at screening and a negative pregnancy test 
prior to the first dose of IP.  
8. Female subject of child bearing potential or male subject must agree to use highly effective 
contraception/preventive exposure measures (as described in Section 6.3.1). 
9. Female subjects of nonchildbearing potential (as defined in Section 6.3.1) must also have a 
negative blood pregnancy test at screening. For surgical sterilization, documented 
confirmation will be requested. 
10. Subject must have a body mass index (BMI) between 17-30 kg/m2, inclusive. 
11. Subject must be able and willing to comply with restrictions on prior and concomitant 
medication (as described in Section 6.3.2). 
12. Subjects currently receiving the following standard of care therapies for UC are eligible 
providing they have been on a stable dose for the designated period of time and are 
anticipated to be stable throughout the study: 
a. 
oral corticosteroids (prednisone ≤20 mg/day or equivalent (see conversion table in 
Appendix 1) or budesonide ≤3 mg/day) stable dose for at least 2 weeks prior to first IP 
dosing. 
b. oral 5-ASA compounds (mesalamine ≤4 g/day or sulfasalazine ≤4 g/day) stable dose for 
at least 4 weeks prior to first IP dosing. 
c. 
oral thiopurines (azathioprine ≤2.5 mg/kg/day and 6-mercaptopurine 1.5 mg/kg/day) 
stable dose for at least 12 weeks prior to first IP dosing, or methotrexate ≤20 mg/week, 
stable dose for at least 12 weeks prior to first IP dosing.  
13. The results of the following laboratory tests at screening must be as specified below: 
a. 
Hemoglobin International System of Units (SI): ≥90 g/L 
b. White blood cells (WBCs) ≥3.0 x 109 cells/L 
c. 
Neutrophils ≥2.0 x 109 cells/L 
d. Lymphocytes ≥1.0 x 109 cells/L 
e. 
Platelets ≥100 x 109 cells/L 
f. 
Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤1.5 x 
upper limit of normal range (ULN) 
g. Total bilirubin level ≤1.5 x ULN unless the subject has been diagnosed with Gilbert's 
disease and this is clearly documented 
h. Alkaline phosphatase ≤1.5 x ULN 
i. 
Creatinine clearance >60 mL/min. Creatinine clearance will be calculated using the 
Cockroft-Gault formula.  


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6.2. 
Exclusion Criteria 
Subjects meeting one or more of the following criteria cannot be selected for this clinical study: 
1. Diagnosis of Crohn’s disease, indeterminate colitis, ischemic colitis, fulminant colitis, or 
toxic megacolon. 
2. Prior surgical intervention for UC (e.g. colectomy, partial colectomy, ileostomy or 
colostomy) or likely requirement for surgery for UC, during the study. 
3. History or evidence of incompletely resected colonic mucosal dysplasia. 
4. Subject has a known hypersensitivity to IP ingredients or history of a significant allergic 
reaction to IP ingredients as determined by the investigator, such as anaphylaxis requiring 
hospitalization. 
5. Currently on any chronic systemic (oral or intravenous) anti-infective therapy for chronic 
infection (such as pneumocystis, cytomegalovirus, herpes zoster, atypical mycobacteria). 
6. Active clinically significant infection OR any infection requiring oral or systemic anti-
infective therapy within 2 weeks prior to screening (including use of oral anti-infective 
therapy for UC). 
7. History of tuberculosis (TB) diagnosis or evidence of active or latent infection with 
Mycobacterium tuberculosis as defined by one of the following assessments: 
a. 
Positive QuantiFERON-TB Gold test result,  
OR 
b. Chest radiograph (posterior anterior view) taken within 12 weeks prior to screening, read 
by a qualified radiologist or pulmonologist, with evidence of current active TB or old 
inactive TB. 
8. Subject has a known or suspected history of or a current immunosuppressive condition, or a 
history of invasive opportunistic infections (e.g. human immunodeficiency virus [HIV] 
infection, histoplasmosis, listeriosis, coccidiodmycosis, pneumocystosis, aspergillosis). 
9. Subject has a history of malignancy within the past 5 years prior to screening with the 
exception of excised and curatively treated non-metastatic basal cell carcinoma or squamous 
cell carcinoma of the skin or carcinoma in situ of cervix which is considered cured with 
minimal risk of recurrence. 
10. Subject has a history or presence of clinically significant abnormalities detected on 12-lead 
ECG of either rhythm or conduction e.g. known long QT syndrome or a QT interval 
corrected for heart rate using Fridericia’s formula [QTcF] >450 ms (male), >460 ms (female) 
detected on the 12-lead ECG. A first-degree atrioventricular block will not be considered as a 
significant abnormality. 


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11. Female subject is pregnant or breast feeding or intending to become pregnant or breastfeed 
during the study. 
12. Dependence on parenteral nutrition. 
13. History of major surgery (requiring regional block or general anesthesia) within the last 
12 weeks prior to screening, including bowel surgery. 
14. Investigator or other study staff or relative thereof who is directly involved in the conduct of 
the study. 
15. Subject has any condition or circumstances that, in the opinion of the investigator, may make 
a subject unlikely or unable to complete the study or comply with study procedures and 
requirements (e.g., active alcohol or drug abuse). 
16. Subject has taken any disallowed therapies before the planned first dose of IP. 
17. Subject has any condition (including but not limited to chronic cardiac or pulmonary disease, 
chronic renal failure) for which, in the opinion of the investigator, participation would not be 
in the best interest of the subject (e.g., compromise the well-being) or that could prevent, 
limit, or confound the protocol-specified assessments. 
18. Exhibit acute severe UC per the following criteria: 
a. 
bloody diarrhea ≥6/day  
AND 
b. any of the following signs of systemic toxicity: 
Body temperature (oral or tympanic) ≥37.8°C 
OR 
Resting pulse (after 5 min seated position) >90 beats per min 
OR 
hemoglobin <105 g/L,  
OR 
erythrocyte sedimentation rate >30 mm/h 
OR 
C-reactive protein (CRP) >30 mg/L. 
19. Screening stool sample positive for ova and/or parasites, Clostridium difficile toxin, 
Escherichia coli, Salmonella species (spp), Shigella spp, Campylobacer spp or Yersinia spp. 
20. Subject has a chronic hepatitis B virus (HBV) infection, as defined by persistent HBV 
surface antigen (HBsAg) positivity. Subject has hepatitis C virus infection, as defined by 
positive hepatitis C virus (HCV) antibody (Ab) at screening and detectable HCV viremia. 
Subjects with positive HCV Ab must undergo reflex HCV RNA testing, and subjects with 
HCV RNA positivity will be excluded. Subjects with positive HCV Ab and negative HCV 
RNA are eligible.  


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21. Subject testing positive at screening for SARS-CoV-2 infection as detected by real time 
polymerase chain reaction (RT-PCR), subjects presenting any signs or symptoms as detected 
at baseline following careful physical examination (e.g. cough, fever, headaches, fatigue, 
dyspnea, myalgia, anosmia, dysgeusia, anorexia, sore throat, others) or reporting any signs 
and symptoms for the 2 preceding weeks, or subjects who have been exposed to individuals 
with confirmed or suspected diagnosis of SARS-CoV-2 within 2 weeks prior to baseline 
(BMJ, 2020). In addition, any other locally applicable standard diagnostic criteria may also 
apply to rule out SARS-CoV-2 infection. 
22. Subject has presence or sequelae of gastrointestinal, liver, kidney (creatinine clearance 
≤90 mL/minute, for elderly ≤60 mL/minute, using the Cockcroft-Gault formula: if calculated 
result is ≤90 mL/minute, for elderly ≤60 mL/minute, if applicable, a 24-hour urine collection 
can be done) or other conditions known to interfere with the absorption, distribution, 
metabolism, or excretion of drugs.  
23. Subject concurrently participates or participated in a drug, drug/device or biologic 
investigational research study within 12 weeks or 5 half-lives of the IP, whichever is longer, 
prior to the first dose. 
6.3. 
Prohibition and Restrictions 
6.3.1. 
Precautions for Sexual Intercourse 
Highly effective contraceptive measures for both males and females of childbearing potential 
must be documented in the source documents. 
6.3.1.1. 
Female Subjects 
Female subjects are considered of non-childbearing potential if they meet one of the following 
criteria: 
− 
No menses for 12 or more months without an alternative medical cause. A high follicle 
stimulating hormone (FSH) level in the post-menopausal range may be used to confirm a 
post-menopausal state in women not using hormonal contraception or hormonal replacement 
therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient. 
− 
Permanently surgically sterile (bilateral oophorectomy, i.e., surgical removal of ovaries, 
bilateral salpingectomy or hysterectomy, i.e., surgical removal of uterus). 
All other female subjects are considered to be of childbearing potential (WOCBP) and must use 
one of the following highly effective methods of birth control prior to the first dose of IP, during 
the clinical study and for at least 35 days after the last dose of IP: 
− 
Combined (estrogen and progesterone containing) (oral, intravaginal, transdermal) hormonal 
contraception associated with inhibition of ovulation plus a barrier method. 
− 
Progesterone-only hormonal (oral, injectable, implantable) contraception associated with 
inhibition of ovulation plus a barrier method. 


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− 
Intrauterine device. 
− 
Intrauterine hormone-releasing system plus a barrier method. 
− 
Bilateral tubal occlusion. 
− 
Sexual abstinence defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments. The reliability of sexual abstinence needs 
to be evaluated in relation to the duration of the clinical study and the preferred and usual 
lifestyle of the subject. 
Periodic abstinence (e.g., calendar, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of a clinical study, withdrawal, spermicides only, and lactational 
amenorrhea method are not acceptable as methods of contraception. 
In case a WOCBP has a vasectomized partner, provided that partner is the sole sexual partner of 
the WOCBP clinical study participant and that the vasectomized partner has received medical 
assessment of the surgical success, then she is not required to use an additional form of 
contraception. 
Within these limits, the specific forms of contraception employed are left to the discretion of the 
subject, the investigator, and/or the subject’s physician. 
The safety of GLPG3970 during breastfeeding is unknown. Nursing women are not allowed to 
take part in this clinical study. 
6.3.1.2. 
Male Subjects 
Non-vasectomized male subjects with female partners of childbearing potential must be willing 
to use a condom from the time of the first dose of IP, during the clinical study, and for at least 
7 days after the last dose of IP, in addition to having their female partner use one of the following 
forms of contraception: 
− 
Intrauterine device. 
− 
Intrauterine hormone-releasing system. 
− 
Combined (estrogen and progesterone containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, transdermal). 
− 
Progesterone-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable, implantable). 
 
Sexual abstinence defined as refraining from heterosexual intercourse is considered a highly 
effective contraceptive measure only if it is the preferred and usual lifestyle of the subject. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical 
study. 
Periodic abstinence (e.g. calendar, symptothermal, 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. 


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In a case where the female partner of a male subject, provided that this partner is the sole sexual 
partner of the subject, 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 the first dose of IP during the clinical study until 7 days after 
the last dose of IP. 
6.3.2. 
Prior and Concomitant Medications 
Prior and concomitant therapies taken for long-term treatment of pre-existing conditions are 
allowed, provided they are in accordance with the inclusion and exclusion criteria (see 
Sections 6.1 and 6.2, respectively) and with the prohibitions and restrictions listed below. 
All medications used for UC within 2 years prior to screening should be recorded with 
approximate dates of use (year, duration in months). In case of multiple courses of steroids, only 
the most recent course needs to be recorded. Information on previous failed courses of UC 
therapy should be reported, indicating the class/product(s). 
In case additional concomitant medications need to be administered or dose adjustments for pre-
existing conditions (except for UC) are needed during the study, the risk/benefit to the subject 
should be carefully assessed by the study physician and consideration given to the timing of any 
necessary introduction of new medications. 
If during the study, the subject’s condition necessitates the use of prohibited medication, the use 
of IP may be interrupted, preferably after consultation with the sponsor’s medical leader. Re-
introduction of IP can be considered after the treatment course with the prohibited medication has 
been stopped and after consultation with the sponsor’s medical leader. 
During the study, subjects will be instructed to record any change in concomitant medication in a 
diary (see Section 8.8.1). 
Permitted Medications: 
All other medications are permitted as long as they are not listed in the section on 
prohibited/restricted medications below. 


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Prohibited/Restricted Medications: 
The following rules should apply: 
Medication  
Restriction 
Antibiotics/ anti-infectives 
Oral antibiotics/ anti-infectives: not allowed within 2 weeks prior to 
screening. 
Intravenous antibiotics/ anti-infectives: not allowed within 8 weeks 
prior to screening. 
 
During the study: not allowed for the treatment of bowel related 
infections up to the follow-up visit (allowed for treatment of other 
infections). Allowed for the treatment of infections (other than 
bowel related infections).  
Corticosteroids (intramuscular or 
intravenous) 
Not allowed within 4 weeks prior to screening and up to the follow-
up visit. 
Corticosteroids (oral) 2 
Oral corticosteroids (prednisone ≤20 mg/day or equivalent (see 
conversion table in Appendix 1) or budesonide ≤3 mg/day) allowed 
at stable dose for at least 2 weeks prior to first IP dosing. (see 
inclusion criterion 12)  
Oral 5-ASA compounds 
Mesalamine ≤4 g/day or sulfasalazine ≤4 g/day allowed at stable 
dose for at least 4 weeks prior to first IP dosing. 
Please also refer to the dosing instructions for sulfasalazine below 
under 'further guidance for the use of concomitant medications’. 
Rectal formulation therapies (5-ASA 
compounds or corticosteroids) 
Not allowed within 2 weeks prior to screening endoscopy and up to 
the last IP dose. 
Oral thiopurines and methotrexate 
Azathioprine ≤2.5 mg/kg/day and 6-mercaptopurine 1.5 mg/kg/day, 
allowed at stable dose for at least 12 weeks prior to first IMP 
dosing.  
Methotrexate ≤20 mg/week, allowed at stable dose for at least 
12 weeks prior to first IP dosing. 
Lymphocyte depleting therapies (including, 
but not limited to, alemtuzumab, 
cyclophosphamide, tacrolimus, 
cyclosporine, leukocyte apheresis, total 
lymphoid radiation or rituximab) 
Rituximab is not allowed 6 months prior to screening and up to the 
follow-up visit. 
Cyclophosphamide and lymphocyte apheresis are not allowed  
3 months prior to screening and up to the follow-up visit. 
Cyclosporine and tacrolimus are not allowed 30 days prior to 
screening and up to the follow-up visit. 
Alemtuzumab treatment and total lymphocyte radiation are not 
prior to the study or at any time during the study up to follow-up. 
Anti-TNF 
Anti-integrin monoclonal antibodies  
Tofacitinib 
Not allowed during screening period and for 5 half-lives prior to 
first MP dosing and up until the follow up visit. 
Vaccines a 
Live or attenuated vaccines not allowed within 60 days prior 
screening. 
Live or attenuated vaccines: not allowed throughout the study and 
up to the follow-up visit 
Inactivated vaccines should be administered according to local 
vaccination standards whenever medically appropriate. 
a  
Refer to Appendix 2 for further vaccination-related recommendations 
 






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Treatment with IP should be discontinued by the investigator (who may consult the sponsor’s 
medical leader) for any of the following conditions: 
− 
Life-threatening adverse event (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 or lactation. 
− 
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 (QTc >500 ms on at least 2 separate ECGs), or clinically significant 
arrhythmia from any grade.  
− 
Liver enzyme increase (see also Appendix 9) 
• 
AST and/or ALT ≥8x the ULN. 
• 
AST and/or ALT elevations ≥3x ULN with signs of liver damage (i.e., with the 
appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash and/or eosinophilia [>5%], and/or total bilirubin ≥2.0x ULN or international 
normalized ratio [INR] >1.5) 
• 
In addition, a dose interruption or reduction (if applicable) should be considered if AST 
and/or ALT ≥3x ULN and <5x ULN and dosing with IP should be interrupted if AST 
and/or ALT ≥5 and <8x ULN. 
− 
Subjects presenting with signs and symptoms of SARS-CoV-2 infection should immediately 
contact the site investigator, who should inform the sponsor’s medical responsible as soon as 
possible, and report an AE/SAE as applicable. In case of suspected SARS-CoV-2 infection 
RT-PCR and serology tests should be performed to confirm the infection. The investigator, 
preferably after consultation with the sponsor’s medical responsible, must discontinue the 
subject from the study. The subject could be tested for SARS-CoV-2 in facilities outside the 
study site and if so, the subject should be instructed to immediately inform the study 
investigator if the test is positive and test results should be shared with the investigator as 
soon as possible. 
For subjects having: 
• 
AST or ALT ≥8xULN 
• 
AST or ALT ≥3xULN with signs of liver damage (i.e. with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or 
eosinophilia [>5%], and/or total bilirubin ≥1.5xULN or INR >1.5) 
The following steps will need to be performed by the investigator: 
• 
The site should immediately contact the subject and require the subject to discontinue IP 
immediately. The subject should be asked to return to the site within a 48-hour window 
from awareness of the result.  
• 
A full evaluation of various causes of hepatitis should be conducted (i.e., infectious, 
alcohol, medications, anatomical).  


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• 
An assessment of other concomitant medications and SoC should be made. The 
investigator should consider whether it is in the best interest of the subject to 
stop/interrupt concomitant medications and SoC treatment.  
• 
A detailed history including relevant information on alcohol use, recreational drug use, 
supplement consumption, any herbal remedies, family history, sexual history, travel 
history, history of contact with a jaundiced subject, surgery, occupational history, blood 
transfusion, history of liver or allergic disease, and any other potential causes of 
attributable to a liver insult should be collected.  
• 
A detailed assessment of the subject’s clinical condition and repeat laboratory tests for 
liver function tests (LFTs), including albumin, creatine kinase, total bilirubin (direct and 
indirect), gamma glutamyl transferase (GGT), INR and alkaline phosphatase should be 
done.  
• 
Further testing for hepatitis A, B, and C, and for autoimmune hepatitis should be done. 
Other causes of viral hepatitis (cytomegalovirus or Eppstein Barr virus etc) should be 
excluded. Liver imaging should be considered.  
• 
Referral to a hepatologist or gastroenterologist should be requested. 
• 
All these cases should be reported as SAEs. 
Every effort should be made to keep subjects in the study and on treatment. However, the 
investigator, who may consult the sponsor’s medical leader, can consider stopping the study 
treatment in case of concerns about the subject’s safety, serious or severe AEs or worsening of 
the disease condition, which in the investigator’s opinion needs an alternative treatment approach 
not being covered in the clinical study (e.g., rescue medication). If IP treatment is interrupted due 
to an SAE, IP could be restarted, as per the investigator’s judgement and after consultation with 
the sponsor medical leader. 
When study treatment is discontinued, the subject will be requested to complete the assessments 
for the ED visit and return for the FU visit. Reason for discontinuation must be documented in 
the case report form (CRF). 
Subjects will be informed prior to clinical study entry that they are allowed to withdraw from the 
clinical study. At any time and for any reason, a subject’s participation in the clinical study may 
terminate at their request, without prejudice to their 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 visit for safety assessments, but will not 
be obliged to do so. 
Subjects who withdraw from the clinical study without contact with the site (lost-to-follow-up) 
should be contacted by the site so that their health status can be assessed and documented in the 
source documents. The site should make every effort to understand whether the subject is alive, 
including checking the medical records and contacting general practitioner or relatives, if 
necessary. All attempts must be documented in the source documents.  
The sponsor has the right to terminate the clinical study at any time and for any reason. In this 
event, the investigator(s) and relevant authorities will be informed of the reason for clinical study 
termination. 


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6.5. 
Measures to Minimize Bias 
6.5.1. 
Randomization 
At screening, subjects will be assigned a subject identification number. When a subject is 
confirmed to be eligible for the clinical study, the subject will be randomized. Allocation of each 
subject to a given treatment will be done using a centralized electronic system (interactive 
voice/web response system [IXRS]). IP will be randomized in a 2:1 ratio to GLPG3970 or 
placebo. 
6.5.2. 
Blinding and Unblinding 
This is a randomized, double-blind clinical study. The subjects and the entire clinical study team, 
including the investigators, clinical study coordinators, and sponsor personnel are blinded to 
treatment assignment. 
Blinded and packaged medication will be provided to the site. All IP formulations will be 
identical in appearance, shape, smell and taste and will be packaged in the proper proportion to 
assure desired dosages and maintenance of the blinding. 
The blind can be broken by the investigator for the safety of a subject. The investigator is 
encouraged to discuss considerations to break the blind with the medical leader, whenever 
possible and where the situation allows. However, the responsibility to break the treatment code 
in emergency situations resides solely with the investigator. The investigator is not required to 
discuss unblinding beforehand if he or she feels rapid emergency unblinding is necessary, but is 
required to inform the sponsor in within 24 hours after unblinded has occurred. 
The blind can be broken by the investigator via IXRS by the investigator.  
If the blind is broken for any reason during the course of the clinical study, the moment on which 
the blind was broken and all other relevant information will be documented by the study site. The 
reason for breaking the blind will be indicated and justified in the source documentation. 
If an AE leads to unblinding, the AE will be given as the reason for unblinding. All subjects who 
are unblinded should, where possible, complete the follow-up visit assessments 14±3 days after 
unblinding. Any AEs will be followed until resolution. 
The code-break information (via IXRS vendor) will be provided to the bioanalytical laboratory 
responsible for PK sample analysis, the person responsible for providing unblinded data to the 
data safety monitoring committee, to the pharmacovigilance vendor for SAE reporting purposes, 
and, if applicable, to the contract research organization (CRO) performing population PK/PD 
analyses. 




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7.3. 
Packaging, Labeling and Distribution 
IP packages will be labeled with clinical study-specific details, including storage conditions. 
All manufacturing, packaging, and labeling operations will be performed according to Good 
Manufacturing Practice for Medicinal Products and the relevant regulatory requirements. 
Each medication kit will be identified with a unique kit number. Multiple kits can be provided to 
a subject at each visit, providing the subject with sufficient IP to cover the period until the next 
scheduled visit. 
The distribution of IP to the site will only occur after the required local documentation is 
obtained, including clinical study approval by regulatory authorities and the IECs/IRBs, 
documentation on which the assessment of the investigator’s qualifications was based (e.g. 
curriculum vitae), and the signed and dated study agreement and financial agreement. 
To ensure study subjects maintain dosing per protocol requirements during this study special 
delivery services through DTP shipments of IP from the investigational site to the subject can be 
implemented in case of SARS-CoV-2 restrictions. DTP should only be used in case of emergency 
where on-site IP dispensation is not possible, and if allowed per local regulations. Local 
guidelines must be followed and regulatory approval or notification of authorities may be 
required. Agreement of the subject to receive IP at home is required prior to the shipment of IP 
from the investigational site to the subject’s home. The DTP process used will be reviewed and 
approved by the sponsor, but the DTP shipments will be coordinated by the investigational site(s) 
in collaboration with the local CRO without the involvement of the sponsor to ensure 
clinical study integrity in case of SARS-CoV-2 restrictions. 
7.4. 
Storage 
Sites are to store IP supplies in a secure area until dispensed. Powder and solvent for oral solution 
are to be stored at room temperature (below 30 °C), should not be refrigerated or frozen and 
protected from light. Both the study sites and subjects will receive additional information on 
preparation and storage of the IP. 
Sites will be required to monitor the storage temperature by using at least a min-max 
temperature-recording device and to keep a minimum to maximum temperature log, which must 
be completed each working day in order to establish a record of compliance with these storage 
conditions.  
The investigator will instruct subjects on how the IP should be stored at home. Storage conditions 
to be taken into account by the subject when taking IP home, are described in the patient leaflet. 
7.5. 
Treatment Compliance and Drug Accountability 
The investigator should discuss treatment compliance with the subject prior to the start of the 
study. Missed doses should be discussed to try to ascertain the reason(s). Every effort should be 
made to ensure the proper subject dose. Subjects with poor compliance will be retrained by the 


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site. Subjects will record IP administration (amount administered, date and time of IP 
administration) done at home in a subject diary. On Visit Day 1, Day 15±2, Day 29±2 and Day 
43±2 administration of IP must occur at the site and will be captured in the eCRF. 
The pharmacist or designated clinical study staff will maintain a log (paper or electronic) of the 
total amount of IP received at site, amount dispensed to the subject, and number of empty and 
full bottles returned to the site. IP supplies for each subject will be inventoried and accounted for 
throughout the clinical study. At the end of the treatment period, these records will be checked 
against the inventory by the study monitor. All clinical supplies will be stored in locked facilities. 
Subjects will return any unused IP and empty IP packages at each study visit and/or ED Visit. 
Upon sponsor approval, all used and unused IP are to be returned from the sites and/or any 
vendor involved in the clinical study supplies management activities to the agreed location 
(depot), if possible. All returns and destructions must be properly documented.  
8. 
CLINICAL STUDY ASSESSMENTS 
Every effort should be made to ensure that CSP-required tests and procedures are completed as 
described in the Schedule of Activities (see Section 8.11). To avoid inter-observer variability, 
every effort should be made to ensure that all safety and efficacy evaluations are completed by 
the same individual who made the initial baseline determinations. In case study assessments are 
not performed for reasons related to SARS-CoV-2 pandemic restrictions, this should be 
documented in the medical records and subject’s e-CRF.  
In case a randomized subject is not available to attend a scheduled study visit on site due to 
SARS-CoV-2 travel restrictions, a phone call or a televisit may be conducted instead. It is 
strongly recommended to conduct planned study assessments for the applicable visit as per 
protocol as much as possible. If possible and if local regulations allow and the subject agrees, 
trained study staff or trained personnel are encouraged to collect study assessments at the study 
subjects’ home or a local facility if social distancing and hygiene rules can be applied.  
Only staff trained in conducting the protocol planned assessments are authorized to perform 
home or local facility visit assessments and the alternative arrangements need to be adequately 
documented. Direct to patient shipments are possible if needed. Subjects presenting with signs 
and symptoms of infection, including SARS-CoV-2 infection should immediately contact the site 
investigator, who should inform the sponsor’s medical responsible as soon as possible, and 
SARS-CoV-2 testing should be performed. 
8.1. 
Timing of Assessments 
The study assessments described below will be performed at time points as specified in the 
Schedule of Activities in Section 8.11. A window of ±2 days is allowed for Visits 2, 3, 4, and 5; 
and a window of ±3 days is allowed for the Follow-up Visit.  
ICF needs to be signed before any study procedure, including screening procedure, is carried out. 




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When multiple assessments are listed on 1 line, the sequence can be determined by the site. 
Additional safety assessments should be performed if clinically indicated (see also Section 6.4). 
8.1.1. 
Retesting During Screening 
During the screening period, one retest of the following assessments is allowed: 
− 
For resting pulse (after 5 min seated position) outside range for defining acute severe UC (as 
defined in exclusion criterion #18).  
− 
For QuantiFERON –TB Gold test with indeterminate result (the subject is not eligible if 
retest result is indeterminate or positive).  
− 
During screening or later during the study, retesting (resampling) of clinical laboratory safety 
tests or SARS-CoV-2 RT-PCR test is allowed once, only for technical or transport reasons 
(e.g., sample hemolyzed, out of stability, late arrival at laboratory impacting sample quality, 
loss, or destruction of the sample before analysis). 
8.1.2. 
Rescreening of Subjects 
If a subject is a screening failure, it is allowed to rescreen the subject once, if the reason for 
failure is temporary and expected to resolve, as judged by the investigator. When a subject is 
rescreened, the subject needs to be reconsented and all screening assessments need to be 
repeated. The subject will be assigned a new subject identification number. The time in between 
2 screening attempts could vary depending on the screen failure reason.  
The following data will be collected for screening failure subjects: ICF signed data, 
demographics, failed inclusion or exclusion criteria, and AEs. 
8.2. 
Unscheduled Visits 
Additional visits can be performed at other time points for any safety assessments, if clinically 
indicated. These unscheduled visits and outcomes of additional assessments need to be recorded 
in the source and, if it is a CSP-specified assessment performed before the subject’s last visit per 
CSP, also in the eCRF. 
8.3. 
Subject and Disease Characteristics 
Subjects will be asked to attend the site for a screening assessment. After giving written informed 
consent, demographic data (year of birth, age, sex , ethnicity and race), medical, and smoking 
history will be taken, including UC history. UC classification and/or extent will be provided per 
 
 (see Appendix 10) 
based on the screening colonoscopy or endoscopy examination (where applicable, as per 
Section 8.7.2) or based on the last available colonoscopy performed before screening. Questions 
regarding prior and concomitant medication intake will be asked. A physical examination will be 
performed, including measurement of weight and height. 
Vital signs (systolic and diastolic blood pressure, pulse, tympanic body temperature) will be 
measured and a triplicate 12-lead ECG will be recorded. Subjects should rest for at least 


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5 minutes, in the supine position before the ECG recording and in a seated position before blood 
pressure and pulse measurement. Blood and urine samples will be collected for clinical 
laboratory safety tests. A stool sample will be collected for microbiology and PD assessments. If 
not possible to collect a stool sample during the visit, the subjects will receive a stool sample 
collection kit to collect the stool sample at home within 24 hours after screening visit 1. A serum 
pregnancy test will be done for all WOCBP as well as an FSH test for nonsurgical 
postmenopausal female subjects. 
UC history will capture the duration of disease, clinical symptoms, number of stools per day 
under normal (healthy/remission) conditions, medication used to treat the disease, and clinical 
response to current and prior UC therapies.  
Flexible sigmoidoscopy or surveillance colonoscopy videos will be centrally reviewed using 
 and MCS-ES indices to confirm active UC. The endoscopy procedure will be done at a 
second screening visit after the other in- and exclusion criteria have been confirmed. 
The inclusion and exclusion criteria (Sections 6.1 and 6.2) will be checked to assess eligibility for 
the study. All screening tests will be reviewed to confirm eligibility before randomization and the 
first dose.  
8.4. 
Efficacy Assessments 
8.4.1. 
Endoscopy 
An endoscopy (either a surveillance colonoscopy or flexible sigmoidoscopy, see below) will be 
performed on the visits specified in the Schedule of Activities in Section 8.11 (see also 
Section 8.1, “Timing of Assessments”). 
At screening visit 2: 
a. 
In subjects with a history of UC ≥8 years: 
i) 
With a colonoscopy performed more than 24 months prior to screening, a 
surveillance colonoscopy will be performed. 
ii) 
With a colonoscopy performed less than 24 months prior to screening, a 
flexible sigmoidoscopy will be performed. 
b. 
In subjects with a history of UC <8 years: 
i) 
A flexible sigmoidoscopy will be performed, irrespective of the time of the 
last colonoscopy. 
At Visit 5 (or at the ED visit, if applicable): 
a. 
A flexible sigmoidoscopy will be performed for all subjects in the study. 
Videos of the flexible sigmoidoscopy or of the screening surveillance colonoscopy, will be 
recorded. These will be reviewed and scored by blinded central reviewer(s) using the MCS-ES 
and 
 indices (refer to Appendix 10 and Appendix 11). The MCS-ES (Schroeder, 


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Tremaine, & Ilstrup, 1987) 
 
 screening scores will be reported 
to the clinical site. 
Details of the endoscopy, including bowel preparation before endoscopy, as well as the collection 
and processing of video films will be provided in a separate imaging charter. 
8.4.2. 
Biopsy Sample Collection 
During the endoscopy (either flexible sigmoidoscopy or surveillance colonoscopy) on the visits 
specified in the Schedule of Activities in Section 8.11 (see also Section 8.1, “Timing of 
Assessments”), 8 colonic biopsies will be collected per visit: 4 biopsies from the distal sigmoid 
colon (the area representative of UC disease activity) at approximately 25 cm proximal to the 
anal verge, and 4 biopsies from the rectum. 
Colon biopsies will be stored at the site until shipment to a central lab for further processing, 
allowing: 
− 
− 
Biopsy sample collection, handling, and processing will be outlined in the laboratory manual 
provided by the central laboratory. 
8.4.3. 
Mayo Clinical Score 
The MCS is composed of 4 subscores (see Appendix 10): 
1. MCS-SF subscore 
2. MCS-RB subscore 
3. MCS-ES subscore 
4. Physician’s global assessment (PGA) 
For calculation of the MCS subscores MCS-RB and MCS-SF (Lewis J. , et al., 2008), subjects 
will be instructed to record symptoms of RB and SF daily in a diary (see Section 8.8.1). 
The information on the UC symptomatology of the last 3 consecutive available days in the diary 
collected from the last week, will be used to score the MCS-RB and MCS-SF subscores, 
excluding the day before the endoscopy (with bowel preparation), the day of the endoscopy and 
the day after the endoscopy. 




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− 
Coagulation:  
INR (only when increase in LFTs, see Section 6.4), activated partial thromboplastin time, 
and prothrombin time. 
− 
Clinical chemistry:  
fasting glucose (at baseline [Visit 1], Day 15 [Visit 3], and Day 43 [Visit 5] and the ED visit, 
if applicable), glycosylated hemoglobin (HbA1c), fasting insulin (at baseline [Visit 1], 
Day 15 [Visit 3], and Day 43 [Visit 5] and the ED visit, if applicable), homeostatic model 
assessment of insulin resistance (HOMA IR) (at baseline [Visit 1], Day 15 [Visit 3], and Day 
43 [Visit 5] and the ED visit, if applicable), urea, creatinine, creatinine clearance (ClCr), uric 
acid, sodium, potassium, calcium (total), reflex calcium (free/ionized; only if serum calcium 
total is elevated), chloride, phosphorus/phosphate, AST, ALT, GGT, total bilirubin, alkaline 
phosphatase (alkaline phosphatase bone fractions only if alkaline phosphatase is elevated), 
lactate dehydrogenase, creatine phosphokinase (CK), albumin, total proteins, triglycerides, 
total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, 
lipase, amylase, high sensitivity CRP, high sensitivity Troponin I and Troponin T (Troponin 
I on Day 1, later during the study only when troponin T is elevated).  
Homeostatic model assessment of insulin resistance (HOMA-IR, see Definition of Terms) 
and HDL/LDL ratio will be derived from clinical chemistry parameters. An estimate of the 
creatinine clearance (ClCr) based on the serum creatinine level will be calculated by the 
central laboratory using the Cockroft-Gault formula (see Definition of Terms). 
− 
Urinalysis:  
Dipstick: pH, glucose, proteins (qualitative), blood, leukocytes, ketones. 
Microscopic examination of the sediment for cellular elements (cylinders, erythrocytes, 
leukocytes), if indicated (when the test strip was positive for blood and/or proteins). 
Quantitative urine proteins, only when the test strip was positive for proteins. 
Calcium, phosphate, creatinine and N-acetyl-β-D-glucosaminidase (NAG). The urine protein 
to creatinine ratio will be derived. 
− 
Serology/blood:  
HBs Ag, (if positive, confirmed by HBV DNA PCR), HCV (Ab and/or PCR) and HIV 1 and 
2 antibodies (at screening). Positive hepatitis and HIV results should be reported by the 
investigator as required by local law. 
FSH test for females of (nonsurgical) nonchildbearing potential at screening to confirm 
menopause, if applicable. 
− 
Pregnancy test for females: 
Serum beta human chorionic gonadotropin at screening, baseline (Visit 1), Day 29 (Visit 4), 
and Day 43 (Visit 5) or ED, if applicable (all female subjects). 
− 
QuantiFERON-TB Gold test to check for latent or active TB (at screening). TB results 
should be reported by the investigator as required by local law.  
− 
Stool culture/ Stool sample for microbiology/microbiome evaluation: 
For enteric pathogens, Clostridium difficile cytotoxin assay and microscopic examination for 
intestinal parasites/ova in stool sample; Escherichia coli, Salmonella species (spp), Shigella 
spp, Campylobacer spp and Yersinia spp assay in stool culture (at screening).  
Note: Details of microbiome assessment are provided in Section 8.7.3.2. 


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− 
SARS-CoV-2: 
RT-PCR from a nasal swab sample to check for SARS-CoV-2 infection at screening and RT-
PCR from a nasal swab sample and serology testing at baseline, and throughout the study as 
needed (when SARS-CoV-2 symptoms present) 
 
The clinical laboratory evaluations will be performed at visits specified in the Schedule of 
Activities in Section 8.11 (see also Section 8.1, “Timing of Assessments”). Reference ranges will 
be supplied by the local and central laboratory, as needed.  
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. At the discretion of the investigator, when 
following up AEs, additional laboratory parameters may be tested, and additional samples taken.  
In case of safety issues, as per decision of the investigator, the local laboratory at site could be 
used to verify some parameters. 
An estimate of the ClCr based on the serum creatinine level will be calculated by the central 
laboratory using the Cockroft-Gault formula (see Definition of Terms). 
Blood, urine, and stool sample handling and shipment instructions will be provided in a separate 
laboratory manual. 
8.5.3. 
Physical Examination 
Physical examinations, including weight and height (at screening), 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 8.11 (see also Section 8.1, 
“Timing of Assessments”). The person conducting the physical examination will document this 
in the subject’s medical source records. Clinically significant abnormal findings should be 
recorded as AEs. 
Particular attention should go to physical examination at all visits, to identify any potential 
SARS-CoV-2 related signs and symptoms, indicating potential infection (e.g. cough, fever, 
headaches, fatigue, dyspnea, myalgia, anosmia, dysgeusia, anorexia, sore throat, others). Subjects 
presenting such symptoms at screening/baseline should not be included/randomized in the study 
(see Section 6.2). Developing such symptoms during the study, should be managed as per 
Section 8.5.6. 
8.5.4. 
Vital Signs 
Vital signs (systolic and diastolic blood pressure taken at the same arm for each measurement, 
pulse, and oral/tympanic body temperature, the same method for measuring body temperate to be 
used throughout the study) will be recorded in a standardized manner (i.e. after the subject has 
rested in a seated position for at least 5 minutes) at visits specified in the Schedule of Activities in 
Section 8.11 (see also Section 8.1, “Timing of Assessments”). Clinically significant abnormal 
values should be recorded as AEs. 


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8.5.5. 
12-lead Electrocardiogram 
At the time points specified in the Schedule of Activities (see Section 8.11 and also Section 8.1, 
“Timing of Assessments”), a triplicate 12-lead ECG will be recorded and results will be sent for 
central reading.  
12-lead ECG recordings will be performed before blood sampling and after subjects rested for at 
least 5 minutes in supine position. In case an indwelling catheter is used, ECGs may be recorded 
after blood sampling, provided that there is at least 30 minutes between catheter insertion and the 
ECG recording. When catheter insertion would fail, the 12-lead ECG needs to be taken before the 
venipuncture and at least 30 minutes after the failed attempt. Triplicate ECGs will be performed 
at the time points specified in the Schedule of Activities (see Section 8.11 and also Section 8.1, 
“Timing of Assessments”) preferably within a time span of 10 minutes, with an approximate 
3-minute interval between ECGs.  
The following parameters need to be recorded: heart rate, PR interval, RR interval, QRS interval, 
uncorrected QT interval, morphology and rhythm analysis. QTcF will be derived. QTcF will be 
considered as normal if ≤450 ms (male) and ≤460 ms (female), while a prolongation of QTcF to 
>500 ms or an increase from baseline >60 ms will be considered a threshold of concern.  
The ECG will be reviewed centrally to detect clinically significant abnormalities. This review 
during the visit needs to be documented in the subject’s source. After receipt of the central report, 
also all flagged ECG abnormalities need to be assessed by the investigator on clinical relevance. 
Clinically significant abnormal values should be recorded as AEs. 
8.5.6. 
Other Safety Assessments 
SARS-CoV-2 infection will be assessed at screening by RT-PCR and at baseline through careful 
physical examination to exclude any potential signs and symptoms of infection, e.g. cough, fever, 
headaches, fatigue, dyspnea, myalgia, anosmia, dysgeusia, anorexia, sore throat, etc. 
Additional RT-PCR and serology testing will be repeated at baseline for documentation and 
throughout the study as needed. The subject could be tested for SARS-CoV-2 in facilities outside 
the study site and if so, the subject should be instructed to immediately inform the study 
investigator if the test is positive and test results should be shared with the investigator as soon as 
possible. 
In addition, on Day 8, the subjects should be contacted by the site via a telephone call. The site 
should remotely check the overall status of the subject and obtain safety related information, if 
applicable (both in the context of the clinical study and linked to the SARS-CoV-2 pandemic). 
8.6. 
Pharmacokinetic Assessments 
Blood samples for the PK assessment of GLPG3970 should be collected on the visits specified in 
the Schedule of Activities in Section 8.11 (see also Section 8.1, “Timing of Assessments”). In 
total 8 blood samples will be used for analysis of GLPG3970 in plasma.  










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8.11. 
Schedule of Activities 
For detailed instructions on the clinical study procedures, please see referred sections and Section 8.1, “Timing of Assessments”. 
EVENT 
SCREENING  
PERIOD 
TREATMENT PERIOD 1, 2 
FOLLOW-UP 
PERIOD3 
Study Visit 
S1 
S24 
1 
2 
3 
4 
5 
ED3 
Follow-up Visit 
Study Day (D) ± Days  
-35 to 0 
1 
8 ± 2 
15 ± 2 
29 ± 2 
43 ± 2 
 
14± 3 after last 
IP dosing 
On-site visit 
 
 
 
 
 
 
 
 
 
Telephone call 
 
 
 
 
 
 
 
 
 
Informed consent (Section 8.3) 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria (Sections 6.1 and 6.2) 
 
 
 
 
 
 
 
 
 
Demographics (Section 8.3) 
 
 
 
 
 
 
 
 
 
Medical and smoking history including UC history 
(Section 8.3)  
 
 
 
 
 
 
 
 
 
Physical examination (Section 8.5.3) 
 
 
 
 
 
 
 
 
 
Body weight and height5 (Section 8.5.3) 
 
 
 
 
 
 
 
 
 
Vital signs (Section 8.5.4) 
 
 
 
 
 
 
 
 
 
                                                 
1 On dosing days, all assessments are to be performed within 3 hours predose, unless otherwise specified. 
2 Subjects must come for the study visits at baseline (Visit 1), Day 15 (Visit 3), and Day 43 (Visit 5) and the early discontinuation (ED) visit, if applicable in the morning in a 
fasting state (no food intake for at least 8 hours). 
3 Subjects who discontinue treatment early will be requested to return for an ED visit to complete all Visit 5 assessments and to return for a follow-up (FU) visit 14±3 days 
after last IP administration. 
4 The endoscopy procedure will be done at Screening Visit 2 once the other in- and exclusion criteria have been confirmed at Screening Visit 1. 
5 Height only to be measured at Screening Visit 1. 
 


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EVENT 
SCREENING  
PERIOD 
TREATMENT PERIOD 1, 2 
FOLLOW-UP 
PERIOD3 
Study Visit 
S1 
S24 
1 
2 
3 
4 
5 
ED3 
Follow-up Visit 
Study Day (D) ± Days  
-35 to 0 
1 
8 ± 2 
15 ± 2 
29 ± 2 
43 ± 2 
 
14± 3 after last 
IP dosing 
12-Lead triplicate ECG (Section 8.5.5) 
 
 
 
 
 
 
 
 
 
QuantiFERON TB Gold test (Section 8.5.2) 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 RT-PCR test6 
 
 
 
As needed 
SARS-CoV-2 serology test 
 
 
 
As needed 
Randomization (Section 6.5.1) 
 
 
 
 
 
 
 
 
 
Blood collection 
 
 
 
 
 
 
 
 
 
• Safety (hematology, coagulation, chemistry) 
(Section 8.5.2) 
 
 
7 
 
7 
 
7 
7 
 
• Serology (HBV, HCV, HIV) (Section 8.5.2) 
 
 
 
 
 
 
 
 
 
• Pregnancy test serum (all WOCBP females) 
(Section 8.5.2)  
 
 
 
 
 
 
 
 
 
• FSH test (WOnonCBP, non-surgical 
postmenopausal women) (Section 8.5.2) 
 
 
 
 
 
 
 
 
 
                                                 
6 RT-PCR from a nasal swab sample at screening may be done at an earlier screening visit on a different day than the other screening assessments (after signature of the study 
informed consent form) and RT-PCR from a nasal swab sample and serology testing at a visit on Day -3, and throughout the study as needed when subject presents signs and 
symptoms of SARS-CoV-2 infection. 
7 Fasted glucose, fasted insulin, and HOMA-IR only at baseline (Visit 1), Day 15 (Visit 3), and Day 43 (Visit 5) and the ED visit, if applicable. 
 


Galapagos 
 
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EVENT 
SCREENING  
PERIOD 
TREATMENT PERIOD 1, 2 
FOLLOW-UP 
PERIOD3 
Study Visit 
S1 
S24 
1 
2 
3 
4 
5 
ED3 
Follow-up Visit 
Study Day (D) ± Days  
-35 to 0 
1 
8 ± 2 
15 ± 2 
29 ± 2 
43 ± 2 
 
14± 3 after last 
IP dosing 
• PK (Section 8.6) 
 
 
8 
 
9 
9 
10 
 
 
Urine collection  
 
 
 
 
 
 
 
 
 
• Safety12 (Section 8.5.2) 
 
 
 
 
 
 
 
 
 
Stool sample collection13  
 
 
 
 
 
 
 
 
 
• Microbiology  
 
 
 
 
 
 
 
 
 
                                                 
8 Visit 1:  predose (within 30 minutes prior to dosing), 1 sample within [0.5-1.5 hours postdose]; 1 sample within [2–2.5 hours postdose] and 1 sample within [3-4 hours 
postdose]. 
9 Visit 3 and 4: predose (within 30 minutes prior to dosing). 
10 Visit 5: 1 sample predose (within 30 minutes prior to dosing) and 1 sample within [4-6 hours postdose].  
11 
 
12 On dosing days, safety urine samples will be taken predose, on the same visit day. Visit 1 and 5: predose and 2 hours postdose. Calcium and phosphate should only be 
evaluated at Visits 1 and 5. 
13 At Screening Visit 1, a stool sample should be collected during the visit. If not possible, the subject can collect the sample at home within 24 hours after start of Screening. 
For Visits 1, 3, and 4, stool samples can be collected within 24 hours prior to the visit or during the visit. At Visit 5 (Day 43) and ED visit, if applicable, when the stool 
sample must be taken before the bowel preparation for endoscopy, stool can be collected more than 24 hours before the visit. One sample can be used for different 
assessments. 
 




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9. 
STATISTICAL METHODS 
All statistical methods shall be detailed in a statistical analysis plan (SAP) that will be finalized 
prior to the database lock and unblinding. All relevant data collected in this clinical study will be 
documented using summary tables, figures, and subject data listings. 
Any deviations from the CSP are to be justified in the SAP. 
9.1. 
Determination of Sample Size 
A sufficient number of subjects with UC will be screened in order to have 30 subjects 
randomized (20 planned subjects on GLPG3970 and 10 planned subjects on placebo).  
The 30 subjects randomized in the study, are expected to be sufficient to provide preliminary 
insight in the safety, tolerability and PK of GLPG3970 in UC patients. In case of drop-outs due to 
SARS-CoV-2 infection, additional subjects may be randomized on top of the planned sample 
size. The number of additional subjects randomized will not exceed the number of subjects 
dropping out of the study in relation to SARS-CoV-2. Randomization of additional subjects will 
ultimately be decided by the sponsor before any study lock or related unblinding has occurred. 
For the efficacy objective, the operating characteristics of the chosen decision framework for the 
most important endpoint (MCS change from baseline at Week 6) at a sample size of 30 subjects 
(10 on placebo and 20 on GLPG3970) are represented in the following graph and table, and were 
deemed acceptable. A common standard deviation of 3.3 was assumed in this small study. Lower 
Reference Value and Target Value for the decision framework were determined based on the 
published studies and the therapies in development or on the market. They were identified by the 
project team as the lowest delta of possible interest and the best case scenario for efficacy 
outcome respectively. 
True 
Treatment 
Difference In 
MCS Change 
From Baseline 
At Week 6 
Signal Score 
Probability 
Of Outcome 
PLC: placebo; GLPG: GLPG3970 
-3.0 
Signal detected 
0.673 
No conclusion 
0.220 
No signal detected 
0.107 
-1.3 
Signal detected 
0.205 
No conclusion 
0.289 
No signal detected 
0.506 
 




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Unless otherwise noted, inferential statistics will be interpreted at the 2-sided 10% significance 
level.  
9.3.2. 
Interim Analysis 
No interim analysis is planned for this clinical study.  
9.3.3. 
Analyses of Demographics and Baseline Characteristics 
Subject disposition (including reasons for ED), CSP deviations, demographics, baseline 
characteristics, medical history, and concomitant therapies will be analyzed descriptively. Unless 
otherwise noted, all analyses will be performed using the Safety Analysis Set 
9.3.4. 
Analyses of Efficacy Parameters 
Efficacy analyses will be performed on the FAS. 
9.3.4.1. 
Analysis for Primary Efficacy Endpoint 
The analysis of the MCS change from baseline will be descriptive by group. As some early 
dropouts or missing data can be expected, the analysis will run a mixed-effects model on 
continuous data. From this model, 90% confidence intervals (CIs) of the treatment differences 
(GLPG3970 versus placebo) will be estimated. 
The signal detection methodology described by Frewer et al. (Frewer, Mitchell, Watkins, & 
Matcham, 2016) will be used to provide further insight into the treatment effect of GLPG3970 
over placebo, and will support scenario analyses. The posterior distribution of this treatment 
effect will be estimated, and from this distribution probabilities of reaching at least a certain 
effect (delta) will be derived, e.g. a range of plausible effect size values going from as high as P 
(delta ≤ -3.0) to as low as P (delta ≤ -1.3).  
The chosen framework is as follows: 
− 
Target value (TV) – 3.0 and lower reference value (LRV) – 1.3 
− 
False stop risk 20% and false go risk 10% 
− 
Framework rules: 
• 
Signal detected if P10 <TV and P80 <LRV 
• 
No signal detected if P10 ≥TV 
• 
No conclusion if P10 < TV 
9.3.4.2. 
Analyses for Secondary Efficacy Endpoints 
Continuous efficacy endpoints, including the primary endpoint: mixed models for repeated 
measures (MMRM) to compare treatment groups, with a 90% CI of the treatment difference at 
each time point. 






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10. 
DATA MONITORING 
10.1. 
Data Safety Monitoring Committee 
An Internal Data Safety Monitoring Committee independent from the study will review 
unblinded data during the course of the study. This Committee may involve external medical 
experts (such as an expert in the field of UC and an infectious diseases expert) to support data 
interpretation. The Committee will review unblinded safety data and assess any potential safety 
issues arising during the conduct of the clinical study, including (but not limited to) any potential 
issues in the context of the SARS-CoV-2 pandemic. The process is described in a separate 
‘Internal Safety Monitoring Committee Charter’. 
11. 
SAFETY REPORTING 
11.1. 
Definitions of Adverse Events, Serious Adverse Events, and 
Special Situations 
11.1.1. 
Adverse Events 
An AE is any untoward medical occurrence, new or worsening of any preexisting condition, in a 
clinical study subject administered a medicinal product and which does not necessarily have to 
have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (e.g. an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related. AEs may also include pre- or post-treatment complications that occur 
as a result of CSP-specified procedures, worsening of the targeted disease, overdose, drug 
abuse/misuse reports, or occupational exposure. Preexisting conditions that increase in severity or 
change in nature during or as a consequence of participation in the clinical study will also be 
considered AEs. 
11.1.2. 
Serious Adverse Events 
An SAE is defined as an AE that: 
− 
Results in death. 
− 
Is life-threatening (Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.). 
− 
Requires in-patient hospitalization or prolongation of existing hospitalization. 
− 
Results in persistent or significant disability/incapacity. 
− 
Is a congenital anomaly / birth defect. 
− 
Is medically significant (medical and scientific judgment should be exercised in deciding 
whether other situations should be considered serious such as important medical events that 
might not be immediately life-threatening or result in death or hospitalization but might 


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jeopardize the subject or might require intervention to prevent one of the other outcomes 
listed in the definition above). 
11.1.3. 
Unlisted (Unexpected) Adverse Events/ Reference Safety Information 
An AE is considered unlisted if the nature or intensity is not consistent with the applicable 
product reference safety information. For an IP, the expectedness of an AE will be determined by 
whether or not it is listed in the reference safety information part of the IB. 
11.1.4. 
Adverse Events of Special Interest 
Not applicable. 
11.1.5. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events 
Laboratory abnormalities without clinical significance based on the investigator’s judgment are 
not considered AEs or SAEs. However, laboratory abnormalities (e.g. clinical chemistry, 
hematology, and urinalysis) or other abnormal (clinical study-specific) assessments (e.g. ECG, 
radiography, vital signs) that require medical or surgical intervention, are associated with signs 
and/or symptoms, and/or lead to IP interruption, modification or discontinuation must be 
recorded as an AE or SAE if they meet the definition as described in Sections 11.1.1 and 11.1.2, 
respectively. If the laboratory abnormality is part of a syndrome, the syndrome or diagnosis is to 
be reported (e.g. anemia instead of decreased hemoglobin). 
The following liver enzyme elevations should be reported as SAEs: 
− 
AST or ALT ≥8xULN. 
− 
AST or ALT ≥3xULN with signs of liver damage (total bilirubin >2xULN OR international 
normalized ratio >1.5, and/or with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia [>5%]). 
11.1.6. 
Special Situations 
Special situations are situations that have a possible impact on the safe use of the IP. These 
situations might be or might not be associated with AEs. 
− 
Pregnancy. 
− 
Overdose with IP. 
An overdose of IP is defined as the administration of a quantity of the IP given per 
administration or cumulatively, which is above the recommended dose in the protocol. 
− 
Medication error with IP. 
A medication error with IP is defined as an unintended failure in the drug treatment process 
that leads to, or has the potential to lead to, harm to the subject. 
− 
Product complaint or quality defect of IP. 


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Product complaint or quality defect of IP is defined as complaints or defects of the IP arising 
from potential deviations in the manufacture, packaging, or distribution of the IP. 
− 
Drug interaction or food interaction with IP. 
A drug interaction with IP is defined as a situation in which there is evidence or a suspicion 
that the IP interacts with another drug when both are administered together. 
A food interaction with IP is defined as a situation in which there is evidence or a suspicion 
that the IP interacts with a food when taken together. 
− 
Occupational exposure to IP. 
Occupational exposure to IP is defined as an exposure to the IP as a result of one’s 
professional or non-professional occupation. 
11.2. 
 Assessment of Adverse Events and Serious Adverse Events 
The investigator is responsible for assessing AEs and SAEs for causality and severity. This is the 
basis for the sponsor’s final review and confirmation of accuracy and completeness of event 
information and causality assessments. 
11.2.1. 
Action Taken Regarding Investigational Product  
The action taken must be described by choosing from: 
− 
Dose not changed: In case no action is taken regarding the IP. 
− 
IP permanently discontinued: In case a subject is permanently discontinued from treatment 
or withdrawn from the study by the investigator (who may consult the sponsor’s medical 
monitor). 
− 
IP temporarily discontinued: In case the IP is temporarily discontinued by the investigator 
(who may consult the sponsor’s medical monitor). 
− 
Not applicable: Other situations (e.g. in case an AE started after the last IP administration). 
11.2.2. 
Assessment of Causality 
The investigator is responsible for assessing the causal relationship to IP(s) administration or 
study procedures (e.g. invasive procedures such as venipuncture) based on her/his clinical 
judgment. The following decision choice will be used by the investigator to describe the causality 
assessment between the reported event or laboratory test abnormality and the IP. 
− 
Unrelated: 
Time relationship to IP intake is improbable. Related to other etiologies such as concomitant 
medications or subject's clinical state. 
− 
Unlikely: 
Time relationship to IP intake is improbable (but not impossible). Concomitant disease or 
other drugs provide plausible explanations. 


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− 
Possible: 
Time relationship to IP intake is reasonable. Event or laboratory test abnormality could also 
be explained by disease or other drugs. Information on IP withdrawal may be lacking or 
unclear. 
− 
Probable: 
Time relationship to IP intake is reasonable. Unlikely to be attributed to concurrent disease 
or other drugs. Response to withdrawal is clinically reasonable and rechallenge not required. 
− 
Certain: 
Time relationship to IP intake is plausible. Cannot be explained by concomitant disease or 
other drugs. Response to withdrawal is plausible (pharmacologically, pathologically). Event 
definitive pharmacologically or phenomenologically (i.e. an objective and specific medical 
disorder or a recognized pharmacological phenomenon). Rechallenge satisfactory, if ethical 
and necessary. 
 
It should be emphasized that ineffective treatment (worsening of the disease) should not be 
considered as causally related in the context of AE reporting. 
11.2.3. 
Assessment of Severity 
The severity of AEs should be graded using the CTCAE version current at the time of 
assessment. If a CTCAE criterion does not exist, the investigator should use the grade or 
adjectives: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or 
Grade 5 (fatal) to describe the maximum intensity of the AE. For purposes of consistency with 
the CTCAE, these intensity grades are defined in Table 1. 
Table 1: Grading of AE Severity 
Grade  
Adjective  
Description  
Grade 1  
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated  
Grade 2  
Moderate 
Local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL*  
Grade 3  
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**  
Grade 4  
Life-threatening 
Urgent intervention indicated  
Grade 5  
Death 
Death-related AE  
* 
Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for groceries or clothes, using the 
 
telephone, managing money, etc. 
** 
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
 
bedridden. 


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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. 
11.2.4. 
Outcome 
Each AE must be rated by choosing among: 
− 
Recovered/resolved; 
− 
Recovered/resolved with sequelae; 
− 
Recovering/resolving; 
− 
Not recovered/not resolved; 
− 
Fatal; 
− 
Unknown. 
11.3. 
Instructions for Reporting Adverse Events, Serious Adverse 
Events, Pregnancies, and Other Special Situations  
11.3.1. 
Adverse Events 
The AE reporting period for safety surveillance begins when the subject signs the ICF and ends at 
the subject’s last follow-up visit (the last follow-up visit after the last dose of IP). In this period, 
all new AEs, regardless of cause or relationship, derived by spontaneous, unsolicited reports of 
subjects, by observation and by routine open questioning (such as “How do you feel?”) need to 
be recorded in the source and in the CRF. 
In case an AE is ongoing at the time of the last follow-up visit, the investigator needs to follow-
up 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 11.3.2). 
11.3.2. 
Serious Adverse Events 
Subjects experiencing an SAE or an emergency situation will be examined by a physician as soon 
as possible. The subject will remain under observation as long as medically indicated. 
Appropriate laboratory tests will be performed until all parameters return to normal or are 
otherwise explained or stable. 


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All SAEs, whether or not deemed IP-related, must be recorded on the SAE form and in the CRF. 
The investigator must report each SAE immediately, and under no circumstances should this 
exceed 24 hours following the knowledge of the SAE, as is indicated on page 2 under 
“Emergency Contact Information”. 
The SAE form should at least contain identifiers of the subject and the reporter, SAE term and 
statement of relatedness to the IP, and at a later stage if not yet available within 24 hours, the 
form needs to be completed with a clearly written narrative describing signs, symptoms, and 
treatment of the event, diagnostic procedures, as well as any relevant laboratory data and any 
sequelae. 
Follow-up and outcomes should be reported and documented in the source documents for all 
subjects that experience an SAE. It is important that the information provided on the SAE form 
matches the information recorded on the CRF for the same event. 
Copies of additional laboratory tests, consultation reports, post-mortem reports, hospital case 
reports, autopsy reports, and other documents should be sent when requested and available. Only 
subject identifiers (subject number) should appear on the copies, and all names and initials should 
be blackened and rendered illegible. Follow-up reports relative to the subject’s subsequent course 
must be submitted until the event has subsided or, in case of permanent impairment, until the 
condition stabilizes. 
Any SAEs that occur after the post-treatment follow-up visit but within 30 days of the last dose 
of IP(s), regardless of causality, should also be reported (Emergency Contact Information on 
page 2) but not entered in the CRF. 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 IP(s), he/she should promptly document and report the event to the sponsor by using 
the SAE form. 
11.3.3. 
Pregnancy 
All initial reports of pregnancy in female subjects and pregnancies in partners of male subjects 
included in the clinical study must be recorded and documented in the source documents and on 
the pregnancy form. The investigator must report each pregnancy immediately, and under no 
circumstances should this exceed 24 hours following the knowledge of the pregnancy, as is 
indicated on page 2 under “Emergency Contact Information”.  
All pregnancies should be followed-up until delivery or pregnancy interruption. The investigator 
will contact the subject or partner of the subject after giving consent, at the expected time of 
delivery for 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 
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11.3.4. 
Reporting of Special Situations (Other Than Pregnancy) With or Without 
Associated Adverse Events 
In case a special situation is not associated with an AE, the special situation should be reported 
within 24 hours by using the Special Situations form as is indicated on page 2 under “Emergency 
Contact Information”.  
In case a special situation is associated with an AE, the special situation should be reported 
within 24 hours by using the Special Situations form and the associated AE should be reported as 
specified in Section 11.3.1. 
In case a special situation is associated with an SAE, the special situation should be reported 
within 24 hours by using the SAE form (and not the Special Situations form) and the associated 
SAE should be reported as specified in Section 11.3.2. 
11.4. 
Sponsor Reporting Requirements 
Depending on relevant local legislation or regulations, including the applicable United States 
Federal Drug Administration Code of Federal Regulations, the EU Clinical Trials Directive 
(2001/20/EC) and relevant updates, and other country-specific legislation or regulations, the 
sponsor may be required to expedite reports of SAEs and serious adverse drug reactions or 
suspected unexpected serious adverse reactions (SUSARs) to worldwide regulatory authorities. 
The sponsor or a specified designee will notify worldwide regulatory authorities and the relevant 
IEC/IRB in concerned Member States of applicable SUSARs as outlined in current regulations. 
Assessment of expectedness for SAEs will be determined using the reference safety information 
section in the IB or relevant local label as applicable. 
All concerned investigators will receive a safety letter notifying them of relevant SUSAR reports 
associated with any IP(s). The investigator should notify the IEC/IRB of SUSAR reports as soon 
as is practical, where this is required by local regulatory authorities, and in accordance with the 
local institutional policy. 
12. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This clinical study will be conducted in compliance with this CSP, the current ICH-GCP 
Guideline E6, and applicable local ethical and legal requirements. 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety and well-being of 
clinical study subjects are protected, consistent with the principles that have their origin in the 
Declaration of Helsinki (1996 and successive amendments), 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. 


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


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12.1.4. 
Insurance 
The sponsor shall maintain insurance coverage that is sufficient to cover its obligations and that 
is consistent with human clinical study local regulations. Provided that the subject has been 
treated according to the CSP and sponsor’s instructions, any injury caused to a subject which is 
the direct result of his/her participation to the clinical study shall be covered by the sponsor’s 
insurance, except in case of gross negligence or willful misconduct by the investigator. 
12.1.5. 
Archiving 
The sponsor will archive the content of the Trial Master File (TMF) for at least 25 years after the 
end of the clinical study. 
12.2. 
Reporting 
Where required by IEC/IRB per local requirements, at least once a year the investigator will 
provide the IEC/IRB with a progress report to allow review of the clinical study (see 
Section 12.6.1). At the end of the clinical study, the results of the clinical study will be reported 
in a clinical study report by the sponsor. The population-PK analysis data, exploratory PD 
microbiome, exploratory RNA, and other exploratory disease and/or drug-related biomarker data 
may be reported separately from the main clinical study report. A summary or full report, 
depending on the requirements, will be provided by the sponsor to the investigators, to the 
relevant regulatory authorities, and IECs/IRBs (if required by the applicable regulatory 
requirements) within one year, or 6 months for pediatric studies, after the end of the clinical 
study. 
12.3. 
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, at least 2 weeks prior to the submission 
for publication. The sponsor shall have the right to review it and to make any comments. In 
accordance with generally accepted scientific collaboration principles, co-authorship with any 
staff member sponsor involved in the clinical study, will be discussed and mutually agreed upon 
before submission of any manuscript to a publisher. 


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12.4. 
Investigator’s Responsibilities 
12.4.1. 
Source Data and Data Capture 
The nature and location of all source documents need to be identified and documented to ensure 
that all sources of original data required to complete the CRF are known and are accessible for 
verification by the monitor. 
Source data may be directly captured from devices transferred from third partners (e.g. laboratory 
data) or entered manually into the CRF. The CRF completion guidelines will be provided to each 
site. 
It is recommended that the author of an entry in the source documents should be identifiable. 
Following ICH-GCP guidelines, direct access to sponsor’s representatives to source documents 
must be granted for the purpose of verifying that the data recorded on the CRF are consistent 
with the original source data. 
12.4.2. 
Archiving 
Unless local legislation requires archiving for a longer period, the investigator shall archive the 
content of the clinical investigator site file (ISF) for at least 25 years after the end of the clinical 
study. However, the medical files of subjects shall be archived in accordance with national law. 
The investigator should take measures to prevent accidental or premature destruction of these 
documents. 
Under no circumstance shall the investigator relocate or dispose any clinical study documents 
before having obtained a written approval of the sponsor. 
If it becomes necessary for the sponsor or the appropriate Regulatory Authority to review any 
documentation relating to this clinical study, the investigator must permit access to such reports. 
The subject is granting access to his/her source data by signing the ICF. 
Any difficulty in storing original documents must be discussed with the monitor prior to the 
initiation of the clinical study. 
12.4.3. 
Participation Cards 
If the subjects are not under 24-hour supervision of the investigator or site staff, they must be 
provided with a subject participation card indicating the name of the IP, the clinical study 
number, the investigator's name, and the site’s 24-hour emergency contact number. The subject 
should be advised to keep the participation card in his/her wallet at all times. 
12.5. 
Confidentiality 
The subject will receive all information as required by the EU General Data Protection 
Regulation, namely the identity and contact details of the controller, the contact details of the data 
protection officer, the clinical research purposes, the legal basis for the processing, the recipients 


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of the personal data, the transfer of the personal data to third countries and respective safeguards, 
the retention periods, the fair processing of his data, and all his/her data subject’s rights. All 
details are listed in the ICF. 
All information concerning the product and the sponsor’s operations (such as patent applications, 
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. 
12.6. 
Ethical Considerations 
12.6.1. 
Independent Ethics Committee / Institutional Review Board  
This clinical study can only be undertaken after IEC/IRB approval of this CSP together with all 
relevant documentation. This approval document must be dated and clearly identify the clinical 
study and the related clinical study documents being approved, including the subject 
compensation programs, if applicable. 
During the course of the clinical study, at least the following documents have to be submitted to 
the IEC/IRB, per local requirements: 
− 
Changes to the IB 
− 
Reports of AEs that are serious, unlisted, and associated with the IP (in compliance with 
IEC/IRB, per local requirements) 
− 
CSP amendments 
− 
ICF amendments 
 
After the subject has completed the study, the subject will receive a financial compensation, or 
depending on the country, the study investigator may offer the option of a course of post-study 
medication approved for the treatment of UC, at no cost and for a duration of up to 6 months. 
Subjects will be eligible for compensation in case a subject received at least 1 dose of study drug 
and completed the study, or discontinued early for e.g. safety reasons. In case a subject withdraws 
from the study early, compensation will be pro rata, unless the reason for withdrawal from the 
study is noncompliance, then no compensation will be provided. If the reason for withdrawal is 
noncompliance, there will be no compensation. Any form of compensation and conditions for 
compensation will require approval by an IEC and documented in the ICF. 


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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. 
12.6.2. 
Informed Consent 
The investigator or designated personnel must explain the clinical study and the implications of 
participation (e.g. objectives, methods, anticipated benefits, possible risks) to potential subjects 
according to applicable regulations prior to any clinical study-related activity. Subjects will be 
informed that their participation is voluntary and that they may withdraw from the clinical study 
at any time. They will be informed that choosing not to participate or to withdraw from the 
clinical study will not have an impact on the care the subject will receive for the treatment of 
his/her disease. 
The subject will be given sufficient time to read the ICF and to ask additional questions. After 
this explanation and before entry in the clinical study, the subject’s consent should be 
appropriately recorded by means of the subject's personally dated signature and by the 
investigator’s dated signature. In case the subject is unable to read and/or write, oral consent in 
the presence of at least one impartial witness who was also included when the affected person 
was being informed, may be given. The witness may not be anyone working at the site nor a 
member of the investigating team. The orally given consent shall be documented in writing, dated 
and signed by the witness. After having obtained the consent, a copy of the signed and dated ICF 
must be given to the subject. 
If new information becomes available relevant to the subject’s willingness to participate in the 
clinical study, the subject will be informed in a timely manner by means of an amended ICF. This 
amended ICF will be signed and dated by the subject (or, if applicable, by an independent 
witness) and the investigator to document the willingness of the subject to continue with the 
clinical study. 
This signed and dated amended version will be filed together with the initial signed and dated 
ICF. 
A pregnant partner, who agrees that information will be gathered about her pregnancy and the 
birth, will be asked to sign a specific ICF to participate in the data collection. Data about the 
health of the baby will be collected if the parent(s)/legal guardian(s) agree with the data 
collection and sign a specific ICF. 
Subjects who agree to participate in the study and who have signed informed consent, will be 
given the option to provide additional (and optional) informed consent for the long-term storage 
of left over samples and associated data, collected during the study, for future scientific research.  


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12.7. 
Data Quality Control/Assurance 
12.7.1. 
Monitoring 
Data quality will be assured through Risk-Based Monitoring, medical monitoring, and other 
relevant activities as described in the Data Management Plan or Medical Review Plan and 
monitoring plans available in the TMF. This clinical study will be monitored by sponsor 
representatives according to their current standard operating procedures.  
To guarantee adequate protection of the subjects and to guarantee the quality of the data, the 
sponsor will ensure oversight of any clinical study-related duties and functions carried out on its 
behalf, including clinical study-related duties and functions that are subcontracted to another 
party by the sponsor’s contracted CRO(s).  
A risk-based Quality Management Plan (QMP) is prepared for the study that evaluates potential 
risks in relation to rights, safety, and well-being of the study subjects as well as the data integrity. 
The QMP describes and evaluates all involved stakeholder interfaces having potential critical 
impact on the above. Risks are considered at both the system level (e.g. standard operating 
procedures, computerized systems, personnel, and vendors) and study level (e.g. IP, study design, 
data collection, informed consent process and recording). 
12.7.2. 
Audit and Inspection 
To ensure compliance with relevant regulations, an independent quality assurance representative, 
regulatory authorities and/or IECs/IRBs may review this clinical study. This implies that 
auditors/inspectors will have the right to inspect the clinical study center(s) at any time during 
and/or after completion of the clinical study and will have access to the data generated during the 
clinical study, source documents, and subject's files. By participating in this clinical study, 
investigators agree to this requirement. 
 


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13. 
REFERENCES 
BMJ, B. M. (2020, May 13). British Medical Journal Best Practice. Retrieved from Coronavirus 
disease 2019 (COVID-19) History and exam: https://bestpractice.bmj.com/topics/en-
gb/3000168/history-exam 
FDA CDER. (2016). Ulcerative Colitis: clinical trial endpoints. Guidance for Industry (Draft). 
Food and Drug Administration, Center for Drug Evaluation and Research (CDER). 
Retrieved from Available at: https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/ulcerative-colitis-clinical-trial-endpoints-guidance-industry. 
Feagan, B., Rutgeerts, P., Sands, B., Hanauer, S., Colombel , J.-F., & et al. (2013). Vedolizumab 
as induction and maintenance therapy for ulcerative colitis. N Engl J Med, 369:699-710. 
Fluenz Tetra nasal spray suspension Influenza vaccine (life attenuated, nasal). Summary of 
Product Characteristics. (Mar 27, 2020). 
Frewer, P., Mitchell, P., Watkins, C., & Matcham, J. (2016). Decision-making in early clinical 
drug development. Pharm Stat, 15(3):255-63. 
GI Society. (2020, May 26). Retrieved from Vaccines for inflammatory bowel disease (First 
published in the Inside Tract® newsletter issue 211 – 2019): 
https://badgut.org/information-centre/a-z-digestive-topics/vaccines-for-ibd/ 
Golimumab. Summary of Product Characteristics. (n.d.). 
Lamb CA, Kennedy, N., Raine, T., Hendy, P., Smith, P., Limdi, J., & et al. (2019). British 
Society of Gastroentereology Consensus Guidelines on the management of inflammatory 
bowel disease in adults. Gut, 68(suppl 3):s1-s103. 
Lewis, J., Chuai, S., Nessel, L., Lichtenstein, G., Aberra F, & et al. (2008). Use of the non-
invasive components of the Mayo score to assess clinical response in Ulcerative Colitis. 
INflamm Bowel Dis, 14(12):1660-6. 


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Lewis, J., Chuai, S., Nessel, L., Lichtenstein, G., Aberra, F., & Ellenberg, J. (2008). Use of the 
non-invasive components of the Mayo Score to assess clinical response in Ulcerative 
Colitis. Inflamm Bowel Dis, 14(12), 1660–1666. 
National Center for Immunization and Respiratory Diseases, C. f., Hamborski, J., Roger, A., & 
Wolfe , C. (2017). Epidemiology and prevention of vaccine-preventable diseases. 13th 
Edition. Rotavirus. National Center for Immunization and Respiratory Diseases, Centers 
for Disease Control and Prevention. 
Rutgeerts, P., Sandborn, W., Feagan , B., Reinisch, W., Olson, A., & et al. (2005). Infliximab for 
induction and maintenance therapy for ulcerative colitis. N Engl J Med, 353(23):2462-76. 
Sands, B., Peyrin-Biroulet, L., Loftus, E., Danese, S., Colombel , J.-F., & et al. (2019). 
Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis. N Engl J Med, 
381:1215-1226. 
Schroeder, K., Tremaine, W., & Ilstrup, D. (1987). Coated oral 5-aminosalicylic acid therapy for 
mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med, 
317(26), 1625-1629. 
Schroeder, K., Tremaine, W., & Ilstrup, D. (1987). Coated oral 5-aminosalicylic acid therapy for 
mildly to moderately active ulcerative colitis. A randomized study. 317(26):1625-29. 
Steriod Conversion Calculator. (n.d.). Retrieved from https://www.mdcalc.com/steroid-
conversion-calculator, accessed 17 Oct 2019. 


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Troy, S., Musingwini, G., Halpern, M., Huang, C., Stranix-Chibanda, L., Kouiavskaia, D., & et 
al. (2013). Vaccine poliovirus shedding and immune response to oral polio vaccine in 
HIV-infection and -unifected Zimbabwean infants. J Infect Dis, 208(4):672-678. 
(n.d.). Vedolizumab. Summary of Product Characteristics.  
 
 


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14. 
APPENDICES 
 
 


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Appendix 1: Prednisolone Conversion Table  
Glucocorticoid Name 
Dose Equivalent to 5 mg Prednisolone 
Prednisone 
5 mg  
Betamethasone 
0.6 mg 
Cortisol (hydrocortisone) 
20 mg 
Cortisone 
25 mg 
Deflazacort 
7.5 mg 
Dexamethasone 
0.75 mg 
Methylprednisolone 
4 mg 
Methylprednisolone Acetate 
4 mg 
Methylprednisolone Sodium Succinate 
4 mg 
Paramethasone 
2 mg 
Prednisolone 
5 mg 
Triamcinolone 
4 mg 
Beclometasone Dipropionate 
1.25 mg 
Budesonide 
1.5 mg 
Hydrocortisone Sodium Succinate 
20 mg 
 (Steriod Conversion Calculator) 
 


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Appendix 2: Vaccinations 
Prior to study participation, it is recommended that the subject’s vaccinations be brought up to 
date according to local vaccination standards.  
Live or attenuated vaccines (including, but not limited to varicella and inhaled flu vaccine) are 
prohibited within 30 days prior screening, throughout the study and up to the follow-up visit 
(Lamb CA, et al., 2019).  
Subjects should be advised to avoid routine household contact with persons vaccinated with 
live/attenuated vaccine components. General guidelines suggest that a study subject’s exposure to 
household contacts should be avoided for the below stated time periods:  
− 
Varicella or attenuated typhoid fever vaccination – avoid contact for 4 weeks following 
vaccination  (GI Society, 2020) 
− 
Oral polio vaccination - avoid contact for 6 weeks following vaccination (Troy, et al., 2013) 
− 
Attenuated rotavirus vaccine - avoid contact for 15 days following vaccination (National 
Center for Immunization and Respiratory Diseases, Hamborski, Roger, & Wolfe , 2017)  
− 
Inhaled flu vaccine - avoid contact for 1 week following vaccination (Fluenz Tetra nasal 
spray suspension Influenza vaccine (life attenuated, nasal). Summary of Product 
Characteristics., 2020)  
Inactivated vaccines (such as inactivated flu vaccines) should be administered according to local 
vaccination standards whenever medically appropriate; however, there are no available data on 
the concurrent use of GLPG3970 and its impact on immune responses following vaccination. 


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G al a p a g o s  
  C O N FI D E N TI A L  
 
D o c i d : 1 3 8 2 2  
G L P G 3 9 7 0 -C L- 2 1 0  
-9 1 - 
 
A p pe n di x  9 : Al g orit h m f or Ele v ate d Li ver F u ncti o n Tests  
 
A S T or A L T i ncre ase t o  
V al ue R a n ge  
≥1. 5 x t o 
3 x U L N  
≥3 x t o < 5 x U L N  
≥5 x t o < 8 x U L N  
≥3 x U L N wit h si g ns 
of li ver da ma ge 1 
≥8 x U L N  
I P Acti o n 
C o nti n ue as 
pla n ne d  
Re d uce or 
i nterr u pt I P f or 
at least 2  wee ks  
Cl ose 
o bser vati o n 2  
Interr u pt I P f or 
at least 2  wee ks  
Cl ose 
o bser vati o n 2 
Disc o nti n ue I P 2 
Disc o nti n ue I P 2 
 
 
 
 
↙ ↘ 
 
After at least 
2  wee ks  
A S T a n d A L T < 3 x U L N  
 
A S T or A L T ≥3 x U L N  
  
W ee kl y L F Ts f or t he first 2  wee ks 
( bi wee kl y f or t he f oll o wi n g 
wee ks, or m ore fre q ue ntl y at 
i n vesti gat or’s discreti o n) 
 
Disc o nti n ue I P  
Re p ort S A E a n d c o m plete li ver e ve nt pa ge f or a n y of 
a b n or malities liste d bel o w 3: 
- 
A S T/ A L T i ncrease ≥8 x U L N  
- 
A S T/ A L T i ncrease ≥3 x U L N wit h si g ns of li ver 
da ma ge 1  
 
1 Si g ns of li ver da ma ge:  
− 
t otal bilir u bi n ≥2. 0 x U L N O R i nter nati o nal n or malize d rati o > 1. 5, a n d/ or  
− 
s y m pt o ms: a p peara nce of fati g ue, na usea, v o miti n g, ri g ht u p per a b d o mi nal q ua dra nt pai n or te n der ness, fe ver, ras h a n d/ or e osi n o p hilia ( > 5 %)  
2 Cl ose o bser vati o n rec o m me n dati o ns:  
− 
M o nit or 2  t o 3  ti mes per wee k all of t he f oll o wi n g para meters: A L T, A S T, al kali ne p h os p hatase, t otal bilir u bi n, e osi n o p hils, I N R. If l ocal 
re g ulati o ns all o w, h o me visits ca n be perf or me d if s u bjects ca n n ot c o me t o t he cli nical st u d y ce nter. 
− 
Fr e q ue nc y of r etesti n g c a n be re d uce d t o o nce a wee k or less if a b n or malities sta bilize or t he I P has bee n disc o nti n ue d; h o we ver, m o nit ori n g 
mi g ht still be nee de d m ore fre q ue ntl y ta ki n g i nt o c o nsi derati o n t he sta n dar d of care a n d/ or c ha n ges t o t his.  
− 
Base d u p o n i n vesti gat or’s disc reti o n gastr oe nter ol o g y or he pat ol o g y c o ns ultati o ns, a d diti o nal ser ol o g y testi n g, i ma gi n g a n d pat h ol o g y 
assess me nts ma y be re q uire d . 
− 
Re -q uer y hist or y of s y m pt o ms, pri or a n d c o nc urre nt diseases, c o nc o mita nt me dicati o n a n d n o n -prescri pti o n me dici nes, her bal,  dietar y 
s u p ple me nts, alc o h ol use, recreati o nal dr u g use, s pecial diets. 
− 
R ule o ut all of t he f oll o wi n g: ac ute viral he patitis, a ut o i m m u ne he patitis, alc o h olic he patitis, n o n -alc o h olic fatt y he patitis, h y p o xic/isc he mic 
he patitis, biliar y tract disease, a n d c h olestasis. 
− 
Re -q uer y e x p os ure t o e n vir o n me ntal c he mical a ge nts.  
3 T he f oll o wi n g ste ps s h o ul d be f oll o we d:  
− 
T he site s h o ul d i m me diatel y c o ntact t he s u bject a n d re q uire t he s u bject t o disc o nti n ue I P i m me diatel y. T he s u bject s h o ul d be as ke d t o ret ur n 
t o t he site wit hi n a 4 8-h o ur wi n d o w fr o m a ware ness of t he res ult.  
− 
A f ull e val uati o n of vari o us ca uses of he patitis  s h o ul d be c o n d ucte d (i.e., i nfecti o us, alc o h ol, me dicati o ns, a nat o mical).  


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










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SIGNATURE PAGE – SPONSOR 
Study Title: 
A randomized, double-blind, placebo-controlled, multicenter study to 
evaluate the safety, tolerability, efficacy, and pharmacokinetics of 
GLPG3970, administered orally for 6 weeks, in adult subjects with 
moderately to severely active ulcerative colitis 
CSP Version: 
1.0 
Date: 29 May 2020 
 
 
This CSP has been reviewed and approved by the sponsor to ensure compliance with this CSP, 
the current ICH-GCP Guideline E6, and applicable local ethical and legal requirements. 
 
 
 
  
  
Medical Leader 
 Signature 
 Date 
 
 
 


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SIGNATURE PAGE – INVESTIGATOR 
Study Title: 
A randomized, double-blind, placebo-controlled, multicenter study to 
evaluate the safety, tolerability, efficacy, and pharmacokinetics of 
GLPG3970, administered orally for 6 weeks, in adult subjects with 
moderately to severely active ulcerative colitis 
CSP Version: 
1.0 
Date: 29 May 2020 
 
 
I, the undersigned, have read this CSP and will conduct the study as described in compliance with 
this CSP, the current ICH-GCP Guideline E6, and applicable local ethical and legal requirements. 
 
 
 
  
  
Investigator Name 
 Signature 
 Date 
 



SAP_001.pdf: 
-1- 
 
 
 
 
Confidentiality Statement 
The information contained in this document is privileged and confidential. It is the property of Galapagos NV and 
may not be used, disclosed, reproduced or otherwise disseminated within your organization or communicated to any 
third parties without the express written authorization of Galapagos NV. 
 
 
STATISTICAL ANALYSIS PLAN  
Project Number: 
GLPG3970 
 
Study Number: 
GLPG3970-CL-210 
Study Title: 
A randomized, double-blind, placebo-controlled, multicenter study to 
evaluate the safety, tolerability, efficacy, and pharmacokinetics of 
GLPG3970, administered orally for 6 weeks in adult subjects with 
moderately to severely active ulcerative colitis 
Development Phase: 
2 
Status: 
Final 
Version: 
3.0 
Date: 
16-Jun-2021 
EudraCT: 
2020-000659-11 
IND: 
Not applicable 
Sponsor: 
Galapagos NV, Generaal De 
Wittelaan L11 A3, 2800 
Mechelen, Belgium 
 
Biostatistician: 
   
Medical Leader: 
 
 


-2- 
 
TABLE OF CONTENTS 
VERSION HISTORY .................................................................................................................................................. 6 
LIST OF ABBREVIATIONS ......................................................................................................................................... 7 
1. 
INTRODUCTION ........................................................................................................................................... 10 
2. 
STUDY DESIGN AND OBJECTIVES ................................................................................................................. 10 
2.1. 
STUDY OBJECTIVES ......................................................................................................................................... 10 
2.1.1. 
Primary Objective ................................................................................................................................. 10 
2.1.2. 
Secondary Objectives ........................................................................................................................... 10 
2.1.3. 
Other Objectives ................................................................................................................................... 10 
2.2. 
STUDY ENDPOINTS ......................................................................................................................................... 10 
2.2.1. 
Primary Endpoint .................................................................................................................................. 10 
2.2.2. 
Secondary Endpoints ............................................................................................................................ 10 
2.2.3. 
Other Endpoints.................................................................................................................................... 11 
2.3. 
STUDY DESIGN .............................................................................................................................................. 11 
2.4. 
CLINICAL STUDY PROTOCOL (CSP) AND CSP AMENDMENTS .................................................................................. 12 
2.5. 
SCHEDULED OF ASSESSMENTS .......................................................................................................................... 12 
2.6. 
SAMPLE SIZE JUSTIFICATION ............................................................................................................................. 17 
2.7. 
RANDOMIZATION AND BLINDING ...................................................................................................................... 18 
2.7.1. 
Randomization ..................................................................................................................................... 18 
2.7.2. 
Blinding and Unblinding ....................................................................................................................... 18 
3. 
STUDY ESTIMANDS ..................................................................................................................................... 19 
4. 
GENERAL METHODOLOGY ........................................................................................................................... 20 
4.1. 
ANALYSIS SETS .............................................................................................................................................. 20 
4.1.1. 
All Screened Analysis Set ...................................................................................................................... 20 
4.1.2. 
All Randomized Analysis Set ................................................................................................................. 20 
4.1.3. 
Safety Analysis Set ................................................................................................................................ 20 
4.1.4. 
Full Analysis Set .................................................................................................................................... 21 
4.1.5. 
Pharmacokinetic Analysis Set ............................................................................................................... 21 
4.2. 
RANDOMIZED VERSUS ACTUAL TREATMENT GROUP ............................................................................................. 21 
4.3. 
ANALYSIS PERIODS AND ANALYSIS TIME POINTS ................................................................................................... 21 
4.3.1. 
Relative Day.......................................................................................................................................... 21 
4.3.2. 
Analysis Periods .................................................................................................................................... 22 
4.3.3. 
Analysis Windows ................................................................................................................................. 23 
4.3.4. 
Definition of Baseline ........................................................................................................................... 29 
4.3.5. 
Selection and Use of Analysis Visits ...................................................................................................... 29 
4.3.6. 
Handling of Missing Data ..................................................................................................................... 30 
4.3.6.1. 
Handling of Missing Date-Time Data ........................................................................................................... 30 
4.3.6.2. 
Handling of Missing Result Data .................................................................................................................. 30 
4.3.6.3. 
Censoring of Time to Event Data ................................................................................................................. 30 
4.3.7. 
Handling of Values Below or Above a Threshold .................................................................................. 30 
4.3.8. 
Handling of Outliers ............................................................................................................................. 31 
4.3.9. 
Stratification Factors ............................................................................................................................ 31 
4.4. 
PRESENTATION OF RESULTS.............................................................................................................................. 31 
4.4.1. 
Presentation of Treatment Groups ....................................................................................................... 31 
4.4.2. 
Calculation of Descriptive Statistics...................................................................................................... 31 
4.4.3. 
Calculation of Percentages ................................................................................................................... 32 




-4- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3. 
SAFETY ANALYSES .......................................................................................................................................... 53 
6.3.1. 
Adverse Events ..................................................................................................................................... 53 
6.3.1.1. 
Definition of Treatment-Emergent Adverse Events .................................................................................... 53 
6.3.1.2. 
Coding of Reported Terms ........................................................................................................................... 53 
6.3.1.3. 
Allocation of Adverse Events to Analysis Periods ........................................................................................ 53 
6.3.1.4. 
Treatment Relatedness ............................................................................................................................... 54 
6.3.1.5. 
Worst-Case Selections ................................................................................................................................. 54 
6.3.1.6. 
Calculation of Relative Days and Duration .................................................................................................. 54 
6.3.1.7. 
Events of Special Interest ............................................................................................................................ 55 
6.3.1.8. 
Presentation of Results ............................................................................................................................... 55 
6.3.1.9. 
EudraCT Adverse Events Reporting ............................................................................................................. 55 
6.3.2. 
Laboratory Safety ................................................................................................................................. 56 
6.3.2.1. 
Available Data.............................................................................................................................................. 56 
6.3.2.2. 
Derivation Rules .......................................................................................................................................... 56 
6.3.2.3. 
Definition of Toxicity Grades ....................................................................................................................... 56 
6.3.2.4. 
Definition of Non-Graded Abnormalities .................................................................................................... 56 
6.3.2.5. 
Urinalysis Tests with Categorical Results ..................................................................................................... 57 
6.3.2.6. 
Treatment-Emergent Principle .................................................................................................................... 57 
6.3.2.7. 
Worst-Case Principle ................................................................................................................................... 57 
6.3.2.8. 
Hepatotoxicity ............................................................................................................................................. 58 
6.3.2.9. 
Presentation of Results ............................................................................................................................... 58 
6.3.3. 
Electrocardiogram ................................................................................................................................ 59 
6.3.3.1. 
Available Data.............................................................................................................................................. 59 
6.3.3.2. 
Derivation Rules .......................................................................................................................................... 59 
6.3.3.3. 
Abnormalities .............................................................................................................................................. 59 
6.3.3.4. 
Presentation of Results ............................................................................................................................... 60 
6.3.4. 
Vital Signs ............................................................................................................................................. 61 
6.3.4.1. 
Available Data.............................................................................................................................................. 61 
6.3.4.2. 
Derivation Rules .......................................................................................................................................... 61 
6.3.4.3. 
Abnormalities .............................................................................................................................................. 61 
6.3.4.4. 
Treatment-Emergent Principle .................................................................................................................... 61 
6.3.4.5. 
Worst-Case Abnormality ............................................................................................................................. 61 
6.3.4.6. 
 
61 
6.3.5. 
Physical Examinations .......................................................................................................................... 62 
6.3.6. 
SARS-CoV-2 Infection ............................................................................................................................ 62 
6.3.7. 
Subgroup Analyses ............................................................................................................................... 62 
6.4. 
PHARMACOKINETIC ANALYSIS ........................................................................................................................... 63 
6.4.1. 
Available Data ...................................................................................................................................... 63 
6.4.2. 
Presentation of Results ......................................................................................................................... 63 
 
 
 
 
 
 
6.6. 
CHANGES TO THE PLANNED ANALYSES, NOT COVERED BY PROTOCOL AMENDMENTS .................................................. 65 


-5- 
 
7. 
REFERENCES ................................................................................................................................................ 66 
APPENDICES ......................................................................................................................................................... 68 
APPENDIX I: LABORATORY: TOXICITY GRADING ...................................................................................................... 68 
APPENDIX II: VITAL SIGNS AND ELECTROCARDIOGRAM GRADING ........................................................................................ 75 
APPENDIX III: MAYO SCORING SYSTEM ......................................................................................................................... 77 
 
 
 
 
 
 
 
 


-6- 
 
VERSION HISTORY 
SAP Amendment # 
Date 
Description of changes 
SAP Version V1.0 
13-Nov-2020 
 
SAP Version V 1.1 
27-Jan-2021 
Section 6.1.1: Updated 
derivation of Duration of UC 
(years) 
SAP version 2.0 
14-jun-2021 
Several updates including 
analysis and derivation of the 
primary endpoint. 
SAP version 3.0 
16-jun-2021 
Update typo to sensitivity 
analysis 1 for primary 
endpoint and a clarification to 
the SAS code in the appendix. 
  
 
 
 
 


-7- 
 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic chemical 
AUC 
area under the curve 
BLOQ 
below lower limit of quantification 
BMI 
body mass index 
CI 
confidence interval 
CL 
clearance 
CMH 
Cochran-Mantel-Haenszel 
CRF 
case report form 
CRO 
contract research organization 
CRP 
c-reactive protein 
CSP 
clinical study protocol 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
trough concentration 
CTx 
serum C terminal telopeptide type I collagen 
CV 
coefficient of variation 
 
 
ECG 
electrocardiogram 
ED 
early discontinuation 
ES 
endoscopy subscore 
FAS 
full analysis set 
FU 
follow-up 
H 
high, above the upper limit of the normal range 
HDL 
high-density lipoprotein 
High 
high specificity test 
 
 
HR 
heart rate 
hsCRP 
high sensitivity C-reactive protein 
 
 
 
 


-8- 
 
ICF 
informed consent form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IP 
investigational product 
IXRS 
interactive voice/web response system 
L 
low, below the lower limit of the normal range 
LDL 
low-density lipoprotein 
LLN 
lower limit of the normal range 
LLOQ 
lower limit of quantification 
LRV 
lower reference value 
LS 
least squares 
LSM 
least square mean 
MCII 
minimum clinically important improvement 
MedDRA 
medical dictionary for regulatory activities 
 
 
MMRM 
mixed models for repeated measures 
n 
number of valid observations 
N 
normal, with the limits of the normal range 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NRI 
non-responder imputation 
OC 
observed cases 
PASS 
patient acceptable symptom state  
 
 
PGA 
physician’s global assessment score 
PK 
pharmacokinetic(s) 
 
 
PR 
pulse rate 
q.d. 
once daily 
QTc 
corrected QT interval 
QTcF 
QT interval corrected for the heart rate using Fridericia’s formula 
RA 
rheumatoid arthritis 
RB 
rectal bleeding 
Reg 
regular test 
 
 
RR 
respiratory rate 


-9- 
 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDTM 
study data tabulation model 
SE 
standard error 
SF 
stool frequency 
SI 
SMC 
standard international 
Safety Monitoring Committee 
TEAE 
treatment-emergent adverse event 
TLF 
tables, listings and figures 
TV 
target value 
UC 
ulcerative colitis 
 
 
ULN 
upper limit of the normal range 
ULOQ 
upper limit of quantification 
 
 
WHO 
World Health Organization 








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Table 1 Schedule of Assessments 
 
EVENT 
SCREENING  
PERIOD 
TREATMENT PERIOD 1, 2 
FOLLOW-UP 
PERIOD3 
Study Visit 
S1 
S24 
1 
2 
3 
4 
5 
ED3 
Follow-up Visit 
Study Day (D) ± Days  
-35 to 0 
1 
8 ± 2 
15 ± 2 
29 ± 2 
43 ± 2 
 
14± 3 after last 
IP dosing 
On-site visit 
 
 
 
 
 
 
 
 
 
Telephone call 
 
 
 
 
 
 
 
 
 
Informed consent (Section 8.3 of CSP) 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria (Sections 6.1 and 6.2 of CSP) 
 
 
 
 
 
 
 
 
 
Demographics (Section 8.3 of CSP) 
 
 
 
 
 
 
 
 
 
Medical and smoking history including UC history 
(Section 8.3 of CSP)  
 
 
 
 
 
 
 
 
 
Physical examination (Section 8.5.3 of CSP) 
 
 
 
 
 
 
 
 
 
Body weight and height5 (Section 8.5.3 of CSP) 
 
 
 
 
 
 
 
 
 
Vital signs (Section 8.5.4 of CSP) 
 
 
 
 
 
 
 
 
 
12-Lead triplicate ECG (Section 8.5.5 of CSP) 
 
 
 
 
 
 
 
 
 
                                                 
1 On dosing days, all assessments are to be performed within 3 hours predose, unless otherwise specified. 
2 Subjects must come for the study visits at baseline (Visit 1), Day 15 (Visit 3), and Day 43 (Visit 5) and the early discontinuation (ED) visit, if applicable in the morning in a 
fasting state (no food intake for at least 8 hours). 
3 Subjects who discontinue treatment early will be requested to return for an ED visit to complete all Visit 5 assessments and to return for a follow-up (FU) visit 14±3 days 
after last IP administration. 
4 The endoscopy procedure will be done at Screening Visit 2 once the other in- and exclusion criteria have been confirmed at Screening Visit 1. 
5 Height only to be measured at Screening Visit 1. 


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EVENT 
SCREENING  
PERIOD 
TREATMENT PERIOD 1, 2 
FOLLOW-UP 
PERIOD3 
Study Visit 
S1 
S24 
1 
2 
3 
4 
5 
ED3 
Follow-up Visit 
Study Day (D) ± Days  
-35 to 0 
1 
8 ± 2 
15 ± 2 
29 ± 2 
43 ± 2 
 
14± 3 after last 
IP dosing 
QuantiFERON TB Gold test (Section 8.5.2 of CSP) 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 RT-PCR test6 
 
 
 
As needed 
SARS-CoV-2 serology test 
 
 
 
As needed 
Randomization (Section 6.5.1 of CSP) 
 
 
 
 
 
 
 
 
 
Blood collection 
 
 
 
 
 
 
 
 
 
• Safety (hematology, coagulation, chemistry) 
(Section8.5.2 of CSP) 
 
 
7 
 
7 
 
7 
7 
 
• Serology (HBV, HCV, HIV) (Section 8.5.2 of 
CSP) 
 
 
 
 
 
 
 
 
 
• Pregnancy test serum (all WOCBP females) 
(Section 8.5.2 of CSP)  
 
 
 
 
 
 
 
 
 
• FSH test (WOnonCBP, non-surgical 
postmenopausal women) (Section 8.5.2 of CSP) 
 
 
 
 
 
 
 
 
 
• PK (Section 8.6 of CSP) 
 
 
8 
 
9 
9 
10 
 
 
                                                 
6 RT-PCR from a nasal swab sample at screening may be done at an earlier screening visit on a different day than the other screening assessments (after signature of the study 
informed consent form) and RT-PCR from a nasal swab sample and serology testing at a visit on Day -3, and throughout the study as needed when subject presents signs and 
symptoms of SARS-CoV-2 infection. 
7 Fasted glucose, fasted insulin, and HOMA-IR only at baseline (Visit 1), Day 15 (Visit 3), and Day 43 (Visit 5) and the ED visit, if applicable. 
8 Visit 1:  predose (within 30 minutes prior to dosing), 1 sample within [0.5-1.5 hours postdose]; 1 sample within [2–2.5 hours postdose] and 1 sample within [3-4 hours 
postdose]. 
9 Visit 3 and 4: predose (within 30 minutes prior to dosing). 
10 Visit 5: 1 sample predose (within 30 minutes prior to dosing) and 1 sample within [4-6 hours postdose].  


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EVENT 
SCREENING  
PERIOD 
TREATMENT PERIOD 1, 2 
FOLLOW-UP 
PERIOD3 
Study Visit 
S1 
S24 
1 
2 
3 
4 
5 
ED3 
Follow-up Visit 
Study Day (D) ± Days  
-35 to 0 
1 
8 ± 2 
15 ± 2 
29 ± 2 
43 ± 2 
 
14± 3 after last 
IP dosing 
Urine collection  
 
 
 
 
 
 
 
 
 
• Safety12 (Section 8.5.2 of CSP) 
 
 
 
 
 
 
 
 
 
Stool sample collection13  
 
 
 
 
 
 
 
 
 
• Microbiology  
 
 
 
 
 
 
 
 
 
• Microbiome (sampling before IP administration) 
(Section 8.7.3.2 of CSP) 
 
 
 
 
 
 
 
 
 
                                                 
11 
 
12 On dosing days, safety urine samples will be taken predose, on the same visit day. Visit 1 and 5: predose and 2 hours postdose. Calcium and phosphate should only be 
evaluated at Visits 1 and 5. 
13 At Screening Visit 1, a stool sample should be collected during the visit. If not possible, the subject can collect the sample at home within 24 hours after start of Screening. 
For Visits 1, 3, and 4, stool samples can be collected within 24 hours prior to the visit or during the visit. At Visit 5 (Day 43) and ED visit, if applicable, when the stool 
sample must be taken before the bowel preparation for endoscopy, stool can be collected more than 24 hours before the visit. One sample can be used for different 
assessments. 




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-17- 
 
 
2.6. 
Sample Size Justification 
A sufficient number of subjects with UC will be screened in order to have 30 subjects 
randomized (20 planned subjects on GLPG3970 and 10 planned subjects on placebo).  
The 30 subjects randomized in the study, are expected to be sufficient to provide preliminary 
insight in the safety, tolerability and PK of GLPG3970 in UC patients. In case of drop-outs due to 
SARS-CoV-2 infection, additional subjects may be randomized on top of the planned sample 
size. The number of additional subjects randomized will not exceed the number of subjects 
dropping out of the study in relation to SARS-CoV-2. Randomization of additional subjects will 
ultimately be decided by the sponsor before any study lock or related unblinding has occurred. 
For the efficacy objective, the operating characteristics of the chosen decision framework for the 
most important endpoint (MCS change from baseline at Week 6) at a sample size of 30 subjects 
(10 on placebo and 20 on GLPG3970) are represented in the following graph and table, and were 
deemed acceptable. A common standard deviation of 3.3 was assumed in this small study. Lower 
Reference Value and Target Value for the decision framework were determined based on the 
published studies and the therapies in development or on the market. They were identified by the 
project team as the lowest delta of possible interest and the best case scenario for efficacy 
outcome respectively. 
True 
Treatment 
Difference In 
MCS Change 
From Baseline 
At Week 6 
Signal Score 
Probability 
Of Outcome 
PLC: placebo; GLPG: GLPG3970 
-3.0 
Signal detected 
0.673 
No conclusion 
0.220 
No signal detected 
0.107 
-1.3 
Signal detected 
0.205 
No conclusion 
0.289 
No signal detected 
0.506 
 
 
 


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-18- 
 
2.7. 
Randomization and Blinding 
2.7.1. 
Randomization 
At screening, subjects will be assigned a subject identification number. When a subject is 
confirmed to be eligible for the clinical study, the subject will be randomized at visit 1. 
Allocation of each subject to a given treatment will be done using a centralized electronic system 
(interactive voice/web response system [IXRS]). Investigational product (IP) will be randomized 
in a 2:1 ratio to GLPG3970 or placebo. 
2.7.2. 
Blinding and Unblinding 
This is a randomized, double-blind clinical study. The subjects and the entire clinical study team, 
including the investigators, clinical study coordinators, and sponsor personnel are blinded to 
treatment assignment. 
Blinded and packaged medication will be provided to the site. All IP formulations will be 
identical in appearance, shape, smell and taste and will be packaged in the proper proportion to 
assure desired dosages and maintenance of the blinding. 
The blind can be broken by the investigator for the safety of a subject. The investigator is 
encouraged to discuss considerations to break the blind with the medical leader, whenever 
possible and where the situation allows. However, the responsibility to break the treatment code 
in emergency situations resides solely with the investigator. The investigator is not required to 
discuss unblinding beforehand if he or she feels rapid emergency unblinding is necessary, but is 
required to inform the sponsor in within 24 hours after unblinded has occurred. 
The blind can be broken by the investigator via IXRS by the investigator.  
If the blind is broken for any reason during the course of the clinical study, the moment on which 
the blind was broken and all other relevant information will be documented by the study site. The 
reason for breaking the blind will be indicated and justified in the source documentation. 
If an AE leads to unblinding, the AE will be given as the reason for unblinding. All subjects who 
are unblinded should, where possible, complete the follow-up visit assessments 14±3 days after 
unblinding. Any AEs will be followed until resolution. 
The code-break information (via IXRS vendor) will be provided to the bioanalytical laboratory 
responsible for PK sample analysis, the person responsible for providing unblinded data to the 
internal safety monitoring committee (SMC), to the pharmacovigilance vendor for serious 
adverse event (SAE) reporting purposes, and, if applicable, to the contract research organization 
(CRO) performing population PK/PD analyses.  
 


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-19- 
 
3. 
STUDY ESTIMANDS 
Estimand for the primary study objective: 
Attribute 
Details 
Treatments 
GLPG3970 (400 mg q.d.) vs. Placebo 
Population 
• Population target defined through the 
inclusion/exclusion criteria (see CSP).  
• Analysis Set: Full Analysis Set (FAS) 
defined as all randomized subjects 
who have received at least 1 dose of 
IP. 
Endpoint 
Change from baseline in total MCS at Week 
6. 
Population-level summary 
Difference (GLPG3970 minus placebo) in 
least square means (LSM). For further details 
see study SAP section 6.2.2.2. 
Intercurrent events and strategies to handle 
those 
• Early treatment discontinuation (for 
any reason) is handled using the  
hypothetical strategy 
• Other intercurrent events (e.g. major 
protocol violations, intake of 
prohibited medication, lack of 
compliance) are handled using the 
treatment policy strategy (i.e. they are 
ignored) 
 
 


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Estimand for the secondary study objective: 
Attribute 
Details 
Treatments 
GLPG3970 (400 mg q.d.) vs. Placebo 
Population 
• Population target defined through the inclusion/exclusion 
criteria (see CSP).  
• Analysis Set: Safety Analysis Set, defined as all subjects 
who were administered study drug at least once. 
Endpoint 
Presence of TEAE  
Population-level 
summary 
Percentage of subjects with TEAEs. 
Intercurrent events and 
strategies to handle 
these 
• Early treatment discontinuation (for any reason): handled 
using the while-on-treatment strategy.  
• Other intercurrent events (e.g. major protocol deviations, 
intake of prohibited/rescue medication, lock of compliance): 
handled using the treatment policy strategy (i.e. adverse 
events are counted regardless the occurrence of these other 
events). 
 
 
4. 
GENERAL METHODOLOGY 
4.1. 
Analysis Sets 
The analysis set will always be indicated in a subtitle in the table, listing or figure. 
4.1.1. 
All Screened Analysis Set 
All subjects who signed and dated an informed consent form (ICF). 
4.1.2. 
All Randomized Analysis Set 
All screened subjects who were randomized into the clinical study. 
4.1.3. 
Safety Analysis Set 
All subjects who used at least 1 dose of IP. 
 




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When the concerned date is the equal to or later than the reference date: 
Relative day (days) = concerned date-reference date +1 day 
where: 
− 
The concerned date could be the measurement date of the assessment, or the start or end date 
of the event. 
− 
The reference date default is the date of the first dose of study drug administration, unless 
specified otherwise. 
− 
Date implies a complete date having day, month and year available. Unless otherwise 
specified, the relative day will remain missing when it cannot be calculated due to absence or 
incompleteness of the concerned and/or reference dates. 
The general terms of this formula also apply when similar relative timings are required in other 
time units, for example in minutes. 
4.3.2. 
Analysis Periods 
For treated subjects, adverse events (AEs) and assessments will be allocated to analysis periods 
according to Table 2. 
Table 2 
Analysis Periods 
Analysis Period 
Start Analysis Period 
End Analysis Period 
Screening 
Date of signing the ICF, with 
00:00 added as time part 
Date (time) of first study drug 
administration - 1 minute 
Treatment 
Date (time) of first study drug 
administration.  
Study termination date (i.e. 
date of last contact), with 
23:59 added as time part  
 
The last analysis period will always end on the date of last contact. 
For every subject, all assessments performed and all events occurring during the study are 
expected to have a (start) date (/time) between the date of informed consent (IC) signature and 
the last contact date. Obvious exemptions are historical records like medical history or 
concomitant therapies having started before the study. 
Assessments and events will be allocated to one of these analysis periods by incidence, meaning 
placing the record (start) date and time between the matching start and end dates and times of the 
subject’s own analysis periods, assuming completeness of all dates and times, or further 
determined by the presence of timing indicators such as tick boxes flagging AEs starting 
before/after first study drug administration, or by worst-case considerations for AEs if needed. 
For the parameters for which the time of assessment was not planned to be collected, their 
assessment on the day of first IP administration will be considered as baseline and will be 
reported under the ‘Screening’ analysis period with the exception of AEs. 


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4.3.3. 
Analysis Windows 
For the efficacy, PK, 
and safety assessments, all data (including data obtained at unscheduled 
visits) will be placed into time windows based on the relative day (ADY) of the assessment 
(relative to the first dose of IP), according to the following allocation tables: 
For endpoints with multiple components, analysis windows will be derived separately for each 
component/parameter. 
 


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Table 3: Analysis visit window for non-PK data 
 
Visit date and time 
Relative day 
(ADY) 
Assessment visit (VISIT) 
Time window 
(in ADY)* 
Target day 
Analysis visit 
(AVISIT) 
On or before first study 
drug administration 
≤1 
Last assessment at any point in time before 
first study drug administration 
≤1 
1 
Baseline 
After first study drug 
administration  
>1 
Any scheduled (non follow-up), 
unscheduled, or early discontinuation visit 
2 to 12 
8 
Week 1 
13 to 22 
15 
Week 2 
23 to 36 
29 
Week 4 
37 to 49* 
43 
Week 6 
Follow-up 
CRF collected 
follow-up visit 
 
Follow-up 
*For Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6, time windows will be applied excluding assessments performed more 
than 2 days after the last dose of IP. Except for Endoscopy and
 where assessments performed more than 7 days after 
last dose will be excluded and the Week 6 analysis window will be 37 to 52 days.  
 
 
 


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Table 4: Analysis visit window for the daily diary data 
Visit date and time 
Relative day 
(ADY) 
Assessment visit (VISIT) Time window (in ADY or 
relative to last dose of IP for 
the follow-up)* 
Analysis visit 
(AVISIT) 
Before first study drug 
administration 
<1 
All days before the first 
IP administration. 
<1 
Baseline 
Same as or after first 
study drug administration  
≥ 1 
Any scheduled (non 
follow-up), unscheduled, 
or early discontinuation 
visit 
1 to 7 
Week 1 
8 to 14 
Week 2 
15 to 21 
Week 3 
22 to 28 
Week 4 
29 to 35 
Week 5 
36 to 42 
Week 6 
Follow-up 
1 to 7, where day 1 = first day 
after the last dose of IP 
Week 7 
8 to 14, where day 1 = first day 
after the last dose of IP 
Week 8 
*For Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6, time windows will be applied excluding assessments performed more 
than 2 days after the last dose of IP.  
 
 


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Table 5: Analysis Visit Window for PK data 
 
Visit date and 
time 
Relative 
day 
(ADY) 
Assessment visit 
(VISIT) 
Time 
window 
(in 
ADY)* 
Target 
day 
Analysis 
visit 
(AVISIT) 
Analysis time point (ATPT) 
Before first 
study drug 
administration 
<1 or 
pre-dose 
at 
ADY=1 
Last assessment at any 
point in time before first 
study drug administration 
<1 or 
pre-dose 
at 
ADY=1 
1 
Baseline 
Pre-dose (within 30 minutes prior 
to dosing) 
Same as or after 
first study drug 
administration  
≥ 1 
Any scheduled (non 
follow-up), unscheduled, 
or early discontinuation 
visit 
1 
1 
Day 1 
As indicated in the database: 
0.5-1.5, 2-2.5, 3-4 hours post-dose 
13 to 22 
15 
Week 2 
As indicated in the database: 
Pre-dose (within 30 minutes prior 
to dosing) 
23 to 36 
29 
Week 4 
As indicated in the database: 
Pre-dose (within 30 minutes prior 
to dosing) 
37 to 49 
43 
Week 6 
As indicated in the database: 


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Visit date and 
time 
Relative 
day 
(ADY) 
Assessment visit 
(VISIT) 
Time 
window 
(in 
ADY)* 
Target 
day 
Analysis 
visit 
(AVISIT) 
Analysis time point (ATPT) 
Pre-dose (within 30 minutes prior 
to dosing) and within [4-6 hours 
post dose]. 
Follow-up 
CRF 
collected 
follow-
up visit 
 
Follow-up 
 
*For Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6, time windows have to be applied excluding assessments performed 
more than 2 days after the last dose of IP. 
 
 


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Table 6: Analysis Visit Window for urine phosphate and urine calcium 
 
Visit date and 
time 
Relative 
day 
(ADY) 
Assessment visit 
(VISIT) 
Time 
window 
(in 
ADY)* 
Target 
day 
Analysis 
visit 
(AVISIT) 
Analysis time point (ATPT) 
Before first 
study drug 
administration 
<1 or 
pre-dose 
at 
ADY=1 
Last assessment at any 
point in time before first 
study drug administration 
<1 or 
pre-dose 
at 
ADY=1 
1 
Baseline 
Pre-dose  
Same as or after 
first study drug 
administration  
≥ 1 
Any scheduled (non 
follow-up), unscheduled, 
or early discontinuation 
visit 
1 
1 
Day 1 
2 hours post-dose 
13 to 22 
15 
Week 2 
 
23 to 36 
29 
Week 4 
 
37 to 49 
43 
Week 6 
As indicated in the database: 
Pre-dose and 2 hours post-dose 
Follow-up 
CRF 
collected 
follow-
up visit 
 
Follow-up 
 
 
 
 


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4.3.4. 
Definition of Baseline 
Baseline is defined as the last available assessment prior to the first intake of IP. For the 
parameters for which the time of assessment was planned to be collected, if for their assessment 
on the day of first intake the time is missing, their assessment at time point “PRE-DOSE” (when 
applicable) will be considered as baseline, otherwise, previous days last available assessment will 
be selected. For the parameters for which the time of assessment was not planned to be collected, 
their assessment on the day of first intake of IP will be considered as baseline. If multiple values 
qualify as last available assessment, the mean of these values will be used in the analysis. 
For electrocardiogram (ECG) data assessed in triplicate, baseline is defined as the average (stored 
without rounding) of the combination of the most complete replicated ECG parameter before first 
intake of IP and at the same time the closest to it, selecting in the following order: 
First consider Day 1, pre-dose: 
- 
Select the average of the last available triplicate ECG parameter on that day; 
- 
If there is no triplicate, select the average of the last available duplicate ECG parameter; 
- 
In the absence of triplicates and duplicates the last available single ECG parameter will 
become baseline. 
 
If baseline is not yet determined, consider the previous day and repeat the above selection 
(average of last triplicate, average of last duplicate, last single ECG on that day). Repeat the 
whole process successively for each previous day(s) as needed until baseline is determined. 
For diary-based efficacy parameters, baseline is defined as the average of the values before the 
first IP administration. The baseline value will be derived only when there are at least 3 days with 
data. Otherwise, the baseline value for that parameter will be treated as missing. The definition 
will exclude the day prior/of/after the colonoscopy. 
4.3.5. 
Selection and Use of Analysis Visits 
Before first administration of IP, only Baseline will be used for the entire statistical analysis. Pre-
baseline assessments will only be listed. After first administration of IP, if multiple valid, non-
missing assessments exist in an analysis window, records will be chosen based on the following 
rules if a single value is needed: 
• The record closest to the nominal day for that visit will be selected, or 
• If there are 2 records that are equidistant from the nominal day, or  more than 1 record (with 
time known) on the selected day, the latest record will be taken 
• If chronological order cannot be determined (e.g., more than 1 record on the same day with 
time missing), the average of the records will be computed and reported in the analysis 
For the
 endpoints including MCS, 
, the following steps 
will be used to derive each composite endpoint, unless otherwise specified: 








G al a p a g o s  
  C O N FI D E N TI A L  
 
D o c i d : 1 3 8 2 2  
G L P G 3 9 7 0 -C L -2 1 0  
 
-3 3 - 
 
all s u bjects wit h ( p ost-baseli ne) data f or t he para m eter, i n t he a n al ysis set a n d a nal ysis 
wi n d o w/ peri o d.  
5.  
I N T E RI M A N A L Y S E S A N D I N T E R N A L D A T A S A F E T Y 
M O NI T O RI N G C O M MI T T E E  
N o f or mal i nteri m a nal ysis is pla n ne d f or t his cli nical st u d y.  
A n i nter nal S M C i n de pe n de nt fr o m t he st u dy will re vie w u n bli n de d safet y data d uri n g t he c o urse 
of t he st u d y. T his C o m mittee ma y i n v ol ve e xter nal me dical e x perts (s uc h as a n e x pert i n t he fiel d 
of U C  a n d a n i nf ecti o us diseases e x pert) t o s u p p ort data i nter pretati o n. T he C o m mittee will 
re vie w u n blin de d safet y data a n d ass ess a n y p ote ntial safet y iss ues arisi n g d uri n g t he c o n d uct of 
t he cli nical st u d y, i ncl u di n g ( b ut n ot li mite d t o) a n y p ote ntial iss ues i n t he c o nte xt of t he S A R S-
C o V -2 pa n de mic. T he cli nical st u d y te a m will re mai n bli n de d t o t he all o cati o n of s u bjects t o 
treat me nts d uri n g t he c o urse of t he st u d y. T he pr ocess is descri be d i n a s e parate S M C  C harter.  
6.  
S T A TI S TI C A L A N A L Y S E S  
6. 1.  
S u bj e ct I nf or m ati o n  
S u bject i nf or mati o n will be ta b ulate d usi n g t he Safet y A nal ysis Set, u nless s pecifie d ot her wise. 
N o i nfere ntial testi n g will be perf or m e 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 descri pti ve statistics per pla n ne d treat me nt gr o u p, as 
well as o verall.  
6. 1. 1.  
D e m o gr a p hi c a n d B a s eli n e Di s e a s e C h ar a ct eri sti c s  
T he f oll o wi n g p ara m eters will be s u m marize d:  
− 
d ate of I C F si g n at ure (liste d) ; 
− 
se x ; 
− 
age at si g ni n g t h e I C F ( years) ; 
− 
age, cate g orize d ( years): 1 8 ≤ a ge < 6 5; 6 5 ≤ a ge < 8 5; a ge ≥8 5 ; 
− 
race a n d et h nicit y; 
− 
h ei g ht at b aseli ne ( c m); 
− 
w ei g ht at baseli ne ( k g) ; 
− 
b o d y mass i n de x ( B MI) at baseli ne ( k g/ m²) =  
 (
)
 (
)   
( B MI will n ot be recal c ulate d if alr ea d y a v aila ble i n t he data base); 
− 
s m o ki n g stat us ( N o n-s m o ker/ E x- s m o ker/ C urre nt s m o ker );  
− 
n u m ber pac k -years;  
− 
d urati o n of U C  ( years)  
=
(𝑑𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑠𝑡𝑢𝑑𝑦 𝑑𝑟𝑢𝑔 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑟𝑎𝑡𝑖𝑜𝑛) −(𝑑𝑎𝑡𝑒 𝑜𝑓  𝑖𝑛𝑖𝑡𝑖𝑎𝑙 𝑑𝑖𝑎𝑔𝑛𝑜𝑠𝑖𝑠) + 1
3 6 5 .2 5
 
 


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If missing day: use 1st day of the month 
If missing both day and month: use 1st of January; 
− 
duration of UC, categorized: <6 months; 6 months ≤ duration<1 year; 1 ≤ duration<3 
years; 3 ≤ duration<5 years; 5≤ duration<10 years; duration≥10 years; 
− 
MCS at baseline;  
− 
 
 
  
− 
MCS-SF at baseline 
− 
MCS-RB at baseline; 
− 
MCS-ES at baseline; 
− 
PGA at baseline; 
− 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic and baseline disease characteristics will be listed.  
6.1.2. 
Allocation and Randomization 
The number of subjects (and percent) per treatment group and overall will be tabulated per 
country and site. 
The following listings will be provided: 
− 
Listing per subject of the study drug kit numbers, study drug batch numbers 
dispensed/returned.  


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− 
Randomization schemes and codes, with the treatment assigned to each subject. This listing 
includes a flag in case of discrepancies or errors between the assigned and the actual 
treatment taken, and should also include flags declaring any (potential) unblinding. 
6.1.3. 
Disposition Information 
The following tabulations will be provided, by treatment group and overall: 
− 
The number of subjects screened, not-randomized (including reasons), randomized (treated 
and not treated), and treated with GLPG3970 and Placebo. 
− 
 Number (percent) of subjects randomized per country and site. 
− 
The number (percent) of subjects in each analysis set as defined in Section 4.1. 
− 
The number (percent) of subjects per analysis window as defined in Section 4.3.3. 
− 
The number (percent) of subjects who completed/discontinued the study drug administration 
schedule and the reasons for discontinuation. 
− 
The number (percent) of subjects who completed/discontinued the study and the reasons for 
discontinuation. 
Additionally, the following information will be provided in listings: 
 
− 
Subject identification and randomization (country, site number, investigator, subject 
number). 
− 
Randomization number and date, planned and actual randomization group, with flags for any 
discrepancies. 
− 
Subjects excluded from the safety and full analysis sets, including reasons. 
 
6.1.4. 
Protocol Deviations and Eligibility 
Major protocol deviations are determined and recorded while the study is ongoing, and the list is 
finalized prior to database lock (and unblinding). For more details, please refer to the Protocol 
Deviations Plan. 
The number (percent) of subjects with major protocol deviations will be tabulated, overall and 
per class of deviation, by treatment group and overall. 
All available information concerning major protocol deviations, including COVID-19 related 
verbatim, violations on eligibility criteria and subjects not treated will be listed. Protocol 
deviations leading to the exclusion of subjects from any analysis set, as applicable, will be 
flagged. 
COVID-19 related protocol deviations will be listed together with the rest of major protocol 
violations. The fact that they are COVID-19 related will be present in that listing. 


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6.1.5. 
Medical History and Concomitant Diseases 
Frequency tabulations, per treatment group and overall, per system organ class and preferred term 
will be provided for the medical history findings (i.e., conditions no longer present at the start of 
the study) as well as for the concomitant diseases (i.e. conditions present at the start of the study) 
using Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary.  
All medical history findings and concurrent diseases will be listed separately. 
6.1.6. 
Ulcerative Colitis History 
Frequency tabulations, per treatment group and overall, per system organ class and preferred term 
will be provided for the UC disease history. 
In addition, frequency tabulations, per treatment group and overall, will be provided for the 
following parameters. 
• extent of disease at time of most extensive disease activity per Montreal Classification; 
• previous treatment failure and corresponding treatments; 
• colonoscopy history (yes/no); 
• stool history (number of stools per day under normal (healthy/remission) conditions) 
All UC history will be listed. 
6.1.7. 
Prior and Concomitant Medications 
6.1.7.1. 
Coding of Reported Terms 
All prior and concomitant medication terms will be coded in the database using the World Health 
Organization (WHO) drug coding dictionary version.  
6.1.7.2. 
Classification of Medications 
All prior and concomitant medication records will be categorized as follows, considering their 
date and flags indicating the relative timing versus study (drug) start or end (before, after, 
ongoing): 
− 
Prior only: when the record ended before the first study drug administration date. 
− 
Concomitant only: when the record started on or after the first study drug administration 
date. 
− 
Prior and concomitant: when the record started before the date of first study drug 
administration, and ended on or after this point, or continued. 
When the start or end date of the prior and concomitant medication records are incomplete (and 
no flags indicating relative timing are available), the date of first study drug administration will 
 


G al a p a g o s  
  C O N FI D E N TI A L  
 
D o c i d : 1 3 8 2 2  
G L P G 3 9 7 0 -C L -2 1 0  
 
-3 7 - 
 
be c o nsi dere d t o t he sa m e le vel of i nf or m ati o n pr o vi de d b y t hes e i nc o m plete dates t o cate g orize 
t he ti mi n g of t hese rec or ds. This mea ns t hat a rec or d o nl y h a vi n g m o nt h a n d year will be 
cate g orize d c o m pari n g o nl y t o t he m o nt h a n d t he year of t h e date of first st u d y dr u g 
a d mi nistrati o n.  
6. 1. 7. 3.  
C al c ul ati o n of R el ati v e D a y s  
F or b ot h t he start a n d t h e e n d dates of t he c o nc o mita nt me dicati o n rec or ds, t heir da y rel ati ve t o 
t he da y of first st u d y dr u g a d mi nistrati o n will be calc ulate d as d escri be d i n S ecti o n 4. 3. 1 . 
6. 1. 7. 4.  
Pr e s e nt ati o n of R e s ult s  
A fre q u e nc y ta b ulati o n p er pla n ne d  tr eat me nt gr o u p a n d o verall of t h e A nat o mical T hera pe utic 
C he mical  ( A T C) classifi cati o n classes le v el 4 b y t hera pe utic s u b gr o u p ( A T C le vel 2) a n d ge n eric 
ter m of t he pri or me di cati o n ( defi ne d as ‘ pri or o nl y’ a n d ‘ pri or a n d c o n c o mita nt’) will be 
pr o vi de d as well as of t he c o nc o mita nt me dicati o n ( defi ne d as ‘c o n c o mita nt o nl y’ a n d ‘ pri or a n d 
c o nc o mita nt’).  
A listi n gs of pri or a n d c o nc o mita nt me dicati o ns  will be pr o vi de d.  Als o, pri or a n d c o nc o mita nt 
c ortic osteri oi d listi n g will be pr o vi de d se paratel y  (t he list of t he A T C c o des t o be selecte d i n t his 
listi n g will be pr o vi de d b y t he G ala pa g os  me di cal ser vices) . 
6. 1. 8.  
Pr o c e d ur e s  
Pr oce d ures  res ults will o nl y be liste d . 
6. 1. 9.  
E x p o s ur e t o St u d y D r u g a n d C o m pli a n c e 
6. 1. 9. 1.  
D eri v ati o n R ul e s  
D eri v e d P ar a m et er s: E xt e nt of E x p o s ur e t o St u d y D r u g 
− 
T ot al tre at me nt d ur ati o n  ( da ys) = l ast st u d y dr u g a d mi nistrati o n date –  first st u d y dr u g 
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 ays off st u dy dr u g : S u m of t he n u m ber of da ys wit h 
a n y st u d y dr u g a d mi nistrati o n.  
− 
T ot a l tre at me nt d ur ati o n, f ull c o m pli a n ce ( da ys): N u m ber of da ys w here t he  c o m plete 
v ol u me of I P h as bee n a d mi nistere d.  
 
Deri ve d P ar a meters: C o m pli a nce  
− 
O verall c o m plia nce ( %) = 1 0 0   ×  
 
 
 
 
 
 
 
 
 
 
 
 
 
− 
Perce nt da ys wit h a n y i nt a ke ( %) = 1 0 0  ×  
 
 
,
 
 
 
 
 
 
 
− 
Perce nt da ys f ull c o m plia nce ( %) = 1 0 0  ×  
 
 
,
 
 
 
 
 


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6.1.9.2. 
Presentation of Results 
Summary statistics per planned treatment group and overall will be provided for each compliance 
and extent of exposure parameter for study drug administration. Frequency tables will be 
provided for the compliance parameters, using the following categories: <80%; 80% ≤ x < 100%; 
100%; 100% < x ≤ 120%; > 120%. 
All original study drug administration records will be listed per subject. The listing will include all 
deviations from study drug schedules such as missed or reduced doses and GLPG3970/placebo 
switches and will also include food intake status at the time of study drug administration.  
Study drug exposure and compliance data will be listed. 
 
 
 
 


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6.2. 
Efficacy Analyses 
Efficacy analyses will be performed on the FAS.  
Tabulations will be shown per planned treatment group. 
6.2.1. 
Level of Significance 
Statistical tests for efficacy analysis will be done at a 2-sided significance level of 10%. 
6.2.2. 
Primary Efficacy Parameter 
The primary endpoint for this study is the change from baseline in total MCS at Week 6. The 
total MCS score will be calculated only at baseline and week 6.  
The MCS ranges from 0 to 12. A lower score means a better subject condition. It consists of 4 
subscores. Each sub-score ranges from 0 to 3. The four components of the MCS are (see 
Appendix III):  
• MCS-SF subscore 
• MCS-RB subscore 
• MCS-ES subscore 
• PGA 
For calculation of the MCS subscores performed by the investigator, MCS-RB and MCS-SF, 
subjects will be instructed to record symptoms of RB and SF daily in a diary. 
The information on the UC symptomatology of the last 3 consecutive available days in the diary 
collected from the last week, will be used to score the MCS-RB and MCS-SF subscores, 
excluding the day before the endoscopy (with bowel preparation), the day of the endoscopy and 
the day after the endoscopy. 
The PGA will be scored by the investigator or trained sub-investigator at visits specified in the 
Schedule of Activities. 
6.2.2.1. 
Derivation Rules 
The MCS will be calculated based on the following formula: 
MCS =  MCS-SF + MCS-RB + MCS-ES + PGA 
If one of the component is missing at a specific analysis window, total score will not be 
calculated for that analysis visit and will be set to missing. 
 
 
 
 
 
 




























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6.3. 
Safety Analyses 
Safety analyses will be performed on the Safety Analysis Set. 
Safety parameters will be analyzed descriptively (see Section 4.4.2 and Section 4.4.3) by 
treatment group and overall. No formal testing will be performed to compare the treatment 
groups. 
6.3.1. 
Adverse Events 
All AEs and changes in attributes (worsening and improvement) of AEs are reported in the 
database. An identification number serves to link the records considered by the investigator as 
describing the evolution of one and the same event. 
6.3.1.1. 
Definition of Treatment-Emergent Adverse Events 
The analysis of AEs will be based on treatment-emergent events (TEAE).  
TEAEs are defined as  
− 
Any AE with an onset date on or after the IP start date and no later than 14 days after last 
dose of IP, or any worsening of any AE on or after the IP start date. 
− 
Improvement or no change of any ongoing AEs on or after the IP start date are not 
considered treatment-emergent. If an AE is ongoing at the time of first IP intake, if there is 
no change or an improvement in its toxicity grade or its seriousness status (reported in the 
‘Change in Adverse event details Entry’ CRF page), this AE will not be considered as 
treatment-emergent. 
6.3.1.2. 
Coding of Reported Terms 
All AE terms will be coded in the database using the latest version of MedDRA coding 
dictionary. AEs will be graded using the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE). 
All tables will show the AE preferred terms grouped into system organ class. Subject listings will 
also show the reported terms (verbatim). Any other coding levels will only be shown in a listing 
summarizing coding unless explicitly mentioned otherwise. 
6.3.1.3. 
Allocation of Adverse Events to Analysis Periods 
All AEs will be placed into analysis periods considering their start date. 
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 
 


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


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Relative days and durations will only be listed. 
See Section 4.3.1 for the calculation of relative days. 
6.3.1.7. 
Events of Special Interest 
Not applicable. 
6.3.1.8. 
Presentation of Results 
The analysis will focus on AEs reported during the treatment period. AEs reported during the 
screening period will only be listed. 
All AEs tables will show the number of subjects with TEAEs. 
AEs which are not treatment-emergent will only be listed. 
A summary table will be provided, showing the number (percent) of subjects with at least one: 
− 
TEAE, 
− 
IP-related TEAE, 
− 
Serious TEAE, 
− 
TEAE leading to death, 
− 
TEAEs by worst intensity (CTCAE toxicity grade), 
− 
TEAE leading to study drug discontinuation. 
 
The AE terms will be presented sorted in descending order of frequency, prioritizing the 
GLPG3970 treatment group and then for placebo, first by system organ class, then by preferred 
term, and then alphabetically. 
Frequency tabulations, by system organ class and preferred term, of the number (percent) of 
subjects with a TEAE will be presented. Similar tables will be provided by worst intensity, and 
for IP-related TEAEs, grade 3-4-5 TEAEs, serious TEAEs and TEAEs leading to study drug 
discontinuation of IP. 
All AE data will also be listed, including separate lists for SAEs, AEs leading to death, and AEs 
leading to study drug discontinuation. Listings will clearly indicate AEs to be treatment-emergent 
or not. 
In addition, AEs related to SARS-Cov-2 will be listed separately. 
6.3.1.9. 
EudraCT Adverse Events Reporting 
For the purpose of EudraCT reporting, the following tabulations will be created: 
Frequency tabulations, by system organ class and preferred term, of the number (percent) of 
subjects with non-serious TEAE will be presented. A similar table will be provided for all serious 
 


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TEAEs, as well as a table for non-serious TEAEs reported in at least 2 subjects in any treatment 
group.   
 
6.3.2. 
Laboratory Safety 
6.3.2.1. 
Available Data 
Laboratory tests scheduled are described in the CSP section 8.5.2. 
The statistical analyses will only present results in Standard International (SI) standardized units. 
Other units will not be presented. 
Only data provided by the central laboratory will be used in tables and figures. Results from local 
labs will be listed only. 
6.3.2.2. 
Derivation Rules 
Derived Laboratory Tests 
Not applicable. 
Fasted and Non-Fasted Results 
Laboratory tests that are sensitive to the fasting status: glucose, triglycerides. 
For these laboratory tests, only results from blood samples drawn in a fasted state will be 
included in the analysis. Results from blood samples taken in a non-fasted (not fasting and fasting 
not declared) state will be listed only and no toxicities or abnormalities will be calculated. 
Laboratory results for which the fasting status is missing will be considered as taken non-fasted. 
6.3.2.3. 
Definition of Toxicity Grades 
Toxicity grades will only be derived for laboratory tests for which toxicity grades are available. 
Toxicity grades will be determined as implemented in the attached table (Appendix I). 
For elevations (H1 to H4), values under the threshold of H1 are reported as 'Grade 0'. For 
elevations (L1 to L4), values above the threshold of L1 are reported as 'Grade 0. 
6.3.2.4. 
Definition of Non-Graded Abnormalities 
For all 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 provided by the lab, 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. 
 
 
 
 
 


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


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− 
L = low: at least one post-baseline result is classified as L. 
− 
N = normal: all post-baseline results are classified as N. 
− 
H = high: at least one post-baseline result is classified as H. 
If, for a subject, both L and H are reported, the subject will be counted twice in the table: once 
with a worst-case L and once with a worst-case H. 
 
6.3.2.8. 
Hepatotoxicity 
Hepatotoxicity will be investigated by tabulating the aspartate aminotransferase (AST) and 
alanine aminotransferase (ALT) values categorized as >3, >5, >10 and >20 times their upper 
limit of normal (per analyte and over both analytes combined), ALP categorized as > 1.5 times 
the upper limit and total bilirubin as > 2 times the upper limit of normal. Elevations of AT (AST 
or ALT) > 3 times their upper limits accompanied by elevated total bilirubin (>1.5×ULN, 
>2×ULN) on the same day will also be tabulated. 
To assess the potential of the drug to cause severe liver damage, possible Hy’s Law cases will be 
identified. These subjects are defined as having any elevated AT (AST or ALT) of >3×ULN, 
ALP <2×ULN, and associated with an increase in total bilirubin >2×ULN on the same day.   
6.3.2.9. 
Presentation of Results 
No formal inferential statistics (p-values) will be derived. 
Continuous laboratory tests17 including glucose, cholesterol, triglycerides, low-density 
lipoprotein (LDL), high-density lipoprotein (HDL) and fasted glucose will be summarized by 
means of descriptive statistics (including 90% CI of the mean change) by laboratory test, 
treatment group and analysis window. Actual values, changes from baseline and percent change 
from baseline will be tabulated separately. Continuous values for metabolic markers will be 
summarized in the PD analysis section (section 6.5). 
Profile line plots by subject of all actual observed values using relative day (ADY) will be 
presented by treatment group. Graphs of the mean (+- SE) actual values over time and of the 
mean (+- SE) change from baseline, and percent changes from baseline will be presented for all 
continuous laboratory parameters, with the exception of the metabolic markers. Also, line plots 
for subjects will be provided by treatment group. 
The analysis of abnormalities will focus on assessments reported during the treatment period. 
Results reported before baseline will only be listed.  
Non-graded abnormalities and toxicities grades of the actual values will be presented as shift 
tables of the worst-case abnormality/toxicity grade versus the baseline abnormality/toxicity 
                                                 
17 With the exception of the metabolic markers [fasted insulin, homeostatic model assessment of insulin resistance 
(HOMA-IR) and HbA1c] and other markers hsCRP and fecal calprotectin . 
 


G al a p a g o s  
  C O N FI D E N TI A L  
 
D o c i d : 1 3 8 2 2  
G L P G 3 9 7 0 -C L -2 1 0  
 
-5 9 - 
 
gra de. T h e ta ble will  be create d p er la b orat or y test, treat me nt gr o u p a n d a nal ysis peri o d. T h e 
res ults of n o n-gra d e d a b n or malities a n d t o xicities gra des will be s h o w n se p aratel y.   
A fre q u e nc y ta ble of t he n u m ber ( perce nt) of s u bjects wit h treat me nt -e mer ge nt w orst -cas e 
a b n or mal ities/t o xicit y gra de per l a b orat or y t est, treat me nt gr o u p a n d a nal ysis peri o d will be 
prese nte d. T h e res ults of n o n -gra de d a b n or malities a n d t o xicities gra des will be s h o w n 
se parat el y. 
A fre q u e nc y ta ble of t he n u m ber ( perce nt) of s u bjects  will be als o pr o v i de d f or t he h e p at ot o xicit y 
fla gs d efi ne d b ef ore. T hese a b n or malities will be als o fla g ge d i n t he i n di vi d ual data la b orat or y 
listi n g. 
Listi n g will be pr o vi de d f or t he la b orat or y t est al o n g wit h fla g f or a b n or malit y res ults.  I n 
a d diti o n, pre g n a nc y res ult will be liste d se paratel y.  
6. 3. 3.  
El e ctr o c ar di o gr a m  
6. 3. 3. 1.  
A v ail a bl e D at a  
T he f oll o wi n g E C G p ara meters will be a nal yse d : heart rate  ( H R), R R i nter val, P R i nter val, Q R S 
i nter val, u nc orrecte d Q T i nter val, Q Tc F ( deri ve d)  
6. 3. 3. 2.  
D eri v ati o n R ul e s  
D eri v e d P ar a m et er s  
T he Fri d ericia’s c u be -r o ot c orrecte d Q T ( Q Tc F) will be calc ulate d usi n g t he f oll o wi n g f or m ula. 
Fri deri cia’s c u b e -r o ot c orrecte d Q T ( Fri derici a, 1 9 2 0): 
𝑑𝑎𝑡𝑒 (𝑜𝑓) = 𝑓𝑖 (𝑟𝑠) ×
 (
) 
If R R is missi n g, t he n it will be deri ve d fr o m H R usi n g t he f or m ula R R( ms)  =  6 0  × H R( b p m) . 
H a n dli n g  of E C G s M e a s ur e d i n Tri pli c at e  
If E C G is c ollecte d i n tri plicates, t he f oll o wi n g a p pr oac h will be ta ke n. 
First, a n y deri vati o n of E C G para meters will be d o ne bef ore ha n dli n g E C G tri plicates. Ne xt, t he 
mea n of t he tri plicate E C G val ues will be cal c ulat e d f or eac h i n di vi d ual E C G para meter, wit h o ut 
r o u n di n g t he res ult. T hes e calc ul ate d mea ns will c o nstit ute t he a nal ysis val ues; a n y deri vati o n 
(e. g. c ha n ge fr o m b aseli n e, assi g n m e nt of a b n or m alities) a n d statistic will be base d o n t he mea n 
val ue of t he tri plicates. 
T he val ues of t he ori gi nal me m bers of a tri plicate will be liste d.  
6. 3. 3. 3.  
A b n or m aliti e s  
 
 
 
 


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The actual analysis values and changes from baseline of the QT and QTcF parameters will be 
categorized into the abnormality classes as defined in the SAP Appendix II. 
Worst-Case Abnormality 
The worst-case post-baseline categorized actual analysis value and the worst-case categorized 
change from baseline for QT and QTcF will be determined per subject, per parameter, and for 
each analysis period, using all non-missing post-baseline records (including unscheduled and FU 
visits). 
The worst-case categorized actual analysis value is the category corresponding to the highest 
post-baseline actual value. In case of several equal highest post-baseline actual values, the earliest 
occurrence will be taken for the analyses and will be flagged in the listings.  
The worst-case change from baseline is the category corresponding to the largest increase 
(positive change) from baseline. In case of several equal largest increase from baseline, the 
earliest occurrence will be taken for the analyses and will be flagged in the listings. 
Treatment-Emergent Abnormalities 
Actual value: An abnormal post-baseline abnormality is defined as treatment-emergent when the 
abnormality is worse compared to the abnormality at baseline or when there is a change in 
direction (from H to L or from L to H). When the baseline value is missing, post-baseline 
abnormalities are considered as treatment-emergent. 
An abnormal category for change from baseline is always treatment-emergent. 
6.3.3.4. 
Presentation of Results 
No formal inferential statistics (p-values) will be derived. 
Continuous parameters will be summarized by means of descriptive statistics (including 90% CI 
of the mean change) by parameter, treatment group and analysis window. Actual values, change 
from baseline and percent changes from baseline will be tabulated separately. 
Profile line plots by subject of all actual observed values using relative day (ADY) will be 
presented by treatment group. Graphs of the mean (+- SE) actual values over time and of the 
mean (+- SE) change from baseline and percent change from baseline will be presented. A line 
plot by subject of the change from baseline will also be provided by treatment group. 
The analysis of abnormalities will focus on assessments reported during the treatment period. 
Results reported during the screening or post-treatment (if defined) period will only be listed. 
Abnormalities of the actual values will be presented as shift tables of the worst-case abnormality 
versus the baseline abnormality. The table will be created per parameter, treatment group and 
analysis period. 
 


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A frequency table of the number (percent) of subjects with treatment-emergent worst-case 
abnormalities and the worst change per parameter, treatment group and analysis period will be 
presented. 
A frequency table per treatment group and time point of the ECG interpretations as recorded in 
the case report form (CRF) will be provided. 
A Listing will be provided along with abnormality. 
6.3.4. 
Vital Signs 
6.3.4.1. 
Available Data 
The following vital signs parameters will be analyzed: weight (kg), BMI (kg/m2), diastolic and 
systolic blood pressure (mmHg), pulse rate (beats/min) and body temperature (C). 
6.3.4.2. 
Derivation Rules 
Not applicable. 
6.3.4.3. 
Abnormalities 
Vital signs data will be categorized according to the cutoffs provided in the SAP Appendix II.  
6.3.4.4. 
Treatment-Emergent Principle 
A post-baseline abnormality class L or H is defined as treatment-emergent when it differs from 
the abnormality class at baseline. If the baseline result is missing, a post-baseline abnormality 
L or H will be considered as treatment-emergent. 
An abnormal category for change from baseline is always treatment-emergent. 
6.3.4.5. 
Worst-Case Abnormality 
The worst-case post-baseline categorized actual analysis value will be determined per subject, per 
parameter, using all non-missing post-baseline records (including unscheduled and FU visits). 
6.3.4.6. 
The worst-case categorized actual analysis value is the category 
corresponding to the highest post-baseline actual value. In case of several 
equal highest post-baseline actual values, the earliest occurrence will be taken 
for the analyses and will be flagged in the listings. Presentation of Results 
No formal inferential statistics (p-values) will be derived. 
Continuous parameters will be summarized by means of descriptive statistics (including 90% CI 
of the mean change) by parameter, treatment group and analysis window. Actual values, change 
from baseline and percent change from baseline will be tabulated separately. 
 


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Graphs of the mean (+- SE) actual values over time and of the mean (+- SE) change from 
baseline, and percent changes from baseline will be presented. 
The analysis of abnormalities will focus on assessments reported during the treatment period. 
Results reported during the screening or post-treatment (if defined) period will only be listed. 
Abnormalities of the actual values will be presented as shift tables of the worst-case abnormality 
versus the baseline abnormality. The table will be created per parameter (and position if 
applicable), treatment group and analysis period. 
A frequency table of the number (percent) of subjects with treatment-emergent worst-case 
abnormalities per parameter, treatment group and analysis period will be presented. 
6.3.5. 
Physical Examinations 
Physical examination results will only be listed. 
6.3.6. 
SARS-CoV-2 Infection 
Results of the SARS-CoV-2 infection test will be listed for the subjects who have at least one 
positive test. 
6.3.7. 
Subgroup Analyses 
No subgroup analysis is planned for this clinical study as the study sample size is too small. 
Thus, any subgroup of this would have small sample size to be relevant or even uninterpretable.  
 
 
 
 
 
 


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6.4. 
Pharmacokinetic Analysis 
6.4.1. 
Available Data 
Blood samples for the PK assessment of GLPG3970 should be collected on the visits specified in 
the Schedule of Assessments in Section 2.5. Pre-dose samples not collected within 22 to 26 hours 
after the last drug intake, or that were taken after the drug administration at the site will be 
excluded from descriptive statistics and flagged in the table with appropriate footnoting. The 
same will be done with post-dose samples taken outside of the defined time intervals. 
6.4.2. 
Presentation of Results 
Descriptive statistics will be provided for GLPG3970, MTX and MTX-7-OH plasma levels at 
each assessment time point. Observed plasma Ctrough for GLPG3970 will be reported in the CSR. 
Individual GLPG3970 plasma concentrations with descriptive statistics will be presented by time 
point/interval. Actual blood sampling times from the last drug intake will be listed. 
For calculation of descriptive statistics of GLPG3970 Ctrough (= pre-dose concentration), the 
following will apply:  
- 
for pre-dose samples not collected within 21-27 hours after the last intake prior to the 
visit, or collected after the intake at the visit, the corresponding concentration will be 
excluded from descriptive statistics and flagged in the listing with appropriate footnoting.  
- 
pre-dose samples collected within 3 days after a missed dose will also be excluded from 
descriptive statistics. 
 
 


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7. 
REFERENCES 
Chan, I. S. F., and Zhang, Z. (1999). “Test-Based Exact Confidence Intervals for the Difference 
of Two Binomial Proportions.” Biometrics 55:1202–1209. 
FDA CDER. (2016). Ulcerative Colitis: clinical trial endpoints. Guidance for Industry (Draft). 
Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Retrieved 
from Available at: https://www.fda.gov/regulatory-information/search-fdaguidance-
documents/ulcerative-colitis-clinical-trial-endpoints-guidance-industry. 
Fridericia, L. (1920). Die Systolendauer im Elektrokardiogramm bei normalen Menschen und bei 
Herzkranken. Acta Medica Scandinavia 53:469-486. 
ICH E3 Structure and Content of Clinical Study Reports (Step 4 Version). 
ICH E9 Statistical Principles for Clinical Trials (Step 4 Version). 
ICH E14 The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential 
for Non-Antiarrhythmic Drugs (Step 4 Version). 
ICH E6 Intergrated Addendum to ICH E6 (R1): Guideline for good clinical practice 
(Step 4 Version). 
ICH E9(R1) Estimands and Sensitivity Analysis in Clinical Trials (Step 2 Version). 
Lu K, Mehrotra D. Specification of covariance structure in longitudinal data analysis for 
randomized clinical trials. Statistics in Medicine. 2010; 29: 474-488. DOI: 10.1002/sim.3820 
Lewis, J., Chuai, S., Nessel, L., Lichtenstein, G., Aberra F, & et al. (2008). Use of the non-
invasive components of the Mayo score to assess clinical response in Ulcerative Colitis. 
INflamm Bowel Dis, 14(12):1660-6. 
Mallinckrodt CH, Clark WS, Carroll RJ, Molenberghs G. Assessing response profiles from 
incomplete longitudinal clinical trial data under regulatory considerations. Journal of 
Biopharmaceutical Statistics 2003; 13: 179-190.1 
 


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Schroeder, K., Tremaine, W., & Ilstrup, D. (1987). Coated oral 5-aminosalicylic acid therapy for 
mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med, 317(26), 1625-
1629. 
 
 




















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APPENDIX III: Mayo Scoring System  
 
0 
1 
2 
3 
Stool frequency  
[MCS-SF] a 
Normal  
1 -2 stools above 
normal  
3 -4 stools above 
normal  
>4 stools above 
normal  
Rectal bleeding  
[MCS-RB] a 
No blood seen  
Streaks of blood 
less than half the 
time  
Obvious blood with 
stool most of the 
time  
Blood alone passed  
Flexible 
sigmoidoscopy  
[MCS-ES] b 
Normal or inactive 
disease  
Mild disease 
(Erythema, 
decreased vascular 
pattern, no 
friability)  
Moderate disease 
(Marked erythema, 
absent vascular 
pattern, friability, 
erosions)  
Severe disease 
(Spontaneous 
bleeding, ulceration) 
Physician’s global 
assessment  
[PGA] a 
Normal  
Mild disease  
Moderate disease  
Severe disease  
a (Lewis, et al., 2008) 
b (Schroeder, Tremaine, & Ilstrup, 1987)  
 


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Signature Page for glpg3970-cl-210-sap 16159
Signature Page for glpg3970-cl-210-sap43952_17539_53034
Approval
16-Jun-2021 08:20:17 GMT+0000
Approval
16-Jun-2021 10:23:48 GMT+0000