A Phase IIa, Randomized, Double-blind, Placebo-controlled Study to Evaluate Multiple Doses of GLPG2222 in Subjects With Cystic Fibrosis Who Are Homozygous for the F508del Mutation
Phase: PHASE2
Conditions: Cystic Fibrosis
Sponsor: Galapagos NV



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CLINICAL STUDY PROTOCOL HISTORY
CSP / Amendment #
Date
Generic / Country / Site 
Specific
Clinical Study Protocol v1.0: initial version 
(not submitted)
5-Dec-2016
Generic
Clinical Study Protocol v2.0: update to fix 
technical template issue (not submitted)
5-Dec-2016
Generic
Clinical Study Protocol v3.0: update to 
specify storage conditions of study drugs
6-Dec-2016
Generic

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EMERGENCY CONTACT INFORMATION
In case of a Serious Adverse Event (SAE), the investigator must fax or e-mail the Galapagos 
Clinical Study SAE Form within 24 hours to the 
 Medical Affairs 
Department:
 Medical Affairs SAE Fax #: 
or
e-mail: 
In case of medical questions during the course of the study, the investigator must contact:

Global and Europe:
, MD

Northern America:
 MD

AsiaPac:
 MD

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TABLE OF CONTENTS
Clinical Study Protocol.........................................................................................................1
Clinical Study Protocol History ...........................................................................................2
Emergency Contact Information .........................................................................................3
Table of Contents..................................................................................................................4
List of Figures.......................................................................................................................7
List of Abbreviations and Definition of Terms....................................................................8
Study Specific Procedures..................................................................................................11
1. Study Flow Chart..........................................................................................................11
2. Introduction ..................................................................................................................13
2.1.
Physical, Chemical and Pharmaceutical Properties and Formulations.....................13
2.2.
Nonclinical Pharmacology .....................................................................................13
2.2.1.Primary and Secondary Pharmacology..........................................................13
2.2.2.Safety Pharmacology ....................................................................................14
2.3.
Nonclinical Pharmacokinetics and Product Metabolism .........................................14
2.4.
Toxicology.............................................................................................................15
2.4.1.General Toxicology ......................................................................................15
2.4.2.Genotoxicity .................................................................................................16
2.5.
Clinical Investigation.............................................................................................16
2.5.1.GLPG2222-CL-101 ......................................................................................16
2.5.2.GLPG2222-CL-102 ......................................................................................17
2.5.3.GLPG2222-CL-104 ......................................................................................17
2.6.
Rationale for Current Study, Study Design and Dose Selection..............................17
2.6.1.Rationale for the Study .................................................................................17
2.6.2.Rationale for the Study Design and Dose Selection.......................................19
3. Study Objectives............................................................................................................19
3.1.
Primary Objective..................................................................................................19
3.2.
Secondary Objectives.............................................................................................19
4. Study Endpoints............................................................................................................19
4.1.
Primary Endpoint...................................................................................................19
4.2.
Secondary Endpoints..............................................................................................20
5. Investigational Plan.......................................................................................................20
5.1.
Overall Study Design.............................................................................................20
5.2.
Study Population....................................................................................................21
5.2.1.Sample Size ..................................................................................................21
5.2.2.Inclusion Criteria ..........................................................................................21
5.2.3.Exclusion Criteria .........................................................................................22
5.2.4.Retesting During the Screening Period..........................................................23
5.2.5.Rescreening ..................................................................................................23
5.2.6.Prohibitions and Restrictions.........................................................................23
5.2.6.1. Medication.......................................................................................23
5.2.6.2. Birth Control....................................................................................25
5.2.7.Removal of Subjects From Therapy or Assessments .....................................26
5.3.
Investigations Medicinal Products..........................................................................27
5.3.1.Identity of the Investigations Medicinal Products..........................................27

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5.3.2.Other Medication Administered ....................................................................28
5.3.3.Dosage and Administration...........................................................................28
5.3.4.Randomization..............................................................................................28
5.3.5.Packaging, Labeling and Distribution............................................................29
5.3.6.Storage .........................................................................................................29
5.3.7.Treatment Compliance and Drug Accountability...........................................29
5.3.7.1. Subject Diary ...................................................................................30
5.3.7.2. Subject Participation Card................................................................30
5.3.8.Prior and Concomitant Therapy ....................................................................30
5.3.8.1. Stable Concomitant CF Medication Regimen ...................................31
5.3.9.Blinding and Unblinding...............................................................................31
6. Study Assessments.........................................................................................................32
6.1.
Timing of Assessments ..........................................................................................32
6.2.
Initial Subject and Disease Characteristics .............................................................32
6.3.
Efficacy Assessments.............................................................................................33
6.3.1.Sweat Chloride Concentration.......................................................................33
6.3.2.Spirometry....................................................................................................33
6.3.3.Cystic Fibrosis Questionnaire-Revised (CFQ-R)...........................................34
6.4.
Safety Assessments................................................................................................34
6.4.1.Adverse Events.............................................................................................34
6.4.2.Physical Examination....................................................................................34
6.4.3.Vital Signs....................................................................................................35
6.4.4.Oxygen Saturation by Pulse Oximetry ..........................................................35
6.4.5.12-lead ECG.................................................................................................35
6.4.6.Clinical Laboratory Evaluations....................................................................35
6.5.
Pharmacokinetics Assessments ..............................................................................36
6.5.1.Blood Samples..............................................................................................36
6.5.2.Sweat Samples..............................................................................................36
6.5.3.Pharmacokinetic Parameters .........................................................................36
6.6.
Exploratory Assessments .......................................................................................37
6.6.1.Exploratory Biomarkers................................................................................37
6.7.
Optional Exploratory Assessment (Substudy).........................................................37
6.7.1.Apical Expression of F508del CFTR Using Nasal Brushing..........................37
7. Statistical Methods........................................................................................................37
7.1.
Determination of Sample Size................................................................................38
7.2.
Populations for Analyses........................................................................................38
7.2.1.All Screened Subjects Analysis Set...............................................................38
7.2.2.All Enrolled Subjects Analysis Set................................................................38
7.2.3.Intent to Treat Analysis Set...........................................................................38
7.2.4.Safety Analysis Set .......................................................................................38
7.2.5.Pharmacokinetics Analysis Set......................................................................38
7.3.
Statistical Analyses ................................................................................................38
7.3.1.General Statistical Considerations.................................................................38
7.3.2.Analyses of Demographics and Baseline Characteristics...............................38
7.3.3.Analyses of Efficacy Parameters...................................................................39
7.3.4.Analyses of Safety Data................................................................................39
7.3.5.Pharmacokinetics Analyses...........................................................................39
7.3.6.Exploratory Biomarkers................................................................................40
7.3.7.Apical Expression of F508del CFTR (Optional Substudy) ............................40

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8. Data Safety Monitoring Board .....................................................................................40
General Procedures............................................................................................................41
9. Adverse Events..............................................................................................................41
9.1.
Definitions.............................................................................................................41
9.2.
Intensity of Adverse Event.....................................................................................41
9.3.
Causality Assessment.............................................................................................42
9.4.
Action Taken Regarding Investigational Product (if Applicable)............................42
9.5.
Outcome ................................................................................................................43
9.6.
Recording Adverse Events.....................................................................................43
9.7.
Managing Serious Adverse Events.........................................................................43
9.8.
Reporting Serious Adverse Events / Pregnancies....................................................43
9.8.1.Serious Adverse Events ................................................................................43
9.8.2.Pregnancy.....................................................................................................44
9.9.
Reporting Serious Adverse Events to Competent Authorities / Ethics 
Committees / Institutional Review Boards..............................................................44
10. Study Closure Considerations ......................................................................................44
11. Study Materials.............................................................................................................45
11.1. Investigational Medical Products ...........................................................................45
11.2. Study Documents...................................................................................................45
11.3. Participation Cards.................................................................................................46
11.4. Source Data ...........................................................................................................46
11.5. Electronic Data Capture.........................................................................................47
12. Archiving.......................................................................................................................47
13. Confidentiality...............................................................................................................48
14. Reporting and Publication............................................................................................48
14.1. Reporting...............................................................................................................48
14.2. Publication.............................................................................................................49
15. Ethics .............................................................................................................................49
15.1. Independent Ethics Committee (IEC) / Institutional Review Board (IRB) ..............49
15.2. Regulatory Approval / Notification ........................................................................50
15.3. ICH Good Clinical Practice....................................................................................50
15.4. Informed Consent ..................................................................................................50
16. Financing and Insurance ..............................................................................................51
16.1. Financial Disclosure...............................................................................................51
16.2. Indemnification......................................................................................................51
16.3. Insurance ...............................................................................................................51
17. Data Quality Control / Assurance ................................................................................51
17.1. Monitoring.............................................................................................................51
17.2. Audit and Inspection..............................................................................................52
References...........................................................................................................................53
Appendices..........................................................................................................................54
Appendix 1
Study Contact Information ...............................................................54
Appendix 2
Normal Ranges for Vital Signs, Pulse Oximetry and ECG 
Parameters
56
Signature Page – Sponsor...................................................................................................57

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Signature Page – Investigator ............................................................................................58
LIST OF FIGURES
Figure 1: Potency of GLPG2222 (A-1622622) versus VX-809 and VX-661 in human 
bronchial epithelial cells from F508del donors................................................18
Figure 2: Characterization of the current increase of GLPG2222 and VX-661/VX-770 
in F508del/F508del-CFTR primary human bronchial epithelial cells
(trans-epithelial clamp circuit assay). Data are represented as equivalent 
current (Ieq; µA/cm2); mean ± standard deviation (N=3 unique donors)..........18
Figure 3: Study design..........................................................................................................20

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviations
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
ATS/ERS
American Thoracic Society/European Respiratory Society
AUC
area under the plasma concentration-time curve
AUC0-24h
area under the plasma concentration-time curve from time zero till 
24 hours post-dose
AUC(t)
area under the plasma concentration-time curve over the dosing interval
BCRP
breast cancer resistance protein
C24h
plasma concentration observed at 24 hours post-dose
cAMP
cyclic adenosine monophosphate
CF
cystic fibrosis
CFQ-R
Cystic Fibrosis Questionnaire-Revised
CFTR
cystic fibrosis transmembrane conductance regulator
Cmax
maximum observed plasma concentration
CRO
Contract Research Organization
CRP
C-reactive protein
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
plasma concentration observed at pre-dose
CYP
cytochrome P450
DBP
diastolic blood pressure
DSMB
Data Safety Monitoring Board
EC50
effective concentration providing 50% of the maximal response
ECG
electrocardiogram
eCRF
electronic Case Report Form
ED
early discontinuation
EDC
electronic Data Capture
FEF25-75
forced expiratory flow between 25% and 75% of exhaled volume
FEV1
forced expiratory volume in one second

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FSH
follicle stimulating hormone
FVC
forced vital capacity
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
HBsAg
hepatitis B virus surface antigen
HCV
hepatitis C virus
HDPE
high-density polyethylene
hERG
human ether-a-go-go-related gene
HIV
human immunodeficiency virus
HR
heart rate
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IWRS
interactive web response system
LSS MA
Life Science Services Medical Affairs
NOAEL
no observed adverse effect level
OAT
organic anion transporter
OATP
organic anion-transporting polypeptide
PK
pharmacokinetic(s)
q.d.
once daily
QTc
corrected QT
QTcF
QT interval corrected for heart rate using Fridericia’s formula
SAE
serious adverse event
SBP
systolic blood pressure
SEM
standard error of the mean
t1/2
terminal elimination half-life
tmax
time to occurrence of Cmax
TEAE
treatment-emergent adverse event
TNF
tumor necrosis factor
UGT
uridine 5'-diphospho-glucuronosyltransferase
ULN
upper limit of normal

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WBC
white blood cell
Definition of Terms
QTcF
Fridericia’s cube-root corrected QT interval: QT (ms) x 

(	
)


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STUDY SPECIFIC PROCEDURES
1.
STUDY FLOW CHART
The schedule of assessments is given in the flow chart below.
EVENT
SCREENING
TREATMENT PERIOD1
FOLLOW-UP
Study days (D)
D-28 till D-1
D1
D15
(±2D)
D29
(±2D)
ED
D43
(±3D)
Informed consent2
X
Inclusion/exclusion criteria
X
X
CFQ-R3
X
X
X
X
X
X
Demographics
X
Medical history
X
Physical examination4
X
X
X
X
X
X
Weight
X
X
X
X
X
X
Vital signs5
X
X
X
X
X
X
Pulse oximetry6
X
X
X
X
X
X
12-lead ECG7
X
X
X
X
X
X
Sweat collection
X
X
X
X
X
X
Spirometry8
X
X
X
X
X
X
                                                            
1 All assessments are to be performed pre-dose. In addition, some assessments are also to be performed at 
defined time points post-dose when specifically mentioned.
2 Written informed consent to be obtained before any study-related procedures and/or assessments are 
performed.
3 CFQ-R to be completed prior to any other assessments scheduled for that visit.
4 Full physical examination at screening (including height); limited physical examination (ear, nose, throat, chest 
and neck) at subsequent visits.
5 Vital signs include heart rate, blood pressure (systolic and diastolic), respiratory rate and oral body 
temperature. Heart rate and blood pressure to be captured after 5 minutes in supine position. Vital signs must 
be recorded pre-dose at all visits, and additionally between 3 and 4 hours post-dose on Day 1.
6 Pulse oximetry to determine oxygen saturation is to be captured after at least 5 minutes of rest in seated or 
supine position.
7 12-lead ECG to be measured after at least 5 minutes of rest in supine position.
8 Spirometry must be performed pre-dose at all visits, and additionally between 1 and 2 hours post-dose on 
Day 1 and Day 29.
CFQ-R = Cystic Fibrosis Questionnaire - Revised; ECG = electrocardiogram; ED = early discontinuation

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2.
INTRODUCTION
Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the gene 
encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a 
cAMP-regulated anion channel expressed primarily at the apical plasma membrane of 
secretory epithelia. Over 2,000 mutations in the CFTR gene (CFTR) have been identified, 
which are grouped into 6 classes (class I-VI). The F508del mutation is by far the most 
common CFTR mutation globally, especially in the Caucasian population. Approximately 
80 to 90% of CF patients in the United States and Europe have at least one copy of this 
mutation on one allele, with almost half of them being F508del homozygous (i.e. the mutation 
is present on both alleles). The F508del mutation impairs CFTR folding, stability at the 
endoplasmic reticulum and plasma membrane, and chloride gating. Thus, the F508del 
mutation results in very little to no CFTR protein in the apical membrane. CFTR dysfunction 
results in viscid secretions that are difficult to clear, affecting most exocrine glands, notably 
the pancreas, intestine, liver, and bile duct. However, most morbidity and mortality results 
from dehydration of the airway surface liquid and impaired airway mucociliary clearance, 
which leads to cycles of bacterial infection, chronic inflammation, bronchiectasis and 
progressive decline in pulmonary function. There is a high medical need for efficacious
therapeutic approaches to treat CF subjects with the F508del mutation.
CFTR modulators are compounds designed to repair the consequences of CFTR mutations on 
protein expression and/or function. Overall, 2 types of small-molecule CFTR modulators are 
being developed: corrector molecules that are designed to restore proper protein folding and 
allowing for increased surface expression, and potentiator molecules targeted at improving 
chloride-channel gating function. In order to bring optimal clinical benefit to the F508del CF 
population, a combination of a potentiator and corrector(s) is needed. GLPG2222 is a CFTR 
corrector in development for the oral treatment of CF and represents the second component of 
a future potentiator/corrector(s) combination therapy targeting the F508del CF population.
2.1.
PHYSICAL, CHEMICAL AND PHARMACEUTICAL 
PROPERTIES AND FORMULATIONS
The chemical name of GLPG2222 is 4-[(2R,4R)-4-[[[1-(2,2-difluoro-1,3-benzodioxol-5-
yl)cyclopropyl]carbonyl]amino]-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic 
acid.
Two formulations are currently available for oral use: an oral suspension and a tablet.
2.2.
NONCLINICAL PHARMACOLOGY
2.2.1. Primary and Secondary Pharmacology
GLPG2222 is a CFTR corrector that exhibits potent in vitro activity in primary patient cells 
harboring F508del/F508del CFTR with an effective concentration providing 50% of the 
maximal response 
 Activity of corrected F508del CFTR channel is measured 
in the presence of a potentiator such as GLPG1837 or GLPG2451, which is needed to obtain 
maximal channel opening.

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4.2.
SECONDARY ENDPOINTS

Change from baseline in sweat chloride concentration through 29 days.

Change from baseline in percent predicted FEV1 through 29 days.

Change from baseline in the respiratory domain of the Cystic Fibrosis Questionnaire-
Revised (CFQ-R) through 29 days.

PK parameters of GLPG2222.
5.
INVESTIGATIONAL PLAN
5.1.
OVERALL STUDY DESIGN
This is a Phase IIa, multi-center, randomized, double-blind, placebo-controlled, parallel-group
study to evaluate 4 different doses of GLPG2222 administered orally and q.d. for 29 days to
adult male and female subjects with a confirmed diagnosis of CF and homozygous for the 
F508del CFTR mutation. Eligible subjects must be on a stable concomitant medication 
regimen for at least 4 weeks prior to the first study drug administration and agree to continue 
the same regimen for the duration of the study.
A schedule of the study design is provided in Figure 3.
Figure 3: Study design

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The study will consist of a screening period of maximum 4 weeks (starting when the subject 
has signed the informed consent form [ICF]), a treatment period of 4 weeks, and a follow-up 
period of 2 weeks. Enrolled subjects will come to the clinical study center at screening, on 
Day 1 (baseline), Day 15, Day 29, and at the follow-up visit (2 weeks after the last study drug 
administration).
Approximately 50 evaluable subjects are planned to be included sequentially in the study: the 
first 25 subjects will be assigned to Cohort A (i.e. subjects 1 to 25) and the next 25 subjects 
will be assigned to Cohort B (i.e. subjects 26 to 50). Subjects participating in Cohort A are not 
allowed to participate in Cohort B. In each study cohort, subjects will be randomized in a 
2:2:1 ratio to receive:

Cohort A: 50 mg GLPG2222, 100 mg GLPG2222 or placebo q.d. for 29 days.

Cohort B: 200 mg GLPG2222, 400 mg GLPG2222 or placebo q.d. for 29 days.
Assessments for efficacy and safety will be performed during the study at the time points 
specified in the flow chart in Section 1.
Additionally, subjects can choose to participate in the optional substudy, in which nasal 
brushings will be collected (Section 6.7).
Subjects will be in the study for a duration of minimum 6 weeks and maximum 10 weeks 
(from screening until the follow-up visit, depending on the duration of the screening period).
The end of the study is defined as the last contact with the last subject.
5.2.
STUDY POPULATION
5.2.1. Sample Size
Sufficient subjects will be screened in order to include approximately 50 evaluable CF 
subjects in the study (see Section 7.1).
5.2.2. Inclusion Criteria
Subjects who meet all of the following criteria are eligible for the study.
1.
Male or female subject ≥18 years of age on the day of signing the ICF.
2.
A confirmed clinical diagnosis of CF and homozygous for the F508del CFTR mutation 
(documented in the subject’s medical record or CF registry).
3.
Weight ≥40 kg during the screening period.
4.
Stable concomitant medication regimen for at least 4 weeks prior to the first study drug 
administration and continuing the same regimen for the duration of the study.
5.
FEV1 ≥40% of predicted normal for age, gender and height at screening (pre- or post-
bronchodilator). The spirometry test must meet the criteria for acceptability and 
repeatability as defined in the 2005 American Thoracic Society/European Respiratory 
Society (ATS/ERS) guidelines on standardization of lung function testing. If screening 
spirometry measurements fail to meet these criteria in the first 3 efforts, up to 8 repeat 
spirometry efforts may be performed. If repeat values of the individual assessment(s) 
satisfy the eligibility criteria and are completed within the screening window, then the 
subject is eligible for the study (see Section 6.3.2).

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17. Abnormal liver function test at screening; defined as aspartate aminotransferase (AST) 
and/or ALT and/or alkaline phosphatase and/or gamma-glutamyl transferase (GGT) 
≥3 x the upper limit of normal (ULN); and/or total bilirubin ≥ 1.5 x the ULN.
18. Estimated creatinine clearance < 60 mL/minute using Cockcroft-Gault equation at 
screening.
19. Smoking or use of nicotine-containing products within 1 year prior to screening.
20. Concurrent participation in another interventional therapeutic clinical study, prior 
participation in an investigational drug study within 8 weeks or 5 terminal half-lives of 
the investigational drug (whichever is longer) prior to the first study drug administration, 
or prior participation in an investigational drug antibody study within 6 months prior to 
the first study drug administration.
21. Any condition or circumstance that, in the opinion of the investigator, makes the subject 
unable to comply with study procedures and requirements.
22. A history of being admitted to an institution under an administrative or court order, if 
applicable to national or local legislation.
5.2.4. Retesting During the Screening Period
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 can be retested once if there is clear evidence of a laboratory error (e.g. 
hemolyzed sample) or equipment malfunction, but only with the documented approval of 
the sponsor’s medical lead.

Exclusionary liver function test levels may be retested once within 14 days of the original 
screening date, but only with the documented approval of the sponsor’s medical lead.

Weight may be retested once within 14 days of the original screening date.
5.2.5. Rescreening
Subjects not meeting one or more inclusion or exclusion criteria will be screen failures and 
may only be rescreened with the documented approval of the sponsor’s medical lead. If a 
subject is rescreened, all screening assessments will be repeated, and the screening window 
will begin once the first rescreening assessment has been initiated.
5.2.6. Prohibitions and Restrictions
5.2.6.1.
Medication
5.2.6.1.1.
Stable concomitant medication regimens
Concomitant medication regimens taken for the long-term treatment of pre-existing 
conditions are allowed if they are in accordance with the inclusion and exclusion criteria, and 
are stable for at least 4 weeks prior to the first study drug administration and continued 
without variation of dose or regimen during the study (see Section 5.3.8).
Subjects must remain on a stable medication regimen for pulmonary health (including dose 
and frequency) for at least 4 weeks prior to the first study drug administration and for the 

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5.2.6.2.
Birth Control
Highly effective contraceptive measures for both male subjects and female subjects of 
childbearing potential must be documented in the source documents.
5.2.6.2.1.
Female subjects of childbearing potential
For female subjects, one of the following criteria must be met for participation in the study:

Postmenopausal, defined as:

Age ≥55 years with no menses for ≥12 months without a medical cause.

Age < 55 years with no menses for ≥12 months without a medical cause AND a 
follicle stimulating hormone (FSH) level > 40 IU/L.

Permanently surgically sterile (bilateral oophorectomy [surgical removal of ovaries], 
bilateral salpingectomy or hysterectomy [surgical removal of uterus]).
If not one of the above 2 categories, a female subject is considered a woman of childbearing 
potential and must use one of the following highly effective methods of birth control starting 
on the day of signing the ICF, during the study, and for at least 3 months after the last dose of 
study drug:

Combined (estrogen and progesterone containing) hormonal contraception (oral, 
intravaginal, transdermal) associated with inhibition of ovulation.

Progesterone-only hormonal contraception (oral, injectable, implantable) associated with 
inhibition of ovulation.

Intrauterine device or intrauterine hormone-releasing system.

Bilateral tubal occlusion.

Have a vasectomized partner, provided that the partner is the sole sexual partner of the 
study participant (woman of childbearing potential) and that the vasectomized partner has 
received medical assessment of the surgical success.

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, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence for the duration of a 
study, and withdrawal are not acceptable methods of contraception.
Within these limits, the specific forms of contraception employed are left to the discretion of 
the subject, the investigator, and/or the subject’s physician.
The safety of GLPG2222 during breastfeeding is unknown. Women who are nursing are not 
allowed to take part in this study.
5.2.6.2.2.
Male subjects with female partners of childbearing potential
Vasectomized male subjects or subjects with bilateral absence of vas deferens with female 
partners of childbearing potential are not required to use an additional form of contraception,
provided that azoospermia has been confirmed and documented.
Non-vasectomized male subjects with female partners of childbearing potential must be 
willing to use a condom starting on the day of signing the ICF, during the study, and for at 

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least 3 months after the last dose of study drug. Their female partner should use one of the 
highly effective methods of birth control as defined in Section 5.2.6.2.1, or one of the 
following methods:

Contraceptive diaphragm, cervical cap, or sponge plus spermicide (if available).
In case a female partner of a male subject has undergone surgical sterilization that was 
performed more than 1 year before screening and is documented, the subject is not required to 
use an additional form of contraception.
No sperm donation is allowed starting on the day of signing the ICF, during the study, and for 
at least 3 months after the last dose of study drug.
5.2.7. Removal of Subjects From Therapy or Assessments
The investigator will comprehensively investigate safety data (e.g. clinical laboratory 
parameters and AEs) to decide whether to stop dosing of individual subjects.
A subject may be discontinued from the 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.
The investigator may decide to withdraw a subject from treatment (preferably after 
consultation with the sponsor’s medical lead) for any of the following reasons:

Subject request.

Use of concurrent therapy that was not permitted.

Noncompliance with the study drug.

Noncompliance with the study procedures.

Lost to follow-up.

Serious or severe AEs.

Investigator request.

Sponsor request.
Treatment with GLPG2222 will be discontinued and the subject will be withdrawn from the 
study (preferably after discussion with the sponsor’s medical lead) for any of the following 
conditions:

Life-threatening AE or an SAE that places the subject at immediate risk.

Serious infection requiring parenteral antimicrobial therapy and/or hospitalization.

Pregnancy.

Arrhythmia or conduction abnormality, including but not limited to prolonged QTcF, 
where the severity is categorized as CTCAE Grade 3 or higher.

Confirmed increase in liver function tests, defined as: 

Two sequential AST and/or ALT elevations > 3 x ULN, with at least 1 total bilirubin 
value > 2 x ULN.

Two sequential AST and/or ALT elevations > 3 x ULN, with 2 sequential increases 
of alkaline phosphatase and/or GGT > 3 x ULN.

Two sequential AST and/or ALT elevations > 3 x ULN, accompanied by clinical 
signs or symptoms suggestive for hepatic injury.

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
Two sequential AST and/or ALT elevations > 5 x ULN, regardless of total bilirubin 
value and/or alkaline phosphatase and/or GGT values and/or clinical signs or 
symptoms suggestive for hepatic injury.
If one of the above is detected, retesting for these laboratory parameters must be 
performed to determine if discontinuation criteria are confirmed. If confirmed, the 
sponsor’s medical lead must be contacted and the subject will be withdrawn from the 
study. In any case, additional investigations are needed (such as: assessment of alcohol or 
recreational drugs intake, hepatitis infection).

The sponsor or Regulatory Authorities close the study.

The subject wishes to withdraw from the study.

The subject shows a worsening of his/her medical condition (CF) which, in the 
investigator’s opinion, requires a withdrawal from the study.
Subjects will be informed prior to study entry that they are free to withdraw from the study at 
any time and for any reason without jeopardizing their clinical care. If a subject is removed 
from the study, the investigator will immediately (at the latest within 24 hours after
discontinuation) notify the sponsor. The reason for withdrawal will be documented. 
Discontinued subjects will not be replaced.
Subjects withdrawing from the study will be encouraged to complete the same final 
evaluations as subjects completing the study (completion of early discontinuation [ED]
assessments and follow-up visit) according to the protocol. In particular, it is in the subject’s 
interest that safety evaluations are performed, allowing for data to be recorded in the same 
way as for subjects who completed the study.
Reasonable efforts (3 attempts) will be made to contact subjects who are lost to follow-up. 
These efforts must be documented in the subject’s file.
The sponsor has the right to terminate the study at any time in case of safety concerns or if 
special circumstances concerning the study drug 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 study termination.
5.3.
INVESTIGATIONS MEDICINAL PRODUCTS
5.3.1. Identity of the Investigations Medicinal Products
The study drugs (GLPG2222 and placebo) will be supplied to the clinical study center 
pharmacist and/or investigator by or under the responsibility of the sponsor, who will also 
provide the pharmacist or investigator with appropriate certificates of analytical conformity 
and Qualified Person release documents.
GLPG2222 will be provided as tablets for oral use, containing 50, 100 or 150 mg active 
substance of G957389 (G957389 is the compound code for GLPG2222).
The matching placebo will be provided as a tablet for oral use.
At the clinical study center, the study drug supplies must be handled and stored safely and 
properly (refer to Section 5.3.6), and kept in a secured location to which only the investigator 
and authorized staff have access.

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5.3.2. Other Medication Administered
Not applicable.
5.3.3. Dosage and Administration
Study drug administration will begin on the morning of Day 1 (at the clinic) and will end on 
the morning of the Day 29 visit (at the clinic).
The following GLPG2222 doses (or placebo) will be evaluated:

Cohort A:

50 mg GLPG2222 q.d.

100 mg GLPG2222 q.d.

placebo q.d.

Cohort B:

200 mg GLPG2222 q.d.

400 mg GLPG2222 q.d.

placebo q.d.
The study drug is to be taken q.d. in the morning with a breakfast or snack. Tablets of 
GLPG2222 and/or placebo will be swallowed as a whole with a glass of water. On visit days, 
when the study drug will be administered at the clinic after pre-dose assessments have been 
completed, a breakfast or snack and a glass of water will be provided by the clinical study 
center.
Participants are recommended to take pancreatic enzyme replacement therapy (if applicable) 
per guidance of the investigator.
During the study visits on Day 1 and Day 15, subjects will be provided with supply of study 
drug to take home.
If a subject misses a dose (e.g. because he/she forgot to take the study drug), he/she must
immediately take the missed dose with food and a glass of water within 12 hours after the 
planned intake time. If the study drug is not taken within 12 hours after the planned time, the 
missed dose must be skipped. Individual dose reductions will not be allowed.
5.3.4. Randomization
Approximately 50 evaluable subjects will be assigned sequentially to Cohort A (first 
25 subjects) or Cohort B (next 25 subjects, i.e. subjects 26 to 50). Within each study cohort, 
subjects will be randomized in a 2:2:1 ratio to receive either 50 mg GLPG2222, 100 mg 
GLPG2222 or placebo q.d. in Cohort A, or 200 mg GLPG2222, 400 mg GLPG2222 or 
placebo q.d. in Cohort B for 29 days. Randomization will take place by means of a 
computerized interactive web response system (IWRS) according to a pre-specified 
randomization scheme prepared by an independent statistician at the Contract Research 
Organization (CRO). Subjects and study personnel will be blinded to the treatment 
assignment.

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For each subject at each visit, the clinic will contact the IWRS to obtain the appropriate kit 
number to be dispensed. The kit will contain the relevant study drugs for the period until the 
next visit (treatment bottle for Cohort A, treatment box for Cohort B).
5.3.5. Packaging, Labeling and Distribution
The study drug packaging, labeling, Qualified Person release and distribution will be 
performed by 
 (Belgium). All manufacturing, packaging, and labeling operations 
will be performed according to Good Manufacturing Practice for Medicinal Products and the 
relevant regulatory requirements. Packaging of tablets will be performed as follows for the 
2 cohorts:
Cohort A:

Eighteen tablets of the same strength will be packaged in high-density polyethylene 
(HDPE) treatment bottles with a child-resistant HDPE closure. At each study drug 
dispensing time point, subjects in Cohort A will receive one treatment bottle to cover for 
2 weeks of treatment. Hence, 2 treatment bottles will be foreseen per subject over the full 
study period. The bottles will be labeled according to local requirements and will have 
unique identifiers. The bottle label will include patient instructions for use.
Cohort B:

Three tablets will be packaged in separate daily HDPE treatment bottles with a child-
resistant HDPE closure. Nine of these daily treatment bottles will be grouped in a weekly 
treatment box. At each study drug dispensing time point, subjects in Cohort B will 
receive 2 treatment boxes to cover for 2 weeks of treatment. Hence, 4 treatment boxes
will be foreseen per subject over the full study period. Both the bottles and the treatment 
boxes will be labeled according to local requirements and will have unique identifiers. 
The box label will include patient instructions for use.
The study drugs are to be dispensed according to the protocol. The distribution will only 
occur after the required local documentation is obtained including study approval by 
Competent Authorities and the IEC(s)/IRB(s).
5.3.6. Storage
The study drugs are to be stored at 15-25°C. Clinical study centers are to store their study 
drug supplies in a secure area until dispensed. The investigator will instruct subjects on how 
the study drug must be stored after it is dispensed.
5.3.7. Treatment Compliance and Drug Accountability
The investigator or designated study personnel will maintain a log of all study drugs 
dispensed and returned. Drug supplies for each subject will be inventoried and accounted for 
throughout the study.
Subjects will return all remaining tablets and empty bottles at each study visit and/or the ED
visit (if applicable). Missed doses must be discussed to try to ascertain the reason(s). Every 
effort must be made to ensure proper subject dosing.

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All unused study drug will be returned to the drug supplier/CRO depot as applicable at the 
closure of the clinical study center, or will be destroyed at the clinical study center upon 
sponsor decision.
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 study drug. If a subject 
demonstrates continued noncompliance despite educational efforts, the investigator must 
contact the sponsor’s medical lead to discuss discontinuation of the subject from the study.
Any discontinuation must be done in consultation with the sponsor’s medical lead.
5.3.7.1.
Subject Diary
Subjects will be given a paper diary at the screening visit to record the following (screening to
follow-up):

Any missed dose, if applicable.

To document that study drug dose has properly been taken on a daily basis.

The time of study drug intake, including whether food and pancreatic enzyme 
replacement therapy (if applicable) was taken with each dose, on the day prior to each 
visit to the clinic.

From screening until the follow-up visit, changes in stable concomitant CF medication 
regimen, including new medicines not captured in medication history, use of inhaled 
antibiotics in the 24 hours prior to spirometry assessment, as well as any emerging AE.
Subjects will be instructed to bring the diary and used/unused study drug at each visit.
5.3.7.2.
Subject Participation Card 
On Day 1 (baseline), subjects will be provided with an emergency card containing 
information about their participation in the study, as well as contact details of the responsible 
investigator (see Section 11.3).
5.3.8. Prior and Concomitant Therapy
Concomitant therapies taken for the long-term treatment of pre-existing conditions can 
continue during the study provided they are in accordance with the inclusion and exclusion 
criteria (see Section 5.2.2 and Section 5.2.3, respectively), and with the prohibitions and 
restrictions (see Section 5.2.6.1). It is required that the concomitant medication regimen is
stable for at least 4 weeks prior to the first study drug administration and continued without 
variation of dose or regimen during the study.
If additional concomitant medication needs to be administered or dose adjustments for pre-
existing conditions are required during the study, this must be discussed with the sponsor’s 
medical lead.
All concomitant therapies are to be recorded on the relevant electronic Case Report Form
(eCRF) page(s), along with the reason for and details of therapy use. All surgeries will be 
recorded on the relevant eCRF page(s).

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5.3.8.1.
Stable Concomitant CF Medication Regimen
All medications in relation to the treatment of CF must be used during the study in accordance 
with the inclusion and exclusion criteria.
Subjects must remain on a stable medication regimen for pulmonary health (including dose 
and frequency) within 4 weeks prior to the first study drug administration and for the entire 
study duration (i.e. until the follow-up visit). Subjects who take inhaled antibiotics for 
suppression of chronic airway infection must be on a stable regimen for at least 8 weeks prior 
to the first study drug administration. Influenza vaccination cannot be administered within 
4 weeks prior to the first study drug administration and for the entire study duration.
Examples of stable medication regimen for pulmonary health are: antibiotics, corticosteroids
(inhaled or oral), inhaled bronchodilators, hypertonic saline, mannitol or dornase alfa; 
ibuprofen and airway clearance techniques.

Subjects can be on stable treatment with chronic use of oral corticosteroids provided that 
the daily dose of prednisone (or equivalent) is ≤10 mg.

Subjects who are using chronically inhaled antibiotics must remain on the same regimen 
for the duration of the study.

Subjects who are on cycling inhaled antibiotics (including ‘on/off’ cycling), must 
continue on the same schedule. The timing of the first dose of study drug must be as close 
as possible to the first day of the inhaled cycling antibiotic in the cycle. This also applies 
to subjects who are cycling 2 different alternate inhaled antibiotics each month.
If the subject shows a worsening of his/her CF disease condition, which in the investigator’s 
opinion needs an alternative treatment approach, treatment with study drug will be 
discontinued and the subject will be withdrawn from the study.
5.3.9. Blinding and Unblinding
This is a randomized, double-blind study.
The subject, the investigator, the study coordinator, the sponsor and the entire study 
processing team will remain blinded to treatment assignment. The blind can be broken only if 
the investigator deems it is necessary for the safe treatment of a subject. The investigator is 
encouraged to discuss considerations to break the blind with the medical monitor whenever 
possible and where the situation allows, and to inform the sponsor. However, the investigator 
is responsible for the medical care of the individual trial subject and the responsibility to 
break the treatment code in emergency situations resides solely with the investigator. The 
investigator is not required to discuss unblinding if he or she feels rapid emergency 
unblinding is necessary.
If the blind is broken for any reason during the course of the study, the moment at which the 
subject’s data were unblinded and all other relevant information will be documented by the 
clinical study center, CRO, and other sponsor designees, as appropriate. The reason for 
breaking the blind will be indicated and justified in the source documentation and in the 
eCRF. The blind can be broken by the investigator via the IWRS.
All subjects who are unblinded while on the study will be withdrawn at the moment of 
unblinding, with the reason for unblinding given as the reason for discontinuation from the 

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study. If an AE leads to unblinding, the AE must be given as the reason for unblinding and the 
AE must also be recorded in the eCRF. All subjects who are unblinded must, where possible, 
complete the ED visit. Any AEs must be followed until resolution or until stabilization.
6.
STUDY ASSESSMENTS
6.1.
TIMING OF ASSESSMENTS
The study assessments described below will be performed at the time points specified in the 
flow chart in Section 1. All assessments should be performed pre-dose. In addition, some 
assessments are also to be performed at defined time points post-dose when specifically 
mentioned. The procedures listed below must be performed in the following order:
1.
CFQ-R
2.
Vital signs and pulse oximetry
3.
12-lead ECG
4.
Sweat collection
5.
Spirometry
6.
Sampling for clinical laboratory tests and PK
7.
Sampling for exploratory biomarkers
8.
Nasal brushings (if applicable)
All other procedures can be performed in any order, unless otherwise stated, as long as they
meet the schedule for pre- or post-dose evaluations.
6.2.
INITIAL SUBJECT AND DISEASE CHARACTERISTICS
Subjects will be asked to come to the clinical study center for the screening visit, which may 
be scheduled between 28 days and 1 day prior to baseline (Day 1). The CFQ-R will be 
completed after informed consent was given by the subject, and prior to any other assessments 
scheduled for that visit. As part of the safety assessments, vital signs will be recorded, a pulse 
oximetry will be performed to measure oxygen saturation, and a 12-lead ECG will be 
recorded. Efficacy assessment tests will be performed, including sweat collection and 
spirometry. Blood and urine samples will be collected for clinical safety laboratory tests, 
serology, pregnancy test, and FSH test (if applicable). In addition, the following assessments 
will be done during screening: a complete check of inclusion and exclusion criteria, 
demographics (recording of year of birth, age and race), a general medical examination
including medical and surgical history (including CF-specific medical history e.g. date of 
diagnosis, sweat chloride concentration prior to any treatment with a CFTR modulator, CFTR 
mutation, etc.) and questions about smoking habits, alcohol and drug intake, a full physical 
examination (including height), and weight. Finally, the subject diary will be dispensed.
All AEs (serious and non-serious) and concomitant medications will be reported continuously 
from the time a signed and dated ICF is obtained until the final follow-up visit.

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6.3.
EFFICACY ASSESSMENTS
6.3.1. Sweat Chloride Concentration
Sweat chloride concentration is a biomarker of CFTR ion channel function. It is a sensitive, 
standardized and non-invasive measure to assess systemic CFTR modulator effects. Chloride 
concentration will be measured in sweat collected by an approved collection device (Wescor 
Macroduct® system) according to the 2009 guidelines issued by the Clinical and Laboratory 
Standards Institute.
To ensure consistency and reproducibility in this multi-center study, ‘trained’ clinical study 
centers will collect sweat according to standardized operating procedures. Two sweat 
collections, one from each arm, will be obtained from each subject at the time points indicated 
in the flow chart. Sweat samples will immediately be frozen and sent to the central laboratory 
for testing and interpretation of results.
The clinical study center should be encouraged to select subjects for the study for which it is 
known that adequate quantities of sweat can be collected.
Clinical study centers and subjects should not be informed of their sweat chloride results 
during the entire study duration, regardless of whether the subject prematurely discontinues 
treatment.
6.3.2. Spirometry
Spirometry will be performed to assess pulmonary function at the time points specified in the 
flow chart. Spirometry must be performed pre-dose at all visits, and additionally between 
1 and 2 hours post-dose on Day 1 and Day 29.
The spirometry test must meet the criteria for acceptability and repeatability as defined in the 
2005 ATS/ERS guidelines on standardization of lung function testing [7].
If screening spirometry measurements fail to meet acceptability and repeatability criteria in 
the first 3 efforts, up to 8 repeat spirometry efforts may be performed. If repeat values of the 
individual assessment(s) satisfy the eligibility criteria and are completed within the screening 
window, then the subject is eligible for the study.
Clinical study centers will be provided with spirometers to be used for all study spirometry 
assessments. Pulmonary function will be measured in a standardized manner. Spirometry data 
will be transmitted to a centralized spirometry service for quality review. Subjects should not 
be informed of their study-related spirometry results during the entire study duration,
regardless of whether the subject prematurely discontinues treatment.
At screening, spirometry to determine subject’s eligibility should preferably be performed 
pre-bronchodilator. If the subject used his/her bronchodilator before the screening visit, 
screening spirometry is allowed to be performed post-bronchodilator. At all other study visits, 
spirometry should be performed pre-bronchodilator. If on Day 1, the subject forgets to 
withhold his/her bronchodilator, all subsequent spirometry testing should be performed post-
bronchodilator, to be consistent with the conditions for the baseline measurement. If on 
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dose of bronchodilator at a subsequent visit, then spirometry should be collected post-
bronchodilator for that visit only.
Pre-bronchodilator spirometry is defined as spirometry testing performed for a subject:

that withheld his/her short-acting β-agonist (e.g. albuterol) or anticholinergic (e.g.
ipratropium bromide) for more than 4 hours prior to the spirometry assessment, AND

that withheld his/her long-acting bronchodilator such as salmeterol or formoterol for at 
least 12 hours, or longer-acting agents such as indacaterol and tiotropium for at least 
24 hours prior to the spirometry assessment.
The following parameters will be measured as part of the spirometry assessment:

FEV1 (L) and percent predicted FEV1 for age, gender, and height;

Forced vital capacity (FVC) (L) and percent predicted FVC for age, gender, and height;

FEV1/FVC ratio;

Forced expiratory flow between 25% and 75% of exhaled volume (FEF25-75).
Predicted values will be estimated using the 2012 Global Lungs Initiative equation.
6.3.3. Cystic Fibrosis Questionnaire-Revised (CFQ-R)
Eligible subjects will be asked to complete the adult version of the CFQ-R in their native 
language at the time points specified in the flow chart. The CFQ-R must be completed before 
study drug administration and prior to the start of any assessments scheduled for that visit.
The CFQ-R questionnaire provides information about: 

Nine quality of life domains: physical, role/school, vitality, emotion, social, body image, 
eating, treatment burden, health perceptions.

Three symptom scales: weight, respiratory and digestion.

Overall health perception.
6.4.
SAFETY ASSESSMENTS
The safety assessments will be based on AEs, physical examinations, vital signs, oxygen 
saturation by pulse oximetry, 12-lead ECG, spirometry (see efficacy assessments), and 
clinical safety laboratory evaluations.
6.4.1. Adverse Events
Adverse events will be recorded from the signature of the ICF until the final follow-up visit, 
as further described in Section 9 of this protocol.
6.4.2. Physical Examination
At each study visit, as specified in the flow chart, the physician will perform a physical 
examination. At screening, this will be a full physical examination including height. At 
subsequent visits, a limited physical examination (ear, nose, throat, chest and neck) will be 
performed. Weight will be measured at each visit (with shoes off).
Any clinically relevant abnormalities should be reported as AEs.

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6.4.3. Vital Signs
Vital signs (i.e. HR, systolic blood pressure [SBP], diastolic blood pressure [DBP], 
respiratory rate and oral body temperature) will be assessed in a standardized manner at the
time points specified in the flow chart. Vital signs must be recorded pre-dose at all visits, and 
additionally between 3 and 4 hours post-dose on Day 1. HR, SBP and DBP will be measured 
after 5 minutes in supine position.
Additional collection times, or changes to collection times of blood pressure, HR and body 
temperature will be permitted, as necessary, to ensure appropriate collection of safety data.
Normal ranges for vital signs parameters are presented in Appendix 2. Any clinically relevant 
abnormalities should be reported as AEs.
6.4.4. Oxygen Saturation by Pulse Oximetry
Arterial oxygen saturation by pulse oximetry will be measured at the time points specified in 
the flow chart. Pulse oximetry will be collected after the subject has been at rest (seated or 
supine) for at least 5 minutes.
Normal ranges for pulse oximetry are presented in Appendix 2. Any clinically relevant 
abnormalities should be reported as AEs.
6.4.5. 12-lead ECG
A resting 12-lead ECG will be recorded at the time points specified in the flow chart. Subjects 
should rest for at least 5 minutes in supine position prior to ECG evaluation. Parameters to be 
recorded include the following: HR, RR interval, PR interval, QRS, uncorrected QT interval, 
morphology, and rhythm analysis. QTcF will be calculated during the statistical analysis.
Normal ranges for ECG parameters are presented in Appendix 2. ECGs will be interpreted by 
the investigator for clinical significance. Any clinically relevant abnormalities should be 
reported as AEs.
6.4.6. Clinical Laboratory Evaluations
Clinical laboratory samples will be collected at the time points specified in the flow chart.
The following clinical laboratory tests will be performed:

Hematology: hematocrit, hemoglobin, red blood cell count, WBC count, WBC 
differential count (absolute and relative), and platelets.

Serum/plasma chemistry: glucose, urea, creatinine, uric acid, sodium, potassium, 
calcium, chloride, phosphorus, AST, ALT, GGT, total bilirubin, indirect bilirubin,
alkaline phosphatase, lactate dehydrogenase, albumin, total proteins, triglycerides, 
cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol.

Coagulation: activated partial thromboplastin time, prothrombin time (International 
Normalized Ratio).

Urinalysis: proteins, ketones, and microscopic examination of the sediment (cylinders, 
erythrocytes, leukocytes), pH, leukocyte esterase, glucose.

Serology: HBsAg, HCV antibody, HIV-1 and HIV-2 antibodies (only at screening).

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
Serum pregnancy testing (β-human chorionic gonadotropin) will be performed in female 
subjects of childbearing potential at screening, while a urine pregnancy test will be 
performed at all other scheduled visits. The urine pregnancy test must be negative prior to 
the first study drug administration.

FSH test for suspected post-menopausal female subjects only, defined as female subjects 
< 55 years with no menses for ≥12 months without a medical cause.

CFTR genotyping (only at baseline).
The laboratory values outside the normal range will be flagged and clinical relevance will be 
assessed by the investigator. Any clinically relevant abnormalities should be reported as AEs.
6.5.
PHARMACOKINETICS ASSESSMENTS
6.5.1. Blood Samples
Blood samples will be collected during the treatment period for the determination of 
GLPG2222 in plasma at the following time points:

Day 15: pre-dose and 0.5, 1, 2, 3, 4, 6 and 8 hours post-dose;

If it is known upfront that the subject is not available for the ‘full’ PK profiling on 
Day 15, it is allowed to schedule and perform this PK profiling on Day 29.

Day 29: pre-dose;

ED (if applicable): one additional sample to be taken pre-dose if study drug is still taken, 
or at any time during the visit if study drug is no longer taken.
Plasma concentrations of GLPG2222 will be measured using a validated liquid 
chromatography tandem mass spectrometry method with a lower limit of quantification of 
1.00 ng/mL. The details of sample handling and shipment instructions will be provided in a 
separate laboratory manual.
After the study is completed, any left-over samples belonging to the study subject may be 
stored for a period of 5 years under the control of the sponsor. These samples may be used by 
the sponsor or sponsor’s partner, or by other companies belonging to the sponsor for 
additional PK investigation (i.e. metabolic profiling, which is the assessment of biochemical 
intermediates – metabolites - in blood in order to describe the metabolic pathway of the 
compound). No characterization of human genetic material will be undertaken. Specific 
consent for storage of samples should be obtained from the subjects. Any research outside the 
context described in this protocol may only be conducted after approval by the IEC(s)/IRB(s)
and Regulatory Authority.
6.5.2. Sweat Samples
Remaining sweat samples (after sweat chloride concentration determination) may be used to 
determine the concentration of GLPG2222.
6.5.3. Pharmacokinetic Parameters
Noncompartmental PK calculations will be performed
by 
 using Phoenix 
WinNonLin® (Version 6.3 or higher).

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7.1.
DETERMINATION OF SAMPLE SIZE
The sample size calculation is based on the expected change from baseline in sweat chloride 
concentration after 29 days of treatment. The standard deviation of the sweat chloride 
concentration change is expected to be 10 mmol/L. With an 80% power, the study will be able 
to detect a difference between study drug doses of 14 mmol/L at a 5% 2-sided type-I error,
assuming 50 subjects are included in the study in both Cohorts A and B. In case the study is 
only performed in Cohort A, it will be able to detect a difference between study drug doses of 
16 mmol/L with 80% power. No adjustment for multiple testing (GLPG2222 doses versus 
placebo) has been done on the sample size calculation as this is an exploratory study.
7.2.
POPULATIONS FOR ANALYSES
7.2.1. All Screened Subjects Analysis Set
All subjects who provided informed consent by signing the ICF.
7.2.2. All Enrolled Subjects Analysis Set
All subjects who were enrolled into the study.
7.2.3. Intent to Treat Analysis Set
All enrolled subjects who received at least one dose of study drug and had at least one post-
baseline assessment with efficacy data.
7.2.4. Safety Analysis Set
All subjects who received at least one dose of study drug.
7.2.5. Pharmacokinetics Analysis Set
Subpopulation of the Safety Analysis Set, including all subjects who were exposed to 
GLPG2222 and who have available and evaluable PK data (e.g. excluding all protocol 
violations/deviations or AEs that may have an impact on the PK analysis).
7.3.
STATISTICAL ANALYSES
7.3.1. General Statistical Considerations
Summary tabulations will display the number of observations, mean, standard error, median, 
minimum, and maximum for continuous variables, and the number and percent category for 
categorical data. Tabulated descriptive statistics and graphical data displays may be used to 
summarize the data. Inferential statistics will be interpreted at the 2-sided 5% level.
7.3.2. Analyses of Demographics and Baseline Characteristics
Subject disposition, protocol deviations, demographics, baseline characteristics, medical 
history, concomitant therapies, and exposure will be analyzed descriptively and/or listed and 
presented overall and by treatment group.

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7.3.3. Analyses of Efficacy Parameters
Descriptive statistics of actual values, changes from baseline (pre-dose on Day 1), and percent 
changes from baseline will be provided.
An analysis of covariance (ANCOVA) model on the changes from baseline at each time 
point, with treatment as factor and baseline value as covariate, will be applied to the following 
parameters:

Sweat chloride concentration;

FEV1;

CFQ-R scores.
Between-group comparisons will be done for each GLPG2222 group versus the pooled 
placebo group (if the study is performed in both Cohorts A and B) or versus placebo in 
Cohort A (if the study is only performed in Cohort A).
Missing data will be imputed, also for subjects who prematurely discontinue the study. The 
primary imputation method will be the last-observation-carried-forward. An observed-case 
analysis will also be performed. Details regarding imputation method will be described in the 
statistical analysis plan.
A sensitivity analysis will be performed by using non-parametric tests. The GLPG2222 
groups and pooled placebo group (if the study is performed in both Cohorts A and B) or the 
GLPG2222 groups and placebo in Cohort A (if the study is only performed in Cohort A) will 
be compared using a Kruskal-Wallis test (overall treatment effect) and Wilcoxon rank sum 
tests (pairwise comparisons versus the corresponding placebo group).
Additional exploratory analyses and graphical presentations may be performed when deemed 
useful to better understand the data.
7.3.4. Analyses of Safety Data
Adverse events will be fully described and coded according to the Medical Dictionary for 
Regulatory Activities. Physical examination, weight, vital signs, oxygen saturation by pulse 
oximetry, 12-lead ECG, spirometry, and clinical safety laboratory data will be analyzed 
descriptively. Changes from baseline (pre-dose on Day 1) and shifts according to normal 
ranges will be presented as well. Analysis will be done per treatment group.
7.3.5. Pharmacokinetics Analyses
Descriptive statistics will be calculated by treatment group and day for the plasma 
concentrations and PK parameters of GLPG2222.
Plasma concentrations of GLPG2222 will be analyzed using a population PK approach 
including the assessment of covariates influencing the PK in CF subjects. The relation
between exposures and selected efficacy and safety endpoints will also be investigated, if 
relevant.

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7.3.6. Exploratory Biomarkers
Exploratory biomarker
data
 
will be analyzed using descriptive statistics of actual values, changes from 
baseline (pre-dose on Day 1), and percent changes from baseline.
7.3.7. Apical Expression of F508del CFTR (Optional Substudy)
For subjects who participate in the optional substudy, data on apical expression of F508del 
CFTR will be analyzed using descriptive statistics of actual values, changes from baseline 
(pre-dose on Day 1), and percent changes from baseline.
8.
DATA SAFETY MONITORING BOARD
To enhance the safety and integrity of the study data, a DSMB consisting of independent 
experts will convene to periodically review the accumulating unblinded data for the study. 
The DSMB will review accumulating data and provide a recommendation on study 
continuation or early termination. The DSMB Charter will outline the specific responsibilities 
and composition of the DSMB, and will contain the details of outputs provided for the 
meetings, as well as the meeting schedule.

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GENERAL PROCEDURES
9.
ADVERSE EVENTS
9.1.
DEFINITIONS
Adverse Event
An AE is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An AE does not necessarily have a 
causal relationship with the treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not 
related to that medicinal (investigational or non-investigational) product.
Serious Adverse Event
An SAE is any untoward medical occurrence that at any dose meets any of the following 
conditions:

results in death;

is life-threatening: the subject is at risk of death at the time of the event. It does not refer 
to an event that hypothetically might cause death if it were more severe;

requires inpatient hospitalization or prolongation of existing hospitalization;

results in persistent or significant disability/incapacity;

is a congenital anomaly/birth defect.

is a medically significant event that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed in the definitions above.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or intensity is not consistent with the 
applicable product reference safety information. For a study drug, the expectedness of an 
adverse event will be determined by whether or not it is listed in the Investigator’s Brochure
[6].
Associated With the Use of the Drug
An AE is considered associated with the use of the drug if the causality is possible, probable, 
or certain by the definitions listed in Section 9.3.
9.2.
INTENSITY OF ADVERSE EVENT
Each AE must be rated on a 3-point scale of increasing intensity:

Mild:
Transient or mild discomfort; no limitation in activity; no medical intervention/therapy 
required.

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
Moderate:
Mild to moderate limitation in activity; some assistance may be needed; no or minimal 
medical intervention/therapy required.

Severe:
Marked 
limitation 
in 
activity; 
some 
assistance 
usually 
required; 
medical 
intervention/therapy required, hospitalization possible.
If there is a change in intensity of an AE, it must be recorded as a separate event.
9.3.
CAUSALITY ASSESSMENT
The following decision choice will be used by the investigator to describe the causality 
assessment between the reported event and the investigational medicinal product. 

Unrelated:
No relationship between the AE and the administration of study drug; related to other 
etiologies such as concomitant medications or subject's clinical state.

Unlikely:
Event or laboratory test abnormality, with a time to drug intake that makes a relationship 
improbable (but not impossible). Disease or other drugs provide plausible explanations.

Possible:
Event or laboratory test abnormality, with reasonable time relationship to drug intake 
which could also be explained by disease or other drugs. Information on drug withdrawal 
may be lacking or unclear.

Probable:
Event or laboratory test abnormality, with reasonable time relationship to drug intake. 
Event unlikely to be attributed to disease or other drugs. Response to withdrawal is 
clinically reasonable and rechallenge not required.

Certain:
Event or laboratory test abnormality, with plausible time relationship to drug intake 
which cannot be explained by disease or other drugs. Response to withdrawal is plausible 
(pharmacologically, 
pathologically). 
Event 
definitive 
pharmacologically 
or 
phenomenologically (i.e. an objective and specific medical disorder or a recognized 
pharmacological phenomenon). Rechallenge satisfactory, if necessary.
9.4.
ACTION TAKEN REGARDING INVESTIGATIONAL PRODUCT 
(IF APPLICABLE)
The action taken must be described by choosing among:

Dose not changed:
In case no action is taken regarding the study drug.

Dose reduced: Not allowed in this study

Drug permanently withdrawn:
In case a subject is permanently withdrawn from the study.

Drug temporarily withdrawn:
In case the study drug is temporarily withdrawn.

Not applicable:
Other situations (e.g. in case an AE started after the last study drug administration)

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9.5.
OUTCOME
Each AE outcome must be rated using one of the following terms:

Recovered/Resolved;

Recovered/Resolved with sequelae;

Not recovered/Not resolved;

Fatal;

Recovering/Resolving;

Unknown.
9.6.
RECORDING ADVERSE EVENTS
Adverse events will be recorded from the signature of the ICF until the final follow-up visit. 
In case an AE is ongoing at that time, it will be followed up as much as possible by the 
investigator until resolution or until stabilization.
It is the responsibility of the investigator to collect all AEs (both serious and non-serious) 
derived by spontaneous, unsolicited reports of subjects, by observation and by routine open 
questioning (such as “How do you feel?”).
Any adverse or unusual event occurring during or after the clinical study (until the follow-up 
visit), whether observed by the investigator or investigational staff, or spontaneously reported 
by the subjects, will be recorded in the eCRF and medical file.
9.7.
MANAGING SERIOUS ADVERSE EVENTS
Subjects experiencing an SAE or an emergency situation will be examined by a physician as 
soon as possible. The physician in attendance will do whatever is medically needed for the 
safety and well-being of the subject. 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. The subject will be followed until the SAE 
resolves or until the subject is medically stabilized.
9.8.
REPORTING SERIOUS ADVERSE EVENTS / PREGNANCIES
9.8.1. Serious Adverse Events
All SAEs, whether or not deemed drug-related, must be recorded in the eCRF and SAE form 
and reported by the investigator to 
 Medical Affairs (
 MA) 
within 24 hours by facsimile. Other means of transmission can be decided where facsimile is 
not possible. The SAE must include a clearly written narrative describing signs, symptoms, 
and treatment of the event, diagnostic procedures, as well as any relevant laboratory data and 
any sequelae.
Follow-up and outcomes must be reported for all subjects that experience an SAE. It is critical 
that the information provided on the 
 
 SAE form matches the information recorded 
on the eCRF for the same event. In addition, the same information is to be recorded in the 
source documents.

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Copies of additional laboratory tests, consultation reports, post mortem reports, hospital case 
reports, autopsy reports, and other documents must be sent when requested and applicable. 
Follow-up reports relative to the subject’s subsequent course must be submitted to 
 
MA until the event has subsided or, in case of permanent impairment, until the condition 
stabilizes.
9.8.2. Pregnancy
All initial reports of pregnancies in female subjects and partners of male subjects included in 
the study must be reported to 
 MA by the investigator within 24 hours of knowledge 
of the event, using a pregnancy form. 
The investigator will contact the subject at the expected time of delivery for follow-up. 
Abnormal pregnancy outcomes are considered SAEs and must be reported using the SAE 
form.
If a subject is found to be pregnant, she must be immediately withdrawn from the study.
9.9.
REPORTING SERIOUS ADVERSE EVENTS TO COMPETENT 
AUTHORITIES / ETHICS COMMITTEES / INSTITUTIONAL 
REVIEW BOARDS
 MA assumes responsibility for appropriate reporting of AEs to the Regulatory 
Authorities. 
 MA will also report to the investigator(s) all SAEs that are unlisted 
(unexpected) and associated with the use of the drug. The investigator(s) (or 
 MA 
where required) must report these events to the appropriate IEC/IRB that approved the 
protocol unless otherwise required and documented by the IEC/IRB.
Adverse events reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations. 
After termination of the clinical study (last subject last contact in the study), any unexpected 
safety issue that changes the risks benefit analysis and is likely to have an impact on the 
subjects who have participated in it, will be reported by the sponsor/
 MA as soon as 
possible to the Competent Authority(ies) concerned together with proposed actions.
10.
STUDY CLOSURE CONSIDERATIONS
The sponsor reserves the right to close the clinical study center or terminate the study at any 
time for any reason. In case of an early termination of the study or temporary halt by the 
sponsor, the IEC/IRB should be notified within 15 calendar days, including a detailed written 
explanation of the reasons for the termination/halt.
When the study ends, the sponsor will submit an “end of trial notification” to both the 
IEC/IRB and Regulatory Authorities, according to local regulations, by using the “Declaration 
of the End of Trial Form”. The declaration will be submitted within 90 days of the end of the 
study. 

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Reasons for the closure of a clinical study center or termination of a trial by the sponsor may 
include but are not limited to:

Successful completion of the trial at the clinical study center,

The overall required number of subjects for the trial has been recruited,

Failure of the investigator to comply with the protocol, International Council for
Harmonisation-Good Clinical Practice (ICH-GCP) guidelines or local requirements,

Safety concerns,

Inadequate recruitment of subjects by the investigator.
11.
STUDY MATERIALS
11.1.
INVESTIGATIONAL MEDICAL PRODUCTS
The investigator acknowledges that the study drugs are investigational and as such must be 
handled strictly in accordance with the clinical study protocol and the container label. 
Supplies must be retained in a limited access area and under the appropriate environmental 
conditions as specified on delivery. Upon receipt of the study drugs, the investigator or 
delegate will verify whether the correct amount of study drugs are delivered and whether 
those are intact. 
Supplies should be dispensed under the supervision of the investigator or sub-investigator, or 
by a hospital pharmacist. Local regulations should be adhered to. It is the investigator's or 
delegate’s responsibility to ensure that subjects return their study drugs (including empty 
packages, e.g. empty bottles). Returned study drugs must not be dispensed again, even not to 
the same subject. Each time study drugs is dispensed to or returned by the subject, this must 
be documented on the Drug Accountability Form. Whenever a subject brings his/her study 
drug to the clinical study center for drug accountability this is not seen as a return of supplies. 
Unused study drug (not dispensed) and study drug returned by the subject must be available 
for verification by the monitor.
All used and unused study drug will be returned to the drug supplier/CRO depot or will be 
passed over for destruction on-site (conform local regulations) or by an authorized destruction 
unit after authorization by the sponsor. This will be documented on the Drug Return Form and 
a destruction certificate, if applicable.
11.2.
STUDY DOCUMENTS
The following documents must be provided to the sponsor or representatives before shipment 
of study drugs to the clinical study center:

A signed and dated protocol and amendment(s), if any.

A copy of the signed and dated written IEC/IRB approval specifying the documents being 
approved: the protocol, amendments, ICF, any other written information provided to the 
subject and subject recruitment materials.
This approval must clearly identify the trial by protocol title and trial number.

Regulatory Authority approval or notification, if required.

Documentation on which the assessment of the investigator’s qualifications was based 
(e.g. curriculum vitae).

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The following documents must be provided to the sponsor or representatives prior to 
enrollment of the first subject:

The names of the current members or composition of the IEC/IRB and their position in 
the health-care institution or their credentials.
In case the (sub) investigator is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the voting for the trial.

Completed Investigator Financial Disclosure Forms from the investigator and all sub-
investigators.

Signed and dated trial agreement, if applicable.

Signed and dated financial agreement.

Documentation on which the assessment of the sub-investigators’ qualifications was 
based (e.g. curriculum vitae).

Current laboratory normal ranges for all tests required by the protocol that will be 
performed.

Laboratory documentation demonstrating competence and test reliability (e.g. 
accreditation/license), if applicable.
11.3.
PARTICIPATION CARDS
If the subjects are not under 24-hour supervision of the investigator or his/her staff (out-
subjects), they must be provided with a Subject Participation Card indicating the name of the 
investigational product, the 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.
11.4.
SOURCE DATA
The nature and location of all source documents will be discussed during the Site Initiation 
Visit and will be documented to ensure that all sources of original data required to complete 
the eCRF are known and are accessible for verification by the monitor. If electronic records 
are maintained, the method of verification must be discussed and agreed upon between the 
investigational staff and the monitor.
The required source data are discussed during the Site Initiation Visit and should include 
sequential notes containing at least the following information for each subject:

Subject identification (name, year of birth, age, gender).

Documentation that subject meets eligibility criteria, i.e. history, physical examination, 
and confirmation of diagnosis (to support inclusion and exclusion criteria).

Participation in trial (including trial number).

Trial discussed and date of informed consent.

Dates of all visits.

Documentation that protocol specific procedures were performed.

Results of efficacy parameters, as required by the protocol.

Start and end date (including dose regimen) of study drugs (preferably drug dispensing 
and return should be documented as well).

Record of all adverse events and other safety parameters (start and end date, and 
preferably including causality and intensity).

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
Concomitant medication (including start and end date, and dose.
If relevant, dose changes should be motivated).

Date of trial completion and reason for ED, if applicable.

Subject Diaries.
Source data may be directly captured from devices transferred from third partners (e.g. 
laboratory data) or entered manually into the clinical study center’s eCRF and medical file.
It is recommended that the author of an entry in the source documents is identifiable. 
Following ICH GCP Guidelines, direct access 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.
11.5.
ELECTRONIC DATA CAPTURE
Electronic Data Capture (EDC) will be used for this study, meaning that all CRF data will be 
entered in eCRFs at the clinical study center. All data related to the study must be recorded in 
the EDC system in English.
The eCRFs should always reflect the latest observations on the subjects participating in the 
study. Therefore, the eCRFs are to be completed as soon as possible during or after the 
subject’s visit. To avoid inter-observer variability, every effort must be made to ensure that all 
efficacy evaluations are completed by the same individual who made the initial baseline 
determinations. The investigator must verify that all data entries in the eCRFs are accurate 
and correct. If certain information is not done, not available or not applicable or unknown, the 
investigator must indicate this in the eCRF. The investigator will be required to electronically 
sign off on the clinical data.
During monitoring visits, the monitor will review the eCRFs, evaluate them for completeness 
and consistency. The eCRF will be compared with the source documents to ensure that there 
are no discrepancies between critical data. All entries, corrections and alterations are to be 
made by the responsible investigator or his/her designee. The monitor cannot enter data in the 
eCRFs. Once clinical data of the eCRF have been submitted to the central server, corrections 
to the data fields will be audit trailed, meaning that the reason for change, the name of the 
person who performed the change, together with time and date will be logged. Roles and 
rights of the site personnel responsible for entering the clinical data into the eCRF will be 
determined in advance.
If additional corrections are needed, the responsible monitor or data manager will raise a 
query in the EDC application. The appropriate investigational staff will answer queries sent to 
the investigator. This will be audit trailed by the EDC system meaning that the name of 
investigational staff, time and date stamp are captured.
12.
ARCHIVING
The investigator maintains the study specific documents as specified in “Essential Documents 
for the Conduct of a Clinical Trial (ICH E6, Section 8)” and as required by the applicable 
regulatory requirement(s). The investigator must take measures to prevent accidental or 
premature destruction of these documents.

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Essential documents must be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents must
be retained for a longer period however if required by the applicable regulatory requirements 
or by an agreement with the sponsor.
It is the responsibility of the sponsor to inform the investigator/institution as to when these 
documents no longer need to be retained.
Under no circumstance shall the investigator re-locate or dispose of any trial 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 trial, 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 trial.
13.
CONFIDENTIALITY
All information concerning the product and the sponsor’s operations (such as patent 
applications, formulae, manufacturing processes, basic scientific data or formulation 
information supplied to the investigator by the sponsor and not previously published) is 
considered confidential by the sponsor and must 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 trial and will not use it for other purposes.
In order to permit easy identification of the individual subject during and after the trial, the 
investigator is responsible for keeping an updated Subject Identification Code List. The 
monitor will review this document for completeness. However, the investigator must 
guarantee the subject’s anonymity will be maintained. Therefore, in order to ensure subject 
confidentiality, the Subject Identification Code List will remain at the clinical study center 
and no copy will be made.
14.
REPORTING AND PUBLICATION
14.1.
REPORTING
The results of the trial will be reported in a single clinical study report. A summary of the 
final report will be provided to the investigators, to the applicable Regulatory Authorities and 
IEC(s)/IRB(s) if required by the applicable regulatory requirements within one year after end 
of study.
One participating investigator will be appointed for review and sign off the final clinical study 
report. The selection of this investigator will be determined by the recruitment performance 
and specific expertise related to the nature and the primary objectives of the study.

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14.2.
PUBLICATION
All information concerning the product and the sponsor’s operations (such as patent 
applications, formulae, manufacturing processes, basic scientific data or formulation 
information supplied to the investigator by the sponsor and not previously published) is 
considered confidential by the sponsor and must 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 study and will not use it for other purposes without the 
written approval of the sponsor.
It is understood by the investigator that the sponsor will use the information developed in this 
clinical study in connection with the development of the compound and therefore, may 
disclose it as required to other clinical investigators and to regulatory agencies. In order to 
allow for the use of the information derived from this clinical study, the investigator 
understands that he has an obligation to provide and disclose test results and all data 
developed during this trial to the sponsor.
The investigator may not submit for publication or presentation, the results of this study 
without the prior written approval of the sponsor. The investigator must understand that it is 
not the sponsor’s intention to prevent publication of such data as is generated in the study. 
However, the sponsor reserves the right to control the route and rate of such publication.
The sponsor will not unreasonably withhold consent to publish the data generated in this 
study. However, it is the policy of the sponsor not to allow the investigators to publish their 
results or findings prior to the sponsor’s publication of the overall study results. The 
investigator agrees that before he/she publishes any results of this trial, he/she shall provide 
the sponsor with at least 90 days for full review of the pre-publication manuscript prior to 
submission of the manuscript to the publisher. In accordance with generally recognized 
principles of scientific collaboration, co-authorship with any company personnel will be 
discussed and mutually agreed upon before submission of a manuscript to a publisher.
15.
ETHICS
15.1.
INDEPENDENT ETHICS COMMITTEE (IEC) /
INSTITUTIONAL REVIEW BOARD (IRB)
This study can only be undertaken after full approval of the clinical study protocol, ICF, any 
other written information given to subjects, and subject recruitment materials has been 
obtained from the IEC/IRB. This approval document must be dated and clearly identify the 
study and the related study documents being approved, including the subject compensation 
programs.
During the course of study the following documents will be sent to the IEC/IRB for review:

Changes to the Investigator’s Brochure

Reports of adverse events that are serious, unlisted and associated with the investigational 
drug
Substantial amendments and applicable ICF revisions must promptly be submitted to the 
IEC/IRB for review and approval prior to implementation of the change(s), except when 
necessary to eliminate an immediate hazard to the study subjects.

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The IEC/IRB is responsible for continuous review of the study. At least once a year, the 
investigator will provide the IEC/IRB with a progress report to allow review of the study. 
Additional progress reports must be provided if required by the IEC/IRB. These requests and 
(re) approvals, if applicable, must be documented in writing.
15.2.
REGULATORY APPROVAL / NOTIFICATION
This clinical study protocol, title and a list of clinical study centers, IEC(s)/IRB(s) approvals, 
as well as other relevant documentation will be submitted to the local Regulatory Authorities 
for review and approval prior to trial start. Upon completion, the Regulatory Authorities will 
be notified the study has ended. The study will only be undertaken in compliance with the 
local regulatory requirements.
15.3.
ICH GOOD CLINICAL PRACTICE
This study will be conducted in accordance with the current ICH-GCP Guideline E6. 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 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.
This study will be conducted in compliance with the Declaration of Helsinki (1964 and 
successive amendments), current GCP and the applicable European and local regulatory 
requirements.
15.4.
INFORMED CONSENT
The investigator or designated personnel must explain the study and the implications of 
participation (e.g. objectives, methods, anticipated benefits and possible risks) to potential 
subjects or their legally acceptable representatives prior to any trial related activity. Subjects 
will be informed that their participation is voluntary and that they may withdraw from the 
study at any time. They will be informed that choosing not to participate or to withdraw from 
the study will not have an impact on the care the subject will receive for the treatment of 
his/her disease. In case the subject is unable to read and write, an impartial witness must 
confirm the informed consent.
The subject will be given sufficient time to read the ICF and to ask additional questions. After 
this explanation and before entry in the study, consent must be appropriately recorded by 
means of the subject's personally dated signature or by the signature of an independent 
witness who certifies the subject's consent in writing. After having obtained the consent, a 
copy of the signed and dated ICF must be given to the subject.
If new information becomes available that may be relevant to the subject’s willingness to 
participate in the study, the subject will be informed in a timely manner by means of an 
updated ICF. This amended ICF will be signed and dated by the subject and the investigator 
to document the willingness of the subject to continue with the study.
This signed and dated amended version will be filed together with the initial signed and dated 
ICF.

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16.
FINANCING AND INSURANCE
16.1.
FINANCIAL DISCLOSURE
The disclosed financial interest of the investigator must be collected before screening of the 
first subject, following study completion at the clinical study center and one year following 
overall study completion. The investigator must promptly update this information if any 
relevant changes occur during this period. Disclosable financial interests will be recorded on 
the Investigator Financial Disclosure Form.
Any investigator(s) added as investigational staff must complete the Investigator Financial 
Disclosure Form at the beginning of their participation in the study. For any investigator(s) 
leaving the clinical study center prior to study completion, an Investigator Financial 
Disclosure Form must be obtained at the end of their contribution to the study.
16.2.
INDEMNIFICATION
The sponsor will indemnify the investigator and hold harmless the investigator and his or her 
medical staff from any claim for damages, demand or cost arising from the activities to be 
carried out in compliance with the clinical study protocol.
The investigator must notify the sponsor immediately upon notice of any claims or lawsuits.
16.3.
INSURANCE
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start 
of clinical study. For subjects treated according to the clinical study protocol, injury possibly 
arising from participating in this study is covered by the liability insurance of the sponsor, 
unless malpractice from the investigator.
17.
DATA QUALITY CONTROL / ASSURANCE
17.1.
MONITORING
This clinical study will be monitored by sponsor representatives according to the current 
Standard Operating Procedure for the monitoring of clinical studies.
The monitor will perform on-site monitoring visits as frequently as necessary which will be 
documented on the monitoring log. Shortly before the study starts, the monitor will meet with 
the investigator and study staff involved to review the study-specific procedures on study 
conduct and recording the data in the eCRF. The first monitoring visit will take place as soon 
as possible after enrollment and the investigator shall permit the monitor to verify the 
progress of the study on a continues basis. The investigator shall make the eCRFs available, 
provide missing or corrected data and sign the eCRFs. Key data transcribed onto the eCRFs, 
such as the subject's sex, age, assessment dates, test results etc., will be reviewed against the 
available source documents. Personal information will be treated as strictly confidential and 
will not be made publicly available. Any inconsistency between source data and data recorded 
in the eCRF will be corrected.

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The sponsor will ensure that appropriate QC steps are included into the different clinical study 
processes to guarantee adequate protection of the subjects and to guarantee the quality of the 
data.
17.2.
AUDIT AND INSPECTION
To ensure compliance with relevant regulations, an independent Quality Assurance 
representative, Regulatory Authorities and/or IEC(s)/IRB(s) may review this 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 study and will have access to the data generated 
during the study, source documents, and subject's files. By participating in this study, 
investigators agree to this requirement.

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REFERENCES
[1
] 
, „A-1622622 [ABT-2222], CFTR Corrector, Report No. 4, In Vitro Pharmacology of 
ABBV-2222; part 4, R&D/16/1268,” 2016.
[2
] 
J. Clancy, S. Rowe, F. Accurso, M. Aitken, R. Amin, M. Ashlock, M. Ballmann, M. Boyle, I. 
Bronsveld, P. Campbell, K. D. S. De Boeck, H. Dorkin, J. Dunitz, P. Durie, M. Jain, A. Leonard, 
K. McCoy, R. Moss, J. Pilewski en e. al, „Results of a phase IIa study of VX-809, an 
investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the 
F508del-CFTR mutation.,” Thorax, pp. 67(1): 12-8, 2012. 
[3
] 
M. Boyle, S. Bell, M. Konstan, S. McColley, S. Rowe, E. Rietschel, X. Huang, D. Waltz, N. Patel, 
D. Rodman en V.-8.-1. s. group, „A CFTR corrector (lumecaftor) and a CFTR potentiator 
(ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a 
phase 2 randomised controlled trial.,” Lancet Respir Med., pp. 2(7): 527-538, 2014. 
[4
] 
Donaldson, S, „VX-661, an investigational CFTR corrector, in combination with ivacaftor, a CFTR 
potentiator, in patients with CF and homozygous for the F508Del-CFTR mutation: interim 
analysis,” in European Cystic Fibrosis Conference, Lisbon, Portugal, 2013. 
[5
] 
I. H. T. ICH E10 Guideline, „Choice of Control Group and Related Issues in Clinical Trials E10,” 
20 July 2000. [Online]. Available: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E10/Step4/E10
_Guideline.pdf. [Geopend 15 November 2016].
[6
] 
Galapagos, „Investigator's Brochure for GLPG2222,” Galapagos NV, 2016.
[7
] 
M. Miller, J. Hankinson en V. Brusasco, „Standardisation of spirometry.,” Eur Respir J Vol 26(2), 
pp. 319-338, 2005. 

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APPENDICES
Appendix 1 Study Contact Information
Role
Contact Information
Sponsor
Galapagos NV
Industriepark Mechelen Noord
Generaal De Wittelaan L11 A3
2800 Mechelen, Belgium
Medical Lead
 MD, MBA - Galapagos NV
Generaal De Wittelaan, L11 A3
2800 Mechelen, Belgium
Tel: 
Mobile: 
E-mail: 
Clinical Study Lead
Galapagos NV
Generaal De Wittelaan, L11 A3
2800 Mechelen, Belgium
Tel: 
Mobile: 
E-mail: 
Head of Development 
Clinical Pharmacology
– Galapagos SASU
102 Avenue Gaston Roussel
93230 Romainville, France
Tel: 
E-mail: 
Lead Biostatistics
– Galapagos NV
Generaal De Wittelaan, L11 A3
2800 Mechelen, Belgium
Tel: 
 
E-mail : 
Pharmacovigilance Lead
 MB ChB
Generaal De Wittelaan, L11 A3
2800 Mechelen, Belgium
Mobile: 
Mobile: 
E-mail: 

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Contract Research 
Organization
United Kingdom

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Appendix 2 Normal Ranges for Vital Signs, Pulse Oximetry and ECG
Parameters
NORMAL RANGES FOR VITAL SIGNS
Normal ranges applicable in supine position (after 5 minutes):
Systolic blood pressure 
(mmHg)
Diastolic blood pressure 
(mmHg)
Heart rate (bpm)
Oral temperature (°C)
90 ≤ SBP ≤ 150
45 ≤ DBP ≤ 90
40 ≤ HR ≤ 100
35.5 ≤ t° ≤ 37.5
For respiratory rate, normal range for an adult person at rest: 12 to 16 breaths per minute.
NORMAL RANGES FOR PULSE OXIMETRY
Normal arterial oxygen saturation level (SpO2): 95% to 100%.
NORMAL RANGES FOR ECG PARAMETERS
Normal ranges applicable in supine position (after 5 minutes): 
PR (ms)
QRS (ms)
QTcF (ms)
Heart rate (bpm)
120 PR 220
QRS 120
QTc 450 (male subjects)
QTc 460 (female subjects)
40 ≤ HR ≤ 100

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SIGNATURE PAGE – SPONSOR
Title
A Phase IIa, randomized, double-blind, placebo-controlled study to evaluate 
multiple doses of GLPG2222 in subjects with Cystic Fibrosis who are 
homozygous for the F508del mutation.
This Clinical Study Protocol has been reviewed and approved by the sponsor to ensure 
compliance with International Conference on Harmonization (ICH) guidelines for Good 
Clinical Practices (GCP) and applicable regulatory requirements.
Medical Lead
Signature
Date

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SIGNATURE PAGE – INVESTIGATOR
Title
A Phase IIa, randomized, double-blind, placebo-controlled study to evaluate 
multiple doses of GLPG2222 in subjects with Cystic Fibrosis who are 
homozygous for the F508del mutation.
I, the undersigned, have read this protocol and will conduct the study as described in 
compliance with the Clinical Study Protocol, in accordance with International Conference on 
Harmonization (ICH) guidelines for Good Clinical Practices (GCP) and applicable regulatory 
requirements.
Investigator Name
Signature
Date