Clinical trial NCT03119649
Conditions: Cystic Fibrosis
Sponsor: Galapagos NV
Start date: 2017-03-18; Completion date: 2017-10-19
Enrollment: 59 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase IIa, multi-center, randomized, double-blind, placebo-controlled, parallel-group study to evaluate 4 different doses of GLPG2222 administered for 4 weeks to adult subjects with a confirmed diagnosis of CF and homozygous for the F508del Cystic Fibrosis Transmembrane conductance Regulator (CFTR) mutation.

Detailed description:

Arms: arm 1: Participants received a single GLPG2222 50 mg tablet and two matching placebo tablets orally, QD for 29 days. arm 2: Participants received a single GLPG2222 100 mg tablet and two matching placebo tablets orally, QD for 29 days. arm 3: Participants received two GLPG2222 100 mg tablets and one matching placebo tablet orally, QD for 29 days. arm 4: Participants received two GLPG2222 150 mg tablets and one GLPG2222 100 mg tablet orally, QD for 29 days. arm 5: Participants received three matching placebo tablets, orally, QD for 29 days. arm 6: Participants received three matching placebo tablets, orally, QD for 29 days.
Interventions: intervention 1: GLPG2222 50 mg intervention 2: GLPG2222 100 mg intervention 3: Placebo intervention 4: GLPG2222 200 mg intervention 5: GLPG2222 400 mg
Intervention descriptions: intervention 1: Oral tablet(s) containing GLPG2222 intervention 2: Oral tablet(s) containing GLPG2222 intervention 3: Matching oral tablet(s) containing placebo intervention 4: Oral tablet(s) containing GLPG2222 intervention 5: Oral tablet(s) containing GLPG2222

Protocol documents:
Prot_000.pdf: 


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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 
Day 1, spirometry is collected pre-bronchodilator, but the subject forgets to withhold his/her 


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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

SAP_001.pdf: 


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TABLE OF CONTENTS
List of Tables ........................................................................................................................6
List of Figures.....................................................................................................................10
List of Listings ....................................................................................................................13
1. Study Design..................................................................................................................15
1.1.
Study Objectives...................................................................................................15
1.1.1.
Primary Objective ....................................................................................15
1.1.2.
Secondary Objectives ...............................................................................15
1.2.
Study Endpoints....................................................................................................15
1.2.1.
Primary Endpoint .....................................................................................15
1.2.2.
Secondary Endpoints................................................................................15
1.3.
Study Design.........................................................................................................15
1.4.
Protocol and Protocol Amendments ......................................................................17
1.5.
Flowchart..............................................................................................................17
2. Analysis Populations .....................................................................................................19
2.1.
All Screened Subjects Population..........................................................................19
2.2.
All enrolled Population .........................................................................................19
2.3.
Intent to Treat population......................................................................................19
2.4.
Safety Population..................................................................................................19
2.5.
Pharmacokinetics population.................................................................................19
3. Treatment Groups.........................................................................................................19
3.1.
Randomized versus Actual Treatment ...................................................................19
3.2.
Treatment Group Labels........................................................................................20
3.3.
Pooling of Groups.................................................................................................20
3.4.
Sub-Groups...........................................................................................................20
3.5.
Totals over Groups................................................................................................21
4. Analysis Periods and Analysis Time Points .................................................................21
4.1.
Relative Number of Days......................................................................................21
4.2.
Analysis Periods for Non-visit Data ......................................................................21
4.3.
Algorithm of Allocating Visits to Time Windows .................................................21
4.4.
Selection of Visits.................................................................................................22
4.5.
Handling of Unscheduled Assessments .................................................................23
5. Handling of Data...........................................................................................................23
5.1.
Calculation of Descriptive Statistics......................................................................23
5.2.
Calculation of Percentages ....................................................................................24
5.3.
Handling of Values below (or above) a Threshold.................................................24
5.3.1.
Safety Data...............................................................................................24
5.3.2.
PK Data....................................................................................................24
5.3.3.
PD Data....................................................................................................25
5.4.
Handling of Missing Data .....................................................................................25
5.4.1.
Observed Cases (OC) ...............................................................................25
5.4.2.
Last Observation Carried Forward (LOCF) ..............................................25
5.4.3.
Handling of Missing Date(Time) or Partially Known Date(Time).............25
5.5.
Handling of Outliers..............................................................................................25
5.6.
Handling of Seconds in Datetime Fields................................................................25


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6. Software and Procedures..............................................................................................26
6.1.
Software................................................................................................................26
6.2.
Procedures ............................................................................................................26
6.3.
Formats.................................................................................................................26
7. Statistical Methods........................................................................................................28
7.1.
Planned Analyses, Protocol Amendments Included ...............................................28
7.1.1.
General Statistical Considerations ............................................................28
7.1.2.
Analyses of Demographics and Baseline Characteristics ..........................28
7.1.3.
Analyses of Efficacy Parameters ..............................................................28
7.1.4.
Analyses of Safety Data ...........................................................................29
7.1.5.
Pharmacokinetics Analyses ......................................................................29
7.1.6.
Exploratory Biomarkers ...........................................................................29
7.1.7.
Apical Expression of F508del CFTR (Optional Substudy)........................29
7.2.
Changes to the Planned Analyses, Not Covered by Protocol Amendments ............29
7.2.1.
Changes before Database Lock.................................................................29
7.2.2.
Changes after Database Lock....................................................................29
8. Definitions of General Analysis Tables, Listings and Figures.....................................30
8.1.
Subject Disposition ...............................................................................................30
8.2.
Protocol Deviations and Eligibility........................................................................31
8.3.
Subjects Excluded from Analysis..........................................................................31
8.4.
Demographics and Baseline Disease Characteristics..............................................32
8.4.1.
Parameters................................................................................................32
8.4.2.
Analysis ...................................................................................................32
8.5.
Baseline disease characteristics .............................................................................34
8.5.1.
Parameters................................................................................................34
8.5.2.
Analysis ...................................................................................................34
8.6.
Medical History and Concurrent Diseases .............................................................35
8.7.
Prior and Concomitant Therapies ..........................................................................36
8.7.1.
Classification of Therapies .......................................................................36
8.7.2.
Coding of Therapies.................................................................................37
8.7.3.
Analysis ...................................................................................................37
8.8.
Exposure to Study Medication and Compliance ....................................................37
8.8.1.
Derivations...............................................................................................37
8.8.2.
Analysis ...................................................................................................38
8.9.
Comments.............................................................................................................38
9. Definitions of Efficacy Tables, Listings and Figures ...................................................39
9.1.
Sweat Chloride......................................................................................................39
9.1.1.
Parameters................................................................................................39
9.1.2.
Tables ......................................................................................................40
9.1.3.
Figures .....................................................................................................44
9.1.4.
Listings ....................................................................................................47
9.2.
Spirometry............................................................................................................47
9.2.1.
Parameters................................................................................................47
9.2.2.
Tables ......................................................................................................48
9.2.3.
Figures .....................................................................................................51
9.2.4.
Listings ....................................................................................................53
9.3.
Cystic Fibrosis Questionnaire – Revised (CFQ-R).................................................53
9.3.1.
Parameters................................................................................................53


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9.3.2.
Tables ......................................................................................................55
9.3.3.
Figures .....................................................................................................58
9.3.4.
Listings ....................................................................................................59
10. Definitions of Pharmacokinetics Analysis Tables, Listings and Figures.....................60
10.1.1. PK Parameter Derivation Rules................................................................60
10.1.2. Tables ......................................................................................................61
10.1.3. Figures .....................................................................................................62
10.1.4. Listings ....................................................................................................64
11. Definitions of Pharmacodynamics Analysis Tables, Listings and Figures..................66
11.1. Parameters ............................................................................................................66
11.2. Tables ...................................................................................................................66
11.3. Figures..................................................................................................................69
11.4. Listings.................................................................................................................70
12. Definitions of PK/Efficacy Analysis Tables, Listings and Figures ..............................72
13. Definitions of safety Analysis Tables, Listings and Figures.........................................79
13.1. Adverse Events .....................................................................................................79
13.1.1. Treatment-Emergent Principle..................................................................79
13.1.2. Treatment Relatedness..............................................................................79
13.1.3. Worst-Case Principle................................................................................79
13.1.4. Adverse Event Onset Day and Duration....................................................79
13.1.5. Calculation of Percentages .......................................................................80
13.1.6. Tables ......................................................................................................80
13.1.7. Listings ....................................................................................................82
13.2. Laboratory Safety..................................................................................................83
13.2.1. Laboratory Units ......................................................................................83
13.2.2. Number of Significant Digits....................................................................83
13.2.3. Baseline and Change from Baseline..........................................................83
13.2.4. Scoring of Laboratory Values and Urinalysis Results ...............................84
13.2.5. Worst-Case Abnormality..........................................................................84
13.2.6. Tables ......................................................................................................84
13.2.7. Figures .....................................................................................................85
13.2.8. Listings ....................................................................................................86
13.3. ECG......................................................................................................................86
13.3.1. Available Data..........................................................................................86
13.3.2. Calculated Parameters ..............................................................................86
13.3.3. Baseline and Change from Baseline..........................................................86
13.3.4. Normal Ranges.........................................................................................87
13.3.5. Worst-case Abnormality of QT and QTc ..................................................87
13.3.6. Tables ......................................................................................................87
13.3.7. Figures .....................................................................................................88
13.3.8. Listings ....................................................................................................88
13.4. Vital Signs ............................................................................................................89
13.4.1. Available Data..........................................................................................89
13.4.2. Baseline and Change from Baseline..........................................................89
13.4.3. Normal Ranges.........................................................................................89
13.4.4. Worst-Case Abnormality..........................................................................89
13.4.5. Tables ......................................................................................................90
13.4.6. Figures .....................................................................................................90


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13.4.7. Listings ....................................................................................................90
13.5. Pulse Oximetry .....................................................................................................91
13.5.1. Available Data..........................................................................................91
13.5.2. Baseline and Change from Baseline..........................................................91
13.5.3. Normal Ranges.........................................................................................91
13.5.4. Worst-Case Abnormality..........................................................................91
13.5.5. Tables ......................................................................................................91
13.5.6. Figures .....................................................................................................92
13.5.7. Listings ....................................................................................................92
13.6. Physical Examinations ..........................................................................................92
14. References .....................................................................................................................94


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LIST OF TABLES
Table 14.1.1.1: 
Subject disposition: Analysis populations ..............................................30
Table 14.1.1.2: 
Subject disposition: Tabulation of the number of subjects at each 
time interval ..........................................................................................30
Table 14.1.1.3: 
Subject disposition: First and last date in the study ................................30
Table 14.1.3.1: 
Demographic data: Descriptive statistics................................................32
Table 14.1.3.2: 
Demographic data: Sub-group analyses: Descriptive statistics ...............32
Table 14.1.3.3: 
Demographic data: Pooled analyses: Descriptive statistics.....................33
Table 14.1.3.4: 
Baseline laboratory data: Tabulation of normal range ............................33
Table 14.1.3.5: 
Baseline ECG data: Tabulation of the normal range...............................33
Table 14.1.3.6: 
Baseline vital signs data: Tabulation of the normal range.......................33
Table 14.1.3.7: 
Baseline physical examination: Tabulation of the normal range .............34
Table 14.1.3.8: 
Baseline pulse oximetry data: Tabulation of the normal range................34
Table 14.1.3.9:
Screening and baseline disease characteristics .......................................34
Table 14.1.3.10: 
Screening and baseline disease characteristics: Sub-group analyses .......35
Table 14.1.3.11: 
Screening and baseline disease characteristics: Pooled analyses.............35
Table 14.1.3.12: 
Prior and concomitant therapies: Tabulation ..........................................37
Table 14.1.4.1: 
Exposure to study drug: Descriptive statistics ........................................38
Table 14.2.1.1.1: 
Sweat Chloride (mmol/L): Descriptive statistics of the actual 
values per time point..............................................................................40
Table 14.2.1.1.2: 
Sweat Chloride (mmol/L): Sub-group analyses: Descriptive 
statistics of the actual values per time point ...........................................40
Table 14.2.1.1.3: 
Sweat Chloride (mmol/L): Pooled analyses: Descriptive statistics 
of the actual values per time point..........................................................40
Table 14.2.1.1.4: 
Sweat Chloride (mmol/L): Descriptive statistics of the changes 
from baseline per time point ..................................................................41
Table 14.2.1.1.5: 
Sweat Chloride (mmol/L): Descriptive statistics of the changes 
from baseline per time point on Placebo groups.....................................41
Table 14.2.1.1.6: 
Sweat Chloride (mmol/L): Sub-group analyses: Descriptive 
statistics of the changes from baseline per time point.............................41
Table 14.2.1.1.7: 
Sweat Chloride (mmol/L): Pooled analyses: Descriptive statistics 
of the changes from baseline per time point ...........................................42
Table 14.2.1.1.8: 
Sweat Chloride (mmol/L): Descriptive statistics of the percent 
changes from baseline per time point.....................................................42
Table 14.2.1.1.9: 
Sweat Chloride (mmol/L): Frequency tabulation per time point.............43
Table 14.2.1.1.1.10: 
Sweat Chloride (mmol/L): Shift table versus baseline per 
time point ..............................................................................................43
Table 14.2.1.1.11: Sweat Chloride (mmol/L): Sensitivity analyses on the changes 
from baseline values..............................................................................43
Table 14.2.1.2.1: 
Spirometry: Descriptive statistics of the actual values per time 
point......................................................................................................48
Table 14.2.1.2.2: 
Spirometry: Sub-group analyses: Descriptive statistics of the actual 
values per time point..............................................................................48


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Table 14.2.1.2.3: 
Spirometry: Pooled analyses: Descriptive statistics of the actual 
values per time point..............................................................................49
Table 14.2.1.2.4: 
Spirometry: Descriptive statistics of the changes from baseline per 
time point ..............................................................................................49
Table 14.2.1.2.5: 
Spirometry: Descriptive statistics of the changes from baseline per 
time point on Placebo groups.................................................................49
Table 14.2.1.2.6: 
Spirometry: Sub-group analyses: Descriptive statistics of the 
changes from baseline per time point.....................................................50
Table 14.2.1.2.7: 
Spirometry: Pooled analyses: Descriptive statistics of the changes 
from baseline per time point ..................................................................50
Table 14.2.1.2.8: 
Spirometry: Descriptive statistics of the percent changes from 
baseline per time point...........................................................................50
Table 14.2.1.2.9: 
Spirometry: Sensitivity analyses on the changes from baseline 
values ....................................................................................................50
Table 14.2.1.3.1: 
CFQ-R: Descriptive statistics of the actual values per time point ...........55
Table 14.2.1.3.2: 
CFQ-R: Sub-group analyses: Descriptive statistics of the actual 
values per time point..............................................................................55
Table 14.2.1.3.3: 
CFQ-R: Pooled analyses: Descriptive statistics of the actual values 
per time point ........................................................................................55
Table 14.2.1.3.4: 
CFQ-R: Descriptive statistics of the changes from baseline per 
time point ..............................................................................................56
Table 14.2.1.3.5: 
CFQ-R: Descriptive statistics of the changes from baseline per 
time point on Placebo groups.................................................................56
Table 14.2.1.3.6: 
CFQ-R: Sub-group analyses: Descriptive statistics of the changes 
from baseline per time point ..................................................................56
Table 14.2.1.3.7: 
CFQ-R: Pooled analyses: Descriptive statistics of the changes 
from baseline per time point ..................................................................57
Table 14.2.1.3.8: 
CFQ-R: Descriptive statistics of the percent changes from baseline 
per time point ........................................................................................57
Table 14.2.1.3.9: 
CFQ-R: Sensitivity analyses on the changes from baseline values..........57
Table 14.2.2.1: 
GLPG2222 Trough plasma concentrations (ng/mL): Individual 
data and descriptive statistics per dose and day......................................61
Table 14.2.2.2: 
GLPG2222 Plasma concentrations (ng/mL): Individual data and 
descriptive statistics per dose level on the day of the full PK 
profile....................................................................................................61
Table 14.2.2.3: 
GLPG2222 PK parameters: Individual data and descriptive 
statistics per dose on the day of the full PK profile.................................61
Table 14.2.2.4: 
GLPG2222 PK parameters: statistical assessment of dose-
proportionality.......................................................................................61
Table 14.2.3.1: 
Biomarker: Descriptive statistics of the actual values per time 
point......................................................................................................66
Table 14.2.3.2: 
Biomarker: Sub-group analyses: Descriptive statistics of the actual 
values per time point..............................................................................66


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Table 14.2.3.3: 
Biomarker: Pooled analyses: Descriptive statistics of the actual 
values per time point..............................................................................67
Table 14.2.3.4: 
Biomarker: Descriptive statistics of the changes from baseline per 
time point ..............................................................................................67
Table 14.2.3.5: 
Biomarker: Descriptive statistics of the changes from baseline per 
time point on Placebo groups.................................................................67
Table 14.2.3.6: 
Biomarker: Sub-group analyses: Descriptive statistics of the 
changes from baseline per time point.....................................................68
Table 14.2.3.7: 
Biomarker: Pooled analyses: Descriptive statistics of the changes 
from baseline per time point ..................................................................68
Table 14.2.3.8: 
Biomarker: Descriptive statistics of the percent changes from 
baseline per time point...........................................................................68
Table 14.2.3.9: 
Biomarker: Sensitivity analyses on the changes from baseline 
values ....................................................................................................68
Table 14.3.1.1: 
Treatment-emergent adverse events: Summary table..............................80
Table 14.3.1.2: 
Treatment-emergent adverse events: Tabulation of all adverse 
events ....................................................................................................81
Table 14.3.1.3: 
Treatment-emergent adverse events: Tabulation per intensity ................81
Table 14.3.1.4: 
Treatment-emergent adverse events: Tabulation of all treatment-
related events.........................................................................................81
Table 14.3.1.5: 
Treatment-emergent adverse events: Tabulation of the intensity of 
treatment-related events.........................................................................81
Table 14.3.1.6: 
Serious treatment-emergent adverse events: Tabulation for 
EudraCT reporting.................................................................................81
Table 14.3.1.7: 
Non-serious treatment-emergent adverse events: Tabulation for 
EudraCT reporting.................................................................................81
Table 14.3.1.8: 
Non-serious treatment-emergent adverse events: Tabulation for 
EudraCT reporting of TEAEs occurring in at least 5% in one of the 
treatment group .....................................................................................81
Table 14.3.2.1: 
Laboratory data: Descriptive statistics of the actual values per time 
point......................................................................................................84
Table 14.3.2.2: 
Laboratory data: Descriptive statistics of the changes from 
baseline per time point...........................................................................84
Table 14.3.2.3: 
Laboratory data: Shift table according to the lab normal range per 
time point ..............................................................................................85
Table 14.3.2.4: 
Laboratory data: Treatment-emergent abnormalities per time point........85
Table 14.3.2.5: 
Laboratory data: Shift table of the categorical lab data per time 
point......................................................................................................85
Table 14.3.3.1: 
ECG: Descriptive statistics of the actual values per time point...............87
Table 14.3.3.2: 
ECG: Descriptive statistics of the changes from baseline per time 
point......................................................................................................87
Table 14.3.3.3: 
ECG: Shift table according to the QT normal range per time point.........87
Table 14.3.3.4: 
ECG: Treatment-emergent QT abnormalities per time point ..................88


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Table 14.3.3.5: 
ECG: Treatment-emergent abnormal change in QT per time point.........88
Table 14.3.3.6:
ECG: Frequency table of the eCRF ECG interpretation per time 
point......................................................................................................88
Table 14.3.4.1: 
Vital signs: Descriptive statistics of the actual values per time 
point......................................................................................................90
Table 14.3.4.2: 
Vital signs: Descriptive statistics of the changes from baseline per 
time point ..............................................................................................90
Table 14.3.4.3: 
Vital signs: Shift table according to the normal range per time 
point......................................................................................................90
Table 14.3.4.4: 
Vital signs: Treatment-emergent abnormalities per time point................90
Table 14.3.5.1: 
Pulse oximetry (%): Descriptive statistics of the actual values per 
time point ..............................................................................................91
Table 14.3.5.2: 
Pulse oximetry (%): Descriptive statistics of the changes from 
baseline per time point...........................................................................92
Table 14.3.5.3: 
Pulse oximetry (%): Shift table according to the normal range per 
time point ..............................................................................................92
Table 14.3.5.4: 
Pulse oximetry (%): Treatment-emergent abnormalities per time 
point......................................................................................................92


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LIST OF FIGURES
Figure 1: Study design..........................................................................................................16
Figure 14.2.1.1.1:
Sweat Chloride (mmol/L): Subject profile plots over time .....................44
Figure 14.2.1.1.2:
Sweat Chloride (mmol/L): Subject profile on change from baseline 
plots over time.......................................................................................44
Figure 14.2.1.1.3:
Sweat Chloride (mmol/L): Mean (+/- SE) plots of the actual values 
over time ...............................................................................................44
Figure 14.2.1.1.4:
Sweat Chloride (mmol/L): Mean (+/- SE) plots of the changes 
from baseline over time .........................................................................44
Figure 14.2.1.1.5:
Sweat Chloride (mmol/L): Sub-group analyses: Mean (+/- SE) 
plots of the changes from baseline over time..........................................45
Figure 14.2.1.1.6:
Sweat Chloride (mmol/L): Pooled analyses: Mean (+/- SE) plots of 
the changes from baseline over time ......................................................45
Figure 14.2.1.1.7:
Sweat Chloride (mmol/L): Mean (+/- SE) plots of the percent 
changes from baseline over time............................................................46
Figure 14.2.1.1.8:
Sweat Chloride (mmol/L): Boxplots on actual values.............................46
Figure 14.2.1.1.9:
Sweat Chloride (mmol/L): Boxplots on change from baseline................46
Figure 14.2.1.2.1:
Spirometry: Subject profile plots over time............................................51
Figure 14.2.1.2.2:
Spirometry: Subject profile on change from baseline plot over time.......51
Figure 14.2.1.2.3:
Spirometry: Mean (+/- SE) plots of the actual values over time..............51
Figure 14.2.1.2.4:
Spirometry: Mean (+/- SE) plots of the changes from baseline over 
time .......................................................................................................51
Figure 14.2.1.2.5:
Spirometry: Sub-group analyses: Mean (+/- SE) plots of the 
changes from baseline over time............................................................52
Figure 14.2.1.2.6:
Spirometry: Pooled analyses: Mean (+/- SE) plots of the changes 
from baseline over time .........................................................................52
Figure 14.2.1.2.7:
Spirometry: Mean plots (+/- SE) of the percent changes from 
baseline over time..................................................................................52
Figure 14.2.1.2.8:
Spirometry: Boxplots on the actual values .............................................52
Figure 14.2.1.2.9:
Spirometry: Boxplots on the change from baseline ................................53
Figure 14.2.1.3.1:
CFQ-R: Subject profile plots over time..................................................58
Figure 14.2.1.3.2:
CFQ-R: Subject profile on change from baseline plot over time.............58
Figure 14.2.1.3.3:
CFQ-R: Mean (+/- SE) plots of the actual values over time....................58
Figure 14.2.1.3.4:
CFQ-R: Mean (+/- SE) plots of the changes from baseline over 
time .......................................................................................................58
Figure 14.2.1.3.5:
CFQ-R: Sub-group analyses: Mean (+/- SE) plots of the changes 
from baseline over time .........................................................................58
Figure 14.2.1.3.6:
CFQ-R: Pooled analyses: Mean (+/- SE) plots of the changes from 
baseline over time..................................................................................59
Figure 14.2.1.3.7:
CFQ-R: Mean plots (+/- SE) of the percent changes from baseline 
over time ...............................................................................................59
Figure 14.2.2.1: 
GLPG2222 Trough plasma concentrations (ng/mL): Subject plots 
(linear-linear scale)................................................................................62


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Figure 14.2.2.2: 
GLPG2222 Trough plasma concentrations (ng/mL): Mean (+/- SE) 
concentration over time (linear-linear scale) ..........................................63
Figure 14.2.2.3: 
GLPG2222 Plasma concentrations (ng/mL): Subject profile plots 
(linear-linear scale) on the day of the full PK profile..............................63
Figure 14.2.2.4: 
GLPG2222 Plasma concentrations (ng/mL): Subject profile plots 
(log-linear scale) on the day of the full PK profile..................................63
Figure 14.2.2.5: 
GLPG2222 Plasma concentrations (ng/mL): Mean (+/- SE) 
concentration over time (linear-linear scale) on the day of the full 
PK profile..............................................................................................63
Figure 14.2.2.6: 
GLPG2222 Plasma concentrations (ng/mL): Mean (+/- SE) 
concentration over time (log-linear scale) on the day of the full PK 
profile....................................................................................................64
Figure 14.2.2.7: 
GLPG2222 PK parameters: Dose-proportionality ..................................64
Figure 14.2.3.1:
Biomarker: Subject profile plots over time.............................................69
Figure 14.2.3.2:
Biomarker: Mean (+/- SE) plots of the actual values over time ..............69
Figure 14.2.3.3:
Biomarker: Mean (+/- SE) plots of the changes from baseline over 
time .......................................................................................................69
Figure 14.2.3.4:
Biomarker: Sub-group analyses: Mean (+/- SE) plots of the 
changes from baseline over time............................................................69
Figure 14.2.3.5:
Biomarker: Pooled analyses: Mean (+/- SE) plots of the changes 
from baseline over time .........................................................................70
Figure 14.2.3.6:
Biomarker: Boxplots on actual values....................................................70
Figure 14.2.4.1: 
Correlation between GLPG2222 trough plasma concentrations and 
sweat chloride (linear-linear plot) ..........................................................72
Figure 14.2.4.2: 
Correlation between GLPG2222 trough plasma concentrations and 
change from baseline in sweat chloride (linear-linear plot).....................72
Figure 14.2.4.3: 
Correlation between GLPG2222 trough plasma concentrations and 
%FEV1 (linear-linear plot) ....................................................................72
Figure 14.2.4.4: 
Correlation between GLPG2222 trough plasma concentrations and 
change from baseline in %FEV1 (linear-linear plot) ..............................72
Figure 14.2.4.5: 
Correlation between change from baseline in sweat chloride and 
change from baseline in %FEV1 (linear-linear plot) ..............................73
Figure 14.2.4.6: 
Mean (+/- SE) sweat chloride (mmol/L) and mean (+/- SE) 
GLPG2222 trough plasma concentrations: Plots over time.....................73
Figure 14.2.4.7: 
Mean (+/- SE) sweat Chloride (mmol/L) and mean (+/- SE) 
GLPG2222 trough plasma concentrations: Sub-group analyses: 
Plots over time.......................................................................................73
Figure 14.2.4.8: 
Mean (+/- SE) sweat Chloride (mmol/L) and mean (+/- SE) 
GLPG2222 trough plasma concentrations: Pooled analyses: Plots 
over time ...............................................................................................73
Figure 14.2.4.9: 
Sweat chloride (mmol/L) and GLPG2222 trough plasma 
concentrations: Plots over time ..............................................................74


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Figure 14.2.4.10: 
Mean (+/- SE) %FEV1 and mean (+/- SE) GLPG2222 trough 
plasma concentrations: Plots over time ..................................................74
Figure 14.2.4.11: 
Mean (+/- SE) %FEV1 and mean (+/- SE) GLPG2222 trough 
plasma concentrations: Sub-group analyses: Plots over time ..................74
Figure 14.2.4.12: 
Mean (+/- SE) %FEV1 and mean (+/- SE) GLPG2222 trough 
plasma concentrations: Pooled analyses: Plots over time........................75
Figure 14.2.4.13: 
%FEV1 and GLPG2222 trough plasma concentrations: Plots over 
time .......................................................................................................75
Figure 14.2.4.14: 
Mean (+/- SE) sweat Chloride (mmol/L) and mean (+/- SE)  in 
%FEV1: Plots over time ........................................................................75
Figure 14.2.4.15: 
Correlation between CFQ-R respiratory domain and change from 
baseline in %FEV1 (linear-linear plot)...................................................75
Figure 14.2.4.16: 
Correlation between CFQ-R respiratory domain and percent 
change from baseline in %FEV1 (linear-linear plot) ..............................76
Figure 14.2.4.17: 
Correlation between change from baseline in CFQ-R respiratory 
domain and change from baseline in %FEV1 (linear-linear plot) ...........76
Figure 14.2.4.18: 
Correlation between change from baseline in CFQ-R respiratory 
domain and percent change from baseline in %FEV1 (linear-linear 
plot).......................................................................................................76
Figure 14.2.4.19: 
Mean (+/- SE) CFQ-R respiratory domain and mean (+/- SE) in 
%FEV1: Plots over time ........................................................................76
Figure 14.2.4.20: 
Mean change from baseline (+/- SE) in CFQ-R respiratory domain 
and mean change from baseline (+/- SE) in %FEV1: Plots over 
time .......................................................................................................76
Figure 14.2.4.21: 
Mean (+/- SE) CFQ-R respiratory domain and mean (+/- SE) 
GLPG2222 trough plasma concentrations: Plots over time.....................76
Figure 14.2.4.22: 
Mean (+/- SE) 
 and 
and mean (+/- SE) GLPG2222 
trough plasma concentrations: Plots over time .......................................77
Figure 14.2.4.23: 
Mean (+/- SE) 
 and 
and mean (+/- SE) GLPG2222 
trough plasma concentrations: Sub-group analyses: Plots over time .......77
Figure 14.2.4.24: 
Mean (+/- SE) 
 and 
and mean (+/- SE) GLPG2222 
trough plasma concentrations: Pooled analyses: Plots over time.............77
Figure 14.2.4.25: 
 and 
and GLPG2222 trough plasma concentrations: 
Plots over time.......................................................................................78
Figure 14.2.4.26:
Waterfall plot on change from baseline in Sweat Chloride .....................78
Figure 14.2.4.27:
Waterfall plot on change from baseline in %FEV1.................................78
Figure 14.3.2.1: 
Laboratory data: Subject profile plots over time.....................................85
Figure 14.3.2.2:
Laboratory data: Mean (+/- SE) plots of the actual values over time ......85
Figure 14.3.2.3: 
Laboratory data: Mean (+/- SE) plots of the changes from baseline 
over time ...............................................................................................85


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LIST OF LISTINGS
Listing 16.2.1.1: 
Subject disposition: Randomization.......................................................30
Listing 16.2.1.2:
Subject disposition: Country and site identification................................30
Listing 16.2.1.3: 
Subject disposition: Number of days in study ........................................30
Listing 16.2.1.4: 
Subject disposition: Study termination...................................................31
Listing 16.2.1.5: 
Subject disposition: Study analysis periods............................................31
Listing 16.2.2.1: 
Protocol deviations ................................................................................31
Listing 16.2.2.2: 
Eligibility criteria: Violations ................................................................31
Listing 16.2.2.3:
Final eligibility statements.....................................................................31
Listing 16.2.3.1: 
Subjects excluded from the safety analysis ............................................31
Listing 16.2.3.2: 
Subjects excluded from the efficacy ITT analysis ..................................32
Listing 16.2.4.1: 
Demographic data..................................................................................33
Listing 16.2.4.2: 
Screening and baseline disease characteristics .......................................35
Listing 16.2.4.3: 
Medical history......................................................................................35
Listing 16.2.4.4: 
Concomitant diseases ............................................................................36
Listing 16.2.4.5: 
Prior and concomitant therapies.............................................................37
Listing 16.2.5.1: 
Exposure to study drug: eCRF data........................................................38
Listing 16.2.5.2: 
Exposure to study drug: Derived data ....................................................38
Listing 16.2.5.3: 
Study drug administration (clinic visit) ..................................................38
Listing 16.2.5.4: 
Comments .............................................................................................38
Listing 16.2.6.1: 
Sweat Chloride (mmol/L): Full listing ...................................................47
Listing 16.2.6.2: 
Spirometry: Full listing..........................................................................53
Listing 16.2.6.3: 
CFQ-R: Full listing................................................................................59
Listing 16.2.7.1: 
PK Data handling ..................................................................................64
Listing 16.2.7.2: 
Actual PK blood sampling times (h) ......................................................64
Listing 16.2.7.3: 
Plasma concentrations (ng/mL): Individual data (ED)............................64
Listing 16.2.8.1: 
Biomarker: Full listing...........................................................................70
Listing 16.2.10.1:
Treatment-emergent adverse events: Summary listing of all events........82
Listing 16.2.10.2:
Treatment-emergent adverse events: Full listing ....................................82
Listing 16.2.10.3:
Pre-treatment adverse events: Full listing...............................................82
Listing 16.2.10.4:
Adverse events: Full listing of the serious adverse events ......................82
Listing 16.2.10.5:
Treatment-emergent adverse events: Full listing of the events 
leading to discontinuation......................................................................83
Listing 16.2.10.6:
Adverse events: Coding information......................................................83
Listing 16.2.11.1:
Laboratory data: Full listing...................................................................86
Listing 16.2.11.2:
Laboratory data: Abnormalities listing...................................................86
Listing 16.2.12.1:
ECG: Full listing ...................................................................................88
Listing 16.2.12.2:
ECG: Abnormalities listing....................................................................88
Listing 16.2.13.1:
Vital signs: Full listing...........................................................................90
Listing 16.2.13.2:
Vital signs: Abnormalities listing...........................................................91
Listing 16.2.14.1:
Pulse oximetry (%): Full listing .............................................................92
Listing 16.2.14.2:
Pulse oximetry (%): Abnormalities listing .............................................92
Listing 16.2.15.1:
Physical examinations: Abnormalities listing.........................................92


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1.
STUDY DESIGN
1.1.
STUDY OBJECTIVES
1.1.1. Primary Objective

To evaluate the safety and tolerability of 4 different doses of GLPG2222 administered 
orally and q.d. for 29 days in adult subjects with CF* who are homozygous for the 
F508del CFTR mutation.
* Cystic Fibrosis
1.1.2. Secondary Objectives

To assess changes in biomarkers of CFTR activity.

To assess changes in respiratory symptoms.

To assess the PK of GLPG2222.
1.2.
STUDY ENDPOINTS
1.2.1. Primary Endpoint

Safety and tolerability, assessed by the incidence of adverse events (AEs), as well as 
changes over time in weight, vital signs, oxygen saturation by pulse oximetry, 12-lead 
ECG, spirometry, and clinical safety laboratory data (hematology, chemistry, coagulation 
and urinalysis).
1.2.2. 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.
1.3.
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 1.


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Figure 1: Study design
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.
Additionally, subjects can choose to participate in the optional substudy, in which nasal 
brushings will be collected.


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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.
1.4.
PROTOCOL AND PROTOCOL AMENDMENTS
Protocol Versions
Date (ddMMMyyyy)
Final
06DEC2016
Protocol Amendments
Date (ddMMMyyyy)
Not Applicable
This SAP was based on the latest version of the protocol.
1.5.
FLOWCHART
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
                                                            
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.


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EVENT
SCREENING
TREATMENT PERIOD1
FOLLOW-UP
Study days (D)
D-28 till D-1
D1
D15
(±2D)
D29
(±2D)
ED
D43
(±3D)
Sweat collection
X
X
X
X
X
X
Spirometry8
X
X
X
X
X
X
Clinical safety laboratory tests9
X
X
X
X
X
X
Serology10
X
Pregnancy test11
X
X
X
X
X
FSH test12
X
CFTR genotyping
X
PK blood samples13
X
X
X
Exploratory biomarkers14
X
X
X
Randomization
X
Breakfast or snack to be 
provided15
X
X
X
Study drug dosing
Study drug dispensing
X
X
Dispense subject diary
X
X
X
X
Collect subject diary
X
X
X
X
X
AE assessment
Concomitant medications
Optional substudy16
                                                            
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
9 Blood and urine samples to be collected for clinical safety laboratory tests.
10 Serology sample for hepatitis B virus surface antigen, hepatitis C virus antibody and human 
immunodeficiency type 1 and 2 antibodies.
11 For female subjects of childbearing potential only; serum pregnancy test at screening, urine pregnancy test
at other scheduled visits.
12 For suspected post-menopausal female subjects only (age < 55 years and no menses for ≥12 months without 
a medical cause).
13 PK blood samples for GLPG2222 to be taken pre-dose and 0.5, 1, 2, 3, 4, 6 and 8 hours post-dose on Day 15 
(or on Day 29 if subject is not available for full PK profiling on Day 15), and pre-dose on Day 29. In case of an 
early discontinuation visit, 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.
14 Exploratory biomarkers 
.
15 Study drug to be taken once daily in the morning with a breakfast or snack.
16 Only for subjects who give separate consent to participate in the optional substudy.
AE = adverse event; CFTR = cystic fibrosis transmembrane conductance regulator; FSH = follicle stimulating 
hormone, PK = pharmacokinetic(s)


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EVENT
SCREENING
TREATMENT PERIOD1
FOLLOW-UP
Study days (D)
D-28 till D-1
D1
D15
(±2D)
D29
(±2D)
ED
D43
(±3D)
Nasal brushing
X
X
X
2.
ANALYSIS POPULATIONS
The analysis population will always be indicated in a subtitle in the table, listing or figure.
2.1.
ALL SCREENED SUBJECTS POPULATION
All subjects who provided informed consent by signing the ICF.
2.2.
ALL ENROLLED POPULATION
All subjects who were enrolled into the study, i.e. randomized into the study.
2.3.
INTENT TO TREAT POPULATION
All enrolled subjects who received at least one dose of study drug and had at least one post-
baseline assessment with efficacy data.
2.4.
SAFETY POPULATION
All subjects who received at least one dose of study drug.
2.5.
PHARMACOKINETICS POPULATION
Subpopulation of the Safety population, 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).
3.
TREATMENT GROUPS
3.1.
RANDOMIZED VERSUS ACTUAL TREATMENT
For efficacy parameters, the treatment group as assigned by the randomization will be used in 
the analysis (i.e., as-randomized analysis).
For safety, the treatment that was actually used by the subject will be applied in the analysis 
(i.e., as-treated analysis).
Differences between as-treated and as-randomized will be flagged in the listing on subject 
randomization.


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3.2.
TREATMENT GROUP LABELS
The following treatment group labels will be used in the tables, listings and figures:

Pooled placebo

GLPG2222 50 mg q.d.

GLPG2222 100 mg q.d.

GLPG2222 200 mg q.d.

GLPG2222 400 mg q.d.
3.3.
POOLING OF GROUPS
Both placebo groups (from cohort A and from cohort B) will be pooled into one placebo 
group for the tables/figures but not for the listings. Note that for some tables and some 
figures, placebo from each cohort can be provided as well. 
3.4.
SUB-GROUPS
In efficacy part, the following sub-groups analyses will be performed and the following labels 
will be used in the tables/figures:

By target Ctrough at Day 15 (only for GLPG2222 dose levels)

Reached target Ctrough at Day 15 (>= 
 ng/mL)

Not reached target Ctrough at Day 15 (< 
 ng/mL)

By target Ctrough at Day 29 (only for GLPG2222 dose levels)

Reached target Ctrough at Day 29 (>= 
 ng/mL)

Not reached target Ctrough at Day 29 (< 
 ng/mL)

By target Ctrough at Day 15 and 29 (only for GLPG2222 dose levels)

Reached target Ctrough at Day 15 and reached target Ctrough at Day 29

Not reached target Ctrough at Day 15 and not reached target Ctrough at Day 29

By sweat chloride (from arm with greatest volume) at baseline 

Baseline sweat < 40 mmol/L

Baseline sweat [40-50[ mmol/L*

Baseline sweat [50-60[ mmol/L*

Baseline sweat >= 60 mmol/L

By sweat chloride (mean value from both arms) at baseline 

Baseline sweat < 40 mmol/L

Baseline sweat [40-50[ mmol/L*

Baseline sweat [50-60[ mmol/L*

Baseline sweat >= 60 mmol/L

By %FEV1 at baseline

Baseline %FEV1 < 40

Baseline %FEV1 [40-50[*

Baseline %FEV1 [50-70[*

Baseline %FEV1 [70-90[*

Baseline %FEV1 >= 90


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*[X1-X2[ means >= X1 and < X2
These sub-group analyses will be mainly for change from baseline tables, specific 
tables/figures will be created when needed (Tables and figures will be repeated for each 
subgroup category). In case no subject has been classified in one of the above category, so the 
table/figure planned for this category will not be displayed.
3.5.
TOTALS OVER GROUPS
A total over all groups will be presented for the general part of the analysis, but not for Safety
or Efficacy. Totals will only be shown on tables, but not on listings nor figures.
4.
ANALYSIS PERIODS AND ANALYSIS TIME POINTS
4.1.
RELATIVE NUMBER OF DAYS
The relative day (DY) is calculated as follows: 
= Visit date – reference date + 1 day, when the visit date is on or after the reference date
= Visit date – reference date, when the visit date is before the reference date.
The reference date in the study is Day 1 pre-dose, which by definition has DY=1. There is no 
DY=0.
4.2.
ANALYSIS PERIODS FOR NON-VISIT DATA
These analysis periods are to be used for allocation of events into periods (e.g., adverse 
events).
Analysis period
Start period
End Period
Screening
Date of signing the ICF, with 00:00 
added as time part.
First treatment administration
date(time) - 1 minute
Treatment
First treatment administration 
date(time)
Study termination date, with 23:59 
added as time part in case the time 
part would be missing or 
incomplete.
Note that the last analysis period in case of early termination will always be ended by the 
study termination date (date of last contact, with 23:59 added as time part in case the time part 
would be missing or incomplete).
4.3.
ALGORITHM OF ALLOCATING VISITS TO TIME WINDOWS
All visits (including unscheduled visits but excluding visits without data) will be placed into 
time windows according to their relative day (DY) in the study, according to the following 
allocation table:


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Visits falling really late in the study will be allocated to a “>Day 29” interval, and will not be 
shown in tables nor figures, but will only be listed.
Time point label
Target day
Interval lower bound
Interval upper bound
Screening3
NAP4
NAP4
NAP4
Baseline1
NAP4
NAP4
NAP4
Day 1 post-dose3
NAP4
NAP4
NAP4
Day 15
15
2
21
Day 29
29
22
36
>Day 292
NAP4
37
+∞
Follow-up3
11-17 days after 
last visit
NAP4
NAP4
1 The actual baseline reference value will be determined per parameter as the last available pre-dosing data point, so might differ 
from this “baseline” visit interval.
2 Visits falling really late in the study (relative day > 36; excluding the follow-up visit) will be allocated to a “>Day 29” interval, 
and will not be shown in tables nor figures, but will only be listed. 
3 For the screening, day1 post-dose (vital signs) and follow-up visits, no time window is defined. The visit as recorded in the CRF 
will be used. 
4 NAP = Not applicable
For efficacy, PD data, all by-time-point summaries will be based on the visit indicated on the 
subject’s CRF and will not be placed in time windows.
Tables, figures and listings will present the time points, not the visits.
4.4.
SELECTION OF VISITS
It is possible that more than one visit gets allocated into the same time window. In that case, 
only one visit will be selected for analysis tables and figures. The nonselected visit(s) will 
only be listed, and flagged as use=no.
The visit with a relative day (DY) closest to the target day will be selected. If there are 
multiple visits at the same distance of the scheduled visit day (meaning: equal ABS(DY –
target day)), then the one latest in time is selected.
In case of multiple screening visits, the last pre-baseline screening measurement (the last visit 
happening before the scheduled 'Day 1 predose') is selected for analysis. This value (not the 
original first screening value) was also used in the clinical center to include the subject in the 
study.
In case more than one parameter is measured per time point (e.g. for lab), the selection is 
performed per parameter and per time point, not per “sample” and per time point. Missing 
values are removed before the selection is made.
As baseline reference point, the last nonmissing pre-dosing value will be used.  This is 
normally the scheduled baseline itself. A missing scheduled baseline value will be imputed 
with the last nonmissing value of a preceding pre-dosing visit. This can be a screening visit or 
an unscheduled visit prior to the first dose of study medication. If there is an unscheduled 
measurement taken after the scheduled baseline, before the first dose of study drug, then this 
unscheduled measurement will be used instead of the scheduled baseline.  If there is an 


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unscheduled measurement at the same datetime as the scheduled baseline, then it is assumed 
that the unscheduled measurement is taken after the scheduled baseline.
In case the screening visit is used to impute the baseline, the original screening visit as well as 
the imputed baseline will be presented in the tables. In the listings, only original screening 
data will be shown: the original screening visit will be shown and flagged as “reference” visit. 
The imputed baseline will not be shown.
In case an unscheduled visit is used to impute the baseline, the visit will be renamed to 
“baseline”. The imputed baseline will be presented in the tables. In the listings, the original 
unscheduled data will be shown and flagged as “reference” visit.
4.5.
HANDLING OF UNSCHEDULED ASSESSMENTS 
If there is an unscheduled measurement at the same datetime as a scheduled visit, then it is 
assumed that the unscheduled measurement is taken after the scheduled visit.
Unscheduled measurements prior to use of the study drug: see section 4.4.
Unscheduled measurements after the first dose of study drug: place into time window (section 
4.3) and selection will be made according rules defined in section 4.4. 
5.
HANDLING OF DATA
5.1.
CALCULATION OF DESCRIPTIVE STATISTICS
For continuous parameters, descriptive statistics will be presented when N≥2 unless otherwise 
specified. When N=1, the observation will not be shown in the table but only in the listing.
Descriptive statistics will include at least the following: 

the number of nonmissing data points (N) 

the arithmetic mean

the standard error (SE)

the median, minimum and maximum

95% confidence interval of the mean (only when requested).
For PK plasma concentrations, descriptive statistics will include: 

the number of nonmissing data points (N)

the number of data points above the lower limit of quantification (LLOQ)

the arithmetic mean

the standard error (SE) and standard deviation (SD)

the median, minimum, and maximum

the coefficient of variation (CV%)
= 100 x (standard deviation / arithmetic mean)

the geometric mean = exp(arithmetic mean of ln-transformed data)

the geometric coefficient of variation (CV%)
= 100 x (	
	 	
  
	
 		)² −1.


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Note that at least 50% of the subjects must have a plasma level above the lower limit of 
quantification before these descriptive statistics are calculated. If less than 50% of values 
were quantifiable, only the arithmetic mean (with minimum and maximum) will be presented 
with the original calculated value, the other descriptive statistics will be listed as “NC” (not 
calculated). If the calculated mean is below the lower limit of quantification, then it will be 
presented as below the limit of quantitation (BLOQ). The minimum will be “BLOQ”, and the 
maximum will be derived from the actual data. Standard deviation (SD) and CV% will be 
reported as “NC”. The plasma concentrations of GLPG2222 will be presented with 3 
significant digits in the original concentration unit (i.e.: 8.356 and 1839 ng/mL will be 
rounded to 8.36 and 1840 ng/mL, respectively). The descriptive statistics should be rounded 
to the same number of significant digits as the individual values. 
For derived PK parameters, descriptive statistics will include:

the number of nonmissing data points (N) 

the arithmetic mean

the standard error (SE ) and/or standard deviation (SD)

the median, minimum, and maximum

the coefficient of variation (CV%)

the geometric mean

the geometric coefficient of variation (CV%).
Note that at least 50% of the subjects must have a nonmissing result before these descriptive 
statistics are calculated. If less than 50% of values were available, only the arithmetic mean 
will be presented with the original calculated value, the other descriptive statistics will be 
listed as “NC” (not calculated). Pharmacokinetic parameters will be presented with 3 
significant digits (i.e.: 8.356 and 1839 ng/mL will be rounded to 8.36 and 1840 ng/mL, 
respectively) except for tmax, which will be presented with 1 decimal. The descriptive statistics 
should be rounded to the same number of significant digits as the individual values.
5.2.
CALCULATION OF PERCENTAGES
Missing values will not be included in the denominator count when computing percentages.
5.3.
HANDLING OF VALUES BELOW (OR ABOVE) A THRESHOLD
5.3.1. Safety Data
Values below (above) the detection limit will be imputed by the value of the detection limit 
itself. Listings will always present the original value.
Example: if the database contains values like “<0.04”, then for the descriptive statistics the 
value of the detection limit (0.04) shall be used. A value like “>1000” will be imputed by 
“1000”.
5.3.2. PK Data
Values below the quantification limit will be imputed by 0 for PK parameters calculation and  
descriptive statistics calculation except for geometric mean and geometric CV% where it will 
be imputed as LLOQ (lower limit of quantitation)/2 and listed as “BLOQ”.


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For the Ctrough, values BLOQ will be imputed by LLOQ/2 when computing inferential 
statistics and between-group comparisons. 
5.3.3. PD Data
PD data correspond to all 
 biomarkers and biomarkers 
 
that have been collected as exploratory assessments.
Values below the lower detection limit will be imputed by the half of value of the detection 
limit itself. Values above the upper detection limit will be imputed by the value of the upper 
detection limit itself. Listings will always present the original value. 
5.4.
HANDLING OF MISSING DATA
5.4.1. Observed Cases (OC)
No imputation is done of missing values.
5.4.2. Last Observation Carried Forward (LOCF)
For efficacy parameters (see section 9), a LOCF analysis will be performed carrying forward 
the last nonmissing result (even if this would be a baseline result) except for the FU timepoint 
(FU timepoint will always provide observed cases values).
As spirometry has been assessed predose and between 1h and 2h post-dose at Day 1 and Day 
29, LOCF imputation should be adapted with the following rule:

If missing value corresponds to a predose timepoint, then the last nonmissing result 
assessed at pre-dose will be used for LOCF imputation.

If missing value corresponds to a post dose timepoint, then the last nonmissing result 
assessed at post dose will be used for LOCF imputation (if there is no last non missing 
timepoint assessed at post-dose, then baseline value will be used).
5.4.3. Handling of Missing Date(Time) or Partially Known Date(Time)
No imputation will be done of missing date(time) fields, nor of the missing parts of partially 
known date(time) fields. When needed (e.g., a double phase allocation), a worst-case selection 
will be made.
5.5.
HANDLING OF OUTLIERS
All measured values will be included in the analyses.
5.6.
HANDLING OF SECONDS IN DATETIME FIELDS
If a datetime field contains seconds, these will be cut off (i.e., rounded down to the minute) 
prior to data analysis. The analysis will only use the date and time up to the minute.


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6.
SOFTWARE AND PROCEDURES
6.1.
SOFTWARE
SAS version 9.4 will be used for programming.
SigmaPlot12.5, or higher (Systat Software, Inc., San Jose, California, United States) will be 
used for PK figures.
Phoenix WinNonlin6.4, or higher will be used for the figures and parameter calculation.
6.2.
PROCEDURES
Analyses will comply with ICH regulations, in particular: (ICH-E3) , (ICH-E6) and (ICH-E9).
The following Galapagos SOPs will be followed:

SOP-CLI-001: Developing Clinical Study Documents (version 1.0)

SOP-CLI-003: Managing Data Processing Activities (version 1.0)

SOP-CLI-004: Managing DSMB Activities (version 1.0)
The following CRO STAT SOPs will be followed:

CS_OP_BS001: Statistical Principles

CS_OP_BS0216: Ensuring Quality in Biostatistical Deliverables

CS_WI_BS002: Randomization

CS_WI_BS003: Unblinding

CS_WI_BS005: Statistical Analysis Plans (Covering Table Shells)

CS_WI_BS009: Interim Analysis

CS_WI_BS011: Analysis Sets

CS_WI_BS013: Derived Datasets

CS_WI_BS014: Statistical Output

CS_WI_BS015: Approaches to QC

CS_WI_BS020: Handling Data transfer.
The following PK SOPs will be followed, unless otherwise specified

PI_OP_PK0206: Pharmacokinetic/Pharmacodynamic Analysis

PI_WI_BS0214: Generation of a WinNonlin Analysis Data File

PI_WI_BS0217:  Rounding of Numerical Values

PI_WI_PK_0202: Pharmacokinetic and Pharmacodynamic Analysis Procedures

PI_WI_PK0205: Standardization of Pharmacokinetic and Pharmacodynamic Symbols
6.3.
FORMATS
Because the locked data is in CDISC SDTM format, the derived data will be following 
CDISC ADaM 2.1  ADAMIG version 1.0 format.


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Tables, listings and figures will follow the Mock TLFs, as provided in a separate document. 


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7.
STATISTICAL METHODS
7.1.
PLANNED ANALYSES, PROTOCOL AMENDMENTS 
INCLUDED
7.1.1. 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.
7.1.2. 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.
7.1.3. 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. 
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 have been described in this SAP
to better understand the data.


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7.1.4. Analyses of Safety Data
Adverse events will be fully described and coded according to the Medical Dictionary for 
Regulatory Activities (version 20.0). 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.
7.1.5. Pharmacokinetics Analyses
Descriptive statistics will be calculated by dose level and day for the plasma concentrations 
and PK parameters of GLPG2222.
Plasma concentrations of GLPG2222 will also 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. The modeling approach will be described and reported separately.
7.1.6. 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.
7.1.7. 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.
7.2.
CHANGES TO THE PLANNED ANALYSES, NOT COVERED BY 
PROTOCOL AMENDMENTS
7.2.1. Changes before Database Lock
Not Applicable
7.2.2. Changes after Database Lock
Not Applicable


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8.
DEFINITIONS OF GENERAL ANALYSIS TABLES, 
LISTINGS AND FIGURES
8.1.
SUBJECT DISPOSITION
Listing 16.2.1.1: 
Subject disposition: Randomization
Listing of subject numbers and randomization groups, any information on code breaking. 
All discrepancies (as-randomized versus as-treated) will be flagged.
Population: all enrolled.
Listing 16.2.1.2:
Subject disposition: Country and site identification
Listing of country and site with the list of all subjects that were enrolled in this study.
Population: all enrolled.
Table 14.1.1.1: 
Subject disposition: Analysis populations
Tabulation per treatment group (and overall) of the number of subjects in each of the analysis 
populations defined in section 2. 
Population: all screened subjects.
Table 14.1.1.2: 
Subject disposition: Tabulation of the number of subjects at each 
time interval
Tabulation per treatment group (and overall) and per analysis time point of the number of 
subjects with data.
Population: safety.
Listing 16.2.1.3: 
Subject disposition: Number of days in study 
Listing per treatment group, per subject and per time point the number of days in study at the 
time of the analysis time point (derivation of these “days”: see section 4.1).
Population: safety.
Table 14.1.1.3: 
Subject disposition: First and last date in the study
List the following:

Date of the first signature on study ICF 

Date of first and last screening

Date of first study drug administration

Last visit date (all visits; including unscheduled visits)

Last date of contact in the study with any subject.


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Population: all screened.
Listing 16.2.1.4: 
Subject disposition: Study termination 
Listing per treatment group and per subject of the reason for completion/discontinuation and 
the number of days since first study drug administration at study termination. In case the 
discontinuation was due to AE, the AE preferred term will be presented in this listing. If there 
is a (verbatim) explanation on the discontinuation reason, this will also be presented in this 
listing.
Population: safety.
Listing 16.2.1.5: 
Subject disposition: Study analysis periods 
Listing per treatment group and per subject of the analysis periods in the study, together with 
the start and end dates of each analysis period. With the date of first and last use of study 
drug, and the study termination date. (Analysis periods: see section 4.2)
Population: safety.
8.2.
PROTOCOL DEVIATIONS AND ELIGIBILITY
Listing 16.2.2.1: 
Protocol deviations 
Listing per treatment group and per subject of all protocol deviations, with indication major / 
minor.
Population: safety.
Listing 16.2.2.2: 
Eligibility criteria: Violations 
Only violated in- and exclusion criteria will be listed per treatment group and per subject.
Population: safety.
Listing 16.2.2.3:
Final eligibility statements
Listing per treatment group and per subject of the final eligibility statements at screening and 
at day 1.
Population: safety.
8.3.
SUBJECTS EXCLUDED FROM ANALYSIS
Note that for the PK data there is a specific PK data handling listing. PK is therefore not 
included in this section, but is in section 10.
Listing 16.2.3.1: 
Subjects excluded from the safety analysis 
Listing of all subjects that were not treated: the study termination reason and/or the reason for 
being a no-treatment subject will be listed, whichever is available.


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Population: all screened subjects population, minus the Safety population.
Listing 16.2.3.2: 
Subjects excluded from the efficacy ITT analysis 
Listing of all subjects that were exposed but who were not included in the ITT population: the 
study termination reason and the reason for being excluded will be listed.
Population: Safety population, minus the ITT population.
8.4.
DEMOGRAPHICS AND BASELINE DISEASE 
CHARACTERISTICS
8.4.1. Parameters

Gender

Age at the moment of signing the ICF (years): the age is not recalculated when already 
available in the database

Date of birth: only listed

Date of signing the ICF: only listed

Race

Ethnicity

Height (cm)

Weight (kg) at screening and baseline

Body mass index BMI = (weight in kg) / (height in m)² (kg/m²), at screening and 
baseline: the BMI will be recalculated and rounded to the first decimal, even when 
already available in the database. The original BMI will not be used in that case

BMI categorized as:
≤ 18.5 kg/m²
]18.5,25.0] kg/m²
]25.0,30.0[ kg/m²
≥ 30.0 kg/m²

Childbearing potential: yes / no, no: tubal ligation / total hysterectomy / other. Only listed
8.4.2. Analysis
Table 14.1.3.1: 
Demographic data: Descriptive statistics
Continuous parameters: descriptive statistics per treatment group (and overall).
Categorical parameters: frequency tabulation per treatment group (and overall).
No formal comparison between the treatment groups is planned.
Population: the table will show 

safety 

ITT.
Table 14.1.3.2: 
Demographic data: Sub-group analyses: Descriptive statistics


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The following sub-groups will be shown:

By target Ctrough at Day 15 

By target Ctrough at Day 29

By target Ctrough at Day 15 and 29

By sweat chloride (from arm with greatest volume) at baseline 

By sweat chloride (mean value from both arms) at baseline 

By %FEV1 at baseline
Population: the table will show 

safety 

ITT.
Table 14.1.3.3: 
Demographic data: Pooled analyses: Descriptive statistics
The following sub-groups will be shown:

By target Ctrough at Day 15 

By target Ctrough at Day 29 

By target Ctrough at Day 15 and 29
Population: the table will show 

safety 

ITT.
Listing 16.2.4.1: Demographic data
Listing per treatment group and per subject of all demographic parameters.
Population: safety.
Table 14.1.3.4: 
Baseline laboratory data: Tabulation of normal range
Frequency tabulation per lab test of the baseline result, categorized as low/normal/high 
according to the normal ranges (see section 13.2.4).
Population: Safety.
Table 14.1.3.5: 
Baseline ECG data: Tabulation of the normal range
Frequency tabulation per parameter (QT, QTcF) of the baseline result, categorized as (same as 
in section 13.3.4):

≤ 450 ms

]450,480] ms

]480,500] ms

> 500 ms
Population: Safety.
Table 14.1.3.6: 
Baseline vital signs data: Tabulation of the normal range


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Frequency tabulation per parameter of the baseline result, categorized as low/normal/high 
according to the normal ranges (see section 13.4.3).
Population: Safety.
Table 14.1.3.7: 
Baseline physical examination: Tabulation of the normal range
Frequency tabulation per CRF body system of the baseline result, categorized as 
normal/abnormal.
Population: Safety.
Table 14.1.3.8: 
Baseline pulse oximetry data: Tabulation of the normal range
Frequency tabulation per parameter of the baseline result, categorized as low/normal 
according to the normal ranges (see section 13.5.3).
Population: Safety.
8.5.
BASELINE DISEASE CHARACTERISTICS
8.5.1. Parameters

Duration of CF (years) = 
(   ! " ##) – (  #"  " % &'() ) *
+,-./-
, rounded to the 
nearest integer. If the date of initial diagnosis is incomplete, then the following rules will 
be applied: Missing day: use the first of the month. Missing month: use January.

Screening and baseline sweat chloride

Change in sweat chloride (baseline – screening)

Screening and baseline %FEV1

Change in %FEV1 (baseline – screening)

Mutation F508del (on both allele): Yes/No

Number of exacerbations requiring hospitalization and/or intravenous antibiotics in the 
last 12 months.

Currently have an infection with pseudomonas aeruginosa: yes / no

Currently on inhaled antibiotics: yes / no

Sweat categorized at baseline: <40, [40,50[, [50,60[, >=60

%FEV1 categorized at Baseline: <40, [40,50[, [50,70[, [70,90[, >= 90

Sweat categorized at screening: <40, [40,50[, [50,60[, >=60

%FEV1 categorized at screening: <40, [40,50[, [50,70[, [70,90[, >= 90
8.5.2. Analysis
Table 14.1.3.9:
Screening and baseline disease characteristics
Continuous parameters: descriptive statistics per treatment group (and overall).
Categorical parameters: frequency tabulation per treatment group (and overall).
No formal comparison between the treatment groups is planned.


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Population: the table will show 

safety 

ITT.
Table 14.1.3.10: 
Screening and baseline disease characteristics: Sub-group analyses
The following sub-groups will be shown:

By target Ctrough at Day 15 

By target Ctrough at Day 29 

By target Ctrough at Day 15 and 29

By sweat chloride (from arm with greatest volume) at baseline 

By sweat chloride (mean value from both arms) at baseline 

By %FEV1 at baseline
Population: the table will show 

safety 

ITT.
Table 14.1.3.11: Screening and baseline disease characteristics: Pooled analyses
The following sub-groups will be shown:

By target Ctrough at Day 15 

By target Ctrough at Day 29 

By target Ctrough at Day 15 and 29
Population: the table will show 

safety 

ITT.
Listing 16.2.4.2: Screening and baseline disease characteristics
Listing per treatment group and per subject of all screening and baseline disease 
characteristics. Genotyping will be listed as well.
Population: Safety.
8.6.
MEDICAL HISTORY AND CONCURRENT DISEASES
When the end date is only partially known, the missing parts will be imputed by the last day 
of the month/year.
Listing 16.2.4.3: 
Medical history
Listing per treatment group and per subject of the medical history data findings (i.e., condition 
no longer present at the start of the study): original terms as well as coded terms.
Population: safety.


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Listing 16.2.4.4: 
Concomitant diseases
Listing per treatment group and per subject of the concomitant diseases data findings (i.e., 
condition still present or unknown): original terms as well as coded terms.
Population: safety.
8.7.
PRIOR AND CONCOMITANT THERAPIES
8.7.1. Classification of Therapies
All prior and concomitant therapies will be allocated into exactly one of the following 
categories:

Prior only: the therapy ended before the first study drug administration.

Concomitant only: the therapy started on or after the first study drug administration.

Post-treatment: the therapy started after the last study drug administration.

Prior and concomitant: the therapy started before the first study drug administration, and 
ended on or after the first study drug administration.
When the start date is missing, the therapy is assumed to have started on the same day as the 
first administration of study drug.
When the end date is missing, the therapy is assumed to be still ongoing after the end of the 
study.
When the start date is only partially known, the missing parts will be imputed by the first day 
of the month/year, or the day of the first medication intake in case the nonmissing part 
matches.
When the end date is only partially known, the missing parts will be imputed by the last day 
of the month/year.
Imputation of start and end dates is only done for the classification into prior / concomitant / 
prior+concomitant. The listing will present the original start and end dates, also when 
incomplete. Fields like start and stop days will not be derived from imputed incomplete dates.
No further classification into analysis periods will be done. 
The relative study day of therapy start and stop will be derived as follows (only listed):
Start day
= (Therapy start date) – (date of first study medication administration) + 1, when the start date 
of therapy is known and complete, and when the therapy start date is on or after the date of 
first study medication;
= (Therapy start date) – (date of first study medication administration), when the start date of 
therapy is known and complete, and when the therapy start date is before the date of first 
study medication;
= missing when the start date of therapy is unknown, missing, or incomplete.


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Stop day
= (Therapy stop date) – (date of first study medication administration) + 1, when the end date 
of therapy is known and complete, and the end date of therapy is on or after the date of first 
study medication;
= (Therapy stop date) – (date of first study medication administration), when the end date of 
therapy is known and complete, and the end date of therapy is before the date of first study 
medication;
= (Study termination date) – (date of first study medication administration) + 1, when the 
therapy is still ongoing when the subject leaves the study; in such cases the stop day will be 
presented as “>XX days” in the listing;
= missing when the end date of therapy is unknown, missing or incomplete and the therapy 
isn’t ongoing after the subject left the study.
8.7.2. Coding of Therapies
All therapies are coded using WHO-DRUG (version 01March2017). In the table(s), the 
generic term will be used. The ATC classification will not be used for analysis. Multiple 
records of the same generic term for the same subject with the same categorization will be 
counted only once. The table will therefore present subjects, not occurrences.
8.7.3. Analysis
Table 14.1.3.12: 
Prior and concomitant therapies: Tabulation
Frequency tabulation per treatment group (and overall) of the generic terms.
Population: safety.
Listing 16.2.4.5: 
Prior and concomitant therapies
Listing per treatment group and per subject of all data on prior and concomitant therapies. 
Flags for prior/concomitant will be added. In case the therapy was due to an AE or medical 
history, the AE preferred term and the original term from medical history page will be 
mentioned in this listing.
Population: safety.
8.8.
EXPOSURE TO STUDY MEDICATION AND COMPLIANCE
8.8.1. Derivations
Derived parameters for GLPG2222/Placebo intakes:

Total treatment duration (days) = (last dose administration date – first dose administration 
date) + 1 day.

Total treatment duration, excluding days off drug (days): sum of all durations (last – first 
+1) in the drug log pages where there is a dose >0 tablets.


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
Percentage days with an intake = 100% x 0
! 12  31 ,56!3 " 7#  13"
! 31 
8

Total compliant treatment duration (days): sum of all durations (last – first +1) in the drug 
log pages where there is a dose with exactly 1 tablet (for cohort A) or exactly 3 tablets 
(cohort B).

Percentage compliance = 100% x 0
! 629!  12  31 
! 31 
8
The “total duration” used as denominator in the above formulae equals: (date of Day 29 visit 
or early termination visit) – (date of first drug intake) + 1.
8.8.2. Analysis
Table 14.1.4.1: 
Exposure to study drug: Descriptive statistics
Descriptive statistics of the treatment duration (days) and the compliance (%) by treatment 
group.
Population: safety.
Listing 16.2.5.1: 
Exposure to study drug: eCRF data
Listing per treatment group and per subject of all eCRF data related to the use of drug.
Population: safety.
Listing 16.2.5.2: 
Exposure to study drug: Derived data
Listing per treatment group and per subject of all derived data related to the use of drug.
Population: safety.
Listing 16.2.5.3: 
Study drug administration (clinic visit)
Listing per treatment group and per subject of all data related to the study drug administration 
(morning dose at clinic and previous day).
Population: safety.
8.9.
COMMENTS
Listing 16.2.5.4: 
Comments
Listing per treatment group and per subject of remarks and comments written in the CRF. 
Comments that are already presented in other parts of the analysis (e.g., lab, ECG, 
exposure…) do not need to be repeated in this Comments listing.
Population: safety.


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9.
DEFINITIONS OF EFFICACY TABLES, LISTINGS AND 
FIGURES
9.1.
SWEAT CHLORIDE
9.1.1. Parameters
Two sweat collections, one from each arm, will be obtained from each subject at each time-
point indicated in the flow chart. Sweat samples will be immediately frozen and sent to the 
central laboratory for testing and interpretation of results. 
For the analysis, the following step should be applied for each time-point:

Select the chloride value obtained from the collection with the greater volume of sweat 
(variable LBORRES when LBTESTCD = ‘VOLUME’ and LBSPEC = ‘SWEAT’ in 
SDTM.LB dataset). And if for a specific visit, the volume of sweat is equal for both arms 
then the value with the highest chloride concentration will be used.

Select only sweat collections that have been performed pre-dose
In tables, figures and listings, this parameter will be called: Sweat Chloride (from arm with 
greatest volume).
A first sensitivity analysis will be done by using another method for the derivation of the
sweat chloride. At each time-point, the sweat chloride value used for the analysis will be 
derived:

by taking the mean of the 2 sweat collection samples (right arm and left arm respectively) 
if the difference between the samples is not exceeding 25 mmol/L. If the difference 
between the 2 samples exceeds 25 mmol/L, the results will be discarded.

by taking the available sweat chloride value if 1) only 1 arm was measured or 2) if 
sufficient volume for 1 arm only was collected.
In tables, figures and listings, this parameter will be called: Sweat Chloride (mean value from 
both arms).
Analysis will present:

Actual values

Categories of actual values:
< 40 mmol/L
[40,50[ mmol/L
[50,60[ mmol/L
≥ 60 mmol/L

Change from baseline (Day 1 pre-dose):
change at time point t = (time point t value) – (baseline value)

Percent change from baseline (Day 1 pre-dose):
%change at time point t = 100 x (time point t value – baseline value) / (baseline value) 


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9.1.2. Tables
Table 14.2.1.1.1: Sweat Chloride (mmol/L): Descriptive statistics of the actual values 
per time point
Descriptive statistics of actual values per treatment group and analysis visit for both 
parameters.
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
The table will show: 

LOCF in ITT.

OC in ITT.
Table 14.2.1.1.2: Sweat Chloride (mmol/L): Sub-group analyses: Descriptive statistics 
of the actual values per time point
Descriptive statistics of the actual values per treatment group and analysis visit for each sub-
group. 
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
The following sub-groups will be shown:

By target Ctrough at Day 15 

By target Ctrough at Day 29 

By target Ctrough at Day 15 and 29

By sweat chloride (from arm with greatest volume) at baseline [This sub-group will be 
applied only for the parameter Sweat Chloride (from arm with greatest volume)]

By sweat chloride (mean value from both arms) at baseline [This sub-group will be 
applied only for the parameter Sweat Chloride (mean value from both arms)]

By %FEV1 at baseline
The table will show:  

LOCF in ITT.

OC in ITT 
Table 14.2.1.1.3: Sweat Chloride (mmol/L): Pooled analyses: Descriptive statistics of 
the actual values per time point
Descriptive statistics of the actual values on pooled treatment group and analysis visit. 
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)


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The following sub-groups will be also provided in this pooled analysis:

By target Ctrough at Day 15 

By target Ctrough at Day 29 

By target Ctrough at Day 15 and 29
The table will show:  

LOCF in ITT.

OC in ITT 
Table 14.2.1.1.4: Sweat Chloride (mmol/L): Descriptive statistics of the changes from 
baseline per time point
Descriptive statistics of changes from baseline per treatment group and analysis visit. The 
actual value at baseline will also be presented in this table. 
P-values are generated from an ANCOVA model on the changes from baseline at each time 
point with treatment as factors and baseline value as covariate. Pairwise comparison (dose 
group vs pooled placebo) will be provided as well.
P-values will be generated also from a Kruskal-Wallis test (overall treatment effect) and 
Wilcoxon rank sum test (pairwise comparison with placebo) as sensitivity analysis.
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
The table will show:  

LOCF in ITT.

OC in ITT (only descriptive, no inferential statistics)
Table 14.2.1.1.5: Sweat Chloride (mmol/L): Descriptive statistics of the changes from 
baseline per time point on Placebo groups
Descriptive statistics of changes from baseline per cohort, analysis visit on placebo (cohort 
A), on placebo (cohort B), on pooled placebo. The actual value at baseline will also be 
presented in this table. 
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
The table will show:  

LOCF in ITT.

OC in ITT 
Table 14.2.1.1.6: Sweat Chloride (mmol/L): Sub-group analyses: Descriptive statistics 
of the changes from baseline per time point


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Descriptive statistics of changes from baseline per treatment group and analysis visit for each 
sub-group. The actual value at baseline will also be presented in this table. 
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
The following sub-groups will be shown:

By target Ctrough at Day 15 

By target Ctrough at Day 29 

By target Ctrough at Day 15 and 29

By sweat chloride (from arm with greatest volume) at baseline [This sub-group will be 
applied only for the parameter Sweat Chloride (from arm with greatest volume)]

By sweat chloride (mean value from both arms) at baseline [This sub-group will be 
applied only for the parameter Sweat Chloride (mean value from both arms)]

By %FEV1 at baseline
The table will show:  

LOCF in ITT.

OC in ITT 
Table 14.2.1.1.7: Sweat Chloride (mmol/L): Pooled analyses: Descriptive statistics of 
the changes from baseline per time point
Descriptive statistics of changes from baseline on pooled treatment group and analysis visit. 
The actual value at baseline will also be presented in this table. 
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
The following sub-groups will be also provided in this pooled analysis:

By target Ctrough at Day 15 

By target Ctrough at Day 29 

By target Ctrough at Day 15 and 29
The table will show:  

LOCF in ITT.

OC in ITT 
Table 14.2.1.1.8: Sweat Chloride (mmol/L): Descriptive statistics of the percent 
changes from baseline per time point
Descriptive statistics of percent changes from baseline per treatment group and analysis visit. 
The actual value at baseline will also be presented in this table. 
Parameters:


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
Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
The table will show:  

LOCF in ITT.

OC in ITT 
Table 14.2.1.1.9: Sweat Chloride (mmol/L): Frequency tabulation per time point
Frequency table per dose group and per time point, showing the sweat chloride concentration 
in the following categories: < 40 mmol/L, [40,50[ mmol/L, [50,60[ mmol/L, ≥60 mmol/L.
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
The table will show:  

LOCF in ITT.

OC in ITT 
Table 14.2.1.1.1.10: Sweat Chloride (mmol/L): Shift table versus baseline per time point
Shift table per dose group and time point versus baseline.
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
The table will show:  

LOCF in ITT.

OC in ITT 
Table 14.2.1.1.11: Sweat Chloride (mmol/L): Sensitivity analyses on the changes from 
baseline values
Additional sensitivity analysis will be explored by using Mixed Effects Model for Repeated 
Measures (MMRM). The model will include treatment and analysis visit as fixed effects and 
baseline as a covariate, treatment*analysis visit as interaction terms and subject as random 
effect. Pairwise comparisons will be presented.
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
The table will show:  

OC in ITT.


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9.1.3. Figures
Figure 14.2.1.1.1: Sweat Chloride (mmol/L): Subject profile plots over time
Subject profile plots over time. Each treatment group will be on a separate plot, with all 
subjects of the same treatment group on the same plot. With horizontal reference lines at 40 
and 60 mmol/L. Any unscheduled results will also be part of this plot.
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
The figure will show:  

OC in ITT.
Figure 14.2.1.1.2: Sweat Chloride (mmol/L): Subject profile on change from baseline
plots over time
Change from baseline subject profile plots over time. Each treatment group will be on a 
separate plot, with all subjects of the same treatment group on the same plot. With a 
horizontal reference line at zero, indicating no change., plots will start with a zero mean at 
baseline. Any unscheduled results will also be part of this plot.
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
The figure will show:  

OC in ITT.
Figure 14.2.1.1.3: Sweat Chloride (mmol/L): Mean (+/- SE) plots of the actual values 
over time
Mean (with SE) plots of the actual values over time. Unscheduled results will not be part of 
this plot.
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
The figure will show:  

LOCF in ITT.

OC in ITT 
Figure 14.2.1.1.4: Sweat Chloride (mmol/L): Mean (+/- SE) plots of the changes from 
baseline over time


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Mean (with SE) plots of the changes from baseline over time. Unscheduled results will not be 
part of this plot. With a horizontal reference line at zero, indicating no change. Plots will start 
with a zero mean at baseline.
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
The figure will show:  

LOCF in ITT.

OC in ITT 
Figure 14.2.1.1.5: Sweat Chloride (mmol/L): Sub-group analyses: Mean (+/- SE) plots 
of the changes from baseline over time
Mean (with SE) plots of the changes from baseline over time for each sub-group. Each sub-
group category will be done in a separate plot. Unscheduled results will not be part of this 
plot. With a horizontal reference line at zero, indicating no change. Plots will start with a zero 
mean at baseline.
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
The following sub-groups will be shown:

By target Ctrough at Day 15 

By target Ctrough at Day 29 

By target Ctrough at Day 15 and 29

By sweat chloride at baseline 

By %FEV1 at baseline
The figure will show:  

LOCF in ITT.

OC in ITT 
Figure 14.2.1.1.6: Sweat Chloride (mmol/L): Pooled analyses: Mean (+/- SE) plots of the 
changes from baseline over time
Mean (with SE) plots of the changes from baseline over time on pooled treatment. Each sub-
group category will be done in a separate plot. Unscheduled results will not be part of this 
plot. With a horizontal reference line at zero, indicating no change. Plots will start with a zero 
mean at baseline.
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
The following sub-groups will be also provided in this pooled analysis:


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
By target Ctrough at Day 15 

By target Ctrough at Day 29 

By target Ctrough at Day 15 and 29
The table will show:  

LOCF in ITT.

OC in ITT 
Figure 14.2.1.1.7: Sweat Chloride (mmol/L): Mean (+/- SE) plots of the percent changes 
from baseline over time
Mean (with SE) plots of the percent changes from baseline over time. Unscheduled results 
will not be part of this plot. With a horizontal reference line at zero, indicating no change. 
Plots will start with a zero mean at baseline.
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
The figure will show:  

LOCF in ITT.

OC in ITT 
Figure 14.2.1.1.8: Sweat Chloride (mmol/L): Boxplots on actual values
Boxplots at each timepoint with all treatment groups in the same figure
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
The figure will show:  

LOCF in ITT.

OC in ITT 
Figure 14.2.1.1.9: Sweat Chloride (mmol/L): Boxplots on change from baseline
Boxplots on change from baseline at each timepoint with all treatment groups in the same 
figure
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
The figure will show:  

LOCF in ITT.

OC in ITT 


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9.1.4. Listings
Listing 16.2.6.1: 
Sweat Chloride (mmol/L): Full listing
Listing per subject and per time point of all data related to the sweat chloride: actual values, 
changes from baseline. A flag “H” and “HH” will be added to values above the upper limit of 
normal (Values > 60 mmol/L will be flagged as “HH”. Values in [40,60[ mmol/L will be 
flagged as “H”).
The listing will show:  OC in ITT population.
9.2.
SPIROMETRY
9.2.1. Parameters
During study visits on Days 1, 15 and 29, spirometry must be performed before the morning 
dose. On Day 1 and Day 29, the spirometry test is to be performed prior to the morning dose 
of study drug and an additional spirometry must be performed after the study drug intake 
around 1-2 hours post-dose.
Spirometry can be performed pre-bronchodilator* or post-bronchodilator at screening but 
should take place prior to bronchodilator use at all other visits. But in practice, if on Day 1, 
the subject forgets to withhold his/her dose of bronchodilator then all subsequent spirometry 
should be collected post-bronchodilator, to be consistent with the conditions for the baseline 
measurement. And if on Day 1 spirometry is collected pre-bronchodilator, but then at a 
subsequent visit the subject forgets to withhold his/her dose of bronchodilator, then 
spirometry should be collected post-bronchodilator for that visit only.
* pre-bronchodilator is defined as:

short-acting more than 4 hours prior to the spirometry assessment

long-acting bronchodilator at least 12 hours or 24 hours prior to the spirometry 
assessment
(a spirometry assessment with no use of bronchodilator is equivalent to a pre-bronchodilator 
assessment)
The values will be used as available via the data transfer from the central laboratory 
(
).
Note that at all post-baseline (Day 1) visits:

Spirometry data taken inconsistently with the baseline will be excluded from the analysis 
(i.e. if spirometry was performed post-bronchodilator and the one at baseline was 
performed pre-bronchodilator or if spirometry was performed pre-bronchodilator and the 
one at baseline was performed post-bronchodilator).

Spirometry that should be assessed pre-dose and was done post-dose will be excluded 
from the analysis.

Spirometry, 1-2h post-dose assessment that was done pre-dose will be excluded from the 
analysis.  
Data with a quality grade of D, E or F will be excluded too.


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Quality*
Criteria
A
At least 3 acceptable efforts AND the difference between the best two FEV1 and FVC 
values is equal to or less than 100 ml (80 ml if FVC < 1.0 L)
B
At least 3 acceptable efforts AND the difference between the best two FEV1 and FVC 
values is equal to or less than 150 ml (100 ml if FVC < 1.0 L)
C
At least 2 acceptable efforts AND the difference between the best two FEV1 and FVC 
values is equal to or less than 200 ml (150 ml if FVC < 1.0 L)
D
At least 2 acceptable efforts but the results are not Reproducible
E
At least 1 acceptable effort
F
No acceptable test available
* SQ_QUALGRAD from SDTM.re dataset.
Available parameters: 

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) 
Analysis will present (to be done on all available parameters unless specified):

Actual values

Change from baseline (Day 1 pre-dose):
change at time point t = (time point t value) – (baseline value)

Percent change from baseline (Day 1 pre-dose):
%change at time point t = 100 x (time point t value – baseline value) / (baseline value)
9.2.2. Tables
Table 14.2.1.2.1: Spirometry: Descriptive statistics of the actual values per time point
Descriptive statistics of actual values per parameter, treatment group and analysis visit.
The table will show:  

LOCF in ITT.

OC in ITT 
Table 14.2.1.2.2: Spirometry: Sub-group analyses: Descriptive statistics of the actual 
values per time point
Descriptive statistics of the actual values per parameter, treatment group and analysis visit for 
each sub-group analysis. 
The following sub-groups will be shown:

By target Ctrough at Day 15 

By target Ctrough at Day 29 

By target Ctrough at Day 15 and 29

By sweat chloride (from arm with greatest volume) at baseline 


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
By sweat chloride (mean value from both arms) at baseline 

By %FEV1 at baseline
The table will show:  

LOCF in ITT.

OC in ITT 
Table 14.2.1.2.3: Spirometry: Pooled analyses: Descriptive statistics of the actual 
values per time point
Descriptive statistics of the actual values per parameter on pooled treatment group and 
analysis visit. 
The following sub-groups will be also provided in this pooled analysis:

By target Ctrough at Day 15 

By target Ctrough at Day 29 

By target Ctrough at Day 15 and 29
The table will show:  

LOCF in ITT.

OC in ITT 
Table 14.2.1.2.4: Spirometry: Descriptive statistics of the changes from baseline per 
time point
Descriptive statistics of changes from baseline per parameter, treatment group and analysis 
visit. The actual value at baseline will also be presented in this table. 
P-values are generated from an ANCOVA model on the changes from baseline at each time 
point with treatment as factors and baseline value as covariate. Pairwise comparison (dose 
group vs placebo) will be provided as well.
P-values will be generated also from a Kruskal-Wallis test (overall treatment effect) and 
Wilcoxon rank sum test (pairwise comparison with placebo) as sensitivity analysis.
Descriptive statistics will be done on all available parameters, but inferential statistics will be
done only on FEV1 and %FEV1.
The table will show:  

LOCF in ITT.

OC in ITT (only descriptive, no inferential statistics)
Table 14.2.1.2.5: Spirometry: Descriptive statistics of the changes from baseline per 
time point on Placebo groups
Descriptive statistics of changes from baseline per cohort, analysis visit on placebo (cohort 
A), on placebo (cohort B), on pooled placebo. The actual value at baseline will also be 
presented in this table. 


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The table will show:  

LOCF in ITT.
Table 14.2.1.2.6: Spirometry: Sub-group analyses: Descriptive statistics of the changes 
from baseline per time point
Descriptive statistics of changes from baseline per parameter, treatment group and analysis 
visit for each sub-group. The actual value at baseline will also be presented in this table. 
The following sub-groups will be shown:

By target Ctrough at Day 15 

By target Ctrough at Day 29 

By target Ctrough at Day 15 and 29

By sweat chloride (from arm with greatest volume) at baseline 

By sweat chloride (mean value from both arms) at baseline 

By %FEV1 at baseline
The table will show:  

LOCF in ITT.

OC in ITT 
Table 14.2.1.2.7: Spirometry: Pooled analyses: Descriptive statistics of the changes 
from baseline per time point
Descriptive statistics of changes from baseline per parameter, per pooled treatment group and 
analysis visit. The actual value at baseline will also be presented in this table. 
The following sub-groups will be also provided in this pooled analysis:

By target Ctrough at Day 15 

By target Ctrough at Day 29 

By target Ctrough at Day 15 and 29
The table will show:  

LOCF in ITT.

OC in ITT 
Table 14.2.1.2.8: Spirometry: Descriptive statistics of the percent changes from 
baseline per time point
Descriptive statistics of percent changes from baseline per parameter, treatment group and 
analysis visit. The actual value at baseline will also be presented in this table. 
The table will show:  

LOCF in ITT.

OC in ITT 
Table 14.2.1.2.9: Spirometry: Sensitivity analyses on the changes from baseline values


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Additional sensitivity analysis will be explored by using Mixed Effects Model for Repeated 
Measures (MMRM). The model will include treatment and analysis visit as fixed effects and 
baseline as a covariate, treatment*analysis visit as interaction terms and subject as random 
effect. Pairwise comparisons will be presented.
This table will be done only on FEV1 and %FEV1.
The table will show:  

OC in ITT.
9.2.3. Figures
Figure 14.2.1.2.1: Spirometry: Subject profile plots over time
Subject profile plots over time for each parameter. Each treatment group will be on a new 
plot, with all subjects of the same treatment group on the same plot. Any unscheduled results 
will also be part of this plot.
The figure will show:  

OC in ITT.
Figure 14.2.1.2.2: Spirometry: Subject profile on change from baseline plot over time
Change from baseline subject profile plots over time for each parameter. Each treatment 
group will be on a new plot, with all subjects of the same treatment group on the same plot. 
Any unscheduled results will also be part of this plot.
The figure will show:  

OC in ITT.
Figure 14.2.1.2.3: Spirometry: Mean (+/- SE) plots of the actual values over time
Mean (with SE) plots of the actual values over time for each parameter. Unscheduled results 
will not be part of this plot.
The figure will show:  

LOCF in ITT.

OC in ITT 
Figure 14.2.1.2.4: Spirometry: Mean (+/- SE) plots of the changes from baseline over 
time
Mean (with SE) plots of the changes from baseline over time for each parameter. 
Unscheduled results will not be part of this plot. With a horizontal reference line at zero, 
indicating no change. Plots will start with a zero mean at baseline.
The figure will show:  

LOCF in ITT.

OC in ITT 


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Figure 14.2.1.2.5: Spirometry: Sub-group analyses: Mean (+/- SE) plots of the changes 
from baseline over time
Mean (with SE) plots of the changes from baseline over time for each sub-group. 
Unscheduled results will not be part of this plot. With a horizontal reference line at zero, 
indicating no change. Plots will start with a zero mean at baseline.
The following sub-groups will be shown:

By target Ctrough at Day 15 

By target Ctrough at Day 29 

By target Ctrough at Day 15 and 29

By sweat chloride (from arm with greatest volume) at baseline 

By sweat chloride (mean value from both arms) at baseline 

By %FEV1 at baseline
The figure will show:  

LOCF in ITT.

OC in ITT 
Figure 14.2.1.2.6: Spirometry: Pooled analyses: Mean (+/- SE) plots of the changes from 
baseline over time
Mean (with SE) plots of the changes from baseline over time on pooled treatment. 
Unscheduled results will not be part of this plot. With a horizontal reference line at zero, 
indicating no change. Plots will start with a zero mean at baseline.
The following sub-groups will be also provided in this pooled analysis:

By target Ctrough at Day 15 

By target Ctrough at Day 29 

By target Ctrough at Day 15 and 29
The table will show:  

LOCF in ITT.

OC in ITT 
Figure 14.2.1.2.7: Spirometry: Mean plots (+/- SE) of the percent changes from baseline 
over time
Mean (with SE) plots of the percent changes from baseline over time for each parameter. 
Unscheduled results will not be part of this plot. With a horizontal reference line at zero, 
indicating no change. Plots will start with a zero mean at baseline.
The figure will show:  

LOCF in ITT.

OC in ITT 
Figure 14.2.1.2.8: Spirometry: Boxplots on the actual values


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Boxplots at each timepoint with all treatment groups in the same figure. Only for %FEV1 
parameter.
The figure will show:  

LOCF in ITT.

OC in ITT 
Figure 14.2.1.2.9: Spirometry: Boxplots on the change from baseline
Boxplots at each timepoint for each treatment. Only for %FEV1 parameter.
The figure will show:  

LOCF in ITT.

OC in ITT 
9.2.4. Listings
Listing 16.2.6.2: 
Spirometry: Full listing
Listing per subject and per time point of all data related to spirometry: actual values, changes 
from baseline and percent changes from baseline. 
The listing will show:  ITT.
9.3.
CYSTIC FIBROSIS QUESTIONNAIRE – REVISED (CFQ-R)
9.3.1. Parameters
The following scores will be derived from CFQ-R questionnaire: 

9 Quality of life domains: Physical, role/school, vitality, emotion, social, body image, 
eating, treatment burden, health perceptions.

3 symptom scales: weight, respiratory and digestion.
Each Score will range from 0 to 100, with higher scores indicating better health.
For the analysis, the derivation of each score will be done with the following step for each 
time-point:

Assigned a value for each questions (question 1  to question 50) with the following rules:
Questions
Categories
Score
Question 1  to 5
A lot of difficulty
1
Some difficulty
2
A little difficulty
3
No difficulty
4
Question 6 to 12, 36 to 38, 
44 to 50
Always
1
Often
2
Sometimes
3


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Never
4
Question 19 to 34
Very true
1
Somewhat true
2
Somewhat false
3
Very false
4
Question 39 to 42
A great deal
1
Somewhat
2
A little
3
Not at all
4
Question 13 to 18 and 35
1.XXXXXX
1 = SUBSTR(qstresn,1,1)
2.XXXXXX
2 = SUBSTR(qstresn,1,1)
3.XXXXXX
3 = SUBSTR(qstresn,1,1)
4.XXXXXX
4 = SUBSTR(qstresn,1,1)
Question 43
Clear
4
Clear to yellow
3
Yellowish-green
2
Green with traces of blood
1
Don’t know
5

Items in the questionnaire are expressed either "negatively" or "positively," therefore a 
number of the items must be recoded before the scores for each of the domains are 
calculated. The following items (6, 10, 13, 15, 17, 18, 23, 28, 30, 32, 34, 35) should be 
recoded by using this formulae: new score = 5-score. 

Calculation of each score
Score
Formulae (Qx = Question x)
Physical
= (Mean(Q1, Q2, Q3, Q4, Q5, Q13, Q19, Q20) -1)/3*100 if at 
least 50% of the question have non-missing data
Role/school
= (Mean (Q35, Q36, Q37, Q38) - 1)/3*100 if at least 50% of the 
question have non-missing data
Vitality
= (Mean(Q6, Q9, Q10, Q11) -1)/3*100 if at least 50% of the 
question have non-missing data
Emotion
= (Mean(Q7, Q8, Q12, Q31, Q33) -1)/3*100 if at least 50% of the 
question have non-missing data
Social
= (Mean(Q22, Q23, Q27, Q28, Q29, Q30) -1)/3*100 if at least 
50% of the question have non-missing data
Body image
= (Mean(Q24, Q25, Q26) -1)/3*100 if at least 2 questions have 
non-missing data
Eating
= (Mean(Q14, Q21, Q50) -1)/3*100 if at least 2 questions have 
non-missing data
Treatment burden
= (Mean(Q15, Q16, Q17) -1)/3*100 if at least 2 questions have 
non-missing data


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Health perceptions
= (Mean(Q18, Q32, Q34) -1)/3*100 if at least 2 questions have 
non-missing data
Weight
= (Q39-1)/3*100 if Q39 has non-missing value
Respiratory
= (Mean(Q40, Q41, Q42, Q44, Q45, Q46) -1)/3*100 if at least 
50% of the question have non-missing data
Digestion
= (Mean(Q47, Q48, Q49) -1)/3*100 if at least 2 questions have 
non-missing data

Select only score that correspond to a pre-dose assessment.
For each score, Analysis will present:

Actual values

Change from baseline (Day 1 pre-dose):
change at time point t = (time point t value) – (baseline value)

Percent change from baseline (Day 1 pre-dose):
%change at time point t = 100 x (time point t value – baseline value) / (baseline value)
9.3.2. Tables
Table 14.2.1.3.1: CFQ-R: Descriptive statistics of the actual values per time point
Descriptive statistics of actual values per treatment group and analysis visit for each score.
The table will show:  

LOCF in ITT.

OC in ITT 
Table 14.2.1.3.2: CFQ-R: Sub-group analyses: Descriptive statistics of the actual 
values per time point
Descriptive statistics of the actual values, treatment group and analysis visit for each sub-
group analysis will be done only for CFQ-R respiratory domain score.  
The following sub-groups will be shown:

By target Ctrough at Day 15 

By target Ctrough at Day 29 

By target Ctrough at Day 15 and 29

By sweat chloride (from arm with greatest volume) at baseline 

By sweat chloride (mean value from both arms) at baseline 

By %FEV1 at baseline
The table will show:  

LOCF in ITT.

OC in ITT 
Table 14.2.1.3.3: CFQ-R: Pooled analyses: Descriptive statistics of the actual values 
per time point


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Descriptive statistics of the actual values on pooled treatment group and analysis visit will be 
done only for CFQ-R respiratory domain score. 
The following sub-groups will be also provided in this pooled analysis:

By target Ctrough at Day 15 

By target Ctrough at Day 29 

By target Ctrough at Day 15 and 29
The table will show:  

LOCF in ITT.

OC in ITT 
Table 14.2.1.3.4: CFQ-R: Descriptive statistics of the changes from baseline per time 
point
Descriptive statistics of changes from baseline per treatment group and analysis visit for each 
score. The actual value at baseline will also be presented in this table. 
P-values are generated from an ANCOVA model on the changes from baseline at each time 
point with treatment as factors and baseline value as covariate. Pairwise comparison (dose 
group vs placebo) will be provided as well.
P-values will be generated also from a Kruskal-Wallis test (overall treatment effect) and 
Wilcoxon rank sum test (pairwise comparison with placebo) as sensitivity analysis.
The table will show:  

LOCF in ITT.

OC in ITT (only descriptive, no inferential statistics)
Table 14.2.1.3.5: CFQ-R: Descriptive statistics of the changes from baseline per time 
point on Placebo groups
Descriptive statistics of changes from baseline per cohort, per treatment group and analysis 
visit. The actual value at baseline will also be presented in this table. 
Descriptive statistics of changes from baseline per cohort, analysis visit on placebo (cohort 
A), on placebo (cohort B), on pooled placebo. The actual value at baseline will also be 
presented in this table. 
The table will show:  

LOCF in ITT.

OC in ITT 
Table 14.2.1.3.6: CFQ-R: Sub-group analyses: Descriptive statistics of the changes 
from baseline per time point
Descriptive statistics of changes from baseline, treatment group and analysis visit for each 
sub-group analysis will be done only for CFQ-R respiratory domain score. The actual value at 
baseline will also be presented in this table. 


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The following sub-groups will be shown:

By target Ctrough at Day 15 

By target Ctrough at Day 29 

By target Ctrough at Day 15 and 29

By sweat chloride (from arm with greatest volume) at baseline 

By sweat chloride (mean value from both arms) at baseline 

By %FEV1 at baseline
The table will show:  

LOCF in ITT.

OC in ITT 
Table 14.2.1.3.7: CFQ-R: Pooled analyses: Descriptive statistics of the changes from 
baseline per time point
Descriptive statistics of changes from baseline per pooled treatment group and analysis visit 
will be done only for CFQ-R respiratory domain score. The actual value at baseline will also 
be presented in this table. 
The following sub-groups will be also provided in this pooled analysis:

By target Ctrough at Day 15 

By target Ctrough at Day 29 

By target Ctrough at Day 15 and 29
The table will show:  

LOCF in ITT.

OC in ITT 
Table 14.2.1.3.8: CFQ-R: Descriptive statistics of the percent changes from baseline 
per time point
Descriptive statistics of percent changes from baseline per treatment group and analysis visit 
for each score. The actual value at baseline will also be presented in this table. 
The table will show:  

LOCF in ITT.

OC in ITT 
Table 14.2.1.3.9: CFQ-R: Sensitivity analyses on the changes from baseline values
Additional sensitivity analysis will be explored by using Mixed Effects Model for Repeated 
Measures (MMRM). The model will include treatment and analysis visit as fixed effects and 
baseline as a covariate, treatment*analysis visit as interaction terms and subject as random 
effect for each score. Pairwise comparisons will be presented.
The table will show:  

OC in ITT.


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9.3.3. Figures
Figure 14.2.1.3.1: CFQ-R: Subject profile plots over time
Subject profile plots over time for each score. Each treatment group will be on a new plot, 
with all subjects of the same treatment group on the same plot. Any unscheduled results will 
also be part of this plot.
The figure will show:  

OC in ITT.
Figure 14.2.1.3.2: CFQ-R: Subject profile on change from baseline plot over time
Change from baseline subject profile plots over time for each score. Each treatment group will 
be on a new plot, with all subjects of the same treatment group on the same plot. Any 
unscheduled results will also be part of this plot.
The figure will show:  

OC in ITT.
Figure 14.2.1.3.3: CFQ-R: Mean (+/- SE) plots of the actual values over time
Mean (with SE) plots of the actual values over time for each score. Unscheduled results will 
not be part of this plot.
The figure will show:  

LOCF in ITT.

OC in ITT 
Figure 14.2.1.3.4: CFQ-R: Mean (+/- SE) plots of the changes from baseline over time
Mean (with SE) plots of the changes from baseline over time for each score. Unscheduled 
results will not be part of this plot. With a horizontal reference line at zero, indicating no 
change. Plots will start with a zero mean at baseline.
The figure will show:  

LOCF in ITT.

OC in ITT 
Figure 14.2.1.3.5: CFQ-R: Sub-group analyses: Mean (+/- SE) plots of the changes from 
baseline over time
Mean (with SE) plots of the changes from baseline over time for each sub-group will be done 
only for CFQ-R respiratory domain score. Unscheduled results will not be part of this plot. 
With a horizontal reference line at zero, indicating no change. Plots will start with a zero 
mean at baseline.
The following sub-groups will be shown:

By target Ctrough at Day 15 


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
By target Ctrough at Day 29 

By target Ctrough at Day 15 and 29

By sweat chloride (from arm with greatest volume) at baseline 

By sweat chloride (mean value from both arms) at baseline 

By %FEV1 at baseline
The figure will show:  

LOCF in ITT.

OC in ITT 
Figure 14.2.1.3.6: CFQ-R: Pooled analyses: Mean (+/- SE) plots of the changes from 
baseline over time
Mean (with SE) plots of the changes from baseline over time on pooled treatment will be 
done only for CFQ-R respiratory domain score. Unscheduled results will not be part of this 
plot. With a horizontal reference line at zero, indicating no change. Plots will start with a zero 
mean at baseline.
The following sub-groups will be also provided in this pooled analysis:

By target Ctrough at Day 15 

By target Ctrough at Day 29

By target Ctrough at Day 15 and 29
The table will show:  

LOCF in ITT.

OC in ITT 
Figure 14.2.1.3.7: CFQ-R: Mean plots (+/- SE) of the percent changes from baseline 
over time
Mean (with SE) plots of the percent changes from baseline over time for each score. 
Unscheduled results will not be part of this plot. With a horizontal reference line at zero, 
indicating no change. Plots will start with a zero mean at baseline.
The figure will show:  

LOCF in ITT.

OC in ITT 
9.3.4. Listings
Listing 16.2.6.3: 
CFQ-R: Full listing
Listing per subject and per time point of all data related to CFQ-R: actual values, changes 
from baseline and percent changes from baseline. 
The listing will show:  ITT.


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10.
DEFINITIONS OF PHARMACOKINETICS ANALYSIS
TABLES, LISTINGS AND FIGURES

Compounds:

GLPG2222

PK parameters are:

Cmax, tmax, Ctrough, AUC0-t

Cmax/dose, Ctrough/dose, AUC0-t/dose
Cmax
Maximum concentration after multiple dosing (ng/mL), obtained 
directly from the observed concentration versus time data.
tmax
Time of occurrence of maximum concentration after multiple 
dosing (h), obtained directly from the observed concentration 
versus time data.
Ctrough
Plasma concentration observed at pre-dose (ng/mL), obtained 
directly from the observed concentration versus time data.
AUC0-t
Area under the concentration-time curve up from time 0 up to 24 h 
following multiple dosing (ng·h/mL), calculated by linear up/log 
down trapezoidal summation.  
On Day 15, all PK parameters will be determined (or on Day 29 if the subject is not available 
for full PK profiling on Day 15). On Day 29, only Ctrough will be determined.
10.1.1. PK Parameter Derivation Rules 
Pharmacokinetic analysis of the plasma concentration data for GLPG2222 will be performed 
at 
, United States.  PK parameters will be derived using 
standard non compartmental methods using Phoenix WinNonlin6.4 or higher (Pharsight 
Corp., Certara Company, Princeton, New Jersey, United States); and/or SASVersion 9.4 or 
higher.  Graphics may be prepared with SASVersion 9.4, or higher; SigmaPlot12.5, or 
higher (Systat Software, Inc., San Jose, California, United States); or Phoenix WinNonlin
6.4, or higher.  For PK analysis, the following rules will be applied:

BLOQ concentration will be imputed according to the rules mentioned in Section 5.3.2

If the concentrations before and after a quantifiable timepoint are below the limit of 
quantification, the quantifiable timepoint will not be included in the PK analysis.

Plasma concentrations that again become quantifiable at time points after being BLOQ at 
earlier time points will be excluded from analysis at those time points.

Subjects with less than 3 concentrations > LOQ are excluded from that day.

Day 15 (or Day 29) 24h post-dose plasma concentrations will be imputed using the pre-
dose value, in order to complete the full dosing interval PK profile (of 24 hours).

Exposures will be calculated according to linear up/log down trapezoidal method using 
theoretical sampling time points.


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
Theoretical sampling time will be used for PK parameters calculation, except if the 
deviation of actual sampling time is >10%, when the actual sampling time will be used.
Handling of other potential anomalies in the plasma PK profiles will be discussed with 
Galapagos before PK parameter derivation.
Excluded data will be flagged in the TLFs.
10.1.2. Tables
Table 14.2.2.1: 
GLPG2222 Trough plasma concentrations (ng/mL): Individual data 
and descriptive statistics per dose and day
Subject data with descriptive statistics per dose, day of the predose plasma concentrations 
(Day 15, Day 29).
Compound: GLPG2222.
Population: PK.
Table 14.2.2.2: 
GLPG2222 Plasma concentrations (ng/mL): Individual data and 
descriptive statistics per dose level on the day of the full PK profile
Subject data with descriptive statistics per dose on the day of the full PK profile (PK profile 
data from day 15 and Day 29 will be pooled).
Compound: GLPG2222.
Population: PK.
Table 14.2.2.3: 
GLPG2222 PK parameters: Individual data and descriptive statistics 
per dose on the day of the full PK profile
Subject data with descriptive statistics per dose of the derived PK parameters (Cmax, tmax, 
Ctrough, AUC0-t, Cmax/dose, Ctrough/dose, AUC0-t/dose) on the day of the full PK profile (PK 
profile data from day 15 and Day 29 will be pooled).
Compound: GLPG2222.
Population: PK.
Table 14.2.2.4: 
GLPG2222 PK parameters: statistical assessment of dose-
proportionality
Dose proportionality of PK parameters Cmax, AUC0-t ,Ctrough (Day 15) and Ctrough (Day 
29) will be assessed statistically using the power model approach.  The power model will be:
log (parameter) = α + β * log (dose) where ‘α’ is the intercept and ‘β’ is the slope.
Prior to the analysis, the assumption of a linear relationship between the log AUC0-t (Cmax, 
Ctrough (Day 15) and Ctrough (Day 29)) and log-dose was tested using analysis of variance 
by partitioning the sums of squares for treatments into those for linearity and departures from 


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linearity. If the departures from linearity were significant then the hypothesis of dose 
proportionality was rejected and the power model analysis was not performed.
The estimate obtained for β is a measure of dose proportionality. The estimate of β together 
with its 90% CI (βl, βu) was presented to quantify the degree of non-proportionality.
The intercept α and the slope β together with 90% CIs will be estimated and presented for 
each PK parameter. The power model parameters will be estimated using least-squares (LS) 
regression or an equivalent method. A minimum of 3 values per dose must be available for a 
given parameter to estimate dose proportionality with the power model.
The dose proportionality was confirmed if the 90% CI of β (βl, βu) was contained completely 
within the following critical region:











)
ln(
)
25
.1
ln(
1;
)
ln(
)
8.0
ln(
1
;
r
r
H
L
where r, defined as the dose ratio, is equal to
l
h
, h being the highest dose and l the lowest 
dose.
In this decision rule, the dose proportionality was analyzed as an equivalence problem. If the 
90% CI was excluded completely from the critical region [ΘL;ΘH] defined here above, the 
hypothesis of dose proportionality was rejected. If the 90% CI of β included the lower or the 
upper bound of the critical region, no conclusion could be done on dose proportionality. The 
proportionality was tested at a 5% significance level.
Assessment of the dose-proportionality will be performed on the complete dose range. In case 
of negative conclusion of dose-proportionality on the complete dose, further investigation 
using the same methodology might be done on a restrained dose range.
The calculation of the increase in AUC, Cmax, Ctrough (Day 15) and Ctrough (Day 29) for a 
two-fold increase in dose was performed by substituting the value of β in the equation 2β. CI 
for this ratio was obtained by substituting βl and βu in the equation 2β.
The non-parametric Kruskal-Wallis test will be applied to the non-transformed tmax to 
determine the difference between doses.
The “raw” SAS PROC output must be provided in a statistical appendix listing.
Population: PK
10.1.3. Figures
Figure 14.2.2.1: 
GLPG2222 Trough plasma concentrations (ng/mL): Subject plots 
(linear-linear scale)
Subject plots of the predose plasma concentrations per Day (Day 15, Day 29). Each dose 
group with all subjects of the same dose group on the same plot. With horizontal line (target 
Ctrough) at 
 ng/mL for GLPG2222.


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Compound: GLPG2222.
Population: PK.
This figure will be created using SAS® 9.4.
Figure 14.2.2.2: 
GLPG2222 Trough plasma concentrations (ng/mL): Mean (+/- SE) 
concentration over time (linear-linear scale)
Arithmetic mean with SE of the predose plasma concentrations per Day (Day 15, Day 29), 
with all dose levels on the same plot using different plot symbols. 
Compound: GLPG2222.
Population: PK.
This figure will be created using SigmaPlot®.
Figure 14.2.2.3: 
GLPG2222 Plasma concentrations (ng/mL): Subject profile plots 
(linear-linear scale) on the day of the full PK profile
Subject profile plots of the plasma concentrations over time on the day of the full PK profile 
(PK profile data from day 15 and Day 29 will be pooled). Each dose group will be on a new 
plot, with all subjects of the same dose group on the same plot.
Compound: GLPG2222.
Population: PK.
This figure will be created using SAS® 9.4.
Figure 14.2.2.4: 
GLPG2222 Plasma concentrations (ng/mL): Subject profile plots 
(log-linear scale) on the day of the full PK profile
Subject profile plots of the plasma concentrations over time on the day of the full PK profile 
(PK profile data from day 15 and Day 29 will be pooled). Each dose group will be on a new 
plot, with all subjects of the same dose group on the same plot. With a log10-scaled vertical 
concentration axis. 
Compound: GLPG2222 
Population: PK.
This figure will be created using SAS® 9.4.
Figure 14.2.2.5: 
GLPG2222 Plasma concentrations (ng/mL): Mean (+/- SE) 
concentration over time (linear-linear scale) on the day of the full PK 
profile
Arithmetic mean with SE of the plasma concentrations over time on the day of the full PK 
profile (PK profile data from day 15 and Day 29 will be pooled)., with all dose levels on the 
same plot using different plot symbols. 


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Compound: GLPG2222.
Population: PK.
This figure will be created using SigmaPlot®.
Figure 14.2.2.6: 
GLPG2222 Plasma concentrations (ng/mL): Mean (+/- SE) 
concentration over time (log-linear scale) on the day of the full PK 
profile
Arithmetic mean with SE of the plasma concentrations over time on the day of the full PK 
profile (PK profile data from day 15 and Day 29 will be pooled)., with all dose levels on the 
same plot using different plot symbols. With a log10-scaled vertical concentration axis.
Compound: GLPG2222.
Population: PK.
This figure will be created using SigmaPlot®.
Figure 14.2.2.7: 
GLPG2222 PK parameters: Dose-proportionality
Arithmetic mean with SE of the GLPG2222 dose-normalized PK parameters (Cmax/dose, 
Ctrough/dose, AUC0-t/dose) (with all individual results included as a scatterplot), with the dose 
levels on the horizontal axis
Population: PK.
This figure will be created using SAS® 9.4.
10.1.4. Listings
Listing 16.2.7.1: 
PK Data handling
Listing per subject, dose group and planned time point of any data issue and how the issue 
will be handled in the analysis.
Population: PK.
Listing 16.2.7.2: 
Actual PK blood sampling times (h)
Listing per treatment group, per day and per subject of the PK sampling times relative to the 
actual drug intake. Deviations from the scheduled sampling times of more than 10% will be 
flagged, as well as pre-dose samples that were actually taken post-dose.
Population: PK.
Listing 16.2.7.3: 
Plasma concentrations (ng/mL): Individual data (ED)
In case of early discontinuation: Subject data on the day of the early discontinuation.
Compound: GLPG2222.


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Population: PK.




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Table 14.2.3.3: 
Biomarker: Pooled analyses: Descriptive statistics of the actual values 
per time point
Descriptive statistics of the actual values on pooled treatment group and analysis visit. 
Parameter: 
 and 
The following sub-groups will be also provided in this pooled analysis:

By target Ctrough at Day 15 

By target Ctrough at Day 29 
The table will show:  

LOCF in ITT.

OC in ITT 
Table 14.2.3.4: 
Biomarker: Descriptive statistics of the changes from baseline per 
time point
Descriptive statistics of changes from baseline for each biomarker per treatment group and 
analysis visit. The actual value at baseline will also be presented in this table. 
P-values are generated from an ANCOVA model on the changes from baseline at each time 
point with treatment as factors and baseline value as covariate. Pairwise comparison (dose 
group vs placebo) will be provided as well.
P-values will be generated also from a Kruskal-Wallis test (overall treatment effect) and 
Wilcoxon rank sum test (pairwise comparison with placebo) as sensitivity analysis.
Parameter: all available biomarkers
The table will show:

LOCF in ITT.

OC in ITT (only descriptive, no inferential statistics)
Table 14.2.3.5: 
Biomarker: Descriptive statistics of the changes from baseline per 
time point on Placebo groups
Descriptive statistics of changes from baseline per cohort, per treatment group and analysis 
visit. The actual value at baseline will also be presented in this table. 
Descriptive statistics of changes from baseline per cohort, analysis visit on placebo (cohort 
A), on placebo (cohort B), on pooled placebo. The actual value at baseline will also be 
presented in this table. 
Parameter: all available biomarkers
The table will show:  

LOCF in ITT.

OC in ITT 


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Table 14.2.3.6: 
Biomarker: Sub-group analyses: Descriptive statistics of the changes 
from baseline per time point
Descriptive statistics of the changes from baseline per treatment group and analysis visit for 
each sub-group. 
Parameter: 
 and 
The following sub-groups will be shown:

By target Ctrough at Day 15 

By target Ctrough at Day 29 
The table will show:  

LOCF in ITT.

OC in ITT 
Table 14.2.3.7: 
Biomarker: Pooled analyses: Descriptive statistics of the changes 
from baseline per time point
Descriptive statistics of the changes from baseline on pooled treatment group and analysis 
visit. 
Parameter: 
 and 
The following sub-groups will be also provided in this pooled analysis:

By target Ctrough at Day 15 

By target Ctrough at Day 29 
The table will show:  

LOCF in ITT.

OC in ITT 
Table 14.2.3.8: 
Biomarker: Descriptive statistics of the percent changes from 
baseline per time point
Descriptive statistics of percent changes from baseline per treatment group and analysis visit. 
The actual value at baseline will also be presented in this table. 
Parameter: all available biomarkers
The table will show:

LOCF in ITT.

OC in ITT 
Table 14.2.3.9: 
Biomarker: Sensitivity analyses on the changes from baseline values
Additional sensitivity analysis will be explored by using Mixed Effects Model for Repeated 
Measures (MMRM) for each biomarker. The model will include treatment and analysis visit 


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as fixed effects and baseline as a covariate, treatment*analysis visit as interaction terms and 
subject as random effect. Pairwise comparisons will be presented.
Parameter: all available biomarkers
The table will show:

OC in ITT.
11.3.
FIGURES
Figure 14.2.3.1:
Biomarker: Subject profile plots over time
Subject profile plots over time for each biomarker. Each treatment group will be on a new 
plot, with all subjects of the same treatment group on the same plot. Any unscheduled results 
will also be part of this plot.
Parameter: all available biomarkers
The figure will show:

OC in ITT.
Figure 14.2.3.2:
Biomarker: Mean (+/- SE) plots of the actual values over time
Mean (with SE) plots of the actual values over time for each biomarker. Unscheduled results 
will not be part of this plot.
Parameter: all available biomarkers
The figure will show:

LOCF in ITT.

OC in ITT 
Figure 14.2.3.3:
Biomarker: Mean (+/- SE) plots of the changes from baseline over 
time
Mean (with SE) plots of the changes from baseline over time for each biomarker. 
Unscheduled results will not be part of this plot. With a horizontal reference line at zero, 
indicating no change. Plots will start with a zero mean at baseline.
Parameter: all available biomarkers
The figure will show:

LOCF in ITT.

OC in ITT 
Figure 14.2.3.4:
Biomarker: Sub-group analyses: Mean (+/- SE) plots of the changes 
from baseline over time


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Mean (with SE) plots of the changes from baseline over time for each sub-group. 
Unscheduled results will not be part of this plot. With a horizontal reference line at zero, 
indicating no change. Plots will start with a zero mean at baseline.
Parameter: 
 and 
The following sub-groups will be shown:

By target Ctrough at Day 15 

By target Ctrough at Day 29 
The figure will show:

LOCF in ITT.

OC in ITT 
Figure 14.2.3.5:
Biomarker: Pooled analyses: Mean (+/- SE) plots of the changes from 
baseline over time
Mean (with SE) plots of the changes from baseline over time on pooled treatment. 
Unscheduled results will not be part of this plot. With a horizontal reference line at zero, 
indicating no change. Plots will start with a zero mean at baseline.
Parameter: 
 and 
The following sub-groups will be also provided in this pooled analysis:

By target Ctrough at Day 15 

By target Ctrough at Day 29 
The figure will show:

LOCF in ITT.

OC in ITT 
Figure 14.2.3.6:
Biomarker: Boxplots on actual values
Boxplots at each timepoint for each biomarker with all treatment groups in the same figure.
Parameter: all available biomarkers
The figure will show:

LOCF in ITT.

OC in ITT 
11.4.
LISTINGS
Listing 16.2.8.1: 
Biomarker: Full listing
Listing per subject and per time point of all data related to biomarkers: actual values, changes 
from baseline and percent changes from baseline. 
The listing will show: OC in ITT.


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12.
DEFINITIONS OF PK/EFFICACY ANALYSIS TABLES, 
LISTINGS AND FIGURES
No tables or listings are currently planned.
Figure 14.2.4.1: 
Correlation between GLPG2222 trough plasma concentrations and 
sweat chloride (linear-linear plot)
Scatterplot of the GLPG2222 trough plasma concentrations versus the sweat chloride 
concentration. With all doses on the same graph, in a different symbol. Time point to present: 
Day 15, Day 29.
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
This figure will show: OC in ITT 
Figure 14.2.4.2: 
Correlation between GLPG2222 trough plasma concentrations and 
change from baseline in sweat chloride (linear-linear plot)
Scatterplot of the GLPG2222 trough plasma concentration versus the change from baseline in 
sweat chloride. With all doses on the same graph, in a different symbol. Time point to present: 
Day 15, Day 29.
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
This figure will show: OC in ITT 
Figure 14.2.4.3: 
Correlation between GLPG2222 trough plasma concentrations and 
%FEV1 (linear-linear plot)
Scatterplot of the GLPG2222 trough plasma concentrations versus the percent predicted 
FEV1. With all doses on the same graph, in a different symbol. Time point to present: Day15, 
Day 29.
This figure will show: OC in ITT 
Figure 14.2.4.4: 
Correlation between GLPG2222 trough plasma concentrations and 
change from baseline in %FEV1 (linear-linear plot)
Scatterplot of the GLPG2222 trough plasma concentrations versus the change from baseline 
in percent predicted FEV1. With all doses on the same graph, in a different symbol. Time 
point to present: Day15, Day 29.
This figure will show: OC in ITT 


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Figure 14.2.4.5: 
Correlation between change from baseline in sweat chloride and 
change from baseline in %FEV1 (linear-linear plot)
Scatterplot of the change from baseline in sweat chloride concentration versus the change 
from baseline in percent predicted FEV1. Time point to present: Day15, Day 29, FU. Placebo 
group will be part of this figure.
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
This figure will show: OC in ITT 
Figure 14.2.4.6: 
Mean (+/- SE) sweat chloride (mmol/L) and mean (+/- SE) 
GLPG2222 trough plasma concentrations: Plots over time
Plots of the mean (+/- SE) in sweat chloride and mean (+/- SE) trough plasma concentration 
over time. Unscheduled results will not be part of this plot. With 2 y-axis on the same plot, 
one for the mean in sweat chloride, one for the mean trough plasma concentrations. With 
horizontal line (target Ctrough) at 
 ng/mL. Each dose level will be in a separate plot.
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
This figure will show: OC in ITT 
Figure 14.2.4.7: 
Mean (+/- SE) sweat Chloride (mmol/L) and mean (+/- SE) 
GLPG2222 trough plasma concentrations: Sub-group analyses: Plots 
over time
Plots of the mean (+/- SE) in sweat chloride and mean (+/- SE) trough plasma concentration 
over time. Unscheduled results will not be part of this plot. With 2 y-axis on the same plot, 
one for the mean in sweat chloride, one for the mean trough plasma concentrations. With 
horizontal line (target Ctrough) at 
 ng/mL. Each dose level and sub-groups will be in a 
separate plot.
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
The following sub-groups will be shown:

By target Ctrough at Day 15 

By target Ctrough at Day 29 
This figure will show: OC in ITT 
Figure 14.2.4.8: 
Mean (+/- SE) sweat Chloride (mmol/L) and mean (+/- SE) 
GLPG2222 trough plasma concentrations: Pooled analyses: Plots 
over time


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Plots of the mean (+/- SE) in sweat chloride and mean (+/- SE) trough plasma concentration 
over time. Unscheduled results will not be part of this plot. With 2 y-axis on the same plot, 
one for the mean in sweat chloride, one for the mean trough plasma concentrations. With 
horizontal line (target Ctrough) at 
 ng/mL. Sub-groups will be in a separate plot.
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
The following sub-groups will be shown:

By target Ctrough at Day 15 

By target Ctrough at Day 29 
This figure will show: OC in ITT 
Figure 14.2.4.9: 
Sweat chloride (mmol/L) and GLPG2222 trough plasma 
concentrations: Plots over time
Plots of the sweat chloride (individual data) and trough plasma concentration (individual data) 
over time. Unscheduled results will be part of this plot. With 2 y-axis on the same plot, one 
for the sweat chloride, one for the trough plasma concentrations. Each dose group will be on a 
new plot, with all subjects of the same dose group on the same plot. With horizontal line 
(target Ctrough) at 
 ng/mL. 
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
This figure will show: OC in ITT 
Figure 14.2.4.10: Mean (+/- SE) %FEV1 and mean (+/- SE) GLPG2222 trough plasma 
concentrations: Plots over time
Plots of the mean (+/- SE) in %FEV1 and mean (+/- SE) trough plasma concentration over 
time. Unscheduled results will not be part of this plot. With 2 y-axis on the same plot, one for 
the mean in %FEV1, one for the mean trough plasma concentrations. With horizontal line 
(target Ctrough) at 
 ng/mL. Each dose level will be in a separate plot.
This figure will show: OC in ITT 
Figure 14.2.4.11: Mean (+/- SE) %FEV1 and mean (+/- SE) GLPG2222 trough plasma 
concentrations: Sub-group analyses: Plots over time
Plots of the mean (+/- SE) in %FEV1 and mean (+/- SE) trough plasma concentration over 
time. Unscheduled results will not be part of this plot. With 2 y-axis on the same plot, one for 
the mean in %FEV1, one for the mean trough plasma concentrations. With horizontal line 
(target Ctrough) at 
 ng/mL. Each dose level and sub-groups will be in a separate plot.
The following sub-groups will be shown:

By target Ctrough at Day 15 


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
By target Ctrough at Day 29 
This figure will show: OC in ITT 
Figure 14.2.4.12: Mean (+/- SE) %FEV1 and mean (+/- SE) GLPG2222 trough plasma 
concentrations: Pooled analyses: Plots over time
Plots of the mean (+/- SE) in %FEV1 and mean (+/- SE) trough plasma concentration over 
time. Unscheduled results will not be part of this plot. With 2 y-axis on the same plot, one for 
the mean change in %FEV1, one for the mean trough plasma concentrations. With horizontal 
line (target Ctrough) at 
 ng/mL. Sub-groups will be in a separate plot.
The following sub-groups will be shown:

By target Ctrough at Day 15 

By target Ctrough at Day 29 
This figure will show: OC in ITT 
Figure 14.2.4.13: 
%FEV1 and GLPG2222 trough plasma concentrations: Plots over 
time
Plots of the  %FEV1 (individual data) and trough plasma concentration (individual data) over 
time. Unscheduled results will be part of this plot. With 2 y-axis on the same plot, one for the 
%FEV1, one for the trough plasma concentrations. Each dose group will be on a new plot, 
with all subjects of the same dose group on the same plot. With horizontal line (target Ctrough) 
at 
 ng/mL. 
This figure will show: OC in ITT 
Figure 14.2.4.14: Mean (+/- SE) sweat Chloride (mmol/L) and mean (+/- SE) in 
%FEV1: Plots over time
Plots of the mean (+/- SE) in sweat chloride and mean in %FEV1 over time. Unscheduled 
results will not be part of this plot. With 2 y-axis on the same plot, one for the mean in sweat 
Chloride (mmol/L), one for the mean in %FEV1. Placebo group should be part of this figure. 
Each treatment group will be in a separate plot.
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
This figure will show: OC in ITT 
Figure 14.2.4.15: Correlation between CFQ-R respiratory domain and change from 
baseline in %FEV1 (linear-linear plot)
Scatterplot of the CFQ-R respiratory domain versus the change from baseline in %FEV1. 
With all treatment groups on the same graph, in a different symbol. Time point to present: 
Day15, Day 29, FU. Placebo group should be part of this figure.
This figure will show: OC in ITT 


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Figure 14.2.4.16: Correlation between CFQ-R respiratory domain and percent change 
from baseline in %FEV1 (linear-linear plot)
Scatterplot of the CFQ-R respiratory domain versus the percent change from baseline in 
%FEV1. With all treatment groups on the same graph, in a different symbol. Time point to 
present: Day15, Day 29, FU. Placebo group should be part of this figure.
This figure will show: OC in ITT 
Figure 14.2.4.17: Correlation between change from baseline in CFQ-R respiratory 
domain and change from baseline in %FEV1 (linear-linear plot)
Scatterplot of the CFQ-R respiratory domain changes versus the change from baseline in 
%FEV1. With all treatment groups on the same graph, in a different symbol. Time point to 
present: Day15, Day 29, FU. Placebo group should be part of this figure.
This figure will show: OC in ITT 
Figure 14.2.4.18: Correlation between change from baseline in CFQ-R respiratory 
domain and percent change from baseline in %FEV1 (linear-linear 
plot)
Scatterplot of the CFQ-R respiratory domain changes versus the percent change from baseline 
in %FEV1. With all treatment groups on the same graph, in a different symbol. Time point to 
present: Day15, Day 29, FU. Placebo group should be part of this figure.
This figure will show: OC in ITT 
Figure 14.2.4.19: Mean (+/- SE) CFQ-R respiratory domain and mean (+/- SE) in 
%FEV1: Plots over time
Plots of the mean (+/- SE) in CFQ-R respiratory domain and mean (+/- SE) in %FEV1 over 
time. Unscheduled results will not be part of this plot. With 2 y-axis on the same plot, one for 
the mean in CFQ-R respiratory domain, one for the mean in %FEV1. Placebo will be part of 
this figure. Each treatment group will be in a separate plot.
This figure will show: OC in ITT 
Figure 14.2.4.20: Mean change from baseline (+/- SE) in CFQ-R respiratory domain 
and mean change from baseline (+/- SE) in %FEV1: Plots over time
Plots of the mean change from baseline (+/- SE) in CFQ-R respiratory domain and mean 
change from baseline (+/- SE) in %FEV1 over time. Unscheduled results will not be part of 
this plot. With 2 y-axis on the same plot, one for the mean change from baseline CFQ-R 
respiratory domain, one for the mean change from baseline in %FEV1. Placebo will be part of 
this figure. Each treatment group will be in a separate plot.
This figure will show: OC in ITT 
Figure 14.2.4.21: Mean (+/- SE) CFQ-R respiratory domain and mean (+/- SE) 
GLPG2222 trough plasma concentrations: Plots over time




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Figure 14.2.4.25: 
 and 
and GLPG2222 trough plasma concentrations: Plots 
over time
Plots of the 
 and 
(individual data) and trough plasma concentration (individual 
data) over time. Unscheduled results will be part of this plot. With 2 y-axis on the same plot, 
one for the 
 and 
 one for the trough plasma concentrations. Each dose group will be 
on a new plot, with all subjects of the same dose group on the same plot. With horizontal line 
(target Ctrough) at 
 ng/mL. 
This figure will show: OC in ITT 
Figure 14.2.4.26:
Waterfall plot on change from baseline in Sweat Chloride 
Waterfall plot on change from baseline in Sweat Chloride at Day 15 and Day 29.
Parameters:

Sweat Chloride (from arm with greatest volume)

Sweat Chloride (mean value from both arms)
This figure will show: OC in ITT 
Figure 14.2.4.27:
Waterfall plot on change from baseline in %FEV1
Waterfall plot on change from baseline in %FEV1 at Day 15 and Day 29.
This figure will show: OC in ITT 


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13.
DEFINITIONS OF SAFETY ANALYSIS TABLES, LISTINGS 
AND FIGURES
13.1.
ADVERSE EVENTS
13.1.1. Treatment-Emergent Principle
All adverse events starting on or after first dosing are considered treatment-emergent adverse 
events (TEAE).
Adverse events will be placed into analysis periods according to their start date(time). 
Analysis periods: see section 4.2. The AE will only be presented in the analysis period during 
which it started. Rule: period start date(time) ≤ AE start date(time) ≤ period end date(time). 
In case the AE start date(time) is incomplete, a worst-case allocation will be done according 
to the available parts of the AE start date(time), i.e. the AE will be allocated to the treatment 
period. If the AE start date is equal to the date of the turning point between the screening and 
treatment analysis periods, and no AE start time is available, then the AE will be allocated to 
the treatment period. This is considered a worst-case allocation.
All adverse events emerging during the screening period will only be listed, not presented in 
any of the tables. These events are not TEAEs. All tables will present TEAEs only.
13.1.2. Treatment Relatedness
Following (ICH-E3), the drug relatedness will be dichotomized as follows:
Drug related: at least possibly drug related, OR with missing drug relatedness (= worst-case)
Not drug related: less than possibly drug related.
In tabulations this dichotomized parameter will be used, but in the listings the original 
parameter will be presented.
13.1.3. Worst-Case Principle
When cross-tabulating AE preferred terms versus an AE attribute (e.g., intensity), the worst-
case is always applied within each analysis period. I.e., when a subject has multiple times the 
same AE preferred term in the same analysis period, then the subject is reported only once: 
only with the worst intensity. If this happens in two different analysis periods, the AE is 
reported twice: once in each analysis period.
13.1.4. Adverse Event Onset Day and Duration
AE onset day in the study
= ((AE start date) – (date of first study drug administration)) + 1, when the AE start date is 
completely known; the “+1” is not needed if the AE start date is before the first study drug 
administration date;


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= missing when the AE start date is incomplete or unknown.
AE onset day in the period
= ((AE start date) – (start date of the period into which the AE was allocated)) + 1, when the 
AE start date is completely known;
= missing when the AE start date is incomplete or unknown.
AE duration 
= ((AE stop date) – (AE start date)) + 1, when both dates are completely known;
= ((Study termination date) – (AE start date)) + 1, when the AE start date is fully known but 
the AE is not resolved at the end of the study; in this case the duration will be presented as 
“>x days” in the listing to identify it as a censored result;
= missing when the AE start date is incomplete or unknown, or when the AE has resolved but 
with an incomplete or unknown end date.
These derived parameters will only be presented in the listings. Note that the start and stop 
times of the AE are not used; only the dates are used. 
13.1.5. Calculation of Percentages
All percentages will be calculated against the total number of subjects that are still in the 
study in that particular analysis period.
13.1.6. Tables
No formal inferential statistics (p-values) will be derived.
Analysis periods will be replaced by their respective treatment via the data captured in the 
CRF (i.e, an as-treated allocation). All tabulations and listings will present treatments rather 
than analysis periods.
Table 14.3.1.1: 
Treatment-emergent adverse events: Summary table
Tabulation per treatment of the number and percentage of subjects with the following:

Subjects with at least one treatment-emergent adverse event (TEAE)

Subjects with at least one serious TEAE

Subjects who died

Subjects with at least one mild TEAE as worst intensity

Subjects with at least one moderate TEAE as worst intensity

Subjects with at least one severe TEAE

Subjects with at least one TEAE that was considered treatment-related

Subjects with at least one TEAE for which the study treatment was temporarily stopped

Subjects with at least one TEAE for which the study treatment was permanently stopped.
Population: safety population.


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Table 14.3.1.2: 
Treatment-emergent adverse events: Tabulation of all adverse events
Tabulation of TEAE preferred terms per body class, per treatment group.
With a frequency tabulation of the number of events (reportings).
Population: safety.
Table 14.3.1.3: 
Treatment-emergent adverse events: Tabulation per intensity
Cross-tabulation of TEAE preferred terms versus their intensity. Use the worst-case intensity 
per TEAE per subject. Per treatment group.
Population: safety.
Table 14.3.1.4: 
Treatment-emergent adverse events: Tabulation of all treatment-
related events
Tabulation of TEAE preferred terms per body class, per treatment group. Selecting only the 
TEAEs that were treatment-related (see section 13.1.2).
Population: safety.
Table 14.3.1.5: 
Treatment-emergent adverse events: Tabulation of the intensity of 
treatment-related events
Cross-tabulation per analysis period of TEAE preferred terms versus their intensity; per body 
class and per treatment group. Use the worst-case intensity per TEAE per subject, selecting 
only the TEAEs that were treatment-related (see section 13.1.2).
Population: safety.
Table 14.3.1.6: 
Serious treatment-emergent adverse events: Tabulation for EudraCT 
reporting
Tabulation of the number of subjects and events per body class, preferred term and per 
treatment.
Population: Safety.
Table 14.3.1.7: 
Non-serious treatment-emergent adverse events: Tabulation for 
EudraCT reporting
Same as the previous table, but only selecting TEAEs that are not serious.
Population: Safety.
Table 14.3.1.8: 
Non-serious treatment-emergent adverse events: Tabulation for 
EudraCT reporting of TEAEs occurring in at least 5% in one of the 
treatment group


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Same as the previous table, selecting all the lines from the table where there is at least 5% 
occurrence in one of the treatment group either at SOC or at preferred term level. If the SOC 
line is selected but none of the associated preferred terms, then the SOC line is still to be 
presented but without preferred term lines.
Population: Safety.
13.1.7. Listings
Listing 16.2.10.1: Treatment-emergent adverse events: Summary listing of all events
Listing per treatment group, per subject of the following:
Period start and end date(time)

AE preferred term (flagging serious TEAEs with an asterisk *)

AE start and end date(time)

AE onset day in study

AE duration

AE intensity

AE drug relatedness

AE action taken

Concomitant therapy started (yes/no)
In such a way that all information fits on one line for each AE.
Periods without an AE will be included as “no AE” records.
Population: safety.
Listing 16.2.10.2: Treatment-emergent adverse events: Full listing
Listing per treatment group, per subject of all AE details, including MedDRA coding. Only 
actual adverse events will be presented here: periods or subjects without a TEAE will be left 
out. If a ConMed was started due to the AE, then the listing will present the ConMed’s 
generic term.
Population: safety.
Listing 16.2.10.3: Pre-treatment adverse events: Full listing
Listing per treatment group and per subject of the screening period of all AE details, like in 
the previous listing.
Population: safety.
Listing 16.2.10.4: Adverse events: Full listing of the serious adverse events
Same as the previous listing, but only selecting SAEs (irrespective their treatment-
emergence).


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Population: safety.
Listing 16.2.10.5: Treatment-emergent adverse events: Full listing of the events leading 
to discontinuation
Same as the previous listing, but only selecting TEAEs that lead to a stop of study medication, 
or of the study itself.
Population: safety.
Listing 16.2.10.6: Adverse events: Coding information
Listing of all available coding steps between AE verbatim and AE system organ class, 
mentioning also the subjects who had this AE. 
Population: safety.
13.2.
LABORATORY SAFETY
13.2.1. Laboratory Units
The statistical analysis will only present results in Standard International (SI) units. Other 
units will not be presented.
Lab tests with only a very low sample size (N<3 overall) will not be presented in the tables, 
but only in the listings. Lab tests that are not part of the planned test panels according to the 
protocol will only be listed.
Urinalysis tests will be presented as part of the descriptive statistics and/or shift tables. 
13.2.2. Number of Significant Digits
In tables and listings, the standardized results will be rounded to present only a relevant 
number of digits. The Mock TLFs contain tables on the expected number of significant digits 
per lab test. This rounding will be done prior to any parameter derivation.
Note that this table also contains the classification of lab tests into categories.
13.2.3. Baseline and Change from Baseline
The baseline is defined as the last sample prior to first dosing. Baseline will be determined per 
lab test individually. It is recognized that baseline tests may thus come from more than one 
lab sample. 
The change from baseline will be calculated for all post-baseline time points as:
Change from baseline at time point t = value at time point t – baseline value.


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13.2.4. Scoring of Laboratory Values and Urinalysis Results
All values will be compared to their matching normal ranges. The normal ranges provided by 
the laboratory will be used for this, as available in the database. Values are scored as 
abnormally low (L), normal (N) or abnormally high (H) by the central lab. The analysis will 
use this scoring (variable LBNRIND from SDTM.LB). 
Tests without normal ranges will not be scored. Any clinical significance flags will be used in 
the listings.
13.2.5. Worst-Case Abnormality
Derived per parameter separately. 
All nonmissing post-baseline values (including unscheduled measurements and follow-up 
measurements) will be used to derive the following worst-case:

H = abnormally high:
at least one  post-baseline measurement is above the normal range, and there are no 
values below the normal range.

L = abnormally low:
at least one post-baseline measurement is below the normal range, and there are no values 
above the normal range.

H+L = abnormally high and low:
at least one post-baseline measurement is above the normal range, and at least one other 
post-baseline measurement is below the normal range.

N = normal:
all post-baseline measurements are within normal limits.
13.2.6. Tables 
No formal inferential statistics (p-values) will be derived.
Table 14.3.2.1: 
Laboratory data: Descriptive statistics of the actual values per time 
point
Descriptive statistics of actual values per lab test category (hematology, biochemistry, 
urinalysis), lab test and unit, treatment group and time point. 
Population: safety.
Table 14.3.2.2: 
Laboratory data: Descriptive statistics of the changes from baseline 
per time point
Descriptive statistics of changes from baseline (including 95% confidence interval of the 
mean change) per lab test category (hematology, biochemistry, urinalysis), lab test and unit, 
treatment group and time point. The actual value at baseline will also be presented in this 
table.
Population: safety.


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Table 14.3.2.3: 
Laboratory data: Shift table according to the lab normal range per 
time point
Shift table per lab test category (hematology, biochemistry, urinalysis), lab test, treatment 
group and time point (including worst-case). The table will present the shift in abnormality 
(L/N/H) at each post-baseline time point versus the baseline abnormality (L/N/H). Tests 
without normal ranges will not be presented in this table.
Population: safety.
Table 14.3.2.4: 
Laboratory data: Treatment-emergent abnormalities per time point
Frequency table of the treatment-emergent lab abnormalities per lab test category 
(hematology, biochemistry, urinalysis), lab test, treatment group and time point (including 
worst-case). A post-baseline abnormality is considered treatment-emergent if it differs from 
the baseline result. Tests without normal ranges will not be presented in this table.
Population: safety.
Table 14.3.2.5: 
Laboratory data: Shift table of the categorical lab data per time point
Shift table per lab test category (hematology, biochemistry, urinalysis), lab test, treatment 
group and time point. Selecting only the tests with categorical data. The table will present the 
shift in value at each post-baseline time point versus the baseline value.
Population: safety.
13.2.7. Figures
Figure 14.3.2.1: 
Laboratory data: Subject profile plots over time
Subject profile plots over time, with each lab test and treatment group on a new page but with 
all subjects of one treatment group on the same plot. Any unscheduled results will also be part 
of this plot.
Population: safety.
Figure 14.3.2.2:
Laboratory data: Mean (+/- SE) plots of the actual values over time
Mean (with SE) plots of the actual values over time, with each lab test on a new page but with 
all treatment groups on the same plot using different plot symbols. Unscheduled results will 
not be part of this plot.
Population: safety.
Figure 14.3.2.3: 
Laboratory data: Mean (+/- SE) plots of the changes from baseline 
over time
Mean (with SE) plots of the changes from baseline over time, with each lab test on a new 
page but with all treatment groups on the same plot using different plot symbols. Unscheduled 
results will not be part of this plot. With a horizontal reference line at zero, indicating no 
change. Plots will start with a zero mean at baseline.


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Population: safety.
13.2.8. Listings
All listings will contain next to the actual data (raw and changes) the following parameters:

an abnormality L/H flag

the test’s normal range

a clinical relevance flag
Listing 16.2.11.1: Laboratory data: Full listing
Listing per treatment group, per subject and per time point of all data.
Population: safety.
Listing 16.2.11.2: Laboratory data: Abnormalities listing
Listing per treatment group, per subject and per time point of all post-baseline time points 
scored as out-of-normal-range or clinically significant, plus also the baseline reference time 
point.
Population: safety.
13.3.
ECG
13.3.1. Available Data
Available parameters: HR (heart rate), RR, QRS, PR and QT (corrected QT).
13.3.2. Calculated Parameters
The QTc will always be derived during the statistical analysis, even when already available in 
the database. The value in the database will not be used in the analysis.
The QTc will be calculated using the following formulae:

Fridericia’s cube-root corrected QT (Fridericia, 1920):
QTcF (ms) = QT (ms) x :
*;;;
<<()
=
QTcF (ms) = QT (ms) x :><(?@)
,;
=
The formula using RR is preferred. In case no RR is available, at a subject level, the formula 
using HR will be applied for all subjects. Derived QTc values will be rounded to the nearest 
first decimal before deriving changes from baseline and categories.
13.3.3. Baseline and Change from Baseline
The baseline is defined as the last nonmissing value prior to dosing. Baseline will be 
determined per ECG parameter individually. It is recognized that baseline parameters may 
thus come from more than one ECG reading. 


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The change from baseline will be calculated for all post-baseline time points as:
Change from baseline at time point t = value at time point t – baseline value.
13.3.4. Normal Ranges
QT and QTc parameters: first round the value as described above, and then apply the 
following categorizations:

of the actual values: 

<= 450 ms, 

]450,480] ms, 

]480,500] ms, 

>500 ms;

of the changes from baseline: 

<= 30 ms (including all decreases in QT), 

]30,60] ms, 

>60 ms.
13.3.5. Worst-case Abnormality of QT and QTc
Derived per parameter separately.
All nonmissing postbaseline values (including unscheduled measurements and follow-up 
measurements) will be used to derive the following worst-case. The worst-case is the largest 
nonmissing post-baseline value and the largest non-missing change from baseline.
13.3.6. Tables
No formal inferential statistics (p-values) will be derived.
Table 14.3.3.1: 
ECG: Descriptive statistics of the actual values per time point
Descriptive statistics of the actual values per test and unit, treatment group and time point. 
Population: safety.
Table 14.3.3.2: 
ECG: Descriptive statistics of the changes from baseline per time 
point
Descriptive statistics of the changes from baseline per test and unit, treatment group and time 
point. The actual value at baseline will also be presented in this table.
Population: safety.
Table 14.3.3.3: 
ECG: Shift table according to the QT normal range per time point
Shift table per test, treatment group and time point. The table will present the shift in 
abnormality at each post-baseline time point (including worst-case) versus the baseline 
abnormality. Parameters: QT, QTcF.


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Population: safety.
Table 14.3.3.4: 
ECG: Treatment-emergent QT abnormalities per time point
Frequency table of the treatment-emergent abnormalities per parameter, treatment group and 
time point (including worst-case). A post-baseline abnormality is considered treatment-
emergent if it is higher than the baseline result. Parameters: QT, QTcF.
Population: safety.
Table 14.3.3.5: 
ECG: Treatment-emergent abnormal change in QT per time point
Frequency table per test, treatment group and time point (including worst-case). The table will 
present the abnormality of the changes at each post-baseline time point according to the 
classifications of section 13.3.4 Parameters: QT, QTcF.
Population: safety.
Table 14.3.3.6:
ECG: Frequency table of the eCRF ECG interpretation per time 
point
Frequency table per treatment group and time point of the ECG interpretation scores as 
recorded in the eCRF. Interpretation scores are:

Cardiac conduction disorders;

Rate and rhythm disorders;

Supraventricular arrhythmias;

Ventricular arrhythmias.
Note that more than one of these items can be ticked.
Population: safety.
13.3.7. Figures
No figures planned.
13.3.8. Listings
Listing 16.2.12.1: ECG: Full listing
Listing per treatment group, per subject and per time point of the ECG parameters (raw values 
as well as changes from baseline), flagging abnormal results. Includes ECG interpretation and 
morphology findings.
Population: safety.
Listing 16.2.12.2: ECG: Abnormalities listing
Listing per treatment group, per subject and per time point of all post-baseline data scored as 
out-of-normal-range (i.e., a QT or QTcF value > 450 ms or a QT or QTcF change > 30 ms) or 
post-baseline clinically significant, plus also the baseline reference time point.


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Population: safety.
13.4.
VITAL SIGNS
13.4.1. Available Data
Available parameters: heart rate, respiratory rate, diastolic and systolic blood pressure, 
temperature and weight.
13.4.2. Baseline and Change from Baseline
The baseline value will be the last nonmissing value prior to first dosing. Baseline will be 
determined per vital signs parameter individually. It is recognized that baseline parameters 
may thus come from more than one vital signs reading.
The change from baseline will be calculated for all post-baseline time points as:
Change from baseline at time point t = value at time point t – baseline value.
13.4.3. Normal Ranges
Parameter (unit)
Normal range
Lower limit
Upper limit
Pulse (bpm)
40
100
DBP (mmHg)
45
90
SBP (mmHg)
90
150
Temperature (°C)
35.5
37.5
Respiratory rate, breaths/min
12
16
Values equal to the boundaries are still considered normal (N). A value is classified as 
abnormally low (L) when the value < lower limit of the normal range. A value is classified as 
abnormally high (H) when the value > upper limit of the normal range.
13.4.4. Worst-Case Abnormality
Derived per parameter separately.
All nonmissing post-baseline values (including unscheduled measurements and follow-up 
measurements) will be used to derive the following worst-case:

H = abnormally high: 
at least one post-baseline measurement is above the normal range, and there are no values 
below the normal range.

L = abnormally low: 
at least one post-baseline  measurement is below the normal range, and there are no 
values above the normal range.

H+L = abnormally high and low: 


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at least one post-baseline measurement is above the normal range, and at least one other 
post-baseline  measurement is below the normal range.

N = normal: 
all post-baseline measurements are within or equal to normal limits.
13.4.5. Tables 
No formal inferential statistics (p-values) will be derived.
Table 14.3.4.1: 
Vital signs: Descriptive statistics of the actual values per time point
Descriptive statistics of the actual values per test and unit, treatment group and time point. 
Population: safety.
Table 14.3.4.2: 
Vital signs: Descriptive statistics of the changes from baseline per 
time point
Descriptive statistics of the changes from baseline per test and unit, treatment group and time 
point. The actual value at baseline will also be presented in this table.
Population: safety.
Table 14.3.4.3: 
Vital signs: Shift table according to the normal range per time point
Shift table per test, treatment group and time point. The table will present the shift in 
abnormality (L/N/H) at each post-baseline time point (including worst-case) versus the 
normal range at baseline (L/N/H).
Population: safety.
Table 14.3.4.4: 
Vital signs: Treatment-emergent abnormalities per time point
Frequency table of the treatment-emergent abnormalities per parameter, treatment group and 
time point (including the worst-case). A post-baseline abnormality is considered treatment-
emergent if it is different from the baseline result. 
Population: safety.
13.4.6. Figures
No figures are planned.
13.4.7. Listings
Listing 16.2.13.1: Vital signs: Full listing
Listing per treatment, per subject and per time point of all parameters: raw values, changes 
from baseline, and flagging abnormal results.
Population: safety.


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Listing 16.2.13.2: Vital signs: Abnormalities listing
Listing per treatment group, per subject and per time point of all treatment emergent  time 
points scored as out-of-normal-range or clinically significant, plus also the baseline reference 
time point. 
Population: safety.
13.5.
PULSE OXIMETRY
13.5.1. Available Data
Available parameter: arterial oxygen saturation level.
13.5.2. Baseline and Change from Baseline
The baseline is defined as the last non-missing value prior to dosing. This will normally be 
Day 1 (pre-dose).
The change from baseline will be calculated for all post-baseline time points as:
Change from baseline at time point t = value at time point t – baseline value.
13.5.3. Normal Ranges
Normal range applicable in seated or supine position (after 5 min):
Parameter
Lower limit of normal
Arterial Oxygen Saturation Level, SpO2
95%
Values equal to the boundary are still considered normal (N). A value is classified as 
abnormally low (L) when the value < lower limit of the normal range. 
13.5.4. Worst-Case Abnormality
All non-missing post-baseline values (including post-baseline unscheduled measurements) 
will be used to derive the overall worst-case:

L = abnormally low: at least one post-baseline measurement is below the normal range.

N = normal: all post-baseline measurements are within normal limits.
13.5.5. Tables
No formal inferential statistics (p-values) will be derived.
Table 14.3.5.1: 
Pulse oximetry (%): Descriptive statistics of the actual values per 
time point
Descriptive statistics of the actual values per time point.
Population: safety.


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Table 14.3.5.2: 
Pulse oximetry (%): Descriptive statistics of the changes from 
baseline per time point
Descriptive statistics of the changes from baseline (including 95% confidence interval of the 
mean change) per time point. The actual value at baseline (Day 1 pre-dose) will also be 
presented in this table.
Population: Safety.
Table 14.3.5.3: 
Pulse oximetry (%): Shift table according to the normal range per 
time point
Shift table per time point. The table will present the shift in abnormality (L/N) at each post-
baseline time point (including the worst-case) versus the normal range at baseline (L/N).
Population: Safety.
Table 14.3.5.4: 
Pulse oximetry (%): Treatment-emergent abnormalities per time 
point
Frequency table of the treatment-emergent abnormalities per time point (including the worst-
case). A post-baseline abnormality is considered treatment-emergent if it is different from the 
baseline result.
Population: Safety.
13.5.6. Figures
No figures planned.
13.5.7. Listings
Listing 16.2.14.1: Pulse oximetry (%): Full listing
Listing per treatment group, per subject and per time point of the arterial oxygen saturation 
level (raw values as well as changes from baseline), flagging abnormal results.
Population: Safety.
Listing 16.2.14.2: Pulse oximetry (%): Abnormalities listing
Listing per treatment group, per subject and per time point of all post-baseline time points 
scored as out-of-normal-range, plus also the baseline reference time point.
Population: Safety.
13.6.
PHYSICAL EXAMINATIONS
Listing 16.2.15.1: Physical examinations: Abnormalities listing
Listing per treatment group, per subject and per time point of the selection of all abnormal 
findings.


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Population: safety.


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14.
REFERENCES
Fridericia, L. (1920). Die systolendauer im elektrokardiogramm bei normalen menschen und bei 
herzkranken. 53:469-486.
ICH-E3. (December 1995). Structure and content of clinical study reports. Step 4 Guideline.
ICH-E6. (17 July 1996). Guideline for good clinical practice. Step 5 Guideline.
ICH-E9. (5 February 1998). Statistical principles for clincal trials. Step 4 guideline.