Clinical trial NCT02738801
Conditions: Idiopathic Pulmonary Fibrosis
Keywords: Idiopathic Pulmonary Fibrosis GLPG1690 Autotaxin
Sponsor: Galapagos NV
Start date: 2016-03-01; Completion date: 2017-05-02
Enrollment: 23 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A multicenter randomized, double-blind, parallel group, placebo-controlled, exploratory phase IIa study in subjects with Idiopathic Pulmonary Fibrosis (IPF) to evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GLPG1690. Male and female subjects aged 40 years or older will be screened to determine eligibility. The screening period will be up to 4 weeks. At baseline, eligible subjects will be randomized in a 3:1 ratio to GLPG1690 or matching placebo administered for 12 weeks. The subjects will visit the study center at screening, baseline, Weeks 1, 2, 4, 8 and 12 and for a follow-up visit 2 weeks after the last administration of study drug. Planned assessments: Adverse event reporting, clinical laboratory tests, vital signs, physical examination, 12-Lead-ECG, PK blood sampling, biomarker blood/bronchoalveolar lavage fluid (BALF), Spirometry, St George's respiratory questionnaire, high-resolution computed tomography (HRCT).

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: GLPG1690 600 mg QD intervention 2: Placebo QD
Intervention descriptions: intervention 1: GLPG1690 capsules, administered at a dose of 600 mg, orally QD intervention 2: Matching placebo capsules, administered orally QD

Protocol documents:
Prot_000.pdf: 


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CLINICAL STUDY PROTOCOL HISTORY
CSP / Amendment #
Date
Generic / Country / Site Specific
CSP v2.0
13-Oct-2015
Section 
2.5 
and 
4.1: 
Details 
independent medical safety review are 
removed as these are described in 
section 7
Section 5.6.2 and 5.7.4: clarified that 
bronchoscopy/HRCT is taken post 
dose if applicable
Section 4.7.1 Timing of home- and 
site-based spirometry versus study 
drug intake
As timing vs study drug intake is 
described in previous paragraph
Reference list: one more author name 
added for several references 
Appendix 4: instructions in CYP3A4 
removed as these are described in 
section 3.4.7
CSP v3.0
15-Oct-2015
History table was not included in CSP 
v2.0 


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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 
(MA) Department:
 MA SAE Fax #: 
or
e-mail: 
In case of medical questions during the course of the study, the investigator must contact:

Europe:
UKRAINE
+
In case of urgent medical questions, the investigator should call the 24/7 emergency #:


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TABLE OF CONTENTS
List of Abbreviations and Definition of Terms....................................................................7
Study Specific Procedures..................................................................................................10
1.
Study Flow Chart...................................................................................................10
2.
Introduction ...........................................................................................................13
2.1.
Idiopathic Pulmonary Fibrosis ......................................................................13
2.2.
Background Autotaxin..................................................................................14
2.3.
Background GLPG1690 – Non-Clinical Data................................................14
2.3.1.
Physical, Chemical, Pharmaceutical Properties, and 
Formulations....................................................................................14
2.3.2.
Pharmacology ..................................................................................15
2.3.3.
Nonclinical Pharmacokinetics and Product Metabolism....................15
2.3.4.
Toxicology.......................................................................................16
2.4.
Background GLPG1690– Clinical Data ........................................................17
2.5.
Clinical Risks/Benefits..................................................................................17
2.6.
Rationale for the Study .................................................................................18
2.7.
Rationale for the Choice of Dose and Dosing Interval...................................21
3.
Study Objectives....................................................................................................22
3.1.
Primary Objectives .......................................................................................22
3.2.
Secondary Objectives....................................................................................22
4.
Investigational Plan................................................................................................23
4.1.
Overall Study Design....................................................................................23
4.2.
Study Population...........................................................................................23
4.2.1.
Sample Size .....................................................................................23
4.2.2.
Inclusion Criteria..............................................................................24
4.2.3.
Exclusion Criteria ............................................................................24
4.2.4.
Prohibition and Restrictions .............................................................25
4.2.5.
Removal of Subjects from Therapy or Assessments..........................26
4.3.
Investigations Medicinal Products.................................................................28
4.3.1.
Identity of the Investigations Medicinal Products .............................28
4.3.2.
Dosage and Administration ..............................................................28
4.3.3.
Randomization.................................................................................28
4.3.4.
Packaging, Labeling, and Distribution..............................................29
4.3.5.
Storage.............................................................................................29
4.3.6.
Treatment Compliance and Drug Accountability..............................29
4.3.7.
Prior and Concomitant Therapy........................................................30
4.3.8.
Blinding and Unblinding ..................................................................31
5.
Study Assessments.................................................................................................31
5.1.
Timing of Assessments .................................................................................31
5.2.
Initial Subject and Disease Characteristics ....................................................32
5.3.
Subject Diary Card........................................................................................32
5.4.
Safety Assessments.......................................................................................33
5.4.1.
Adverse Events ................................................................................33
5.4.2.
Clinical Laboratory Evaluations .......................................................34
5.4.3.
Vital Signs .......................................................................................34
5.4.4.
Physical Examination.......................................................................35
5.4.5.
Electrocardiogram............................................................................35
5.5.
Pharmacokinetic Assessments.......................................................................35
5.5.1.
Biological Samples...........................................................................35


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5.5.2.
Pharmacokinetic Parameters.............................................................35
5.6.
Pharmacodynamic Assessments....................................................................36
5.6.1.
Biological Samples (Blood)..............................................................36
5.6.2.
Biological Samples (BALF) .............................................................36
5.6.3.
Pharmacodynamic Parameters..........................................................36
5.7.
Exploratory Efficacy Assessments ................................................................36
5.7.1.
Pulmonary Function by Spirometry..................................................36
5.7.2.
Biomarker Analysis..........................................................................37
5.7.3.
Quality of Life .................................................................................38
5.7.4.
Functional Respiratory Imaging .......................................................38
5.8.
Total Blood Volume .....................................................................................39
6.
Statistical Methods.................................................................................................41
6.1.
Determination of Sample Size.......................................................................41
6.2.
Population for Analyses ................................................................................41
6.2.1.
All Screened Subjects.......................................................................41
6.2.2.
All Randomized Subjects .................................................................41
6.2.3.
Safety Analysis Set ..........................................................................41
6.2.4.
Pharmacokinetics Analysis Set.........................................................41
6.2.5.
Pharmacodynamics Analysis Set ......................................................41
6.2.6.
Intent to Treat Analysis Set ..............................................................41
6.3.
Statistical Analyses.......................................................................................42
6.3.1.
General Statistical Considerations ....................................................42
6.3.2.
Analyses of Demographics and Baseline Characteristics ..................42
6.3.3.
Analyses of Safety Data ...................................................................42
6.3.4.
Pharmacokinetic Analyses................................................................42
6.3.5.
Pharmacodynamic Analyses.............................................................42
6.3.6.
Exploratory Efficacy Assessments....................................................43
6.3.7.
Pharmacokinetic/ Pharmacodynamic and Pharmacokinetic/ 
Exploratory Efficacy Correlations ....................................................43
7.
Independent Medical Safety Review ......................................................................44
General Procedures............................................................................................................45
8.
Adverse Events......................................................................................................45
8.1.
Definitions....................................................................................................45
8.2.
Intensity of Adverse Event............................................................................45
8.3.
Causality Assessment....................................................................................46
8.4.
Action Taken Regarding Investigational Product (If Applicable)...................46
8.5.
Outcome .......................................................................................................47
8.6.
Recording Adverse Events............................................................................47
8.7.
Managing Serious Adverse Events................................................................47
8.8.
Reporting Serious Adverse Events / Pregnancies...........................................47
8.8.1.
Serious Adverse Events....................................................................47
8.8.2.
Pregnancy ........................................................................................48
8.9.
Reporting Serious Adverse Events to Competent Authorities/Ethics 
Committees...................................................................................................48
9.
Study Closure Considerations ................................................................................48
10.
Study Materials......................................................................................................49
10.1. Investigational Medical Products ..................................................................49
10.2. Study Documents..........................................................................................49
10.3. Participation Cards........................................................................................50
10.4. Source Data ..................................................................................................50


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10.5. Electronic Data Capture................................................................................51
11.
Archiving...............................................................................................................52
12.
Confidentiality.......................................................................................................52
13.
Reporting and Publication......................................................................................53
13.1. Reporting......................................................................................................53
13.2. Publication....................................................................................................53
14.
Ethics.....................................................................................................................53
14.1. IEC...............................................................................................................53
14.2. Regulatory Approval / Notification...............................................................54
14.3. ICH GCP ......................................................................................................54
14.4. Informed Consent .........................................................................................54
15.
Financing and Insurance.........................................................................................55
15.1. Financial Disclosure......................................................................................55
15.2. Indemnification.............................................................................................55
15.3. Insurance ......................................................................................................55
16.
Data Quality Control / Assurance...........................................................................55
16.1. Monitoring....................................................................................................55
16.2. Audit and Inspection.....................................................................................56
References...........................................................................................................................57
Appendices..........................................................................................................................61
Appendix 1
Study Contact Information ........................................................................61
Appendix 2
HRCT/Biopsy Central Review Criteria......................................................64
Appendix 3
DLCO .......................................................................................................66
Appendix 4
CYP3A4 Inducers .....................................................................................67
Appendix 5
Normal Ranges..........................................................................................68
Signature Page – Sponsor...................................................................................................69
Signature Page – Investigator ............................................................................................70


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviations
AE
adverse event
ANCOVA
analysis of covariance
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATS
American Thoracic Society
ATX
autotaxin
AUC
area under the curve
AUC0-24h
area under the concentration-time curve from time 0 to 24 hours
AUC0-Ʈ
area under the plasma drug concentration-time curve of a dosing 
interval
AUEC
area under the effect-time curve
BAL
bronchoalveolar lavage
BALF
bronchoalveolar lavage fluid
b.i.d.
bis in die, twice daily
BLM
bleomycin
BW
body weight
CƮ
trough plasma concentration (just before the next dosing i.e. predose 
sample)
CCL18
chemokine motif ligand 18
Cl
clearance
Cmax
maximum concentration
CRO
contract research organization
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTGF
connective tissue growth factor
CYP
cytochrome P450
D
day
DBP
diastolic blood pressure
DLCO
diffusing capacity for the lungs for carbon monoxide
ECG
electrocardiogram
ECM
extracellular matrix
eCRF
electronic case report form


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EDC
electronic data capture
EDV
early discontinuation visit
Emax
maximum % reduction from baseline
ENPP
ectonucleotide pyrophosphatase/phosphodiesterase 
EOS
end of study
ERS
European Respiratory Society
EU
European Union
FC
food consumption
FEF
forced expiratory flow
FEF25-75
forced expiratory flow between 25 and 75% of exhaled volume
FEV1
forced expiratory volume in 1 second
FIH
first in human
FRC
functional residual capacity
FRI
functional respiratory imaging
FSH
follicle-stimulating hormone
FU
follow-up
FVC
forced vital capacity
GCP
Good Clinical Practice
HIV
human immunodeficiency virus
HRCT
high-resolution computed tomography
IC50
inhibitory concentration 50%
ICAM-1
intercelullar adhesion molecule type 1
ICF
informed consent form
ICH
International Conference on Harmonization
IEC
independent ethics committee
IL8
interleukin 8
ILD
interstitial lung disease
IPF
idiopathic pulmonary fibrosis
KL-6
Krebs von den Lungen 6
LC-MS/MS
liquid chromatography-mass spectrometry
LFT
liver function test
LPA
lysophosphatidic acid
LPC
lysophosphatidylcholine
MMP
matrix metalloproteinase
Muc1
mucin type 1


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NOAEL
no observed adverse effect level
PD
pharmacodynamics
PDE
phosphodiesterase
PK
pharmacokinetics
PLA
phospholipase A
PLC
phospholipase C
QA
quality assurance
q.d.
quaque die, once daily
S100A12
S100 calcium-binding protein A12
SAE
serious adverse event
SAS
Statistical Analysis Software
SBP
systolic blood pressure
SE
standard error
SGRQ
St. George's Respiratory Questionnaire
 
 MA
 Medical Affairs
SLB
surgical lung biopsy
SP
safety pharmacology
SP-A
surfactant protein A
SP-D
surfactant protein D
TEAE
treatment-emergent adverse event
TGFβ
transforming growth factor 
TLC
total lung capacity
tmax
time to maximum plasma concentration
t1/2
terminal half life
ULN
upper limit of normal
US
United States
VCAM-1
vascular cell adhesion molecule type 1
Vss
volume of distribution
WBC
white blood cell
Definition of Terms
QTc
corrected QT interval
QTcF
QT interval corrected for heart rate according to Fridericia’s formula: 
QTcF = QT x (1000/RR)1/3


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STUDY SPECIFIC PROCEDURES
1.
STUDY FLOW CHART
EVENT
Visit 1
Screening
Visit 2
Baseline
DOSING PERIOD
EDV
FU
Visit
Visit 3 1
W1
Visit 4 1
W2
Visit 5 1
W4
Visit 6 1
W8
Visit 7 1
W12
Visit 8/
EOS
W14
Study days (D)
D-28 to 
D-4
D-1
D1
D7
±2 days
D14
±2 days
D28
±3 days
D56
±3 days
D84
±3 days
D98
±3 days
Informed consent
X
Historical HRCT sent to central review 2
X
SLB sent to central review 2, 3
X
Demographics
X
Medical history/Concurrent illnesses
X
Inclusion/exclusion criteria
X
Serology
X
FSH test
4
X
DLCO 
X
Confirm all eligibility criteria
X
Randomization
X
                                                            
1 Subjects will be asked to come to the study center in the morning at approximately the same time on every visit. 
2 The HRCT and SLB need to be sent to central review at least 8 days prior to the baseline visit to allow for central reading and confirmation of diagnosis.
3 If available
4 Only at screening in case there is doubt on whether a female subject is postmenopausal.






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2.
INTRODUCTION
2.1.
IDIOPATHIC PULMONARY FIBROSIS
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, severely debilitating, and 
ultimately lethal lung disease predominantly affecting elderly male smokers or ex-smokers 
with a median age of 65-70 years (Cordier & Cottin, 2013). The disease is characterized by 
progressive worsening of dyspnea and lung function and is associated with a poor prognosis 
(i.e., median survival of 2-5 years following diagnosis) (Kim, Collard, & King, 2006; Collard, 
et al., 2007; Meltzer & Noble PW, 2008; Ley, Collard, & King, 2011; Raghu, et al., 2011). 
The estimated IPF prevalence ranges from 14.0 to 27.9 cases per 100,000 population in the 
United States (US) and from 1.3 to 23.4 cases per 100,000 population in Europe (data from 
1990-2011). The estimated IPF incidence in these studies ranges from 6.8-8.8 cases per 
100,000 population in the US and from 0.2-7.4 cases per 100,000 population in Europe
(Thomeer, Costabe, Rizzato, Poletti, & Demedts, 2001; Raghu, Weycker, Edelsberg, 
Bradford, & Oster, 2006; Fernández, et al., 2010; Navaratnam, et al., 2011)
Over the past decade, extensive research has been conducted to address the unmet medical 
need for effective IPF treatment. Two treatments (pirfenidone and nintedanib) targeting the 
biologic processes that drive fibrosis are currently approved in the European Union (EU) and 
US. Pirfenidone (antifibrotic, antiinflamatory, and antioxidant treatment marketed as Esbriet®; 
indicated in adults for the treatment of mild to moderate IPF), was the first drug to be licensed 
specifically for IPF. Phase III studies had varying results but overall, it was demonstrated that 
the drug improved progression-free survival and slowed the decline in forced vital capacity 
(FVC). Moreover, pirfenidone may have a mortality benefit (Spagnolo, et al., 2010; 
Taniguchi, et al., 2010; Noble, et al., 2011; King, et al., 2014). The drug was approved in the 
EU in 2011 and in the US in 2014. Nintedanib (tyrosine kinase inhibitor marketed as Ofev®;
indicated in adults for the treatment of IPF), was initially developed as an anticancer agent. In 
phase III studies, it significantly reduced the decline in FVC compared with placebo. A trend 
towards a reduced death rate was also observed; however, the studies were not powered to 
detect differences in mortality (Richeldi, et al., 2014). The drug was approved in the US in 
2014 and in the EU in 2015. Both treatments appear to slow disease progression but are 
frequently associated with side effects potentially limiting the use in clinical practice (Esbriet. 
Summary of Product Characteristics.; Ofev. Summary of Product Characteristics.; Raghu, et 
al., 2015).
There thus remains a significant unmet medical need for the investigation and development of 
novel IPF treatments targeting disease-relevant pathways and several other candidate 
treatments with different mechanism of action are currently in phase II and III or in earlier 
phases of clinical development. 
Galapagos is currently pursuing the development of GLPG1690, a small-molecule autotaxin 
(ATX) inhibitor targeting disease-relevant signal transduction pathways, for the treatment of 
IPF.


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2.2.
BACKGROUND AUTOTAXIN
GLPG1690 is a novel, potent, and selective small molecule inhibitor of ATX.
ATX, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) or 
lysophospholipase D, is a ~120 kDa protein that belongs to the ENPP family of enzymes. 
ATX is the only ENPP enzyme with lysophospholipase D activity and is responsible for the 
hydrolysis of lysophosphatidylcholine (LPC) to produce the bioactive lipid lysophosphatidic 
acid (LPA). The term LPA covers several chemical species able to activate LPA receptors 
depending on the nature of the fatty acid side chain on the glycerol backbone. The most 
abundant LPA species in human plasma is LPA C18:2 with a fatty acid side chain of 
18 carbon atoms including 2 unsaturated bonds (Bandoh, Aoki, Taira, Tsujimoto, Arai, & 
Inoue, 2000). Literature data have identified the ATX/LPC axis as the main source of LPA in 
blood (Tsuda, et al., 2006; Tanaka, et al., 2006). In serum from heterozygous mice, for 
example, both ATX activity and LPA level were about half of those from wild-type mice, 
showing that ATX is responsible for the bulk of LPA production in serum.
Several publications suggest a role for ATX in the control of disease-affected lung function 
through effects on lung epithelial cells, fibroblasts, and smooth muscle cells (Magkrioti & 
Aidinis, 2013). In general, inflammatory conditions in the lung are often described as 
associated with increased ATX and LPA levels. Studies related to IPF indicated an increase in 
LPA levels in the BALF of patients (Tager, et al., 2008), an increase of ATX levels in human 
fibrotic lung (Oikonomou, et al., 2012) and an elevation of LPA 22:4 in exhaled breath 
condensate of patients (Montesi, et al., 2014). Further, LPA1 knock-out and inhibitor studies 
revealed a key role for LPA in fibrotic processes in lung and were complemented by studies 
using cell-specific knock-out mice lacking ATX in bronchial epithelial cells and 
macrophages. These mice were shown to be less sensitive to models of lung fibrosis
(Oikonomou, et al., 2012). The role of LPA in lung remodeling relates to the effects of LPA 
on both lung fibroblasts (through LPA1) and epithelial cells (through LPA2). It has been 
demonstrated that LPA2 plays a key role in the activation of transforming growth factor 
(TGFin epithelial cells under fibrotic conditions (Xu, et al., 2009). 
Available literature and preclinical pharmacology data generated by Galapagos, suggest that 
interventions targeting the ATX/LPA pathway could lead to a new class of therapy for IPF.
More information on the study drug is provided in the Investigator’s Brochure and 
summarized in the sections below. (Investigator Brochure GLPG1690, Edition 2, October 
2015)
2.3.
BACKGROUND GLPG1690 – NON-CLINICAL DATA
2.3.1. Physical, Chemical, Pharmaceutical Properties, and Formulations
The chemical name of GLPG1690 is 2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-
oxoethyl)-piperazin-1-yl)-8-methylimidazo[1,2-α]pyridin-3-yl)-(methyl)amino)-4-(4-
fluorophenyl)-thiazole-5-carbonitrile.
The clinical formulation used in this study is an oral capsule containing GLPG1690 as the free 
base.


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2.3.2. Pharmacology
2.3.2.1.
Primary and Secondary Pharmacology
GLPG1690 is an ATX inhibitor (inhibitory concentration 50% [IC50] of 131 nM and 224 nM 
in biochemical assays with human enzyme and mouse enzyme, respectively). The LPA 
production after human plasma incubation was inhibited by GLPG1690 with an IC50 of 
242 nM demonstrating the low impact of plasma protein binding on the activity of the 
compound. 
The 
compound 
was 
selective 
over 
related 
enzymes 
like 
ENPP1, 
phosphodiesterase 4 (PDE4) and PDE5 (enzymes with phosphodiesterase activity), and 
phospholipase A (PLA) or phospholipase C (PLC) (enzymes with phospholipase A or C 
activity, respectively). Moreover, GLPG1690 showed no inhibition in a panel of kinases. In a 
Cerep diversity panel (98 targets including receptors and ion channels), only 3 targets 
displayed more than 50% inhibition at 10 µM. LPA is the biomarker of choice for the ATX 
inhibitor program as it is quantifiable in plasma and other biological fluids by liquid 
chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). 
GLPG1690 dose-dependently inhibited the production of connective tissue growth factor 
(CTGF) upon TGFβ-triggering in normal human dermal fibroblasts.
Pharmacokinetic (PK)/pharmacodynamic (PD) experiments in mice demonstrated an inverse 
relationship between LPA level and GLPG1690 concentration in plasma in vivo. 
The efficacy of GLPG1690 in a prophylactic bleomycin (BLM) 21-days mouse model of lung 
fibrosis, measured as the reduction in lung weight and Ashcroft score, was similar to that of 
the pirfenidone comparator. Significant prevention of collagen deposit in the lung was 
observed in the GLPG1690 group only. After GLPG1690 treatment, the increase of LPA 
levels in bronchoalveolar lavage fluid (BALF) after BLM exposure was reduced for several 
LPA species. In addition, the efficacy of GLPG1690 in the tobacco smoke challenge model in 
mice, measured as the capacity to reduce inflammatory cell recruitment to the lungs, was 
indicative of the anti-inflammatory capacity of GLPG1690. This is seen as relevant, as 
inflammation is one important component in the pathophysiology of IPF. 
2.3.2.2.
Safety Pharmacology
The safety pharmacology (SP) package conducted to investigate the potential effect of 
GLPG1690 on cardiovascular, respiratory, and central nervous systems did not show any 
biologically relevant effects.
2.3.3. Nonclinical Pharmacokinetics and Product Metabolism
The absolute oral bioavailability was moderate in rodents (25-36%), low in monkeys (14%), 
and high in dogs (102%). 
GLPG1690 was highly bound to plasma proteins: 99.1% in human and 97.9-99.6% in rat, 
dog, mouse, rabbit, and monkey. 
Overall, GLPG1690 did not extensively distribute into tissues as shown by the low volume of 
distribution (Vss) ranging from 0.35 L/kg in the mouse to 0.55 L/kg in the monkey.


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Upon repeated once daily (q.d.) oral dosing of GLPG1690, no significant accumulation was 
observed in the rat and some accumulation (up to approximately 9-fold) was observed in the 
dog at the highest tested dose of 100 mg/kg/day. Gender differences in PK profiles were 
observed in rats but not in dogs.
The total plasma clearance (Cl) of GLPG1690 was low in mice, rats, monkeys, and dogs, 
ranging between 3 and 23% of the hepatic blood flow. Therefore, GLPG1690 is expected to 
undergo a low first-pass effect after oral dosing. 
The only cytochrome P450 (CYP) enzyme involved in GLPG1690 metabolism was CYP3A4. 
In vitro metabolism studies in hepatocytes revealed 26 potential metabolites. Metabolites 
formed in human hepatocytes were all present to a similar or higher extent in rat and/or dog 
hepatocytes, the animal species selected for toxicity studies. In human, 8 metabolites resulting 
from hydrolysis, hydroxylation, addition of water, demethylation, or reduction were detected
in plasma and/or urine. These metabolites were also observed in rat and dog plasma.
In vitro interaction studies of GLPG1690 with CYPs showed some degree of inhibition, with 
IC50 values ≥13-fold the free steady state maximum plasma concentration (Cmax) expected in 
human after a 600 mg dose, as well as some induction at concentrations ≥60-fold the 
expected free steady state Cmax. Towards key drug transporters, some inhibition by 
GLPG1690 was observed, with IC50 values ≥7-fold the free steady state Cmax expected in 
human after a 600 mg dose. Therefore, it can be concluded that drug-drug interactions with 
GLPG1690 are unlikely.
2.3.4. Toxicology
2.3.4.1.
General Toxicology
The dose-limiting effects in the repeated dose toxicity studies with GLPG1690 in the rat 
consisted of reduced food consumption (FC) and markedly decreased body weight (BW) gain 
at 1000 mg/kg/day for 4 weeks. In dogs, the dose-limiting effects corresponded to decreased 
white blood cells (WBCs) and FC, emesis and BW loss, associated with poor clinical 
conditions as reported at the dose of 150 mg/kg/day in the 13-week study.
In the 13-week study in rats, the no observed adverse effects level (NOAEL) was at the dose 
of 40 mg/kg/day in males and 400 mg/kg/day in females, corresponding to area under the 
concentration-time curve from time 0 to 24 hours (AUC0-24h) values of 68.3 µg.h/mL and 
1680 µg.h/mL, respectively (which is approximately 0.9- and 22-fold higher, respectively, 
than the anticipated free plasma AUC0-24h [0.532 µg.h/mL] in human after a 600 mg dose). In 
the 13-week study in dogs, the NOAEL was considered to be the dose of 50 mg/kg/day, 
corresponding to a mean AUC0-24h of 1010 μg.h/mL (which is approximately 21-fold higher 
than the anticipated free plasma AUC0-24h [0.532 µg.h/mL] in human after a 600 mg dose). 
The clinical signs, the changes in hematological and clinical biochemistry, and the 
pathological findings observed at the NOAEL in the rat and dog were considered non-adverse 
because they were mild in intensity, had no functional or morphological adverse correlate, and 
were fully reversible after a 4-week treatment-free recovery period.
Reproductive embryo-fetal development studies were performed in rats and rabbits with 
GLPG1690. In rats, the maternal and developmental NOAELs for GLPG1690 were 
determined at 60 mg/kg/day and 10 mg/kg/day, respectively. These NOAELs correspond to a 
mean AUC0-24h of 324 and 21.4 μg.h/mL on Day 17 post-coitum, respectively, which is 


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approximately 4-
and 0.3-fold higher than the anticipated free plasma AUC0-24h
(0.532 µg.h/mL) in human after a 600 mg dose. In rabbits, the maternal and developmental 
NOAELs were concluded to be 15 mg/kg/day and 5 mg/kg/day, respectively. These NOAELS 
correspond to a mean AUC0-24h of 50.8 µg.h/mL and 8.10 µg.h/mL on Day 16 post-coitum, 
respectively (which is approximately 0.4- and 0.06-fold higher than the anticipated free 
plasma in human after a 600 mg dose).
GLPG1690 did not show genotoxic effects in vitro or in vivo. No phototoxic effects with 
GLPG1690 have been observed in vivo in rats.
2.4.
BACKGROUND GLPG1690– CLINICAL DATA
To date, GLPG1690 (or placebo) has been administered in fed state to 40 healthy male 
subjects in a Phase I first-in-human (FIH) study (Study GLPG1690-CL-101). GLPG1690 (or 
placebo) was administered as a single oral suspension at a dose ranging from 20 mg to 
1500 mg or a 300 mg capsule (Part 1 of the study). GLPG1690 (or placebo) was administered 
as a twice daily (b.i.d.) dose of 150 mg or a q.d. dose of 600 mg or 1000 mg for 14 days 
(Part 2 of the study).
Administration of single (up to 1500 mg) and multiple ascending oral doses of GLPG1690 
(up to 1000 mg q.d.) for 14 days in healthy male subjects can be considered safe and well 
tolerated. No deaths, other serious adverse events (SAEs), or treatment-emergent adverse 
events (TEAEs) leading to study drug discontinuation have been reported. All TEAEs were at 
most moderate in severity. No clinically relevant abnormalities related to laboratory 
parameters, electrocardiogram (ECG), vital signs, or physical examinations were reported.
Single (up to 1500 mg) and multiple ascending oral doses of GLPG1690 (up to 1000 mg q.d.) 
for 14 days were assessed in healthy male subjects under fed conditions. GLPG1690 was 
rapidly absorbed with a median time to maximum plasma concentration (tmax) of 0.5-2 h. The 
terminal half-life (t1/2) after q.d. oral dosing for 14 days was 5.8 h. Steady-state exposure of 
GLPG1690 increased in proportion with the dose between 300 to 1000 mg total daily dose. 
Excretion of unchanged GLPG1690 in human urine was low (< 1.8% in 24 h) and rapid. 
There was no impact on the urinary 6β-OH-cortisol/cortisol ratio after repeated dosing 
suggesting a lack of CYP3A4 induction by GLPG1690.
After a single administration of GLPG1690, a significant dose-dependent percentage
reduction of LPA 18:2 was observed in plasma. This effect started from 0.5 h post dose, 
reached a plateau, and was sustained over time up to 24 h post dose. Multiple q.d. or b.i.d.
ascending doses resulted in a similar effect on LPA 18:2. A strong reduction in LPA 18:2 
levels was already observed at predose Day 14, pointing to a sustained effect over 14 days. 
The effect on LPA 18:2 was also confirmed by area under the effect-time curve (AUEC) for 
the % reduction from baseline and maximum % reduction from baseline (Emax). 
2.5.
CLINICAL RISKS/BENEFITS
IPF is a chronic and progressive lethal lung disease for which two treatments (pirfenidone and 
nintedanib) are currently approved in the EU and US. These treatments appear to slow disease 
progression but are frequently associated with side effects potentially limiting the use in 
clinical practice. There thus remains a significant unmet medical need for the investigation 
and development of novel IPF treatments targeting disease-relevant pathways.


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GLPG1690 is the first ATX inhibitor in clinical development for the oral treatment of IPF.
As with any new compound in early development, no benefit can be expected for the 
individual subjects and safety is paramount. The subjects therefore need to be closely 
monitored by repeated assessment of clinical and vital signs, ECG, and laboratory safety 
parameters.
GLPG1690 has been evaluated in a phase I FIH study whereby the administration of single 
(up to 1500 mg) and multiple ascending oral doses of GLPG1690 (up to 1000 mg q.d. for 
14 days) in healthy male subjects was considered safe and well tolerated. All TEAEs, the 
most common ones being headache and diarrhea were at most moderate in severity and 
transient in nature. No clinically relevant abnormalities related to laboratory parameters, 
ECG, vital signs, or physical examination were reported.
As there is limited clinical experience with GLPG1690 so far, the study drug should not be 
administered to subjects with moderate to severe renal impairment, hepatic impairment 
(Child-Pugh B or Child-Pugh C), or pediatric subjects. The study drug may be administered to 
elderly subjects. Based on available pre-clinical data, the impact of aging on the elimination 
of GLPG1690 should not be significant. The hepatic clearance is predicted to be low 
suggesting GLPG1690 undergoes low metabolism in humans. In terms of renal elimination, 
< 2% of GLPG1690 is excreted unchanged in urine. Consequently, the fecal route is likely the 
main route of elimination with secretion of GLPG1690 and potential metabolites via the bile 
into the feces.
The risk of treatment with GLPG1690 in adult subjects is primarily related to fertility, 
pregnancy, and lactation. GLPG1690 induced reversible changes in sperm parameters as well 
as reversible microscopic findings in the seminiferous tubules in the 13-week oral toxicity 
studies in rats and dogs. Even though no animal fertility studies have been performed so far, a 
decreased male fertility cannot be excluded in patients while on treatment with GLPG1690.
Moreover, GLPG1690 showed teratogenic effects in both rats and rabbits, with induction of 
major skeletal and visceral abnormalities at doses > 10 mg/kg/day (rats) and > 5 mg/kg/day 
(rabbits). No data have been generated in lactating women and no data are available on 
excretion in milk. In view of the limited knowledge of the possible effects of GLPG1690 on 
pregnancy and lactation at this stage of development, GLPG1690 should not be given to 
pregnant or lactating women. In addition, highly effective contraceptive measures should be 
taken in women of childbearing potential and in men who have expressed the will to father a 
child to prevent pregnancy and to avoid the risk of exposure of the embryo or fetus.
To enhance the safety and integrity of the study data, an independent medical safety review
will be implemented. (See Section 7 for additional information).
Please refer to the Investigator’s Brochure for additional information. (Investigator Brochure 
GLPG1690, Edition 2, October 2015)
2.6.
RATIONALE FOR THE STUDY
Recent literature has suggested a role for ATX, an enzyme with lysophospholipase D activity 
responsible for the production of LPA, in disease-affected lung function. Interventions 
targeting the ATX/LPA pathway could lead to a new class of therapy for IPF. 


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GLPG1690 is the first ATX inhibitor in clinical development for the oral treatment of IPF. 
Preclinical studies suggested a high level of target engagement (21-day BLM mouse models): 
after GLPG1690 treatment, the increase of LPA levels in BALF after BLM exposure was 
reduced for several LPA species. Moreover, GLPG1690 provided similar or better results than 
pirfenidone - in the same model - in terms of the reduction in lung weight and Ashcroft score 
and prevention of collagen deposit in the lung. In addition, GLPG1690 dose-dependently 
inhibited the production of CTGF upon TGFβ-triggering in normal human dermal fibroblasts.
Results from a FIH study generated promising PD results (LPA reduction) and indicated the 
study drug was generally safe and well tolerated in a population of healthy subjects. 
As a next step in the clinical development of GLPG1690, its safety, tolerability, PK, and PD
properties will be evaluated in this Phase IIa study in subjects with IPF.
Rationale for the Study Design
This is a randomized, double-blind, parallel group, placebo-controlled, multicenter, 
exploratory Phase IIa study including subjects with IPF. The randomized double-blind study 
design was chosen as it is the most rigorous method to generate high quality scientific data. In 
addition, a placebo-controlled study contains internal evidence of assay sensitivity (i.e., when 
a difference is demonstrated, it is interpretable without reference to external findings),
measures absolute safety and efficacy (i.e., it measures the total pharmacologically mediated 
effect of treatment), is very efficient (i.e., can measure treatment effects with a smaller sample 
size compared with any other type of controlled study), and minimizes the effect of subject 
and investigator expectations (ICH E10, 2000).
The subject eligibility criteria are typical for patient studies in IPF. Since the disease typically 
affects elderly subjects, it was chosen to include subjects aged ≥40 years. Subjects could 
neither use the 2 drugs approved for the treatment of IPF (i.e., pirfenidone and nintedanib) nor 
warfarin, imatinib, ambrisentan, azathioprine, cyclophosphamide, cyclosporine A, prednisone 
at steady dose > 15 mg/day, and any other experimental IPF therapy within 4 weeks prior to 
screening and during the study in order to avoid any confounding effects these drugs may 
have on the safety, tolerability, PK, PD, or exploratory endpoints evaluated in the current 
study.  
The treatment duration of 12 weeks was chosen as currently, the preclinical safety of the drug 
has been evaluated up to a maximum of 13 weeks treatment duration. 
Rationale for the Outcome Measures
Safety and tolerability will be assessed by the evaluation of adverse events (AEs), selected 
clinical laboratory parameters, vital signs, physical examinations, and ECG, all of which are 
standard safety evaluations in clinical development. 
The PK assessments are included since the PK profile in IPF patients may differ from that of 
healthy subjects included in the FIH study. Information obtained on the PK of GLPG1690 
will guide dose selection in future clinical studies.
The PD properties of GLPG1690 will be assessed through the analysis of plasma LPA, a PD 
biomarker of ATX inhibition. The effect of GLPG1690 on LPA in plasma has been confirmed 


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in the FIH study, where GLPG1690 reduced LPA levels in a dose-dependent way. The current 
PD analysis will confirm the effect in a population of IPF patients. 
In addition, effects of GLPG1690 on different LPA species will be assessed pre- and post-
treatment in the BALF, representative for target engagement in a matrix closer to the lung. 
Such data were already generated in the mouse BLM model: several LPA species increased in 
the BALF after BLM inhalation and were reduced again after GLPG1690 treatment. These 
data correlated with a positive effect of GLPG1690 on a series of fibrotic readouts (lung 
weight, Ashcroft score, collagen deposit in lung).
Pulmonary function will be assessed using standard spirometry; FVC is currently the most 
commonly used and accepted endpoint in clinical studies investigating IPF treatments 
(Saketkoo, et al., 2014). Spirometry, or more specifically FVC reflects the burden of the IPF 
progress, and is relatively easy to measure and reproducible (Nathan & Meyer, 2014). 
However, since conventional pulmonary function tests such as spirometry have their 
limitations (e.g., they cannot detect early signs of disease due to the compensatory behavior of 
healthy lung areas; in IPF, many spirometry endpoints remain normal even though the disease 
progresses) and since a study duration of 12 weeks may be considered too short to detect any 
differences in FVC, pulmonary function will also be assessed through high-resolution 
computed tomography (HRCT) scans used for generating functional respiratory imaging 
(FRI). FRI provides regional information about lung structure and allows for earlier 
demonstration of disease progression and/or therapeutic effects (De Backer, et al., 2015; Vos, 
et al., 2015). Furthermore, central reading of these images should reduce assessment bias.
In addition, change in the levels of a selection of biomarkers in blood and BALF (through 
bronchoscopy) will be assessed. Even though there currently are no validated biomarkers that 
track IPF progression or response to IPF treatment, a number of protein biomarkers have been 
shown to be increased in IPF (e.g., ATX, Krebs von den Lungen 6/mucin type 1
[KL-6/Muc1], surfactant protein A (SP-A), chemokine motif ligand 18 [CCL18], surfactant 
protein D (SP-D), matrix metalloproteinase (MMP) 1, MMP7, intercelullar adhesion molecule 
type 1 (ICAM1), vascular cell adhesion molecule type 1 (VCAM1), interleukin 8 (IL8), and 
S100 calcium-binding protein A12 (S100A12) (Greene, et al., 2002; Rosas, et al., 2008; Hara, 
et al., 2012; Kaminski, et al., 2012; Oikonomou, et al., 2012; Richards, et al., 2012; Jenkins & 
Goodwin, 2014; Nathan & Meyer, 2014) (Jenkins, et al., 2015). Change in a selection of 
biomarkers of disease activity will be evaluated in the current study.  Results will help to 
refine our current understanding of the effect of GLPG1690 on IPF pathophysiology and will 
guide endpoint selection in future clinical studies.
Finally, since IPF is a chronic, severely debilitating, and ultimately lethal disease, any 
treatment should aim to improve subject’s quality of life; therefore, patient-reported outcomes 
are important parameters in any study in IPF. The St. George’s Respiratory Questionnaire 
(SGRQ), a quality of life measurement tool, was selected for the current study (Nathan & 
Meyer, 2014; Swirgis, Esser, Conoscenti, & Brown, 2014). 
Information on the rationale for dose selection is provided in Section 2.7.


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2.7.
RATIONALE FOR THE CHOICE OF DOSE AND DOSING 
INTERVAL 
A dose of 600 mg GLPG1690 administered q.d. has been selected to be evaluated for this 
phase IIa study. 
Both preclinical and clinical study results were used to predict an efficacious dose. In the 
21-day prophylactic BLM mouse model, GLPG1690’s efficacy was reached (in terms of 
reduction of Ashcroft score) with AUC of 11 µg.h/mL, corresponding to 26 µg.h/mL in 
humans after correction for plasma protein binding. Moreover, a GLPG1690 plasma 
concentration of 1 µg/mL in healthy subjects allowed triggering maximum LPA 18:2 (PD) 
biomarker reduction (90%) which could be maintain over 24 hours with an AUC of 
24 µg.h/mL. Both study results predict GLPG1690’s efficacious dose to be around 220 mg. 
A dose of 600 mg GLPG1690 q.d. is expected to be high enough to reach a plateau in the PD 
response in a population of subjects with IPF. In addition, 600 mg GLPG1690 is lower than 
the highest dose assessed in the FIH study in healthy subjects. In this study, administration of 
single (up to 1500 mg) and multiple ascending oral doses of GLPG1690 (up to 1000 mg q.d.
for 14 days) in healthy male subjects was considered safe and well tolerated.


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3.
STUDY OBJECTIVES
3.1.
PRIMARY OBJECTIVES

to evaluate the safety and tolerability of GLPG1690

to characterize the PK and PD properties of GLPG1690
3.2.
SECONDARY OBJECTIVES

to evaluate the change from baseline in FVC

to explore the change in biomarkers in blood and BALF

to evaluate the change in FRI parameters

to evaluate the change in quality of life measures


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4.
INVESTIGATIONAL PLAN
4.1.
OVERALL STUDY DESIGN
This study is a randomized, double-blind, parallel group, placebo-controlled, multicenter, 
exploratory phase IIa study to evaluate the safety, tolerability, PK, and PD of GLPG1690 in 
subjects with IPF. In addition, several exploratory assessments will be performed. Male and 
female subjects of non-child-bearing potential with a confirmed diagnosis of IPF aged 
40 years or older will be screened to determine eligibility as per the inclusion and exclusion 
criteria (see Section 4.2.2 and 4.2.3, respectively). The screening period will be up to 4 weeks. 
Written informed consent must be obtained before any study-related procedures take place. 
During the screening period, following signing of the informed consent form (ICF), the 
subject’s historical HRCT and surgical lung biopsy (SLB; if available) will be sent to central 
review for the confirmation of the IPF diagnosis through a:

central review of the chest HRCT

central review of the SLB (if available)
Note that both the chest HRCT and SLB need to be sent to central review at least 8 days prior 
to the baseline visit to allow for central reading and confirmation of IPF diagnosis. Additional 
details are provided in Appendix 2.
At baseline, after the subject’s eligibility for the study has been confirmed, subjects will be 
randomized in a 3:1 ratio to GLPG1690 600 mg q.d. or matching placebo administered 
for 12 weeks.
The subjects will visit the clinical study center at screening (Day-28 to Day -4), Day -1 
(baseline), Week 1 (Day 7), Week 2 (Day 14), Week 4 (Day 28), Week 8 (Day 56), and 
Week 12 (Day 84) or the early discontinuation visit (EDV). In addition, a follow-up visit will 
be planned 2 weeks after the last administration of study drug (Week 98 [Day 98]). Each 
subject will be in the study for up to approximately 18 weeks (from screening to follow-up). 
The end of the study (EOS) will be defined as the last contact with the last subject in the 
study.
The assessments performed at each visit are detailed in the study flow chart (Section 1).
To enhance the safety and integrity of the study data, an independent medical safety review 
will be implemented. (See Section 7 for additional information).
4.2.
STUDY POPULATION
4.2.1. Sample Size
Approximately 24 evaluable subjects with a centrally confirmed IPF diagnosis are planned to 
be randomized.


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4.2.2. Inclusion Criteria
Subjects who meet all of the following criteria are eligible for the study:
1.
Subjects who are able and willing to sign the ICF as approved by the independent ethics 
committee (IEC). 
2.
Male or female subjects of non-child-bearing potential aged ≥40 years on the day of 
signing the ICF.
Note: Female subjects will be considered of non-childbearing potential if they are either 
sterilized, ovariectomized, hysterectomized, or postmenopausal (i.e., at least 24 months 
of amenorrhea in the absence of other biological or physiological causes [in case of 
doubt, the subject’s follicle stimulating hormone [FSH] levels will be determined and the 
subject will be considered postmenopausal if the FSH level is ≥35 mIU/mL).
3.
Subjects with a chest HRCT performed within 12 months prior to screening visit. 
4.
Subjects with IPF diagnosed by a multidisciplinary team and confirmed by central review 
of the subject’s HRCT pattern and SLB (if available) (see Appendix 2 for additional 
details).
5.
Subjects meeting all of the following criteria: 
a.
FVC ≥50% predicted of normal
b.
Diffusing capacity for the lungs for carbon monoxide (DLCO) ≥30% predicted of 
normal (corrected for hemoglobin) (see Appendix 3 for additional details).
6.
Subjects with a forced expiratory volume in 1 second (FEV1)/FVC (Tiffeneau-Pinelli 
index) ratio ≥0.70 (based on pre-bronchodilator spirometry).
7.
Subjects who are on stable supportive care (e.g., supplemental oxygen, pulmonary 
rehabilitation) for at least 3 weeks prior to screening and during screening period.
8.
Subjects must be in a stable condition and acceptable for study participation based upon 
the results of a medical history, physical examination, vital signs, 12-lead ECG, and 
laboratory evaluation.
9.
Subjects must have an estimated minimum life expectancy of 12 months in the opinion of 
the investigator.
10. Male subjects and their female partners must use a highly effective method of birth 
control. Additional details on these methods are provided in Section 4.2.4. 
11. Subjects who are able to understand the importance of adherence to study treatment, 
study procedures and requirements, including the concomitant medication restrictions.
4.2.3. Exclusion Criteria
Subjects meeting one or more of the following criteria cannot be selected for this study:
1.
Subjects with a known hypersensitivity to any of the study drug ingredients or a history 
of a significant allergic reaction to any drug as determined by the investigator (e.g.,
anaphylaxis requiring hospitalization). 
2.
Subjects with a history of or a current immunosuppressive condition (e.g., human 
immunodeficiency virus [HIV] infection). 
3.
Subjects with a history of malignancy within the past 5 years (except for carcinoma in 
situ of the uterine cervix, basal cell carcinoma of the skin that has been treated with no 
evidence of recurrence, and prostate cancer medically managed through active 
surveillance or watchful waiting).


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4.
Subjects with clinically significant abnormalities detected on ECG regarding either 
rhythm or conduction (e.g., QT interval corrected for heart rate using Fridericia’s formula 
[QTcF] ≥450 ms, or a known long QT syndrome). 
Note: A first degree heart block will not be considered as a significant abnormality.
5.
Subjects with acute IPF exacerbation within 6 weeks prior to screening and during the 
screening period.
6.
Subject with a lower respiratory tract infection requiring antibiotics within 4 weeks prior 
to screening and during the screening period.
7.
Subjects who have been smoking within 3 months prior to screening.
8.
Interstitial lung disease (ILD) associated with known primary diseases (e.g., sarcoidosis, 
amyloidosis, etc.), exposures (e.g., radiation, silica, asbestos, coal dust, etc.), and drugs 
(e.g., amiodarone, etc.).
9.
Subjects with a history of lung volume reduction surgery or lung transplant.
10. Subjects with an unstable cardiac or pulmonary disease (other than IPF) within 6 months 
prior to screening or during the screening period, including but not limited to:
a.
unstable angina pectoris, myocardial infarction
b.
congestive heart failure requiring hospitalization
11. Subjects with any clinical condition or circumstance that in the opinion of the investigator 
may make a subject unsuitable for inclusion or unable to complete the study or comply 
with study procedures and requirements.
12. Subjects with a contra-indication for bronchoscopy and bronchoalveolar lavage in the 
opinion of the investigator.
13. Subjects with an abnormal liver function defined as aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), or bilirubin >3 x upper limit of the normal range (ULN).
14. Subjects with an abnormal renal function defined as creatinine clearance < 50 mL/min 
using the Cockroft-Gault equation.
15. Subjects participating in a drug/device or biologic investigational research study 
(concurrently with the current study or within 8 weeks prior to screening).
16. Subjects using of any of the following therapies within 4 weeks before screening:
a.
Pirfenidone
b.
Nintedanib
c.
Warfarin
d.
Imatinib
e.
Ambrisentan
f.
Azathioprine
g.
Cyclophosphamide
h.
Cyclosporine A
i.
Prednisone at steady dose > 15 mg/day (for details, see Section 4.2.4)
j.
Any experimental IPF therapy
17. Subjects with active alcohol or substance abuse in the opinion of the investigator.
4.2.4. Prohibition and Restrictions
Smoking is forbidden at all times (from 3 months before screening to the end of the study).


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The following therapies are not allowed during the course of the study (and within 4 weeks 
prior to screening): pirfenidone, nintedanib, warfarin, imatinib, ambrisentan, azathioprine, 
cyclophosphamide, cyclosporine A, prednisone at steady dose > 15 mg/day (i.e., the use of 
prednisone is precluded unless subjects have been on a stable dose ≤15 mg daily and it is 
anticipated that they will continue on this stable dose for the duration of the study), and any 
experimental IPF therapy. 
Male subjects and their female partners must use 2 generally accepted adequate contraceptive 
methods, 1 of which is a barrier method (e.g., condom in combination with hormonal 
contraception stabilized for at least 1 month) from screening until 3 months after the study. In 
addition, sperm donation is not allowed until 3 months after the last study visit. In a case 
where the female partner of a male subject has undergone documented surgical sterilization 
that was performed more than 1 year before screening, the subject is not required to use an 
additional form of contraception.
4.2.5. Removal of Subjects from Therapy or Assessments
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.
Subjects may withdraw from the study at any time, for any reason, without jeopardizing their 
clinical care. 
Subjects may be withdrawn from the study for any of the following reasons:

noncompliance with the study drug

noncompliance with the study procedures

lost to follow-up

SAEs or severe AEs can be considered a reason for discontinuation of treatment, 
preferably after consultation with the medical monitor

investigator request

sponsor request
A subject may be withdrawn from the study after discussion between the investigator 
and the medical monitor for any of the following reasons:

use of concurrent therapy that was not permitted

prolonged interruption of study drug (i.e., interruption > 7 days)

life-threatening AE or an SAE that places the subject at immediate risk

increase in liver function tests (LFTs) to 3 x ULN (if the baseline LFTs are normal) or an 
increase that exceeds an absolute value of 5 x ULN (regardless of whether baseline LFTs 
are normal)
A subject must be withdrawn from the study for any of the following reasons:

serious infections (those requiring parenteral antimicrobial therapy and/or hospitalization)


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
arrhythmia or conduction abnormality (including but not limited to prolonged QTcF, 
where the severity is categorized as Common Terminology Criteria for Adverse Events 
[CTCAE] grade 3 or higher)

clinical laboratory test results, which are determined by the investigator in consultation 
with the medical monitor to be clinically significant and require discontinuation of study 
drug; changes in LFTs are defined as follows (confirmed upon repeat testing):

elevated ALT or AST of > 8 x ULN

elevated ALT or AST of > 5 x ULN for > 2 weeks

total bilirubin > 2 x ULN and/or clinical jaundice, in association with elevation of 
ALT or AST > 3 x ULN

no convincing alternative etiology (e.g., viral hepatitis, alcohol ingestion, trauma) for 
the elevated transaminase is identified, regardless of whether ALT or AST levels had 
improved

unblinding of a subject’s study treatment assignment to the subject, the site staff, or the 
blinded sponsor staff while on study drug

close of the study by the sponsor or regulatory authorities 

wish of the subject to withdraw (At any time and for any reason, a subject’s participation 
in the study may terminate at his/her request without prejudice to his/her future medical 
care.)

worsening of the subject’s disease condition, which in the investigator’s opinion needs an 
alternative treatment approach
In case clinically significant laboratory test results are a potential reason for discontinuation 
from the study drug and withdrawal from the study, retesting should be prompted (within 3 to 
5 days) after the investigator has consulted with the medical monitor. A decision regarding 
subject discontinuation should be made only after the results from the retest are available.
Subjects who stop study drug for any reason will not be replaced. Subjects withdrawing from 
the study will be encouraged to complete the same final evaluations as subjects completing 
the study according to the protocol, particularly safety evaluations in the subject’s interest so 
that data can be recorded in the same way as for subjects who completed the study. The 
reason(s) for withdrawal will be documented in the electronic case report form (eCRF). Note 
that randomized subjects who drop out before the first administration of the study drug will be 
replaced.
Reasonable efforts (3 attempts) will be made to get confirmation on the reasons for dropout
for subjects who are lost to follow-up. These attempts 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.


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4.3.
INVESTIGATIONS MEDICINAL PRODUCTS
4.3.1. Identity of the Investigations Medicinal Products
The study drug GLPG1690 will be supplied to the study center, by and under the 
responsibility of the sponsor, who will also provide the investigator with appropriate 
certificates of analytical conformity and EU QP release documents.
The study drug GLPG1690 will be presented as oral capsules (size 00), containing 200 mg 
G451990 (G451990 is the compound code for GLPG1690). The placebo will be provided as a 
matching capsule.
A full list of excipients used in the oral capsule formulation is available in the Investigator’s 
Brochure. (Investigator Brochure GLPG1690, Edition 2, October 2015) At the investigational 
site, the study drug supplies must be handled and stored safely and properly, and kept in a 
secured location to which only the investigator and authorized staff have access.
4.3.2. Dosage and Administration
A dose of 600 mg q.d. or placebo q.d., administered in the morning, will be evaluated.
Subjects will receive 600 mg GLPG1690 (3 capsules of 200 mg) or placebo q.d. for 12 weeks.
Study drug dosing will take place at the time points indicated in the study flow chart 
(Section 1). When dosing takes place at the clinical study center, a volume of 240 mL water 
will be provided to each subject to be consumed immediately and completely at the time of 
dosing. Subjects will be instructed to swallow the study drug whole, and not chew the drug prior 
to swallowing.
If a subject misses a dose (e.g., because he/she forgot to take the medication), he/she should 
take the missed dose within 12 hours after the planned intake time. If the study drug is not 
taken within 12 hours after the planned time, the missed dose should be skipped.
Dose changes during the study are not allowed. Instead, the subject should either temporarily 
stop all intake or permanently stop study drug. Every effort should be made to contact the 
medical monitor before stopping study drug (temporarily or permanently).
4.3.3. Randomization
A total of approximately 24 subjects will be randomized in a 3:1 allocation ratio to active 
treatment with GLPG1690 or placebo.
Allocation of each subject to a given treatment will be described in a randomization list 
prepared by the CRO. This randomization list will be created using permuted blocks. Upon 
qualification for the study, subjects will be randomized using a computerized interactive 
voice/web response system (
) to placebo or GLPG1690. 
For each subject at each visit, the study center will contact the 
 system for 
the appropriate treatment number to be dispensed. Each medication kit will contain the 
relevant study drug for the period until the next visit.


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Subjects and study personnel will be blinded to the treatment assignment. Additional details 
on blinding and unblinding are provided in Section 4.3.8.
4.3.4. Packaging, Labeling, and Distribution
The study drug packaging, labeling, QP release, and distribution will be performed by 
 
 (Belgium). Study drug manufacturing will be performed by 
 (Belgium).
The oral capsules will be packaged in high density polyethylene bottles with a high density 
polyethylene closure and grouped in a carton box for shipment. 
All manufacturing, packaging, and labeling operations will be performed according to Good 
Manufacturing Practices for Medicinal Products and the relevant regulatory requirements.
The study drug is to be dispensed according to the protocol. The distribution will only occur 
after all required documentation is obtained including study approval by the Competent 
Authorities and the IEC.
Each medication kit will be identified with a unique kit number and will contain sufficient 
capsules for the subject until the next scheduled study visit. The medication kits will be 
labeled according to local requirements.
4.3.5. Storage
Sites are to store all drug supplies in a secured location to which only the investigator and 
authorized staff have access. 
Study drug must be stored at room temperature (15-25°C). Sites will be required to monitor 
the storage temperature by using a min-max temperature-recording device and to keep a 
temperature log, completed each working day, to establish a record of compliance with 
storage conditions. The investigator will instruct subjects on how to store the study drug after 
it has been dispensed.
In accordance with the International Conference on Harmonization (ICH) Good Clinical 
Practice (GCP), the investigator will be responsible for the monitoring, receipt, storage, 
dispensing, and accounting of all study drug supplies according to accepted medical and 
pharmaceutical practice. All details of study drug supplies receipt, storage, administration and 
return will be recorded and the records must be retained in the investigator’s site file. 
Accurate site records of drug inventory and dispensing must be maintained. All records must 
be made available to Galapagos, the contract research organization (CRO), and appropriate 
regulatory agencies upon request. At the end of the study, this record will be checked against 
all used and unused medication by the monitor.
4.3.6. Treatment Compliance and Drug Accountability
For each dose taken, the date, time and number of capsules taken should be recorded on the 
subject’s diary card (see Section 5.3 for additional information). 
The investigator or designated study personnel will maintain a log of all study drug dispensed 
and returned. Drug supplies for each subject will be inventoried and accounted for throughout 
the study. All clinical supplies will be stored in locked facilities.


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Subjects will return any unused study drug and empty bottles at each study visit and/or early 
discontinuation visit (if applicable). Missed doses should be discussed to try to ascertain the 
reason(s). Every effort should be made to ensure proper subject dosing.
All unused medication and empty bottles will be returned to the drug supplier/CRO depot as 
applicable at the closure of the study site or will be destroyed at the site, upon sponsor 
decision.
4.3.7. Prior and Concomitant Therapy
Should any treatment other than the study drug be used during the course of the study, the 
name of the drug, the dosage, the route, and the dates (and time) of administration must be 
recorded in the eCRF system. Prior and concomitant medications (taken up to 8 weeks prior 
to Day 1) will be recorded from the study inclusion date (ICF signed) until the last visit.
Concomitant therapies taken for the long-term treatment of preexisting conditions can 
continue during the study provided they are in accordance with the inclusion and exclusion 
criteria (see Section 4.2.2 and Section 4.2.3, respectively). It is required that these medications 
be stabilized prior to study entry and continued without variation of dose or regimen during 
the study.
In a case additional concomitant medication needs to be administered or dose adjustments for 
preexisting conditions need to be performed during the study, the risk/benefit to the subject 
should be carefully assessed and consideration given to the timing of any necessary 
introduction of new medications. It is recommended that the medical monitor is contacted to 
check if the subject could be included in the study or if some of the concomitant drugs should 
be stopped and/or replaced.
If the subject shows a worsening of his/her IPF disease condition (acute IPF exacerbation), all 
treatment options are allowed at the investigator’s discretion. The decision to continue 
treatment with study drug should be taken on a case-by-case basis, preferably after discussion 
with the study’s medical monitor. 
Drug-drug Interactions
The only CYP enzyme involved in GLPG1690 metabolism is CYP3A4. Therefore, caution 
should be exercised when coadministering GLPG1690 with drugs/nutraceutics known as 
CYP3A4 inducer in order to ascertain GLPG1690 exposure. A (non-exhaustive) list of 
CYP3A4 inducers is provided in Appendix 4.
In vitro interaction studies of GLPG1690 with CYPs showed some degree of inhibition, with 
IC50 values ≥13-fold the free steady state Cmax expected in human after a 600 mg dose, as 
well as some induction at concentrations ≥60-fold the expected free steady state Cmax. 
Towards key drug transporters, some inhibition by GLPG1690 was observed, with IC50 values
≥7-fold the free steady state Cmax expected in human after a 600 mg dose. Therefore, it can be 
concluded that drug-drug interactions with GLPG1690 are unlikely. However, in case of 
coadministration of drugs with narrow therapeutic index, like warfarin, theophylline, or 
digoxin, precautions and specific monitoring should be considered.


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It is recommended that the medical monitor is contacted to check whether the subject could be 
included in the study or if some of the concomitant drugs/nutraceutics should be stopped 
and/or replaced prior to dosing with GLPG1690. 
4.3.8. Blinding and Unblinding
This is a randomized, double-blind study.
The subject, investigator, study coordinator, sponsor, and the entire study processing team 
will remain blinded to treatment assignment. The blind can be broken only if the investigator 
deems it necessary for the safe treatment of a subject, and whenever possible the medical 
monitor and sponsor should be consulted before breaking the blind.
If the blind is broken for any reason during the course of the study, the moment on which the 
subject’s data were unblinded and all other relevant information will be documented by the 
investigative site, the CRO, and other sponsor designees, as appropriate. The reason for 
breaking the blind will be indicated and justified in the source documentation and in the 
eCRF. The blind can be broken by the investigator via the 
 system.
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 
study. If an AE leads to unblinding, the AE should be given as the reason for unblinding and 
the AE should also be recorded in the eCRF. All subjects who are unblinded should, where 
possible, complete the EDV. AEs 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 until resolution or 
until stabilization by the investigator as much as possible.
5.
STUDY ASSESSMENTS
5.1.
TIMING OF ASSESSMENTS
The study assessments as described below will be performed at the time points specified in 
the study flow chart, provided in Section 1. Visits are to be scheduled within a window of ±2 
(Visits 3 and 4) or 3 days (Visits 5, 6, 7, and the follow-up visit) and in such a way that the 
total study duration from baseline to last dosing does not exceed 13 weeks.
The sequence of study assessments, if planned at one study visit, will be as follows (if 
applicable):
1.
physical examination, oral body temperature, ECG, systolic and diastolic blood pressure
(SBP and DBP), supine heart rate, respiratory rate
2.
SGRQ
3.
assessment of (S)AE(s) and concomitant medication
4.
blood sampling for PK
5.
blood sampling for safety laboratory analysis
6.
blood sampling for PD
7.
blood sampling for biomarkers 


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8.
spirometry 16
9.
DLCO 16
10. HRCT-scan 16
11. bronchoscopy (biomarkers and PD in BALF)
5.2.
INITIAL SUBJECT AND DISEASE CHARACTERISTICS
Written informed consent must be obtained before any study-related procedures take place. 
During the screening period, following signing of the ICF, the subject’s historical HRCT and 
SLB (if available) will be sent to the central reader for the confirmation of the IPF diagnosis 
through a:
-
central review of chest HRCT
-
central review of SLB (if available)
Note that both the chest HRCT and SLB need to be sent to central review at least 8 days prior 
to the baseline visit to allow for central reading and confirmation of IPF diagnosis. 
Additional details are provided in Appendix 2.
In addition, information on demographics and medical history/concomitant diseases 
(including the multidisciplinary diagnosis of IPF at the site, the duration of disease, disease 
progression prior to screening, the medications used to treat the disease, drinking, and 
smoking habits) will be collected. A physical examination will take place and vital signs, 
ECG, clinical laboratory assessments (including serology, FSH [if applicable]), spirometry,
and DLCO will be conducted to determine the subject’s eligibility for study participation.
Note that if screening spirometry measurements fail to meet acceptability and repeatability 
criteria as specified by the American Thoracic Society (ATS)/European Respiratory Society 
(ERS) guidelines (Miller, Hankinson, & Brusasco, 2005), repeat spirometry evaluation may 
be performed once. If repeat values are within the acceptability criteria and completed within 
the screening window, the subject is eligible for the study. 
At baseline, after the subject’s eligibility for the study has been confirmed, the subject will be 
randomized into the study to receive treatment with GLPG1690 600 mg q.d. or placebo. Study 
drug will be dispensed and all subjects will be handed a diary card (additional information is 
provided in Section 5.3). All baseline assessments are specified in the study flow chart, 
provided in Section 1.
5.3.
SUBJECT DIARY CARD
Subjects will be given a diary card at Day -1 (baseline) to record the following:

From Day 1 through Day 84 (or the EDV), subjects will be asked to record the date (and 
time) of study drug intake and the number of capsules taken for each administration.

From Day 1 to Day 84 (or the EDV), subjects will be asked to indicate whether a home-
based spirometry test was done and if no such test was done, the reason(s) why should be 
provided.
                                                            
16 Subjects taking inhaled bronchodilators can do this after spirometry assessments (and DLCO) and prior to the 
performance of the HRCT.


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
From Day 1 to Day 84 (or the EDV), subjects will be asked to record changes in 
concomitant medication regimen, including new medicines not captured in medication 
history, use of bronchodilators, any other concomitant medication used as well as any 
emerging AE.
Subjects will be instructed to bring the diary card and used/unused study drug to each visit.
All diary card data will be entered in the eCRF by the designated site personnel.
5.4.
SAFETY ASSESSMENTS
The safety and tolerability assessment will be based on the collection of AEs (including IPF 
exacerbations), physical examinations, vital signs measurements, 12-lead ECG, and safety 
laboratory assessments (standard hematology, serum/plasma chemistry, coagulation tests, and 
urinalysis).
5.4.1. Adverse Events
AEs will be reported and documented as described in Section 8.
5.4.1.1.
Acute IPF Exacerbation
All acute IPF exacerbations will be reported and documented as (S)AEs (see Section 8). An 
acute IPF exacerbation is defined as an acute and clinically significant deterioration of 
unidentifiable cause in patients with underlying IPF. Diagnostic criteria are defined as follows
(Collard, et al., 2007):
1.
The subject has a previous or concurrent diagnosis of IPF.
2.
The subject shows unexplained worsening or development of dyspnea within 30 days.
3.
The HRCT shows new bilateral ground-glass abnormality and/or consolidation 
superimposed on a background reticular or honeycomb pattern consistent with usual 
interstitial pneumonia pattern.
4.
There is no evidence of pulmonary infection by endotracheal aspirate or bronchoalveolar 
lavage 17.
5.
Alternative causes, including the following, are excluded: 
-
left heart failure
-
pulmonary embolism
-
identifiable cause of acute lung injury 18
                                                            
17 Evaluation of samples should include studies for routine bacterial organisms, opportunistic pathogens and 
common viral pathogens.
18 Causes of acute lung injury include sepsis, aspiration, trauma, reperfusion pulmonary edema, pulmonary 
contusion, fat embolization, inhalational injury, cardiopulmonary bypass, drug toxicity, acute pancreatitis, 
transfusion of blood products, and stem cell transplantation.


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5.4.2. Clinical Laboratory Evaluations
Blood samples of approximately 16 mL (or approximately 21 mL at screening only) will be 
collected predose by venipuncture (or indwelling catheter for pharmacokinetic sampling days) 
in the arm at the time points indicated in the study flow chart (provided in Section 1) and
according to sequence of study assessments as described in Section 5.1. In addition, urine 
samples for the clinical laboratory assessments will be collected. Subjects do not need to be 
fasted at the time of sampling.
Blood and urine samples will be collected for the following clinical laboratory tests:

hematology: hematocrit, hemoglobin, red blood cell count, WBC total count, WBC 
differential count (absolute and relative), and platelets

serum/plasma chemistry: glucose, urea, creatinine, uric acid, sodium, potassium, calcium, 
chloride, phosphorus, AST, ALT, gamma glutamyl transferase, total bilirubin, alkaline 
phosphatase, albumin, total proteins, triglycerides, cholesterol, and brain natriuretic 
peptide 

coagulation parameters: international normalized ratio and partial thromboplastin time 

urinalysis: pH, glucose, proteins (quantitative); ketones, and microscopic examination of 
the sediment (cylinders, erythrocytes, leucocytes)

serology: hepatitis B surface antigen, hepatitis B virus antibody, HIV-1 and HIV-2 
antibody (only at screening)

FSH (only at screening in case there is doubt on whether a female subject is 
postmenopausal)
The laboratory values outside the normal range will be flagged and clinical relevance will be 
assessed by the investigator. More frequent sampling as well as additional tests may be 
performed as deemed necessary by the investigator to follow-up and resolve any safety 
concerns. 
Note that in case clinically significant laboratory test results are a potential reason for 
discontinuation from the study drug and withdrawal from the study, retesting should be 
prompt (within 3 to 5 days) after the investigator has consulted with the medical monitor. A 
decision regarding subject discontinuation should be made only after the results from the 
retest are available (see Section 4.2.5 for additional information).
The details of sample handling and shipment instructions will be provided in a separate 
laboratory manual.  
5.4.3. Vital Signs
Vital signs will be measured predose at the time points indicated in the study flow chart
(provided in Section 1) and according to sequence of study assessments as described in 
Section 5.1. Vital signs must be taken after 5 min in the supine position, prior to the 
bronchoscopy.
Vital signs will include supine heart rate, respiratory rate, SBP, DBP, and oral body 
temperature.


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Normal ranges are provided in Appendix 4.
5.4.4. Physical Examination
The physician (or a trained assistant or nurse practitioner, as applicable by local regulations) 
will perform a full physical examination (including ear, nose, throat, neck, chest, abdomen,
and extremities) predose at the time points indicated in the study flow chart (provided in 
Section 1) and according to sequence of study assessments as described in Section 5.1. 
Height and weight will be measured at screening only (with shoes off).
5.4.5. Electrocardiogram
A 12-lead ECG will be performed predose at the time points indicated in the study flow chart
(provided in Section 1) and according to sequence of study assessments as described in 
Section 5.1. The ECG must be taken after 5 min in the supine position, prior to any blood 
sampling. Each ECG will be interpreted by the investigator for clinical significance.
Normal ranges are provided in Appendix 4.
5.5.
PHARMACOKINETIC ASSESSMENTS
PK assessments will include analysis of GLPG1690. Plasma concentrations of GLPG1690 
will be measured using a validated LC-MS/MS method, and will be performed by the 
bioanalytical laboratory in charge of these analyses (
 
.
Other measurements (e.g., metabolism studies, stability studies) may be performed if deemed 
appropriate.
5.5.1. Biological Samples
Blood samples of 1 mL will be collected by venipuncture (or indwelling catheter for 
pharmacokinetic sampling day) in the arm at the time points indicated in the study flow chart
(provided in Section 1) and according to sequence of study assessments as described in 
Section 5.1.
All details on sample handling and shipment instructions will be provided in a separate 
laboratory manual.
5.5.2. Pharmacokinetic Parameters
PK parameters will be derived with Phoenix WinNonlin (Version 6.2 or higher).
The 
following 
PK 
parameters, 
where 
appropriate, 
will 
be 
determined 
using 
non-compartmental analysis for GLPG1690 from individual concentration-time profiles in 
plasma:  

Cmax
maximum observed plasma concentration

tmax
the time of occurrence of Cmax

AUC0-τ
area under the plasma drug concentration-time curve of a dosing interval 


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
Cτ
trough plasma concentration (just before the next dosing i.e. predose sample) 
Additional PK parameters may be calculated if appropriate. 
5.6.
PHARMACODYNAMIC ASSESSMENTS
5.6.1. Biological Samples (Blood)
Blood samples of 2 mL will be collected by venipuncture (or indwelling catheter for 
pharmacokinetic sampling days) in the arm at the time points indicated in the study flow chart 
(provided in Section 1) and according to sequence of study assessments as described in 
Section 5.1.
All details on sample handling and shipment instructions will be provided in a separate 
laboratory manual.
5.6.2. Biological Samples (BALF)
Bronchoscopies for the collection of BALF samples will be conducted (post dose if 
applicable) at the time points indicated in the study flow chart (provided in Section 1) and
according to sequence of study assessments as described in Section 5.1.
All details on sample collection through bronchoscopy will be provided in a separate, 
study-specific bronchoscopy/BALF manual. All details on sample handling and shipment 
instructions will be provided in a separate laboratory manual.
5.6.3. Pharmacodynamic Parameters
LPA species (C18:2) will be determined in plasma. Other LPA species might be analyzed if 
deemed appropriate.
All detectable LPA species will be determines in the supernatant of the BALF.
5.7.
EXPLORATORY EFFICACY ASSESSMENTS
5.7.1. Pulmonary Function by Spirometry
Pulmonary function will be assessed through spirometry both performed at the study center
(at screening, baseline, and thereafter post dose at the time points indicated in the study flow 
chart [provided in Section 1] and according to sequence of study assessments as described in 
Section 5.1) and at home (at baseline and thereafter post dose; on a daily basis in the 
morning). Specific instructions on how to perform the spirometry at home are provided in a 
separate spirometry user manual. 
The site-based spirometry must meet the criteria for acceptability and repeatability as defined 
in the ATS/ERS guidelines (Miller, Hankinson, & Brusasco, 2005)
Pulmonary function will be measured in standardized manner, results will be transmitted 
electronically and confirmed by a central reader. 


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Timing of home- and site-based spirometry 
The spirometry test is to be performed in the morning, preferably at approximately the same 
time (± 1 h) every day/visit.
Timing of home- and site-based spirometry versus bronchodilator use
All spirometry evaluations should be performed pre-bronchodilator. Pre-bronchodilator 
spirometry is defined as spirometry testing performed for a subject who has:

withheld their short-acting β-agonist (e.g., albuterol) or anticholinergic (e.g., ipratropium 
bromide) for >6 h prior to the spirometry assessment AND

withheld their long-acting bronchodilator (e.g., salmeterol, formoterol) for ≥12 h and 
other longer-acting agents (e.g., indacaterol, tiotropium) for ≥24 h prior to the spirometry 
assessment
In case the subject is on bronchodilators, he/she can use the bronchodilator after the 
spirometry but prior to HRCT for FRI parameters. 
Spirometry parameters and calculation of predicted values
The following parameters will be measured as part of the spirometry assessment:

FEV1 (L) and percent predicted FEV1

FVC (L) and percent predicted FVC 

FEV1/FVC ratio

Forced expiratory flow (FEF) between 25 and 75% of exhaled volume (FEF25-75)
The ‘2012 Global Lung Function Initiative Equations’ will be used to estimate the predicted 
values (Quanjer, et al., 2012).
5.7.2. Biomarker Analysis
5.7.2.1.
Biological Samples (Blood)
Blood samples of 14 mL will be collected predose by venipuncture (or indwelling catheter for 
pharmacokinetic sampling days) in the arm at the time points indicated in the study flow chart 
(provided in Section 1) and according to sequence of study assessments as described in 
Section 5.1.
All details on sample handling and shipment instructions will be provided in a separate 
laboratory manual.
5.7.2.2.
Biological Samples (BALF)
See Section 5.6.2 for details on bronchoscopies.


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5.7.2.3.
Biomarkers to be Analyzed
The following exploratory biomarkers will be evaluated in blood samples:

KL-6/Muc1

surfactant protein A and D

CCL18

ATX

MMP1, MMP7

markers of extracellular matrix (ECM) turnover (neoepitope assay)
The following additional biomarkers may be analyzed in blood samples if deemed appropriate 
after results of the above exploratory markers have become available:

oxydative stress: ICAM-1 and VCAM-1 

neutrophil recruitment, activation: IL8, S100A12

other biomarkers might be analyzed if deemed appropriate (e.g., serique protein, serique 
miRNA)
ATX will be determined in the supernatant of the BALF. Bronchoalveolar lavage (BAL) cell 
count will be performed. BAL cell pellets will be stored for possible future analyses 
(transcriptomics, proteomics).
5.7.3. Quality of Life
The SGRQ will be completed predose at the time points indicated in the study flow chart
(provided in Section 1) and according to sequence of study assessments as described in 
Section 5.1.
The SGRQ is a 50-item questionnaire split into 3 domains: symptoms (assessing the 
frequency and severity of respiratory symptoms), activity (assessing the effects of 
breathlessness on mobility and physical activity), and impact (assessing the psychosocial 
impact of the disease). Scores are weighted such that every domain score and the total score 
range from 0 to 100, with higher scores indicating a poorer health-related quality of life.
Subjects must be able to read and complete the SGRQ by themselves. They should not receive 
any help from anyone (such as family and friends) or study staff in interpreting or responding 
to the questions. The study staff will review the questionnaires after completion to ensure that 
all questions are completed. In case of missing information, the subject will be asked to 
complete the missing items.
5.7.4. Functional Respiratory Imaging
HRCT will be performed (post dose if applicable) at the time points indicated in the study 
flow chart (provided in Section 1) and according to sequence of study assessments as 
described in Section 5.1. HRCT scans will be used to generate FRI measurements allowing 
for an evaluation of regional IPF disease manifestation and disease progression. In case the 
subject is on bronchodilators, he/she can use the bronchodilator after the spirometry but prior 
to HRCT for FRI parameters. 




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belonging to the sponsor for future research on the mode of action of GLPG1690 and/or 
future research in IPF.


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6.
STATISTICAL METHODS
All statistical calculations will be performed by the CRO using the SAS (Version 9.1.3 or 
higher) software for statistical computations and SAS for graphical purposes. 
The statistical analysis and visualization of the FRI parameters will be implemented in R 
version 3.0.2 or higher (The R Foundation for Statistical Computing, Vienna, Austria) by 
All statistical methods will be detailed in a statistical analysis plan that will be finalized prior 
to the database lock.
All data collected in this study will be documented using summary tables, figures and subject 
data listings. 
6.1.
DETERMINATION OF SAMPLE SIZE
Strict statistical criteria were not used to determine the sample size for this study. The number 
of subjects included in this study should give reasonable precision around the estimates 
derived for the safety, PK, and PD evaluation.
6.2.
POPULATION FOR ANALYSES
6.2.1. All Screened Subjects
All subjects who signed an ICF.
6.2.2. All Randomized Subjects
All subjects randomized into the study.
6.2.3. Safety Analysis Set
All randomized subjects who received at least 1 dose of study drug.
6.2.4. Pharmacokinetics Analysis Set
All randomized subjects who received at least 1 dose of study drug and for whom evaluable 
PK data were available. Subjects with a protocol deviation that may impact the PK results will 
be excluded from this population.
6.2.5. Pharmacodynamics Analysis Set
All randomized subjects who have at least one dose of study drug and have at least one 
post-baseline assessment with PD data.
6.2.6. Intent to Treat Analysis Set
All randomized subjects who have at least one dose of study drug and have at least one 
post-baseline assessment with exploratory endpoint data.


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6.3.
STATISTICAL ANALYSES
6.3.1. General Statistical Considerations
Summary tabulations will be presented and will display the number of observations, mean, 
standard error (SE), median, minimum, and maximum for continuous variables, and the 
number and percentage per category for categorical data. In addition to tabulated descriptive 
statistics, graphical data displays may be used to summarize the data. Unless otherwise noted, 
inferential statistics will be interpreted at the 2-sided 5% level. Data will be pooled across 
centers and countries.
No formal interim analysis is planned for this study.
6.3.2.
Analyses of Demographics and Baseline Characteristics
Subject disposition (including reasons for early discontinuation), protocol deviations, 
demographics, baseline characteristics, medical history, will be presented descriptively. 
Use of study drug and concomitant medications will also be presented descriptively.
6.3.3. Analyses of Safety Data
A descriptive analysis of the TEAEs, laboratory assessments, 12-lead ECG, and vital signs 
will be performed. Changes from baseline and shifts according to normal ranges will be 
presented as well.
Physical examination results will be listed only.
AEs will be fully described and coded according to the Medical Dictionary for Regulatory 
Activities Dictionary.
6.3.4. Pharmacokinetic Analyses
Descriptive statistics will be calculated for the plasma concentrations and PK parameters. 
Mean (± SE) concentration-time profile will be generated.
Individual subject GLPG1690 concentrations and PK parameters will be listed. 
6.3.5. Pharmacodynamic Analyses
In blood, LPA C18:2 species peak area ratio will be used to calculate the percentage reduction 
versus baseline. Baseline will be the average of the predosing duplicates (predose sample 
from Day -1). 
The percentage reduction from baseline will be calculated as follows:
% reduction = 100-(100 x visit/baseline).
Individual and mean percentage reduction from baseline over time plots will be generated. 
The AUEC as well as Emax on Day 28 will be determined from individual effect time profiles.


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PD marker percent reduction, AUECs and Emax will be compared between the treatment 
groups using an analysis of covariance (ANCOVA) model with the following covariates: 
disease severity (baseline FVC, baseline DLCO), age, gender, treatment group, country, and 
baseline value.
Within-group comparisons of PD marker level obtained on Day 28 at 1.5 h and 6 h 
post-dosing, and on Day 84, versus baseline will be investigated using a paired t-test
PD data will also be summarized descriptively per treatment and per time point.
The analysis will be performed for the LPA C18:2 species. Other LPA species might be 
analyzed if deemed appropriate.
In BALF, data for all LPA species detectable will be used for the analysis. LPA species peak 
area ratio will be used to calculate the percentage reduction versus baseline. Baseline will be 
the average of the predosing duplicates (predose sample from Day -1). 
6.3.6. Exploratory Efficacy Assessments
Exploratory endpoint data at each post-dosing visit will be analyzed descriptively. 
Comparison between GLPG1690 and the placebo group will be done exploratively.
Analysis methods:

Continuous parameters will be analyzed using descriptive statistics of actual values, 
changes from baseline, and percent changes from baseline. GLPG1690 and placebo will 
be compared using an ANCOVA model on the changes from baseline, with the following 
covariates: disease severity (baseline FVC, baseline DLCO), age, gender, treatment 
group, country, and baseline value. Within-group comparisons of each visit versus 
baseline will be investigated using a paired t-test. For FRI parameters these analyses will 
be performed using a mixed effects ANCOVA model with subject as a random factor and 
the factors listed above as fixed factors.

Missing data will be imputed, also for subjects who prematurely discontinue the study. 
The primary imputation method will be last-observation-carried-forward. An
observed-case analysis will also be performed. 

Additional exploratory analyses and graphical presentations may be performed when 
deemed useful to better understand the data.
6.3.7. Pharmacokinetic/ Pharmacodynamic and Pharmacokinetic/ 
Exploratory Efficacy Correlations
Individual and/or mean ± SE, safety, PD, exploratory efficacy endpoint, and/or GLPG1690 
plasma concentrations may be plotted against one another.
PK/PD, PK/exploratory efficacy endpoint and safety correlation will be explored between 
GLPG1690 concentrations or PK parameters and selected exploratory PD or safety endpoints, 
but only if the latter are significantly altered by the treatment.
Exploratory safety/PK/PD/exploratory efficacy endpoint analyses may be added when 
deemed useful to better understand the collected data.


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7.
INDEPENDENT MEDICAL SAFETY REVIEW
In order to enhance the safety and integrity of the study, an independent medical safety review 
will be implemented. The review will be conducted by an independent pulmonologist 
experienced in the field of IPF. The independent expert will regularly review unblinded safety 
data to monitor the risk/benefit and assess any potential safety issues arising during the 
conduct of the study. This process will be described in a separate ‘Independent Medical safety 
Review Charter’.


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GENERAL PROCEDURES
8.
ADVERSE EVENTS
8.1.
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 (i.e., 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.
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 8.3.
8.2.
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.
8.3.
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
8.4.
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.

Drug permanently withdrawn:
In case a subject is permanently withdrawn from the study.


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
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)
8.5.
OUTCOME
Each AE must be rated by choosing among:

recovered/resolved

recovered/resolved with sequelae

not recovered/not resolved

fatal

recovering/resolving

unknown
8.6.
RECORDING ADVERSE EVENTS
AEs will be recorded from the signature of ICF until the final follow-up visit. In case an AE is 
ongoing at that time, it will be followed up until resolution or until stabilization by the 
investigator as much as possible.
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 e-source system.
8.7.
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.
8.8.
REPORTING SERIOUS ADVERSE EVENTS / PREGNANCIES
8.8.1. Serious Adverse Events
All SAEs, whether or not deemed drug-related, must be recorded on the eCRF and SAE form 
and reported by the investigator to 
 Medical Affairs (
 
MA) within 24 h by facsimile. Other means of transmission can be decided where facsimile is 
not possible. The SAE should include a clearly written narrative describing signs, symptoms, 


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and treatment of the event, diagnostic procedures, as well as any relevant laboratory data and 
any sequelae.
Follow-up and outcomes should 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.
Copies of additional laboratory tests, consultation reports, post mortem reports, hospital case 
reports, autopsy reports, and other documents should 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.
8.8.2. Pregnancy
All initial reports of pregnancies in partners of male subjects included in the study must be 
reported to 
 MA by the investigator within 24 h 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.
8.9.
REPORTING SERIOUS ADVERSE EVENTS TO COMPETENT 
AUTHORITIES/ETHICS COMMITTEES
 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 that approved the protocol 
unless otherwise required and documented by the IEC.
AEs 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.
9.
STUDY CLOSURE CONSIDERATIONS
The sponsor reserves the right to close the investigational site 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 and regulatory authority should be notified within 15 calendar days, 
including a detailed written explanation of the reasons for the termination/halt.
The end of study declaration will be submitted to the regulatory authorities and IEC after the 
complete study has ended in all participating centers, in all countries. This notification will 
also be submitted within 90 days of the end of the study.


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Reasons for the closure of an investigational site or termination of a study by the sponsor may 
include but are not limited to:

successful completion of the study at the center

the overall required number of subjects for the study has been recruited

failure of the investigator to comply with the protocol, ICH-GCP guidelines or local 
requirements

safety concerns

sufficient data suggesting lack of efficacy

inadequate recruitment of subjects by the investigator
10.
STUDY MATERIALS
10.1.
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 blisters). 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 
medication to the site for pill count this is not seen as a return of supplies. Unused medication 
and medication returned by the subject must be available for verification by the monitor.
All used and unused investigational medication will be returned to the sponsor 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.
10.2.
STUDY DOCUMENTS
The following documents must be provided to the sponsor or representatives before shipment 
of study drugs to the study center:

a signed and dated protocol and amendment(s), if any

a copy of the signed and dated written IEC approval specifying the documents being 
approved: the protocol, amendments, informed consent form, any other written 
information provided to the subject and subject recruitment materials
This approval must clearly identify the study by protocol title and study number.

regulatory authority approval or notification, if required


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
documentation on which the assessment of the investigator’s qualifications was based 
(e.g., curriculum vitae)
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 and their position in the 
health-care institution or their credentials
In case the (sub) investigator is a member of the IEC, documentation must be obtained to 
state that this person did not participate in the voting for the study.

completed Investigator Financial Disclosure Forms from the investigator and all
sub-investigators

signed and dated study 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
10.3.
PARTICIPATION CARDS
If the subjects are not under 24-h 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-h emergency 
contact number. The subject should be advised to keep the participation card in his/her wallet 
at all times.
10.4.
SOURCE DATA
The nature and location of all source documents will be discussed during the Site Initiation 
Visit and will be documented in the site initiation visit report 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, should include 
sequential notes containing at least the following information for each subject:

subject identification (name, date of birth, gender)

documentation that subject meets eligibility criteria, i.e., history, physical examination, 
and confirmation of diagnosis (to support inclusion and exclusion criteria)

participation in study (including study number)

study discussed and date of informed consent

dates of all visits


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
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 drug (preferably drug dispensing and 
return should be documented as well)

record of all AEs and other safety parameters (start and end date, and preferably 
including causality and intensity)

concomitant medication (including start and end date, and dose
If relevant, dose changes should be motivated).

date of study completion and reason for early discontinuation, if applicable
Source data may be directly captured from devices transferred from 3rd partners (e.g.,
laboratory data) or entered manually into the eCRF system. 
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.
10.5.
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 investigational site. 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 should 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 CRFs are accurate and 
correct. If certain information is not done, not available or not applicable or unknown, the 
investigator should 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 manger 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.


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11.
ARCHIVING
The investigator shall maintain 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 should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should 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 study documents 
before having obtained a written approval of the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator must permit access to such reports. The 
subject is granting access to his/her source data by signing the informed consent.
Any difficulty in storing original documents must be discussed with the monitor prior to the 
initiation of the study.
12.
CONFIDENTIALITY
All information concerning the product and the sponsor’s operations (such as patent 
applications, formulae, manufacturing processes, basic scientific data or formulation 
information supplied to the investigator by the sponsor and not previously published) is 
considered confidential by the sponsor and should not be disclosed by the investigator to any 
third party without the sponsor’s prior written approval. The investigator agrees to use this 
information only in accomplishing the study and will not use it for other purposes.
In order to permit easy identification of the individual subject during and after the study, the 
investigator is responsible for keeping an updated Subject Identification Code List. The 
monitor will review this document for completeness. However, the investigator must 
guarantee the subject’s anonymity will be maintained. Therefore, in order to ensure subject 
confidentiality, the Subject Identification Code List will remain at the center and no copy will 
be made. Subject data like HRCT, blood samples, or BALF will be anonymized using Subject 
Identification Code List to prevent site from patient confidentiality breach when shared with 
third party for analysis.


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13.
REPORTING AND PUBLICATION
13.1.
REPORTING
The results of the study 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 
IECs 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.
13.2.
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 should not be disclosed by the investigator to any 
third party without the sponsor’s prior written approval. The investigator agrees to use this 
information only in accomplishing the 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 study 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 should 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 study, he/she shall provide 
the sponsor with at least 60 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.
14.
ETHICS
14.1.
IEC
This study can only be undertaken after full approval of the clinical study protocol, informed 
consent, any other written information given to subjects, and subject recruitment materials has 
been obtained from the IEC. This approval document must be dated and clearly identify the 


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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 for review:

changes to the Investigator’s Brochure

reports of AEs that are serious, unlisted and associated with the investigational drug
Substantial amendments and applicable informed consent form revisions must promptly be 
submitted to the IEC for review and approval prior to implementation of the change(s), except 
when necessary to eliminate an immediate hazard to the study subjects.
The IEC is responsible for continuous review of the study. At least once a year, the 
investigator will provide the IEC with a progress report to allow review of the study according 
to local requirements. Additional progress reports should be provided if required by the IEC. 
These requests and (re) approvals, if applicable, should be documented in writing.
14.2.
REGULATORY APPROVAL / NOTIFICATION
This clinical study protocol, title, and a list of investigational sites, IEC approvals, as well as 
other relevant documentation will be submitted to the local Regulatory Authorities for review 
and approval prior to study 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.
14.3.
ICH GCP
This study will be conducted in accordance with the current ICH-GCP Guideline E6. GCP is 
an international ethical and scientific quality standard for designing, conducting, recording 
and reporting studies that involve the participation of human subjects. Compliance with this 
standard provides public assurance that the rights, safety and well-being of 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.
14.4.
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 study-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 should 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 informed consent must be given to the subject.


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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 informed consent form. This amended informed consent form 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 
informed consent form.
15.
FINANCING AND INSURANCE
15.1.
FINANCIAL DISCLOSURE
The disclosed financial interest of the investigator must be collected before screening of the 
first subject, following study completion at the investigator site and one year following 
overall study completion. The investigator should promptly update this information if any 
relevant changes occur during this period. Disclosable financial interests will be recorded on 
the Investigator Financial Disclosure Form.
Any investigator(s) added as investigational staff must complete the Investigator Financial 
Disclosure Form at the beginning of their participation in the study. For any investigator(s) 
leaving the site prior to study completion, an Investigator Financial Disclosure Form should 
be obtained at the end of their contribution to the study.
15.2.
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.
15.3.
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.
16.
DATA QUALITY CONTROL / ASSURANCE
16.1.
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 


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as possible after first enrollment at the site 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, date of birth, 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.
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.
16.2.
AUDIT AND INSPECTION
To ensure compliance with relevant regulations, an independent Quality Assurance (QA) 
representative, regulatory authorities and/or IEC(s) may review this study. This implies that 
auditors/inspectors will have the right to inspect the 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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Peripheral blood proteins predict mortality in idiopathic pulmonary fibrosis. Am J Respir Crit 
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Ley, B., Collard, H., & King, T. (2011). Clinical course and prediction of survival in idiopathic 
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ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis.
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Richards, T., Kaminski, N., Baribaud, F., Flavin, S., Brodmerkel, C., Horowitz, D., et al. (2012). 
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lysophophatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating 
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Xu, M., Porte, J., Knox, A., Weinreb, P., Maher, T., Violette, S., et al. (2009). Lysophosphatidic acid 
induces αvβ6 integrin-mediated TGF-β activation via the LPA2 receptor and the small G 
protein Gαq. Am J Pathol, 174(4), 1264-79.


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APPENDICES
Appendix 1 Study Contact Information
Role
Contact Information
SPONSOR
GALAPAGOS NV
Generaal De Wittelaan, L11 A3
2800 Mechelen, Belgium
Clinical Project Manager
, MSc – Galapagos NV
Tel: 
Mobile: 
Email: 
Medical Monitor
, MD MBA - Galapagos NV
Tel: 
 
Mobile: 
Email: 
Pharmacokineticist
, PhD - Galapagos SASU
102 Avenue Gaston Roussel
93230 Romainville, France
Tel: 
Fax: 
Email: 
Pharmacodynamic Expert
 PhD - Galapagos SASU
102 Avenue Gaston Roussel
93230 Romainville, France
Tel: 
Email: 
Lead Biostatistics
 MSc – Galapagos NV
Tel: 
Email: 


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Head Clinical Operations
, PhD - Galapagos NV
Tel: 
Mobile:
Email: 
Development Project Leader 
, PhD - Galapagos NV
Tel: 
Mobile:
Email: 
(Home) 
Spirometry 
and 
central diagnosis (HRCT & 
Pathology)
Belgium
Tel: 
E-mail: 
Functional 
Respiratory 
Imaging
 – Project Manager
Belgium
Tel: 
Mobile: 
E-mail: 
Central Laboratory: safety 
lab
 
Belgium
Tel: 
E-mail: 
Bioanalytical Laboratory
(Biomarkers)




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Appendix 2 HRCT/Biopsy Central Review Criteria
All chest HRCTs and histopathology slides of surgical lung biopsies (if available) will be 
centrally reviewed by an independent radiologist and an independent histopathologist in order 
to confirm the diagnosis of IPF.
Confirmed IPF Diagnosis Based on HRCT only (No Lung Biopsy Available)
In the absence of a surgical lung biopsy, HRCT must qualify as “consistent with IPF”. This 
will be defined as meeting either criteria A, B and C, or criteria A and C, or criteria B and C 
provided below.
A) Definite honeycomb lung destruction with basal and peripheral predominance.
B) Presence of reticular abnormality AND traction bronchiectasis consistent with fibrosis with 
basal and peripheral predominance.
C) Atypical features are ABSENT, specifically: nodules and consolidation. Ground glass 
opacity, if present, is less extensive than reticular opacity pattern.
Appearances of a fibrosing lung disease with no definite HRCT features of a specific etiology 
will be considered “possible IPF”. Convincing HRCT appearances of a diffuse lung disease 
other than IPF will be considered “definitely not IPF”. Subjects with “possible IPF” (unless 
clear IPF diagnosis based on the SLB data) and “definitely not IPF” will not be allowed for 
inclusion in the study.
Confirmed IPF Diagnosis Based on Both HRCT and Lung Biopsy
In the presence of a surgical lung biopsy, the histology will be reviewed, based on the most 
recent ATS/ERS/JRS/ALAT Guideline. In such case, there will be a multi-disciplinary team 
approach to confirm or exclude the diagnosis of IPF. An HRCT "possible IPF" coupled with a 
surgical biopsy of “definite IPF” or "probable IPF", upon multidisciplinary team discussion, 
could qualify for inclusion as “consistent with IPF”.
The decision-schedule used to decide whether a subject is eligible for study entry is provided 
below. 
SLB:
Definite IPF
SLB:
Probable IPF
SLB:
Possible IPF
SLB:
Non Classifiable 
IPF
HRCT: 
Consistent with IPF 
Eligible
Eligible
Eligible
Eligible
HRCT: 
Possible IPF 
Eligible
Eligible
Not Eligible
Not Eligible
HRCT: 
Definitely not IPF 
Not Eligible
Not Eligible
Not Eligible
Not Eligible
HRCT=high-resolution computed tomography; IPF=idiopathic pulmonary fibrosis; SLB=surgical lung biopsy 


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An overview of the histopathological criteria for definite-probable-possible-non classifiable 
IPF is provided below.
SLB:
Definite IPF
(all 4 criteria met)
SLB:
Probable IPF
SLB:
Possible IPF
(all 3 criteria met)
SLB:
Non Classifiable IPF
(any of the 6 criteria)

Evidence of marked 
ﬁbrosis/ architectural 
distortion, ± 
honeycombing in a 
predominantly 
subpleural/ paraseptal 
distribution

Presence of patchy 
involvement of lung 
parenchyma by 
ﬁbrosis

Presence of ﬁbroblast 
foci

Absence of features 
against a diagnosis of 
IPF suggesting an 
alternate diagnosis 
(see fourth column)

Evidence of marked 
ﬁbrosis / architectural 
distortion, ±
honeycombing 

Absence of either 
patchy involvement 
or ﬁbroblastic foci, 
but not both 

Absence of features 
against a diagnosis of 
IPF suggesting an 
alternate diagnosis 
(see fourth column) 
OR

Honeycomb changes 
only

Patchy or diffuse 
involvement of 
lung parenchyma 
by ﬁbrosis, with 
or without 
interstitial 
inﬂammation

Absence of other 
criteria for IPF 
(see IPF 
PATTERN 
column) 

Absence of 
features against a 
diagnosis of IPF 
suggesting an 
alternate 
diagnosis (see 
fourth column)

Hyaline 
membranes

Organizing 
pneumonia

Granulomas

Marked interstitial 
inﬂammatory cell 
inﬁltrate away from 
honeycombing

Predominant 
airway centered 
changes 

Other features 
suggestive of an 
alternate diagnosis
IPF=idiopathic pulmonary fibrosis; SLB=surgical lung biopsy 


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Appendix 3 DLCO
At visit 1, DLCO must meet the following criteria (Macintyre, et al., 2005): 

30% predicted of normal ≤DLCO corrected for hemoglobin
For predicted normal values, different sites may use different prediction formulas, based on 
the method used to measure DLCO. In any case, the method used must be in compliance with 
the ATS/ERS guideline on DLCO measurements (Macintyre, et al., 2005), and the prediction 
formula appropriate for that method. 
Raw data (gas mixture, equation used for prediction of normal) must be captured. 
DLCO corrected for hemoglobin:

Males: DLCO corrected for hemoglobin = DLCO measured x (10.22+Hb) /1.7Hb 

Females: DLCO corrected for hemoglobin = DLCO measured x (9.38+Hb)/ 1.7Hb 
Hemoglobin is expressed in g/dL.


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Appendix 4 CYP3A4 Inducers 
The following drugs/nutraceutics are known CYP3A4 inducers (non-exhaustive list):
-
Carbamazepine
-
Phenytoin
-
Oxcarbazepine
-
Phenobarbital
-
Butalbital
-
St. John’s wort
-
Rifampicin
-
Rifabutin
-
Pioglitazone
-
Troglitazone
-
Glucocorticoids


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Appendix 5 Normal Ranges
NORMAL RANGES FOR VITAL SIGNS
SBP (mmHg)
DBP (mmHg)
Heart rate
(bpm)
Oral temperature (°C)
90 ≤ SBP ≤ 150
45 ≤ DBP ≤ 90
40 ≤ HR ≤ 100
35.5 ≤ t° ≤ 37.5
NORMAL RANGES FOR ECG PARAMETERS
PR
(ms)
QRS
(ms)
QTcF
(ms)
Heart rate
(bpm)
120 PR 220
QRS 120
QTc 450
40 ≤ HR ≤ 100
These normal ranges are applicable in supine position (after 5 min).


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SIGNATURE PAGE – SPONSOR
Title
Randomized, Double-Blind, Parallel Group, Placebo-Controlled, Multicenter, 
Exploratory Phase IIa Study to Assess Safety, Tolerability, Pharmacokinetic 
and Pharmacodynamic Properties of GLPG1690 Administered for 12 Weeks in 
Subjects with Idiopathic Pulmonary Fibrosis (IPF)
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
Randomized, Double-Blind, Parallel Group, Placebo-Controlled, Multicenter, 
Exploratory Phase IIa Study to Assess Safety, Tolerability, Pharmacokinetic 
and Pharmacodynamic Properties of GLPG1690 Administered for 12 Weeks in 
Subjects with Idiopathic Pulmonary Fibrosis (IPF)
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




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TABLE OF CONTENTS
1. Rationale..........................................................................................................................3
2. Summary of Changes from Previous Version................................................................4
3. Changes in Title Page......................................................................................................5
Emergency Contact Information .........................................................................................5
4. Changes in Clinical Study Specific Procedures .............................................................6
Change in section 4.1. Overall Study Design.....................................................................6
Change in section 5.4.5 Electrocardiogram........................................................................6
Change in section 5.8. Total Blood Volume ......................................................................6
Signature Page – Sponsor.....................................................................................................7
Signature Page – Investigator ..............................................................................................8


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1.
RATIONALE
The description for storage and use of left over BALF samples was missing while the purpose 
of these samples is fully explained in the PIS/ICF. The protocol is updated to align both 
documents, to correct typo’s and to record the change of Medical Monitor and Medical Lead 
responsibility. These updates are considered non-substantial.


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2.
SUMMARY OF CHANGES FROM PREVIOUS VERSION
Section
Summary of Changes
Cover page 
Update Medical Lead
Emergency Contact information
Update Medical Monitor
4.1
Correct typo in section 4.1: Week 98 [Day 98] should be 
Week 14 [Day 98].
5.4.5
Correct typo for reference to Appendix 4, should be 
Appendix 5
5.8
Text corrected to align with the approved PIS/ICF




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4.
CHANGES IN CLINICAL STUDY SPECIFIC PROCEDURES
Change in section 4.1. Overall Study Design
…
The subjects will visit the clinical study center at screening (Day-28 to Day -4), Day -1 
(baseline), Week 1 (Day 7), Week 2 (Day 14), Week 4 (Day 28), Week 8 (Day 56), and 
Week 12 (Day 84) or the early discontinuation visit (EDV). In addition, a follow-up visit will 
be planned 2 weeks after the last administration of study drug (Week 98 Week 14 [Day 98]). 
Each subject will be in the study for up to approximately 18 weeks (from screening to follow-
up). The end of the study (EOS) will be defined as the last contact with the last subject in the 
study.
Change in section 5.4.5 Electrocardiogram
A 12-lead ECG will be performed predose at the time points indicated in the study flow chart 
(provided in Section 1) and according to sequence of study assessments as described in 
Section 5.1. The ECG must be taken after 5 min in the supine position, prior to any blood 
sampling. Each ECG will be interpreted by the investigator for clinical significance.
Normal ranges are provided in Appendix 4 Appendix 5
Change in section 5.8. Total Blood Volume
…
After the study is completed, any left-over blood samples and bronchoalveolar lavage 
samples may be stored under the control of the sponsor. These samples may be used by the 
sponsor/partner, or by other companies belonging to the sponsor for future research on the 
mode of action of GLPG1690 and/or future research in IPF.


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SIGNATURE PAGE – SPONSOR
Title
Randomized, Double-Blind, Parallel Group, Placebo-Controlled, Multicenter, 
Exploratory Phase IIa Study to Assess Safety, Tolerability, Pharmacokinetic 
and Pharmacodynamic Properties of GLPG1690 Administered for 12 Weeks in 
Subjects with Idiopathic Pulmonary Fibrosis (IPF)
This Clinical Study Protocol Amendment 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
Randomized, Double-Blind, Parallel Group, Placebo-Controlled, Multicenter, 
Exploratory Phase IIa Study to Assess Safety, Tolerability, Pharmacokinetic 
and Pharmacodynamic Properties of GLPG1690 Administered for 12 Weeks in 
Subjects with Idiopathic Pulmonary Fibrosis (IPF)
I, the undersigned, have read this Clinical Study Protocol Amendment and will conduct the 
study as described in compliance with the Clinical Study Protocol Amendment, 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: 


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 2/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
T A B L E O F C O N T E N T S
List of T a bles ........................................................................................................................6
List of Fi g ures .......................................................................................................................9
List of Listi n gs ....................................................................................................................1 2
1.
St u d y Desi g n ..................................................................................................................1 4
1. 1.
St u d y  O bjecti ves...................................................................................................1 4
1. 1. 1.
Pri mar y O bject i ves...................................................................................1 4
1. 1. 2.
Sec o n dar y  O bjecti ves...............................................................................1 4
1. 2.
St u d y  Desi g n.........................................................................................................1 4
1. 3.
Cli nical St u d y  Pr ot oc ol ( C S P) a n d C S P A me n d me nts...........................................1 5
1. 4.
Fl o wc hart ..............................................................................................................1 6
2.
A n al ysis P o p ul ati o ns .....................................................................................................1 9
2. 1.
All Scree ne d S u bjects ...........................................................................................1 9
2. 2.
All Ra n d o mize d S u bjects ......................................................................................1 9
2. 3.
S af et y A nal ysis Set ...............................................................................................1 9
2. 4.
P har mac o ki net ics A nal ysis Set ..............................................................................1 9
2. 5.
P har mac o d y na mics A nal ysis Set ...........................................................................1 9
2. 6.
I nte nt t o Treat A nal ysis Set ...................................................................................1 9
3.
Tre at me nt Gr o u ps .........................................................................................................1 9
3. 1.
Ra n d o mize d vers us Act ual Treat me nt ...................................................................1 9
3. 2.
Treat me nt Gr o u p La bels ........................................................................................2 0
3. 3.
T ot al s o ver Gr o u ps................................................................................................2 0
4.
A n al ysis Peri o ds a n d A n al ysis Ti me P oi nts ................................................................. 2 0
4. 1.
Relati ve N u m ber of Da ys ......................................................................................2 0
4. 2.
A nal ysis Peri o ds f or N o n -Visit Data .....................................................................2 0
4. 3.
Al g ori t h m of Allocati n g Visi ts t o Ti me Wi n d o ws .................................................2 1
4. 4.
S el ect i on of Visits ................................................................................................. 2 1
5.
H a n dli n g of D at a ...........................................................................................................2 2
5. 1.
Calc ulati o n o f Descri pti ve Statist ics ......................................................................2 2
5. 2.
Calc ulati o n o f Perce nta ges ....................................................................................2 3
5. 3.
Cate g orizati o n of C o nt i n u o us Para meters..............................................................2 3
5. 4.
Ha n dli n g of Val ues bel o w ( or a b o ve) a T hres h o l d.................................................2 3
5. 4. 1.
S af et y a n d Efficac y Data ..........................................................................2 3
5. 4. 2.
P K Data ....................................................................................................2 3
5. 4. 3.
P D Data ....................................................................................................2 4
5. 5.
Ha n dli n g of Missi n g Data .....................................................................................2 4
5. 5. 1.
Ha n dli n g of Missi n g Val ues a n d Earl y  Dr o p o uts i n t he Ge neral, Safety a n d 
P K A nal yses .............................................................................................2 4
5. 5. 2.
Ha n dli n g of Missi n g Val ues a n d Earl y  Dr o p o uts i n t he E x plor at or y  
Efficac y a n d P D A nal yses ........................................................................2 4
5. 5. 3.
Ha n dli n g of Missi n g Dat e or Partiall y K n o w n Date ..................................2 5
5. 6.
Ha n dli n g of O ut liers..............................................................................................2 5
5. 7.
Ha n dli n g of Sec o n ds i n Date( Ti me) Fiel ds ............................................................2 5
6.
S oft w are a n d Pr oce d ures ..............................................................................................2 5
6. 1.
S of t ware................................................................................................................2 5


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C o nfi de ntial I nf or mati o n
6. 2.
Pr oce d ures ............................................................................................................2 5
6. 3.
F or mats .................................................................................................................2 6
7.
St atistic al Met h o ds ........................................................................................................2 6
7. 1.
Pl a n ne d A nal yses, Pr ot oc ol A me n d me nts I ncl u de d ...............................................2 6
7. 1. 1.
Ge neral Statist ical C o nsi derat i ons ............................................................2 6
7. 1. 2.
A nal yses of De m o gra p hics a n d Baseli ne C haracterist ics ..........................2 6
7. 1. 3.
E x pl or at or y  Efficac y Assess me nts............................................................2 6
7. 1. 4.
P har mac o ki net ic A nal yses ........................................................................2 7
7. 1. 5.
P har mac o d y na mic A nal yses .....................................................................2 7
7. 1. 6.
P har mac o ki net ic / P har mac o d y na mic a n d P har mac o ki netic / E x pl orat or y 
Efficac y C orrelati o ns ................................................................................2 7
7. 1. 7.
A nal yses of Safet y Data ...........................................................................2 8
7. 2.
C ha n ges t o t he Pla n ne d A nal yses, N ot C o vere d b y Pr ot oc ol A me n d me nts ............2 8
7. 2. 1.
C ha n ges bef ore Data base L oc k ................................................................. 2 8
7. 2. 2.
C ha n ges after Data base L oc k ....................................................................2 8
8.
Defi niti o ns of Ge ner al A n al ysis T a bles, Listi n gs a n d Fi g u res .....................................2 8
8. 1.
S u bject Dis p osit i on ...............................................................................................2 8
8. 2.
Pr ot oc ol  De viati ons a n d Eli gi bilit y ........................................................................3 0
8. 3.
S u bjects E xcl u de d fr o m A nal ysis ..........................................................................3 0
8. 4.
D e m o gra p hics a n d Baseli ne C haracterist ics ..........................................................3 1
8. 4. 1.
Para m eters ................................................................................................3 1
8. 4. 2.
A nal ysis ...................................................................................................3 1
8. 5.
Baseli n e disease c haracteristics .............................................................................3 3
8. 5. 1.
Para m eters ................................................................................................3 3
8. 5. 2.
A nal ysis ...................................................................................................3 4
8. 6.
Me dical Hist or y  a n d C o nc urre nt Diseases .............................................................3 4
8. 7.
Pri or a n d C o nc o mi ta nt T hera pies ..........................................................................3 5
8. 7. 1.
Cl assificat i on of T hera pies .......................................................................3 5
8. 7. 2.
C o di n g of T hera pies .................................................................................3 6
8. 7. 3.
A nal ysis ...................................................................................................3 6
8. 8.
E x p os ure t o St u d y  Dr u g a n d C o mplia nce ..............................................................3 7
8. 8. 1.
Deri vat i ons ...............................................................................................3 7
8. 8. 2.
A nal ysis ...................................................................................................3 7
8. 9.
C o m me nt s.............................................................................................................3 8
9.
Defi niti o ns of E x pl or at or y Effic ac y T a bles, Listi n gs a n d Fi g ures ..............................3 8
9. 1.
P ul m o nar y  Fu nct i on b y S pir o met r y.......................................................................3 8
9. 1. 1.
Para m eters ................................................................................................3 8
9. 1. 2.
Ta bles ......................................................................................................3 9
9. 1. 3.
Fi g ures .....................................................................................................4 1
9. 1. 4.
List i n gs ....................................................................................................4 2
9. 2.
Bi o m ar kers ...........................................................................................................4 2
9. 2. 1.
Para m eters ................................................................................................4 2
9. 2. 2.
Ta b les ......................................................................................................4 3
9. 2. 3.
Fi g ures .....................................................................................................4 4
9. 2. 4.
List i n gs ....................................................................................................4 5
9. 3.
Q ualit y of  Life: S G R Q..........................................................................................4 5
9. 3. 1.
Para m eters ................................................................................................4 5
9. 3. 2.
Ta bles ......................................................................................................5 0


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C o nfi de ntial I nf or mati o n
9. 3. 3.
Fi g ures .....................................................................................................5 1
9. 3. 4.
List i n gs ....................................................................................................5 2
9. 4.
F u nct i onal Res pirat or y  I ma gi n g ............................................................................5 2
9. 4. 1.
Para m eters ................................................................................................5 2
9. 4. 2.
Ta bles ......................................................................................................5 3
9. 4. 3.
Fi g ures .....................................................................................................5 4
9. 4. 4.
List i n gs ....................................................................................................5 4
1 0. Defi niti o ns of P h ar m ac o ki netics A n al ysis T a bles, Listi n gs a n d Fi g ures .....................5 4
1 0. 1. Para m eters ............................................................................................................5 4
1 0. 2. Ta bles ...................................................................................................................5 5
1 0. 3. Fi g ures ..................................................................................................................5 5
1 0. 4. List i n gs.................................................................................................................5 6
1 1. Defi niti o ns of P h ar m ac o d y n a mics A n al ysis T a bles, Listi n gs a n d Fi g ures ..................5 7
1 1. 1. Para m eters ............................................................................................................5 7
1 1. 2. Ta bles ...................................................................................................................5 7
1 1. 3. Fi g ures ..................................................................................................................5 9
1 1. 4. List i n gs.................................................................................................................6 0
1 2. Defi niti o n s of P K/ P D a n d P K/ E x pl or at or y Effic ac y A n al ysis T a bles, Listi n gs 
a n d Fi g ures ....................................................................................................................6 1
1 3. Defi niti o ns of S afet y A n al ysis T a bles, Listi n gs a n d Fi g ures ........................................6 3
1 3. 1. A d verse E ve nts .....................................................................................................6 3
1 3. 1. 1. Treat me nt -E m er ge nt Pri nci ple ..................................................................6 3
1 3. 1. 2. Treat me nt Relate d ness ..............................................................................6 3
1 3. 1. 3. W o rst-Case Pri nci ple ................................................................................6 4
1 3. 1. 4. A d verse E ve nt O nset Da y  a n d D urati o n....................................................6 4
1 3. 1. 5. Calc ulati o n o f Perce nta ges .......................................................................6 4
1 3. 1. 6. Ta bles ......................................................................................................6 5
1 3. 1. 7. List i ngs ....................................................................................................6 6
1 3. 2. La b orat or y  S afet y ..................................................................................................6 8
1 3. 2. 1. La b orat or y  U nits ......................................................................................6 8
1 3. 2. 2. N u m ber of Si g nifica nt Di git s....................................................................6 8
1 3. 2. 3. Baseli ne a n d C ha n ge fr o m Baseli ne ..........................................................6 8
1 3. 2. 4. Scree ni n g a n d F o ll ow- u p Vi sits................................................................6 8
1 3. 2. 5. Sc ori n g of La b orat or y  Val ues...................................................................6 9
1 3. 2. 6. W o rst-Case A b n or malit y ..........................................................................6 9
1 3. 2. 7. Ta bles ......................................................................................................6 9
1 3. 2. 8. Fi g ures .....................................................................................................7 0
1 3. 2. 9. List i n gs ....................................................................................................7 1
1 3. 3. E C G ......................................................................................................................7 1
1 3. 3. 1.
A vaila ble Data ..........................................................................................7 1
1 3. 3. 2 .
Calc ulate d Para meters..............................................................................7 1
1 3. 3. 3. Baseli ne a n d C ha n ge fr o m Baseli ne ..........................................................7 2
1 3. 3. 4. Scree ni n g a n d F o ll ow- u p Vi sits................................................................7 2
1 3. 3. 5. N or m al Ra n ges.........................................................................................7 2
1 3. 3. 6 . W o rst-case A b n or malit y of  Q T a n d Q Tc F................................................7 2
1 3. 3. 7. Ta bles ......................................................................................................7 2
1 3. 3. 8. List i n gs ....................................................................................................7 3
1 3. 4. Vi t al Sig ns............................................................................................................ 7 3


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C o nfi de ntial I nf or mati o n
1 3. 4. 1. A v aila ble Data..........................................................................................7 3
1 3. 4. 2. Baseli ne a n d C ha n ge fr o m Baseli ne ..........................................................7 4
1 3. 4. 3. Scree ni n g a n d F o ll ow- u p Vi sits................................................................7 4
1 3. 4. 4. N or m al Ra n ges.........................................................................................7 4
1 3. 4. 5. W o rst-Case A b n or malit y ..........................................................................7 4
1 3. 4. 6. Ta bles ......................................................................................................7 5
1 3. 4. 7. List i n gs ....................................................................................................7 5
1 3. 5. P h ysical E xa mi nat i ons ..........................................................................................7 5
1 4. Refere nces .....................................................................................................................7 6


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
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C o nfi de ntial I nf or mati o n
LI S T O F T A B L E S
Ta ble 1 4. 1. 1. 1:
S u bject dis p osit i on: Ta b ulat i on b y c o u ntr y  a n d i n vestig at or ...................2 8
Ta ble 1 4. 1. 1. 2:
S u bject dis p osit i on: A nal ysis p o p ulat i ons ..............................................2 9
Ta ble 1 4. 1. 1. 3:
S u bject dis p osit i on: N o -treat me nt s u bjects: Ta b ulati o n of t he 
reas o ns ..................................................................................................2 9
Ta ble 1 4. 1. 1. 4:
S u bject dis p osit i on: Ta b ulat i on of t he n u m ber of s u bjects at eac h 
ti me i nter val ..........................................................................................2 9
Ta ble 1 4. 1. 1. 5:
S u bject dis p osit i on: First a n d last date i n t he st u d y ................................2 9
Ta ble 1 4. 1. 1. 6:
S u bject dis p osit i on: Ta b ulat i on of t he st u d y  ter mi natio n reas o ns ............2 9
Ta ble 1 4. 1. 2. 1:
Pr ot oc ol  de viati ons: Ta b ulati o n .............................................................3 0
Ta ble 1 4. 1. 3. 1:
D e m o gra p hic data: Descri pti ve stati stics................................................3 1
Ta ble 1 4. 1. 3. 2:
Baseli ne la b orat or y  data: Ta b ulat i on of a b n or malit ies............................3 2
Ta ble 1 4. 1. 3. 3:
Baseli ne E C G data: Ta b ulati o n of a b n or malit ies....................................3 2
Ta ble 1 4. 1. 3. 4:
Baseli ne vital si g ns data: Ta b ulat i on of a b n or malit ies............................3 2
Ta ble 1 4. 1. 3. 5:
Baseli ne p h ysical e xa mi nat i on: Ta b ulat i on of a b n or m alities ..................3 2
Ta ble 1 4. 1 . 3. 6:
Scree ni n g a n d baseli ne disease c haracteristics .......................................3 4
Ta ble 1 4. 1. 3. 7:
Pri or a n d c o nc o mita nt all o we d I P F treat me nt .........................................3 4
Ta ble 1 4. 1. 3. 8:
Me dical hist or y : Ta b ulati on ...................................................................3 4
Ta ble 1 4. 1. 3. 9:
C o nc urre nt diseases: Ta b ulat i on ............................................................3 4
Ta ble 1 4. 1. 3. 1 0:
Pri or t hera pi es: Fre q ue nc y ta ble .............................................................3 6
Ta ble 1 4. 1. 3. 1 1:
C o nc o mita nt t hera pies: Fre q ue nc y  ta ble.................................................3 6
Ta ble 1 4. 1. 3. 1 2:
P os t-treat me nt t hera pies: Fre q ue nc y ta ble..............................................3 6
Ta ble 1 4. 1. 4. 1:
Use of st u d y  dr u g: Descripti ve stati stics.................................................3 7
Ta ble 1 4. 2. 1. 1. 1:
S pi r o metr y: Descri pti ve statistics per ti me p oi nt....................................3 9
Ta ble 1 4. 2. 1. 1. 2:
% F V C: Desc ript i ve statistics per ti me p oi nt b y s u b-gr o u ps ....................3 9
Ta ble 1 4. 2. 1. 1. 3:
% F V C: Statist ical e val uati on per ti me p oi nt ...........................................4 0
Ta ble 1 4. 2. 1. 1. 4:
% F V C: Fre q ue nc y ta b ulat i on of t he cate g orize d act ual val ues per 
ti me p oi nt ..............................................................................................4 0
Ta ble 1 4. 2. 1. 1. 5:
% F V C: Fre q ue nc y ta b ulat i on of t he cate g orize d c ha n ges fr o m 
baseli ne per ti me p o i nt...........................................................................4 0
Ta ble 1 4. 2. 1. 1. 6:
H o m e s pir o metr y - Wee kl y a vera ges: Descri pti ve statist ics per 
ti me p oi nt ..............................................................................................4 0
Ta ble 1 4. 2. 1. 2. 1:
Bi o m ar kers: Descript i ve statistics per ti me p oi nt ...................................4 3
Ta ble 1 4. 2. 1. 2. 2:
Bi o m ar kers: Descri pt i ve statistics per ti me p oi nt b y s u b-gr o u ps .............4 3
Ta ble 1 4. 2. 1. 2. 3:
Bi o m ar kers: Statist ical e val uati on per ti me p o i nt ...................................4 3
Ta ble 1 4. 2. 1. 3. 1:
S G R Q: Prese nt healt h per ti me p o i nt .....................................................5 0
Ta ble 1 4. 2. 1. 3. 2:
S G R Q: S hift ta ble of t he prese nt healt h per ti me p oi nt ...........................5 0
Ta ble 1 4. 2. 1. 3. 3:
S G R Q: Descri pt i ve statistics per ti me p oi nt ...........................................5 0
Ta ble 1 4. 2. 1. 3. 4:
S G R Q: Descri pt i ve statistics per ti me p oi nt b y s u b-gr o u ps ....................5 0
Ta ble 1 4. 2. 1. 3. 5 :
S G R Q: Stati stical e val uat i on per ti me p o i nt...........................................5 1
Ta ble 1 4. 2. 1. 4. 1:
F RI: Descri pti ve statist ics per ti me p oi nt ...............................................5 3
Ta ble 1 4. 2. 1. 4. 2:
F RI: Descri pti ve statistics per ti me p oi nt b y s u b -gr o u ps .........................5 3
Ta ble 1 4. 2. 1. 4. 3:
F RI: Statist ical e val uati on per ti me p oi nt ...............................................5 3


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C o nfi de ntial I nf or mati o n
Ta ble 1 4. 2. 2. 1:
G L P G 1 6 9 0 pl as ma c o nce ntrati o ns ( n g/ m L): I n di vi d ual data a n d 
descri pt i ve statistics per da y a n d ti me p oi nt ...........................................5 5
Ta ble 1 4. 2. 2. 2:
G L P G 1 6 9 0 P K para meters: I n di vi d ual data a n d descri pt i ve 
statistics – Wee k 4 .................................................................................5 5
Ta ble 1 4. 2. 3. 1:
L P A s pecies pea k area rati o: Descri pt i ve statistics per ti me p oi nt...........5 7
Ta ble 1 4. 2. 3. 2:
L P A s pecies pea k area rati o: Statist ical e val uati on per ti me p o i nt ..........5 7
Ta ble 1 4. 2. 3. 3:
L P A s pecies % re d ucti o n fr o m baseli ne: Descri pti ve statist ics per 
ti me p oi nt ..............................................................................................5 7
Ta ble 1 4. 2. 3. 4:
L P A s pecies % re d ucti o n fr o m baseli ne: Descri pti ve statist ics per 
ti me p oi nt b y s u b-gr o u ps .......................................................................5 8
Ta ble 1 4. 2. 3. 5:
L P A s pecies % re d ucti o n fr o m baseli ne: Fre q ue nc y ta b ulati o n per 
ti me p oi nt ..............................................................................................5 8
Ta ble 1 4. 2. 3. 6:
L P A s pecies % re d ucti o n fr o m baseli ne: Statist ical e val uati on per 
ti me p oi nt ..............................................................................................5 8
Ta ble 1 4. 2. 3. 7:
L P A s pecies ma xi m u m % re d ucti o n fr o m baseli ne E ma x : 
Descri pt i ve statistics..............................................................................5 8
Ta ble 1 4. 2. 3. 8:
L P A s pecies ma xi m u m % re d ucti o n fr o m baseli ne E ma x : Fre q ue nc y 
ta b ulat i on ...............................................................................................5 9
Ta ble 1 4. 2. 3. 9:
L P A s pecies ma xi m u m % re d ucti o n fr o m baseli ne E ma x : Statistical 
e val uat i on ..............................................................................................5 9
Ta ble 1 4. 2. 3. 1 0:
L P A s pecies area u n der t he % re d ucti o n c ur ve A U E C: Descri pt i ve 
statistics................................................................................................. 5 9
Ta ble 1 4. 2. 3. 1 1:
L P A s pecies area u n der t he % re d ucti o n c ur ve A U E C: Statist ical 
e val uat i on ..............................................................................................5 9
Ta ble 1 4. 3. 1. 1:
Treat me nt -e mer ge nt a d verse e ve nts: S u m mar y ta ble ..............................6 5
Ta ble 1 4. 3. 1. 2:
Treat me nt -e mer ge nt a d verse e ve nts: Ta b ulati o n o f all a d verse 
e ve nts ....................................................................................................6 5
Ta ble 1 4. 3. 1. 3:
Treat me nt -e mer ge nt a d verse e ve nts: Ta b ulati o n per i nte nsit y ................6 5
Ta ble 1 4. 3. 1. 4:
Treat me nt -e mer ge nt a d verse e ve nts: Ta b ulati o n o f all treat me nt -
r elate d e ve nts .........................................................................................6 5
Ta ble 1 4. 3. 1. 5:
Treat me nt -e mer ge nt a d verse e ve nts: Ta b ulati o n o f t he i nte nsit y of  
treat me nt -relate d e ve nts.........................................................................6 5
Ta ble 1 4. 3. 1. 6:
Treat me nt -e mer ge nt a d verse e ve nts: Ta b ulati o n o f serio us e ve nts ..........6 6
Ta ble 1 4. 3. 1. 7:
Treat me nt -e mer ge nt a d verse e ve nts: Ta b ulati o n o f e ve nts lea di n g 
t o a per ma ne nt st o p ................................................................................6 6
Ta ble 1 4. 3. 1. 8:
Treat me nt -e mer ge nt seri o us a d verse e ve nts: Ta b ulati o n f or 
E u dra C T re p orti n g .................................................................................6 6
Ta bl e 1 4. 3. 1. 9:
Treat me nt -e mer ge nt n o n-serio us a d verse e ve nts: Ta b ulat i on f or 
E u dra C T re p orti n g .................................................................................6 6
Ta ble 1 4. 3. 1. 1 0:
Treat me nt -e mer ge nt n o n-serio us a d verse e ve nts: Ta b ulat i on f or 
E u dra C T re p orti n g of T E A Es occ urri n g i n at least 5 % i n eit her 
treat me nt gr o u p .....................................................................................6 6
Ta bl e 1 4. 3. 2. 1:
La b orat or y  data: Descripti ve stati stics per ti me p oi nt.............................6 9


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
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C o nfi de ntial I nf or mati o n
Ta ble 1 4. 3. 2. 2:
La b orat or y  data: S hift ta ble of t h e la b orat or y a b n or malities per 
ti me p oi nt ..............................................................................................6 9
Ta ble 1 4. 3. 2. 3:
La b orat or y  data: Treat me nt -e mer ge nt la b orat or y a b n or malit ies per 
ti me p oi nt ..............................................................................................7 0
Ta ble 1 4. 3. 2. 4:
La b orat or y  data: S hift ta ble of t he cate g oric al la b orat or y data per 
ti me p oi nt ..............................................................................................7 0
T a ble 1 4. 3. 3. 1:
E C G: Descri pt i ve statistics per ti me p oi nt..............................................7 2
Ta ble 1 4. 3. 3. 2:
E C G: S hift ta ble of t he Q T a b n or malit ies per ti me p oi nt ........................7 2
Ta ble 1 4. 3. 3. 3:
E C G: Treat m e nt -e mer ge nt Q T a b n or malit ies per ti me p oi nt ..................7 3
Ta ble 1 4. 3. 3. 4:
E C G: Treat m e nt -e mer ge nt a b n or mal c ha n ge i n Q T per ti me p oi nt.........7 3
Ta ble 1 4. 3. 4. 1:
Vi t al si g ns: Descript i ve statistics per ti me p oi nt.....................................7 5
Ta ble 1 4. 3. 4. 2:
Vi t al si g ns: S hift ta ble of t he a b n or malities per ti me p oi nt .....................7 5
Ta ble 1 4. 3. 4. 3:
Vi t al si g ns: Treat me nt -e mer ge nt a b n or malities per ti me p oi nt ................7 5


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 9/ 7 6
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C o nfi de ntial I nf or mati o n
LI S T O F F I G U R E S
Fi g ure 1 4. 2. 1. 1. 1:
S pi r o metr y: S u bject pr ofile pl ots o ver ti me............................................4 1
Fi g ure 1 4. 2. 1. 1. 2:
S pi r o metr y: Mea n ( +/- S E) pl ots of t he act ual val ues o ver ti me ..............4 1
Fi g ure 1 4. 2. 1. 1. 3:
S pi r o metr y: Mea n ( +/- S E) pl ots of t he c ha n ges fr o m baseli ne o ver 
ti me.......................................................................................................4 1
Fi g ure 1 4. 2. 1. 1. 4:
S pi r o metr y: Mea n ( +/- S E) pl ots of t he perce nt c ha n ges fr o m 
baseli ne o ver ti me ..................................................................................4 1
Fi g ure 1 4. 2. 1. 1. 5:
H o m e s pir o metr y - Dail y val ues: S u bject pr ofile pl ots o ver ti me ............4 1
Fi g ure 1 4. 2. 1. 1. 6:
H o m e s pir o metr y - Dail y val ues: Mea n ( +/ - S E) pl ots of t he act ual 
val ues o ver ti me .....................................................................................4 1
Fi g ure 1 4. 2. 1. 1. 7:
H o m e s pir o metr y - Wee kl y a vera ges: S u bject pr ofile pl ot s o ver 
ti me.......................................................................................................4 1
Fi g ure 1 4. 2. 1. 1. 8:
H o m e s pir o metr y - Wee kl y a vera ges: Mea n ( +/ - S E) pl ots of t he 
act ual val ues o ver ti me ..........................................................................4 1
Fi g ure 1 4. 2. 1. 1. 9:
H o m e s pir o metr y - Wee kl y a vera ges: Mea n ( +/ - S E) pl ots of t he 
c ha n ges fr o m baseli ne o ver ti me ............................................................4 1
Fi g ure 1 4. 2. 1. 1. 1 0: H o m e s pir o metr y - Wee kl y a vera ges: Mea n ( +/ - S E) pl ots of t he 
perce nt c ha n ges fr o m baseli ne o ver ti me ................................................4 1
Fi g ure 1 4. 2. 1. 2. 1:
Bi o m ar kers (i n bl o o d): S u bject pr ofile pl ots o ver ti me ...........................4 4
Fi g ure 1 4. 2. 1. 2. 2:
Bi o m ar kers (i n bl o o d): Mea n ( +/ - S E) pl ots of t he act ual val ues 
o ver ti me ...............................................................................................4 4
Fi g ure 1 4. 2. 1. 2. 3:
Bi o m ar kers (i n bl o o d): Mea n ( +/ - S E) pl ots of t he c ha n ges fr o m 
baseli ne o ver ti me ..................................................................................4 4
Fi g ure 1 4. 2. 1. 2. 4:
Bi o m ar kers (i n bl o o d): Mea n ( +/ - S E) pl ots of t he perce nt c ha n ges 
fr om baseli ne o ver ti me .........................................................................4 4
Fi g ure 1 4. 2. 1. 2. 5:
Bi o m ar kers (i n B A L F) : Distri b uti on ......................................................4 4
Fi g ure 1 4. 2. 1. 2. 6:
Bi o m ar kers: B o x pl ots o ver ti me ............................................................4 4
Fi g ure 1 4. 2. 1. 3. 1:
S G R Q: S u bject pr ofile pl ots o ver ti me ...................................................5 1
Fi g ure 1 4. 2. 1. 3. 2:
S G R Q: Mea n ( +/- S E) pl ots of t he act ual val ues o ver ti me .....................5 1
Fi g ure 1 4. 2. 1. 3. 3:
S G R Q: Mea n ( +/ - S E) pl ots of t he c ha n ges fr o m baseli ne o ver 
ti me.......................................................................................................5 1
Fi g ure 1 4. 2. 1. 3. 4:
S G R Q: Mea n ( +/- S E) pl ots of t he perce nt c ha n ges fr o m baseli ne 
o ver ti me ...............................................................................................5 1
Fi g ure 1 4. 2. 1. 4. 1:
F RI: Mea n pl ots .....................................................................................5 4
Fi g ure 1 4. 2. 2. 1:
G L P G 1 6 9 0 pre -d ose pl as ma c o nce ntrati o ns ( n g/ m L): S u bject 
pr ofile pl ots (li near -li near scale) ............................................................5 5
Fi g ure 1 4. 2. 2. 2:
G L P G 1 6 9 0 pre -d ose pl as ma c o nce ntrati o ns ( n g/ m L): Mea n ( +/ -
S E) c o nce ntrati o n o ver ti me (li near -li near scale)....................................5 5
Fi g ure 1 4. 2. 2. 3:
G L P G 1 6 9 0 plas ma c o nce ntrati o ns ( n g/ m L): S u bject pr ofile pl ots –
Wee k 4 (li near -li near scale) ...................................................................5 6
Fi g ure 1 4. 2. 2. 4:
G L P G 1 6 9 0 plas ma c o nce ntrati o ns ( n g/ m L): S u bject pr ofile pl ots –
Wee k 4 (l o g -li near scale).......................................................................5 6


S tatistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 1 0/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
Fi g ure 1 4. 2. 2. 5:
G L P G 1 6 9 0 plas ma c o nce ntrati o ns ( n g/ m L): Mea n ( +/ - S E) 
c o nce ntrati o n o ver ti me – Wee k 4 (li near -li near scale)...........................5 6
Fi g ure 1 4. 2. 2. 6:
G L P G 1 6 9 0 plas ma c o nce ntrati o ns ( n g/ m L): Mea n ( +/ - S E) 
c o nce ntrati o n o ver ti me – Wee k 4 (l o g -li near scale)...............................5 6
Fi g ure 1 4. 2. 3. 1:
L P A 1 8: 2 s pecies pea k area rati o (i n bl o o d): S u bject pr ofile pl ots 
o ver ti me ...............................................................................................5 9
Fi g ure 1 4. 2. 3. 2:
L P A 1 8: 2 s pecies pea k area rati o (i n bl o o d): Mea n ( +/- S E) pl ot 
o ver ti me ...............................................................................................6 0
Fi g ure 1 4. 2. 3. 3:
L P A 1 8: 2 s pecies % re d ucti o n fr o m baseli ne (i n bl o o d): S u bject 
pr ofile pl ots o ver ti me ............................................................................6 0
Fi g ure 1 4. 2. 3. 4:
L P A 1 8: 2 s pecies % re d ucti o n fr o m baseli ne (i n bl o o d): Mea n ( +/ -
S E) pl ot o ver ti me ..................................................................................6 0
Fi g ure 1 4. 2. 3. 5:
L P A s pecies pea k area rati o (i n B A L F): Mea n plots ...............................6 0
Fi g ure 1 4. 2. 4. 1:
C orrel at i on bet wee n G L P G 1 6 9 0 plas ma c o nce ntrati o n a n d L P A 
s pecies % re d ucti o n fr o m baseli ne (li near-li near pl ot)............................6 1
Fi g ure 1 4. 2. 4. 2 :
C orrel at i on bet wee n G L P G 1 6 9 0 plas ma c o nce ntrati o n a n d L P A 
s pecies % re d ucti o n fr o m baseli ne (l o g-li near pl ot)................................6 1
Fi g ure 1 4. 2. 4. 3 :
C orrel at i on bet wee n G L P G 1 6 9 0 C ma x a n d L P A s pecies ma xi m u m 
% re d ucti o n f r o m baseli ne Ema x ..............................................................6 1
Fi g ure 1 4. 2. 4. 4 :
C orrel at i on bet wee n G L P G 1 6 9 0 C ma x a n d L P A s pecies area u n der 
t he % re d uctio n c ur ve A U E C ................................................................. 6 1
Fi g ure 1 4. 2. 4. 5 :
C orrel at i on bet wee n G L P G 1 6 9 0 A U C 0- τ a n d L P A s pecies area 
u n der t he % re d ucti o n c ur ve A U E C .......................................................6 1
Fi g ure 1 4. 2. 4. 6:
C orrel at i on bet wee n G L P G 1 6 9 0 pl as ma c o nce ntratio n a n d % F V C 
(li near-li near pl ot)..................................................................................6 1
Fi g ure 1 4. 2. 4. 7:
C orrel at i on bet wee n G L P G 1 6 9 0 pl as ma c o nce ntratio n a n d % F V C 
(lo g -li near pl ot) .....................................................................................6 2
Fi g ure 1 4. 2. 4. 8:
C orrel at i on bet wee n G L P G 1 6 9 0 pl as ma c o nce ntratio n a n d c ha n ge 
fr om baseli ne i n % F V C (li near-li near pl ot)............................................6 2
Fi g ure 1 4. 2. 4. 9:
C orrel at i on bet wee n G L P G 1 6 9 0 pl as ma c o nce ntratio n a n d c ha n ge 
fr om baseli ne i n % F V C (lo g -li near pl ot)................................................6 2
Fi g ure 1 4. 2. 4. 1 0:
C orrel at i on bet wee n t he L P A s pecies % re d ucti o n fr o m baseli ne 
a n d efficac y ...........................................................................................6 2
Fi g ure 1 4. 2. 4. 1 1:
C orrel at i on bet wee n t he L P A s pecies % re d ucti o n fr o m baseli ne 
(in bl o o d) a n d L P A s pecies % re d ucti o n fr o m baseli ne (i n B A L F) .........6 2
Fi g ure 1 4. 2. 4. 1 2:
C orrel at i on bet wee n c ha n ge fr o m baseli ne i n % F V C a n d 
bi o mar kers .............................................................................................6 2
Fi g ure 1 4. 2. 4. 1 3:
C orrel at i on bet wee n c ha n ge fr o m baseli ne i n % F V C a n d F RI 
para m eters .............................................................................................6 2
Fi g ure 1 4. 2. 4. 1 4:
C orrel at i on bet wee n c ha n ge fr o m baseli ne i n bi o mar kers a n d F RI 
para m eters .............................................................................................6 3
Fi g ure 1 4. 2. 4. 1 5:
C orrel at i on bet wee n c ha n ge fr o m baseli ne i n s pir o metr y  at t he 
st u d y ce nter a n d s pir o metr y at h o me ......................................................6 3


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 1 1/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
Fi g ure 1 4. 3. 2. 1:
La b orat or y  data: S u bject pr ofile pl ots o ver ti me f or s u bjects wit h a 
treat me nt -e mer ge nt a b n or malit y ............................................................7 0
Fi g ure 1 4. 3. 2. 2:
La b orat or y  data: Mea n ( +/- S E) pl ots of t he act ual val ues o ver ti me ......7 0
Fi g ure 1 4. 3. 2. 3:
La b orat or y  data: Mea n ( +/- S E) pl ots of t he c ha n ges fr o m baseli ne 
o ver ti me ...............................................................................................7 0


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 1 2/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
LI S T O F L I S TI N G S
List i n g 1 6. 2. 1. 1:
S u bject dis p osit i on: Ra n d o mizat i on .......................................................2 8
List i n g 1 6. 2. 1. 2:
S u bject dis p osit i on: N u m ber of da ys i n st u d y ........................................2 9
List i n g 1 6. 2. 1. 3:
S u bject dis p osit i on: St u d y  ter mi nati on ...................................................2 9
List i n g 1 6. 2. 2. 1:
Pr ot oc ol  de viati ons ................................................................................3 0
List i n g 1 6. 2. 2. 2:
Eli gi bilit y crit eri a: Viol at i ons ................................................................3 0
List i n g 1 6. 2. 3. 1:
S u bjects e xcl u de d fr o m t he safet y a nal ysis ............................................3 0
List i n g 1 6. 2. 3. 2:
S u bjects e xcl u de d fr o m t he I T T a nal ysis ................................................3 0
List i n g 1 6. 2. 3. 3:
S u bjects e xcl u de d fr om t he P D a nal ysis .................................................3 1
List i n g 1 6. 2. 4. 1:
D e m o gra p hic data ..................................................................................3 2
List i n g 1 6. 2. 4. 2:
Alc o h o l a n d s mo ki n g stat us ...................................................................3 2
List i n g 1 6. 2. 4. 3:
Bi rt h c o ntr ol met h o ds ............................................................................3 2
List i n g 1 6. 2. 4. 4:
Scree ni n g a n d baseli ne disease c haracteristics .......................................3 4
List i n g 1 6. 2. 4. 5:
Pri or a n d c o nc o mita nt all o we d I P F treat me nt .........................................3 4
List i n g 1 6. 2. 4. 6:
Me dical hist or y ......................................................................................3 4
List i n g 1 6. 2. 4. 7:
C o nc o mita nt diseases ............................................................................3 5
List i n g 1 6. 2. 4. 8:
Pri or a n d c o nc o mita nt t hera pies .............................................................3 7
List i n g 1 6. 2. 5. 1:
E x p os ure t o st u d y  dr u g: e C R F data........................................................3 7
List i n g 1 6. 2. 5. 2:
E x p os ure t o st u d y  dr u g: Deri ve d data ....................................................3 8
List i n g 1 6. 2. 5. 3:
Di s pe nse d kit n u m bers...........................................................................3 8
List i n g 1 6. 2. 5. 4:
C o m me nts .............................................................................................3 8
List i n g 1 6. 2. 6. 1:
S pi r o metr y: F ull listi n g..........................................................................4 2
List i n g 1 6. 2. 6. 2:
H o m e s pir o metr y - Dail y val ues: F ull list i n g..........................................4 2
List i n g 1 6. 2. 6. 3:
H o m e s pir o metr y - Wee kl y a vera ges: F ull list i n g...................................4 2
List i n g 1 6. 2. 6. 4:
Bi o m ar kers i n bl o o d: F ull list i n g............................................................4 5
List i n g 1 6. 2. 6. 5:
Bi o m ar kers i n B A L F: F ull list i n g ..........................................................4 5
List i n g 1 6. 2. 6. 6:
S G R Q: Ori gi nal ite ms ............................................................................5 2
List i n g 1 6. 2. 6. 7:
S G R Q: Sc ores .......................................................................................5 2
List i n g 1 6. 2. 6. 8:
F RI: F ull list i n g .....................................................................................5 4
List i n g 1 6. 2. 7. 1:
P K data ha n dli n g ...................................................................................5 6
List i n g 1 6. 2. 7. 2:
Act ual  P K blo o d s a m pli n g ti mes ( h) ......................................................5 6
List i n g 1 6. 2. 8. 1:
P D: F ull list i n g ......................................................................................6 0
List i n g 1 6. 2. 9. 1:
Treat me nt -e mer ge nt a d verse e ve nts: F ull li sti n g ....................................6 6
List i n g 1 6. 2. 9. 2:
Pre -treat me nt a d verse e ve nts: F ull list i n g...............................................6 7
List i n g 1 6. 2. 9. 3:
S eri o us a d verse e ve nts: F ull list i n g........................................................6 7
List i n g 1 6. 2. 9. 4:
Treat me nt -e mer ge nt a d verse e ve nts: F ull list i n g of t he e ve nts 
lea di n g t o disc o nti n uati o n......................................................................6 7
List i n g 1 6. 2. 9. 5:
Tr eat me nt -e mer ge nt a d verse e ve nts: F ull list i n g of t he e ve nts 
lea di n g t o a te m p orar y st o p....................................................................6 7
List i n g 1 6. 2. 9. 6:
A d verse e ve nts: C o di n g i nf or mat i on ......................................................6 7
List i n g 1 6. 2. 9. 7:
A d verse e ve nts: List i n g of s u bjects f or w h o m a narrati ve is 
re q uire d ................................................................................................. 6 7
List i n g 1 6. 2. 1 0. 1:
La b orat or y  data: F ull listi n g...................................................................7 1


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 1 3/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
List i n g 1 6. 2. 1 0. 2:
La b orat or y  data: A b n or malities list i n g...................................................7 1
List i n g 1 6. 2. 1 1. 1:
E C G: F ull list i n g ...................................................................................7 3
List i n g 1 6. 2. 1 1. 2:
E C G: A b n or malit ies listi n g....................................................................7 3
List i n g 1 6. 2. 1 2. 1:
Vi t al si g ns: F ull listi n g...........................................................................7 5
List i n g 1 6. 2. 1 2. 2:
Vi t al si g ns: A b n or malities list i n g...........................................................7 5
List i n g 1 6. 2. 1 3. 1:
P h ysical e xa mi nat i ons: A b n or malit ies listi n g.........................................7 5


Statistic al A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 1 4/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
1.
S T U D Y D E SI G N
1. 1.
S T U D Y O B J E C TI V E S
1. 1. 1.
Pri m ar y O bjecti ves

T o e val uate t he safet y a n d t olera bilit y of G L P G 1 6 9 0.

T o c haracterize t he P K a n d P D pr o perties of G L P G 1 6 9 0 .
1. 1. 2.
Sec o n d ar y O bjecti ves

T o e val uate t he c ha n ge fr o m baseli ne i n F V C .

T o e x pl ore t he c ha n ge i n bi o mar kers i n bl o o d a n d B A L F.

T o e val uate t he c ha n ge i n F RI para meters .

T o e val uate t he c ha n ge i n q ualit y of  life meas ures.
1. 2.
S T U D Y D E SI G N
T his st u d y is a ra n d o mize d, d o u bl e- bli n d, parallel gr o u p, place b o -c o ntr olle d, m ult ice nter, 
e x pl orat or y p hase IIa st u d y to e val uate t he safety,  tol era bilit y, P K , a n d P D of G L P G 1 6 9 0 i n 
s u bjects wi t h IP F. I n a d ditio n , se veral e x plorat or y assess me nts will be p erf or m e d. Male a n d 
fe male s u bjects of  no n -c hil d-beari n g p ote ntial wi t h a co nfir me d dia g n osis of  IP F a ge d 4 0
years or ol der will be scree ne d t o deter mi ne eli gi bilit y as per t he i ncl usi on a n d e x clusi o n 
criteria. T he scree ni n g peri o d will be u p t o 4 wee ks.
W ritte n i nf or me d c o nse nt m ust be o btai ne d bef ore a n y st u d y-r elate d pr oce d ures ta ke pl a c e. 
D uri n g t he scree ni n g p eri o d , fol l owi n g si g ni n g of  the i nf or me d c o nse nt f or m (I C F), t he 
s u bject’s hist ori cal H R C T a n d s ur gic al l u n g bi o ps y (S L B; if a vaila ble) will be se nt t o ce ntral 
re vie w f or t he c o nfir mati on of t he I P F dia g n osis t hr o u g h a:

ce ntral re vie w of t he c hest H R C T,

ce ntral re vie w of t he S L B (if a vaila ble).
N ote t hat b ot h t he c hest H R C T a n d S L B n ee d t o be se nt t o ce ntral r e vi e w at least 8 da ys prior 
t o t he baseli ne visit t o all o w f or ce ntral rea di n g a n d c o nfir mati on of I P F dia g n osis.
At  baseli ne, aft er t he s u bject’s eli gi bilit y f or t he st u d y has bee n c o nfir me d, s u bjects will be 
ra n d omize d i n a 3: 1 r atio t o G L P G 1 6 9 0 6 0 0 m g q. d. or m atc hi n g place b o a d mi nistere d f or 1 2
wee ks.
T he s u bjects will visit t he cli nical st u d y ce nter at scree ni n g ( Da y - 2 8 t o Da y
-4), Da y
-1 
( baseli ne), Wee k 1 ( Da y 7), Wee k 2 ( Da y 1 4), Wee k 4 ( Da y 2 8), Wee k 8 ( Da y 5 6), a n d Wee k 
1 2 ( D a y 8 4) or t he earl y disc o nt i n uati on visit ( E D V). I n a d dit i on, a f oll ow- u p visit will be 
pl a n ne d 2 wee ks after t he last a d ministrati o n of  st u d y dr u g ( Wee k 1 4 [ Da y 9 8]). Eac h s u bject 
will be i n t he st u d y for u p t o a p pr o xi matel y 1 8 w e e ks (f r o m screeni n g t o f ol l ow- u p). T he e n d 
of  t he st u d y ( E O S) will be defi ne d as t he last c o ntact wit h t he last s u bject i n t he st u d y.
T he assess me nts perf or me d at eac h visit are detaile d i n t he st u d y fl ow c hart.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 1 5/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
T o e n ha nce t he safet y an d i nte grit y of t he st u d y data, a n in de pe n de nt me d ical safet y re vie w 
will be i m ple me nte d.
1. 3.
C LI NI C A L S T U D Y P R O T O C O L ( C S P) A N D C S P
A M E N D M E N T S
Pr ot oc ol Versi o ns
D ate ( d d M M M y y y y)
Fi nal
1 6 O C T 2 0 1 5
Pr ot oc ol A me n d me nts
D ate ( d d M M M y y y y)
Ital y C o u ntr y S pecific A me n d me nt
2 1 A P R 2 0 1 6
Ge neral A me n d me nt I
1 9 D E C 2 0 1 6
T his S A P was base d o n t he latest versi o n o f t he pr ot oc ol.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 1 6/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
1. 4.
F L O W C H A R T
E V E N T
Visit 1
Scree ni n g
Visit 2
B aseli ne
D O SI N G P E RI O D
E D V
F U
Visit
Visit 3
1
W 1
Visit 4
1
W 2
Visit 5
1
W 4
Visit 6
1
W 8
Visit 7
1
W 1 2
Visit 8 / 
E O S 
W 1 4
St u d y d a ys ( D)
D- 2 8 t o 
D- 4
D- 1
D 1  
D 7
± 2 d a ys
D 1 4
± 2 d a ys
D 2 8
± 3 d a ys
D 5 6
± 3 d a ys
D 8 4
± 3 d a ys
D 9 8
± 3 d a ys
I nf or me d c o nse nt
X
Hist orical H R C T se nt t o ce ntral re vie w 2
X
S L B se nt t o ce ntral re vie w 2, 3
X
De m o gra p hics
X
Me dical hist or y/ C o nc urre nt ill nesses
X
I ncl usi o n/e xcl usi o n criteria
X
Ser ol o g y
X
F S H test  4
X
D L C O 
X
C o nfir m all eli gi bilit y criteria 
X
Ra n d o mizati o n
X
Dis pe nse st u d y dr u g
X 
X  
X  
X  
X
                                                            
1 S u bjects will be as ke d t o c o me t o t he st u d y ce nter i n t he m or ni n g at a p pr o xi matel y t he sa me ti me o n e ver y visit.
2 T he H R C T a n d S L B nee d t o be se nt t o ce ntral re vie w at least 8 da y s pri or t o t he baseli ne visit t o all o w f or ce ntral rea di n g a n d c o nfir mati o n of dia g n osis.
3 If a vaila ble.
4 O n l y at scree ni n g i n case t here is d o u bt o n w het her a fe male s u bject is p ost me n o pa usal.






Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 1 9/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
2.
A N A L Y SI S P O P U L A TI O N S
T he a nal ysis p o p ulat i on will al wa ys be i n dicate d i n a s u btit le i n t he ta ble, listi n g or fi g ure.
2. 1.
A L L S C R E E N E D S U B J E C T S
All s u bjects w h o si g ne d a n I C F.
2. 2.
A L L R A N D O MI Z E D S U B J E C T S
All s u bjects ra n d omize d i nt o t he st u d y .
2. 3.
S A F E T Y A N A L Y SI S S E T
All ra n d o mize d s u bjects w h o recei ve d at least o ne d ose of st u d y  dr u g.
I n case a partic ular s u bject w o ul d be u n bli n de d (e. g., i n case of a n S A E), all safety data of  t his 
s u bject rec or de d i n t he data base will still be i ncl u de d i n t he safet y a nal ysis.
2. 4.
P H A R M A C O KI N E TI C S A N A L Y SI S S E T
All ra n d o mize d s u bjects w h o recei ve d at least o ne d ose of  G L P G 1 6 9 0
a n d f or w h o m 
e val ua ble P K data were a vaila ble. S u bjects wi t h a prot oc ol  de viat i on t hat ma y i m pact t he P K
res ults will be e xcl u de d fr o m t his p o p ulat i on.
2. 5.
P H A R M A C O D Y N A MI C S A N A L Y SI S S E T
All ra n d omize d s u bjects w h o ha ve at least o ne d ose of  st u d y dr u g a n d ha ve at least o ne p ost -
baseli ne assess me nt wit h P D data.
2. 6.
I N T E N T T O T R E A T A N A LY SI S S E T
All ra n d o mize d s u bjects w h o recei ve d at least o ne d ose of  st u d y dr u g a n d ha ve at least o ne 
p ost -baseli ne assess me nt wit h e x pl orat or y e n d p oi nt data.
I n case a partic ular s u bject w o ul d be u n bli n de d (e. g., i n case of  a n S AE), all efficac y data of  
t his s u bject u p t o t he p oi nt of  un bli n di n g will  still be i ncl u de d i n t he I T T a nal ysis. Rec or de d 
efficac y data fr om t he m o me nt  of un bl i n di n g o n war ds will be dis q ualifie d fr om t he a nal ysis. 
S uc h data will st ill be part of t he listi n gs, b ut will be la bele d as use = n o. Missi n g data after t he 
m o me nt of u n bli n di n g will be i m p ute d usi n g t he sa me r ules as use d f or ot her s u bjects.
3.
T R E A T M E N T G R O U P S
3. 1.
R A N D O MI Z E D V E R S U S A C T U A L T R E A T M E N T
F or efficac y a n d P D para meters, t he treat m e nt gr o u p as assi g ne d b y t he ra n d o mizatio n will be 
use d i n t he a nal ysis (i.e., as -ra n d o mize d a nal ysis).


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 2 0/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
F or safety a n d P K para meters, t he treat me nt t hat was act uall y use d d uri n g m o st of t he time 
(i.e., > 5 0 % of  the d urati o n of  int a kes) b y t he s u bject will be a p plie d i n t he a nal ysis (i.e., as-
treate d a nal ysis).
Differe nces bet wee n as-treate d a n d as-ra n d o mize d will be fla g ge d i n t he listi n g o n s u bject 
ra n d omiz at i on.
3. 2.
T R E A T M E N T G R O U P L A B E L S
T he f o ll owi n g treat m e nt gr o u p la bels will be use d i n t he ta bles, list i n gs a n d fi g ures:

Pl ace b o q. d.

G L P G 1 6 9 0 6 0 0 m g q . d.
3. 3.
T O T A L S O V E R G R O U P S
A t ot al over all gr o u ps will be prese nte d f or t he ge neral part of  the a nal ysis, b ut n ot f or t he 
ot her parts ( P K, P D, efficac y a n d safet y ). T otals will o nl y  be s h o w n o n ta bles, b ut n ot o n 
listi n gs or fi g ures.
4.
A N A L Y SI S P E RI O D S A N D A N A L Y SI S TI M E P OI N T S
4. 1.
R E L A TI V E N U M B E R O F D A Y S
T he rel at i ve da y ( D Y) is calc ulate d as f oll o ws:
= Vi sit d at e – refere nce date + 1 da y, w he n t he visit date is o n or after t he refere nce date
= Vi sit d at e – refere nce date, w he n t he visit date is bef ore t he r efere nce date
T he refere nce date i n t he st u d y is t he first st u d y dr u g i nta ke date , w hic h b y defi ni tio n  has 
D Y = 1. T here is n o D Y = 0.
4. 2.
A N A L Y SI S P E RI O D S F O R N O N - VI SI T D A T A
T hese a nal ysis p eri o ds are t o be use d f or all ocati o n of  eve nts i nto peri o ds (e. g., a d verse 
e ve nts, c o nc o mita nt me dicati o n).
A n al ysis peri o d
St art peri o d
E n d Peri o d
Scree ni n g
Date of si g ni n g t he I C F
First treat me nt a d mi nistrati o n date - 1 da y
Treat me nt
First treat me nt a d mi nistrati o n date
St u d y ter mi nati o n date
N ote t hat t he last a nal ysis p eri o d i n case of  earl y ter mi nati on will al wa ys be e n de d b y t he 
st u d y ter mi nati on date ( date of last c o ntact, as rec or de d i n t he e C R F).
I n t he a nal ysis, t he a nal ysis p eri o ds will be re place d b y t he act ual tr e at me nt ta ke n d uri n g t he 
p eri o d (see secti o n 3. 1 ).


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 2 1/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
4. 3.
A L G O RI T H M O F A L L O C A TI N G V I SI T S T O T I M E W I N D O W S
All visits (incl u di n g earl y ter mi nati on visits a n d u nsc he d ule d visits b ut e xcl u di n g visit s 
wi t ho ut data) wil l be place d i nto ti me wi n d o ws acc or di n g t o t heir r elat i ve da y ( D Y) i n t he 
st u d y, acc or di n g t o t he f oll o wi n g all ocati on ta ble:
Ti me p oi nt l a bel
T ar get d a y
I nter v al l o wer b o u n d
I nter v al u p per b o u n d
Scree ni n g 3
N A 4
N A 4
N A 4
Baseli ne 1
N A 4
N A 4
1
Wee k 1
7
2
1 0
Wee k 2
1 4
1 1
2 0
Wee k 4
2 8
2 1
4 1
Wee k 8
5 6
4 2
6 9
Wee k 1 2
8 4
7 0
9 7
> Wee k 1 2 2
N A 4
9 8
+ ∞
F oll o w - u p3
2 wee k s after last visit
N A 4
N A 4
1 T h e a ct u al b as eli n e r ef er e n c e v al u e will b e d et er mi n e d p er p ar a m et er as t h e l ast a v ail a bl e pr e -d osi n g d at a p oi nt, s o mi g ht diff er 
fr o m t his “ baseli ne” visit i nter val. If t he baseli ne is o n t h e sa me da y of t he first st u d y dr u g i nta ke we ass u me t hat t he assess me nts 
were d o ne bef ore.
2 Visits falli n g reall y late i n t he st ud y (relati ve da y > 9 8; e xcl u di n g t he f oll o w- u p visit) will be all ocate d t o a “ > Wee k 1 2 ” 
i nter val, a n d will n ot be s h o w n i n ta bles or fi g ures, b ut will o nl y be liste d.
3 F or t he scree ni n g a n d f oll o w -u p visits, n o ti me wi n d o w is defi ne d. T he visit as rec or de d i n t he e C R F will be use d.
4 N A = N ot a p plica ble
Ta bles, fi g ures a n d list i n gs will prese nt t he ti me p oi nts, n ot t he visits.
4. 4.
S E L E C TI O N O F V I SI T S
It is p ossi ble t hat m o re t ha n o ne visit gets allocate d i nto t h e sa me ti me wi n d o w. I n t hat case, 
o nl y o ne visit will  be selecte d f or a nal ysis ta bles a n d fi g ures. T he n o n-selecte d visit(s) will 
o nl y  be liste d, a n d fla g ge d as use = n o.
T he visit wi t h a relat i ve d a y  (D Y) clos est t o t he tar get da y will be selecte d. If t here are 
m ult i ple visit s at t he sa me dista nce of  the sc he d ule d visi t da y ( mea ni n g: e q ual A B S( D Y –
tar get da y)), t he n t he o ne latest in t i me is selecte d.
I n case of m ult i ple scree ni n g visits, t he last pre -baseli ne scree ni n g meas ure me nt is selecte d 
f or a nal ysis. T his val ue ( not t he ori gi nal first scree ni n g val ue) was als o use d i n t he cli nical 
ce nter t o i ncl u de t he s u bject i n t he st u d y.
I n case m o re t ha n o ne para meter is meas ure d p er ti me p oi nt (e. g. f or lab), t he selecti on is 
perf or m e d per para meter a n d per ti me p oi nt, n ot per “sa m ple” a n d per ti me p oi nt. Mi ssi n g 
val ues are re m o ve d bef ore t he select i on is ma de.
As baseli ne refere nce p oi nt, t he last n o n- missi n g pre -d osi n g val ue will be use d. T his is 
n or m all y t he sc he d ule d baseli ne itself. A missi n g sc he d ule d baseli ne val ue will be i m p ute d 
wi t h the last n o n- missi n g val ue of  a prece di n g pre -d osi n g visit. T his ca n be a scree ni n g visit  
or a n u nsc he d ule d visit pri or t o t he first d ose of  st u d y dr u g . If t here is a n u nsc he d ule d 
meas ure me nt ta ke n aft er t he sc he d ule d baseli ne, b ef or e t he first d ose of  st u d y dr u g, t he n t his 
u nsc he d ule d meas ure me nt will be use d i nstea d of  the sc he d ule d baseli ne. If t here is a n 


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 2 2/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
u nsc he d ule d meas ure me nt at t he sa me date as t he sc he d ule d baseli ne, t he n it is ass u me d t hat 
t he u nsc he d ule d meas ure me nt is ta ke n after t he sc he d ule d baseli ne.
I n case t he scree ni n g visit is use d t o i m p ute t he b aseli ne, t he visit will be d u plicate d i n t h e 
deri ve d dataset. T h e ori gi nal  scree ni n g visi t as w ell as t he i m p ute d baseli ne will be prese nte d 
i n t he ta bles. I n t he listi n gs, o nl y origi nal scree ni n g data will be s h o w n: t he origi nal scree ni n g 
visit will be s h o w n a n d fla g ge d as “refere nce” visit . T he i m p ute d baseli ne will n ot be s h o w n.
I n case a n u nsc he d ule d visit is use d t o i m p ute t he baseli ne, t he visit will be re na me d t o 
“ baseli ne” i n t he deri ve d dataset. T he i m p ute d baseli ne will be prese nte d i n t he ta bles. I n t h e 
listi n gs, t he ori gi nal u nsc he d ule d data will be s h o w n a n d fla g ge d as “refere nce” visit.
5.
H A N D LI N G O F D A T A
5. 1.
C A L C U L A TI O N O F D E S C RI P TI V E S T A TI S TI C S
F or c o nti n u o us para m eters, descript i ve st atistics will be prese nte d w he n N ≥2. W he n N = 1, t he 
o bser vat i on w ill n ot be s h o w n i n t he ta ble/fi g ure b ut o nl y i n t he listi n g(s). S a m e h ol ds f or 
s u m mar y gra p hs.
Descri pt i ve statistics will i ncl u de at least t he f oll owi n g:

T he n u m ber of n o n -missi n g data p oi nts ( N)

T he ari t h metic me a n

T he sta n dar d err or ( S E)

T he m e dia n, mi ni m u m a n d ma xi m u m

9 5 % c o nfi de nce i nter val o f t he mea n ( o nl y w he n re q ueste d)
F or P K plas ma c o nce ntrati o ns a n d deri ve d P K para meters , descript i ve statistics will i ncl u de:

T he n u m ber of n o n -missi n g data p oi nts ( N)

T he n u m ber of  data p oi nts a b o ve t he li mit o f q ua nt ificati on
( G L P G 1 6 9 0 pl as ma 
c o nce ntrati o ns o nl y)

T he ari t h metic me a n

T he sta n dar d err or ( S E) a n d sta n dar d de viati o n ( S D)

T he m e dia n, mi ni m u m, a n d ma xi m u m

T he c oefficie nt of variat i on ( C V %)
= 1 0 0 x (sta n dar d de viat i on / ari t h metic me a n)

T he ge o metric mea n = e x p(arit h met ic mea n of l n -tra nsf or me d data)

T he ge o metric c oefficie nt of variat i on ( C V %)
= 1 0 0 x   (                               )² −1
N otes:

S i nce a hi g h pr o p orti o n of B L O Q ( < L L O Q) v al u es ma y affect t he statistics; if m o re t ha n 
5 0 % of  val ues are i m p ute d or n o n- missi n g r es ults, t he n o nl y t he arit hmetic mea n will be 
calc ulate d f or t hat ti me p oi nt. T he ot her descri pt i ve statistics will  be liste d as “ N C” ( not 
calc ulate d) .

If t he ca lc ulate d mea n is less t ha n L L O Q , t he n it will be prese nte d as B L O Q. T he 
mi ni m u m will be “ B L O Q”, a n d t he ma xi m u m will be deri ve d fr o m t he act ual data.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 2 3/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n

T he pl as ma c o nce ntratio ns will be prese nte d wit h 3 si gnifica nt di git s i n t he ori gi nal 
c o nce ntrati o n u ni t. P K para m eters will be prese nte d wi t h 3 si gnifica nt di git s (i.e.: 8. 3 5 6 
a n d 1 8 3 9 n g/ m L will be r o u n de d t o 8. 3 6 a n d 1 8 4 0 n g/ m L, res pecti vel y) e xce pt f or tma x , 
w hic h will be prese nte d wi t h 1 deci mal. T he descri pt i ve statistics s h o uld be r o u n de d t o 
t he sa me n u m ber of si g nifica nt di gits as t he i n di vi d ual val ues.

I n listi n gs, B L O Q will be prese nte d f or all val ues of < L L O Q a n d a val ue of L L O Q a d de d 
t o a f o ot n ote.
5. 2.
C A L C U L A TI O N O F P E R C E N T A G E S
Missi n g val ues will n ot be i ncl u de d i n t he de n o mi nat or c o u nt w he n c o m p uti n g perce nta ges.
I mp ute d missi n g val ues are n o l o n ger c o nsi dere d t o be missi n g val ues.
5. 3.
C A T E G O RI Z A TI O N O F C O N TI N U O U S P A R A M E T E R S
W he n 
a c o nt i n u o us para meter (e g a ge) is als o cate g orize d t o be prese nte d i n a fre q ue nc y 
ta ble, discre pa ncies ca n arise beca use of r o u n di n g. T o pre ve nt t his, t he r o u n di n g will b e d o n e 
first o n t he c o nti n u o us para meter. T his r o u n de d c o nti n u o us para m eter will be use d f or t he 
descri pt i ve statistics a n d will als o be use d f or t he cate g orizati on.
5. 4.
H A N D LI N G O F V A L U E S B E L O W ( O R A B O V E) A T H R E S H O L D
5. 4. 1.
S afet y a n d Effic ac y D at a
V al ues b el o w (a b o ve) t he detecti o n li mit will  be i m p ute d b y t he val ue of  the detecti o n li mit 
itself. Listi n gs will al wa ys prese nt t he ori gi nal val ue.
E xa m ple: if t he data base c o ntai ns val ues li ke “ < 0. 0 4”, t he n f or t he descri pt i ve st atistics t h e 
val ue of  the detecti o n li mit ( 0. 0 4) s hall be use d. A val ue li ke “ > 1 0 0 0” will be i m p ute d b y 
“ 1 0 0 0”.
5. 4. 2.
P K D at a
T he l o wer li mit of q ua nt ificati on ( L L O Q) will be X. X X < u nit > .
C o nce ntrati o n s u m maries:

Pri or t o calc ulati o n of  su m mar y statistics: a n y i n di vi d ual v al ues less t ha n l ower li mit of 
q ua nt ificati on ( < L LO Q) will be re place d wi t h zer o f or t he calc ulati o n of  descri pti ve 
statistics e xce pt f or ge o m etric mea n a n d ge o me tric C V w here it will be i m p ute d b y 
L L O Q/ 2 a n d liste d as “ B L O Q”.
D uri n g calc ulati o n o f P K para meters:

A n y B L O Q ( < L L O Q) val ues t hat occ ur bef ore t he first q ua ntifia ble c o nce ntrati o n will be 
r e place d wi t h zer o f or t he calc ulat i on of  descri pti ve statistics e xce pt f or ge o metric mea n 
a n d ge o met ric C V w here it will be i m p ute d b y L L O Q/ 2 a n d liste d as “ B L O Q” .

If a B L O Q ( < L L O Q) val ue occ urs aft er a q ua nt ifia ble c o nce ntratio n i n a pr ofile a n d is 
f oll owe d b y a val ue of  LL O Q or a b o ve, t he q ua nt ifia ble ti me p oi nt will be treate d as 
' missi n g'.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 2 4/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n

If t w o B L O Q ( < L L O Q) val ues occ ur i n s uccessi on, t he pr ofile will be dee me d t o ha ve 
ter mi nate d at  t he fi nal q ua nt ifia ble c o nce ntratio n a n d s u bse q ue nt L L O Q or a b o ve val ues 
will be treate d as ' missi n g'.
F or i n di vi d ual p har mac o ki net ic pr ofiles/ plots :

A ' missi n g' val ue will be s u bstit ut e d f or a n y B L O Q ( < LL O Q) irres pecti ve of  w h er e t h e y 
are i n t he pr ofile a n d t he plas ma c o nce ntratio n -ti me data will be pl ott e d as s uc h, e xce pt 
f or t he pre-d ose were it s h o ul d be re place b y zer o.
Mea n c o nce ntrati o n pr ofiles / plots :

W he n est i mati n g t he mea n val ue f or t he c o nce ntrati o n at a gi ve n time p oi nt ( descript i ve 
mea n c ur ve), t he f oll owi n g g ui deli nes s h o uld be c o nsi dere d: the mea n val ue at a ti me 
wi t h one or m o re B L O Q ( < L L O Q) v al ues will be calc ulate d b y assi g ni n g zer o. If t he 
calc ulate d mea n val ue is less t ha n L L O Q of t he assa y, t he n t hat ti me p oi nt will be plotte d 
as zer o i n t he mea n p har m ac o ki netic pr ofiles.
5. 4. 3.
P D D at a
V al ues bel o w t he q ua nt ificati on li mit will be i m p ute d b y 0 a n d liste d as “ B L O Q”.
5. 5.
H A N D LI N G O F M I S SI N G D A T A
5. 5. 1.
H a n dli n g of Missi n g V al ues a n d E arl y Dr o p o uts i n t he Ge ner al, 
S afet y a n d P K A n al yses
N o i m p utati o n is d o n e of  missi n g val ues or missi n g visits. T he a nal ysis will be o bser ve d -case 
o nl y , e xce pt f or t he f oll o wi n g P K a nal yses:

Missi n g Wee k 4 pre -d ose pl as ma c o nce ntratio ns will be i m p ute d b y t he c o nce ntratio n 
val ues f ou n d at Wee k 
2 pre -d ose (ass u mi n g t hat stea d y st at e will be reac he d aft er 2 
wee ks d osi n g) .

W e e k 4 2 4 h p ost -d ose pl as ma c o nce ntratio ns will be i m p ute d usi n g t he W e e k 4 pr e -d ose 
val ues, i n or der t o c o mplete t he f ull d osi n g i nter val P K pr ofile ( of 2 4 h o urs).
5. 5. 2. H a n dli n g of Missi n g V al ues a n d E arl y Dr o p o uts i n t he E x pl or at or y 
Effic ac y a n d P D A n al yses
Missi n g visit s as well as earl y dr o p o uts will be i m p ute d usi n g t he last o bser vat i on carrie d 
f or war d ( L O C F) al g orit h m. S o t o i m p ute a missi n g val ue, t he last prece di n g n o n- missi n g 
val ue will be use d ( w hic h c o ul d e ve n be a baseli ne val ue).
N ote t hat f or s pir o metr y para meters, data e xcl u de d beca use of  a po or q ualit y gra di n g ( cf. 
secti on 9. 1. 1 ) will be i m p ute d f oll owi n g t he r ul es defi ne d a b o ve.
A n d n ot e  that missi n g p ost -d ose ( wee k 4 1. 5 h a n d 6 h) P D ( L P A i n bl o o d) data w o n’t be 
i m p ute d.
F or all para meters, a n o bser ve d -case ( O C) a nal ysis will  als o be p erf or m e d (i.e., wi t ho ut a n y 
i m p utatio n).


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 2 5/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
5. 5. 3.
H a n dli n g of Missi n g D ate or P arti all y K n o w n D ate
U nless s pecifie d ot her wise, n o i m p utati o n will be d o ne of  missi n g date fiel ds, or of  the 
missi n g parts of  partiall y k n o w n d at e fiel ds. W he n nee de d, a w orst -case selecti on will be 
ma de. S uc h w orst- case select i on r ul es are ela b orate d i n t he s pecific sect i ons.
5. 6.
H A N D LI N G O F O U T LI E R S
All meas ure d val ues will be i ncl u de d i n t he a nal yses.
F or t he (s pecific) ai r wa y resista nce at F R C a n d T L C i n t he F RI data (sectio n 9. 4 ), o utliers ca n 
o c c ur t h at ar e r e al  val ues b ut affect t he m o d el  esti mates e xtre mel y. I n t hese cases, val ues t hat 
are lar ger t ha n t he t hir d q ua nt ile + 3 ti mes t he i nter q uartile ra n ge ma y be r e mo v e d. I nfi nite 
val ues f or resista nce are p ossi ble a n d t hese will be liste d, b ut will be r e mo ve d fr om t he data 
bef ore stati stical a nal ysis.
5. 7.
H A N D LI N G O F S E C O N D S I N D A T E( TI M E) FI E L D S
If a date(ti me) fiel d c o ntains sec o n ds, t hese will be c ut off (i.e., r o u n de d d o w n t o t he mi n ute) 
pri or t o data a nal ysis. T he a nal ysis will o nl y  use t he date a n d ti me u p t o t he mi n ute.
6.
S O F T W A R E A N D P R O C E D U R E S
6. 1.
S O F T W A R E
S A S versi o n 9. 2 ( or hig her) will be use d f or pr o gra m mi n g (
P h oe ni x Wi n N o n Li n versi o n  6. 4 ( or hi g her) will be use d f or P K deri vat i ons (
T he statistical a nal ysis a n d vis ualizati o n of  the F RI para m eters will be i m ple me nte d i n R 
v ersio n  3. 2. 5 (or hi g her ) (T he R F o u n dat i on f or Statist ical Co m p ut i n g, Vi e n na, A ustri a)
(
6. 2.
P R O C E D U R E S
A nal yses will c o m p l y wit h I C H re g ulat i ons, i n partic ular: (I C H-E 3) , (I C H-E 6) a n d (I C H-E 9) .
T he f o ll owi n g Gal a pa g os S O Ps will be f o ll owe d:

S O P -C LI -0 0 1: De vel o pi n g Cli nical St u d y  D o c u me nts ( versi o n 1. 0)

S O P -C LI -0 0 3: Ma na gi n g Data Pr ocessi n g Act i vities ( versi on 1. 0)
T he f o ll owi n g 
S T A T S O Ps will be f o ll owe d:

CI 5 0 2: Pre parati o n of Statistical A nal ysis Pla n a n d D oc u me ntati o n of Statist ical Met h o ds

CI 5 0 3: Deter mi nat i on Of A nal ysis Sets

CI 5 0 4 : Pr o gra m mi n g S pecificat i ons f or A nal ysis Data Sets

CI 5 0 5: Verificat i on Of Statist ical Pr o gra ms A n d O ut p uts

CI 5 1 0: U n bli n di n g of C li nical Trials
T he f o ll owi n g 
P K w or k i nstr ucti o ns will  be fol l owe d:


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 2 6/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n

W B S 0 0 3: Creati o n a n d Verificat i on of Data Sets f or P har mac o ki net ic A nal ysis
6. 3.
F O R M A T S
Beca use t he l oc ke d data is i n C DI S C S D T M f or mat, t he deri ve d d at a will be f oll owi n g 
C DI S C A Da M versi o n 2. 1 A Da MI G versi o n 1. 0 f or m at.
Ta bles, list i n gs a n d fi g ures will f oll o w t he M oc k T L Fs, as pr o vi de d i n a se parate d oc u me nt.
7.
S T A TI S TI C A L M E T H O D S
7. 1.
P L A N N E D A N A L Y S E S, P R O T O C O L A M E N D M E N T S 
IN C L U D E D
7. 1. 1.
Ge ner al St atistic al C o nsi der ati o ns
S u m mar y  ta b ulat i ons wil l be prese nte d a n d will di s pla y t he n u m ber of  obser vat i ons, mea n,  
sta n dar d err or ( S E), me d ia n, mi ni m u m, a n d ma xi m u m f or c o nti n u o us varia bles, a n d t he 
n u m ber a n d perce nta ge per cate g or y for cate g oric al data. I n a d ditio n t o t a bul ate d descri pt i ve 
statistics, gra p hical data di s pla ys ma y be use d t o s u m marize t he data. U nl ess ot her wise n ote d, 
i nfere ntial st atistics will be i nter prete d at  the 2- si de d 5 % le vel. Data will be p o ol e d acr oss 
ce nters a n d c o u ntries.
7. 1. 2.
A n al yses of De m o gr a p hics a n d B aseli ne C h ar acteristics
S u bject dis p osit i on (incl u di n g reas o ns f or earl y disc o nt i n uati on), pr ot oc ol de viat i ons,  
d e m o gra p hics, baseli ne c haracterist ics, me dical hist or y, will be prese nte d descri pt i vel y.
Use of st u d y  dr u g a n d c o nc o mita nt me dicat i ons will als o be prese nte d descri pt ivel y.
7. 1. 3.
E x pl or at or y Effic ac y Assess me nts
E x pl or at or y  en d p o i nt data at eac h p ost -d osi n g visit  
will be a nal yze d descri pt i vel y. 
C o m paris o n bet wee n G L P G 1 6 9 0 a n d t he place b o gr o u p will be d o ne e x pl orati vel y .
A nal ysis met h o ds:

C o nti n u o us para m eters will be a nal yzed usi n g descri pt i ve st atistics of  act u al val ues, 
c ha n ges fr om baseli ne, a n d perce nt c ha n ges fr o m baseli ne. G L P G 1 6 9 0 a n d place b o will 
be c o m pare d usi n g a n A N C O V A m o del o n t he c ha n ges fr o m baseli ne, wit h t he f oll o wi n g 
c o variates: disease se verity ( baseli ne % F V C, scree ni n g % D L C O), a ge, ge n der, treat m e nt 
gr o u p, c o u ntr y , a n d baseli ne val ue. Wit hi n -gr o u p c o mparis o ns of  eac h visit vers us 
baseli ne will be i n vest i gate d usi n g a paire d t-test.

Missi n g data will be i m p ute d, als o f or s u bjects w h o pr e m at urel y disc o nt i n ue t he st u d y. 
T he pri mar y i m p utatio n met h o d will be last-o bser vat i on -carrie d-f or war d. A n o bser ve d -
case a nal ysis will als o be perf or me d.

A d dit i onal e x plor at or y  anal yses a n d gra p hical prese ntati o ns ma y be p erf or m e d w he n 
dee m e d usef ul t o better u n dersta n d t he d ata.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 2 7/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
7. 1. 4.
P h ar m ac o ki netic A n al yses
Descri pt i ve st atistics will be calc ulate d f or t he pl as ma c o nce ntratio ns a n d P K para meters. 
Mea n ( ± S E) c o nce ntrati o n -ti me pr ofile will be ge nerate d.
I n di vi d ual s u bject G L P G 1 6 9 0 c o nce ntrati o ns a nd P K para meters will be liste d.
7. 1. 5.
P h ar m ac o d y n a mic A n al yses
I n bl o o d, L P A C 1 8: 2 s pecies pea k area rati o will be use d t o calc ulate t he perce nta ge re d ucti o n 
vers us baseli ne. Baseli ne will  be t he a vera ge of  the pre -d osi n g d u plicates ( pre-d ose sa mpl e 
fr om D a y -1).
T he perce nta ge re d ucti o n fr o m baseli ne will be calc ulate d as f o ll ows:
% re d ucti o n = 1 0 0 -( 1 0 0 x visit/ baseli ne)
P D data will be s u m marize d descri pt i vel y per treat me nt a n d per ti me p oi nt.
I n di vi d ual a n d mea n a bs o l ute v al ues, in di vi d ual a n d mea n %
re d ucti on fr om baseli ne o ve r 
ti me pl ots will be ge nerate d.
T he A U E C (area u n der t he effecti ve-ti me c ur ve) as well as E ma x ( ma xi m u m % re d uct i on fr om 
baseli ne) o n Da y  2 8 will be deter mi ne d fr o m i n di vi d ual effect ti me pr ofiles.
A bs ol ute v al ues, %
re d uctio n fr om baseli ne , A U E C a n d E ma x will be c o m p ar e d bet wee n t he 
treat me nt gr o u ps usi n g a n a nal ysis of  co vari a nce ( A N C O V A) m o d el  with t he f oll owi n g 
c o variates: di sease se verit y (baseli ne F V C, scree ni n g D L C O), a ge, ge n der, treat me nt gr o u p, 
c o u ntr y, a n d baseli ne val ue.
Wit hi n -gr o u p c o m par is o ns of P D mar ker le vel o btai ne d ( a bs olute val ues a n d % re d ucti on 
fr om baseli ne) o n D a y  28 pre -d ose, 1. 5 h a n d 6 h p ost - d ose, a n d o n Da y 8 4 pre -d ose , vers us
baseli ne will be i n vest i gate d usi n g a paire d t-test.
T he a nal ysis will be p erf or m e d f or t he L P A C 1 8: 2 s pecies. Ot her L P A s pecies mi g ht b e 
a nal yze d if dee me d a p pr o priate.
I n B A L F , d at a for all  LP A s pecies detecta bl e will  be use d f or t he a nal ysis. L P A s pecies pea k 
area r atio will be use d t o calc ulate t he perce nta ge re d uctio n fr om
baseli ne. Baseli ne will b e 
t he a vera ge of t he pre -d osi n g d u plicates ( pre -d ose sa m ple fr o m Da y -1).
7. 1. 6.
P h ar m ac o ki netic / P h ar m ac o d y n a mic a n d P h ar m ac o ki netic / 
E x pl or at or y Effic ac y C orrel ati o ns
I n di vi d ual a n d/ or me a n ± S E, safety,  PD, e x pl orat or y efficac y e n d p o i nt, a n d/ or G L P G 1 6 9 0 
pl as ma c o nce ntrati o ns ma y be pl otte d a gai nst o ne a n ot her.
P K/ P D, P K/e x pl orat or y  efficac y en d p o i nt an d safety c orrelat i on will be e x plore d bet wee n 
G L P G 1 6 9 0 c o nce ntrati o ns or P K para meters a n d sel ecte d e x plorat or y P D or safet y e n d p oi nts, 
b ut o nl y if t he latter are si g nifica nt l y a ltere d b y t he treat me nt.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 2 8/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
E x pl or at or y  safet y/ P K / P D/e x plor at or y  efficac y e n d p o i nt anal yses ma y 
be a d de d w he n 
dee m e d usef ul t o better u n dersta n d t he c ollecte d data.
7. 1. 7.
A n al yses of S afet y D at a
A descri pt i ve a nal ysis of  the T E A Es, lab orat or y  assess me nts, 1 2- lea d E C G, a n d vit al si g ns 
will be p erf or m e d. C ha n ges fr om baseli ne a n d s hifts acc or di n g t o n or m al ra n ges will  be 
prese nte d as well.
P h ysical e xa mi nat i on res ults will be liste d o nl y.
A Es will be f ull y descri be d a n d c o de d acc or di n g t o t he Me di c al Dicti o nar y for Re g ulat or y 
Act i vities Dicti onar y .
7. 2.
C H A N G E S T O T H E P L A N N E D A N A L Y S E S, N O T C O V E R E D B Y 
P R O T O C O L A M E N D M E N T S
7. 2. 1.
C h a n ges bef ore D at a b ase L oc k
F or F RI para meters , t he c o m par is o n bet wee n G L P G 1 6 9 0 a n d t he place b o gr o u p will o nl y b e 
d o ne f or 2 z o nes (lo wer l obes a n d u p per l obes se paratel y). T hese a nal yses will be p erf or me d 
usi n g a n A N C O V A m o d el (li ke t he ot her efficac y para meters) i nstea d of  a mi xe d effects 
A N C O V A m o del (t he re gio nal  nat ure of t he data bei n g discar de d).
A n d t he F RI data bei n g m o stl y n ot n or m all y distri b ute d a n d bei n g meas ure d o n a r e gio n al 
scale, m o re c o mple x a d ditio n al e x plor at or y  anal yses (m o dels wi t h e xtra c o variates, neste d 
ra n d om fact ors, i nteracti o n ter ms …) ma y be nee de d t o better u n dersta n d t he data.
7. 2. 2.
C h a n ges after D at a b ase L oc k
N o ne
8.
D E FI NI TI O N S O F G E N E R A L A N A L Y SI S T A B L E S, 
LI S TI N G S A N D F I G U R E S
8. 1.
S U B J E C T D I S P O SI TI O N
Listi n g 1 6 . 2. 1. 1:
S u bject dis p ositi o n: R a n d o miz ati o n
List i n g of s u bject n u m bers a n d ra n d o mizati on gr o u ps, a n y i nf or mat i on o n c o de b rea ki n g, 
p o p ul at i ons, c o u ntr y a n d sit e.
All discre pa ncies (as -ra n d omize d vers us as -treate d) will be fla g ge d.
P o p ul at i on: all ra n d o mize d s u bjects.
T a ble 1 4 . 1. 1.1:
S u bject dis p ositi o n: T a b ul ati o n b y c o u ntr y a n d i n vesti g at or
Ta b ulat i on per tr e at me nt gr o u p (a n d o verall) of t he n u m ber of  su bjects i n eac h of t he 
c o u ntries a n d sites.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 2 9/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
P o p ul at i on: safet y .
T a ble 1 4 . 1. 1.2:
S u bject dis p ositi o n: A n al ysis p o p ul ati o ns
Ta b ulat i on per treat m e nt gr o u p (a n d o verall) of t he n u m ber of s u bjects i n e a c h of t he a nal ysis 
p o p ul at i ons defi ne d i n sect i on 2.
P o p ul at i on: all sc ree ne d s u bjects.
T a ble 1 4. 1. 1. 3:
S u bject dis p ositi o n: N o -tre at me nt s u bjects: T a b ul ati o n of t he re as o ns
Ta b ulat i on of disc o nt i n uati o ns a n d t he reas o ns f or disc o nti n uati on.
P o p ul at i on: all scree ne d s u bjects, mi n us t he safet y p o p ul at i on (s o selecti n g o nl y s u bjects w h o 
were ne ver e x p ose d t o t he st u d y  dr u g : s u bjects eit her ne ver ra n d o mize d or ra n d o mize d b ut n ot 
e x p ose d).
T a ble 1 4 . 1. 1.4 :
S u bject dis p ositi o n: T a b ul ati o n of t he n u m ber of s u bjects at e ac h 
ti me i nter v al
Ta b ulat i on per treat me nt gr o u p (a n d o verall) a n d per ti me p oi nt of  the n u m ber of  su bjects 
wi t h data.
P o p ul at i on: safet y .
Listi n g 1 6. 2. 1. 2:
S u bject dis p ositi o n: N u m ber of d a ys i n st u d y 
List i n g per tr e at me nt gr o u p, per s u bject a n d per time p oi nt of t he n u m ber of  da ys i n st u d y at 
t he ti me o f t he visit ( deri vat i on of t hese “ da ys”: see secti o n 4. 1 ).
P o p ul at i on: safet y .
T a ble 1 4 . 1. 1.5:
S u bject dis p ositi o n: First a n d l ast d ate i n t he st u d y
List t he f o ll owi n g ( o verall, n ot per s u bject):

Date of t he first si g nat ure o n st u d y  I C F.

Date of first a n d last scree ni n g visit.

Date of first st u d y  dr u g a d mi nistratio n .

Last visit date (all visit s; i ncl u di n g u nsc he d ule d visits).

Last date of c o ntact i n t he st u d y  wit h a n y s u bject.
P o p ul at i on: all scree ne d s u bjects.
T a ble 1 4 . 1. 1.6: 
S u bject dis p ositi o n: T a b ul ati o n of t he st u d y ter mi n ati o n re as o ns
Ta b ulat i on per treat me nt gr o u p (a n d o verall) of  co m plet i on/ disc o nt i n uati ons a n d t he reas o ns 
f or disc o nti n uati on.
P o p ul at i on: safet y .
Listi n g 1 6. 2. 1. 3:
S u bject dis p ositi o n: St u d y ter mi n ati o n


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 3 0/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
List i n g per treat me nt gr o u p a n d per s u bject of  the reaso n f or c o mpleti o n/ disc o nti n uati o n a n d 
t he n u m b er of da ys si nce first st u d y tr e at me nt a d mi nistratio n at st u d y  t er mi n atio n. I n c as e t h e 
di sc o nti n uati on was d ue t o A E, t he A E ver bati m ter m  will be prese nte d i n t his listi n g. If t here 
is a ( ver bati m) e x pla nat i on o n t he di sc o nti n uati on reas o n, t his will als o be prese nte d i n t his 
listi n g.
P o p ul at i on: safet y .
8. 2.
P R O T O C O L D E VI A TI O N S A N D E LI GI BI LI T Y
Pr ot oc ol  de viat i ons are deter mi ne d a n d rec or de d w hilst t he st u d y is o n g oi n g, a n d t he list is 
fi nalize d pri or t o data base loc k (a n d u n bli n di n g). All de viat i ons are classifie d as eit her 
“ maj or” or “ mi n or”. F or m ore details, please refer t o t he Pr ot oc ol De viat i on Pl a n.
T a ble 1 4. 1. 2. 1:
Pr ot oc ol de vi ati o ns: T a b ul ati o n
Ta b ulat i on per treat me nt gr o u p (a nd o verall) of t he pr ot oc ol  de viatio ns cate g ories (eac h 
sc ore d as maj or / mi n or).
Ta b ulat i on per treat me nt gr o u p (a n d o verall) of t he maj or pr ot oc ol de viat i ons.
P o p ul at i on: safet y .
Listi n g 1 6. 2. 2. 1:
Pr ot oc ol de vi ati o ns
List i n g per treat me nt gr o u p a n d per s u bject of all pr ot oc ol de viat i ons, wi t h in dicati o n maj or / 
mi n or.
P o p ul at i on: safet y .
Listi n g 1 6. 2. 2. 2:
Eli gi bilit y criteri a: Vi ol ati o ns
O nl y vi o late d i n- a n d e xcl usi o n crit eria will  be liste d per tr e at me nt gr o u p a n d per s u bject. 
T hese are criteria as tic ke d b y t he i n vesti gat or i n t he e C R F ( not f r o m t he pr ot oc ol  de viat i ons 
list, t h o u g h eli gi bility vi o lati ons will als o be liste d i n t he pr ot oc ol de viat i ons).
P o p ul at i on: safet y .
8. 3.
S U B J E C T S E X C L U D E D F R O M A N A L Y SI S
Listi n g 1 6 . 2. 3. 1:
S u bjects e xcl u de d fr o m t he s afet y a n al ysis
List i n g of  all s u bjects t hat were ra n d o mize d a n d/ or n ot treate d: t he st u d y ter mi nati on reas o n 
a n d/ or t he reas o n f or bei n g a n o -treat me nt s u bject will be liste d, w hic he ver is a vaila ble.
P o p ul at i on: all scree ne d s u bjects, mi n us t he safet y p o p ul at i on.
Listi n g 1 6 . 2. 3. 2:
S u bjects e xcl u de d fr o m t he I T T a n al ysis
List i n g of all s u bjects t hat were e x p ose d b ut w h o were n ot i ncl u de d i n t he I T T p o p ulatio n: t he 
st u d y ter mi nati on reas o n a n d t he reas o n f or bei n g e xcl u de d will be liste d.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 3 1/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
P o p ul at i on: s afet y, mi n us t he I T T p o p ulat i on.
Listi n g 1 6. 2. 3. 3:
S u bjects e xcl u de d fr o m t he P D a n al ysis
List i n g of  all s u bjects t hat were e x p ose d b ut w h o were n ot i ncl u de d i n t h e P D p o p ulat i on: t he 
st u d y ter mi nati on reas o n a n d t he reas o n f or bei n g e xcl u de d will be liste d.
P o p ul at i on: safet y , mi n us t he P D p o p ulat i on .
8. 4.
D E M O G R A P HI C S A N D B A S E LI N E C H A R A C T E RI S TI C S
8. 4. 1.
P ar a meters

Ge n der

A ge at t he m o me nt  of si g ni n g t he I C F ( years): t he a ge is n ot recalc ulate d w he n alrea d y 
a vaila ble i n t he data base

A ge cate g ories:
[ 40 , 50 [ years
[ 50, 6 0 [ years
[ 6 0, 7 0[ years
≥ 7 0 years

Date of birt h: o nl y  liste d

Date of  sig ni n g t he I C F: o nl y liste d

Race

“ Ot her” race: o nl y liste d

Et h nicit y

H ei g ht (c m )

Wei g ht ( k g)

B o d y mass i n de x B MI = ( wei g ht i n k g) / ( hei g ht i n m) ² ( k g/ m²): t he B MI will be 
recalc ulate d a n d r o u n de d t o t he first deci mal, e ve n w he n
alrea d y a vaila ble i n t he 
data base. T he ori gi nal B M I will n ot be use d i n t hat case

B MI cate g ories:
≤ 1 8. 5 k g/ m ²
] 1 8. 5, 2 5. 0] k g/ m²
] 2 5. 0, 3 0. 0[ k g/ m²
≥ 3 0. 0 k g/ m ²

Alc o h o l stat us: ne v er / c urre nt / f or mer

S m o ki n g stat us: ne ver / c urre nt / f or mer

Alc o h o l a n d s mo ki n g stat us details: o nl y liste d

Fe male of c hil d -beari n g p ote nti al: yes / n o, n o: s ur gicall y sterile / p ost -me n o pa usal

Fe male of c hil d -beari n g p ote nti al: b irt h c o ntr ol met h o ds details: o nl y liste d
8. 4. 2.
A n al ysis
T a ble 1 4 . 1. 3.1:
De m o gr a p hic d at a : Descri pti ve st atistics
C o nti n u o us para meters: descri pt i ve statistics per treat me nt gr o u p (a n d o verall).


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 3 2/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
Cate g orical para meters: fre q ue nc y ta b ulat i on per treat me nt gr o u p (a n d o verall).
P o p ul at i on: safet y .
Listi n g 1 6 . 2. 4. 1:
De m o gr a p hic d at a
List i n g per treat me nt gr o u p a n d per s u bject of all de m o gra p hic para meters.
P o p ul at i on: safet y .
Listi n g 1 6. 2. 4. 2:
Alc o h ol a n d s m o ki n g st at us
List i n g per treat me nt gr o u p a n d per s u bje ct of all details o n alc o h o l a n d s m o ki n g stat us .
P o p ul at i on: safet y .
Listi n g 1 6. 2. 4. 3:
Birt h c o ntr ol met h o ds
List i n g per treat me nt gr o u p a n d per s u bject of all details o n birt h c o ntr ol met h o ds.
P o p ul at i on: safet y , w o me n of c hil d beari n g p ote ntial o nl y.
T a ble 1 4. 1. 3. 2: 
B aseli ne l a b or at or y d at a: T a b ul ati o n of a b n or m alities
Fre q ue nc y ta b ulati on per la b test per treat me nt gr o u p (a n d o verall) of  the baseli ne res ult, 
cate g orize d as lo w / n or m al / hi g h acc or di n g t o t he n or mal ra n ges (see secti on 1 3. 2. 5 ).
P o p ul at i on: safet y .
T a ble 1 4. 1. 3. 3:
B aseli ne E C G d at a: T a b ul ati o n of a b n or m alities
Fre q ue nc y ta b ulati on per para meter ( Q T a n d Q Tc F) per treat me nt gr o u p (a n d o verall) of  the 
baseli ne res ult, cate g orize d as (sa me as i n secti o n 1 3. 3. 5 ):

≤ 4 5 0 ms

] 4 5 0, 4 8 0] ms

] 4 8 0, 5 0 0] ms

> 5 0 0 ms
P o p ul at i on: safet y .
T a ble 1 4. 1. 3. 4:
B aseli ne vit al si g ns d at a: T a b ul ati o n of a b n or m alities
Fre q ue nc y ta b ulati on per para meter a n d per treat me nt gr o u p (a n d o verall) of  the baseli ne 
res ult, cate g orize d a s lo w / n or m al / hi g h acc or di n g t o t he n or mal ra n ges (see secti on 1 3. 4. 4 ).
P o p ul at i on: safet y .
T a ble 1 4. 1. 3. 5: 
B aseli ne p h ysic al e x a mi n ati o n : T a b ul ati o n of a b n or m alities
Fre q ue nc y ta b ulatio n per C R F b o d y  syste m  an d per treat me nt gr o u p (a n d o verall) of  the 
baseli ne res ult, cate g orize d as n or mal / a b n or mal


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 3 3/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
P o p ul at i on: safet y .
8. 5.
B A S E LI N E DI S E A S E C H A R A C T E RI S TI C S
8. 5. 1.
P ar a meters

D urati o n of  I P F ( years) = 
(              ) – (                 )
   . , r o u n de d t o 
t he first deci mal . If t he date of  ini tial dia g n osis is i nc om p lete, t he n t he f oll owi n g r ules 
will be a p plie d: Missi n g da y : use t he first of t he m ont h. Missi n g m o nt h: use Ja n uar y

D urati o n of  I P F, cate g orize d as:
< 0. 5 year
[0. 5 , 1[ year
[ 1, 2[ years
≥2 years

Date of i nit ial dia g n osis: o nl y liste d

N u m ber of I P F e xacer bat i ons wit hi n 6 wee ks pri or t o scree ni n g

A bs ol ute decli ne i n F V C wit hi n t he last 6 m o nt hs:
< 5 %
5- 1 0 %
> 1 0 %
U n k n o w n

Relati ve decli ne i n F V C > 1 0 wit hi n last 6 m o nt hs:
Yes
N o
U n k n o w n

A bs ol ute decli ne i n D L C O wit hi n t he last 6 m o nt hs:
≤ 1 5 %
> 1 5 %
U n k n o w n

Scree ni n g D L C O, % pre dicte d of n or mal

Scree ni n g D L C O, c orrecte d f or he m o gl o bi n

Scree ni n g a n d baseli ne F V C

C ha n ge i n F V C: baseli ne - scree ni n g *

Scree ni n g a n d baseli ne % F V C

Scree ni n g a n d baseli ne % F V C , cate g orize d as:
< 5 0 %
[ 50, 7 0[ %
[ 7 0, 9 0[ %
≥ 9 0 %

C ha n ge i n % F V C: baseli ne - scree ni n g *
*o nl y  calc ulate d if t he baseli ne val ue has n ot bee n i m p ute d b y t he scree ni n g val ue.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 3 4/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
8. 5. 2. A n al ysis
T a ble 1 4. 1. 3. 6:
Scree ni n g a n d b aseli ne dise ase c h ar acteristics
C o nti n u o us para meters: descri pt i ve statistics per treat me nt gr o u p (a n d o verall).
Cate g orical para meters: fre q ue nc y ta b ulat i on per treat me nt gr o u p (a n d o verall).
P o p ul at i on: safet y .
Listi n g 1 6. 2. 4. 4:
Scree ni n g a n d b aseli ne dise ase c h ar acteristics
List i n g per treat me nt gr o u p a n d per s u bject of all disease c haracteristics.
P o p ul at i on: safet y .
T a ble 1 4. 1. 3. 7:
Pri or a n d c o nc o mit a nt all o we d I P F tre at me nt
Ta b ulat i on per treat me nt gr o u p a n d o verall of pri or I P F me dicati o ns.
N o f or m al c o mparis o n of t he t w o treat me nt gr o u ps pla n ne d.
P o p ul at i on: safet y .
Listi n g 1 6. 2. 4. 5:
Pri o r a n d c o nc o mit a nt all o we d I P F tre at me nt
List i n g per treat me nt gr o u p a n d per s u bject.
P o p ul at i on: safet y .
8. 6.
M E DI C A L HI S T O R Y A N D C O N C U R R E N T D I S E A S E S
T a ble 1 4. 1. 3. 8:
Me dic al hist or y: T a b ul ati o n
Fre q ue nc y ta b ulati on per treat me nt gr o u p (a n d o verall) of  the s yste m or ga n classes a n d 
preferre d t er ms, selecti n g o nl y t he me dical hist or y fi n di n gs (i.e., c o n ditio n n o l on ger prese nt 
at t he start of t he st u d y).
P o p ul at i on: safet y .
T a ble 1 4. 1. 3. 9:
C o nc urre nt dise ases: T a b ul ati o n
Fre q ue nc y ta b ulati on per treat me nt gr o u p (a n d o verall) of  the s yste m or ga n classes a n d 
preferre d ter ms.
P o p ul at i on: safet y .
Listi n g 1 6. 2. 4. 6 :
Me dic al hist or y
List i n g per treat me nt gr o u p a n d per s u bject of t he me dical hist or y data fi n di n gs (i.e., c o n dit i on 
n o l o n ger prese nt at t he start of t he st u d y ): origi nal ter ms as well as c o de d ter ms.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 3 5/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
P o p ul at i on: safet y .
Listi n g 1 6. 2. 4. 7:
C o nc o mit a nt dise ases
List i n g per tr e at me nt gr o u p a n d per s u bject of  the c o nc o mi t a nt di seases data fi n di n gs (i.e., 
c o n ditio n st ill prese nt or u n k n o w n): ori gi nal ter ms as well as c o de d ter ms.
P o p ul at i on: safet y .
8. 7.
P RI O R A N D C O N C O MI T A N T T H E R A PI E S
8. 7. 1.
Cl assific ati o n of T her a pies
All pri or a n d c o nc o mit a nt t hera pies will be all ocate d i nto e xact ly o ne of  the f oll owi n g 
cate g ories:

Pri or o nl y: t he t hera p y  e n de d bef ore t he first st u d y dr u g a d mi nistrati o n.

C o nc o mita nt o nl y: t he t hera p y  starte d o n or after t he first st u d y dr u g a d mi nistratio n .

P os t-treat me nt: t he t hera p y starte d after t he last st u d y dr u g a d mi nistrati o n.

Pri or a n d c o nc o mit a nt: t he t hera p y starte d bef ore t he first st u d y dr u g a d mi nistratio n, a n d 
e n de d o n or after t he first st u d y dr u g a d mi nistratio n .
W he n t he start date is missi n g, t he t hera p y is ass u me d t o ha ve starte d o n t he sa me da y as t he 
first a d mi nistratio n of  st u d y dr u g .
W he n t he e n d date is missi n g, t he t hera p y is ass u me d t o be still o n g oi n g aft er t he e n d of  th e 
st u d y.
W he n t he start date is o nl y partiall y k n o w n, t he missi n g parts will be i m p ute d b y t he first da y 
of  the m o nt h/ year, or t he da y of  the first st u d y dr u g i nta ke i n case t he n o n- missi n g part 
matc hes.
W he n t he e n d date is o nl y part iall y k n o w n, t he missi n g parts will be i m p ute d b y t he last da y 
of  t h e mo nt h/ year.
I mp utati o n of  st art a n d e n d dates is o nl y d o ne f or t he classificat i on i nto pri or / c o n c o mita nt / 
pri or +c o nc o mita nt. T he listi n g will prese nt t he ori gi nal start a n d e n d dates, als o w he n 
i nc om p lete. Fiel ds li ke start a n d st o p da ys will n ot be deri ve d fr o m i m p ute d i nc om p lete dates.
T he rel at i ve st u d y d a y of t hera p y start a n d st o p will be deri ve d as f o ll ows ( o nl y  liste d):
St art d a y
= ( T hera p y st art date) – ( date of  first st u d y dr u g a d mi nistrati o n) + 1, w he n t he st art date of 
t hera p y is k no w n a n d c o mplete, a n d w he n t he t hera p y start date is o n or af t er t h e d at e of first 
st ud y dr u g .
= ( T hera p y st art date) – ( date of  first st u d y dr u g a d mi nistrati o n), w he n t he st art date of 
t hera p y is k n o w n a n d c o m p lete, a n d w he n t he t hera p y start date is bef ore t he date of  first 
st u d y dr u g .
= Mi ssi n g w he n t he start date of t hera p y is u n k n o w n, missi n g, or i nc o m p lete.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 3 6/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
St o p d a y
= ( T hera p y st o p date) – ( date of  first st u d y dr u g a d mi nistrati o n) + 1, w he n t he e n d d at e of 
t hera p y is k n o w n a n d c o m p lete, a n d t he e n d date of  thera p y is o n or aft er t he date of  first 
st u d y dr u g .
= ( T hera p y st o p date) – ( dat e of first st u d y dr u g a d mi nistratio n), w he n t he e n d date of t hera p y 
is k n o w n a n d c o m plete, a n d t he e n d date of t hera p y is bef ore t he date of first st u d y dr u g .
= ( St u d y  ter mi natio n d at e) – ( d at e of first st u d y dr u g a d mi nistrati o n) + 1, w he n t he t hera p y is 
still o n g oi n g w he n t he s u bject lea ves t he st u d y; i n s uc h cases t he st o p da y will be prese nte d as 
“ > X X da ys” i n t he list i n g.
= Missi n g w he n t he e n d date of  thera p y is u n k n o w n, missi n g or i nc om p lete a n d t he t hera p y 
is n’t o n g oi n g after t he s u bject left t he stu d y.
8. 7. 2.
C o di n g of T her a pies
All t hera pies are c o de d usi n g W H O -D R U G. I n the ta ble(s), t he ge neric ter m will b e use d. 
M ul tiple rec or ds of t he sa me ge neric t er m for t he sa me s u bject wi t h the sa me cate g oriz atio n 
will be c o u nte d o nl y  o nce. T he ta ble will t heref ore prese nt s u bjects, n ot occ urre nces.
8. 7. 3.
A n al ysis
T a ble 1 4. 1. 3. 1 0:
Pri or t her a pies: Fre q ue nc y t a ble 
Fre q ue nc y ta b ulati on per treat me nt gr o u p (a n d o verall) of  the A T C classes (le vel 2) a n d
ge neric ter ms, of “pri or ” a n d “ pri or +c o nc o mita nt ” t hera pies o nl y.
T hese are all t he t hera pies t hat were use d bef ore t he first i nta ke of st u d y  dr u g .
P o p ul at i on: safet y .
T a ble 1 4. 1. 3. 1 1:  
C o nc o mit a nt t her a pies: Fre q ue nc y t a ble 
Fre q ue nc y ta b ulati on per treat me nt gr o u p (a n d o verall) of  the A T C classes (le vel 2) a n d
ge neric ter ms, selecti n g “c o nc o mit a nt” a n d “ pri or +c o nc o mita nt” t hera pies o nl y.
T hese are all t he t hera pies t hat were use d d uri n g t he st u d y , c o nc o mita ntl y t o t he st u d y d r u g.
P o p ul at i on: safet y .
T a ble 1 4. 1. 3. 1 2:
P ost -tre at me nt t her a pies: Fre q ue nc y t a ble 
Fre q ue nc y ta b ulati on per treat me nt gr o u p (a n d o verall) of  the A T C classes (le vel 2) a n d
ge neric ter ms, selecti n g “ p ost -treat me nt” t hera pies o nl y.
T hese are all t he t h er a pies t hat were use d d uri n g t he st u d y, b ut starte d aft er t he last d ose of 
st u d y dr u g .
P o p ul at i on: safet y .


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 3 7/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
Listi n g 1 6. 2. 4. 8:
Pri or a n d c o nc o mit a nt t her a pies
List i n g per treat me nt gr o u p a n d per s u bject of  all da t a o n pri or a n d c o nc o mit a nt t hera pies. 
Fla gs f or pri or/c o nc o mita nt / p ost-treat me nt will be a d de d. I n case t he t hera p y was d ue t o a n 
A E, t he A E preferre d ter m will be me nt i one d i n t his list i n g.
P o p ul at i on: safet y .
8. 8.
E X P O S U R E T O S T U D Y D R U G A N D C O M P LI A N C E
8. 8. 1.
Deri v a ti o ns
Deri ve d para meters:

T ot al  treat me nt d urati o n ( da ys) = (last st u d y dr u g i nta ke date – first st u d y dr u g i nta ke
date) + 1 da y .

T ot al  treat me nt d uratio n, e xcl u di n g da ys off dr u g ( d a ys): s u m of all d ur atio ns (last – first 
+ 1) i n t he dr u g l o g pa ges w here t here is a m o r ni n g d ose > 0 ca ps ules.

Perce nta ge da y s wit h a n i nta ke = 1 0 0 % x                 ,                       
T ot al  c o mplia nt treat m e nt d uratio n ( da ys): s u m  of all d ur atio ns (l ast – first + 1) i n t he dr u g 
l og pa ges w here t here is a mor ni n g d ose wi t h e xactl y 3 ca ps ules.

Perce nta ge c o m plia nce = 1 0 0 % x                              T he “t otal  d uratio n” use d as de n o mi nat or i n t he a b o ve f or m ulae e q uals: ( date of Wee k 1 2 visit 
or earl y ter mi nat i on visit) – ( date of first st u d y dr u g i nta ke) + 1.
8. 8. 2.
A n al ysis
T a ble 1 4. 1. 4. 1:
Use of st u d y dr u g : Descri pti ve st atistics
Des cript i ve st atistics per tr e at me nt gr o u p (a n d o verall) of  the t otal treat me nt d urati o n ( da ys) 
a n d t he o verall c o m p lia nce ( %).
Fre q ue nc y ta b ulati on p er treat me nt gr o u p (a n d o verall) of t he t w o treat me nt d urati o n 
para m eters, cate g orize d i n wee ks.
Fre q ue nc y ta b ulati on per treat me nt gr o u p (a n d o verall) of  the da ys wi t h int a ke a n d 
c o mplia nce, cate g ori ze d as:

< 8 0 %,

[ 8 0 %, 1 0 0 %[,

1 0 0 %,

] 1 0 0 %, 1 2 0 %],

> 1 2 0 %.
P o p ul at i on: safet y .
Listi n g 1 6. 2. 5. 1:
E x p os ure t o st u d y dr u g : e C R F d at a
List i n g per treat me nt gr o u p a n d per s u bject of all e C R F data relate d t o t he use of dr u g .


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 3 8/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
P o p ul at i on: safet y .
Listi n g 1 6. 2. 5. 2:
E x p os ure t o st u d y dr u g: Deri ve d d at a
List i n g per treat me nt gr o u p a n d per s u bject of all deri ve d da ta relate d t o t he use of st u d y dr u g.
P o p ul at i on: safet y .
Listi n g 1 6. 2. 5. 3:
Dis pe nse d kit n u m bers
List i n g per treat me nt gr o u p a n d per s u bject of  all di s pe nse d place b o/ G L P G 1 6 9 0 ki t nu m bers, 
fla g gi n g a n y mista kes i n dis pe nsi n g.
P o p ul at i on: safet y .
8. 9.
C O M M E N T S
Listi n g 1 6 . 2. 5. 4:
C o m me nts
List i n g per tr e at me nt gr o u p a n d p er s u bject of r e mar ks a n d c o m me nts wri tte n i n t he C R F.
C o m me nts t hat are alrea d y prese nte d i n ot h er parts of  the a nal ysis (e. g., lab, E C G, 
e x p os ur e …) d o not nee d t o be re peate d i n t his c o m me nts list i n g.
P o p ul at i on: safet y .
9.
D E FI NI TI O N S O F E X P L O R A T O R Y E F FI C A C Y T A B L E S, 
LI S TI N G S A N D F I G U R E S
9. 1.
P U L M O N A R Y F U N C TI O N B Y S PI R O M E T R Y
9. 1. 1.
P ar a meters
P ul m o nar y  fu nct i on will be assesse d t hr o u g h s pir o metr y bot h  perf or me d at t he st u d y ce nter
a n d at h o me. All s pir o m etr y e v alu ati o ns s h o ul d b e p erfor m e d pre-br o nc h o dilat or *. T he val ues 
will be use d as a vaila ble via t he data tra nsfer fr o m 
.
* pre -br o nc h o dilat or is defi ne d as:

s h ort-acti n g m ore t ha n ( >) 6 h o urs pri or t o t he s pi r o metr y assess me nt

l on g -act i n g br o nc h o dilat or at  least (≥) 1 2 h o urs or 2 4 h o urs pri or t o t he s pir o metr y 
assess me nt
(a s pir o metr y assess me nt wi t h no use of  br o nc h o dilat or is e q ui vale nt t o a pre -br o nc h o dilat or 
assess me nt)
N ote t hat s pir omet r y data ta ke n p ost -br o nc h o dilat or will be e xcl u de d fr om t he a nal ysis ( n ot 
a p plica ble f or h o me s pir o met r y).
N ote t hat data wit h a q ualit y gra de of D, E or F will be e xcl u de d t o o.
Q u alit y  
Criteri a


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 3 9/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
A
At least 3 acce pta ble eff orts A N D t he differe nce bet wee n t he best t w o F E V 1 a n d F V C 
val ues is e q ual t o or less t ha n 1 0 0 ml ( 8 0 ml if F V C < 1. 0 L)
B
At least 3 acce pta ble eff orts A N D t he differe nce bet wee n t he best t w o F E V 1 a n d F V C 
val ues is e q ual t o or less t ha n 1 5 0 ml ( 1 0 0 ml if F V C < 1. 0 L)
C
At least 2 acce pta ble eff orts A N D t he differe nce bet wee n t he best t w o F E V 1 a n d F V C 
val ues is e q ual t o or less t ha n 2 0 0 ml ( 1 5 0 ml if F V C < 1. 0 L)
D
At least 2 acce pta ble eff orts b ut t h e  res ults are n ot Re pr o d uci ble
E
At least 1 acce pta ble eff ort
F
N o acce pta ble test a vaila ble
T he f o ll owi n g para m eters will be meas ure d as part of t he s pir o metr y assess me nt:

F orce d E x pirat or y  V olu me i n 1 sec o n d ( F E V 1) ( L) a n d perce nt pre dicte d F E V 1 *

F orce d Vital Ca pacit y ( F V C) ( L) a n d perce nt pre dicte d F V C*

F E V 1/ F V C rati o

F orce d e x pirat o r y fl ow bet wee n 2 5 a n d 7 5 % of e x hale d v o l ume ( F E F 2 5 -7 5) *
* para meters n ot a vaila ble f or h o me s pir o met r y.
S pi r o metr y para meters a n d deri ve d *:

Act ual  val ues

C ha n ge fr o m baseli ne ( Da y -1):
c ha n ge at ti me p o i nt t = (ti me p oi nt t val ue) – ( baseli ne val ue)

Perce nt c ha n ge fr o m baseli ne ( Da y  -1):
%c ha n ge at ti me p o i nt t = 1 0 0 x (ti me p oi nt t valu e – baseli ne val ue) / ( baseli ne val ue)
* dail y val ues a n d wee kl y a vera ges f or h o me s pir o m etr y.
Wee kl y a vera ges f or h o me s pir o metr y are defi ne d as t he mea n of  the meas u re me nts ta ke n 
d uri n g 7 da y  wee kl y i nter vals (starti n g fr o m st u d y d a y 1). If t here are less t ha n 5 da ys of data
per wee kl y i nter val, t he mea n will be “ missi n g”. If t here is m o re t ha n o ne meas ure me nt per 
d a y , t he n t he w orst -case will be ta ke n (t he l owest val ue). F or t he calc ulat i on of  cha n ge fr om 
baseli ne, t he baseli ne meas ure me nt 
is t he c orres p o n di n g baseli ne at st u d y ce nter 
meas ure me nt. Wee kl y a vera ges f or L O C F s h o uld b e c o m p ut e d af ter a p pl yi n g L O C F f or d a ys 
wi t h missi n g meas ure me nts.
9. 1. 2.
T a bles
T a ble 1 4. 2. 1. 1. 1:
S pir o metr y: Descri pti ve st atistics per ti me p oi nt
Descri pt i ve statistics per para meter, per treat me nt gr o u p a n d per time p oi nt of  the act ual 
val ues, t he c ha n ges fr om baseli ne a n d t he perce nt c ha n ges fr om baseli ne. I ncl u di n g a 9 5 % 
c o nfi de nce i nter val o f t he mea n c ha n ges a n d mea n perce nt c ha n ges.
P o p ul at i on: I T T, L O C F + O C.
T a ble 1 4. 2. 1. 1. 2:
% F V C: Descri pti ve st atistics per ti me p oi nt b y s u b -gr o u ps


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 4 0/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
Descri pt i ve st atistics per treat me nt gr o u p a n d per ti me p oi nt of  t he act ual val ue s, t he c ha n ges 
fr om baseli ne a n d t he perce nt c ha n ges fr o m baseli ne b ut s plit u p b y:

baseli ne % F V C: < 5 0 % / [ 5 0, 7 0[ % / [ 7 0, 9 0[ % / ≥ 9 0 %

scree ni n g D L C O, % pr e di ct e d of nor m al: < 3 0 % / [ 3 0, 4 0[ % / [ 4 0, 5 0[ % / [ 5 0, 6 0[ % / ≥ 
6 0 %

age: [ 4 0, 5 0[ years / [ 5 0, 6 0[ years / [ 6 0, 7 0[ years / ≥ 7 0 years

ge n der: male / fe male

c o u ntr y: U krai ne / U K
P o p ul at i on: I T T, L O C F + O C.
T a ble 1 4. 2. 1 . 1. 3:
%F V C : St atistic al e v al u ati o n per ti me p oi nt
Bet wee n -gr o u p c o mparis o n of  place b o a n d G L P G 1 6 9 0 : A N C O V A m o del o n t he c ha n ge s
fr om 
baseli ne wi t h disease se verit y (baseli ne % F V C, scree ni n g % D L C O), a ge, ge n der, 
treat me nt a n d c o u ntr y as c o variat es *. T h e ta ble will prese nt t ype III p- val ues, L S -mea ns p er 
gr o u p, L S -mea n differe nce bet wee n t he t w o gr o u ps a n d a 9 5 % c o nfi de nce i nter val of t his L S -
mea n differe nce.
* if t he m o del d oes n ot c o n ver ge nce, c o u ntr y will be dr o p pe d.
Wit hi n -gr o u p c o m paris o n s of eac h visit vers us baseli ne: paire d t -test.
T he “ra w” S A S P R O C o ut p ut m ust be pr o vi de d i n a statist ical a p pe n di x listi n g.
P o p ul at i on: I T T, L O C F + O C .
T a ble 1 4. 2. 1. 1. 4 :
%F V C : Fre q ue nc y t a b ul ati o n of t he c ate g orize d act u al v al ues per 
ti me p oi nt
Fre q ue nc y ta b ulati o n o f t he cate g orize d % F V C p er treat me nt gr o u p a n d per ti me p oi nt.
P o p ul at i on: I T T, L O C F + O C.
T a ble 1 4. 2. 1. 1. 5 :
%F V C : Fre q ue nc y t a b ul ati o n of t he c ate g orize d c h a n ges fr o m 
b aseli ne per ti me p oi nt
Fre q ue nc y ta b ulati on of t he cate g orize d c ha n ge fro m  baseli ne i n % F V C per tr e at me nt gr o u p 
a n d per ti me p oi nt.
P o p ul at i on: I T T, L O C F + O C.
T a ble 1 4. 2. 1. 1. 6 :
H o me s pir o metr y - Wee kl y a ver a ges : Descri pti ve st atistics per ti me 
p oi nt
Descri pt i ve statistics per para meter, per treat me nt gr o u p a n d per time p oi nt of  the act ual 
val ues, t he c ha n ges fr om baseli ne a n d t he perce nt c ha n ges fr om baseli ne. I ncl u di n g a 9 5 % 
c o nfi de nce i nter val o f t he mea n c ha n ges a n d mea n perce nt c ha n ges.
P o p ul at i on: I T T, L O C F + O C.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 4 1/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
9. 1. 3.
F i g ures
Fi g ure 1 4. 2. 1. 1. 1:
S pir o metr y: S u bject pr ofile pl ots o ver ti me
S u bject pr ofile pl ots of act ual val ues o v er ti m e, wi t h e a c h tr e at me nt gr o u p o n a ne w pa ge b ut 
wi t h all s u bjects of  one gr o u p o n t he sa me pl ot. A n y u nsc he d ule d res ults will als o be part of 
t his plot.
P o p ul at i on: I T T, L O C F + O C .
Fi g ure 1 4. 2. 1. 1 . 2: S pir o metr y: Me a n ( +/ - S E) pl ots of t he act u al v al ues o ver ti me
Mea n ( wit h SE) pl ots of  the act ual val ues o ver ti me, wi t h all tr e at me nt gr o u ps o n t he sa me 
pl ot usi n g differe nt pl ot s y m b o ls. U nsc he d ule d res ults wi ll n ot be part of t his pl ot.
P o p ul at i on: I T T, L O C F + O C .
Fi g ure 1 4. 2. 1. 1 . 3: S pir o metr y: Me a n ( +/ - S E) pl ots of t he c h a n ges fr o m b aseli ne o ver 
ti me
Mea n ( wi t h S E) plots of  t he c ha n ges fr o m baseli ne o ver ti me, wit h all tr e at me nt gr o u ps o n t he 
sa me plot usi n g diff er e nt pl ot s y m b ols. U nsc he d ule d res ul ts will n ot b e p art of  t his plot. Wi t h 
a h ori z o nt al refere nce li ne at zer o, i n dicati n g n o c ha n ge. Pl ots will st art wit h a zer o mea n at  
ba seli ne.
P o p ul at i on: I T T, L O C F + O C .
Fi g ure 1 4. 2. 1. 1 . 4: S pir o metr y: Me a n ( +/ - S E) pl ots of t he perce nt c h a n ges fr o m b aseli ne 
o ver ti me
Mea n ( wit h SE) pl ots of  the perce nt c ha n ges fro m  baseli ne o ver ti me, wi t h all tr e at me nt 
gr o u ps o n t he sa me pl ot usi n g differe nt pl ot s y m b ol s. U nsc he d ule d res ults will n ot be p art of 
t his plot. Wi t h a hori z o nt al r efere nce li ne at zer o, i n dicati n g n o c ha n ge. Pl ots will st art wi t h a 
zer o mea n at baseli ne.
P o p ul at i on: I T T, L O C F + O C .
Fi g ure 1 4. 2. 1. 1. 5:
H o me s pir o metr y - D ail y v al ues : S u bject pr ofile pl ots o ver ti me
Fi g ure 1 4. 2. 1. 1. 6:
H o me s pir o metr y - D ail y v al ues : Me a n ( +/- S E) pl ots of t he act u al
v al ues o ver ti me
Fi g ure 1 4. 2. 1. 1. 7:
H o me s pir o metr y - Wee kl y a ver a ges: S u bject pr ofile pl ots o ver ti me
Fi g ure 1 4. 2. 1. 1. 8:
H o me s pir o metr y - Wee kl y a ver a ges: Me a n ( +/ - S E) pl ots of t he 
act u al v al ues o ver ti me
Fi g ure 1 4. 2. 1. 1. 9 : H o me s pir o metr y - Wee kl y a ver a ges: Me a n ( +/ - S E) pl ots of t he 
c h a n ges fr o m b aseli ne o ver ti me
Fi g ure 1 4. 2. 1. 1. 1 0: H o me s pir o metr y - Wee kl y a ver a ges: Me a n ( +/ - S E) pl ots of t he 
perce nt c h a n ges fr o m b aseli ne o ver ti me


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 4 2/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
F or Fi g ures 5 a n d 6, P o p ulat i on: I T T, O C.
F or Fi g ures 7 t o 1 0, P o p ulat i on: I T T, L O C F + O C.
9. 1. 4.
L isti n gs
Listi n g 1 6. 2. 6. 1:
S pir o metr y: F ull listi n g
List i n g per treat me nt gr o u p, per s u bject a n d per ti me p oi nt of  all data r elate d t o s pir o metr y:
use of  br o nc h o dilat or, act ual val ues, c ha n ges fr om 
baseli ne a n d perc e nt c ha n ges fr om 
baseli ne.
P o p ul at i on: I T T.
Listi n g 1 6. 2. 6. 2:
H o me spir o metr y - D ail y v al ues : F ull listi n g
List i n g per tr e at me nt gr o u p, per s u bject a n d per d a y of all data relate d t o h o me s pir o metr y: 
use o f br o nc h o dilat or, act ual dail y val ues .
P o p ul at i on: I T T.
Listi n g 1 6. 2. 6. 3:
H o me s pir o metr y - Wee kl y a ver a ges: F ull listi n g
List i n g per treat me nt gr o u p, per s u bject a n d per wee k of  wee kl y a vera ges: act ual val ues, 
c ha n ges fr o m baseli ne a n d perce nt c ha n ges fr o m  baseli ne.
P o p ul at i on: I T T.
9. 2.
BI O M A R K E R S
9. 2. 1.
P ar a meters
T he f o ll owi n g e x pl orat or y  bio m ar kers will be e val uate d i n bl o o d sa m ples :

K L -6/ M uc 1

s urfacta nt pr otei n A a n d D

C C L 1 8

A T X

M M P 1, M M P 7

mar kers of  ext racell ular mat rix ( E C M) t ur n o ver ( ne oe pit o pe assa ys): B G M, C 1 M, C 3 M, 
C 6 M, C R P M, E L -N E a n d VI C M
T he f o ll owi n g a d di tio n al bio m ar kers ma y be a nal yze d i n bl o o d sa m ples if dee me d a p pr o priate 
after res ults of t he a b o ve e x pl orat or y mar kers ha ve bec o me a vaila ble:

o x y dat i ve stress: I C A M-1 a n d V C A M - 1 

ne utr o p hil recr uit me nt , acti vati on: I L 8, S 1 0 0 A 1 2

ot her bi o mar kers mi g ht be a nal yze d if dee me d a p pr o priate (e. g. , seriq ue pr otei n, seri q ue 
mi R N A)


Sta tistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 4 3/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
A T X will be deter mi ne d i n t he s u per nata nt of  t he B A L F . Br o nc h oal ve olar lava ge ( B A L) c ell 
c o u nt (t otal a n d differe ntial cell c o u nt f or alve o lar macr o p ha ge, l y m p h oc yt e, ne utr o p hil a n d 
e osi n o p hil) will be perf or me d.
T he val ues will be use d as a vaila ble via t he data tra nsfer fr o m 
.
Bi o m ar kers para meters a n d deri ve d:

Act ual  val ues

C ha n ge fr o m baseli ne ( Da y -1):
c ha n ge at ti me p o i nt t = (ti me p oi nt t val ue) – ( baseli ne val ue)

Perce nt c ha n ge fr o m baseli ne ( Da y  -1):
%c ha n ge at ti me p o i nt t = 1 0 0 x (ti me p oi nt t valu e – baseli ne val ue) / ( baseli ne val ue)
9. 2. 2.
T a bles
T a ble 1 4. 2. 1. 2. 1:
Bi o m ar ker s: Descri pti ve st atistics per ti me p oi nt
Descri pt i ve statistics p er t yp e of  sa m ple ( blo o d or B A L F), per bi o m ar ker , per tr e at me nt gr o u p 
a n d per time p oi nt of  the act ual val ues, t he c ha n ges fr om baseli ne a n d t he perce nt c ha n ges 
fr om baseli ne. I ncl u di n g a 9 5 % c o nfi de nce i nter val of  the mea n c ha n ges a n d mea n perce nt 
c ha n ges.
P o p ul at i on: I T T, L O C F + O C.
T a ble 1 4. 2. 1. 2. 2:
Bi o m ar kers : Descri pti ve st atistics per ti me p oi nt b y s u b -gr o u ps
Descri pt i ve statistics p er t y p e of  sa m ple ( blo o d or B A L F), per bi o m ar ker, per tr e at me nt gr o u p 
a n d per time p oi nt of  the act ual val ues, t he c ha n ges fr om baseli ne a n d t he perce nt c ha n ges 
fr om baseli ne b ut s plit u p b y:

baseli ne % F V C: < 5 0 % / [ 5 0, 7 0[ % / [ 7 0, 9 0[ % / ≥ 9 0 %

scree ni n g D L C O, % pre dicte d of n or m al: < 3 0 % / [ 3 0, 4 0[ % / [ 4 0, 5 0[ % / [ 5 0, 6 0[ % / ≥ 
6 0 %

a ge: [ 4 0, 5 0[ years / [ 5 0, 6 0[ years / [ 6 0, 7 0[ years / ≥ 7 0 years

ge n der: male / fe male

c o u ntr y: U krai ne / U K
P o p ul at i on: I T T, L O C F.
T a ble 1 4. 2. 1 . 2. 3:
Bi o m ar kers : St atistic al e v al u atio n per ti me p oi nt
Bet wee n -gr o u p c o mparis o n of  place b o a n d G L P G 1 6 9 0 : A N C O V A m o del o n t he c ha n ge s
fr om 
baseli ne wi t h disease se verit y (baseli ne % F V C, scree ni n g % D L C O), a ge, ge n der, 
treat me nt , c o u ntr y a n d baseli ne val ue as c o variates *. T he ta ble will prese nt t ype III p- val ues, 
L S -mea ns per gr o u p, L S -mea n differe nce bet wee n t he t w o gr o u ps a n d a 9 5 % c o nfi de nce 
i nter val of t his L S-mea n differe nce.
* if t he m o del d oes n ot c o n ver ge nce, c o u ntr y will be dr o p pe d.
Wit hi n -gr o u p c o m paris o n s of eac h visit vers us baseli ne: p ai re d t-test.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 4 4/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
T he “ra w” S A S P R O C o ut p ut m ust be pr o vi de d i n a statist ical a p pe n di x listi n g.
P o p ul at i on: I T T, L O C F.
9. 2. 3.
Fi g ures
Fi g ure 1 4. 2. 1. 2. 1:
Bi o m ar kers (i n bl o o d): S u bject pr ofile pl ots o ver ti me
S u bject pr ofile pl ots o v er t i me of  t he act ual val ues, wit h eac h bi o mar ker a n d treat me nt gr o u p 
o n a ne w pa ge b ut wi t h all s u bjects of  one gr o u p o n t he sa me pl ot. A n y u nsc he d ule d res ults 
will als o be part of t his pl ot.
P o p ul at i on: I T T, L O C F.
Fi g ure 1 4. 2. 1. 2 . 2: Bi o m ar kers (i n bl o o d): Me a n ( +/- S E) pl ots of t he act u al v al ues o ver 
ti me
Mea n ( wit h SE) pl ots of  t he act ual val ues o ver ti me per bi o mar ker , wi t h all tr e at me nt gr o u ps 
o n t he sa me pl ot usi n g differe nt pl ot s y m b ols. U nsc he d ule d res ults will n ot be part of  th is 
pl ot.
P o p ul at i on: I T T, L O C F.
Fi g ure 1 4. 2. 1. 2 .3:
Bi o m ar kers (i n bl o o d): Me a n ( +/- S E) pl ots of t he c h a n ges fr o m 
b aseli ne o ver ti me
Mea n 
( wit h SE) pl ots of  the c ha n ges fr om baseli ne o ver ti me per bi o mar ker , wi t h all 
treat me nt gr o u ps o n t he sa me pl ot usi n g differe nt pl ot s y m b ols. U nsc he d ule d res ults will  not 
be p art of  this pl ot. Wit h a h ori z o nt al refere nce li ne at zer o, i n dicati n g n o c ha n ge. Pl ots will 
start wit h a zer o mea n at baseli ne.
P o p ul at i on: I T T, L O C F.
Fi g ure 1 4. 2. 1. 2 . 4: Bi o m ar kers (i n bl o o d): Me a n ( +/- S E) pl ots of t he perce nt c h a n ges 
fr o m b aseli ne o ver ti me
Mea n ( wit h SE) pl ots of  t he p er c e nt c ha n ges fr om baseli ne o ver time per bi o mar ker , wit h all 
treat me nt gr o u ps o n t he sa me pl ot usi n g differe nt  pl ot s y m b ols. U nsc he d ule d res ults will  not 
be p art of  this pl ot. Wit h a h ori z o nt al refere nce li ne at zer o, i n dicati n g n o c ha n ge. Pl ots will 
start wit h a zer o mea n at baseli ne.
P o p ul at i on: I T T, L O C F.
Fi g ure 1 4. 2. 1. 2. 5:
Bi o m ar kers (i n B A L F): Distri b uti o n
Mea n 
( wit h SE) per bi o mar ker a n d treat me nt gr o u p at  baseli ne a n d Wee k 
1 2, wit h all 
i n di vi d ual res ults i ncl u de d as a scatter pl ot.
P o p ul at i on: I T T, L O C F.
Fi g ure 1 4. 2. 1. 2 . 6: Bi o m ar kers : B o x pl ots o ver ti me


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 4 5/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
B o x pl ots per treat me nt gr o u p at  baseli ne, wee ks 4, 1 2 a n d f oll ow- u p f or bi o mar kers i n bl o o d 
a n d at baseli ne a n d wee k 1 2 f or bi o mar kers i n B A L F .
P o p ul at i on: I T T, L O C F.
9. 2. 4.
Listi n gs
Listi n g 1 6. 2. 6. 4:
Bi o m ar kers i n bl o o d: F ull listi n g
List in g per treat me nt gr o u p a n d per ti me p oi nt of  all data r elate d t o bi o mar kers
i n bl o o d : 
act ual val ues, c ha n ges fr o m baseli ne a n d perce nt c ha n ges fr o m baseli ne.
P o p ul at i on: I T T.
Listi n g 1 6. 2. 6. 5:
Bi o m ar kers i n B A L F : F ull listi n g
List i n g per treat me nt gr o u p a n d per ti me p oi nt of all data r elate d t o bi o mar kers i n B A L F : 
act ual val ues, c ha n ges fr o m baseli ne, perce nt c ha n ges fr o m baseli ne a n d als o details a b o ut t he 
la va ge.
P o p ul at i on: I T T.
9. 3.
Q U A LI T Y O F LI F E: S G R Q
9. 3. 1.
P ar a meters
T he S G R Q is a 5 0- ite m quest i on naire s plit i nt o 3 d o mai ns: s y m pt o ms (assessi n g t he 
fre q ue nc y a n d se verity of  res pirat or y sy m pt o m s), acti vit y (assessi n g t he effects of 
breat hless ness o n m o bilit y a n d p h ysical act i vity) , a n d i m pacts (assessi n g t he ps yc h os ocial 
i m pact of  th e disease). Sc ores are wei g hte d s uc h t hat e ver y d o m ai n sc ore a n d t he t otal sc ore 
ra n ge fr om 0 t o 1 0 0, wit h hi g her sc ores i n dicat i n g a p o orer healt h-r elate d q ualit y of life.
N ote t hat bef ore c o m p leti n g t he q uest i on naire t he patie nt will ha ve t o a ns wer a q u e sti on o n 
his/ her prese nt healt h. T his i nf o will be ta b ulate d.
T he q uest i ons/ite ms a n d t heir wei g hts (fr o m 0 t o 1 0 0) are:
P art 1
Q #
I #
Q u esti o n
A ns wer
Wei g ht
1 
1
O ver t he past 4 wee ks, I ha ve c o u g he d:
M ost da ys a wee k
8 0. 6
Se veral da ys a wee k
6 3. 2
A fe w da y s a m o nt h
2 9. 3
O nl y wit h c hest i nfecti o ns
2 8. 1
N ot at all
0. 0
2 
2
O ver t he past 4 wee ks, I ha ve br o u g ht u p p hle g m 
(s p ut u m):
M ost da ys a wee k
7 6. 8
Se veral da ys a wee k
6 0. 0
A fe w da y s a m o nt h
3 4. 0
O nl y wit h c hest i nfecti o ns
3 0. 2


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 4 6/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
N ot at all
0. 0
3 
3
O ver t he past 4 wee ks, I ha ve ha d s h ort ness of 
br eat h:
M ost da ys a wee k
8 7. 2
Se veral da ys a wee k
7 1. 4
A fe w da y s a m o nt h
4 3. 7
O nl y wit h c hest i nfecti o ns
3 5. 7
N ot at all
0. 0
4 
4
O ver t he past 4 wee ks, I ha ve ha d attac ks of 
w h eezi n g:
M ost da ys a wee k
8 6. 2
Se veral da ys a wee k
7 1. 0
A fe w da y s a m o nt h
4 5. 6
O nl y wit h c hest i nfecti o ns
3 6. 4
N ot at all
0. 0
5 
5
D uri n g t he last year, h o w ma n y se vere or ver y ba d 
u n pleasa nt attac ks of c hest tr o u ble ha ve y o u ha d?
M ore t ha n 3 attac ks
8 6. 7
3 attac ks
7 3. 5
2 attac ks
6 0. 3
1 attac k
4 4. 2
N o attac ks
0. 0
6 
6
H o w l o n g di d t he w orst attac k of c hest tr o u ble last?
A wee k or m ore
8 9. 7
3 da y s or m or e
7 3. 5
1 or 2 da ys
5 8. 8
Less t ha n a da y
4 1. 9
7 
7
O ver t he past 4 wee ks, i n a n a vera ge wee k, h o w 
ma n y  g o o d da ys ( wit h little c hest tr o u ble) ha ve y o u 
ha d?
N o g o o d da ys
9 3. 3
1 or 2 g o o d da ys
7 6. 6
3 or 4 g o o d da ys
6 1. 5
Nearl y  e ver y d a y was g o o d
1 5. 4
E ver y da y was g o o d
0. 0
8 
8
If y o u ha ve a w h eeze, is it w orse i n t he m or ni n g?
N o
0. 0
Yes
6 2. 0
P art 2
Q #
I #
Q u esti o n
A ns wer
Wei g ht
9 
9
H o w w o ul d y o u descri be y o ur c hest c o n diti o n? 
T he m ost i m p orta nt pr o ble m I ha ve
8 3. 2
Ca uses me q uite a l ot of pr o ble ms
8 2. 5
Ca uses me a fe w pr o ble ms
3 4. 6
Ca uses me n o pr o ble m
0. 0
1 0 
1 0
If y ou ha ve e ver ha d pai d e m pl o y me nt.
M y  c hest tr o u ble ma de me st o p 
w or k alt o get her
8 8. 9
M y  c hest tr o u ble i nterferes wit h m y 
w or k or ma de me c ha n ge m y w or k
7 7. 6
M y  c hest tr o u ble d oes n ot affect m y 
w or k
0. 0


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 4 7/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
1 1 
1 1
Sitti n g o r l yi n g still.
False
0. 0
Tr ue
9 0. 6
1 2
Getti n g was he d or dresse d .
False
0. 0
Tr ue
8 2. 8
1 3
Wal ki n g ar o u n d at h o me .
False
0. 0
Tr ue
8 0. 2
1 4
Wal ki n g o utsi de o n t he le vel .
False
0. 0
Tr ue
8 1. 4
1 5
Cli m bi n g u p a fli g ht of stairs .
False
0. 0
Tr ue
7 6. 1
1 6
Cli m bi n g hills.
False
0. 0
Tr ue
7 5. 1
1 7
Pla y i n g s p orts or ga mes.
False
0. 0
Tr ue
7 2. 1
1 2 
1 8
M y  c o u g h h urts.
False
0. 0
Tr ue
8 1. 1
1 9
M y  c o u g h ma kes me tire d.
False
0. 0
Tr ue
7 9. 1
2 0
I get b reat hless w he n I tal k.
False
0. 0
Tr ue
8 4. 5
2 1
I get breat hless w he n I be n d o ver.
False
0. 0
Tr ue
7 6. 8
2 2
M y  c o u g h or breat hi n g dist ur bs m y slee p.
False
0. 0
Tr ue
8 7. 9
2 3
I get e x ha uste d easil y.
False
0. 0
Tr ue
8 4. 0
1 3 
2 4
M y  c o u g h or  breat hi n g is e m barrassi n g i n p u blic. 
False
0. 0
Tr ue
7 4. 1
2 5
M y  c hest tr o u ble is a n uisa nce t o m y fa mil y, frie n ds 
or  nei g h b o urs.
False
0. 0
Tr ue
7 9. 1
2 6
I get afrai d or pa nic w he n I ca n n ot get m y breat h. 
False
0. 0
Tr ue
8 7. 7
2 7
I feel t hat I a m n ot i n c o ntr ol of m y c hest pr o ble m. 
False
0. 0
Tr ue
9 0. 1
2 8
I d o n ot e x pect m y c hest t o get a n y better.
False
0. 0
Tr ue
8 2. 3
2 9
I ha ve bec o me frail or a n i n vali d beca use of m y 
c hest .
False
0. 0
Tr ue
8 9. 9


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 4 8/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
3 0
E xercise is n ot safe f or m e .
False
0. 0
Tr ue
7 5. 7
3 1
E ver yt hi n g see ms t o o m uc h of a n eff ort .
False
0. 0
Tr ue
8 4. 5
1 4 
3 2
M y  me dicati on d oes n ot hel p me ver y m uc h . 
False
0. 0
Tr ue
8 8. 2
3 3
I get e m barrasse d usi n g m y me dicati o n i n p u blic. 
False
0. 0
Tr ue
5 3. 9
3 4
I ha ve u n pleasa nt si de effects fr o m m y me dicati o n . 
False
0. 0
Tr ue
8 1. 1
3 5
M y  me dicati on i nterferes wit h m y life a l ot . 
False
0. 0
Tr ue
7 0. 3
1 5 
3 6
I ta ke a l on g ti me t o get was he d or dresse d . 
False
0. 0
Tr ue
7 4. 2
3 7
I ca n n ot ta ke a bat h or s ho wer, or I ta ke a l o n g ti me . 
False
0. 0
Tr ue
8 1. 0
3 8
I wal k sl o wer t ha n ot her pe o ple, or I st o p f or rests. 
False
0. 0
Tr ue
7 1. 7
3 9
J o bs s uc h as h o use w or k ta ke a l o n g ti me, or I ha ve 
t o st o p f or rests.
False
0. 0
Tr ue
7 0. 6
4 0
If I wal k u p o ne fli g ht of stairs, I ha ve t o g o sl o wl y 
or  st o p.
False
0. 0
Tr ue
7 1. 6
4 1
If I h urr y or wal k fast, I ha ve t o st o p or sl o w d o w n. 
False
0. 0
Tr ue
7 2. 3
4 2
M y  breat hi n g ma kes it diffic ult t o d o t hi n gs s uc h as 
cli m bi n g u p hills, carr y i n g t hi n gs u pstairs , li g ht 
gar de ni n g s uc h as wee di n g, da nc i n g, pla yi n g b o wls 
or  g olf.
False
0. 0
Tr ue
7 4. 5
4 3
M y  breat hi n g ma kes it diffic ult t o d o t hi n gs s uc h as 
carr yi n g hea v y  l oa ds, di ggi n g t he gar de n or 
s h o velli n g s no w, j o g gi n g or  wal ki n g at 5 miles per 
h o ur, pla y i n g te n nis or s wi mmi n g.
False
0. 0
Tr ue
7 1. 4
4 4
M y  breat hi n g ma kes it diffic ult t o d o t hi n gs s uc h as 
ver y hea v y  ma n ual w or k, r u nni n g , c ycl i n g, 
s wi mmi n g fast or pla yi n g c o m petiti ve s p orts.
False
0. 0
Tr ue
6 3. 5
1 6 
4 5
I ca n n ot pla y s p orts or ga mes.
False
0. 0
Tr ue
6 4. 8
4 6
I ca n n ot g o o ut f or e ntertai n me nt or recreati o n. 
False
0. 0
Tr ue
7 9. 8
4 7
I ca n n ot g o o ut of t he h o use t o d o t he gr oceries.
False
0. 0
Tr ue
8 1. 0


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 4 9/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
4 8
I ca n n ot d o h o use w or k.
False
0. 0
Tr ue
7 9. 1
4 9
I ca n n ot m o ve far fr o m m y be d or c hair.
False
0. 0
Tr ue
9 4. 0
1 7 
5 0
Tic k t he state me nt w hic h y o u t hi n k best descri bes 
h o w y o ur c hest affects y o u :
It d oes n ot st o p me d oi n g a n yt hi n g I 
w o ul d li ke t o d o
0. 0
It st o ps me d oi n g o ne or t w o t hi n gs 
I w o ul d li ke t o d o
4 2. 0
It st o ps me d oi n g m ost of t he t hi n gs 
I w o ul d li ke t o d o
8 4. 2
It st o ps me d oi n g e ver yt hi n g I 
w o ul d li ke t o d o
9 6. 7
D o m ai n sc ores a n d t otal sc ore:

S y m pt o m s sc or e: q uesti o ns 1 - 8.

Act i vity sc or e: q uesti o ns 1 1 a n d 1 5. 

I mpacts sc or e: q u esti o ns 9-1 0, 1 2 -1 4 a n d 1 6- 1 7.

T ot al  sc or e: all q uest i ons .
Eac h d o m ai n sc ore is calc ulate d se paratel y i n t hree ste ps:

T he wei g hts f or all ite ms wit h p osi tive res p o nses are s u m me d.

T he wei g hts f or misse d ite ms are de d ucte d fr om t he ma xi m u m p ossi ble w ei g ht f or eac h 
c o mp o ne nt. T he w ei g hts f or all misse d ite ms are de d ucte d fr o m t he ma xi m u m p ossi ble 
w ei g ht f or t he t otal  sc ore.

T he sc ore is calc ulate d b y di vi di n g t he s u m me d wei g hts b y t he a dj uste d ma xi m u m 
p ossi ble wei g ht f or t hat c o m p o ne nt a n d e x pressin g t he res ul t as a perce nta ge:
Sc ore = 1 0 0 x
                                                                            T he t otal  sc ore is calc ulate d i n si milar wa y:
Sc ore = 1 0 0 x
                                                                                 S u m  of ma xi m u m p ossi ble wei g ht s for eac h sc ore:

S y m pt o m s: 6 6 2. 5

Act i vity: 1 2 0 9. 1

I mpacts: 2 1 1 7. 8

T ot al : 3 9 8 9. 4
N ote t hat t he q uest i on naire re q uests a si n gle res p o nse t o q uesti o ns 1- 7, 9- 1 0 a n d 1 7. If 
m ult i ple res p o nses are gi ve n t o o ne of  these q uesti o ns t he n t he wei g hts f or t he p osi ti ve 
res p o nses f or t hat q uestio n will be a vera ge d .
I n case of missi n g ite ms, t he f oll owi n g r ul e s will be a p plie d:

T he s y m pt o ms sc ore will o nl y be calc ulate d w he n n o m ore t ha n 2 ite ms are miss i n g.

T he a cti vit y sc ore will o nl y be calc ulate d w he n n o m ore t ha n 4 i te ms are miss i n g.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 5 0/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n

T he i m pacts sc ore will o nl y be calc ulate d w he n n o m ore t ha n 6 i t e ms are miss i n g.

T he t otal sc ore will o nl y be calc ulat e d w he n t he 3 d o m ai n sc ores c o uld be calc ulate d.
N ote t hat n o i m p utati o n of  in di vi d ual missi n g 
ite ms will 
be d o ne, o nl y t he missi n g 
d o m ai n/t otal sc ores will be i m p ute d.
S G R Q para m eters a n d deri ve d:

Act ual  val ues

C ha n ge fr o m basel i ne ( Da y -1):
c ha n ge at ti me p o i nt t = (ti me p oi nt t val ue) – ( baseli ne val ue)

Perce nt c ha n ge fr o m baseli ne ( Da y  -1):
%c ha n ge at ti me p o i nt t = 1 0 0 x (ti me p oi nt t valu e – baseli ne val ue) / ( baseli ne val ue)
9. 3. 2.
T a bles
T a ble 1 4. 2. 1. 3. 1:
S G R Q : Prese nt he alt h per ti me p oi nt
Fre q ue nc y ta b ulatio n per treat m e nt gr o u p.
P o p ul at i on: I T T, L O C F + O C .
T a ble 1 4. 2. 1. 3. 2:
S G R Q: S hift t a ble of t he prese nt he alt h per ti me p oi nt
S hift ta ble per treat m e nt gr o u p a n d ti me p oi nt. T he ta ble will prese nt t he s hift i n prese nt heat h 
at eac h p ost -baseli ne t i me p oi nt vers us t he baseli ne.
P o p ul at i on: I T T, L O C F + O C.
T a ble 1 4. 2. 1. 3. 3:
S G R Q : Descri pti ve st atistics per ti me p oi nt
Descri pt i ve statistics per sc ore, per treat me nt gr o u p a n d per ti me p oi nt of  the act ual v al u es, 
t he c ha n ges fr o m baseli ne a n d t he perce nt c ha n ges fr o m baseli ne. I ncl u di n g a 9 5 % c o nfi de nce 
i nter val of t h e mea n c ha n ges a n d mea n perce nt c ha n ges.
P o p u lati on: I T T, L O C F + O C.
T a ble 1 4. 2. 1. 3. 4:
S G R Q : Descri pti ve st atistics per ti me p oi nt b y s u b-gr o u ps
Descri pt i ve statistics per sc ore, per treat me nt gr o u p a n d per ti me p oi nt of  the act ual v al u es, 
t he c ha n ges fr o m baseli ne a n d t he per ce nt c ha n ges fr o m baseli ne b ut s plit u p b y:

baseli ne % F V C: < 5 0 % / [ 5 0, 7 0[ % / [ 7 0, 9 0[ % / ≥ 9 0 %

scree ni n g D L C O, % pre dicte d of n or m al: < 3 0 % / [ 3 0, 4 0[ % / [ 4 0, 5 0[ % / [ 5 0, 6 0[ % / ≥ 
6 0 %

a ge: [ 4 0, 5 0[ years / [ 5 0, 6 0[ years / [ 6 0, 7 0[ years / ≥ 7 0 years

ge n der: m ale / fe male

c o u ntr y: U krai ne / U K
P o p ul at i on: I T T, L O C F.


Statistical A nal ysi s Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 5 1/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
T a ble 1 4. 2. 1. 3. 5:
S G R Q : St atistic al e v al u ati o n per ti me p oi nt
Bet wee n -gr o u p c o mparis o n of  place b o a n d G L P G 1 6 9 0: A N C O V A m o del o n t he c ha n ges 
fr om 
baseli ne wi t h disease se verit y (baseli ne % F V C, scree ni n g % D L C O), a ge, ge n der, 
treat me nt, c o u ntr y  an d baseli ne val ue as c o variates *. T he ta ble will prese nt t ype III p- val ues,
L S -mea ns per gr o u p, L S -mea n differe nce bet wee n t he t w o gr o u ps a n d a 9 5 % c o nfi de nce 
i nter val of t his L S-mea n differe nce.
* if t he m o del d oes n ot c o n ver ge nce, c o u ntr y will be dr o p pe d.
Wit hi n -gr o u p c o m paris o ns of eac h visit vers us baseli ne: paire d t -test.
T he “ra w” S A S P R O C o ut p ut m ust be pr o vi de d i n a statist ical a p pe n di x listi n g.
P o p ul at i on: I T T, L O C F.
9. 3. 3.
Fi g ures
Fi g ure 1 4. 2. 1. 3. 1:
S G R Q : S u bject pr ofile pl ots o ver ti me
S u bject pr ofile pl ots o v er ti me of  t he act ual val ues , wit h eac h treat me nt gr o u p o n a ne w pa ge 
b ut wi t h all s u bj e cts of o n e gr o u p o n t he sa me plot. A n y u nsc he d ule d res ul ts will als o b e p art 
of  t his plot.
P o p ul at i on: I T T, L O C F.
Fi g ure 1 4. 2. 1. 3 . 2: S G R Q : Me a n ( +/- S E) pl ots of t he act u al v al ues o ver ti me
Mea n ( wit h SE) pl ots of  the act ual val ues o ver ti me, wi t h all tr e at me nt gr o u ps o n t he sa me 
pl ot usi n g differe nt pl ot s y m b o ls. U nsc he d ule d res ults will n ot be part of t his pl ot.
P o p ul at i on: I T T, L O C F.
Fi g ure 1 4. 2. 1. 3 . 3:
S GR Q : Me a n ( +/- S E) pl ots of t he c h a n ges fr o m b aseli ne o ver ti me
Mea n ( wi t h S E) plots of  t he c ha n ges fr o m baseli ne o ver ti me, wit h all tr e at me nt gr o u ps o n t he 
sa me plot usi n g diff er e nt pl ot s y m b ols. U nsc he d ule d res ul ts will n ot b e p art of  t his plot. Wi t h 
a h ori z o nt al refere nce li ne at zer o, i n dicati n g n o c ha n ge. Pl ots will st art wit h a zer o mea n at  
ba seli ne.
P o p ul at i on: I T T, L O C F.
Fi g ure 1 4. 2. 1. 3 . 4:
S G R Q: Me a n ( +/- S E) pl ots of t he perce nt c h a n ges fr o m b aseli ne o ver 
ti me
Mea n ( wit h SE ) pl ots of  the perce nt c ha n ges fro m  baseli ne o ver ti me, wi t h all tr e at me nt 
gr o u ps o n t he sa me pl ot usi n g differe nt pl ot s y m b ol s. U nsc he d ule d res ults will n ot be p art of 
t his plot. Wi t h a hori z o nt al r efere nce li ne at zer o, i n dicati n g n o c ha n ge. Pl ots will s t art wit h a 
zer o mea n at baseli ne.
P o p ul at i on: I T T, L O C F.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 5 2/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
9. 3. 4.
Listi n gs
Listi n g 1 6. 2. 6. 6:
S G R Q : Ori gi n al ite ms
List i n g per treat me nt gr o u p, per s u bject a n d per ti me p oi nt of t he ra w i n di vi d ual 5 0 ite ms.
P o p ul at i on: I T T.
Listi n g 1 6. 2. 6. 7:
S G R Q : S c ores
List i n g per treat me nt gr o u p, per s u bject a n d per ti me p oi nt of t he t otal sc ore a n d t he 3 d o m ai n 
sc ores (ra w, c ha n ge, %c ha n ge).
P o p ul at i on: I T T.
9. 4.
F U N C TI O N A L R E S PI R A T O R Y I M A GI N G
9. 4. 1.
P ar a meters
Hi g h -R es ol uti o n C o m p ute d T o m o gra p h y (H R C T ) sca ns will be use d t o ge nerate F u ncti o na l 
Res pirat or y I ma gi n g (F RI ) meas ure me nts. I n case t he s u bject is on br o nc h o dilat ors, he/s he 
ca n use t he br o nc h o dilat or aft er t he s pir o metr y but pr i or t o H R C T f or F RI para m eters. T he 
val ues will be u se d as a vaila ble via t he data tra nsfer fr om 
(a n d will  be a nal yze d
[ T L Fs] b y 
T he f o ll owi n g F RI para meters will be e val uate d :

( Pre dicte d) l obar v o l umes 
at F u n cti o nal R esi d ual Ca pacit y (F R C ) a n d T ot al  Lu n g 
C a pacit y (T L C )

T ri m me d a n d u ntri m me d (s pecific) air wa y v olu mes at F R C a n d T L C

( Specific) air w a y resista nce at F R C a n d T L C

L o w atte n uati o n or e m p h yse ma sc ore at T L C

B l oo d vessel de nsit y or fi br osi s sc ore at T L C

( Specific) air w a y wall t hic k ness at T L C

A ir tra p pi n g at F R C

Ma ss of de p osite d particles per defi ne d air wa y sectio n
I n differe nt z o nes:

Ri g ht u p per l o be ( R U L)

Ri g ht mi d dle l o b e ( R M L)

Ri g ht l o wer l o be ( R L L)

Left u p per l o be ( L U L)

Left l o wer l o be ( L L L)

U p per l o bes ( U L = c o m bi nat i on of R U L, R M L a n d L U L)

L o wer l o bes ( L L = c o m bi nat i on of R L L a n d L L L)

Ce ntral  r e gio n (for ai r wa y relate d para meters)

Di st al r e gio n (f or air w a y relate d para meters)

P eri p heral  r e gio n  (for parti cle relate d para meters)


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 5 3/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n

T ot al  r e gio n
F or t he de p osite d particles, t he 7 first z o nes i nstea d of bei n g s plitt e d i n a dist al a n d perip heral 
r e gio n are c o nsi dere d c o m bi ne d.
F RI para m eters a n d deri ve d:

Act ual  val ues

C ha n ge fr o m baseli ne ( Da y -1):
c ha n ge at ti me p o i nt t = (ti me p oi nt t val ue) – ( baseli ne val ue)

Perce nt c ha n ge fr o m baseli ne ( Da y  -1):
%c ha n ge at ti me p oi nt t = 1 0 0 x (ti me p o i nt t valu e – baseli ne val ue) / ( baseli ne val ue)
9. 4. 2.
T a bles
T a ble 1 4. 2. 1. 4. 1:
F RI : Descri pti ve st atistics per ti me p oi nt
Descri pt i ve st atistics per para meter, per z o ne, per treat me nt gr o u p a n d per ti me p oi nt of  th e 
act ual val ues, t he c ha n ges fr om baseli ne a n d t he perce nt c ha n ges fr om baseli ne. I ncl u di n g a 
9 5 % c o nfi de nce i nter val o f t he mea n c ha n ges a n d mea n perce nt c ha n ges.
P o p ul at i on: I T T, L O C F + O C.
T a ble 1 4. 2. 1. 4. 2:
F RI : Descri pti ve st atistics per ti me p oi nt b y s u b -gr o u ps
Descri pt i ve st atistics per para meter, per z o ne (lo wer a n d u p per l obes o nl y) , per treat me nt
gr o u p a n d per ti me p oi nt of  the a ct u al val ues, t he c ha n ges fr om baseli ne a n d t he perce nt 
c ha n ges fr o m baseli ne b ut s plit u p b y:

baseli ne % F V C: < 5 0 % / [ 5 0, 7 0[ % / [ 7 0, 9 0[ % / ≥ 9 0 %

scree ni n g D L C O, % pre dicte d of n or m al: < 3 0 % / [ 3 0, 4 0[ % / [ 4 0, 5 0[ % / [ 5 0, 6 0[ % / ≥ 
6 0 %

a ge: [ 4 0, 5 0[ years / [ 5 0, 6 0[ years / [ 6 0, 7 0[ years / ≥ 7 0 years

ge n der: male / fe male

c o u ntr y: U krai ne / U K
P o p ul at i on: I T T, L O C F.
T a ble 1 4. 2. 1 . 4. 3:
FRI : St atistic al e v al u ati o n per ti me p oi nt
Bet wee n -gr o u p c o mparis o n of  place b o a n d G L P G 1 6 9 0 : A N C O V A
m o d el o n t he c ha n ges 
fr om 
baseli ne wi t h disease se verit y (baseli ne % F V C, scree ni n g % D L C O ), a ge, ge n der, 
treat me nt , c o u ntr y a n d baseli ne val ue as c o variates *. T he ta ble will prese nt t ype III p- val ues, 
L S -mea ns per gr o u p, L S -mea n differe nce bet wee n t he t w o gr o u ps a n d a 9 5 % c o nfi de nce 
i nter val of t his L S-mea n differe nce.
* if t he m o del d oes n ot c o n ver ge nce, c o u ntr y will be dr o p pe d.
Wit hi n -gr o u p c o m paris o n s of eac h visit vers us baseli ne: paire d t -test.
T he “ra w” R o ut p ut m ust be pr o vi de d i n a statistical a p pe n di x list i n g.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 5 4/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
P o p ul at i on: I T T, L O C F.
N ote: t o be d o ne f or t he l o wer a n d u p per l o bes o nl y (a n d se paratel y).
9. 4. 3.
Fi g ures
Fi g ure 1 4. 2. 1. 4. 1:
F RI : Me a n pl ots
Mea n (wi t h S E) bar c hart per treat me nt gr o u p at  baseli ne a n d Wee k 1 2 . F or eac h para m eter
a n d z o ne.
P o p ul at i on: I T T p o p ulat i on, L O C F .
9. 4. 4.
Listi n gs
Listi n g 1 6. 2. 6. 8:
F RI : F ull listi n g
List i n g per treat me nt gr o u p, per s u bject a n d per ti me p oi nt of  all data r elate d t o F RI : use of 
br o nc h o dilat or, z o ne, act ual val ues, c ha n ges fr o m baseli ne a n d perce nt c ha n ges fr o m b aseli ne.
P o p ul at i on: I T T.
1 0.
D E FI NI TI O N S O F P H A R M A C O KI N E TI C S A N A L Y SI S 
T A B L E S, LI S TI N G S A N D F I G U R E S
1 0. 1.
P A R A M E T E R S
C o m p o u n d:

G L P G 1 6 9 0
Ti me p o i nts:

P K pre -d ose sa mples are c ollecte d at eac h visit – i.e. Wee ks 1, 2, 4, 8 a n d 1 2

At  Wee k 4, P K sa m ples are c ollecte d at pre-d ose a n d 1. 5 h, 4 h, 6 h p ost -d ose
Deri ve d P K para meters:

C ma x *, C τ , A U C 0- τ *, tma x *
* wee k 4 o nl y
P ar a meter n a me
Defi niti o n
U nits
C ma x
Ma xi m u m o bser ve d plas ma c o nce ntrati o n
µ g/ m L
C τ
T r ou g h plas ma c o nce ntrati o n (j ust bef ore t he n e xt d osi n g i.e. 
pr e -d ose sa m ple)
µ g/ m L
A U C 0-τ
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me 0 
t o ti me τ o ver a d osi n g i nter val, w h er e τ is t he le n gt h of t he 
d osi n g i nter val
µ g h/ m L
tma x
Ti me of ma xi m u m o bser ve d plas ma c o nce ntrati o n
h
N ot e : for A U C 0-τ, τ re prese nts t he d osi n g i nter val, w hic h i n t his st u d y is 2 4 h.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 5 5/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
P K para meters deri vat i on r ul es:

C o nce ntrati o n B L O Q will be i m p ute d acc or di n g t o t he r ules me nt i one d i n sect i on 5. 4. 2 .

S u bjects wit h less t ha n 3 c o nce ntrati o ns > B L O Q will be re vie we d t o assess w het her t heir 
P K res ults ca n st ill be i ncl u de d i n t he st atistical a nal ysis.

P K para meters will be calc ulate d acc or di n g t o li near u p/l o g d o w n tra pez oid al  met h o d
usi n g t he t he oretical sa m pli n g ti me.

T he oretical sa m pli n g time will be use d f or P K para m eters calc ulat i on, e xce pt if t he 
de viat i on of act ual sa m pli n g ti me is > 1 0 %, w he n t he a ct u al sa m pli n g ti me will be use d.

D a y  1 pr e-d ose val ues e xcee di n g 5 % of  the C ma x will be fla g ge d i n t he listi n g. A nal ysis 
will be re peate d, e xcl u di n g s uc h s u bjects .
E xcl u de d data will be fla g ge d i n t he T L Fs.
Ha n dli n g of ot h er p ote nti al a n o ma lies i n t he pl a s ma P K pr ofiles will be disc usse d wi t h 
G al a pa g os bef ore P K para meter deri vat i on.
N ote t hat 
will deri ve t he P K  para meters, defi ne t he P K  po p ul at i on a n d pr o d uce t he 
T L Fs.
1 0. 2.
T A B L E S
T a ble 1 4. 2. 2. 1:  
G L P G 1 6 9 0 pl as m a c o nce ntr ati o ns ( n g/ m L): I n di vi d u al d at a a n d 
descri pti ve st atistics per d a y a n d ti me p oi nt
S u bject data wit h descri pti ve st atistics per d a y a n d pla n ne d ti me p oi nt of  the pl as ma 
c o nce ntrati o ns.
P o p ul at i on: P K.
T a ble 1 4. 2. 2. 2:  
G L P G 1 6 9 0 P K p ar a meters: I n di vi d u al d at a a n d descri pti ve st atistics 
– Wee k 4
S u bject data wit h descri pt i ve statistics at wee k 4 of  the deri ve d P K  para meters ( Cma x , C τ , 
A U C 0- τ , tma x ).
P o p ul at i on: P K.
1 0. 3.
FI G U R E S
Fi g ure 1 4. 2. 2. 1:  
G L P G 1 6 9 0
p r e- d ose pl as m a c o nce ntr ati o ns ( n g/ m L): S u bject pr ofile 
pl ots (li ne ar-li ne ar sc ale)
S u bject pr ofile pl ots of  t he G L P G 1 6 9 0 pre -d ose plas ma c o nce ntrati o ns o ver ti me .
P o p ul at i on: P K.
Fi g ure 1 4. 2. 2. 2:  
G L P G 1 6 9 0
p r e- d ose pl as m a c o nce ntr ati o ns ( n g/ m L): Me a n
( +/- S E)
c o nce ntr ati o n o ver ti me (li ne ar- li ne ar sc ale)
Ar ith metic mea n wit h S E of t he G L P G 1 6 9 0 pre -d ose pl as ma c o nce ntrati o ns o ver ti me .


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 5 6/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
P o p ul at i on: P K.
Fi g ure 1 4. 2. 2. 3:  
G L P G 1 6 9 0
pl as m a c o nce ntr ati o ns ( n g/ m L): S u bject pr ofile pl ots –
Wee k 4
(li ne ar-li ne ar sc ale)
S u bject pr ofile pl ots of t he G L P G 1 6 9 0 pl as ma c o nce ntrati o ns o ver ti me. 
P o p ul at i on: P K.
Fi g ure 1 4. 2. 2. 4:  
G L P G 1 6 9 0
pl as m a c o nce ntr ati o ns ( n g/ m L): S u bject pr ofile pl ots –
Wee k 4
(l o g-li ne ar sc ale)
S a m e as pre vio us pl ot, b ut wi t h a lo g 1 0 -scale d vertical c o nce ntrati o n a xis.
P o p ul at i on: P K.
Fi g ure 1 4. 2. 2. 5:  
G L P G 1 6 9 0
pl as m a 
c o nce ntr ati o ns
( n g/ m L): 
Me a n
( +/-
S E)
c o nce ntr ati o n o ver ti me – Wee k 4
(li ne ar-li ne ar sc ale)
Ar ith metic mea n wit h S E of t he G L P G 1 6 9 0 pl as ma c o nce ntrati o ns o ver ti me .
P o p ul at i on: P K.
Fi g ure 1 4. 2. 2. 6:  
G L P G 1 6 9 0
pl as m a 
c o nce ntr ati o ns
( n g/ m L): 
Me a n
( +/-
S E)
c o nce ntr ati o n o ver ti me – Wee k 4
(l o g-li ne ar sc ale)
S a m e as pre vio us pl ot, b ut wi t h a lo g 1 0 -scale d vertical c o nce ntrati o n a xis.
P o p ul at i on: P K.
1 0. 4.
L I S TI N G S
Listi n g 1 6. 2. 7. 1:
P K d at a h a n dli n g
List i n g per s u bject a n d pla n ne d ti me p oi nt of a n y data iss ue a n d h o w t he iss ue will be ha n dle d 
i n t he a nal ysis.
P o p ul at i on: P K.
Listi n g 1 6. 2. 7. 2 :
Act u al P K bl o o d s a m pli n g ti mes ( h)
List i n g per da y a n d s u bject of  the P K  sa mpli n g ti mes relati ve t o t he act ual dr u g i nta ke. 
De viat i ons fr om t he sc he d ule d s a mpli n g ti mes of  mor e t ha n 1 0 % will be fla g ge d, as well as 
pre -d ose sa m ples t hat were act uall y ta ke n p ost -d osi n g.
P o p ul at i on: P K.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 5 7/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
1 1.
D E FI NI TI O N S O F P H A R M A C O D Y N A MI C S A N A L Y SI S
T A B L E S , LI S TI N G S A N D FI G U R E S
1 1. 1.
P A R A M E T E R S
Para m eters:

L P A 1 8: 2 s pecies pea k area r atio, i n bl o o d ( ot her L P A s pecies mi g ht be a nal yze d if 
dee m e d a p pr o priate).

All detecta ble L P A s pecies pea k area rati o , i n B A L F.
T he perce nt re d ucti o n fr o m baseli ne is deri ve d as :
% re d ucti o n fr o m b aseline = 1 0 0 -( 1 0 0 × visit/b aseli ne)
T he baseli ne is t he a vera ge of t he pre- d osi n g d u plicates ( Da y  -1 pre -d ose).
F urt her deri ve d para m eters (f or L P A i n bl o o d o nl y):

E ma x at Wee k 4 = ma xi m u m % re d uctio n val ue o ver all time p oi nts, starti n g fr om t he 
Wee k 4 pre -d ose val ue a n d e n di n g at t he 6 h val ue.

A U E C at Wee k 4 = area u n der t he % re d uctio n c ur ve usi n g t he tra pez oidal s u m mati on 
r ule, starti n g fr om t he % re d ucti o n at t he Wee k 4 pre -d ose val ue a n d e n di n g at t he 6 h 
val ue. T he s u m mat i on will use t he sc he d ule d ti me p oi nts rat her t ha n t he act ual t i mes.
1 1. 2.
T A B L E S
T a ble 1 4. 2. 3. 1:
L P A s pecies pe a k are a r ati o : Descri pti ve st atistics per ti me p oi nt
Descri pt i ve statistics of t he a bs olute val ues a n d t h e c ha n ges fr om baseli ne p er t y pe of sa m ple 
( blo o d or B A L F), L P A s pecies, treat me nt gr o u p a n d ti me p o i nt.
P o p ul at i on: P D , L O C F + O C.
T a ble 1 4. 2. 3. 2:
L P A s pecies pe a k are a r ati o : St atistic al e v al u ati o n per ti me p oi nt
Bet wee n -gr o u p c o mparis o n of  place b o a n d G L P G 1 6 9 0: A N C O V A m o del o n t he c ha n ges 
fr om 
baseli ne wi t h disease se verit y (baseli ne % F V C, scree ni n g % D L C O), a ge, ge n der, 
treat me nt, c o u ntr y  an d baseli ne val ue as c o variates *. T he ta ble will prese nt t ype III p- val ues, 
L S -mea ns per gr o u p, L S -mea n differe nce bet wee n t he t w o gr o u ps a n d a 9 5 % c o nfi de nce 
i nter val of t his L S-mea n differe nce.
* if t he m o del d oes n ot c o n ver ge nce, c o u ntr y will be dr o p pe d.
Wit hi n -gr o u p c o m paris o ns of eac h visit vers us baseli ne: paire d t -test.
T he “ra w” S A S P R O C o ut p ut m ust be pr o vi de d i n a statistical a p pe n di x listi n g.
P o p ul at i on: P D , L O C F .
T a ble 1 4. 2. 3. 3:
L P A s pecies % re d ucti o n fr o m b aseli ne: Descri pti ve st atistics per 
ti me p oi nt


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 5 8/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
Descri pt i ve st atistics of  the %
re d ucti on val ues p er t ype of  sa m ple ( blo o d or B A L F), L P A 
s pecies, treat me nt gr o u p a n d ti me p oi nt.
P o p ul at i on: P D , L O C F + O C .
T a ble 1 4. 2. 3 . 4:
L P A s pecies % re d ucti o n fr o m b aseli ne: Descri pti ve st atistics per 
ti me p oi nt b y s u b -gr o u ps
Descri pt i ve st atistics of  the %
re d ucti on val ues p er t ype of  sa m ple ( blo o d or B A L F), L P A 
s pecies, treat me nt gr o u p a n d ti me p oi nt b ut s plit u p b y:

baseli ne % F V C: < 5 0 % / [ 5 0, 7 0[ % / [ 7 0, 9 0[ % / ≥ 9 0 %

scree ni n g D L C O, % pre dicte d of n or m al: < 3 0 % / [ 3 0, 4 0[ % / [ 4 0, 5 0[ % / [ 5 0, 6 0[ % / ≥ 
6 0 %

a ge: [ 4 0, 5 0[ years / [ 5 0, 6 0[ years / [ 6 0, 7 0[ years / ≥ 7 0 years

ge n der: male / fe male

c o u ntr y: U krai ne / U K
P o p ul at i on: P D , L O C F.
T a ble 1 4. 2. 3. 5:
L P A s pecies % re d ucti o n fr o m b aseli ne: Fre q ue nc y t a b ul ati o n per 
ti me p oi nt
Fre q ue nc y ta ble per t yp e of s a m pl e ( bl o o d or B A L F), L P A s pecies, tr e at me nt gr o u p a n d ti me 
p oi nt, s h o wi n g t he % re d uctio n i n t he f oll owi n g cate g ories: < 5 0 %, [ 5 0, 6 0[ %, [ 6 0, 7 0[ %, 
[ 7 0, 8 0[ %, [ 8 0, 9 0[ %, [ 9 0, 1 0 0] %. 
P o p ul at i on: P D , L O C F + O C .
T a ble 1 4. 2. 3. 6:
L P A s pecies % re d ucti o n fr o m b aseli ne: St atistic al e v al u ati o n per 
ti me p oi nt
Bet wee n -gr o u p c o mparis o n of place b o a n d G L P G 1 6 9 0 : A N C O V A m o del wi t h disease 
se verity ( baseli ne % F V C, scree ni n g % D L C O), a ge, ge n der, treat me nt , co u ntr y a n d baseli ne 
val ue as c o variates *. T h e ta ble will prese nt t yp e III p- val ues, L S -mea ns p er gr o u p, L S -mea n 
differe nce bet wee n t he t w o gr o u ps a n d a 9 5 % c o nfi de nce i nter val o f t his L S-mea n differe nce.
* if t he m o del d oes n ot c o n ver ge nce, c o u ntr y will be dr o p pe d.
T he “ra w” S A S P R O C o ut p ut m ust be pr o vi de d i n a statist ical a p pe n di x listi n g.
P o p ul at i on: P D , L O C F.
T a ble 1 4. 2. 3. 7:
L P A s pecies m a xi m u m % re d ucti o n fr o m b aseli ne E m a x : Descri pti ve 
st atistics
Descri pt i ve statistics of  the E ma x v al u es per treat me nt gr o u p at Wee k 4 (for bl o o d sa m ples
o nl y s o f or L P A 1 8: 2 s pecies o nl y).
P o p ul at i on: P D , L O C F + O C .


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 5 9/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
T a ble 1 4. 2. 3. 8:
L P A s pecies m a xi m u m % re d ucti o n fr o m b aseli ne E m a x : Fre q ue nc y 
t a b ul ati o n
Fre q ue nc y ta ble per treat me nt gr o u p at Wee k 
4 (f or bl o o d sa mples o nl y s o f or L P A 1 8: 2 
s pecies o nl y ), s h o wi n g t he E ma x
i n t he f oll owi n g cate g ories: < 5 0 %, [ 5 0, 6 0[ %, [ 6 0, 7 0[ %, 
[ 7 0, 8 0[ %, [ 8 0, 9 0[ %, [ 9 0, 1 0 0]%.
P o p ul at i on: P D , L O C F + O C.
T a ble 1 4. 2. 3. 9:
L P A s pecies m a xi m u m % re d ucti o n fr o m b aseli ne E m a x : St atistic al 
e v al u ati o n
Bet wee n -gr o u p c o mparis o n of place b o a n d G L P G 1 6 9 0 : A N C O V A m o del wi t h disease 
se verity ( baseli ne % F V C, scree ni n g % D L C O), a ge, ge n der, treat me nt , c o u ntr y a n d baseli ne 
val ue as c o variat es *. T h e ta ble will prese nt t yp e III p- val ues, L S -mea ns p er gr o u p, L S -mea n 
differe nce bet wee n t he t w o gr o u ps a n d a 9 5 % c o nfi de nce i nter val o f t his L S-mea n differe nce.
* if t he m o del d oes n ot c o n ver ge nce, c o u ntr y will be dr o p pe d.
T he “ra w” S A S P R O C o ut p ut m ust be pr o vi de d i n a statist ical a p pe n di x listi n g.
P o p ul at i on: P D , L O C F .
T a ble 1 4. 2. 3. 1 0:
L P A s pecies are a u n der t he % re d ucti o n
c ur ve A U E C: Descri pti ve 
st atistics
Descri pt i ve st atistics of  the A U E C v al ues per tr e at me nt gr o u p at We e k 4 (f or bl o o d sa mples
o nl y s o f or L P A 1 8: 2 s pecies o nl y).
P o p ul at i on: P D , L O C F + O C .
T a ble 1 4. 2. 3. 1 1:
L P A s pecies are a u n der t he % re d ucti o n c ur ve A U E C: St atistic al 
e v al u ati o n
Bet wee n -gr o u p c o mparis o n of place b o a n d G L P G 1 6 9 0 : A N C O V A m o del wi t h disease 
se verity ( baseli ne % F V C, scree ni n g % D L C O), a ge, ge n der, treat me nt , c o u ntr y a n d baseli ne 
val ue as c o variates *. T h e ta ble will prese nt t yp e III p- val ues, L S -mea ns p er gr o u p, L S -mea n 
differe nce bet wee n t he t w o gr o u ps a n d a 9 5 % c o nfi de nce i nter val o f t his L S-mea n differe nce.
* if t he m o del d oes n ot c o n ver ge nce, c o u ntr y will be dr o p pe d.
T he “ra w” S A S P R O C o ut p ut m ust be pr o vi de d i n a statist ical a p pe n di x listi n g.
P o p ul at i on: P D , L O C F.
1 1. 3.
F I G U R E S
Fi g ure 1 4. 2. 3. 1:
L P A 1 8: 2 s pecies pe a k are a r ati o (i n bl o o d): S u bject pr ofile pl ots o ver 
ti me


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 6 0/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
S u bject pr ofile pl ots o ver ti me of  the act ual val ues, wi t h a ne w pl ot per treat me nt gr o u p a n d 
all s u bjects wi t hi n a treat me nt gr o u p o n t he sa me pl ot. A n y u nsc he d ule d res ults will als o b e 
part of t his pl ot.
P o p ul at i on: P D, L O C F .
Fi g ure 1 4. 2. 3. 2:
L P A 1 8: 2 s pecies pe a k are a r ati o (i n bl o o d): Me a n ( +/- S E) pl ot o ver 
ti me
Mea n ( wit h SE) pl ot o ver ti me wi t h all tr e at me nt gr o u ps o n o ne pl ot usi n g differe nt pl ot 
s y m b ols. U nsc he d ule d res ults will n ot be part of t his pl ot.
P o p ul at i on: P D , L O C F.
Fi g ure 1 4. 2. 3. 3:
L P A 1 8: 2 s pecies % re d ucti o n fr o m b aseli ne (i n bl o o d): S u bject 
pr ofile pl ots o ver ti me
S u bject pr ofile pl ots o v er ti me, wi t h a ne w pl ot per treat me nt gr o u p a n d all s u bjects wi t hi n a 
treat me nt gr o u p o n t he sa me pl ot. A n y u nsc he d ule d res ults will als o be part of t his pl ot.
P o p ul at i on: P D , L O C F.
Fi g ure 1 4. 2. 3. 4:
L P A 1 8: 2 s pecies % re d ucti o n fr o m b aseli ne (i n bl o o d): Me a n ( +/-
S E) pl ot o ver ti me
Mea n ( wit h SE) pl ot o ver ti me wi t h all tr e at me nt gr o u ps o n o ne pl ot usi n g differe nt pl ot 
s y m b ols. U nsc he d ule d res ults will n ot be part of t his pl ot.
P o p ul at i on: P D , L O C F.
Fi g ure 1 4. 2. 3. 5:
L P A s pecies pe a k are a r ati o (i n B A L F): Me a n pl ots
Mea n ( wi t h S E) bar c hart per L P A s pecies a n d treat me nt gr o u p at baseli ne a n d Wee k 1 2.
P o p ul at i on: P D , L O C F.
1 1. 4.
L I S TI N G S
Listi n g 1 6. 2. 8. 1:
P D: F ull listi n g
List i n g per t yp e of sa m ple ( blo o d or B A L F), L P A s pecies, treat me nt gr o u p, s u bject, a n d 
pl a n ne d time p oi nt of  the act ual sa m pli n g ti mes r elat i ve t o dr u g a d mi nistrati o n. T he act uall y 
meas ure d L P A s p e ci es p e a k ar e a r ati os , t he mea n of  t he pr e-d osi n g d u plicates val ues ( Day -1 
pre -d ose) , t he deri ve d % re d ucti on vers us baseli ne , t he Ema x a n d A U E C will als o be prese nte d 
i n t his listi n g.
P o p ul at i on: P D.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 6 1/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
1 2.
D E FI NI TI O N S O F P K/ P D A N D P K/ E X P L O R A T O R Y 
E F FI C A C Y A N A L Y SI S T A B L E S, L I S TI N G S A ND F I G U R E S
N o t a bl es or listi n gs are pla n ne d. T hese pl ots will o nl y be pr o d uce d i n case t here is a n effect 
o bser ve d o n P D / efficac y para meters.
Fi g ure 1 4. 2. 4. 1:
C orrel ati o n bet wee n G L P G 1 6 9 0 pl as m a c o nce ntr ati o n a n d L P A 
s pecies % re d ucti o n fr o m b aseli ne (li ne ar-li ne ar pl ot)
Scatter pl ot of  t he G L P G 1 6 9 0 plas ma c o nce ntratio n vers us t he L P A s pecies % re d uctio n fr om 
baseli ne (in bl o o d a n d i n B A L F) . O verall a n d per ti me p oi nt. Wit h all treat me nt gr o u ps o n t he 
sa me gra p h, i n a differe nt s y m b ol. Place b os will be a d de d as a zer o plas ma c o nce ntrati o n.
P o p ul at i on: P D , L O C F.
Fi g ure 1 4. 2. 4. 2:
C orrel ati o n bet wee n G L P G 1 6 9 0 pl as m a c o nce ntr ati o n a n d L P A 
s pecies % re d ucti o n fr o m b aseli ne (l o g-li ne ar pl ot)
S a m e plot as t h e pr e vi o us o n e, b ut wi t h a lo g 1 0 s c al e d G L P G 1 6 9 0 plas ma c o nce ntratio n a xis. 
Pl ace b os will n ot be o n t hi s plot.
P o p ul at i on: P D , L O C F.
Fi g ure 1 4. 2. 4. 3:
C orrel ati o n bet wee n G L P G 1 6 9 0 C m a x a n d L P A s pecies m a xi m u m
% 
re d ucti o n fr o m b aseli ne E m a x
Scatter pl ot (li near -li near scale), li ke a b o ve.
P o p ul at i on: P D , L O C F.
Fi g ure 1 4. 2. 4. 4:
C orrel ati o n bet wee n G L P G 1 6 9 0 C m a x a n d L P A s pecies are a u n der 
t he % re d ucti o n c ur ve A U E C
Scatter pl ot (li near -li near scale), li ke a b o ve.
P o p ul at i on: P D , L O C F.
Fi g ure 1 4. 2. 4. 5:
C orrel ati o n bet wee n G L P G 1 6 9 0 A U C 0- τ a n d L P A s pecies are a u n der 
t he % re d ucti o n c ur ve A U E C
Scatter pl ot (li near -li near scale), li ke a b o ve.
P o p ul at i on: P D, L O C F.
Fi g ure 1 4. 2. 4. 6:
C orrel ati o n bet wee n G L P G 1 6 9 0 pl as m a c o nce ntr ati o n a n d % F V C 
(li ne ar-li ne ar pl ot)
Scatter pl ot of  t he G L P G 1 6 9 0 plas ma c o nce ntratio n vers us % F V C. O verall a n d per ti me p oi nt. 
Wit h all tr e at me nt gr o u ps o n t he sa me gra p h, i n a differe nt s y m b ol. Pl ace b os will be a d de d as 
a zer o plas ma c o nce ntrati o n.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 6 2/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
P o p ul at i on: I T T, L O C F.
Fi g ure 1 4. 2. 4. 7:
C orrel ati o n bet wee n G L P G 1 6 9 0 pl as m a c o nce ntr ati o n a n d % F V C 
(l o g-li ne ar pl ot)
S a m e plot as t h e pr e vi o us o n e, b ut wi t h a lo g 1 0 s c al e d G L P G 1 6 9 0 plas ma c o nce ntratio n a xis. 
Pl ace b os will n ot be o n t his pl ot.
P o p ul at i on: I T T, L O C F.
Fi g ure 1 4. 2. 4. 8:
C orrel ati o n bet wee n G L P G 1 6 9 0 pl as m a c o nce ntr ati o n a n d c h a n ge 
fr o m b aseli ne i n % F V C (li ne ar-li ne ar pl ot)
Scatter pl ot of  the G L P G 1 6 9 0 plas ma c o nce ntrati o n vers us c ha n ge fr om baseli ne i n % F V C. 
O verall a n d per time p oi nt. Wit h all tr e at me nt gr o u ps o n t he sa me gra p h, i n a differe nt 
s y m b ol. Pl ace b os will be a d de d as a zer o plas ma c o nce ntrati o n.
P o p ul at i on: I T T, L O C F.
Fi g ure 1 4. 2. 4. 9:
C orrel ati o n bet wee n G L P G 1 6 9 0 pl as m a c o nce ntr ati o n a n d c h a n ge 
fr o m b aseli ne i n % F V C (l o g-li ne ar pl ot)
S a m e plot as t h e pr e vi o us o n e, b ut wi t h a lo g 1 0 s c al e d G L P G 1 6 9 0 plas ma c o nce ntratio n a xis. 
Pl ace b os will n ot be o n t his pl ot.
P o p ul at i on: I T T, L O C F.
Fi g ure 1 4. 2. 4. 1 0:
C orrel ati o n bet wee n t he L P A s pecies % re d ucti o n fr o m b ase li ne a n d 
effic ac y
Scatter pl ots bet wee n t he L P A s pecies % re d ucti o n f r o m baseli ne (in bl o o d a n d i n B A L F) a n d 
t he c ha n ge fr om baseli ne of t he f oll owi n g para meters: % F V C, bi o mar kers
(in bl o o d) , F RI 
para m eters (z o nes: lo wer a n d u p per l o bes) .
P o p ul at i on: I T T , L O C F .
Fi g ure 1 4. 2. 4. 1 1:
C orrel ati o n bet wee n t he L P A s pecies % re d ucti o n fr o m b aseli ne (i n 
bl o o d) a n d L P A s pecies % re d ucti o n fr o m b aseli ne (i n B A L F)
Scatter pl ots bet wee n t he L P A s pecies % re d ucti o n fr om baseli ne (in bl o o d) a n d t he L P A 
s pecies % re d ucti o n fr o m baseli ne (in B A L F).
P o p ul at i on: I T T , L O C F.
Fi g ure 1 4. 2. 4. 1 2:
C orrel ati o n bet wee n c h a n ge fr o m b aseli ne i n % F V C a n d bi o m ar kers
Scatter pl ots bet wee n t he c ha n ge fr o m baseli ne i n % F V C a n d bi o mar kers (in bl o o d).
P o p ul at i on: I T T, L O C F.
Fi g ure 1 4. 2. 4. 1 3:
C orrel ati o n bet wee n c h a n ge fr o m b aseli ne i n % F V C a n d F RI 
p ar a meters


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 6 3/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
Scatter pl ots bet wee n t he c ha n ge fr om baseli ne i n % F V C a n d F RI para meters (z o nes: l ower 
a n d u p per l o bes) .
P o p ul at i on: I T T, L O C F.
Fi g ure 1 4. 2. 4. 1 4:
C orrel ati o n bet wee n c h a n ge fr o m b aseli ne i n bi o m ar kers a n d F RI 
p ar a meters
Scatter pl ots bet wee n t he c ha n ge fr om baseli ne i n bi o mar kers a n d F RI p ar a m eters (z o nes: 
l ower a n d u p per l o bes).
P o p ul at i on: I T T, L O C F.
Fi g ure 1 4. 2. 4. 1 5:
C orrel ati o n bet wee n c h a n ge fr o m b aseli ne i n s pir o metr y at t he st u d y 
ce nter a n d s pir o metr y at h o me
Scatter pl ots b et wee n t he c ha n ge fr om baseli ne i n s pir o metr y at t he st u d y ce nter ( F E V 1, F V C 
a n d F E V 1/ F V C rati o) a n d s pir o metr y at h o me (F E V 1, F V C a n d F E V 1/ F V C r atio - wee kl y 
a vera ges).
P o p ul at i on: I T T, L O C F.
1 3.
D E FI NI TI O N S O F S A F E T Y A N A L Y SI S T A B L E S, LI S TI N G S 
A N D F I G U R E S
1 3. 1.
A D V E R S E E V E N T S
1 3. 1. 1. Tre at me nt -E mer ge nt P ri nci ple
All a d verse e ve nts st artin g o n or af t er first d osi n g are c o nsi dere d tr e at me nt -e mer ge nt a d verse 
e ve nts ( T E A E).
A d verse e ve nts will be place d i nto a nal ysis peri o ds acc or di n g t o t heir start date. A nal ysis 
p eri o ds: s e e s e cti o n 4. 2 . T h e A E will o nl y be prese nte d i n t he a nal ysis perio d d uri n g w hic h it 
starte d. R ule: peri o d start date ≤ A E start date ≤ peri o d st o p date.
I n case t he A E st art date is i nc om p lete, a w orst -case allo c ati o n will be d o ne acc or di n g t o t he 
a vaila ble p arts of  the A E start date. W he n t o o m uc h of  the A E st art date is missi n g t o a p pl y 
t he a b o ve selectio n r ule, t he A E will be all ocate d t o t he treat me nt peri o d. If t he A E start date 
is e q u al t o t h e d at e of t he t ur ni n g p oi nt bet wee n t he scree ni n g a n d treat me nt a nal ysis perio ds, 
t he n t he A E will be allocate d t o t he tr e at me nt p eri o d. T his is c o nsi dere d a w orst -case 
all ocat i on.
All a d verse e ve nts e mer gi n g d uri n g t he scree ni n g p eri o d will o nl y be liste d, n ot prese nte d i n 
a n y of t he ta bles. T hese e ve nts are n o T E A Es . All ta bles will prese nt T E A Es o nl y.
1 3. 1. 2. Tre at me nt Rel ate d ness
F o ll owi n g (I C H-E 3) , t he dr u g relate d ness will be dic h ot o mize d as f oll ows:
Dr u g rel ate d: at least p ossi bl y dr u g relate d, O R wit h missi n g dr u g relate d ness ( = w orst-case)


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 6 4/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
N ot dr u g relate d: less t ha n p ossi bl y  dr u g relate d.
I n ta b ulati ons t his dic h ot o mize d para meter will be use d, b ut i n t he listi n gs t he ori gi nal 
para m eter will be prese nte d.
1 3. 1. 3. W orst -C ase P ri nci ple
W he n cr oss-ta b ulati n g A E preferre d t er ms vers us a n A E attrib ute (e. g., i nte nsit y), t he w orst -
case is al wa ys a p plie d wit hi n eac h a nal ysis perio d. I.e., w he n a s u bject has m ult i ple times t he 
sa me A E pr ef erre d t er m in t he sa me a nal ysis peri o d, t he n t he s u bject is re p orte d o nl y o nce: 
o nl y wi t h the w orst i nte nsit y.  If t his ha p pe ns i n t wo differe nt a nal ysis p eri o ds, t he A E is 
re p orte d t wice: o nce i n eac h a nal ysis peri o d.
1 3. 1. 4. A d verse E ve nt O nset D a y a n d D ur ati o n
A E o nset d a y i n t he st u d y
= ( A E start date) – ( date of  first st u d y dr u g a d mi nistrati o n) + 1, w he n t he A E start date is 
c o mpletel y k n o w n a n d is o n or after t he date of first st u d y  dr u g a d mi nistratio n
= ( A E start date) – ( date of  first st u d y dr u g a d mi nistratio n), w he n t he A E st art date is 
c o mpletel y k n o w n a n d is bef ore t he date of first st u d y  dr u g a d mi nistrati o n
= Mi ssi ng w he n t he A E start date is i nc o m p lete or u n k n o w n
A E o nset d a y i n t he peri o d
= ( A E st art date) – (start date of  the p eri o d i nto w hic h t he A E w as allocate d) + 1, w he n t he 
A E start date is c o m pletel y k n o w n.
= Mi ssi n g w he n t he A E start date is i nc o m plete or un k n o w n.
A E d ur ati o n
= ( A E st o p date) – ( A E start date) + 1, w he n b ot h dates are c o m pletel y k n o w n.
= (st u d y ter mi nat i on date) – ( A E start date) + 1, w he n t he A E start date is f ull y k n o w n b ut t he 
A E is n ot res ol ve d at t he e n d of  the st u d y; i n t his case t he d urat i on will be prese nte d as “ > x 
da ys” i n t he list i n g t o i de ntif y it as a ce ns ore d res ult.
= Missi n g w he n t he A E start date i s i nc om p lete or u n k n o w n, or w he n t he A E has res ol ve d b ut 
wi t h a n i nc om p lete or u n k n o w n e n d date.
T hese deri ve d para meters will o nl y be prese nte d i n t he list i n gs.
1 3. 1. 5. C alc ul ati o n of P erce nt a ges
All perce nta ges will be calc ulate d a gai nst t he t otal nu m ber of  su bjects w h o are still i n t he 
st u d y in t hat parti c ular a nal ysis peri o d.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 6 5/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
1 3. 1. 6. T a bles
N o f or m al infere nt ial st atistics ( p-val ues) will be deri ve d.
A nal ysis p eri o ds will be re place d b y t heir res pecti ve tr e at me nt via t he data ca pt ure d i n t he 
C R F (i. e, a n as-treate d all ocati o n). All ta b ulati ons a n d listi n gs will prese nt treat me nts rat her 
t ha n a nal ysis peri o ds.
T a ble 1 4 . 3. 1.1:
Tre at me nt -e mer ge nt a d verse e ve nts: S u m m ar y t a ble
Ta b ulat i on per treat me nt gr o u p of  t he n u m ber a n d perce nta ge of s u bjects wit h t he f oll owi n g:

S u bjects wit h at least o ne treat me nt -e mer ge nt a d verse e ve nt ( T E A E)

S u bjects wit h at least o ne seri o us T E A E

S u bjects w h o die d

S u bjects wit h at least o ne mil d T E A E as w orst i nte nsit y

S u bjects wit h at least o ne m o derate T E A E as w orst i nte nsit y

S u bjects wit h at least o ne se vere T E A E as w orst i nte nsit y

S u bjects wit h at least o ne T E A E t hat was c o nsi dere d treat me nt-relate d

S u bjects wit h at least o ne T E A E f or w hic h t he st u d y treat me nt was te m p oraril y st o p pe d

S u bjects wit h at least o ne T E A E f or w hic h t he st u d y treat me nt was per ma ne nt l y st o p pe d
P o p ul at i on: safet y .
T a ble 1 4 . 3. 1.2:
Tre at m e nt -e mer ge nt a d verse e ve nts: T a b ul ati o n of all a d verse e ve nts
Ta b ulat i on of T E A E preferre d ter ms per b o d y  class a n d per treat me nt gr o u p.
P o p ul at i on: safet y .
T a ble 1 4 . 3. 1.3:
Tre at me nt -e mer ge nt a d verse e ve nts: T a b ul ati o n per i nte nsit y
Cr oss -ta b ulatio n of  TE A E pr ef err e d ter ms vers us t heir i nte nsit y. Use t he w orst -case i nte nsit y 
per T E A E per s u bject. Per treat me nt gr o u p.
P o p ul at i on: safet y .
T a ble 1 4 . 3. 1.4:
Tre at me nt -e mer ge nt a d verse e ve nts: T a b ul ati o n of all tre at me nt -
rel ate d e ve nts
Ta b ulat i on of  TE A E pr ef erre d ter ms per b o d y  class a n d per treat me nt gr o u p. Selecti n g o nl y 
t he T E A Es t hat were treat me nt -relate d (see secti o n 1 3. 1. 2 ).
P o p ul at i on: safet y .
T a ble 1 4 . 3. 1.5:
Tre at me nt -e mer ge nt a d verse e ve nts: T a b ul ati o n of t he i nte nsit y of 
tre at me nt-rel ate d e ve nts
Cr oss -ta b ulatio n of  TE A E preferre d t er ms vers us t heir i nte nsit y, per b o d y  class a nd p er 
treat me nt gr o u p. Use t he w orst -case i nte nsit y per T E A E per s u bject, select i n g o nl y t he T E A Es 
t hat were treat me nt -relate d (see secti on 1 3. 1. 2 ).


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 6 6/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
P o p ul at i on: safet y .
T a ble 1 4. 3. 1. 6:
Tre at me nt -e mer ge nt a d verse e ve nts: T a b ul ati o n of seri o us e ve nts
Ta b ulat i on of  TE A E pr ef erre d ter ms per b o d y  class a n d per treat me nt gr o u p. Selecti n g o nl y 
t he treat me nt -e mer ge nt serio us a d verse e v e nts.
P o p ul at i on: safet y .
T a ble 1 4. 3. 1. 7:
Tre at me nt -e mer ge nt a d verse e ve nts: T a b ul ati o n of e ve nts le a di n g t o 
a per m a ne nt st o p
Ta b ulat i on of  TE A E pr ef erre d ter ms per b o d y  class a n d per treat me nt gr o u p. Selecti n g o nl y 
t he T E A Es f or w h ic h t he st u d y tr e at me nt was p er m a ne nt l y disc o nt i n ue d ( AE pa ge ), or f or
w hic h t he st u d y  was disc o nti n ue d (st u d y ter mi nati o n pa ge).
P o p ul at i on: safet y .
T a ble 1 4. 3. 1. 8: 
T re at me nt -e mer ge nt seri o us a d verse e ve nts: T a b ul ati o n f or 
E u dr a C T re p orti n g
Ta b ulat i on of  t he n u m ber of  su bjects a n d e ve nts per b o d y  class, pr ef erre d t er m a n d per 
treat me nt gr o u p.
P o p ul at i on: safet y.
T a ble 1 4. 3. 1. 9 : 
Tre at me nt -e mer ge nt n o n -seri o us a d verse e ve nts: T a b ul ati o n f or 
E u dr a C T re p orti n g
S a m e as t he pre vi o us ta ble, b ut o nl y selecti n g T E A Es t hat are n ot seri o us.
P o p ul at i on: s afet y.
T a ble 1 4. 3. 1. 1 0: 
T re at me nt -e mer ge nt n o n -seri o us a d verse e ve nts: T a b ul ati o n f or 
E u dr a C T re p orti n g of T E A Es occ urri n g i n at le ast 5 % i n eit her 
tre at me nt gr o u p
S a m e as t he pre vi o us ta ble, selecti n g all t he li nes fr o m t he ta ble w here t here is at least 5 % 
occ urre nce i n eit her tr e at me nt gr o u p. If t he S O C li ne is selecte d b ut n o ne of  the ass ociat e d 
preferre d ter ms, t he n t he S O C li ne is st ill t o be prese nte d b ut wit h o ut preferre d ter m li nes.
P o p ul at i on: s afet y.
1 3. 1. 7. L isti n gs
Listi n g 1 6 . 2. 9. 1:
Tre at me nt -e mer ge nt a d verse e ve nts: F ull listi n g
List i n g per tr e at me nt gr o u p , per s u bject a n d per a nal ysis p eri o d (e xcl u di n g scree ni n g) of t he 
f oll owi n g :

P eri o d start a n d e n d date

A E preferre d ter m


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 6 7/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n

A E start a n d e n d date

A E o nset da y  in st u d y

A E o nset da y  in peri o d

A E d urati o n

A E i nte nsit y

A E dr u g relate d ness

A E o utc o me

A E acti o n ta ke n

C o nc o mit a nt t hera p y starte d ( yes/ n o)
P o p ul at i on: safet y .
Listi n g 1 6 . 2. 9. 2:
Pre -tre at me nt a d verse e ve nts: F ull listi n g
List i n g per treat me nt gr o u p a n d per s u bject of  the scree ni n g p eri o d of  all A E details, li ke i n 
t he pre vi o us list i n g.
P o p ul at i on: safet y .
Listi n g 1 6 . 2. 9. 3:
Seri o us a d verse e ve nts: F ull listi n g
S a m e as t he pre vio us listi n g, b ut o nl y selecti n g S A Es (irres pecti ve t hei r tr e at me nt -e mer ge nce, 
s o als o s h o wi n g a n y S A Es d uri n g t he scree ni n g a nal ysis peri od ).
P o p ul at i on: safet y .
Listi n g 1 6 . 2. 9. 4:
Tre at me nt -e mer ge nt a d verse e ve nts: F ull listi n g of t he e ve nts le a di n g 
t o disc o nti n u ati o n
S a m e as t h e pr e vio us listi n g, b ut o nl y selecti n g T E A Es t hat lea d t o a per ma ne nt st o p of st u d y 
dr u g ( o n t he A E C R F pa ge), or of t he st u d y its elf ( o n t he St u d y Ter mi nati o n C R F pa ge) .
P o p ul at i on: safet y .
Listi n g 1 6. 2. 9 .5 :
Tre at me nt -e mer ge nt a d verse e ve nts: F ull listi n g of t he e ve nts le a di n g 
t o a te m p or ar y st o p
S a m e as t h e pr e vio us listi n g, b ut o nl y selecti n g T E A Es t hat lea d t o a t e mp or ar y st o p of  st u d y 
dr u g .
P o p ul at i on: safet y .
Listi n g 1 6 . 2. 9. 6:
A d verse e ve nts: C o di n g i nf or m ati o n
List i n g of  all a vaila ble c o di n g ste ps bet wee n A E ver bat i m a n d A E s yste m or ga n class, 
me nt i oni n g als o t he s u bjects w h o ha d t his A E. 
P o p ul at i on: safet y .
Listi n g 1 6 . 2. 9. 7:
A d verse e ve nts: Listi n g of s u bjects f or w h o m a n arr ati ve is re q uire d


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 6 8/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
List i n g a n d fla g gi n g s u bjects w h o:

Di e d

Ha d a n S A E

Ha d a n A E lea di n g t o st u d y disc o nti n uati on

Ha d a n A E lea di n g t o a per ma ne nt st o p of st u d y  dr u g.
P o p ul at i on: all scree ne d s u bjects.
T he cli nical st u d y re p ort will a d d s u bject case narrati ves i n t he b o d y  of t he r e p ort a n d/ or i n 
secti on 1 4. 3. 1. N o sta n dar d pr o gra m mi n g is pla n ne d f or t his.
1 3. 2.
L A B O R A T O R Y S A F E T Y
1 3. 2. 1. L a b or at or y U nits
T he st atistical a nal ysis will o nl y  prese nt res ults i n Sta n dar d I nter nati o nal ( SI) u nits. Ot her 
u nits will n ot be prese nte d.
La b orat or y  tests wi t h onl y a ver y l ow sa m ple size ( N < 3 o verall) will n ot be prese nte d i n t he 
ta bles, b ut o nl y i n t he listi n gs. La b orat or y  tests t hat are n ot part of  the pla n ne d t est pa nels 
acc or di n g t o t he pr ot oc ol will o nl y be liste d.
Uri nal ysis tests will be prese nte d as part of t he descri pt i ve statistics a n d/or s hift ta bles.
T h e para met ers fr o m t he P D secti o n will n ot be re peate d i n t his sect i on.
1 3. 2. 2. N u m ber of Si g nific a nt D i gits
I n ta bles a n d listi n gs, t he origi nal  r es ults will be r o u n de d t o prese nt o nl y a r ele va nt n u m ber of 
di gi ts. T h e M oc k 
T L Fs c o ntai n ta bles o n t he e x pecte d n u m be r of  si g nifica nt di gi ts p er 
la borat or y t est. T hi s r o u n di n g will be d o ne pri or t o a n y para meter deri vati on.
N ote t hat t his ta ble als o c o ntai ns t he classificat i on of la b or at or y tests i nt o cate g ories.
1 3. 2. 3. B aseli ne a n d C h a n ge fr o m B aseli ne
T he baseli ne is defi ne d as t he last sa m ple pri or t o d osi n g. Baseli ne will be deter mi ne d p er 
la borat or y test i n di vi d uall y. It is rec o g nize d t hat baseli ne tests ma y t h us c o me fr o m  mor e t h a n 
o ne l a borat or y sa m ple a n d n ot just fr o m t he “ baseli ne visit” sa m ple. 
T he c ha n ge fr o m baseli ne will be calc ulate d f or all p ost -baseli ne t i me p oi nts as:
C ha n ge fr o m baseli ne at ti me p oi nt t = val ue at ti me p oi nt t – baseli ne val ue.
1 3. 2. 4. Scree ni n g a n d F oll o w - u p Visits
Scree ni n g a n d f o ll ow- u p visits will be s h o w n f or eac h treat me nt gr o u p; n ot p o ole d.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 6 9/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
1 3. 2. 5. Sc o ri ng of L a b or at or y V al ues
All ori gi nal val ues will be c o m pare d t o t heir matc hi n g n or mal ra n ges. T he n or m al ra n ges 
pr o vi de d b y t he la b orat or y will be use d f or t his, as a vaila ble i n t he data base. Val ues will  be 
s c or e d as a b n or mall y l ow ( L), n or m al ( N) or a b nor m all y hi g h ( H): t he varia ble L B N RI N D i n 
S D T M. L B dataset will be use d i n t he a nal ysis. 
A n y cli nical si g nifica nce fla gs will be use d i n t he list i n gs.
1 3. 2. 6. W orst -C ase A b n or m alit y
Deri ve d per para meter se paratel y.
All n o n- missi n g p ost -baseli ne val ues (incl u di n g p ost -baseli ne u nsc he d ule d meas ure me nts, 
retests a n d f oll o w-u p meas ure me nts) will be use d t o deri ve t he f oll o wi n g w orst -case:

H = a b n or mall y hi g h:
at least o ne p ost -baseli ne meas ure me nt is a b o ve t he n or mal ra n ge, a n d t here are n o val ues 
bel o w t he n or mal ra n ge.

L = a b n or mall y l o w:
at least o ne p ost -baseli ne meas ure me nt is bel o w t he n or mal ra n ge, a n d t here are n o val ues 
a b o ve t he n or mal ra n ge.

L + H = a b n or m all y hi g h a n d lo w:
at least o ne p ost -baseli ne meas ure me nt is a b o ve t he n or m al ra n ge, a n d at least o ne ot her 
p ost -baseli ne meas ure me nt is bel o w t he n or mal ra n ge.

N = n or m al:
all p ost -baseli ne meas ure me nts are wit hi n n or mal li mits.
1 3. 2. 7. T a bles 
N o f or m al infere nt ial st atistics ( p-val ues) will be deri ve d.
T a ble 1 4. 3. 2. 1:
L a b or at or y d at a: Descri pti ve st atistics per ti me p oi nt
Descri pt i ve st atistics of  act u al val ues a n d c ha n ges fr o m baseli ne p er lab orat or y  test cate g or y 
( he mat olo g y , bi oc he mistr y , uri nal ysis), la b orat or y t est a n d u ni t, treat me nt gr o u p a n d time 
p oi nt.
P o p ul at i on: safet y .
T a ble 1 4 . 3. 2.2: 
L a b or at or y d at a: S hift t a ble of t he l a b or at or y a b n or m alities per ti me 
p oi nt
S hift  ta ble per la borat or y test cate g or y ( he mat olo g y , bioc he mistr y , uri nal ysis), la borat or y test, 
treat me nt gr o u p a n d time p oi nt. T he ta ble will prese nt t he s hift i n a b n or malit y (L/ N/ …) at 
eac h p ost -baseli ne ti me p oi nt (i ncl u di n g t he w ors t-case) vers us t he baseli ne a b n or malit y 
( L/ N/ H). Tests wit h o ut n or mal ra n ges will n ot be prese nte d i n t his ta ble.
P o p ul at i on: safet y .


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 7 0/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
T a ble 1 4 . 3. 2. 3:
L a b or at or y d at a: Tre at me nt -e mer ge nt l a b o r at or y a b n or m alities per 
ti me p oi nt
Fre q ue nc y ta ble of  the tr e at me nt -e mer ge nt lab orat or y a b n or malities per la borat or y t est 
cate g or y (he mat ol o g y , bi oc he mistr y , uri nal ysis), lab or at or y t est, treat me nt gr o u p a n d time 
p oi nt (i ncl u di n g t he w orst -case). A p ost -baseli ne
a b n or malit y is c o nsi dere d tr e at me nt -
e mer ge nt if it differs fr om t he baseli ne res ult. Tests wi t ho ut n or m al ra n ges will n ot be 
prese nte d i n t his ta ble.
P o p ul at i on: safet y .
T a ble 1 4 . 3. 2.4:
L a b or at or y d at a: S hift t a ble of t he c ate g oric al l a b or at or y d at a per 
ti me p oi nt
S hift  ta ble per la borat or y test cate g or y ( he mat olo g y , bioc he mistr y , uri nal ysis), la borat or y test, 
treat me nt gr o u p a n d ti me p oi nt. S el ect i n g o nl y t he tests wit h cate g orical data. T he ta ble will 
prese nt t he s hift i n val ue at eac h p ost- baseli ne t i me p oi nt vers us t he baseli ne val ue.
P o p ul at i on: safet y .
1 3. 2. 8. F i g ures
Fi g ure 1 4 . 3. 2.1:
L a b or at or y d at a: S u bject pr ofile pl ots o ver ti me f or s u bjects wit h a 
tre at me nt-e mer ge nt a b n or m alit y
S u bject pr ofile pl ots o ver ti me, wi t h eac h lab or at or y t est a n d treat me nt gr o u p o n a ne w p a g e 
b ut wi t h all s u bjects of o ne tr e at me nt gr o u p o n t he sa me pl ot. A n y u nsc he d ule d r es ults will 
als o be part of t his pl ot.
P o p ul at i on: safet y , selecti n g s u bjects wit h a treat me nt-e mer ge nt a b n or malit y.
Fi g ure 1 4 . 3. 2.2:
L a b or at or y d at a: Me a n ( +/- S E) pl ots of t he act u al v al ues o ver ti me
Mea n ( wi t h S E ) plots of  t he a ct u al val ues o ver ti me, wit h eac h la bor at or y test o n a ne w pa ge 
b ut wi t h all treat me nt gr o u ps o n t he sa me pl ot usi n g differe nt pl ot s y mb o ls. U nsc he d ule d 
res ults will not be part of t his pl ot.
P o p ul at i on: safet y .
Fi g ure 1 4 . 3. 2.3:
L a b or at or y d at a: Me a n ( +/- S E) pl ots of t he c h a n ges fr o m b aseli ne 
o ver ti me
Mea n ( wit h SE ) pl ots of  t he c ha n ges fr om baseli ne o ver time, wi t h eac h la borat or y t est o n a 
ne w pa ge b ut wi t h all tr e at me nt gr o u ps o n t he sa me pl ot usi n g differe nt pl ot s y m b ols. 
U nsc he d ule d r es ults will n ot be part of  this pl ot. Wit h a h ori z o ntal refere nce li ne at zer o, 
i n dicati n g n o c ha n ge. Pl ots will start wit h a zer o mea n at baseli ne.
P o p ul at i on: safet y .


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 7 1/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
1 3. 2. 9. L isti n gs
All listi n gs will c o ntai n ne xt t o t he act ual data (ra w a n d c ha n ges) t he f oll owi n g para meters:

A faste d Y/ N fla g

A n a b n or malit y L/ H fla g

T he test’s n or mal ra n ge

A cli nical rele va nce fla g
Listi n g 1 6 . 2. 10. 1:
L a b or at or y d at a: F ull listi n g
List i n g per treat me nt gr o u p, per s u bject a n d per ti me p oi nt of all data.
P o p ul at i on: safet y .
Listi n g 1 6 . 2. 10. 2:
L a b or at or y d at a: A b n or m alities listi n g
List i n g per treatme nt  gr o u p, per s u bject a n d p er ti me p oi nt of  all p ost -baseli ne time p oi nts
sc ore d as treat me nt -e mer ge nt o ut -of -n or m al-ra n ge or cli nicall y si g nifica nt, pl us als o t he 
baseli ne refere nce ti me p o i nt.
P o p ul at i on: safet y .
1 3. 3.
E C G
1 3. 3. 1. A v ail a ble D at a
A vaila ble para meters: P R, H R, R R, Q R S a n d Q T.
1 3. 3. 2. C alc ul ate d P ar a meters
T he Q Tc will al wa ys be deri ve d d uri n g t he stati stical a nal ysis, e ve n w he n alrea d y a vaila ble i n 
t he data base. T he val ue i n t he data base will n ot be use d i n t he a nal ysis.
T he Q Tc will be calc ulate d usi n g t he f o ll owi n g f or m ulae:
Fr i der icia’s c u be-r o ot c orrecte d Q T ( Frid eri cia, 1 9 2 0) :
Q Tc F ( m s) = Q T ( ms) x      (   )
Q Tc F ( m s) = Q T ( ms) x    (   )
 T he f or mula usi n g R R is preferre d. I n case n o R R is availa ble, t he f or mula usi n g H R will b e 
a p plie d. Deri ve d Q Tc F val ues will first be r o u n de d t o t he nearest first deci mal bef ore deri vi n g 
c ha n ges fr o m baseli ne a n d cate g ories.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 7 2/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
1 3. 3. 3. B aseli ne a n d C h a n ge fr o m B aseli ne
T he baseli ne is defi ne d as t he last n o n- missi n g v al ue pri or t o d osi n g. Baseli ne will  be 
deter mi ne d per E C G para meter i n di vi d uall y. It is rec o g nize d t hat baseli ne para meters ma y 
t hus c o m e fr o m more t ha n o ne E C G rea di n g a n d n ot j ust fr o m t he “ baseli ne visit” rea di n g. 
T he c ha n ge fr o m baseli ne will be calc u late d f or all p ost-baseli ne t i me p oi nts as:
C ha n ge fr o m baseli ne at ti me p oi nt t = val ue at ti me p oi nt t – baseli ne val ue.
1 3. 3. 4. Scree ni n g a n d F oll o w -u p V isits
Scree ni n g a n d f o ll ow- u p visits will be s h o w n f or eac h treat me nt gr o u p; n ot p o ole d.
1 3. 3. 5. N or m al R a n ges
Q T a nd Q Tc F para meters: first r o u n d t he val ue as descri be d a b o ve a n d t he n a p pl y t he 
f oll owi n g cate g ori zat i ons:

of  t he act ual val ues (a val ue > 4 5 0 ms is c o nsi dere d as a b n or mal):

≤ 4 5 0 ms

] 4 5 0, 4 8 0] ms

] 4 8 0, 5 0 0] ms

> 5 0 0 ms

of  t he c ha n ges fr o m baseli ne (a c ha n ge > 3 0 m s is c o nsi dere d as a b n or mal):

≤ 3 0 ms (i ncl u di n g all decreases i n Q T)

] 3 0, 6 0] ms

> 6 0 ms
1 3. 3. 6. W orst -c ase A b n or m alit y of Q T a n d Q Tc F
Deri ve d per para meter se paratel y.
All n o n- missi n g 
p ost -baseli ne v al ues (incl u di n g u nsc he d ule d meas ure me nts, retests 
a n d 
f oll ow- u p meas ure me nts) will be use d t o deri ve t he f oll o wi n g w orst -case. T he w orst -case is 
t he lar gest n o n-missi n g p ost -baseli ne val ue as well as c ha n ge fr o m baseli ne.
1 3. 3. 7. T a bles
N o f or m al infere nt ial st atistics ( p-val ues) will be deri ve d.
T a ble 1 4. 3. 3. 1:
E C G: Descri pti ve st atistics per ti me p oi nt
Descri pt i ve st atistics of  the act ual val ues a n d c ha n ges fr om baseli ne per t est a n d u nit, 
treat me nt gr o u p a n d ti me p oi nt.
P o p ul at i on: safet y .
T a ble 1 4. 3. 3. 2: 
E C G: S hift t a ble of t he Q T a b n or m alities per ti me p oi nt


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 7 3/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
S hift  ta ble p er t est, treat me nt gr o u p a n d time p oi nt. T he ta ble will prese nt t he s hift in 
a b n or malit y at eac h p ost -baseli ne ti me p oi nt (i ncl u di n g t he w orst -case) vers us t he baseli ne 
a b n or malit y. P ar a meters: Q T a n d Q Tc F.
P o p ul at i on: safet y .
T a ble 1 4. 3. 3. 3:
E C G: Tre at me nt -e mer ge nt Q T a b n or m alities per ti me p oi nt
Fre q ue nc y ta ble of  the treat me nt -e mer ge nt a b n or malit ies p er para meter, treat me nt gr o u p a n d 
ti me p oi nt (incl u di n g t he w orst -case). A p ost -baseli ne a b n or malit y is c o nsi dere d tr e at me nt -
e mer ge nt if it is hi g her t ha n t he baseli ne res ult. Para meters: Q T a n d Q Tc F.
P o p ul at i on: safet y .
T a ble 1 4. 3. 3. 4 :
E C G: Tre at me nt -e mer ge nt a b n or m al c h a n ge i n Q T per ti me p oi nt
Fr e q ue nc y ta ble per test, treat me nt gr o u p a n d ti me p oi nt (i nclu di n g t he w orst -case). T he ta ble 
will prese nt t he a b n or malit y of  the c ha n ges at eac h p ost -baseli ne time p oi nt acc or di n g to t h e 
classificat i ons of secti o n 1 3. 3. 5 . Para meters: Q T a n d Q Tc F .
P o p ul at i on: safet y .
1 3. 3. 8. L isti n gs
Listi n g 1 6. 2. 1 1. 1:
E C G: F ull listi n g
List i n g per treat me nt gr o u p, per s u bject a n d per ti me p oi nt of t he E C G para meters (ra w valu es 
as well as c ha n ges fr o m baseli ne), fla g gi n g a b n or mal res ults. I ncl u des E C G i nter pretatio n a n d 
m o r p h olo g y  fi n di n gs.
P o p ul at i on: safet y .
Listi n g 1 6. 2. 1 1. 2:
E C G: A b n or m alities listi n g
List i n g per treat me nt gr o u p, per s u bject a n d per ti me p oi nt of  all p ost -baseli ne d at a sc ore d as 
treat me nt -e mer ge nt o ut-of -n or m al-ra n ge (i.e., a Q T or Q Tc F val ue > 4 5 0 ms or a Q T or Q Tc F 
c ha n ge > 3 0 ms) or p ost -baseli ne cli nicall y si g nifica nt, pl us als o t he baseli ne r efere nce ti me 
p oi nt. 
P o p ul at i on: safet y .
1 3. 4.
VI T A L S I G N S
1 3. 4. 1. A v ail a ble D a t a
A vaila ble para meters: heart rate, res pirat or y r at e, diast olic a n d s yst olic bl o o d press ure, 
t e mperat ure.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 7 4/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
1 3. 4. 2. B aseli ne a n d C h a n ge fr o m B aseli ne
T he baseli ne val ue will be t he last n o n- missi n g v al ue pri or t o first d osi n g. Baseli ne will b e 
deter mi ne d p er vit al si g ns para meter i n di vi d uall y. It is rec o g nize d t hat baseli ne para meters 
ma y t hus c o me fr om m o re t ha n o ne vit al si g ns rea di n g a n d n ot j ust fr o m t he “ baseli ne visit” 
rea di n g.
T he c ha n ge fr o m baseli ne will be calc ulate d f or all p ost -baseli ne t i me p oi nts as:
C ha n ge fr o m baseli ne at ti me p oi nt t = val ue at ti me p oi nt t – baseli ne val ue.
1 3. 4. 3. Scree ni n g a n d F oll o w -u p V isits
Scree ni n g a n d f o ll ow- u p visits will be s h o w n f or eac h treat me nt gr o u p; n ot p o ole d.
1 3. 4. 4. N or m al R a n ges
P ar a meter, u nit
N or m al r a n ge
L o we r li mit
U p p er li mit
H R , b p m
4 0
1 0 0
R R, breat hs/ mi n
1 2
1 6
D B P, m m H g
4 5
9 0
S B P, m m H g
9 0
1 5 0
Te m perat ure, ° C
3 5. 5
3 7. 5
V al ues e q ual t o t he b o u n daries are still c o nsidere d n or m al ( N). A val ue is classifie d as 
a b n or mall y lo w ( L) w he n t he val ue < l ower li mit of  t he n or mal ra n ge. A val ue is classifie d as 
a b n or mall y hi g h ( H) w he n t he val ue > u p per li mit of t he n or mal ra n ge.
1 3. 4. 5. W orst -C ase A b n or m alit y
Deri ve d per para meter se paratel y.
All n o n- missi n g 
p ost -baseli ne v al ues (incl u di n g u nsc he d ule d meas ure me nts, retests 
a n d 
f oll ow- u p m eas ure me nts) will be use d t o deri ve t he f o ll owi n g w orst -case:

H = a b n or mall y hi g h: 
at least o ne p ost -baseli ne meas ure me nt is a b o ve t he n or mal ra n ge, a n d t here are n o val ues 
bel o w t he n or mal ra n ge.

L = a b n or m all y l o w: 
at least o ne p ost -baseli ne meas ure me nt is bel o w t he n or mal ra n ge, a n d t here are n o val ues 
a b o ve t he n or mal ra n ge.

L + H = a b n or m all y hi g h a n d lo w: 
at least o ne p ost -baseli ne meas ure me nt is a b o ve t he n or m al ra n ge, a n d at least o ne ot her 
p ost -baseli ne meas ure me nt is bel o w t he n or mal ra n ge.

N = n or m al: 
all p ost -baseli ne meas ure me nts are wit hi n n or mal li mits.


Statistical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 7 5/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
1 3. 4. 6. T a bles 
N o f or m al infere nt ial st atistics ( p-val ues) will be deri ve d.
T a ble 1 4. 3. 4. 1:
Vit al si g ns: Descri pti ve st atistics per ti me p oi nt
Descri pt i ve st atistics of  the act ual val ues a n d c ha n ges fr om baseli ne per t est a n d u nit, 
treat me nt gr o u p a n d ti me p oi nt.
P o p ul at i on: safet y .
T a ble 1 4. 3. 4. 2:
Vit al si g ns: S hift t a ble of t he a b n or m alities per ti me p oi nt
S hift  ta ble p er t est, treat me nt gr o u p a n d time p oi nt. T he ta ble will prese nt t he s hift in 
a b n or malit y (L/ N/ …) at eac h p ost -baseli ne time p oi nt (incl u di n g t he w orst -case) vers us t he 
baseli ne a b n or malit y ( L/ N/ H).
P o p ul at i on: safet y .
T a ble 1 4. 3. 4. 3:
Vit al si g ns: Tre at me nt -e mer ge nt a b n or m alities per ti me p oi nt
Fre q ue nc y ta ble of  the treat me nt -e mer ge nt a b n or malit ies p er para meter, treat me nt gr o u p a n d 
ti me p oi nt (incl u di n g t he w orst -case). A p ost -baseli ne a b n or mality is c o nsi dere d tr e at me nt -
e mer ge nt if it is differe nt fr o m t he baseli ne res ult. 
P o p ul at i on: safet y .
1 3. 4. 7. L isti n gs
Listi n g 1 6. 2. 1 2. 1:
Vit al si g ns: F ull listi n g
List i n g per treat me nt gr o u p , per s u bject a n d per ti me p oi nt of  all para meters: ra w val ues, 
c ha n ges fr o m baseli ne, a n d fla g gi n g a b n or mal res ults.
P o p ul at i on: safet y .
Listi n g 1 6. 2. 1 2. 2:
Vit al si g ns: A b n or m alities listi n g
List i n g per treat me nt gr o u p, per s u bject a n d p er ti me p oi nt of  all p ost -baseli ne ti me p oi nts 
sc ore d as treat me nt -e mer ge nt o ut- of -n or m al-ra n ge or cli nicall y si g nifica nt, pl us als o t he 
baseli ne refere nce ti me p o i nt.
P o p ul at i on: safet y .
1 3. 5.
P H Y SI C A L E X A MI N A TI O N S
Listi n g 1 6 . 2. 13. 1:
P h ysic al e x a mi n ati o ns: A b n or m al ities listi n g
List i n g per tr e at me nt gr o u p, per s u bject a n d per ti me p oi nt of  the selecti on of all a b n or mal 
fi n di n gs.
P o p ul at i on: safet y .


Stati stical A nal ysis Pla n G L P G 1 6 9 0- C L - 2 0 2
Pa ge 7 6/ 7 6
Versi o n 1. 0 0 , Fi nal , 1 6- J u n-2 0 1 7
C o nfi de ntial I nf or mati o n
1 4.
R E F E R E N C E S
Fri dericia, L. ( 1 9 2 0). Die s yst ole n da uer i m ele ktr o kar di o gra m m bei n or male n me nsc he n u n d bei 
herz kra n ke n. 5 3: 4 6 9 - 4 8 6.
I C H-E 3. ( Dece m ber 1 9 9 5). Str uct ure a n d c o nte nt of cli nic al st u dy re p orts. Ste p 4 G ui deli ne.
I C H-E 6. ( 1 7 J ul y 1 9 9 6). G ui deli ne f or g o o d cli nic al pr actice. Ste p 5 G ui deli ne.
I C H-E 9. ( 5 Fe br uar y 1 9 9 8). St atistic al pri nci ples f or cli nc al tri als. Ste p 4 g ui deli ne.
Miller, M., Ha n ki ns o n, J., & Br usasc o, V. e. ( 2 0 0 5). Sta n dar disati o n of s pir o metr y. E ur Res pir J, 2 6 , 
3 1 9- 3 3 8.
Q ua njer, P., Sta n oje vic, S., C ole, T., Ba ur, X., Hall, G., C ul ver, B., . . . St oc ks, J. ( 2 0 1 2). M ulti -et h nic 
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e q uati o ns: Re p ort of t he Gl o bal L u n g F u ncti o n I nitiati ve ( G LI), E R S Tas k F orce t o 
esta blis he d i mr p o ve d L u n g F u ncti o n Refere nce Val ues. E ur Res pir J 4 0 ( 6) , 1 3 2 4- 43.
U S N R C. ( 2 0 1 4, Dec 1 2). U nite d St ates N ucle ar Ref ul at ory C o m missi o n. F act s heet o n bi ol o gic al 
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c ollecti o ns/fact -s heets/ bi o-ef f ects-ra diati o n. ht ml
W N A. ( 2 0 1 5, Ma y 2 2). W orl d N ucle ar Ass oci ati o n . O p ger oe pe n o p J u n 0 5, 2 0 1 5, va n N uclear 
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