Conditions: Idiopathic Pulmonary Fibrosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 68
Healthy volunteers: no

Brief summary:
This is a randomized, double-blind, parallel-group, placebo-controlled, multicenter, exploratory Phase 2 study including participants with Idiopathic Pulmonary Fibrosis (IPF), investigating GLPG1205 in addition to the local standard of care (defined as receiving nintedanib, pirfenidone, or neither nintedanib nor pirfenidone).

Detailed description:

Arms:
arm 1: Participants will receive GLPG1205 100 milligrams (mg) (2 capsules x 50 mg), orally once daily for 26 weeks in addition to the local standard of care. Standard of care includes nintedanib, pirfenidone, or neither nintedanib nor pirfenidone. arm 2: Participants will receive GLPG1205 matching placebo, orally once daily (as 2 capsules) for 26 weeks in addition to the local standard of care. Standard of care includes nintedanib, pirfenidone, or neither nintedanib nor pirfenidone.

Interventions: intervention 1: GLPG1205 intervention 2: Placebo
Intervention descriptions: intervention 1: GLPG1205 will be provided as an oral hard gelatin capsule. intervention 2: GLPG1205 matching placebo will be provided as an oral hard gelatin capsule.

Protocol document:
Prot_000.pdf: 
CONFIDENTIALITY STATEMENT 
The information contained in this document is privileged and confidential. It is the property of Galapagos NV and may not be 
used, disclosed, reproduced or otherwise disseminated within your organization or communicated to any third parties without 
the express written authorization of Galapagos NV. 
 
 
CLINICAL STUDY PROTOCOL 
 
Project Number: 
GLPG1205 
 
Study Number: 
GLPG1205-CL-220 
Study Title: 
A Phase II randomized, double-blind, placebo-controlled, 26-week 
study to evaluate the efficacy, safety and tolerability of GLPG1205 
in subjects with idiopathic pulmonary fibrosis 
Development Phase: 
II 
Status: 
Final 
CSP Version: 
3.00 
Date: 30-Apr-2020 
Amendment: 
2 
EudraCT: 
2017-004302-18 
CT.gov No.: 
NCT03725852 
IND No.: 
Not applicable 
Sponsor: 
Galapagos NV 
Generaal De Wittelaan L11 A3 
2800 Mechelen, Belgium 
  
Study Physician: 
, MD 
General Protocol 
 


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EMERGENCY CONTACT INFORMATION 
In case of a serious adverse event (SAE) or in case of pregnancy occurring during the clinical 
study the investigator must report this immediately, and under no circumstances later than 
24 hours following the knowledge of the SAE or pregnancy, as follows:  
 
 Fax #: 
 
or 
E-mail: 
 
 
 
In case of medical questions during the course of the study, the investigator must contact 
the contract research organization (CRO) Medical Monitor or, if unavailable, his/her back up.  
 
 
Sponsor Back-up contact: 
CRO Medical Monitor: 
, 
, 
 
Back up: 
, 
, 
 


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TABLE OF CONTENTS 
Clinical Study Protocol ............................................................................................................ 1 
Emergency Contact Information ............................................................................................ 2 
Table of Contents ..................................................................................................................... 3 
Clinical Study Protocol History .............................................................................................. 7 
Summary of Changes ............................................................................................................... 7 
List of Abbreviations and Definition of Terms .................................................................... 15 
1. Summary ........................................................................................................................... 18 
2. Introduction ...................................................................................................................... 20 
2.1. Background - Nonclinical Studies ............................................................................ 21 
2.1.1. Nonclinical Pharmacology ............................................................................... 21 
2.1.1.1. Primary and Secondary Pharmacology .............................................. 21 
2.1.2. Safety Pharmacology ....................................................................................... 21 
2.1.3. Nonclinical Pharmacokinetics and Product Metabolism ................................. 22 
2.1.4. Toxicology ....................................................................................................... 22 
2.2. Background - Clinical Studies .................................................................................. 23 
2.2.1. Clinical Pharmacokinetics ............................................................................... 23 
2.2.2. Clinical Pharmacodynamics ............................................................................ 23 
2.2.3. Clinical Efficacy .............................................................................................. 24 
2.2.4. Clinical Safety ................................................................................................. 24 
2.3. Clinical Study Rationale ........................................................................................... 24 
2.3.1. Dosing Rationale ............................................................................................. 25 
2.3.2. Clinical Study Design Rationale ...................................................................... 25 
2.4. Potential Risks and Benefits ...................................................................................... 27 
3. Study Objectives ............................................................................................................... 28 
3.1. Primary Objective ..................................................................................................... 28 
3.2. Secondary Objectives ................................................................................................ 28 
3.3. Other Objectives ........................................................................................................ 28 
4. Investigational Plan .......................................................................................................... 29 
4.1. Endpoints ................................................................................................................... 29 
4.1.1. Primary Endpoint ............................................................................................. 29 
4.1.2. Secondary Endpoints ....................................................................................... 29 
4.1.3. Other Endpoints ............................................................................................... 29 
4.2. Overall Study Design ................................................................................................ 29 
4.3. Study Population ....................................................................................................... 30 
4.3.1. Sample Size ..................................................................................................... 30 
4.3.2. Inclusion Criteria ............................................................................................. 30 
4.3.3. Exclusion Criteria ............................................................................................ 32 
4.3.4. Prohibition and Restrictions ............................................................................ 34 
4.3.4.1. Precautions for Sexual Intercourse ..................................................... 34 
4.3.4.2. Prior and Concomitant Medications ................................................... 34 
4.3.4.3. Food and Beverage Restrictions ......................................................... 36 
4.3.4.4. Other Prohibitions and Restrictions .................................................... 36 
4.3.5. Removal of Subjects from Therapy or Assessments ....................................... 36 
4.4. Measures to Minimize Bias ....................................................................................... 38 
4.4.1. Randomization ................................................................................................. 38 
4.4.2. Blinding and Unblinding ................................................................................. 38 




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7.3.5.1. Extent of Exposure ............................................................................. 62 
7.3.5.2. Adverse Events ................................................................................... 62 
7.3.5.3. Clinical Laboratory Evaluations ......................................................... 62 
7.3.6. Pharmacokinetic Analyses ............................................................................... 62 
 
7.3.8. Analysis of Other Assessments ....................................................................... 63 
8. Data Monitoring ............................................................................................................... 63 
8.1. Independent Data Monitoring Committee ................................................................ 63 
8.2. Clinical Endpoint Adjudication ................................................................................. 63 
9. Safety Reporting ............................................................................................................... 63 
9.1. Definitions of Adverse Events, and Serious Adverse Events ................................... 63 
9.1.1. Adverse Events ................................................................................................ 63 
9.1.2. Serious Adverse Events ................................................................................... 64 
9.1.3. Unlisted (Unexpected) Adverse Event/Reference Safety Information ............ 64 
9.1.4. Adverse Events of Special Interest .................................................................. 64 
9.1.5. Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events ..................................................... 64 
9.2. Assessment of Adverse Events and Serious Adverse Events ................................... 64 
9.2.1. Assessment of Causality .................................................................................. 65 
9.2.2. Assessment of Severity .................................................................................... 65 
9.2.3. Outcome ........................................................................................................... 66 
9.3. Investigator Requirements and Instructions for Reporting Adverse Events / 
Serious Adverse Events /Pregnancies to the Sponsor ............................................... 66 
9.3.1. Adverse Events ................................................................................................ 66 
9.3.2. Serious Adverse Events ................................................................................... 67 
9.3.3. Pregnancy ........................................................................................................ 67 
9.4. Sponsor Reporting Requirements ............................................................................. 68 
10. Sponsor’s and Investigator’s Responsibilities ................................................................ 68 
10.1. Sponsor’s Responsibilities ........................................................................................ 68 
10.1.1. Regulatory Approval / Notification ............................................................... 68 
10.1.2. Clinical Study Closure Considerations .......................................................... 69 
10.1.3. Indemnification .............................................................................................. 69 
10.1.4. Insurance ........................................................................................................ 69 
10.1.5. Reporting ....................................................................................................... 69 
10.1.6. Publication ..................................................................................................... 70 
10.2. Investigator’s Responsibilities .................................................................................. 70 
10.2.1. Financial Disclosure ...................................................................................... 70 
10.2.2. Source Data and Data Capture ....................................................................... 70 
10.2.3. Archiving ....................................................................................................... 70 
10.2.4. Participation Cards ......................................................................................... 71 
10.3. Confidentiality ........................................................................................................... 71 
10.4. Ethical Considerations .............................................................................................. 72 
10.4.1. Independent Ethics Committee / Institutional Review Board ....................... 72 
10.4.2. Informed Consent .......................................................................................... 72 
10.5. Data Quality Control / Assurance ............................................................................. 73 
10.5.1. Monitoring ..................................................................................................... 73 
10.5.2. Audit and Inspection ...................................................................................... 73 
References ............................................................................................................................... 74 


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Appendices .............................................................................................................................. 77 
11. 
High-resolution Computed Tomography/Biopsy Central Review Criteria .............. 77 
12. 
Definition of Acute Idiopathic Pulmonary Fibrosis Exacerbation ............................ 78 
13. 
Contraindications for 6-Minute Walk Test ............................................................... 79 
14. 
Normal Ranges .......................................................................................................... 80 
15. 
Non-exhaustive List of Known Breast Cancer Resistance Protein Substrates ......... 81 
16. 
Non-exhaustive List of Known Organic Cation Transporter 2 Substrates................ 82 
17. 
Exposure to Radiation ............................................................................................... 83 
18. 
Non-exhaustive List of Medications Known to be Dual Inhibitors of CYP3A4 
and CYP2C19 Enzymes ............................................................................................ 84 
19. 
Non-exhaustive List of Medications Known to be Strong Inducers of 
CYP3A4 or CYP2C19 .............................................................................................. 85 
20. 
Non-exhaustive List of Medications Known to Prolong QT interval ....................... 86 
Signature Page – Sponsor ...................................................................................................... 87 
Signature Page – Investigator ............................................................................................... 88 


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CLINICAL STUDY PROTOCOL HISTORY 
 
CSP / Amendment # 
Date 
General / Country Specific 
CSP Version 1.00 
30-Mar-2018 
General 
CSP Version 1.00 Amendment 1  
12-Sep-2018 
 
CSP Version 1.00 Amendment 1 
12-Sep-2018 
 
CSP Version 2.00 Amendment 1 
24-Jan-2019 
General 
CSP Version 3.00 Amendment 2 
30-Apr-2020 
General  
  
 
SUMMARY OF CHANGES 
Amendment 2 Global (dated 30 Apr 2020) 
The overall reason for this amendment: 
The main reason for this amendment is to include the Urgent Safety Measures (USMs dated 02-
April-2020) in the clinical study protocol. These USMs aim to mitigate the risk for patients 
diagnosed with idiopathic pulmonary fibrosis (IPF) participating in the GLPG1205-CL-220 
(PINTA) study with regard to the Coronavirus 2019 disease (COVID-19) pandemic.  
To this end, the visit window at the end of the treatment period (Visit 9, Week 26) is enlarged (from 
-28 days up to +56 days) including extension of study medication intake, i.e. up to a maximum of 
56 days beyond 26 weeks of treatment.  
The chronic preclinical good laboratory practice toxicology studies up to a duration of 39 weeks 
support this approach (see Section 2.1.4 of this clinical study protocol and the Investigator’s 
Brochure). Furthermore, the 2 reviews of unblinded PINTA study data by the independent Data 
Monitoring Committee have not raised any safety concerns.  
In addition, the window for the End of Study follow-up Visit 10 (± 4 days) is increased to -7 days 
up to +28 days.  
If the originally planned Visit 9 or Visit 10 are postponed, then an alternative approach is to conduct 
unscheduled remote or home visits at that initial visit date, and thereafter at least every 14 days until 
the newly scheduled Visit 9 or Visit 10 can be performed on site within the enlarged visit window.  
Alternative visit strategies applicable for Visits 3 to 8 and the early end of treatment Visit (EOT) are 
also included in this amendment, as well as the option of direct-to-patient shipment of the 
Investigational Medical Product (IMP) in case a subject is not able to visit the site for IMP resupply. 
The measures intend to mitigate the impact of the current COVID-19 pandemic for the participating 
IPF subjects. The objective is to reduce the risk of infection for the participating subjects by 
increasing the flexibility of study visits and thereby avoiding exposure risk. 
Due to COVID-19 measures, for individual subjects the overall study duration may be extended up 
to a maximum of 84 days (12 weeks) from the originally planned duration. 
The changes made to the general clinical study protocol version 2.0, dated 24-Jan-2020, are 
described below, with a brief rationale / description of each change and the applicable sections.  


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Amendment 2 Global (dated 30 Apr 2020) 
Increase of Visit 9 and Visit 10 windows due to the COVID-19 pandemic. 
Applicable Sections: 
6.1 Timing of Assessments 
6.1.1 Description of Visits 
6.10 Schedule of Activities 
Addition of an alternative approach for scheduling Visit 9, Visit 10, and early EOT Visit due to the 
COVID-19 pandemic. 
Applicable Sections: 
6.1.1 Description of Visits 
6.10 Schedule of Activities 
Addition of instructions for Unscheduled Visits due to the COVID-19 pandemic. 
Applicable Sections: 
6.1 Timing of Assessments 
6.2 Unscheduled Visits 
Addition of an alternative approach for scheduling Visit 3 to Visit 8 due to the COVID-19 
pandemic. 
Applicable Sections: 
6.1.1 Description of Visits 
Enabling Direct-to-patient (DTP) shipment of the IMP due to the COVID-19 pandemic. 
Applicable Sections: 
5.3 Packaging, Labeling, and Distribution 
 
Amendment 1 Global (dated 24 Jan 2019) 
The overall reason for this amendment: 
The main reasons for this amendment are: clarification of the protocol; incorporation of feedback 
from health authorities (including changes made in local amendments), ethics committees and 
investigators; updates to permitted and prohibited concomitant medications; clarification of safety 
monitoring; and enhancing the feasibility of the study. 
The changes made to the general clinical study protocol version 1.0, dated 30-Mar-2018, are 
described below, with a brief rationale / description of each change and the applicable sections.  
Incorporation of changes made in 2 local amendments, Amendment 1 
 and Amendment 1 
 as detailed in the summary of changes for each local amendment below. 
Applicable Sections: 
2.3.2 Clinical Study Design Rationale 
4.3.3 Exclusion Criteria  
4.3.4.2 Prior and Concomitant Medications 
The study physician has changed, and the CT.gov number has been added. 
Applicable Section: 
Title page 
Sponsor Signature page 


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Amendment 1 Global (dated 24 Jan 2019) 
The protocol has been edited for clarity and minor corrections have been made. 
Applicable Section: 
Throughout the protocol 
The secondary objective/endpoints evaluating time to major clinical endpoints has been modified:  
− 
“All cause mortality” will be assessed in addition to only respiratory-related mortality to 
complement this endpoint.  
− 
“Need for placement on the lung transplant list” was removed because of differences in 
management of transplants and lists of candidates between countries preventing the analysis as 
an aligned endpoint. This event has also been removed from the events that will be adjudicated. 
Applicable Sections: 
Summary 
Section 3.2 Secondary objectives 
Section 4.1.2 Secondary endpoints 
Section 6.4.3 Clinical Endpoints 
Section 7.3.4.2 Secondary Efficacy Endpoints Analysis 
Section 8.2 Clinical Endpoint Adjudication 
Eligibility criteria 
− 
Inclusion criterion 3: The time from first diagnosis of idiopathic pulmonary fibrosis (IPF) has 
been increased from 3 years to 5 years, to facilitate recruitment to the study considering the 
longer survival rates after introduction of nintedanib and pirfenidone as standard of care 
treatments for IPF, and to align with other Phase 3 studies in IPF.  
The diagnostic guideline used should be that applicable at the time of diagnosis of IPF. 
Accordingly, a patient diagnosed in 2015 is eligible using the 2011 American Thoracic Society 
(ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Latin 
American Thoracic Association (ALAT) guidelines, but a new diagnosis should follow the 
2018 guidelines. The references have been updated. 
The requirement for subjects receiving treatment with pirfenidone or nintedanib to be on a 
stable dose for at least 8 weeks before screening, and during screening has been introduced. A 
stable dose is defined as the highest tolerated dose. 
− 
The prednisone (or equivalent) dose allowed has been reduced to ≤10 mg/day (inclusion 
criterion 3 and exclusion criterion 18) to reduce background medications with drug-drug 
interaction (DDI) potential (cytochrome P450 3A4 [CYP3A4] inducer). 
− 
All forms of lung biopsy will be accepted, rather than only surgical lung biopsy (inclusion 
criterion 4). 
− 
The definition of disease progression within the last 9 months as assessed by forced vital 
capacity has been clarified (inclusion criterion 5). 
− 
The requirement for stability of co-medication for pre-existing conditions has been restricted to 
treatment for chronic diseases and conditions, and the stability of treatment relaxed to limit 
only to clinically relevant changes (inclusion criterion 6 and Section 4.3.4.2) to reflect the real 
life situation of the patient and to facilitate study participation of IPF subjects.  
− 
The requirements for completion of the 6-Minute Walk Test have been further clarified 
(inclusion criterion 9) by adding “without a condition putting the subject at risk of falling 
during the test (at investigator’s discretion). The use of a cane is allowed, while the use of a 
stroller is not allowed at all, under any circumstances”. 
− 
Exclusion criterion 2 has been modified to exclude only a current immunosuppressive 
condition.  


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Amendment 1 Global (dated 24 Jan 2019) 
− 
The exclusion criterion 3 hepatitis test requirements have been modulated because GLPG1205 
is not a strong immunosuppressor and the risk for hepatitis reactivation is considered to be low. 
The following changes have been made: 
− 
Hepatitis B surface antigen and hepatitis B core antibody have been replaced with 
hepatitis B surface antigen only 
− 
Hepatitis C virus (HCV) antibody testing is replaced with an assay for anti-HCV 
antibody that is, if positive, confirmed by HCV RNA positivity  
− 
“History of hepatitis from any cause with the exception of hepatitis A” has been 
removed, and replaced with “Subjects with a resolved hepatitis A at least 3 months prior 
to first dosing of the investigational medicinal product (IMP) can be included.”  
− 
Addition of moderate to severe liver impairment to exclusion criterion 13 to increase the safety 
of the subjects and to be in line with Section 2.4.  
− 
The threshold for creatinine clearance defining abnormal renal function in exclusion criterion 
14 has been lowered from <60 mL/min to <30 mL/min, to reflect the advanced age of IPF 
population and considering the limited renal excretion of GLPG1205. 
− 
Exclusion criterion 15 excludes subjects who underwent major surgery within 3 months prior 
to screening or who have major surgery planned during the study period. A note that being on a 
lung transplant list is allowed has been added because being on a list is not associated with a 
high chance of a lung transplant occurring and should not exclude the patient from treatment in 
the study. 
− 
The minimum interval between participation in a drug, device or biologic investigational 
research study and this study has been set as within 12 weeks or 5 half-lives of the agent 
whichever is longer (exclusion criterion 17). 
− 
Additional medications have been added to exclusion criterion 19 for subjects on medications 
with known drug-drug interactions (DDI) with GLPG1205 
• 
Medications which are known dual CYP3A4 and CYP2C19 inhibitors (non-exhaustive list 
provided in Appendix 8). Rationale: GLPG1205 primary metabolism pathways are 
CYP3A4 and CYP2C19. A strong inhibition of those pathways could lead to increased 
exposure to GLPG1205 and potential safety/tolerability issues. 
• 
Medications which are known to be CYP3A4 or CYP2C19 strong inducers (non-
exhaustive list provided in Appendix 9). Rationale: GLPG1205 primary metabolism 
pathways are CYP3A4 and CYP2C19. A strong induction of these pathways could lead to 
decreased exposure to GLPG1205 and lack of efficacy. 
Applicable Section: 
Section 4.3.2 Inclusion Criteria 
Section 4.3.3 Exclusion Criteria 
Section 4.3.4.2 Prior and Concomitant Medications 
Section 6.5.2 Clinical Laboratory Evaluations 
Appendix 1 High-resolution Computed Tomography/Biopsy Central Review Criteria 
Appendix 8 Non-exhaustive List of Medications Known to be Dual Inhibitors of CYP3A4 and 
CYP2C19 Enzymes 
Appendix 9 Non-exhaustive List of Medications Known to be Strong Inducers of CYP3A4 or 
CYP2C19 


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Amendment 1 Global (dated 24 Jan 2019) 
The prohibition of medications known to prolong QT interval has been removed because there is no 
evidence for QT prolongation potential when taking GLPG1205 in the existing  
− 
nonclinical (hERG assay, monkey telemetry) and  
− 
clinical data (new GLPG1205 concentration/QTcF analysis of single-read electrocardiogram 
(ECG) data from the first in human single ascending dose (SAD)/multiple ascending dose 
(MAD) study in healthy subjects showing no significant relationship between deltaQTcF and 
GLPG1205 concentrations for the range of exposures investigated and also that all 90% for 
delta/deltaQTcF estimated at Cmax of each cohort were below 10 ms).  
Instead, chronic use or initiation of medication known to prolong the QT interval needs to be 
evaluated on a case-by-case basis.  
− 
A list of medications that should be used with caution has been added in Appendix 10 as 
guidance (non-exhaustive list).  
− 
Exclusion criterion 6 excluding subjects using medications known to prolong QT interval has 
been removed. 
− 
Exclusion criterion 5 defining QTc findings for exclusion of subjects from the study has been 
clarified. 
− 
The rule for discontinuation of subjects based on QTc interval has been adjusted to an increase 
from baseline (Visit 2) in QTcF of >60 ms or QTcF ≥501 ms (in line with CTCAE Version 5.0 
Grade 3) on at least 2 separate ECGs at the same visit. 
− 
Vital signs and ECG normal ranges have been adjusted to better reflect the IPF patient 
population. 
 
Applicable Sections: 
Section 2.4 Potential risks and benefits 
Section 4.3.3 Exclusion criteria 
Section 4.3.4.2 Prior and concomitant medications 
Section 4.3.5 Removal of subjects from therapy or assessments 
Section 6.5.4 12-lead electrocardiogram 
Appendix 4 Normal ranges 
Appendix 8 Medications known to prolong QT interval 
The categories of liver function test findings that should lead to discontinuation of treatment with 
IMP have been revised in line with guidance on drug-induced liver injury (US Food and Drug 
Administration. Guidance for Industry. Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation. 2009). 
Applicable Section: 
Section 4.3.5 Removal of subjects from therapy or assessments 








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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations 
6MWT 
6-Minute Walk Test 
AE 
adverse event 
ALAT 
Latin American Thoracic Association 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATS 
American Thoracic Society 
AUC 
area under the plasma drug concentration-time curve  
AUEC 
area under the effect-time curve 
BCRP 
breast cancer resistance protein 
BLM 
bleomycin 
Cavg 
average plasma concentration 
CK 
creatine kinase 
Cmax 
maximum observed plasma concentration 
COVID-19 
Corona virus disease 2019 
CRF 
case report form 
CRO 
contract research organization 
CSP 
clinical study protocol 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DBP 
diastolic blood pressure 
DLCO 
diffusing capacity for the lungs for carbon monoxide 
DNA 
deoxyribonucleic acid 
DTP 
direct-to-patient 
ECG 
electrocardiogram 
EMA 
European Medicines Agency 
Emax 
maximum effect (expressed as a % reduction from baseline) 
EOT 
end of treatment 
ERS 
European Respiratory Society 
EU 
European Union 
FDA 
Food and Drug Administration 
FEF25-75 
forced expiratory flow between 25% and 75% of exhaled volume 
FEV1 
forced expiratory volume in one second 


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FFA 
free fatty acid 
FFA1, FFA2, 
FFA3, FFA4 
free fatty acid sensing receptors 
 
 
 
 
FSH 
follicle stimulating hormone 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GPCR 
G protein-coupled receptor 
HBs Ag 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HRCT 
high-resolution computed tomography 
IB 
investigator’s brochure 
IC50 
half maximal inhibitory concentration (concentration resulting in 50% 
inhibition) 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IPF 
idiopathic pulmonary fibrosis 
IRB 
Institutional Review Board 
IWRS 
interactive web response system 
JRS 
Japanese Respiratory Society 
LB 
lung biopsy 
LFT 
liver function test(s) 
MAD 
multiple ascending dose 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MRP2 
multidrug resistance-associated protein 2 
NOAEL 
no observed adverse effect level 


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OCT 
organic cation transporter 
 
 
P-gP 
P-glycoprotein 
PK 
pharmacokinetic(s) 
q.d. 
quaque die, once daily 
QTc 
corrected QT interval 
QTcF 
QT interval corrected for the heart rate using Fridericia’s formula 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SGRQ 
St. George’s Respiratory Questionnaire 
SUSAR 
suspected unexpected serious adverse reaction 
TBL 
total bilirubin 
TEAE 
treatment emergent adverse event 
 
ULN 
upper limit of normal 
US 
United States 
 
Definition of Terms 
QTcF 
QTcF = QT x (1000/RR)⅓ with RR= direct ECG measurement of the 
distance between R waves in msec 
 
 


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1. 
SUMMARY 
Rationale: 
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lethal lung disease for which 
two oral treatments (pirfenidone and nintedanib) are approved in the European Union (EU), 
United States (US) and other regions around the world. 
These treatments appear to slow disease progression however, the residual decline in lung 
function (as measured by forced vital capacity [FVC]) remains substantial. In addition, both 
compounds are frequently associated with side effects potentially limiting the use in clinical 
practice. 
There thus remains a significant unmet medical need for the development of additional 
therapies targeting different disease pathways that could potentially prove to be more 
effective by further preventing the decline in FVC with an acceptable safety profile. 
Recent published data suggest the relevance of GPR84 in fibrotic pathways. In humans, first 
signs of clinical efficacy have been shown in a clinical study in subjects with IPF 
investigating a compound targeting GPR84 as well as GPR40. It thus can be anticipated that 
compounds targeting GPR84 could lead to a new class of therapy for IPF. 
GLPG1205 is a novel, selective, and potent GPR84 antagonist, which has shown a good 
safety and tolerability profile at the targeted dose of 100 mg once daily (quaque die [q.d.]) in 
clinical studies. 
Consequently, it seems appropriate to investigate the efficacy, safety, tolerability and 
pharmacokinetics (PK) of GLPG1205 compared to placebo in subject with IPF on top of 
local standard of care (defined as receiving nintedanib, pirfenidone, or neither nintedanib nor 
pirfenidone). 
Objectives: 
Primary Objective 
− 
To evaluate the efficacy of GLPG1205 treatment in subjects with IPF on pulmonary 
function as evaluated by FVC compared to placebo over 26 weeks. 
Secondary Objectives 
− 
To evaluate the safety and tolerability of GLPG1205 treatment compared to placebo over 
26 weeks. 
− 
To evaluate the impact of GLPG1205 treatment compared to placebo on time to any 
major events (whichever occurs first) defined as: 
• 
Mortality (all cause and respiratory-related) 
• 
Hospitalization (all-cause and respiratory-related) 
− 
To evaluate the changes from baseline in functional exercise capacity measured by the 
6-Minute Walk Test (6MWT), in IPF subjects treated with GLPG1205 compared to 
placebo at Week 26. 
− 
To evaluate the changes in quality of life measures in IPF subjects treated with 
GLPG1205 compared to placebo over 26 weeks. 
− 
To evaluate the PK of GLPG1205, nintedanib and pirfenidone in IPF subjects. 




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2. 
INTRODUCTION 
IPF is a chronic, progressive, severely debilitating and ultimately lethal lung disease 
predominantly affecting elderly male smokers or ex-smokers with a median age of 65-
70 years [1]. The disease is characterized by progressive worsening of dyspnea and lung 
function and is associated with a poor prognosis (i.e. median survival of 2-5 years following 
diagnosis) [2, 3, 4, 5, 6]. 
The estimated IPF prevalence ranges from 14.0 to 27.9 cases per 100,000 population in the 
US and from 1.3 to 23.4 cases per 100,000 population in Europe (data from 1990-2011). The 
estimated IPF incidence ranges from 6.8-8.8 cases per 100,000 population in the US and from 
0.2-7.4 cases per 100,000 population in Europe [7, 8, 9, 10]. The incidence and prevalence of 
IPF increases dramatically with age; and in patients >65 years, the estimated prevalence of 
IPF is as high as 400 cases per 100,000 people [11]. 
Over the past decade, extensive research has been conducted to address the unmet medical 
need for effective IPF treatment. Two treatments (pirfenidone and nintedanib), targeting the 
biological processes that drive fibrosis, are currently approved in the European Union, the 
United States, and other regions around the world. 
• Pirfenidone (antifibrotic, anti-inflammatory and antioxidant treatment marketed as 
Esbriet®; indicated in adults for the treatment of mild to moderate IPF), was the first 
drug to be licensed specifically for IPF. Phase III studies had varying results but 
overall demonstrated that the drug improved progression-free survival and slowed the 
decline in FVC. Moreover, pirfenidone may have a mortality benefit [12, 13, 14, 15]. 
The drug was approved in the EU in 2011 and in the US in 2014.  
• Nintedanib (tyrosine kinase inhibitor marketed as Ofev®; indicated in adults for the 
treatment of IPF), was initially developed as an anticancer agent. In Phase III studies it 
significantly reduced the decline in FVC compared with placebo in subjects with IPF. 
A trend towards a reduced death rate was also observed; however, the studies were not 
powered to detect differences in mortality [16]. The drug was approved in the US in 
2014 and in the EU in 2015. Both treatments appear to slow disease progression but 
are frequently associated with side effects (e.g. gastrointestinal related side effects) 
potentially limiting the use in clinical practice [17, 18, 19]. 
There thus remains a significant unmet medical need for the investigation and development of 
novel IPF treatments targeting disease-relevant pathways. Several other candidate treatments 
with different mechanism of action are currently in Phase II and III or in earlier phases of 
clinical development. Considering the progressive and irreversible nature of this disease, it is 
highly desirable to evaluate efficacy of new potential treatments when added on top of the 
local standard of care. 
Over the last decade, a growing number of G protein-coupled receptors (GPCRs) have been 
identified for which the ligands are energy substrates or metabolic intermediates. Free fatty 
acids (FFAs) have been reported to activate different GPCRs, including FFA1, FFA2, FFA3, 
FFA4, and GPR84. These FFA-sensing receptors are proposed to play important roles in the 
pathophysiology of a variety of diseases, including neuro-inflammatory diseases and 
metabolic disorders. GPR84 has been described as a pro-inflammatory receptor. The ligand-
induced activation of GPR84 mediates both activation and migration of neutrophils and 








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suggesting that the compound could be able to prevent and/or decrease at least one step in 
neutrophil migration and/or activation induced by activation of the GPR84 receptor. The 
inhibitory effect can be maintained over 24 hours with q.d. dosing. Ligand binding inhibition 
(area under the effect-time curve [AUEC] and maximum effect [Emax]) was correlated with 
the exposure to GLPG1205 (Cmax and average plasma concentration [Cavg]) in plasma. 
2.2.3. Clinical Efficacy 
So far, only patients with moderate to severe ulcerative colitis were exposed to GLPG1205 for 
12 weeks. The analyses revealed no clear evidence of efficacy. 
2.2.4. Clinical Safety 
Administration of single (up to 800 mg) and multiple (up to 100 mg q.d. for 14 days) oral 
doses of GLPG1205 in healthy male subjects can be considered well tolerated. No deaths, 
serious adverse events (SAEs) or treatment-emergent adverse events (TEAEs) leading to 
study drug discontinuation were reported. The most frequently reported treatment-related 
TEAEs were headache and gastrointestinal disorders like nausea and all TEAEs were rated at 
most moderate in intensity. None of the treatment-emergent abnormalities in laboratory, 
electrocardiogram (ECG) and vital signs parameters or physical examination abnormalities 
were considered clinically significant by the investigator. 
Multiple dosing with GLPG1205 200 mg q.d. (first-in-human study - multiple ascending dose 
[MAD] part) did not show an acceptable safety profile with three subjects discontinuing the 
study drug due to headache after dosing with GLPG1205. Two subjects in the GLPG1205 
200 mg q.d. group showed abnormally high laboratory values for hematocrit, hemoglobin and 
in red blood cell count, which were considered clinically significant by the investigator. This 
resulted in 100 mg q.d. being considered as the maximum tolerated dose after multiple dosing, 
which may be used in future clinical studies with GLPG1205. 
Administration of a single GLPG1205 100 mg dose in fasted or fed state and co-
administration of multiple doses of GLPG1205 100 mg with a single dose of a cocktail of 
CYP2C9, CYP2C19 and CYP1A2 substrates was considered well tolerated. Age or 
administration of a GLPG1205 loading dose (250 mg) did not affect the safety profile of 
GLPG1205. 
In a Phase II study in subjects with ulcerative colitis, 63 subjects were dosed with 100 mg 
GLPG1205 q.d. or placebo for up to 12 weeks. No deaths were observed. Three subjects in 
the GLPG1205 group presented with treatment-related SAEs: worsening of ulcerative colitis 
(2 subjects) and macular rash (1), which led to study discontinuation. In addition, 5 subjects 
reported SAEs which were not considered treatment-related by the investigator, including 
worsening of colitis ulcerative (1 subject), anemia (1), worsening of colitis ulcerative and 
anemia (1), head injury (1) and tendon rupture (1). 
2.3. 
CLINICAL STUDY RATIONALE 
IPF is a chronic and progressive lethal lung disease for which two oral treatments (pirfenidone 
and nintedanib) are approved in the EU and US. These treatments appear to slow disease 
progression however, the residual decline of FVC over one year remains substantial, with a 
further decline of FVC over 52 weeks of 125 mL and 114 mL in INPULSIS I and II 
(nintedanib) [16], respectively, and around 200 mL in the ASCEND study (pirfenidone) [15]. 


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In addition, both compounds are frequently associated with side effects potentially limiting 
the use in clinical practice. 
There thus remains a significant unmet medical need for the development of additional 
therapies targeting different disease pathways that could potentially prove to be more 
effective by further preventing the decline in FVC with an acceptable safety profile [22]. 
Recent published data suggest the relevance of GPR84 in fibrotic pathways underlined by 
GPR84 knock out mice used in models of kidney fibrosis [20]. In addition, PBI-4050 a 
compound in clinical development targeting both GPR84 and GPR40, has demonstrated first 
clinical benefit after 12 weeks of treatment in patients with IPF with and without addition of 
nintedanib [21]. It thus can be anticipated that compounds targeting GPR84 could lead to a 
new class of therapy for IPF. 
GLPG1205 is a novel, selective, and potent GPR84 antagonist that has a good safety and 
tolerability profile at the targeted dose of 100 mg q.d.in clinical studies. 
Consequently, it seems appropriate to investigate the efficacy, safety, tolerability and PK of 
GLPG1205 in subjects with IPF. 
2.3.1. Dosing Rationale 
A dose of 100 mg GLPG1205 administered q.d. has been selected to be evaluated for this 
Phase II study. It is the highest oral dose of GLPG1205 administered in healthy male subjects 
that can be considered safe and well tolerated for repeated administration. GLPG1205 caused 
an extensive and sustained reduction in ligand binding to the GPR84 receptor in whole blood, 
suggesting that the compound could be able to prevent and/or decrease at least one step in 
neutrophil and macrophage migration and/or activation induced by activation of the GPR84 
receptor. The inhibitory effect can be maintained over 24h with q.d. dosing. Ligand binding 
inhibition (AUEC and Emax) was correlated with the exposure to GLPG1205 (Cmax and Cavg) 
in plasma and at a dose of 100 mg q.d. at least 80% of binding inhibition is expected. 
GLPG1205 100 mg q.d. was also used in a prior proof of concept study in which GLPG1205 
or placebo was administered over 12 weeks in 63 subjects with ulcerative colitis. Overall, the 
intensities of the treatment-related AEs for the placebo and GLPG1205 treatment groups were 
moderate. There were no clinically meaningful trends in changes from baseline for any vital 
signs, ECG, or physical examination variables. There were no clinically relevant 
abnormalities reported on laboratory assessments. GLPG1205 given at repeated doses of 
100 mg was, in general, safe and well-tolerated. 
In light of significant unmet medical need for the investigation and development of novel IPF 
treatments, GLPG1205 100 mg q.d. is considered an adequate dose for the proposed proof of 
concept study in subjects with IPF. 
2.3.2. Clinical Study Design Rationale 
This is a randomized, double-blind, parallel group, placebo-controlled, multicenter, 
exploratory Phase II study including subjects with IPF. The randomized double-blind study 
design was chosen as it is the most rigorous method to generate high quality scientific data. In 
addition, a placebo-controlled study contains internal evidence of assay sensitivity (i.e. when 
a difference is demonstrated, it is interpretable without reference to external findings), 


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measures absolute safety and efficacy (i.e. it measures the total pharmacologically mediated 
effect of treatment), is very efficient (i.e. can measure treatment effects with a smaller sample 
size compared with any other type of controlled study), and minimizes the effect of subject 
and investigator expectations (International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use [ICH] E10, 2000). The 2:1 randomization 
to GLPG1205 100 mg avoids unnecessary exposure of subjects to placebo. 
The subject eligibility criteria are typical for patient studies in IPF. The disease typically 
affects elderly subjects, so it was chosen to include subjects aged ≥40 years. Considering the 
progressive and irreversible nature of this disease, it is highly desirable to evaluate efficacy of 
new potential treatments when added on top of the local standard of care. Standard of care is 
defined as receiving nintedanib, pirfenidone, or neither nintedanib nor pirfenidone. Thus, this 
study will include all IPF subjects, independently of their (prior) use of standard of care. 
Subjects eligible for this study will be randomized to either GLPG1205 or placebo. Subjects 
who are either on nintedanib or pirfenidone may vary dosing during the study conduct if 
needed (e.g. due to dose limiting side effects) according to the discretion of the investigator. 
For subjects initially neither on nintedanib nor on pirfenidone, the addition of nintedanib or 
pirfenidone during the course of the study is allowed.  
Subjects are not allowed to use non-evidenced based medication being used to treat IPF (i.e. 
warfarin; imatinib; endothelin inhibitors such as ambrisentan, bosentan, and macitenan; 
azathioprine; cyclophosphamide; cyclosporine A; methotrexate; sildenafil ; prednisone at 
steady dose >10 mg/day or equivalent glucocorticoid dose) within 4 weeks before screening 
and during screening, or planned during the study. Subjects are also not allowed to use any 
other experimental oral IPF therapy within 12 weeks or 5-half-lives of the agent, whichever is 
longer, prior to screening, or to have participated in an investigational drug antibody / 
biologic study within 6 months prior to screening. This is necessary in order to avoid any 
confounding effects these drugs may have on the safety, tolerability, PK, 
 
endpoints evaluated in the current study. 
According to the analysis of the course of disease in placebo treated IPF subjects in clinical 
studies over 12 months by Nathan et al. [23] approximately 9.5% IPF subjects may 
experience a ≥10% decline in % predicted FVC after 6 months compared with baseline. 
Nintedanib and pirfenidone have been shown to have a beneficial effect on the rate of decline 
in lung function. It is anticipated that a potential efficacious effect of GLPG1205 in IPF can 
be substantiated after this period of time and distinguished from individual courses of the 
disease in both populations – patients receiving nintedanib, pirfenidone, or neither nintedanib 
nor pirfenidone. 
Pirfenidone is primarily metabolized in humans via CYP1A2 with minor contributions from 
other CYP isoenzymes. A clinical study assessing the effect of GLPG1205 on a CYP1A2 
probe substrate (caffeine) demonstrated that there was no impact of GLPG1205 on the 
CYP1A2 probe substrate (no inhibition nor induction). 
Pirfenidone is a weak P-glycoprotein (P-gp) inhibitor and is a weak CYP2C9, 2C19 or 1A2, 
2D6, and 3A4 inhibitor. GLPG1205 is not an efflux substrate (P-gp, BCRP, multidrug 
resistance-associated protein 2 [MRP2]) and has multiple CYPs involved in its metabolism 
(3A4, 2C19). Consequently, the coadministration of GLPG1205 with pirfenidone should not 
lead to drug interactions however plasma levels of both GLPG1205 and pirfenidone will be 
measured and tolerability will be closely monitored. 


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Nintedanib is a P-gp substrate and the fraction absorbed is metabolized via hydrolytic 
cleavage by esterases then glucuronidation and to a lower extend by CYP3A4. From in vitro 
data, GLPG1205 is likely to be a weak P-gp inhibitor and the likelihood that GLPG1205 may 
increase exposure to nintedanib can be considered low. In addition, the US product 
information for Ofev (nintedanib) states that coadministration with the strong P-gp and 
CYP3A4 inhibitor, ketoconazole, increased exposure to nintedanib 1.61-fold based on AUC 
and 1.83-fold based on Cmax in a dedicated drug-drug interaction study. A contra-indication is 
not warranted but patients should be monitored closely for tolerability. 
Nintedanib demonstrated in in vitro studies little or no inhibition of CYP enzymes 1A2, 2A6, 
2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, 4A11, and of UGT1A1 or UGT2B7 activities and is a 
weak inhibitor of P-gp. GLPG1205 is not an efflux substrate (P-gp, BCRP, MRP2) and has 
multiple CYPs involved in its metabolism (3A4, 2C19). 
Consequently, co-administration of GLPG1205 with nintedanib should not lead clinically 
significant to drug interactions. However, plasma concentration of both GLPG1205 and 
nintedanib will be measured and tolerability will be closely monitored. 
2.4. 
POTENTIAL RISKS AND BENEFITS 
As IPF is characterized by progressive worsening of dyspnea and lung function and is 
associated with a poor prognosis. A significant unmet medical need for the investigation and 
development of novel IPF treatments with different mechanism of action remains for this 
targeted patient population. 
Nonclinical data with GLPG1205 have demonstrated efficacy in the 21-day BLM mouse 
model similar to nintedanib. One other compound (PBI-4050) known to target both GPR84 
and GPR40 has shown signals of beneficial efficacy in patients with IPF in an open-label 
study. GLPG1205 is anticipated to be the first inhibitor of only GPR84 in clinical 
development to be investigated for the oral treatment of IPF. 
As there is limited clinical experience with GLPG1205 so far, the investigational medicinal 
product (IMP) should not be administered to subjects with moderate to severe renal 
impairment or hepatic impairment (Child-Pugh B or Child-Pugh C). Based on the 
bioavailability and safety results of a Phase I study in elderly healthy male subjects of 65 
years and older, the IMP was well tolerated and can be administered to elderly subjects. 
Throughout the study, safety of the individual patient is paramount. The subjects therefore 
need to be closely monitored by repeated assessment of clinical and vital signs, ECG, and 
laboratory safety parameters. 
The allowed disease-related concomitant drugs were selected to minimize the risk of drug-
drug interactions. However, precautions and specific monitoring as per standard medical 
practice is recommended. 
The most frequently reported treatment-related TEAEs so far observed in patients or healthy 
volunteers in clinical studies with GLPG1205 were headache and nausea and all TEAEs were 
rated at most moderate in intensity. Potential side effects will be closely monitored and 
followed-up. In case of intolerance to GLPG1205 the dose may be decreased to 50 mg q.d. 






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early IMP discontinuation), the end of treatment visit (EOT). In addition, a follow-up visit 
will be planned 4 weeks after the last administration of IMP (i.e. Week 30/EoS). The end of 
the study is reached when the last follow-up visit as planned according the schedule of 
activities (Section 6.10) of the last subject is performed. 
Subjects who stop IMP early need to be encouraged to complete the EOT and follow-up visit 
for safety assessments and pulmonary function, but will not be obliged to do so.  
To enhance the safety of the subjects and integrity of the study data, an Independent Data 
Monitoring Committee (IDMC) will be implemented and clinical endpoint adjudication will 
be performed (see Section 8 for additional information). 
For the in- and exclusion criteria please refer to Section 4.3.2, “Inclusion Criteria” and 
Section 4.3.3, “Exclusion Criteria”. 
A schematic diagram of clinical study design is provided (Figure 1). 
 
Figure 1 
GLPG-1205-CL-220 Study Design 
The subjects will be in the study for a duration of approximately 34 weeks: up to 4 weeks of 
screening, 26 weeks of treatment, and 4 weeks of follow-up. 
For detailed info regarding dosage form, packaging and labeling of the IMP please refer to 
Section 5.2, “Dosage and Administration” and Section 5.3, “Packaging, Labeling and 
Distribution”. 
4.3. 
STUDY POPULATION 
4.3.1. Sample Size 
Approximately 60 subjects are planned to be randomized into the study. In principle, it is 
aimed to achieve a balanced study population with regards to the background standard of care. 
For the justification of sample size, including assumptions and power considerations please 
refer to Section 7.1 “Determination of Sample Size”. 
4.3.2. Inclusion Criteria 
Subjects who meet all of the following criteria are eligible for the study: 
1. Signed informed consent form (ICF) obtained prior to any study-related procedures and/or 
assessments performed. 
2. Males or females of non-child-bearing potential, aged ≥40 years on the day of signing the 
ICF. 


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Note: 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 AND a 
follicle-stimulating hormone (FSH) level >40 IU/L 
− Permanently surgically sterile (bilateral oophorectomy, i.e. surgical removal of 
ovaries, bilateral salpingectomy or hysterectomy, i.e. surgical removal of uterus) 
3. Criterion modified per amendment. 
3.1 A diagnosis of IPF within 5 years prior to the screening visit as per applicable 
American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese 
Respiratory Society (JRS)/Latin American Thoracic Association (ALAT) guideline 
[6, 24]. Subjects receiving local standard of care for the treatment of IPF, defined as 
either pirfenidone or nintedanib at a stable dose for at least 8 weeks before screening, 
and during screening; or neither pirfenidone nor nintedanib (for any reason). A stable 
dose is defined as the highest tolerated dose. Prednisone at steady dose ≤10 mg/day 
or equivalent glucocorticoid dose is allowed (stabilized 4 weeks prior to screening 
and continued without variation of dose or regimen). Supportive care like 
supplemental oxygen or pulmonary rehabilitation is allowed. 
4. Criterion modified per amendment. 
4.1 Chest HRCT historically performed within 12 months prior to the screening visit and 
according to the minimum requirements for IPF diagnosis by central review (see 
Appendix 1) based on subject’s HRCT only (if no lung biopsy [LB] available), or 
based on both HRCT and LB (with application of the different criteria in either 
situation). If an evaluable HRCT <12 months is not available, a HRCT can be 
performed at screening to determine eligibility, according to the same requirements 
as the historical HRCT. 
5. Criterion modified per amendment. 
5.1 Meeting all of the following criteria at screening and during the screening period: 
a. 
FVC ≥50% predicted of normal 
b. Disease progression, defined as a decline of FVC (% predicted or mL) at the 
investigator’s discretion, during the 9 months prior to the screening period and 
confirmed at the screening visit 
c. 
Diffusing capacity for the lungs for carbon monoxide (DLCO) ≥30% predicted of 
normal (corrected for hemoglobin) (see Section 6.4.4) 
d. Ratio of forced expiratory volume in one second (FEV1) to FVC ≥0.70 
6. Criterion modified per amendment. 
6.1 In a stable condition and suitable for study participation based on the results of a 
medical history, physical examination, vital signs, 12-lead ECG, and laboratory 
evaluation. Stable condition is based on the clinical judgment of the investigator, co-
morbidities should be treated according to the local applicable guidelines. 
Concomitant medication for chronic co-morbidities should be stabilized from 
4 weeks before screening and during the screening period (stable defined as no 
clinically relevant change according to the investigator’s judgement). 
7. Estimated minimum life expectancy of 12 months for non-IPF related disease in the 
opinion of the investigator. 


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8. Male subjects with female partners of child bearing potential are willing to comply with 
the contraceptive methods described in the protocol (see Section 4.3.4.1) prior to the first 
dose of the IMP, during the clinical study, and for at least12 weeks after the last dose of 
the IMP. 
9. Criterion modified per amendment. 
9.1 Able to walk at least 150 meters during the 6MWT at screening; without having a 
contra-indication to perform the 6MWT (see Appendix 3), or without a condition 
putting the subject at risk of falling during the test (at investigator’s discretion). The 
use of a cane is allowed, the use of a stroller is not allowed at all under any 
circumstances. 
10. Able to understand the importance of adherence, and willing to comply to study 
treatment, study procedures and requirements as per study protocol, including the 
concomitant medication restrictions. 
4.3.3. Exclusion Criteria 
Subjects meeting one or more of the following criteria cannot be selected for this study: 
1. Known hypersensitivity to any of the IMP ingredients or a history of a significant allergic 
reaction to any drug as determined by the investigator (e.g. anaphylaxis requiring 
hospitalization). 
2. Criterion modified per amendment. 
2.1 
Current immunosuppressive condition (e.g. human immunodeficiency virus [HIV] 
infection, congenital, acquired, medication induced, organ transplantation). 
3. Criterion modified per amendment. 
3.1 
Positive blood testing for hepatitis B surface antigen (HBS Ag) or hepatitis C virus 
antibody (if positive, confirmed by hepatitis C virus (HCV) RNA positivity). Note: 
Subjects with a resolved hepatitis A at least 3 months prior to first dosing of the 
IMP can be included. 
4. History of malignancy within the past 5 years (except for carcinoma in situ of the uterine 
cervix, basal cell carcinoma of the skin that has been treated with no evidence of 
recurrence, and prostate cancer medically managed through active surveillance or 
watchful waiting, and squamous cell carcinoma of the skin if fully resected). 
5. Criterion modified per amendment. 
5.1 
Clinically significant abnormalities detected on 12-lead ECG of either rhythm or 
conduction, including prolongation of QTc or known long QTc syndrome. For any 
interval measurements e.g. when deciding if QT interval corrected for heart rate 
using Fridericia’s formula [QTcF] is >450 ms [male], OR >460 ms [female], when 
triplicate ECG are performed (baseline), a single outlier value per interval should 
be considered (i.e. worst case scenario). Of note, a first-degree heart block will not 
be considered as a significant abnormality. 
6. Criterion deleted per amendment. 
7. Acute IPF exacerbation within 3 months prior to screening and during the screening 
period (see Appendix 2). 
8. Lower respiratory tract infection requiring antibiotics within 4 weeks prior to screening 
and/or during the screening period. 


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9. Interstitial lung disease associated with known primary diseases (e.g. sarcoidosis, 
amyloidosis), exposures (e.g. radiation, silica, asbestos, coal dust), and drugs (e.g. 
amiodarone). 
10. History of lung volume reduction surgery or lung transplant. 
11. Unstable cardiovascular, pulmonary (other than IPF) or other disease within 6 months 
prior to screening or during the screening period (e.g. coronary heart disease, heart 
failure, stroke). 
12. Any other clinical condition or circumstance that in the opinion of the investigator may 
make him or her unsuitable for inclusion or unable to complete the study or comply with 
study procedures and requirements. 
13. Criterion modified per amendment. 
 13.1 Moderate to severe hepatic impairment (Child-Pugh B or C) and/or abnormal liver 
function test (LFT) at screening, defined as aspartate aminotransferase (AST) 
and/or alanine aminotransferase (ALT) and/or bilirubin 1.5x and/or gamma 
glutamyl transferase (GGT) 3x upper limit of normal (ULN) range. Retesting is 
allowed once for abnormal LFT. 
14. Criterion modified per amendment. 
14.1 Abnormal renal function defined as estimated creatinine clearance <30 mL/min 
using Cockcroft-Gault equation. Retesting is allowed once. 
15. Criterion modified per amendment. 
15.1 Underwent major surgery within 3 months prior to screening or who has major 
surgery planned during the study period. Note: being on a lung transplant list is 
allowed. 
16. Hemoglobin level <10 g/dl. Retesting is allowed once. 
17. Criterion modified per amendment. 
17.1 Subject participating in a drug, device or biologic investigational research study, 
concurrently with the current study, within 12 weeks or 5-half-lives of the agent , 
whichever is longer, prior to screening, or prior participation in an investigational 
drug antibody/biologic study within 6 months prior to screening. 
18. Criterion modified per amendment. 
18.1 Use any of the following therapies within 4 weeks before screening and during 
screening, or planned during the study: 
a. 
Warfarin 
b. Imatinib 
c. 
Endothelin receptor antagonists (e.g. ambrisentan, bosentan and macitentan) 
d. Azathioprine 
e. 
Cyclophosphamide 
f. 
Cyclosporine A 
g. Methotrexate 
h. Sildenafil  
i. 
Prednisone at steady dose >10 mg/day or equivalent  
19. Criterion modified per amendment. 


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19.1 Use any of the following therapies within 5 half-lives before screening and during 
screening, or planned during the study  
a. 
medications which are known BCRP substrates (see Appendix 5) 
b. medications which are known dual CYP3A4 and CYP2C19 inhibitors (see Appendix 
8) 
c. 
medications which are known to be CYP3A4 or CYP2C19 strong inducers (see 
Appendix 9)  
20. Current alcohol or substance abuse in the opinion of the investigator. 
4.3.4. Prohibition and Restrictions 
4.3.4.1. 
Precautions for Sexual Intercourse 
Highly effective contraceptive measures for males must be documented in the source 
documents. 
Non-vasectomized male subjects with female partners of childbearing potential must be 
willing to use a condom from the time of the first dose of IMP, during the clinical study, and 
for at least 12 weeks after the last dose of IMP, in addition to having their female partner use 
one of the following forms of contraception: 
− 
Combined (estrogen and progesterone containing) (oral, intravaginal, transdermal) 
hormonal contraception associated with inhibition of ovulation 
− 
Progesterone-only hormonal (oral, injectable, implantable) contraception associated with 
inhibition of ovulation 
− 
Intrauterine device or intrauterine hormone-releasing system 
Periodic abstinence (e.g., calendar, symptothermal, postovulation 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 where the female partner of a male subject has undergone documented surgical 
sterilization (bilateral oophorectomy, i.e. surgical removal of ovaries, bilateral salpingectomy 
or hysterectomy, i.e. surgical removal of uterus) that was performed more than 1 year before 
screening, then the subject is not required to use an additional form of contraception. 
Vasectomized male subjects with female partners of childbearing potential are not required to 
use an additional form of contraception providing that surgical sterilization has been 
successful (documented azoospermia by semen analysis). 
No sperm donation is allowed from first dose of the clinical study during the clinical study 
until 12 weeks after the last dose. 
4.3.4.2. 
Prior and Concomitant Medications 
Concomitant therapies taken for the long-term treatment of preexisting chronic conditions can 
continue during the study provided they are in accordance with the inclusion and exclusion 
criteria (see Section 4.3.2 and Section 4.3.3, respectively). All concomitant medicines must be 
locally approved and administered at a dose that is considered standard-of-care for the treated 
indication. It is required that these medications be stabilized prior to study entry and if 


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possible continued without clinically relevant changes (at the discretion of the investigator) 
during the study. 
In a case where additional concomitant medication needs to be administered or dose 
adjustments for IPF and other preexisting conditions need to be performed during the study, 
the risk/benefit to the subject should be carefully assessed and consideration given to the 
timing of any necessary introduction of new medications. As such, adaptation or initiation of 
treatment with nintedanib or pirfenidone (both post randomization) or other non-excluded 
concomitant medications are allowed throughout the study based on the medical need of the 
individual patient.  
Note: Subjects receiving either pirfenidone or nintedanib have to be on a stable dose for at 
least 8 weeks before screening, and during screening. A stable dose is defined as the highest 
tolerated dose. 
All decisions on the start and stop of the intake of nintedanib or pirfenidone or the need for 
dose adjustments during the study will be made by the investigator and recommendations of 
the respective local SmPCs should be followed, as done in normal clinical practice. 
In vitro assays indicated an inhibition by GLPG1205 of the drug transporters BCRP and 
OCT2, at a concentration being equivalent to human exposure of 100 mg GLPG1205. 
Preliminary in vivo data from a clinical drug-drug interaction study assessing the effect of 
GLPG1205 on OCT2 and BRCP probe substrates show that there is only clinically relevant 
inhibition of BCRP by GLPG1205 (approximately 3 fold exposure increase), therefore 
inclusion of subjects with stable chronic illness on stable medications which are transported 
by known BCRP is not allowed and known BRCP substrates are prohibited during the study. 
A (non-exhaustive) list of BCRP substrates is provided in Appendix 5. 
Inclusion of patients with stable chronic illness on stable medications which are transported 
by OCT2 transporters (less than 2 fold exposure increase observed) should be decided on a 
case-by-case basis, taking into account the medical history, concomitant medication of the 
patient and benefit/risk profile. The CRO’s medical monitor or sponsor’s medical lead can be 
contacted when deemed necessary by the investigator, specifically for medication with a 
narrow therapeutic index and/or a risk of (un)predictable AEs. This is specifically to be done 
for medication that is transported by OCT2 and has the risk to prolong QT interval. A (non-
exhaustive) list of OCT2 substrates is provided in Appendix 6. 
Statins have different pathways involved in their disposition (either via metabolic enzymes 
and/or via transporters) and since it cannot be ruled out that GLPG1205 could interfere with 
some of those pathways (leading to cumulative net effect difficult to predict from in vitro 
studies) and to date, no in vivo clinical drug-drug interaction studies have been conducted yet, 
there is a need to further monitor subjects who may be on statin background therapy. 
Monitoring of liver function tests and creatine kinase (CK) is implemented during the study as 
per local guidance for statins in clinical practice. 
The use of medication known to prolong QT interval during the study needs to be based on a 
benefit-risk evaluation by the investigator, e.g. in the case of atrial fibrillation. In other 
situations (e.g. the initiation of macrolides or fluoroquinolones in case of a lower respiratory 
tract infection), when a medication known to prolong or potentially prolonging QT is indicated, 
IMP can be interrupted after clinical assessment of the subject’s profile, including the baseline 
QTcF and how this has changed over time. If the investigator elects to continue IMP, additional 


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monitoring will be performed as per investigator’s judgment. A non-exhaustive list of 
medication known to prolong QT interval is provided in Appendix 10. 
All medications that are not allowed in accordance with the inclusion and exclusion criteria 
should not be used during the study.  
It is highly recommended that the CRO medical monitor (as per study contact list) or sponsor’s 
study physician (if the former is not available) are consulted before the initiation of new 
medications, in particular medication known to prolong QT interval, and medication known to 
be transported by OCT2 transporters. 
All concomitant therapies, as well as their changes occurring during the study are to be 
recorded on the relevant case report form (CRF) page(s), along with the reason for and details 
of therapy use. All prior surgeries will be recorded on the relevant CRF page(s). 
4.3.4.3. 
Food and Beverage Restrictions 
The comparison of exposures to GLPG1205 achieved after oral administration of GLPG1205 
as a capsule in fed or fasted state (GLPG1205-CL-102) indicates that food has no influence on 
exposure, therefore there is no food restriction in the current study. 
4.3.4.4. 
Other Prohibitions and Restrictions 
No blood donation is allowed during the study. 
4.3.5. Removal of Subjects from Therapy or Assessments 
A subject may be withdrawn from the clinical study at any time without the subject’s consent 
if the investigator or sponsor determines that it is not in the best interest of the subject to 
continue participation. In such case, the reason for withdrawal will be documented in the 
source documents, and the subject will be asked to complete the EOT visit and follow-up visit 
for safety assessments and pulmonary function. 
Study treatment should be discontinued by the investigator (preferably after discussion with 
the CRO medical monitor, for any of the following conditions: 
− 
Life-threatening AE or a SAE that places the subject at immediate risk 
− 
Serious infections (those requiring parenteral antimicrobial therapy and/or 
hospitalization) 
− 
Arrhythmia or conduction abnormality, including but not limited to prolonged QT 
interval corrected for the heart rate using Fridericia’s formula (QTcF), where the 
severity is categorized as Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0 Grade 3 or higher (i.e. QTcF ≥501 ms or an increase from baseline (Visit 2) 
in QTcF of >60 ms) on at least 2 separate ECGs at the same visit 
− 
Increase in liver function tests: 
• 
AST and/or ALT elevations >8x ULN: IMP treatment should be withheld and the 
LFTs should be repeated. IMP should be discontinued if the results are confirmed 
• 
AST and/or ALT elevations >3x ULN and <8xULN: IMP treatment should be 
withheld. If LFTs do not return to normal within 2 weeks then the IMP should be 
discontinued. If LFTs return to normal within 2 weeks then IMP could be restarted 
with close monitoring (e.g. repeat testing twice per week for the first 2 weeks then 


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weekly for the following month). In the event LFTs become abnormal at any 
subsequent point during the study (i.e. after rechallenge) then the IMP should be 
discontinued. 
• 
AST and/or ALT elevations >3x ULN and total bilirubin level (TBL) >2xULN or 
international normalized ratio (INR) >1.5: IMP treatment should be withheld and the 
LFTs should be repeated. IMP should be discontinued if the results are confirmed. 
• 
AST and/or ALT elevations >3x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash and/or eosinophilia 
(>5%): IMP treatment should be withheld, LFT repeated and IMP discontinued if 
LFT confirmed or if symptoms and signs persist 
When test results need to be confirmed, the subject should return to the investigational 
site and be evaluated as soon as possible, preferably within 48 hours from awareness of 
the abnormal results. This evaluation should include laboratory tests, detailed history and 
physical assessment. In addition to repeating AST and ALT, laboratory tests should 
include albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-
glutamyl transferase (GGT), INR, and alkaline phosphatase. A detailed history, including 
relevant information (e.g. review of ethanol, recreational drug and supplement 
consumption, family history, sexual history, travel history, history of contact with a 
jaundiced subject, surgery, blood transfusion, history of liver or allergic disease, and 
work exposure) should be collected. Further testing for acute hepatitis A, B or C infection 
and liver imaging (e.g. biliary tract) may be warranted. All cases confirmed on repeat 
testing with no other cause for LFT abnormalities identified at the time should be 
considered potential Hy’s Law cases irrespective of availability of all the results of the 
investigations performed to determine etiology of the abnormal LFTs. Such potential 
Hy’s Law cases should be reported as SAEs. 
The investigator may also decide to discontinue IMP (preferably after discussion with the 
CRO medical monitor, who may consult and must inform the sponsor’s study physician) for 
any of the following reasons: 
− 
Use of concurrent therapy that was not permitted 
− 
Noncompliance with the IMP treatment 
− 
Noncompliance with the clinical study procedures (e.g. missing more than 2 visits) 
− 
Serious or severe AEs 
− 
Worsening of disease condition, which in the investigator’s opinion needs an alternative 
treatment approach not being covered in the clinical study (e.g. rescue medication) 
− 
In case of interruption of IMP for cumulatively >30 days 
Every effort should be made to keep subjects in the study and on treatment. However, the 
investigator can consider stopping the treatment with IMP, preferably after consultation with 
the sponsor’s study physician, in case of concerns about the subject’s safety, major protocol 
noncompliance, serious or severe AEs or worsening of the disease condition, which in the 
investigator’s opinion needs an alternative treatment approach not being covered in the 
clinical study (e.g. rescue medication). 
When IMP is discontinued, the subject will be requested to return for the EOT and EOS Visits 
to allow safety Follow- up. 
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 


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study may terminate at his/her request without prejudice to his/her future medical care. The 
subject will be encouraged to share the reason(s) for withdrawal so this can be documented in 
the source documents, and to complete the EOT visit and follow-up visit for safety 
assessments and pulmonary function, 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, contacting general practitioner or relatives, if 
necessary. All attempts (at least 3) must be documented in the source documents. 
Subjects who drop out before the first administration of the IMP will be replaced. Subjects 
who stop taking IMP for any reason will not be replaced.  
The sponsor has the right to terminate the clinical study at any time in case of safety concerns 
or if special circumstances concerning the IMP or the company itself occur, making further 
treatment of subjects impossible. In this event, the investigator(s) and relevant authorities will 
be informed of the reason for clinical study termination. 
4.4. 
MEASURES TO MINIMIZE BIAS 
4.4.1. Randomization 
At screening, subjects will be assigned a subject identification number using a centralized 
electronic system (interactive web response system [IWRS]). When subjects are confirmed to 
be eligible for the clinical study, the subject will be randomized in a 2:1 ratio to GLPG1205 or 
placebo. Allocation of each subject to a given treatment will be done via IWRS and will be 
stratified for background standard of care (subjects receiving nintedanib, pirfenidone, or 
neither nintedanib nor pirfenidone).  
4.4.2. Blinding and Unblinding 
This is a randomized, double-blind study. The subject, investigator, clinical study coordinator 
and the entire clinical study team, will remain blinded to treatment assignment. 
Blinded and packaged medication will be provided to the clinical center. All IMP 
formulations will be identical in appearance, shape, smell and taste, and packaged in the 
proper proportion to assure desired dosages and maintenance of the blinding. 
The blind can be broken only if the investigator deems it necessary for the safety of a subject. 
The investigator is encouraged to discuss considerations to break the blind with the CRO 
medical monitor, 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 a 
timely fashion after unblinding has occurred, without disclosing the treatment allocation to the 
team. 
The blind can be broken by the investigator via IWRS. 


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All subjects who are unblinded while on the clinical study will be withdrawn at the moment 
of unblinding, with the reason for unblinding given as the reason for withdrawal from the 
clinical study. If an AE leads to unblinding, the AE will be given as the reason for unblinding, 
and the AE will be followed up as described in Section 9.3.1. All subjects who are unblinded 
should, where possible, complete the EOT visit and the follow-up visit, 4 weeks after EOT. 
If necessary code-break information (via IWRS vendor) will be provided to the bioanalytical 
laboratory responsible for plasma drug determination sample analysis, and the sponsor 
pharmacovigilance lead for SAE reporting purposes. 
An unblinded review of data will be performed on a regular basis by an IDMC. See Section 8 
for further details. 
An interim analysis may be performed in order to allow sponsor planning of following 
clinical studies, while maintaining the blind at an individual subject level. All efforts will be 
made to restrict the access to results so that personnel involved with the study conduct 
remains blinded to the extent possible. See Section 7.3.2 for further details. 
5. 
INVESTIGATIONS MEDICINAL PRODUCTS 
5.1. 
IDENTITY OF THE INVESTIGATIONS MEDICINAL 
PRODUCTS 
The chemical name of GLPG1205 is 9-cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-lmethoxy)-
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one. 
GLPG1205 will be provided as an oral hard gelatin capsule containing 50 mg of G321605 
(active ingredient) or a matching placebo. Both active and placebo capsule will be identical in 
appearance, shape, smell and taste. 
5.2. 
DOSAGE AND ADMINISTRATION 
The following doses will be tested:  
− 
GLPG1205 100 mg q.d. (as 2 capsules of 50 mg) 
− 
Matching placebo q.d. (as 2 capsules) 
The IMP is to be taken q.d. at approximately the same time every morning with or without 
food. Subjects will be instructed to swallow the capsules of GLPG1205 or placebo as a whole 
with a glass of water and to not chew the drug prior to swallowing. At the baseline visit, IMP 
will be administered on site after predose assessments have been completed. On all other visit 
days subjects also need to take their IMP on site. If subjects are taking pirfenidone or 
nintedanib then these must also be taken on site at Visit 2, Visit 4 and Visit 8 in order to 
perform appropriate PK sampling (see Section 6.6). 
If a subject misses a dose (e.g. because he/she forgot to take the medication), he/she should 
take the missed dose within 5 hours after the planned intake time. If IMP is not taken within 
5 hours after the planned time, the missed dose should be skipped. For each dose taken, the 
time, date and number of capsules taken should be recorded in the subject’s diary card. 
During each visit, the investigator will record a summary of IMP intake data in the CRF. 


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In case of an AE at least possibly related to GLPG1205 as per the investigator’s judgement 
requiring dose reduction, or in the case of intolerance to or toxicity of the IMP, subjects may 
have their dose of IMP reduced from 2 capsules q.d. (100 mg) to 1 capsule q.d. (50 mg) for 
the remainder of the study. Should the intolerance or toxicity continue, IMP may be 
discontinued, and the subject may be withdrawn from the study. 
In the event of temporary interruption of IMP due to e.g. an AE, IMP can be re-introduced at 
the investigator’s discretion, depending on the reason for interruption. The investigator should 
inform the medical monitor immediately of interruption or events leading to interruption in 
order to help with subject retention. 
5.3. 
PACKAGING, LABELING AND DISTRIBUTION 
An IMP kit will consist of 3 Alu/Alu blisters, each containing 12 capsules, packaged in an 
outer box and labeled with a clinical study-specific label. Each IMP kit contains medication to 
cover 2 weeks of treatment, including spares. All manufacturing, packaging, and labeling 
operations will be performed according to Good Manufacturing Practice for Medicinal 
Products and the relevant regulatory requirements. 
The distribution will only occur after the required local documentation is obtained including 
clinical study approval by Competent Authorities and the Independent Ethics Committees 
(IECs)/Institutional Review Boards (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. 
 
Addendum for IMP Distribution: 
Direct-to-patient (DTP) shipment of IMP due to Coronavirus disease 19 (COVID-19) 
pandemic 
In case a subject is not able to visit the site for IMP resupply, DTP shipment of IMP can be 
implemented. DTP IMP shipment will follow the ICH GCP principles and be in compliance 
with national legislation. DTP IMP shipment will occur from an investigational site to the 
subject by a logistics provider in a traceable and preferably temperature-controlled manner 
and will be documented adequately. The patient will be asked to return any unused IMP and 
empty IMP packages by a logistics provider or during the next on-site visit. 
5.4. 
STORAGE 
Sites are to store the IMP (GLPG1205 and matching placebo) supplies in a secure area below 
+30°C (may not be frozen) until dispensed. 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 that is to be completed each working day in order to establish a 
record of compliance with these storage conditions. The investigator will instruct subjects on 
how the IMP should be stored at home after it is dispensed. 
5.5. 
TREATMENT COMPLIANCE AND DRUG ACCOUNTABILITY 
The pharmacist or designated clinical study personnel will maintain a log of the total amount 
of IMP received at site, amount dispensed to the subject, and the amount of IMP returned by 
the subject to the site. Drug supplies for each subject will be inventoried and accounted for 


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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 be given a diary card at every visit in the treatment period starting at Visit 2 
(Day 1) to record the following: 
− 
From Day 1 through Week 26, subjects will be asked to record the date, time and number 
of capsules taken 
− 
From Day 1 through Week 26, subjects will be asked to record changes in concomitant 
medication regimen, including new medicines not captured in medication history, use of 
bronchodilators, use of pirfenidone or nintedanib, and any other concomitant medication 
used as well as any emerging AE.  
Subjects will be instructed to bring their diary card and to return any unused IMP and empty 
IMP packages at each visit during the treatment period and/or EOT visit. A summary of the 
diary card data will be entered in the CRF by the designated site personnel. Missed doses 
should be discussed to try to ascertain the reason(s). Every effort should be made to ensure 
proper subject dosing.  
Subjects with a poor compliance (<80% or >120%) will be retrained by the study site. If study 
drug compliance remains <80% or >120% between study visits, the subject will be evaluated 
for potential discontinuation. Any discontinuation should be done in consultation with the 
medical monitor. 
Upon sponsor approval all unused IMP and empty IMP packages should be returned to the 
drug supplier/drug depot or will be destroyed at the site. In case of destruction by the site or 
the supplier/drug depot, an acceptable destruction process should be in place and a destruction 
certificate should be provided to the sponsor. 
6. 
CLINICAL STUDY ASSESSMENTS 
Every effort should be made to ensure that CSP-required tests and procedures are completed 
as described (see Section 6.10). 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. 
6.1. 
TIMING OF ASSESSMENTS 
The study assessments will be undertaken at time points as specified in the schedule of 
activities in Section 6.10. Screening assessments need to be performed within 28 days before 
Day 1 and may be split into multiple days or visits. A window of ±2 days is allowed for 
Visit 3 and 4, a window of ±4 days is allowed for Visit 5, 6, 7, 8 and 10; and a window of 
±6 days is allowed for Visit 9. All visits should preferably be performed in the morning. 
If an on-site Visit 9 cannot be performed at the scheduled timepoint due to factors related to 
the COVID-19 pandemic, the visit window and the study medication intake period can be 
either extended up to +56 days or shortened up to -28 days, to allow flexibility in scheduling 
the visit. For more details and other visits see Section 6.1.1. 












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Addendum for Early treatment discontinuation Visit (EOT) 
Alternative approach due to COVID-19 pandemic 
 
In case of an early treatment discontinuation, the following EOS visit, planned regularly 
28 days after the last IMP intake, can occur either earlier by up to 7 days or later up to 28 days 
to enable the conduct of  the EOS Visit on site (for more details see below in the Visit 10/EOS 
addendum). In addition: 
- 
if the decision to discontinue the treatment was made during an on-site visit, and 
without any safety findings or ongoing AEs, the EOS Visit may be performed 
remotely. 
- 
if the decision to discontinue the treatment was not made during an on-site visit, or in 
case of any safety observations or ongoing AEs, an EOS Visit on site is required to 
monitor the safety of the subject. In addition, remote or home unscheduled visits 
should be conducted at least every 14 days, until the on-site EOS Visit can be 
performed. 
 
Addendum for Visit 9: 
Alternative approach due to COVID-19 pandemic 
  
• If Visit 9 cannot be conducted on site according to the original schedule of activities 
(Section 6.10; see also Section 6.1, “Timing of Assessments”) due to the COVID-19 
pandemic, the treatment period can be extended up to +56 days or shortened up 
to -28 days to enable the conduct of Visit 9 on site.  
• If the study treatment is prolonged beyond the originally planned Visit 9 date, remote 
(e.g., telephone contact, virtual contact) or home unscheduled visits should be 
conducted at the originally planned visit date, and thereafter at least every 14 days, to 
closely monitor the patient’s safety until the on-site visit can be performed. 
• If no on-site visit is possible within the 56 days of treatment prolongation, then a 
remote or home visit should be planned and conducted within the extended Visit 9 
window. However, every effort should be made to perform the end of study (EOS) 
Visit 10 on site. If this is not feasible the medical monitor or sponsor should be 
contacted. 
 
Addendum for Visit 10/EOS: 
Alternative approach due to COVID-19 pandemic 
 
• If Visit 10 cannot be conducted on site according to the original schedule of activities 
(Section 6.10; see also Section 6.1, “Timing of Assessments”) due to COVID-19 
pandemic, the visit window can be extended up to +28 days or shortened up to -7 days 
to enable the conduct of Visit 10 on site.  
• If the Visit 10 window is extended, a remote or home unscheduled visit 28 days after 
last IMP intake should be conducted and thereafter at least every 14 days, until the on-
site visit can be performed.  
• If within the +28 days of Visit 10 window prolongation no on-site visit is possible, and 
Visit 9/EOT was performed on site without relevant findings and/or safety concerns, 




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and confirmed by central reader, one repeat spirometry can be done during the screening 
period (according to the criteria in Appendix 1). 
6.4. 
EFFICACY ASSESSMENTS 
All efficacy assessments will be performed at the visits specified in the schedule of activities 
in Section 6.10 (see also Section 6.1, “Timing of Assessments”). 
6.4.1. Pulmonary Function by Spirometry 
Spirometry will be performed at the study center to assess pulmonary function. 
Pulmonary function will be measured in a standardized manner, using standardized 
equipment, and results will be transmitted electronically preferably during the visit (required 
to do so at first spirometry at baseline [Visit 2]) and evaluated by a central reader. 
The following parameters will be measured as part of the spirometry assessment: 
− 
FVC (mL) and % predicted FVC 
− 
FEV1 (mL) and % predicted FEV1 
− 
FEV1/FVC ratio 
− 
Forced expiratory flow between 25 and 75% of exhaled volume (FEF25-75) 
The ‘2012 Global Lung Function Initiative Equations’ will be used to calculate the predicted 
values [25]. 
6.4.2. Quality of Life 
The SGRQ is a 50-item paper questionnaire split into 3 domains:  
− 
symptoms (assessing the frequency and severity of respiratory symptoms),  
− 
activity (assessing the effects of breathlessness on mobility and physical activity), 
− 
impact (assessing the psychosocial impact of the disease).  
Scores are weighted such that every domain score and the total score range from 0 to 100, 
with higher scores indicating a poorer health-related quality of life. 
6.4.3. Clinical Endpoints 
The time to any of the following clinical endpoints (whichever is first) will be evaluated: 
− 
Death (all-cause and respiratory-related) 
− 
First hospitalization (all-cause and respiratory-related) 
Clinical endpoint adjudication will be performed by an independent expert (or his/her back-up) 
who will review and adjudicate these endpoints in a blinded manner (refer to Section 8.2). 
6.4.4. Diffusing Capacity for the Lungs for Carbon Monoxide 
DLCO will be assessed using a method in compliance with the current ATS/ERS/JRS/ALAT 
guideline on DLCO measurements [26] and corrected for hemoglobin using the following 
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6.5. 
SAFETY ASSESSMENTS 
This section describes methods and timing for all safety assessments and recording. 
Additional assessments (e.g. unscheduled clinical laboratory tests including further testing of 
already available samples or extra vital signs recordings) are allowed to ensure appropriate 
collection of safety data and to assess any perceived safety concerns. 
6.5.1. Adverse Events 
The AE reporting period for safety surveillance begins when the subject signs the ICF and 
ends at their last follow-up visit.  
Detailed definitions, severity grades and reporting requirements for AEs and SAEs are found 
in Section 9. 
6.5.2. Clinical Laboratory Evaluations 
The following clinical laboratory safety tests will be performed: 
− 
Hematology: hematocrit, mean corpuscular volume (MCV), mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), hemoglobin, 
red blood cell count, white blood cell count, white blood cell differential count (absolute 
and relative), red blood cell differential count / morphology (if indicated) and platelets 
− 
Coagulation: INR, thromboplastin time and partial thromboplastin time 
− 
Clinical chemistry: glucose, urea, creatinine, uric acid, sodium, potassium, calcium, 
chloride, phosphorus, AST, ALT, GGT, TBL, alkaline phosphatase, lactate 
dehydrogenase, CK including isotypes (if needed), total serum bile acid, albumin, total 
proteins, triglycerides, cholesterol (total, high density lipoprotein, low density 
lipoprotein), and brain natriuretic peptide 
− 
Urinalysis: dipstick: pH, glucose, proteins, blood, leukocytes; microscopic examination 
of the sediment for cellular elements, casts, crystals, microorganism, miscellaneous 
elements if indicated 
− 
Serology/blood: Hepatitis B surface antigen and HCV antibody (if positive confirmed by 
HCV RNA polymerase chain reaction assay), 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 at screening to confirm menopause if applicable 
− 
Pregnancy test for females: serum beta human chorionic gonadotropin at screening 
The clinical laboratory evaluations will be performed at visits specified in the schedule of 
activities in Section 6.10 (see also Section 6.1, “Timing of Assessments”). Reference ranges 
will be supplied by the central laboratory. At the discretion of the investigator, when 
following up adverse events, additional laboratory parameters may be tested, and additional 
samples taken. 
Clinical laboratory values outside the normal range will be flagged and clinical relevance will 
be assessed by the investigator. Only clinically significant laboratory test abnormalities as 
judged by the principal investigator should be recorded as AEs. 


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During screening one retest of the following lab values is allowed: AST, ALT, bilirubin, 
alkaline phosphatase, GGT, creatinine and hemoglobin. 
The total amount of blood to be taken during the clinical study for scheduled laboratory 
assessments will not exceed 306 mL. This also includes sampling for PK, 
 
 
The details of blood and urine sample handling and shipment instructions will be provided in 
a separate laboratory manual. 
6.5.3. Physical Examination 
Physical examinations will be conducted by a physician, trained physician’s assistant, or 
nurse practitioner as acceptable according to local regulation at visits specified in the schedule 
of activities in Section 6.10 (see also Section 6.1, “Timing of Assessments”). The person 
conducting the physical examination will document this in the subject’s medical records. 
Clinically significant abnormal findings should be recorded as AEs. At screening the physical 
examination will include height and weight, and weight should be measured at Visit 9/EOT 
and Visit 10/EOS. 
6.5.4. 12-lead Electrocardiogram 
At the time points specified in the schedule of activities Section 6.10 (see also Section 6.1, 
“Timing of Assessments”), a 12-lead ECG will be recorded and results will be sent for central 
reading. ECG recordings will be performed before blood/urine sampling and after subjects 
rested for 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 baseline (Visit 2) only within a time span of 6 minutes, with an 
approximate 3-minute interval between ECGs. Parameters to be recorded include the 
following: heart rate, PR interval, QRS interval, uncorrected QT interval, morphology and 
rhythm analysis (QTcF will be derived during the statistical analysis). ECG parameter normal 
ranges are presented in Appendix 4. QTcF will be considered as normal if ≤450 ms (male) 
and ≤460 ms (female), while subjects experiencing a prolongation of QTcF to ≥501 ms or an 
increase from baseline >60 ms should be discontinued from IMP (see Section 4.3.5). 
Immediately after recording, the ECGs will be reviewed by the investigator on clinical 
significant abnormalities. This immediate review during the visit needs to be documented in 
the subject’s source. After receipt of the central report, also all flagged ECG abnormalities 
need to be assessed by the investigator on clinical relevance. All clinically significant 
abnormal ECG values should be recorded as AEs.  
6.5.5. Vital Signs 
Vital signs (SBP and DBP, heart rate, oral or tympanic body temperature and respiratory rate) 
will be recorded in a standardized manner (i.e. after the subject has rested in a supine position 
for 5 minutes; consistent way of measuring body temperature: all measurements per subject 
oral or tympanic) at visits specified in the schedule of activities in Section 6.10 (see also 
Section 6.1, “Timing of Assessments”). Vital sign parameter normal ranges are presented in 
Appendix 4. Clinically significant abnormal values should be recorded as AEs. 






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Lung Biopsy 
If a LB is available for central IPF diagnosis then this biopsy is sent by the clinical center to 
the central reading vendor, if allowed by local regulations. Once the central reading (HRCT or 
HRCT+LB) is done and the results are acceptable the LB is shipped back to the clinical 
center. 


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6.10. SCHEDULE OF ACTIVITIES 
For detailed instructions on the clinical study procedures, please see referred Sections and Section 6.1, “Timing of Assessments”. 
EVENT 
SCR 
TREATMENT PERIOD 
FU 
Study visit 
11 
2 
3 
4 
5 
6 
7 
8 
9 
EOT 
10/ EOS 
Study week (W) or day (D) ± days (d) 
D-28 to D-1 
D1 
W2 
±2d 
W4 
±2d 
W8 
±4d 
W12 
±4d 
W16 
±4d 
W20  
±4d 
W266  
±6d 
 
W307 
±4d 
Informed consent (Section 6.3 and Section 10.4.2) 
 
 
 
 
 
 
 
 
 
 
 
Dispense subject participation card (Section 10.2.4) 
 
 
 
 
 
 
 
 
 
 
 
Send HRCT (historical or new2) for central review 
(Section 6.3) 
 
 
 
 
 
 
 
 
 
 
 
Send LB (if available) for central review (Section 6.3) 
 
 
 
 
 
 
 
 
 
 
 
Demographics (Section 6.3) 
 
 
 
 
 
 
 
 
 
 
 
Medical history/concurrent illnesses (Section 6.3) 
 
 
 
 
 
 
 
 
 
 
 
Alcohol consumption and smoking habits (Section 6.3) 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria (Section 6.3) 
 
 
 
 
 
 
 
 
 
 
 
Physical examination (Section 6.5.3) 
3 
 
 
 
 
 
 
 
3 
3 
3 
12-Lead ECG (Section 6.5.4) 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (Section 6.5.5) 
 
 
 
 
 
 
 
 
 
 
 
                                                     
1  Screening assessments need to be performed within 28 days before Day 1 and may be split into multiple days or visits. 
2  If there is no historical HRCT available, a new HRCT needs to be planned and performed. Only if for logistic reasons it is not possible to perform a new HRCT within the 
planned screening period and after approval of the medical monitor it is allowed to extend the screening period with maximum 2 weeks. 
3  At screening include height and weight; at Visit 9/EOT and Visit 10/EOS include weight. 
 






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7. 
STATISTICAL METHODS 
All statistical methods shall be detailed in a statistical analysis plan (SAP) that will be 
finalized before treatment unblinding and data analysis. All data collected in this clinical 
study will be documented using summary tables, figures, and/or subject data listings. 
7.1. 
DETERMINATION OF SAMPLE SIZE 
The aim of this proof-of-concept study is to show a trend in treatment difference for the 
primary endpoint (change from baseline in FVC over 26 weeks), therefore no formal sample 
size calculation was performed. In the following paragraph, the variability of the estimated 
treatment difference for the proposed sample size of 60 subjects is illustrated.  
Consider 40 and 20 evaluable subjects in the GLPG1205 and placebo arm, respectively, and 
an aim of a 50:50 balanced study population being either on nintedanib/pirfenidone or neither. 
Further, assume for FVC change from baseline at Week 26 a common standard deviation of 
200 mL, a true treatment difference of 50 mL in the population receiving nintedanib or 
pirfenidone and a true treatment difference of 80 mL in the population receiving neither 
nintedanib nor pirfenidone. Under these assumptions and taking into account 10% dropout, 
the probability to observe a treatment effect of more than 40 mL in the total study population 
is 67% and the probability to observe a treatment effect of more than 20 mL is 78%. 
Approximately 60 subjects are planned to be randomized into the study. 
7.2. 
POPULATION FOR ANALYSES 
7.2.1. All Screened Subjects 
All subjects who signed an ICF. 
7.2.2. All Randomized Subjects 
All subjects who were randomized into the clinical study. 
7.2.3. Full Analysis Set 
All randomized subjects who have received/used at least 1 dose of IMP. 
7.2.4. Per-Protocol Set 
All full analysis set subjects who did not have a major protocol deviation impacting the 
efficacy results (as defined in a protocol deviation plan). If needed, the determination of the 
per-protocol population will be finalized and documented prior to database lock and 
unblinding. 
7.2.5. Pharmacokinetic Analysis Set 
Subset of the safety set, selecting all subjects who have available and evaluable plasma 
concentration data (e.g. excluding all protocol deviations or AEs that may have an impact on 
the PK analysis). 










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that increase in severity or change in nature during or as a consequence of participation in the 
clinical study will also be considered AEs. 
9.1.2. Serious Adverse Events 
An SAE is defined as an AE that, results in the following: 
− 
Death. 
− 
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.). 
− 
In-subject hospitalization or prolongation of existing hospitalization. 
− 
Persistent or significant disability/incapacity. 
− 
A congenital anomaly/birth defect. 
− 
Medically significant (medical and scientific judgment should be exercised in deciding 
whether other situations should be considered serious such as important medical events 
that might not be immediately life-threatening or result in death or hospitalization but 
might jeopardize the subject or might require intervention to prevent one of the other 
outcomes listed in the definition above).  
9.1.3. Unlisted (Unexpected) Adverse Event/Reference Safety Information 
An AE is considered unlisted if the nature or intensity is not consistent with the applicable 
product reference safety information. For an IMP, the expectedness of an AE will be 
determined by whether or not it is listed in the reference safety information part of the IB. 
9.1.4. Adverse Events of Special Interest 
Not applicable. 
9.1.5. Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as Adverse Events or Serious Adverse Events 
Laboratory abnormalities without clinical significance based on the investigator’s judgement, 
are not considered AEs or SAEs. However, laboratory abnormalities (e.g. clinical chemistry, 
hematology and urinalysis) or other abnormal (clinical study specific) assessments (e.g. ECG, 
radiography, vital signs) that require medical or surgical intervention, are associated with 
signs and/or symptoms, lead to IMP interruption, modification, or discontinuation must be 
recorded as an AE or SAE if they meet the definition as described in Sections 9.1.1 and 9.1.2, 
respectively. If the laboratory abnormality is part of a syndrome, the syndrome or diagnosis is 
to be reported (e.g. anemia instead of decreased hemoglobin). 
9.2. 
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. 


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9.2.1. Assessment of Causality 
The investigator is responsible for assessing the causal relationship to IMP(s) administration 
or study procedures (e.g. invasive procedures such as venipuncture) based on her/his clinical 
judgment. The following decision choice will be used by the investigator to describe the 
causality assessment between the reported event or laboratory test abnormality and the IMP. 
− 
Unrelated: 
Time relationship to drug intake is improbable. Related to other etiologies such as 
concomitant medications or subject's clinical state.  
− 
Unlikely: 
Time relationship to drug intake is improbable (but not impossible). Concomitant disease 
or other drugs provide plausible explanations. 
− 
Possible: 
Time relationship to drug intake is reasonable. Event or laboratory test abnormality, 
could also be explained by disease or other drugs. Information on IMP withdrawal may 
be lacking or unclear. 
− 
Probable: 
Time relationship to drug 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 drug 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 by the IMP) 
should not be considered as causally related in the context of AE reporting. 
9.2.2. Assessment of Severity 
The severity of AEs should be graded using CTCAE Version 5.  
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening) or Grade 5 
(fatal) to describe the maximum intensity of the AE. For purposes of consistency with the 
CTCAE, these intensity grades are defined in the table below. 


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Table 1 
Grading of Adverse Event Severity 
Grade  
Adjective  
Description  
Grade 1  
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated  
Grade 2  
Moderate 
Local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL*  
Grade 3  
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**  
Grade 4  
Life-threatening 
Urgent intervention indicated  
Grade 5  
Death 
Death-related AE  
* Activities of Daily Living (ADL) Instrumental ADL refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
** Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
For AEs associated with laboratory abnormalities, the event should be graded on the basis of 
the clinical severity in the context of the underlying conditions; this may or may not be in 
agreement with the grading of the laboratory abnormality. This is upon the investigator’s 
assessment. 
If there is a change in intensity (worsening or improvement) of an AE, it must be recorded. 
9.2.3. Outcome 
Each AE must be rated by choosing among: 
− 
Recovered/Resolved 
− 
Recovered/Resolved with sequelae 
− 
Recovering/Resolving 
− 
Not recovered/Not resolved 
− 
Fatal 
− 
Unknown 
9.3. 
INVESTIGATOR REQUIREMENTS AND INSTRUCTIONS FOR 
REPORTING ADVERSE EVENTS / SERIOUS ADVERSE 
EVENTS /PREGNANCIES TO THE SPONSOR 
9.3.1. Adverse Events 
The AE reporting period for safety surveillance begins when the subject signs the ICF and 
ends at the subject’s follow-up visit (the last follow up visit after the last dose of IMP). 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 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.  


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If a subject is documented as lost-to-follow-up, ongoing/unknown outcome AEs will not be 
followed up. 
If the AE meets the criteria for seriousness, the SAE form must be completed and sent to the 
sponsor within 24 hours (see Section 9.3.2 here after). 
9.3.2. Serious Adverse Events 
Subjects experiencing an SAE or an emergency situation will be examined by a physician as 
soon as possible. The subject will remain under observation as long as medically indicated. 
Appropriate laboratory tests will be performed until all parameters return to normal or are 
otherwise explained or stable.  
Any SAEs that occur after the post treatment follow-up visit but within 30 days of the last 
dose of IMP(s), regardless of causality, should also be reported. Investigators are not 
obligated to actively seek SAEs after the CSP-defined follow up period, however, if the 
investigator learns of any SAEs that occur after clinical study participation has concluded and 
the event is deemed relevant to the use of IMP(s), he/she should promptly document and 
report the event to the sponsor at any time by using the SAE form. 
All SAEs, whether or not deemed drug-related, must be recorded in the CRF and on the SAE 
form. The investigator must report each SAE immediately, and under no circumstances 
should this exceed 24 hours following the knowledge of the SAE, as is indicated on Page 2 
under “Emergency Contact Information”. 
The SAE form should at least contain identifiers of the subject and the reporter, SAE term and 
statement of relatedness to the IMP, and at a later stage if not yet available within 24 hours, 
the form needs to be completed with a clearly written narrative describing signs, symptoms, 
and treatment of the event, diagnostic procedures, as well as any relevant laboratory data and 
any sequelae. 
Follow-up and outcomes should be reported and documented in the source documents for all 
subjects that experience an SAE. It is important that the information provided on the SAE 
form matches the information recorded on the CRF for the same event. In case an AE is 
ongoing at the time of the last follow-up visit, only the SAE form is to be updated, not the 
CRF. 
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 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. 
9.3.3. Pregnancy 
All initial reports of pregnancies in partners of male subjects included in the clinical study 
must be recorded and documented in the source documents (after specific informed consent is 
provided, see Section 10.4.2). The investigator must report each pregnancy immediately after 
getting knowledge about this on the pregnancy form, and under no circumstances should this 


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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/partner of the subject at the expected time of delivery for 
follow-up and for information regarding the outcome of the newborn. Abnormal pregnancy 
and/or newborn outcomes are considered SAEs and must be reported using the SAE form. 
9.4. 
SPONSOR REPORTING REQUIREMENTS 
Depending on relevant local legislation or regulations, including the applicable US Federal 
Drug Administration Code of Federal Regulations, the EU Clinical Trials Directive 
(2001/20/EC) and relevant updates, and other country-specific legislation or regulations, the 
sponsor may be required to expedite to worldwide regulatory agencies reports of SAEs, 
serious adverse drug reactions, or suspected unexpected serious adverse reactions (SUSARs). 
The sponsor or a specified designee will notify worldwide regulatory agencies and the 
relevant IEC/IRB in concerned Member States of applicable SUSARs as outlined in current 
regulations. 
Assessment of expectedness for SAEs will be determined using reference safety information 
section in the IB or relevant local label as applicable.  
All concerned investigators will receive a safety letter notifying them of relevant SUSAR 
reports associated with any IMP(s). The investigator should notify the IEC/IRB of SUSAR 
reports as soon as is practical, where this is required by local regulatory agencies, and in 
accordance with the local institutional policy. 
10. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This clinical study is conducted in accordance with the current applicable regulations, ICH- 
Good Clinical Practice (GCP) Guideline E6, EU Directive 2001/20/EC and its updates, and 
local ethical and legal requirements. 
GCP is an international ethical and scientific quality standard for designing, conducting, 
recording and reporting studies that involve the participation of human subjects. Compliance 
with this standard provides public assurance that the rights, safety and well-being of clinical 
study subjects are protected, consistent with the principles that have their origin in the 
Declaration of Helsinki, and that the clinical study data are credible. 
The name and address of each third-party vendor (e.g. CRO) used in this study and the 
sponsor’s study team members will be maintained in the investigator’s and sponsor’s files as 
appropriate. 
10.1. SPONSOR’S RESPONSIBILITIES 
10.1.1. Regulatory Approval / Notification 
Prior to clinical study start, this CSP together with all relevant documentation will be 
submitted to the local Regulatory Authorities for review and approval and/or notification in 
compliance with local requirements.  


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10.1.2. Clinical Study Closure Considerations 
The sponsor reserves the right to close the investigational site or end the clinical study at any 
time for any reason. In case of an early termination of the clinical study or temporary halt by 
the sponsor, the IEC/IRB should be notified within 15 calendar days unless otherwise 
specified by the IEC/IRB, including a detailed written explanation of the reasons for the 
termination/halt. 
The end of clinical study declaration will be submitted to the regulatory authorities and 
IEC/IRB after the complete clinical study has ended in all participating centers, in all 
countries. This notification will also be submitted within 90 days of the end of the clinical 
study in a given country/member state or within the timelines required by the local 
regulations. 
Reasons for the closure of an investigational site include but are not limited to: 
− 
Successful completion of the clinical study at the center 
− 
The overall required number of subjects for the clinical study has been recruited 
− 
Failure of the investigator to comply with the CSP, ICH-GCP guidelines or local 
requirements 
− 
Inadequate recruitment of subjects by the investigator 
Reasons for early termination of a clinical study by the sponsor may include but are not 
limited to: 
− 
Safety concerns 
− 
Sufficient data suggesting lack of efficacy 
10.1.3. Indemnification 
Under the conditions of a contract concluded between investigator, site and sponsor or 
designee, which shall prevail, sponsor shall, except in case of gross negligence or willful 
misconduct, indemnify and hold harmless the investigator and his/her medical staff from any 
claim arising from the clinical study activities carried out in compliance with the CSP, 
sponsor’s instructions and applicable local regulations. 
The investigator must notify the sponsor immediately upon notice of any claims or lawsuits. 
10.1.4. Insurance 
Sponsor shall maintain insurance coverage that is sufficient to cover its obligations and that is 
consistent with human clinical study local regulations. Save in case of gross negligence or 
willful misconduct of the investigator, and provided that the subject has been treated 
according to the CSP and sponsor’s instructions, any injury caused to a subject which is the 
direct result of his/her participation to the clinical study shall be covered by sponsor’s 
insurance. 
10.1.5. Reporting 
Where required by IEC/IRB per local requirements, at least once a year the investigator will 
provide the IEC/IRB with a progress report to allow review of the clinical study (see 


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Section 10.4.1). After the end of the clinical study, the results of the clinical study will be 
reported in a single clinical study report. A summary or full report, depending on the 
requirements, will be provided to the investigators, to the applicable regulatory authorities and 
IECs/IRBs if required by the applicable regulatory requirements within one year, or 6 months 
for pediatric studies, after end of clinical study. 
10.1.6. Publication 
It is understood by the investigator that the sponsor shall be free to use the compound-related 
information which is generated during the clinical study and may disclose it to other clinical 
investigators and to regulatory agencies. As a consequence, the investigator agrees to provide 
all clinical study results and data generated during this clinical study to 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 sponsor with a draft copy of the intended publication. Sponsor shall have the right to 
review it and to make any comments. In accordance with generally accepted scientific 
collaboration principles, co-authorship with any staff member sponsor involved in the clinical 
study, will be discussed and mutually agreed upon before submission of any manuscript to a 
publisher. 
10.2. INVESTIGATOR’S RESPONSIBILITIES 
10.2.1. Financial Disclosure 
Not applicable. 
10.2.2. Source Data and Data Capture 
The nature and location of all source documents need to be identified and documented to 
ensure that all sources of original data required to complete the CRF are known and are 
accessible for verification by the monitor.  
Source data may be directly captured from devices transferred from third partners (e.g. 
laboratory data) or entered manually into the CRF. The CRF completion guidelines will be 
provided to each investigational site. 
It is recommended that the author of an entry in the source documents should be identifiable. 
Following ICH GCP Guidelines, direct access to source documents must be granted for the 
purpose of verifying that the data recorded on the CRF are consistent with the original source 
data. 
10.2.3. Archiving 
The investigator shall maintain the clinical study specific documents as specified in Section 8 
“Essential Documents for the Conduct of a Clinical Study” of the ICH GCP Guidelines and as 


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required by the applicable regulatory requirement(s). The investigator should take measures to 
prevent accidental or premature destruction of these documents. 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the IMP. These documents should be retained for a 
longer period however if required by the applicable regulatory requirements or by an 
agreement with the sponsor. 
Under no circumstance shall the investigator relocate or dispose of 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 informed consent. 
Any difficulty in storing original documents must be discussed with the monitor prior to the 
initiation of the clinical study.  
10.2.4. Participation Cards 
If the subjects are not under 24-hour supervision of the investigator or his/her staff (out-
subjects), they must be provided with a subject participation card indicating the name of the 
IMP, the clinical study number, the investigator's name and a 24-hour emergency contact 
number. The subject should be advised to keep the participation card in his/her wallet at all 
times. 
10.3. CONFIDENTIALITY 
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 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 by the sponsor 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 will remain at the center and no copy will 
be made. 


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10.4. ETHICAL CONSIDERATIONS 
10.4.1. Independent Ethics Committee / Institutional Review Board 
This clinical study can only be undertaken after full approval of the CSP, informed consent, 
any other written information given to subjects, and subject recruitment materials has been 
obtained from the IEC/IRB. This approval document must be dated and clearly identify the 
clinical study and the related clinical study documents being approved, including the subject 
compensation programs, if applicable. 
During the course of clinical study at least the following documents will be provided to the 
IEC/IRB per local requirements: 
− 
Changes to the IB 
− 
Reports of AEs that are serious, unlisted and associated with the investigational drug (in 
compliance with IEC/IRB, per local requirements) 
− 
CSP amendments 
− 
Informed consent revision(s) 
CSP amendments and applicable ICF revisions must promptly be submitted to the IEC/IRB 
for review and approval prior to implementation of the change(s), except when necessary to 
eliminate an immediate hazard to the clinical study subjects, or according to local 
requirements. 
The IEC/IRB is responsible for continuous review of the clinical study. Where required by 
IEC/IRB per local requirements, at least once a year the investigator will provide the IEC/IRB 
with a progress report to allow review of the clinical study. Additional progress reports should 
be provided according to local legal requirements. These requests and (re) approvals, if 
applicable, should be documented in writing. 
10.4.2. Informed Consent 
The investigator or designated personnel must explain the clinical study and the implications 
of participation (e.g. objectives, methods, anticipated benefits, and possible risks) to potential 
subjects according to applicable regulations prior to any clinical study related activity. 
Subjects will be informed that their participation is voluntary and that they may withdraw 
from the clinical study at any time. They will be informed that choosing not to participate or 
to withdraw from the clinical study will not have an impact on the care the subject will 
receive for the treatment of his/her disease. In case the subject is unable to read and write, an 
impartial witness must confirm the informed consent.  
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, consent should be appropriately 
recorded by means of the subject's personally dated signature (or, if applicable, by the 
signature of an independent witness who certifies the subject's consent in writing) and by the 
investigator’s signature. After having obtained the consent, a copy of the signed and dated 
informed consent must be given to the subject. 
If new information becomes available that may be 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 updated ICF. This amended ICF will be signed and dated by the subject (or, if applicable, 




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[8]  Raghu G, Weycker D, Edelsberg J. et al. Incidence and prevalence of idiopathic pulmonary 
fibrosis, Am J Respir Crit Care Med 2006;174:810-6.  
[9]  Fernández PER, Daniels CE, Schroeder DR, et al. Incidence, prevalence, and clinical course of 
idiopathic pulmonary fibrosis: a population-based study, Chest 2010;137(1):129.37.  
[10] Navaratnam V, Fleming KM, West J, et al. The rising incidence of idiopathic pulmonary fibrosis 
in the UK, Thorax 2011;66(6):462-7.  
[11] G. Raghu, S. Chen, W. Yeh, B. Maroni, Q. Li, Y. Lee en H. Collard, „Idiopathic pulmonary 
fibrosis in US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and 
survival, 2001-11,” Lancet Respir Med, vol. 2(7), pp. 566-572, 2014.  
[12] Spagnolo P, Del Giovane C, Luppi F, et al. Non-steroid agents for idiopathic pulmonary fibrosis 
(review), Cochrance Database Syst Rev 2010; Sep 8 CD003134.  
[13] Taniguchi H, Ebina M, Kondoh Y, et al. Pirfenidone in idiopathic pulmonary fibrosis, Eur 
Respir J 2010;35:821-9.  
[14] Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary 
fibrosis, Lancet 2011;377:1760-9.  
[15] King TE, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with 
idiopathic pulmonary fibrosis, N Eng J Med 2014;370:2083-92.  
[16] Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic 
pulmonary fibrosis, N Engl J Med 2014;370:2071-82.  


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Confidential Information 
 
[17] Esbriet. Summary of Product Characteristics.  
[18] Ofev. Summary of Product Characteristics.  
[19] Raghu G, Rochwerg B, Zhang Y, et al. n official ATS/ERS/JRS/ALAT clinical practice 
guideline: treatment of idiopathic pulmonary fibrosis, Am J Respir Crit Care Med 2015;192:e3-
e19.  
[20] Gagnon L, Leduc M, Thibodeau JF, et al. A newly discovered antifibrotic pathway regulated by 
two fatty acid receptors: GPR40 and GPR84, Am J Pathol 2018 Feb;15:1-17.  
[21] Parker J, et al. PBI-4050 is safe and well tolerated and shows evidence of benefit in ideopathic 
lung fibrosis, Am J Respir Crit Care Med 2017;195:A7606.  
[22] Wuyts W, Antoniou K, Borensztajn K, et al. Combination therapy: the future of management for 
idiopathic pulmonary fibrosis?, Lancet Resp Med 2014;2:933-42.  
[23] Nathan SD, Albera C, Bradford WZ, et al. Effect of continued treatmnet with pirfenidone 
following clinically meaningful declines in forced vital capacity: analysis of data from three 
phase 3 trials in patienst with ideopathic pulmonary fibrosis, Thorax 2016;71(5):429-35.  
[24] G. Raghu, M. Remy-Jardin, J. Myers, L. Richeldi and C. Ryerson, "Diagnosis of Idiopathic 
Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline," Am J Respir 
Crit Care Med, vol. 198, pp. e44-e68, 2018.  
[25] Quanjer PH, Stanojevic S, Cole TJ, et al. Multi-ethnic reference values for spirometry for the 3-
95 year age range: the global lung function2012 equations: Report of the Global Lung Function 
Initiative (GLI), ERS Task Force to established imrpoved Lung Fu, Eur Respir J 2012; 
40(6):1324-43.  
[26] Macintyre N, Crapo RO, Johnson DC, et al. Standardisation of the single-breath determination 
of carbon monoxide uptake in the lung, Eur Respir J 2005;26(4):710-35.  
[27] American Thoracic Society. ATS Statement: Guidelines for the Six-Minute Walk Test, Am J 
Respir Crit Care Med 2002;166:117.  
[28] Lynch DA, Sverzellati N, Travis WD, et al. Diagnostic criteria for idiopathic pulmonary fibrosis: 
a Fleischner Society White Paper, Lancet Respir Med 2018 Feb;6(2):138-54.  
[29] H. Collard, C. Ryerson, T. Corte, G. Jenkins, Y. Kondoh en D. Lederer, „Acute exacerbation of 
idiopathic pulmonary fibrosis,” Am J Respir Crit Care Med, vol. 194, pp. 265-275, 2016.  
[30] du Bois R, Weycker D, Albera C, et al. Six-Minute-Walk Test in Idiopathic Pulmonary Fibrosis, 
Am J Respir Crit Care Med 2011;183:1231-7.  
[31] USNRC, "United States Nuclear Refulatory Commission. Fact sheet on biological effects of 
radiation.," May 2017. [Online]. Available: https://www.nrc.gov/reading-rm/doc-
collections/fact-sheets/bio-effects-radiation.html. [Accessed Mar 2018]. 
[32] WNA, "World Nuclear Association," Jul 2016. [Online]. Available: http://www.world-
nuclear.org/info/safety-and-security/radiation-and-health/nuclear-radiation-and-health-effects/. 
[Accessed Mar 2018]. 




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APPENDICES 
Appendix 1 High-resolution Computed Tomography/Biopsy Central 
Review Criteria 
All chest HRCTs and histopathology slides of lung biopsies (if available and indicated) will be 
centrally reviewed by two independent radiologists with adjudication by a third radiologist if 
indicated and one independent histopathologist to confirm the diagnosis of IPF and therefore 
eligibility of the subject for the study. 
The diagnostic criteria for IPF, published as the Fleishner Society White Paper [28], will be 
used to determine eligibility of the subject for the study. 
In case a historical lung biopsy is available, this will be used as complementary information 
and will allow confirmation of UIP-IPF in certain cases. An algorithm to be used by the 
radiologists and the histopathologist to determine eligibility is available in the relevant manual. 
 
 
 
 
 


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Appendix 2 Definition of Acute Idiopathic Pulmonary Fibrosis 
Exacerbation 
Definition and diagnostic criteria are defined as follows [29]: 
Definition: 
An acute, clinically significant respiratory deterioration characterized by evidence of new 
widespread alveolar abnormality. 
Diagnostic criteria: 
- 
Previous or concurrent diagnosis of IPF 
- 
Acute worsening or development of dyspnea typically < 1 month duration 
- 
Computed tomography with new bilateral ground-glass opacity and/or consolidation 
superimposed on a background pattern consistent with usual interstitial pneumonia 
pattern 
- 
Deterioration not fully explained by cardiac failure or fluid overload 
 
 
 


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Appendix 3 Contraindications for 6-Minute Walk Test 
Absolute contraindications: 
− 
Unstable angina during the previous month [27] 
− 
Myocardial infarction during the previous month [27] 
− 
Oxygen saturation measured by pulse oximetry <88 % after 10 minutes of rest of 
breathing room air or at baseline oxygen flow rate [30]. 
Relative contraindications [27] 
- 
Resting heart rate >120 beats per minute 
- 
SBP >180 mmHg 
- 
DBP >100 mmHg 
Source: [27] 
 
 


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Appendix 4 Normal Ranges 
NORMAL RANGES FOR VITAL SIGNS 
Normal ranges applicable in supine position (after 5 minutes): 
Systolic blood 
pressure 
(mmHg) 
Diastolic blood 
pressure 
(mmHg) 
Heart rate 
(bpm) 
Oral/Tympanic 
temperature (°C) 
Respiratory rate 
(RR) 
(breaths/minute) 
90≤ SBP ≤150 
45≤ DBP ≤90 
50≤ HR ≤100 
35.5≤ t° ≤37.5 
12 ≤ RR ≤ 18 
NORMAL RANGES FOR ECG PARAMETERS 
Normal ranges applicable in supine position (after 5 minutes): 
PR (ms) 
QRS (ms) 
QTcF (ms) 
Heart rate (bpm) 
120≤ PR ≤220 
QRS ≤120 
QTcF ≤450 (male) 
QTcF ≤460 (female)  
50≤ HR ≤100 
 
 


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Appendix 5 Non-exhaustive List of Known Breast Cancer Resistance 
Protein Substrates 
Substrate liability demonstrated in vitro: 
4-methylumbelliferone sulfate 
Daunorubicin 
Doxorubicin 
Estradiol-17beta-glucuronide 
Estrone 3-sulfate 
Hematoporphyrin 
Imatinib 
Methotrexate 
Mitoxantrone 
Pheophorbide A 
Pitavastatin 
Rosuvastatin 
SN-38 
SN-38 glucuronide 
Sulfasalazine 
Topotecan 
 
In vivo substrates, from clinical studies:  
Rosuvastatin 
Pitavastatin 
Topotecan 
 
 


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Appendix 6 Non-exhaustive List of Known Organic Cation Transporter 2 
Substrates 
 
Known OCT2 substrates: 
Amantadine 
Amiloride 
Cimetidine 
Dopamine 
Epinephrine 
Famotidine 
Histamine 
Lamivudine 
Memantine 
Metformin* 
N-methylpyridinium 
Norepinephrine 
Prostaglandin E2 
Prostaglandin F2alpha 
Ranitidine 
Serotonin 
Tetraethylammonium 
Varenicline* 
 
* denotes drugs that can potentially be used for in vivo (clinical) studies of the designated 
transporter 
 
 
 




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Appendix 8 Non-exhaustive List of Medications Known to be Dual 
Inhibitors of CYP3A4 and CYP2C19 Enzymes 
Medications known to be dual inhibitors of CYP3A4 and CYP2C19 are prohibited during the 
study. The following is a non-exhaustive list of these medications as guidance for the 
investigator.  
− 
Chloramphenicol 
− 
Cimetidine 
− 
Fluvoxamine 
− 
Ketoconazole 
− 
Voriconazole 
 
 
 


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Appendix 9 Non-exhaustive List of Medications Known to be Strong 
Inducers of CYP3A4 or CYP2C19 
Medications known to be strong inducers of CYP3A4 or CYP2C19 are prohibited during the 
study. The following is a non-exhaustive list of these medications as guidance for the 
investigator.  
− 
Barbiturates 
− 
Carbamazepine 
− 
Modafinil 
− 
Oxcarbazepine 
− 
Phenobarbital 
− 
Phenytoin 
− 
Pioglitazone 
− 
Rifabutin 
− 
Rifampin 
− 
St. John’s Wort 
− 
Norethindrone 
 
 
 
 


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Appendix 10 Non-exhaustive List of Medications Known to Prolong QT 
interval  
Medications known to prolong QT interval are to be used with caution during the study. The 
following is a non-exhaustive list of these medications as guidance for the investigator.  
− 
Disopyramide 
− 
Dofetilide 
− 
Flecainide 
− 
Ibutilide 
− 
Quinidine 
− 
Sotalol 
 
 


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SIGNATURE PAGE – SPONSOR 
Study Title: 
A Phase II randomized, double-blind, placebo-controlled, 26-week study to 
evaluate the efficacy, safety and tolerability of GLPG1205 in subjects with 
idiopathic pulmonary fibrosis 
This clinical study protocol has been reviewed and approved by the sponsor to ensure 
compliance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidelines for Good Clinical Practices (GCP) and 
applicable regulatory requirements. 
 
An electronic signature for the sponsor is provided at the end of the document. 
 
 
 MD 
  
  
Study Physician 
 Signature 
 Date 
 
 
 


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SIGNATURE PAGE – INVESTIGATOR 
Study Title: 
A Phase II randomized, double-blind, placebo-controlled, 26-week study to 
evaluate the efficacy, safety and tolerability of GLPG1205 in subjects with 
idiopathic pulmonary fibrosis 
I, the undersigned, have read this clinical study protocol and will conduct the study as 
described in compliance with the clinical study protocol, in accordance with International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use 
(ICH) guidelines for Good Clinical Practices (GCP) and applicable regulatory requirements. 
 
 
 
  
  
Investigator Name 
 Signature 
 Date 
 


Signature Page for glpg1205-cl-220-protocol 10923
Signature Page for glpg1205-cl-220-protocol 10923
Approval
Translational Medicine Leader
Translational Medicine
30-Apr-2020 17:48:03 GMT+0000

SAP_001.pdf: 






-4- 
 
5.3.1.6. 
Calculation of Relative Days and Duration .........................43 
5.3.1.7. 
Presentation of Results ......................................................43 
5.3.1.8. 
Adverse Events Related to Nintedanib or Pirfenidone ........44 
5.3.1.9. 
EudraCT Adverse Events Reporting ..................................45 
5.3.1.10. Subgroup Analyses............................................................45 
5.3.2. 
Laboratory Safety ...............................................................................45 
5.3.2.1. 
Available Data ...................................................................45 
5.3.2.2. 
Derivation Rules ................................................................45 
Derived Laboratory Tests ....................................................................45 
Fasted and Non-Fasted Results..........................................................45 
5.3.2.3. 
Definition of Toxicity Grades ..............................................46 
5.3.2.4. 
Definition of Non-Graded Abnormalities .............................47 
5.3.2.5. 
Urinalysis Tests with Categorical Results ..........................47 
5.3.2.6. 
Treatment-Emergent Principle ...........................................47 
Toxicity Grades ...................................................................................47 
Non-graded Abnormalities ..................................................................47 
5.3.2.7. 
Worst-Case Principle .........................................................47 
Toxicity Grading ..................................................................................47 
Non-graded Abnormalities ..................................................................48 
5.3.2.8. 
Presentation of Results ......................................................48 
5.3.3. 
Electrocardiogram ...............................................................................49 
5.3.3.1. 
Available Data ...................................................................49 
5.3.3.2. 
Derivation Rules ................................................................49 
Derived Parameters ............................................................................49 
Handling of ECGs Measured in Triplicate ...........................................49 
5.3.3.3. 
Abnormalities .....................................................................49 
Worst-Case Abnormality .....................................................................50 
Treatment-Emergent Abnormalities ....................................................50 
5.3.3.4. 
Presentation of Results ......................................................50 
5.3.4. 
Vital Signs ...........................................................................................51 
5.3.4.1. 
Available Data ...................................................................51 
5.3.4.2. 
Abnormalities .....................................................................51 
5.3.4.3. 
Treatment-Emergent Principle ...........................................51 
5.3.4.4. 
Worst-Case Abnormality ....................................................51 
5.3.4.5. 
Presentation of Results ......................................................52 
5.3.5. 
Physical Examinations ........................................................................52 
5.4. 
Pharmacokinetic Assessments ..........................................................................52 
5.5. 
Changes to the Planned Analyses, Not Covered by Protocol Amendments .......53 
6. 
REFERENCES ..............................................................................................................53 
APPENDIX ...........................................................................................................................53 
APPENDIX I: LABORATORY: TOXICITY GRADING ....................................................53 
APPENDIX II: ADDITIONAL DETAILS ON MIXED MODEL PRIMARY ANALYSIS .......58 
 
 
 
 




-6- 
 
LIST OF ABBREVIATIONS 
6MWT 
6-Minute Walk Test 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic classification 
ATS 
American Thoracic Society 
BMI 
body mass index 
CCr 
creatinine clearance 
CEAC 
clinical endpoint adjudication committee 
CI 
confidence interval 
COVID-19 
Corona virus disease 2019 
CRF 
case report form 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLCO 
diffusing capacity of the lung for carbon monoxide 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
end of study  
EOT 
end of treatment 
ETD 
early treatment discontinuation 
EU 
European Union 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FEF25-75 
forced expiratory flow between 25% and 75% of exhaled volume  
FEV1 
forced expiratory volume in 1 second  
 
 
 
 
FVC 
forced vital capacity 
FSH 
follicle-stimulating hormone 
Hb 
hemoglobin  
HR 
heart rate 
HRCT 
high-resolution computed tomography 
ICF 
informed consent form 


-7- 
 
ICH 
International Council for Harmonization 
IDMC 
Independent Data Monitoring Committee 
IMP 
investigational medicinal product 
INF 
infinity 
IPF  
idiopathic pulmonary fibrosis 
IWRS 
interactive web response system 
LB 
lung biopsy 
LLN 
lower limit of normal  
LS 
least squares 
MAR 
missing-at-random 
MNAR 
missing not at random 
OC 
observed cases 
 
 
PFT 
pulmonary function test 
PK 
pharmacokinetic(s) 
PP 
per protocol 
q.d. 
once daily (quaque die) 
QTcF 
QT interval corrected for the heart rate using Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SE 
standard error 
SGRQ 
St. George’s Respiratory Questionnaire 
SOC 
standard of care 
TEAE 
treatment-emergent adverse event 
 
 
ULN 
upper limit of the normal range 
US 
United States 
USM 
urgent safety measure 


-8- 
 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the final and potential interim statistical analyses of 
study GLPG1205-CL-220 (PINTA). An interim analysis may be performed upon sponsor 
decision to allow planning of future clinical studies. In addition, an unblinded review of data will 
be performed on a regular basis by an Independent Data Monitoring Committee (IDMC). The 
IDMC analyses are detailed in a separate SAP and will be provided to the IDMC by an 
independent, unblinded statistical support group. 
A separate pharmacometric analysis plan will be written for the population pharmacokinetics 
(PK)
 analyses. 
Technical details on derivations and mock tables, listings and figures (TLFs) will be presented in 
a separate document. 
The statistical analysis will process and present the results following the International Council for 
Harmonization (ICH) standards, particularly the ICH-E3, ICH-E6, ICH-E9, ICH-R9 (R1) and 
ICH-E14 guidelines. 
2. 
STUDY DESIGN AND OBJECTIVES 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective 
− 
To evaluate the efficacy of GLPG1205 treatment in subjects with idiopathic pulmonary 
fibrosis (IPF) on pulmonary function as evaluated by forced vital capacity (FVC) compared 
to placebo over 26 weeks. 
2.1.2. 
Secondary Objectives 
− 
To evaluate the safety and tolerability of GLPG1205 treatment compared to placebo over 26 
weeks. 
− 
To evaluate the impact of GLPG1205 treatment compared to placebo on time to any major 
events (whichever occurs first) defined as: 
• 
Mortality (all-cause and respiratory-related)  
• 
Hospitalization (all-cause and respiratory-related) 
− 
To evaluate the changes from baseline in functional exercise capacity measured by the 6-
minute walk test (6MWT), in IPF subjects treated with GLPG1205 compared to placebo at 
Week 26. 
− 
To evaluate the changes in quality of life measures in IPF subjects treated with GLPG1205 
compared to placebo over 26 weeks. 
− 
To evaluate the PK of GLPG1205, nintedanib and pirfenidone in IPF subjects. 




-10- 
 
2.3. 
Study Design 
This study is a randomized, double-blind, parallel group, placebo-controlled, multicenter, Phase 2 
study. 
Approximately 60 eligible subjects with a centrally confirmed IPF diagnosis are planned to be 
randomized in a 2:1 ratio to GLPG1205 100 mg q.d. taken as 2 capsules, or matching placebo 
once daily (q.d.) administered for 26 weeks on top of local standard of care (SOC). Standard of 
care is defined as receiving nintedanib, pirfenidone, or neither nintedanib nor pirfenidone. 
Individual dose reductions of GLPG1205 will be allowed once in case of intolerance or toxicity 
at the discretion of the investigator. Subjects may have their dose of investigational medicinal 
product (IMP) reduced from 100 mg (2 capsules) q.d. to 50 mg (1 capsule) q.d. for the remainder 
of the study. Should the intolerance or toxicity continue, IMP may be discontinued, and the 
subject may be withdrawn from the study. 
During the course of the study (post randomization) further adaptations of the treatment with 
nintedanib or pirfenidone due to e.g. intolerance or initiation of either nintedanib or pirfenidone is 
allowed based on the medical needs of the individual as judged by the investigator.  
Enrolled subjects will come to the clinical study center at screening, Day 1 (baseline), Week 2, 
Week 4, Week 8, Week 12, Week 16, Week 20, Week 26, and, if applicable (i.e. for early IMP 
discontinuation), the end of treatment visit (EOT). In addition, a follow-up visit will be planned 
4 weeks after the last administration of IMP (i.e. Week 30/EoS). The end of the study is reached 
when the last follow-up visit as planned according the Schedule of Activities (Section 2.5) of the 
last subject is performed. 
Subjects who stop IMP early need to be encouraged to complete the EOT and follow-up visit for 
safety assessments and pulmonary function, but will not be obliged to do so.  
To enhance the safety of the subjects and integrity of the study data, an IDMC will be 
implemented and clinical endpoint adjudication will be performed. Details are stipulated in the 
study protocol and the respective charters. 
A schematic diagram of the clinical study design is provided below. 
 
 
The subjects will be in the study for a duration of approximately 34 weeks: up to 4 weeks of 
screening, 26 weeks of treatment, and 4 weeks of follow-up. 


-11- 
 
2.4. 
Clinical Study Protocol (CSP) and CSP Amendments 
This SAP is based on the protocol version 3.0 (amendment 2), dated 30-Apr-2020. 


-12- 
 
2.5. 
Schedule of Assessments 
For detailed instructions on the clinical study procedures, please see Section 6.1 of the protocol. 
EVENT 
SCR 
TREATMENT PERIOD 
FU 
Study visit 
11 
2 
3 
4 
5 
6 
7 
8 
9 
EOT 
10/ EOS 
Study week (W) or day (D) ± days (d) 
D-28 to D-
1 
D1 
W2 
±2d 
W4 
±2d 
W8 
±4d 
W12 
±4d 
W16 
±4d 
W20  
±4d 
W266 
±6d 
 
W307 
±4d 
Informed consent  
 
 
 
 
 
 
 
 
 
 
 
Dispense subject participation card  
 
 
 
 
 
 
 
 
 
 
 
Send HRCT (historical or new2) for central review  
 
 
 
 
 
 
 
 
 
 
 
Send LB (if available) for central review  
 
 
 
 
 
 
 
 
 
 
 
Demographics  
 
 
 
 
 
 
 
 
 
 
 
Medical history/concurrent illnesses  
 
 
 
 
 
 
 
 
 
 
 
Alcohol consumption and smoking habits  
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria  
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
3 
 
 
 
 
 
 
 
3 
3 
3 
12-Lead ECG  
 
 
 
 
 
 
 
 
 
 
 
Vital signs  
 
 
 
 
 
 
 
 
 
 
 
                                                 
1  Screening assessments need to be performed within 28 days before Day 1 and may be split into multiple days or visits. 
2  If there is no historical HRCT available, a new HRCT needs to be planned and performed. Only if for logistic reasons it is not possible to perform a new 
HRCT within the planned screening period and after approval of the medical monitor it is allowed to extend the screening period with maximum 2 weeks. 
3  At screening include height and weight; at Visit 9/EOT and Visit 10/EOS include weight. 
 


-13- 
 
EVENT 
SCR 
TREATMENT PERIOD 
FU 
Study visit 
11 
2 
3 
4 
5 
6 
7 
8 
9 
EOT 
10/ EOS 
Study week (W) or day (D) ± days (d) 
D-28 to D-
1 
D1 
W2 
±2d 
W4 
±2d 
W8 
±4d 
W12 
±4d 
W16 
±4d 
W20  
±4d 
W266 
±6d 
 
W307 
±4d 
Spirometry  
4 
4 
 
 
 
 
 
 
4 
 
 
SGRQ  
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests (hematology, coagulation, 
clinical chemistry, urinalysis) 
 
 
 
 
 
 
 
 
 
 
 
Serology  
 
 
 
 
 
 
 
 
 
 
 
FSH test  
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test  
 
 
 
 
 
 
 
 
 
 
 
PK blood samples  
 
 
 
 
 
 
 
 
 
 
 
DLCO  
 
6MWT  
 
 
 
 
 
 
 
 
 
 
 
                                                 
4  Spirometry can be repeated once if acceptability and repeatability criteria as specified by ATS/ERS/JRS/ALAT are not met after confirmation by central 
reader. 
5  
 
6    In case Visit 9 cannot be performed on site within the visit window due to the COVID-19 pandemic, the study medication intake and the corresponding time 
window for Visit 9 can be extended up to +56 days or shortened up to -28 days.  
7    In case Visit 10 cannot be performed on site within the visit window due to the COVID-19 pandemic, the corresponding time window for Visit 10 can be 
extended up to +28 days or shortened up to -7 days.   




-15- 
 
2.6. 
Sample Size Justification 
See Section 7.1 of the CSP. 
2.7. 
Randomization and Blinding 
See Section 4.4 of the CSP.  
It is acknowledged that the sponsor may be unblinded by a potential interim analysis. However, 
all efforts will be made to restrict the access to the study results so that personnel involved with 
the study conduct remain blinded, at least at an individual subject level. 
3. 
GENERAL METHODOLOGY 
3.1. 
Analysis Sets 
The analysis set will always be indicated in a subtitle in the table, listing, or figure. 
3.1.1. 
All Screened Analysis Set 
All subjects who signed an informed consent form (ICF) to participate in this study. 
3.1.2. 
All Randomized Analysis Set 
All screened subjects who were randomized in this study. 
3.1.3. 
Full Analysis Set 
All randomized subjects who have used at least 1 dose of IMP. 
3.1.4. 
Per-Protocol Analysis Set 
Subpopulation of the Full Analysis Set (FAS), excluding all subjects/data points with major 
protocol deviations impacting the efficacy results (determined during the blinded data review 
meeting). These protocol deviations are determined prior to unblinding and database lock and are 
entered in the database. 
The Per-Protocol analysis is only planned if at least 10% of the subjects are omitted from the Per-
Protocol Analysis Set. 
If a subject is unblinded (e.g. in case of a serious adverse event [SAE]), all their efficacy data will 
be disqualified from the Per-Protocol Analysis Set. 
3.1.5. 
Pharmacokinetic Analysis Set 
Subset of the FAS, selecting all subjects who have available and evaluable PK plasma 
concentration data (e.g. excluding all protocol deviations or AEs that may have an impact on the 
PK analysis). 




-17- 
 
Table 1 
Analysis Periods 
Analysis Period 
Start Analysis Period 
End Analysis Period 
Screening 
Date of signing the ICF 
Date of first study drug 
administration - 1 day 
Treatment 
Date of first study drug 
administration  
Date of last study drug 
administration + 30 days 
Follow-up# 
End date of the preceding 
analysis period + 1 day 
Date of last contact 
 ICF: informed consent form  
# If the last study drug administration plus 30 days is after date of last contact, the study will not include a follow-up period. The last analysis 
period will end on the date of last contact. 
 
If times are collected or other information with respect to timing (e.g. before or IMP intake) this 
information will be taken into account in addition to the dates. The last analysis period will 
always end on the date of last contact. 
3.3.3. 
Analysis Windows 
All assessments, including data collected on unscheduled visits, will be allocated to analysis 
windows based on the relative day of the assessment (see Section 3.3.1) and according to the 
algorithm in Table 2. TLFs will present the analysis windows. 
Table 2 
Analysis Windows for All Endpoints: 
Time point label 
Target day 
Interval lower bound 
Interval upper bound 
Baseline 
1 
-INF 
1 
Week 2 
15 
2 
22 
Week 4 
29 
23 
43 
Week 8 
57 
44 
71 
Week 12 
85 
72 
99 
Week 16 
113 
100 
127 
Week 20 
141 
128 
162 
Week 26 
183 
163 
197 
Week 30 
211 
198 
+INF 
 INF=infinity 


-18- 
 
Addendum: alternative approach due to COVID-19 pandemic 
The Urgent Safety Measures (USMs dated 02-April-2020) described in CSP Amendment 2 allow 
to enlarge the visit window at the end of the treatment period (Visit 9, Week 26; from -28 days up 
to +56 days) including extension of study medication intake, i.e. up to a maximum of 56 days 
beyond 26 weeks of treatment. Hence, for patients having to extend treatment due to COVID-19, 
this could potentially result in end-of-treatment assessments being allocated to the FU/W30 
analysis window and thus having missing data for the primary analysis time point W26. To assess 
the impact of this ‘missing’ data on the efficacy results, sensitivity analyses will be included in 
which these specific assessments are assigned to W26.       
Definition of Baseline 
For all endpoints, except ECG parameters and spirometry, baseline is defined as the last non-
missing value before the first study drug administration. If multiple values qualify as last value, 
the mean of these values will be used in the analysis. 
For spirometry endpoints, the mean of the analysis values (detailed in Section 5.2.2 for 
spirometry) before the first dose of study medication (including screening, baseline and 
unscheduled values as applicable) will be used to define the baseline value to reduce variability. 
For electrocardiogram (ECG), the baseline is defined as the mean of the last recorded triplicate 
before the first study drug administration. If no triplicate is available before the first dose of study 
medication intake, the mean of the last duplicate ECG will be used, otherwise, the last ECG value 
will be considered as baseline. 
Selection of Visits 
Per parameter and analysis window, the value closest to the target date will be used in analysis 
tables and figures. Other values will be listed only. If more than one value is located at the same 
distance from the target day, then the latest in time will be selected. If, after the previous 
selection, multiple values still qualify, the mean of these values will be used in the analysis. 
3.4. 
Handling of Data 
3.4.1. 
Handling of Missing Data 
3.4.1.1. 
Handling of Missing Date-Time Data 
No imputations will be done in case of missing date (time) fields, nor for the missing parts of 
partially known date (time) fields.  
Assessments with missing date (time) will be omitted from the analysis.  
Event-type data (e.g. adverse events, concomitant medications) with missing date (time) will be 
allocated to analysis periods using a worst-case approach as explained in the respective sections. 


-19- 
 
3.4.1.2. 
Handling of Missing Result Data 
No imputation will be done of missing result data. That is, an observed cases (OC) analysis will 
be performed. Details on the sensitivity analyses to investigate the impact of missing data on 
efficacy parameters are described in Section 6.2. 
3.4.1.3. 
Censoring of Time-to-Event Data 
Subjects who do not report the event at the moment of the analysis, are censored at the date of 
last contact. The date of last contact is defined as the latest date collected in the CRF from the 
date of death, visit or assessment dates, AE dates, concomitant treatment dates, drug intake dates 
or lab test dates and trial completion date. 
3.4.2. 
Handling of Values Below or Above a Threshold 
Values below (above) the detection limit will be imputed by the value one unit smaller (larger) 
than the detection limit itself. In listings, the original value will be presented. 
Example: if the database contains the value “<0.04”, then for the descriptive statistics the value 
“0.03” will be used. The value “>1000” will be imputed by “1001”. 
3.4.3. 
Handling of Outliers 
There will be no outlier detection, all measured values will be included in the analyses. 
In the PK part of the analysis, exclusion of abnormal PK concentration results will be formally 
discussed and determined after data base lock and before running the final statistical analysis in 
the PK
 Data Review Report. 
3.4.4. 
Stratification Factors 
The analyses will be stratified by the type of IPF SOC medication taken at randomization: 
nintedanib or pirfenidone or neither. In all analyses, except if indicated otherwise, the stratum 
will be the SOC at randomization and will not change if the subject switches SOC during the 
study.  
The 3 strata could differ in their safety profile, in addition, they might have different effects on 
the biomarker results (depending on the biomarker) and efficacy results. Therefore, for all 
analyses, 3 strata will be used (nintedanib, pirfenidone, neither), unless indicated otherwise.  
The stratum reported in the case report form (CRF) will be used in the analyses. Any 
discrepancies in stratification reported in the interactive web response system (IWRS) versus 
CRF will be listed. 


-20- 
 
3.5. 
Presentation of Results 
3.5.1. 
Presentation of Treatment Groups 
Results will be presented by treatment group: 
− 
GLPG1205 100 mg  
− 
Placebo 
 
In the section Subject Information, a grand total “All Subjects” will be added to summarize all 
subjects over all treatment groups in tables and figures. 
3.5.2. 
Calculation of Descriptive Statistics 
Descriptive statistics will include:  
− 
the number of non-missing data points (N)  
− 
the arithmetic mean 
− 
the standard error (SE) and standard deviation (SD) 
− 
the median, minimum and maximum 
− 
95% confidence interval (CI) of the mean (if indicated in the relevant section). 
3.5.3. 
Calculation of Percentages 
Frequencies and percentages will be generated for categorical parameters. 
For event-type data (e.g. adverse events), the denominator will be all subjects in the analysis set 
and analysis period. For other data (e.g. worst-case analysis of assessments), the denominator 
will be all subjects with (post-baseline) data for the parameter, in the analysis set and analysis 
window/period. 
4. 
INTERIM ANALYSES AND DATA MONITORING COMMITTEE 
REVIEW 
4.1. 
Independent Data Monitoring Committee 
To protect the safety of the subjects in the study and integrity of the study data, an IDMC will be 
implemented. The IDMC will regularly review the accumulating unblinded safety data and assess 
the benefit risk of the study by further examining pulmonary function per treatment group as 
evaluated by spirometry and adjudicated clinical endpoints (if available). At each meeting, the 
IDMC will provide a recommendation to the sponsor on clinical study continuation, suggestions 
for clinical study adaptation(s) or early termination. No premature study termination is planned 
for favorable or unfavorable efficacy treatment effect. Specific details on responsibility, 
composition, meeting formats, and timing are outlined in an IDMC charter. Analysis for the 
IDMC are detailed in a separate SAP and will be provided to the IDMC by an independent, 
unblinded statistical support group. 


-21- 
 
4.2. 
Interim Analysis 
Given the exploratory nature of the study, an interim analysis may be performed in order to allow 
sponsor planning of following clinical studies. No premature study termination is planned for 
favorable treatment effect reason based on this potential interim analysis. It is acknowledged that 
the sponsor may be unblinded by the potential interim analysis. However, all efforts will be made 
to restrict the access to the study results so that personnel involved with the study conduct 
remains blinded. 
For the interim analysis, a subset of the final analyses will be provided:  
- 
Subject disposition 
- 
Demographics and baseline disease characteristics  
- 
Listings for prior and concomitant therapies and summary table of change in SOC 
- 
Exposure to study medication and compliance 
- 
Primary and selected secondary efficacy assessments:  
o Change from baseline in FVC (mL)  
o Change from baseline in 6MWT  
o Change from baseline in SGRQ total score and domains, and proportion of SGRQ 
responders  
- 
Listing of adjudicated events 
- 
Safety:  
o Summary table for treatment-emergent AEs (TEAE) (by stratum) 
o Frequency tables by system organ class and preferred term for  
 TEAEs (by stratum) 
 TEAEs by severity 
 TEAEs of grade 3/4 
 Serious TEAEs 
 TEAEs related to GLPG1205/placebo 
 TEAEs related to SOC (pirfenidone or nintedanib) 
o Listings for  
 All AEs (summary) 
 AEs with severity grade 3 or 4  
 SAEs 
 AEs leading to death 
 AEs leading to respiratory-related hospitalization 
 TEAEs leading to discontinuation of GLPG1205/placebo 
 TEAEs leading to temporary stop or dose reduction of GLPG1205/placebo 
 AEs leading to a permanent stop, temporary stop, or dose reduction of 
SOC 


-2 2 - 
 
o  Descri pti ve statistics (a n d fi g ures ) of l a b orat or y d ata , E C G a n d vital si g ns 
o  Fre q u e nc y ta bles a n d s hift ta bles of treat me nt -e m er ge nt la b orat or y t o xicit y gra des 
a n d a b n or malities , E C G a b n or malities a n d vital si g ns a b n or malities 
o  A b n or malit y listi n gs  f or la b orat or y d ata, E C G, vital si g ns a n d p h ysic al 
e x a mi nati o n 
 
O ut p ut s will be prese nte d bli n de d  at t he I A, wit h t he e x ce pti o n of de m o gra p hics, baseli ne diseas e 
c haracteristics, e x p os ure a n d effi cac y o ut p ut w hic h will be prese nte d u n bli n de d at t he gr o u p 
le vel. F urt her d etails of t hese a nal ys es are pr o vi de d i n Secti o n 5 . P K a nal ys es will be c o vere d i n a 
se parat e a nal ysis pla n. 
Gi ve n t here is n o pla n t o ter mi nate t he st u d y earl y f or fa vora ble  efficac y res ults, n o a dj ust me nt of 
t he al p ha le vel is c o nsi dere d nee d e d. 
5.  
S T A TI S TI C A L A N A L Y S E S  
5. 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 F A S . N o i nfere ntial testi n g will be perf or me d n or 
will p -val ues be pr o vi de d.  
S u bject i nf or mati o n will be ta b ulate d wit h descri pti ve statistics per treat me nt gr o u p a n d o verall. 
5. 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  
S u m maries will als o be pr o vi de d b y strat u m  ( 3 le v els; ni nte da ni b, pirfe ni d o ne, or neit her) . T he 
f oll o wi n g para meters will be c o nsi dere d : 
− 
Date of I C F si g n at ure (liste d o nl y)  
− 
Se x  
− 
A ge at si g ni n g t he I C F ( years)  
− 
A ge, cat e g orize d ( years):  
•  
4 0 ≤ a ge < 5 0  
•  
5 0 ≤ a ge < 6 0  
•  
6 0 ≤ a ge < 7 0  
•  
a ge ≥7 0  
− 
Race a n d et h nicit y  
− 
Hei g ht at baseli ne (c m)  
− 
Wei 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)  
− 
B MI, cate g orize d ( k g/ m²):  
•  
B MI ≤ 1 8. 5  


-2 3 - 
 
•  
1 8. 5 < B MI ≤ 2 5. 0  
•  
2 5. 0 < B MI ≤ 3 0. 0  
•  
> 3 0. 0  
− 
Baseli ne s yst olic a n d d i ast olic bl o o d press ure a n d heart rate  
− 
Baseli ne alc o h ol stat us: n o, yes  (“ D oes t he patie nt dri n k alc o h ol? ”) 
− 
Baseli ne s m o ki n g stat us: n o ns m o ker, c urre nt s m o ker, e x -s m o ker 
− 
D urati o n of I P F ( years) = 
(
 
 
 
 
 
 
)
(
 
 
 
) 
.
. If t he date 
of i nitial dia g n osis is i nc o m plete, t he n t he f oll o wi n g r ules will be a p plie d: Missi n g da y: 
use t he first of t he m o nt h. Missi n g m o nt h: use J a n uar y.  
− 
D urati o n of I P F, cate g orize d ( years):  
•  
d urati o n < 0. 5  
•  
0. 5 ≤ d urati o n < 1  
•  
1 ≤ d urati o n < 2  
•  
2 ≤ d urati o n < 3  
•  
d urati o n ≥ 3   
− 
Baseli ne b ac k gr o u n d S O C :  
•  
c urre ntl y ta ki n g pirfe ni d o ne  
•  
c urre ntl y ta ki n g ni nte da ni b  
•  
ne ver t o o k pirfe ni d o ne or ni nte da ni b  
•  
st o p pe d ta ki n g pirfe ni d o ne a n d/ or ni nte da ni b 
− 
Baseli ne s pir o m etr y:  
•  
F V C ( m L)  
•  
perce nt pre dicte d F V C ( %)  
•  
f orce d e x pirat or y v ol u me i n 1 sec o n d ( F E V1) ( m L) 
•  
perce nt pre dicte d F E V 1 ( %) 
•  
F E V 1/ F V C rati o 
•  
f orce d e x pirat or y fl o w bet wee n 2 5 % a n d 7 5 % of e x hale d v ol u me ( F E F2 5 -7 5) ( m L/s) 
− 
Ot her baseli ne effi cac y meas ures:  
•  
S G R Q t otal sc ore a n d d o ma i ns:  
•  
s y m pt o ms (assessi n g t he fre q ue n c y a n d se v erit y of res pirat or y s y m pt o ms),  
•  
acti vit y (assessi n g t h e effects of breat hless ness o n m o bilit y a n d p h ysic al 
acti vit y),  
•  
i m pact (assessi n g t he ps yc h os ocial i m pact of t he disease).  
•  
6 M W T dista nce  
•  
  
− 
D L C O (c orrecte d f or H b)  


-24- 
 
5.1.2. 
Baseline Physical Examination 
A frequency tabulation per body system of the baseline physical examination results, categorized 
as normal/abnormal, will be provided by treatment group and overall. 
5.1.3. 
Disposition Information 
The following tabulations will be provided, by treatment group and overall: 
− 
The number of subjects screened, randomized (treated and not treated), not-randomized and 
the number (percent) of subjects in each analysis set as defined in Section 3.1. 
− 
The number (percent) of subjects who completed/discontinued the study/treatment and the 
reasons for discontinuation. This table will also be provided by stratum. 
− 
The number (percent) of subjects per analysis window as defined in Section 3.3.3. 
− 
Number (percent) of subjects randomized per country and investigator. 
 
In addition, the following listings will also be provided:  
− 
Subject identification and randomization (country, site number, investigator, subject number, 
randomization number, planned and actual randomization group and stratum, with flags for 
discrepancies). 
− 
Subjects excluded from the FAS and the reason for exclusion. 
− 
Date of the earliest ICF signed for this study and date of last scheduled visit performed in 
this study. 
5.1.4. 
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, violations on eligibility criteria, 
and subjects not treated will be listed. The major protocol deviations leading to exclusion from 
the Per-Protocol Analysis Set (see Section 3.1.4) will be flagged. 
5.1.5. 
Medical History and Concomitant Diseases 
Frequency tabulations per system organ class and preferred term will be provided for the medical 
history findings (i.e. condition 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). 


-25- 
 
5.1.6. 
Prior and Concomitant Therapies 
5.1.6.1. 
Coding of Reported Terms 
All prior and concomitant therapy terms will be coded in the database using the World Health 
Organization drug coding dictionary. 
5.1.6.2. 
Classification of Therapies 
All prior and concomitant therapy records will be categorized as follows, considering their date 
and flags indicating the relative timing versus study (drug) start or end (e.g. before, after, 
ongoing: 
− 
Prior only: when the record ended before the first dose of IMP. 
− 
Concomitant only: when the record started on or after the first dose of IMP. 
− 
Prior and concomitant: when the record started before the first dose of IMP, and ended on or 
after this point, or continued. 
 
Records without a start date are assumed to have started before the date of first study drug 
administration. Records without an end date are assumed to be ongoing.  
 
When the start or end date of the prior and concomitant therapy records are incomplete (and no 
flags indicating relative timing are available), the date of first IMP administration will be 
considered to the same level of information provided by these incomplete dates to categorize the 
timing of these records. This means that a record only having month and year will be categorized 
comparing only to the month and the year of the date of first IMP administration. If the start date 
is unknown but the medication is flagged to have started prior to the first dose of IMP, this 
information will be taken into account. 
5.1.6.3. 
Calculation of Relative Days 
For both the start and the end dates of the concomitant therapy records, their day relative to the 
day of first study drug administration will be calculated as described in Section 4.3.1. 
5.1.6.4. 
Presentation of Results 
A frequency tabulation per treatment group and overall of the Anatomical Therapeutic 
Classification (ATC) classes level 4 by therapeutic subgroup (ATC level 2) and generic term of 
the prior medications (defined as ‘prior only’ and ‘prior and concomitant’) will be provided as 
well as of the concomitant medications (defined as ‘concomitant only’ and ‘prior and 
concomitant’). 
Additional tables will be provided for respiratory-related concomitant and prior medications. The 
definition of respiratory-related medications will be provided in a separate document before 
unblinding for the final study report.  


-26- 
 
A frequency table per treatment group, summarizing the IPF SOC intake during the study, of the 
number and percentage of subjects with the following: 
− 
Baseline SOC pirfenidone: 
• 
Stable dose until study end date 
• 
Reduced dose at least once 
• 
Temporarily stopped at least once 
• 
Permanently stopped and started nintedanib 
• 
Permanently stopped (without starting nintedanib) 
− 
Baseline SOC nintedanib: 
• 
Stable dose until study end date 
• 
Reduced dose at least once 
• 
Temporarily stopped at least once 
• 
Permanently stopped and started pirfenidone 
• 
Permanently stopped (without starting pirfenidone) 
− 
Baseline SOC neither: 
• 
Stable until study end date 
• 
Started nintedanib or pirfenidone and permanently stopped (without restarting other 
SOC) 
• 
Started nintedanib or pirfenidone and temporarily stopped (i.e. period without any SOC) 
at least once 
• 
Started nintedanib or pirfenidone and continued until study end date (includes subjects 
that switch SOC without temporary stop) 
Note: these categories should be counted in a worst-case manner i.e. a subject appears only once 
in one of the categories (in the order as specified above with “permanent stop” or “starting SOC” 
as the worst cases). 
 
In addition, a listing will be provided of the subjects who had any change in IPF SOC medication 
(pirfenidone, nintedanib or neither) during the treatment period compared to baseline e.g. 
switching between nintedanib and pirfenidone, starting pirfenidone/nintedanib, stopping 
pirfenidone/nintedanib, down-titration or up-titration of pirfenidone/nintedanib. All SOC therapy 
records are to be included. 
5.1.7. 
Exposure to Study drug and Compliance 
5.1.7.1. 
Derivation Rules 
Derived Parameters: Extent of Exposure to Study Drug 
− 
Total treatment duration (days) = last study drug administration date – first study drug 
administration date + 1 day. 
− 
Total treatment duration, excluding days off study drug: Number of days with any study 
drug administration.  


-2 7 - 
 
− 
T ot al tre at me nt d ur ati o n, f ully c o m pli a nt  ( da ys): N u m ber of da ys wit h st u d y dr u g 
a d mi nistrati o n of e x actl y 2 ca ps ules.  
 
D eri v e d P ar a m et er s: C o m pli a n c e  
St u d y dr u g co m plia nce is defi ne d b y  t he pla n n e d treat me nt d osa ge ( 1 0 0 m g q. d.; 2 ta blets of 5 0 
m g  per da y) wit h o ut ta ki n g i nt o acc o u nt p ote ntial d o w n -titrati o ns (as all o we d b y t h e pr ot oc ol).  
− 
Over all c o m pli a nce  ( %) = 1 0 0  ×  
 
 
 
 
 
 
 
 
 
 
 
 (acc or di n g t o 
ra n d o mizati o n) 
 
− 
Perce nt d ays wit h a ny i nt ake  ( %) = 1 0 0  ×  
 
 
,
 
 
 
 
 
 
− 
Perce nt d ays f ully c o m pli a nce  ( %) = 1 0 0  ×  
 
 
,
 
 
 
 
 
5. 1. 7. 2.  
Pr e s e nt ati o n of R e s ult s  
S u m mar y statistics per treat me nt gr o u p a n d o v erall will be pr o vi de d f or eac h c o m plia nce a n d 
e xte nt of e x p os ure para m eter. Fre q u e nc y ta bles will be pr o vi de d f or t he c o m plia nce para meters, 
usi n g t he f oll o wi n g cate g ories: < 8 0 %; 8 0 %  ≤ x < 1 0 0 %; 1 0 0 %; 1 0 0 % < x ≥ 1 2 0 %; > 1 2 0 %.  
A listi n g will be pr o vi de d of t he s u bjects w h o t o o k i nc orrect st u d y me dicati o n  ( G L P G 1 2 0 5 
i nstea d of place b o, or vic e versa) f or at least part of t he treat me nt peri o d, all G L P G 1 2 0 5 / place b o 
rec or ds are t o b e i ncl u de d t o pr o vi de a n o ver vi e w of t he a m o u nt of cr oss -tr eat me nt relati ve t o t he 
t otal treat me nt peri o d.  
I n a d diti o n, a listi n g of t h e s u bjects w h o ha d t heir st u d y me dicati o n d o w n-titrate d or i nterr u pte d  
f or at least part of t he treat me nt peri o d will be pr o vi de d . A ll G L P G 1 2 0 5 / pl ace b o rec or ds are t o be 
i ncl u de d t o pr o vi de a n o v er vie w of t h e a m o u nt of d o w n-titrati o n/i nterr u pti o n relati ve t o t he t otal 
treat me nt peri o d. 
Fi nall y, a listi n g of t he s u bjects recei vi n g i n v esti gati o nal pr o d uct fr o m s pecific batc hes, w here 
m ore t ha n o ne bat c h was use d (s h o wi n g t he batc h n u m bers of t he i n vesti gati o nal pr o d ucts 
act uall y use d, i ncl u di n g t he e x pirati o n dates) will als o be pr o vi de d.  
5. 2.  
Effi c a c y A n al y s e s  
Efficac y a nal ys es will be perf or me d o n t he F A S , e x cl u di n g all data c ollecte d after l u n g 
tra ns pla nt. T o i n vesti gate t he i m pact of n o n-c o m plia nce a n d pr ot oc ol vi olat ors a Per -Pr ot oc ol 
a nal ysis will als o be p erf or me d f or t he pri mar y e n d p oi nt, if at least 1 0 % of t he s u bjects are 
o mitte d fr o m t he Per -Pr ot oc ol A nal ysis Set . 
T a b ulati o ns will be s h o w n per treat me nt gr o u p.  


-28- 
 
5.2.1. 
Level of Significance 
Statistical tests will be done at a 2-sided significance level of 5%.  
Given there is no plan to terminate the study early for favorable efficacy results, no adjustment of 
the alpha level is considered needed due to the interim analysis. 
No multiplicity adjustment will be applied for the secondary endpoints, since this is a non-
confirmatory proof-of-concept study.  
5.2.2. 
Pulmonary Function by Spirometry 
Pulmonary function will be assessed through spirometry at the study center. All spirometry 
evaluations should be performed pre-bronchodilator*. Spirometry data taken post-bronchodilator 
will be excluded from the analysis. Values will be used as provided by the central reading 
vendor. 
* pre-bronchodilator is defined as: 
− 
short-acting more than (>) 6 hours prior to the spirometry assessment 
− 
long-acting bronchodilator at least (≥) 12 hours prior to the spirometry assessment 
Note that a spirometry assessment with no use of bronchodilator is equivalent to a pre-
bronchodilator assessment. 
The data will be coded as “acceptable”, “borderline acceptable” and “unacceptable”. 
“Unacceptable” values will be excluded from analyses. The following quality grades as provided 
in the database will be used. 
Table 3 
Spirometry Quality Grades Based on Acceptability and Repeatability criteria 
Quality 
Criteria 
Acceptable 
≥ 3 efforts that meet the American Thoracic Society / European Respiratory 
Society (ATS/ERS) Guidelines (Raghu, Collard, Egan, & al, 2011; Raghu, Remy-
Jardin, Myers, Richeldi, & Ryerson, 2018) and the criteria for Acceptability and 
Repeatability 
Borderline 
acceptable 
≥ 2 efforts that meet the ATS/ERS Guidelines and the criteria for Acceptability 
and Repeatability, or 
≥ 3 efforts that meet the ATS/ERS Guidelines and the criteria for Acceptability 
but not Repeatability 
Unacceptable 
≤ 1 effort that meets the ATS/ERS Guidelines and the criteria for Acceptability 
and Repeatability 
Acceptability:  


-29- 
 
• 
Time to Peak Expiratory Flow < 250 ms 
• 
Absence of artifact or cough 
• 
Exhalation ≥ 6 seconds however demonstrated a 1 second plateau 
• 
Lack of technical problems during effort 
Repeatability: 
• 
Will be based on the computer selected Best effort (highest) compared to next Best effort 
(second highest) based upon FVC values to be within 150 ml or within 100 ml when FVC ≤ 
1L 
Source: Pulmonary Function Test (PFT) OverRead Guidelines for GLPG1205-CL-220 
The following parameters will be presented as part of the spirometry assessment: 
− 
FVC (mL)  
− 
Percent predicted FVC (%) 
− 
FEV1 (mL) 
− 
Percent predicted FEV1 (%) 
− 
FEV1/FVC ratio 
− 
FEF25-75 
 
Derived values: 
− 
Change from baseline: 
Change at time point t = (time point t value) – (baseline value) 
− 
Percent change from baseline: 
Percent change at time point t = 100 x (change at time point t) / (baseline value) 
 
For each of the spirometry parameters, descriptive statistics will be provided for the actual 
values, changes and percent change from baseline per time point and per treatment group. Results 
will also be graphically displayed by means of subject profile plots, boxplots over time by 
treatment group for the actual values, and line plots of the mean (+/- SE) over time by treatment 
group for change from baseline, and percent change from baseline. 
5.2.2.1. 
Primary Endpoint: Change from Baseline in FVC over 26 Weeks 
The change from baseline in FVC over 26 weeks will be compared between treatment groups by 
means of an analysis of covariance (ANCOVA) model at each planned time point (as specified in 
Section 2.5 and 3.3.3) including treatment, sex, and stratum as categorical covariates and age, 
height, and baseline FVC value as continuous covariates. LS means and 95% CIs will be 
presented per time point and treatment group as well as the LS mean differences between 
treatment groups with 95% CI. 


-30- 
 
Missing data will not be imputed and thus this analysis is conducted on OC only.  
Percent predicted FVC will be analyzed using a similar ANCOVA model. 
5.2.2.2. 
Sensitivity Analyses to the Primary Analysis 
The following sensitivity analyses are planned to investigate the impact of missing data and 
protocol violators. If during the blinded review of the data more sensitivity analyses are deemed 
necessary these will be added to this SAP before unblinding for the final analysis of the CSR. 
5.2.2.2.1. Linear Mixed Model 
A random coefficient regression model including sex, and stratum as categorical fixed effects and 
age, and height as continuous fixed effects and a random intercept and slope will be used to 
analyze the yearly rate of decline in FVC. The treatment effect will be determined by using 
estimated slopes for each study group on the basis of the time-by-treatment interaction term from 
the mixed model. The model will be fit using the SAS Proc Mixed procedure, details are in 
Appendix II. The assumptions of the model will be investigated graphically. 
This approach provides another estimate for the primary endpoint. In addition, this model 
implicitly takes into account missing data under the assumption of missing-at-random (MAR).  
5.2.2.2.2. Repeated Measures Analysis 
The change from baseline in FVC over 26 weeks will also be compared between treatment 
groups by means of a mixed effect repeated measures model (MMRM) including sex, stratum 
and a treatment-by-time point interaction (planned time points as specified in Section 2.5 and 
3.3.3) as categorical fixed effects, age, height, and baseline FVC as continuous fixed effects and 
correlated within-subject residuals. LS means and 95% CIs will be presented per time point and 
treatment group as well as the LS mean difference with 95% CI. The model will be fit using the 
SAS Proc Mixed procedure, details are in Appendix II.  
This approach provides another estimate for the primary endpoint. In addition, this model 
implicitly takes into account MAR.  
5.2.2.2.3. Per-Protocol Analysis 
To investigate the impact of non-compliance and protocol violators a Per-Protocol analysis may 
also be performed for the primary endpoint using the ANCOVA model described in Section 
5.2.2.1. Protocol violations potentially impacting the results will be excluded and identified 
before database lock and unblinding for the final analysis. 
This Per-Protocol analysis is only planned if at least 10% of the subjects are omitted from the 
Per-Protocol Analysis Set. 
This approach provides another estimate than the primary one, namely the estimate in the 
population of subjects who follow procedures according to protocol. 


-31- 
 
5.2.2.2.4. Impact COVID-19 
To investigate the impact on the primary endpoint of V9 assessments being assigned to the W30 
analysis window due to COVID-19, a sensitivity analysis in which these assessments are 
assigned to the W26 analysis window will be performed for the descriptive statistics, the 
summary plots over time and the ANCOVA model described in Section 5.2.2.1.  
5.2.3. 
Secondary Endpoints 
5.2.3.1. 
Time to Major Events 
A time to (first) event analysis will be conducted for major events, defined as  
− 
Death (all-cause and respiratory-related) 
− 
Hospitalization (all-cause and respiratory-related) 
 
Deaths and hospitalizations will be adjudicated by the CEAC. The analysis will be based on the 
results from the adjudication, not on the investigator-reported information. Differences will be 
investigated and listed, if any. 
The number and proportion of subjects with an event during the study will be summarized per 
treatment group. Treatment effect on time to first event will be assessed using the log-rank test. 
In addition, time to first event will be graphically displayed and tabulated (at each planned time 
point as described in Section 3.3.3, Week 2, Week 4, etc, and last available time point) per 
treatment group using Kaplan-Meier estimates. 
In addition, for all-cause hospitalization and all-cause mortality a frequency table will be 
provided for the event classification categories as determined by the CEAC. These categories are 
described in the CEAC charter. 
Censoring  
Time-to-event endpoints are defined from the date of first dose of study medication. 
If the subject did not have an event, the time to event will be censored at the last contact date, as 
defined in Section 3.4.1.3. 
5.2.3.2. 
Change from Baseline in 6MWT over 26 Weeks 
The actual values, changes from baseline, and percent changes from baseline in 6MWT total 
distance walked in 6 minutes 
 will be presented descriptively for each time point 
by treatment group. Results will also be graphically displayed by means of subject profile plots, 
boxplots over time by treatment group for the actual values, and line plots of the mean (+/- SE) 
over time by treatment group for (percent) changes from baseline. 
The change from baseline in 6MWT over 26 weeks will be compared between treatment groups 
by means of an ANCOVA model at Week 26 (as defined in Section 3.3.3) including treatment 
and stratum as categorical covariates and baseline 6MWT distance as continuous covariates. LS 


-32- 
 
means and 95% CIs will be presented per treatment group as well as the LS mean difference 
between treatment groups with 95% CI. 
5.2.3.3. 
Change from Baseline in SGRQ over 26 Weeks 
The St. George’s Respiratory Questionnaire (SGRQ) is a 50-item paper questionnaire split into 3 
domains:  
− 
symptoms (assessing the frequency and severity of respiratory symptoms),  
− 
activity (assessing the effects of breathlessness on mobility and physical activity), 
− 
impact (assessing the psychosocial impact of the disease).  
Scores are weighted such that every domain score and the total score range from 0 to 100, with 
higher scores indicating a poorer health-related quality of life. 
Note that before completing the questionnaire the subject will have to answer a question on 
his/her present health. This info will be tabulated. 
 
 


-33- 
 
Table 4 
SGRQ Questions/Items and Their Weights (from 0 to 100)  
General 
Q# 
Question 
Answer 
Weight 
 
Check how you describe your current health 
Very good 
NA 
Good 
NA 
Fair 
NA 
Poor  
NA 
Very poor 
NA 
Part 1 
Describe how often your respiratory problems have affected you over the past 3 months. 
Q# 
Question 
Answer 
Weight 
1 
Over the past 3 months, I have coughed: 
Almost every day 
80.6 
Several days a week 
63.2 
A few days a month 
29.3 
Only with respiratory infections 
28.1 
Not at all 
0.0 
2 
Over the past 3 months, I have brought up phlegm 
(sputum): 
Almost every day 
76.8 
Several days a week 
60.0 
A few days a month 
34.0 
Only with respiratory infections 
30.2 
Not at all 
0.0 
3 
Over the past 3 months, I have had shortness of breath: 
Almost every day 
87.2 
Several days a week 
71.4 
A few days a month 
43.7 
Only with respiratory infections 
35.7 
Not at all 
0.0 
4 
Over the past 3 months, I have had wheezing attacks: 
Almost every day 
86.2 
Several days a week 
71.0 
A few days a month 
45.6 
Only with respiratory infections 
36.4 
Not at all 
0.0 
5 
How many times during the past 3 months have you 
suffered from severe or very unpleasant respiratory 
attacks? 
More than 3 times 
86.7 
3 times 
73.5 
2 times 
60.3 
1 time 
44.2 
None of the time 
0.0 
6 
How long did the worst respiratory attack last? 
A week or more 
89.7 
3 or more days 
73.5 
1 or 2 days 
58.8 
Less than a day 
41.9 
7 
Over the past 3 months, in a typical week, how many 
good days (with few respiratory problems) have you had? 
No good days 
93.3 
1 or 2 good days 
76.6 


-34- 
 
3 or 4 good days 
61.5 
Nearly every day was good 
15.4 
Every day was good 
0.0 
8 
If you have a wheeze, is it worse when you get up in the 
morning? 
No 
0.0 
Yes 
62.0 
Part 2 – Section 1 
Q# 
Question 
Answer 
Weight 
9 
How would you describe your respiratory condition? 
The most important problem I have 
83.2 
Causes me quite a lot of problems 
82.5 
Causes me a few problems 
34.6 
Causes me no problems 
0.0 
10 
If you ever held a job: 
My respiratory problems made me 
stop working altogether 
88.9 
My respiratory problems interfere 
with my job or made me change my 
job 
77.6 
My respiratory problems do not 
affect my job 
0.0 
Part 2 – Section 2 
Questions about what activities usually make you feel short of breath these days. 
I# 
Question 
Answer 
Weight 
11 
Sitting or lying still. 
False 
0.0 
True 
90.6 
12 
Washing or dressing yourself. 
False 
0.0 
True 
82.8 
13 
Walking around at home. 
False 
0.0 
True 
80.2 
14 
Walking outside on level ground. 
False 
0.0 
True 
81.4 
15 
Walking up a flight of stairs. 
False 
0.0 
True 
76.1 
16 
Walking up hills. 
False 
0.0 
True 
75.1 
17 
Playing sports or other physical activities. 
False 
0.0 
True 
72.1 
Part 2 – Section 3 
Questions about your cough and shortness of breath these days. 
I# 
Question 
Answer 
Weight 
18 
Coughing hurts. 
False 
0.0 
True 
81.1 
19 
Coughing makes me tired. 
False 
0.0 
True 
79.1 
20 
I am short of breath when I talk. 
False 
0.0 


-35- 
 
True 
84.5 
21 
I am short of breath when I bend over. 
False 
0.0 
True 
76.8 
22 
My coughing or breathing disturbs my sleep. 
False 
0.0 
True 
87.9 
23 
I get exhausted easily. 
False 
0.0 
True 
84.0 
Part 2 – Section 4 
Questions about other effects that your respiratory problems may have on you these days. 
I# 
Question 
Answer 
Weight 
24 
My cough or breathing is embarrassing in public. 
False 
0.0 
True 
74.1 
25 
My respiratory problems are a nuisance to my family, 
friends, or neighbors. 
False 
0.0 
True 
79.1 
26 
I get afraid or panic when I cannot catch my breath. 
False 
0.0 
True 
87.7 
27 
I feel that I am not in control of my respiratory problems. 
False 
0.0 
True 
90.1 
28 
I do not expect my respiratory problems to get any better. 
False 
0.0 
True 
82.3 
29 
I have become frail or an invalid because of my 
respiratory problems. 
False 
0.0 
True 
89.9 
30 
Exercise is not safe for me. 
False 
0.0 
True 
75.7 
31 
Everything seems too much of an effort. 
False 
0.0 
True 
84.5 
Part 2 – Section 5 
Questions about your respiratory treatment. 
I# 
Question 
Answer 
Weight 
32 
My treatment does not help me very much. 
False 
0.0 
True 
88.2 
33 
I get embarrassed using my medication in public. 
False 
0.0 
True 
53.9 
34 
I have unpleasant side effects from my medication. 
False 
0.0 
True 
81.1 
35 
My treatment interferes with my life a lot. 
False 
0.0 
True 
70.3 
Part 2 – Section 6 
Questions about how your activities might be affected by your respiratory problems. 
I# 
Question 
Answer 
Weight 
36 
I take a long time to get washed or dressed. 
False 
0.0 
True 
74.2 


-36- 
 
37 
I cannot take a bath or shower, or I take a long time to do 
it. 
False 
0.0 
True 
81.0 
38 
I walk slower than other people my age, or I stop to rest. 
False 
0.0 
True 
71.7 
39 
Jobs such as household chores take a long time, or I have 
to stop to rest. 
False 
0.0 
True 
70.6 
40 
If I walk up one flight of stairs, I have to go slowly or 
stop. 
False 
0.0 
True 
71.6 
41 
If I hurry or walk fast, I have to stop or slow down. 
False 
0.0 
True 
72.3 
42 
My breathing makes it difficult to do things such as walk 
up hills, carry things up stairs, light gardening such as 
weeding, dance, bowl, or play golf. 
False 
0.0 
True 
74.5 
43 
My breathing makes it difficult to do things such as carry 
heavy loads, dig in the garden, or shovel snow, jog or 
walk briskly (5 miles per hour), play tennis, or swim. 
False 
0.0 
True 
71.4 
44 
My breathing makes it difficult to do things such as very 
heavy manual work, ride a bike, run, swim fast, or play 
competitive sports 
False 
0.0 
True 
63.5 
Part 2 – Section 7 
Questions about how your respiratory problems usually affect your daily life. 
I# 
Question 
Answer 
Weight 
45 
I cannot play sports or do other physical activities. 
False 
0.0 
True 
64.8 
46 
I cannot go out for entertainment or recreation. 
False 
0.0 
True 
79.8 
47 
I cannot go out of the house to do the shopping. 
False 
0.0 
True 
81.0 
48 
I cannot do household chores. 
False 
0.0 
True 
79.1 
49 
I cannot move far from my bed or chair. 
False 
0.0 
True 
94.0 
50 
Tick the statement which you think best describes how 
your respiratory problems affects you: 
It does not stop me from doing 
anything I would like to do 
0.0 
It stops me from doing one or 2 
things I would like to do 
42.0 
It stops me from doing most of the 
things I would like to do 
84.2 
It stops me from doing everything I 
would like to do 
96.7 
 
Domain scores and total score: 
− 
Symptoms score: questions 1-8. 
− 
Activity score: questions 11 to 17 and 36 to 44.  


-3 7 - 
 
− 
I m pa cts sc ore: q uesti o ns 9-1 0, 1 8 t o 3 5 , a n d 4 5 t o 5 0.  
T otal sc ore : all q uesti o ns. 
Eac h d o mai n sc ore is cal c ulate d se paratel y i n 3  st e ps 
− 
T he wei g hts f or all ite ms are s u m me d.  
− 
T he ma xi m u m wei g hts f or misse d ite ms are de d u cte d fr o m t he ma xi m u m p ossi ble wei g ht f or 
eac h c o m p o ne nt. T he ma xi m u m wei g hts f o r all misse d ite ms are de d u cte d fr o m t he 
ma xi m u m p ossi ble wei g ht f or t he t otal sc ore.  
 
S u m of ma xi m u m p ossi ble wei g hts f or eac h sc ore:  
•  
S y m pt o ms: 6 6 2. 5  
•  
Acti vit y: 1 2 0 9. 1  
•  
I m pa cts: 2 1 1 7. 8 
•  
T otal: 3 9 8 9. 4  
 
− 
T he sc ore is calc ulate d b y di vi di n g t h e s u m me d wei g hts b y  t he a dj uste d m a xi m u m p ossi ble 
wei g ht f or t hat c o m p o ne nt a n d e x pressi n g t he res ult as a perce nta ge  
 
Sc ore = 1 0 0 x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
T he t otal sc ore is c alc ulat e d i n a si mil ar wa y:  
 
Sc ore = 1 0 0  x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N ote t hat t he q uesti o n naire re q u ests a si n gle res p o nse t o q uesti o ns 1 -7, 9 -1 0 , a n d 5 0. If m ulti ple 
res p o nses are gi ve n t o o n e of t hese q u esti o ns t he n t he wei g hts f or t he res p o nses f or t hat q uesti o n 
will be a vera ge d.  
I n case of missi n g ite ms, t he f oll o wi n g r ul es will be a p plie d: 
− 
T he s y m pt o ms sc ore will o nl y be calc ulate d w he n n o m ore t ha n 2 ite ms are missi n g.  
− 
T he acti vit y s c ore wi ll o nl y be calc ulate d w he n n o m ore t ha n 4 ite ms are missi n g. 
− 
T he i m pacts sc ore will o nl y be calc ulate d w he n n o m ore t ha n 6 ite ms are missi n g.  
− 
T he t otal sc ore will o nl y be calc ul ate d w he n t he 3 d o mai n sc ores c o ul d be calc ulate d . 
S o urce: St. Ge or ge’s Res pirat or y Q uesti o n nair e Ma n ual ( 2 0 0 9).  
 
F or act ual val ues a n d c ha n ges fr o m baseli ne i n S G R Q t otal sc ore, as w ell as s y m pt o m, acti vit y, 
a n d i m pact sc ores, descri pti ve statistics will be pr o vi de d per ti me p oi nt a n d treat me nt gr o u p. 
Res ults will als o be gra p hicall y dis pla ye d b y m ea ns of s u bject pr ofile pl ots , b o x pl ots o ver ti me 










-42- 
 
5.3.1. 
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. 
5.3.1.1. 
Definition of Treatment-Emergent Adverse Events 
The analysis of AEs will be based on treatment-emergent events (TEAE).  
TEAEs are defined as  
AEs (or worsening6 of an existing event) having a start date equal or after the date of the first 
administration of study drug and before the last dosing date plus 30 days. Improvements are not 
considered treatment-emergent. 
5.3.1.2. 
Coding of Reported Terms 
All AE terms will be coded in the database using the Medical Dictionary for Regulatory 
Activities (MedDRA) coding dictionary. 
All tables will show the AE preferred terms grouped into system organ class. Subject listings will 
also show the reported terms. Any other coding levels will only be shown in a listing 
summarizing coding unless explicitly mentioned otherwise. 
5.3.1.3. 
Allocation of Adverse Events to Analysis Periods 
All AEs will be placed into analysis periods considering their start date, aiming to report the 
incidence of these events only in the analysis period during which they started. 
The general rule for allocation of AEs to analysis periods follows: 
Analysis period start date ≤ AE start date ≤ analysis period end date  
If the start date of an AE is missing or incomplete to a level preventing a clear allocation of the 
AE to one single analysis period and no flag indicating timing relative to study medication is 
available, a worst-case consideration (see below) will be done aiming to allocate the AE to one 
single analysis period, if possible. When a worst-case consideration is needed, the end date of the 
AE, if and as available, should also be considered; if such AEs clearly end on a given point, this 
will exclude the possibility to allocate the AE to an analysis period after that point. 
− 
An AE which according to the available information of its start date could belong to the 
screening as well as to the treatment period will only be placed in the treatment period. 
                                                 
6  ‘Worsening’ is defined as worsening in at least one of the following attributes: seriousness, severity, relationship 
and/or action taken. 


-43- 
 
− 
An AE which according to the available information of its start date could belong to the 
treatment period as well as to the follow-up period will only be placed in the treatment 
period. 
− 
An AE with a missing start date will be allocated to the treatment period. 
5.3.1.4. 
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. 
5.3.1.5. 
Worst-Case Selections 
When cross-tabulating AE preferred terms versus an AE attribute (e.g. severity), only the worst-
case within each analysis period will be considered, i.e. when a subject has more than once the 
same AE preferred term reported in the same analysis period, the subject will be counted only 
once and will be shown under the worst outcome (e.g. the worst severity for that AE in the 
concerned analysis period). If this happens in 2 different analysis periods, the AE is reported 
twice: once in each analysis period. 
5.3.1.6. 
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. 
Relative days and durations will only be listed. 
See Section 3.3.1 for the calculation of relative days. 
5.3.1.7. 
Presentation of Results 
The analysis will focus on AEs reported during the treatment period. AEs reported during the 
screening or follow-up period will only be listed. 
All adverse events tables will show the number of subjects with TEAEs.  


-44- 
 
A summary table will be provided, showing the number (percent) of subjects with at least one: 
− 
TEAE 
− 
serious TEAE 
− 
TEAE leading to death  
− 
TEAEs by worst severity 
− 
TEAE that was considered related to GLPG1205/placebo 
− 
TEAE that was considered related to pirfenidone 
− 
TEAE that was considered related to nintedanib 
− 
TEAE for which GLPG1205/placebo was reduced 
− 
TEAE for which GLPG1205/placebo was temporarily stopped 
− 
TEAE for which GLPG1205/placebo was permanently stopped 
− 
TEAE for which pirfenidone was reduced 
− 
TEAE for which pirfenidone was temporarily stopped 
− 
TEAE for which pirfenidone was permanently stopped 
− 
TEAE for which nintedanib was reduced 
− 
TEAE for which nintedanib was temporarily stopped 
− 
TEAE for which nintedanib was permanently stopped 
 
For each line, the difference in percentage of subject with an AE between placebo and 
GLPG1205 will be included, together with the 95% CI of the difference using the method of 
Miettinen and Nurminen. 
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 severity) for 
TEAEs of grade 3/4, TEAEs related to GLPG1205/placebo and for TEAEs related to SOC. 
Serious adverse events (including AEs leading to hospitalization), AEs leading to death, leading 
to respiratory-related hospitalization (as reported by the investigator), of grade 3/4, leading to 
discontinuation of GLPG1205/placebo, leading to a temporary stop or dose reduction of 
GLPG1205/placebo, leading to a permanent stop, temporary stop, or dose reduction of SOC, pre- 
and post-treatment adverse events will be listed. 
5.3.1.8. 
Adverse Events Related to Nintedanib or Pirfenidone 
To investigate the events expected to be associated with pirfenidone and/or nintedanib a 
frequency table by system organ class and preferred term, by treatment group, as well as by 
stratum and treatment group, will be provided for the preferred terms of events of specific interest 
to nintedanib (e.g. diarrhea, nausea, vomiting, dehydration, weight decrease and decreased 
appetite adverse events) and pirfenidone (e.g. photosensitivity reactions, nausea, diarrhea, 
dyspepsia, vomiting, gastro-esophageal reflux disease, and abdominal pain). The full list of 
preferred terms to be investigated will be detailed before unblinding for the final CSR. 


-45- 
 
5.3.1.9. 
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 serious TEAE and the number of serious TEAEs will be presented. A similar table 
will be provided for all non-serious TEAEs.   
5.3.1.10. 
Subgroup Analyses 
The AE summary table, the frequency table by system organ class and preferred term, and the 
frequency table for events of specific interest will be provided for each stratum (3 strata; 
nintedanib, pirfenidone, neither).  
5.3.2. 
Laboratory Safety 
5.3.2.1. 
Available Data 
Laboratory tests scheduled are described in the protocol. In addition, the derived laboratory tests 
described in Section 5.3.2.2 will be added. 
The statistical analyses will only present results in Standard International (SI) units. Other units 
will not be presented. 
Only data provided by the central laboratory will be used. 
5.3.2.2. 
Derivation Rules 
Derived Laboratory Tests 
Creatinine clearance (CCr), estimated according to Cockcroft-Gault calculation: 
CCr (in mL/min) = [(140-age) x weight]/[72 x SCr] (x 0.85 for women), with SCr = serum 
creatinine in mg/dL, age in years, and weight in kg 
For the calculation of estimated creatinine clearance, the age at screening and the weight, closest 
to the assessment for which creatinine clearance is calculated, will be used. 
Fasted and Non-Fasted Results 
Laboratory tests that are sensitive to the fasting status: glucose, triglycerides. 
For these laboratory tests, descriptive statistics and tabulations of Common Terminology Criteria 
for Adverse Events (CTCAE) toxicities (fasting only) will be shown by fasting status. 
Tabulations of scorings according to normal ranges will be created for both fasting and non-
fasting results pooled. Laboratory results for which the fasting status is missing, will be 
considered as taken fasted. 






-48- 
 
missing post-baseline records (including unscheduled and follow-up visits, but excluding local 
lab results). 
The worst-case toxicity grade is the highest toxicity grade scored for the laboratory test (in each 
sense, if below and above). 
Non-graded Abnormalities 
The following worst-case post-baseline abnormalities L, N, or H will be determined per subject, 
per laboratory test and for each analysis period, using all non-missing post-baseline records 
(including unscheduled and follow-up visits, but excluding local lab results): 
− 
L = low: at least one post-baseline result is classified as L. 
− 
N = normal: all post-baseline results are classified as N. 
− 
H = high: at least one post-baseline result is classified as H. 
If, for a subject, both L and H are reported, the subject will be counted twice in the table: once 
with a worst-case L and once with a worst-case H. 
5.3.2.8. 
Presentation of Results 
No formal inferential statistics (p-values) will be derived. 
Continuous laboratory tests will be summarized by means of descriptive statistics of the actual 
values and changes from baseline (including 95% CI of the mean change) by laboratory test, 
treatment group, and analysis window.  
Boxplots of the actual values over time and of the mean (+- SE) change from baseline will be 
prepared for all laboratory tests. 
The analysis of abnormalities will focus on assessments reported during the treatment period. 
Results reported during the screening or follow-up period will only be listed. 
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 grade. The table 
will be created per laboratory test and treatment group. The results of non-graded abnormalities 
and toxicities grades will be shown separately. 
A frequency table of the number (percent) of subjects with treatment-emergent worst-case 
abnormalities/toxicity grade per laboratory test and treatment group will be presented. The results 
of non-graded abnormalities and toxicities grades will be shown separately.  
A listing per treatment group, per subject, and per time point of all post-baseline time points 
scored as treatment-emergent and out-of-normal-range, plus also the baseline reference time 
point will be provided. In addition, laboratory parameters with insufficient data to be presented in 
the tables will be listed. 




-50- 
 
QT and QTcF (ms) 
QT change ≤ 30 
≤ 30 
 
30 < QT change ≤ 60 
30 < change ≤ 60 
 
QT change > 60 
> 60 
  
Worst-Case Abnormality 
The worst-case post-baseline categorized actual analysis value and the worst-case categorized 
change from baseline will be determined per subject, per parameter, and for each analysis period, 
using all non-missing post-baseline records (including unscheduled and follow-up visits). 
For QT and QTcF, the worst-case categorized actual analysis value is the category corresponding 
to the highest post-baseline actual value. The worst-case change from baseline is the category 
corresponding to the largest increase (positive change) from baseline. 
For PR and HR, the worst-case post-baseline abnormality L, N or H is determined as follows: 
− 
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 a table: once with 
a worst-case L and once with a worst-case H. 
Treatment-Emergent Abnormalities 
For QT and QTcF, an abnormal post-baseline category for actual values is defined as treatment-
emergent when the abnormality is worse compared to the abnormality at baseline. When the 
baseline value is missing, post-baseline abnormalities are considered as treatment-emergent. An 
abnormal category for change from baseline is always treatment-emergent. 
For PR and HR, post-baseline abnormalities L or H are defined as treatment-emergent when they 
differ from the abnormality class of the baseline result. When the baseline result is missing, post-
baseline abnormalities L or H are considered as treatment-emergent. 
5.3.3.4. 
Presentation of Results 
No formal inferential statistics (p-values) will be derived. 
Continuous parameters will be summarized by means of descriptive statistics (including 95% CI 
of the mean change) by parameter, treatment group, and analysis window. Actual values and 
changes from baseline will be tabulated separately.  
Boxplots of the actual values over time and of the mean (+- SE) change from baseline will be 
prepared for all parameters. 


-51- 
 
The analysis of abnormalities will focus on assessments reported during the treatment period. 
Results reported during the screening or follow-up 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 (QT, QTcF, PR and HR) 
and treatment group. 
A frequency table of the number (percent) of subjects with treatment-emergent worst-case 
abnormalities (QT, QTcF, PR and HR) and the worst change (QT and QTcF) per parameter and 
treatment group will be presented. 
A frequency table per treatment group and time point of the ECG interpretation findings as 
transferred from the central reader may be provided. 
A listing per treatment group, per subject, and per time point of all post-baseline time points 
scored as out-of-normal-range, plus also the baseline reference time point will be provided. 
5.3.4. 
Vital Signs 
5.3.4.1. 
Available Data 
The following vital signs parameters will be analyzed: heart rate, respiratory rate, diastolic and 
systolic blood pressure, oral or tympanic body temperature. If blood pressure is collected 
standing and supine, then results are presented by assessment position. 
5.3.4.2. 
Abnormalities 
Vital signs data will be evaluated for abnormalities based on the normal ranges as defined in 
Appendix 4 of the CSP. 
Values equal to the boundaries are still considered normal (N). A value is classified as 
abnormally low (L) when the value < lower limit of the normal range. A value is classified as 
abnormally high (H) when the value > upper limit of the normal range. 
5.3.4.3. 
Treatment-Emergent Principle 
A post-baseline abnormality class L or H is defined as treatment-emergent when it differs from 
the abnormality class at baseline. If the baseline result is missing, a post-baseline abnormality 
L or H will be considered as treatment-emergent. 
5.3.4.4. 
Worst-Case Abnormality 
The following worst-case post-baseline abnormalities L, N, or H will be determined per subject, 
per parameter, and for each analysis period, using all non-missing post-baseline records 
(including unscheduled and follow-up visits): 
− 
L = low: at least one post-baseline result is classified as L. 
− 
N = normal: all post-baseline results are classified as N. 


-52- 
 
− 
H = high: at least one post-baseline result is classified as H. 
If, for a subject, both L and H are reported, the subject will be counted twice in the table: once 
with a worst-case L and once with a worst-case H. 
5.3.4.5. 
Presentation of Results 
No formal inferential statistics (p-values) will be derived. 
Continuous parameters will be summarized by means of descriptive statistics (including 95% CI 
of the mean change) by parameter (and position if applicable), treatment group, and analysis 
window. Actual values and changes from baseline will be tabulated separately.  
Boxplots of the actual values over time and of the mean (+- SE) change from baseline will be 
prepared for all parameters. 
The analysis of abnormalities will focus on assessments reported during the treatment period. 
Results reported during the screening or follow-up 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) and treatment group. 
A frequency table of the number (percent) of subjects with treatment-emergent worst-case 
abnormalities per parameter and treatment group will be presented. 
A listing per treatment group, per subject, and per time point of all post-baseline time points 
scored as treatment-emergent and out-of-normal-range, plus also the baseline reference time 
point will be provided. 
The vital signs measurements collected at the start and finish of the 6MWT will be listed 
separately. 
5.3.5. 
Physical Examinations 
A listing per treatment group, per subject, and per time point of the selection of all abnormal 
findings will be provided. 
5.4. 
Pharmacokinetic Assessments 
Blood samples for the PK assessment of GLPG1205, pirfenidone and nintedanib should be 
collected as specified in the Schedule of Activities in section 2.5. 
PK concentrations of GLPG1205, pirfenidone, and nintedanib will be described graphically. In 
addition, listings of all individual plasma concentration data will be created. 
 




-54- 
 
− 
Laboratory results for which the fasting status is missing will be considered as taken non-
fasted. 
− 
Analysis results scoring below the lowest grade limits (< grade 1) are defined as grade 0. 
Table 8 
Laboratory Toxicity Grades based on CTCAE v5.0 






-57- 
 
Calcium increased 
>ULN - 11.5 
mg/dl 
>ULN - 2.9  
mmol/L 
G1 
>11.5 - 12.5 
mg/dl 
>2.9 - 3.1  
mmol/L 
G2 
>12.5 - 13.5 
mg/dl 
>3.1 - 3.4  
mmol/L 
G3 
>13.5 
mg/dl 
>3.4  
mmol/L 
G4 
AST (asparatate 
aminotransferase) 
>ULN - 3 x ULN 
>ULN - 3 x ULN 
G1 
>3 - 5 x ULN 
>3 - 5 x ULN 
G2 
>5 - 20 x ULN 
>5 - 20 x ULN 
G3 
>20 x ULN 
>20 x ULN 
G4 
ALT (alanine 
aminotransferase) 
>ULN - 3 x ULN 
>ULN - 3 x ULN 
G1 
 
>3 - 5 x ULN 
>3 - 5 x ULN 
G2 
>5 - 20 x ULN 
>5 - 20 x ULN 
G3 
>20 x ULN 
>20 x ULN 
G4 
GGT (gama-glutamyl 
transferase) 
>ULN - 2.5 x ULN 
>ULN - 2.5 x ULN 
G1 
>2.5 - 5 x ULN 
>2.5 - 5 x ULN 
G2 
>5 - 20 x ULN 
>5 - 20 x ULN 
G3 
>20 x ULN 
>20 x ULN 
G4 
Total bilirubin  
>ULN - 1.5 x ULN 
>ULN - 1.5 x ULN 
G1 
>1.5 - 3 x ULN 
>1.5 - 3 x ULN 
G2 
>3 - 10 x ULN 
>3 - 10 x ULN 
G3 
>10 x ULN 
>10 x ULN 
G4 
Alkaline phosphatase (aP) 
>ULN - 2.5 x ULN 
>ULN - 2.5 x ULN 
G1 
 
>2.5 - 5 x ULN 
>2.5 - 5 x ULN 
G2 
>5 - 20 x ULN 
>5 - 20 x ULN 
G3 
>20 x ULN 
>20 x ULN 
G4 
Albumin 
<LLN - 3 
g/dL 
<LLN - 30  
g/L 
G1 
<3 - 2 
g/dL 
<30 - 20  
g/L 
G2 
<2 
g/dL 
<20  
g/L 
G3 
Triglycerides (fasting) 
>ULN - 500 
mg/dL 
>ULN - 5.7  
mmol/L 
G1 
>500 - 1000 
mg/dL 
>5.7 - 11.4  
mmol/L 
G3 
>1000 
mg/dL 
>11.4  
mmol/L 
G4 
Cholesterol 
>ULN - 400 
mg/dL 
>ULN - 10.34  
mmol/L 
G1 
 
>400 - 500 
mg/dL 
>10.34 - 12.92  
mmol/L 
G3 
 
>500 
mg/dL 
>12.92  
mmol/L 
G4 
Creatine kinase (CK)  
>ULN - 2.5 x ULN 
>ULN - 2.5 x ULN 
G1 


-5 8 - 
 
 
> 2. 5 - 5 x U L N  
> 2. 5 - 5 x U L N  
G 2  
 
> 5 - 1 0 x U L N  
> 5 - 1 0 x U L N  
G 3  
 
> 1 0 x U L N  
> 1 0 x U L N  
G 4  
G = gra de; L L N =l o wer li mit of n or mal; U L N = u p per li mit of n or mal; N A = n ot a p plica ble  
 
A P P E N DI X II: A D DI TI O N A L D E T AI L S O N MI X E D M O D E L  P RI M A R Y 
A N A L Y SI S  
Li ne ar Mi xe d M o del  
As a se nsiti vit y a nal ysis f or t he pri mar y a n al ysis, t he rate of decli ne i n F V C o ver 6 m o nt hs  will 
be a nal yz e d usi n g a ra n d o m c oeffici e nt re gressi o n m o del i ncl u di n g se x , a n d strat u m as 
cate g orical fi x e d effects a n d a ge , a n d hei g ht as c o nti n u o us fi x e d effects a n d a ra n d o m i nterce pt 
a n d sl o pe. T he treat me nt effect will be deter mi ne d b y usi n g esti mate d sl o pes f or eac h st u d y gr o u p 
o n t he basis of t he ti me -b y -tr eat me nt i nteracti o n ter m fr o m t he mi x e d m o del. O nl y p ost -bas eli ne 
F V C val ues at pla n n e d ti me p oi nts , as s pecifie d i n Secti o n 2. 5  a n d 3. 3. 3 , will be use d. T he m o del 
will be fit usi n g t he S A S Pr oc Mi x e d pr oce d ure, d etails are b el o w. T he ass u m pti o ns of t he m o del 
will be i n vesti gate d  gra p hicall y .  
T he statistical m o del ca n be writte n as f oll o ws:  
𝑌
 =  (𝛼  +  𝑎) +  (𝜃 + (𝛽𝜃) ∗𝑇𝑟𝑡 +  𝑔) ∗𝑡
 +  𝛽
∗𝑆𝑒𝑥 +  𝛽
∗𝐴𝑔𝑒 +  𝛽
∗𝐻𝑒𝑖𝑔ℎ𝑡 +  𝛽
∗(𝑆𝑡𝑎𝑛𝑑𝑎𝑟𝑑 𝑜𝑓 𝑐𝑎𝑟𝑒)  +  𝜀 
W here  
•  𝑌 is t he F V C val ue f or s u bject i at ti me 𝑡,  
•  𝛼 a n d 𝜃 are t h e fi x e d effects f or t he i nterce pt a n d sl o pe, res pecti vel y , 
•  𝑎 a n d 𝑔 are ra n d o m effects f or t he i nterce pt a n d sl o pe f or s u bject i , wit h 𝒃𝒊 =  (𝑎𝒊,𝑔) 
ass u me d t o be i n de pe n d e nt a n d i de nticall y n or mall y distri b ute d wit h mea n 0 a n d 
u nstr uct ure d varia nce -c o varia nce matri x f or all i , 
•  (𝛽𝜃) is t he effect of G L P G 1 2 0 5 o n t he sl o pe, 
•  𝛽, 𝛽, 𝛽
 a n d 𝛽
 are s u bject s pecific de m o gra p hic c oefficie nts f or se x, a ge, 
stratificati o n fact or (S O C ; 2 le vels) a n d hei g ht at b aseli ne, 
•  𝑇𝑟𝑡= 0  f or place b o a n d 𝑇𝑟𝑡= 1  f or G L P G 1 2 0 5, (𝑆𝑡𝑎𝑛𝑑𝑎𝑟𝑑 𝑜𝑓 𝑐𝑎𝑟𝑒) = 0  f or neit her 
a n d (𝑆𝑡𝑎𝑛𝑑𝑎𝑟𝑑 𝑜𝑓 𝑐𝑎𝑟𝑒) = 1  f or pirfe ni d o ne or ni nte da ni b, 
•  𝜀 is t he ra n d o m err or f or s u bject i at ti me 𝑡, ass u me d t o be i n de pe n de nt a n d i d e nticall y 
n or mall y distri b ute d wit h mea n 0 a n d varia nce 𝜎 f or all i,j. 


-5 9 - 
 
If t his m o del fails t o c o n ver ge, ot her str uct ures will be teste d f or t he varia n ce-c o v aria n ce matri x 
f or t he err or ter ms (e. g. h eter o ge n e o us T oe plitz). De pe n di n g on t he str uct ure use d, t he ra n d o m 
sl o pe a n d ra n d o m i nterce pt ma y nee d t o be dr o p p e d fr o m t he m o del. T he str uct ure wit h t he best 
fit, base d o n A kai ke’s i nf or mati o n criteri o n, will t he n be use d. 
T he li nearit y ass u m pti o n of t he m o del will be e x pl ore d gra p hi cal l y by  t he li ne pl ots o ver ti me of 
t he o bser ve d F V C val ues ( m L) as well as c ha n ge fr o m baseli ne a n d L S mea ns at eac h ti me p oi nt. 
T he f oll o wi n g S A S c o d e is t o be use d:  
pr oc S O R T data = F V C;  
  B Y  s u bject visit;  
r u n; 
p r oc MI X E D d ata = F V C or der = i nter nal; 
  C L A S S s u bject treat me nt visit se x strat u m; 
  M O D E L F V C =  treat m e nt * ti me se x a ge hei g h t strat u m / s ol uti o n C L d df m = K R; 
  R A N D O M i nterce pt t i me / t y pe = U N s u bject = s u bject; 
  R E P E A T E D visit / t y pe =  Si m ple s u bject = s u bject; 
  E S TI M A T E ‘G L P G 1 2 0 5 –  Place b o’  treat me nt *ti me -1  1 / e C L; 
ru n ; 
Re pe ate d Me as ures A n al ysis  
As a se nsiti vit y a nal ysis f or t he pri mar y a n al ysis, t he c ha n ge fr o m bas eli ne i n F V C o ver 2 6 
wee ks will als o be c o m p are d bet w ee n tr eat me nt gr o u ps b y M M R M  i ncl u di n g se x, strat u m, a n d a 
treat me nt-b y -ti me p oi nt i nteracti o n as cate g ori cal fi x e d effects, a ge, hei g ht , a n d baseli ne F V C  as 
c o nti n u o us fi x e d effects a n d c orrelate d wit hi n -s u bject resi d uals. O nl y  p ost -baseli ne F V C val ues  
at pla n ne d ti me p oi nts , as s pecifie d i n Secti o n 2. 5  a n d 3. 3. 3 , will be use d. T he m o del will be fit 
usi n g t he S A S Pr oc Mi x e d pr oce d ure, details are b el o w.  
T he statistical m o del ca n be writte n as f oll o ws:  
𝑌
 =  𝛼  +  (𝑎 +  (𝜃𝛽) ∗𝜃𝑇𝑟)  +  𝑡
∗𝑔𝑡𝛽 +  𝑆
∗𝑒𝑥𝛽 +  𝐴
∗𝑔𝑒𝛽𝐻ℎ𝑒 +  𝑖
∗(𝑔𝑡𝛽𝑆𝑡𝑎𝑛𝑑 𝑎𝑟 𝑑𝑜𝑓𝑐)  +  𝑎
∗𝑟𝑒𝜀𝑌𝑡𝛼𝜃𝑎 +  𝑔 
W here  
•  𝒃 is t he F VC c ha n ge fr o m baseli ne f or s u bject i at ti me p oi nt j (e x cl u di n g bas eli ne),  
•  𝒊 is t he i nterce pt a n d 𝑎 is t he place b o  ti me effect at ti me p oi nt j, 
•  (𝒊𝑔)  is t he effect of G L P G 1 2 0 5 at ti me p oi nt j, 
•  𝛽, 𝜃, 𝛽
 a n d 𝛽
 are s u bject s pecific de m o gra p hic c oefficie nts f or se x, a ge, 
stratificati o n fact or (S O C ; 2 le vels) a n d hei g ht at b aseli ne,