Conditions: Autosomal Dominant Polycystic Kidney Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 66
Healthy volunteers: no

Brief summary:
This is an exploratory, randomized, double-blind, placebo-controlled, parallel group, multicenter, proof of concept study (Phase 2a), evaluating orally administered GLPG2737 for a double-blind (DB) treatment period of 52 weeks and 4 weeks of follow up as well as an open-label extension (OLE) treatment period of 52 weeks and 4 weeks of follow-up, in participants with rapidly progressing ADPKD.

Detailed description:

Arms:
arm 1: Participants received 150 milligrams (mg) GLPG2737 capsules orally once daily for 52 weeks in the double-blind (DB) treatment period. Eligible participants were rolled over to an open-label extension (OLE) period to receive 150 mg GLPG2737 orally once daily for 52 weeks. arm 2: Participants received placebo matched to GLPG2737 capsules orally once daily for 52 weeks in the DB treatment period. Eligible participants were rolled over to an OLE period to receive 150 mg GLPG2737 orally once daily for 52 weeks.

Interventions: intervention 1: GLPG2737 intervention 2: Placebo
Intervention descriptions: intervention 1: Capsules administered orally intervention 2: Matching placebo capsules administered orally

Protocol document:
Prot_000.pdf: 
Galapagos 
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Confidentiality Statement 
The information contained in this document is privileged and confidential. It is the property of Galapagos NV and 
may not be used, disclosed, reproduced or otherwise disseminated within your organization or communicated to any 
third parties without the express written authorization of Galapagos NV. 
  
CLINICAL STUDY PROTOCOL 
Project Number: 
GLPG2737 
Protocol 
Version:  
6.00 
Study Number: 
GLPG2737-CL-203 
Amendment: 
5 
 
 
 
Date: 
20-Dec-2021 
Study Title: 
An exploratory, randomized, double-blind, placebo-controlled, multicenter 
study to evaluate the efficacy, safety, tolerability and pharmacokinetics of 
orally administered GLPG2737 for 52 weeks, followed by an open-label 
extension period of 52 weeks in subjects with autosomal dominant 
polycystic kidney disease  
Short Title:  
A study to evaluate the effects of GLPG2737 in subjects with autosomal 
dominant polycystic kidney disease 
Status 
Final 
Development 
Phase: 
2a 
 
 
EudraCT No: 
2019-003521-21 
CT.gov No: 
NCT04578548 
IND No: 
not applicable 
Sponsor: 
Galapagos NV, Generaal De Wittelaan L11 A3, 2800 Mechelen, Belgium 
Study Physician: 
 
General Protocol / 
Applicable 
Country(ies): 
General protocol 
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EMERGENCY CONTACT INFORMATION 
In case of a serious adverse event (SAE), a special situation (see Section 8.1.6) or in case of 
pregnancy during the clinical study the investigator must report this immediately, and under no 
circumstances later than 24 hours following the knowledge of the SAE or pregnancy, as follows: 
 
SGS Medical Affairs 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: 
 
 
 
PPD
PPD
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TABLE OF CONTENTS 
EMERGENCY CONTACT INFORMATION ........................................................................... 2 
TABLE OF CONTENTS ........................................................................................................ 3 
CLINICAL STUDY PROTOCOL HISTORY ............................................................................ 7 
SUMMARY OF CHANGES ................................................................................................... 8 
LIST OF TABLES .................................................................................................................15 
LIST OF FIGURES ...............................................................................................................15 
LIST OF LISTINGS ..............................................................................................................15 
LIST OF APPENDICES ........................................................................................................15 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................16 
PROTOCOL SYNOPSIS ......................................................................................................20 
1. 
INTRODUCTION ...........................................................................................................25 
1.1. 
Background - Nonclinical Studies .......................................................................26 
1.2. 
Background - Clinical Studies ............................................................................26 
2. 
CLINICAL STUDY OBJECTIVES ..................................................................................29 
2.1. 
Primary Objectives .............................................................................................29 
2.2. 
Secondary Objectives ........................................................................................29 
2.3. 
Other Objectives ................................................................................................29 
3. 
INVESTIGATIONAL PLAN ............................................................................................29 
3.1. 
Clinical Study Design .........................................................................................29 
3.2. 
End of Study Definition ......................................................................................30 
3.3. 
Clinical Study Rationale .....................................................................................31 
3.3.1. 
Dose Rationale ...................................................................................31 
3.3.2. 
Clinical Study Design Rationale ..........................................................32 
3.4. 
Endpoints ...........................................................................................................32 
3.4.1. 
Primary Endpoint ................................................................................32 
3.4.2. 
Secondary Endpoints ..........................................................................33 
3.4.3. 
Other Endpoints ..................................................................................33 
3.5. 
Potential Risks and Benefits ..............................................................................33 
3.6. 
Clinical Study Population ...................................................................................34 
3.6.1. 
Inclusion Criteria .................................................................................34 
3.6.2. 
Exclusion Criteria ................................................................................35 
3.6.3. 
Rescreening and Retesting .................................................................36 
3.6.4. 
Prohibition and Restrictions ................................................................37 
3.6.4.1. 
Precautions for Sexual Intercourse ....................................37 
3.6.4.1.1. 
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3.6.4.1.2. 
Male subjects .................................................38 
3.6.4.2. 
Prior and Concomitant Medications ...................................38 
3.6.4.3. 
Food and Beverage Restrictions ........................................39 
3.6.5. 
Treatment Discontinuation (Temporarily and Permanently), 
Subject Withdrawal, and Study Termination ........................................39 
3.7. 
Measures to Minimize Bias ................................................................................41 
3.7.1. 
Randomization ....................................................................................41 
3.7.2. 
Blinding and Unblinding ......................................................................41 
4. 
INVESTIGATIONAL PRODUCTS ..................................................................................42 
4.1. 
Identity of the Investigational Product(s) ............................................................42 
4.2. 
Dosage and Administration ................................................................................42 
4.3. 
Packaging, Labeling and Distribution .................................................................43 
4.4. 
Storage ..............................................................................................................43 
4.5. 
Treatment Compliance and Drug Accountability ................................................43 
4.5.1. 
Subject Diary ......................................................................................44 
5. 
CLINICAL STUDY ASSESSMENTS ..............................................................................44 
5.1. 
Timing of Assessments ......................................................................................44 
5.2. 
Unscheduled Visits ............................................................................................47 
5.3. 
Initial Subject and Disease Characteristics ........................................................47 
5.4. 
Efficacy Assessments ........................................................................................48 
5.4.1. 
htTKV and 
 by MRI ....................................................................48 
5.4.2. 
Estimated GFR
FR (eGFR) ......................................................................48 
5.5. 
Safety Assessments ..........................................................................................48 
5.5.1. 
Adverse Events ...................................................................................48 
5.5.2. 
Clinical Laboratory Evaluations ...........................................................49 
5.5.3. 
Physical Examination ..........................................................................50 
5.5.4. 
Vital Signs ...........................................................................................50 
5.5.5. 
12-lead Electrocardiogram ..................................................................50 
5.5.6. 
Other Safety Assessments - Control of Raised Blood Pressure ..........51 
5.6. 
Pharmacokinetic Assessments ..........................................................................51 
5.7. 
Pharmacodynamic Assessments .......................................................................52 
5.8. 
Other Assessments ............................................................................................52 
5.8.1. 
Genotyping .........................................................................................52 
5.8.2. 
Future Scientific Research ..................................................................53 
5.9. 
Sample Management .........................................................................................53 
5.10. 
Long Term Storage of Samples and Associated Data for Future Scientific 
and Genetic Research .......................................................................................53 
5.11. 
Schedule of Activities .........................................................................................55 
5.11.1. 
Double-blind Treatment Period ...........................................................55 
5.11.2. 
Open-label Treatment Period ..............................................................61 
6. 
STATISTICAL METHODS .............................................................................................64 
6.1. 
Determination of Sample Size ............................................................................64 
6.2. 
Population for Analyses .....................................................................................64 
6.2.1. 
All Screened Subjects .........................................................................64 
6.2.2. 
All Enrolled Subjects ...........................................................................64 
6.2.3. 
All Randomized Subjects ....................................................................65 
6.2.4. 
Full Analysis Set .................................................................................65 
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6.2.5. 
Per Protocol Set ..................................................................................65 
6.2.6. 
Safety Analysis Set .............................................................................65 
6.2.7. 
Pharmacokinetic Analysis Set .............................................................65 
6.2.8. 
Pharmacodynamic Analysis Set ..........................................................65 
6.2.9. 
Pharmacokinetic/Pharmacodynamic Analysis Set ...............................65 
6.2.10. 
All OLE Enrolled Subjects ...................................................................65 
6.2.11. 
OLE Full Analysis Set .........................................................................65 
6.2.12. 
OLE Safety Analysis Set .....................................................................66 
6.2.13. 
OLE Pharmacodynamic Analysis Set ..................................................66 
6.3. 
Statistical Analyses ............................................................................................66 
6.3.1. 
General Statistical Considerations ......................................................66 
6.3.2. 
Interim Analysis ..................................................................................66 
6.3.3. 
Analyses of Demographics and Baseline Characteristics ....................66 
6.3.4. 
Analyses of Primary Efficacy Parameters ...........................................67 
6.3.4.1. 
Analysis for Primary Efficacy Endpoint...............................67 
6.3.4.2. 
Analysis for Other Efficacy Endpoints ................................67 
6.3.5. 
Analyses of Primary Safety Data .........................................................67 
6.3.5.1. 
Extent of Exposure ............................................................67 
6.3.5.2. 
Adverse Events .................................................................67 
6.3.5.3. 
Clinical Laboratory Evaluations ..........................................68 
6.3.5.4. 
Vital Signs .........................................................................68 
6.3.5.5. 
12-Lead Electrocardiogram ................................................68 
6.3.6. 
Pharmacokinetics Analysis .................................................................69 
6.3.7. 
Pharmacodynamic Analyses ...............................................................69 
6.3.8. 
Analysis of Other Assessments...........................................................69 
6.3.9. 
Additional Statistical Considerations ...................................................69 
7. 
DATA MONITORING .....................................................................................................70 
7.1. 
Independent Data Monitoring Committee ...........................................................70 
8. 
SAFETY REPORTING ..................................................................................................70 
8.1. 
Definitions of Adverse Events, Serious Adverse Events and Special 
Situations ...........................................................................................................70 
8.1.1. 
Adverse Events ...................................................................................70 
8.1.2. 
Serious Adverse Events ......................................................................70 
8.1.3. 
Unlisted (Unexpected) Adverse Events/ Reference Safety 
Information ..........................................................................................71 
8.1.4. 
Adverse Events of Special Interest .....................................................71 
8.1.5. 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as Adverse Events or Serious Adverse Events .............71 
8.1.6. 
Special Situations ...............................................................................71 
8.2. 
Assessment of Adverse Events and Serious Adverse Events ............................72 
8.2.1. 
Assessment of Causality .....................................................................72 
8.2.2. 
Assessment of Severity ......................................................................73 
8.2.3. 
Outcome .............................................................................................73 
8.3. 
Investigator Requirements and Instructions for Reporting Adverse Events, 
Serious Adverse Events, Pregnancies, and Other Special Situations to the 
Sponsor .............................................................................................................74 
8.3.1. 
Adverse Events ...................................................................................74 
8.3.2. 
Serious Adverse Events ......................................................................74 


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8.3.3. 
Pregnancy ..........................................................................................75 
8.3.4. 
Reporting of Special Situations (Other Than Pregnancy) and 
Associated Adverse Events ................................................................75 
8.4. 
Sponsor Reporting Requirements ......................................................................76 
9. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES .........................................76 
9.1. 
Sponsor’s Responsibilities .................................................................................76 
9.1.1. 
Regulatory Approval / Notification .......................................................76 
9.1.2. 
Clinical Study Closure Considerations ................................................77 
9.1.3. 
Indemnification ....................................................................................77 
9.1.4. 
Insurance ............................................................................................77 
9.2. 
Investigator’s Responsibilities ............................................................................78 
9.2.1. 
Source Data and Data Capture ...........................................................78 
9.2.2. 
Archiving .............................................................................................78 
9.2.3. 
Participation Cards ..............................................................................78 
9.2.4. 
Reporting ............................................................................................78 
9.2.5. 
Publication ..........................................................................................79 
9.3. 
Confidentiality ....................................................................................................79 
9.4. 
Ethical Considerations .......................................................................................80 
9.4.1. 
Independent Ethics Committee / Institutional Review Board ...............80 
9.4.2. 
Informed Consent ...............................................................................80 
9.5. 
Data Quality Control/Assurance .........................................................................81 
9.5.1. 
Monitoring ...........................................................................................81 
9.5.2. 
Audit and Inspection ...........................................................................81 
10. REFERENCES ..............................................................................................................83 
11. APPENDICES ...............................................................................................................85 
SIGNATURE PAGE – SPONSOR ........................................................................................90 
SIGNATURE PAGE – INVESTIGATOR ...............................................................................91 
 
 


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CLINICAL STUDY PROTOCOL HISTORY 
Clinical Study Protocol (CSP) / 
Amendment # 
Date 
Main Rationale 
General / Country-Specific 
CSP Version 1.00 
16-Sep-2019 
Initial Protocol Version 
General  
Amendment 1, CSP Version 2.00 
18-Dec-2019 
Clarification of prohibited medication was 
added. 
General 
Amendment 2, CSP Version 3.00 
11-Feb-2020 
Update of CSP in order to extend 
treatment period from 24 weeks to 52 
weeks. 
General 
Amendment 3, CSP Version 4.00 
25-June-2020 
Update of CSP: change in contraceptive 
language, mitigation on the SARS-CoV-2 
pandemic, updated wording related to 
IDMC, collection and storage of biological 
samples. 
General 
Amendment 4, CSP Version 5.00 
13-Aug-2021 
Update of CSP: incorporation of an open-
label extension period, removal of the 
interim analysis in combination with a 
change in the composition from iDMC to 
DMC, clarification on vaccinations 
including covid vaccination, and 
operational changes (including update of 
timing of MRI assessments). 
General 
Amendment 5, CSP Version 6.00 
20-Dec-2021 
Update of CSP to change DMC to 
Independent DMC 
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SUMMARY OF CHANGES 
Amendment 5 (20-Dec-2021) 
The overall reason for this amendment: The protocol was updated to change the 
composition of the data monitoring committee (DMC) to a fully independent DMC.  
The change made to the CSP GLPG2737-CL-203 (Version 5.00, 13-Aug-2021) is listed 
below, reflecting a brief rationale of each change and the applicable section. 
Rationale: The CSP was updated to change the composition of the DMC by removing the 
sponsor’s representative to create a fully independent DMC. 
Applicable Section: 7.1 (Independent Data Monitoring Committee) 
 
Amendment 4 (13-Aug-2021) 
The overall reason for this amendment: The protocol was updated to incorporate an 
open-label extension period after the completion of the double-blind period of the study, 
removal of the interim analysis in combination with a change in the composition from 
iDMC to DMC due to the inclusion of a representative from the sponsor, clarification on 
vaccinations including covid vaccination, as well as operational changes (including update 
of timing of MRI assessments and timing/collection of assessments). 
The changes made to the CSP GLPG2737-CL-203, Version 4.00, 25-Jun-2020, are listed 
below, reflecting a brief rationale of each change and the applicable sections. 
Rationale: The protocol was updated to include the possibility to roll-over to an open-label 
extension (OLE) period, after the completion of the double-blind period of the study. Due 
to the chronic, progressive nature of the disease, subjects would be expected to receive 
long-term treatment. To acquire additional data on long-term safety, tolerability, and 
efficacy and 
 of G
 of GLPG2737 in ADPKD, an OLE period is now foreseen. 
The primary endpoint analysis will be performed at the end of the double-blind period.  
Applicable Sections: List of Abbreviations, Protocol Synopsis, 3.1 (Clinical Study 
Design), 3.2 (End of Study Definition), 3.4.3 (Other Endpoints), 3.6.1 (Inclusion Criteria), 
3.6.2 (Exclusion Criteria), 3.7.2 (Blinding and Unblinding), 4.5.1 (Subject Diary), 5.1 
(Timing of Assessments), 5.5.5 (12-lead Electrocardiogram), 5.6 (Pharmacokinetic 
Assessments), 5.7 (Pharmacodynamic Assessments), 5.8.2 (Future Scientific Research), 
5.11.1 (Double-blind Treatment Period), 5.11.2 (Open-label Treatment Period), 6.2 
(Population for Analyses), 6.3.1 (General Statistical Considerations), 6.3.4 (Analyses of 
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Primary Efficacy Parameters), 6.3.5 (Analyses of Primary Safety Data), 6.3.7 
(Pharmacodynamic Analyses) 
Rationale: The protocol was updated to delete the planned interim analysis in combination 
with a change in the composition from independent Data Monitoring Committee (IDMC) to 
DMC due to the inclusion of a sponsor's representative. This change was made as the 
sponsor will appoint to the DMC a senior medical expert in the field of clinical 
development who will not be involved in management of the study. By the change in DMC 
composition, with regular review of unblinded safety and efficacy data, a separate interim 
analysis is not needed anymore. 
Applicable Sections: List of Abbreviations, Protocol Synopsis, 3.1 (Clinical Study 
Design), 6.3.2 (Interim Analysis), 7.1 (Independent Data Monitoring Committee) 
Rationale: The protocol was updated to add clarification on vaccinations including 
COVID-19 vaccination prior / during the study and to explain in more detail replacement of 
a visit by a phone call or a televisit in case travel restrictions apply. 
Applicable Sections: Appendix 4 
Mitigation Plan as a Consequence of SARS-CoV-2 
Pandemic) 
Operational changes 
− Rationale: In case MRI at screening is performed according to study specifications and 
centrally read, this MRI can be used for screening and baseline. In this case, there is no 
need to repeat MRI at Visit 2 (Day 1). 
Applicable Sections: 5.1 (Timing of Assessments), 5.4.1 (htTKV and 
 by MRI), 
5.11.1 (Double-blind Treatment Period) 
− Rationale: At the screening visit a random urine sample can be collected instead of first 
morning urine. 
Applicable Section: 5.1 (Timing of Assessments), 5.11.1 (Double-blind Treatment 
Period) 
− Rationale: As an OLE period is now included in the study, a longer time window at 
Week 56 is foreseen (from +/- 4 days to +/- 10 days), to have some more flexibility to 
roll-over to the OLE period. 
Applicable Section: 5.11.1 (Double-blind Treatment Period) 
− Rationale: As an OLE period is now included in the study, the 
 a at 
Week 52 plus 5/6 days is now removed. More data on 
 will be collected during the 
OLE period. 
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Applicable Sections: 3.1 (Clinical Study Design), 5.1 (Timing of Assessments), 5.6 
(Pharmacokinetic Assessments), 5.11.1 (Double-blind Treatment Period) 
Administrative changes 
− Rationale: Removal of eGFR as a separate assessment from the section describing the 
individual study visits, as this is derived from safety laboratory evaluations and not a 
separate assessment. 
Applicable Sections: 5.1 (Timing of Assessments) 
− Rationale: Calcium measurement was clarified in more detail, to explain that it also 
includes ionized calcium. 
Applicable Sections: 5.5.2 (Clinical Laboratory Evaluations) 
− Rationale: Alignment between sections that blood and urine samples can be kept up to 
30 years for optional future research. 
Applicable Sections: 5.9 (Sample Management), 5.10 (Long Term Storage of Samples 
and Associated Data for Future Scientific and Genetic Research). 
 
Amendment 3 (25-June-2020) 
The overall reason for this amendment: The protocol was updated to incorporate updates 
regarding contraceptive language for male subjects participating in the study, to mitigate 
the impact of the current SARS-CoV-2 pandemic, description of an Independent Data 
Monitoring Committee, addition of safety parameters, and addition of wording on 
collection and longterm storage of biological samples. 
The changes made to the CSP GLPG2737-CL-203, Version 3.00, 11-Feb-2020, are listed 
below, reflecting a brief rationale of each change and the applicable sections. 
Rationale: The protocol was updated regarding contraceptive language. From existing data 
it is clear that there is no risk for genotoxicity, teratogenicity/fetotoxicity or gonadal 
abnormalities. Therefore, no contraceptive measures are required for male subjects 
participating in the study and no data needs to be collected for female partners of male 
subjects. 
Applicable Section: 1.1 (Background - Nonclinical Studies), 3.6.1 (Inclusion Criteria) 
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Rationale: The protocol was updated to mitigate the impact of the current SARS-CoV-2 
pandemic for subjects participating in the study. 
Applicable Sections: 3.5 (Potential Risks and Benefits), 6.1 (Determination of Sample 
Size), Appendix 4 
Mitigation Plan as a Consequence of SARS-CoV-2 Pandemic) 
Rationale: The protocol was updated to collect optional samples for future scientific and 
genetic research, and specify long term storage of biological samples. 
Applicable Sections: 5.1 (Timing of Assessments), 5.8.2 (Future Scientific Research), 
5.10 (Long Term Storage of Samples and Associated Data for Future Scientific and Genetic 
Research), 5.11 (Schedule of Activities), 9.4.2 (Informed Consent) 
Rationale: The protocol was updated regarding addition of safety parameters, requested by 
the independent safety reviewer. During compilation of the independent safety review 
charter it became clear that collection of data regarding pancreas and albumin, creatinine 
would be of added value to review the safety data during the study. 
Applicable Sections: 5.5.2 (Clinical Laboratory Evaluations) 
Rationale: The protocol was updated regarding definition of a committee performing the 
safety review. As a consequence of change of management approach within Galapagos, an 
Independent Data Monitoring Committee will be implemented. 
Applicable Section: 7.1 (Independent Data Monitoring Committee) 
Rationale: The protocol was updated to include that certain liver enzyme elevations should 
be reported as an SAE. This definition is included to allow for uniform safety reporting 
across studies within Galapagos. 
Applicable Section: 8.1.5 (Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as Adverse Events or Serious Adverse Events) 
Rationale: Some minor textual changes have been implemented to improve readability of 
the protocol. 
Applicable Sections:  
− 
Synopsis: addition of the word “baseline” in other endpoint. 
− 
1 (Introduction):  deletion of reference occurring twice. 
− 
3.6.5 (Treatment Discontinuation (Temporarily and Permanently), Subject Withdrawal, 
and Study Termination): Addition of subtitle. 
− 
5.4.1 (htTKV and 
 by MRI): addition of “TKV” before MRI. 
− 
5.7 (Pharmacodynamic Assessments): Addition of “blood samples analysis including 
but not limited to” 
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− 
Signature Page: Addition of the word “exploratory” to the title. 
 
Amendment 2 (11-Feb-2020) 
The overall reason for this amendment: The protocol was updated in order to incorporate 
changes regarding treatment duration, definition of primary and secondary outcome, 
deletion of mGFR as secondary outcome, addition of height-adjusted liver volume as other 
outcome, update on wording of sample size calculation, description of collection of 
physical examinations, update on wording of safety review committee, and more detailed 
information on the dosing rationale.  
The changes made to the CSP GLPG2737-CL-203 (Version 2.00, 18-Dec-2019) are listed 
below, reflecting a brief rationale of each change and the applicable sections. 
Rationale: The treatment period has been extended from 24 weeks to 52 weeks. The 
probability of detecting an effect is higher by increasing the duration of exposure to 
52 weeks, as shown in other studies with other compounds in the same indication. 
Applicable Sections: 2 (Clinical Study Objectives), 3.1 (Clinical Study Design), 3.3.2 
(Clinical Study Design Rationale), 3.4 (Endpoints), 5.1 (Timing of Assessments), 5.6 
(Pharmacokinetic Assessments), 5.11 (Schedule of Activities), 6.1 (Determination of 
Sample Size) 
Rationale: The protocol was updated to clarify the wording of the primary outcome. The 
wording now clarifies that mean percent change and not absolute change of total kidney 
volume (TKV) will be determined. 
Applicable Sections: 3.4.1 (Primary Endpoint), 6.1 (Determination of Sample Size), 
6.3.4.1 (Analysis for Primary Efficacy Endpoint) 
Rationale: The protocol was updated to remove measured GFR as secondary objective, due 
to complexity and burden of the measurement at this stage of product development. 
Applicable Sections: 2.2 (Secondary Objectives), 3.4.2 (Secondary Endpoints), 5.1 
(Timing of Assessments), Previous Section 5.4.3, 5.11 (Schedule of Activities) 
Rationale: 
 
 
Applicable Sections: 
s: 
 
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Rationale: Exclusion criterion 3 was updated to clarify that in case tolvaptan is not being 
administered, this should be because of e.g. non-availability, intolerance, or physician’s 
clinical judgment. 
Applicable Sections: Protocol synopsis, 3.6.2 (Exclusion Criteria) 
Rationale: The protocol was adapted to update the wording regarding sample size 
calculation. The description of the sample size calculation changed (power to detect a 
significant difference increased) as a consequence of the extended treatment period (from 
24 weeks to 52 weeks) and the change of the primary outcome (from absolute change to % 
change). 
Applicable Section: 6.1 (Determination of Sample Size) 
Rationale: The protocol was updated to change of timing of interim analysis from 4 weeks 
to 26 weeks, as a consequence of the longer treatment duration. 
Applicable Sections: 3.1 (Clinical Study Design), 6.3.2 (Interim Analysis) 
Rationale: As both safety and efficacy related assessments (i.e. MRI) can be repeated 
during unscheduled visits, to word safety has been removed. 
Applicable Section: 5.2 (Unscheduled Visits) 
Rationale: The protocol was updated regarding the description of collection of physical 
examinations. Physical examination should be reported by the investigator as AE when 
clinical significant. Therefore, they are already part of the AE listing. 
Applicable Section: Previous Section 6.3.5.4 
Rationale: Analysis for other efficacy endpoints has been added, as this section was 
missing. 
Applicable Section: 6.3.4.2 (Analysis for Other Efficacy Endpoints) 
Rationale: The protocol was updated regarding the wording of independent safety review. 
As the independent safety review will only include safety data and not efficacy data, the 
name was changed to independent safety review. 
Applicable Section: 7.1 (Independent Data Monitoring Committee) 
Rationale: The protocol was updated to provide more information regarding expected 
pharmacological activity at a dose regimen of 150 mg q.d., based on the available clinical 
data, in vitro pharmacology data, and observed GLPG2737 and M4 plasma concentrations 
in humans. 


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Applicable Section: 3.3.1 (Dose Rationale) 
 
Amendment 1 (18-Dec-2019) 
The overall reason for this amendment: The protocol was updated in order to clarify 
prohibited medication. 
The changes made to the CSP GLPG2737-CL-203, Version 1.00, 16-sep-2019, are listed 
below, reflecting a brief rationale of each change and the applicable sections. 
Rationale: The protocol was updated to prohibit the use of tolvaptan during the study. If 
during the course of the study the investigator decides to initiate tolvaptan based on benefit-
risk evaluation, then investigational product (IP) needs to be discontinued for the remainder 
of the study. The patient will continue to be followed up as per protocol. 
Applicable Sections: 3.6.4.2 (Prior and concomitant medications)  
Rationale: The protocol was updated to add “Initiation of tolvaptan treatment” as reason 
for permanent discontinuation of treatment. 
Applicable Sections: 3.6.5 (Permanent discontinuation of treatment) 
 
 
 


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LIST OF TABLES 
Table 1 
Grading of AE Severity .....................................................................................73 
 
LIST OF FIGURES 
Figure 1 
Schematic Diagram ..........................................................................................30 
 
LIST OF LISTINGS 
None 
 
LIST OF APPENDICES 
Appendix 1 Ranges for Vital Signs and ECG ......................................................................85 
Appendix 2 List of Moderate and Strong Inhibitor(s) of Cytochrome P450 (CYP)3A4 ..........86 
Appendix 3 List of Moderate and Strong Inducer(s) of Cytochrome P450 (CYP)3A4 ..........87 
Appendix 4 Mitigation Plan as a Consequence of SARS-CoV-2 Pandemic .........................88 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations 
ADL 
activities of daily living 
ADPKD 
autosomal dominant polycystic kidney disease 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
Bpm 
beats per minute 
 
 
cAMP 
cyclic adenosine monophosphate 
CF 
cystic fibrosis 
CFTR 
cystic fibrosis transmembrane conductance regulator 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
maximum plasma concentration 
CRF 
case report form 
CRO 
contract research organization 
CSP 
clinical study protocol 
CTCAE 
common terminology criteria for adverse events 
Ctrough 
trough concentration 
DB 
double-blind 
DBP 
diastolic blood pressure 
DMC 
Data Monitoring Committee 
DTP 
direct to patient 
ECG 
electrocardiogram 
eGFR 
estimated glomerular filtration rate 
ETD 
early treatment discontinuation 
EoS 
end of the study 
EoSA 
end of study assessments - visit at the end of the foreseen treatment period 
but when the subject has discontinued IP before the visit 
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EoST 
end of study treatment - visit at the end of the treatment period when the 
subject has continued taking IP till this visit 
ETD 
early treatment discontinuation 
EU 
European Union 
FDA 
Food and Drug Administration 
FIH 
first in human 
FSH 
follicle stimulating hormone 
GCP 
good clinical practice 
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyl transferase 
HBs Ag 
hepatitis B surface antigen 
HBs 
hepatitis B surface 
HCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HDPE 
high-density polyethylene 
HIV 
human immunodeficiency virus 
HMA 
Heads of Medicines Agency 
HR 
heart rate 
htTKV 
height-adjusted total kidney volume 
 
 
IB 
investigator’s brochure 
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 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
Institutional Review Board 
IWRS 
interactive web response system 
KDOQI 
Kidney Disease Outcomes Quality Initiative 
KO 
knock-out 
LFT 
liver function test 
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MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCS 
microscopy culture and sensitivity 
MCV 
mean corpuscular volume 
MRI 
magnetic resonance imaging 
NASH 
nonalcoholic steatohepatitis 
NOAEL 
no observed adverse effect level 
OLE 
open-label extension 
PD 
pharmacodynamics 
 
 
PK 
pharmacokinetics 
PC 
polycystin 
q.d. 
quaque die, once daily 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SBP 
systolic blood pressure 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TKV 
total kidney volume 
 
 
tmax 
time to reach maximum plasma concentration 
 
 
ULN 
upper limit of normal 
WOCBP 
women of childbearing potential 
Definition of Terms 
BMI 
body mass index: Weight (kg) / (height [m])2 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula: 
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PROTOCOL SYNOPSIS 
Title of Study 
An exploratory, randomized, double-blind, placebo-controlled, multicenter study to evaluate 
the efficacy, safety, tolerability and pharmacokinetics of orally administered GLPG2737 for 
52 weeks, followed by an open-label extension period of 52 weeks in subjects with 
autosomal dominant polycystic kidney disease (ADPKD)  
Phase of Development: Phase 2a 
Planned Number of Subjects 
A total of 60 adult ADPKD subjects (n=40 for GLPG2737 and n=20 for placebo) will be 
enrolled in this study.  
Study Duration 
Each subject will be in the study for up to 60 weeks for the double-blind period (up to 4 
weeks of screening, double-blind treatment period of 52 weeks, and 4 weeks of follow-up). 
For subjects who are eligible and consent to roll-over to the open-label extension (OLE) 
period, another 52 weeks of treatment and 4 weeks follow-up will be added. 
Study Design 
This is an exploratory, randomized, double-blind, placebo-controlled, parallel group, 
multicenter, proof of concept study (Phase 2a), evaluating orally administered GLPG2737 
(150 mg q.d.) for a double-blind treatment period of 52 weeks and 4 weeks of follow up as 
well as an OLE treatment period of 52 weeks and 4 weeks of follow up, in approximately 60 
subjects with rapidly progressing ADPKD.  
The primary analysis will be performed when all subjects have reached the end of the double-
blind period, or discontinued earlier. 
A follow-up visit should occur 4 weeks after the 52-weeks double-blind treatment period 
(Week 56). Subjects will be offered OLE treatment for a period of 52 weeks. The follow-up 
visit will be used to roll-over to the OLE period.  
Refer to the study scheme below for further details. 
 
 
 


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Objectives and Endpoints 
Objectives 
Endpoints 
The following objectives will be determined in adult 
subjects with ADPKD until the end of the double-
blind period: 
Primary  
The following endpoints will be measured from 
baseline until the end of the double-blind period: 
Primary 
− 
To characterize the effect of GLPG2737 on 
growth in total kidney volume (TKV) compared 
to placebo. 
− 
Mean percent change from baseline of height-
adjusted TKV (htTKV). 
 
− 
To evaluate the safety and tolerability of oral 
doses of GLPG2737 compared to placebo. 
− 
Frequency and severity of treatment-emergent 
adverse events (TEAEs), treatment-emergent 
serious AEs (SAEs), and TEAEs leading to 
treatment discontinuation. 
Secondary 
Secondary 
− 
To characterize the effect of GLPG2737 on 
renal function (estimated glomerular filtration 
rate; eGFR) compared to placebo. 
− 
To characterize the pharmacokinetics (PK) of 
oral doses of GLPG2737 and its major 
metabolite G1125498 (M4) using population 
PK 
K an
analalyses. 
− 
Mean change from baseline of estimated GFR 
(eGFR). 
 
− 
Estimated exposure (area under the curve 
[AUC], maximum plasma concentration [Cmax]), 
based on population PK analyses for GLPG2737 
and its major metabolite M4. 
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Main Criteria for Inclusion and Exclusion 
Main inclusion criteria for the double-blind period of the study, clinically most relevant for 
the investigator: 
1. Male and female subject aged 18 to 50 years, inclusive. 
2. Documented diagnosis of typical ADPKD, using the Ravine criteria. 
3. Rapidly progressive disease, defined as presence of all of the following: 
a. 
TKV >750 mL, as determined on imaging not older than 5 years before screening. If 
historical imaging is not available or older than 5 years, imaging can be performed 
during the screening period according to local clinical practice (i.e. echography, 
magnetic resonance imaging [MRI]). 
b. Mayo ADPKD Classification Classes 1C to 1E. 
4. eGFR at screening between 30-90 mL/min/1.73 m2 for subjects aged 18 to 40 years1 
(inclusive), and between 30-60 mL/min/1.73 m2 for subjects aged 40 to 50 years. 
5. Blood pressure ≤ 150/90 mmHg. In case the subject is treated for hypertension, it should 
be on a stable treatment regimen of antihypertensive therapy for at least 8 weeks prior to 
the screening visit, and during the screening period. 
Main exclusion criteria for the double-blind period of the study, clinically most relevant for 
the investigator: 
1. Congenital absence of 1 kidney, or subject had a previous nephrectomy or has a 
transplanted kidney or a transplantation is planned in the foreseeable future. 
2. Administration of polycystic kidney disease-modifying agents (e.g. tolvaptan, 
somatostatin analogues) or interventions (such as cyst aspiration or cyst fenestration) 
within 12 weeks prior to the screening visit and during the screening period. In case 
tolvaptan is not being administered, this should be because of e.g. non-availability, 
intolerance, or physician’s clinical judgment. 
3. Any condition or circumstances that, in the opinion of the investigator, may make a 
subject unlikely or unable to complete the study or comply with study procedures and 
requirements (e.g. unable to undergo MRI. For example subject's weight exceeds weight 
capacity of the MRI, ferromagnetic metal prostheses, aneurysm clips, severe 
claustrophobia, etc.). 
Main inclusion criteria for the OLE period of the study, clinically most relevant for the 
investigator: 
1. Male and female subjects who completed the 52-week double-blind treatment period on 
IP.  
2. Subject, according to the investigator’s judgment, may benefit from long-term treatment 
with GLPG2737. 
Main exclusion criterion for the OLE period of the study, clinically most relevant for the 
investigator: 
1. Clinically significant abnormalities detected on 12-lead ECG of either rhythm or 
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Treatment and Treatment Schedule 
Subjects will be randomized in a 2:1 ratio to GLPG2737 150 mg q.d., or matching placebo 
q.d., administered for 52 weeks. 
During the OLE period, each subject will receive 150 mg GLPG2737 q.d. for 52 weeks. 
Investigational Product, Dosage, and Mode of Administration 
GLPG2737 will be provided as 2 capsules for oral use, containing 75 mg 
 each 
 is the compound code for GLPG2737). 
The matching placebo will be provided as 2 capsules for oral use. 
Statistical Analysis 
Strict statistical criteria were not used to determine the sample size for this study. The 
number of subjects (n=60) should give reasonable precision around the estimates of the 
endpoints for design of future studies. 
For the primary analysis a longitudinal analysis of the htTKV percent change from baseline 
until the end of the double-blind period will be performed and appropriate inferential 
measures on the treatment difference will be obtained. 
Safety analysis during the double-blind period will be descriptive and should be focused on 
changes from baseline and treatment-emergent findings with GLPG2737 treatment as 
compared to placebo. 
Observed GLPG2737 and M4 plasma concentrations will be analyzed using a population PK 
analysis. PK parameters, estimated based on the population PK model will be reported. 
 
 
 
 
 
 
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1. 
INTRODUCTION 
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney 
disease with an estimated prevalence of 1-5 in 10.000 individuals (Orphanet, 2019; Willey, et al., 
2017). Its course is characterized by the development and inexorable expansion of multiple cysts 
scattered throughout the kidney parenchyma. Progressive loss of kidney function takes place over 
many decades and frequently leads to end-stage kidney disease during or after the sixth decade of 
life. As ADPKD is a multisystem disorder, other organs can also be affected. Hepatic cysts are 
the most common extra-renal manifestations; occurring in up to 83% of cases (Bae, et al., 2006), 
with enlarged total liver volume in up to nearly 60 % of cases (van Aerts, et al., 2019). 
ADPKD is caused by loss-of-function mutation in the PKD1 or PKD2 genes that encode 
polycystin-1 (PC-1) and polycystin-2 (PC-2), respectively. In 75% of cases of ADPKD, the 
mutations occur in PKD1, 15% present mutations in PKD2, and the other 10% are undetermined. 
PC-1 is an important regulator of several signaling pathways, and PC-2 is a non-selective calcium 
channel. Mutations in PC-1 and PC-2 appear to disrupt intracellular calcium regulation, leading 
to reduced intracellular Ca2+ levels. It is believed that reduced intracellular Ca2+ levels contribute 
to the increased cyclic adenosine monophosphate (cAMP) levels observed in ADPKD human 
kidney epithelial cells (Wallace, 2011). Increased levels of cAMP contribute to the progression of 
cystogenesis, by stimulating epithelial cell proliferation as well as by stimulating fluid secretion. 
cAMP-dependent anion secretion to the cyst lumen has been reported to be mediated by the 
luminal cystic fibrosis transmembrane conductance regulator (CFTR). 
The mechanism underlying this regulation has not been totally elucidated, although the CFTR 
chloride channel has been shown to contribute to disease progression by driving fluid secretion to 
the cyst lumen, promoting cyst growth. Cyst and kidney growth is hypothesized to cause loss of 
functioning renal mass, and eventually leads to end-stage kidney disease. 
GLPG2737 is a CFTR inhibitor. In vitro, CFTR inhibitors have been shown to reduce cyst 
growth in mouse and human cells of renal tubular origin. In vivo, CFTR inhibitors have been 
shown to reduce cyst growth in models of ADPKD, in conditional PKD1 knock-out (KO) mouse 
(Yang, Sonawane, Zhao, Somlo, & Verkman, 2008). In patients with both ADPKD and cystic 
fibrosis (CF) with a deletion of phenylalanine in position 508 of the CFTR (F508del-CFTR; 
lacking functional CFTR), renal function declines at a slower rate than that in family members 
who have ADPKD alone (Xu, et al., 2006). CFTR is present in the apical membrane of the 
cholangiocytes (Fiorotto & Strazzabosco, 2019). 
It is expected that administration of the CFTR inhibitor GLPG2737 to patients with ADPKD will 
lead to a reduction in cyst growth, slowing down kidney volume growth, and reducing the rate of 
decline of renal function and delay progression to end-stage kidney disease. 
For more details refer to the investigator’s brochure (IB) (GLPG2737-ADPKD, Version 2.0, 
20-Nov-2020) and relevant updates/addenda. 
This clinical study will be conducted in accordance with the current International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use - Good Clinical 
Practice (ICH-GCP) Guideline E6 (see also Section 9). 


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1.1. 
Background - Nonclinical Studies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
1.2. 
Background - Clinical Studies 
 
 
 
 
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Clinical Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Safety 
 
 
 
 
 
 
 
 
 
 
 
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2. 
CLINICAL STUDY OBJECTIVES 
The following objectives will be determined in adult subjects with rapidly progressing ADPKD 
until the end of the double-blind period: 
2.1. 
Primary Objectives 
− 
To characterize the effect of GLPG2737 on growth in total kidney volume (TKV) compared to 
placebo. 
− 
To evaluate the safety and tolerability of oral doses of GLPG2737 compared to placebo. 
2.2. 
Secondary Objectives 
− 
To characterize the effect of GLPG2737 on renal function (estimated glomerular filtration rate; 
eGFR) compared to placebo. 
− 
To characterize the pharmacokinetics (PK) of oral doses of GLPG2737 and its major metabolite 
G1125498 (M4) using population PK analyses. 
2.3. 
Other Objectives 
− 
− 
− 
 
− 
− 
− 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Clinical Study Design 
This is an exploratory, randomized, double-blind, placebo-controlled, parallel group, multicenter, 
proof of concept study (Phase 2a), evaluating orally administered GLPG2737 (150 mg q.d.) for a 
treatment period of 52 weeks and 4 weeks follow-up, followed by an open-label extension (OLE) 
period of 52 weeks and 4 weeks follow-up in approximately 60 subjects with rapidly progressing 
ADPKD. 
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The eligibility screening period of maximally 28 days will consist of the assessments as presented 
in the Schedule of Activities (see Section 5.11). For the in- and exclusion criteria please refer to 
3.6.1 and 3.6.2. 
At Day 1 (baseline), subjects will be randomized in a 2:1 ratio to GLPG2737 150 mg q.d. taken 
as 2 capsules of 75 mg each, or matching placebo q.d. administered for 52 weeks. 
An unblinded primary endpoint analysis will be performed when all subjects have reached the 
end of the double-blind period, or discontinued earlier. 
A follow-up visit should occur 4 weeks after the 52-weeks double-blind treatment period (Week 
56). Subjects will be offered OLE treatment for a period of 52 weeks. The follow-up visit of the 
double-blind period will be used to roll-over to the OLE period.  
A schematic diagram of clinical study design, procedures and stages is provided in  
Figure 1.  
 
Figure 1 
Schematic Diagram 
 
For detailed information regarding dosage form, packaging and labeling of the investigational 
product (IP) please refer to Section 4.2, “Dosage and Administration” and Section 4.3, 
“Packaging, Labeling and Distribution”. 
3.2. 
End of Study Definition 
The end of the study (EoS) is reached when the last follow-up visit (i.e. Week 112 of the OLE 
period), as planned according to the Schedule of Activities (Section 5.11), of the last subject is 
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3.3. 
Clinical Study Rationale 
ADPKD is a chronic and progressive disease for which there exists only 1 approved drug at the 
moment (i.e. the vasopressin receptor antagonist tolvaptan), indicating a high unmet medical need 
for the development of novel therapies. 
GLPG2737 is a CFTR inhibitor. In vitro, CFTR inhibitors have been shown to reduce cyst 
growth in mouse and human cells of renal tubular origin. In vivo, CFTR inhibitors have been 
shown to reduce cyst growth in models of ADPKD, in conditional PKD1 KO-mouse (Yang, 
Sonawane, Zhao, Somlo, & Verkman, 2008). In patients with both ADPKD and CF with a 
deletion of phenylalanine in position 508 of the CFTR (F508del-CFTR; lacking functional 
CFTR), renal function declines at a slower rate than that in family members who have ADPKD 
alone. 
Therefore it is expected that administration of the CFTR inhibitor GLPG2737 to patients with 
ADPKD will lead to a reduction in cyst growth, slowing down kidney volume growth, reducing 
the rate of decline of renal function, and delay progression to end-stage kidney disease. 
3.3.1. 
Dose Rationale 
A dose of GLPG2737 150 mg q.d. for oral administration has been selected for use in this 
Phase 2a study. This dose is considered safe and well tolerated based on the results of the 
multiple ascending dose study in healthy subjects (evaluated for 2 weeks up to 250 mg q.d.) and a 
study in subjects with CF, treated for up to 4 weeks with 150 mg q.d.. GLPG2737 exposure is not 
expected to be higher in subjects with ADPKD as compared to healthy subjects, as the kidney 
plays a minor role in the elimination of GLPG2737 and its major active metabolite M4. After 
repeated once daily dosing of GLPG2737 at 250 mg q.d., less than 1% of the dose was excreted 
in urine as unchanged GLPG2737, and around 3% of the dose was excreted as M4. 
GLPG2737 has been shown to have a clinical effect at 150 mg q.d., by reducing the open 
probability of rescued CFTR channels in the development of a combination therapy in CF. In 
addition, modest increases in sweat chloride (a marker of CFTR activity) were observed in 
healthy subjects, providing indirect proof of ion transport channels being affected (see 
Section 5.1.5 of the IB). 
Furthermore, in an in vitro cyst swelling assay using patient-derived cyst cells, GLPG2737 and 
M4 showed a decrease in the number of cysts in a concentration-dependent manner, both 
compounds showing an activity (p<0.05) at concentrations starting at 100 nM. In addition to the 
cyst number quantification, the cyst size was quantified. At 10 µM, GLPG2737 and at 1 µM its 
metabolite M4 showed a decrease (p<0.05) in the area of cysts formed by ADPKD patient-
derived cells (see IB addendum). The observed steady-state mean trough and maximum levels at 
the intended dose level of 150 mg q.d. are respectively 448 ng/mL (730 nM) and 1300 ng/mL 
(2118 nM) for GLPG2737, and 648 ng/mL (1080 nM) and 921 ng/mL (1536 nM) for M4 (see 
Section 5.1.1.2 of the IB ). 
Finally, 2 in vitro target engagement assays involving human CFTR, measuring inhibition of 
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TECC assay, see Section 4.1.1.1.1 and 4.1.1.1.3 of the IB). Of these assays the latter is 
considered to be most physiologically relevant as there was no overexpression of CFTR. The IC50 
values from this assay were 108 nM for GLPG2737 and 32 nM for M4. Based on this data the 
combined unbound plasma concentrations for GLPG2737 and M4 (free fraction 0.0205 for 
GLPG2737 and 0.0240 for M4, see Section 4.2.2.1 of the IB) that are maintained during the 
dosing interval at the 150 mg q.d. dosing regimen are situated within the pharmacodynamic range 
observed in the TECC assay. 
Taken together, pharmacological activity can be expected at a dose regimen of 150 mg q.d. based 
on the available clinical data, in vitro pharmacology data and observed GLPG2737 and M4 
plasma concentrations in humans. 
3.3.2. 
Clinical Study Design Rationale 
Rationale for study design: the placebo-controlled, randomized, parallel group design is a 
standard design for an exploratory study in patients. 
Rationale for selection of progressive ADPKD subjects: to be able to detect a signal, defined as a 
change in kidney volume, subjects with progressive disease will be selected, as those outcome 
parameters may change within the timeframe of the study in this study population compared to 
less severe subjects. 
Rationale for 52 weeks treatment: the acute effects on TKV as seen in tolvaptan treated patients 
are a result of hemodynamic effects and the profound aquaresis. These acute effects have not 
been seen with GLPG2737 treatment, and are therefore not expected at short study duration. 
Structural chronic changes are expected at a longer study duration of 52 weeks (Torres, et al., 
2012) (Torres, et al., 2017) (Caroli, et al., 2013). 
A substantial treatment effect has been defined by the cardio-renal division of the Food and Drug 
Administration (FDA) as halting the increase in TKV (Smith, et al., 2018). Preventing the growth 
of the ADPKD kidneys would provide compelling evidence of efficacy and could provide a basis 
for approval of drugs to treat ADPKD. The average increase in TKV in patients with progressive 
ADPKD is approximately 6% per year. 
Rationale for OLE: due to the chronic, progressive nature of the disease, subjects would be 
expected to receive long-term treatment. To acquire additional data on long-term safety, 
tolerability, efficacy and 
nd 
 of GLPG2737 in ADPKD, an OLE period up to 
52 weeks of treatment will be foreseen. In addition, this will enable the subjects assigned to 
placebo to receive active treatment during the OLE. 
3.4. 
Endpoints 
The following endpoints will be measured from baseline until end of the double-blind period: 
3.4.1. 
Primary Endpoint 
− 
Mean percent change from baseline of height-adjusted TKV (htTKV). 
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− 
Frequency and severity of treatment-emergent adverse events (TEAEs), treatment-emergent 
serious AEs (SAEs), and TEAEs leading to treatment discontinuation. 
3.4.2. 
Secondary Endpoints 
− 
Mean change from baseline of estimated GFR (eGFR). 
− 
Estimated exposure (area under the curve [AUC], maximum plasma concentration [Cmax]), based 
on population PK analyses for GLPG2737 and its major metabolite M4. 
3.4.3. 
Other Endpoints 
− 
− 
− 
− 
− 
− 
− 
− 
3.5. 
Potential Risks and Benefits 
GLPG2737 has been well tolerated to date in healthy subjects in single and repeated doses up to 
150 mg for 14 days. It has been administered to subjects with CF in combination with a CFTR 
potentiator and a CFTR corrector molecule for up to 28 days at a dose of 150 mg daily. 
GLPG2737 was well tolerated in this population. To date, no GLPG2737 related SAEs have been 
reported. 
There is a potential risk with drugs that are inhibitors or inducers of CYP3A4. Only the drugs 
inhibiting CYP3A4, potentially leading to an increase in exposure of GLPG2737, will be 
prohibited during the study. . 
 
 Refer to Section 3.6.4.2 for prohibited medication. 
Based upon its mechanism of action and its potential to decrease the rate of decline of renal 
function in patients with ADPKD, together with its safety profile and clinical risk mitigation built 
into the study design it is believed that the GLPG2737 benefit-risk profile is positive. 
Given this study may be performed during a SARS-CoV-2 pandemic, appropriate measures 
should be taken to minimize the risk of SARS-CoV-2 infection for subjects participating in the 
study as well as study site personnel. Local guidelines to prevent SARS-CoV-2 infection should 
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be adhered to. Protocol specific instructions in case of travel restrictions due to a pandemic or 
infection with SARS-CoV-2 are described in Appendix 4. 
Subjects presenting with signs and symptoms of infection, including SARS-CoV-2 infection 
should immediately contact the site investigator, who should inform the sponsor’s medical 
responsible as soon as possible. 
3.6. 
Clinical Study Population 
3.6.1. 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for participation in the 
double-blind period of the study: 
1. 
Able and willing to comply with the protocol requirements and to sign the informed consent form 
(ICF) as approved by the Independent Ethics Committee (IEC) / Institutional Review Board 
(IRB), prior to any screening evaluations. 
2. 
Male and female subject aged 18 to 50 years, inclusive. 
3. 
Documented diagnosis of typical ADPKD, using the Ravine criteria (Ravine, et al., 1994). 
4. 
Rapidly progressive disease, defined as presence of all of the following: 
− TKV >750 mL, as determined on imaging not older than 5 years before screening. If 
historical imaging is not available or older than 5 years, imaging can be performed during 
the screening period according to local clinical practice (i.e. echography, magnetic 
resonance imaging [MRI]). 
− Mayo ADPKD Classification Classes 1C to 1E. 
5. 
eGFR at screening between 30-90 mL/min/1.73 m2 for subjects aged 18 to 40 years1 (inclusive), 
and between 30-60 mL/min/1.73 m2 for subjects aged 40 to 50 years. 
6. 
Blood pressure ≤ 150/90 mmHg. In case the subject is treated for hypertension, he/she should be 
on a stable treatment regimen of antihypertensive therapy for at least 8 weeks prior to the 
screening visit, and during the screening period. 
7. 
Subject must be able and willing to comply with restrictions on prior and concomitant medication 
as described in Section 3.6.4.2. 
8. 
Female subjects of childbearing potential must have a negative blood pregnancy test at screening 
and a negative urinary human chorionic gonadotropin (HCG) test at randomization. 
9. 
Female subjects of childbearing potential are willing to comply with the contraceptive methods 
described in Section 3.6.4.1 from signing of the ICF, during the clinical study, and for at least 7 
days after the last dose of the IP. 
10. A body mass index (BMI) between 18–35 kg/m2, inclusive. 
11. Apart from ADPKD, judged to be in good health by the investigator, based upon the results of a 
medical history, physical examination, vital signs, 12-lead electrocardiogram (ECG), and clinical 
laboratory safety tests. 
                                                 
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Subjects must meet all of the following inclusion criteria to be eligible for participation in the 
OLE period of the study: 
12. Able and willing to comply with the protocol requirements of the OLE period and to sign the ICF 
for the OLE period as approved by the Independent Ethics Committee (IEC) / Institutional 
Review Board (IRB). 
13. Male and female subjects who completed the 52-week double-blind treatment period on IP.  
14. Subject, according to the investigator’s judgment, may benefit from long-term treatment with 
GLPG2737. 
3.6.2. 
Exclusion Criteria 
Subjects meeting 1 or more of the following criteria cannot be enrolled in this clinical study: 
1. Known hypersensitivity to IP ingredients or history of a significant allergic reaction to IP 
ingredients as determined by the investigator, such as anaphylaxis requiring hospitalization. 
2. Congenital absence of 1 kidney, or subject had a previous nephrectomy or has a transplanted 
kidney or a transplantation is planned in the foreseeable future. 
3. Original criterion (CSP Version 4.0, dated 25-Jun-2020): 
Administration of polycystic kidney disease-modifying agents (e.g. tolvaptan) or interventions 
(such as cyst aspiration or cyst fenestration) within 12 weeks prior to the screening visit and 
during the screening period. In case tolvaptan is not being administered, this should be because of 
e.g. non-availability, intolerance, or physician’s clinical judgment. 
3.1 Criterion modified as per Amendment 4, Version 5.0, dated 13-Aug-2021): 
Administration of polycystic kidney disease-modifying agents (e.g. tolvaptan, somatostatin 
analogues) or interventions (such as cyst aspiration or cyst fenestration) within 12 weeks prior to 
the screening visit and during the screening period. In case tolvaptan is not being administered, 
this should be because of e.g. non-availability, intolerance, or physician’s clinical judgement. 
4. Any condition or circumstances that, in the opinion of the investigator, may make a subject 
unlikely or unable to complete the study or comply with study procedures and requirements (e.g. 
unable to undergo MRI. For example subject's weight exceeds weight capacity of the MRI, 
ferromagnetic metal prostheses, aneurysm clips, severe claustrophobia, etc.). 
5. Subjects with clinically significant incontinence, overactive bladder, or urinary retention (e.g. 
benign prostatic hyperplasia). 
6. Current immunosuppressive condition (e.g. human immunodeficiency virus [HIV] infection). 
7. Having any illness, judged by the investigator as clinically significant, in the 12 weeks prior to 
the screening visit and during the screening period. 
8. Presence or sequelae of gastrointestinal, liver, or other conditions known to interfere with the 
absorption, distribution, metabolism, or excretion of drugs. 
9. 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). 


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10. Concurrent participation or participation in a drug, drug/device or biologic investigational 
research study within 12 weeks or 5 half-lives of the IP, whichever is longer, prior to the 
screening visit and during the screening period. 
11. Positive blood test 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. 
12. Clinically significant abnormalities detected on 12-lead ECG of either rhythm or conduction, 
QTcF >450 ms, or long QT syndrome. 
13. Pregnant or breast feeding female or subject intending to become pregnant or breastfeed. 
14. Systemic administration of any moderate and strong inhibitor(s) or inducer(s) of CYP3A4 
currently taking or going to take 4 weeks prior to screening and during the screening period (see 
Appendix 2 and Appendix 3 for a list with examples). 
15. Moderate to severe hepatic impairment (Child-Pugh B or C) and/or abnormal liver function test 
(LFT) at screening, defined as AST, and/or ALT ≥2x upper limit of normal (ULN), and/or total 
bilirubin ≥1.5x ULN. Retesting is allowed once for abnormal LFT. 
16. Investigator or other study staff or relative thereof who is directly involved in the conduct of the 
study. 
Subjects meeting the following criterion cannot be enrolled in the OLE period of the study: 
17. Clinically significant abnormalities detected on 12-lead ECG of either rhythm or conduction, 
QTcF >450 ms, or long QT syndrome. 
3.6.3. 
Rescreening and Retesting 
Screen failures will be defined as subjects not complying with 1 or more in-/exclusion criteria. 
Subjects may only be rescreened with the approval of the sponsor’s study physician. 
− If a subject is rescreened, all screening assessments will be repeated, apart from historical TKV 
imaging that was used for screening purposes only (i.e. not centrally read). 
− 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. 
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 and eGFR can be retested once. 
− 
Assessment of blood pressure. 
− 
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3.6.4. 
Prohibition and Restrictions 
3.6.4.1. 
Precautions for Sexual Intercourse 
Highly effective contraceptive measures for females of childbearing potential must be 
documented in the source documents. 
3.6.4.1.1. Female subjects 
In line with the Heads of Medicines Agencies (HMA)’s Clinical Trial Facilitation Group 
recommendation, female subjects are considered of non-childbearing potential if they meet one of 
the following criteria: 
− 
No menses for 12 or more months without an alternative medical cause. A high follicle 
stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal replacement 
therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient. 
− 
Permanently surgically sterile (bilateral oophorectomy, surgical removal of ovaries, bilateral 
salpingectomy or hysterectomy, surgical removal of uterus). 
All other female subjects are considered to be of childbearing potential (WOCBP) and must use 
one of the following highly effective methods of birth control from signing of the ICF, during the 
clinical study and for at least 7 days after the last dose of IP: 
− 
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. 
− 
Bilateral tubal occlusion. 
− 
Sexual abstinence defined as refraining from heterosexual intercourse during the entire period of 
risk associated with the study treatments. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of 
the subject. 
Periodic abstinence (e.g. calendar, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of a clinical study, withdrawal, spermicides only, and lactational 
amenorrhea method are not acceptable as methods of contraception. 
In case a WOCBP has a vasectomized partner, provided that partner is the sole sexual partner of 
the WOCBP clinical study participant and that the vasectomized partner has received medical 
assessment of the surgical success, then she is not required to use an additional form of 
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Within these limits, the specific forms of contraception employed are left to the discretion of the 
subject, the investigator, and/or the subject’s physician.  
The safety of GLPG2737 during breastfeeding is unknown. Nursing women are not allowed to 
take part in this clinical study. 
3.6.4.1.2. Male subjects 
As there is no risk for genotoxicity, teratogenicity/fetotoxicity, or gonadal abnormalities (see 
Section 1.1), no contraceptive measures are required for men with WOCBP partners and no 
restrictions are required for sperm donation.   
3.6.4.2. 
Prior and Concomitant Medications 
Should any treatment other than the IP be used during the course of the study, the name of the 
medication, the dosage, the route, the reason for medication, and the start and stop dates of 
administration must be recorded in the case report form (CRF). 
Concomitant medications taken for the long-term treatment of pre-existing conditions can 
continue during the study, provided they are in accordance with the in- and exclusion criteria (see 
Sections 3.6.1 and 3.6.2), as well as the restrictions indicated below. It is required that these 
medications are stabilized prior to study entry and preferably continue without variation of dose 
or regimen during the study. 
Tolvaptan is prohibited during the study. If during the course of the study the investigator decides 
to initiate tolvaptan based on benefit-risk evaluation, then the IP needs to be discontinued for the 
remainder of the study. The patient will continue to be followed up as per protocol. 
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. 
Use of dietary/herbal supplements including (but not limited to) St. John’s wort, kava, ephedra 
(ma huang), gingko biloba, dehydro-epiandrosteron, yohimbe, saw palmetto, ginseng, red yeast 
rice, and excessive doses of vitamins (2-fold greater than the recommended daily allowance) is 
prohibited within 28 days, or 5 half-lives, prior to screening and during the entire study period. 
During the study, concomitant use of any moderate or strong inhibitor(s) of CYP3A4 is not 
allowed, as GLPG2737 (is predominantly metabolized by CYP3A4 (See Appendix 2 for a non-
exhaustive list of inhibitors). If during the study, the subject’s condition necessitates the use of 
this prohibited medication, the use of IP should be interrupted; after consultation with the CRO 
medical monitor (as per study contact list) and/or sponsor’s study physician. Re-introduction of 
IP can be considered after the treatment course with the prohibited medication has been stopped.  
 
 
 
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In case of questions on concomitant medications, the CRO medical monitor (as per study contact 
list) and sponsor’s study physician can be contacted. 
3.6.4.3. 
Food and Beverage Restrictions 
Consumption of grapefruit-containing products or Seville orange juice is prohibited. Subjects 
should be asked not to consume these products throughout the study period. 
3.6.5. 
Treatment Discontinuation (Temporarily and Permanently), Subject 
Withdrawal, and Study Termination 
A subject may be withdrawn from the clinical study at any time without the subject’s consent if 
the investigator or sponsor determines that it is not in the best interest of the subject to continue 
participation. In such case, the reason for withdrawal will be documented in the source 
documents, and the subject will complete the early treatment discontinuation (ETD) visit and, or 
follow-up visit for safety assessments. The subject should complete all end of study procedures. 
Permanent Discontinuation of Treatment 
Treatment with IP should be discontinued by the investigator (preferably after discussion with the 
CRO medical monitor, who may consult and must inform the sponsor’s study physician) for any 
of the following reasons: 
− 
Life-threatening AE or a 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 IP 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 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 2) or QTcF >500 ms at any ECG recording 
(any recording of triplicate ECG after Visit 2) needs to be confirmed by an ECG recording as 
soon as possible from the original abnormal recording at the same visit. In case of an abnormal 
QTcF as described above, ECG on both of these 2 recordings, the IP will be discontinued for this 
subject. 
After Visit 2 (Day 1), if a normal QTcF (e.g. no increase of >60 ms from baseline (i.e. Visit 2) or 
QTcF >500 ms) is reported during the visit, but the central cardiologist reports it as abnormal 
(any of the 2 criteria above), then the IP should be discontinued as soon as possible. 
At Visit 2 (Day 1, predosing), if the QTcF ≤450 ms at the local recording, and the central reading 
cardiology conclusion reports a QTcF >450 ms; than the subject needs to discontinue IP as soon 
as possible. 
− 
Increase in LFTs 
• 
 
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• AST or ALT ≥8x ULN. 
• AST or ALT elevations >3x ULN and <8x ULN: IP treatment should be withheld. If 
AST and/or ALT do not return to ≤3x ULN within 2 weeks then the IP should be 
discontinued permanently. 
• AST or ALT ≥3x ULN with signs of severe liver damage (i.e. with the appearance of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or 
eosinophilia [>5%], and/or total bilirubin ≥2x ULN or international normalized ratio 
[INR] >1.5). 
For all abnormal LFTs described above a repeat sample should be taken within 48 hours to 
confirm the abnormality. If not possible, then the IP needs to be withheld or discontinued 
permanently as soon as possible as described above. 
For any of the above abnormalities, close observation and follow-up is recommended, defined as: 
• 
Repeating liver enzyme and serum bilirubin tests 2 or 3 times weekly. Frequency 
of retesting can decrease to once a week or less if abnormalities stabilize or the trial drug 
has been discontinued and the subject is asymptomatic. 
• 
Obtaining a more detailed history of symptoms and prior or concurrent diseases. 
Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets. 
• 
Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; nonalcoholic steatohepatitis (NASH); hypoxic/ischemic hepatopathy; and 
biliary tract disease. 
• 
Obtaining a history of exposure to environmental chemical agents. 
• 
Obtaining additional tests to evaluate liver function (investigator is requested to use the 
central lab LFT kits), as appropriate (e.g. INR, direct bilirubin). 
• 
Considering gastroenterology or hepatology consultations (including imaging). 
− 
Initiation of tolvaptan treatment. 
− 
Closing of the study by the sponsor or regulatory authorities. 
− 
Wish of the subject to stop taking IP. 
 
Temporary Discontinuation of Treatment 
For the management of AEs, the investigator can interrupt or discontinue the IP. Once the AE has 
stabilized or improved, IP can be reintroduced if applicable. 
When the subject needs treatment based on the risk/benefit analysis with a prohibited medication 
(see Section 3.6.4.2 and Appendix 2), the IP can be reintroduced after end of the treatment 
course. 
Management of Permanent or Temporary Treatment Discontinuation 
Every effort should be made to keep subjects in the study and on treatment. However, the 
investigator can consider stopping treatment with IP, preferably after consultation with the CRO 


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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). 
When study treatment is discontinued, the subject will be requested to return for all visits and 
assessments. In case the subject is not able to return to the visits, a phone call can replace the 
onsite visit. 
Subject Withdrawal 
Subjects will be informed prior to clinical study entry that they are allowed to withdraw from the 
clinical study. At any time and for any reason, a subject’s participation in the clinical study may 
terminate at his/her request without prejudice to his/her future medical care. The subject will be 
encouraged to share the reason(s) for withdrawal so this can be documented in the source 
documents. The subject will be asked to complete the ETD visit and, or follow-up visit for safety 
assessments, but will not be obliged to do so. 
For a subject who is considered lost-to-follow-up sites should make every effort to understand 
whether the subject is alive, including checking the medical records and contacting general 
practitioner or relatives, if necessary. All attempts must be documented in the source documents. 
Study Termination 
The sponsor has the right to terminate the clinical study at any time in case of safety concerns or 
if special circumstances concerning the IP or the company itself occur, making further treatment 
of subjects impossible. In this event, the investigator(s) and relevant authorities will be informed 
of the reason for clinical study termination. 
3.7. 
Measures to Minimize Bias 
3.7.1. 
Randomization 
At screening, subjects will be assigned a subject identification number. When a subject is 
confirmed to be eligible for the clinical study, the subject will be randomized. Allocation of each 
subject to a given treatment will be done using a centralized electronic system (interactive web 
response system [IWRS]). IP will be randomized in a 2:1 ratio to GLPG2737 or placebo. 
3.7.2. 
Blinding and Unblinding 
The first period of the study is a randomized, double-blind clinical study. During this double-
blind period of the study the clinical study team, including the subjects, investigators, clinical 
study coordinators and sponsor personnel (except assigned personnel involved in unblinded 
procedures) are blinded to treatment assignment. 
During the double-blind period of the study blinded and packaged medication will be provided to 
the clinical center. All IP formulations will be identical in appearance, shape, smell and taste, and 
packaged in the proper proportion to assure desired dosages and maintenance of the blinding. 
During the OLE period, unblinded packaged medication will be provided. 


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The blind can be broken only if the investigator deems it necessary for the safety of a subject. 
The investigator is encouraged to discuss considerations to break the blind with the CRO medical 
monitor, whenever possible and where the situation allows. However, the responsibility to break 
the treatment code in emergency situations resides solely with the investigator. The investigator 
is not required to discuss unblinding beforehand if he or she feels rapid emergency unblinding is 
necessary, but is required to inform the sponsor in a timely fashion after unblinding has occurred. 
The blind can be broken by the investigator via IWRS. Code-breaking information (via IWRS 
vendor) will be provided to the bioanalytical laboratory responsible for plasma drug 
determination sample analysis. 
4. 
INVESTIGATIONAL PRODUCTS 
4.1. 
Identity of the Investigational Product(s) 
The IP (GLPG2737 and placebo) will be supplied to the pharmacist of the clinical study center by 
and under the responsibility of the sponsor, who will also provide the investigator with 
appropriate certificates of analytical conformity and European Union Qualified Person release 
documents. 
GLPG2737 will be provided as capsules for oral use, containing 75 mg 
 is 
the compound code for GLPG2737). The matching placebo will be provided as capsules for oral 
use. 
A full list of excipients used in the capsule formulation is available in the IB for GLPG2737 
(Edition 2, 20-Nov-2020) and relevant updates/addenda. 
4.2. 
Dosage and Administration 
The following dose will be used: 
− 150 mg GLPG2737 q.d. (as 2 GLPG2737 capsules of 75 mg). 
− Placebo q.d. (as 2 placebo capsules, only during double-blind period). 
The IP has to be taken q.d. with food (i.e. breakfast or lunch, whatever is the biggest meal; as 
long as IP is taken approximately the same time every day). Capsules of GLPG2737 or placebo 
will be swallowed whole with a glass of water. 
On visit days, the IP will be administered at the clinical study center after predose assessments 
have been completed. A breakfast and a glass of water will be provided by the clinical study 
center. During the visits, subjects will be provided with a supply of IP to take home (see 
Section 4.5 for measurement of compliance by diary). 
If a subject misses a dose (e.g. because they forgot to take the IP), they must immediately take the 
missed dose with food and a glass of water, within 12 hours after the planned intake time. If the 
IP is not taken within 12 hours after the planned time, the missed dose must be skipped. 
Individual dose reductions will not be allowed. 
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Detailed information regarding the records documenting the total amount of received IP and 
return/destruction of the used/unused medication can be found in Section 4.5. 
4.3. 
Packaging, Labeling and Distribution 
IP packages will be labeled with clinical study-specific details. 
All manufacturing, packaging and labeling operations will be performed according to Good 
Manufacturing Practice for Medicinal Products and the relevant regulatory requirements. 
The distribution will only occur after the required local documentation is obtained, including 
clinical study approval by Competent Authorities and the IECs/IRBs, documentation on which 
the assessment of the investigator’s qualifications was based (e.g. curriculum vitae), and the 
signed and dated study agreement and financial agreement. 
GLPG2737 and placebo capsules will be packaged in high-density polyethylene (HDPE) 
treatment bottles with a child-resistant HDPE closure. At each IP dispensing time point, subjects 
will receive treatment bottles to cover for the next visit. The bottles will be labeled according to 
local requirements and will have unique identifiers. 
4.4. 
Storage 
Sites are to store IP supplies in a secure area below 30°C, not to be stored at refrigerated or 
frozen condition, until dispensed. Sites will be required to monitor the storage temperature by 
using at least a min-max temperature-recording device and to keep a minimum to maximum 
temperature log, which must be completed each working day in order to establish a record of 
compliance with these storage conditions. The investigator will instruct subjects on how the IP 
should be stored at home. 
4.5. 
Treatment Compliance and Drug Accountability 
The pharmacist or designated clinical study personnel will maintain a log of the total amount of 
IP received at site, amount dispensed to the subject, and the amount of IP returned by the subject 
to the site. IP supplies for each subject will be inventoried and accounted for throughout the 
clinical study. At the end of the treatment period, these records will be checked against the 
inventory by the study monitor. All clinical supplies will be stored in locked facilities. 
Subjects will return any unused IP and empty IP packages at each visit and/or ETD Visit. Missed 
doses should be discussed to try to ascertain the reason(s). Every effort should be made to ensure 
the proper subject dose. Subjects with poor compliance will be retrained by the clinical study site. 
Upon sponsor approval, all unused IP and empty IP packages will be destroyed at the site. If 
destruction by the site is not possible or the destruction process is found unacceptable by the 
sponsor, the IP should be returned to the drug supplier/drug depot as appropriate. 
Treatment compliance will be assessed by the investigator or designee. At each visit, site staff 
will review treatment compliance by assessing the number of returned IP. If a subject 


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demonstrates continued noncompliance despite educational efforts, the investigator must contact 
the sponsor’s study physician to discuss discontinuation of the subject from the study. 
Any discontinuation must be done in consultation with the sponsor’s study physician. 
4.5.1. 
Subject Diary 
Subjects will be given a paper diary at the time points specified in the Schedule of Activities in 
Section 5.11 to record the following (screening until the EoS Visit 15 [Week 56] of the double-
blind period): 
− 
Any missed dose, if applicable. 
− 
To document that IP dose has been taken properly on a daily basis, if applicable. 
− 
The time of study drug intake, including whether food was taken with each dose. 
− 
Changes in stable concomitant medication regimen, including new medicines not captured in 
medication history, as well as any emerging AEs.Subjects will be instructed to bring the diary 
and all remaining capsules at each visit. 
5. 
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 5.11). To avoid inter-observer variability, 
every effort should be made to ensure that all safety and efficacy evaluations are completed by 
the same individual who made the initial baseline determinations. 
5.1. 
Timing of Assessments 
The study assessments will be undertaken at time points and time windows as specified in the 
Schedule of Activities in Section 5.11. Screening and study procedures can only start after the ICF 
has been signed. 
The preferred sequence of study assessments will be as follows: 
Visit 1 (Screening): 
1. In- and exclusion criteria, demographics, medical history 
2. 12-lead ECG (triplicate) 
3. Assessment of (S)AE(s) and prior and concomitant medication, and dispense diary 
4. Physical examination, vital signs (supine heart rate, systolic and diastolic blood pressure 
[SBP and DBP], and body temperature), weight and height 
5. Blood sampling for clinical laboratory testing FSH (if applicable), serum pregnancy test (if 
applicable), urine analysis (including random urine sample) 
6. TKV imaging if historical imaging is older than 5 years or not available. In case MRI is 
performed according to study specifications and centrally read, this MRI can be used for 
screening and randomization. In this case, there is no need to repeat MRI at Visit 2 (Day 1). 
 


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Visit 2 (Day 1, randomization): 
1. Before randomization: the below 2 criteria need to be met before proceeding to the other 
assessments of Visit 2: 
a. 12-lead ECG (triplicate); repeat if abnormal QTcF > 450 ms; screen failure if 
confirmed abnormal by the investigator (3 recordings with QTcF ≤ 450 ms need to be 
present) 
b. For female: urine pregnancy test; if positive a serum pregnancy test needs to be 
performed; screen failure if serum pregnancy test is positive 
a. 
Only proceed to the following assessments if the subject is not screen failed by the criteria 
above: 
2. Retrieve 24 hour urine collection from the subject upon arrival 
3. Urine analysis on first morning urine 
4. Assessment of (S)AE(s) and concomitant medication, and collect and dispense diary 
5. Physical examination, vital signs (supine heart rate, SBP and DBP, and body temperature), 
and weight 
6. Blood sampling for clinical laboratory tests; for genotype analysis (optional, if applicable); 
for 
; ; for PK of GLPG2737 and its metabolite 
M4 (predose sample) 
7. Optional blood sampling (1 for RNA sequencing, 1 plasma, and 1 serum sample) for future 
scientific research 
8. IP intake 
9. Blood sampling for PK analysis of GLPG2737 and M4, between 1.5 and 4 hours postdose 
10. htTKV and 
 MRI. In case screening MRI was performed according to the study 
specifications and centrally read, screening MRI can be used for Day 1 and no MRI should be 
performed at the Day 1 visit. 
 
Visit 3-Visit 14: (apart from the Optional Visit and EoS Visit below) 
1. Retrieve 24 hour urine collection from the subject upon arrival (if applicable) 
2. Urine analysis and urine pregnancy test (if applicable) on first morning urine 
3. Assessment of (S)AE(s) and concomitant medication, and collect and dispense diary 
4. 12-lead ECG (triplicate, as indicated in Schedule of Activities, Section 5.11) 
5. Physical examination, vital signs (supine heart rate, SBP and DBP, and body temperature), 
and weight 
6. Blood sampling for clinical laboratory tests; for 
 
 ( (on visits as indicated in Schedule of Activities, Section 5.11); for PK concentration 
analysis of GLPG2737 and M4 (predose sample within 30 minutes prior to IP intake at 
selected visits [see Section 5.6]) 
7. IP intake 
8. htTKV and 
 MRI (Visit 5 [Week 4], Visit 10 [Week 26] and Visit 14 [Week 52], apart 
from subjects having discontinued earlier) 
9. Blood sampling for postdose PK concentration analysis of GLPG2737 and M4 in parallel 
with htTKV / 
 MRI (Visit 5 [Week 4]; Refer to Section 5.6 for timing) 
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10. Optional blood sampling (1 for RNA sequencing, 1 plasma, and 1 serum sample) for future 
scientific research (Visit 14 [Week 52]) 
 
Visit 15 (EoS of double-blind period) / Roll-over visit at Week 56): 
1. ICF collection for OLE period. 
2. In- and exclusion criteria for OLE period. 
3. Retrieve 24 hour urine collection from the subject upon arrival 
4. Urine analysis and urine pregnancy test (if applicable) on first morning urine 
5. 12-lead ECG (triplicate) 
6. Physical examination, vital signs (supine heart rate, SBP and DBP, and body temperature), 
and weight 
7. Assessment of (S)AE(s) and concomitant medication, and collect diary 
8. htTKV and 
 MRI (apart from subjects with ETD) 
9. Blood sampling for clinical laboratory tests and for 
 
 a and optional for future scientific research 
10. IP intake (only in case of participation in OLE period) 
Visit 16-Visit 22 (OLE period) 
1. Retrieve 24 hour urine collection from the subject upon arrival (if applicable) 
2. Urine analysis and urine pregnancy test (if applicable) on first morning urine 
3. Assessment of (S)AE(s) and concomitant medication 
4. 12-lead ECG (single, as indicated in Schedule of Activities, Section 5.11) 
5. Physical examination, vital signs (supine heart rate, SBP and DBP, and body temperature), 
and weight 
6. Blood sampling for clinical laboratory tests-and for 
 (on visits as indicated in Schedule 
of Activities, Section 5.11) and for Visit 22 [Week 108]: optional sample for future scientific 
research 
7. Visit 17 [Week 60] and Visit 18 [Week 66]: : 
 
 
  
8. IP intake 
9. Visit 17 [Week 60]: : 
 
  
10. Visit 20 [Week 84] Visit 22 [Week 108]: : 
 
Visit 23 (EoS) at Week 112 of the OLE Period 
1. Urine analysis and urine pregnancy test (if applicable) on first morning urine 
2. 12-lead ECG (single) 
3. Physical examination, vital signs (supine heart rate, SBP and DBP, and body temperature), 
and weight 
4. Assessment of (S)AE(s) and concomitant medication 
5. Blood sampling for clinical laboratory tests and for 
  
 
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ETD visit: 
When IP is discontinued permanently, an ETD visit will be performed. 
1. Urine analysis and urine pregnancy test (if applicable) on first morning urine 
2. Assessment of (S)AE(s) and concomitant medication, and collect diary 
3. 12-lead ECG (triplicate during double-blind period or single during OLE period) 
4. Physical examination, vital signs (supine heart rate, SBP and DBP, and body temperature), 
and weight 
5. Blood sampling for clinical laboratory tests; for 
 (during double-blind and OLE 
period) and 
 (only during double-blind period); for PK 
concentration analysis of GLPG2737 and M4  
6. Optional blood sampling (1 for RNA sequencing, 1 plasma, and 1 serum sample) for future 
scientific research 
7. In case of treatment discontinuation: ETD visit assessments 1-5 need to be done plus 
htTKV/
 MRI depending on the time of discontinuation: 
− Between Week 0 and Week 4 (included): no MRI 
− Between Week 4 and Week 8 (included): final MRI 4 weeks after ETD visit 
− Between Week 8 and Week 26 (included): MRI at ETD visit, and final MRI 4 weeks later 
− Between Week 26 and Week 30 (included): final MRI 4 weeks after ETD visit 
− Between Week 30 and Week 56: MRI at ETD visit, and final MRI 4 weeks later 
− After Week 56: MRI htTKV to be performed if > 6 months since last MRI 
Note:  
In case of blood sampling via catheter, the order of assessments is less important when there is at 
least 30 minutes between the placement of the catheter/blood sampling via catheter and vital 
signs/ECG. 
5.2. 
Unscheduled Visits 
Additional visits can be performed at other time points for any assessments, if clinically 
indicated. 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 CSP, also in the CRF. 
5.3. 
Initial Subject and Disease Characteristics 
Subjects will be asked to attend the clinical center for a screening assessment. After giving 
written informed consent, demographic data (age, sex and race) and a medical history will be 
taken, including questions regarding medication intake. A physical examination will be 
performed, including measurement of weight and height. 
Vital signs (SBP, DBP, supine heart rate, body temperature) will be measured and a 12-lead ECG 
will be recorded. Subjects should rest for at least 5 minutes in the supine position before the ECG 
recording, blood pressure, and heart rate measurement. 
The inclusion and exclusion criteria will be checked to assess eligibility for the study. All 
screening tests will be reviewed to confirm eligibility before randomization and the first dose. 
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5.4. 
Efficacy Assessments 
5.4.1. 
htTKV and 
 by MRI 
htTKV and 
 will be determined by MRI at time points defined in the Schedule of 
Activities (see Section 5.11). MRI has been shown to be accurate, reproducible and able to detect 
small changes in TKV over a short period of time (Chapman, Bost, & Torres, 2012). Subjects 
will undergo MRI using a standardized protocol. 
If imaging needs to be performed for screening purposes as described in Inclusion Criterion 3, 
MRI can be selected as imaging method. In this case, when MRI signal acquisition procedures 
have been applied and centrally read, the screening MRI can be used as baseline measurement. 
There is no need to repeat MRI on Day 1 of the double-blind period (as long as screening MRI 
meets the quality criteria). 
MRI signal acquisition procedures will be described in a specific laboratory manual. MRI images 
will be obtained at each clinical site by a trained imaging specialist. Following MRI acquisition, 
the images will be transferred to an Imaging Core Laboratory for centralized reading. In case the 
TKV MRI does not meet the quality criteria, the site is requested to perform another MRI within 
10 business days of the original visit, with a maximum of 1 repetition.  
Further details regarding the methodology will be provided in a separate study reference manual. 
5.4.2. 
Estimated GFR (eGFR) 
eGFR is a mathematically derived value based on a subjects serum creatinine level. The eGFR 
values will be based on the CKD-EPI equation, calculated from serum creatinine concentrations 
taken at screening and during every visit (see Schedule of Activities, Section 5.11), and will be 
reported by the central laboratory. 
Further details regarding the methodology will be provided in a separate study reference manual 
and details regarding eGFR calculations will be provided in the statistical analysis plan (SAP). 
5.5. 
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. 
5.5.1. 
Adverse Events 
The AEs reporting period for safety surveillance begins when the subject signs the ICF and ends 
at his/her last follow-up visit. 
Detailed definitions, ratings and reporting requirements for AEs and SAEs are found in Section 8. 
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5.5.2. 
Clinical Laboratory Evaluations 
The following clinical laboratory safety tests will be performed: 
− 
Hematology: 
hematocrit, hemoglobin, red blood cell count, white blood cell count, white blood cell 
differential count (absolute and relative), platelets MCV, MCH, mean corpuscular 
hemoglobin concentration (MCHC), Vitamin B12. 
− 
Coagulation: 
activated partial thromboplastin time, prothrombin time, and INR. 
− 
Clinical chemistry: 
glucose, urea, creatinine, uric acid, sodium, potassium, calcium (including ionized), chloride, 
phosphorus, AST, ALT, GGT, total bilirubin, alkaline phosphatase, albumin, total proteins, 
triglycerides, cholesterol, high-density lipoprotein, low density lipoprotein, C-reactive 
protein, lactate dehydrogenase, amylase, lipase, Urinalysis: 
Proteins (quantitative) and ketones can be tested via standard test strip; microscopic 
examination of the sediment (cylinders, erythrocytes, leukocytes) if indicated (when the test 
strip was positive for blood and/or proteins), first morning urine for microscopy culture and 
sensitivity (MCS), albumin, creatinine (quantitative and ratio)  
− Serology (only at screening): 
Hepatitis B surface antigen and hepatitis C antibody (confirmation of hepatitis C virus RNA 
positivity should be performed), and HIV 1 and HIV 2 antibodies only at screening. Positive 
hepatitis and HIV results should be reported by the investigator as required by local law. 
− 
FSH test for females of non-childbearing potential at screening to confirm menopause, if 
applicable. 
− 
Pregnancy test for females: 
Serum pregnancy testing (β-human chorionic gonadotropin [β-hCG]) will be performed at 
screening in females of childbearing potential; on the other specified days, a urine pregnancy 
test will be performed. The urine pregnancy test must be negative prior to the first 
administration of IP. 
The clinical laboratory evaluations will be performed at visits specified in the Schedule of 
Activities in Section 5.11 (see also Section 5.1, “Timing of Assessments”). Reference ranges will 
be supplied by the central laboratory. Clinical laboratory values outside the normal range will be 
flagged and clinical relevance will be assessed by the investigator. Only laboratory test 
abnormalities judged as clinically significant by the principal investigator should be recorded as 
AEs. 
The total amount of blood to be taken during the clinical study will not exceed 500 mL over a 
duration of 112 weeks. This includes sampling for pharmacokinetic (PK) and/or 
pharmacodynamic (PD) assessments. 
The details of blood and urine sample handling and shipment instructions will be provided in a 
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5.5.3. 
Physical Examination 
Physical examinations will be conducted by a physician, trained physician’s assistant, or nurse 
practitioner as acceptable according to local regulation at visits specified in the Schedule of 
Activities in Section 5.11 (see also Section 5.1, “Timing of Assessments”). The person 
conducting the physical examination will document this in the subject’s medical records. 
Clinically significant abnormal findings should be recorded as AEs. 
5.5.4. 
Vital Signs 
Vital signs (SBP, DBP, supine heart rate, and body temperature) will be recorded in a 
standardized manner (i.e. after the subject has rested in a supine position for 5 minutes) at visits 
specified in the Schedule of Activities in Section 5.11 (see also Section 5.1, “Timing of 
Assessments”). For blood pressure, 3 measurements need to be taken within 5 minutes and the 
mean needs to be recorded. Vital sign parameter ranges are presented in Appendix 1. Clinically 
significant abnormal values should be recorded as AEs. 
Height will only be assessed at screening. Weight will be assessed at screening, and on every 
visit as per Schedule of Activities (See Section 5.11). 
5.5.5. 
12-lead Electrocardiogram 
During the double-blind period, at every visit (see Section 5.11) an ECG will be recorded in 
triplicate. During the OLE period (from Visit 16 [Week 58] onwards), ECG recording will be 
performed as a single measurement. Single ECG recordings during the OLE period will be read 
locally. The ECG must be taken after subjects rested for at least 5 minutes in the supine position.  
Triplicate ECGs will be taken within preferably 15 minutes. 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 and interpreted by the investigator. 
Central reading will be performed for all triplicate ECGs at all time points. 
For Visit 2 (Day 1) of the double-blind period and Visit 15 (Week 56) of the OLE period, 
triplicate abnormal QTcF >450 ms (each recording of the triplicate ECG must be ≤450 ms) 
before IP dosing needs to be confirmed by a second recording. In case there are no 3 readings 
with a QTcF ≤450 ms after the second recording, then the subject cannot be randomized and will 
be considered a screen failure. 
At Visit 2 (Day 1), if the predose QTcF recording is reported during the visit as normal by the 
investigator, but the overread by the cardiologist reports a QTcF >450 ms, then the subject should 
be discontinued as soon as possible. 
At all other visits, the conclusion/evaluation of the central cardiologist reader will also overrule 
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Parameters to be recorded include the following: heart rate, PR interval, QRS interval, 
uncorrected QT interval, QTcF and rhythm. 
QTcF will be considered as normal if ≤450 ms. After Visit 2, 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 3.6.5). Normal ranges for ECG are provided 
in Appendix 1. 
In case of abnormal QTcF, the investigator should adhere to clinical practice for follow-up of the 
subject. 
ECG abnormalities will be interpreted by the investigator for clinical significance. Clinically 
significant abnormal values should be recorded as AEs. 
In case an indwelling catheter is used, ECGs may be recorded after blood sampling, provided that 
there is at least 30 minutes between catheter insertion and the ECG recording. When catheter 
insertion would fail, the ECG needs to be taken before the venipuncture and at least 30 minutes 
after the failed attempt. 
5.5.6. 
Other Safety Assessments - Control of Raised Blood Pressure 
The target blood pressure for subjects with chronic renal failure should be ≤150/90 mm Hg 
during the study. The principles outlined in the Kidney Disease Outcomes Quality Initiative 
(KDOQI) hypertension guideline should be followed to ensure maintenance of blood pressure 
control (KDIGO_CKD_Work_Group, 2013). 
5.6. 
Pharmacokinetic Assessments 
Blood samples for the PK assessment should be collected on the time points specified below (see 
also Timing of Assessments in Section 5.1 and Schedule of Activities in Section 5.11). 
Sparse PK sampling will be applied postdose on Visit 2 (Day 1) and Visit 5 (Week 4) to capture 
information on GLPG2737 and M4, absorption, distribution, and elimination. 
During the course of the study, in total, 19 blood samples per subject will be collected for 
analysis of GLPG2737 and its metabolite M4, in plasma. Samples will be obtained by 
venipuncture (or indwelling cannula), preferably in the forearm. 
Blood samples will be collected into vacuum tubes containing K2EDTA and will be immediately 
chilled (ice bath). Within 30 min after blood collection, the plasma will be separated by 
centrifugation at 4°C for 10 min at ca. 1500 g and transferred into storage tubes with 
approximately 400 μL of plasma per tube. After appropriate labeling, the plasma samples will be 
stored between -15 and -30°C at the clinical research center until shipment. The details of blood 
sample collection, handling, storage and shipment instructions will be provided in a separate 
laboratory manual. 
The following PK sampling scheme will be applied (GLPG2737 and M4): 


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During double-blind period: 
− 
Visit 2 (Day 1): predose and 1.5-4 hours postdose (i.e. 2 samples) 
− 
Visit 5 (Week 4): predose (within 30 minutes prior to dosing), 1, 2, 3, 4 hours postdose 
(+/- 20 min), 5-7 hours postdose and 8-9 hours postdose (7 samples) 
− 
Visit 3 (Week 1), 4 (Week 2), 8 (Week 16), 10 (Week 26), 14 (Week 52): predose sample 
(within 30 minutes prior to dosing) 
  
 
  
 
 
For reliable analyses of the PK data, it is vital that the actual times of drug intake and PK 
sampling are recorded accurately in the CRF. 
5.7. 
Pharmacodynamic Assessments 
Double-blind period:  
 
 
 
 
 
 
OLE period:  
  
 
 
 
 
5.8. 
Other Assessments 
5.8.1. 
Genotyping 
 
 
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5.8.2. 
Future Scientific Research 
For subjects who give additional informed consent, 12 optional  samples (1 for RNA sequencing, 
1 plasma, and 1 serum sample each at 4 time points) will be obtained for future scientific 
research. These samples are scheduled to be collected before exposure (baseline, Day 1) and at 
the end of the double-blind treatment period (Week 52 and Week 56) and at the end of the OLE 
period (Week 108), or at ETD (see Schedule of Activities Section 5.11). 
5.9. 
Sample Management 
Blood and Urine Samples for Routine Safety Tests, Serology, FSH and Pregnancy Tests 
All blood and urine samples for routine safety tests, serology, FSH, and pregnancy tests (if 
applicable) will be analyzed in a central laboratory and will be destroyed after analysis. Urinary 
pregnancy tests will be performed locally. 
Blood and Urine Samples for PK and PD 
After the end of the study (defined in Section 3.2), all biological samples obtained during the 
clinical study may be stored for a maximum period of 5 years (or up to 30 years for samples for 
future scientific or genetic research, see Section 5.10), after which the samples will be destroyed. 
The sample storage period will be in accordance with the IRB/EC-approved ICF and applicable 
laws (e.g. health authority requirements). 
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 CSP may only be conducted after approval by the IRB/IEC and 
Regulatory Authority and after obtaining informed consent from the subject. 
 
 
 
 
5.10. 
Long Term Storage of Samples and Associated Data for Future 
Scientific and Genetic Research 
A total of 12 additional samples will be obtained from subjects who agree to participate and 
provide their optional informed consent for the additional collection and use of samples for future 
scientific research, including long term storage of samples and associated data (see 
Section 5.8.2). Collection and storage of samples is detailed in a separate laboratory manual. 
For subjects who agree to participate and provide their optional informed consent for long term 
storage of left over samples from samples already collected during the study and associated data 
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for future scientific and genetic research, blood and urine samples obtained during the study will 
be stored for 30 years or according to local legislation. 
The samples and associated data collected for future scientific and genetic research will be stored 
in the Galapagos Biobank and may be used by the sponsor, sponsor partners and/or other 
companies contracted by the sponsor. The objective of biobanking is to allow the gathering of 
additional knowledge on the compound GLPG2737 and/or diseases it may target both 
investigated during this study and beyond. 
Subjects are not required to consent for the collection of samples and for the long term storage of 
samples and associated data for future scientific and genetic research in order to participate to the 
study. Subjects will also be informed that consent to sample collection and storage for future 
research is voluntary and that they may withdraw their consent at any time. If a subject chooses 
to withdraw consent for the collection or storage of samples and associated data for future 
research then the investigator or designated personnel must inform the sponsor 
(withdrawal@glpg.com). 
Withdrawal from the study does not, by itself, implicate withdrawal of consent for the collection 
or storage of samples and associated data for future research. Likewise, withdrawal of consent for 
the storage of samples and associated data for future research does not implicate withdrawal from 
the study.  
In the event of subject’s death or loss of competence, the already collected samples and data will 
continue to be used as part of the future scientific and genetic research.  
The samples and associated data for future research, e.g. body fluids, solid tissue, and derivatives 
thereof (e.g. protein, peptides) will be destroyed no later than 30 years after the end of the study 
or according to local legislation. The samples and associated data storage period will be in 
accordance with the IRB/EC-approved ICF and applicable legislation (e.g. regulatory authority 
requirements). 
The subject will receive additional information specific to the longterm processing of their 
personal data for future scientific and genetic research purposes, as required by the EU General 
Data Protection Regulation. This includes information about the broader scientific purposes of 
future research, the lawful bases of the processing activities involved, as well as the retention 
period of their personal data for these additional purposes. The details are included in the optional 
informed consent form. 


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5.11. 
Schedule of Activities 
5.11.1. 
Double-blind Treatment Period 
For detailed instructions on the clinical study procedures, please see referred sections and Section 5.1, “Timing of Assessments”. 
EVENT 
SCREEN 
ING 
PERIOD 
TREATMENT PERIOD 
EoST / EoSA1 
FOLLOW-
UP 
Study visit 
1 
2 
3 
4 
5 
6/7/8/9 
10/11/12/13 
ETD2 
14 
EoST  
14 
EoSA 
15 (EoS DB 
Period)3 
Study Day (D) or Week (W) 
(± D) 
D-28 to 
D-1 
D1 
W1 
± 3 
W2 
± 3 
W4 
± 3 
W8/W12/ 
W16/W20 
 ± 4 
W26/W34/ 
W42/W48 
± 4 
 
W52 
± 4 
W52 
± 4 
W56 
± 10 
Informed consent (Section 5.3) 
✓ 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
(Sections 3.6 and 5.3) 
✓ 
✓ 
 
 
 
 
 
 
 
 
 
Demographics (Section 5.3) 
✓ 
 
 
 
 
 
 
 
 
 
 
Medical history (Section 5.3) 
✓ 
 
 
 
 
 
 
 
 
 
 
Pregnancy test4,5 (Section 5.5.2) 
✓ 
✓ 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
✓ 
                                                 
1 At Visit 14 either EoST (Treatment) or EoSA (Assessment) should be performed. 
2 Early treatment discontinuation (ETD) visit, if applicable.  
3 In case subject rolls over to the OLE period, roll-over visit in the SoA described in Open-label Treatment Period  (Section 5.11.2) is also applicable. 
4 Assessment needs to be done prior to dosing, on dosing days.  
5 Serum Pregnancy test or FSH at screening. Urine pregnancy test at Day 1and subsequent visits, as indicated in the SoA. 
 


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EVENT 
SCREEN 
ING 
PERIOD 
TREATMENT PERIOD 
EoST / EoSA1 
FOLLOW-
UP 
Study visit 
1 
2 
3 
4 
5 
6/7/8/9 
10/11/12/13 
ETD2 
14 
EoST  
14 
EoSA 
15 (EoS DB 
Period)3 
Study Day (D) or Week (W) 
(± D) 
D-28 to 
D-1 
D1 
W1 
± 3 
W2 
± 3 
W4 
± 3 
W8/W12/ 
W16/W20 
 ± 4 
W26/W34/ 
W42/W48 
± 4 
 
W52 
± 4 
W52 
± 4 
W56 
± 10 
Physical examination 
(Section 5.5.3)6 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Vital signs4 (Section 5.5.4) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Weight and Height7 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
12-lead ECG4,8 (Section 5.5.5) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Serology (Section 5.5.2) 
✓ 
 
 
 
 
 
 
 
 
 
 
Safety blood samples 
(Section 5.5.2) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Safety urine samples (Section 
5.5.2) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
                                                 
6 Full physical examinaton should be performed at screening, randomization, Visit 5 (Week 4), Visit 10 (Week 26), and Visit 14 (Week 52). At all other visits at investigators 
discretion. 
7 Height only at screening. 
8 Triplicate ECG at each visit.  
 


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EVENT 
SCREEN 
ING 
PERIOD 
TREATMENT PERIOD 
EoST / EoSA1 
FOLLOW-
UP 
Study visit 
1 
2 
3 
4 
5 
6/7/8/9 
10/11/12/13 
ETD2 
14 
EoST  
14 
EoSA 
15 (EoS DB 
Period)3 
Study Day (D) or Week (W) 
(± D) 
D-28 to 
D-1 
D1 
W1 
± 3 
W2 
± 3 
W4 
± 3 
W8/W12/ 
W16/W20 
 ± 4 
W26/W34/ 
W42/W48 
± 4 
 
W52 
± 4 
W52 
± 4 
W56 
± 10 
MRI based htTKV and 
 
(Section 5.4.1)  
(✓)9 
✓9 
 
 
✓ 
 
✓10 
✓11 
✓ 
 
✓ 
eGFR (Section 5.4.2) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
                                                 
9 At screening TKV should be determined in case historical imaging is not available from the last 5 years (other imaging can be performed depending on local clinical 
practice). In case MRI is performed at screening according to study specifications and centrally read, this MRI can be used for screening and randomization. In this case, there 
is no need to repeat MRI at Visit 2 (Day 1). 
10 at Visit 10 (Week 26) only. 
11 For subjects discontinuing IP prematurely, the instructions of the ETD need to be followed (see Section 5.1). 
12 24 hours urine collection to be performed 24 hours before Visit 2 (Day1), Visit 5 (Week 4), Visit 7 (Week 12), Visit 10 (Week 26), EoST Visit 14 (Week 52), and EoS 
Visit 15 (Week 56) – not applicable for subjects who discontinued IP. 
13 At Visit 7 (Week 12) only. 
14 PD samples directly after PK sampling (predose). 
 
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EVENT 
SCREEN 
ING 
PERIOD 
TREATMENT PERIOD 
EoST / EoSA1 
FOLLOW-
UP 
Study visit 
1 
2 
3 
4 
5 
6/7/8/9 
10/11/12/13 
ETD2 
14 
EoST  
14 
EoSA 
15 (EoS DB 
Period)3 
Study Day (D) or Week (W) 
(± D) 
D-28 to 
D-1 
D1 
W1 
± 3 
W2 
± 3 
W4 
± 3 
W8/W12/ 
W16/W20 
 ± 4 
W26/W34/ 
W42/W48 
± 4 
 
W52 
± 4 
W52 
± 4 
W56 
± 10 
First morning urine for 
Microscopy Culture and 
Sensitivity (MCS) 
(Section 5.5.2) 
✓17 
✓ 
 
 
✓ 
 
 
✓ 
✓ 
✓ 
 
Randomization (Section 3.7.1) 
 
✓ 
 
 
 
 
 
 
 
 
 
                                                 
15 At Visit 6 (Week 8), Visit 7 (Week 12), Visit 8 (Week 16) only. 
16 At Visit 10 (Week 26) and Visit 11 (Week 34) only. 
17 A random urine sample can be used at the screening visit. 
18 Only in case not determined in the past. 
19 Only at Visit 8 (Week 16) and Visit 10 (Week 26). 
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EVENT 
SCREEN 
ING 
PERIOD 
TREATMENT PERIOD 
EoST / EoSA1 
FOLLOW-
UP 
Study visit 
1 
2 
3 
4 
5 
6/7/8/9 
10/11/12/13 
ETD2 
14 
EoST  
14 
EoSA 
15 (EoS DB 
Period)3 
Study Day (D) or Week (W) 
(± D) 
D-28 to 
D-1 
D1 
W1 
± 3 
W2 
± 3 
W4 
± 3 
W8/W12/ 
W16/W20 
 ± 4 
W26/W34/ 
W42/W48 
± 4 
 
W52 
± 4 
W52 
± 4 
W56 
± 10 
PK blood sample, any time of 
the day (Section 5.6) 
 
 
 
 
 
 
 
✓ 
 
 
 
Optional blood samples for 
future scientific research 
(Section 5.10) 
 
✓(pre
dose) 
 
 
 
 
 
✓ 
✓ 
 
✓ 
Dispense subject diary (Section 
4.5.1) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
 
Collect subject diary (Section 
4.5.1) 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
✓ 
Dispense subject participation 
card 
 
✓ 
 
 
 
 
 
 
 
 
 
Randomization 
 
✓ 
 
 
 
 
 
 
 
 
 
Dispense IP (Section 4.3) 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
 
 
Review IP compliance in paper 
diary (Section 4.5) 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
Dose IP (Section 4.2) 
 
q.d. throughout the treatment period starting at Day 1 
 
✓ 
 
 
AE assessment (Section 5.5.1) 
throughout the study 


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EVENT 
SCREEN 
ING 
PERIOD 
TREATMENT PERIOD 
EoST / EoSA1 
FOLLOW-
UP 
Study visit 
1 
2 
3 
4 
5 
6/7/8/9 
10/11/12/13 
ETD2 
14 
EoST  
14 
EoSA 
15 (EoS DB 
Period)3 
Study Day (D) or Week (W) 
(± D) 
D-28 to 
D-1 
D1 
W1 
± 3 
W2 
± 3 
W4 
± 3 
W8/W12/ 
W16/W20 
 ± 4 
W26/W34/ 
W42/W48 
± 4 
 
W52 
± 4 
W52 
± 4 
W56 
± 10 
Prior / Concomitant medication 
(Section 3.6.4.2) 
throughout the study 
 
 
 


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5.11.2. 
Open-label Treatment Period  
EVENT 
TREATMENT PERIOD 
FOLLOW-UP 
Study Visit / Phone Call 
Roll-over 
Visit 15 1 
16 
17/18/19 
20/21 
22 
ETD2 
23 (EoS OLE 
Period) 
Week (W) 
(± Days) 
Week 56 
W58 
± 3 days 
W60/W66
/ W72 
± 3 days 
W84/W96  
± 4 days 
W108 
± 4 days 
 
W112 
± 4 days 
Informed consent (Section 5.3) 
✓ 
 
 
 
 
 
 
Inclusion/exclusion criteria  
(Sections 3.6 and 5.3) 
✓ 
 
 
 
 
 
 
Pregnancy test (Section 5.5.2) 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
Physical examination (Section 5.5.3) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Vital signs (Section 5.5.4) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Weight 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
12-lead ECG (Section 5.5.5) 
✓ 
(triplicate) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Safety blood samples (Section 5.5.2) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Safety urine samples (Section 5.5.2) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
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EVENT 
TREATMENT PERIOD 
FOLLOW-UP 
Study Visit / Phone Call 
Roll-over 
Visit 15 1 
16 
17/18/19 
20/21 
22 
ETD2 
23 (EoS OLE 
Period) 
Week (W) 
(± Days) 
Week 56 
W58 
± 3 days 
W60/W66
/ W72 
± 3 days 
W84/W96  
± 4 days 
W108 
± 4 days 
 
W112 
± 4 days 
First morning urine for MSC  
(Section 5.7) 
✓4 
 
✓ (W60) 
 
 
 
 
Optional blood samples for future 
scientific research (Section 5.10) 
 
 
 
 
✓ 
✓ 
 
Dispense IP (Section 4.3) 
✓ 
 
✓ 
✓ 
 
 
 
Review IP compliance 
 
✓ 
✓ 
✓ 
✓ 
 
 
Dose IP (Section 4.2) 
q.d. throughout the treatment period 
 
 
AE assessment (Section 5.5.1) 
throughout the study 
Concomitant medication  
(Section 3.6.4.2) 
throughout the study 
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1 Roll-over visit will take place at FU visit of the double-blind period (Week 56). 
2 Early treatment discontinuation (ETD) visit, if applicable. 
3 For subjects discontinueing IP prematurely, the instructions of the ETD need to be followed (see Section 5.1) 
4 A random urine sample can be used. 
                                                 


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6. 
STATISTICAL METHODS 
All statistical methods shall be detailed in a SAP that will be finalized prior to the primary 
analysis. All data collected in this clinical study will be documented using summary tables, 
figures, and subject data listings. 
Any deviations from the protocol are to be justified in the SAP. 
6.1. 
Determination of Sample Size 
A total of 60 adult ADPKD subjects will be enrolled in this study. Subjects will be randomized in 
a 2:1 allocation ratio to GLPG2737 or placebo treatment, resulting in approximately n=40 for 
GLPG2737 and approximately n=20 for placebo. 
The primary aim of this study is to show that GLPG2737 treatment is generally safe and well 
tolerated, and to show a trend in treatment difference for the active treatment versus placebo for 
the primary endpoint (mean percent change from baseline in htTKV over 52 weeks). Therefore, 
no formal sample size calculation was performed. Merely for statistical reference, the variability 
of the estimated treatment difference for the proposed sample size of 60 subjects is illustrated in 
the following paragraph: 
For htTKV, prior knowledge for an existing treatment of ADPKD suggests a mean percent 
change from baseline to 52 weeks of 5.6% for placebo.  
Assuming a common standard deviation of 4.5 for the percent change from baseline and a true 
mean treatment difference of 2.8% between the 2 groups, this implies a power of 83% to detect a 
statistically significant difference at a 2-sided significance level of 20% (using 2-sample t-test). If 
the dropout rate is around 10%, the power will be around 80%. 
In case subjects discontinue from the study or from study treatment due to SARS-CoV-2 
restrictions, additional subjects may be randomized on top of the planned sample size. The 
number of additional subjects randomized will not exceed the number of subjects discontinuing 
the study or study treatment in relation to SARS-CoV-2 restrictions. Randomization of additional 
subjects will ultimately be decided by the sponsor before any study lock or related unblinding has 
occurred. 
6.2. 
Population for Analyses 
6.2.1. 
All Screened Subjects 
All subjects who signed and dated an ICF and underwent screening assessments to check whether 
or not they are eligible to participate in the clinical study. 
6.2.2. 
All Enrolled Subjects 
All subjects who were found eligible to participate in the clinical study and could be randomized. 


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6.2.3. 
All Randomized Subjects 
All enrolled subjects who were randomized into the clinical study. 
6.2.4. 
Full Analysis Set 
All randomized subjects who have received/used at least one dose of IP. Subjects will be grouped 
according to the treatment they were randomized to. 
6.2.5. 
Per Protocol Set 
All full analysis set subjects who did not have a major protocol deviation that impacts the 
efficacy results (as defined in a protocol deviation plan). The determination of the per protocol 
population will be finalized and documented prior to database lock and unblinding. 
6.2.6. 
Safety Analysis Set 
All randomized subjects who used at least one dose of IP. Subjects will be grouped according to 
the treatment they received. 
6.2.7. 
Pharmacokinetic Analysis Set 
Subset of the Safety Analysis Set for which plasma concentration data are available to facilitate 
development of the Population PK model and for whom the time of the dose on the days of PK 
sampling is known. 
6.2.8. 
Pharmacodynamic Analysis Set 
Subset of the Safety Analysis Set, selecting all subjects who have a baseline and at least one post-
baseline PD value excluding subjects with protocol deviations that may have an impact on PD 
analysis. 
6.2.9. 
Pharmacokinetic/Pharmacodynamic Analysis Set 
Intersection of the PK and PD Analysis Sets. 
6.2.10. 
All OLE Enrolled Subjects 
All randomized subjects who were found eligible to participate in OLE study period. 
6.2.11. 
OLE Full Analysis Set 
All OLE enrolled subjects who have used at least one dose of IP during the OLE study period. 
Subjects will be grouped according to the treatment they were randomized to (i.e. for the double-
blind study period). 


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6.2.12. 
OLE Safety Analysis Set 
All OLE enrolled subjects who used at least one dose of IP during the OLE period. Subjects will 
be grouped according to the treatment they received in the double-blind study period. 
6.2.13. 
OLE Pharmacodynamic Analysis Set 
 
 
 
6.3. 
Statistical Analyses 
6.3.1. 
General Statistical Considerations 
Summary tabulations will be presented and will display the number of observations, mean, 
standard deviations and/or standard error (as appropriate), median, minimum and maximum (for 
continuous variables), and the number and percentage per category (for categorical data). In 
addition to tabulated descriptive statistics, graphical data displays may be used to summarize the 
data. Unless otherwise noted, inferential statistics will be interpreted at the 2-sided 20% 
significance level. 
All summary tabulations will be presented by treatment group and by study period (i.e. by 
considering double-blind treatment period and OLE period separately). Analysis will be provided 
by considering baseline as the last measurement before the first dose of IP.  
 
 
 
 
The primary analysis will be performed when all subjects have reached the end of the double-
blind period, or discontinued earlier. The details of the primary analysis will be described in the 
SAP. 
6.3.2. 
Interim Analysis 
No interim analysis is planned for this study.  
6.3.3. 
Analyses of Demographics and Baseline Characteristics 
Subject disposition (including reasons for early discontinuation), protocol deviations, 
demographics, baseline characteristics, medical history, and concomitant therapies will be 
described using summary statistics. 
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6.3.4. 
Analyses of Primary Efficacy Parameters 
6.3.4.1. 
Analysis for Primary Efficacy Endpoint 
A longitudinal analysis of the htTKV percent change from baseline until the end of the end of the 
double-blind period will be performed and appropriate inferential measures on the treatment 
difference will be obtained. 
6.3.4.2. 
Analysis for Other Efficacy Endpoints 
Combined double-blind treatment period and OLE period: 
Efficacy assessments will be analyzed descriptively. Change from baseline and/or percent change 
from baseline will be computed as well by treatment group and by study period. 
Inferential analyses may be performed on the double-blind treatment period and will be described 
in the SAP. 
Only for the OLE period: 
Efficacy assessments will be analyzed only descriptively. 
 
 
6.3.5. 
Analyses of Primary Safety Data 
All safety analyses will be performed using the Safety Analysis Set (Section 6.2.6). Subjects will 
be analyzed according to the treatment they actually received. The actual treatment received will 
differ from the randomized treatment only when their actual treatment differs from randomized 
treatment for the entire treatment duration. All safety data collected on or after the first dose of IP 
administration up to the last contact after the last dose of IP, unless specified otherwise, will be 
summarized by treatment group and by study period (i.e. double-blind treatment period and OLE 
period) according to the IP received. Clinical safety will be addressed by assessing AEs, 
laboratory assessments, physical examinations, vital signs, and 12-lead ECGs. 
6.3.5.1. 
Extent of Exposure 
A subject’s extent of exposure to the IP will be generated from the IP administration page of the 
CRF. Exposure data will be summarized by treatment group and by study period. Duration of 
exposure to the IP will be expressed as the number of months between the first and last dose of 
IP, inclusive, regardless of temporary interruptions in IP administration and summarized by 
treatment group. 
6.3.5.2. 
Adverse Events 
Clinical and laboratory AEs will be coded using the latest version of the Medical Dictionary for 
Regulatory Activities. System Organ Class (SOC), High-Level Group Term, High-Level Term, 
Preferred Term, and Lower-Level Term will be attached to the clinical database. 
The following AEs will be considered as treatment-emergent adverse events (TEAEs): 
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Any AE with an onset date on or after the IP start date and no later than 30 days after last dose of 
IP, or any worsening of any AE on or after the IP start date. 
Summaries (number and percentage of subjects) of TEAEs per subject by SOC and Preferred 
Term will be provided by treatment group and by study period. TEAEs will also be summarized 
by causal relationship to the IP and severity. In addition, TEAEs leading to premature 
discontinuation of the IP will be summarized and listed. Also, all SAEs, including the 
nontreatment-emergent SAEs, will be listed. 
6.3.5.3. 
Clinical Laboratory Evaluations 
Combined double-blind treatment period and OLE period: 
Laboratory assessments will be analyzed descriptively. Changes from baseline (Day 1 predose) 
and shifts according to normal ranges and/or CTCAE grades will be presented as well. Analyses 
will be done per treatment group and per study period. 
Only for the OLE period: 
Laboratory assessments will be analyzed descriptively. 
 
 
 
6.3.5.4. 
Vital Signs 
Combined double-blind treatment period and OLE period: 
Vital signs will be analyzed descriptively. Changes from baseline (Day 1 predose) and shifts 
according to normal ranges will be presented as well. Analyses will be done per treatment group 
and per study period. 
Only for the OLE period: 
Vital signs will be analyzed descriptively. 
 
 
6.3.5.5. 
12-Lead Electrocardiogram 
Combined double-blind treatment period and OLE period: 
A descriptive analysis will be done for the 12-lead ECG. Changes from baseline (Day 1 predose) 
and shifts according to normal ranges (Appendix 1) will be presented as well. Frequency analyses 
of subjects with a QTcF prolongation of >450ms, >480 ms, >500 ms and change from baseline in 
QTcF interval with 30 ms and 60 ms will be presented. Analyses will be done per treatment 
group and per study period. 
Only for the OLE period: 
 
 
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6.3.6. 
Pharmacokinetics Analysis 
Observed GLPG2737 and M4 plasma concentrations will be analyzed using a population PK 
approach to characterize the PK profiles of GLPG2737 and M4 in ADPKD subjects, and explore 
the covariates that might influence the PK in this population. 
The aforementioned analysis will be described in detail in a separate pharmacometric analysis 
plan and will be reported separately from the clinical study report. A summary of the population 
PK analysis may be included in the clinical study report. Individual GLPG2737 and M4 exposure 
will be estimated based on the population PK model and included in the clinical study report. 
Visual exploratory assessment of the relationship between exposure and response (as surrogate 
, efficacy and safety endpoints) will be performed to evaluate putative 
correlations. If applicable, the time course of the response and the effects of treatment thereupon 
will be described using a longitudinal model of disease progression. 
The aforementioned population PK/PD analysis will be described in detail in a separate 
pharmacometric analysis plan and will be reported separately from the clinical study report. 
Descriptive statistics will be calculated by treatment group, study period and time points for the 
plasma concentrations. 
6.3.7. 
Pharmacodynamic Analyses 
Combined double-blind period and OLE period: 
PD data 
) ) will be summarized using descriptive statistics of 
actual values, changes from baseline and percent changes from baseline by treatment group and 
by study period. 
 
 
 
6.3.8. 
Analysis of Other Assessments 
In case a treatment effect is observed, exploratory efficacy, safety/PK/PD analyses may be added 
when deemed useful to better understand the collected data. Where possible, individual and/or 
mean ± standard error efficacy, safety, PD, and/or GLPG2737 plasma concentrations may be 
plotted against one another. If performed, these analyses will be described in a separate analysis 
plan and reported separately from the clinical study report. 
6.3.9. 
Additional Statistical Considerations 
Not applicable. 
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7. 
DATA MONITORING 
7.1. 
Independent Data Monitoring Committee 
To monitor the safety of the subjects, an Independent Data Monitoring Committee (IDMC) 
consisting of an independent statistician and independent experts in the field of ADPKD will be 
convened to regularly review the accumulating unblinded safety data for the clinical study. The 
IDMC will provide a recommendation to the sponsor on clinical study continuation, suggestions 
for clinical study adaptation(s), or early termination. Ultimately, the final decision remains with 
the sponsor. The specific responsibilities, composition, meeting formats, and details of output 
provided for the meetings of the IDMC will be outlined in detail in the IDMC Charter. 
8. 
SAFETY REPORTING 
8.1. 
Definitions of Adverse Events, Serious Adverse Events and 
Special Situations 
8.1.1. 
Adverse Events 
An AE is any untoward medical occurrence, new or worsening of any condition, in a clinical 
study subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (e.g. an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related. AEs may also include pre- or post-treatment complications that occur 
as a result of CSP-specified procedures, worsening of the targeted disease, overdose, drug 
abuse/misuse reports, or occupational exposure. 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. 
8.1.2. 
Serious Adverse Events 
An SAE is defined as an AE that: 
− 
Results in death; 
− 
Is life-threatening (Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.); 
− 
Requires in-patient hospitalization or prolongation of existing hospitalization; 
− 
Results in persistent or significant disability/incapacity; 
− 
Is a congenital anomaly / birth defect; 
− 
Is medically significant (medical and scientific judgment should be exercised in deciding 
whether other situations should be considered serious such as important medical events that 
might not be immediately life-threatening or result in death or hospitalization but might 


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jeopardize the subject or might require intervention to prevent one of the other outcomes 
listed in the definition above). 
8.1.3. 
Unlisted (Unexpected) Adverse Events/ Reference Safety Information 
An AE is considered unlisted if the nature or intensity is not consistent with the applicable 
product reference safety information. For an IP, the expectedness of an AE will be determined by 
whether or not it is listed in the reference safety information part of the IB. 
8.1.4. 
Adverse Events of Special Interest 
Not applicable. 
8.1.5. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events 
Laboratory abnormalities without clinical significance based on the investigator’s judgment are 
not considered AEs or SAEs. However, laboratory abnormalities (e.g. clinical chemistry, 
hematology, and urinalysis) or other abnormal (clinical study-specific) assessments (e.g. ECG, 
radiography, vital signs) that require medical or surgical intervention, are associated with signs 
and/or symptoms, and/or lead to IP interruption, modification, or discontinuation must be 
recorded as an AE or SAE if they meet the definition as described in Sections 8.1.1 and 8.1.2, 
respectively. If the laboratory abnormality is part of a syndrome, the syndrome or diagnosis is to 
be reported (e.g. anemia instead of decreased hemoglobin). 
The following liver enzyme elevations should be reported as SAEs: AST or ALT ≥3x ULN with 
signs of liver damage (total bilirubin >2x ULN OR international normalized ratio >1.5, and/or 
with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash and/or eosinophilia [>5%]). 
8.1.6. 
Special Situations 
Special situations are situations that have a possible impact on the safe use of the IP. These 
situations might be or might not be associated with AEs. 
− 
Pregnancy 
− 
Abuse or misuse of IP 
• 
Abuse of IP is defined as the persistent or sporadic, intentional excessive use of the IP, 
which is accompanied by harmful physical or psychological effects. 
• 
Misuse of IP is defined as a situation where the IP is intentionally and inappropriately 
used not in accordance with the product information. 
− 
Drug interaction or food interaction with IP 
• 
A drug interaction with IP is defined as a situation in which there is evidence or a 
suspicion that the IP interacts with another drug when both are administered together. 
• 
A food interaction with IP is defined as a situation in which there is evidence or a 
suspicion that the IP interacts with a food when taken together. 


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− 
 Medication error with IP 
• 
A medication error with IP is defined as an unintended failure in the drug treatment 
process that leads to, or has the potential to lead to, harm to the subject. 
− 
Occupational exposure to IP 
• 
Occupational exposure to IP is defined as an exposure to the IP as a result of one’s 
professional or non-professional occupation. 
− 
 Overdose with IP 
• 
An overdose of IP is defined as the administration of a quantity of the IP given per 
administration or cumulatively, which is above the maximum recommended dose as per 
protocol (i.e. >2 tablets per day). In cases of a discrepancy in drug accountability, 
overdose will be established only when it is clear that the subject has taken the excess 
dose(s). Overdose cannot be established when the subject cannot account for the 
discrepancy except in cases in which the investigator has reason to suspect that the 
subject has taken the additional dose(s). 
− 
 Product complaint or quality defect of IP 
• 
Product complaint or quality defect of IP is defined as complaints or defects of the IP 
arising from potential deviations in the manufacture, packaging or distribution of the IP. 
8.2. 
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. 
8.2.1. 
Assessment of Causality 
The investigator is responsible for assessing the causal relationship to IP(s) administration or 
study procedures (e.g. invasive procedures such as venipuncture) based on her/his clinical 
judgment. The following decision choice will be used by the investigator to describe the causality 
assessment between the reported event or laboratory test abnormality and the IP. 
− 
Unrelated: 
Time relationship to IP intake is improbable. Related to other etiologies such as concomitant 
medications or subject's clinical state. 
− 
Unlikely: 
Time relationship to IP intake is improbable (but not impossible). Concomitant disease or 
other drugs provide plausible explanations. 
− 
Possible: 
Time relationship to IP intake is reasonable. Event or laboratory test abnormality could also 
be explained by disease or other drugs. Information on IP withdrawal may be lacking or 
unclear. 
− 
Probable: 
Time relationship to IP intake is reasonable. Unlikely to be attributed to concurrent disease 
or other drugs. Response to withdrawal is clinically reasonable and re-challenge not required. 


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− 
Certain: 
Time relationship to IP intake is plausible. Cannot be explained by concomitant disease or 
other drugs. Response to withdrawal is plausible (pharmacologically, pathologically). Event 
definitive pharmacologically or phenomenologically (i.e. an objective and specific medical 
disorder or a recognized pharmacological phenomenon). Re-challenge 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. 
8.2.2. 
Assessment of Severity 
The severity of AEs should be graded using the CTCAE version 5.0. If a CTCAE criterion does 
not exist, the investigator should use the grade or adjectives: Grade 1 (mild), Grade 2 (moderate), 
Grade 3 (severe), Grade 4 (life-threatening) or Grade 5 (fatal) to describe the maximum intensity 
of the AE. For purposes of consistency with the CTCAE, these intensity grades are defined in the 
table below. 
Table 1 
Grading of AE Severity 
Grade  
Adjective  
Description  
Grade 1  
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated  
Grade 2  
Moderate 
Local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL*  
Grade 3  
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**  
Grade 4  
Life-threatening 
Urgent intervention indicated  
Grade 5  
Death 
Death-related AE  
* 
Instrumental activities of Daily Living (ADL) refer to preparing meals, shopping for groceries or clothes, using the 
 
telephone, managing money, etc. 
** 
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
 
bedridden. 
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. 
8.2.3. 
Outcome 
Each AE must be rated by choosing among: 


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− 
Recovered/resolved; 
− 
Recovered/resolved with sequelae; 
− 
Recovering/resolving; 
− 
Not recovered/not resolved; 
− 
Fatal; 
− 
Unknown. 
8.3. 
Investigator Requirements and Instructions for Reporting Adverse 
Events, Serious Adverse Events, Pregnancies, and Other Special 
Situations to the Sponsor 
8.3.1. 
Adverse Events 
The AE reporting period for safety surveillance begins when the subject signs the ICF and ends at 
the subject’s last follow-up visit (the last follow-up visit after the last dose of IP). In this period, 
all new AEs, regardless of cause or relationship, derived by spontaneous, unsolicited reports of 
subjects, by observation and by routine open questioning (such as “How do you feel?”) need to 
be recorded in the source and in the CRF. 
In case an AE is ongoing at the time of the last follow-up visit, the investigator needs to follow-
up on the subject until AE resolution or reasonable stabilization and to document in the subject’s 
source documentation. No related updates or additional data on the AE should be reported in the 
CRF. 
If a subject is documented as lost-to-follow-up, ongoing/unknown outcome AEs will not be 
followed up. 
If the AE meets the criteria for seriousness, the SAE form must be completed and sent to the 
sponsor within 24 hours (see Section 8.3.2). 
8.3.2. 
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 IP-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 IP, and at a later stage if not yet available within 24 hours, the 
form needs to be completed with a clearly written narrative describing signs, symptoms, and 


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treatment of the event, diagnostic procedures, as well as any relevant laboratory data and any 
sequelae. 
Follow-up and outcomes should be reported and documented in the source documents for all 
subjects that experience an SAE. It is important that the information provided on the SAE form 
matches the information recorded on the CRF for the same event. 
Copies of additional laboratory tests, consultation reports, post-mortem reports, hospital case 
reports, autopsy reports, and other documents should be sent when requested and available. Only 
subject identifiers (subject number) should appear on the copies, and all names and initials should 
be blackened and rendered illegible. Follow-up reports relative to the subject’s subsequent course 
must be submitted until the event has subsided or, in case of permanent impairment, until the 
condition stabilizes. 
Any SAEs that occur after the post-treatment follow-up visit but within 30 days of the last dose 
of IP(s), regardless of causality, should also be reported in the source document (Emergency 
Contact Information on page 2). Investigators are not obligated to actively seek SAEs after the 
CSP-defined follow-up period. However, if the investigator is informed about an SAE that occurs 
at any time after the subjects’ post-treatment follow-up visit and the event is deemed relevant to 
the use of IP(s), he/she should promptly document and report the event to the sponsor by using 
the SAE form. 
8.3.3. 
Pregnancy 
All initial reports of pregnancy in female subjects 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 after giving consent, at the expected time of delivery for follow-up and 
for information regarding the outcome of the newborn. Abnormal pregnancy and/or abnormal 
newborn outcomes are considered SAEs and must be reported using the SAE form. 
8.3.4. 
Reporting of Special Situations (Other Than Pregnancy) and Associated 
Adverse Events 
In case a special situation is not associated with an AE, the special situation should be reported 
within 24 hours by using the Special Situations form as is indicated on page 2 under “Emergency 
Contact Information”. 
In case a special situation is associated with an AE, the special situation should be reported 
within 24 hours by using the Special Situations form and the associated AE should be reported as 
specified in Section 8.3. 


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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 8.3.2. 
8.4. 
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 (EU) Clinical 
Trials Directive (2001/20/EC) and relevant updates, and other country-specific legislation or 
regulations, the sponsor may be required to expedite to worldwide regulatory agencies reports of 
SAEs, serious adverse drug reactions or suspected unexpected serious adverse reactions 
(SUSARs). The sponsor or a specified designee will notify worldwide regulatory agencies and 
the relevant IEC/IRB in concerned Member States of applicable SUSARs as outlined in current 
regulations. 
Assessment of expectedness for SAEs will be determined using the reference safety information 
section in the IB or relevant local label as applicable. 
All concerned investigators will receive a safety letter notifying them of relevant SUSAR reports 
associated with any IP(s). The investigator should notify the IEC/IRB of SUSAR reports as soon 
as is practical, where this is required by local regulatory agencies, and in accordance with the 
local institutional policy. 
9. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This clinical study is conducted in accordance with the current applicable regulations, ICH-GCP 
Guideline E6 and its updates, and local ethical and legal requirements. 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety and well-being of 
clinical study subjects are protected, consistent with the principles that have their origin in the 
Declaration of Helsinki, 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. 
9.1. 
Sponsor’s Responsibilities 
9.1.1. 
Regulatory Approval / Notification 
Prior to clinical study start, this CSP together with all relevant documentation will be submitted 
to the local regulatory authorities for review and approval and/or notification in compliance with 
local requirements. 


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9.1.2. 
Clinical Study Closure Considerations 
The sponsor reserves the right to close the investigational site or end the clinical study at any 
time for any reason. In case of an early termination of the clinical study or temporary halt by the 
sponsor, the IEC/IRB should be notified within 15 calendar days, unless otherwise specified by 
the IEC/IRB, including a detailed written explanation of the reasons for the termination/halt. 
The end of clinical study declaration will be submitted to the regulatory authorities and IEC/IRB 
after the complete clinical study has ended in all participating centers, in all countries. This 
notification will also be submitted within 90 days of the end of the clinical study in a given 
country/member state or within the timelines required by the local regulations. 
Reasons for the closure of an investigational site may include, but are not limited to: 
− 
Successful completion of the clinical study at the center. 
− 
The overall required number of subjects for the clinical study has been recruited. 
− 
Failure of the investigator to comply with the CSP, ICH-GCP guidelines or local 
requirements. 
− 
Inadequate recruitment of subjects by the investigator. 
 
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. 
9.1.3. 
Indemnification 
Under the conditions of a contract concluded between investigator, site and sponsor or designee, 
which shall prevail, the sponsor shall, except in case of gross negligence or willful misconduct, 
indemnify and hold harmless the investigator and his/her medical staff from any claim arising 
from the clinical study activities carried out in compliance with the CSP, sponsor’s instructions 
and applicable local regulations. 
The investigator must notify the sponsor immediately upon notice of any claims or lawsuits. 
9.1.4. 
Insurance 
The sponsor shall maintain insurance coverage that is sufficient to cover its obligations and that 
is consistent with human clinical study local regulations. Provided that the subject has been 
treated according to the CSP and sponsor’s instructions, any injury caused to a subject which is 
the direct result of his/her participation to the clinical study shall be covered by the sponsor’s 
insurance, except in case of gross negligence or willful misconduct by the investigator. 


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9.2. 
Investigator’s Responsibilities 
9.2.1. 
Source Data and Data Capture 
The nature and location of all source documents need to be identified and documented to ensure 
that all sources of original data required to complete the eCRF 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 eCRF. The eCRF completion guidelines will be provided to 
each investigational site. 
It is recommended that the author of an entry in the source documents should be identifiable. 
Following ICH-GCP guidelines, direct access to sponsor’s representatives to source documents 
must be granted for the purpose of verifying that the data recorded on the eCRF are consistent 
with the original source data. 
9.2.2. 
Archiving 
Unless other European Union Law require archiving for a longer period, the investigator shall 
archive the content of the clinical Investigator Site file (ISF) for at least 25 years after the end of 
the clinical study. However, the medical files of subjects shall be archived in accordance with 
national law. 
The investigator should take measures to prevent accidental or premature destruction of these 
documents. 
Under no circumstance shall the investigator relocate or dispose any clinical study documents 
before having obtained a written approval of the sponsor. 
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this clinical study, the investigator must permit access to such reports. 
The subject is granting access to his/her source data by signing the ICF. 
Any difficulty in storing original documents must be discussed with the monitor prior to the 
initiation of the clinical study. 
9.2.3. 
Participation Cards 
If the subjects are not under 24-hour supervision of the investigator or site staff, they must be 
provided with a subject participation card indicating the name of the IP, the clinical study 
number, the investigator's name, and a 24-hour emergency contact number. The subject should be 
advised to keep the participation card in his/her wallet at all times. 
9.2.4. 
Reporting 
Where required by IEC/IRB per local requirements, at least once a year the investigator will 
provide the IEC/IRB with a progress report to allow review of the clinical study (see 


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Section 9.4.1). At the end of the clinical study, the results of the clinical study will be reported in 
a clinical study report by the sponsor. A summary or full report, depending on the requirements, 
will be provided by the sponsor to the investigators, to the applicable regulatory authorities, and 
IECs/IRBs (if required by the applicable regulatory requirements) within one year, or 6 months 
for pediatric studies, after the end of the clinical study. 
9.2.5. 
Publication 
It is understood by the investigator that the sponsor shall be free to use the compound-related 
information, which is generated during the clinical study and may disclose it to other clinical 
investigators and to regulatory agencies. As a consequence, the investigator agrees to provide all 
clinical study results and data generated during this clinical study to the sponsor. 
The investigator shall not be authorized to submit the results of this clinical study and any data 
for public disclosure (e.g. publication or presentation) without the prior written approval of the 
sponsor, which shall not be unreasonably withheld. 
However, it is understood and agreed by the investigators that their results and/or findings shall 
not be authorized for publication prior to sponsor’s publication of the overall clinical study 
results. The investigator agrees that prior to the publication of any results, he/she shall provide 
the sponsor with a draft copy of the intended publication. The sponsor shall have the right to 
review it and to make any comments. In accordance with generally accepted scientific 
collaboration principles, co-authorship with any staff member sponsor involved in the clinical 
study, will be discussed and mutually agreed upon before submission of any manuscript to a 
publisher. 
9.3. 
Confidentiality 
The subject will receive all information as required by the EU General Data Protection 
Regulation, namely the identity and contact details of the controller, the contact details of the data 
protection officer, the clinical research purposes, the legal basis for the processing, the recipients 
of the personal data, the transfer of the personal data to third countries and respective safeguards, 
the retention periods, the fair processing of his/her data, and all his/her data subject’s rights. All 
details are listed in the ICF. 
All information concerning the product and the sponsor’s operations (such as patent applications, 
formulae, manufacturing processes, basic scientific data, or formulation information supplied to 
the investigator by the sponsor and not previously published) is considered confidential and 
should not be disclosed by the investigator to any third party without the sponsor’s prior written 
approval. The investigator agrees to use this information only in accomplishing the clinical study 
and will not use it for other purposes. 
In order to permit easy identification of the individual subject during and after the clinical study, 
the investigator is responsible for keeping an updated Subject Identification Code List. The 
monitor will review this document for completeness. However, the investigator must guarantee 
the subject’s anonymity will be maintained. Therefore, in order to ensure subject confidentiality, 
the Subject Identification Code List must remain at the center and no copy will be made. 


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9.4. 
Ethical Considerations 
9.4.1. 
Independent Ethics Committee / Institutional Review Board 
This clinical study can only be undertaken after full approval of the CSP, ICF, any other written 
information given to subjects and subject recruitment materials has been obtained from the 
IEC/IRB. This approval document must be dated and clearly identify the clinical study and the 
related clinical study documents being approved, including the subject compensation programs, if 
applicable. 
During the course of the clinical study, at least the following documents will be submitted to the 
IEC/IRB, per local requirements: 
− 
Changes to the IB 
− 
Reports of AEs that are serious, unlisted, and associated with the IP (in compliance with 
IEC/IRB, per local requirements) 
− 
CSP amendments 
− 
ICF amendments 
 
CSP amendments and applicable ICF amendments must promptly be submitted to the IEC/IRB 
for review and approval prior to implementation of the change(s), except when necessary to 
eliminate an immediate hazard to the clinical study subjects, or according to local requirements. 
The IEC/IRB is responsible for continuous review of the clinical study. Where required by 
IEC/IRB, per local requirements, at least once a year the investigator will provide the IEC/IRB 
with a progress report to allow review of the clinical study. Additional progress reports should be 
provided according to local legal requirements. These requests and (re-)approvals, if applicable, 
should be documented in writing. 
9.4.2. 
Informed Consent 
The investigator or designated personnel must explain the clinical study and the implications of 
participation (e.g. objectives, methods, anticipated benefits, possible risks) to potential subjects 
according to applicable regulations prior to any clinical study-related activity. Subjects will be 
informed that their participation is voluntary and that they may withdraw from the clinical study 
at any time. They will be informed that choosing not to participate or to withdraw from the 
clinical study will not have an impact on the care the subject will receive for the treatment of 
his/her disease. 
The subject will be given sufficient time to read the ICF and to ask additional questions. After 
this explanation and before entry in the clinical study, the subject’s consent should be 
appropriately recorded by means of the subject's personally dated signature and by the 
investigator’s dated signature. In case the subject is unable to read and write, an impartial witness 
must certify the subject’s consent in writing on the ICF. After having obtained the consent, a 
copy of the signed and dated ICF must be given to the subject. 


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If new information becomes available relevant to the subject’s willingness to participate in the 
clinical study, the subject will be informed in a timely manner by means of an amended ICF. This 
amended ICF will be signed and dated by the subject (or, if applicable, by an independent 
witness) and the investigator to document the willingness of the subject to continue with the 
clinical study. 
This signed and dated amended version will be filed together with the initial signed and dated 
ICF. 
Subjects who agree to participate in the optional genetic research assessment will sign a genetic 
ICF for this assessment (see Section 5.8.1). Additionally, subjects who agree on collection or 
long term storage of their samples for future scientific and genetic research will sign a separate 
ICF (see Section 5.8.2 and 5.10). The subject will be given sufficient time to read the genetic ICF 
and to ask additional questions. This consent should be appropriately recorded by means of the 
subject's personally dated signature and by the investigator’s signature. After having obtained the 
consent, a copy of the signed and dated informed consent must be given to the subject. 
Subjects are not required to consent for the genetic research assessment in order to participate to 
the main clinical study. Subjects will also be informed that their participation for the optional 
genetic research is voluntary and that they may withdraw their consent at any time. If a 
subject chooses to withdraw consent for the genetic assessment then the investigator or 
designated personnel must inform the sponsor. 
Withdrawal from the main clinical study does not, by itself, constitute withdrawal of samples 
from the optional genetic research that were already taken before that time point. Likewise 
withdrawal from the optional genetic research does not constitute withdrawal from the main 
clinical study. 
9.5. 
Data Quality Control/Assurance 
9.5.1. 
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). 
9.5.2. 
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 


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clinical study, source documents, and subject's files. By participating in this clinical study, 
investigators agree to this requirement. 
 


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10. 
REFERENCES 
Bae, K., Zhu, F., Chapman, A., Torres, V., Grantham, J., Guay-Woodford, L., . . . Miller, J. 
(2006). Magnetic Resonance Imaging Evaluation of Hepatic Cysts in Early Autosomal-
Dominant Polycystic Kidney Disease: The Consortium for Radiologic Imaging Studies of 
Polycystic Kidney Disease Cohort. Clin J Am Soc Nephrol, 64-9. 
Caroli, A., Perico, N., Perna, A., Antiga, L., Brambilla, P., Pisani, A., . . . Ruggenenti, P. (2013). 
Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal 
dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, 
multicentre trial. Lancet, 1485-95. 
Chapman, A., Bost, J., & Torres, V. (2012). Kidney Volume and Functional Outcomes in 
Autosomal Dominant Polycystic Kidney Disease. Clinical Journal of the American 
Society of Nephrology, 479–486. 
Chebib, F., Perrone, R., Chapman, A., Dahl, N., Harris, P., Mrug, M., . . . Torres, V. (2018). A 
Practical Guide for Treatment of Rapidly Progressive ADPKD with Tolvaptan. . Journal 
of the American Society of Nephrology, 2458-2470. 
FDA. (2019). https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers#table5-1.  
Fiorotto, R., & Strazzabosco, M. (2019). Pathophysiology of Cystic Fibrosis Liver Disease: A 
Channelopathy Leading to Alterations in Innate Immunity and in Microbiota. Cell Mol 
Gastroenterol Hepatol, 197-207. 
Jouret, F., & Devuyst, O. (2020). Targeting chloride transport in autosomal dominant polycystic 
kidney disease. Cellular Signalling, 109703. 
KDIGO_CKD_Work_Group. (2013). KDIGO 2012 clinical practice guideline for the evaluation 
and management of chronic kidney disease. Kidney Int Suppl, 1-150. 
Orphanet. (2019). https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=730. 
Ravine, D., Gibson, R., Walker, R., Sheffield, L., Kincaid-Smith, P., & Danks, D. (1994). 
Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic 
kidney disease 1. Lancet, 824-7. 
Smith, K., Thompson, A., Baron, D., Broadbent, S., Lundstrom, G., & Perrone, R. (2018). 
Addressing the Need for Clinical Trial End Points in Autosomal Dominant Polycystic 
Kidney Disease: A Report From the Polycystic Kidney Disease Outcomes Consortium 
(PKDOC). AJKD, 533-41. 
Torra, R. (2019). Recent advances in the clinical management of autosomal dominant polycystic 
kidney disease. F1000Research; https://doi.org/10.12688/f1000research.17109.1, 116. 


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Torres, V., Chapman, A., Devuyst, O., Gansevoort, R., Grantham, J., Higashihara, E., . . . 
TEMPO. (2012). Tolvaptan in patients with autosomal dominant polycystic kidney 
disease. N Engl J, 2407-18. 
Torres, V., Chapman, A., Devuyst, O., Gansevoort, R., Perrone, R., Koch, G., . . . REPRISE. 
(2017). Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease. N 
Engl J Med, 1930-42. 
van Aerts, R., Kievit, W., D'Agnolo, H., Blijdorp, C., Casteleijn, N., Dekker, S., . . . Salih, M. 
(2019). Lanreotide Reduces Liver Growth In Patients With Autosomal Dominant 
Polycystic Liver and Kidney Disease. Gastroenterology, 481-491. 
Wallace, D. (2011). Cyclic AMP-mediated cyst expansion. Biochim Biophys Acta. 
Willey, C., Blais, J., Hall, A., Krasa, H., Makin, A., & Czerwiec, F. (2017). Prevalence of 
autosomal dominant polycystic kidney disease in the European Unio. Nephrol Dial 
Transplant, 1356-63. 
Xu, N., Glockner, J., Rossetti, S., Babovich-Vuksanovic, D., Harris, P., & Torres, V. (2006). 
Autosomal dominant polycystic kidney disease coexisting with cystic fibrosis. J Nephrol, 
529-34. 
Yang, B., Sonawane, N., Zhao, D., Somlo, S., & Verkman, A. (2008). Small-molecule CFTR 
inhibitors slow cyst growth in polycystic kidney disease. J Am Soc Nephrol, 1300-1310. 
 
 


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11. 
APPENDICES 
Appendix 1 Ranges for Vital Signs and ECG 
Ranges for Vital Signs 
Ranges applicable in supine position (after 5 minutes): 
Systolic blood pressure 
(mmHg) 
Diastolic blood pressure 
(mmHg) 
Heart rate (bpm) 
Temperature (°C) 
90≤ SBP ≤150 
45≤ DBP ≤90 
50≤ HR ≤100 
35.5≤ t° ≤37.5 
bpm = beats per minute; DPB = diastolic blood pressure; HR = heart rate; SBP = systolic blood pressure 
Ranges for ECG Parameters 
Ranges applicable in supine position (after 5 minutes): 
PR (ms) 
QRS (ms) 
QTcF (ms) 
Heart rate (bpm) 
110≤ PR ≤220 
QRS ≤120 
QTcF ≤450  
 
50≤ HR ≤100 
bpm = beats per minute; HR = heart rate 


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Appendix 2 List of Moderate and Strong Inhibitor(s) of Cytochrome P450 (CYP)3A4 
Non-exhaustive lists based on (FDA, 2019) 
Strong CYP3A4 
Inhibitors 
Moderate CYP3A4 
Inhibitors 
Clarithromycin 
Aprepritant 
Cobicistat 
Ciprofloxacin 
Itraconazole 
Crizotinib 
Ketoconazole 
Dronedarone 
Nefazodone 
Erythromycin 
Ritonavir 
Fluconazole 
Posaconazole 
Imatinib 
Telithromycin 
Tofisopam 
Voriconazole 
Verapamil 
Grapefruit juice 
 
 
 
 


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Appendix 3 List of Moderate and Strong Inducer(s) of Cytochrome P450 (CYP)3A4 
Non-exhaustive lists based on (FDA, 2019) 
Strong CYP3A4 
Inducers 
Moderate CYP3A4 
Inducers 
Carbamazepine 
Bosentan 
Enzalutamide 
Efavirenz 
Fosphenytoine 
Etravirine 
Lumacaftor 
Modafinil 
Mitotane 
 
Phenobarbital 
 
Phenytoin 
 
Primidone 
 
Rifabutin 
 
Rifampin 
 
Rifapentine 
 
 
 
 


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Appendix 4 Mitigation Plan as a Consequence of SARS-CoV-2 Pandemic 
In case of travel restrictions as a consequence of SARS-CoV-2 pandemic the following should be 
considered:  
− 
Case-by-case evaluation between the investigator and the sponsor study physician. This may 
include the following:  
• 
The ability to guarantee the safety of the subjects and the integrity of the study based on 
assessment of local restrictions with respect to traveling and access to local routine 
healthcare 
• 
An assessment of the availability of resources at the investigational site 
• 
An assessment of the feasibility of possible alternatives to collect safety data, including 
telephone calls for monitoring AEs and use of local resources such as local laboratories, 
local measuring of vital signs, and local ECGs   
• 
Assessment of the individual risk of subjects based on subject characteristics and safety 
data collected thus far. 
− Vaccination, including all COVID-19 vaccinations, is allowed prior to and during the study, 
according to the investigator’s clinical judgment. Vaccine information should be recorded in 
the eCRF as prior medication if administered prior to the first dose of study drug and as 
concomitant medication if administered during study conduct, including administration 
date(s), brand name, and manufacturer. 
− 
From Visit 10 (Week 26) onwards a visit window of >4 days could be allowed, with a 
maximum of 20 days of the total window.  
− 
To ensure study subjects maintain dosing per protocol requirements during this study special 
delivery services through Direct to Patient (DTP) shipments of IP from the investigational 
site to the subject can be implemented. DTP should only be used in case of emergency where 
on-site IP dispensation is not possible, and if allowed per local regulations. Local guidelines 
must be followed and regulatory approval or notification of authorities may be required. 
Agreement of the subject to receive IP at home is required prior to the shipment of IP from 
the investigational site to the subject’s home and should be documented by the 
investigational site staff in the medical records of the subject. The DTP process used will be 
reviewed and approved by the sponsor, but the DTP shipments will be coordinated by the 
investigational site(s) in collaboration with the local CRO without the involvement of the 
sponsor to ensure clinical study integrity. 
− 
In case a randomized subject is not able to attend a scheduled study visit on site because of 
SARS-CoV-2 travel restrictions, a phone call or a televisit may be conducted. It is strongly 
recommended to conduct planned study assessments for the applicable visit as per protocol 
as much as possible. If possible and if local regulations allow and the subject agrees, trained 
study staff or trained personnel are encouraged to collect study assessments at the study 
subjects’ home or a local facility if social distancing and hygiene rules can be applied. Only 
staff trained in conducting the protocol planned assessments are authorized to perform home 
or local facility visit assessments and the alternative arrangements need to be adequately 


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documented.In case there are problems with the shipment of central safety laboratory 
assessments the investigator is allowed to perform local safety laboratory assessments at the 
investigational site. 
 
 
 
 
 
 
 


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SIGNATURE PAGE – SPONSOR 
Study Title: 
An exploratory, randomized, double-blind, placebo-controlled, multicenter 
study to evaluate the efficacy, safety, tolerability and pharmacokinetics of 
orally administered GLPG2737 for 52 weeks, followed by an open-label 
extension period of 52 weeks in subjects with autosomal dominant polycystic 
kidney disease 
CSP Version: 
6.00 
Date:  
20-Dec-2021 
 
 
 
 
 
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 e-signature is provided at the end of this document  
 
Study Physician 
 Signature 
 Date 
 
 
 


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SIGNATURE PAGE – INVESTIGATOR 
Study Title: 
An exploratory, randomized, double-blind, placebo-controlled, multicenter 
study to evaluate the efficacy, safety, tolerability and pharmacokinetics of 
orally administered GLPG2737 for 52 weeks, followed by an open-label 
extension period of 52 weeks in subjects with autosomal dominant polycystic 
kidney disease 
CSP Version: 
6.00 
Date: 
20-Dec-2021 
 
 
 
 
 
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 glpg2737-cl-203-protocol 11559
Signature Page for glpg2737-cl-203-protocol43952_11562_62729
Approval
20-Dec-2021 18:07:29 GMT+0000
20-Dec-2021 18:07:29 GMT+0000
PPD

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Confidentiality Statement 
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STATISTICAL ANALYSIS PLAN  
Project Number: 
GLPG2737  
 
Study Number: 
GLPG2737-CL-203 
Study Title: 
An exploratory, randomized, double-blind, placebo-controlled, 
multicenter study to evaluate the efficacy, safety, tolerability and 
pharmacokinetics of orally administered GLPG2737 for 52 weeks, 
followed by an open-label extension period of 52 weeks in subjects 
with autosomal dominant polycystic kidney disease 
Development Phase: 
2a 
Status: 
Final 
Version: 
1.0 
Date: 
16-Jan-2023 
EudraCT: 
2019-003521-21 
IND: 
Not applicable 
Sponsor: 
Galapagos NV 
Generaal De Wittelaan L11 A3 
2800 Mechelen, Belgium 
 
Biostatistician: 
 
Medical Leader: 
 
PPD
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TABLE OF CONTENTS 
VERSION HISTORY ............................................................................................................. 5 
LIST OF ABBREVIATIONS ................................................................................................... 6 
1. 
INTRODUCTION ............................................................................................................ 9 
2. 
STUDY DESIGN AND OBJECTIVES ............................................................................. 9 
2.1. 
Study Objectives ................................................................................................. 9 
2.2. 
Study Endpoints .................................................................................................10 
2.3. 
Study Design .....................................................................................................10 
2.4. 
Clinical Study Protocol and Amendments ..........................................................11 
2.5. 
Scheduled of Assessments ................................................................................11 
2.6. 
Sample Size Justification ...................................................................................11 
2.7. 
Randomization and Blinding ..............................................................................12 
3. 
STUDY ESTIMANDS ....................................................................................................12 
4. 
GENERAL METHODOLOGY ........................................................................................13 
4.1. 
Analysis Sets .....................................................................................................13 
4.1.1. 
All Screened Analysis Set ...................................................................13 
4.1.2. 
All Enrolled Subjects ...........................................................................13 
4.1.3. 
All Randomized Analysis Set ..............................................................13 
4.1.4. 
Full Analysis Set .................................................................................13 
4.1.5. 
Safety Analysis Set .............................................................................13 
4.1.6. 
Pharmacokinetic Analysis Set .............................................................13 
4.1.7. 
Pharmacodynamic Analysis Set ..........................................................13 
4.1.8. 
All OLE Enrolled Subjects ...................................................................13 
4.1.9. 
OLE Full Analysis Set .........................................................................14 
4.1.10. 
OLE Safety Analysis Set .....................................................................14 
4.1.11. 
OLE Pharmacodynamic Analysis Set ..................................................14 
4.2. 
Randomized Versus Actual Treatment Group ....................................................14 
4.3. 
Analysis Periods and Analysis Time Points ........................................................14 
4.3.1. 
Relative Day .......................................................................................14 
4.3.2. 
Analysis Periods .................................................................................15 
4.3.3. 
Analysis Windows ...............................................................................15 
4.3.4. 
Definition of Baseline ..........................................................................18 
4.3.5. 
Selection of Visits ...............................................................................19 
4.4. 
Handling of Data ................................................................................................19 
4.4.1. 
Handling of Missing Data ....................................................................19 
4.4.1.1. 
Handling of Missing Date-Time Data .................................19 
4.4.1.2. 
Handling of Missing Result Data ........................................19 
4.4.2. 
Handling of Values Below or Above a Threshold ................................19 
4.4.3. 
Handling of Outliers ............................................................................20 


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4.5. 
Presentation of Results ......................................................................................20 
4.5.1. 
Presentation of Treatment Groups ......................................................20 
4.5.2. 
Calculation of Descriptive Statistics ....................................................20 
4.5.3. 
Calculation of Percentages .................................................................20 
5. 
DATA MONITORING COMMITTEE/ DATA AND SAFETY MONITORING BOARD 
REVIEW ........................................................................................................................20 
6. 
STATISTICAL ANALYSES ............................................................................................22 
6.1. 
Subject Information ............................................................................................22 
6.1.1. 
Demographic and Baseline Disease Characteristics ...........................22 
6.1.2. 
Disposition Information .......................................................................23 
6.1.2.1. 
Derivation Rules ................................................................23 
6.1.2.2. 
Presentation of Results ......................................................24 
6.1.3. 
Protocol Deviations and Eligibility .......................................................24 
6.1.4. 
Medical History and Concomitant Diseases ........................................24 
6.1.5. 
Prior and Concomitant Therapies ........................................................24 
6.1.5.1. 
Coding of Reported Terms .................................................24 
6.1.5.2. 
Classification of Therapies .................................................25 
6.1.5.3. 
Calculation of Relative Days ..............................................25 
6.1.5.4. 
Presentation of Results ......................................................25 
6.1.6. 
Exposure to Study drug and Compliance ............................................25 
6.1.6.1. 
Derivation Rules ................................................................25 
6.1.6.2. 
Presentation of Results ......................................................26 
6.2. 
Efficacy Analyses ...............................................................................................27 
6.2.1. 
Level of Significance ...........................................................................27 
6.2.2. 
Primary Efficacy Parameter: Total Kidney Volume ..............................27 
6.2.2.1. 
Definition ...........................................................................27 
6.2.2.2. 
Derivation Rules ................................................................27 
6.2.2.3. 
Analyses Methods .............................................................27 
6.2.3. 
Estimated GFR (Efficacy analysis) ......................................................29 
6.2.3.1. 
Definition ...........................................................................29 
6.2.3.2. 
Derivation Rules ................................................................29 
6.2.3.3. 
Analyses Methods .............................................................29 
6.2.4. 
Total Liver Volume ..............................................................................30 
6.2.4.1. 
Definition ...........................................................................30 
6.2.4.2. 
Derivation Rules ................................................................30 
6.2.4.3. 
Analyses Methods .............................................................30 
6.3. 
 
 
 
6.3.
6.3.1.2.
2. 
Deriv
erivatio
ation Ru
n Rules
es ................................
................................................................
................................32
32 
 
 
6.4. 
Pharmaco
acokine
netics 
cs Ana
nalysisis ................................
................................................................
................................................
................33
33 
6.4.1.1. 
Available Data ...................................................................33 
6.4.1.2. 
Derivation Rules ................................................................33 
6.4.1.3. 
Presentation of Results ......................................................33 
6.5. 
Safety Analyses .................................................................................................34 
6.5.1. 
Adverse Events ...................................................................................34 
6.5.1.1. 
Definition of Treatment-Emergent Adverse Events ............34 
6.5.1.2. 
Coding of Reported Terms .................................................34 
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6.5.1.3. 
Allocation of Adverse Events to Analysis Periods ..............34 
6.5.1.4. 
Treatment Relatedness .....................................................35 
6.5.1.5. 
Worst-Case Selections ......................................................35 
6.5.1.6. 
Calculation of Relative Days and Duration .........................36 
6.5.1.7. 
Presentation of Results ......................................................36 
6.5.1.8. 
EudraCT Adverse Events Reporting ..................................37 
6.5.2. 
Laboratory Safety ...............................................................................38 
6.5.2.1. 
Available Data ...................................................................38 
6.5.2.2. 
Derivation Rules ................................................................38 
6.5.2.3. 
Definition of Toxicity Grades ..............................................39 
6.5.2.4. 
Definition of Non-Graded Abnormalities .............................39 
6.5.2.5. 
Urinalysis Tests with Categorical Results ..........................39 
6.5.2.6. 
Treatment-Emergent Principle ...........................................39 
6.5.2.7. 
Worst-Case Principle .........................................................39 
6.5.2.8. 
Hepatotoxicity ....................................................................40 
6.5.2.9. 
Presentation of Results ......................................................41 
6.5.3. 
Electrocardiogram ...............................................................................43 
6.5.3.1. 
Available Data ...................................................................43 
6.5.3.2. 
Derivation Rules ................................................................43 
6.5.3.3. 
Abnormalities .....................................................................43 
6.5.3.4. 
Presentation of Results ......................................................44 
6.5.4. 
Vital Signs ...........................................................................................45 
6.5.4.1. 
Available Data ...................................................................45 
6.5.4.2. 
Derivation Rules ................................................................45 
6.5.4.3. 
Abnormalities .....................................................................45 
6.5.4.4. 
Treatment-Emergent Principle ...........................................46 
6.5.4.5. 
Worst-Case Abnormality ....................................................46 
6.5.4.6. 
Presentation of Results ......................................................46 
6.5.5. 
eGFR (as Safety Parameter) ..............................................................48 
6.6. 
CHANGES TO THE PLANNED ANALYSES, NOT COVERED BY 
PROTOCOL AMENDMENTS ............................................................................49 
7. 
REFERENCES ..............................................................................................................50 
APPENDIX ...........................................................................................................................51 
APPENDIX I: Statistical Models .....................................................................................51 
 
 
 
 
APPENDIX III: Sche
chedu
dule o
e of Actctivities
es ................................
................................................................
.............................................
.............62
62 
Double-Blind Treatment Period ..........................................................................62 
Open-label Treatment Period .............................................................................67 
 
 
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VERSION HISTORY 
SAP Amendment # 
Date 
Description of changes 
Not applicable 
 
 
  
 
 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
ADPKD 
autosomal dominant polycystic kidney disease 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic chemical 
AUC 
area under the curve 
BMI 
body mass index 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CSP 
clinical study protocol 
CSR 
clinical study report 
CRF 
case report form 
D 
day 
DB 
double-blind 
DBP 
diastolic blood pressure 
ECG 
electrocardiogram 
eGFR 
estimated glomerular filtration rate 
H 
high, above the upper limit of the normal range 
htTKV 
height-adjusted total kidney volume 
 
 
ICF 
informed consent form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IDMC 
independent data monitoring committee 
IP 
investigational product  
In this study: either GLPG2737 or Placebo in the double-blind period or 
GLPG2737 in the open-label extension period 
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IWRS 
interactive web response system 
MRI 
magnetic resonance imaging 
MPXI 
neutrophil myeloid peroxidase activity index 
L 
low, below the lower limit of the normal range 
LLN 
lower limit of the normal range 
LS 
least squares 
MAR 
missing at random 
MedDRA 
medical dictionary for regulatory activities 
MMRM 
mixed effect repeated measures model 
N 
normal, with the limits of the normal range 
NAP 
not applicable 
OLE 
open-label extension 
PD 
pharmacodynamics(s) 
PK 
pharmacokinetic(s) 
PYE 
patient-years of exposure 
QTc 
corrected QT interval 
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 
SDTM 
study data tabulation model 
SE 
standard error 
TEAE 
treatment-emergent adverse event 
TLF 
tables, listings and figures 
TKV 
total kidney volume 
 
 
ULN 
upper limit of the normal range 
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W 
week 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the primary and final statistical analyses of study 
GLPG2737-CL-203. The primary analysis will be performed when all subjects have reached the 
end of the double-blind (DB) period (Week 56) or discontinued earlier. At this time, the primary 
and secondary endpoints will be completed and the sponsor will be unblinded. At the same time, 
the interim analysis results of the OLE period will allow the sponsor to plan subsequent trials. 
The final analysis will be performed when all subjects have reached the end of the open-label 
extension (OLE) period or discontinued earlier. The results of the final analysis will be described 
in the clinical study report (CSR). 
Technical details on derivations and mock tables, listings and figures (TLFs) will be presented in 
a separate document. 
The statistical analysis will process and present the results following the International Council for 
Harmonization (ICH) standards, particularly the ICH-E3, ICH-E6, ICH-E9, ICH-R9 (R1) and 
ICH-E14 guidelines. 
2. 
STUDY DESIGN AND OBJECTIVES 
2.1. 
Study Objectives 
Primary Objectives: 
˗ 
To characterize the effect of GLPG2737 on growth in total kidney volume (TKV) compared 
to placebo. 
˗ 
To evaluate the safety and tolerability of oral doses of GLPG2737 compared to placebo. 
Secondary Objectives: 
˗ 
To characterize the effect of GLPG2737 on renal function (estimated glomerular filtration 
rate [eGFR]) compared to placebo. 
˗ 
To characterize the pharmacokinetics (PK) of oral doses of GLPG2737 and its major 
metabolite G1125498 (M4) using population PK analyses. 
Other Objectives 
˗ 
˗ 
˗ 
 
 
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˗ 
˗ 
˗ 
2.2. 
Study Endpoints 
The following endpoints will be measured from baseline until end of the DB period: 
Primary Endpoint 
˗ 
Mean percent change from baseline of height adjusted TKV (htTKV). 
˗ 
Frequency and severity of treatment-emergent adverse events (TEAEs), treatment-emergent 
serious AEs (SAEs), and TEAEs leading to treatment discontinuation. 
Secondary Endpoints 
˗ 
Mean change from baseline of eGFR. 
˗ 
Estimated exposure (area under the curve [AUC], maximum plasma concentration [Cmax]), 
based on population PK analyses for GLPG2737 and its major metabolite M4. 
Other Endpoints 
 
2.3. 
Study Design 
This is an exploratory, randomized, double-blind, placebo-controlled, parallel group, multicenter, 
proof of concept study (Phase 2a), evaluating orally administered GLPG2737 (150 mg q.d.) for a 
DB treatment period of 52 weeks and 4 weeks of follow up as well as an OLE treatment period of 
52 weeks and 4 weeks of follow up, in approximately 60 subjects with rapidly progressing 
ADPKD. 
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The unblinded primary endpoint analysis will be performed when all subjects have reached the 
end of the DB treatment period or discontinued earlier. 
A follow-up visit should occur 4 weeks after the 52-weeks DB treatment period (Week 56). 
Subjects will be offered OLE treatment for a period of 52 weeks. The follow-up visit will be used 
to roll-over to the OLE period. 
 
Figure 1: Schematic diagram of the study design. 
2.4. 
Clinical Study Protocol and Amendments 
This SAP was based on the clinical study protocol (CSP) version 6.00 (amendment 5), dated 20 
Dec 2021. 
2.5. 
Scheduled of Assessments 
See Section APPENDIX III: Schedule of Activities. 
2.6. 
Sample Size Justification 
A total of 60 adult ADPKD subjects will be enrolled in this study. Subjects will be randomized in 
a 2:1 allocation ratio to GLPG2737 or placebo treatment, resulting in approximately n=40 for 
GLPG2737 and approximately n=20 for placebo. 
The primary aim of this study is to show that GLPG2737 treatment is generally safe and well 
tolerated, and to show a trend in treatment difference for the active treatment versus placebo for 
the primary endpoint (mean percent change from baseline in htTKV over 52 weeks). Therefore, 
no formal sample size calculation was performed. Merely for statistical reference, the variability 
of the estimated treatment difference for the proposed sample size of 60 subjects is illustrated in 
the following paragraph: 
For htTKV, prior knowledge for an existing treatment of ADPKD suggests a mean percent 
change from baseline to 52 weeks of 5.6% for placebo.  


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Assuming a common standard deviation of 4.5 for the percent change from baseline and a true 
mean treatment difference of 2.8% between the 2 groups, this implies a power of 83% to detect a 
statistically significant difference at a 2-sided significance level of 20% (using 2-sample t-test). If 
the dropout rate is around 10%, the power will be around 80%. 
In case subjects discontinue from the study or from study treatment due to SARS-CoV-2 
restrictions, additional subjects may be randomized on top of the planned sample size. The 
number of additional subjects randomized will not exceed the number of subjects discontinuing 
the study or study treatment in relation to SARS-CoV-2 restrictions. Randomization of additional 
subjects will ultimately be decided by the sponsor before any study lock or related unblinding has 
occurred. 
2.7. 
Randomization and Blinding 
At screening, subjects will be assigned a subject identification number. When a subject is 
confirmed to be eligible for the clinical study, the subject will be randomized. Allocation of each 
subject to a given treatment will be done using a centralized electronic system (interactive web 
response system [IWRS]). Subjects will be randomized in a 2:1 ratio to GLPG2737 or placebo. 
3. 
STUDY ESTIMANDS 
Estimands are defined for the primary efficacy endpoint (htTKV) and for the key secondary 
efficacy endpoint (eGFR), during the DB period only: 
˗ 
htTKV:  
• Main estimand: relative difference in estimated slope between GLPG2737 and placebo 
while being on treatment (i.e. up to 14 days after the last investigational product [IP] 
intake) and regardless of any cyst aspiration/ drainage that may have occurred.  
˗ 
eGFR: 
• Main estimand: absolute difference in estimated slope between GLPG2737 and placebo 
while being on treatment (i.e. until 7 days after the last IP intake included).  
 
 


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4. 
GENERAL METHODOLOGY 
4.1. 
Analysis Sets 
The analysis set will always be indicated in a subtitle in the table, listing or figure. 
4.1.1. 
All Screened Analysis Set 
All subjects who signed an informed consent form to participate in this study. 
4.1.2. 
All Enrolled Subjects 
All screened subjects who were found eligible to participate in the clinical study and could be 
randomized. 
4.1.3. 
All Randomized Analysis Set 
All screened subjects who were randomized in this study. 
4.1.4. 
Full Analysis Set 
All randomized subjects who have received/used at least one dose of IP. Subjects will be grouped 
according to the treatment they were randomized to (i.e. planned treatment). 
4.1.5. 
Safety Analysis Set 
All randomized subjects who used at least one dose of IP. Subjects will be grouped according to 
the treatment they received (i.e. actual treatment). 
4.1.6. 
Pharmacokinetic Analysis Set 
Subset of the Safety Analysis Set for which plasma concentration data are available to facilitate 
development of the Population PK model and for whom the time of the dose on the days of PK 
sampling is known. 
4.1.7. 
Pharmacodynamic Analysis Set 
Subset of the Safety Analysis Set, selecting all subjects who have a baseline and at least one post-
baseline pharmacodynamics (PD) value (any PD parameter) excluding subjects with protocol 
deviations that may have an impact on the PD analysis. 
4.1.8. 
All OLE Enrolled Subjects 
All randomized subjects who were found eligible to participate in OLE study period. 


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4.1.9. 
OLE Full Analysis Set 
All OLE enrolled subjects who have used at least one dose of IP during the OLE study period. 
Subjects will be grouped according to the treatment they were randomized to during the DB 
study period. 
4.1.10. 
OLE Safety Analysis Set 
All OLE enrolled subjects who used at least one dose of IP during the OLE period. Subjects will 
be grouped according to the treatment they received in the DB study period. 
4.1.11. 
OLE Pharmacodynamic Analysis Set 
 
 
 
4.2. 
Randomized Versus Actual Treatment Group 
For subject information (excluding concomitant medication and exposure) and efficacy 
parameters, the treatment group as assigned by the randomization (DB period) will be used in the 
analysis (i.e. as-randomized analysis). Concomitant medication, exposure, safety, PD and PK 
parameters will be analyzed using the actual treatment group (received during the DB period). 
Differences between the randomized and actual treatment group will be listed. 
4.3. 
Analysis Periods and Analysis Time Points 
4.3.1. 
Relative Day 
The timing of an assessment or an event relative to a reference date will be calculated as follows: 
When the concerned date is before the reference date: 
Relative day (days) = concerned date-reference date 
When the concerned date is the equal or later than the reference date: 
Relative day (days) = concerned date-reference date +1 day 
Where: 
˗ 
The concerned date could be the measurement date of the assessment, or the start or end date 
of the event. 
˗ 
The reference date default is the date of the first dose of study drug administration, unless 
specified otherwise. 
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˗ 
Date implies a complete date having day, month and year available. Unless otherwise 
specified, the relative day will remain missing when it cannot be calculated due to absence or 
incompleteness of the concerned and/or reference dates. 
The general terms of this formula also apply when similar relative timings are required in other 
time units, for example in minutes. 
4.3.2. 
Analysis Periods 
All event-type data (e.g. adverse events) and assessments will be allocated to analysis periods 
according to Table 1. 
Table 1 
Analysis Periods 
Analysis Phase 
Analysis Period 
Start Analysis Period 
End Analysis Period 
Screening 
Screening** 
Date of signing the ICF, with 
00:00 added as time part 
Date time of start DB - 1 minute 
Treatment 
Double-Blind 
Period 
Date time of first IP 
administration in DB 
Date time of start OLE - 1 minute  
or  
Date of last contact, with 23:59 
added as time part, if the subject 
was not enrolled in OLE 
Open-label Extension 
Period 
Date time of first IP 
administration in OLE 
Note: if time is missing: use 
00h (exception see *) 
Date of last contact, with 23:59 
added as time part 
 ICF: informed consent form 
* For OLE IP administrations only the date is collected, not the time. The Week 56 visit is planned to be performed pre-dose at the day of first 
OLE administrations. In this case ([VISIT = WEEK 56 & DATE VISIT = DATE FIRST OLE INTAKE], the assessment should be attributed 
to the DB period and considered in the OLE Baseline derivation. Any unscheduled visit at that same day will be considered post-dose and 
attributed to the OLE period.  
** For MRI assessments: MRI’s taken at Day 1 (same date as first IP intake in DB) will be attributed to the screebning phase, redaless the time 
of the assessments. The MRIs are candidated for the Baseline derivation. 
 
Notes:  
˗ 
The first IP administration in the OLE period is expected to be the administration around 
Week 56. The exact start of IP administration will be derived from the OLE case report form 
(CRF) page. 
˗ 
The last analysis period will always end on the date of last contact. 
 
4.3.3. 
Analysis Windows 
All safety and eGFR assessments, including data collected on unscheduled visits, will be 
allocated to analysis visits based on the relative day of the assessment (see Section 4.3.1) and 
according to the analysis windows in Table 2 
All magnetic resonance imaging (MRI) assessments - including unscheduled visits -will be 
mapped according to the analysis visit windows specified in Table 3.  


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All PD assessments - including unscheduled visits - will be mapped - according to the analysis 
visit windows specified in Table 4 and Table 5. 
TLFs will present the planned (per protocol) analysis windows. 
 
Table 2 
Analysis Visits (Safety, PK and eGFR) 
Analysis Visit Label 
Target Day 
Interval Lower Bound 
Interval Upper Bound 
Baseline 
1 
- 
1 (predose) 
Week 1 
8 
1 (post-dose) 
12 
Week 2 
15 
13 
22 
Week 4 
29 
23 
43 
Week 8 
57 
44 
71 
Week 12 
85 
72 
99 
Week 16 
113 
100 
127 
Week 20 
141 
128 
162 
Week 26 
183 
163 
211 
Week 34 
239 
212 
267 
Week 42 
295 
268 
316 
Week 48 
337 
317 
351 
Week 52 
365 
352 
379 
Week 56* 
393 
380 
First IP administration in 
OLE or  
+ if not dosed in OLE 
OLE Baseline 
1 
- (but post-dose in DB) 
1  
Week 58 (OLE Week 2) 
15 
1 (OLE post-dose) 
22 
Week 60 (OLE Week 4) 
29 
23 
50 
Week 66 (OLE Week 10) 
71 
51 
92 
Week 72 (OLE Week 16) 
113 
93 
155 
Week 84 (OLE Week 28) 
197 
156 
239 
Week 96 (OLE Week 40) 
281 
240 
323 
Week 108 (OLE Week 
52) 
365 
324 
379 
Week 112 (OLE Week 
56) 
393 
380 
+ 
 
Table 3 
Analysis Visits (MRI) 
Analysis Visit Label 
Target Day 
Interval Lower Bound 
Interval Upper Bound 
Baseline 
1 
- 
15 
Week 4 
29 
16 
minimum (106, Last IP 
administration in DB + 14 
days (Incl)) 
Week 26 
183 
107 
minimum (274, Last IP 
administration in DB + 14 
days (Incl)) 
Week 52 
365 
275 
Last IP administration in 
DB + 14 days (Incl) 
FU (4 weeks after last DB 
intake) 
Last DB intake + 28 days  
Last IP administration in 
DB + 15 days (Incl) 
First IP administration in 
OLE + 14 days 


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Analysis Visit Label 
Target Day 
Interval Lower Bound 
Interval Upper Bound 
or  
+ if not dosed in OLE 
 
Note: This timepoints 
includes the W56 visit or 
early discontinuation visit. 
OLE Baseline 
1 
- (post dose) 
minimum (15, Last IP 
administration in OLE + 
14 days (Incl)) 
Week 84 (OLE Week 28) 
197 
16 
minimum (281, Last IP 
administration in OLE + 
14 days (Incl)) 
Week 108 (OLE Week 
52) 
365 
282 
Last IP administration  in 
OLE + 14 days (incl.) 
Week 112 (OLE Week 
56) 
393 
Last IP administration in 
OLE + 15 days 
+ 
 
 
Table 4 
Analysis Visits 
 ) 
Analysis Visit Label 
Target Day 
Interval Lower Bound 
Interval Upper Bound 
Baseline 
1 
- 
1 (predose) 
Week 4 
29 
1 (post-dose) 
57 
Week 12 
85 
58 
134 
Week 26 
183 
135 
274 
Week 52 
365 
275 
379 
Week 56* 
393 
380 
First IP administration in 
OLE 
or  
+ if not dosed in OLE 
OLE Baseline 
1 
- (but post-dose in DB) 
1  
Week 66 (OLE Week 10) 
71 
2 
218 
Week 108 (OLE Week 
52) 
365 
219 
+ 
 
Table 5 
Analysis Visits (
ts (
 ) ) 
Analysis Visit Label 
Target Day 
Interval Lower Bound 
Interval Upper Bound 
Baseline 
1 
- 
1 (predose) 
Week 4 
29 
1 (post-dose) 
106 
Week 26 
183 
107 
274 
Week 52 
365 
275 
379 
Week 56* 
393 
380 
First IP administration in 
OLE 
or  
+ if not dosed in OLE 
OLE Baseline 
1 
- (but post-dose in DB) 
1  
Week 108 (OLE Week 
52) 
365 
1 (post-dose) 
379 
Week 112 (OLE Week 
56) 
393 
380 
+ 
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Table 6 
Analysis Visits 
ts 
 
Analysis Visit Label 
Target Day 
Interval Lower Bound 
Interval Upper Bound 
Baseline 
1 
- 
1 (predose) 
Week 2 
15 
1 (post-dose) 
22 
Week 4 
29 
23 
43 
Week 8 
57 
44 
71 
Week 12 
85 
72 
99 
Week 16 
113 
100 
148 
Week 26 
183 
149 
211 
Week 34 
239 
212 
302 
Week 52 
365 
303 
379 
Week 56 
393 
380 
+ 
 
Note:  
− 
analysis windows are assigned based on relative days. The reference day is the first IP 
administration in the study for the analysis visits in the DB period and first IP administration 
in the OLE period for the OLE timepoints. 
− 
*Week 56: For OLE IP administrations only the date is collected, not the time. The Week 56 
visit is planned to be performed pre-dose at the day of first OLE administrations. In this case 
([VISIT = WEEK 56 & DATE VISIT = DATE FIRST OLE INTAKE], the assessment 
should be attributed to Week 56.  
4.3.4. 
Definition of Baseline 
Two types of baselines will be defined: study and OLE Baseline. 
˗ 
Study Baseline – further referred to as simply “Baseline” is defined as the last non-missing 
value before the first IP administration in the study. 
For MRI,  all MRI’s performed at  day1 should be counted as Baseline, regardless the timing 
vs first intake. 
˗ 
MRI Baseline: For MRI assessments, all non-missing values before the first IP administration 
in the study +14 days (included) will be considered as the primary Baseline definition. In case 
multiple assessments are available, the MRI assessment closest to the target day will be 
selected as the baseline.  
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For electrocardiogram (ECG), where triplicates results are planned (DB study part), the baseline 
is defined as the mean of the last recorded triplicate before the first study drug administration. If 
no triplicate is available before the first dose of study drug administration, then the mean of the 
last recorded duplicate will be considered as baseline, if no duplicate is available then the last 
ECG value will be considered as baseline. 
4.3.5. 
Selection of Visits 
Per parameter and analysis window, the value closest to the target date will be used in analysis 
tables and figures. Other values will be listed only. If more than one value is located at the same 
distance from the target day, then the latest in time will be selected. If - after the previous 
selection - still multiple values qualify, the mean of these values will be used in the analysis. 
4.4. 
Handling of Data 
4.4.1. 
Handling of Missing Data 
4.4.1.1. 
Handling of Missing Date-Time Data 
No imputations will be done in case of missing date (time) fields, nor for the missing parts of 
partially known date (time) fields. 
Assessments with missing date (time) will be omitted from the analysis. 
Event-type data (e.g. adverse events, concomitant medications) with missing date (time) will be 
allocated to analysis periods using a worst-case approach as explained in the respective sections. 
4.4.1.2. 
Handling of Missing Result Data 
No imputation will be done of missing result data. That is, an observed cases analysis will be 
performed. 
4.4.2. 
Handling of Values Below or Above a Threshold 
Values below (above) the detection limit will be imputed by the value one unit smaller (larger) 
than the detection limit itself. In listings, the original value will be presented. 
Example: if the database contains the value “<0.04”, then for the descriptive statistics the value 
“0.03” will be used. The value “>1000” will be imputed by “1001”. 
For PK data, values below the limit of quantification will be imputed by 0 for the calculation of 
descriptive statistics presentation; except for the geometric mean and the geometric coefficient of 
variation (CV%), where it will be imputed as lower limit of quantification (LLOQ)/2. These 
values will be listed as “below lower limit of quantification (BLOQ)”. 
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4.4.3. 
Handling of Outliers 
There will be no outlier detection, all measured values will be included in the analyses. 
4.5. 
Presentation of Results 
4.5.1. 
Presentation of Treatment Groups 
All analyses will be done and shown per treatment group. The treatment group (either actual of 
planned, see section 4.5.1) is the initial treatment allocation at the start of the DB period. 
˗ 
Placebo 
˗ 
GLPG2737 150 mg q.d. 
In the section Subject Information, a grand total “All Subjects” will be added to summarize all 
subjects over all treatment groups in tables and figures. 
4.5.2. 
Calculation of Descriptive Statistics 
For continuous parameters, descriptive statistics will be presented when N ≥ 2. When N = 1, the 
observation will not be shown in the tables or figures but only listed. 
Descriptive statistics will include: 
˗ 
the number of non-missing data points (N) 
˗ 
the arithmetic mean 
˗ 
the standard error (SE) and standard deviation (SD) 
˗ 
the median, minimum and maximum 
˗ 
95% confidence interval (CI) of the mean (if indicated in the relevant section). 
˗ 
Geometric mean and geometric SD (if indicated in the relevant section) 
˗ 
CV and geometric CV (for plasma concentrations) 
4.5.3. 
Calculation of Percentages 
Frequencies and percentages will be generated for categorical parameters. 
For event-type data (e.g. adverse events), the denominator will be all subjects in the analysis set 
and analysis period. For other data (e.g. worst-case analysis of assessments), the denominator 
will be all subjects with (post-baseline) data for the parameter, in the analysis set and analysis 
window/period. 
5. 
DATA MONITORING COMMITTEE/ DATA AND SAFETY 
MONITORING BOARD REVIEW 
To monitor the safety of the subjects, an Independent Data Monitoring Committee (IDMC) 
consisting of an independent statistician and independent experts in the field of ADPKD was 
convened to regularly review the accumulating unblinded safety data for the clinical study. The 


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IDMC provided a recommendation to the sponsor on clinical study continuation, suggestions for 
clinical study adaptation(s), or early termination. Ultimately, the final decision remained with the 
sponsor. The specific responsibilities, composition, meeting formats, and details of output 
provided for the meetings of the IDMC are outlined in detail in the IDMC Charter. The analyses 
provided to the IDMC are described in a separate SAP. 
 


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6. 
STATISTICAL ANALYSES 
6.1. 
Subject Information 
No inferential testing will be performed, nor will p-values be provided. 
Subject information will be tabulated with descriptive statistics per treatment group and overall. 
6.1.1. 
Demographic and Baseline Disease Characteristics 
The following parameters will be analyzed: 
˗ 
Date of ICF signatures (at the start of the study and roll-over to OLE, listed only) 
˗ 
Sex 
˗ 
Age at signing the study ICF (years) 
˗ 
Age, categorized (years): 
• 
18 ≤ age < 40 
• 
40 ≤ age < 50 
• 
50 ≤ age < 60 
• 
60 ≤ age < 70 
• 
70 ≤ age < 85 
• 
age ≥85 
˗ 
Age, categorized (years): 
• 
18 ≤ age ≤ 40 
• 
40 < age ≤  50 
˗ 
Race and ethnicity 
˗ 
Height at baseline (cm) 
˗ 
Weight at baseline (kg) 
˗ 
Body mass index (BMI) at baseline (kg/m²) = 
௪௘௜௚௛௧ (௞௚)
௛௘௜௚௛௧మ (௠మ)   
(round to 1 decimal, BMI will not be recalculated if already available in the database) 
˗ 
Body mass index (BMI) at baseline, categorized (kg/m²): 
• 
BMI ≤ 18.5 
• 
18.5 < BMI ≤ 25.0 
• 
25.0 < BMI ≤ 30.0 
• 
BMI > 30.0 
˗ 
Duration of ADPKD (years) = 
(ୢୟ୲ୣ ୭୤ ୤୧୰ୱ୲ ୧୬୲ୟ୩ୣ ୭୤ ୱ୲୳ୢ୷ ୢ୰୳୥)ି(ୢୟ୲ୣ ୭୤ ୧୬୧୲୧ୟ୪ ୢ୧ୟ୥୬୭ୱ୧ୱ) 
ଷ଺ହ.ଶହ
. 
If the date of initial diagnosis is incomplete, then the following rules will be applied: Missing 
day: use the first of the month. Missing month: use January. 
˗ 
htTKV (mL) at baseline 
 
 
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˗ 
 
˗ 
 
 
 
 
 
 
  
 
 
6.1.2. 
Disposition Information 
6.1.2.1. 
Derivation Rules 
The disposition status by study part will be derived as shown in Table 7. Based on the disposition 
status in the CRF and the start of the OLE period, the disposition status can be derived for each 
study part. This approach applies to treatment and study disposition. 
 
The following definitions will be used: 
˗ 
OLE period - Not enrolled:  the question “Will the subject participate in the open label 
extension period?” has been answered with “no”. 
˗ 
OLE period - Started: 
any IP intake during the OLE period 
˗ 
OLE period - Not started: 
no IP intake during the OLE period 
Table 7: Disposition status by period 
Disposition Status 
as collected in the CRF 
OLE period 
Disposition Status by Study Part 
DB 
OLE 
Completed 
Not enrolled 
Completed 
Not Roll-Over 
 
Started 
Completed 
Completed 
 
Not started 
Completed 
Not started 
Discontinued 
Not enrolled 
Discontinued 
Not Roll-Over 
 
Started 
Completed 
Discontinued 
Missing* 
Started 
Completed 
Ongoing 
* Missing disposition info can only occur at the time of the PA. For the final analysis, all disposition info should 
be available. 
 
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6.1.2.2. 
Presentation of Results 
The following tabulations will be provided, by treatment group and overall: 
˗ 
The number of subjects screened, randomized and not randomized into DB, (with the reason 
for not being randomized) and rolled over into OLE. 
˗ 
Number (percent) of subjects randomized per country and investigator. 
˗ 
The number (percent) of subjects in each analysis set as defined in Section 4.1. 
˗ 
The number (percent) of subjects per analysis window (as defined in Section 4.3.3) and 
analysis period 
˗ 
By study part, the number (percent) of subjects who completed/discontinued the study drug 
administration and the reasons for discontinuation.  
˗ 
By study part, the number (percent) of subjects who completed/discontinued the study and the 
reasons for discontinuation. 
The randomization information and study/treatment completion for the safety subjects will be 
listed. 
6.1.3. 
Protocol Deviations and Eligibility 
Major protocol deviations are determined and recorded while the study is ongoing, and the list of 
PDs is finalized prior to database lock. This is at interim lock (and unblinding) for PDs related to 
the DB period and the final database for PDs related to the OLE period. For more details, please 
refer to the Protocol Deviations Plan. 
The number (percent) of subjects with major protocol deviations will be tabulated, overall and 
per class of deviation, by treatment group and by period. 
All available information concerning major protocol deviations, violations on eligibility criteria 
and subjects not treated will be listed. 
6.1.4. 
Medical History and Concomitant Diseases 
Frequency tabulations per system organ class and preferred term will be provided for the medical 
history findings (i.e. condition no longer present at the start of the study) as well as for the 
concomitant diseases (i.e. conditions present at the start of the study). 
6.1.5. 
Prior and Concomitant Therapies 
6.1.5.1. 
Coding of Reported Terms 
All prior and concomitant therapy terms will be coded in the database using the World Health 
Organization (WHO) drug coding dictionary. 


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6.1.5.2. 
Classification of Therapies 
All prior and concomitant therapy records will be categorized as follows, considering their date 
(time) and flags indicating the relative timing versus study (drug) start or end (before, after, 
ongoing…): 
˗ 
Prior only: when the record ended before first study administration 
˗ 
DB concomitant: when the record started/ended/is ongoing during the DB analysis period 
 
 
For each record, multiple categories can apply. 
When the start or end date of the prior and concomitant therapy records are incomplete (and no 
flags indicating relative timing are available), the date of first study drug administration will be 
considered to the same level of information provided by these incomplete dates to categorize the 
timing of these records. This means that a record only having month and year will be categorized 
comparing only to the month and the year of the date of first study drug administration. 
6.1.5.3. 
Calculation of Relative Days 
For both the start and the end dates of the concomitant therapy records, their day relative to the 
day of first study drug administration will be calculated as described in Section 4.3.1. 
6.1.5.4. 
Presentation of Results 
A frequency tabulation of the anatomical therapeutic chemical (ATC) classes Level 4 
(CM.CMCLAS) by therapeutic subgroup (ATC Level 2) and anatomical main group (ATC Level 
1) of the prior medications (defined as ‘prior only’) will be provided as well as of the 
concomitant medications (defined as ‘concomitant only’ and ‘prior and concomitant’). 
Concomitant medications will be tabulated by period and overall. 
6.1.6. 
Exposure to Study drug and Compliance 
6.1.6.1. 
Derivation Rules 
Derived Parameters: Extent of Exposure to Study Drug 
˗ 
Total treatment duration (weeks) = (last study drug administration date – first study drug 
administration date + 1 day)/7. 
˗ 
Total treatment duration, excluding days off study drug: Number of weeks with any study 
drug administration. 
˗ 
Total treatment duration, fully compliant (weeks): Number of weeks with study drug 
administration, as planned per CSP. 
Derived Parameters: Compliance 
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˗ 
Overall compliance (%) = 100  × 
௡௨௠௕௘௥ ௢௙ ௗ௢௦௘௦ ௔௖௧௨௔௟௟௬ ௨௦௘ௗ
௡௨௠௕௘௥ ௢௙ ௗ௢௦௘௦ ௧௛௔௧ ௦௛௢௨௟ௗ ௛௔௩௘ ௕௘௘௡ ௨௦௘ௗ 
6.1.6.2. 
Presentation of Results 
Summary statistics will be provided for each compliance and extent of exposure parameter, by 
period (BD and OLE). Frequency tables will be provided for the compliance parameters, using 
the following categories: <80%; 80% ≤ x < 100%; 100%; 100% < x ≥ 120%; > 120%. 
Exposure and compliance data will be listed. 
 


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6.2. 
Efficacy Analyses 
Efficacy analyses will be performed on the Full Analysis Set (when presenting analysis on the 
DB and DB&OLE combined period) and the OLE Full Analysis Set (when presenting analysis on 
the OLE period).  
All summary tabulations will be presented by treatment group and by study period. 
6.2.1. 
Level of Significance 
Statistical tests will be done at a 2-sided significance level of 20% and 95% confidence intervals 
will be provided. Given the exploratory nature of this study, no multiplicity adjustments will be 
applied. 
6.2.2. 
Primary Efficacy Parameter: Total Kidney Volume 
6.2.2.1. 
Definition 
TKV and htTKV will be determined by MRI at the timepoints defined in APPENDIX III: 
Schedule of Activities.  
6.2.2.2. 
Derivation Rules 
TKV/htTKV will be measured using 2 readers: 
˗ 
The mean (not rounded) of the 2 readers will be considered in the analysis. 
˗ 
If adjudication information is available, the result selected by the adjudicator (URACPTFL = 
‘Y’) will be used. 
6.2.2.3. 
Analyses Methods 
Descriptive Statistics 
Descriptive statistics (including 95% CI of the mean, geometric mean and geometric SD) will be 
provided for the TKV
KV
 actual values and (percent) changes from baseline per analysis 
visit, treatment group and analysis period: 
˗ 
For the DB period, OLE period and DB&OLE combined, (percent) change from MRI 
baseline will be presented. 
˗ 
 
Descriptive statistics will be repeated - for the DB period only - by subgroups: 
˗ 
Age group at baseline: [18-40 year] [41-50 years] 
˗ 
eGFR levels at baseline: < 15, [15-29], [30-44], [45-59], [60-89], 90+ (mL/min/1.73m²) 
Results will be graphically displayed by line plots of the mean (+/- SE) actual values and 
(percent) changes by treatment group, overlayed with subject profiles.  
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As a sensitivity analysis, descriptive statistics versus Baseline and OLE Baseline will be 
provided. 
Linear Mixed Effects Model 
The primary endpoint will be evaluated by means of the slope of the htTKV growth by including 
all data up to 14 days (incl.) after the last double-blind intake and by including all htTKV 
measurements performed after any cyst aspiration/drainage. 
A random coefficient regression model (linear slope model) with (relative) time (weeks) as 
continuous variable, treatment, time-by-treatment interaction and a random intercept and slope 
will be fitted to the log-transformed htTKV actual values (including baseline). 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. Anti-log of these statistics will provide an 
estimate of the ratio of the geometric means of annual percent changes from Baseline of the two 
treatment groups and its 95% CI. The model will be fit using the SAS Proc Mixed procedure, as 
detailed in Appendix I. The assumptions of the model will be investigated. 
The model-derived mean percent change over time will be graphically presented, overlayed with 
subject profiles. 
The model will be repeated for unadjusted TKV values.  
Linear Mixed Effects Model – Additional Estimand 
Intercurrent events are defined as  
˗ 
All major PDs identified as impacting efficacy assessments. The determination of those PDs 
will be done prior database lock and unblinding. 
˗ 
Any occurrence of cyst aspirate/drainage 
As an additional estimand, the above models will be repeated excluding all TKV/htTKV 
assessments performed after an intercurrent event.  
A frequency tabulation of the number (and %) of subjects with intercurrent events during DB will 
be provided by treatment group.  
Mixed Effect Repeated Measures Model  
To complement the primary analysis, a fixed timepoint analysis will also be performed by 
estimating the relative difference in treatment effect at each timepoint. The log-transformed 
htTKV ratio of the actual values vs baseline (log AVAL/BASE) from Week 4 up to Week 52 will 
also be compared between treatment groups by means of a mixed effect repeated measures model 
(MMRM) including treatment-by-time point interaction (time as categorical, as specified in 
Section 4.3.3) and log-transformed MRI baseline htTKV as covariate and correlated within-
subject residuals. Anti-log of these statistics will provide an estimate of the ratio of the geometric 
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The model will be fit using the SAS Proc Mixed procedure, as detailed in Appendix I.  
This approach provides another estimate for the primary endpoint. In addition, this model 
implicitly takes into account “Missing at Random” (MAR). 
The model will be repeated for unadjusted TKV values.  
Listings 
All TKV data will be listed. Assessments occurring after intercurrent events will be flagged. 
Intercurrent events will be listed. 
6.2.3. 
Estimated GFR (Efficacy analysis) 
6.2.3.1. 
Definition 
eGFR is a mathematically derived value based on a subjects serum creatinine level. The eGFR 
values will be based on the CKD-EPI equation, calculated from serum creatinine concentrations 
taken at screening and during every visit.  
Note: only data up to 7 days (incl.) after the last DB/OLE intake will be included in tabulation, 
figures and statistical models. 
6.2.3.2. 
Derivation Rules 
The eGFR values will be based on the CKD-EPI equation, calculated from serum creatinine 
concentrations taken at screening and during every visit, and will be reported by the central 
laboratory. 
6.2.3.3. 
Analyses Methods 
Descriptive Statistics 
Descriptive statistics (including 95% CI of the mean) will be provided for the eGFR actual values 
and changes from baseline per analysis visit, treatment group and analysis period: 
˗ 
For the DB period, OLE period and DB&OLE combined, change from baseline will be 
presented. 
˗ 
 
˗ 
For the DB period, change from Week 2 will be presented 
Results will be graphically displayed by line plots of the mean (+/- SE) by treatment group, 
overlayed with subject profiles. The graphs will present the DB, OLE and the DB&OLE 
combined period. 
Linear Mixed Effects Model 
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The effect of GLPG2737 on eGFR will be evaluated by means of the difference in slope of eGFR 
change over time. All data up to 7 days (incl.) after the last double-blind IP intake will be 
included. 
A random coefficient regression model (linear slope model) with (relative) time (weeks) as 
continuous variable, treatment, time-by-treatment interaction and a random intercept and slope 
will be fitted to the eGFR change from baseline. 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. The model will be fit using the SAS Proc Mixed procedure, as detailed in 
Appendix I. The assumptions of the model will be investigated. 
Mixed Effect Repeated Measures Model  
To complement the primary analysis, a fixed timepoint analysis will also be performed by 
estimating the difference in treatment effect at each timepoint up to Week 52. The change from 
baseline in eGFR at each time point will also be compared between treatment groups by means of 
a MMRM including treatment, time (categorical, as specified in Section 4.3.3) and treatment-by-
time point interaction as categorical fixed effects, and baseline eGFR as covariate and correlated 
within-subject residuals. LS means estimate and 95% CI will be presented per time point and 
treatment group as well as the LS means estimate of the difference with 95% CI. The model will 
be fit using the SAS Proc Mixed procedure, as detailed in Appendix I.  
This approach provides another estimate for the primary endpoint. In addition, this model 
implicitly takes into account MAR. 
The model will be repeated for change from Week 2. 
6.2.4. 
Total Liver Volume  
6.2.4.1. 
Definition 
 
6.2.4.2. 
Derivation Rules 
 
 
 
 
 
 
 
6.2.4.3. 
Analyses Methods 
Descriptive Statistics 
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Listings 
All data will be listed.  
 
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6.3. 
 
 
 
 
 
 
 
 
 
 
 
 
6.3.1.2. 
Derivation Rules 
Values for the markers measured in urine will need to be corrected for hydration status using 
creatinine content before any further calculation of mean, change from baseline and percent 
change from baseline:  
• corrected value (ug/mmol) = value (ng/mL) / urine creatinine (mmol/L). 
If the urea or creatinine result is below LLOQ or above ULOQ, the parameter will not be derived 
and the value will be missing. The applicable correction method will be mentioned with a 
footnote in the applicable TLFs. 
In addition to the corrected version of these parameters, their original uncorrected precursors will 
also be considered for analysis, clearly identified as 'uncorrected' in their parameter name. 
 
 
 
 
 
 
Descriptive Statistics over Time 
Both the raw and normalized parameters will be presented. 
Descriptive statistics (including 95% CI of the mean) will be provided for the actual values and 
(percent) changes from baseline per analysis visit, treatment group and analysis period: 
˗ 
For the DB period, OLE period and DB&OLE combined, (percent) change from baseline will 
be presented. 
˗ 
 
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Graphs of the mean (+- SE) actual values over time and of the mean (+- SE) (percent) change 
from baseline will be prepared for all parameters, overlayed with the individual profiles printed 
on the same graph. The graphs will be repeated for the DB, OLE and the DB&OLE combined 
period. 
Listings 
 
6.4. 
Pharmacokinetics Analysis 
6.4.1.1. 
Available Data 
Information on plasma concentrations of GLPG2737 and its metabolite M4 is collected.  
6.4.1.2. 
Derivation Rules 
Only pre-dose assessments within 20 and 28 (inclusive) hours after the previous IP 
administration will be considered for descriptive statistics. To this selection, analysis windows 
will be applied. 
6.4.1.3. 
Presentation of Results 
Pharmacokinetics data will be analyzed on the PK analyses set. 
For each parameter (GLPG2737, metabolite M4), pre-dose plasma concentrations will be 
descriptively analyzed at each analysis visit in the DB period, including the CV and geometric 
CV. 
All plasma concentration data will be listed.  
 
 
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6.5. 
Safety Analyses 
Safety analyses will be performed on the Safety Analysis Set (when presenting analysis on the 
DB and DB&OLE combined period) and 
 
 
Safety tables will be presented by treatment group and analysis period. 
Safety parameters will be analyzed descriptively (see Section 4.5.2 and Section 4.5.3). No formal 
testing will be performed to compare the treatment groups. 
6.5.1. 
Adverse Events 
All adverse events (AEs) and changes in attributes (worsening and improvement) of AEs are 
reported in the database. An identification number serves to link the records considered by the 
investigator as describing the evolution of one and the same event. 
6.5.1.1. 
Definition of Treatment-Emergent Adverse Events 
The analysis of AEs will be based on TEAEs.  
TEAEs are defined – for the DB 
 - as 
˗ 
AEs having a start date equal or after the date of the first administration of study drug and no 
later than 30 days after the last administration of study drug in the study period. 
Note: to determine TEAEs in the DB study part, the following will be considered: 30 days 
after the last  DB administration or 1 day before the first OLE administration, whichever 
occurs first.  
˗ 
And is either a newly reported event, or a worsening1 of an existing event. Improvements are 
not considered treatment-emergent. 
6.5.1.2. 
Coding of Reported Terms 
All AE terms will be coded in the database using the medical dictionary for regulatory activities 
(MedDRA) coding dictionary. 
All tables will show the AE preferred terms grouped into system organ class. Subject listings will 
also show the reported terms. Any other coding levels will only be shown in a listing 
summarizing coding unless explicitly mentioned otherwise. 
6.5.1.3. 
Allocation of Adverse Events to Analysis Periods 
All AEs will be placed into analysis periods considering their start date, aiming to report the 
incidence of these events only in the analysis period during which they started. 
                                                 
1  ‘Worsening’ is defined as worsening in at least one of the following attributes: seriousness, intensity, relationship 
and/or action taken. 
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The general rule for allocation of AEs to analysis periods follows: 
Analysis period start date ≤ AE start date ≤ analysis period end date 
If the start date of an AE is missing or incomplete to a level preventing a clear allocation of the 
AE to one single analysis period and no flag indicating timing relative to study medication is 
available, a worst-case consideration (see below) will be done aiming to allocate the AE to one 
single analysis period, if possible. When a worst-case consideration is needed, the end date of the 
AE, if and as available, should also be considered; if such AEs clearly end on a given point, this 
will exclude the possibility to allocate the AE to an analysis period after that point. 
˗ 
An AE which according to the available information of its start date could belong to the 
screening as well as to the (first) analysis period with treatment will only be placed in the 
(first) 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 (e.g. follow-up period) 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 two (or 
more) subsequent analysis periods with treatment will be allocated to all the matching 
analysis periods with treatment (i.e. these AEs will be replicated and reported once in each of 
these matching analysis periods). 
˗ 
An AE with a missing start date will be allocated to all analysis periods with treatment (i.e. 
these AEs will be replicated and reported once in each of these analysis periods). 
6.5.1.4. 
Treatment Relatedness 
Following the guideline ICH-E3 Structure and Content of Clinical Study Reports (Step 4 
Version), the originally reported relatedness to study drug of an AE will be dichotomized as 
follows: 
˗ 
Not study drug related: all non-missing weaker levels of relatedness than ‘possibly drug 
related’. 
˗ 
Study drug related: ‘possibly drug related’ and all stronger levels of relatedness (this class 
also includes any missing drug relatedness, as a worst-case consideration). 
Only this dichotomized relatedness will be used in tables and can apply to different study drugs 
when relatedness has been collected separately per study drug; relatedness as originally reported 
will only be listed. 
6.5.1.5. 
Worst-Case Selections 
When cross-tabulating AE preferred terms versus an AE attribute (like intensity), only the worst-
case within each same preferred term, same subject and same analysis period will be considered, 
i.e. when the same subject has more than once the same AE preferred term reported in the same 
treatment group, the subject will be counted only once and will be shown under the worst 
outcome (like the worst intensity for that AE in the concerned treatment period). 


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6.5.1.6. 
Calculation of Relative Days and Duration 
For each newly reported event, and reported worsening or improvement of an existing event, the 
start day in the study (the day of the AE start date relative to the date of first study drug 
administration), the start day in the analysis period, and the duration (in days) will be calculated. 
In addition, the relative day and duration will be derived for the entire event; that is, the full 
evolution of the event, including the initial reporting and all subsequent worsening and/or 
improvement. 
Relative days and durations will only be listed. 
See Section 4.3.1 for the calculation of relative days. 
6.5.1.7. 
Presentation of Results 
The analysis will focus on AEs reported during the treatment period. AEs reported during the 
screening period will only be listed. 
All AEs tables will show the number of subjects with TEAEs. 
AEs will be presented by period and overall. Tables presenting AE information collected during 
the DB or OLE separately, will show the number (percent) of subjects. Tabulations combining 
the DB and OLE periods will show the number of subjects per patient-years of exposure (PYE). 
PYE is defined as the duration of the observation period or TE events. I.e.:  
˗ 
For DB: minimum (last IP intake in DB + 30 days, end date DB  period) – first IP intake in 
DB + 1 day    
 
     
Note: At the time of the primary analysis, if subjects are on going during the OLE period, the 
data cutoff date (or date of last contact for completed/discontinued subjects) will be used to 
impute the last dosing date for the calculation of duration of exposure to study drug and 
adherence to the study drug. 
A summary table will be provided, showing the number (percent) of subjects with at least one: 
˗ 
TEAE, 
˗ 
related TEAE, 
˗ 
serious TEAE, 
˗ 
TEAE leading to death, 
˗ 
TEAEs by worst severity, 
˗ 
TEAE leading to premature study drug discontinuation. 
Frequency tabulations, by system organ class and preferred term, of the number (percent) of 
subjects with a TEAE will be presented for the DB and OLE period separately. Results for the 
DB&OLE combined period will show number of subjects per 100 patient years of exposure. 
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Similar tables will be provided by worst intensity, and for related TEAEs, serious TEAEs and 
TEAEs leading to early study drug discontinuation. 
All adverse events, all TEAEs, serious adverse events (including non-TE), AEs leading to death 
and leading to study drug discontinuation will be listed. In listings, flag TEAEs emerging in each 
analysis period separately. 
6.5.1.8. 
EudraCT Adverse Events Reporting 
For the purpose of EudraCT reporting, the following tabulations will be created: 
Frequency tabulations, by system organ class and preferred term, of the number (percent) of 
subjects with non-serious TEAE will be presented.  
 
 


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6.5.2. 
Laboratory Safety 
6.5.2.1. 
Available Data 
Laboratory tests scheduled are described in the protocol.  
The following clinical laboratory safety tests are performed: 
˗ 
Hematology: 
hematocrit, hemoglobin, red blood cell count, white blood cell count, white blood cell 
differential count (absolute and relative), platelets, MCV, MCH, mean corpuscular 
hemoglobin concentration (MCHC), Vitamin B12. 
˗ 
Coagulation: 
activated partial thromboplastin time, prothrombin time, and INR. 
˗ 
Clinical chemistry: 
glucose, urea, creatinine, uric acid, sodium, potassium, calcium (including ionized), chloride, 
phosphorus, AST, ALT, GGT, total bilirubin, alkaline phosphatase, albumin, total proteins, 
triglycerides, cholesterol, high-density lipoprotein, low density lipoprotein, C-reactive 
protein, lactate dehydrogenase, amylase, lipase,  
˗ 
Urinalysis: 
Proteins (quantitative) and ketones tested via a standard test strip; microscopic examination of 
the sediment (cylinders, erythrocytes, leukocytes) if indicated (when the test strip was 
positive for blood and/or proteins), albumin, creatinine (quantitative and ratio)  
˗ 
Urinalysis (Microbiology): 
first morning urine for microscopy culture and sensitivity (MCS) 
˗ 
Serology (only at screening): 
Hepatitis B surface antigen and hepatitis C antibody (confirmation of hepatitis C virus RNA 
positivity should be performed), and HIV 1 and HIV 2 antibodies only at screening.  
˗ 
FSH test for females of non-childbearing potential at screening to confirm menopause, if 
applicable. 
˗ 
Pregnancy test for females: 
Serum pregnancy testing (β-human chorionic gonadotropin [β-hCG]) will be performed at 
screening in females of childbearing potential; on the other specified days, a urine pregnancy 
test will be performed.  
The statistical analyses will only present results in Standard International (SI) units. Other units 
will not be presented. 
Only data provided by the central laboratory will be used in tables and figures. Results from local 
labs will be listed only. 
6.5.2.2. 
Derivation Rules 
Fasted and Non-Fasted Results 
Laboratory tests that are sensitive to the fasting status: glucose, triglycerides. 


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For these laboratory tests, only results from blood samples drawn in a fasted state will be 
included in the analysis. Results from blood samples taken in a non-fasted state will be listed 
only, no toxicities or abnormalities will be calculated. Laboratory results for which the fasting 
status is missing will be considered as taken non-fasted. 
6.5.2.3. 
Definition of Toxicity Grades 
Toxicity grades will only be derived for laboratory tests for which toxicity grades are available. 
Toxicity grades will be determined as implemented in the appendix table (APPENDIX II: 
Laboratory: Toxicity Grading). 
6.5.2.4. 
Definition of Non-Graded Abnormalities 
For laboratory tests provided by the laboratory, the position of the actual analysis values (AVAL) 
versus their normal ranges (ANRLO/ANRHI) will be determined, expressing the classes for these 
analysis values as low (L), normal (N) or high (H). L, N and H are further referred to as non-
graded abnormalities. 
6.5.2.5. 
Urinalysis Tests with Categorical Results 
Results of urinalysis with qualitative results will be tabulated by time point. No toxicity grading 
or non-graded abnormalities will be derived. 
6.5.2.6. 
Treatment-Emergent Principle 
Toxicity Grades 
A post-baseline toxicity grade 1, 2, 3 or 4 is defined as treatment-emergent when higher than the 
toxicity grade of the baseline result. If the baseline result is missing, a post-baseline toxicity 
grade 1, 2, 3 or 4 will be considered as treatment-emergent. 
Non-graded Abnormalities 
A post-baseline non-graded abnormality class L or H is defined as treatment-emergent when it 
differs from the abnormality class of the baseline result. If the baseline result is missing, a post-
baseline abnormality L or H will be considered as treatment-emergent. 
6.5.2.7. 
Worst-Case Principle 
Toxicity Grading 
The worst-case post-baseline toxicity grade 0, 1, 2, 3 or 4 will be determined per subject, per 
laboratory test (and sense, if below and above) and for each analysis period (and the DB&OLE 
combined period), using all non-missing post-baseline records (including unscheduled and 
follow-up visits, but excluding local lab results). 


-40- 
 
The worst-case toxicity grade is the highest toxicity grade scored for the laboratory test (in each 
sense, if below and above). 
Non-graded Abnormalities 
The following worst-case post-baseline abnormalities L, N or H will be determined per subject, 
per laboratory test and for each analysis period (and the DB&OLE combined period), using all 
non-missing post-baseline records (including unscheduled and follow-up visits, but excluding 
local lab results): 
˗ 
L = low: at least one post-baseline result is classified as L. 
˗ 
N = normal: all post-baseline results are classified as N. 
˗ 
H = high: at least one post-baseline result is classified as H. 
If, for a subject, both L and H are reported, the subject will be counted twice in the table: once 
with a worst-case L and once with a worst-case H. 
6.5.2.8. 
Hepatotoxicity 
To investigate elevated liver function, the following (combination of) liver parameters will be 
investigated.  
Tests 
Thresholds 
AST 
AST >1.5 - <=3 x ULN 
AST >3 - <=5 x ULN 
AST >5 - <=10 x ULN 
AST >10 - <=20 x ULN 
AST >20 x ULN 
ALT 
ALT >1.5 - <=3 x ULN 
ALT >3 - <=5 x ULN 
ALT >5 - <=10 x ULN 
ALT >10 - <=20 x ULN 
ALT >20 x ULN 
AST / ALT combination 
 
ALT and/or AST >1.5 - <=3 x ULN 
ALT and/or AST >3 - <=5 x ULN 
AST and /or ALT >5 - <=10 x ULN 
AST and /or ALT >10 - <=20 x ULN 
AST and /or ALT >20 x ULN 
TB 
> 1.5 ULN until <= 2.ULN 
> 2 ULN 
ALP / TB combination 
ALP > 1.5 x ULN AND TB > 2x ULN 
AST / ALT / TB combination 
TB >2 x ULN AND (AST or ALT >3 x ULN)  
AST / ALT / INR combination 
INR >1.5 AND 
(AST or ALT >3 x ULN) 
AST / ALT / eosinophils relative count combination 
Eosinophils >5% AND 
(AST or ALT >3 x ULN) 
 


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To assess the potential of the drug to cause severe liver damage, possible Hy’s Law cases will be 
identified. These subjects are defined as having any elevated AT (AST or ALT) of ≥3×ULN, 
ALP <2×ULN, and associated with an increase in total bilirubin ≥2×ULN. 
For all combined parameters and Hy’s law parameter, the derivation should proceed in that order: 
˗ 
All laboratory results combined should come from the same sample, i.e. within the same CRF 
visit.  
˗ 
Each combination should be evaluated according to the threshold defined above. 
˗ 
Worst-case result should be considered within all visits performed after the last study drug 
administration by analysis period. 
6.5.2.9. 
Presentation of Results 
No formal inferential statistics (p-values) will be derived. Results reported during the screening 
period will only be listed. 
Descriptive Statistics over Time 
Descriptive statistics (including 95% CI of the mean) will be provided for the continuous 
laboratory parameters actual values and changes from baseline per analysis visit, treatment group 
and analysis period: 
˗ 
For the DB period, OLE period and DB&OLE combined, change from baseline will be 
presented. 
˗ 
 
Graphs of the mean (+- SE) actual values over time and of the mean (+- SE) change from 
baseline will be prepared for all laboratory parameters, overlayed with the individual profiles 
printed on the same graph. The graphs will be repeated for the DB, OLE and the DB&OLE 
combined period. 
Abnormalities and Toxicities 
The analysis of abnormalities will focus on assessments reported during each treatment period. 
Abnormalities will only be shown for those laboratory parameters without toxicity grading. 
Abnormalities and toxicities grades of the actual values will be presented as shift tables of the 
worst-case abnormality/toxicity grade versus the baseline abnormality/toxicity grade. The table 
will be created per laboratory test, treatment group and analysis period. The results of non-graded 
abnormalities and toxicities grades will be shown separately.  
˗ 
For the DB period, OLE period and DB&OLE combined, shift tables versus baseline will be 
presented. 
˗ 
 
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A frequency table of the number (percent) of subjects with treatment-emergent worst-case 
abnormalities/toxicity grade per laboratory test, treatment group and analysis period will be 
presented. The results of non-graded abnormalities and toxicities grades will be shown 
separately.  
˗ 
For the DB period, OLE period and DB&OLE combined, treatment-emergent worst-case 
abnormalities/toxicity grade relative to baseline will be presented. 
˗ 
 
 
Hepatotoxicity 
The hepatotoxicity analysis will include similar shift and frequency tables. 
Listings 
Subjects who were reported to have an at least grade 2 toxicity and/or non-graded abnormality 
will be listed. 
Data on screening serology, FSH and pregnancy tests will be listed only. 
Data on hepatotoxicity will be listed. 
 
 
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6.5.3. 
Electrocardiogram 
6.5.3.1. 
Available Data 
The following electrocardiogram (ECG) parameters will be analyzed: QTcF, QRS, PR (or PQ) , 
HR and RR. The information captured in SDTM about the seconds of the measurement time will 
not be considered. 
6.5.3.2. 
Derivation Rules 
ECGs Measured in Triplicate Versus Single Measurement 
According to the protocol, ECG is recorded in triplicates during the double-blind period. During 
the OLE period, the ECG recordings will be performed as a single measurements. During the 
analysis, this idea will be reflected in the approach: 
− 
When selecting the record in the per-timepoint analysis in the DB period, the triplicate 
recording has preference over the singlet. In the OLE period, the singlet has preference over 
the triplicate recording. 
− 
When selecting the worst-case with a period, all measurments – triplicate and singlet -  will 
be considered equally.    
Handling of ECGs Measured in Triplicate 
If ECG is collected in triplicates, the following approach will be taken. 
First, any derivation of ECG parameters will be done before handling ECG triplicates. Next, the 
mean of the triplicate ECG values will be calculated for each individual ECG parameter, without 
rounding the result. These calculated means will constitute the analysis values; any derivation 
(e.g. change from baseline, assignment of abnormalities) and statistic will be based on the mean 
value of the triplicates. 
The values of the original members of a triplicate will be listed. 
6.5.3.3. 
Abnormalities 
The actual analysis values and changes from baseline of the QTcF parameters will be categorized 
into the abnormality classes as defined in ICH-E14 The Clinical Evaluation of QT/QTc Interval 
Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs (Step 4 Version), see 
Table 8. 
Table 8 
Abnormalities on ECG Parameters 
Parameter 
Category 
Limits 
Abnormalities on actual values 
QTcF (ms) 
QT≤ 450 
450 < QT ≤ 480 
480 < QT ≤ 500 
QT > 500 
≤ 450 
450 < value ≤ 480 
480 < value ≤ 500 
> 500 
Abnormalities on change from reference 


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QTcF (ms) 
QT change ≤ 30 
≤ 30 
 
30 < QT change ≤ 60 
30 < change ≤ 60 
 
QT change > 60 
> 60 
  
Worst-Case Abnormality 
The worst-case post-baseline categorized actual analysis value and the worst-case categorized 
change from baseline for 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. 
Treatment-Emergent Abnormalities 
Actual value: An abnormal post-baseline abnormality is defined as treatment-emergent when the 
abnormality is worse compared to the abnormality at baseline. When the baseline value is 
missing, post-baseline abnormalities are considered as treatment-emergent. 
An abnormal category for change from baseline is always treatment-emergent. 
6.5.3.4. 
Presentation of Results 
No formal inferential statistics (p-values) will be derived. Results reported during the screening 
period will only be listed. 
Descriptive Statistics over Time 
Descriptive statistics (including 95% CI of the mean) will be provided for the continuous 
parameters actual values and changes from baseline per analysis visit, treatment group and 
analysis period: 
˗ 
For the DB period and OLE period, change from baseline will be presented. 
˗ 
 
Graphs of the mean (+- SE) actual values over time and of the mean (+- SE) change from 
baseline will be prepared for all parameters, overlayed with the individual profiles printed on the 
same graph. The graphs will be repeated for the DB and OLE period. 
Abnormalities  
The analysis of abnormalities will focus on assessments reported during each treatment period. 
Results reported during the screening period will only be listed. 
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Abnormalities of the actual values will be presented as shift tables of the worst-case abnormality 
versus the baseline abnormality. The table will be created per parameter, treatment group and 
analysis period.  
˗ 
For the DB period and OLE period, shift tables versus baseline will be presented. 
˗ 
 
A frequency table of the number (percent) of subjects with treatment-emergent worst-case 
abnormalities and the worst change per parameter, treatment group and analysis period will be 
presented.  
˗ 
For the DB period and OLE period, treatment-emergent worst-case abnormalities grade 
relative to baseline will be presented. 
˗ 
 
 
ECG Interpretations 
A frequency table per treatment group and time point of the ECG interpretations as recorded in 
the CRF will be provided. 
Listings 
All data will be listed. 
6.5.4. 
Vital Signs 
6.5.4.1. 
Available Data 
The following selected vital signs parameters will be recorded: weight, diastolic and systolic 
blood pressure, heart rate and temperature.  
6.5.4.2. 
Derivation Rules 
6.5.4.3. 
Abnormalities 
Vital signs data will be evaluated for abnormalities based on Table 1. 
Table 9 
Abnormalities on Vital Signs Parameters 
Parameter 
Category 
Limits 
Abnormalities on actual values 
Systolic blood pressure (SBP, 
mmHg) 
Abnormally Low (L) 
SBP <90 
Normal (N) 
90≤SBP≤150 
Abnormally High (H) 
SBP>150 
Diastolic blood pressure (DBP, 
mmHg) 
Abnormally Low (L) 
DBP <45 
Normal (N) 
45≤DBP≤90 
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Parameter 
Category 
Limits 
Abnormally High (H) 
DBP>90 
  
6.5.4.4. 
Treatment-Emergent Principle 
A post-baseline abnormality class L or H is defined as treatment-emergent when it differs from 
the abnormality class at baseline. If the baseline result is missing, a post-baseline abnormality 
L or H will be considered as treatment-emergent. 
6.5.4.5. 
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 (and the DB&OLE combined 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. 
6.5.4.6. 
Presentation of Results 
No formal inferential statistics (p-values) will be derived. Results reported during the screening 
period will only be listed. 
Descriptive Statistics over Time 
Descriptive statistics (including 95% CI of the mean) will be provided for the continuous 
parameters actual values and changes from baseline per analysis visit, treatment group and 
analysis period: 
˗ 
For the DB period, OLE period and DB&OLE combined, change from baseline will be 
presented. 
˗ 
 
Graphs of the mean (+- SE) actual values over time and of the mean (+- SE) change from 
baseline will be prepared for all parameters, overlayed with the individual profiles printed on the 
same graph. The graphs will be repeated for the DB, OLE and the DB&OLE combined period. 
Abnormalities  
The analysis of abnormalities will focus on assessments reported during each treatment period. 
Results reported during the screening period will only be listed. 
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Abnormalities of the actual values will be presented as shift tables of the worst-case abnormality 
versus the baseline abnormality. The table will be created per parameter, treatment group and 
analysis period.  
˗ 
For the DB period, OLE period and DB&OLE combined, shift tables versus baseline will be 
presented. 
˗ 
 
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.  
˗ 
For the DB period, OLE period and DB&OLE combined, treatment-emergent worst-case 
abnormalities grade relative to baseline will be presented. 
˗ 
 
 
Listings 
All data will be listed. 
 
 
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6.5.5. 
eGFR (as Safety Parameter) 
In addition to the efficacy analysis described in section 6.2.3, eGFR will be analyzed as a safety 
following the rules for laboratory parameters as described in section 6.5.2.  
 
 


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6.6. 
CHANGES TO THE PLANNED ANALYSES, NOT COVERED BY 
PROTOCOL AMENDMENTS 
No per-protocol set will be defined. Instead, all major protocol deviations identified as impacting 
efficacy results will be considered as intercurrent events and will be handled as an additional 
estimand. This is indicated in the respective sections. 
 
 


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7. 
REFERENCES 
Fridericia, L. (1920). Die Systolendauer im Elektrokardiogramm bei normalen Menschen und bei 
Herzkranken. Acta Medica Scandinavia 53:469-486. 
ICH E3 Structure and Content of Clinical Study Reports (Step 4 Version). 
ICH E9 Statistical Principles for Clinical Trials (Step 4 Version). 
ICH E14 The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential 
for Non-Antiarrhythmic Drugs (Step 4 Version). 
ICH E6 Intergrated Addendum to ICH E6 (R1): Guideline for good clinical practice 
(Step 4 Version). 
ICH E9(R1) Estimands and Sensitivity Analysis in Clinical Trials (Step 2 Version). 
 
 


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APPENDIX 
APPENDIX I: Statistical Models 
Linear Mixed Effects Model 
The model can be written as: 
Yij = β1 + β2 tij + β3 Groupi + β4 tij * Groupi + b1i + b2i tij + eij, 
Where 
˗ 
Yij is the response variable of subject i at visit j (j = 0, 1, 2, 3),  
˗ 
t is the relative date (in months) as a continuous variable 
˗ 
Group is the treatment group (0 = placebo, 1 = GLPG2737) 
˗ 
β1, β2, β3 and β4 denote fixed effects (β1 is the intercept of placebo, β1 + β3 is the intercept 
of GLPG2737 , β2 is the slope of placebo, β2 + β4 is the slope of GLPG2737),  
˗ 
b1i and b2i are random effects assumed to be normally distributed with mean 0 and 
unstructured variance covariance structure.  
˗ 
The error terms in the model, eij, are assumed independent and normally distributed as N 
(0,σ2); and they are also assumed to be independent of the random effects, b1i and b2i. 
 
proc mixed data = <input dataset> ; 
  class usubjid trt01pn(ref='2'); 
  model <response[1]> = trt01pn timew trt01pn*timew /ddfm=KR s; 
  random intercept timew/type=un subject=usubjid g gcorr s; 
  estimate 'Slope GLPG (up to 52 weeks)' timew 52 trt01pn*timew 52 0/e cl; 
  estimate 'Slope pbo (up to 52 weeks)' timew 52 trt01pn*timew 0 52/e cl; 
  estimate 'Slope GLPG vs[2] slope pbo (in 52 weeks)'  trt01pn*timew 52 -52 /e 
cl ; 
run; 
 
[1] response = log([ht]TKV actual value) for MRI / actual value for eGFR 
[2] vs = ratio for [ht]TKV / difference for eGFR 
 
Data steps for anti-log estimates, i.e.: 
˗ 
Exp(estimates) to derive geometric mean for each treatment group and geometric mean ratio 
GLPG over PBO 
˗ 
Exp(estimates) – 1 to derive geometric mean growth for each treatment group and geometric 
mean growth GLPG vs PBO   
 


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Mixed Effect Repeated Measures Model  
An additional estimand for the primary analysis will be developed by means of a MMRM 
including treatment, time (categorical), a treatment-by-time point interaction as categorical fixed 
effects, and the baseline value[1] as continuous effect and correlated within-subject residuals.  
Yij  = α  + (θj  + (β_T θ)_j*Trt_i) +  β_B*Baseline_i + ε_ij 
Where  
˗ 
Yij is the change from baseline for subject i at time point j (excluding baseline)  
˗ 
α is the intercept and θj is the placebo time effect at time point j 
˗ 
(β_T θ)_j is the effect of GLPG at time point j 
˗ 
β_B is the coefficient for baseline value 
˗ 
Trt_i=0 for placebo and Trt_i=1 for GLPG 
˗ 
ε_ij is the random error for subject i at time point j, with ε_iassumed to be independent and 
identically normally distributed with mean 0 and unstructured variance-covariance matrix, for 
all i. 
If this model fails to converge, other structures will be tested for the variance-covariance matrix 
for the error terms (e.g. heterogenous Toeplitz, AR(1),…). The structure with the best fit, based 
on Akaike’s information criterion, will then be used. 
The following SAS code is to be used: 
proc sort data = <data>; 
  by subject avisit;  
run; 
proc mixed data = <data> order = internal; 
  class subject treatment avisit ; 
  model <response> = treatment * avisit base[1] / solution cl ddfm=kr; 
  repeated avisit / type= un subject = subject; 
  lsmeans treatment*avisit /cl diff; 
run ; 
 
Response = log([ht]TKV actual value/baseline value) for MRI / Change from baseline for eGFR 
[1]= log-transformed MRI baseline value for MRI and baseline value for eGFR. 
 
 


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APPENDIX III: Schedule of Activities 
Double-Blind Treatment Period 
For detailed instructions on the clinical study procedures, please see referred CSP sections and CSP Section 5.1 “Timing of 
Assements”. 
EVENT 
SCREEN 
ING 
PERIOD 
TREATMENT PERIOD 
EoST / EoSA2 
FOLLOW-
UP 
Study visit 
1 
2 
3 
4 
5 
6/7/8/9 
10/11/12/13 
ETD3 
14 
EoST  
14 
EoSA 
15 (EoS DB 
Period)4 
Study Day (D) or Week (W) 
(± D) 
D-28 to 
D-1 
D1 
W1 
± 3 
W2 
± 3 
W4 
± 3 
W8/W12/ 
W16/W20 
 ± 4 
W26/W34/ 
W42/W48 
± 4 
 
W52 
± 4 
W52 
± 4 
W56 
± 10 
Informed consent (Section 
5.3) 
✓ 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
(Sections 3.6 and 5.3) 
✓ 
✓ 
 
 
 
 
 
 
 
 
 
Demographics (Section 5.3) 
✓ 
 
 
 
 
 
 
 
 
 
 
Medical history (Section 5.3) 
✓ 
 
 
 
 
 
 
 
 
 
 
Pregnancy test5,6 (Section 
5.5.2) 
✓ 
✓ 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
✓ 
                                                 
2 At Visit 14 either EoST (Treatment) or EoSA (Assessment) should be performed. 
3 Early treatment discontinuation (ETD) visit, if applicable.  
4 In case subject rolls over to the OLE period, roll-over visit in the SoA described in OLE Treatment Period (Section 5.11.2) is also applicable. 
5 Assessment needs to be done prior to dosing, on dosing days.  
6 Serum Pregnancy test or FSH at screening. Urine pregnancy test at Day 1and subsequent visits, as indicated in the SoA. 


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EVENT 
SCREEN 
ING 
PERIOD 
TREATMENT PERIOD 
EoST / EoSA2 
FOLLOW-
UP 
Study visit 
1 
2 
3 
4 
5 
6/7/8/9 
10/11/12/13 
ETD3 
14 
EoST  
14 
EoSA 
15 (EoS DB 
Period)4 
Study Day (D) or Week (W) 
(± D) 
D-28 to 
D-1 
D1 
W1 
± 3 
W2 
± 3 
W4 
± 3 
W8/W12/ 
W16/W20 
 ± 4 
W26/W34/ 
W42/W48 
± 4 
 
W52 
± 4 
W52 
± 4 
W56 
± 10 
Physical examination 
(Section 5.5.3)7 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Vital signs5 (Section 5.5.4) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Weight and Height8 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
12-lead ECG5,9 (Section 
5.5.5) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Serology (Section 5.5.2) 
✓ 
 
 
 
 
 
 
 
 
 
 
Safety blood samples 
(Section 5.5.2) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Safety urine samples (Section 
5.5.2) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
                                                 
7 Full physical examinaton should be performed at screening, randomization, Visit 5 (Week 4), Visit 10 (Week 26), and Visit 14 (Week 52). At all other visits 
at investigators discretion. 
8 Height only at screening. 
9 Triplicate ECG at each visit.  


-64- 
 
EVENT 
SCREEN 
ING 
PERIOD 
TREATMENT PERIOD 
EoST / EoSA2 
FOLLOW-
UP 
Study visit 
1 
2 
3 
4 
5 
6/7/8/9 
10/11/12/13 
ETD3 
14 
EoST  
14 
EoSA 
15 (EoS DB 
Period)4 
Study Day (D) or Week (W) 
(± D) 
D-28 to 
D-1 
D1 
W1 
± 3 
W2 
± 3 
W4 
± 3 
W8/W12/ 
W16/W20 
 ± 4 
W26/W34/ 
W42/W48 
± 4 
 
W52 
± 4 
W52 
± 4 
W56 
± 10 
MRI based htTKV and 
 (Section 5.4.1)  
(✓)10 
✓10 
 
 
✓ 
 
✓11 
✓12 
✓ 
 
✓ 
eGFR (Section 5.4.2) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
                                                 
10 At screening TKV should be determined in case historical imaging is not available from the last 5 years (other imaging can be performed depending on local 
clinical practice). In case MRI is performed at screening according to study specifications and centrally read, this MRI can be used for screening and 
randomization. In this case, there is no need to repeat MRI at Visit 2 (Day 1). 
11 at Visit 10 (Week 26) only. 
12 For subjects discontinuing IP prematurely, the instructions of the ETD need to be followed (see Section 5.1). 
13 24 hours urine collection to be performed 24 hours before Visit 2 (Day1), Visit 5 (Week 4), Visit 7 (Week 12), Visit 10 (Week 26), EoST Visit 14 (Week 52), 
and EoS Visit 15 (Week 56) – not applicable for subjects who discontinued IP. 
14 At Visit 7 (Week 12) only. 
15 PD samples directly after PK sampling (predose). 
16 At Visit 6 (Week 8), Visit 7 (Week 12), Visit 8 (Week 16) only. 
17 At Visit 10 (Week 26) and Visit 11 (Week 34) only. 
CCI
CCI


-65- 
 
EVENT 
SCREEN 
ING 
PERIOD 
TREATMENT PERIOD 
EoST / EoSA2 
FOLLOW-
UP 
Study visit 
1 
2 
3 
4 
5 
6/7/8/9 
10/11/12/13 
ETD3 
14 
EoST  
14 
EoSA 
15 (EoS DB 
Period)4 
Study Day (D) or Week (W) 
(± D) 
D-28 to 
D-1 
D1 
W1 
± 3 
W2 
± 3 
W4 
± 3 
W8/W12/ 
W16/W20 
 ± 4 
W26/W34/ 
W42/W48 
± 4 
 
W52 
± 4 
W52 
± 4 
W56 
± 10 
First morning urine for 
Microscopy Culture and 
Sensitivity (MCS) 
(Section 5.5.2) 
✓18 
✓ 
 
 
✓ 
 
 
✓ 
✓ 
✓ 
 
Randomization (Section 3.7.1) 
 
✓ 
 
 
 
 
 
 
 
 
 
PK blood sample, any time of 
the day (Section 5.6) 
 
 
 
 
 
 
 
✓ 
 
 
 
Optional blood samples for 
future scientific research 
(Section 5.10) 
 
✓(predose) 
 
 
 
 
 
✓ 
✓ 
 
✓ 
                                                 
18 A random urine sample can be used at the screening visit. 
19 Only in case not determined in the past. 
20 Only at Visit 8 (Week 16) and Visit 10 (Week 26). 
CCI
CCI


-66- 
 
EVENT 
SCREEN 
ING 
PERIOD 
TREATMENT PERIOD 
EoST / EoSA2 
FOLLOW-
UP 
Study visit 
1 
2 
3 
4 
5 
6/7/8/9 
10/11/12/13 
ETD3 
14 
EoST  
14 
EoSA 
15 (EoS DB 
Period)4 
Study Day (D) or Week (W) 
(± D) 
D-28 to 
D-1 
D1 
W1 
± 3 
W2 
± 3 
W4 
± 3 
W8/W12/ 
W16/W20 
 ± 4 
W26/W34/ 
W42/W48 
± 4 
 
W52 
± 4 
W52 
± 4 
W56 
± 10 
Dispense subject diary 
(Section 4.5.1) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
 
Collect subject diary (Section 
4.5.1) 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
✓ 
Dispense subject participation 
card 
 
✓ 
 
 
 
 
 
 
 
 
 
Randomization 
 
✓ 
 
 
 
 
 
 
 
 
 
Dispense IP (Section 4.3) 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
 
 
Review IP compliance in 
paper diary (Section 4.5) 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
Dose IP (Section 4.2) 
 
q.d. throughout the treatment period starting at Day 1 
 
✓ 
 
 
AE assessment (Section 
5.5.1) 
throughout the study 
Prior / Concomitant 
medication (Section 3.6.4.2) 
throughout the study 
 
 
 


-67- 
 
Open-label Treatment Period  
EVENT 
TREATMENT PERIOD 
FOLLOW-UP 
Study Visit / Phone Call 
Roll-
over 
Visit 15 i 
16 
17/18/19 
20/21 
22 
ETDii 
23 (EoS OLE Period) 
Week (W) 
(± Days) 
Week 56 
W58 
± 3 days 
W60/W66/ 
W72 
± 3 days 
W84/W96  
± 4 days 
W108 
± 4 days 
 
W112 
± 4 days 
Informed consent (Section 5.3) 
✓ 
 
 
 
 
 
 
Inclusion/exclusion criteria  
(Sections 3.6 and 5.3) 
✓ 
 
 
 
 
 
 
Pregnancy test (Section 5.5.2) 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
Physical examination (Section 5.5.3) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Vital signs (Section 5.5.4) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Weight 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
12-lead ECG (Section 5.5.5) 
✓ 
(triplicate) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Safety blood samples (Section 5.5.2) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Safety urine samples (Section 5.5.2) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
CCI


-68- 
 
EVENT 
TREATMENT PERIOD 
FOLLOW-UP 
Study Visit / Phone Call 
Roll-
over 
Visit 15 i 
16 
17/18/19 
20/21 
22 
ETDii 
23 (EoS OLE Period) 
Week (W) 
(± Days) 
Week 56 
W58 
± 3 days 
W60/W66/ 
W72 
± 3 days 
W84/W96  
± 4 days 
W108 
± 4 days 
 
W112 
± 4 days 
First morning urine for MSC  
(Section 5.7) 
✓iv 
 
✓ (W60) 
 
 
 
 
Optional blood samples for future scientific 
research (Section 5.10) 
 
 
 
 
✓ 
✓ 
 
Dispense IP (Section 4.3) 
✓ 
 
✓ 
✓ 
 
 
 
Review IP compliance 
 
✓ 
✓ 
✓ 
✓ 
 
 
Dose IP (Section 4.2) 
q.d. throughout the treatment period 
 
 
AE assessment (Section 5.5.1) 
throughout the study 
Concomitant medication (Section 3.6.4.2) 
throughout the study 
 
i Roll-over visit will take place at FU visit of the double-blind period (Week 56). 
ii Early treatment discontinuation (ETD) visit, if applicable. 
iii For subjects discontinueing IP prematurely, the instructions of the ETD need to be followed (see Section 5.1) 
iv A random urine sample can be used. 
                                                 
CCI