Conditions: Idiopathic Pulmonary Fibrosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 781
Healthy volunteers: no

Brief summary:
The main purpose of this study was to see how GLPG1690 works together with the current standard treatment on your lung function and IPF disease in general. The study also investigated how well GLPG1690 is tolerated (for example if you get any side effects while on study drug).

Detailed description:

Arms:
arm 1: Participants received GLPG1690 (ziritaxestat) 600 mg as film-coated tablet orally, once daily (mean treatment duration was 332.9 days). Standard of care included either pirfenidone or nintedanib at a stable dose for at least 2 months before screening, and during screening; or neither pirfenidone or nintedanib (for any reason). arm 2: Participants received GLPG1690 (ziritaxestat) 200 mg as film-coated tablet orally, once daily (mean treatment duration was 336.9 days). Standard of care included either pirfenidone or nintedanib at a stable dose for at least 2 months before screening, and during screening; or neither pirfenidone or nintedanib (for any reason). arm 3: Participants received GLPG1690 (ziritaxestat) matching placebo tablets orally, once daily (mean treatment duration was 346.2 days). Standard of care included either pirfenidone or nintedanib at a stable dose for at least 2 months before screening, and during screening; or neither pirfenidone or nintedanib (for any reason).

Interventions: intervention 1: GLPG1690 intervention 2: Placebo
Intervention descriptions: intervention 1: GLPG1690, film-coated tablets for oral use. intervention 2: Matching placebo, film-coated tablets for oral use.

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: 
GLPG1690 
 
Study Number: 
GLPG1690-CL-304 
Study Title: 
A Phase 3, randomized, double-blind, parallel-group, placebo-
controlled multicenter study to evaluate the efficacy and safety of 
two doses of GLPG1690 in addition to local standard of care for 
minimum 52 weeks in subjects with idiopathic pulmonary 
fibrosis.  
Development Phase: 
3 
Status: 
Final 
CSP Version: 
7.00 
Date: 
8-Jun-2020 
Amendment 5 
EudraCT No.: 
2018-001406-29 
CT.gov No.: 
NCT03733444 
IND No.: 
130687 
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 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:  
 SAE 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. 
Please refer to the study contact list in the investigator site file for the CRO medical contact 
details.  
 
 
 
Sponsor Contact number: 
  


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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.................................................................................................... 8 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................. 24 
1. 
SUMMARY ................................................................................................................... 29 
2. 
INTRODUCTION .......................................................................................................... 33 
2.1. 
Background - Nonclinical Studies ...................................................................... 34 
2.1.1. 
Physical, Chemical, Pharmaceutical Properties, and 
Formulations ...................................................................................... 34 
2.1.2. 
Pharmacology .................................................................................... 34 
2.1.2.1. 
Primary and Secondary Pharmacology ............................. 34 
2.1.2.2. 
Safety Pharmacology ........................................................ 35 
2.1.3. 
Nonclinical Pharmacokinetics and Product Metabolism ..................... 35 
2.1.4. 
Toxicology.......................................................................................... 36 
2.1.4.1. 
General Toxicology ........................................................... 36 
2.2. 
Background - Clinical Studies ........................................................................... 38 
2.2.1. 
Clinical Safety .................................................................................... 38 
2.2.2. 
Clinical Pharmacokinetics .................................................................. 39 
2.2.3. 
Clinical Pharmacodynamics ............................................................... 40 
3. 
CLINICAL STUDY OBJECTIVES ................................................................................. 41 
3.1. 
Primary Objective .............................................................................................. 41 
3.2. 
Secondary Objectives ....................................................................................... 41 
3.2.1. 
Key Secondary Objectives ................................................................. 41 
3.2.2. 
Other Secondary Objectives .............................................................. 41 
3.3. 
 ............................................................................................... 42 
4. 
INVESTIGATIONAL PLAN ........................................................................................... 42 
4.1. 
Clinical Study Design ........................................................................................ 42 
4.1.1. 
Definition of End of Trial ..................................................................... 44 
4.1.2. 
Guidance for dose modification in case of adverse events ................. 44 
4.2. 
Clinical Study Rationale .................................................................................... 47 
4.2.1. 
Dose Rationale .................................................................................. 48 
4.2.2. 
Clinical Study Design Rationale ......................................................... 48 
4.3. 
Endpoints .......................................................................................................... 49 
4.3.1. 
Primary Endpoint ............................................................................... 50 
4.3.2. 
Secondary Endpoints ......................................................................... 50 
4.3.2.1. 
Key Secondary Endpoints ................................................. 50 
4.3.2.2. 
Other Secondary Endpoints .............................................. 50 
4.3.3. 
 ................................................................................. 51 
4.4. 
Potential Risks and Benefits ............................................................................. 51 
4.5. 
Clinical Study Population .................................................................................. 54 




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7. 
STATISTICAL METHODS ............................................................................................ 98 
7.1. 
Determination of Sample Size ........................................................................... 98 
7.2. 
Populations for Analyses ................................................................................... 99 
7.2.1. 
All Screened Subjects ........................................................................ 99 
7.2.2. 
All Randomized Subjects ................................................................... 99 
7.2.3. 
Full Analysis Set ................................................................................ 99 
7.2.4. 
Per-Protocol Set ................................................................................ 99 
7.2.5. 
Pharmacokinetic Analysis Set ............................................................ 99 
7.2.6. 
 ...............................................................100 
7.3. 
Statistical Analyses ..........................................................................................100 
7.3.1. 
General Statistical Considerations ....................................................100 
7.3.2. 
Interim Analysis ................................................................................100 
7.3.3. 
Analyses of Demographics and Baseline Characteristics ..................100 
7.3.4. 
Analyses of Efficacy Parameters .......................................................100 
7.3.5. 
Analyses of Safety Data ....................................................................103 
7.3.5.1. 
Extent of Exposure ..........................................................104 
7.3.5.2. 
Adverse Events ...............................................................104 
7.3.5.3. 
Clinical Laboratory Evaluations ........................................104 
7.3.5.4. 
Physical Examinations .....................................................104 
7.3.5.5. 
Vital Signs .......................................................................104 
7.3.5.6. 
Electrocardiogram............................................................104 
7.3.6. 
Pharmacokinetics and 
 .......................................105 
7.3.7. 
 ........................................................................105 
8. 
DATA MONITORING ...................................................................................................105 
8.1. 
Independent Data Monitoring Committee .........................................................105 
8.2. 
Clinical Endpoint Adjudication Committee ........................................................106 
8.3. 
Additional Optional Independent Review of Safety Data ..................................106 
9. 
SAFETY REPORTING ................................................................................................106 
9.1. 
Definitions of Adverse Events, Serious Adverse Events, and Special 
Situations .........................................................................................................106 
9.1.1. 
Adverse Events .................................................................................106 
9.1.2. 
Serious Adverse Events ....................................................................106 
9.1.3. 
Unlisted (Unexpected) Adverse Event/Reference Safety 
Information ........................................................................................107 
9.1.4. 
Adverse Events of Special Interest ...................................................107 
9.1.5. 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as Adverse Events or Serious Adverse Events ...........107 
9.1.6. 
Special Situations .............................................................................107 
9.2. 
Assessment of Adverse Events and Serious Adverse Events ..........................108 
9.2.1. 
Assessment of Causality ...................................................................108 
9.2.2. 
Assessment of Severity.....................................................................109 
9.2.3. 
Outcome ...........................................................................................109 
9.3. 
Investigator Requirements and Instructions for Reporting Adverse 
Events / Serious Adverse Events /Pregnancies and Other Special 
Situations to the Sponsor .................................................................................110 
9.3.1. 
Adverse Events .................................................................................110 
9.3.2. 
Serious Adverse Events ....................................................................110 
9.3.3. 
Pregnancy.........................................................................................111 
9.3.4. 
Reporting of Special Situations (Other Than Pregnancy) and 
Associated Adverse Events ..............................................................111 
9.4. 
Sponsor Reporting Requirements ....................................................................111 


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10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES .......................................112 
10.1. 
Sponsor’s Responsibilities ...............................................................................112 
10.1.1. 
Regulatory Approval / Notification .....................................................112 
10.1.2. 
Clinical Study Closure Considerations ..............................................112 
10.1.3. 
Indemnification ..................................................................................113 
10.1.4. 
Insurance ..........................................................................................113 
10.1.5. 
Reporting ..........................................................................................113 
10.1.6. 
Publication ........................................................................................113 
10.2. 
Investigator’s Responsibilities ..........................................................................114 
10.2.1. 
Financial Disclosure ..........................................................................114 
10.2.2. 
Source Data and Data Capture .........................................................114 
10.2.3. 
Archiving ...........................................................................................114 
10.2.4. 
Participation Cards ............................................................................115 
10.3. 
Confidentiality ..................................................................................................115 
10.4. 
Ethical Considerations .....................................................................................115 
10.4.1. 
Independent Ethics Committee / Institutional Review Board .............115 
10.4.2. 
Informed Consent .............................................................................116 
10.5. 
Data Quality Control / Assurance .....................................................................117 
10.5.1. 
Monitoring .........................................................................................117 
10.5.2. 
Audit and Inspection .........................................................................117 
REFERENCES ...................................................................................................................118 
APPENDICES ....................................................................................................................121 
SIGNATURE PAGE – SPONSOR ......................................................................................134 
SIGNATURE PAGE – INVESTIGATOR .............................................................................135 
 
 




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SUMMARY OF CHANGES 
Amendment 5 (General) 
The overall reason for this amendment: is to implement the urgent safety measures (USMs) for 
protection of study subjects during the Coronavirus disease (COVID-19) pandemic. These were 
detailed in the USM letter dated 07 May 2020 and sent to investigators, Competent Authorities, 
Ethics Committees, and Institutional Review Boards. 
The USMs are introduced due to the exceptional situation generated by the COVID-19 pandemic. 
The objective of these USMs is to limit the risk of exposure to COVID-19 infection to ensure the 
safety and well-being of study subjects. 
The USMs are: 
− 
phone visits or televisits as alternative to on-site visits; 
− 
collection of study assessments at the subject's home or other remote location (if possible and 
available); 
− 
extension of visit windows; 
− 
additional guidance for on-site visits; 
− 
direct-to-patient (DTP) shipment of investigational medicinal product (IMP) and other supplies 
to the subject’s home; 
− 
additional guidance on the decision for continuation of IMP after missed visits. 
In addition:  
− Exclusion criterion 15 has been amended to include all lower respiratory tract infections 
requiring treatment, rather than those requiring antibiotic treatment. 
− Clarification has been added that the investigator will be responsible for managing COVID-19 
infected subjects. 
− Exclusion criterion 5 was modified to clarify that subjects are permitted to take stable doses of 
immunosuppressive medication for reasons other than treatment of idiopathic pulmonary fibrosis 
(IPF). 
− The possibility was added to perform source data review remotely when access to hospitals is 
restricted. 
− The international nonproprietary name, ziritaxestat, was added. 
The changes made to the clinical study protocol (CSP) GLPG1690-CL-304 Version 6.00 (17-Dec-
2019) are listed below, with a brief rationale of each change and the applicable sections. 
If a randomized subject is not able to attend a scheduled study visit on site for any COVID-19 
related reason, then the investigator should perform a phone call or use a virtual platform such as 
Skype, Facetime, etc., to evaluate safety and assess well-being of the study subject.  
Subject visits at home or at a remote location (other than the investigational site) can be considered 
at the investigator’s discretion. 
Applicable Sections: 
Section 4.1 Clinical Study Design 
Section 6 Clinical Study Assessments 
Section 6.1.1 Alternative Timing and Assessment Procedures for Subjects who, due to any 
Covid-19-related Reason, Cannot Perform the Study Procedures  
Section 6.11.1 Schedule of Activities: Screening and First 52 Weeks of Study Treatment 
Section 6.11.2 Schedule of Activities: After 52 Weeks of Study Treatment 


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Amendment 5 (General) 
To allow for the flexibility of obtaining safety and efficacy data when subjects are unable or 
unwilling to complete the study procedures due to any COVID-19-related issue, the visit windows 
for Visits 5, 6, 7, 8, 10, and 11 may be increased to ±7 days and the visit windows for Visit 9 and 
Visit 12 may be increased to ±28 days.  
Applicable Sections: 
Section 4.1 Clinical Study Design 
Section 6 Clinical Study Assessments 
Section 6.1.1 Alternative Timing and Assessment Procedures for Subjects who, due to any 
Covid-19-related Reason, Cannot Perform the Study Procedures  
Section 6.11.1 Schedule of Activities: Screening and First 52 Weeks of Study Treatment 
At all times, the intent should be to ensure that study subjects can continue to take IMP without 
interruptions, if safe and deemed appropriate by the investigator. Guidance on when IMP should be 
interrupted and on re-start is provided. 
Applicable Section: 
Section 6.1.1 Alternative Timing and Assessment Procedures for Subjects who, due to any 
Covid-19-related Reason, Cannot Perform the Study Procedures 
Information on the assessments/activities that should be performed (if possible) is provided for the 
on-site visits, for the home (or remote other location) visits, and for the phone/televisits. 
Applicable Sections: 
Section 4.1 Clinical Study Design 
Section 6 Clinical Study Assessments 
Section 6.1.1 Alternative Timing and Assessment Procedures for Subjects who, due to any 
Covid-19-related Reason, Cannot Perform the Study Procedures 
Section 6.4 Subject Diary Card 
Section 6.5.1.1 Spirometry 
Section 6.5.1.2 DLCO 
Section 6.5.1.3 
 
Section 6.5.3 Quality of Life 
Section 6.5.4 Functional Exercise Capacity Testing: 6MWT 
Section 6.6. Safety Assessments 
Section 6.6.5 Electrocardiogram 
Section 6.7 Pharmacokinetic Assessments 
Section 6.8 
 
Section 6.9.1. 
 
Section 6.11.1 Schedule of Activities: Screening and First 52 Weeks of Study Treatment 
Section 6.11.2 Schedule of Activities: After 52 Weeks of Study Treatment 


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Amendment 5 (General) 
Exclusion criterion 15 has been amended to exclude all lower respiratory tract infections requiring 
treatment (rather than those requiring antibiotic treatment) within 4 weeks prior to screening and/or 
during the screening period. This is to exclude subjects with suspected or confirmed COVID-19 
lower respiratory tract infections.  
A clarification has been added that the investigator will be responsible for managing COVID-19 
infected subjects, and that the decision to continue or interrupt IMP for subjects with confirmed or 
suspected cases of COVID-19 infection is at the investigator’s discretion.  
Guidance for reporting of suspected and confirmed COVID-19 cases in randomized subjects has 
been added. 
Applicable Sections: 
Section 4.1.2 Guidance for Dose Modification in Case of Adverse Events 
Section 4.4 Potential Risks and Benefits 
Section 4.5.2 Exclusion Criteria 
Exclusion criterion 5 was modified to clarify that subjects are permitted to take stable doses of 
immunosuppressive medication for reasons other than treatment of idiopathic pulmonary fibrosis 
(IPF). 
The rationale is to ensure that subjects who are on immunosuppressives due to conditions other than 
IPF (such as post solid organ transplants and inflammatory bowel disease) are not excluded from 
the study. 
Applicable Section: 
Section 4.5.2 Exclusion Criteria 
If a randomized subject is not able to attend a scheduled study visit on site for any COVID-19 
related reason, IMP and other supplies can be shipped via DTP shipment to the study subject when 
required due to the COVID-19 situation as per ICH-GCP principles.  
Applicable Sections: 
Section 5.3 Packaging, Labelling, and Distribution 
Section 6.1.1 Alternative Timing and Assessment Procedures for Subjects who, due to any Covid 
19-related Reason, Cannot Perform the Study Procedures 
Section 6.4 Subject Diary Card 
The possibility was added to perform source data verification remotely.  
Applicable Section: 
Section 10.5.1 Monitoring 
The international nonproprietary name, ziritaxestat, has been added. 
Applicable Section: 
Section 2.1.1 Physical, Chemical, Pharmaceutical Properties, and Formulations 
 
 


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Amendment 4 (General) 
The overall reason for this amendment: is an update of the exclusion criteria, and addition of the 
possibility to receive investigational medicinal product (IMP) in an extension study. 
The changes made to the clinical study protocol (CSP) GLPG1690-CL-303 Version 5.00 (12 Nov 
2019), are listed below, with a brief rationale of each change and the applicable sections. 
The information on GLPG1690 has been updated according to Edition 6 of the Investigator’s 
Brochure (28-Jun-2019). 
Applicable Sections: 
Section 2 Introduction 
The possibility of IMP being offered to eligible subjects in an extension study has been added. 
Applicable Section: 
Section 4.1 Clinical Study Design 
Additional clarification is given with relation to study visits for subjects who permanently 
discontinue IMP but remain in the study. Subjects will still be encouraged to complete all following 
visits and evaluations as originally planned per protocol. If not possible to complete all visits, 
preference should be given to complete: 
• 
the first scheduled visit after their Early Treatment Discontinuation (ETD) 
• 
the Week 26 visit (if not done before IMP discontinuation) 
• 
the Week 52 visit (if not done before IMP discontinuation) 
• 
after Week 52, visits every 24 weeks up to End of Study Assessments (EoSA), as described 
in Section 6.11.2 
Applicable Sections: 
Section 4.1 Clinical study design 
Section 4.5.4 Treatment Discontinuation, Subject Withdrawal, and Study Termination 
For subjects still taking IMP and who had their last scheduled visit more than 6 weeks before the 
date that the last subject reaches 52 weeks into the study (Visit 12), the timing of the End of Study 
Treatment (EoST) visit has been reduced from 4 weeks to 2 weeks after the last subject reached 52 
weeks. 
Applicable sections: 
Section 4.1 Clinical Study Design 
Section 6.1 Timing of assessments 




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Amendment 4 (General) 
The description of the high-resolution computed tomography (HRCT) evaluation process for 
assessing eligibility has been removed from Section 4.1 and Section 6.1, and is now described and 
clarified in Appendix 1. 
Applicable sections: 
Section 4.1 Clinical study design 
Section 4.2.2 Clinical study design rationale 
Section 6.1 Timing of assessments 
Appendix 1 HRCT/biopsy central review criteria 
Events meeting the following defined criteria must be reported as a serious adverse event (SAE) and IMP 
must be discontinued: 
• 
AST or ALT ≥8xULN 
• 
AST or ALT ≥3xULN with signs of severe liver damage (i.e. with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash and/or eosinophilia [>5%], and/or total 
bilirubin ≥1.5xULN or International Normalized Ratio [INR] >1.5)  
The investigations and steps to be taken by the investigator have been described in Section 4.5.4. 
In addition, an optional review of safety data associated with liver function tests has been added. 
Applicable Sections: 
Section 4.5.4 Treatment Discontinuation, Subject Withdrawal, and Study Termination 
Section 8.3 Additional optional independent review of safety data 
Section 9.1.5. Clinical laboratory abnormalities and other abnormal assessments as adverse events or serious 
adverse events 
Appendix 9 Algorithm for elevated liver function tests 
 
The collection of history of progression of disease, as defined by a relative decline in the forced 
vital capacity (FVC) of at least 10% of the predicted value, during the 1 year prior to screening has 
been included. 
Applicable Section: 
Section 6.3 Initial Subject and disease characteristics 
Suboxone was removed from the list of known strong Cytochrome P450 (CYP) CYP3A4 inhibitors 
because its constituents, naloxone and bupenophine are not known to be strong inhibitors. 
Azelastine was removed from the list of known potent P-glycoprotein (P-gp) inhibitors in Appendix 
6 because it is primarily used as a nasal spray to treat allergic rhinitis and as eye drops for allergic 
conjunctivitis, therefore the risk of drug-drug interaction is negligible. 
Applicable Section: 
Appendix 5 Known strong CYP3A4 inhibitors 
Appendix 6 Known potent P-gp inhibitors 


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Amendment 4 (General) 
It was clarified that decisions on eligibility for rescreening, permitted comedications, and 
discontinuation of treatment in case of worsening of IPF can be taken on a case-by-case basis by the 
investigator and in case of doubt can be discussed with the CRO medical monitor (as per study 
contact list) or sponsor’s study physician (if the former is not available). 
Applicable Sections: 
Section 4.5.3.2 Prior and concomitant medications 
Section 6.3 Initial subject and disease characteristics 
The timing when vital status should be collected for subjects who withdraw from the study has been 
clarified. 
Applicable Sections: 
Section 4.5.4 Treatment discontinuation, subject withdrawal, and study termination 
Section 6.11 Schedule of  Activities 
A table has been added to clarify the PK sampling times. 
Applicable Section: 
Section 6.7 Pharmacokinetic Assessments 
Typographical corrections were made to Appendices 3 and 4. 
Further clarifications and corrections have been made throughout the protocol. 
 
 
 
Amendment 3 (General) 
The overall reason for this amendment: is to add new data from the GLPG1690-CL-113 drug-
drug interaction study on interaction of GLPG1690 with nintedanib, and to change the IMP intake 
time for all subjects taking nintedanib to approximately 4 hours after the morning nintedanib dose.  
The changes made to the CSP GLPG1690-CL-304 Version 4.00 (11 Feb 2019), are listed below, 
with a brief rationale of each change and the applicable sections. 
Subjects taking nintedanib are recommended to take the daily dose of IMP at or after lunch, i.e. 
approximately 4 hours after the morning dose of nintedanib.  
All subjects taking nintedanib will be asked to indicate via a tick box on the diary card for each 
record of IMP whether the IMP administration was approximately 4 hours after the nintedanib 
morning dose.   
Applicable Sections: 
Section 4.4 Potential Risks and Benefits 
Section 5.2 Dosage and Administration 
Section 6.4 Subject Diary Card 




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Amendment 2 (General) 
 
 
Applicable Sections: 
Section 1 Summary 
Section 7.3.4 Analyses of efficacy parameters 
The following clarifications and corrections have been made: 
− 
The liver function test (LFT) threshold at Visit 3 that would lead to IMP discontinuation for 
aspartate aminotransferase [AST] and alanine aminotransferase [ALT] has been corrected in 
Section 4.1.2 from ≥1.5 x  to <3 x upper limit of normal (ULN) to ≥1.5x ULN, and is now in 
line with exclusion criterion 22 and Section 4.6.4. 
− 
Figure 2 depicting the dose modification strategy has been updated for clarification. 
− 
The statement that IMP should not be administered to subjects with moderate to severe renal 
impairment has been corrected to only include severe renal impairment, in line with exclusion 
criterion 23.  
Applicable Sections: 
Section 4.1.2 Guidance for dose modification 
Section 4.1.2 Guidance for dose modification in case of adverse events 
Section 4.4 Potential risks and benefits – special populations 


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Amendment 2 (General) 
Subject Eligibility. The clinical diagnostic requirements have been clarified and corrected. 
− 
Inclusion criterion 4: Diagnosis of IPF should be made using the guideline current at the time 
of diagnosis.  
− 
The reference to the ATS/ERS/JRS/ALAT diagnostic criteria 2011 has been corrected, and 
reference to the latest ATS/ERS/JRS/ALAT diagnostic criteria of 2018 has been added (Raghu 
G, Remy-Jardin M, Myers JL, et al. American Thoracic Society, European Respiratory Society, 
Japanese Respiratory Society, and Latin American Thoracic Society. “Diagnosis of Idiopathic 
Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline.” Am J 
Respir Crit Care Med. 2018 Sep 1;198(5):e44-e68). 
− 
Subjects with typical and probable usual interstitial pneumonia – idiopathic pulmonary fibrosis 
(UIP-IPF) pattern on high-resolution computed tomography (HRCT) will be eligible unless a 
historical lung biopsy, if available, is not in accordance with this diagnosis. Indeterminate UIP-
IPF pattern on HRCT will need confirmation through review of historical lung biopsy, if 
available.  
− 
The interval of 6 weeks before a patient can be rescreened was replaced by an interval 
determined at the investigator’s discretion, taking into account the inclusion and exclusion 
criteria. Rescreening with the purpose to repeat a HRCT scan, is not allowed.  
− 
The instructions for screening assessments have been clarified.  
Applicable Sections: 
Section 4.2.2 Clinical study design rationale 
Section 4.5.1 Inclusion criteria 
Section 6.1 Timing of assessments 
Section 6.3 Initial subject and disease characteristics 
Eligibility Criteria: Stability of Standard of care before enrolment 
Inclusion criterion 6: has been updated to require stability of standard of care treatment prior to 
randomization.  
− 
Subjects receiving local standard of care for the treatment of IPF, defined as either pirfenidone 
or nintedanib at a stable dose for at least 2 months before start of screening, and during 
screening; or neither pirfenidone or nintedanib (for any reason). A stable dose is defined as the 
highest dose tolerated by the subject during those two months. 
Applicable Sections: 
Summary 
Section 4.5.1 Inclusion criteria 
4.5.3.2 Prior and concomitant medications 
The oxygen titration test requirements at Visit 2 for the 6-Minute Walk Test have been clarified; the 
oxygen saturation (SpO2) during the walk has been clarified to ≥83% with 6 L O2/minute or ≥88% 
with 0, 2 or 4 L O2/minute (instead of ≥83% with 6 L O2/minute or ≥88% with ≤4 L O2/minute). 
Applicable Sections: 
Section 4.5.1 Inclusion criteria 
Section 6.5.4 6-Minute Walk Test 
Section 6.3 Initial subject and disease characteristics 




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Amendment 2 (General) 
Interactions 
− 
The information on interaction with transporters in nonclinical studies has been updated. 
− 
The clinical safety and clinical pharmacokinetics sections have been updated based on recent 
data from two drug-drug interaction studies, one study with itraconazole and voriconazole, and 
one study with pirfenidone and nintedanib. Increased exposures of nintedanib, one of the 
standard of care treatments for IPF, was observed when coadministered with GLPG1690. 
− 
Additional PK sampling has been introduced to assess nintedanib levels.  
− 
A population PK analysis for nintedanib and pirfenidone has been added in the Statistical 
methods section. 
Applicable Sections: 
Section 2.1.3 Nonclinical pharmacokinetics and product metabolism 
Section 2.2.1 Clinical Safety 
Section 2.2.2 Clinical Pharmacokinetics 
Section 4.4 Potential risks and benefits 
Section 6.1 Timing of assessments 
Section 6.3 Initial subject and disease characteristics  
Section 6.4 Subject diary card 
Section 6.7 Pharmacokinetic assessments 
Section 6.11 Schedule of activities 
Section 7.3.6 Pharmacokinetics 
 
The QTcF thresholds leading to discontinuation have been clarified, and the following has been 
added: 
− 
“If a normal QTcF is reported during the visit, but the central cardiologist reports it as 
abnormal (any of the two criteria above), then the IMP should be discontinued as soon as 
possible”  
Applicable Sections: 
Section 4.5.4 Treatment discontinuation, subject withdrawal, and study termination 
The list of clinical laboratory tests has been revised  
− 
Mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean 
corpuscular hemoglobin concentration (MCHC) have been added to the hematology parameters 
to reflect the standard panel of investigations typically used in the IPF patient population. 
− 
If creatine kinase (CK) is elevated, then CK-muscle/brain (CK-MB) is to be measured, to 
monitor for muscle breakdown indicative of coronary heart disease. 
− 
Amylase and lipase have been added to monitor risk of pancreatitis, a reported risk/ adverse 
drug reaction for nintedanib. 
Applicable Section: 
Section 6.6.2 Clinical laboratory evaluations 


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Amendment 2 (General) 
Statistical analysis 
− 
The description of the statistical analysis of efficacy has been updated, to describe the 
determination of sample size multiple testing approach and multiplicity adjustment.  
− 
The proportion of St. George’s Respiratory Questionnaire (SGRQ) responders and the 
proportion of subjects with hospitalization analysis was changed from Fisher exact test to a 
logistic regression model 
− 
The derivation of the IPF-specific version of St. George’s Respiratory Questionnaire (SGRQ-I) 
(using 34 of the 50 test items) has been removed from the protocol (Yorke J, Jones P, and 
Swigris J. Development and validity testing of an IPF specific version of the St. George's 
Respiratory Questionnaire. Thorax, 2010;65(10):921 926). 
Some SGRQ items in SGRQ-I have weaker measurement properties than others when applied 
to patient populations other than the one for which SGRQ was developed. SGRQ-I has some 
missing components when derived from SGRQ.  
− 
 
Applicable Sections: 
Section 6.5.3 Quality of Life 
Section 7.1 Determination of sample size 
Section 7.3.4  Analyses of efficacy parameters 
The non-exhaustive list of strong CYP3A4 inducers and potent P-gp inducers has been modified. 
Phenobarbital was removed because it is already included within the barbiturate group, and 
glucocorticoids (prednisone or equivalent) at > 10mg/day was specified, because high doses of 
glucocorticoids have been reported to be potential CYP3A4 inducers. 
Instructions for subjects to avoid double-strength grapefruit juice, which is potentially a potent 
CYP3A4 inhibitor have been added. 
Applicable Section  
Section 4.5.3.3 Food and beverage restrictions 
Appendix 4 Known strong CYP3A4 inducers and potent P-gp inducers 
Voriconazole, a strong CYP3A4 inhibitor, has been added to the non-exhaustive list of strong 
CYP3A4 inhibitors in Appendix 5. 
Applicable Section  
Appendix 5 Known strong CYP3A4 inhibitors  
 
 






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Amendment 1  
Rationale for the sample size was added. 
Applicable Section: 
Section 7.1 
Clarification of the planned pooled data analysis of the two identical studies, GLPG1690-CL-303 
and GLPG1690-CL-304 
Applicable Section: 
Section 7.3.4 
The language related to the Declaration of Helsinki was updated to conform with EU Directives 
2001/20/EC and 2005/28/EC 
Applicable Sections: 
Section 10 
The procedure for collection of informed consent of a patient unable to read and/or write was 
amended
 
Applicable Section: 
Section 10.4.2 
 
Update 1 
Minor edits and edits based on ad hoc IB update – General 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations 
%FEV1 
percent predicted forced expiratory volume in 1 second 
%FVC 
percent predicted forced vital capacity 
6MWT 
6-Minute Walk Test 
AE 
adverse event 
ALAT 
Latin American Thoracic Association 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AT1 
angiotensin II receptor type 1  
ATC 
Anatomical Therapeutic Classification 
ATS 
American Thoracic Society 
ATX 
autotaxin  
AUC 
area under the plasma concentration-time curve 
AUC0-∞ 
area under the concentration-time curve from time 0 to infinity 
AUC0-24h 
area under the plasma concentration-time curve from time 0 to 
24 hours 
BLM 
bleomycin 
BCRP 
breast cancer resistance protein 
b.i.d. 
bis in die, twice daily 
BSEP 
bile salt export pump 
BW 
body weight 
CCr 
estimated creatinine clearance, calculated according to 
Cockcroft-Gault calculation 
CEAC 
clinical endpoint adjudication committee 
CK 
creatine kinase 
Cmax 
maximum observed plasma concentration 
COVID-19 
Coronavirus disease 
CRO 
contract research organization 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTFG 
Clinical Trial Facilitation Group 
CTGF 
connective tissue growth factor 
CYP 
cytochrome P450 


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DBP 
diastolic blood pressure 
DDI 
drug-drug interaction 
DLCO 
diffusing capacity of the lung for carbon monoxide 
DTP 
direct-to-patient 
ECG 
electrocardiogram 
Emax 
maximum effect (expressed as a percentage reduction from baseline) 
ENPP1/2 
ectonucleotide pyrophosphatase/phosphodiesterase 1 or 2 
eCOA 
electronic clinical outcome assessment 
EoSA 
end of study assessments 
EoST 
end of study treatment 
EQ-5D 
EuroQOL 5-Dimensions Questionnaire 
EQ-5D-3L 
3-level version of EuroQOL 5-Dimensions Questionnaire 
EQ VAS 
EuroQOL visual analogue scale 
ERS 
European Respiratory Society 
ETD 
early treatment discontinuation 
FAS 
full analysis set 
FC 
food consumption 
 
 
FEF25-75 
forced expiratory flow between 25% and 75% of exhaled volume 
FEV1 
forced expiratory volume in 1 second  
FIH 
first-in-human 
FSH 
follicle-stimulating hormone 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practices 
GLP 
Good Laboratory Practice 
GGT 
gamma glutamyl transferase 
Hb 
hemoglobin  
HIV 
human immunodeficiency virus 
HMA 
Heads of Medicines Agencies 
HRCT 
high-resolution computed tomography 
IB 
Investigator’s Brochure 
IC50 
50% inhibitory concentration (concentration resulting in 50% 
inhibition) 


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IC80 
80% inhibitory concentration (concentration resulting in 80% 
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 
Imax 
predicted maximum concentration in the portal vein 
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 
K-BILD 
King's Brief Interstitial Lung Disease 
LB 
lung biopsy 
LC-MS/MS 
liquid chromatography with tandem mass spectrometry 
LCQ 
Leicester Cough Questionnaire 
LFT 
liver function test 
LPA 
lysophosphatidic acid 
LPC 
lysophosphatidylcholine  
LPD 
lysophospholipase D 
MCID 
Minimal Clinical Important Difference 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL 
no observed adverse effects level 
OATP 
organic anion transporting polypeptide 
OCT1 
organic cation transporter 1 
 
 
PDE 
phosphodiesterase 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PLA 
phospholipase A 


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PLC 
phospholipase C 
q.d. 
quaque die, once daily 
QTc 
corrected QT interval 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
QTcV 
QT interval corrected for heart rate using Van de Water’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SGRQ 
St. George’s Respiratory Questionnaire 
SpO2 
oxygen saturation 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TGFβ 
transforming growth factor β 
tmax 
time to maximum observed plasma concentration 
UGT 
uridine 5’-diphospho-glucuronosyltransferase 
UIP-IPF 
usual interstitial pneumonia – idiopathic pulmonary fibrosis 
ULN 
upper limit of the normal range 
VAS 
Visual Analogue Scale 
Vss 
volume of distribution at steady state 
WBC 
white blood cell 
WHO 
World Health Organization 
WOCBP 
women of child bearing potential 
 
 
 


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Definition of Terms 
BMI 
weight (kg) / (height [m])2 
CCr 
estimated creatinine clearance, calculated 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 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula: 
QTcF = QT/RR⅓, with RR = mean interval duration between 
consecutive RR peaks 
QTcV 
QT interval corrected for heart rate using Van de Water’s formula: 
QTcV = QT − 0.087 (60/HR − 1), with HR = heart rate 
 
 


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1. 
SUMMARY 
Objectives: 
Primary Objective 
− To evaluate the efficacy of two doses of GLPG1690 in addition to local standard of care 
compared to placebo in subjects with idiopathic pulmonary fibrosis (IPF) as evaluated by 
the rate of decline of forced vital capacity (FVC) over a period of 52 weeks 
Secondary Objectives 
Key Secondary Objectives 
− To evaluate the impact of two doses of GLPG1690 in addition to local standard of care 
compared to placebo in subjects with IPF on: 
• disease progression defined as deterioration of FVC or all-cause mortality at 
52 weeks 
• respiratory-related hospitalization until the end of the study 
• changes in quality of life (measured by St. George’s Respiratory Questionnaire 
[SGRQ] total score) at 52 weeks 
Other Secondary Objectives 
− To evaluate the efficacy of two doses of GLPG1690 in addition to local standard of care 
compared to placebo in subjects with IPF as evaluated by the rate of decline of FVC until 
the end of the study 
− To evaluate the impact of two doses of GLPG1690 in addition to local standard of care 
compared to placebo in subjects with IPF on: 
• disease progression defined as deterioration of FVC or all-cause mortality until 
the end of the study 
• changes in quality of life (measured by SGRQ total score) until the end of the 
study 
• all-cause non-elective hospitalization until the end of the study 
• respiratory-related mortality until the end of the study 
• lung transplant until the end of the study 
• acute IPF exacerbation until the end of the study 
• all-cause mortality or lung transplant until the end of the study 
• all-cause mortality, or lung transplant, or qualifying for lung transplant until the 
end of the study 
• all-cause mortality, deterioration of FVC, or respiratory-related hospitalization 
until the end of the study 
• all-cause mortality or respiratory-related hospitalizations until the end of the study 
− To evaluate the effect of two doses of GLPG1690 in addition to local standard of care 
compared to placebo on the changes from baseline in FVC at 52 weeks and until the end 
of the study 
− To evaluate the safety and tolerability of two doses of GLPG1690 in addition to local 
standard of care compared to placebo until the end of the study 




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remains a considerable unmet medical need. In a proof-of-concept Phase 2a study, FVC 
values remained stable in the majority of subjects after 12 weeks of treatment with 
GLPG1690 600 mg q.d. Moreover, 12 weeks of treatment with GLPG1690 600 mg q.d. was 
generally well tolerated. The current Phase 3 study is the next step in the clinical development 
of GLPG1690, evaluating the efficacy and safety of two doses of orally administered 
GLPG1690 (200 mg q.d. and 600 mg q.d.) compared to placebo in subjects with IPF in 
addition to local standard of care. 
Endpoints: 
Primary Endpoint 
− Rate of decline of FVC (in mL) over a period of 52 weeks 
Secondary Endpoints 
Key Secondary Endpoints 
− Disease progression defined as the composite endpoint of first occurrence of ≥10% 
absolute decline in percent predicted forced vital capacity (%FVC) or all-cause mortality 
at 52 weeks  
− Time to first respiratory-related hospitalization until the end of the study  
− Change from baseline in the SGRQ total score at 52 weeks  
Other Secondary Endpoints 
− Rate of decline of FVC (in mL) until the end of the study 
− Disease progression defined as the composite endpoint of first occurrence of ≥10% 
absolute decline in %FVC or all-cause mortality until the end of the study 
− Change from baseline in the SGRQ total score until the end of the study 
− Time to first all-cause non-elective hospitalization until the end of the study  
− Time to respiratory-related mortality until the end of the study  
− Time to lung transplant until the end of the study  
− Time to first acute IPF exacerbation until the end of the study  
− Time to all-cause mortality or lung transplant until the end of the study  
− Time to all-cause mortality, or lung transplant, or qualifying for lung transplant until the 
end of the study  
− Time to all-cause mortality, ≥10% absolute decline in %FVC, or respiratory-related 
hospitalizations until the end of the study 
− Time to all-cause mortality or respiratory-related hospitalizations until the end of the 
study 
− FVC analyses at 52 weeks and until the end of the study: 
• absolute and relative change from baseline of FVC and %FVC  
• absolute categorical change of %FVC until the end of the study: decrease by >5, 
increase by >5, and change within ≤5  
• absolute categorical change of %FVC until the end of the study: decrease by >10, 
increase by >10, and change within ≤10  
− Safety and tolerability over time until the end of the study  




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2. 
INTRODUCTION 
For details of GLPG1690, refer to the Investigator’s Brochure (IB) (Edition 6, 28-June-2019) 
and any relevant updates/addenda/errata. 
This clinical study will be conducted in accordance with the current International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use - Good Clinical 
Practice (ICH-GCP) Guideline E6 (see also Section 10). 
Idiopathic Pulmonary Fibrosis 
Idiopathic pulmonary fibrosis (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 to 70 years [5]. 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) [4, 12, 14, 18, 28]. 
The estimated IPF prevalence ranges from 14.0 to 27.9 cases per 100,000 population in the 
United States and from 1.3 to 23.4 cases per 100,000 population in Europe (data from 
1990-2011). The estimated IPF incidence in these studies ranges from 6.8 to 8.8 cases per 
100,000 population in the United States and from 0.2 to 7.4 cases per 100,000 population in 
Europe [8, 22, 31, 38]. 
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. Consequently, these treatments are standard 
of care for many patients. Pirfenidone (antifibrotic, anti-inflammatory, and antioxidant 
treatment marketed as e.g. Esbriet®; indicated in adults for the treatment of mild to moderate 
IPF), was the first drug to be licensed specifically for IPF. Phase 3 studies demonstrated that 
the drug improved progression-free survival and slowed the decline in forced vital capacity 
(FVC). Moreover, pirfenidone may have a mortality benefit [13, 23, 34, 37]. The drug was 
approved in the European Union in 2011 and in the United States in 2014. Nintedanib (tyrosine 
kinase inhibitor marketed as e.g. Ofev®; indicated in adults for the treatment of IPF), was 
initially developed as an anticancer agent. In Phase 3 studies, it significantly reduced the decline 
in FVC compared with placebo. A trend towards a reduced death rate was also observed; 
however, the studies were not designed to detect differences in mortality [32]. The drug was 
approved in the United States in 2014 and in the European Union in 2015. Both treatments 
appear to slow disease progression but are frequently associated with side effects potentially 
limiting their use in clinical practice [7, 24, 29]. 
There thus remains a considerable unmet medical need for the investigation and development 
of novel IPF treatments targeting disease-relevant pathways.  
The sponsor is currently pursuing the development of GLPG1690, a small-molecule autotaxin 
(ATX) inhibitor targeting disease-relevant signal transduction pathways, for the treatment of 
IPF. 


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Mode of Action 
GLPG1690 is a novel, potent, and selective small-molecule inhibitor of ATX. 
ATX, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) or 
lysophospholipase D (LPD), is a ~120 kDa protein that belongs to the ENPP family of enzymes. 
ATX is the only ENPP enzyme with LPD activity and is responsible for the hydrolysis of 
lysophosphatidylcholine (LPC) to produce the bioactive lipid lysophosphatidic acid (LPA). The 
term LPA covers several chemical species able to activate LPA receptors depending on the 
nature of the fatty acid side chain on the glycerol backbone. The most abundant LPA species in 
human plasma is LPA C18:2 with a fatty acid side chain of 18 carbon atoms including 
two unsaturated bonds [2]. Literature data have identified the ATX/LPC axis as the main source 
of LPA in blood [36, 39].  
Several publications suggest a role for ATX in the control of disease-affected lung function 
through effects on lung epithelial cells, fibroblasts, and smooth muscle cells [17]. In general, 
inflammatory conditions in the lung are often described as associated with increased ATX and 
LPA levels. Studies related to IPF indicated an increase in LPA levels in the bronchoalveolar 
lavage fluid of patients [35], an increase of ATX levels in human fibrotic lung [25], and an 
elevation of LPA C22:4 in exhaled breath condensate of patients [20]. Further, LPA1 knock-out 
and inhibitor studies revealed a key role for LPA in fibrotic processes in lung and were 
complemented by studies using cell-specific knock-out mice lacking ATX in bronchial 
epithelial cells and macrophages. These mice were shown to be less sensitive to models of lung 
fibrosis [25]. The role of LPA in lung remodeling relates to the effects of LPA on both lung 
fibroblasts (through LPA1) and epithelial cells (through LPA2). It has been demonstrated that 
LPA2 plays a key role in the activation of transforming growth factor β (TGFβ) in epithelial 
cells under fibrotic conditions [40].  
Available literature and preclinical pharmacology data generated by the sponsor, suggest that 
interventions targeting the ATX/LPA pathway could lead to a new class of therapy for IPF. 
2.1. 
Background - Nonclinical Studies 
2.1.1. 
Physical, Chemical, Pharmaceutical Properties, and Formulations 
The chemical name of GLPG1690 (international nonproprietary name ziritaxestat) is 2-[[2-
ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-
a]pyridin-3-yl](methyl)amino]-4-(4-fluorophenyl)-1,3-thiazole-5-carbonitrile. 
The clinical formulation used in this study is a film-coated tablet. 
2.1.2. 
Pharmacology 
2.1.2.1. 
Primary and Secondary Pharmacology 
GLPG1690 is an ATX inhibitor (50% inhibitory concentration [IC50] of 131 nM and 224 nM 
in biochemical assays with human enzyme and mouse enzyme, respectively). The 
LPA production after human plasma incubation was inhibited by GLPG1690 with an IC50 of 
242 nM, demonstrating the low impact of plasma protein binding on the activity of the 
compound. The compound was selective over related enzymes like ENPP1, phosphodiesterase 
(PDE)4 and PDE5, and phospholipase A (PLA) and phospholipase C (PLC). Moreover, 
GLPG1690 showed no inhibition in a panel of kinases. In a Cerep diversity panel (98 targets 




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Upon repeated once daily (q.d.) oral dosing of GLPG1690, no significant accumulation was 
observed in plasma, except in male rats (20 mg/kg/day) and dogs (50/65 mg/kg/day at 
Week 39). Gender differences in PK profiles were observed in rats but not in dogs. 
The total plasma clearance of GLPG1690 was low in mice, rats, monkeys, and dogs, ranging 
between 3% and 23% of the hepatic blood flow. Therefore, GLPG1690 is expected to undergo 
a low first-pass effect after oral dosing.  
The primary cytochrome P450 (CYP) enzyme involved in GLPG1690 metabolism was 
CYP3A4. In vitro metabolism studies in hepatocytes revealed 26 potential metabolites. 
Metabolites formed in human hepatocytes were all present to a similar or higher extent in rat 
and/or dog hepatocytes, the animal species selected for toxicity studies. 
An in vitro study with GLPG1690 in human hepatocytes showed no clinically relevant 
induction of human CYP2B6 and CYP2C enzymes. Regarding CYP1A2 and CYP3A4, weak 
induction cannot be excluded at a GLPG1690 dose of 600 mg q.d. in human, with a maximal 
decrease of around 30% in the exposure of a sensitive probe substrate for both CYP enzymes. 
An in vitro study with GLPG1690 in human liver microsomes indicated no clinically relevant 
inhibition of the majority of CYP enzymes. Weak competitive reversible inhibition of CYP2C8 
and CYP3A4/5 cannot be excluded at a GLPG1690 dose of 600 mg q.d. in human, with a 
maximal increase of approximately 1.7- and 1.5-fold, respectively, in the exposure of a sensitive 
probe substrate. 
In addition, GLPG1690 demonstrated a strong time-dependent, irreversible inhibition potential 
against CYP2C8-mediated metabolism. This could likely lead to a pronounced interaction with 
a sensitive CYP2C8 probe substrate (increased exposure) if co-administered with a GLPG1690 
dose of 600 mg q.d. in human. 
No interaction by GLPG1690 is expected for renal uptake transporters organic cation 
transporter (OCT)2, organic anion transporter (OAT)1 and OAT3 and hepatic efflux 
transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). For the hepatic 
uptake transporters organic anion transporter polypeptide (OATP) OATP1B1, OATP1B3, and 
OCT1, and efflux transporters MATE1 (hepatic/renal) and MATE2K (renal) a clinical 
interaction with GLPG1690 cannot be ruled out; however substantial interactions are not 
anticipated. For the intestinal efflux P-gp and BCRP transporters and the hepatic efflux bile salt 
export pump (BSEP) transporters an interaction cannot be ruled out. 
 
2.1.4. 
Toxicology 
2.1.4.1. 
General Toxicology 
A comprehensive toxicology program has been conducted with GLPG1690. This program 
includes Good Laboratory Practice (GLP) oral repeat-dose toxicity studies of up to 26 weeks in 
rats and 39 weeks in dogs, embryofetal development studies in rats and rabbits, fertility studies 
in male and female rats, non-TgrasH2 mice preliminary studies, preliminary carcinogenicity 
studies, and in vivo and in vitro genotoxicity studies. Additional toxicology studies conducted 
include phototoxicity studies and dose-range finding studies in rats and dogs. 


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In rats, no GLPG1690-related mortality was observed. The dose-limiting adverse effects 
consisted of reduced food consumption (FC) and markedly decreased body weight (BW) gain 
at 1,000 mg/kg/day in the 4-week toxicity study, histopathological changes in the testes with 
reduced sperm parameters at ≥130 mg/kg/day in the 13- and 26-week GLP studies, and the 
presence of vacuolated alveolar macrophages, with alveolar amorphous material and 
perivascular inflammatory cell infiltration in the lungs of females in the 26-week GLP study. 
The no observed adverse effects level (NOAEL) values in rats were set at 40 and 130 mg/kg/day 
in males and females, respectively, in the 26-week GLP study.  
In repeat oral dose toxicity studies in dogs, the dose-limiting effects consisted of decreased 
white blood cell (WBC) count and FC, emesis and BW loss, associated with poor clinical 
conditions at doses ≥100 mg/kg/day in the 13  and 39 week GLP studies, respectively. 
QT prolongation, which was considered non-adverse, was also observed in repeat oral dose 
toxicity studies in dogs (4-, 13-, and 39-week studies). Additional findings in dogs consisted of 
adverse altered sperm parameters and inflammatory cell infiltrates in the liver and minimal bile 
duct hyperplasia at 150/100 mg/kg/day (in the 13 week GLP toxicity study). The safety margins 
obtained from the mean (AUC) exposures at the NOAEL for dogs in the 39-week study when 
compared with the highest clinical dose currently being tested in healthy subjects (600 mg q.d. 
Study GLPG1690-CL-116) was 31-fold. 
Male and female fertility studies in rats showed that there were no effects of GLPG1690 on 
mating performance, fertility, or reproduction in either male or female rats at the different dose 
levels tested. As the effects on sperm and testis proved reversible and had no functional impact 
on animal fertility parameters, the risk of an impact on male fertility in adult subjects is 
considered low. In males, the no observed effect level (NOEL) for mating performance and 
fertility was set at 400 mg/kg/day and the NOAEL for sperm changes was determined at 40 
mg/kg/day; the latter is in line with previous studies (i.e., 13 week rat study). In females, the 
NOEL for mating performance and fertility was considered to be 120 mg/kg/day. 
In reproductive embryofetal development studies with GLPG1690 in rats and rabbits, major 
external, visceral, and skeletal abnormalities were seen in fetuses of both species as well as 
increased incidences of postimplantation losses. In rats, the maternal and developmental 
NOAELs were determined at 60 mg/kg/day and 10 mg/kg/day, respectively. In rabbits, the 
maternal and developmental NOAELs were determined at 15 mg/kg/day and 5 mg/kg/day.  
GLPG1690 showed no genotoxic effects in vitro or in vivo. 
GLPG1690 showed a phototoxic potential in vitro. However, this potential has not been 
confirmed in a rat in vivo study, investigating the phototoxic effects on the eyes and the skin in 
female pigmented Long-Evans rats. No evidence of cutaneous or ocular phototoxicity was 
noted at doses of 100 and 300 mg/kg.  


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2.2. 
Background - Clinical Studies 
2.2.1. 
Clinical Safety 
As of the safety data cut-off date of IB Edition 6, in clinical pharmacology studies, GLPG1690 
had been administered to 85 healthy subjects as single doses (dose range: 20 to 1500 mg), to 96 
healthy subjects in repeated doses (dose range: 100 to 1000 mg for either 7 or 14 days).  
Administration of GLPG1690 was considered safe and well tolerated during these studies. No 
deaths, serious treatment-emergent adverse events (TEAEs), or TEAEs leading to 
investigational medicinal product (IMP) discontinuation were reported after dosing with 
GLPG1690. All GLPG1690 TEAEs were at most moderate in severity. In Study, GLPG1690-
CL-109, one SAE (ECG repolarization abnormality) was reported after a single dose of 
nintedanib, but before dosing with GLPG1690 (IMP). 
The safety profile of single doses of nintedanib and pirfenidone in Study GLPG1690-CL-109 
both alone and in combination with GLPG1690 was consistent with the respective nintedanib 
and pirfenidone prescribing information. 
An additional DDI study (GLPG1690-CL-113) evaluated the effect of multiple oral doses of 
GLPG1690 on the safety and tolerability of nintedanib 150 mg twice daily (b.i.d.) under 
different dosing conditions; i.e. the GLPG1690 dose and the timing of GLPG1690 
administration versus the nintedanib morning intake. Subjects received 150 mg nintedanib b.i.d. 
on Days 1 and 7, and GLPG1690 200 mg q.d. 0 (i.e. concomitantly) or 2 hours after nintedanib 
morning intake time, or 600 mg q.d. 0, 2, or 4 hours after the nintedanib morning intake time 
on Days 3 to 9. Cohorts 1 and 2 evaluated the morning and evening PK of nintedanib (150 mg 
b.i.d.) when administered alone and when the morning dose was administered simultaneously 
with GLPG1690 200 mg (in Cohort 1) or 600 mg (in Cohort 2). Cohorts 3 and 4 evaluated the 
morning and evening PK of nintedanib 150 mg b.i.d. when administered alone and in 
combination with GLPG1690 200 mg or 600 mg administered 2 h or 4 h after the nintedanib 
morning dose (i.e., 600 mg 2 h [Cohort 3a]; 600 mg 4 h [Cohort 3b] or 200 mg 2 h [Cohort 4a]).  
There were no serious adverse events and all TEAEs were at most moderate in severity. There 
was one TEAE (herpes zoster) that led to discontinuation of treatment in the cohort that received 
GLPG1690 200 mg at the same time as the nintedanib morning dose. GLPG1690 at doses of 
200 mg and 600 mg q.d. was well-tolerated. 
The frequency of TEAEs was generally similar between cohorts and treatments. The frequency 
of diarrhea adverse events was higher in most cohorts after nintedanib alone than after 
GLPG1690 alone. In contrast to the previous DDI study (GLPG1690-CL-109), the incidence 
of diarrhea events did not increase when nintedanib was administered with GLPG1690. 
Administration of oral doses of GLPG1690 600 mg q.d. for 12 weeks in 17 subjects with IPF 
was well tolerated (Phase 2a study GLPG1690-CL-202). No deaths were reported. Serious 
TEAEs were experienced by one subject in the GLPG1690 600 mg q.d. group 
(cholangiocarcinoma, led to permanent discontinuation) and by two subjects in the placebo 
group (atrioventricular block second degree in one subject, led to permanent discontinuation; 
and lower respiratory tract infection, urinary tract infection, and acute kidney injury in the other 
subject). None of these serious TEAEs were considered related to IMP according to the 
investigator. No notable differences were observed in the incidences of treatment-emergent 


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abnormalities between subjects with IPF treated with GLPG1690 600 mg q.d. or placebo. The 
majority of TEAEs were mild to moderate in severity.  
2.2.2. 
Clinical Pharmacokinetics 
Single (up to 1,500 mg) and multiple ascending oral doses of GLPG1690 (up to 1,000 mg q.d.) 
for 14 days were assessed in healthy male subjects under fed conditions. GLPG1690 was 
rapidly absorbed with a median time to maximum plasma concentration (tmax) of 0.5-2 h. Steady 
state exposure of GLPG1690 increased approximately in proportion with the dose between 300 
to 1,000 mg total daily. Excretion of unchanged GLPG1690 in human urine was low (<1.8% in 
24 hours [h] based on unchanged GLPG1690) and rapid. There was no impact on the urinary 
6β-OH-cortisol/cortisol ratio after repeated dosing suggesting a lack of CYP3A4 induction by 
GLPG1690.  
The PK of GLG1690 was similar between Caucasian and Japanese healthy male subjects. The 
PK of GLPG1690 in subjects with IPF was not markedly different from those observed in 
healthy subjects at the same dose level. 
Food decreased the rate of absorption of GLPG1690 given as tablet (as expected by delay in 
gastric emptying), but there was no clinically relevant difference in the bioavailability of 
GLPG1690. A higher between-subject variability was observed in fasted state, with 4 subjects 
out of 12 having 5- to 10-fold lower exposure than the other subjects. The rate of elimination 
was not impacted by food. The mean terminal half-life (t1/2) after a single 600 mg dose as 
tablets was approximately 11 h. 
After q.d. dosing with the strong CYP3A4/potent P-gp inducer rifampin (600 mg q.d.) for 
10 days, GLPG1690 (600 mg) exposure was decreased (by 6.0- and 9.3-fold for maximum 
observed plasma concentration (Cmax) and area under the plasma concentration-time curve from 
time 0 to 24 h [AUC0-24h], respectively) without any significant change in the apparent rate of 
elimination.  
Exposure of GLPG1690, as measured by area under the concentration-time curve from time 0 
to infinity (AUC0-∞), was 3- and 4-fold greater when administered in combination with 
itraconazole and voriconazole, respectively, than when GLPG1690 was administered alone. 
Maximum exposure (Cmax) of GLPG1690 increased slightly following administration of 
GLPG1690 in combination with itraconazole or voriconazole compared with administration of 
GLPG1690 only (Cmax values were 1.4-fold greater following administration in combination 
with itraconazole or voriconazole). This increase is unlikely to be clinically significant. 
GLPG1690 can therefore be classified as a moderately sensitive substrate of CYP3A4 as it 
demonstrated an increase in AUC of ≥2 to <5-fold with strong index inhibitors. Comparison of 
the plasma profiles showed no impact on the apparent rate of elimination of GLPG1690. 
The potential impact of GLPG1690 600 mg on the PK of single doses of pirfenidone and 
nintedanib was evaluated. Exposure of pirfenidone and its metabolite 5-carboxypirfenidone, as 
measured by Cmax, AUC0-∞, and terminal elimination half-life (t1/2) was not affected when 
administered in combination with GLPG1690, compared to when pirfenidone was administered 
alone. Exposure of nintedanib, as measured by Cmax, AUC0-∞ was approximately 2-fold greater 
when administered in combination with GLPG1690, than when GLPG1690 was administered 
alone. Nintedanib t1/2 was not affected by coadministration of GLPG1690. 




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3. 
CLINICAL STUDY OBJECTIVES 
3.1. 
Primary Objective 
− To evaluate the efficacy of two doses of GLPG1690 in addition to local standard of care 
compared to placebo in subjects with IPF as evaluated by the rate of decline of FVC over a 
period of 52 weeks 
3.2. 
Secondary Objectives 
3.2.1. 
Key Secondary Objectives 
− To evaluate the impact of two doses of GLPG1690 in addition to local standard of care 
compared to placebo in subjects with IPF on: 
• disease progression defined as deterioration of FVC or all-cause mortality at 
52 weeks 
• respiratory-related hospitalization until the end of the study 
• changes in quality of life (measured by St. George’s Respiratory Questionnaire 
[SGRQ] total score) at 52 weeks 
3.2.2. 
Other Secondary Objectives 
− To evaluate the efficacy of two doses of GLPG1690 in addition to local standard of care 
compared to placebo in subjects with IPF as evaluated by the rate of decline of FVC until 
the end of the study 
− To evaluate the impact of two doses of GLPG1690 in addition to local standard of care 
compared to placebo in subjects with IPF on: 
• disease progression defined as deterioration of FVC or all-cause mortality until the 
end of the study 
• changes in quality of life (measured by SGRQ total score) until the end of the study 
• all-cause non-elective hospitalization until the end of the study 
• respiratory-related mortality until the end of the study 
• lung transplant until the end of the study 
• acute IPF exacerbation until the end of the study 
• all-cause mortality or lung transplant until the end of the study 
• all-cause mortality, or lung transplant, or qualifying for lung transplant until the end 
of the study 
• all-cause mortality, deterioration of FVC, or respiratory-related hospitalization until 
the end of the study 
• all-cause mortality or respiratory-related hospitalizations until the end of the study 
− To evaluate the effect of two doses of GLPG1690 in addition to local standard of care 
compared to placebo on the changes from baseline in FVC at 52 weeks and until the end of 
the study 
− To evaluate the safety and tolerability of two doses of GLPG1690 in addition to local 
standard of care compared to placebo until the end of the study 
− To evaluate changes compared to placebo in subjects with IPF in:  




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Figure 1: 
Schematic Study Overview 
D=Day, EoST/EoSA=end of study treatment/end of study assessments, FU=follow-up, V=Visit, W=Week. 
Enrolled subjects will come to the clinical study center at screening (two visits from Day -28 to 
Day -1). Visit 2 of screening can only take place after confirmed IPF diagnosis on HRCT and 
LB (if applicable) (for details, refer to Section 6.3 and Appendix 1). 
For the in- and exclusion criteria, please refer to Section 4.5.1 and Section 4.5.2, respectively. 
At Visit 3, eligible subjects will be randomized in a 1:1:1 ratio to receive 
GLPG1690 600 mg q.d., GLPG1690 200 mg q.d., or matching placebo for at least 52 weeks. 
Randomization will be stratified for background local standard of care for treatment of IPF. 
Subjects will come to the clinical study center on Day 1 (baseline), Weeks 2, 4, 8, 12, 18, 26, 
34, 42, 52, and every 12 weeks thereafter. Additional unscheduled visits are allowed if, in the 
investigator’s opinion, further evaluation (clinical, laboratory, or other) is needed. 
When the last subject reaches 52 weeks (Visit 12), subjects still taking IMP and who had a 
scheduled visit at the clinical study center within 6 weeks before this date will be contacted by 
their investigator (phone call) to discontinue IMP within 7 days after this date. Then the last 
scheduled visit will be documented as the end of study treatment (EoST) visit. These subjects 
will be invited to their follow-up visit scheduled at the clinical study center 4 weeks after their 
last dose of IMP (±7 days). For subjects still taking IMP and who had their last scheduled visit 
more than 6 weeks before the date that the last subject reaches 52 weeks into the study 
(Visit 12), a scheduled visit will be planned within 2 weeks of this date for an EoST visit, 
followed by a follow-up visit 4 weeks later (visit at clinical center or phone call). Note that 
these subjects will continue IMP intake until their EoST visit. 
For subjects who, for any Coronavirus disease (COVID-19)-related reason, cannot perform 
study procedures, extended visit windows, the possibility to conduct phone/televisits and home 
(or other remote location) visits, and alternative assessment procedures are detailed in Section 
6.1.1. 


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Subjects who discontinue IMP early (early treatment discontinuation [ETD]), with the 
exception of patients lost to follow-up and patients who withdraw consent, will be encouraged 
to complete all following visits and evaluations as originally planned per protocol.  
In particular, the subject will be requested if at all possible to attend:  
− 
the first scheduled visit after their Early Treatment Discontinuation (ETD)  
− 
The Week 26 visit (if not done before IMP discontinuation) 
− 
the Week 52 visit (if not done before IMP discontinuation) 
− 
after Week 52, visits every 24 weeks up to End of Study Assessments (EoSA), as 
described in Section 6.11.2 
 
For procedures in case of ETD, refer to Section 4.5.4. In the exceptional case that a clinical 
study center visit cannot be attended, a phone call by the investigator will be made to evaluate 
safety, in combination with scheduled clinical study center visits. 
Each subject will have a screening period of maximum 28 days. The duration of study treatment 
for individual subjects will vary from 52 weeks for the last enrolled subject to e.g. 132 weeks 
for the first enrolled subject (assuming a recruitment period of 80 weeks, the actual duration 
will depend on the actual time to recruit subjects for the study). A follow-up visit (at the clinical 
study center or by phone call, decided by the investigator) is planned 4 weeks after the 
EoST/end of study assessment (EoSA) visit.  
At the end of this study, treatment with IMP in an optional extension study (under a separate 
study protocol) may be offered to all eligible subjects, provided Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB) and Competent Authority approvals for such an 
extension are granted.  
To protect the safety and integrity of the study data, an independent data monitoring committee 
(IDMC) will be implemented, as well as a clinical endpoint adjudication committee (CEAC). 
Charters are in place for all committees. For additional information, refer to Sections 8.1 (for 
IDMC) and 8.2 (for CEAC). 
For detailed information regarding dosage form, packaging, and labeling of the IMP, please 
refer to Sections 5.2 and 5.3. 
4.1.1. 
Definition of End of Trial 
The global end of trial will be reached when the last subject has completed the last follow-up 
visit (scheduled clinical study center visit or phone call), i.e. four weeks (±7 days) after the end 
of study treatment (EoST) or end of study assessments (EoSA) visit (Section 4.1 and Section 
6.11.2). 
4.1.2. 
Guidance for dose modification in case of adverse events 
At any stage, the investigator can decide to permanently discontinue IMP for concerns 
regarding safety and tolerability, i.e. an AE including clinically significant abnormal laboratory 
tests. For abnormal liver function tests (LFTs), specific guidance is described in Appendix 9. 




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Discontinuation of IMP: 
− AST or ALT >8xULN: permanently discontinue IMP with close observation*.  
− AST or ALT ≥3xULN with signs or symptoms of severe liver damage**: permanently 
discontinue IMP with close observation*. 
− AST or ALT ≥3xULN for more than 2 weeks 
− AST or ALT ≥3xULN during re-escalation (described below) 
Down-titration to reduced dose level or interruption of IMP:  
− AST or ALT ≥3x to 5xULN without signs of severe liver damage**:  
Down-titrate to low (reduced) dose level or interrupt IMP for at least 2 weeks (to be decided 
by the investigator, based on the subject’s risk assessment). 
− AST or ALT ≥5x to 8xULN without signs of severe liver damage**: 
Interrupt IMP for at least 2 weeks.  
During these periods of at least 2 weeks: Re-test AST, ALT, alkaline phosphatase, total 
bilirubin, and eosinophils within 48 to 72 hours, approximately at 7 days, thereafter 
approximately at 14 days, and also assess signs of severe liver damage**. If local regulations 
allow, home visits can be performed if subjects cannot come to the clinical study center. 
Re-escalation after each period of at least 2 weeks at any dose level: 
− 
Remain on the highest tolerated dose at investigator’s discretion. Monitoring of LFTs can 
return to the planned study assessments once the LFTs have stabilized at the highest 
tolerated dose level for 8 weeks. 
− 
AST and ALT <3xULN: 
Re-escalate to the next dose level for at least 2 weeks, with regular LFT monitoring 
(weekly for the first 2 weeks, biweekly for the following weeks, or more frequently at 
investigator’s discretion) and repeat re-escalation to next higher dose level every 2 weeks 
(or longer at investigator’s discretion) if AST and ALT <3xULN.  
− 
AST or ALT ≥3xULN: 
Discontinue IMP.  
*Close observation is defined as: 
− Monitor two to three times per week all of the following parameters: ALT, AST, alkaline 
phosphatase, total bilirubin, eosinophils, and International Normalized Ratio (INR). If local 
regulations allow, home visits can be performed if subjects cannot come to the clinical study 
center. 
− Frequency of retesting can be reduced to once a week or less if abnormalities stabilize or 
the IMP has been discontinued; however, monitoring might still be needed more frequently 
taking into consideration the standard of care and/or changes to this. 
− Re-query history of symptoms, prior and concurrent diseases, concomitant medication and 
non-prescription medicines, herbal, dietary supplements, alcohol use, recreational drug use, 
special diets. 
− Rule out all of the following: acute viral hepatitis, auto-immune hepatitis, alcoholic 
hepatitis, non-alcoholic fatty hepatitis, hypoxic/ischemic hepatitis, biliary tract disease, and 
cholestasis. 
− Re-query exposure to environmental chemical agents. 


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− Consider gastro-enterology or hepatology consultations. 
** Signs of severe liver damage:  
− Increase of liver transaminases is accompanied by appearance of fatigue, nausea, vomiting, 
right upper abdominal quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%), 
and/or 
− Total bilirubin ≥1.5x ULN, or 
− INR >1.5. 
Each blinded treatment kit will have blisters for the high (original) dose level, intermediate 
(reduced) dose level, and low (reduced) dose level, allowing the clinical study center to 
modulate the IMP dose for a particular subject, even without knowing the original treatment 
allocation (also see Section 5.2).  
The Investigator will be responsible for managing COVID-19 infected subjects and the decision 
to continue or interrupt IMP for subjects with confirmed or suspected cases of COVID-19 
infection is at the investigator’s discretion. Guidance on continuation of IMP and requirements 
for assessments conducted during the COVID-19 pandemic are provided in Section 6.1.1. 
4.2. 
Clinical Study Rationale 
Since 2010, disease-modifying drugs such as pirfenidone and nintedanib are indicated for 
patients with IPF and available in most parts of the world. These drugs have been shown to 
have a beneficial effect on the rate of decline in lung function (as measured by FVC over 1 year) 
and show a trend in favor of a reduction in mortality [32]. Both drugs have received conditional 
recommendation for use in the American Thoracic Society (ATS) / European Respiratory 
Society (ERS) / Japanese Respiratory Society (JRS) / Latin American Thoracic Association 
(ALAT) 2015 guidelines [29].  
However, the residual decline of FVC over 1 year remains substantial, with a further decline of 
FVC over 52 weeks of 125 mL and 114 mL in INPULSIS I and II (nintedanib) [33], 
respectively, and around 200 mL in the ASCEND study (pirfenidone) [13].  
Additional therapies targeting different disease pathways could potentially prove to be more 
effective by further preventing the decline in FVC with an acceptable safety profile [41]. 
In the proof-of-concept Phase 2a study GLPG1690-CL-202, FVC values remained stable in the 
majority of subjects on GLPG1690 600 mg q.d. (+8 mL mean change from baseline). 
Moreover, 12 weeks of treatment with GLPG1690 600 mg q.d. was generally well tolerated 
(refer to Section 2.2.1).  
The current Phase 3 study is a next step in the clinical development of GLPG1690, evaluating 
the efficacy and safety of two doses of orally administered GLPG1690 (200 mg q.d. and 
600 mg q.d.) compared to placebo in subjects with IPF in addition to local standard of care.  
The primary objective of the study is to evaluate the efficacy of GLPG1690 in addition to local 
standard of care on the rate of decline of FVC over a period of 52 weeks. FVC has been accepted 
as a clinically relevant efficacy measure in IPF, as a benefit in terms of FVC decline showed a 
trend toward decreased mortality [11]. 




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effects with a smaller sample size compared with any other type of controlled study) and 
minimizes the effect of subject and investigator expectations [10].  
Subject eligibility 
Subject eligibility criteria are similar to previous clinical studies in IPF, differing in the IMP 
being evaluated in addition to local standard of care for the treatment of IPF. Subjects clinically 
diagnosed with IPF based on ATS/ERS/JRS/ALAT guidelines [28, 29] are eligible for the 
study, if complying with all the study in- and exclusion criteria. The disease typically affects 
elderly patients, so subjects ≥40 years are to be included.  
The clinical diagnosis of IPF will be confirmed by central reading of the chest HRCT and by 
central review of a historical LB if available, if required, based on the Fleischner White Paper 
[15] as described in Section 6.3 and Appendix 1. 
Refer to the in- and exclusion criteria in Sections 4.5.1 and 4.5.2, respectively, and to the 
prohibitions and restrictions in Section 4.5.3 for medications that are not allowed prior to or 
during the study. 
Rationale for chosen endpoints 
A rationale for the chosen endpoints is provided in Section 4.3. 
Duration of the study 
Each subject will have a screening period of maximum 28 days. The duration of study treatment 
for individual subjects will vary from 52 weeks for the last enrolled subject to e.g. 132 weeks 
for the first enrolled subject (assuming a recruitment period of 80 weeks, the actual duration 
will depend on the actual time to recruit subjects for the study). A follow-up visit (at the clinical 
study center or by phone call) is planned 4 weeks after the EoST/EoSA visit. This duration 
ensures long-term collection of efficacy and safety data in a blinded manner, and increases the 
probability of demonstrating an effect on clinical endpoints. Note that subjects who discontinue 
IMP early (ETD) will be encouraged to complete all following visits and evaluations as 
originally planned per protocol (refer to Section 4.5.4). 
Dose modification in case of adverse events 
For the management of AEs, the investigator can reduce, interrupt, or permanently discontinue 
IMP (see Section 4.1.2 and Section 4.5.4). This allows the subject to remain on the highest 
tolerated dose during the study. 
4.3. 
Endpoints 
The rate of decline of FVC over a period of 52 weeks has been chosen as primary efficacy 
endpoint, as this has been recognized as a clinically relevant efficacy measure in IPF [11]. 
Key secondary endpoints are disease progression defined as deterioration of FVC (expressed 
as categorical decline of ≥10% predicted FVC) or all-cause mortality, respiratory-related 
hospitalizations, and quality of life as measured by SGRQ total score. 
All-cause and respiratory-related mortality have been chosen as secondary endpoints to provide 
supportive evidence that the treatment affects the disease. Other (secondary) endpoints include 








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Clinical DDI studies showed that exposure of nintedanib (150 mg single dose or b.i.d. dose), as 
measured by Cmax, and AUCs was approximately 2-fold greater when administered on the same 
day (b.i.d) as, and simultaneously with, GLPG1690 600 mg than when administered alone. The 
increased exposure of nintedanib was in the same order of magnitude to that observed with 
concomitant administration of ketoconazole (a P-gp and CYP3A4 inhibitor) and that did not 
warrant a contraindication in the nintedanib label, but a warning for monitoring tolerability.  
The interaction (increased exposure of nintedanib) observed when GLPG1690 and nintedanib 
150 mg b.i.d. were administered concomitantly was reduced when GLPG1690 was 
administered 2 or 4 hours after the nintedanib morning dose.  
This clinical study protocol contains specific precautions and exclusions to manage use of 
GLPG1690 on top of standard of care (pirfenidone and nintedanib). The plasma concentrations 
of GLPG1690, pirfenidone and nintedanib will be collected. The potential for increased 
exposure to nintedanib when co-administered with GLPG1690 can be managed by separating 
the intake times of the morning dose of nintedanib and the IMP daily dose. It is therefore 
recommended that all subjects on nintedanib take IMP at or after lunch (approximately 4 hours 
after nintedanib morning intake);  refer to Section 5.2. Additionally all subjects taking 
nintedanib will be evaluated by monitoring adverse events and managing them according to the 
guidance in the nintedanib prescribing information. 
Management of adverse events 
For the management of AEs, guidance for the investigator should be followed, as described in 
Section 4.1.2. As noted above, the investigator needs to evaluate the potential of increased 
exposure to nintedanib when coadministered with IMP by monitoring adverse events and 
managing them according to the guidance in the nintedanib prescribing information and the 
guidance provided in this protocol. 
Details for capture of the suspected and confirmed cases of COVID-19 based on the symptoms 
and the confirmatory test, respectively, have been provided in data entry guidance issued to the 
sites, and will be included in the CRF completion guidelines.  
All these cases, whether suspected or confirmed, should be documented in the CRF. 
Clinical studies 
GLPG1690 has been evaluated in several Phase 1 studies and in the GLPG1690-CL-202 study 
with patients. Administration of GLPG1690 was generally safe and well tolerated. In the 
GLPG1690-CL-202 study, FVC values remained stable in the majority of subjects on 
GLPG1690 600 mg q.d. (+8 mL mean change from baseline) when administered for 12 weeks 
(refer to Section 2.2.1).  
Special populations 
As there is limited clinical experience with GLPG1690 so far, the IMP should not be 
administered to subjects with severe renal impairment or with moderate to severe hepatic 
impairment. 
Refer to the IB (Edition 6, 28-June-2019) and any relevant updates/addenda/errata for 
additional information on the safety of the IMP. 


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4.5. 
Clinical Study Population 
4.5.1. 
Inclusion Criteria 
Subjects who meet all of the following criteria are eligible for this clinical study: 
1. Able and willing to comply with the protocol requirements and signed the informed 
consent form (ICF) as approved by the Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB), prior to any screening evaluations. 
2. Subject must be able and willing to comply with restrictions on prior and concomitant 
medication as described in Section 4.5.3.2. 
3. Male or female subject aged ≥40 years on the day of signing the ICF.  
4. Criterion modified per amendment. 
4.1 A diagnosis of IPF within 5 years prior to the screening visit, as per applicable 
ATS/ERS/JRS/ALAT guideline at the time of diagnosis [28, 29]. 
5. Chest HRCT historically performed within 12 months prior to the screening visit and 
according to the minimum requirements for IPF diagnosis by central review based on 
subject’s HRCT only (if no LB available), or based on both HRCT and LB (with 
application of the different criteria in either situation) (see Appendix 1). If an evaluable 
HRCT <12 months prior to screening is not available, an HRCT can be performed at 
screening to determine eligibility, according to the same requirements as the historical 
HRCT.  
6. Criterion modified per amendment. 
6.1 Subjects receiving local standard of care for the treatment of IPF, defined as either 
pirfenidone or nintedanib at a stable dose for at least two months before screening, 
and during screening; or neither pirfenidone or nintedanib (for any reason). A stable 
dose is defined as the highest dose tolerated by the subject during those two months. 
7. The extent of fibrotic changes is greater than the extent of emphysema on the most recent 
HRCT scan (investigator-determined).  
8. Meeting all of the following criteria during the screening period: 
• FVC ≥45% predicted of normal. 
• Forced expiratory volume in 1 second (FEV1)/FVC ≥0.7. 
• DLCO corrected for Hb ≥30% predicted of normal (see Appendix 2).  
9. Criterion modified per amendment. 
9.1 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 have been stable from 
4 weeks prior to screening and during the screening period (stable defined as no 
clinically relevant change according to the investigator’s judgment). 
10. Estimated minimum life expectancy of at least 30 months for non-IPF related disease in 
the opinion of the investigator. 
11. Male subjects and female subjects of childbearing potential agree to use highly effective 
contraception/preventive exposure measures (as described in Section 4.5.3.1) from the 
time of first dose of IMP (for the male subject) or the signing of the ICF (for the female 


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subject), during the study, and until 90 days (male) or 30 days (female) after the last dose 
of IMP. 
12. Criterion modified per amendment. 
12.1 Able to walk at least 150 meters during the 6MWT at screening Visit 1; without 
having a contraindication to perform the 6MWT (see Appendix 10) or without a 
condition putting the subject at risk of falling during the test (investigator’s 
discretion). The use of a cane is allowed, the use of a stroller is not allowed at all for 
any condition. At Visit 2, for the oxygen titration test, resting SpO2 should be ≥88% 
with maximum 6 L O2/minute; during the walk, SpO2 should be ≥83% with 
6 L O2/minute or ≥88% with 0, 2 or 4 L O2/minute. 
13. Able to read and complete the EQ-5D, SGRQ, LCQ, K-BILD questionnaire, and VAS by 
themselves.  
14. 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 (described in Section 4.5.3.2). 
4.5.2. 
Exclusion Criteria 
Subjects meeting one or more of the following criteria cannot be selected for this clinical study: 
1. Investigator or other study staff or relative thereof who is directly involved in the conduct 
of the study. 
2. Any clinical condition or other condition or circumstance that, in the opinion of the 
investigator, may make a subject unsuitable for inclusion or unlikely or unable to 
complete the study or comply with study procedures and requirements. 
3. Previous participation in a clinical study with GLPG1690 (active or placebo). 
4. 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). 
5. Criterion modified per amendment. 
5.2 A current immunosuppressive condition (e.g. human immunodeficiency virus 
[HIV] infection, congenital, acquired, medication-induced). Subjects treated with 
stable doses of immunosuppressive medications for reasons other than IPF are 
allowed to participate in the study on a case-by-case basis based on discussion with 
the sponsor’s medical monitor. 
6. Criterion modified per amendment. 
6.1 Positive blood testing for hepatitis B surface antigen (HBS Ag) or hepatitis C virus 
(antibody, confirmed by hepatitis C virus (HCV) RNA positivity). Note: Subjects 
with a resolved hepatitis A at least 3 months prior to screening can be screened. 
7. History of malignancy within the past 5 years (except for carcinoma in situ of the uterine 
cervix, basal cell carcinoma of the skin that has been treated with no evidence of 
recurrence, prostate cancer that has been medically managed through active surveillance 
or watchful waiting, squamous cell carcinoma of the skin if fully resected, and Ductal 
Carcinoma In Situ). 
8. Criterion modified per amendment. 
8.1 Clinically significant abnormalities detected on ECG of either rhythm or 
conduction, a QTcF >450 ms, or a known long QT syndrome. Patients with 
implantable cardiovascular devices (e.g. pacemaker) affecting the QT interval time 


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may be enrolled in the study based upon investigator judgment following 
cardiologist consultation if deemed necessary, and only after discussion with the 
medical monitor.  
9. Currently taking medication known to be a substrate mainly metabolized by CYP2C8 
(see Appendix 3). 
10. Currently taking medication known to be strong inducers of CYP3A4 (Appendix 4), and 
also including St-John’s Wort. 
11. Currently taking medication known to be strong inhibitors of CYP3A4 (Appendix 5). 
12. Currently taking medication known to be potent inducers of P-gp (Appendix 4). 
13. Currently taking medication known to be potent inhibitors of P-gp (Appendix 6). 
14. Criterion modified per amendment. 
14.1 Acute IPF exacerbation within 6 months prior to screening and/or during the 
screening period. The definition of an acute IPF exacerbation is as follows:  
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 and deterioration not fully 
explained by cardiac failure or fluid overload (see Appendix 11). 
15. Criterion modified per amendment. 
15.1 Lower respiratory tract infection requiring treatment within 4 weeks prior to 
screening and/or during the screening period. 
16. Interstitial lung disease associated with known primary diseases (e.g. sarcoidosis and 
amyloidosis), exposures (e.g. radiation, silica, asbestos, and coal dust), or drugs 
(e.g. amiodarone). 
17. History of lung volume reduction surgery or lung transplant. Note: being on a transplant 
list is allowed.  
18. Diagnosis of severe pulmonary hypertension (investigator-determined). 
19. Unstable cardiovascular, pulmonary (other than IPF), or other disease within 6 months 
prior to screening or during the screening period (e.g. acute coronary disease, heart 
failure, and stroke).  
20. Criterion modified per amendment. 
20.1 Had gastric perforation within 3 months prior to screening or during screening, 
and/or underwent major surgery within 3 months prior to screening, during 
screening or have major surgery planned during the study period. 
21. Criterion modified per amendment. 
21.1 A history of being admitted to an institution under an administrative or court order, 
if applicable by local legislation, as well as any subjects falling into any of the 
categories of persons listed by applicable law and regulations as protected persons 
for which participation in a study is prohibited or subject to restrictions. 
22. Criterion modified per amendment. 
22.2 History of nintedanib-related increase in ALT and/or AST of >5xULN and 
increased susceptibility to elevated LFT; moderate to severe hepatic impairment 
(Child-Pugh B or C); and/or abnormal LFT at screening, defined as AST, and/or 
ALT, and/or total bilirubin ≥1.5xULN, and/or GGT ≥3xULN. Retesting is allowed 
once for abnormal LFT. 
23. Abnormal renal function defined as estimated creatinine clearance, calculated according 
to Cockcroft-Gault calculation (CCr) <30 mL/min. Retesting is allowed once. 


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24. Hb level <10 g/dL. Retesting is allowed once. 
25. Criterion modified per amendment  
25.1 Concurrent participation in another interventional drug, device, or biological 
investigational research study, or use of an investigational agent within 5 half-lives 
of the agent (or within 8 weeks when half-life is unknown, or within 6 months if 
the investigational agent is an antibody) prior to screening, is not allowed.  
26. Use of any of the following therapies within 4 weeks prior to screening and during the 
screening period, or planned during the study: warfarin, imatinib, ambrisentan, 
azathioprine, cyclophosphamide, cyclosporine A, bosentan, methotrexate, sildenafil 
(except for occasional use), prednisone at steady dose >10 mg/day or equivalent. 
27. Current alcohol or substance abuse in the opinion of the investigator. 
28. Pregnant, breastfeeding, or planning to become pregnant or breastfeed during the study 
treatment or within 30 days after the last dose of IMP. 
29. Clinical laboratory test suggestive of cholestasis with total serum bile acid levels >3xULN. 
4.5.3. 
Prohibition and Restrictions 
4.5.3.1. 
Precautions for Sexual Intercourse 
Highly effective contraceptive measures for both males and females of childbearing potential 
must be documented in the source documents. 
4.5.3.1.1. Female Subjects 
In line with the Heads of Medicines Agencies (HMA)’s Clinical Trial Facilitation Group 
(CTFG) recommendation [3], female subjects are considered of non-childbearing potential if 
they meet one of the following criteria: 
− 
No menses for 12 or more months without an alternative medical cause. A high 
follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
− 
Permanently surgically sterile (bilateral oophorectomy [i.e. surgical removal of ovaries], 
bilateral salpingectomy, or hysterectomy [i.e. surgical removal of uterus]). 
All other female subjects are considered to be of childbearing potential and are required to have 
a negative serum pregnancy test before treatment. They must use one of the following highly 
effective methods of birth control from the time of signing of the ICF, during the clinical study, 
and for at least 30 days after the last dose of IMP:  
− 
Combined (estrogen- and progesterone-containing) (oral, intravaginal, transdermal) 
hormonal contraception associated with inhibition of ovulation plus a barrier method1. 
− 
Progesterone-only hormonal (oral, injectable, implantable) contraception associated with 
inhibition of ovulation plus a barrier method1.  
− 
Intrauterine device.  
                                                 
1 As there are no current data available regarding potential interactions between IMP and hormonal contraceptives, 
female subjects who use hormonal contraception should supplement this with a barrier method (preferably male 
condom). 


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− 
Intrauterine hormone-releasing system. 
− 
Bilateral tubal occlusion. 
− 
Sexual abstinence defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the clinical study and the preferred and 
usual lifestyle of the subject. 
Periodic abstinence (e.g. calendar, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of a clinical study, withdrawal, spermicides only, and lactational 
amenorrhea method are not acceptable as methods of contraception.  
In case a woman of childbearing potential has a vasectomized partner, provided that partner is 
the sole sexual partner of the participant and that the vasectomized partner has received medical 
assessment of surgical success, then she is not required to use an additional form of 
contraception. 
Within these limits, the specific forms of contraception employed are left to the discretion of 
the subject, the investigator, and/or the subject’s physician.  
Female subjects of childbearing potential will be requested to do a monthly urine pregnancy 
test during the study. The monthly pregnancy test outcome must be documented on the subject 
diary card and at the next visit in the source and case report form (CRF). In case of a positive 
urine pregnancy test at home, the subject should immediately contact the clinical study center 
and the investigator must report this immediately, and under no circumstances later than 
24 hours after being made aware.  
The safety of GLPG1690 during breastfeeding is unknown. Women who are nursing are not 
allowed to take part in this clinical study. 
Pregnant women or women planning to become pregnant during the study are not allowed to 
take part in this study. 
4.5.3.1.2. Male Subjects 
Men should be advised not to father a child while receiving treatment and must use effective 
contraception during and up to 90 days after treatment. Male subjects intending to father a child, 
should discontinue treatment with IMP and wait for at least 90 days before stopping the 
contraceptive measures detailed in this section. 
Non-vasectomized male subjects with female partners of childbearing potential must be willing 
to use a condom from the time of the first dose of IMP, during the clinical study, and for at least 
90 days after the last dose of IMP in addition to having their female partner use one of the 
following forms of contraception: 
− 
Combined (estrogen- and progesterone-containing) (oral, intravaginal, transdermal) 
hormonal contraception associated with inhibition of ovulation.  
− 
Progesterone-only hormonal (oral, injectable, implantable) contraception associated with 
inhibition of ovulation.  
− 
Intrauterine device.  
− 
Intrauterine hormone-releasing system. 


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Sexual abstinence defined as refraining from heterosexual intercourse during the entire period 
of risk associated with the study treatments is considered a highly effective contraceptive 
measure. The reliability of sexual abstinence needs to be evaluated in relation to the duration 
of the clinical study and the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g. calendar, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of a clinical study, withdrawal, spermicides only, and lactational 
amenorrhea method are not acceptable methods of contraception.  
In a case where the female partner of a male subject has undergone documented surgical 
sterilization that was performed more than 1 year before screening, then the subject is not 
required to use an additional form of contraception.  
Vasectomized male subjects with female partners of childbearing potential are not required to 
use an additional form of contraception, provided that surgical sterilization has been successful 
(documented azoospermia by semen analysis). 
Male subjects with a pregnant or breastfeeding partner should use a condom to prevent exposure 
through seminal fluid. 
No sperm donation is allowed from the first dose of the IMP until 90 days after the last dose. 
4.5.3.2. 
Prior and Concomitant Medications 
Prior therapy 
Prior therapy taken up to 12 weeks prior to and during the screening period, and pirfenidone 
and nintedanib taken any time prior to and during the screening period will be recorded after 
signing of the ICF, at Visit 1. 
Concomitant therapy 
Should any treatment other than the IMP be used during the course of the study, the name of 
the therapy, the dosage, the route, the reason for therapy, and the start and stop dates of 
administration must be recorded until the last visit. For subjects receiving oxygen, the volume 
administered per minute will also be recorded at each visit. 
Concomitant therapies taken for the long-term treatment of pre-existing conditions can continue 
during the study, provided they are in accordance with the in- and exclusion criteria (see 
Sections 4.5.1 and 4.5.2, respectively). It is required that the use of these medications should 
have been stable from 4 weeks prior to screening and during the screening period (at the 
investigator’s discretion). For nintedanib and pirfenidone, subjects need to have received a 
stable dose for at least two months prior to screening and during screening; stable being defined 
as the highest dose tolerated by the subject during those two months. 
In case additional concomitant medication needs to be administered or dose adjustments for 
pre-existing conditions need to be performed during the study, the benefit-risk to the subject 
should be carefully assessed and consideration given to the timing of any necessary introduction 
of new medications. 
The following therapies are prohibited during the course of the study and within 4 weeks prior 
to screening, because of lack of benefit or suggestion of harm in IPF: warfarin, imatinib, 


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ambrisentan, azathioprine, cyclophosphamide, cyclosporine A, bosentan, methotrexate, 
sildenafil (except occasional use), prednisone at steady dose >10 mg/day or equivalent. 
If during the study, the subject’s condition necessitates the use of one of the abovementioned 
medications (excluding high-dose steroids), the use of IMP should be interrupted until 
resolution or stabilization of this condition, preferably after consultation with the CRO medical 
monitor (as per study contact list) or sponsor’s study physician (if the former is not available).  
Precautions with concomitant medication known to prolong the QT interval 
The use of medication known to prolong QT interval during the study needs to be based on a 
benefit-risk evaluation by the investigator, e.g. in the case of atrial fibrillation. In certain other 
situations (e.g. the initiation of macrolides or fluoroquinolones in case of a lower respiratory 
tract infection), when the benefit-risk evaluation necessitates the administration of medication 
known to or potentially prolonging QT, IMP can be interrupted as evaluated by the investigator 
after clinical assessment of the subject’s profile, including the baseline QTcF and how this has 
changed over time for this specific subject. If the investigator elects to continue IMP, additional 
monitoring will be performed as per investigator’s judgment. A non-exhaustive list of 
medication known to prolong QT interval is provided in Appendix 7. 
Precautions with other concomitant medications 
At dose levels of 600 mg q.d., GLPG1690 has the potential to influence substantially the 
metabolism of substrates of CYP2C8 and to potentially be influenced by known strong 
CYP3A4/potent P-gp inducers/inhibitors. 
• GLPG1690 demonstrated a strong time-dependent inhibition potential against 
CYP2C8-mediated metabolism. Consequently, GLPG1690 should not be used 
concomitantly with medications primarily or solely metabolized via CYP2C8 (see 
Appendix 3). For other medications involving part of their metabolism pathway via 
CYP2C8, caution should be applied on a case-by-case basis taking into consideration 
the benefit/risk ratio. Statins such as fluvastatin and pitavastatin are metabolized to some 
degree by CYP2C8, and need to be used with caution. Other statins such as simvastatin, 
lovastatin, and atorvastatin are theoretically less metabolized by CYP2C8. Monitoring 
of LFTs and creatine kinase is implemented during the study, and guidance to the 
subject aligned with guidance for statins in clinical practice is therefore strongly 
recommended. Loperamide is also a substrate of CYP2C8, and special caution should 
be applied in alignment with clinical practice. 
• GLPG1690 is a substrate of CYP3A4 and P-gp, and could therefore be influenced by 
their respective inhibitors and inducers. GLPG1690 exposure is reduced up to 90% by 
the strong CYP3A4/potent P-gp inducer rifampin. As a consequence, strong inducers of 
CYP3A4 and/or P-gp are part of the exclusion criteria and should be avoided during the 
study to ensure proper exposure to GLPG1690 (see Appendix 4). For inhibition, strong 
CYP3A4 and dual strong 3A4 and potent P-gp inhibitors have shown that GLPG1690 
exposure increased by 3 to 4 fold when coadministered therefore use of known strong 
CYP3A4 inhibitors and potent P-gp inhibitors is prohibited during the study (see 
Appendix 5 and Appendix 6). Antibiotics from the macrolide therapeutic class are 
excluded, unless they are used for the short-term treatment of a lower respiratory tract 


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infection with interruption of IMP, which is restarted as soon as possible after the 
completion of the treatment with macrolides. 
It is highly recommended that the CRO medical monitor (as per study contact list) or sponsor’s 
study physician (if the former is not available) are consulted before the initiation of medication 
known to prolong QT interval, to be a CYP2C8 substrate, or to inhibit or induce P-gp/CYP3A4. 
In certain situations, when the benefit-risk evaluation necessitates the administration of 
medication excluded from use during the study, IMP should be interrupted and restarted as soon 
as possible.  
As a rule, inclusion of subjects with stable chronic illness on stable medications which are 
metabolized/transported by the abovementioned CYP/transporter enzymes should be decided 
on a case-by-case basis if not excluded or prohibited, taking into account the medical history, 
concomitant medication of the subject, the therapeutic index of the medication, and safety 
profile.  
As indicated in the study contact list, the CRO medical monitor should be contacted, or the 
sponsor’s study physician in case the former is not available (when deemed necessary by the 
investigator), specifically for medication with a narrow therapeutic index and/or a risk of 
(un)predictable AEs.  
Rescue medication  
If the subject shows a worsening of his/her IPF disease condition (e.g. acute IPF exacerbation), 
all treatment options are allowed at the investigator’s discretion. The decision to continue the 
IMP should be taken on a case-by-case basis by the investigator, and in case of doubt can be 
discussed with the CRO medical monitor (as per study contact list) or sponsor’s study physician 
(if the former is not available). 
4.5.3.3. 
Food and Beverage Restrictions 
The use of St-John’s Wort, a strong CYP3A4 inducer, is prohibited during the study. 
Double-strength grapefruit juice is potentially a potent CYP3A4 inhibitor and therefore should 
be avoided during the study. 
4.5.3.4. 
Other Prohibitions and Restrictions 
Not applicable. 
4.5.4. 
Treatment Discontinuation, Subject Withdrawal, and Study Termination 
All subjects will continue on IMP until the last subject reaches 52 weeks into the study 
(Visit 12) (for details, please refer to Section 4.1 and to Section  6.1 “Specific study visits when 
the last subject reaches 52 weeks into the study (Visit 12)”).  
Subjects will be informed prior to clinical study entry that they are allowed to withdraw from 
the clinical study. At any time and for any reason, a subject’s participation in the clinical study 
may terminate at his/her request, without prejudice to his/her future medical care. The subject 


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will be encouraged to share the reason(s) for withdrawal so this can be documented in the source 
documents.  
Subjects who choose to withdraw from study participation will be asked if they are prepared to 
complete a last visit. In this case, either the EoST or EoSA visit should be performed. The 
subjects’ vital status information will be collected at the time of the EoST/EoSA visit of the last 
subject who reaches 52 weeks in the study (Visit 12) according to national, ethical, and 
regulatory guidelines, and as per the subjects’ confirmation in the signed main ICF. If the 
subject initially confirmed no vital status information to be collected, but reconsiders at the time 
of actual withdrawal of consent, the subject has to re-consent for this in writing. 
Subjects who withdraw from the clinical study without contacting the clinical study center (lost 
to follow-up) should be contacted by the clinical study center so that their health status can be 
assessed and documented in the source documents. The clinical study center should make every 
effort to understand whether the subject is alive, including checking the medical records, 
contacting general practitioner or relatives, if necessary. All attempts must be documented in 
the source documents.  
Subjects who discontinue IMP early (ETD), with the exception of patients who withdraw 
consent and patients lost to follow-up, will be encouraged to complete all following visits and 
evaluations as originally planned per protocol (see below, “Procedures in case of early treatment 
discontinuation (ETD)”). 
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 subjects, investigator(s), and relevant 
authorities will be informed of the reason for clinical study termination. 
Discontinuation of IMP 
Treatment with IMP will be discontinued by the investigator (preferably after discussion with 
the CRO medical monitor, who may consult and must inform the sponsor’s study physician) 
for any of the following reasons: 
− 
Life-threatening AE or a serious adverse event (SAE) that places the subject at immediate 
risk. 
− 
Confirmed pregnancy: if a subject becomes pregnant during the study (to be confirmed by 
local serum pregnancy test; central measurement will also be performed), the IMP has to 
be stopped immediately and the subject has to be followed up until birth or otherwise 
termination of pregnancy. The subject needs to be unblinded immediately and repeat 
counseling on birth defect risk must be offered in case she was on active drug. 
− 
Arrhythmia or conduction abnormality, including but not limited to prolonged QTcF, 
where the severity is categorized as Common Terminology Criteria for Adverse Events 
(CTCAE) Grade 3 or higher. 
− 
An increase for QTcF of >60 ms from baseline (Visit 3) or QTcF >500 ms at any ECG 
recording (any recording of triplicate ECG or single ECG) needs to be confirmed by an 
ECG recording as soon as possible from the original abnormal recording at the same visit. 
If the abnormal recording is discovered after the visit, the recording should be confirmed 
as soon as possible. In case of an abnormal ECG on both of these two recordings is 
confirmed, the investigator needs to send an immediate alert to the central reader for 
confirmation as well as to the CRO medical monitor (as per study contact list) or sponsor’s 


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study physician (if the former is not available). If the ECG abnormality is before IMP 
intake, IMP administration will be withheld until the central reader has reviewed the ECG 
registration. In case of confirmation of the ECG abnormality, IMP will be discontinued for 
this subject. Only in case a response of the central reader is not available within the 
timeframe of the visit, the investigator can proceed to discontinue the treatment of the 
subject. 
If a normal QTcF is reported during the visit, but the central cardiologist reports it as 
abnormal (any of the two criteria above), then the IMP should be discontinued as soon as 
possible. 
− 
Increase in LFTs (also see Appendix 9): 
• 
At Visit 3 immediately after randomization: test results will only be available after the 
first IMP intake. If the subject meets the exclusion criteria for AST, ALT, total 
bilirubin, and GGT, then treatment with IMP will be discontinued. 
• 
Any other visit: 
• 
AST or ALT ≥8xULN 
• 
AST or ALT ≥3xULN with signs of severe liver damage (i.e. with the 
appearance of fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash and/or eosinophilia [>5%], and/or total bilirubin 
≥1.5xULN or INR >1.5) 
• 
AST or ALT ≥3xULN for more than 2 weeks 
• 
AST or ALT ≥3xULN during re-escalation 
− 
Clinical laboratory test suggestive of cholestasis with total serum bile acid levels >3xULN 
on a sample taken in fasted state (at least 8 hours fasted). If the routine random or 
postprandial total serum bile acid sample is >3xULN, then the subject should have a fasted 
sample taken within 1 to 5 days. The results of this test will determine whether the subject 
should discontinue IMP or not. 
− 
Chronic (defined as: anticipated to be administered for more than 3 months) use of 
concomitant medication not permitted during the study. 
− 
Closing of the study by the sponsor or regulatory authorities.  
− 
Wish of the subject to stop taking IMP. 
 
For a subject having: 
• AST or ALT ≥8xULN 
• AST or ALT ≥3xULN with signs of severe liver damage (i.e. with the appearance of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or 
eosinophilia [>5%], and/or total bilirubin ≥1.5xULN or INR >1.5) 
the following steps will need to be performed by the investigator.  
− 
The site should immediately contact the subject and require the subject to discontinue 
IMP immediately. The subject should be asked to return to the site within a 48-hour 
window from awareness of the result.  
− 
An assessment of other concomitant medications and SoC should be made. The 
investigator should consider whether it is in the best interest of the subject to interrupt 
concomitant medications and SOC treatment.  


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− 
A detailed history including relevant information on alcohol use, recreational drug use, 
supplement consumption, any herbal remedies, family history, sexual history, travel 
history, history of contact with a jaundiced subject, surgery, occupational history, blood 
transfusion, history of liver or allergic disease, and any other potential causes of a liver 
insult should be collected.  
− 
A detailed assessment of the subject’s clinical condition and repeat laboratory tests for 
LFT, including albumin, creatine kinase, total bilirubin (direct and indirect), GGT, INR 
and alkaline phosphatase should be done  
− 
Further testing for Hepatitis A, B, and C, and for autoimmune hepatitis should be done. 
Other causes of viral hepatitis (CMV or EBV etc) should be excluded.  Liver imaging 
should be considered.  
− 
Referral to a hepatologist or gastroenterologist should be considered. 
− 
All these cases should be reported as SAEs.  
 
Every effort should be made to keep subjects in the study and on treatment. However, the 
investigator can consider stopping treatment with IMP, preferably after consultation with the 
CRO medical monitor (as per study contact list) or sponsor’s study physician (if the former is 
not available), 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).  
− 
At Visit 3: as the blood sample is taken before first IMP intake and the results are only 
available after first IMP intake, the investigator needs to justify continuation of IMP in 
writing for abnormal results (based on the exclusion criteria) for: 
• 
Creatinine clearance 
• 
Hb 
The reason(s) for stopping the IMP will be documented in the CRF.  
Procedures in case of early treatment discontinuation (ETD) 
Subjects who discontinue IMP early will complete an ETD visit. They will be encouraged to 
complete all following visits and evaluations as originally planned per protocol (i.e. including 
an EoSA visit when the last subject reaches 52 weeks into the study [Visit 12]). The subject 
will be informed about this at signing of the ICF. 
In particular, the subject will be requested if at all possible to attend:  
− 
the first scheduled visit after their Early Treatment Discontinuation (ETD)  
− 
The Week 26 visit (if not done before IMP discontinuation) 
− 
the Week 52 visit (if not done before IMP discontinuation) 
− 
after Week 52, visits every 24 weeks up to EoSA, as described in Section 6.11.2 
 
An ETD visit will be scheduled as soon as possible from the day of early discontinuation of 
IMP. In case the subject discontinues IMP on a scheduled visit, that visit should be completed 
and, in addition, the assessments from the ETD visit that are not part of the scheduled visit 


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should be performed. If the subject is not able or not willing to come back for an ETD visit, the 
investigator will contact the subject by phone, and if the subject has agreed to this in the ICF, 
may consult the subject’s medical record and/or contact the subject’s general practitioner or 
relatives, if necessary, to obtain the needed information.  
4.6. 
Measures to Minimize Bias 
4.6.1. 
Randomization 
At screening, subjects will be assigned a subject identification number. When a subject is 
confirmed to be eligible for the clinical study, he/she will be randomized.  
A total of approximately 750 subjects will be randomized in a 1:1:1 ratio to receive 
GLPG1690 600 mg q.d., GLPG1690 200 mg q.d., or matching placebo for at least 52 weeks. 
Allocation of each subject to a given treatment will be described in a randomization list prepared 
by a CRO. This randomization list will be stratified in a balanced manner for background local 
standard of care for treatment of IPF (nintedanib, pirfenidone, or neither). Recruitment may 
stop earlier in one or more strata to maintain the balance as indicated, while the other strata(s) 
continue to recruit. Upon qualification for the study, allocation of each subject to a given 
treatment will be done using a centralized electronic system (interactive web response system 
[IWRS]) with permuted blocks. 
For each subject at each visit, the clinical study center will contact the IWRS for the appropriate 
treatment number to be assigned. Each medication kit will contain the relevant IMP for the 
period until the next visit. 
Subjects and study personnel will be blinded to the treatment assignment. Additional details on 
blinding and unblinding are provided in Section 4.6.2. 
4.6.2. 
Blinding and Unblinding 
This is a randomized, double-blind clinical study. The subject and the entire clinical study team, 
including the investigators, clinical study coordinators, and sponsor personnel are blinded to 
treatment assignment, except for situations described in the last paragraph of this section. 
Blinded and packaged medication will be provided to the clinical study center. All IMP 
formulations will be packaged in the proper proportion to assure desired dosages and 
maintenance of the blinding. In case of down-titration, interruption, or re-escalation, a sham 
dose level is available for the treatment allocation arm of GLPG1690 200 mg in order to ensure 
the same number of steps as the other treatment allocation arms and to ensure blinding (for 
details, refer to Sections 4.1 and 5.2). The different steps are blinded for treatment allocation 
but not for dose level. 
The blind can be broken only if the investigator deems it necessary for the safety of a subject. 
The investigator is encouraged to discuss considerations to break the blind with the CRO 
medical monitor (as per study contact list) or the sponsor’s study physician (in case the former 
is not available), whenever possible and where the situation allows. However, the responsibility 
to break the treatment code in emergency situations resides solely with the investigator. The 
investigator is not required to discuss unblinding beforehand if he/she feels rapid emergency 
unblinding is necessary, but is required to inform the CRO medical monitor and sponsor in a 
timely fashion after unblinding has occurred. 


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The blind can be broken by the investigator via the IWRS. If the blind is broken for any reason 
during the course of the study, the moment on which the subject’s data were unblinded and all 
other relevant information will be documented by the clinical study center, the CRO, and other 
sponsor designees, as appropriate. The reason for breaking the blind will be indicated and 
justified in the source documentation and in the CRF. 
Code-break information (via IWRS vendor/randomization list) will be provided to the 
bioanalytical laboratory responsible for plasma drug determination sample analysis and to the 
sponsor pharmacovigilance lead for SAE reporting purposes. The IDMC will have access to 
unblinded data (for details, refer to Section 8.1). 
5. 
INVESTIGATIONAL MEDICINAL PRODUCT 
5.1. 
Identity of the Investigational Medicinal Product 
The IMPs (GLPG1690 and placebo) will be supplied to the clinical study center, by and under 
the responsibility of the sponsor, who will also provide the investigator with European Union 
Qualified Person release documents. 
GLPG1690 will be provided as film-coated tablets for oral use, containing 100 mg or 
200 mg G451990 each (G451990 is the compound code for GLPG1690). The placebo will be 
provided as matching film-coated tablets for oral use. The GLPG1690 100-mg tablets and the 
placebo tablets matching the GLPG1690 100-mg tablets will be smaller than the 
GLPG1690 200-mg tablets and the placebo tablets matching the GLPG1690 200-mg tablets. 
A full list of excipients used in the film-coated tablet formulation is available in the IB 
(Edition 6, 28-June-2019) and any relevant updates/addenda/errata.  
5.2. 
Dosage and Administration 
The following doses will be tested; three tablets will be provided per dose (high [original] dose 
level): 
− 
GLPG1690 600 mg q.d. (as three GLPG1690 200-mg tablets) 
− 
GLPG1690 200 mg q.d. (as one GLPG1690 200-mg tablet and two placebo tablets, 
matching the GLPG1690 200-mg tablet) 
− 
placebo q.d. (as three placebo tablets, matching the GLPG1690 200-mg tablet) 
The following doses will be provided for down-titration and re-escalation; two tablets will be 
provided per dose: 
Low (reduced) dose level: 
− 
GLPG1690 200 mg q.d. (as one GLPG1690 200-mg tablet and one placebo tablet, 
matching the GLPG1690 100-mg tablet) 
− 
GLPG1690 100 mg q.d. (as one GLPG1690 100-mg tablet and one placebo tablet, 
matching the GLPG1690 200-mg tablet)  
− 
placebo q.d. (as one placebo tablet, matching the GLPG1690 200-mg tablet and one 
placebo tablet, matching the GLPG1690 100-mg tablet) 
Intermediate (reduced) dose level: 
− 
GLPG1690 400 mg q.d. (as two GLPG1690 200-mg tablets) 


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− 
GLPG1690 200 mg q.d. (as one GLPG1690 200-mg tablet and one placebo tablet, 
matching the GLPG1690 200-mg tablet) 
− 
placebo q.d. (as two placebo tablets, matching the GLPG1690 200-mg tablet)  
Refer to Figure 2 in Section 4.1.2 for an overview of number of tablets to be taken per dose 
level. 
The IMP is to be taken q.d. at the same time every day with food (e.g. breakfast, small meal, or 
a snack) or after food intake, taking into account the timing of the planned visits, with a 
maximum of 2 hours between the food intake and IMP intake. Subjects will be instructed to 
swallow the tablets as a whole with a glass of water and to not chew the drug prior to 
swallowing. On visit days, subjects will be instructed to take their IMP at the clinical study 
center, to allow for predose (i.e. before IMP intake) assessments to be completed.  
At Visits 3, 9, and 12, the subject will be asked to take pirfenidone or nintedanib (if applicable) 
at the clinical study center. 
If a subject misses a dose (e.g. because he/she forgot to take the medication), he/she should take 
the missed dose within 12 hours after the planned intake time and within 2 hours of food intake. 
If the IMP is not taken within 12 hours after the planned time, the missed dose should be 
skipped. 
For subjects who are taking nintedanib as standard of care medication at screening or 
randomization or who start nintedanib during the study, it is recommended to take the IMP at 
or after lunch (approximately 4 hours after nintedanib morning intake). 
5.3. 
Packaging, Labeling, and Distribution 
The film-coated tablet for oral use will be packaged in blisters.  
All manufacturing, packaging, and labeling operations will be performed according to Good 
Manufacturing Practices (GMP) for Medicinal Products and the relevant regulatory 
requirements. 
Each medication kit will be identified with a unique kit number. A multiple of kits will be 
provided to the subject at each visit, providing the subject with sufficient tablets to cover the 
period until the next scheduled visit.  
The distribution to the clinical study center will only occur after all required documentation is 
obtained including clinical study approval by Competent Authorities and the IECs/IRBs, 
documentation on which the assessment of the investigator’s qualifications was based 
(e.g. curriculum vitae), and the signed and dated study agreement and financial agreement. The 
IMP is to be dispensed according to the protocol. 
In case study subjects cannot attend site visits, due to any COVID-19-related reason, direct-to-
patient (DTP) shipment of IMP has been implemented and can be used to ensure the dosing 
regimen per protocol requirement can be maintained. DTP should only be used in case of 
emergency where on-site IMP dispensing is not possible, and if allowed per local regulations. 
Local guidelines must be followed and regulatory approval or notification of authorities may 
be required. The DTP process used will be reviewed and approved by the sponsor. If the DTP 
shipments originate from the investigational site(s), their coordination will be ensured by the 


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investigational site(s) in collaboration with the CRO to ensure clinical integrity without the 
involvement of the sponsor. Detailed guidance on the shipment has been provided to the sites 
in COVID-19 guidance documents. Consent of the subjects to receive IMP at home is required 
prior to the shipment of IMP, and should be documented in the source data. Return shipment of 
unused IMP from the subjects to the site may be implemented if allowed per local regulations. 
5.4. 
Storage 
Clinical study centers are to store all drug supplies in a secure, locked area with limited access 
below 30°C, protected from light, until dispensed. Clinical study centers will be required to 
monitor the storage temperature by using at least a calibrated minimum-maximum 
temperature-recording device and to keep a minimum to maximum temperature log, which must 
be completed each working day in order to establish a record of compliance with these storage 
conditions. The investigator will instruct subjects on how the IMP should be stored at home. 
5.5. 
Treatment Compliance and Drug Accountability 
For each dose taken at home, the date and number of tablets taken should be recorded on the 
subject diary card (see Section 6.4 for additional information). A new diary card will be 
provided together with each new medication kit. Any interruption or change in treatment 
(together with the reason for change) should be documented on the subject diary card. 
The investigator or designated clinical study personnel will maintain a log of the total amount 
of IMP received at the clinical study center, amount dispensed to the subject, and the amount 
of IMP returned by the subject to the clinical study center. IMP supplies for each subject will 
be inventoried and accounted for throughout the clinical study. These records will be checked 
against the inventory by the study monitor on a regular basis. All clinical supplies will be stored 
in locked facilities. 
Subjects will return any unused IMP and empty IMP packages at each study visit. Missed doses 
should be discussed to try to ascertain the reason(s). Every effort should be made to ensure 
proper subject dosing. Subjects with poor compliance will be re-trained by the clinical study 
center. 
Treatment compliance will be assessed by the investigator or designee. At each visit, clinical 
study center staff will review treatment compliance by assessing the number of returned IMP.  
6. 
CLINICAL STUDY ASSESSMENTS 
Every effort should be made to ensure that protocol-required tests and procedures are completed 
as described in the Schedule of Activities (see Section 6.11). To avoid inter-observer variability, 
a reasonable effort should be made to ensure that all safety and efficacy evaluations are 
completed by the same individual who made the initial baseline determinations. 
For subjects who, for any COVID-19-related reason, cannot perform study procedures, 
extended visit windows, the possibility to conduct phone/televisits followed by home (or other 
remote location) visits, and alternative assessment procedures are detailed in Section 6.1.1. 


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6.1. 
Timing of Assessments 
The study assessments will be undertaken at time points as specified in the Schedule of 
Activities in Section 6.11. A window of ±2 days is allowed for Visits 4 and 5, ±4 days for 
Visits 6 to 12, and ±7 days for all visits after Visit 12. 
The ICF needs to be signed before any study procedure, including screening procedure, is 
carried out. The ICF signature is the start of the 28-day screening period and will be used as the 
date of Visit 1. 
Please note that the both Visit 1 and Visit 2 can have a duration of more than one day to 
accommodate all screening assessments. 
Visit 1: The preferred sequence of study assessments will be as follows (urine analysis can be 
done at any stage during the visit): 
1. Only for subjects taking nintedanib: the time of nintedanib intake will be recorded.  
2. In- and exclusion criteria, demographics, medical history, alcohol consumption, and 
smoking habits 
3. EQ-5D, SGRQ, LCQ, K-BILD, VAS Cough and Urge to Cough questionnaires 
4. ECG (triplicate)* 
5. 
 
6. Spirometry** (Spirometry should not be repeated until notification from the central 
reader is received) 
7. DLCO 
8. Assessment of (S)AE(s) and prior and concomitant medication 
9. Physical examination and vital signs (supine heart rate, respiratory rate, systolic and 
diastolic blood pressure [SBP and DBP], and body temperature)  
10. Blood sampling for safety, FSH (if applicable), serum pregnancy test, and clinical 
laboratory tests  
11. Only for subjects taking nintedanib: blood sampling for nintedanib concentration 
assessment 2-4 hours after nintedanib intake 
12. 
 
13. 
 
14. 6MWT 
 
15. Repeat spirometry** if acceptability and repeatability criteria as defined in the 
ATS/ERS/JRS/ALAT guidelines are not met as confirmed by the central spirometry 
reader 
16. Only for subjects taking nintedanib: blood sampling for nintedanib concentration 
assessment 5-10 hours after nintedanib intake 
 
*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 
(for details, refer to Section 6.6.5). 
**Subjects using inhaled bronchodilators can do this after the confirmed spirometry 
assessment, unless clinically indicated to administer earlier. 


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Note: If needed, an HRCT needs to be planned and performed during the screening period 
before Visit 2. This can be done during an unscheduled visit in the screening period. A repeat 
HRCT is only allowed to be performed once for study eligibility, if the HRCT is >12 months 
old, or if the available historic HRCT cannot be evaluated. 
As soon as possible after signing the ICF, the investigator will transmit the HRCT images and 
the LB specimens (if available) for review (for details, refer to Section 6.3 and Appendix 1). 
 
Subjects can only proceed to Visit 2 if the diagnosis of IPF is confirmed by central reading of 
the chest HRCT and (if available) LB, and if all other test results with the exception of ECG 
(if a retest is needed) allow the subject to proceed. 
Visit 2: 
1. Repeat abnormal ECG if the central reading of the Visit 1 ECG report confirms that 
QTcF does not meet eligibility criterion. 
2. Spirometry* (Spirometry should not be repeated until notification from the central 
reader is received) 
3. 
 
4. Oxygen titration test for the 6MWT 
 
5. Assessment of (S)AE(s) and concomitant medication 
6. Repeat spirometry* if acceptability and repeatability criteria as defined in the 
ATS/ERS/JRS/ALAT guidelines are not met as confirmed by the central spirometry 
reader 
7. Repeat liver function tests, creatinine clearance and Hb if needed 
8. Repeat total serum bile acid if needed on a sample taken in fasted state (at least 8 hours 
fasted) 
*Subjects using inhaled bronchodilators can do this after the confirmed spirometry 
assessment, unless clinically indicated to administer earlier. 
Subsequent visits: the preferred sequence of study assessments during the IMP intake period, 
will be as follows (please take note of assessments that may be only required at certain visits 
and refer to the Schedule of Activities for further details): 
1. Randomization via IWRS (at Visit 3 only) 
2. Urine pregnancy test (if applicable) with urine analysis 
3. EQ-5D, SGRQ, LCQ, K-BILD, VAS Cough and Urge to Cough 
4. ECG (triplicate) at Visits 3 and 4; ECG (single) for any following visit* 
 
For subjects on nintedanib either at screening and randomization or starting nintedanib during 
the study, the blood sampling at Visits 3, 9, and 12 (i.e. items 10 to 14 in this list) can be 
performed after the ECG assessment and before the oxygen saturation test. 
 
5. 
 
6. Spirometry** 
7. DLCO 






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visit windows (as described in Section 5.3). Urine pregnancy tests (if applicable) and subject 
diary cards may also be supplied to the subject’s home. 
Assessments and Activities to be performed at remote and on-site visits 
For Visit 4 and all visits thereafter, if a randomized subject is not able to attend a scheduled 
study visit on site and a phone/televisit is conducted instead, then the study assessments should 
be conducted according to the Schedule of Activities (Section 6.11) as much as possible, in 
particular for Visits 9 and 12.  
If possible and available, trained study staff or trained personnel are encouraged to carry out 
study assessments at the subject’s home or another remote location (i.e. conduct phone call first, 
then conduct home/remote location visit).  
Sites should assess risk to subjects’ safety incurred by home (or other remote location) visits 
and ensure that the staff sent to the subject’s home do not pose a risk of infection to the subject 
or vice versa. 
At the phone/televisits or home (or other remote location) visits, the investigator should collect 
information on adverse events (changes of ongoing or new events), changes in concomitant 
medications or standard of care, and enquire about ongoing IMP intake (completion of subject 
diary cards).  
At the home (or other remote location) visits, the following assessments should be performed 
(if appropriate as per Schedule of Activities, Section 6.11). If it is not possible to perform all 
assessments, every effort should be made to complete the assessments indicated with an asterisk 
(*) 
− 
physical examination (including weight) * 
− 
vital signs assessment *  
− 
safety blood sample collection for central laboratory assessment where possible or local 
laboratory assessment (if sampling conditions as per laboratory manual cannot be 
ensured) * 
− 
spirometry (using the study device) * 
− 
12-lead electrocardiogram (ECG) using the study device if possible or local assessment * 
− 
electronic Clinical Outcome Assessment (eCOA) collection using the tablet device 
provided for the study * 
− 
  
− 
urine pregnancy test (if applicable) *  
 
In addition, all efforts should be made to review and collect the subject diary cards and perform 
drug accountability as well as retrieving the (un)used IMP blisters. 
The 6MWT and DLCO can be performed if circumstances allow.  
Blood samples for PK, 
 
should not be collected at home visits. 


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Additional guidance for on-site visits 
If an on-site visit for randomized subjects is feasible, all assessments for the applicable visit 
should be performed according to the Schedule of Activities (Section 6.11). However, if it is 
not possible to conduct all the assessments, then the following assessments/activities should be 
prioritized: 
− 
adverse events (changes of ongoing or new events) as well as information on 
hospitalization between visits 
− 
changes in concomitant medications or standard of care, enquiring about ongoing IMP 
intake (completion of subject diary cards), as well accountability and return of (un)used 
IMP blisters  
− 
vital signs 
− 
safety blood sample collection (for central laboratory) 
− 
spirometry and ECG (using the study devices) 
− 
eCOA (using the tablet device provided for the study) 
− 
6MWT 
− 
DLCO 
− 
Urine pregnancy test (if applicable) 
 
Guidance on continuation of IMP during the COVID-19 pandemic 
The ultimate decision to continue or interrupt IMP remains with the investigator except when 
three consecutive on-site visits have been missed and could not be replaced by phone/televisits, 
home (or other remote location) visits, and/or local lab assessments, or if the safety assessments 
could not be performed within the indicated time periods. In these cases, IMP should be 
interrupted. 
In general, the decision on IMP continuation shall depend on the investigator’s assessment of 
the subject’s clinical condition, and on the occurrence and severity of adverse events and the 
results of laboratory assessments.  
Timely (in accordance to adjusted visit windows) local safety laboratory assessment and 
home/local ECG (if possible), are strongly recommended to support the decision regarding 
continuation of IMP. If these assessments are not feasible, then the investigator should collect 
minimal assessments, such as physical condition, adverse events, and concomitant medication 
to help decide on the subject’s continuation of IMP. If only phone/televisits are possible, the 
decision to continue IMP may be based on this information.  
The following criteria should be adhered to when making the decision on continuation of IMP 
and every effort should be made to capture safety assessments to ensure IMP can be continued. 
The recommendations are specific to the study phase: 
First phase: In case of missing visits between Visit 4 to Visit 8 (Week 2 to Week 18), safety 
assessments must be performed within an 8-week timeframe.  
Second phase: In case of missing visits between Visit 9 to Visit 12 (Week 26 to Week 52), 
safety assessments must be performed within a 12-week timeframe.  


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Third phase: After Visit 12 (Week 52 to End of Study), safety assessments must be performed 
within a 16-week timeframe.  
If during any of these phases, safety assessments at home or at another remote location are not 
feasible, then at a minimum, local laboratory evaluations are needed to evaluate if the subject 
can continue IMP. ECG alternatives are to be discussed with the medical monitor. 
If IMP was interrupted, once safety assessments as specified above have been performed, the 
investigator may consider the re-start of IMP. 
6.2. 
Unscheduled Visits 
Additional visits can be performed at other time points for any safety assessment if clinically 
indicated. If local regulations allow, home visits can be performed for safety laboratory 
sampling at the investigator’s discretion. These unscheduled visits and outcomes of additional 
assessments need to be recorded in the source and, if performed before the subject’s last visit 
per protocol, also in the CRF. 
6.3. 
Initial Subject and Disease Characteristics 
Subjects will be asked to attend the clinical study center for two screening visits, after giving 
written informed consent. 
The subject can only proceed to Visit 2 (screening visit 2) if the diagnosis of IPF is confirmed 
by central reading of the chest HRCT and by central review of the available LB, if required 
(according to the criteria in Appendix 1), and if all other test results of Visit 1 allow the subject 
to proceed.  
Retesting of individual screening assessment(s) that did not meet eligibility criteria is not 
permitted, with the following exceptions AND only in case it is still possible to randomize the 
subject within the per protocol defined screening period of 28 days: 
− 
Laboratory values for LFTs, creatinine clearance, and Hb can be retested once 
− 
Lost or invalid blood or urine samples 
Rescreening: in case of screening failure, subjects are allowed to be rescreened a maximum of 
two times, with an interval taking into account the eligibility criteria at the investigator’s 
discretion. When in doubt, the investigator can discuss rescreening with the CRO medical 
monitor (as per study contact list) or sponsor’s study physician (if the former is not available), 
on a case-by-case basis. Rescreening with the purpose to repeat a HRCT scan, is not allowed. 
If rescreened, the subject must be reconsented. The subject will be assigned a new subject 
number which will be linked to the first screening number.  
Visit 1 
The subject’s historical HRCT and LB (if available) will only be sent for review if the minimum 
requirement of HRCT slide thickness of <1.5 mm is met. Central reading will be performed by 
two readers for the confirmation of the IPF diagnosis through: 
− 
Central review of chest HRCT, with adjudication by a third reader, if necessary 




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6.4. 
Subject Diary Card 
Subjects will be given a diary card at Visit 3 to record the following: 
− 
from Day 1 until EoST/EoSA visit, subjects will be asked to record the date of IMP intake 
and the number of tablets taken for each administration 
− 
all subjects taking nintedanib (i.e. subjects taking nintedanib at screening and 
randomization or starting nintedanib during the study) until they stop taking nintedanib, 
will be asked to indicate via tick box whether each IMP administration was approximately 
4 hours after the nintedanib morning dose 
− 
only for subjects taking nintedanib at screening and randomization until they stop taking 
nintedanib, subjects will be asked to record the time they take nintedanib at home in the 
morning on the day of Visits 4, 5, 6, 7, 8, 10, and 11, and after Visit 12 (Week 52), in the 
morning on the day of the Visits every 12 weeks until the EoST/EoSA visit 
− 
from Day 1 until EoST/EoSA visit, subjects will be asked to record changes in concomitant 
medication regimen, including new medicines not captured in medication history, use of 
bronchodilators, monthly urine pregnancy test outcome (only for WOCBP), and any other 
concomitant medication used as well as any emerging AE 
Subjects will be instructed to bring their diary card and used/unused IMP to each visit. At each 
visit, review of compliance with the diary card and subject re-training if needed, will be 
performed.  
If subjects, due to any COVID-19-related reason, cannot attend visits on site, subject diary 
cards may be sent and should be completed as has been done prior to the COVID-19 outbreak. 
All efforts should be made to review and collect the diary cards at home or other remote location 
visits (where feasible), but certainly at the next on-site visit. 
6.5. 
Efficacy Assessments 
6.5.1. 
Pulmonary Function  
6.5.1.1. 
Spirometry 
Spirometry will be performed at the clinical study center before IMP intake and repeated after 
IMP intake if indicated (see below) to assess pulmonary function at the time points specified in 
the Schedule of Activities (Section 6.11) and according to the sequence of study assessments 
described in Section 6.1.  
Clinical study centers will be provided with spirometers to be used for all study spirometry 
assessments. Spirometry devices will not be used for other purposes than this study. 
The clinical study center-based spirometry must meet the criteria for acceptability and 
repeatability as defined in the ATS/ERS/JRS/ALAT guidelines [19] for screening, and will be 
based on ATS/ERS/JRS/ALAT guidelines after randomization. 
Pulmonary function will be measured in a standardized manner and results should be 
transmitted electronically during the visit immediately after performing the spirometry and 






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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. 
The K-BILD health status questionnaire is a 15-item questionnaire split into three domains: 
psychological, breathlessness and activities, and chest symptoms. Scores are weighted such that 
every domain score and the total score range from 0 to 100, with higher scores indicating a 
better health status.  
Subjects with IPF commonly present with a (severe) non-productive cough. Cough will be 
evaluated using the LCQ. The LCQ is a 19-item questionnaire split into three domains: 
physical, psychological, and social. Scores are calculated by domain (range from 1 to 7) and 
then added to obtain the total score (range from 3 to 21, with higher scores indicating a better 
health status). 
VAS Cough and Urge to Cough will use a VAS of 100 mm with extremes “no cough” to “worst 
possible cough”, and “no urge” to “highest urge to cough”.  
These questionnaires will be completed electronically, using a tablet device at the clinical study 
center. Subjects must be able to read and complete the EQ-5D, SGRQ, K-BILD questionnaire, 
LCQ, and VAS Cough and Urge to Cough by themselves. They should not receive any help 
from anyone (such as family and friends or study staff) in interpreting or responding to the 
questions and need to complete the questionnaires in a quiet environment at the clinical study 
center.  
If subjects, due to any COVID-19-related reason, cannot attend visits on site, see Section 
6.1.1. 
6.5.4. 
Functional Exercise Capacity Testing: 6MWT 
A 6MWT will be performed at the clinical study center to assess pulmonary function at the time 
points specified in the Schedule of Activities (Section 6.11), and according to the manual 
provided. 
The 6MWT measures the distance that a subject can walk at his/her pace on measured, flat hard 
surface in a period of 6 minutes. The 6MWT has been established as the walk test of choice in 
cardiorespiratory diseases. The change in 6-Minute Walk Distance has been found to be highly 
predictive of mortality [6]. Also, the Minimal Clinical Important Difference (MCID) has been 
validated [21]. 
The 6MWT will be performed based on the ATS recommendations [1]
 
. The subject should not have a contraindication to perform the 
6MWT at any visit during screening and during the treatment period. Contraindications for 
performing the 6MWT are provided in Appendix 10. 
At Visit 1, the 6MWT distance of 150 meters will have to be met to be eligible to proceed to 
Visit 2. The subject should not have a contraindication to perform the 6MWT (Appendix 10) 
or should not have a condition putting the subject at risk of falling during the test (investigator’s 
discretion). The use of a cane is allowed, the use of a stroller is not allowed at all for any 
condition. The test is performed under the usual conditions for the patient, with or without 
oxygen as applicable. 


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At Visit 2, an oxygen titration test will be performed, according to the manual description. The 
subject should not have a contraindication to perform the 6MWT. For the oxygen titration test, 
resting SpO2 should be ≥88% with maximum 6 L O2/min. During the walk, SpO2 should be 
≥83% with maximum 6 L O2/minute or ≥88% with 0, 2 or 4 L O2/minute. A subject will not be 
eligible if these criteria are not met. 
For each following visit, the subject should not have a contraindication to perform the 6MWT. 
At Visit 3, 6MWT will be performed before IMP intake. For all visits after Visit 3 (Visits 9 and 
12, and every 24 weeks thereafter), 6MWT will be performed after IMP intake. The 6MWT 
will be done under the same oxygen requirements as the final result in the oxygen titration 
period (Visit 2). 
If subjects, due to any COVID-19-related reason, cannot attend visits on site, see Section 
6.1.1. 
6.5.5. 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
6.6. 
Safety Assessments 
This section describes methods and timing for all safety assessments and recording. Additional 
assessments (e.g. unscheduled clinical laboratory tests or extra vital signs recordings) are 
allowed to ensure appropriate collection of safety data and to assess any perceived safety 
concerns.  
If subjects, due to any COVID-19-related reason, cannot attend visits on site, see Section 
6.1.1. 
6.6.1. 
Adverse Events 
The AE reporting period for safety surveillance begins when the subject signs the ICF and ends 
at his/her last follow-up visit.  
Detailed definitions, ratings, and reporting requirements for AEs and SAEs are found in 
Section 9. 
6.6.2. 
Clinical Laboratory Evaluations 
Blood samples will be collected before IMP intake by venipuncture (or indwelling catheter) at 
the time points indicated in the Schedule of Activities provided in Section 6.11 (see also 
Section 6.1). In addition, urine samples for the clinical laboratory evaluations will be collected. 


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Subjects do not need to be fasted at the time of sampling, unless specifically indicated. Clinical 
laboratory evaluations will be performed by the central laboratory. 
Blood and urine samples will be collected for the following clinical laboratory safety tests: 
- 
Hematology: hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin 
(MCH), mean corpuscular hemoglobin concentration (MCHC), Hb, red blood cell count, 
white blood cell (WBC) count, WBC differential count (absolute and relative), and platelets. 
- 
Coagulation: activated partial thromboplastin time and prothrombin time, INR. 
- 
Clinical chemistry: random glucose, urea, creatinine, uric acid, sodium, potassium, calcium, 
chloride, phosphorus, AST, ALT, GGT, total bilirubin, alkaline phosphatase, lactate 
dehydrogenase, total serum bile acid, albumin, total proteins, triglycerides, cholesterol, high 
density lipoprotein, low density lipoprotein, amylase, lipase, low density lipoprotein, and 
creatine kinase (CK) (CK- muscle/brain [CK-MB] to be performed if CK is elevated). 
- 
Urinalysis:  
• Dipstick: pH, glucose, proteins, blood, leucocytes; 
• Microscopic examination of the sediment (cylinders, erythrocytes, leucocytes), if 
indicated. 
- 
Serology: hepatitis B surface antigen and hepatitis C antibody, and HIV 1 and HIV 2 
antibodies only at screening. Positive hepatitis and HIV results should be reported by the 
investigator as required by local law. To assess eligibility, a positive hepatitis C antibody 
test should be confirmed by hepatitis C virus (HCV) RNA test. 
- 
FSH test for females at screening to confirm menopause, if applicable. 
- 
Urine pregnancy tests will be performed (only for WOCBP) on a monthly basis at home or 
at the clinical study center, with one additional test at the clinical study center at Visit 4. At 
screening, a serum pregnancy test (beta-human chorionic gonadotropin) will be performed. 
A positive urine pregnancy test needs to be confirmed as soon as possible by a serum 
pregnancy test (local sample; central sample to be sent as well). 
Reference ranges will be supplied by the central laboratory. Clinical laboratory values outside 
the normal range will be flagged and clinical relevance will be assessed by the investigator. 
Clinically significant laboratory test abnormalities as judged by the investigator should be 
recorded as AEs. More frequent sampling as well as additional tests may be performed as 
deemed necessary by the investigator to follow up and resolve any safety concerns. In some 
circumstances, local laboratory results are allowed to be used (e.g. positive urine pregnancy 
test, abnormal liver function tests) for diagnosis of decision, but a central sample should also 
be collected and analyzed. 
The details of sample collection, handling, storage, and shipment instructions will be provided 
in a separate laboratory manual. 
6.6.3. 
Physical Examination 
Physical examinations (including weight) will be conducted by a physician, trained physician’s 
assistant, or nurse practitioner (as acceptable according to local regulations) before IMP intake 
at visits specified in the Schedule of Activities in Section 6.11 (see also Section 6.1). At 
screening, height will be measured as well. The person conducting the physical examinations 
will document this in the subject’s medical records. Clinically significant abnormal findings 
should be recorded as AEs. 


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6.6.4. 
Vital Signs 
Vital signs (heart rate, respiratory rate, SBP and DBP, and body temperature) will be recorded 
before IMP intake in a standardized manner (i.e. after the subject has rested in a supine position 
for 5 minutes) at visits specified in the Schedule of Activities in Section 6.11 (see also 
Section 6.1). Vital sign parameter normal ranges are presented in Appendix 8. Clinically 
significant abnormal values should be recorded as AEs. 
6.6.5. 
Electrocardiogram 
At the time points specified in the Schedule of Activities (see Section 6.11 and also Section 6.1), 
an ECG will be recorded. Triplicate ECGs will be performed at Visit 1 and at Visits 3 and 4 
(before and 2-3 hours after IMP intake). At all other time points, a single ECG will be performed 
before IMP intake (or irrespective of IMP intake at the ETD [if applicable] and EoST/EoSA 
visits). In addition, a single ECG will also be performed between 2 to 3 hours after IMP intake 
at Visits 5, 7, and 10. Central reading will be performed for all ECGs at all time points. The 
ECG must be taken after subjects rested for at least 5 minutes in the supine position. Triplicate 
ECGs will be taken within preferably 6 minutes, with an approximate 2-minute interval 
between ECGs. Each ECG will be interpreted by the investigator for clinical significance at the 
moment of the measurement. In case of abnormal findings, even if not clinically significant, a 
repeat ECG will be performed as soon as possible after the original abnormal recording within 
the same visit (if possible) and interpreted by the investigator. If the abnormal recording is 
discovered after the visit, the recording should be confirmed as soon as possible. 
For Visit 3, triplicate abnormal QTcF >450 msec (as described in exclusion criterion 8) predose 
readings (and confirmatory repeat as soon as possible after the abnormal recording within the 
same visit if possible) need to be transmitted immediately to the central reader for review before 
IMP intake by the subject. The result of the review will be transmitted to the investigator and 
preferably the CRO medical monitor (as per study contact list) or sponsor’s study physician (if 
the former is not available). The decision to dose the subject will be taken by the investigator, 
after consultation with the CRO medical monitor (as per study contact list) or sponsor’s study 
physician (if the former is not available). In case a timely response from the central reader is 
not available, the investigator will decide whether to dose the subject or not. If the QTcF at 
Visit 3 predose is reported during the visit as normal, but the overread by the cardiologist reports 
a QTcF >450 ms, then the recording should be confirmed as soon as possible and the 
investigator needs to justify the continuation of IMP documenting this in the source and 
continue to monitor the patient. 
At Visit 3 (after IMP intake) and Visit 4 (before and after IMP intake), abnormal triplicate 
ECGs and their confirmatory repeat reading will be transmitted to the central reader for 
expedited review. Refer to Section 4.5.4 for details on abnormal ECG readings. 
For other time points with abnormal ECG reading, the investigator should alert the central 
reader. In that case, the ECG will be reviewed as soon as possible on the same day. The 
conclusion/evaluation of the central cardiologist reader will overrule the reading of the ECG 
device. 
At other time points with normal ECG reading, the standard review times will be adhered to. 
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 


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catheter insertion would fail, the ECG needs to be taken before the venipuncture and at least 
30 minutes after the failed attempt.  
ECG parameters to be recorded include the following: heart rate, PR interval, QRS interval, 
uncorrected QT interval, QTc, morphology, and rhythm. QTcF will be considered as normal if 
≤450 ms. A prolongation of QTcF to >500 ms or an increase from baseline of >60 ms will be 
considered a threshold of concern and the subject should be discontinued (for details, refer to 
Section 4.5.4). Normal ranges for ECG are provided in Appendix 8. 
ECG abnormalities will be interpreted by the investigator for clinical significance. Clinically 
significant abnormal values should be recorded as AEs. 
If subjects, due to any COVID-19-related reason, cannot attend visits on site, see Section 
6.1.1. 
6.7. 
Pharmacokinetic Assessments 
PK assessments will include concentration analysis of GLPG1690, pirfenidone and nintedanib.  
Plasma concentrations of GLPG1690, pirfenidone or nintedanib will be measured using a 
validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method and 
will be performed by the bioanalytical laboratory in charge of these analyses (ARDENA 
Biochemical Laboratory).  
To be able to investigate the potential interactions between GLPG1690 and pirfenidone or 
nintedanib, the following samples will be collected to measure levels of GLPG1690 and 
pirfenidone or nintedanib (also see  Table 1and Schedule of Activities in Section 6.11). For 
subjects taking neither pirfenidone nor nintedanib, the samples need to be collected in relation 
to the specified IMP intake. 
− 
At Visit 1 (screening), for patients on nintedanib, the time of morning nintedanib intake 
will be verified by the investigator. Blood samples will be taken between 2-4 hours; and 
5-10 hours after the morning intake of nintedanib. 
− 
At Visits 3, 9, and 12, samples will be collected before IMP and pirfenidone or 
nintedanib morning intake. At these visits, the subject needs to take pirfenidone or 
nintedanib (as applicable) at the clinical study center. 
− 
For subjects taking nintedanib at screening and randomization, until they stop taking 
nintedanib:  
• 
At Visit 4, 5, 6, 7, 8, 10, and 11, samples will be collected 2-6 hours after the 
morning nintedanib intake and before IMP intake. At these visits, the subject needs 
to take nintedanib (as applicable) as per his or her regular routine, and record the 
time of intake on the diary card. In addition, at Visits 7 and 10, samples will be 
collected 2-3 hours after IMP intake. 
• 
After Week 52 (Visit 12), samples will be collected 2-6 hours after the morning 
nintedanib intake and before IMP intake with a 12-week interval (until EoST/EoSA). 
At these visits, the subject needs to take nintedanib as per their regular routine, and 
record the time of intake on the diary card. 
− 
For subjects not taking nintedanib at screening and randomization and those stopping 
nintedanib during the study: 


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• 
At Visits 7 and 10, samples will be collected after the pirfenidone or nintedanib 
morning intake and before IMP intake. At these visits, the subject needs to take 
pirfenidone or nintedanib (as applicable) as per his or her regular routine. In addition, 
samples will be collected 2 to 3 hours after IMP intake during these two visits. 
• 
After Week 52 (Visit 12), samples will be collected after the pirfenidone or 
nintedanib morning intake if applicable, but before IMP intake, with a 24-week 
interval (until EoST/EoSA). At these visits, the subject needs to take pirfenidone or 
nintedanib (as applicable) as per their regular routine.  
− 
At the ETD (if applicable) and EoST/EoSA visits, samples will be collected irrespective 
of IMP, pirfenidone, or nintedanib intake.  
The details on blood sample collection, handling, storage, and shipment instructions will be 
provided in a separate laboratory manual. 
If subjects, due to any COVID-19-related reason, cannot attend visits on site, see Section 
6.1.1. 
 






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The stored samples shall only be used by the sponsor, sponsor partners and/or other companies 
contracted by the sponsor, for research related to this clinical study. Any research outside the 
context described in this protocol may only be conducted after approval by the IRB/IEC and 
Regulatory Authority and after obtaining informed consent from the subject. 
No characterization of human genetic material (genes, DNA, RNA) will be undertaken on these 
samples. If research is performed on genetic material of the samples then this can only be 
performed in context of the described protocol (e.g. 
) and the data obtained 
may in no case be used for the purpose of identification or re-identification of subjects. 


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6.11. 
Schedule of Activities 
For detailed instructions on the clinical study procedures, please see referred Sections and Section 6.1. 
6.11.1. 
Schedule of Activities: Screening and First 52 Weeks of Study Treatment 
For subjects who, for any COVID-19-related reason, cannot perform study procedures, extended visit windows, the possibility to conduct 
phone/televisits and home (or other remote location) visits, and alternative assessment procedures are detailed in Section 6.1.1. 
EVENT 
SCREENING 
PERIOD 
FIRST 52 WEEKS OF STUDY TREATMENT 
Study visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
ETD 
Study days (D) or weeks 
(W) 
± visit window  
D-28 to D-1 
D1 
W2 
(D15) 
±2 d 
W4 
(D29) 
±2 d 
W8 
(D57) 
±4 d 
W12 
(D85) 
±4 d 
W18 
(D127) 
±4 d 
W26 
(D183) 
±4 d 
W34 
(D237) 
±4 d 
W42 
(D295) 
±4 d 
W52 
(D365) 
±4 d 
 
Informed consent 
(Section 6.3) 
1 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (if applicable) and 
serology (Section 6.6.2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
HRCT sent for central 
review (Section 6.3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
LB (if available) sent for 
central review (Section 6.3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria  
(Sections 4.5.1, 4.5.2, 6.3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
(Section 6.3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
(Section 6.3) 
 
 
 
 
 
 
 
 
 
 
 
 
 


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EVENT 
SCREENING 
PERIOD 
FIRST 52 WEEKS OF STUDY TREATMENT 
Study visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
ETD 
Study days (D) or weeks 
(W) 
± visit window  
D-28 to D-1 
D1 
W2 
(D15) 
±2 d 
W4 
(D29) 
±2 d 
W8 
(D57) 
±4 d 
W12 
(D85) 
±4 d 
W18 
(D127) 
±4 d 
W26 
(D183) 
±4 d 
W34 
(D237) 
±4 d 
W42 
(D295) 
±4 d 
W52 
(D365) 
±4 d 
 
Alcohol consumption and 
smoking habits 
(Section 6.3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
(Section 6.6.3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (Section 6.6.4) 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG triplicate recording 
(Section 6.6.5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG triplicate recording 
before IMP intake 
(Section 6.6.5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG triplicate recording 
2-3 hours after IMP intake 
(Section 6.6.5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG single recording 
before IMP intake 
(Section 6.6.5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG single recording 
2-3 hours after IMP intake 
(Section 6.6.5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG single recording 
(Section 6.6.5) 
 
 
 
 
 
 
 
 
 
 
 
 
 


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EVENT 
SCREENING 
PERIOD 
FIRST 52 WEEKS OF STUDY TREATMENT 
Study visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
ETD 
Study days (D) or weeks 
(W) 
± visit window  
D-28 to D-1 
D1 
W2 
(D15) 
±2 d 
W4 
(D29) 
±2 d 
W8 
(D57) 
±4 d 
W12 
(D85) 
±4 d 
W18 
(D127) 
±4 d 
W26 
(D183) 
±4 d 
W34 
(D237) 
±4 d 
W42 
(D295) 
±4 d 
W52 
(D365) 
±4 d 
 
Pregnancy test (serum) 
(Sections 6.6.2 
and 4.5.3.1.1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (urine) 
(Sections 6.6.2 
and 4.5.3.1.1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests 
(Section 6.6.2)2 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spirometry 
(Section 6.5.1.1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
DLCO (Section 6.5.1.2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(Section 6.5.1.3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
6MWT 
 
(Section 6.5.4) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization by IWRS 
(Section 4.6.1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense IMP (Section 5.2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect IMP/perform drug 
accountability (Section 5.5) 
 
 
 
 
 
 
 
 
 
 
 
 
 


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EVENT 
SCREENING 
PERIOD 
FIRST 52 WEEKS OF STUDY TREATMENT 
Study visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
ETD 
Study days (D) or weeks 
(W) 
± visit window  
D-28 to D-1 
D1 
W2 
(D15) 
±2 d 
W4 
(D29) 
±2 d 
W8 
(D57) 
±4 d 
W12 
(D85) 
±4 d 
W18 
(D127) 
±4 d 
W26 
(D183) 
±4 d 
W34 
(D237) 
±4 d 
W42 
(D295) 
±4 d 
W52 
(D365) 
±4 d 
 
Diary card dispensing and 
collection (as applicable 
per visit) for drug 
accountability (Sections 5.5 
and 6.4) 
 
 
 
 
 
 
 
 
 
 
 
 
 
EQ-5D and SGRQ (ePRO) 
(Section 6.5.3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
LCQ and K-BILD 
questionnaire (ePRO) 
(Section 6.5.3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
VAS Cough and Urge to 
Cough (Section 6.5.3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intake P and N at clinical 
study center (Section 5.2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood samples 2-4 
hours after N morning 
intake (Section 6.7)3 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood samples 5-10 
hours after N morning 
intake (Section 6.7) 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood samples before 
IMP and P or N intake 
(Section 6.7) 
 
 
 
 
 
 
 
 
 
 
 
 
 






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6.11.2. 
Schedule of Activities: After 52 Weeks of Study Treatment 
For subjects who, for any COVID-19-related reason, cannot perform study procedures, the possibility to conduct phone/televisits and home (or 
other remote location) visits, and alternative assessment procedures are detailed in Section 6.1.1. 
EVENT 
AFTER 52 WEEKS OF STUDY TREATMENT 
Study visit 
Every 12 weeks up to 
EoST/EoSA 
±7 d 
Every 24 weeks up 
to EoST/EoSA3 
±7 d 
ETD 
EoST/EoSA* 
FU* 
Study weeks  
± visit window  
 
 
(4 weeks after 
EoST/EoSA) 
±7 d 
Alcohol consumption and smoking habits (Section 6.3) 
 
 
 
 
 
Physical examination (Section 6.6.3) 
 
 
 
 
 
Vital signs (Section 6.6.4) 
 
 
 
 
 
ECG single recording (Section 6.6.5) 
 
 
 
 
 
ECG single recording before IMP intake (Section 6.6.5) 
 
 
 
 
 
Pregnancy test (urine) (Sections 6.6.2 and 4.5.3.1.1) 
 
 
 
 
 
Clinical laboratory tests (Section 6.6.2) 
 
 
 
 
 
Spirometry (Section 6.5.1.1) 
 
 
 
 
 
DLCO (Section 6.5.1.2) 
 
 
 
 
 
 (Section 6.5.1.3) 
 
 
 
 
 
6MWT 
 (Section 6.5.4) 
 
 
 
 
 
Dispense IMP (Section 5.2) 
 
 
 
 
 
Collect IMP/perform drug accountability (Section 5.5) 
 
 
 
 
 






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7. 
STATISTICAL METHODS 
All statistical methods shall be detailed in the statistical analysis plan (SAP) that will be 
finalized prior to the database lock and unblinding. Data collected in this clinical study will be 
documented using summary tables, figures, and subject data listings, as appropriate. 
All statistical analyses will be performed by the CRO using the SAS (Version 9.1.3 or higher) 
software for statistical computations and SAS or R Studio for graphical purposes.  
Any deviations from the statistical analyses planned in this protocol will be documented in the 
SAP. 
A protocol deviations plan will include the definition of major and minor protocol deviations 
and the identification of major protocol deviations which will be excluded from the per-protocol 
analysis. The assessments of protocol deviations (major/minor) will be done prior to database 
lock and unblinding. 
7.1. 
Determination of Sample Size 
To account for multiple testing due to multiple doses, a Bonferroni approach [9] will be applied 
to the alpha level with higher priority given to the high-dose group. The primary endpoint will 
be tested at a 4% level when comparing GLPG1690 600 mg to placebo and a 1% level for 
GLPG1690 200 mg group versus placebo.  
Denoting ∆600 and ∆200, the true treatment differences of the two GLPG1690 treatment groups 
with placebo, and assuming a common standard deviation (SD) on the 52 weeks decline in FVC 
of 275 mL, the probabilities that 0, 1, or 2 treatment comparisons with placebo are statistically 
significant, are presented in Table 2. The family-wise error rate is protected at 5% using the 
Bonferroni procedure. The so-called disjuncture power of the study is the probability that 1 or 
2 hypotheses are rejected and is displayed in the right-most column of Table 2.  
A meta-analysis of the seven placebo-controlled studies that have been conducted on 
nintedanib, pirfenidone, and pamrevlumab has revealed that the treatment effect at 52 weeks is 
estimated to be approximately 119 mL in a treatment-naïve population, the effect observed with 
nintedanib alone is similar (112 mL) [32]. Little information is available on the expected 
treatment effect of GLPG1690 in addition to pirfenidone or nintedanib. Table 2 gives an 
overview of the power for different scenarios for the overall treatment effect in the population 
of subjects on standard of care (either pirfenidone or nintedanib, or neither pirfenidone nor 
nintedanib).  
Since the linear-slope model on the annual rate of decline in FVC accounts for missing data, 
the number of subjects randomized and the number of subjects included in the model is 
expected to be equal. An equal number of 250 subjects will be randomized to each treatment 
group to have at least 80% power to show a significant effect assuming the 600-mg group has 
a treatment effect of at least 80 mL in the overall population of treatment naïve and patients on 
standard of care. 


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Table 2: 
Probability of Statistical Significance of 0, 1, or 2 Treatment Comparisons With Placebo 
mL 
 
0 Successful 
1 Successful 
2 Successful 
Power 
∆600=80 
∆200=80 
6.8% 
23.4% 
69.9% 
93.2% 
∆600=80 
∆200=60 
10.1% 
46.9% 
43.0% 
89.9% 
∆600=80 
∆200=20 
11.5% 
84.4% 
4.1% 
88.5% 
∆600=80 
∆200=0 
11.2% 
88.0% 
0.7% 
88.8% 
∆600=90 
∆200=60 
5.1% 
51.1% 
43.8% 
94.9% 
∆600=50 
∆200=50 
43.9% 
34.3% 
21.9% 
56.1% 
∆600=50 
∆200=0 
50.6% 
48.9% 
0.5% 
49.4% 
∆600=0 
∆200=0 
95.2% 
4.5% 
0.3% 
4.8% 
Based on a review of the blinded data, the SD may be reassessed.  
7.2. 
Populations for Analyses 
7.2.1. 
All Screened Subjects 
All enrolled subjects who underwent screening assessments to check whether or not they are 
eligible to participate in the clinical study. 
7.2.2. 
All Randomized Subjects 
All enrolled subjects who underwent all screening assessments and were found to be eligible 
for the clinical study and who were randomized into the clinical study. 
7.2.3. 
Full Analysis Set 
All randomized subjects who received at least one dose of IMP. 
7.2.4. 
Per-Protocol Set 
All randomized subjects who received at least one dose of IMP, excluding subjects/data points 
with a major protocol violation which impacts the efficacy results. 
7.2.5. 
Pharmacokinetic Analysis Set 
All randomized subjects who received at least one dose of IMP and for whom evaluable PK 
data were available (e.g. excluding all protocol violations/deviations or AEs that may have an 
impact on the PK analysis). 






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Figure 4 
Multiplicity adjustment within study approach 
. 
No interim analysis for early termination for efficacy will be performed and therefore, no 
adjustment of the alpha level is needed. 
Efficacy Analyses 
All efficacy parameters (e.g. spirometry, clinical endpoints, quality of life) will be analyzed 
descriptively and FVC and %FVC will also be analyzed for a series of subgroups (such as 
baseline characteristics, background treatment, and stratum). The primary analyses will be 
conducted on the FAS population. 
Spirometry Data 
- 
The primary time point will be Week 52. Analyses at the end of the study are secondary.  
- 
The rate of decline in FVC will be analyzed using a random coefficient regression model 
(linear slope model) including sex, age, height, and stratification factor as covariates and a 
random intercept and slope. The treatment effect is determined by using estimated average 
slopes for each treatment group on the basis of the treatment*time interaction term from the 
above mixed model, with time as a continuous factor and treatment as a categorical factor. 
All available FVC values from baseline to Week 52 will primarily be used, including those 
from the ETD visit for subjects who discontinued early and do not complete their study 
visits up to Week 52. 
- 
As a secondary analysis, the same model will be fit using all data until the end of the study. 
- 
The proportion of subjects who have an absolute decline ≥10% in %FVC at least once 
during the study or who die will be analyzed using logistic regression including sex, age, 
height, and stratum as factors using data up to Week 52. 
- 
In addition, the same will be presented using all data up to the end of the study. A 
time-to-event analysis may also be used to analyze the composite endpoint of %FVC 
decline and mortality up to the end of the study. 
- 
The %FVC change from baseline will be analyzed using a similar random coefficient 
regression model (linear slope model) as FVC in mL. 




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7.3.5.1. 
Extent of Exposure 
A subject’s extent of exposure to IMP will be generated from the IMP administration page of 
the CRF. Exposure data will be summarized by treatment group. Duration of exposure to IMP 
will be expressed as the number of weeks between the first and last dose of IMP, inclusive, 
regardless of temporary interruptions in IMP administration and summarized by treatment 
group. Results will be presented for the 52-week and for the complete study period, separately. 
7.3.5.2. 
Adverse Events 
Clinical and laboratory AEs will be coded using the latest version of the Medical Dictionary 
for Regulatory Activities. System Organ Class, High-Level Group Term, High-Level Term, 
Preferred Term, and Lower-Level Term will be attached to the clinical database. 
The following AEs will be considered as TEAEs:  
Any AE with an onset date on or after the start of IMP intake and no later than 30 days after 
last dose of IMP, or any worsening of any AE on or after the start of IMP intake.  
Selected tables will also be presented including all AEs which occurred after the start of IMP 
intake up to the end of the study. 
Summaries (number and percentage of subjects) of TEAEs by System Organ Class and 
Preferred Term will be provided by treatment group. TEAEs will also be summarized by causal 
relationship to IMP and severity. In addition, TEAEs leading to premature discontinuation of 
IMP will be summarized and listed. Also, all SAEs, including the non-treatment-emergent 
SAEs, will be listed. 
7.3.5.3. 
Clinical Laboratory Evaluations 
Laboratory assessments will be analyzed descriptively. Changes from baseline (Day 1 before 
IMP intake) and shifts according to normal ranges will be presented as well. Analyses will be 
done per treatment group.  
7.3.5.4. 
Physical Examinations 
Physical examination results will be summarized by body system and treatment group. 
7.3.5.5. 
Vital Signs 
Vital signs will be analyzed descriptively. Changes from baseline (Day 1 before IMP intake) 
and shifts according to normal ranges will be presented as well. Analyses will be done per 
treatment group.  
7.3.5.6. 
Electrocardiogram 
ECG will be analyzed descriptively. Changes from baseline (Day 1 before IMP intake) and 
shifts according to normal ranges will be presented as well. Frequency analyses of subjects with 
a QTc or QTcF prolongation of >500 ms and with a QTc or QTcF increase >60 ms change from 
baseline will be presented as well. Analyses will be done per treatment group. 




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be detailed in the IDMC charter or SAP, as appropriate. To allow collection of as much safety 
information as possible on a potential down-titration dose, a futile dose will continue if the other 
dose does not show futility. Either the study will continue as planned or both doses (and the 
study) will be terminated. Sponsor personnel will remain blinded and the study will not be 
stopped for a beneficial effect.  
8.2. 
Clinical Endpoint Adjudication Committee 
The CEAC will consist of an independent group of experts that reviews and adjudicates clinical 
endpoints (see Section 6.5.2), as defined by the charter, in a blinded manner. This objective 
data adjudication will reduce variation in outcome reporting and observer bias. 
8.3. 
Additional Optional Independent Review of Safety Data  
Selected safety data associated with liver function test (with or without symptoms) may be 
subjected to review in blinded manner by an independent expert panel as needed. 
 
9. 
SAFETY REPORTING 
9.1. 
Definitions of Adverse Events, Serious Adverse Events, and 
Special Situations 
9.1.1. 
Adverse Events 
An AE is any untoward medical occurrence, new or worsening of any preexisting condition, in 
a clinical study subject administered a medicinal product and which does not necessarily has to 
have a causal relationship with this treatment.  
An AE can therefore be any unfavorable and unintended sign (for example, an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related. AEs may also include pre- or posttreatment 
complications that occur as a result of protocol-specified procedures, worsening of the targeted 
disease, overdose, drug abuse/misuse reports, or occupational exposure. Preexisting conditions 
that increase in severity or change in nature during or as a consequence of participation in the 
clinical study will also be considered AEs. 
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 


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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 (Edition 6, 
28-June-2019) and any relevant updates/addenda. 
9.1.4. 
Adverse Events of Special Interest 
Not applicable. 
9.1.5. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as Adverse Events or Serious Adverse Events 
Laboratory abnormalities without clinical significance based on the investigator’s judgment, 
are not considered AEs or SAEs. However, laboratory abnormalities (e.g. clinical chemistry, 
hematology, and urinalysis) or other abnormal (clinical study-specific) assessments (e.g. ECG, 
radiography, vital signs) that require medical or surgical intervention, are associated with signs 
and/or symptoms, or 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 Hb). 
The following liver enzyme elevations should be reported as SAEs: 
− 
AST or ALT ≥8xULN 
− 
AST or ALT ≥3xULN with signs of severe liver damage (i.e. with the appearance of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or 
eosinophilia [>5%], and/or total bilirubin ≥1.5xULN or INR >1.5)  
9.1.6. 
Special Situations 
Special situations are situations that have a possible impact on the safe use of IMP. These 
situations might be or might not be associated with AEs. 
The investigator must report the following special situations within 24 hours of becoming 
aware, as indicated on Page 2 under “Emergency Contact Information”: 
− Pregnancy 
− Abuse or misuse of study drug 
• Abuse of study drug is defined as the persistent or sporadic, intentional excessive 
use of the study drug, which is accompanied by harmful physical or psychological 
effects. 
• Misuse of study drug is defined as a situation where the study drug is intentionally 
and inappropriately used not in accordance with the product information. 
− Drug interaction or food interaction with study drug 


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• A drug interaction with study drug is defined as a situation in which there is evidence 
or a suspicion that the study drug interacts with another drug when both are 
administered together. 
• 
A food interaction with study drug is defined as a situation in which there is evidence 
or a suspicion that the study drug interacts with a food when taken together. 
− Medication error with study drug 
• A medication error with study drug is defined as an unintended failure in the drug 
treatment process that leads to, or has the potential to lead to, harm to the patient. 
− Occupational exposure to study drug 
• Occupational exposure with study drug is defined as an exposure to the study drug 
as a result of one’s professional or non-professional occupation. 
− Overdose with study drug 
• An overdose of study drug is defined as the administration of a quantity of the study 
drug given per administration or cumulatively, which is the intake of more than 
three tablets/day. 
− Product complaint or quality defect of study drug 
• Product complaint or quality defect of study drug is defined as complaints or defects 
of the study drug arising from potential deviations in the manufacture, packaging, 
or distribution of the study drug. 
9.2. 
Assessment of Adverse Events and Serious Adverse Events 
The investigator is responsible for assessing AEs and SAEs for causality and severity. This is 
the basis for the sponsor’s final review and confirmation of accuracy and completeness of event 
information and causality assessments. 
9.2.1. 
Assessment of Causality 
The investigator is responsible for assessing the causal relationship to IMP 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: 
− Relationship in time to IMP intake is improbable. Related to other etiologies such as 
concomitant medications or subject's clinical state.  
- 
Unlikely: 
− Relationship in time to IMP intake is improbable (but not impossible). Concomitant 
disease or other drugs provide plausible explanations. 
- 
Possible: 
− Relationship in time to IMP intake is reasonable. Event or laboratory test abnormality, 
could also be explained by disease or other drugs. Information on IMP withdrawal may 
be lacking or unclear. 
- 
Probable: 
− Relationship in time to IMP intake is reasonable. Unlikely to be attributed to 
concurrent disease or other drugs. Response to withdrawal is clinically reasonable and 
rechallenge not required. 


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


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


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Any SAEs that occur after the posttreatment follow-up visit but within 30 days of the last dose 
of IMP, regardless of causality, should also be reported (Emergency Contact Information on 
page 2). Investigators are not obligated to actively seek SAEs after the protocol-defined 
follow-up period. However, if the investigator is informed about an SAE that occurs at any time 
after the subject’s posttreatment follow-up visit and the event is deemed relevant to the use of 
IMP(s), he/she should promptly document and report the event to the sponsor by using the SAE 
form. 
9.3.3. 
Pregnancy 
All initial reports of pregnancy in female subjects and pregnancies in partners of male subjects 
included in the clinical study must be recorded and documented in the source documents and 
on the pregnancy form. The investigator must report each pregnancy immediately, and under 
no circumstances should this exceed 24 hours following the knowledge of the pregnancy, as is 
indicated on Page 2 under “Emergency Contact Information”. 
All pregnancies should be followed up until delivery or pregnancy interruption. The 
investigator will contact the subject/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 abnormal newborn outcomes are considered SAEs and must be reported using the SAE 
form. 
9.3.4. 
Reporting of Special Situations (Other Than Pregnancy) and 
Associated Adverse Events 
In case a special situation is not associated with an AE, the special situation should be reported 
within 24 hours by using the Special Situations form. 
In case a special situation is associated with an AE, the special situation should be reported 
within 24 hours by using the Special Situations form and the associated AE should be reported 
as specified in Section 9.3.1. 
In case a special situation is associated with an SAE, the special situation should be reported 
within 24 hours by using the SAE form (and not the Special Situations form) and the associated 
SAE should be reported as specified in Section 9.3.2. 
9.4. 
Sponsor Reporting Requirements 
Depending on relevant local legislation or regulations, including the applicable United States 
Federal Drug Administration Code of Federal Regulations, the European Union 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 (Edition 6, 28-June-2019) and any relevant updates/addenda or relevant local 
label, as applicable.  


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All concerned investigators will receive a safety letter notifying them of relevant 
SUSAR reports associated with any IMP. The investigator should notify the IEC/IRB of 
SUSAR reports as soon as is practical, where this is required by local regulatory agencies, and 
in accordance with the local institutional policy. 
10. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This clinical study is conducted in accordance with the current applicable regulations, 
ICH-GCP Guideline E6, EU Directive 2001/20/EC and its updates, and local ethical and legal 
requirements. 
GCP is an international ethical and scientific quality standard for designing, conducting, 
recording, and reporting studies that involve the participation of human subjects. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of clinical 
study subjects are protected, consistent with the principles that have their origin in the 
Declaration of Helsinki (1996 and successive amendments), and that the clinical study data are 
credible. 
The name and address of each third-party vendor (e.g. CRO) used in this study and the sponsor’s 
study team members will be maintained in the investigator’s and sponsor’s files as appropriate. 
10.1. 
Sponsor’s Responsibilities 
10.1.1. Regulatory Approval / Notification 
Prior to clinical study start, this protocol together with all relevant documentation will be 
submitted to the local Regulatory Authorities for review and approval and/or notification in 
compliance with local requirements.  
10.1.2. Clinical Study Closure Considerations 
The sponsor reserves the right to close the clinical study center 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 clinical study 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 a clinical study center include, but are not limited to: 
- 
Successful completion of the clinical study at the clinical study center. 
- 
The overall required number of subjects for the clinical study has been recruited.  
- 
Failure of the investigator to comply with the protocol, ICH-GCP guidelines or local 
requirements. 
- 
Inadequate recruitment of subjects by the investigator. 


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Reasons for early termination of a clinical study by the sponsor may include but are not limited 
to: 
- 
Safety concerns. 
- 
Sufficient data suggesting lack of efficacy. 
10.1.3. Indemnification 
Under the conditions of a contract concluded between investigator, clinical study center, 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 protocol, 
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 protocol 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 
Section 10.4.1). At 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 1 year, or 6 months for pediatric 
studies, after the end of the clinical study. 
10.1.6. Publication 
It is understood by the investigator that the sponsor shall be free to use the compound-related 
information which is generated during the clinical study and may disclose it to other clinical 
investigators and to regulatory agencies. As a consequence, the investigator agrees to provide 
all clinical study results and data generated during this clinical study to the sponsor. 
The investigator shall not be authorized to submit the results of this clinical study and any data 
for 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 


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


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If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this clinical study, the investigator must permit access to such reports. 
The subject is granting access to his/her source data by signing the ICF. 
Any difficulty in storing original documents must be discussed with the monitor prior to the 
initiation of the clinical study.  
10.2.4. Participation Cards 
If the subjects are not under 24-hour supervision of the investigator or 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 
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 clinical study center and 
no copy will be made. 
The subject will receive all information as required by the EU General Data Protection 
Regulation, including the identity of the controller, the clinical research purposes, the fair 
processing of his/her data, and all his/her data subject rights. All details are listed in the ICF. 
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 protocol, ICF, any other 
written information given to subjects, and subject recruitment materials has been obtained from 
the IEC/IRB. This approval document must be dated and clearly identify the clinical study and 
the related clinical study documents being approved, including the subject compensation 
programs, if applicable. 
During the course of the 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) 


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- 
Protocol amendments 
- 
Informed consent revision(s) 
Protocol 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/or write, oral consent in 
the presence of at least one impartial witness who was also included when the affected person 
was being informed may be given. The witness may not be anyone working at the trial site nor 
a member of the investigating team. The orally given consent shall be documented in writing, 
dated and signed by the witness.  
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 ICF 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, by 
an independent witness) and the investigator to document the willingness of the subject to 
continue with the clinical study. 
This signed and dated amended version will be filed together with the initial signed and dated 
ICF. 
Additional consent needs to be obtained from the subjects to allow collection of the 
 
 if approved by the local IEC/IRB (see also Section 6.9.2).  
A pregnant partner, who agrees that information will be gathered about her pregnancy, will sign 
a specific ICF to participate in the data collection.  
Data about the health of the baby will be collected if the parents agree with the data collection 
and sign the specific ICF. 


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10.5. 
Data Quality Control / Assurance 
10.5.1. Monitoring 
This clinical study will be monitored by sponsor representatives according to their current 
Standard Operating Procedures for the monitoring of clinical studies as described in the 
monitoring plan. 
To guarantee adequate protection of the subjects and to guarantee the quality of the data, the 
sponsor will ensure oversight of any clinical study-related duties and functions carried out on 
its behalf, including clinical study-related duties and functions that are subcontracted to another 
party by the sponsor’s contracted CRO(s). 
To ensure subjects’ safety, protocol compliance, and the quality of the data at all times, remote 
data monitoring may be utilized for this study. If allowed by local regulations, study monitors 
may perform remote source data verification, as per monitoring plan, to confirm that source 
data entered into the eCRFs by authorized site personnel are accurate and complete. 
10.5.2. Audit and Inspection 
To ensure compliance with relevant regulations, an independent quality assurance 
representative, regulatory authorities and/or IECs/IRBs may review this clinical study. This 
implies that auditors/inspectors will have the right to inspect the clinical study center(s) at any 
time during and/or after completion of the clinical study and will have access to the data 
generated during the clinical study, source documents, and subject's files. By participating in 
this clinical study, investigators agree to this requirement. 
 


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REFERENCES 
1. American Thoracic Society, "ATS Statement: Guidelines for the Six-Minute Walk 
Test," Am J Respir Crit Care Med, vol. 166, pp. 117-117, 2002.  
2. Bandoh K., Aoki J., Taira A., et al., "Lysophosphatidic acid (LPA) receptors of the 
EDG family are differentially activated by LPA species. Structure-activity relationship 
of cloned LPA receptors," FEBS Lett, vol. 478(1-2), pp. 59-65, 2000.  
3. Clinical Trial Facilitation Group (CTFG) (2014), "Recommendations related to 
contraception and pregnancy testing in clinical trials," [Online]. Available: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
[Accessed 2 February 2018]. 
4. Collard H., Ryerson T., Corte G., et al., "Acute exacerbation of idiopathic pulmonary 
fibrosis," Am J Respir Crit Care Med, vol. 194, pp. 265-275, 2016.  
5. Cordier J. and Cottin V., "Neglected evidence in idiopathic pulmonary fibrosis: from 
history to earlier diagnosis," Eur Respir J, vol. 183, pp. 916-923, 2013.  
6. du Bois R., Weycker D., Albera C., et al., "Six-Minute-Walk Test in Idiopathic 
Pulmonary Fibrosis," Am J Respir Crit Care Med, vol. 183, pp. 1231-1237, 2011.  
7. Esbriet. Summary of Product Characteristics.  
8. Fernández P., Daniels C., Schroeder D., et al., "Incidence, prevalence, and clinical 
course of idiopathic pulmonary fibrosis: a population-based study," Chest, vol. 137(1), 
pp. 129-137, 2010.  
9. Hochberg Y., "A Sharper Bonferroni Procedure for Multiple Tests of Significance" 
Biometrika. 75 (4): 800–802. 
10. ICH E10, International Conference on Harmonisation of Technical Requirement for 
Registration of Pharmaceuticals for Human Use. Choice of control group and related 
issues in clinical trials E10, 2000.  
11. Karimi-Shah B. and Chowdhury B., "Forced Vital Capacity in Idiopathic Pulmonary 
Fibrosis - FDA Review of Pirfenidone and Nintedanib," N Eng J Med, vol. 372(13), 
pp. 1189-1191, 2015.  
12. Kim D., Collard H. and King T. J., "Classifications and natural history of the idiopathic 
interstitial pneumonias," Am Thorac Soc, vol. 3, pp. 285-292, 2006.  
13. King T., Bradford W., Castro-Bernardini S., et al., "A phase 3 trial of pirfenidone in 
patients with idiopathic pulmonary fibrosis," N Eng J Med, vol. 370, pp. 2083-2092, 
2014.  
14. Ley B., Collard H. and King T. J., "Clinical course and prediction of survival in 
idiopathic pulmonary fibrosis," Am J Respir Crit Care Med, vol. 183, pp. 431-440, 
2011.  
15. Lynch D., Sverzellati N., Travis W., et al., "Diagnostic criteria for idiopathic pulmonary 
fibrosis: a Fleischner Society White Paper," Lancet Respir Med, vol. 6(2), pp.138-153, 
2017. 
16. Macintyre N., Crapo R., Johnson D., et al., "Standardisation of the single-breath 
determination of carbon monoxide uptake in the lung," Eur Respir J, vol. 26(4), pp. 
720-735, 2005. 
17. Magkrioti C. and Aidinis V., "Autotaxin and lysophosphatidic acid signalling in lung 
pathophysiology," World J Respirol, vol. 3(3), pp. 77-103, 2013.  
18. Meltzer E. and Noble P.W., "Idiopathic pulmonary fibrosis," Orphanet J Rare Dis, 
vol. 3, p. 8, 2008.  


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19. Miller M., Hankinson J., Brusasco V., et al., "Standardisation of spirometry," Eur 
Respir J, vol. 26, pp. 319-338, 2005.  
20. Montesi S., Mathai S., Brenner L., et al., "Docosatetraenoyl LPA is elevated in exhaled 
breath condensate in IPF," BMD Pulm Med, vol. 14(5), pp.1-7, 2014.  
21. Nathan S.D., du Bois R.M., Albera C., et al., "Validation of test performance 
characteristics and minimal clinically important difference of the 6-minute walk test in 
patients with idiopathic pulmonary fibrosis," Respir Med, vol. 109(7), pp. 914-922, 
2015. 
22. Navaratnam V., Fleming K., West J., et al., "The rising incidence of idiopathic 
pulmonary fibrosis in the UK," Thorax, vol. 66(6), pp. 462-467, 2011.  
23. Noble P., Albera C., Bradford W., et al., "Pirfenidone in patients with idiopathic 
pulmonary fibrosis," Lancet, vol. 377, pp. 1760-1769, 2011.  
24. Ofev. Summary of Product Characteristics.  
25. Oikonomou N., Mouratis M., Tzouvelekis A., et al., "Pulmonary autotaxin expression 
contributes to the pathogenesis of pulmonary fibrosis," Am J Respir Cell Mol Biol, 
vol. 47(5), pp. 566-574, 2012.  
26. Paterniti M.O., Bi Y., Rekic D., et al., "Acute exacerbation and decline in forced vital 
capacity are associated with increased mortality in idiopathic pulmonary fibrosis," Ann 
Am Thorac Soc., vol. 14(9), pp. 1395-1402, 2017. 
27. Quanjer P., Stanojevic S., Cole T., et al., "Multi-ethnic reference values for spirometry 
for the 3-95 year age range: the global lung function 2012 equations: Report of the 
Global Lung Function Initiative (GLI), ERS Task Force to establish improved Lung 
Function Reference Values.," Eur Respir J, vol. 40(6), pp. 1324-1343, 2012.  
28. Raghu G., Collard H., Egan J., et al., "An official ATS/ERS/JRS/ALAT statement: 
idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and 
management," Am J Respir Crit Care Med vol. 183, pp. 788-824, 2011.  
29. Raghu G, Remy-Jardin M, Myers JL, et al. American Thoracic Society, European 
Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society. 
“Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical 
Practice Guideline.” Am J Respir Crit Care Med. Vol. 198(5), e44-e68, 2018. 
30. Raghu G., Rochwerg B., Zhang Y., et al., "An official ATS/ERS/JRS/ALAT clinical 
practice guideline: treatment of idiopathic pulmonary fibrosis," Am J Respir Crit Care 
Med, vol. 192, pp. e3-e19, 2015.  
31. Raghu G., Weycker D., Edelsberg J., et al., "Incidence and prevalence of idiopathic 
pulmonary fibrosis," Am J Respir Crit Care Med, vol. 174, pp. 810-816, 2006.  
32. Richeldi L., Cottin V., du Bois RM., et al., "Nintedanib in patients with idiopathic 
pulmonary fibrosis: Combined evidence from the TOMORROW and INPULSIS® 
trials," Resp Med, vol 113, pp. 74-79, 2016. 
33. Richeldi L., du Bois R., Raghu G., et al., "Efficacy and safety of nintedanib in 
idiopathic pulmonary fibrosis," N Engl J Med, vol. 370, pp. 2071-2082, 2014.  
34. Spagnolo P., Del Giovane C., Luppi F., et al., "Non-steroid agents for idiopathic 
pulmonary fibrosis (review)," Cochrance Database Syst Rev, (9):CD003134, 2010.  
35. Tager A., LaCamera P., Shea B., et al., "The lysophophatidic acid receptor LPA1 links 
pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular 
leak," Nat Med, vol. 14(1), pp. 45-54, 2008.  
36. Tanaka M., Okudaira S., Kishi Y., et al., "Autotaxin stabilizes blood vessels and is 
required for embryonic vasculature by producing lysophosphatidic acid," J Biol Chem, 
vol. 281(35), pp. 25822-25830, 2006.  


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37. Taniguchi H., Ebina M., Kondoh Y., et al., "Pirfenidone in idiopathic pulmonary 
fibrosis," Eur Respir J, vol. 35, pp. 821-829, 2010.  
38. Thomeer M., Costabe U., Rizzato G., et al., "Comparison of registries of interstitial lung 
diseases in three European countries," Eur Respir J Suppl, vol. 32, pp. 114s-118s, 2001.  
39. Tsuda S., Okudaira S., Moriya-Ito K., et al., "Cyclic phosphatidic acid is produced by 
autotaxin in blood," J Biol Chem, vol. 281(36), pp. 26081-26088, 2006. 
40. Xu M., Porte J., Knox A., et al., "Lysophosphatidic acid induces αvβ6 integrin-mediated 
TGF-β activation via the LPA2 receptor and the small G protein Gαq," Am J Pathol, 
vol. 174(4), pp. 1264-1279, 2009.  
41. Wuyts W., Antoniou K., Borensztajn K., et al., "Combination therapy: the future of 
management for idiopathic pulmonary fibrosis?," Lancet Respiratory Medicine, vol. 2, 
pp. 933-942, 2014. 
 
 


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APPENDICES 
APPENDIX 1: 
HRCT/BIOPSY CENTRAL REVIEW CRITERIA 
All chest HRCTs and histopathology slides of LBs (if available) will be centrally reviewed by 
two radiologists with adjudication by a third radiologist if indicated and one histopathologist to 
confirm the diagnosis of IPF (if required) and therefore eligibility of the subject for the study. 
The diagnostic criteria for idiopathic pulmonary fibrosis, published as the Fleischner Society 
White Paper [15], will be used to determine eligibility of the subject for the trial. 
In case a historical LB 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. 
After central review of the HRCT, subjects will be considered eligible if:  
− 
The majority of the central readers evaluate the HRCT as showing a typical and/or 
probable IPF pattern, unless a historical LB, if available, is not in accordance with this 
diagnosis (i.e. is most consistent with an alternative diagnosis) 
− 
The majority of the central readers evaluate the HRCT as showing a pattern indetermined 
for IPF and/or a pattern most consistent with non-IPF diagnosis, but an available 
historical LB, shows a definite UIP-IPF pattern. 
 
The LB will not be evaluated if both 2 initial central reviewers evaluate the HRCT as showing 
the following pattern: 
− 
Typical UIP-IPF pattern + Typical UIP-IPF pattern 
− 
IPF pattern most consistent with Non-IPF diagnosis + IPF pattern most consistent with 
Non-IPF diagnosis 
 
 


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APPENDIX 2: 
DLCO 
At Visit 1 (screening visit 1), DLCO must meet the following criteria [16]:  
− 
DLCO corrected for Hb ≥30% predicted of normal 
For predicted normal values, different clinical study centers may use different prediction 
formulas, based on the method used to measure DLCO. In any case, the method used must be 
in compliance with the ATS/ERS task force guideline on DLCO measurements [16] and the 
prediction formula appropriate for that method.  
Raw data (gas mixture, equation used for prediction of normal) must be captured.  
DLCO corrected for Hb:  
− 
Males: DLCO corrected for Hb = DLCO measured x (10.22+Hb) /1.7Hb  
− 
Females: DLCO corrected for Hb = DLCO measured x (9.38+Hb)/1.7Hb  
Hb is expressed in g/dL.  


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APPENDIX 3: 
KNOWN CYP2C8 SUBSTRATES 
Excluded and prohibited medication: 
Amiodarone 
Buprenorphine 
Amodiaquine; Chloroquine 
Repaglinide 
Rosiglitazone, pioglitazone 
Verapamil 
Zopiclone 
This list is intended as a guidance for the investigator. 


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APPENDIX 4: 
KNOWN STRONG CYP3A4 INDUCERS AND POTENT 
P-GP INDUCERS 
Excluded and prohibited medication: 
Barbiturates  
Carbamazepine 
Glucocorticoids: prednisone or equivalent > 10 mg/day 
Modafinil 
Oxcarbazepine 
Phenytoin 
Pioglitazone 
Rifabutin 
Rifampin 
St. John’s Wort 
This list is intended as a guidance for the investigator. 


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APPENDIX 5: 
KNOWN STRONG CYP3A4 INHIBITORS 
Excluded and prohibited medication: 
Clarithromycin 
Itraconazole 
Ketoconazole 
Nefazodone 
Telithromycin 
Voriconazole 
This list is intended as a guidance for the investigator. 


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APPENDIX 6: 
KNOWN POTENT P-GP INHIBITORS  
Excluded and prohibited medication: 
Amiodarone 
Azithromycin – Clarithromycin – Erythromycin – Roxithromycin – Telithromycin 
(unless used under the condition described in Section 4.5.3.2) 
Cyclosporine 
Itraconazole - Ketoconazole 
Tamoxifen 
Verapamil 
This list is intended as a guidance for the investigator. 


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APPENDIX 7: 
MEDICATION KNOWN TO PROLONG QT 
INTERVAL  
Medication to be used with caution: 
Disopyramide 
Dofetilide 
Flecainide 
Ibutilide 
Quinidine 
Sotalol 
This list is intended as a guidance for the investigator. 


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APPENDIX 8: 
NORMAL RANGES FOR VITAL SIGNS, 
 
AND ECG PARAMETERS 
NORMAL RANGES FOR VITAL SIGNS 
Normal ranges applicable in supine position (after at least 5 minutes): 
SBP (mmHg) 
DBP (mmHg) 
Heart 
rate 
(bpm) 
Body 
temperature 
(°C) 
Respiratory rate 
(RR) 
(breaths/minute) 
90≤ SBP ≤150 
45≤ DBP ≤90 
50≤ HR 
≤100 
35.5≤ t ≤37.5 
12≤ RR ≤18 
bpm = beats per minute 
 
 
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  
50≤ HR ≤100 


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APPENDIX 9: 
ALGORITHM FOR ELEVATED LIVER FUNCTION 
TESTS 
 
AST or ALT increase to 
 
≥1.5x to 
3xULN 
≥3x to 5xULN 
≥5x to 8xULN 
≥3xULN with signs 
of severe liver 
damage1 
≥8xULN 
Visit 1 
(screening) 
Not eligible 
Not eligible 
Not eligible 
Not eligible 
Not eligible 
Visit 3 
(randomization) 
Discontinue 
IMP2 
Discontinue 
IMP2 
Discontinue 
IMP2 
Discontinue IMP2 
Discontinue 
IMP2 
From Visit 4 
onwards 
Continue as 
planned 
Down-
titration: 
reduce or 
interrupt IMP 
for at least 
2 weeks 
Close 
observation2  
Down-
titration: 
interrupt IMP 
for at least 
2 weeks 
Close 
observation2 
Discontinue IMP2 
Discontinue 
IMP2 
 
 
 
 
↙ ↘ 
 
After at least 
2 weeks 
AST and ALT <3xULN 
 
AST or ALT ≥3xULN 
  
Re-escalate to next dose level for 
at least 2 weeks 
Weekly LFTs for the first 2 weeks 
(biweekly for the following 
weeks, or more frequently at 
investigator’s discretion) 
Repeat re-escalation to next 
higher dose level every 2 weeks 
(or longer at investigator’s 
discretion) if AST and ALT 
<3xULN 
Discontinue IMP 
Report SAE and complete liver event page for any of 
abnormalities listed below3: 
- 
AST/ALT increase ≥8xULN 
- 
AST/ALT increase ≥3xULN with signs of severe 
liver damage1  
 
1 Signs of severe liver damage: 
 
total bilirubin ≥1.5xULN OR international normalized ratio >1.5, and/or 
 
symptoms: appearance of fatigue, nausea, vomiting, right upper abdominal quadrant pain or tenderness, fever, rash and/or eosinophilia 
(>5%)  
2 Close observation recommendations:  
 
Monitor two to three times per week all of the following parameters: ALT, AST, alkaline phosphatase, total bilirubin, eosinophils, INR. 
If local regulations allow, home visits can be performed if subjects cannot come to the clinical study center. 
 
Frequency of retesting can be reduced to once a week or less if abnormalities stabilize or the IMP has been discontinued; however, 
monitoring might still be needed more frequently taking into consideration the standard of care and/or changes to this. 
 
Based upon Investigator’s discretion gastroenterology or hepatology consultations, additional serology testing, imaging and pathology 
assessments may be required 
 
Re-query history of symptoms, prior and concurrent diseases, concomitant medication and non-prescription medicines, herbal, dietary 
supplements, alcohol use, recreational drug use, special diets. 
 
Rule out all of the following: acute viral hepatitis, auto-immune hepatitis, alcoholic hepatitis, non-alcoholic fatty hepatitis, 
hypoxic/ischemic hepatitis, biliary tract disease, and cholestasis. 
 
Re-query exposure to environmental chemical agents. 
 


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3 The following steps (as defined in Section 4.5.4) should be followed: 
• 
The site should immediately contact the subject and require the subject to discontinue IMP immediately. The subject should be 
asked to return to the site within a 48-hour window from awareness of the result.  
• 
An assessment of other concomitant medications and SoC should be made. The investigator should consider whether it is in the 
best interest of the subject to interrupt concomitant medications and SOC treatment.  
• 
A detailed history including relevant information on (alcohol use, recreational drug use, supplement consumption, any herbal 
remedies, family history, sexual history, travel history, history of contact with a jaundiced subject, surgery, occupational 
history, blood transfusion, history of liver or allergic disease, and any other potential causes of a liver insult should be collected.  
• 
A detailed assessment of the subject’s clinical condition and repeat laboratory tests for LFT, including albumin, creatine kinase, 
total bilirubin (direct and indirect), GGT, INR and alkaline phosphatase should be done  
• 
Further testing for Hepatitis A, B, and C, and for autoimmune hepatitis should be done. Other causes of viral hepatitis (CMV or 
EBV etc) should be excluded.  Liver imaging should be considered.  
• 
Referral to a hepatologist or gastroenterologist should be considered. 
• 
All these cases should be reported as SAEs 
 


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APPENDIX 10: CONTRAINDICATIONS FOR 6MWT 
Absolute contraindications: 
- 
Unstable angina during the previous month [1] 
- 
Myocardial infarction during the previous month [1] 
- 
SpO2 measured by 
 <88% after 10 minutes of rest of breathing room air 
or at baseline oxygen flow rate [6] 
Relative contraindications [1]: 
- 
Resting heart rate >120 beats per minute 
- 
SBP >180 mmHg 
- 
DBP >100 mmHg 


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APPENDIX 11: DEFINITION OF ACUTE IPF EXACERBATION 
Definition and diagnostic criteria are defined as follows [4]: 
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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SIGNATURE PAGE – SPONSOR 
 
Study Title: 
A Phase 3, randomized, double-blind, parallel-group, placebo-controlled 
multicenter study to evaluate the efficacy and safety of two doses of 
GLPG1690 in addition to local standard of care for minimum 52 weeks in 
subjects with idiopathic pulmonary fibrosis..A Phase 3, randomized, double-
blind, parallel-group, placebo-controlled multicenter study to evaluate the 
efficacy and safety of two doses of GLPG1690 in addition to local standard 
of care for minimum 52 weeks in subjects with idiopathic pulmonary 
fibrosis.A Phase 3, randomized, double-blind, parallel-group, placebo-
controlled multicenter study to evaluate the efficacy and safety of two doses 
of GLPG1690 in addition to local standard of care for minimum 52 weeks 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 3, randomized, double-blind, parallel-group, placebo-controlled 
multicenter study to evaluate the efficacy and safety of two doses of 
GLPG1690 in addition to local standard of care for minimum 52 weeks in 
subjects with idiopathic pulmonary fibrosis..A Phase 3, randomized, double-
blind, parallel-group, placebo-controlled multicenter study to evaluate the 
efficacy and safety of two doses of GLPG1690 in addition to local standard 
of care for minimum 52 weeks in subjects with idiopathic pulmonary 
fibrosis.A Phase 3, randomized, double-blind, parallel-group, placebo-
controlled multicenter study to evaluate the efficacy and safety of two doses 
of GLPG1690 in addition to local standard of care for minimum 52 weeks 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 glpg1690-cl-304-protocol 11188
Signature Page for glpg1690-cl-304-protocol 11188
Approval
09-Jun-2020 10:11:40 GMT+0000

SAP_001.pdf: 
 
-1- 
 
 
Confidentiality Statement 
The information contained in this document is privileged and confidential. It is the property of Galapagos NV and 
may not be used, disclosed, reproduced or otherwise disseminated within your organization or communicated to any 
third parties without the express written authorization of Galapagos NV. 
 
STATISTICAL ANALYSIS PLAN  
Project Number: 
GLPG1690 
 
Study Number: 
GLPG1690-CL-303 & 304 
Study Title: 
Two Phase 3, randomized, double-blind, parallel-group, placebo-
controlled multicenter studies to evaluate the efficacy and safety of two 
doses of GLPG1690 in addition to local standard of care for minimum 
52 weeks in subjects with idiopathic pulmonary fibrosis  
 
Development Phase: 
3 
Status: 
Final 
Version: 
2.0 
Date: 
25-Mar-2021 
EudraCT: 
2018-001405-87  &  2018-
001406-29 
IND: 
130687 
Sponsor: 
Galapagos NV, Generaal De 
Wittelaan L11 A3, 2800 
Mechelen, Belgium 
 
Biostatistician 
, MSc 
, MSc 
Medical director 
, MD 


Galapagos 
CONFIDENTIAL 
Doc id 402993
GLPG1690-CL-303 & 304 
 
 
 
-2- 
 
TABLE OF CONTENTS 
LIST OF TABLES .................................................................................................................. 6 
LIST OF FIGURES ................................................................................................................ 6 
VERSION HISTORY ............................................................................................................. 7 
LIST OF ABBREVIATIONS ................................................................................................... 8 
1. 
INTRODUCTION .......................................................................................................... 10 
2. 
STUDY DESIGN AND OBJECTIVES ........................................................................... 10 
2.1. 
STUDY OBJECTIVES ...................................................................................... 11 
2.1.1. 
Primary Objectives ............................................................................. 11 
2.1.2. 
Key Secondary Objectives ................................................................. 11 
2.1.3. 
Other Secondary Objectives .............................................................. 11 
2.1.4. 
 ................................................................................ 12 
2.2. 
Study Endpoints ................................................................................................ 12 
2.2.1. 
Primary Endpoint ............................................................................... 12 
2.2.2. 
Secondary Endpoints ......................................................................... 12 
2.2.2.1. 
Key Secondary Endpoints ................................................. 12 
2.2.3. 
Other Secondary Endpoints ............................................................... 12 
2.2.4. 
 ................................................................................. 13 
2.2.5. 
Adjudication ....................................................................................... 13 
2.3. 
Study Design .................................................................................................... 14 
2.4. 
Clinical Study Protocol ...................................................................................... 16 
2.5. 
Schedule of Activities ........................................................................................ 16 
2.5.1. 
Schedule of Activities: Screening and First 52 Weeks of Study 
Treatment .......................................................................................... 17 
2.5.2. 
Schedule of Activities: After 52 Weeks of Study Treatment ................ 22 
2.6. 
Sample Size Justification .................................................................................. 25 
2.7. 
Randomization and Blinding ............................................................................. 25 
3. 
ANALYSIS POPULATIONS .......................................................................................... 25 
3.1. 
All Screened Subjects Set ................................................................................. 25 
3.2. 
All Randomized Set .......................................................................................... 25 
3.3. 
Full Analysis Set (FAS) ..................................................................................... 25 
3.4. 
Per Protocol (PP) Set ........................................................................................ 26 
3.5. 
Pharmacokinetic Analysis Set ........................................................................... 26 
3.6. 
 ............................................................................... 26 
4. 
PRIMARY ESTIMAND .................................................................................................. 26 
5. 
TREATMENT GROUPS ............................................................................................... 27 
5.1. 
Randomized Versus Actual Treatment .............................................................. 27 
5.2. 
Totals over Groups ........................................................................................... 27 
6. 
ANALYSIS PERIODS AND ANALYSIS TIME POINTS ................................................. 27 
6.1. 
Relative Number of Days .................................................................................. 27 
6.2. 
Analysis Periods for Non-visit Data ................................................................... 28 
6.3. 
Algorithm of Allocating Visits to Time Analysis Windows ................................... 28 
6.4. 
Definition of Baseline ........................................................................................ 30 
6.5. 
Definition of Last Contact and End of Study (Censoring Rules) ......................... 30 


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7. 
HANDLING OF DATA .................................................................................................. 31 
7.1. 
Calculation of Descriptive Statistics................................................................... 31 
7.2. 
Calculation of Percentages ............................................................................... 31 
7.3. 
Handling of Values Below (or Above) a Threshold ............................................ 31 
7.4. 
Handling of Missing Data .................................................................................. 31 
7.4.1. 
Primary Approach .............................................................................. 31 
7.4.2. 
Handling of Missing Date Time Data .................................................. 32 
7.4.3. 
Sensitivity Analyses ........................................................................... 32 
7.5. 
Handling of Outliers .......................................................................................... 32 
7.6. 
Stratification Factors ......................................................................................... 32 
7.7. 
Exclusion of Data in Case of Quality Issues ...................................................... 32 
8. 
INTERIM ANALYSES AND DATA MONITORING COMMITTEE REVIEW ................... 33 
9. 
STATISTICAL ANALYSES ........................................................................................... 33 
9.1. 
Changes to the Planned Analyses, Not Covered by Protocol 
Amendments ..................................................................................................... 33 
Functional Exercise Capacity and SpO2: all analyses omitted, except for total 
distance walked in 6 minutes, this parameter will be analyzed. ................... 35 
9.2. 
Subject Information ........................................................................................... 35 
9.2.1. 
Demographic and Baseline Disease Characteristics .......................... 35 
9.2.2. 
Disposition Information....................................................................... 37 
9.2.3. 
Protocol Deviations and Eligibility ...................................................... 38 
9.2.4. 
Medical History and Concomitant Diseases ....................................... 38 
9.2.5. 
Prior and Concomitant Therapies ....................................................... 38 
9.2.5.1. 
Classification of Therapies ................................................ 38 
9.2.5.2. 
Coding of Therapies ......................................................... 39 
9.2.5.3. 
Analyses ........................................................................... 39 
9.2.6. 
Exposure to IP and Compliance ......................................................... 39 
9.2.7. 
Exposure to Standard of Care (SOC) ................................................. 40 
9.3. 
Efficacy Analyses .............................................................................................. 42 
9.3.1. 
Level of Significance .......................................................................... 42 
9.3.2. 
Spirometry Parameters ...................................................................... 44 
9.3.2.1. 
Primary Endpoint: Rate of Decline in FVC over a 
Period of 52 Weeks .......................................................... 45 
9.3.2.2. 
Sensitivity Analyses to the Primary Analyses .................... 45 
9.3.2.2.1. 
Sensitivity Analysis not Assuming a 
Linear Trend over Time ................................. 46 
9.3.2.2.2. 
Sensitivity Analyses – Per Protocol to 
Investigate the Impact of Protocol 
Violators ....................................................... 46 
9.3.2.2.3. 
Sensitivity On-treatment Analysis ................. 46 
9.3.2.2.4. 
Sensitivity Analysis Including Data 
After Lung Transplant ................................... 46 
9.3.2.2.5. 
Sensitivity Analysis on All Study Data 
(also beyond Week 52) ................................. 46 
9.3.2.2.6. 
Sensitivity Analysis for Completers 
versus those Who Discontinued Early ........... 47 
9.3.2.2.7. 
Sensitivity Analyses to Investigate the 
Impact of Missing Data – Control-
Based Pattern Mixture Approach .................. 47 
9.3.2.2.8. 
Sensitivity Analyses to Investigate the 
Impact of Changes in Standard of 
Care (Stratum) .............................................. 48 




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9.4.4.1. 
Normal Ranges ................................................................. 74 
9.4.4.2. 
Worst-Case Abnormality ................................................... 74 
9.4.4.3. 
Analyses ........................................................................... 75 
9.4.5. 
Physical Examinations ....................................................................... 75 
9.5. 
Pharmacokinetic Assessments ......................................................................... 75 
10. REFERENCES ............................................................................................................. 76 
11. APPENDICES .............................................................................................................. 77 
1. 
ADDITIONAL DETAILS ON PRIMARY ANALYSIS ....................................................... 77 
2. 
IMPLEMENTATION OF MULTIPLE IMPUTATIONS FOR PATTERN MIXTURE 
APPROACH ................................................................................................................. 78 
3. 
ADDITIONAL DETAILS ON MIXED-EFFECT MODEL FOR REPEATED 
MEASURES ANALYSIS ............................................................................................... 79 
4. 
LEICESTER COUGH QUESTIONNAIRE ..................................................................... 79 
5. 
SUMMARY OF THE FUTILITY APPROACH ................................................................ 80 
 
 
 




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VERSION HISTORY 
 
SAP Amendment # 
Date 
Description of changes 
SAP Version 1.0 
13/02/2019 
First version 
SAP Version 2.0 
25/25/2021 
- Changes to planned analysis due to termination GLPG1690-
CL-303/304 program (text in Italic font will not be performed) 
- Addition Section 7.7: exclusion of data in case of quality 
issues. 
- Section 9.2.7: addition more details on standard of care 
analyses 
- Section 9.4.2.5: Scoring based on CTCAE/Other Gradings: 
updated in agreement with clinicians 
- Addition COVID-19 analyses 
- Changes to CSP sections due to amendments CSP 
- General editorial changes to improve wording 


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LIST OF ABBREVIATIONS 
%FVC 
percent predicted forced vital capacity 
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 
estimated creatinine clearance, calculated according to 
Cockcroft-Gault calculation 
CEAC 
clinical endpoint adjudication committee 
CI 
confidence interval 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
diastolic blood pressure 
DLCO 
diffusing capacity of the lung for carbon monoxide 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EoSA 
end of study assessments 
EoST 
end of study treatment 
EQ-5D 
5-Dimensions Questionnaire 
ETD 
early treatment discontinuation 
EU 
European Union 
FAS 
full analysis set 
 
 
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  
HRCT 
high-resolution computed tomography 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IDMC 
independent data monitoring committee 
IP 
investigational product 
IPF  
idiopathic pulmonary fibrosis 


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ISE 
integrated summary of efficacy 
IWRS 
interactive web response system 
K-BILD 
King's brief interstitial lung disease 
LB 
lung biopsy 
LCQ 
Leicester Cough Questionnaire 
LLN 
lower limit of normal range 
LS 
least squares 
MAR 
missing at random 
MMRM 
mixed-effects model for repeated measures  
MNAR 
missing not at random 
 
 
PK 
pharmacokinetic(s) 
PP 
per protocol 
QTcF 
QT interval corrected for the heart rate using Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SE 
standard error 
SGRQ 
St. George’s Respiratory Questionnaire 
SI 
international system of units 
SOC 
standard of care 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of the normal range 
US 
United States 
VAS 
Visual Analogue Scale 
WBC 
white blood cell 
WHO 
world health organization 
 
 
 


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1. 
INTRODUCTION  
This statistical analysis plan (SAP) describes the analyses for each of the GLPG1690-CL-303 
and GLPG1690-CL-304 final analyses for the clinical study reports (CSR). Since the studies 
are identically designed, only one SAP is covering both CSRs.  
A decision was taken to halt the ISABELA Phase 3 clinical studies (study numbers 
GLPG1690-CL-303 and GLPG1690-CL-304) with the investigational autotaxin inhibitor 
ziritaxestat (GLPG1690) in patients with idiopathic pulmonary fibrosis. The decision was 
based on the recommendations of the Independent Data Monitoring Committee (IDMC) 
which, following a regular review of unblinded data on February 9, concluded that 
ziritaxestat’s benefit-risk profile no longer supported continuing these studies. 
In view of the above, no market authorisation application will be submitted for ziritaxtestat 
for the treatment of IPF. Therefore, it was decided to limit the analyses to the primary, key 
secondary and safety endpoints and any analyses important to better understand the reason for 
the results seen, or relevant for scientific knowledge for future compounds. Since no treatment 
effect was observed and the study was stopped for lack of efficacy, sensitivity analyses to 
investigate the robustness of results will also be limited. 
The results will be presented in an abbreviated CSR. 
All descriptions as documented in the original SAP were kept for reference, but endpoints and 
analyses deemed not applicable for the abbreviated CSR are in Italic font, and will not be 
included for the final analysis. A list of the analyses that will not be performed can be found 
in section 9.1. 
Analyses on the pooled data from both studies for the integrated summaries of efficacy and 
safety were planned to be very similar (adjusted for study as appropriate) and to be detailed 
in a separate pooled-analysis SAP. As no market authorisation application will be submitted, 
these pooled analyses will not be performed and the pooled-analysis SAP will not be written. 
Technical details on derivations and mock tables, listings and figures will be presented in a 
separate document. 
A separate SAP will be written for the population pharmacokinetics
 
(PK
) analyses. 
2. 
STUDY DESIGN AND OBJECTIVES 
The studies are identically designed with the same objectives, endpoints, etc. 
All objectives and endpoints as described in the CSP were kept as reference in the below 
sections, but endpoints that will not be described in the abbreviated CSR are in Italic font. 
Details on the analyses that will not be performed can be found in section 9.1. 
 


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2.1. 
STUDY OBJECTIVES 
2.1.1. 
Primary Objectives 
To evaluate the efficacy of two doses of GLPG1690 in addition to local standard of care 
compared to placebo in subjects with idiopathic pulmonary fibrosis (IPF) as evaluated by the 
rate of decline of forced vital capacity (FVC) over a period of 52 weeks. 
2.1.2. 
Key Secondary Objectives 
To evaluate the impact of two doses of GLPG1690 in addition to local standard of care 
compared to placebo in subjects with IPF on: 
− 
disease progression defined as deterioration of FVC or all-cause mortality at 52 weeks 
− 
respiratory-related hospitalization until the end of the study 
− 
changes in quality of life (measured by St. George’s Respiratory Questionnaire [SGRQ] 
total score) at 52 weeks 
2.1.3. 
Other Secondary Objectives 
− To evaluate the efficacy of two doses of GLPG1690 in addition to local standard of care 
compared to placebo in subjects with IPF as evaluated by the rate of decline of FVC until 
the end of the study 
− To evaluate the impact of two doses of GLPG1690 in addition to local standard of care 
compared to placebo in subjects with IPF on: 
• disease progression defined as deterioration of FVC or all-cause mortality until the 
end of the study 
• changes in quality of life (measured by SGRQ total score) until the end of the study 
• all-cause non-elective hospitalization until the end of the study 
• respiratory-related mortality until the end of the study 
• lung transplant until the end of the study 
• acute IPF exacerbation until the end of the study 
• all-cause mortality or lung transplant until the end of the study 
• all-cause mortality, or lung transplant, or qualifying for lung transplant until the end 
of the study 
• all-cause mortality, deterioration of FVC, or respiratory-related hospitalization until 
the end of the study 
• all-cause mortality or respiratory-related hospitalizations until the end of the study 
− To evaluate the effect of two doses of GLPG1690 in addition to local standard of care 
compared to placebo on the changes from baseline in FVC at 52 weeks and until the end of 
the study 
− To evaluate the safety and tolerability of two doses of GLPG1690 in addition to local 
standard of care compared to placebo until the end of the study 
− To evaluate changes compared to placebo in subjects with IPF in:  
• cough-related quality of life (measured by the Leicester Cough Questionnaire 
[LCQ] and by the Visual Analogue Scale [VAS] Cough and Urge to Cough) at 
52 weeks and until the end of the study 






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− 
All-cause mortality, or hospitalization for non-elective lung transplant, or hospitalization 
for qualifying for lung transplant (composite endpoint) 
− 
All-cause mortality, hospitalization for ≥10% absolute decline in %FVC, or respiratory-
related hospitalizations (composite endpoint) 
− 
All-cause mortality or respiratory-related hospitalizations (composite endpoint) 
 
Adjudication endpoints will be used in the analyses and not the corresponding investigator-
reported events. Consistency with the investigator-reported information will be investigated, 
however. 
2.3. 
Study Design 
This clinical Phase 3 study is a randomized, double-blind, parallel-group, placebo-controlled 
multicenter study designed to evaluate the efficacy and safety of two doses (200 mg q.d. and 
600 mg q.d.) of orally administered GLPG1690 in addition to local standard of care for at least 
52 weeks in adult subjects with a centrally confirmed diagnosis of IPF. Local standard of care 
for IPF is defined as receiving either pirfenidone or nintedanib at a stable dose for at least two 
months before screening, and during screening; or neither pirfenidone or nintedanib (for any 
reason). A stable dose is defined as the highest dose tolerated by the subject during those two 
months. A total of approximately 750 subjects with confirmed diagnosis of IPF will be 
randomized, 250 subjects in each treatment group (GLPG1690 600 mg q.d., GLPG1690 
200 mg q.d., or matching placebo). 
The diagnosis of IPF will be confirmed by central reading of the chest high-resolution computed 
tomography (HRCT) and by central review of the available lung biopsy (LB), if required, based 
on the Fleischner White Paper as described in Section 6.3 and Appendix 1 of the CSP. 
A schematic diagram of the clinical study design, procedures, and stages is provided CSP 
 
Figure 1: 
Schematic Study Overview 
D=Day, EoST/EoSA=end of study treatment/end of study assessments, FU=follow-up, V=Visit, W=Week. 


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Enrolled subjects will come to the clinical study center at screening (two visits from Day -28 to 
Day -1). Visit 2 of screening can only take place after confirmed IPF diagnosis on HRCT and 
LB (if applicable). 
At Visit 3, eligible subjects will be randomized in a 1:1:1 ratio to receive 
GLPG1690 600 mg q.d., GLPG1690 200 mg q.d., or matching placebo for at least 52 weeks. 
Randomization will be stratified for background local standard of care for treatment of IPF. 
Subjects will come to the clinical study center on Day 1 (baseline), Weeks 2, 4, 8, 12, 18, 26, 
34, 42, 52, and every 12 weeks thereafter. Additional unscheduled visits are allowed if, in the 
investigator’s opinion, further evaluation (clinical, laboratory, or other) is needed. 
When the last subject reaches 52 weeks (Visit 12), subjects still taking IP and who had a 
scheduled visit at the clinical study center within 6 weeks before this date will be contacted by 
their investigator (phone call) to discontinue IP within 7 days after this date. Then the last 
scheduled visit will be documented as the end of study treatment (EoST) visit. These subjects 
will be invited to their follow-up visit scheduled at the clinical study center 4 weeks after their 
last dose of IP (±7 days). For subjects still taking IP and who had their last scheduled visit more 
than 6 weeks before the date that the last subject reaches 52 weeks into the study (Visit 12), a 
scheduled visit will be planned within 2 weeks of this date for an EoST visit, followed by a 
follow-up visit 4 weeks later (visit at clinical center or phone call). Note that these subjects will 
continue IP intake until their EoST visit. 
For subjects who, for any Coronavirus disease (COVID-19)-related reason, cannot perform 
study procedures, extended visit windows, the possibility to conduct phone/televisits and home 
(or other remote location) visits, and alternative assessment procedures are detailed in Section 
6.1.1 of the CSP. 
Subjects who discontinue IP early (early treatment discontinuation [ETD]), with the exception 
of patients lost to follow-up and patients who withdraw consent, will be encouraged to complete 
all following visits and evaluations as originally planned per protocol.  
In particular, the subject will be requested if at all possible to attend:  
− 
the first scheduled visit after their Early Treatment Discontinuation (ETD)  
− 
The Week 26 visit (if not done before IP discontinuation) 
− 
the Week 52 visit (if not done before IP discontinuation) 
− 
after Week 52, visits every 24 weeks up to End of Study Assessments (EoSA), as 
described in Section 6.11.2 of the CSP. 
For procedures in case of ETD, refer to Section 4.5.4 of the CSP. In the exceptional case that a 
clinical study center visit cannot be attended, a phone call by the investigator will be made to 
evaluate safety, in combination with scheduled clinical study center visits. 
Each subject will have a screening period of maximum 28 days. The duration of study treatment 
for individual subjects will vary from 52 weeks for the last enrolled subject to e.g. 132 weeks 
for the first enrolled subject (assuming a recruitment period of 80 weeks, the actual duration 
will depend on the actual time to recruit subjects for the study). A follow-up visit (at the clinical 
study center or by phone call, decided by the investigator) is planned 4 weeks after the 
EoST/end of study assessment (EoSA) visit.  


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At the end of this study, treatment with IP in an optional extension study (under a separate study 
protocol) may be offered to all eligible subjects, provided Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB) and Competent Authority approvals for such an 
extension are granted.  
To protect the safety and integrity of the study data, an independent data monitoring committee 
(IDMC) will be implemented, as well as a clinical endpoint adjudication committee (CEAC). 
Charters are in place for all committees.  
2.4. 
Clinical Study Protocol  
This SAP was based on the version 7 dated 08 June 2020 of the two clinical study protocols. 
2.5. 
Schedule of Activities 
For detailed instructions on the clinical study procedures, please see referred Section 6.1 of 
the protocols. 


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2.5.1. 
Schedule of Activities: Screening and First 52 Weeks of Study Treatment 
For subjects who, for any COVID-19-related reason, cannot perform study procedures, extended visit windows, the possibility to conduct 
phone/televisits and home (or other remote location) visits, and alternative assessment procedures are detailed in the CSP 
EVENT 
SCREENING 
PERIOD 
FIRST 52 WEEKS OF STUDY TREATMENT 
Study visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
ETD 
Study days (D) or weeks 
(W) 
± visit window  
D-28 to D-1 
D1 
W2 
(D15) 
±2 d 
W4 
(D29) 
±2 d 
W8 
(D57) 
±4 d 
W12 
(D85) 
±4 d 
W18 
(D127) 
±4 d 
W26 
(D183) 
±4 d 
W34 
(D237) 
±4 d 
W42 
(D295) 
±4 d 
W52 
(D365) 
±4 d 
 
Informed consent  
1 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (if applicable) and 
serology  
 
 
 
 
 
 
 
 
 
 
 
 
 
HRCT sent for central 
review  
 
 
 
 
 
 
 
 
 
 
 
 
 
LB (if available) sent for 
central review  
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria   
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol consumption and 
smoking habits  
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs  
 
 
 
 
 
 
 
 
 
 
 
 
 


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EVENT 
SCREENING 
PERIOD 
FIRST 52 WEEKS OF STUDY TREATMENT 
Study visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
ETD 
Study days (D) or weeks 
(W) 
± visit window  
D-28 to D-1 
D1 
W2 
(D15) 
±2 d 
W4 
(D29) 
±2 d 
W8 
(D57) 
±4 d 
W12 
(D85) 
±4 d 
W18 
(D127) 
±4 d 
W26 
(D183) 
±4 d 
W34 
(D237) 
±4 d 
W42 
(D295) 
±4 d 
W52 
(D365) 
±4 d 
 
ECG triplicate recording  
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG triplicate recording 
before IP intake  
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG triplicate recording 
2-3 hours after IP intake  
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG single recording 
before IP intake  
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG single recording 
2-3 hours after IP intake  
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG single recording  
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (serum)  
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (urine)  
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spirometry  
 
 
 
 
 
 
 
 
 
 
 
 
 
DLCO  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
6MWT 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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EVENT 
SCREENING 
PERIOD 
FIRST 52 WEEKS OF STUDY TREATMENT 
Study visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
ETD 
Study days (D) or weeks 
(W) 
± visit window  
D-28 to D-1 
D1 
W2 
(D15) 
±2 d 
W4 
(D29) 
±2 d 
W8 
(D57) 
±4 d 
W12 
(D85) 
±4 d 
W18 
(D127) 
±4 d 
W26 
(D183) 
±4 d 
W34 
(D237) 
±4 d 
W42 
(D295) 
±4 d 
W52 
(D365) 
±4 d 
 
Randomization by IWRS  
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense IP  
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect IP/perform drug 
accountability  
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary card dispensing and 
collection (as applicable 
per visit) for drug 
accountability  
 
 
 
 
 
 
 
 
 
 
 
 
 
EQ-5D and SGRQ (ePRO)  
 
 
 
 
 
 
 
 
 
 
 
 
 
LCQ and K-BILD 
questionnaire (ePRO)  
 
 
 
 
 
 
 
 
 
 
 
 
 
VAS Cough and Urge to 
Cough  
 
 
 
 
 
 
 
 
 
 
 
 
 
Intake P and N at clinical 
study center  
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood samples 2-4 
hours after N morning 
intake 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood samples 5-10 
hours after N morning 
intake 3 
 
 
 
 
 
 
 
 
 
 
 
 
 






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2.5.2. 
Schedule of Activities: After 52 Weeks of Study Treatment 
For subjects who, for any COVID-19-related reason, cannot perform study procedures, the possibility to conduct phone/televisits and home (or 
other remote location) visits, and alternative assessment procedures are detailed in the CSP. 
EVENT 
AFTER 52 WEEKS OF STUDY TREATMENT 
Study visit 
Every 12 weeks up to 
EoST/EoSA 
±7 d 
Every 24 weeks up 
to EoST/EoSA3 
±7 d 
ETD 
EoST/EoSA* 
FU* 
Study weeks  
± visit window  
 
 
(4 weeks after 
EoST/EoSA) 
±7 d 
Alcohol consumption and smoking habits  
 
 
 
 
 
Physical examination  
 
 
 
 
 
Vital signs  
 
 
 
 
 
ECG single recording  
 
 
 
 
 
ECG single recording before IP intake  
 
 
 
 
 
Pregnancy test (urine)  
 
 
 
 
 
Clinical laboratory tests  
 
 
 
 
 
Spirometry  
 
 
 
 
 
DLCO  
 
 
 
 
 
  
 
 
 
 
 
6MWT 
  
 
 
 
 
 
Dispense IP  
 
 
 
 
 
Collect IP/perform drug accountability  
 
 
 
 
 




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d=days, ETD=early treatment discontinuation (i.e. before the EoST/EoSA visit), ePRO=electronical patient-reported outcome, EoST/EoSA=end of study treatment/end of study assessments, N=nintedanib, 
P=pirfenidone. 
The preferred sequence of study assessments is described in the CSP. 
1 
Only for subjects taking nintedanib at screening and randomization, until they stop taking nintedanib 
2 
For subjects not taking nintedanib at screening and randomization and those stopping nintedanib during the study 
3 
At these visits, the assessments from both the Every 12 weeks up to EoST/EoSA and the Every 24 weeks up to EoST/EoSA columns are included 
* This can be a scheduled clinical study center visit or a phone call. 


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2.6. 
Sample Size Justification 
See Section 7.1 of the clinical study protocols. 
2.7. 
Randomization and Blinding 
Details on randomization and blinding are in Section 4.6 of the study protocols. 
An independent data monitoring committee (IDMC) will monitor the safety of the subjects in the 
study on a regular basis and will also assess the effect of treatment with GLPG1690 on lung 
function as assessed by rate of decline in FVC to evaluate the risk-benefit. In addition, an interim 
analysis to assess futility will therefore be performed when a reasonable number of subjects have 
completed 52 weeks of treatment (e.g. at least 25% subjects from the two studies combined) (see 
Section 7.3.2 of the CSP). The results will be reviewed by the IDMC, who will then make a 
recommendation to the sponsor on the progress of the study. Specific details on timing of the 
analyses, futility criteria, and statistical analyses to be performed will be detailed in the IDMC 
charter or SAP, as appropriate. To allow collection of as much safety information as possible on a 
potential down-titration dose, a futile dose will continue if the other dose does not show futility. 
Either the study will continue as planned or both doses (and the study) will be terminated. 
Sponsor personnel will remain blinded and the study will not be stopped for a beneficial effect. 
The IDMC and statistical support group reporting to the IDMC will be unblinded, but they are 
independent of the study team. Sponsor personnel will remain blinded. 
After it was decided to terminate the trial, part of the study team was unblinded in order to be 
able to investigate the findings. 
3. 
ANALYSIS POPULATIONS 
The analysis population will always be indicated in a subtitle in the table, listing or figure. 
3.1. 
All Screened Subjects Set 
All enrolled subjects who underwent screening assessments to check whether or not they are 
eligible to participate in the clinical study. 
3.2. 
All Randomized Set 
All enrolled subjects who underwent all screening assessments and were found to be eligible for 
the clinical study and who were randomized into the clinical study. 
3.3. 
Full Analysis Set (FAS) 
All randomized subjects who received at least one dose of IP.  
All data will be included irrespective of IP interruption or termination and changes in standard of 
care. Only efficacy data after lung transplant will be excluded. 




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address a specific scientific question of interest. A description of an estimand includes four 
attributes. The attributes in the CL-303 and CL-304 studies are underlined: 
A. the population, that is, the patients targeted by the scientific question:  
Patients with IPF, defined through appropriate inclusion/exclusion criteria to reflect the 
targeted patient population for approval;  
B. the variable (or endpoint), to be obtained for each patient, that is required to address the 
scientific question: 
Rate of decline in FVC to Week 52;  
C. the specification of how to account for intercurrent events to reflect the scientific question 
of interest: 
The primary approach will include all data before lung transplant, irrespective of protocol 
violations, changes in SOC or IP interruptions or discontinuations. 
Sensitivity analyses are planned to investigate the impact of the intercurrent events;  
D. the population-level summary for the variable which provides, as required, a basis for a 
comparison between treatment conditions: 
Difference in estimated slopes for each of the GLPG1690 doses versus placebo. 
Together these attributes describe the estimand, defining the treatment effect of interest. 
The design of the CL-303 and CL-304 studies targets this estimand as they are randomized 
parallel-group studies where every attempt is made to collect all measurements throughout the 
study. 
5. 
TREATMENT GROUPS 
5.1. 
Randomized Versus Actual Treatment 
For efficacy, 
and safety analyses, the treatment group as assigned by the randomization will 
be used in the analysis (i.e. as-randomized analysis). 
For PK analyses, the actual treatment will be used in the analyses. 
Differences between as-treated and as-randomized will be flagged in the listing of subject 
randomization. 
5.2. 
Totals over Groups 
A total over all groups will be presented for the General and Baseline Characteristics part of the 
analysis, but not for efficacy, safety, PK nor 
 analyses.  
6. 
ANALYSIS PERIODS AND ANALYSIS TIME POINTS 
6.1. 
Relative Number of Days 
The timing of an assessment or an event relative to a reference date will be calculated as follows:  
R݈݁ܽݐ݅ݒ݁ ݀ܽݕ =ܿ݋݊ܿ݁ݎ݊݁݀ ݀ܽݐ݁−ݎ݂݁݁ݎ݁݊ܿ݁ ݀ܽݐ݁ +1 ݀ܽݕ,  


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                                   when concerned date ≥ reference date  
                                 =ܿ݋݊ܿ݁ݎ݊݁݀ ݀ܽݐ݁−ݎ݂݁݁ݎ݁݊ܿ݁ ݀ܽݐ݁,  
                                   when the concerned date<reference date  
 
The reference date is the date of the first dose of IP administration, unless specified 
otherwise.  
 
The concerned date could be the measurement date of the assessment, or the start or end date 
of the event. 
 
Date implies a complete date having day, month and year available. Unless otherwise 
specified, the relative day will remain missing when it cannot be calculated due to absence or 
incompleteness of the concerned and/or reference dates.  
6.2. 
Analysis Periods for Non-visit Data 
These analysis periods are to be used for allocation of events into periods (e.g. adverse events). 
Table 1 
Analyses Periods for Non-Visit Data  
Analysis period 
Start period 
End period 
Screening 
Date of signing the ICF. 
1 day before the date of first dose of IP 
Treatment 
First dose of IP date. 
Last dose of IP date + 30 days. 
Follow-up 
Last dose of IP date + 31 days. 
Study termination date. 
Note: if the study termination date is 
before the last dose of IP + 30 days no 
follow-up period will be created. 
Note: 
- 
If times are collected or other information with respect to timing (e.g. before or IP intake) 
this information will be taken into account in addition to the dates. 
- 
The last analysis period in case of early termination will always end by the study 
termination date (date of last contact in the study or last known alive). 
6.3. 
Algorithm of Allocating Visits to Time Analysis Windows 
For the FAS analysis for efficacy, 
 and safety endpoints, all data (including data obtained at 
unscheduled visits) will be placed into time analysis windows according to their relative day in 
the study, using to the following allocation tables (Table 2 to Table 4). 
Table 2 
Analysis Windows for Efficacy and Safety Endpoints Recorded at All Time 
points (FAS and PP Approach) 
Time point label 
Target day 
Interval lower bound 
Interval upper bound 
Baseline 
1 
-INF 
1 






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For endpoints not including vital status: 
The last contact, not including mortality information is defined as the latest date collected in the 
eCRF from the date of death, visit dates, AE dates, concomitant treatment dates, drug intake dates 
or laboratory test dates, study completion date. Information from the vital status form is not to be 
taken into account for this calculation. 
7. 
HANDLING OF DATA 
7.1. 
Calculation of Descriptive Statistics 
For continuous parameters, descriptive statistics will be presented when N≥2 per group. When 
N=1, the observation will not be shown in the table/figure but only in the listing(s).  
Descriptive statistics will include at least the following:  
− 
the number of non-missing data points (n)  
− 
the arithmetic mean 
− 
the standard deviation (SD) and standard error (SE) of the arithmetic mean 
− 
the median, minimum and maximum 
− 
95% confidence interval (CI) of the mean (only when requested). 
7.2. 
Calculation of Percentages 
For event-type data (e.g. adverse events), the denominator for calculation of percentages will be 
all subjects in the analysis set and analysis period. For other data (e.g. worst-case analysis of 
assessments, demographic data), the denominator will be all subjects with (postbaseline) data for 
the parameter, in the analysis set and analysis window/period. Missing values will not be 
included in the denominator count. 
7.3. 
Handling of Values Below (or Above) a Threshold 
Except for 
, values below (above) the detection limit will be imputed by the value one unit 
smaller or 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”. 
For 
 data, values below the detection limit will be imputed by zero. 
7.4. 
Handling of Missing Data 
7.4.1. 
Primary Approach 
As the primary approach, there will be no imputation of missing values and missing values will 
be excluded from analyses and data is assumed to be missing at random (MAR). Missing data 
resulting from stopping the study is assumed to be missing completely at random (MCAR). 


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Missing data/visits due to the study conduct being affected by the COVID-19 pandemic (e.g. 
lockdown rules) can be considered MAR. 
 
7.4.2. 
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. 
7.4.3. 
Sensitivity Analyses 
Since no treatment effect was observed and the study was stopped for lack of efficacy, sensitivity 
analyses to investigate the robustness of results will be limited. Description of sensitivity 
analyses are kept as documented in the original SAP for reference but most of them will not be 
performed (details in sections 9.1 and 9.3.2.2) 
Several sensitivity analyses will be performed to investigate the impact of missing data, including 
analyses assuming missing not at random (MNAR), of protocol deviations, early study 
termination and treatment interruptions or discontinuation as well as changes in standard of 
care. Details are in the relevant efficacy sections below. 
7.5. 
Handling of Outliers 
All measured values will be included in the analyses. Extreme outliers will be evaluated before 
unblinding and if needed, additional sensitivity analyses will be added. 
7.6. 
Stratification Factors 
The analyses will be stratified by the type of standard of care taken at randomization: nintedanib, 
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. 
In case there is a discrepancy in the stratification reported in interactive web response system 
(IWRS) versus in the eCRF, then the stratum reported in the eCRF will be used in analyses, and 
the discrepancy will be flagged in the appropriate listing. 
7.7. 
Exclusion of Data in Case of Quality Issues 
In case of serious breach or other site-related quality concerns the study team in collaboration 
with the quality department will assess the impact on the data and may decide to exclude the data 
from analyses, this will be documented in the eTMF.  


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8. 
INTERIM ANALYSES AND DATA MONITORING COMMITTEE 
REVIEW 
To protect the safety of the subjects in the study and integrity of the study data, an IDMC will be 
implemented.  
In parallel to assessing potential safety risks on a regular basis, the IDMC will also examine the 
effect of treatment with GLPG1690 on lung function as assessed by rate of decline in FVC using 
the data from the identically designed studies GLPG1690-CL-303 and GLPG1690-CL-304. An 
interim analysis to assess futility will be performed when a reasonable number of subjects have 
completed 52 weeks of treatment (at least 25% subjects completing Week 52 or 70% information 
available, whichever comes latest, the exact timing will be determined based on the actual 
recruitment). The results will be reviewed by the IDMC, who will then make a recommendation 
to the sponsor on the progress of the study. The Sponsor will remain blinded to treatment 
allocations and results of the analyses. To allow collection of as much safety information as 
possible on a potential down-titration dose, a futile dose will continue if the other dose does not 
show futility. Either the study will continue as planned or both doses (and the study) will be 
terminated. Specific details on timing of the analyses, futility criteria, and statistical analyses to 
be performed will be detailed in the IDMC charter and SAP, as appropriate. A summary of the 
futility approach is also provided in Appendix 5. 
Given there is no plan to terminate the study early for overwhelming efficacy results, no 
adjustment of the alpha level is considered needed. 
No other interim analyses are planned for these studies. 
9. 
STATISTICAL ANALYSES 
9.1. 
Changes to the Planned Analyses, Not Covered by Protocol 
Amendments 
In view of the termination of the ISABELA studies and the decision to write an abbreviated CSR, 
it was decided to limit the analyses to the primary, key secondary and safety endpoints and any 
analyses important to better understand the reason for the results seen, or relevant for scientific 
knowledge for future compounds. Since no treatment effect was observed and the study was 
stopped for lack of efficacy, sensitivity analyses to investigate the robustness of results will also 
be limited.  
A detailed list of the analyses that will not be performed can be found in the table below. In the 
remainder of the document the descriptions as documented in the original SAP are kept for 
reference; but analyses that will not be performed are in Italic font. 


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Section SAP 
Analyses to be omitted 
9.2.1 
- Baseline EQ_5D 
- Baseline LCQ total score and domains 
- Baseline K-BILD total score and domains 
- Baseline VAS Cough and Urge to Cough 
- 
 
- Baseline SpO2 during 6MWT (%) 
- Frequency tabulation baseline Physical examinations 
 
9.2.2 
- The number (percent) of subjects in the different analysis populations 
- The number (percent) of subjects per analysis window as defined in   
   Section 6.3 for analysis. 
- Descriptive statistics of the duration of the analysis periods  
- Number of subjects with a deviation of more than the number of days      
  allowed per protocol from the target of the analysis windows, per     
  window.  
- Descriptive statistics of the number of days distance from the target of  
   the window, as specified in the protocol, as well as of the relative day  
   per window. These will allow to assess if the later visits (especially the  
   close-out visits) are done close to scheduled visits. 
9.2.3 
All major protocol deviations will be tabulated, not only the ones 
impacting efficacy, as this assessment will not be done. A list of all major 
protocol deviations will be provided without the flag for impacting 
efficacy. 
9.2.5.3 
Analyses restricted to medications taken up to 30 days after the last dose 
of IP. 
9.2.6 
Analyses on exposure and compliance parameters on data up to 52 weeks 
9.2.7 
KM analyses for time to first switch in standard of care 
9.3.1 
Pooled analyses will not be performed. 
9.3.2.2 
9.3.2.2.2 Per protocol analysis 
9.3.2.2.3 On-treatment 
9.3.2.2.4 After Lung Transplant 
9.3.2.2.6 Completers vs Non-completers 
9.3.2.2.7 Impact of missing data – Pattern mixture 
9.3.2.2.8 Impact of SOC 
 
9.3.3 
-On-treatment analysis 
-Negative binomial model 
9.3.5 
-Per protocol analysis 
-Random coefficient regression model 




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 
Ethnicity  
 
Height at baseline (cm) 
 
Weight at baseline (kg)  
 
Body mass index (BMI) at baseline (kg/m²) ൌ 
௪௘௜௚௛௧ ሺ௞௚ሻ
௛௘௜௚௛௧మ ሺ௠మሻ 
 
BMI at baseline, categorized: 
x 
≤ 18.5 kg/m² 
x 
>18.5- ≤ 25.0 kg/m² 
x 
>25.0- ≤ 30.0 kg/m² 
x 
> 30.0 kg/m² 
 
Systolic and diastolic blood pressure (mmHg), heart rate (beats/min ) , respiratory rate 
(breaths/min) and oxygen saturation (%) at baseline 
 
Alcohol status: never, current, former 
 
Smoking status: never, current, former 
 
Duration of IPF (years) = (date of first intake of IP - date of initial diagnosis)/365.25. If the 
date of initial diagnosis is incomplete, then the following rules will be applied: Missing day: 
use the first day of the month. Missing month: use January. 
 
Duration of IPF, categorized as: 
x 
<0.5 year 
x 
≥0.5- <1 year 
x 
≥1- <2 year 
x 
≥ 2 year 
 
Baseline spirometry values: 
x 
forced vital capacity (FVC) (mL),  
x 
percent predicted FVC (%),  
x 
forced expiratory volume in 1 second (FEV1) (mL),  
x 
percent predicted FEV1 (%),  
x 
FEV1/FVC ratio,  
x 
forced expiratory flow between 25% and 75% of exhaled volume (FEF25-75) (mL/s). 
 
Other baseline efficacy measures: 
x 
SGRQ total score and domains:  
x 
symptoms (assessing the frequency and severity of respiratory symptoms),  
x 
activity (assessing the effects of breathlessness on mobility and physical 
activity),  
x 
impact 
x 
EQ-5D,  
x 
LCQ total score and domains,  
x 
K-BILD total score and domains,  
x 
VAS Cough and Urge to Cough,  
x 
6MWT distance,  


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• 
 
• 
SpO2 during 6MWT (%) 
• 
DLCO (corrected for Hb) 
A frequency tabulation per system organ class and treatment group (and overall) of the baseline 
physical exam results, categorized as normal/abnormal will also be provided. 
9.2.2. 
Disposition Information 
The following tabulations will be provided by treatment group and overall: 
− 
The number of subjects screened, randomized and not-randomized, with the reason for not 
being randomized. Number randomized and not treated. 
− 
Number of subjects randomized per country and investigator. 
− 
The number (percent) of subjects in the different analysis populations as defined in Section 3.  
− 
Descriptive statistics of the duration of the analysis periods will be provided. 
− 
The number (percent) of subjects per analysis window as defined in Section 6.3 for analysis. 
− 
Number of subjects with a deviation of more than the number of days allowed per protocol 
from the target of the analysis windows, per window.  
− 
In addition, descriptive statistics will be provided of the number of days distance from the 
target of the window, as specified in the protocol, as well as of the relative day per window. 
These will allow to assess if the later visits (especially the close-out visits) are done close to 
scheduled visits. 
− 
Overall summary of number of subjects (percent) per number of missed and virtual visits due 
to COVID-19 per treatment group 
− 
Summary of number of subjects (percent) with missed, virtual visits due to COVID-19, 
missed visits not due to COVID-19 and complete visits per study visit and treatment group  
− 
The number (percent) of subjects with completion/discontinuations and the reasons for 
discontinuation from study and from IP. This table will also be provided by stratum. 
− 
The number (percent) of subjects with discontinuations due to COVID-19 and the reasons for 
discontinuation from study and from IP.  
− 
Kaplan-Meier estimates (graphical and tabular) of the time in the study, defined as time from 
the date of the first intake of IP to the last contact in the study, excluding data from the vital 
status eCRF. See Section 6.5 for the censoring rules. 
− 
Kaplan-Meier estimates (graphical and tabular) of the time on treatment, defined as time 
from the date of the first to last intake of IP. 
If a high number of discontinuations is seen in a blinded fashion during the course of the study, 
more descriptions may be added to further investigate the reasons for discontinuations over time. 
Details will then be added to this SAP before unblinding for the final analysis. 
 
 


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In addition, the following listings will also be provided:  
− 
Subjects receiving investigational product from specific batches, where more than one batch 
was used (showing the batch numbers of the investigational products actually used, including 
the expiration dates),  
− 
Randomization scheme and codes (subject identification, treatment assigned, with a flag if 
the code was broken and the reason). 
− 
Date of the earliest ICF signed for this study and date of last scheduled visit performed in 
this study. 
− 
Listing of missed and virtual visits due to COVID-19. 
− 
Listing of Study and/or study drug discontinuations due to COVID-19 
− 
Listing of comments containing information related to COVID-19 
9.2.3. 
Protocol Deviations and Eligibility 
Listings will be provided for the subjects excluded from the different analyses sets with the 
reason for exclusion. 
Tabulation per treatment group (and overall) of the major protocol deviations impacting the 
efficacy analyses will be provided. The same table will also be provided by stratum. A listing will 
be provided for all major protocol deviations with a flag indicating which impact efficacy 
analyses and are thus excluded from the PP analysis. 
Tabulation per treatment group (and overall) of the number (percent) of subjects with major 
protocol deviations related to COVID-19, overall and per COVID-19 related protocol deviation 
will be provided. Listings of major and minor COVID-19 related protocol deviations will be 
created. 
9.2.4. 
Medical History and Concomitant Diseases 
Frequency tabulations per treatment group (and overall) per system organ classes and preferred 
terms 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 concurrent diseases (i.e. conditions present at the start of the 
study). 
9.2.5. 
Prior and Concomitant Therapies 
9.2.5.1. 
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 (before, after, ongoing…): 
− 
Prior only: when the record ended before the first IP administration date. 
− 
Concomitant only: when the record started on the same date or after the first IP 
administration date. 


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− 
Prior and concomitant: when the record started before the date of first IP administration, and 
ended on a date after first IP administration (or on the same date), or continued. 
Records without a start date are assumed to have started before the date of first IP 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, the date 
of first IP administration will be considered to the same level of information provided by these 
incomplete dates in order to categorize the timing of these records. This means a record only 
having month and year will be categorized comparing only to the month and the year of the date 
of first IP administration. If the start date is unknown but the medication is flagged to have 
started prior to the first dose of IP, this information will be taken into account. 
For both the start and the end dates of the concomitant therapy records, their day relative to the 
day of first IP administration will be calculated as described in Section 6.1.  
9.2.5.2. 
Coding of Therapies 
All therapies are coded using WHO Drug coding. In the table(s), the generic term will be used. 
The anatomical therapeutic classification (ATC) classes level 2 and 4 will be used for analysis. 
Multiple records of the same generic term for the same subject with the same categorization will 
be counted only once. The table will therefore present subjects, not occurrences. 
9.2.5.3. 
Analyses 
A frequency tabulation per treatment group (and overall) of the ATC classes level 2 and 4 and 
generic terms of the prior medications (defined as ‘prior only’ or ‘prior and concomitant’) will be 
provided and as well as of the concomitant medications (defined as ‘concomitant only’ or ‘prior 
and concomitant’).  
Additional tables will be created 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.  
Similar tables will be provided restricted to medications taken up to 30 days after the last dose of 
IP. 
9.2.6. 
Exposure to IP and Compliance 
The following parameters will be calculated for the compliance and extent of exposure to IP: 
− 
Overall compliance (%) = 100 x (number of tablets actually used) / (number of tablets that 
should have been used, according to the randomization). 
− 
Total treatment duration (days) = last dose of IP intake date – first dose of IP intake date + 1 
day. 
− 
Total treatment duration, excluding days off drug (days): sum of all durations (last – first +1) 
in the drug log pages where there is at least one dose taken, i.e. the sum of the number of 
days with at least one dose of IP. 


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 
Percentage days with an intake = 100% x ቀ
୲୭୲ୟ୪ ୲୰ୣୟ୲୫ୣ୬୲ ୢ୳୰ୟ୲୧୭୬,ୣ୶ୡ୪୳ୢ୧୬୥ ୢୟ୷ୱ ୭୤୤ ୢ୰୳୥
୲୭୲ୟ୪ ୲୰ୣୟ୲୫ୣ୬୲ ୢ୳୰ୟ୲୧୭୬
ቁ 
 
Total compliant treatment duration (days): sum of all durations (last – first +1) in the drug 
log pages where there is a dose with exactly 3 tablets. 
 
Percentage compliance of treatment duration = 100% x ቀ
୲୭୲ୟ୪ ୡ୭୫୮୪୧ୟ୬୲ ୲୰ୣୟ୲୫ୣ୬୲ ୢ୳୰ୟ୲୧୭୬
୲୭୲ୟ୪ ୲୰ୣୟ୲୫ୣ୬୲ ୢ୳୰ୟ୲୧୭୬
ቁ) 
Similar calculations will be done using only the data up to Week 52. 
Summary tables will be provided for the different compliance and extent of exposure parameters 
by treatment and overall. In addition, frequency tables will also be provided for the compliance 
parameters (overall compliance, percentages days with an intake and percentage compliance of 
treatment duration), using the following categories: <80%, ≥80%-<100%, 100%, >100%-≤120%, 
>120%.  
Frequency tables with the number of subjects who had at least one down-titration and with the 
number of subjects who had at least one dose interruption, and the reasons for down-titration and 
interruption by treatment group and overall, will also be provided.  
Patient-years of exposure to IP by treatment group and overall. 
The same tables will be created by stratum and treatment. 
A listing will be provided of the subjects who took incorrect IP for at least part of the treatment 
period, all prime therapy records are to be included to provide an overview of the amount of 
incorrect treatment relative to the total treatment period.  
In addition, listings of the subjects who had their IP down-titrated and interrupted for at least part 
of the treatment period will be provided, all prime therapy records are to be included to provide 
an overview of the amount of down-titration and interruption relative to the total treatment 
period.  
9.2.7. 
Exposure to Standard of Care (SOC) 
The following parameters will be derived per type of SOC (nintedanib, pirfenidone and neither): 
- 
Duration of SOC= last dose of SOC – first dose of SOC + 1 day 
- 
Compliance to SOC (%) = 100 x (number of SOC tablets actually used) / (number of SOC 
tablets that should have been used in the study). 
Where the number of SOC tablets is to be calculated based on the total study duration 
(from first dose of IP to last contact). 
Summary tables by treatment, type of SOC will be provided for these two parameters.  
 
 


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A frequency table per treatment group, summarizing the 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). 
 
Additionally, a frequency table of the type of switch with the reasons for switching SOC will be 
provided per treatment group. 
A frequency table describing the doses taken of Pirfenidone and Nintedanib per treatment group 
will also be created. 
Patient-years exposure to each SOC by treatment group and stratum and overall will be provided. 
 
A frequency table, summarizing SOC intake prior (e.g. Currently taking Pirfenidone; Never took 
Nintedanib, … ) to the study by treatment group and stratum and overall will be created. 
 
In addition, a listing will be provided of the subjects who had any change in 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. 


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In addition, Kaplan-Meier tables and graphs will be created for the time from first dose of IP to 
switch of SOC, where a switch in SOC is defined as: 
- 
switching from nintedanib to pirfenidone or vice versa for those in the ‘nintedanib’ or 
‘pirfenidone’ strata,  
- 
starting nintedanib or pirfenidone, for those in the ‘neither’ stratum. 
Furthermore, for those in the ‘pirfenidone’ or ‘nintedanib’ stratum, a Kaplan-Meier curve and 
table will be provided for the time to discontinuation of the SOC they started on. 
For the neither stratum, a tabulation of the number of subjects (%) by reason for not taking 
Pirfenidone and Nintedanib. 
A listing of COVID-19 related SOC intake changes will be provided. 
Heterogeneity between countries (and/or regions) will be investigated. 
If a high number of subjects switching SOC are observed in a blinded fashion during the course 
of the study, more descriptions may be added to further investigate the patterns over time. Details 
will then be added to this SAP before unblinding for the final analysis. 
9.3. 
Efficacy Analyses 
This section provides an overview of the efficacy analyses performed for this study.  
9.3.1. 
Level of Significance 
Given no market authoristation applicaton for ziritaxestat for the treatment of IPF will be 
submitted  anymore, no pooled analyses combining data from both studies will be performed and 
the below multiplicity adjustment strategy for countries outside US, does not apply. Only 
abbreviated CSRs per study will be written as explained earlier in this document. 
Statistical tests will be done at a 2-sided level. For the analysis of the primary endpoint, to 
account for the multiple testing due to two doses being compared to placebo, a Bonferroni 
approach (Hochberg, 1988) will be used with higher priority given to the high-dose group. The 
primary endpoint will be tested at a 4% level when comparing GLPG1690 600 mg to placebo and 
a 1% level for GLPG1690 200 mg group versus placebo.  
With respect to the multiplicity adjustment for the key secondary endpoints an additional 
approach was requested by the
 
compared to European Union (EU) countries. For countries outside US and EU, the EU approach 
will be applied. 
For 
 
The 
 requested a multiplicity adjustment for the key secondary endpoints within each study. 
A closed-testing hierarchical approach will therefore be used for each dose group separately. The 


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key secondary endpoints will be ordered as listed in Section 2.2.2.1 and they will be tested at a 
4% level when comparing GLPG1690 600 mg to placebo and a 1% level for GLPG1690 200 mg 
group versus placebo. In this approach, the first key secondary endpoint in a dose group will only 
be tested if the primary endpoint for that dose group showed significance. The next one will only 
be tested if the previous one showed significance. These analyses will be presented in the study 
CSR. Figure 2 details the testing order within each of the identically designed studies. 
 
Figure 2 
Multiplicity adjustment within study for 
 approach 
For Countries outside the US: 
To increase the probability to detect a potential treatment effect on the key secondary endpoints, 
some of which are rare but clinically important events, they will be analyzed using the pooled 
data from the two studies (GLPG1690-CL-303 and GLPG1690-CL-304). The confirmatory 
testing on these secondary endpoints will be done only if the primary endpoints in both studies 
show significance and a step-down closed-testing multiplicity adjustment will be applied, as 
shown in Figure 3. A key secondary endpoint in the pooled analysis will only be tested for a dose 
if the higher order endpoint also showed significant for that dose. This analysis will be presented 
in the Section 2.7.3 Summary of Clinical Efficacy (and Module 5 Integrated Summary of 
Efficacy). Details of the pooled analyses will be provided in the pooled-analysis SAP.  
Results for the key secondary endpoints for each individual study will be summarized within its 
CSR and will enable the evaluation of consistency of the results between the studies. An 
overview of the multiplicity adjustment for the primary and key secondary endpoints is provided 
in Figure 3. 


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Figure 3 
Multiplicity adjustment within study for Countries outside the US 
 
9.3.2. 
Spirometry Parameters 
All spirometry evaluations should be performed pre-bronchodilator. Spirometry data taken post-
bronchodilator will be excluded from the analysis. 
The clinical study center-based spirometry must meet the criteria for acceptability and repeatability 
as defined in the American Thoracic Society / European Respiratory Society / Japanese Respiratory 
Society / Latin American Thoracic Association (ATS/ERS/JRS/ALAT) guidelines (Miller, et al., 
2005) for screening, and will be based on ATS/ERS/JRS/ALAT guidelines after randomization. 
Pulmonary function will be measured in a standardized manner and results should be transmitted 
electronically during the visit immediately after performing the spirometry and evaluated by a 
central reader. In case the acceptability and repeatability criteria as specified by 
ATS/ERS/JRS/ALAT guidelines are not met, a repeat spirometry should be performed during the 
same visit of the screening period. After randomization, a repeat spirometry should be performed 
during the same visit, based on the ATS/ERS/JRS/ALAT guidelines. 
The data will be coded as “acceptable”, “borderline acceptable” and “unacceptable”, 
“unacceptable” values will be excluded from analyses. 
The following parameters will be measured or calculated as part of the spirometry assessment: 
− 
FVC (mL)  
− 
Percent predicted FVC (%), as available in the database  
− 
FEV1 (L) and percent predicted FEV1(%) 
− 
FEV1/FVC ratio 
− 
FEF25-75 (mL/s). 


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The ‘2012 Global Lung Function Initiative Equations’ will be used to calculate the predicted 
values (Ratitch B, 2013) . 
The spirometry endpoints will be analyzed using the FAS, including all available data before 
lung transplant for subjects who took at least one dose of IP, and excluding values post-
bronchodilator. 
For each of the spirometry parameters, descriptive statistics will be provided for the values, 
changes and percent change from baseline per time point up to the end of the study and per 
treatment group. Results will also be graphically displayed by means of line plots of the mean 
(SE) over time-by-treatment group. 
A similar summary table and graph will also be provided by stratification factor (standard of 
care) and reason for not being on SOC. 
9.3.2.1. 
Primary Endpoint: Rate of Decline in FVC over a Period of 52 Weeks 
The primary endpoint of annual rate of decline in FVC at Week 52 (in mL) will be analyzed, 
including data up to and including the 52-week analysis window defined in Section 6.3. A 
random coefficient regression model (linear slope model) will be used including sex, age, height 
and stratification factor as covariates and a random intercept and slope. The treatment effect is 
determined by using estimated slopes for each treatment group on the basis of the time-by-
treatment interaction term from the mixed model. All available FVC values (as defined by the 
analysis windows) from baseline to Week 52 will be used including FVC measurements at the 
follow-up visit for subjects who discontinue IP prematurely and do not complete the study visits 
through Week 52. The model will be fit using the SAS PROC MIXED procedure, details are in 
Appendix 1.  
The assumptions of the model will be investigated.  
The same model will be used for the pooled analysis for the integrated summary of efficacy 
adjusted for study. More detail will be in a separate SAP. 
A similar analysis will also be provided by stratification factor (standard of care). 
The percent predicted FVC will be analyzed using a similar random coefficient regression model 
(linear slope model) as FVC expressed in mL. 
9.3.2.2. 
Sensitivity Analyses to the Primary Analyses 
Since no treatment effect was observed and the study was stopped for lack of efficacy, sensitivity 
analyses to investigate the robustness of results will be limited. Description of sensitivity 
analyses are kept as documented in the original SAP for reference, analyses that will not be 
performed are in italic font. 
Several sensitivity analyses are planned to investigate the impact of protocol violators, missing 
data, treatment discontinuation, and changes in standard of care. If during the blinded review of 


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the data more sensitivity analyses are deemed necessary these will be added to this SAP before 
unblinding for the final analysis of the CSR. 
For the below sensitivity analyses and per dose group (600 mg, 200 mg) the estimate, 95% CI of 
the treatment effect compared to placebo will be presented on the same forest plot together with 
those of the primary analysis. 
9.3.2.2.1. Sensitivity Analysis not Assuming a Linear Trend over Time 
A mixed-effects model for repeated measures (MMRM) with treatment, time (as a categorical 
factor defined by the analysis windows in Section 6.3), treatment*time, stratum and baseline 
value as factors in the model will be applied to the change from baseline in FVC value in mL. 
Least squares (LS) means (with 95% CI) will be estimated from the model at each time point for 
each treatment group as well as the differences from placebo in LS means (and 95% CIs). Details 
on the model are in Appendix 3. 
This approach provides another estimate (LS mean difference) for the primary estimand. 
9.3.2.2.2. Sensitivity Analyses – Per Protocol to Investigate the Impact of Protocol 
Violators 
To investigate the impact of non-compliance and protocol violators a Per Protocol analysis will 
also be performed for the primary endpoint of decline in FVC using the random coefficient 
regression model. Protocol violations potentially impacting the results will be excluded and 
identified before database lock and unblinding for the final analysis. 
This approach provides another estimand than the primary one, namely the estimate in the 
population of subjects who take treatment according to protocol. 
9.3.2.2.3. Sensitivity On-treatment Analysis 
The same random coefficient regression model will be run for the rate of decline in FVC, using 
only the data up to the last intake of IP. Data after lung transplant and taken post-bronchodilator 
will be excluded.  
This approach provides another estimand than the primary one, namely the estimate in the 
population of subjects who are on treatment. 
9.3.2.2.4. Sensitivity Analysis Including Data After Lung Transplant 
The same random coefficient regression model will be run including all data, also after lung 
transplant. 
9.3.2.2.5. Sensitivity Analysis on All Study Data (also beyond Week 52) 
The same random coefficient regression model will be run using all data up to the end of the 
study for FVC in mL and percent predicted FVC. Data after lung transplant and taken post-
bronchodilator will be excluded. 


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This approach provides another estimate of the primary estimand. 
9.3.2.2.6. Sensitivity Analysis for Completers versus those Who Discontinued Early 
The same random coefficient regression model will be run up to Week 52, for those who 
completed the study up to Week 52 separately from those who discontinued the study before Week 
52. 
9.3.2.2.7. Sensitivity Analyses to Investigate the Impact of Missing Data – Control-Based 
Pattern Mixture Approach 
Data after lung transplant and taken post-bronchodilator will be excluded.  
Non-monotone missing data and missing data at visits before Week 52 will not be imputed. This 
assumes that the number of non-monotone missing data is either negligible or MAR, which is 
probably a reasonable assumption.  
Multiple imputations will be used to handle missing data at Week 52. The imputation model is 
similar to the random coefficient regression model of the primary analysis.  
In the pattern mixture approach, patterns of missing data are defined by subjects being classified 
in the following five categories: 
1. Those with Week 52 data who received treatment till Week 52 
2. Those with Week 52 data who discontinued treatment before Week 52 
3. Those without Week 52 data who discontinued treatment before Week 52 and are still alive 
4. Those without Week 52 data and continued treatment till Week 52 or later 
5. Those who died before Week 52. 
The number of imputations will be set to 1000 in order to ensure adequate efficiency for the 
estimation of the missing data. For each imputed dataset, the same model will be run as for the 
primary analysis and results will be combined using the standard multiple imputations approach 
of (Rubin, 1987). Imputations of the missing Week 52 value will be based on the estimates of the 
slope (SE), using data from prespecified groups depending on the assumptions. The assumptions 
behind are that the rate of decline in FVC in the subset of subjects imputed is similar to the rate 
of decline in the subset used for the imputation. A frequency table will be provided of the number 
(%) of subjects in each pattern.  
Given the groups may become small, the strata with SOC (either nintedanib or pirfenidone) will 
be combined and the combined stratum with 2 levels (nintedanib or pirfenidone vs neither) will 
be used. If the groups are still very small and less than 10% of subjects discontinue this approach 
will not be performed and will only be performed on the pooled data. 
Appendix 2 provides more information on the multiple imputations approach. 
Pattern Mixture Approach 1: 


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Pattern 3 will be imputed based on the data from Pattern 2 for the same treatment group and 
combined stratum (with 2 levels nintedanib or pirfenidone vs neither). 
Pattern 4 will be imputed based on data from Pattern 1 for the same treatment group and 
combined stratum 
Pattern 5 will be imputed based on data from the placebo groups of Pattern 2 for the same 
combined stratum. 
This approach assumes that subjects who discontinue and are alive have the same rate of decline 
as the other subjects in the same treatment group and combined stratum, while subjects who died 
have a rate of decline similar to the discontinued placebo subjects in the same stratum after their 
last available FVC value. 
Pattern Mixture Approach 2: 
Patterns 3, 4, and 5 will be imputed based on the data from Pattern 1, 2 placebo subjects in the 
same combined stratum. This is a conservative approach which assumes that subjects who 
discontinued IP have a similar rate of decline in FVC as the placebo subjects after 
discontinuation. 
Note:  
The missing data will be investigated during the study in a blinded manner, especially if the 
monotone missingness assumption is reasonable, especially in the context of the bronchodilators 
use. If a high percentage of data is missing in a non-monotone pattern, appropriate measures 
will be taken (e.g. using an Markov chain Monte Carlo imputation of this data).  
9.3.2.2.8. Sensitivity Analyses to Investigate the Impact of Changes in Standard of Care 
(Stratum) 
Data after lung transplant and taken post-bronchodilator will be excluded. The below sensitivity 
analyses will be performed for the primary endpoint of annual rate of decline in FVC using the 
random coefficient regression model. 
Sensitivity Analysis 1: 
Subjects who were on the same standard of care less than 75% of the time will be 
excluded, i.e. in the ‘neither’ stratum, subjects will be excluded if they took either 
nintedanib or pirfenidone for more than 25% of the time, and in the ‘nintedanib’ and 
‘pirfenidone’ strata they will be excluded if they did not take the SOC from their stratum 
for at least 75% of the time up to Week 52. Results will be presented overall and by 
stratum. 
Sensitivity Analysis 2: 
A similar approach as sensitivity analysis 1 will be performed combining the ‘nintedanib’ 
and ‘pirfenidone’ strata. In other words, if a patient starts on nintedanib treatment and 


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switches to pirfenidone or vice versa, they will be considered as still being on SOC for the 
calculation of the 75% of time on SOC. 
The pattern of changes in SOC will be evaluated during the course of the study in a blinded (to 
randomization) manner and additional sensitivity analyses may be added as deemed necessary. 
9.3.2.3. 
First Key Secondary Endpoint – Disease Progression 
Disease progression is defined as the composite endpoint of first occurrence of ≥10% absolute 
decline in percent predicted forced vital capacity (%FVC) or all-cause mortality at 52 weeks.  
The number (%) of subjects who experience disease progression up to Week 52 will be presented 
and analyzed using logistic regression with similar factors in the model as for FVC rate of 
decline. The odds ratios (with 95% CI) versus placebo will be estimated from the model. This 
analysis corresponds to the key secondary endpoint and will be used in the multiplicity approach. 
A similar summary analysis will also be provided by stratification factor (standard of care). 
9.3.2.4. 
Other Spirometry Endpoints 
The same will be used to describe the disease progression up to the end of the study.  
Additionally, the two components of this composite endpoint of disease progression will also be 
summarized separately (number of subjects who died and number of subjects have either an 
absolute decline of 10 percentage point or more in percent predicted FVC). 
Furthermore, to account for the differential periods of observation in the study a time to event 
analysis similar as described below for time to respiratory hospitalization, will be used to analyze 
the composite endpoint of percent predicted FVC decline and mortality up to the end of the 
study. See below for details on analyses of time to event endpoints. 
In addition, a cumulative incidence table and graph will be presented for absolute change from 
baseline in percent predicted FVC per time point  and worst-case up to the end of the study for 
the categories ≤-10, ≤-9, ≤-8,…, ≤0, …, ≤8, ≤9, ≤10  , by treatment group.  
9.3.3. 
Second Key Secondary Endpoint - Time to First Respiratory-related 
Hospitalization until the end of the study 
Respiratory 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 (%) of subjects with an event during the study will be summarized as well as the 
number of events per 100 patients-years of follow-up. In addition, time to first event will be 
graphically displayed and tabulated (at each planned time point as described in Section 6.3, Week 
2, Week 4, etc, and last available time point) using Kaplan-Meier estimates. 


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A Cox proportional hazards model with terms for age, sex, height, and stratum will be used to 
estimate the hazard ratios (and 95% CI) for each dose compared to placebo and to compare the 
active doses to placebo.  
Censoring  
Time to event endpoints are defined from the date of first dose of IP. 
If the subject did not have an event, the time to event will be censored at the last contact date, as 
defined in Section 6.5. 
Sensitivity Analyses 
An on-treatment approach will be performed for the key secondary endpoint of time to first 
respiratory hospitalization.  
Additional Analysis  
The number of subjects with 0, 1, 2, 3, >3 respiratory-related hospitalizations will be presented 
by treatment group. 
Since it is expected that a relatively high number of subjects will have more than one 
hospitalization, the rate of hospitalizations will be compared between each of the dose groups 
and placebo using a negative binomial model (generalized linear model) as explained in Keene et 
al. (2007). 
9.3.3.1. 
Other Adjudicated Events (Secondary) Endpoints 
A time to (first) event analysis will be conducted for each of the following secondary endpoints: 
• Mortality: all-cause and respiratory-related 
• Hospitalization: all-cause  
• Hospitalization for non-elective Lung transplant 
• Acute IPF exacerbation 
• All-cause mortality or hospitalization for non-elective lung transplant 
• All-cause mortality, or hospitalization for non-elective lung transplant, or hospitalization 
for qualifying for lung transplant 
• All-cause mortality, hospitalization for ≥10% absolute decline in %FVC, or respiratory-
related hospitalizations 
• All-cause mortality or respiratory-related hospitalizations 
Results will be based on the results coming from adjudication. Time to first event will be 
presented for each type of adjudicated event, similarly as time to first respiratory-related 
hospitalizations, using Kaplan-Meier tables, graphs and Cox PH models based. 


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In addition, for all-cause hospitalization and all-cause mortality a frequency table will be 
provided for the primary cause of death/hospitalization as defined by the CEAC. 
Respiratory related events analyses will also be provided by stratification factor (standard of 
care). 
In addition to the analysis of all-cause mortality based on adjudication, a time to all-cause 
mortality analysis will also be performed on all-cause mortality as reported by the investigator.  
Analyses to assess the impact of COVID-19 cases (infection and suspected) on mortality and 
disease progression will be provided. 
9.3.4. 
Other Time-to-Event Endpoints 
The number (%) of subjects with an event during the study will be summarized as well as the 
number of events per 100 patients-years of follow-up. In addition, time to first event will be 
graphically displayed and tabulated (at each planned time point as described in Section 6.3, Week 
2, Week 4, etc, and last available time point) using Kaplan-Meier estimates.  
A Cox proportional hazards model with terms for age, sex, height, and stratum will be used to 
estimate the hazard ratios (and 95% CI) for each dose compared to placebo.  
Censoring  
Time to event endpoints are defined from the date of first dose of IP. 
If the subject did not have an event, the time to event will be censored at the last contact date, as 
defined in Section 6.4. 
9.3.5. 
Third Key Secondary Endpoint: SGRQ Scores 
This questionnaire will be completed electronically, using a tablet device at the clinical study 
center. The SGRQ is a 50 item questionnaire split into three 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. 
 
 


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Table 5 
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 
 
 


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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 
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 
 
 


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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 
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 
 
 


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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 
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 
 
 


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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 two 
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.  
 
Impacts score: questions 9-10, 18 to 35 and 45 to 50. 
Total score: all questions. 
Each domain score is calculated separately in three steps 
 
The weights for all items with positive responses are summed. 
 
The maximum weights for missed items are deducted from the maximum possible weight for 
each component. The maximum weights for all missed items are deducted from the 
maximum possible weight for the total score. 
 
The score is calculated by dividing the summed weights by the adjusted maximum possible 
weight for that component and expressing the result as a percentage 
Score = 100 x 
ୱ୳୫୫ୣୢ ୵ୣ୧୥୦୲ୱ ୤୰୭୫ ୮୭ୱ୧୲୧୴ୣ ୧୲ୣ୫ୱ ୧୬ ୲୦ୟ୲ ୡ୭୫୮୭୬ୣ୬୲
ୱ୳୫ ୭୤ ୫ୟ୶୧୫୳୫ ୵ୣ୧୥୦୲ୱ ୤୭୰ ୟ୪୪ ୬୭୬ି୫୧ୱୱ୧୬୥ ୧୲ୣ୫ୱ ୧୬ ୲୦ୟ୲ ୡ୭୫୮୭୬ୣ୬୲ 
 
The total score is calculated in a similar way: 
Score = 100 x 
ୱ୳୫୫ୣୢ ୵ୣ୧୥୦୲ୱ ୤୰୭୫ ୮୭ୱ୧୲୧୴ୣ ୧୲ୣ୫ୱ ୧୬ ୲୦ୣ ୯୳ୣୱ୲୧୭୬୬ୟ୧୰ୣ
ୱ୳୫ ୭୤ ୫ୟ୶୧୫୳୫ ୵ୣ୧୥୦୲ୱ ୤୭୰ ୟ୪୪ ୬୭୬ି୫୧ୱୱ୧୬୥ ୧୲ୣ୫ୱ ୧୬ ୲୦ୣ ୯୳ୣୱ୲୧୭୬୬ୟ୧୰ୣ 
 
Sum of maximum possible weights for each score: 
 
Symptoms: 662.5 
 
Activity: 1209.1 
 
Impacts: 2117.8 
 
Total: 3989.4 
Note that the questionnaire requests a single response to questions 1-7, 9-10 and 50. If multiple 
responses are given to one of these questions then the weights for the positive responses for that 
question will be averaged. 
In case of missing items, the following rules will be applied: 
 
The symptoms score will only be calculated when no more than 2 items are missing. 
 
The activity score will only be calculated when no more than 4 items are missing. 
 
The impacts score will only be calculated when no more than 6 items are missing. 
 
The total score will only be calculated when the 3 domain scores could be calculated. 


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Note that no imputation of individual missing items will be done, only the missing domain/total 
scores will be imputed. 
Values and changes from baseline in SGRQ total score, as well as symptom, activity, and impact 
scores will be summarized per time point and treatment group by descriptive statistics. 
A mixed-effects model with treatment, time (as a categorical factor defined by the analysis 
windows in Section 6.3), treatment*time, and baseline total score as factors in the model will be 
applied to the SGRQ total score change from baseline. LS means (with 95% CI) will be estimated 
from the model at each time point for each treatment group as well as the differences from 
placebo in LS means (and 95% CIs). This model will be used to calculate the p-values for the 
SGRQ total score (key secondary endpoint) to use in the multiplicity adjustment. 
A patient is an SGRQ responder if his absolute change from baseline in SGRQ total score is ≤ -4 
points. The number (%) of SGRQ responders at each analysis time point up to the end of the 
study will be presented and a logistic regression will be used to analyze the data similarly as 
described above for FVC responders. 
In addition, a cumulative incidence table and graph will be presented for absolute change from 
baseline in total SGRQ score per time point  and worst-case up to the end of the study for the 
categories ≤-4, ≤-3, ≤-2,…, ≤0, …, ≤2, ≤3, ≤4 , by treatment group.  
Sensitivity Analyses 
A per protocol analysis will be performed for the key secondary analysis of change in total SGRQ 
score.  
If the graphical presentations over time indicate a linear trend a similar slope model as for the 
similar slope model as for the primary endpoint of rate of decline in FVC may be performed as a 
supportive analysis for SGRQ.  
9.3.6. 
Other Questionnaires 
The following questionnaires will be completed electronically, using a tablet device at the clinical 
study center. 
9.3.6.1. 
EQ-5D 
EQ-5D will not be analysed for the abbreviated CSR. 
The 3-level version of EuroQOL 5-Dimensions Questionnaire (EQ-5D-3L) consists of two pages:  
− 
EQ-5D descriptive system:  
The EQ-5D descriptive system is split into five domains: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has three levels, which results in a 
1-digit number that expresses the level selected for that dimension. The digits for the five 
dimensions can be combined into a 5-digit number that describes the subject’s health state 
(e.g. ‘11231’). Results will be presented as frequency of subjects having no problem, some 


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problems, and high problems in each domain. In addition, the 5-digit number will be 
converted into a single summary index score applying a formula that applies weights to each 
of the levels in each domain. The formula (value set) is obtained from EuroQol Research 
Foundation and is derived according to the preferences of the general population of a 
country / region (EuroQol Research Foundation. EQ-5D-3L User Guide, 2018). 
− 
EuroQOL visual analogue scale (EQ VAS) 
The EQ VAS records the subject’s self-rated health on a vertical VAS and can be used as a 
quantitative measure of health outcome that reflects the subject’s own judgment. 
EQ-5D and EQ VAS will be presented using descriptive statistics by treatment group of actual 
values and changes from baseline at all time points. 
9.3.6.2. 
Leicester Cough Questionnaire (LCQ) 
LCQ will not be analysed for the abbreviated CSR. 
Subjects with IPF commonly present with a (severe) non-productive cough. Cough will be 
evaluated using the LCQ. The LCQ is a 19-item questionnaire (Appendix 4) split into three 
domains: physical, psychological, and social. Scores are calculated by domain (range from 1 to 
7) by summing the items and dividing by the number of completed items. Then these scores are 
added to obtain the total score (range from 3 to 21, with higher scores indicating a better health 
status). 
Domains (questions): 
− 
Physical: 1,2,3,9,10,11,14,15 
− 
Psychological: 4,5,6,12,13,16,17 
− 
Social: 7,8,18,19 
Domain scores: total score from items in domain/number of items completed in domain (range 
1-7). 
Total scores: addition of domain scores (range 3–21). 
LCQ total score and domain scores will be presented using descriptive statistics by treatment 
group of actual values and changes from baseline at all time points. 
9.3.6.3. 
King’s Brief ILD Questionnaire (K-BILD) 
K-BILD questionnaire will not be analysed for the abbreviated CSR. 
The K-BILD health status questionnaire is a 15-item questionnaire split into three domains: 
psychological, breathlessness and activities, and chest symptoms. Scores are weighted, using 
information obtained from the authors (Patel, et al., 2012) such that every domain score and the 
total score range from 0 to 100, with higher scores indicating a better health status. If an item is 
not completed it will not be counted in the numerator. 
The final K-BILD questionnaire consisted of 15 items and three domains: 






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9.4. 
Safety Analyses 
Safety analyses will be performed using the FAS. 
Continuous variables will be summarized using descriptive statistics. Frequencies and 
percentages will be generated for categorical variables. No formal testing will be performed to 
compare the treatment groups.  
Safety tables will be presented by treatment group, as randomized.  
9.4.1. 
Adverse Events 
AEs will be coded according to the most recent version of the Medical Dictionary for Regulatory 
Activities.  
A listing will be provided for all available coding steps between AE verbatim and AE system 
organ class, mentioning also the subjects who had the AE. 
9.4.1.1. 
Treatment-Emergent Principle.  
All adverse events starting on or after the first dose of IP and up to the last dose plus 30 days, are 
considered treatment-emergent adverse events (TEAE).  
All AEs and changes in attributes (worsening and improvement) of AEs are reported in the 
database. Only worsenings of a pre-existing adverse event, after first dose of IP up to the last 
dose plus 30 days are to be considered as a TEAE, improvements after first dose of IP are not. A 
worsening is defined if at least one of the attributes of the events worsens (severity, seriousness, 
relationship or action taken).  
Selected tables will also be created for all AEs (or worsenings) which started after the first dose 
of IP (till the end of the study). Adverse events starting before the first dose of IP and 
improvements will be excluded, but will be in the listings. 
9.4.1.2. 
Allocation of Adverse Events to Analysis Periods 
All adverse events records will be placed into analysis periods considering their start date and 
flag indicating the relative timing versus study (drug) start, 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, a worst-case consideration (see below) will be done aiming to 
allocate the AE record to one single analysis period, if possible. When a worst-case consideration 
is needed, the end date of the AE record, if and as available, and the flag indicating the relative 


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timing versus study end should also be considered; if such AEs clearly ends 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 analysis period with treatment will only be placed in the analysis 
period with treatment. 
− 
An AE which according to the available information of its start date could belong to an 
analysis period with treatment as well as to a next analysis period for which no treatment is 
defined (follow-up) will only be placed in the analysis period with treatment. 
− 
An AE with a missing start date will be allocated to the analysis period with treatment. 
9.4.1.3. 
Treatment Relatedness 
Following (ICH-E3), the drug relatedness will be dichotomized as follows: 
Drug related: at least possibly drug related as assessed by the investigator, OR with missing drug 
relatedness (= worst-case) 
Not drug related: less than possibly drug related. 
In tabulations this dichotomized parameter will be used, but in the listings the original parameter 
will be presented. 
9.4.1.4. 
Worst-Case Principle 
When cross-tabulating AE preferred terms versus an AE attribute (e.g. severity), the worst-case is 
always applied within each analysis period, i.e. when a subject has multiple times the same AE 
preferred term starting in the same analysis period, then the subject is reported only once: only 
with the worst severity. If this happens in two different analysis periods, the AE is reported twice: 
once in each analysis period. 
9.4.1.5. 
Adverse Event Onset Day and Durations 
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 IP administration), 
the start day in the analysis period, and the duration (in days) will be calculated. In addition, the 
relative days and duration will be derived for the entire event; that is, the full evolution of the 
event, including the initial reporting and all subsequent worsenings and/or improvements. 
Relative start- and end days of the entire event will be derived based on the start date of the first 
event and the end date of the last event respectively; and the duration of the entire event will be 
calculated by subtracting the start date of the first event of the end date of the last event + 1 day. 
See section 6.1 for the calculation of relative days. 


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9.4.1.6. 
Analyses 
9.4.1.6.1. Treatment-emergent AEs during the treatment period 
A summary table of the number of subjects with at least one TEAE, at least one IP/SOC related 
TEAE, one serious TEAE, a TEAE leading to death, TEAEs by worst severity, and TEAE 
leading to IP/ SOC discontinuation, down-titration and interruption per treatment group will be 
provided. The table will also include the difference in percentage of subjects with an TEAE from 
placebo for each of the two dose groups, together with the 95% CI using the method of Miettinen 
and Nurminen (Miettinen & Nurminen, 1985). 
The number (percent) of subjects with a TEAE by system organ class and preferred term will be 
presented. Similar tables will be provided by worst severity, by IP/SOC relationship and, by 
worst severity and relationship. Furthermore serious TEAEs, deaths, TEAEs leading to IP/SOC 
down-titration, TEAEs leading to IP/SOC interruption and TEAEs leading to IP/SOC 
discontinuation will be tabulated by system organ class and preferred term. 
A table will also be presented, with the difference from placebo and 95% CI based on the method 
of Miettinen and Nurminen for the number (percent) of subjects with a TEAE by system organ 
class and preferred term, for events with an incidence of at least 5% in at least one of the 
treatment groups (600, 200 mg or placebo). 
Kaplan-Meier estimates will be presented graphically and in tabular format for the following time 
to first event endpoints, by treatment, as well as by treatment and stratum: 
− 
first TEAE 
− 
first serious TEAE 
− 
first TEAE leading to early IP discontinuation 
 
Treatment-emergent COVID-19 infections and suspected infections will be tabulated  and listed. 
9.4.1.6.2. AEs from First Dose of IP up to the End of the Study 
A summary table of the number of subjects with at least one AE, at least one IP/SOC related AE, 
one serious AE, an AE leading to death, AEs by worst severity, and AE leading to IP/SOC 
discontinuation, down-titration and interruption per treatment group will be provided for all AEs 
starting after the first dose of IP (up to the end of the study). The table will also include the 
difference in percentage of subjects with an AE from placebo for each of the 2 dose groups, 
together with the 95% CI using the method of Miettinen and Nurminen. 
The number (percent) of subjects with an AE by system organ class and preferred term will also 
be presented, for AEs, deaths, SAEs, AEs leading to IP/SOC discontinuation down-titration and 
interruption. 
A table will also be presented, with the difference from placebo and 95% CI based on the method 
of Miettinen and Nurminen for the number (percent) of subjects with an AE by system organ 


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class and preferred term, for events with an incidence of at least 5% in at least one of the 
treatment groups (600, 200 mg or placebo). 
COVID-19 infections and suspected infections will also be tabulated and listed. 
Listings will be provided for the serious adverse experiences (including AEs leading to 
hospitalization), deaths, AEs leading to death and AEs leading to down-titration, interruption and 
early treatment discontinuation of IP, Pirfenidine and Nintedanib.  
9.4.1.6.3. EudraCT Adverse Events Reporting 
For the purpose of EudraCT reporting, the following frequency tabulations will be added: 
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 the all non-serious TEAEs and for non-serious TEAEs reported in at least 
5% of the subjects in any treatment group.  
9.4.1.6.4. Adverse Events Related to Nintedanib or Pirfenidone 
To investigate the events expected to be associated with pirfenidone and nintedanib, Kaplan-
Meier curve and table, as well as a counts table by system organ class and preferred term, by 
treatment, as well as by stratum and treatment 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 CSR. 
9.4.1.7. 
Subgroup Analyses 
For each subgroup, a summary table of the number of subjects with at least one TEAE, at least 
one related TEAE, a serious TEAE, leading to death, TEAEs by worst severity, and TEAE 
leading to down-titration, interruption and discontinuation of IP/SOC per treatment group will be 
provided. The number (percent) of subjects with a TEAE by system organ class and preferred 
term will also be presented per subgroup. 
The following subgroups will be investigated:  
− 
Age (<65 and ≥65 years),  
− 
Race, 
− 
Sex,  
− 
Stratum,  
− 
Geographic region (NA, EMEA, Latin-America, Asia-Pacific) 
Since the two studies are identically designed, more subgroups may be investigated in the pooled 
safety analysis in the ISS/SCS to increase the size of small subgroups. 
 








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> 160  
mmol/L > 160  
mmol/L 
G4 
Potassium decreased 
< LLN - 3  
mmol/L < LLN - 3  
mmol/L 
G1 
  
< 3 - 2.5  
mmol/L < 3 - 2.5  
mmol/L 
G3 
  
< 2.5  
mmol/L < 2.5  
mmol/L 
G4 
  
  
 
  
 
 
Potassium increased 
> ULN – 5.5  
mmol/L > ULN – 5.5  
mmol/L 
G1 
  
> 5.5 – 6  
mmol/L > 5.5 – 6  
mmol/L 
G2 
  
> 6 – 7  
mmol/L > 6 – 7  
mmol/L 
G3 
  
> 7  
mmol/L > 7  
mmol/L 
G4 
Calcium decreased 
< LLN - 8  
mg/dl 
< LLN - 2.0  
mmol/L 
G1 
  
< 8-7  
mg/dl 
< 2-1.75  
mmol/L 
G2 
  
< 7-6  
mg/dl 
< 1.75-1.5  
mmol/L 
G3 
  
< 6  
mg/dl 
< 1.5  
mmol/L 
G4 
  
  
 
  
 
 
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  
>ULN-3 x ULN 
>ULN-3 x ULN 
G1 
> 3 -5 xULN  
> 3 -5 xULN  
G2 
> 5 -20 xULN  
> 5 -20 xULN  
G3 
> 20 xULN  
> 20 xULN  
G4 
ALT  
>ULN-3 x ULN  
>ULN-3 x ULN  
G1 
> 3 -5 xULN  
> 3 -5 xULN;  
G2 
> 5 -20 xULN  
> 5 -20 xULN  
G3 
> 20 xULN  
> 20 xULN  
G4 
GGT  
  
> ULN – 2.5 x ULN  
> ULN – 2.5 x ULN 
G1 
>2.5 -5 x ULN  
>2.5 -5 x ULN  
G2 
> 5 -20 *ULN  
> 5 -20 *ULN  
G3 
> 20 *ULN  
> 20 *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 




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− 
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. 
Tables will be created for treatment-emergent abnormalities, i.e. postbaseline abnormalities 
which differ from (and are not better than) the baseline result. If the baseline result is missing, a 
postbaseline abnormality L or H will always be considered as treatment-emergent. 
9.4.2.7.2. According to CTCAE Toxicity Grades 
The worst-case postbaseline toxicity grade 0, 1, 2, 3 or 4 will be determined per subject, per 
laboratory test (and sense, if below and above) and for each analysis period, using all non-
missing postbaseline records (including unscheduled and follow-up visits, but excluding local 
laboratory results). 
The worst-case toxicity grade is the highest toxicity grade scored for the laboratory test (in each 
sense, if below and above).  
Tables will be created for treatment-emergent toxicity grades. A postbaseline toxicity grade 1, 2, 
3 or 4 is defined as treatment-emergent when higher than the toxicity grade of the baseline result. 
If the baseline result is missing, a postbaseline toxicity grade 1, 2, 3 or 4 will always be 
considered as treatment-emergent. 
9.4.2.8. 
Analyses  
No formal inferential statistics (p-values) will be derived. 
For each laboratory test, descriptive statistics and graphical presentation (line plot of the mean 
and SE) will be provided for the actual laboratory values and change from baseline over time-by-
treatment group. 
A summary table per laboratory test category (hematology, biochemistry, urinalysis and 
coagulation), laboratory test and unit, treatment group and time point, showing only the mean 
value of actual values and changes from baseline will also be provided. 
All laboratory abnormalities after the first dose of IP up to 30 days after the last dose will be 
included, consistently with AE reporting. 
A shift table per laboratory test category (hematology, biochemistry, urinalysis and coagulation), 
laboratory test and treatment group will be provided for laboratory tests with normal ranges, for 
which CTCAE grades are not available. The table will present the worst shift in abnormality 
(L/N/…) during the treatment period versus the baseline abnormality (L/N/H). 
Frequency table will be provided of the worst treatment-emergent laboratory abnormalities per 
laboratory test category (hematology, biochemistry, urinalysis and coagulation), laboratory test, 
and treatment group. This table will be created for those laboratory tests for which CTCAE 
grades are not available. 






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• 
Normal: ≥50- ≤ 100 bpm,  
• 
High: >100 bpm; 
 
9.4.3.4. 
Worst-case Abnormality of QT and QTcF 
The worst-case post-baseline categorized actual analysis value and the worst-case categorized 
change from baseline for QT and QTcF will be determined per subject, per parameter, and for 
each analysis period, using all non-missing post-baseline records (including unscheduled and 
follow-up visits). 
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. 
Tables will be created for treatment-emergent abnormalities. For actual values, an abnormal post-
baseline abnormality 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. 
9.4.3.5. 
Worst-case Abnormality of PR and HR 
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.  
− 
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. 
Tables will be created for treatment-emergent abnormalities, i.e. postbaseline abnormalities 
which differ from (and are not better than) the baseline result. If the baseline result is missing, a 
postbaseline abnormality L or H will always be considered as treatment-emergent. 
9.4.3.6. 
Analyses 
No formal inferential statistics (p-values) will be derived. 
Descriptive statistics will be summarized of the actual values and change from baseline 
(including 95% CI of the mean change) per parameter and unit, treatment group and time point. 
The actual value at baseline will also be presented in this table. Only pre-dose assessments will 
be used for this table. A similar summary table as for labs will also be provided. 


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In addition to the predose measurements, ECGs are also taken 2-3 hours postdose on selected 
visits (Day 1, Week 2, 4, 12 and 34 for ECG). These postdose measurements will not be taken 
into account in the windowing for the above tables, but an additional table will be created 
summarizing the pre- and postdose values at these selected visits. 
All ECG abnormalities after the first dose of IP up to 30 days after the last dose will be included 
for consistency with AE reporting. 
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 
heart rate),  treatment group and analysis period. 
A frequency table of the number (percent) of subjects with treatment-emergent worst-case 
abnormalities and the worst change per parameter (QT, QTcF, PR and heart rate), treatment 
group and analysis period will be presented. 
Frequency table per treatment group and time point of the ECG interpretation scores as 
recorded in the eCRF. Note that more than one of these items can be ticked. 
No figures are planned for ECGs. 
Listing will be provided per treatment group, per subject and per time point of all postbaseline 
data scored as out-of-normal-range or postbaseline clinically significant, plus also the baseline 
reference time point.  
9.4.4. 
Vital Signs 
Summaries will be provided for the vital signs heart rate, diastolic and systolic blood pressure, 
temperature, respiratory rate and oxygen saturation. 
9.4.4.1. 
Normal Ranges 
Normal ranges are defined in Appendix 8 of the Clinical Study Protocols. 
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. 
9.4.4.2. 
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.  
− 
H = high: at least one post-baseline result is classified as H. 


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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. 
Tables will be created for treatment-emergent abnormalities, i.e. postbaseline abnormality which 
differ from (and are not better than) the baseline result. If the baseline result is missing, a 
postbaseline abnormality L or H will always be considered as treatment-emergent. 
9.4.4.3. 
Analyses 
No formal inferential statistics (p-values) will be derived. 
Descriptive statistics will be summarized of the actual values and change from baseline 
(including 95% CI of the mean change) per parameter and unit, treatment group and time point. 
The actual value at baseline will also be presented in this table. A similar summary table as for 
labs will also be provided. 
All vital signs abnormalities after the first dose of IP up to 30 days after the last dose will be 
included. 
Abnormalities of the actual values will be presented as shift tables of the worst-case abnormality 
versus the baseline abnormality. The table will be created per parameter (and position if 
applicable), treatment group and analysis period. 
A frequency table of the number (percent) of subjects with treatment-emergent worst-case 
abnormalities per parameter, treatment group and analysis period will be presented. 
No figures are planned for vital signs. 
A listing will be created per treatment group, per subject and per time point of all postbaseline 
time points scored as treatment-emergent out-of-normal-range, plus also the baseline reference 
time point.  
9.4.5. 
Physical Examinations 
A counts table will be created for the number (%) of subjects with at least one treatment-
emergent abnormality by system organ class. 
A listing will be created per treatment group, per subject and per time point of the selection of all 
abnormal findings. 
9.5. 
Pharmacokinetic Assessments 
Blood samples for the PK assessment of GLPG1690, pirfenidone and nintedanib should be 
collected as specified in the Schedule of Activities in section 2.5. 
Subject profile plots over time will be provided for the PK concentrations of GLPG1690, 
pirfenidone and nintedanib. In addition, listings of all individual plasma concentration data will 
be created. More detailed population PK
 analyses will be described in a separate SAP. 


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10. 
REFERENCES 
EuroQol Research Foundation. EQ-5D-3L User Guide. (2018). Retrieved from 
https://euroqol.org/publications/user-guides 
Fridericia, L. (1920). Die Systolendauer im Elektrokardiogramm bei normalen Menschen und bei 
Herzkranken. J Int med, 53(1), 469-486. 
Halperin, M., Lan, K., Wright, E., & Foulkes, M. (1987). Stochastic curtailing for comparison of 
slopes in longitudinal studies. Controlled Clinical Trials, 8(4), 315-326. 
Hochberg, Y. (1988). A sharper Bonferroni procedure for multiple tests of significance. 
Biometrika, 75, 800-2. 
Jennison, C., & Turnbull, B. (2000). Group Sequential Methods with Applications to Clinical 
Trials. Boca Raton: Chapman & Hall/CRC. 
Keene, O., Jones, M., Lane, P., & Anderson, J. (2007). Analysis of exacerbation rates in asthma 
and chronic obstructive pulmonary disease: example from the TRISTAN study. Pharm 
Stat, 6(2), 89-97. 
Miettinen, O., & Nurminen, M. (1985). Comparative analysis of two rates. Statistics in Medicine, 
4, 232-226. 
Miller, M., Hankinson, J., Brusasco, V., Burgos, F., Casaburi, R. C., Casaburi, R., & Coates, A. 
(2005). Standardisation of spirometry. Eur Respiratory J, 26(2), 319-338. 
Patel, A., Siegert, R., Brignall, K., Gordon, P., Steer, S., & Desai, S. (2012). The development 
and validation of the King's Brief Interstitial Lung Disease (K-BILD) health status 
questionnaire. Thorax, 67(9), 804-810. 
Ratitch B, O. M. (2013). Missing data in clinical trials: from clinical assumptions to statistical 
analysis using pattern mixture models. . Pharm Stat , 40(6), 12 (6):337-47. 
Rubin, D. (1987). Multiple Imputation for nonresponse in surveys. New York: John Wiley and 
Sons. 
 
 
 
 
 


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11. 
APPENDICES 
1. 
ADDITIONAL DETAILS ON PRIMARY ANALYSIS 
For both parameters (FVC [in mL] or percent predicted FVC, separately), the annual rate of 
decline will be analyzed using a random coefficient regression model (linear slope model) 
including sex, age, height and stratification factor (stratum: pirfenidone, nintedanib and neither) 
as covariates and a random intercept and slope. The treatment effect is determined by using 
estimated slopes for each treatment group on the basis of the time-by-treatment interaction term 
from the mixed model. All available FVC values, as defined by the analysis windows will be 
used, including FVC measurements at the follow-up visit for subjects who discontinue the IP 
prematurely and do not complete the study visits. The model will be fit using the SAS Proc 
Mixed procedure, details are below. The assumptions of the model will be investigated.  
In the primary analysis only data up to the Week 52 will be used, before a lung transplant. In a 
secondary analysis all data will be used up to the end of the study, before a lung transplant. 
The statistical model can be written as follows: 
Yitk = (α + ai) + (γ + βT1Tk1 + βT2Tk2 + gi)t + βg Gender + βa age + βh Height + βsP Stratum (P)+ 
βsN Stratum (N) + εit 
Where Yitk is the FVC value for the ith subject at time t in treatment group k, Tk1=0 for placebo 
and Tk1=1 for GLPG1690 200 mg, Tk2=0 for placebo and Tk2=1 for GLPG1690 600 mg, βT1, βT2 
are the effects of GLPG1690 on the slope. 
α and γ are the fixed effects for the intercept and slope, respectively 
ai and gi are random effects for the intercept and slope for subject i, these are assumed to be 
normally distributed with mean 0 and unstructured variance-covariance matrix. 
βg, βa, βsP, βsN and βh are subject specific demographic coefficients for gender, age, stratification 
factor (standard of care) and height at baseline. 
εit is the random error for subject i at time t, assumed to be normally distributed with mean 0 and 
variance σε2. 
An unstructured variance-covariance matrix will be used to model the variance-covariances for 
the random slope, random intercept. The variance-covariance matrix for the error terms is 
assumed to have a variance-component structure. 
If this model fails to converge, other structures will be tested for the variance-covariance matrix 
for the error terms (e.g. heterogeneous Toeplitz). Depending on the structure used, the random 
slope and random intercept may need to be dropped from the model. The structure with the best 
fit, based on Akaike’s information criterion, will then be used. 
 


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The linearity assumption of the model will be explored graphically be the lineplots over time of 
the observed FVC values (mL) as well as change from baseline and LS means at each time point. 
The following SAS code is to be used: 
proc SORT data = FVC ; 
  By subject visit ;  
run ; 
Proc MIXED data = FVC order = internal; 
    CLASS subject treatment visit gender stratum; 
    MODEL FVC = treatment * time gender age height stratum / solution CL ddfm=KR ; 
    RANDOM intercept time / type=UN subject = subject ; 
    REPEATED visit / type= Simple subject = subject ; 
    ESTIMATE “GLPG 1690 600 mg qd - Placebo” treatment*time -1 0 1 / e CL ; 
    ESTIMATE “GLPG 1690 200 mg qd - Placebo” treatment*time -1 1 0 / e CL ; 
run ; 
2. 
IMPLEMENTATION OF MULTIPLE IMPUTATIONS FOR 
PATTERN MIXTURE APPROACH 
The following steps provide a guidance on how missing FVC data at Week 52 will be imputed in 
the pattern mixture approach for subjects of pattern 3, 4 and 5 using multiple imputation.  
1. Run the random coefficient regression model for the primary analysis to get the slope 
estimates by treatment group and stratum.  
2. Assume that the true slopes follow a normal distribution with mean and standard error 
obtained in step 1. 
3. Impute missing values multiple times (1000 imputations per subject). To do so, draw random 
slopes from the distributions in step 2. Considering that the withdrawal of a subject leading 
to missing data can occur at any time during the study, the time point of the last available 
FVC value has to be taken into account to impute the missing FVC value at 52 weeks: 
FVC week 52 imputedij = last FVC value availablei + ߚపఫ
෢ (time between last available FVC 
and Day 365 in days) 
 
where i denotes the indicator of the ith subject, j the indicator of the jth imputation and 
ߚ௜௝ denotes a random slope sampled from the distribution mentioned in step 2.  
Depending on the sensitivity analysis, use either random slopes drawn from the distribution 
for the slope obtained for subjects randomized to active treatment or placebo. 
4. Run the same random coefficient regression model for each of the 1000 imputed datasets. 
5. Combine the estimates of the 1000 analyses in step 4 using SAS PROC MIANAYZE 


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3. 
ADDITIONAL DETAILS ON MIXED-EFFECT MODEL FOR 
REPEATED MEASURES ANALYSIS 
A mixed-effects model for repeated measures (MMRM) with treatment*time (categorical) , 
stratum, gender, age, height and baseline value as factors in the model will be applied to the 
change from baseline in FVC value in mL. Least squares (LS) means (with 95% CI) will be 
estimated from the model at each time point for each treatment group as well as the differences 
from placebo in LS means (and 95% CIs).  
The SAS code for the MMRM model for FVC change from baseline is given below. The same 
model will be used for SGRQ. 
proc SORT data= FVC; 
BY patient visit; 
run; 
proc MIXED data=FVC order=internal covtest ; 
      
CLASS patient treatment visit; 
MODEL change_from_baseline= treatment*visit baseline  gender age height stratum 
/solution ddfm=KR; 
REPEATED visit/type=UN subject =patient; 
LSMEANS treatment*visit / cl diff; 
run; 
If the model does not converge with an unstructured variance-covariance model, other structures 
will be tried (e.g. heterogenous Toepliz, AR(1),…). The structure with the best fit, based on 
Akaike’s information criterion, will then be used. 
4. 
LEICESTER COUGH QUESTIONNAIRE 
This questionnaire is designed to assess the impact of your cough on various aspects of your life. Read each question carefully and answer by CIRCLING the 
response that best applies to you. Please answer ALL questions, as honestly as you can.  
1. In the last 2 weeks, have you had chest or stomach pains as a result of your cough? 
 
1 
2 
3 
4 
5 
6 
7 
 
All of the time 
Most of the time 
A lot of the time 
Some of the time 
A little of the time 
Hardly any of the time 
None of the time 
2. In the last 2 weeks, have you been bothered by phlegm production when you cough? 
 
1 
2 
3 
4 
5 
6 
7 
 
Every time 
Most times 
Several times 
Sometimes 
Occasionally 
Rarely 
Never 
3. In the last 2 weeks, have you been tired because of your cough? 
 
1 
2 
3 
4 
5 
6 
7 
 
All of the time 
Most of the time 
A lot of the time 
Some of the time 
A little of the time 
Hardly any of the time 
None of the time 
4. In the last 2 weeks, have you felt in control of your cough? 
 
1 
2 
3 
4 
5 
6 
7 
 
None of the time 
Hardly any of the time 
A little of the time 
Some of the time 
A lot of the time 
Most of the time 
All of the time 
5. How often during the last 2 weeks have you felt embarrassed by your coughing? 
 
1 
2 
3 
4 
5 
6 
7 
 
All of the time 
Most of the time 
A lot of the time 
Some of the time 
A little of the time 
Hardly any of the time 
None of the time 
6. In the last 2 weeks, my cough has made me feel anxious 
 
1 
2 
3 
4 
5 
6 
7 
 
All of the time 
Most of the time 
A lot of the time 
Some of the time 
A little of the time 
Hardly any of the time 
None of the time 
7. In the last 2 weeks, my cough has interfered with my job, or other daily tasks 


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1 
2 
3 
4 
5 
6 
7 
 
All of the time 
Most of the time 
A lot of the time 
Some of the time 
A little of the time 
Hardly any of the time 
None of the time 
8. In the last 2 weeks, I felt that my cough interfered with the overall enjoyment of my life 
 
1 
2 
3 
4 
5 
6 
7 
 
All of the time 
Most of the time 
A lot of the time 
Some of the time 
A little of the time 
Hardly any of the time 
None of the time 
9. In the last 2 weeks, exposure to paints or fumes has made me cough 
 
1 
2 
3 
4 
5 
6 
7 
 
All of the time 
Most of the time 
A lot of the time 
Some of the time 
A little of the time 
Hardly any of the time 
None of the time 
10. In the last 2 weeks, has your cough disturbed your sleep? 
 
1 
2 
3 
4 
5 
6 
7 
 
All of the time 
Most of the time 
A lot of the time 
Some of the time 
A little of the time 
Hardly any of the time 
None of the time 
11. In the last 2 weeks, how many times a day have you had coughing fits? 
 
1 
2 
3 
4 
5 
6 
7 
 
All of the time 
(continuously) 
Most times during the day Several times during 
the day 
Sometimes during the day Occasionally through 
the day 
Rarely 
None 
12. In the last 2 weeks, my cough has made me feel frustrated 
 
1 
2 
3 
4 
5 
6 
7 
 
All of the time 
Most of the time 
A lot of the time 
Some of the time 
A little of the time 
Hardly any of the time 
None of the time 
13. In the last 2 weeks, my cough has made me feel fed up 
 
1 
2 
3 
4 
5 
6 
7 
 
All of the time 
Most of the time 
A lot of the time 
Some of the time 
A little of the time 
Hardly any of the time 
None of the time 
14. In the last 2 weeks, have you suffered from a hoarse voice as a result of your cough? 
 
1 
2 
3 
4 
5 
6 
7 
 
All of the time 
Most of the time 
A lot of the time 
Some of the time 
A little of the time 
Hardly any of the time 
None of the time 
15. In the last 2 weeks, have you had a lot of energy? 
 
1 
2 
3 
4 
5 
6 
7 
 
None of the time 
Hardly any of the time 
A little of the time 
Some of the time 
A lot of the time 
Most of the time 
All of the time 
16. In the last 2 weeks, have you worried that your cough may indicate a serious illness? 
 
1 
2 
3 
4 
5 
6 
7 
 
All of the time 
Most of the time 
A lot of the time 
Some of the time 
A little of the time 
Hardly any of the time 
None of the time 
17. In the last 2 weeks, have you been concerned that other people think something is wrong with you because of your cough? 
 
1 
2 
3 
4 
5 
6 
7 
 
All of the time 
Most of the time 
A lot of the time 
Some of the time 
A little of the time 
Hardly any of the time 
None of the time 
18. In the last 2 weeks, my cough has interrupted conversations or telephone calls 
 
1 
2 
3 
4 
5 
6 
7 
 
Every time 
Most times 
A lot of the time 
Some of the time 
A little of the time 
Hardly any of the time 
None of the time 
19. In the last 2 weeks, I feel that my cough has annoyed my partner, family or friends 
 
1 
2 
3 
4 
5 
6 
7 
 
Every time I cough 
Most times when I cough 
Several times when 
I cough 
Sometimes when I cough 
Occasionally when I cough Rarely 
Never 
Thank you for completing this questionnaire. 
5. 
SUMMARY OF THE FUTILITY APPROACH 
In view of the termination of the trial, the below section is not applicable. 
As mentioned in Section 8, an interim analysis will be performed to assess futility based on the 
effect of treatment with GLPG1690 on the annual rate of decline in FVC using the pooled interim 
data from studies GLPG1690-CL-303 and GLPG1690-CL-304. The IDMC will review the 
results of this analysis and make a recommendation to the sponsor on the continuation of both 
studies. To allow collection of as much safety information as possible, a study will only be 
considered futile when both doses show futility. In addition, a study will only be stopped, when 
both studies meet the condition for futility. 
Futility of a dose in a study will be assessed by a conditional power approach (Jennison & 
Turnbull, 2000). Conditional power is defined as the probability to conclude a significant effect 
for the final analysis, given the interim data and an assumption for the effect in the unobserved 
data after the interim. In the primary analysis (see Section 9.3.2.1) all data up to and including the 


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52-week time window will be included, therefore conditional power in the context of stochastic 
curtailing for longitudinal data will be implemented (Halperin, Lan, Wright, & Foulkes, 1987). A 
dose will be considered futile if the conditional power is lower or equal to a certain stopping 
boundary, assuming the effect size in the unobserved data is equal to the point estimate from the 
interim analysis. 
To determine the best choice for the timing of the interim analysis and the stopping boundary, 
simulations were run under different scenarios of the true treatment effect for a range of timings 
of the interim and stopping boundaries. Based on the results of these simulations, values were 
selected such that the probability to stop in the interim is high if there is no effect and low for 
effects around 80 mL and higher. This led to the selection of a stopping boundary of 40% .i.e. a 
dose will be considered futile if the conditional power is lower than 40%, the interim analysis 
will be planned when approximately 70% of total information is collected or when at least 25% 
of subjects from the two studies combined have completed 52 weeks of treatment (whichever 
comes latest). Note that the term ‘information’ in this context is defined as the information level 
associated with the primary test statistic (i.e. the inverse of the variance of the treatment estimate 
at interim) (Jennison & Turnbull, 2000).