A Prospective, Multicenter, Open Label, Single Arm, Phase 2 Study to Investigate the Safety, Tolerability and Pharmacokinetics of Selexipag in Children With Pulmonary Arterial Hypertension
Phase: PHASE2
Conditions: Pulmonary Arterial Hypertension
Sponsor: Actelion

Actelion Pharmaceuticals Ltd*
(a Janssen Pharmaceutical Company of Johnson & Johnson)
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Selexipag / ACT-293987/ JNJ-67896049
Pulmonary arterial hypertension
Protocol AC-065A203
A prospective, multicenter, open-label, single-arm, Phase 2 study to investigate the
safety, tolerability and pharmacokinetics of selexipag in children with pulmonary
arterial hypertension
Study Phase: 
2
EudraCT Number: 
2018-000145-39
Status and version: 
Approved Version 8
Date: 
30 September 2021
Document type 
Amended global protocol
EDMS number: 
EDMS-RIM-265015, 7.0
*Actelion Pharmaceuticals Ltd (“Actelion”) is a global organization that operates through different legal
entities in various countries. Therefore, the legal entity acting as the sponsor for Actelion studies may vary,
such as, but not limited to Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; or
Janssen Research & Development, LLC. The term “sponsor” is used throughout the protocol to represent
these various legal entities; the sponsor is identified on the Contact Information page that accompanies the
protocol
Confidentiality statement
The information provided herein contains Company trade secrets, commercial or financial information that
the Company customarily holds close and treats as confidential. The information is being provided under the
assurance that the recipient will maintain the confidentiality of the information under applicable statutes,
regulations, rules, protective orders or otherwise.
NCT03492177

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SPONSOR CONTACT DETAILS
Sponsor 
Actelion Pharmaceuticals Ltd*
Gewerbestrasse 16
CH-4123 Allschwil
Switzerland
 
+41 61 565 65 65
Clinical Trial Physician 
Contact details of the Clinical Trial Physician can
be found in the Investigator Site File
Local Safety Officer 
Toll phone number: [number] 
Site-specific toll telephone numbers and toll-free
numbers for the Local Safety Officer can be found
in the Investigator Site File
*Actelion Pharmaceuticals Ltd. is a Janssen pharmaceutical company of Johnson & Johnson
and is hereafter referred to as the sponsor of the study
SPONSOR CONTRIBUTORS TO THE PROTOCOL
Clinical Trial Scientist 
Clinical Trial Pharmacologist 
Clinical Trial Statistician  
Clinical Trial Physician  
Drug Safety Physician  
CONTRACT RESEARCH ORGANIZATIONS INFORMATION
CENTRAL LABORATORY 
Labcorp (Covance) Central Laboratory Sárl
Rue Moise-Marcinhes 7
CH-1217 Meyrin/Genève
Switzerland
CENTRAL RANDOMIZATION  ALMAC
20, Seagoe Industrial Estate
Craigavon, BT63 5QD, UK
BIOANALYTICAL 
LABORATORY 
PRA Health Sciences Early Development
Services
Bioanalytical Laboratory
Amerikaweg 18, 9407 TK Assen,
The Netherlands
Frontage Laboratories (Shanghai) Co. Ltd., (For
China Only)
Building 13, Lane 67, Libing Road,
Zhangjiang, Hi-Tech Park
PPD
PPD
PPD
PPD
PPD

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Amendment 7 Version 8
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201203, Shanghai, China
CENTRAL ECG  
ERT
Peterborough Business Park
Lynch Wood, Peterborough, PE2 6FZ
UK
CENTRAL ECHO  
Bioclinica
7707 Gateway Blvd, 3rd Fl
Newark, CA94560
US

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PROTOCOL AMENDMENT SUMMARY OFCHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 7, Protocol Version 8 
30 Sep 2021
COVID-19 Appendix Version 2 (EDMS-RIM- 263660, 5.0) 
19 May 2021
Amendment 6, Protocol Version 7 
19 May 2021
Amendment 5, Protocol Version 6 
05 Oct 2020
COVID-19 Appendix Version 1 (EDMS-RIM- 263660, 1.0) 
16 Jun 2020
Amendment 4, Protocol Version 5 
18 Mar 2020
Amendment 3, Protocol Version 4 
06 May 2019
Amendment 2, Protocol Version 3 
01 Mar 2019
Amendment 1, Protocol Version 2 
17 Sep 2018
Original Protocol 
25 Jan 2018
Amendment 7 (30 September 2021)
Overall Rationale for the Amendment: To include an optional pharmacokinetic (PK) interim
analysis 3 including data from age Cohort 3. If supported by the results, this will allow for
confirmation of a dosing recommendation with fewer than 15 PK evaluable participants in Cohort
3 and enrollment in Cohort 3 can be stopped earlier.
The updates are indicated in bold for new text and in strikethrough for deletion in the following
table.
Section Number 
and Name
Description of Change 
Brief Rationale
PROTOCOL 
SYNOPSIS 
AC-065A203- 
(Design) 
Statement was revised as follows: ‘The
selection of the dosing regimen for the Phase
3 study will be based on the safety,
tolerability, and PK results evaluated in the
interim PK analyses (interim 1 and 2) and or
final PK analysis (as applicable).
To adjust for the added optional
third interim analysis.
3.1. Study design  
Description of an optional third interim PK
analysis including criteria for a dose
confirmation with a sample size of fewer than
15 PK evaluable participants in Cohort 3 was
added.
Given the rareness of pediatric
pulmonary arterial hypertension
(PAH), combined with the
ongoing global Corona Virus
Disease-2019 (COVID-19)
pandemic, it has proven difficult
to enroll participants in age
Cohort 3 (≥ 2 to < 6 years of
age). The option of confirming
the selexipag dosing for
participants in this age cohort
based on the results of fewer
than 15 PK evaluable Cohort 3
participants, was introduced.

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Section Number
and Name
Description of Change 
Brief Rationale
5.1.4. Study drug
starting dose and
up-titration
Text was amended as follows: 
‘At any time during study treatment, study 
drug interruptions (eg, missed doses for any 
reason) of 3 days or more (but less than 2 
weeks, refer to Section 5.1.8) will require a 
new up-titration according to the scheme from 
Day 1.’ 
In this Phase 2 study with only
exploratory efficacy
assessments, re-uptitration of
study treatment is appropriate
even after interruption >14 days,
given that the investigators deem
continued treatment with
selexipag as appropriate for a
given patient.
5.1.8. Study
treatment dose
adjustments and
interruptions
Text was amended as follows: 
‘Study treatment interruptions exceeding 2 
consecutive weeks must lead to In case of
permanent discontinuation offrom study
treatment .In that case, the EOT visit must
occur within 7 days of the discontinuation
criterion being met.’
9.2.5. Reporting
procedures
Updated information about reporting of 
suspected unexpected serious adverse reaction 
(SUSAR) as follow:
‘Any SAE that is assessed as related and
unexpected against the RSI is known as a
suspected unexpected serious adverse reaction
(SUSAR) and must be reported by the
Sponsor to concerned health authorities
(including the EudraVigilance database if the
study is conducted in Europe), IECs/IRBs,
and investigators. the sponsor assumes
responsibility for appropriate reporting of
AEs to the regulatory authorities. The
sponsor will also report to the investigator
(and the head of the investigational
institute where required) all SUSARs. The
investigator (or sponsor where required)
must report SUSARs to the appropriate
Independent Ethics
Committee/Institutional Review Board
(IEC/IRB) that approved the protocol
unless otherwise required and documented
by the IEC/IRB. A SUSAR will be reported
to regulatory authorities unblinded.
Participating investigators and IEC/IRB
will receive a blinded SUSAR summary,
unless otherwise specified.’
To align with Janssen safety
reporting process.
10.2.1.1. PK
analysis and
modeling
Text was amended as follows: ‘More details 
will be described in modeling data analysis 
plan, which will be finalized before the PK 
interim analysis 1 and any updates thereof.’ 
As the  modeling data analysis
plan will be updated to include
the details of third interim
analysis.

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Section Number
and Name
Description of Change 
Brief Rationale
10.4. Interim
analyses
Text was amended as follows: ‘Additional 
assessments of PK profiles and interim 
analyses may be performed, as deemed
appropriate by the sponsor.
To provide clarity on additional
interim analysis.
Throughout the
protocol
Minor grammatical, formatting, or spelling 
changes were made.
Minor errors were noted.

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TABLE OF CONTENTS
SPONSOR CONTACT DETAILS......................................................................................2
SPONSOR CONTRIBUTORS TO THE PROTOCOL.......................................................2
CONTRACT RESEARCH ORGANIZATIONS INFORMATION ...................................2
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE................................4
TABLE OF CONTENTS.....................................................................................................7
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................15
PROTOCOL SYNOPSIS AC-065A203............................................................................18
PROTOCOL ......................................................................................................................33
1 BACKGROUND.........................................................................................................33
1.1 
Indication......................................................................................................33
Definition and diagnosis...................................................................33
Classification ....................................................................................34
Epidemiology....................................................................................34
Current treatment and unmet clinical need.......................................34
1.2 
Study treatment(s).........................................................................................36
Introduction.......................................................................................36
Nonclinical data................................................................................36
Clinical data......................................................................................37
1.2.3.1 
Exposure ...........................................................................................37
1.2.3.2 
Pharmacokinetics and metabolism....................................................38
1.2.3.3 
Efficacy results in adult patients with PAH......................................39
1.2.3.4 
Safety................................................................................................40
1.2.3.4.1 
Phase 1 studies..................................................... 40
1.2.3.4.2 
Safety data from GRIPHON................................ 40
1.3 
Purpose and rationale of the study................................................................42
1.4 
Summary of known potential benefits and risks ..........................................43
Benefits.............................................................................................43
Risks..................................................................................................43
Conclusion........................................................................................45
2 STUDY OBJECTIVES...............................................................................................45

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2.1 
Primary objective(s) .....................................................................................45
2.2 
Secondary objectives....................................................................................46
2.3 
Exploratory objectives..................................................................................46
2.4 
Other objectives............................................................................................46
3 OVERALL STUDY DESIGN AND PLAN...............................................................46
3.1 
Study design .................................................................................................46
Study periods ....................................................................................50
Study duration...................................................................................53
3.2 
Study design rationale ..................................................................................53
3.3 
Study committees .........................................................................................55
4 SUBJECT POPULATION..........................................................................................55
4.1 
Subject population description .....................................................................55
4.2 
Rationale for the selection of the study population......................................55
4.3 
Inclusion criteria...........................................................................................56
4.4 
Exclusion criteria..........................................................................................57
4.5 
Criteria for female subjects of childbearing potential ..................................59
Definition of childbearing potential..................................................59
Acceptable methods of contraception...............................................59
5 TREATMENTS ..........................................................................................................60
5.1 
Study treatment.............................................................................................60
Investigational treatment: description and rationale.........................60
Study treatment administration.........................................................61
Treatment assignment.......................................................................62
Study drug starting dose and up-titration..........................................63
Blinding ............................................................................................68
Study treatment supply .....................................................................68
5.1.6.1 
Study treatment packaging and labeling...........................................68
5.1.6.2 
Study treatment distribution and storage ..........................................68
5.1.6.3 
Study treatment dispensing...............................................................68
5.1.6.4 
Study treatment return and destruction.............................................69
Study treatment accountability and compliance with study
treatment ...........................................................................................69
5.1.7.1 
Study treatment accountability.........................................................69
5.1.7.2 
Study treatment compliance..............................................................70
Study treatment dose adjustments and interruptions ........................70
Premature discontinuation of study treatment ..................................71

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Study-specific criteria for pause in up-titration / interruption /
premature discontinuation of study treatment ..................................72
5.2 
Previous and concomitant therapy................................................................73
Mandatory treatment.........................................................................74
Allowed concomitant therapy...........................................................74
Forbidden concomitant therapy........................................................74
5.3 
Treatment of Overdose.................................................................................75
6 STUDY ENDPOINTS ................................................................................................75
6.1 
Pharmacokinetic endpoints...........................................................................75
Primary pharmacokinetic endpoint(s)...............................................75
Secondary pharmacokinetic endpoints:............................................76
6.2 
Safety endpoints ...........................................................................................76
6.3 
Exploratory endpoints...................................................................................76
6.4 
Other endpoints.............................................................................................77
7 VISIT SCHEDULE AND STUDY ASSESSMENTS................................................78
7.1 
Study visits ...................................................................................................78
Screening/re-screening......................................................................78
Unscheduled visits............................................................................79
7.2 
Study assessments.........................................................................................85
Demographics / baseline characteristics...........................................85
Exploratory assessments...................................................................86
7.2.2.1 
Monitoring of disease progression signs and symptoms of
PAH ..................................................................................................86
7.2.2.2 
WHO functional class.......................................................................86
7.2.2.3 
NT-proBNP.......................................................................................86
7.2.2.4 
6-minute walk distance test...............................................................87
7.2.2.5 
Echo/Doppler....................................................................................87
7.2.2.6 
Palatability and acceptability............................................................87
Safety assessments............................................................................88
7.2.3.1 
Physical examination........................................................................88
7.2.3.2 
Vital signs .........................................................................................89
7.2.3.3 
ECG ..................................................................................................89
7.2.3.4 
Weight and height.............................................................................89
7.2.3.5 
Tanner stage......................................................................................90
7.2.3.6 
Childbearing potential.......................................................................90
Laboratory assessments ....................................................................90
7.2.4.1 
Type of laboratory ............................................................................90
7.2.4.2 
Laboratory tests.................................................................................92

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Pharmacokinetic assessments ...........................................................93
7.2.5.1 
Pharmacokinetic assessments ...........................................................93
7.2.5.2 
Instructions regarding meals.............................................................93
7.2.5.3 
Procedure for sampling.....................................................................94
7.2.5.4 
Labeling............................................................................................94
7.2.5.5 
Bioanalysis........................................................................................94
7.2.5.6 
Shipping procedures .........................................................................95
8 STUDY COMPLETION AND POST-STUDY TREATMENT / MEDICAL
CARE ..........................................................................................................................95
8.1 
Study completion as per protocol.................................................................95
8.2 
Premature withdrawal from study ................................................................95
8.3 
Premature termination or suspension of the study........................................96
8.4 
Medical care of subjects after study completion / withdrawal from
study..............................................................................................................97
9 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS...........................97
9.1 
Adverse events..............................................................................................97
Definition of adverse events .............................................................97
Intensity of adverse events................................................................98
Relationship to study treatment ........................................................99
Reporting of adverse events..............................................................99
Follow-up of adverse events.............................................................99
9.2 
Serious adverse events................................................................................100
Definitions of serious adverse events .............................................100
Reporting of serious adverse events ...............................................100
Follow-up of serious adverse events...............................................101
After the 30-day follow-up period..................................................101
Reporting procedures......................................................................101
9.3 
Pregnancy ...................................................................................................102
Reporting of pregnancy ..................................................................102
Follow-up of pregnancy..................................................................102
9.4 
Special Reporting Situations ......................................................................102
9.5 
Study safety monitoring..............................................................................103
9.6 
Product quality complaint handling............................................................103
10 STATISTICAL METHODS .....................................................................................104
10.1 
Analysis Sets...............................................................................................104
Screened Analysis Set.....................................................................104
Full Analysis Set.............................................................................104

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Pharmacokinetic Analysis Set ........................................................104
Safety Analysis Set.........................................................................104
Usage of the analysis sets ...............................................................104
10.2 
Variables.....................................................................................................105
Primary pharmacokinetic variable(s)..............................................105
10.2.1.1 
PK analysis and modeling...............................................................105
Secondary pharmacokinetic variables ............................................105
Exploratory pharmacokinetic / pharmacodynamic analysis ...........105
Safety variables...............................................................................105
Exploratory efficacy variables........................................................106
Other variables................................................................................107
10.3 
Description of statistical analyses...............................................................107
Overall testing strategy...................................................................107
Analysis of the primary pharmacokinetic variable(s).....................107
10.3.2.1 
Hypotheses and statistical model....................................................107
10.3.2.2 
Handling of missing data................................................................107
10.3.2.3 
Main analysis..................................................................................107
10.3.2.4 
Supportive/sensitivity analyses.......................................................108
Analysis of secondary pharmacokinetic variable(s) .......................108
Exploratory pharmacokinetic / pharmacodynamic analysis ...........108
Analysis of the safety variable(s)....................................................108
10.3.5.1 
Treatment-emergent adverse events ...............................................108
10.3.5.2 
Treatment-emergent death..............................................................109
10.3.5.3 
Laboratory variables .......................................................................109
10.3.5.4 
ECG ................................................................................................109
10.3.5.5 
Vital signs .......................................................................................109
10.3.5.6 
Height and Weight..........................................................................109
10.3.5.7 
Sexual maturation...........................................................................109
Analysis of the exploratory efficacy variables ...............................110
10.3.6.1 
Time to disease progression / clinical worsening...........................110
10.3.6.2 
NYHA / WHO FC ..........................................................................110
10.3.6.3 
6MWD ............................................................................................110
10.3.6.4 
Panama FC......................................................................................110
10.3.6.5 
NT-proBNP.....................................................................................110
10.3.6.6 
Echo/Doppler..................................................................................111
Analysis of the other variables........................................................111
10.3.7.1 
Palatability and acceptability..........................................................111
10.4 
Interim analyses..........................................................................................111
10.5 
Sample size.................................................................................................111
11 DATA HANDLING..................................................................................................113

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11.1 
Data collection............................................................................................113
11.2 
Maintenance of data confidentiality...........................................................113
11.3 
Database management and quality control.................................................113
12 PROCEDURES AND GOOD CLINICAL PRACTICE...........................................114
12.1 
Ethics and Good Clinical Practice..............................................................114
12.2 
Independent Ethics Committee / Institutional Review Board....................114
12.3 
Informed consent........................................................................................115
12.4 
Indemnification, compensation, and refund of expenses to subjects’
parent(s)/LAR(s) and investigators ............................................................116
12.5 
Protocol adherence/compliance..................................................................116
12.6 
Protocol amendments .................................................................................117
12.7 
Essential documents and retention of documents.......................................117
12.8 
Monitoring..................................................................................................118
12.9 
Investigator Site File...................................................................................119
12.10 Audit...........................................................................................................119
12.11 Inspections..................................................................................................120
12.12 
Reporting of study results and publication.................................................120
13 REFERENCES..........................................................................................................122
14 APPENDICES...........................................................................................................128
14.1 
Appendix 1  WHO Functional Class..........................................................128
14.2 
Appendix 2  Panama Functional Class For Pediatrics................................129
14.3 
Appendix 3  Palatability And Acceptability Of Selexipag.........................131
14.4 
Appendix 4  Child-Pugh Classification......................................................133
14.5 
Appendix 5  Tanner Scale ..........................................................................134
14.6 
Appendix 6  Echo/Doppler.........................................................................135
14.7 
Appendix 7 Sample Size Calculation Related To Dosing Scheme
Confirmation In Pediatric PK Study...........................................................136
INTRODUCTION..........................................................................140
Analysis ..........................................................................................141
14.7.2.1 
Sample size calculations based on observed AUCτ,ss,combined
(NCA analysis) ...............................................................................141
14.7.2.2 
Sample size calculations based on clinical trial simulations
(model-based analysis) ...................................................................142
14.7.2.2.1 
Preparatory assessments based on the Fisher
information matrix............................................. 142
14.7.2.2.2 
Simulations ........................................................ 143

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14.7.2.2.3 
Parameter estimation and assessment of exposure
estimation precision........................................... 144
14.7.2.2.3.1 First and second PK interim analysis................. 145
14.7.2.2.3.2 Final PK analysis ............................................... 146
DISCUSSION AND CONCLUSIONS ..........................................147
REFERENCES ...............................................................................149
ADDITIONAL TABLES ...............................................................150
14.8 
Appendix 8  Protocol Amendment History................................................153
INVESTIGATOR AGREEMENT...................................................................................154

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LIST OF TABLES
Table 1 
Up-titration dosing scheme for body weight category ≥ 50 kg....................65
Table 2 
Up-titration dosing scheme for body weight category ≥ 25 to < 50 kg........66
Table 3 
Up-titration dosing scheme for body weight category ≥ 9 to < 25 kg..........67
Table 4 
Visit and assessment schedule until Week 16 ..............................................80
Table 5 
Visit and assessment schedule after Week 16 ..............................................83
Table 6 
Child Pugh Classification...........................................................................133
LIST OF FIGURES
Figure 1 
Estimated starting doses based on the GRIPHON PK model achieving the
same exposure as in adult patients of 50 kg, 70 kg, and 96 kg treated with
200 μg b.i.d. selexipag..................................................................................48
Figure 2 
Study design .................................................................................................52

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LIST OF ABBREVIATIONS AND ACRONYMS
6MWD  
6-minute walk distance
AE 
Adverse event
aPAH-CHD  
Pulmonary arterial hypertension associated with congenital heart
disease
ASO  
Arteriosclerosis
AUC  
Area under the plasma concentration-time curve
AUCτ,ss 
Area under the plasma concentration-time curve over one dosing
interval at steady-state
AUCτ,ss,combined 
Combined exposure over one dosing interval at steady-state
b.i.d. 
Twice daily
BP 
Blood pressure
CES  
Carboxylesterase
CFR  
Code of Federal Regulations
CHD  
Congenital heart disease
CHMP  
Committee for Medicinal Products for Human Use
CI 
Confidence interval
CL 
Confidence limit
Cmax  
Maximum plasma concentration
Cmax,ss 
Maximum concentration at steady state
CRA  
Clinical research associate
CRO  
Contract research organization
CSR  
Clinical study report
CTEPH  
Chronic thromboembolic pulmonary hypertension
Ctrough,ss 
Trough concentration at steady state
CYP  
Cytochrome P450
ECG  
Electrocardiogram
Echo 
Echocardiography
eCRF  
Electronic Case Report Form
EDC  
Electronic data capture
EMA  
European Medicines Agency
EOS  
End-of-Study

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EOT  
End-of-Treatment
EP4 
prostaglandin-E2 subtype 4
ERA  
Endothelin receptor antagonist
EU  
European Union
FAS  
Full Analysis Set
FC  
Functional class
GCP  
Good Clinical Practice
GRIPHON  
Prostacyclin (PGI2G) receptor agonist in Pulmonary arterial
HypertensiON
HIV  
Human immunodeficiency virus
i.v. 
Intravenous(ly)
IB  
Investigator’s Brochure
IC  
Intermittent claudication
ICF  
Informed Consent Form
ICH  
International Council for Harmonisation
IDMC  
Independent Data Monitoring Committee
IEC  
Independent Ethics Committee
iMTD  
Individual maximum tolerated dose
iPAH  
Idiopathic pulmonary arterial hypertension
IRB  
Institutional Review Board
IRT  
Interactive Response Technology
ISF  
Investigator site file
LAP  
Left atrium pressure
LAR  
Legally authorized representative
LVEDP  
Left ventricular end-diastolic pressure
MedDRA  
Medical Dictionary for Regulatory Activities
mPAP  
Mean pulmonary arterial pressure
NCA  
Non-compartmental analysis
NT pro-BNP  
N-terminal pro b-type natriuretic peptide
NYHA  
New York Heart Association
PAH  
Pulmonary arterial hypertension

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PAH-aCTD  
Pulmonary arterial hypertension associated with connective tissue
disease
PAWP  
Pulmonary arterial wedge pressure
PDE-5 
Phosphodiesterase type-5
PI 
Principal investigator
PK 
Pharmacokinetic(s)
PKS  
Pharmacokinetic Analysis Set
PT  
Preferred term
PVOD  
Pulmonary veno-occlusive disease
PVR  
Pulmonary vascular resistance
PVRi 
Pulmonary vascular resistance index
RHC  
Right heart catheterization
RSI 
Reference safety information
SAE 
Serious adverse event
SAP  
Statistical Analysis Plan
SBP 
Systolic blood pressure
SD 
Standard deviation
SE 
Standard error
SIV  
Site initiation visit
SOC  
System Organ Class
SSc 
Systemic sclerosis
TEAE 
Treatment-emergent adverse event
TESAE 
Treatment-emergent serious adverse event
Tmax  
Time at which Cmax is observed
TSH  
Thyroid-stimulating hormone
UGT  
Uridine 5’-diphospho-glucuronosyltransferase
WHO  
World Health Organization
WU  
Wood units

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PROTOCOL SYNOPSIS AC-065A203
TITLE
A prospective, multicenter, open-label, single-arm, Phase 2
study 
to 
investigate 
the 
safety, 
tolerability 
and
pharmacokinetics of selexipag in children with pulmonary
arterial hypertension
OBJECTIVES
Primary objective(s)
The primary objective of the study is to confirm the selexipag
starting dose(s), selected based on pharmacokinetic (PK)
extrapolation from adults, that leads to similar exposures as
adult doses in  children from ≥ 2 to ˂ 18 years of age with
pulmonary arterial hypertension  (PAH) by investigating the
PKof selexipag and its active metabolite ACT-333679 in this
population.
Secondary objectives
To evaluate the safety and tolerability of selexipag in children
from ≥ 2 to ˂ 18 years of age with PAH.
Other objectives
Other objectives are described in Section 2.3. and Section 2.4.
DESIGN
This is a prospective, multicenter, open-label, single-arm,
Phase 2 study.
Approximately 60 participants will be enrolled in three
different age cohorts (based on age at Baseline / Enrollment /
Visit 2) to obtain at least 45 participants with evaluable PK
profiles:
 Cohort 1: ≥ 12 to < 18 years of age (approximately
20 enrolled participants to obtain at least 15 participants
with evaluable PK profiles)
 Cohort 2: ≥ 6 to < 12 years of age (approximately
20 enrolled participants to obtain at least 15 participants
with evaluable PK profiles)
 Cohort 3: ≥ 2 to < 6 years of age (approximately
20 enrolled participants to obtain at least 15 participants
with evaluable PK profiles).
The starting dose is based on body weight, using the data from
the population PK model in the GRIPHON/AC-065A302
study targeting the exposure observed in adult participants with

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PAH at a starting dose of 200 μg [Modeling and Simulation
Report AC-065A302 (GRIPHON) 2014]. The continuous
relationship between dose and body weight is used to define
bodyweight categories and starting dose for each body weight
category, such that  on average  the exposure (combined
exposure over one dosing interval at steady-state
[AUCτ,ss,combined]) will be comparable to that in a 70 kg adult
but will not exceed the exposure in a 50 kg adult [Modeling
and Simulation Report, Pediatric dose selection 2016]:
 100 μg for participants with a body weight from 9 to
< 25 kg.
 150 μg for participants with a body weight from ≥25 to
< 50 kg.
 200 g for participants with a body weight ≥50 kg.
The starting dose selection will be confirmed or adjusted after
the completion of each age cohort by updating the population
PK model (interim analysis).
Enrollment will start with both Cohort 1 and Cohort 2
(participants ≥12 to < 18 and ≥ 6 to < 12 years of age,
respectively). After completion of PK assessments in at least
15 participants from Cohort 1 at Week 12, the dose-exposure
relationship will be established using a population PK model
[Modeling and Simulation Report, Pediatric dose selection
2016]. The PK data from any participants in Cohort 2 who have
completed their PK assessments at this time will be included in
this first interim analysis.
Results of this model-based analysis will be used to confirm or
adjust the selexipag doses initially selected. Enrollment of
Cohort 3 (participants ≥2 to < 6 years of age) will start once
the appropriate doses have been confirmed through modelling
and simulation in a second interim analysis of PK data from
the participants older than 6 years of age (i.e., Cohorts 1 and 2)
and, if there is no safety concern, based on Independent Data
Monitoring Committee (IDMC) reviews.
Finally, the PK data pooled from all three age cohorts will be
modelled to allow dosing recommendations for all participants

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≥2 years of age. A final PK analysis will be prepared based on
the overall PK and safety data up to Week 16 evaluation.
The selection of the dosing regimen for the Phase 3 study will
be based on the safety, tolerability, and PK results evaluated in
the interim or final PK analysis (as applicable).
Participants who discontinue treatment any time before the
profile PK sampling day may  be replaced within their age
cohort.
PERIODS
The study consists of the following consecutive periods:
Screening period: Lasts up to 6 weeks; starts with the
signature of the informed consent form (ICF) and ends with the
administration of the first study treatment dose.
Treatment period: Starts from the first dose of study
treatment at Baseline/Enrollment visit and ends on the day of
the last dose of selexipag (End-of-Treatment [EOT] visit). This
includes:
 Up-titration period:
From the first dose of study treatment until the participant
reaches their individual maximum tolerated dose (iMTD). This
period is estimated to last up to 12 weeks.
 Maintenance period:
 After Week 12: the participants will continue study
treatment at the same dose up to Week 16.
 After Week 16: study treatment will continue as long
as it remains beneficial for the participant [see Section
3.1.2 for details].
EOT visit: this visit should be conducted within 1 week of the
last dose of study treatment. The participant will then enter the
Safety follow-up period.
Safety follow-up period: Starts on the day after the last dose
of study treatment and ends 30 days thereafter. This period
ends with a phone call that indicates the End-of-Study (EOS).

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PLANNED DURATION
Approximately 7 years from first participant, first visit to last
participant, last visit.
SITE(S)
/ COUNTRY(IES)
Approximately 30 sites in 20 countries (planned).
PARTICIPANTS 
/
GROUPS
Approximately 60 participants will be enrolled in three
different age cohorts (based on age at Baseline / Enrollment /
Visit 2) to obtain at least 45 participants with evaluable PK
profiles:
 Cohort 1: ≥ 12 to < 18 years of age (approximately
20 enrolled participants to obtain at least 15 participants
with evaluable PK profiles).
 Cohort 2: ≥ 6 to < 12 years of age (approximately
20 enrolled participants to obtain at least 15 participants
with evaluable PK profiles).
 Cohort 3: ≥ 2 to < 6 years of age (approximately
20 enrolled participants to obtain at least 15 participants
with evaluable PK profiles).
INCLUSION CRITERIA
1. Signed and dated ICF by the parent(s) or legally authorized
representative AND assent from developmentally capable
children.
2. Males or females between ≥ 2 and < 18 years of age (at
Baseline / Enrollment / Visit 2) with weight ≥ 9 kg.
3. PAH diagnosis confirmed by a documented historical right
heart catheterization performed at any time before
participant’s enrollment, and characterized by:
 Mean 
pulmonary 
arterial 
pressure 
(mPAP)
≥25 mmHg;
and
 
Pulmonary 
arterial 
wedge 
pressure 
(PAWP)
≤15 mmHg (in the absence of pulmonary vein
obstruction and/or significant lung disease, PAWP can
be replaced by left atrium pressure or, in the absence
of mitral stenosis, by left ventricular end-diastolic
pressure);
and

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Pulmonary vascular resistance index > 3 Wood units 
m2.
4. PAH  belonging to Nice 2013 Updated Classification
Group 1 (including Down syndrome) and of one of the
following etiologies:
 
Idiopathic.
 
Heritable.
 
PAH associated with congenital heart disease:
 PAH with co-incidental CHD.
 Post-operative PAH (persisting / recurring /
developing ≥ 6 months after repair of CHD).
 
Drug or toxin induced PAH.
 
PAH associated with HIV.
 
PAH associated with connective tissue disease.
5. World Health Organization functional class (WHO FC) II
to III.
6. Participants treated with an endothelin receptor antagonist
and/or a phosphodiesterase type-5 inhibitor, provided that
the treatment dose(s) has been  stable for at least three
months prior to enrollment, or participants who are not
candidates for these therapies.
7. Females of childbearing potential must have a negative
pregnancy test at Screening and at Enrollment and must
agree to undertake monthly pregnancy tests and to use a
reliable method of contraception (if sexually active) from
Screening up to study drug discontinuation + 30 days
(EOS).
EXCLUSION CRITERIA
Etiology
1. Participants with PAH due to portal hypertension,
schistosomiasis, pulmonary veno-occlusive disease, and/or
pulmonary capillary hemangiomatosis.
2. Participants with PAH associated with Eisenmenger
syndrome.

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3. Participants with moderate to large left-to-right shunts1.
4. Participants with cyanotic congenital cardiac lesions such
as transposition of the great arteries, truncus arteriosus,
univentricular heart, or pulmonary atresia with ventricular
septal defect, as well as participants with Fontan palliation.
5. Participants with pulmonary hypertension (PH) due to lung
disease and/or hypoxia. For participants with Down
syndrome, exclusion of lung disease and hypoxia causing
PH shouldbe documented (eg, computed tomographyscan,
polysomnography, lung function tests).
Treatment and intervention
6. Previous treatment with Uptravi® (selexipag) within
2 weeks prior to enrollment.
7. Participants having received prostacyclin (epoprostenol) or
prostacyclin analogs2 (i.e., treprostinil, iloprost, beraprost)
within 2 months prior to enrollment or who are scheduled
to receive any of these compounds during the trial.
8. Treatment with another investigational drug within 4
weeks prior to enrollment.
9. Treatment with strong and moderate inhibitors of CYP2C8
(eg, gemfibrozil, clopidogrel, deferasirox, teriflunomide)
within 2 weeks prior to enrollment until the last dose of
selexipag + 3 days.
10. Treatment with inhibitors of UGT1A3 and UGT2B7
(valproic acid, probenecid, and fluconazole) are prohibited
from 2 weeks prior to enrollment and until the last dose of
selexipag + 3 days.
11. Any PAH-related surgical intervention planned, or
participants listed for organ transplantation related to PAH.
1
Left to right shunts with a pulmonary to systemic flow ratio > 1.5 are considered moderate to large [Driscoll 1999].
The size and magnitude of left to right shunts, if applicable, is assessed by the investigator based on local clinical
practice.
2
Single administration of drugs used for acute vasodilator testing during the RHC procedure is allowed (eg,
intravenous/inhaled prostacyclin or inhaled nitric oxide or oral sildenafil).

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12. History or current suspicion of intussusception or ileus or
gastrointestinal obstruction, per investigator’s judgment.
Baseline abnormalities
13. Known concomitant life-threatening disease with a life
expectancy < 12 months.
14. Uncontrolled thyroid disease, per investigator’s judgment.
15. Hemoglobin or hematocrit < 75% of the lower limit of
normal range.
16. 13 Moderate or severe hepatic impairment, eg, Child-Pugh
Class B or C 4 [see Section 14.4 Appendix 4].
17. Clinical signs of hypotension that, in the investigator’s
judgment, would preclude the initiation of a PAH-specific
therapy.
18. Participants with severe renal insufficiency (estimated
creatinine clearance < 30 mL/min or serum creatinine
> 221 µmol/L).
19. Severe coronary heart disease or unstable angina as
assessed by the investigator.
20. Myocardial infarction within the last 6 months prior to
enrollment.
21. Decompensated cardiac failure if not under close
supervision.
22. Severe arrhythmias as assessed by the investigator.
23. Cerebrovascular events (eg, transient ischemic attack,
stroke) within the last 3 months prior to enrollment.
24. Congenital or acquired valvular defects with clinically
relevant myocardial function disorders not related to PH.
Pregnancy and breastfeeding
3
Sub numbering introduced to highlight change from previous protocol version.
4
The assessment for hepatic impairment at Screening (Child Pugh Score, see Section 14.4 Appendix 4) must be fully
documented for participants with hepatic impairment as part of medical history and clinical signs and evidence
(from central and/or local lab) of hepatic impairment.

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25. Pregnancy (including family planning) or breastfeeding.
Other categories
26. Known hypersensitivity to the investigational treatment or
to any of the excipients of the drug formulations.
27. Drug or substance abuse, or any condition that, in the
opinion of the investigator, may prevent compliance with
the protocol or adherence to study treatment.
28. Loss of 250 mL or more of blood within 3 months prior to
screening.
29. History or clinical evidence of any disease and/or existence
of any surgical or medical condition that might interfere
with the absorption, distribution, metabolism, or excretion
of the study treatment(s) (eg, cholecystectomy).
30. “Criterion deleted per Amendment 6.”
STUDY TREATMENT
Investigational treatment
Selexipag is supplied by the sponsor as child-proof bottles
containing tablets for oral administration twice daily (b.i.d.)
with the following dosage strengths:
 Film-coated tablets containing 200 g of selexipag.
 Film-coated mini-tablets containing 50 g of selexipag.
Study medication administration will start in the evening of
Day 1, and continue thereafter with b.i.d. dosing, i.e., once in
the morning and once in the evening. During the up-titration
period of 12 weeks, it is recommended that the doses are
increased weekly in increments equal to the starting dose until
the participants reach their iMTD, or until the maximum dose
corresponding to their baseline weight category is achieved. To
improve tolerability, it is recommended that the study drug,
selexipag, is taken with food and, at the beginning of each
up-titration phase, that the first increased dose is taken in the
evening. Participants can take 200 g tablets and 50 g mini-
tablets with soft food (i.e., yoghurt, apple sauce/puree/mousse
or mashed banana). The 50 g mini-tablets can also be
dispersed in apple- or orange-juice. The maximum dose
allowed will be 8-fold the corresponding starting dose:

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 Body weight category ≥ 50 kg: starting dose of 200 µg
titrated up to the iMTD or the maximum of 1,600 µg b.i.d.
 Body weight category ≥ 25 to < 50 kg: starting dose of
150 µg titrated up to the iMTD or the maximum of 1,200
µg b.i.d.
 Body  weight category ≥ 9 to < 25 kg: starting dose of
100 µg titrated up to the iMTD or the maximum of 800 µg
b.i.d.
Up-titration will be agreed upon during scheduled telephone
calls or visits. At Week 12, the iMTD for each participant will
be determined. This dose should be kept unchanged until
Week 16. Bodyweight category, starting dose, and up-titration
scheme determined at Baseline/Enrollment will be kept
unchanged until Week 16. After Week 16, if the body weight
category of the participant has changed, the study drug can be
up-titrated further or down-titrated to the corresponding dose
level of the next body weight category, if deemed appropriate
by the investigator. In addition, irrespective of whether the
body  weight category  changes or not, after Week 16 the
investigator will be allowed to change the participant’s study
drug dose further if needed (up to the maximum allowed dose
based on body weight category).
If a participant has tolerability issues or experiences adverse
reactions reflecting the mode of action for selexipag [see
Section 5.1.10], the dose can remain the same without further
up-titration (pause in up-titration). Up-titration can be resumed
after the pause, or the dose can be reduced to the previous dose
level. The decision to pause up-titration, to up-titrate or
down-titrate study drug, or to permanently discontinue the
study drug will be based on the investigator’s medical
judgment.
ENDPOINTS
Primary pharmacokinetics endpoint(s)
The 
primary 
endpoint 
is 
model-based 
exposure
(AUCτ,ss,combined) of selexipag and ACT-333679, corrected for
their potency, determined during the 12-week up-titration
period.

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Secondary pharmacokinetics endpoints
 Area under the plasma concentration-time curve over one
dosing interval at steady-state (AUCτ,ss), maximum
concentration at steady state (Cmax,ss), and the time at which
Cmax,ss is observed (tmax,ss) for selexipag and ACT-333679,
based on non-compartmental analysis (NCA).
 Trough concentration at steady state (Ctrough,ss) on Day 15,
and at Weeks 4 and 6 (i.e., Visits 4, 5, 6) for selexipag and
ACT-333679.
Safety endpoints
 Treatment-emergent adverse events (TEAEs) occurring up
to EOT + 3 days.
 Treatment-emergent serious adverse events (TESAEs)
occurring up to EOT + 3 days.
 Adverse 
events 
(AEs) 
leading 
to 
permanent
discontinuation of study drug.
 Treatment-emergent deaths (all causes) occurring up to
EOT + 3 days.
 Treatment-emergent marked laboratory abnormalities
(hematology and blood chemistry tests) over time,
occurring up to EOT + 3 days.
 Change from baseline in selected hematology and blood
chemistry laboratory parameters over time up to
EOT + 3 days.
 Treatment-emergent 
electrocardiogram 
(ECG)
abnormalities over time, occurring up to EOT + 3 days.
 Change from baseline in thyroid-stimulating hormone over
time, up to EOT + 3 days.
 Change from baseline in vital signs (blood pressure, heart
rate) over time, up to EOT + 3 days.
 Change from baseline in height and body mass index over
time, up to EOT + 3 days.

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 Change from baseline in sexual maturation (Tanner stage)
over time, up to EOT + 3 days.
Exploratory endpoints
 Change from Baseline/Enrollment up to each time point of
assessment in modified New York Heart Association /
WHO FC.
 Change from baseline up to each time point of assessment
in exercise capacity, as measured by the 6-minute walk
distance (6MWD).
 Change from baseline in Panama FC up to each time point
of assessment.
 Percent of baseline in plasma NT pro-brain natriuretic
peptide at each time point of assessment.
 Change from baseline up to each time point of assessment
in echocardiographic variables (imaging and Doppler
evaluation):
 Right ventricular systolic pressure.
 Tricuspid annular plane systolic excursion.
 Pulmonary artery acceleration time.
 Left ventricular eccentricity index.
 Right atrial area index (from apical 4 chamber view).
 Tricuspid annular diameter (from apical 4 chamber
view).
 Time to the first of the following disease progression
events occurring between enrollment and EOT:
 Death (all causes)
 Atrial septostomy or Potts’anastomosis, or registration
on lung transplant list
 Hospitalization due to worsening PAH§
 Clinical 
worsening* 
of 
PAH 
defined 
as:
Need for, or initiation of new PAH-specific therapy# or

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i.v. diuretics or continuous oxygen use AND at least
one of the following:
o Worsening in WHO FC, or
o New occurrence or worsening of syncope (in
frequency or severity as per medical judgment), or
o New occurrence or worsening of at least two PAH
symptoms (i.e., shortness of breath/dyspnea, chest
pain, cyanosis, dizziness/ near syncope, or fatigue),
or
o New occurrence or worsening of signs of right heart
failure not responding to oral diuretics
§excluding hospitalizations that are elective, routine or clearly
attributable to appearance/worsening of comorbidities (eg,
pneumonia).
*worsening from baseline.
#eg, ERA, PDE-5 inhibitor, prostanoids, prostacyclin receptor
(IP receptor) agonist, soluble guanylate cyclase stimulator.
Other endpoints
 Palatability of selexipag formulation at Day 1, Week 12,
and EOT, assessed using a 5-point facial hedonic scale.
 Acceptability of selexipag formulation at Day 1, Week 12,
and EOT, as assessed through a 3-point categorical scale
determining whether the child swallowed the medication.
ASSESSMENTS
Refer to the schedule of assessments in Table 4 and Table 5.
STATISTICAL
METHODOLOGY
Analysis Sets
The Screened Analysis Set includes all participants who
are screened and have a participant identification number.
The Full Analysis Set includes all enrolled participants who
were eligible to receive the study drug.
The Pharmacokinetic Analysis Set comprises all participants
included in the Safety Set who complied with the protocol
sufficiently and did not deviate from the protocol in a way that
might affect the PK outcome of the study. Criteria for sufficient
compliance include exposure to treatment, availability of PK

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measurements, and absence of major protocol deviations that
have an impact on the PK.
The Safety Analysis Set includes all participants who received
at least one dose of study treatment.
The observed PK data will be described by a population PK
model using the same model structure as for the adult
participants with PAH in the GRIPHON study [Modeling and
Simulation Report AC-065A302 (GRIPHON) 2014, Modeling
and Simulation Report, Pediatric dose selection 2016].
This population PK model describes the PK of selexipag and
ACT-333679 by 2-compartmental distribution models with
linear elimination. Selexipag is absorbed by a first-order
process and part of the elimination from the central
compartment is a metabolic transformation to form
ACT-333679 [Modeling and Simulation Report AC-065A302
(GRIPHON) 2014].
Analysis of secondary PK variable(s)
Plasma concentrations will be summarized per time point, by
dose and body weight cohort using arithmetic mean, geometric
mean, minimum, median, maximum, standard deviation (SD),
standard error (SE), and two-sided 95% confidence interval
(CI) of the mean.
AUCτ,ss, Cmax,ss, Ctrough,ss, and tmax,ss for selexipag and
ACT-333679 based on NCA for selexipag and ACT-333679
will be listed and summarized by dose and body weight cohort,
with arithmetic mean, geometric mean, minimum, median,
maximum, SD, SE, coefficient of variation in %, and 95% CI
of the arithmetic and geometric means.
Dose proportionality for AUCτ,ss and Cmax,ss of selexipag and
ACT-333679 will be explored by the power model as described
by [Gough 1995].
Safety variables

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All analyses of safety variables will be carried out descriptively
using the Safety  Analysis Set, consisting of all treated
participants, and will be performed as follows:
 in the overall population.
 by iMTD dose groups.
 by age cohort.
The number and percentage of participants with at least one
TEAE / TESAE / AE leading to study treatment
discontinuation will be described by system organ class (SOC)
and preferred term (PT) up to EOT + 3 days, and separately for
the up-titration period (until Week 12) and the maintenance
phase (> Week 12 until EOT + 3 days).
The same analysis will be performed according to the
maximum intensity of reported AEs and their relationship to
the study drug.
The number and percentage of treatment-emergent deaths will
be described by SOC and PT up to EOT + 3 days.
For each laboratory and ECG variable, the number and
percentage of participants with at least one treatment-emergent
marked abnormality will be summarized up to EOT + 3 days.
Vital signs and sexual maturation variables will be summarized
over time up to EOT + 3 days, using descriptive statistics for
continuous variables.
STUDY COMMITTEES
An IDMC has the overall responsibility for safeguarding the
interests of participants by monitoring safety data obtained in
the study and by making appropriate recommendations based
on the reported data, thus ensuring that the study is being
conducted with the highest scientific and ethical standards. The
PK results of the interim analyses (after completion by
Cohorts 1 and 2, and final PK results of all three cohorts) will
be provided to the IDMC for review, if requested by the
committee. The IDMC will be fully operational prior to
enrollment of the first participant into the study. The

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composition and operation of the IDMC is described in the
IDMC charter.

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PROTOCOL
1 
BACKGROUND
1.1 Indication
Pulmonary arterial hypertension (PAH) in children.
Definition and diagnosis
PAH is a rare, progressive and eventually fatal disease, characterized by vasoconstriction
and progressive remodelling of pulmonary arteries leading to increased resistance to blood
flow in the pulmonary circulation, right ventricular failure, and death. With regards to the
definition, pathophysiology, symptoms, and response to PAH-specific medicines, PAH
disease in children shares similarities with adult PAH [Barst 2011].
The definition of PAH in adults and children is the same and is based on pulmonary
hemodynamics measured by right heart catheterization (RHC): a mean pulmonary artery
pressure (mPAP) ≥ 25 mmHg at rest demonstrates pulmonary hypertension  (PH). In
patients with PAH, the PH is pre-capillary; thus, they have a normal pulmonary artery
wedge pressure (PAWP) ≤ 15 mmHg and an elevated pulmonary vascular resistance (PVR)
> 3 Wood units (WU) (mmHg/L·min) [Hoeper 2013, Ivy 2013]. In children, PVR index
(PVRi) is used instead of PVR in order to account for growth; PAH is defined as PVRi
> 3 WU × m2 [Ivy 2013, Abman 2015, Hansmann 2016].
PVRi [WU × m2]  mPAP [mmHg] PAWP [mmHg] / cardiac index [(L/min) / m2]
cardiac index [(L/min) / m2]  cardiac output [L/min] / body surface area [m2]
A PAH diagnosis can be confirmed only if elevated left heart pressures are excluded as a
reason for PH. PAWP is used for this purpose as a surrogate for directly measured left atrial
pressure (LAP) [Galiè 2015]. In the absence of mitral stenosis, left ventricular end diastolic
pressure (LVEDP) can also be used as an alternative surrogate for LAP [Grignola 2011,
Takala 2003].
Beyond the neonatal period, the pathology of pulmonary vascular disease is generally the
same across all age ranges. The histopathological findings seen in adults with PAH are also
observed in children. Both populations have vascular and endothelial dysfunction, and
present at diagnosis with elevations in PVR and pulmonary artery pressure [Barst 2011].
The distribution between etiologies in pediatric PAH is different to that of adults. There
are no indications from clinical experience that this translates into differences in response
to PAH-specific medicines.

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Classification
According to the revised clinical classification of PH [Simonneau 2013] PAH comprises:
idiopathic PAH (iPAH); heritable PAH (hPAH); drug-and toxin-induced PAH; and PAH
associated with connective tissue diseases (PAH-aCTD), HIV infection, portal
hypertension, congenital heart disease (aPAH-CHD), and schistosomiasis; it also includes
the subcategories pulmonary veno-occlusive disease [PVOD] and/or pulmonary capillary
hemangiomatosis, as well as persistent pulmonary hypertension of the newborn [Ivy 2013].
This protocol addresses iPAH, hPAH, and aPAH-CHD with some restrictions in order to
take into account information gathered from the GRIPHON study in adult patients with
PAH. Patients with PAH associated with HIV, PAH-aCTD, and drug or toxin-induced
PAH are also included in this trial, even though they represent only a minor proportion of
the pediatric PAH population.
This protocol excludes patients with Eisenmenger syndrome, as well as patients with open
left-to-right shunts.
Epidemiology
In the majority of pediatric patients, PAH presents as iPAH or aPAH-CHD [Ivy 2013].
A retrospective, nationwide registry-based study performed in the Netherlands from
1991 2005 revealed an annual incidence and point prevalence of 0.7 and 4.4 cases per
million children for iPAH, and 2.2 and 15.6 cases per million children for aPAH-CHD,
respectively [van Loon 2011]. In 2005, the estimated annual prevalence per million
children in France was 2.2 cases of iPAH [Fraisse 2010]. Data from the UK National
Pulmonary Hypertension Service between 2001 and 2007 showed that the incidence of
iPAH was 0.48 cases per million children per year, and the prevalence was 2.1 cases per
million children [Moledina 2010]. A US database study (2012 2013) published an annual
incidence range of pediatric iPAH  of 0.5 0.9 cases per million  children-years, and a
prevalence range of 4.4 6.0 cases per million [Li 2017].
Current treatment and unmet clinical need
The current management of pediatric PAH is based primarily on results from studies in
adult patients, together with expert recommendations, such as those from the 5th  World
Symposium for Pulmonary Hypertension [Galiè 2013, Ivy 2013], which were recently
adopted by the European Society  of Cardiology and European Respiratory Society
[Galiè 2015]. The treatment algorithm takes into account risk factors for mortality (clinical
evidence of right heart failure, progression of symptoms, syncope, failure to thrive,
functional class [FC] III and IV, b-type natriuretic [BNP] / N-terminal pro-BNP
[NT pro-BNP], echocardiography [Echo], and hemodynamics) [Ivy 2016]. Consensus
treatment guidelines recommend similar therapeutic algorithms in children  (based on
expert opinion) and adults (evidence-based) [Ivy 2013, Abman 2015, Hansmann 2016].

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This applies to all PAH-specific medications, including prostacyclin and its analogs.
Observational data with epoprostenol, the synthetic prostacyclin, showed similar
effectiveness in children with PAH compared to adults with respect to improving survival
and hemodynamics, and relieving symptoms [Barst 1996, Barst 1999, Yung 2004]. Prior
to the development of PAH-specific therapies, the median survival of adult patients
diagnosed with idiopathic PAH was reported to be approximately 2.8 years; the median
survival of pediatric patients was 10 months [D’Alonzo 1991]. Yung et al. confirmed the
significantly improved long-term survival in children with iPAH/hPAH treated with
intravenous (i.v.) epoprostenol compared with children for whom i.v. epoprostenol was not
available [Yung 2004]. Survival for all children treated with epoprostenol at 1, 5, and
10 years was 94%, 81%, and 61%, respectively. Doses of epoprostenol need to be gradually
increased to the individually tolerated dose depending on the emergence of prostacyclin
receptor-related side effects. Since the introduction of epoprostenol, the efficacy of this
product in children with PAH using an up-titration regimen has been documented in
clinical practice and in registries [Barst 2010]. The appropriateness of the up-titration
concept when applied to selexipag was proven in the GRIPHON study. Despite this
survival improvement, PAH remains a fatal disease. Therefore, there is an unmet clinical
need for additional treatment options in children and earlier use of oral medication
activating the prostacyclin pathway.
Similarity in treatment response between adult and pediatric patients has been observed in
all classes of PAH-specific therapies, typically reflected in a 20% or greater reduction in
PVR, a key pathophysiological characteristic of the disease. Similarity in treatment
response between adults and children with PAH is also to be expected with the IP-receptor
agonist selexipag, given the similar expression of IP receptors driving the pharmacological
response in adults and children. Specifically, selexipag has been shown to be efficacious
in adult patients with iPAH and aPAH-CHD, the most frequent etiologies in pediatric
patients with PAH.
The expression of IP receptors is similar in smooth muscle cells from adult and pediatric
patients. In particular, IP receptor expression in pulmonary arterial smooth muscle cells
derived from lungs of adults and children with iPAH is reduced to approximately 65% of
that observed in normal human lungs [Falcetti 2010]. As the potency and efficacy of
selexipag and its active metabolite in inducing intracellular signaling (cyclic adenosine
monophosphate production) correlate with the density of IP receptors [Gatfield 2016,
Research Report ACT-333679 2014], it is anticipated that selexipag will have similar
effects in target cells expressing comparable levels of IP receptors, irrespective of age,
provided that other components of the signaling pathway remain unchanged.

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1.2 Study treatment(s)
Introduction
Selexipag (ACT-293987) is an orally available, selective, and long-acting non-prostanoid
agonist of the prostacyclin receptor (IP receptor) approved and commercially available for
the treatment of adult patients with PAH in the US, the European Union, Japan, and other
countries. Selexipag is currently under development for chronic thromboembolic
pulmonary hypertension (CTEPH) and arteriosclerosis obliterans (ASO) with intermittent
claudication (IC). Selexipag was approved in the US in December 2015 (brand name:
Uptravi® [Uptravi® USPI]), and in Europe in May 2016 [Uptravi® SmPC].
Nonclinical data
While active itself, selexipag is hydrolyzed to an active metabolite with prolonged terminal
half-life and a high selectivity for the prostacyclin receptor. Selexipag and its metabolite
possess anti-fibrotic, anti-proliferative, and anti-thrombotic properties. Oral selexipag is
effective in an animal model of PAH, improving hemodynamic and structural factors
leading to increased survival. Selexipag seems to induce minimal or no tachyphylaxis in
rats.
The efficacy of selexipag after oral administration was demonstrated in several nonclinical
models of systemic hypertension and PH. In a rat model of PH, selexipag preserved
endothelial function, decreased mPAP and media thickening of pulmonary arteries, and
diminished right ventricular wall hypertrophy. Selexipag treatment also led to significant
improvement of survival [Selexipag IB, Section 1.2].
Unlike prostacyclin (PGI2) analogs, selexipag and its active metabolite ACT-333679bind
to the human IP receptor with high selectivity over other prostanoid receptors. As shown
in cellular assays, IP receptor activation by selexipag or ACT-333679 leads to vascular
smooth muscle relaxation, anti-proliferation, and anti-fibrotic effects. Selexipag and
ACT-333679 do not activate the molecular processes involved in desensitization of human
IP receptors, avoiding receptor internalization and tachyphylaxis [Selexipag IB,
Section 1.2].
Safety pharmacology studies revealed effects secondary  to expected or exaggerated
pharmacology. There was no indication of an effect on ventricular repolarization.
In the repeat-dose toxicity studies in rodents, strong blood pressure decrease as a result of
exaggerated pharmacology induced transient clinical signs, reduced food consumption, and
body weight gain. In adult and juvenile dogs, intestine and bone / bone marrow were
identified as the main target organs after treatment with selexipag. In dogs less than 1 year
old, intussusception due to prostacyclin-related effects on intestinal motility was observed
sporadically. The effect occurred at 5-fold the human exposure (i.e., corrected for potency;

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415-fold based on total exposure; active metabolite). Safety margins based on no-observed-
adverse-effect levels for the active metabolite, corrected for difference in receptor potency
between human and dog, were 2-fold (i.e., corrected for potency; 180-fold based on total
exposure) in relation to human exposure at a dose of 1,600 µg of selexipag twice daily
(b.i.d.). The intussusception did not occur in mouse or rat toxicity studies. Because of the
species-specific propensity of dogs to develop intussusception and the safety margin, this
finding is not considered relevant for adult humans. However, as young children are known
to be prone to developing intussusception, the use of selexipag in children below 2 years
of age is not recommended based on the nonclinical findings.
Increased bone ossification and related changes in the bone marrow in dog studies are
considered to be due to the activation of prostaglandin-E2 subtype 4 (EP4) receptors in
dogs. As human EP4 receptors are not activated by selexipag or its active metabolite, this
effect is species-specific and, therefore, not relevant to humans.
Selexipag and its active metabolite are not genotoxic on the basis of the overall evidence
of conducted genotoxicity studies.
In the 2-year carcinogenicity studies, selexipag caused an increased incidence of thyroid
adenomas in mice and Leydig cell adenomas in rats [Selexipag IB, Section 1.2]. The
mechanisms are rodent-specific. The findings were observed at exposures that were more
than 25-fold higher than  the exposure in humans and are, therefore, not relevant for
humans. Tortuosity of retinal arterioles was noted after 2 years of treatment only in rats
[Selexipag IB, Section 1.2]. Mechanistically, the effect is considered to be induced by
life-long vasodilation and subsequent changes in ocular hemodynamics. The finding is
considered to be species-specific.
Selexipag was not teratogenic in rats and rabbits and had no effect on the fertility of male
and female rats. In the rat pre- and post-natal development study, selexipag induced no
effects on maternal or pup reproductive function.
Selexipag and its active metabolite were phototoxic in vitro. A dedicated clinical study did
not indicate any potential phototoxicity  of selexipag in humans [Selexipag IB,
Section 5.5.2.1].
Clinical data
1.2.3.1 Exposure
As of 20 June 2017, a total of 1,705 subjects have received one or more doses of selexipag
in completed, clinically completed, or ongoing open-label clinical studies. This includes
510 subjects in clinical pharmacology studies, 1,065 patients with PAH, 32 patients with
CTEPH, 62 patients with ASO, and 36 patients with Raynaud’s Phenomenon secondary to

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systemic sclerosis (SSc). In addition, a total of 262 subjects have been enrolled in the
ongoing double-blind studies AC-065A308/TRITON, NS-304C P3-1, and NS-304A P2-2.
In Phase 1 studies, subjects received multiple doses of up to 1,800 μg b.i.d. of selexipag
and the entire treatment duration was up to 24 days.
For a tabular summary of Phase 2 3 studies with selexipag, see the Investigator’s Brochure
(IB) [Selexipag IB, Section 1.3].
1.2.3.2 Pharmacokinetics and metabolism
The pharmacokinetics (PK) of selexipag and its active metabolite ACT-333679 were dose-
proportional up to a single dose of 800 μg and multiple doses of up to 1,800 μg b.i.d.
Steady-state conditions of selexipag and its active metabolite were reached within 3 days.
No accumulation in plasma was observed.
Selexipag is rapidly absorbed and is hydrolyzed by carboxylesterase (CES) enzymes to its
active metabolite. Maximum observed plasma concentrations of selexipag and its active
metabolite after oral administration are reached within 1 3 hours and 3 4 hours,
respectively. Oxidative metabolism primarily catalyzed by cytochrome P450 (CYP) 2C8
and to a smaller extent by CYP3A4 leads to the formation of hydroxylated and dealkylated
products. Uridine 5’-diphosphoglucuronosyltransferase (UGT) 1A3 and UGT2B7 are
involved in the glucuronidation of the active metabolite. Except for the active metabolite,
none of the circulating metabolites in human plasma exceed 3% of the total drug-related
material [Selexipag IB, Section 5.2.2]. After oral administration, exposure at steady-state
to the active metabolite in both healthy subjects and patients with PAH is approximately
3- to 4-fold higher than to the parent compound. In the presence of food, the exposure to
selexipag after a single dose of 400 μg was increased by 10% in Caucasian subjects and
decreased by 15% in Japanese subjects, whereas exposure to the active metabolite was
decreased by 27% (Caucasian subjects) and 12% (Japanese subjects). In the presence of
food, the time to reach maximum plasma concentration (tmax) of selexipag was delayed by
approximately 1 1.5 h. More subjects reported adverse events (AEs) after administration
in the fasted than in the fed state. Elimination of selexipag is predominantly via metabolism
with a mean terminal half-life of 0.8 2.5 h. The active metabolite has a half-life of
6.2 13.5 h. The total body clearance of selexipag is, on average, 17.93 L/h. Excretion in
healthy subjects was complete 5 days after administration and occurred primarily via feces
(accounting for 93% of the administered dose) compared to 12% in urine. The absolute
bioavailability of selexipag is approximately 49%.
Multiple-dose treatment with selexipag (800 μg b.i.d. and 1,600 μg b.i.d.) did not have an
effect on cardiac repolarization in healthy subjects. No adjustment to the dosing regimen
is needed in elderly patients. No clinically relevant effects of sex, race, disease severity, or
body weight on the PK of selexipag and its active metabolite have been observed in PAH

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patients. In vitro experiments showed that selexipag and ACT-333679 are highly bound to
plasma proteins (> 99%) [In vitro Study ACT-293987A and ACT-333679A 2009].
1.2.3.3 Efficacy results in adult patients with PAH
In the multicenter, double-blind, placebo-controlled, event-driven Phase 3 clinical trial
GRIPHON, conducted in 1,156 subjects > 18 years of age with PAH, selexipag
demonstrated a clinically and statistically significant 40% risk reduction compared to
placebo in the occurrence of a first morbidity/mortality event up to End-of-Treatment
(EOT) + 7 days (hazard ratio for selexipag versus placebo: 0.60; 99% confidence interval
[CI]: 0.46 0.78; 1-sided unstratified log-rank P < 0.0001). Results of all supportive
analyses on the primary endpoint were consistent with that of the main analysis, and the
observed treatment effect was also consistent across subgroups (PAH etiology, region,
ethnicity, gender, age, WHO FC, baseline PAH background medication) [Sitbon 2015,
Selexipag IB].
The secondary endpoints of change from baseline to Week 26 in 6-minute walk distance
(6MWD) measured at trough and time to first PAH-related death or hospitalization due to
PAH showed a statistically significant effect favoring selexipag over placebo. The
secondary endpoints of absence of worsening in WHO FC from baseline to Week 26 and
of time to death (all causes) up to study closure did not show a difference between selexipag
and placebo [Selexipag IB].
Study NS-304/-02: This Phase 2a study in patients with PAH enrolled 43 patients who were
randomized in a 3:1 ratio to selexipag (n  33) and placebo (n  10). Patients were
up-titrated from the starting dose of 200 μg b.i.d. to a maximum of 800 μg b.i.d. based on
the tolerability of each subject. All patients received either an endothelin receptor
antagonist (ERA) and/or a phosphodiesterase type-5 (PDE-5) inhibitor at baseline. After
17 weeks of treatment, a significant 30.3% reduction in PVR with selexipag compared with
placebo (P  0.0045, Wilcoxon rank sum test, Per-protocol Set) was observed, as well as a
mean treatment effect on 6MWD of 24.2 ±23.7 meters (p
 0.2218, Wilcoxon rank sum
test, Per-protocol Set).
Study AC-065A201: This Phase 2, multicenter, uncontrolled, open-label study in Japan
enrolled 37 patients with PAH who received selexipag. Patients were allowed to receive
PDE-5 inhibitors and ERAs. Patients were up-titrated from the starting dose of 200 μg b.i.d.
up to a maximum of 1,600 μg b.i.d. based on the tolerability of each subject. The
maintenance dose for each patient was determined by Week 12 and maintained up to
Week 16. The efficacy evaluation took place at Week 16 of treatment. Long-term treatment
continued up to Week 144. Patients could be treated further at the investigator’s request.
After 16 weeks of treatment, the median change in PVR from baseline 120.9dyn⋅sec/cm5
(95% confidence limits [CLs]): 
184.5, 
59.5 dyn⋅sec/cm5) was observed in  the
Per-protocol Set (two-sided p-value of the Wilcoxon signed rank test < 0.0001). The

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geometric mean percentage ratio in PVR (Week 16/baseline × 100) was 79.7% (95% CLs:
74.0, 86.0). In a supportive analysis using the All-treated Set, similar results to those in the
Per-protocol Set were observed. The long-term treatment phase of the study is currently
ongoing.
For efficacy data from other completed or ongoing selexipag clinical studies in adult
patients with PAH, CTEPH, Raynaud’s Phenomenon secondary to SSc and ASO-IC, see
the Investigator’s Brochure (IB) [Selexipag IB].
1.2.3.4 Safety
1.2.3.4.1  Phase 1 studies
In the Phase 1 studies, selexipag was well tolerated after single doses of up to 400 μg
(fasted, oral, or i.v.) and multiple daily oral doses of up to and including 1,600 μg b.i.d.
(fed). The most frequent AEs were headache, myalgia, arthralgia, jaw pain, nausea,
vomiting, diarrhea, and dizziness. No treatment-related effects of selexipag on
electrocardiogram (ECG) morphology or cardiac repolarization were noted. There were no
clinically relevant changes in vital signs, thyroid markers, or laboratory tests. No changes
were observed in the platelet aggregation test, bone turnover, or coagulation markers. An
exploratory Phase 1 study was performed to evaluate the photosensitizing potential of
selexipag under steady-state conditions. The study did not indicate that selexipag has
clinically relevant photosensitizing potential in humans. More subjects reported AEs after
administration in the fasted state than in the fed state in the food effect study. In a study
performed in subjects with impaired liver function, one serious related event of hepatic
encephalopathy was reported. No further subjects with severe hepatic impairment
(Child-Pugh C) were enrolled in the study. In the thorough QT study (AC-065-106), there
was one serious adverse event (SAE) of symptomatic hypotension reported by a female
subject following administration of multiple doses of selexipag (at 1200 μg dose). This
event was severe in intensity and resolved without sequelae on the same day after
discontinuation of study treatment.
1.2.3.4.2  Safety data from GRIPHON
In the GRIPHON trial, patients were treated for up to 4.2 years. The most frequent adverse
drug reactions observed with selexipag were related to its mode of action and were of the
same type as those seen with other IP-receptor agonists, i.e., prostacyclin analogs. These
included: headache (65% vs 32% in placebo group), diarrhea (42% vs 18%), nausea (33%
vs 18%), jaw pain (26% vs 6%), vomiting (18% vs 9%), pain in extremity (17% vs 8%),
and myalgia (16% vs 6%). A total of 43.8% and 47.1% of patients in the selexipag and
placebo groups, respectively, had at least one SAE. The great majority of SAEs were
consistent with the underlying PAH condition. PAH worsening and right ventricular failure
were the most frequently reported SAEs, and both were reported at lower frequencies in
the selexipag group (14.4% and 5.9%, respectively) than in the placebo group (22.0% and

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7.1%, respectively). A total of 31.7% of patients in the selexipag group and 37.1% in the
placebo group had at least one AE leading to discontinuation of study treatment. Other than
prostacyclin-associated AEs, most of the AEs that led to discontinuation of study treatment
were SAEs associated with the underlying PAH disease.
Overall, in the GRIPHON study, the nature and incidence of typical
prostacyclin-associated AEs (i.e., headache, flushing, diarrhea, nausea, vomiting, jaw pain,
myalgia, and arthralgia) on selexipag was largely in line with that observed with
prostacyclin and prostacyclin analogs [Sitbon 2015; Selexipag IB Section 1.3.4]
Hypotension was reported more frequently in the selexipag group than in the placebo group
(5.9% and 3.8%, respectively). In the selexipag group 9.7% of patients had systolic blood
pressure (SBP) ˂ 90 mmHg on at least one occasion, compared to 6.7% in the placebo
group. A decrease from baseline of > 40 mmHg in SBP was reported for 2.3% and 3.0%
ofpatients in the selexipag and placebo groups, respectively.
In the GRIPHON trial, a transient increase in mean heart rate of 3 4 beats per minute at
2 4 hours post-dose was observed. ECG investigations showed sinus tachycardia in 11.3%
of patients in the selexipag group, compared to 8.8% in the placebo group.
Bleeding was not observed more frequently in selexipag-treated patients compared to
placebo, including in those patients treated concomitantly with anticoagulants. Anemia was
reported more frequently in the selexipag group and a small reduction in hemoglobin was
observed at most post-baseline visits.
Hyperthyroidism was reported more frequently in the selexipag group than in the placebo
group. The corresponding laboratory changes were small reductions in thyroid-stimulating
hormone (TSH) at most post-baseline visits. A possible association between thyroid
disorders and PAH is described in the literature [Marvisi 2013]. Previously published
investigations showed that prostaglandins may influence thyroid function by a direct effect
on specific prostaglandin membrane receptors [Chadha 2009].
Other AEs included nasopharyngitis (very common); decreased appetite, weight decreased,
nasal congestion, rash, urticaria, erythema, abdominal pain, and pain (all reported as
common).
Importantly, there were no additional safety and tolerability findings in the GRIPHON
study in those patients receiving selexipag on top of both an ERA and a PDE-5 inhibitor.
Safety data from other completed selexipag clinical studies in adult patients with PAH,
CTEPH, Raynaud’s Phenomenon secondary to SSc, and ASO-IC  show a safety profile
consistent with that of the GRIPHON study [Selexipag IB]. Safety data in this study are

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reviewed on an ongoing basis by the Independent Data Monitoring Committee (IDMC)
(see Section 3.3).
1.3 Purpose and rationale of the study
The overall rationale for the development of selexipag in children with PAH is based on
the robust and conclusive results of the pivotal study with selexipag in adult patients with
PAH (GRIPHON/AC-065A302, N  1,156) demonstrating efficacy in delaying disease
progression in adults [Sitbon 2015].
In the US, Uptravi is indicated for the treatment of PAH (WHO Group I) to delay disease
progression and reduce the risk of hospitalization for PAH.
In Europe, Uptravi is indicated for the long-term treatment of PAH in adult patients with
WHO FC II III, either as combination therapy in patients insufficiently controlled with an
ERA and/or PDE-5 inhibitor, or as monotherapy in patients who are not candidates for
these therapies.
The selection of the starting dose for pediatric participants is based on their body weight
category, using the data from the population PK model in the GRIPHON study, targeting
the exposure observed in adult PAH patients at a starting dose of 200 µg [Modeling and
Simulation Report AC-065A302 (GRIPHON) 2014].
As in adults, selexipag will be up-titrated to the individual maximum tolerated dose
(iMTD). Tolerability will be assessed based on prostacyclin-related side effects. Therefore,
in the absence of major PK differences between adults and children, applying an equivalent
dose up-titration regimen in children should lead to exposures in pediatric participants
similar to those in adults, and should also result in consistent efficacy results and safety
profiles.
The development plan of selexipag in children will consist of this Phase 2 studyto establish
the selexipag dose(s) and determine the PK of selexipag and its active metabolite, followed
by a Phase 3 study to assess the efficacy, safety, and tolerability of selexipag in this
population.
Therefore, the purpose of this study is to confirm the selexipag doses in children from
≥2 to < 18 years of age with PAH that lead to an exposure similar to that in adult
participants. The selection of the selexipag starting dose is based on a PK extrapolation
from adults to pediatric participants. In addition, the safety and tolerability of selexipag in
children from ≥2 to < 18 years of age will be assessed.

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1.4 Summary of known potential benefits and risks
Benefits
Selexipag, a non-prostanoid IP (prostacyclin) receptor agonist, is an orally available
medicine with PK characteristics suitable for b.i.d. dosing.
The efficacy of selexipag in the treatment of adult patients with symptomatic PAH was
demonstrated in GRIPHON, the largest (N  1,156) and only long-term (mean duration
1.5 years and up to 4.2 years), controlled outcome study conducted with an IP-receptor
agonist. The treatment effect was consistent across WHO FC II III and was fully preserved
in patients already treated with an approved PAH-specific medicine at baseline (80% of
the study population), as well as in patients treated with two such medicines (30% of the
study population).
GRIPHON was the first study to demonstrate the outcome benefit of an IP-receptor agonist,
in particular when added sequentially to therapies acting on other pathogenic pathways in
PAH (endothelin and nitric oxide pathways), i.e., within a treatment strategy consistent
with current consensus guidelines whereby selexipag is the only IP-receptor agonist given
a Class I evidence recommendation for sequential drug combination therapy [Galiè 2015].
Pediatric PAH is a rare and progressive disorder associated with considerable morbidity
and mortality. Current treatment recommendations in the pediatric population include
PDE-5 inhibitors, ERAs, and inhaled, subcutaneous, and i.v. prostacyclin-pathway
agonists [Ivy 2013, Galiè 2015]. However, in the absence of randomized controlled clinical
trials powered to show the efficacy of those therapies in pediatric patients, the treatment
algorithm is based on evidence from adult studies.
Further clinical trials in the pediatric population are therefore extremely important to
provide more data for the management ofPAH in children.
Given the pathophysiological and clinical similarities of pediatric and adult PAH disease,
it is believed that pediatric participants with PAH could benefit from selexipag treatment.
This study aims to determine the appropriate dose and to investigate the PK, safety, and
tolerability of selexipag in pediatric participants over 2 years of age with PAH.
Risks
The tolerability and safety profile of selexipag administered to children is expected to be
consistent with that ofadult patients [see Section 1.2.3.4].

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The following measures are being taken to minimize the potential risks for the pediatric
participants participating in the study:
 The selection of the starting dose for pediatric participants is based on their bodyweight
category, using the data from the population PK model in the GRIPHON study,
targeting the exposure observed in adult participants with PAH at a starting dose of 200
µg.
 At the interim and final PK analyses, all available PK results will be used to update the
PK model and to confirm or adjust the dose selection.
 Enrollment of Cohort 3 (children aged from 2 to less than 6 years old) will only be
performed after the PK interim analysis in Cohorts 1 and 2 (pediatric participants older
than 6 years) have been completed, and selexipag safety and tolerability profiles in
Cohorts 1 and 2 have been confirmed.
 The number of PK samples and blood volume collected per participant will be
optimized to reduce the total amount of blood drawn from pediatric participants [see
Section 7.2.5.1].
 Inclusion and exclusion criteria are carefully designed in this protocol [see Section 4].
 Close monitoring during the initial up-titration period up to Week 12 includes weekly
phone calls or site visits, followed by 3-monthly contacts (phone calls and site visits
alternating every 3 months) [see Figure 2, Table 4, and Table 5].
 Specific recommendations are made regarding the management ofAEs associated with
tolerability during the initial up-titration phase [see Section 5.1.4], along with the
recommendation that participants take study drug with food to improve tolerability
[see Section 5.1.4].
 Specific recommendations are made for study drug interruption and/or permanent
discontinuation [see Section 5.1.10].
 Guidance to investigator and parents/participants in case of clinical signs compatible
with gastrointestinal ileus or obstruction [see Sections 1.2.2 and 5.1.10].
 Guidance to investigator and parents/participants in case of clinical signs of
hyperthyroidism [see Sections 1.2.3.4 and 5.1.10].
 Monitoring of participants’ growth and development throughout their study
participation [see Sections 7.2.3.4. and 7.2.3.5].
Safety surveillance for participants participating in study AC-065A203 will additionally
be ensured by an Independent Data Safety Monitoring Committee (IDMC), which will
periodically review available safety data [see Section 3.3].

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Participants will receive additional care as result of being in a clinical trial including close
monitoring at an expert PAH center.
It is the investigator’s responsibility to monitor the benefit-risk ratio of study treatment
administration, as well as the degree of distress caused by study procedures on an
individual participant level, and to discontinue study treatment or study procedures if, on
balance, they  determine that continuation would be detrimental to the participants’
well-being.
Conclusion
The benefit of medicines acting on the prostacyclin pathway (IP-receptor agonists) in the
treatment of PAH in adults is established, as acknowledged by current treatment guidelines
[Galiè 2015].
Uptravi (selexipag) is a selective IP-receptor agonist for oral use with proven efficacy and
safety in adults with PAH. To date, selexipag is the only IP-receptor agonist approved
globally for long-term treatment across WHO FC II III, and primarily in combination with
current first-line oral PAH-specific medicines, in adult patients in need of additional
therapy because of insufficient disease control. Uptravi represents an important additional
treatment option for these patients.
Selexipag is not indicated or foreseen for use as an alternative to i.v. prostacyclin analogs
(epoprostenol, treprostinil) in patients with the most severe PAH (WHO FC IV).
The availability of selexipag, a highly selective IP-receptor agonist for oral use and with
demonstrated benefit for PAH disease outcomes in add-on therapy, provides an important
rationale for initiating prostacyclin-pathway therapy at a medically appropriate stage of
PAH disease without major consequences for the patient’s lifestyle.
Based on the known similarities between PAH disease in adult and pediatric patients and
the need to develop treatments that may be disease-modifying in pediatric patients with
PAH, this study is the first clinical study conducted with selexipag in children with PAH.
2 
STUDY OBJECTIVES
2.1 Primary objective(s)
The primary objective of the study is to confirm the selexipag starting dose(s), selected
based on PK extrapolation from adults, that leads to similar exposure as adults doses in
children from ≥2 to ˂ 18 years of age with PAH, by investigating the PKof selexipag and
its active metabolite ACT-333679in this population.

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2.2 Secondary objectives
 To evaluate the safety and tolerability of selexipag in children from ≥ 2 to ˂ 18 years
of age with PAH.
2.3 Exploratory objectives
 To explore the relationship between drug exposure at the iMTD and 6MWD at each
time point of assessment.
 To explore the relationship between drug exposure and NT pro-BNP at each time
point of assessment.
 To explore the relationship between drug exposure and Echo variables at each time
point of assessment.
 To explore the time to disease progression / clinical worsening from first study drug
dose up to EOT + 7 days.
2.4 Other objectives
 To assess the palatability of selexipag formulation at each time point of assessment
using a 5-point facial hedonic scale.
 To assess the acceptability ofselexipag formulation at each time point of assessment
using a 3-point categorical scale.
3 
OVERALL STUDY DESIGN AND PLAN
3.1 Study design
This is a prospective, multi-center, open-label, single-arm Phase 2 study.
Approximately 60 participants will be enrolled in 3 different age cohorts (based on age at
Baseline / Enrollment /Visit 2) to obtain at least 45 participants with evaluable PK profiles:
 Cohort 1: ≥ 12 to < 18 years of age (approximately 20 enrolled participants to obtain at
least 15 participants with evaluable PK profiles)
 Cohort 2: ≥ 6 to < 12 years of age (approximately 20 enrolled participants to obtain at
least 15 participants with evaluable PK profiles)
 Cohort 3: ≥ 2 to < 6 years of age (approximately 20 enrolled participants to obtain at
least 15 participants with evaluable PK profiles).

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The starting dose is based on the body weight category of the participants, using the data
from the population PK model in the GRIPHON/AC-065A302 study targeting the exposure
observed in adult participants with PAH at a starting dose of 200 μg [Modeling and
Simulation Report AC-065A302 (GRIPHON) 2014]. The continuous relationship between
dose and body weight is used to define body weight categories and starting dose for each
body weight category such that on average the exposure (combined exposure over one
dosing interval at steady state [AUCτ,ss,combined]) will be comparable to that in a 70 kg adult
but not exceeding the exposure in a 50 kg adult [Figure 1, Modeling and Simulation Report,
Pediatric dose selection 2016]:
 100 μg for participants with a body weight from 9 to < 25 kg.
 150 μg for participants with a body weight from ≥25 to < 50 kg.
 200 g for participants with a body weight ≥50 kg.
The body weight-exposure relationship is extrapolated from the body weight-exposure
relationship determined by the population PK model in participants with PAH in the
GRIPHON study with body weights ranging from 40 148 kg. In this model, body weight
was a covariate on selexipag and ACT-333679 volume of distribution and elimination rate
[Modeling and Simulation Report AC-065A302 (GRIPHON) 2014].

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Figure 1 
Estimated starting doses based on the GRIPHON PK model achieving
the same exposure as in adult patients of 50 kg, 70 kg, and 96 kg
treated with 200 μg b.i.d. selexipag
AUC  area under the curve; b.i.d.  twice daily; GRIPHON  prostacyclin (PG12G) receptor agonist in pulmonary
arterial hypertension; PK  pharmacokinetic.
The exposure is defined as the combined exposure to selexipag and ACT-333679 corrected
for potency (AUCτ,ss,combined). It is derived accordingly:
AUCτ,ss,combined  1/38 × AUCτ,ss, selexipag + 37/38 × AUCτ,ss ACT 333679
The potency of ACT-333679 was estimated to be 37 times that of selexipag. ACT-333679
is, therefore, the major contributor to the efficacy of selexipag [Menyhart 2014]. The
starting dose selection will be confirmed or adjusted after the completion of each age cohort
by updating the population PK model (interim analysis).
The study will be conducted in approximately 30 sites in 20 countries.
Enrollment will start with both Cohort 1 and Cohort 2 (participants ≥12 to < 18 and ≥6 to
< 12 years old, respectively). After completion of PK assessments in at least 15 participants
from Cohort 1 at Week 12, the dose-exposure relationship will be established using a
population PK model [Modeling and Simulation Report, Pediatric dose selection 2016].
The PK data from any participants in Cohort 2 who have completed their PK assessments
at this time will be included in this first interim analysis.

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Results of this model-based analysis will be used to confirm or adjust the selexipag doses
initially selected. If the population PK model results suggest that the administered
selexipag doses lead to exposures deviating from the currently predicted target exposures,
the recommended starting dose, increments of up-titration, and maximum allowed dose
(equivalent to 1,600 µg b.i.d. in adult participants with PAH) for the remaining participants
to be enrolled in Cohort 2 and Cohort 3 will be adjusted. The decision on dose-adjustment
will take into account the inter-individual variability in the pediatric population and the
difference in exposure between lower and upper limits of body weight in the GRIPHON
study. The inter-individual variability in the GRIPHON study was more than 30%
(comparing the 10th  and 90th  percentiles), and difference in exposure between lower and
upper limits of body weight was 50% [Modeling and Simulation Report AC-065A302
(GRIPHON) 2014]. It is expected that the dosing regimen does not need to be adjusted if
the revised point estimate body weight-starting dose relationship deviates from the current
estimate by less than 30%. The dosing regimen must be adjusted if the revised point
estimate body weight-starting dose relationship deviates from the current estimate by more
than 50%. If this difference between the revised and the current point estimate is between
30% and 50%, the decision on dose adjustment will depend on the results of safety
assessments after the first dose. Enrollment of Cohort 3 (children ≥ 2 to < 6 years of age)
will start once the appropriate doses have been confirmed by modelling and simulation in
a second interim analysis of PK data from the children older than 6 years (i.e., Cohorts 1
and 2), and if there is no safety concern based on IDMC reviews.
The PK data pooled from all three age cohorts will be modelled to allow dosing
recommendations for all children ≥ 2 years of age. A final PK analysis will be prepared
based on the overall PK and safety data up to Week 16 evaluation.
Given the rareness of pediatric PAH, combined with the ongoing global Corona virus
disease-2019 (COVID-19) pandemic, enrolling participants in age Cohort 3 (≥ 2 to < 6
years of age) into this study has been difficult and as such the planned sample size of at
least 15 PK evaluable Cohort 3 participants remains a challenge. The option of confirming
the selexipag dosing recommendation for participants aged ≥ 2 to < 6 years based on a
smaller sample size is, therefore, being considered. To assess this, a third interim PK
analysis may be conducted, as deemed appropriate by the sponsor.
All available PK and safety data from participants in Cohorts 1, 2, and 3 up to Week 16 at
the time of the data cut-off date, will be included in interim analysis 3. The analytical
approach for interim analysis 3 will be the same as applied for interim analyses 1 and 2.
For the dosing confirmation of Cohort 3 with fewer than the planned 15 PK evaluable
participants, one of the following criteria is to be achieved:
 The 90% CI of the point estimate describing the body weight-starting dose relationship
relative to the current estimate is within 0.70-1.30.

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Or
 The 90% CI of the point estimate describing the body weight-starting dose relationship
relative to the current estimate is within 0.50-1.50 and at the same time, no dose
adjustment is warranted by the available safety data.
If, however, the 90% CI of the relative point estimate exceeds 0.70-1.30 and a dose
adjustment may be warranted by the available safety data or the 90% CI of the relative
point estimate exceeds 0.50-1.50, a final PK analysis including the PK data pooled from
all 3 age cohorts and at least 15 PK available participants in Cohort 3, will be conducted.
Following this final PK analysis, the dosing recommendation will be confirmed based on
the revised point estimate body weight-starting dose relationship, irrespective ofthe 90%
CI, as originally planned.
In case the dosing recommendation for age Cohort 3 is confirmed based on the third interim
PK analysis, further enrolment into the trial will be terminated. The PK of all enrolled
participants, including participants completing their PK assessments after the data cut-off
date for interim analysis 3 will be included in the PK analysis to be reported in the clinical
study report (CSR).
The selection of the dosing regimen for the Phase 3 study will be based on the safety,
tolerability, and PK results evaluated in the interim or final PK analysis (as applicable).
Participants who discontinue the treatment any time before the profile PK sampling day
may be replaced within the age cohort.
Study periods
The study consists of the following consecutive periods:
Screening period: Lasts up to 42 days; starts with the signature of the informed consent
form (ICF) and ends with the administration ofthe first study treatment dose.
Treatment period: Starts from the first dose of study treatment at Baseline/Enrollment
visit and ends on the day of the last dose of selexipag (EOT). This includes:
 Up-titration period:
 From the first dose of study treatment until the participant reaches their iMTD. This
period is estimated to last up to 12 weeks.
 Details of up-titration are described in Section 5.1.4.
 Maintenance period:
 After Week 12: The participants will continue study treatment at the same dose up
to Week 16.

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 After Week 16: Study treatment will continue as long as it remains beneficial for
the participant, but up to a maximum of 5 years after last participant first visit [see
Section 3.1.2 for details].
EOT visit: This visit should be conducted within 1 week of the last dose of study treatment.
Safety Follow-up period: Starts on the day after the last dose of study treatment and ends
about 30 days thereafter with a phone call that will serve as the End-of-Study (EOS).
The visit schedule and protocol-mandated procedures will be performed according to the
table of assessments [Table 4, Table 5] and are described in Section 7.
The overall study design is depicted in Figure 2.

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Figure 2 
Study design
b.i.d  twice daily; D  day; eq.  equivalent; EOS  End of Study; EOT  End of Treatment; FU  follow up;
M
month; q  every; V  visit; W
week.
Equivalent (eq.) refers to the equivalent dose according to the body weight category as described in Section 5.1.4.

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Study duration
The study starts with the first act of recruitment (i.e., first ICF signed) and ends with the
last visit of the last participant (i.e., last EOS).
The study will last until 5 years after last participant, first visit.
Participants will be treated with selexipag as long as the treatment is beneficial to the
participant, per the investigator’s decision. After the last dose of selexipag, participants
will be followed up for safety until 30 days after the last dose (  EOS visit). The
participant’s participation is completed with the EOS visit.
3.2 Study design rationale
The objective of this pediatric study is to confirm the selexipag starting doses, selected by
PK extrapolation from adults, that are expected to lead to similar exposure of selexipag and
its active metabolite ACT-333679 in children  as in  adult PAH subjects(GRIPHON),
following the same principle of up-titration to the iMTD. The primary PK endpoint is
defined as exposure (AUCτ,ss,combined) to selexipag and ACT-333679 corrected for potency,
determined during the 12-week up-titration period. The PK parameters will be described
with a population PK model and will be used to confirm/adjust the selected selexipag doses
[Modeling and Simulation Report AC-065A302 (GRIPHON) 2014, Modeling and
Simulation Report, Pediatric dose selection 2016]. The AUCτ,ss,combinedin adult participants
with PAH was also determined based on population PK modeling [Modeling and
Simulation Report AC-065A302 (GRIPHON) 2014].
The following assumptions were used for the calculation of the starting dose in pediatric
participants with PAH based on the GRIPHON model.
 In adults, the PK of selexipag and the active metabolite ACT-333679, after
multiple-dose administration, are dose-proportional up to 1,800 µg, given b.i.d.
[Clinical Study Report AC-065A-101 2012, QGUY/2006/NS304/-01].
 It is assumed that the PK are also dose proportional in the pediatric population, and this
will be further evaluated in the proposed study.
 The enzyme systems involved in selexipag metabolism (CES1, CES2, CYP2C8,
UGT1A3, and UGT2B7), and CYP3A4, are essentially mature in children aged 2 years
and older [Song 2017, Hines 2016, Smits 2012, McNamara 2002, Zhu 2009, Shi 2011,
Yang 2009, Strassburg 2002, Oo 2003].
 No other major differences between the PK of selexipag in adults and children are
expected.
The PK of selexipag and its active metabolite ACT-333679 in adult PAH subjects were
characterized by a population PK model based on data from the GRIPHON study

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[Modeling and Simulation Report AC-065A302 (GRIPHON) 2014]. Body weight was
identified as a statistically significant covariate for the volume of distribution of selexipag
and ACT-333679, as well as for drug clearance. The model-predicted concentrations of
selexipag and ACT-333679 for a reference subject of 70 kg were compared to model-
predicted concentrations for subjects with body weights of 51 and 96 kg, corresponding to
the 10th  and 90th  percentile of the body weight distribution of subjects included in the
GRIPHON study, at steady-state doses of 1,600 µg b.i.d.
Compared to a 70 kg subject, a subject with a body weight of 51 kg is predicted to have
30% and 20% higher exposure to selexipag and to ACT-333679, respectively, whereas a
subject with a body weight of 96 kg is predicted to have 20% and 10% lower exposure,
respectively.
The selection of the starting dose for pediatric participants is based on body weight
categories, using the data from the population PK model in the GRIPHON study, targeting
the exposure observed in adult participants with PAH at a starting dose of 200 µg
[Modeling and Simulation Report AC-065A302 (GRIPHON) 2014]. The exposure is
defined as the combined exposure to selexipag and ACT-333679 corrected for potency
(AUCτ,ss,combined). The potency of ACT-333679 was estimated to be 37 times that of
selexipag. ACT-333679 is, therefore, the major contributor to the efficacy of selexipag.
The continuous relationship between dose and body weight is used to define body weight
categories and starting dose for each body weight category such that on average the
exposure (AUCτ,ss,combined) will be comparable to that in a 70 kg adult patient but not
exceeding the exposure in a 50 kg adult patient [Figure 1].
The starting dose of selexipag expressed on a per kg basis increases in the lower body
weight categories, as the relationship between body weight and dose is not linear. This is
analogous with the pediatric experience with epoprostenol, where the doses in pediatric
patients are generally higher than in adults on a per kg basis. However, assuming the body
weight-to-exposure relationship observed in GRIPHON, AUCτ,ss,combined at the starting dose
for pediatric patients in different body weight categories will not be higher than
AUCτ,ss,combined at a starting dose of 200 μg b.i.d. in a 50 kg adult patient in the GRIPHON
study.
In adult PAH patients, the recommended starting dose of 200 μg b.i.d. is up-titrated in
increments of 200 μg b.i.d. at approximately weekly intervals up to the iMTD or 1,600 μg
b.i.d. [Clinical Study Report AC-065A302 (GRIPHON) 2014]. Individual up-titration in
children will be similar to that in adult PAH patients, i.e., the dose will be increased by
increments equal to the starting dose up to the iMTD and will not exceed the dose with
predicted equivalent exposure to 1,600 μg b.i.d. in each body weight category. Based on

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the dose-proportional PK of selexipag/ACT-333679, the ratio of the maximum pediatric
dose to the adult dose for each dose level is the same as for the starting dose.
The identification of starting doses, the increment to be applied to children treated with
selexipag according to their body weight category, and the maximum allowed dose in this
study will serve as a basis for the Phase 3 trial design.
3.3 Study committees
An IDMC has the overall responsibility for safeguarding the interests of participants by
monitoring safety data obtained in the study and by making appropriate recommendations
based on the reported data, thus ensuring that the study is being conducted to the highest
scientific and ethical standards. The PK results of the interim analyses (after completion of
Cohort 1 and 2), and overall PK results of all three cohorts will be provided to the IDMC
for review, if requested by the committee. The IDMC will be fully operational prior to the
enrollment of the first participant in the study. The composition and operation of the IDMC
is described in the IDMC charter.
4 SUBJECT POPULATION
4.1 Subject population description
Participants with iPAH or hPAH, as well as aPAH-CHD, drug or toxin-induced PAH,
PAH-aCTD, or PAH associated with HIV are enrolled if they are of WHO FC II or III.
Eligible participants are participants treated with  an ERA and/or a PDE-5 inhibitor or
participants who are not candidates for these therapies.
Participants will be enrolled in age cohorts, starting with participants from 6 to less than
18 years of age.
The population is vulnerable according to the ICH-GCP E6 1.61 definition. Parent(s) /
legally authorized representative(s) (LAR[s]) will be required to provide informed consent
for the participation of their child in the clinical study, and assent will be obtained from
developmentally capable study participants.
4.2 Rationale for the selection of the study population
Pediatric participants with PAH from ≥ 2 to ˂ 18 years of age and of all etiologies relevant
in children with PAH are enrolled to cover a generalizable pediatric PAH population.
Within the subgroup of aPAH-CHD, the protocol excludes participants with Eisenmenger
syndrome, as well as participants with open left-to-right shunts, due to a lack of sufficient
adult data supporting the efficacy of selexipag in children.
Participants under 2 years of age are not part of the study population due to concerns of a
potentially increased risk of intestinal intussusception, based on toxicological findings of
intestinal intussusception in young dogs treated with selexipag and the high background

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incidence of intussusception in infants [Newman 1987, Hutchison 1980, Pollack 1991,
Waseem 2008, Stringer 1992].
4.3 Inclusion criteria
For inclusion in the study, all of the following inclusion criteria must be fulfilled. It is not
permitted to waive any of the criteria for any participant:
1. Signed and dated informed consent by the parent(s) or LAR(s) AND assent from
developmentally capable children.
2. Males or females between ≥ 2 and < 18 years of age at Baseline / Enrollment / Visit 2
weighing ≥ 9kg.
3. PAH diagnosis confirmed by documented historical RHC performed at any time before
the participant’s enrollment, and characterized by:
 
mPAP ≥ 25 mmHg;
and
 
PAWP ≤15 mmHg
(in the absence of pulmonary vein obstruction and/or significant lung
disease, PAWP can be replaced by LAP or, in the absence of mitral stenosis,
by LVEDP);
and
 
PVRi > 3 WU m2.
4. PAH belonging to Nice 2013 Updated Classification Group 1 (including Down
syndrome) and of one of the following etiologies:
 
iPAH.
 
hPAH.
 
aPAH-CHD:
 PAH with co-incidental CHD.
 Post-operative PAH (persisting / recurring / developing ≥ 6 months after
repair of CHD).
 
Drug or toxin-induced PAH.
 
PAH associated with HIV.
 
PAH-aCTD.
5. 
WHO FC II to III.
6. 
Subjects treated with an ERA and/or a PDE-5 inhibitor, provided that the treatment
dose(s) has been stable for at least 3 months prior to enrollment, or participants who
are not candidates for these therapies.

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7. 
Females of childbearing potential must have a negative pregnancy test at Screening
and at Enrollment, and must agree to undertake monthly pregnancy tests and to use
a reliable method of contraception (if sexually active) from Screening up to study
drug discontinuation + 30 days (EOS).
4.4 Exclusion criteria
Participants must not fulfill any of the following exclusion criteria. It is not permitted to
waive any of the criteria for any participant:
Etiology
1. Participants with PAH due to portal hypertension, schistosomiasis, PVOD, and/or
pulmonary capillary hemangiomatosis.
2. Participants with PAH associated with Eisenmenger syndrome.
3. Participants with moderate to large left-to-right shunts5.
4. Participants with cyanotic congenital cardiac lesions such as transposition of the great
arteries, truncus arteriosus, univentricular heart, or pulmonary atresia with ventricular
septal defect, as well as participants with Fontan palliation.
5. Participants with PH due to lung disease and/or hypoxia. For participants with Down
syndrome, exclusion of lung disease and hypoxia causing PH should be documented
(eg, computed tomography scan, polysomnography, lung function tests).
Treatment and intervention
6. Previous treatment with Uptravi (selexipag) within 2 weeks prior to enrollment.
7. Participants who have received prostacyclin (epoprostenol) or prostacyclin analogs6
(i.e., treprostinil, iloprost, beraprost) within 2 months prior to enrollment or who are
scheduled to receive any of these compounds during the trial.
8. Treatment with another investigational drug within 4 weeks prior to enrollment.
9. Treatment with strong and moderate inhibitors of CYP2C8 (eg, gemfibrozil,
clopidogrel, deferasirox, teriflunomide) within 2 weeks prior to enrollment until the
last dose of selexipag + 3 days.
5 Left to right shunts with a pulmonary to systemic flow ratio > 1.5 are considered moderate to large [Driscoll 1999].
The size and magnitude of left to right shunts, if applicable, is assessed by the investigator based on local clinical
practice.
6 Single administration of drugs used for acute vasodilator testing during RHC procedure is allowed (eg, i.v./inhaled
prostacyclin, inhaled nitric oxide, or oral sildenafil).

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10. Treatment with inhibitors of UGT1A3 and UGT2B7 (valproic acid, probenecid, and
fluconazole) is prohibited from 2 weeks prior to enrollment and until the last dose of
selexipag + 3 days.
11. Any PAH-related surgical intervention planned, or participants listed for organ
transplantation related to PAH.
12. History or current suspicion of intussusception or ileus or gastrointestinal obstruction,
per investigator’s judgment.
Baseline abnormalities
13. Known concomitant life-threatening disease with a life expectancy < 12 months.
14. Uncontrolled thyroid disease, per investigator’s judgment.
15. Hemoglobin or hematocrit < 75% of the lower limit of normal range.
16. 17. Moderate or severe hepatic impairment, eg, Child-Pugh Class B or C8.
17. Clinical signs of hypotension that in the investigator’s judgment would preclude
initiation of a PAH-specific therapy.
18. Participants with severe renal insufficiency (estimated creatinine clearance
< 30 mL/min or serum creatinine > 221 µmol/L).
19. Severe coronary heart disease or unstable angina as assessed by the investigator.
20. Myocardial infarction within the last 6 months prior to enrollment.
21. Decompensated cardiac failure if not under close supervision.
22. Severe arrhythmias as assessed by the investigator.
23. Cerebrovascular events (eg, transient ischemic attack, stroke) within the last 3 months
prior to enrollment.
24. Congenital or acquired valvular defects with clinically relevant myocardial function
disorders not related to PH.
Pregnancy and breastfeeding
25. Pregnancy (including family planning) or breastfeeding.
7 Sub numbering introduced to highlight change from previous protocol version.
8 The assessment for hepatic impairment at Screening (Child Pugh Score, see Section 14.4 Appendix 4) must be fully
documented for participants with hepatic impairment as part of medical history and clinical signs and evidence
(from central and/or local lab) of hepatic impairment.

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Other categories
26. Known hypersensitivity to the investigational treatment or to any of the excipients of
the drug formulations.
27. Drug or substance abuse, or any condition that, in the opinion of the investigator, may
prevent compliance with the protocol or adherence to study treatment.
28. Loss of 250 mL or more of blood within 3 months prior to Screening.
29. History or clinical evidence of any disease and/or existence of any surgical or medical
condition that might interfere with the absorption, distribution, metabolism, or
excretion of the study treatment(s) (eg, cholecystectomy).
30. “ Criterion deleted per Amendment 6.”
4.5 Criteria for female subjects of childbearing potential
Pregnancy is associated with maternal mortality in participants with PAH [Bédard 2009].
Therefore, female participants of childbearing potential who are heterosexually active must
use a reliable method of contraception.
Definition of childbearing potential
A female participant is considered to be of childbearing potential unless she meets at least
one of the following criteria:
 Prepubescence
 Previous bilateral salpingectomy, bilateral salpingo-oophorectomy, or hysterectomy
 Tubal sterilization
 Premature ovarian failure confirmed by a specialist
 XY genotype or any other genetic disorder associated with permanent sterility, uterine
agenesis
In the case of prepubescence, potential childbearing status will be assessed at each visit
and recorded in the electronic case report form (eCRF). The reason for not being considered
to be of childbearing potential will be recorded in the eCRF.
Acceptable methods of contraception
For female participants who are of childbearing potential [see definition in Section 4.5.1]
and heterosexually active, it is mandatory to use one of the following methods of birth
control from Screening up to at least 30 days after study treatment discontinuation.
 Oral or injectable contraceptive agents, implants or transdermal contraceptive hormone

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 Intrauterine device
 Vasectomized partner (a vasectomized partner is a highly effective contraceptive
method provided that the partner is the sole sexual partner of the woman of childbearing
potential and the absence of sperm has been confirmed. If not, additional highly
effective method of contraception should be used).
 Diaphragm; female condom or cervical cap; or partner’s use of a condom, and any of
these used in combination with a spermicide.
If a hormonal contraceptive is chosen, it must be taken for at least 30 days prior to
randomization.
Rhythm methods are not considered acceptable methods of contraception for this study.
It is the responsibility of the investigator to ensure appropriate counseling, including
consultation with a specialist (if needed), to the participant and/or parent(s)/LAR(s) on the
acceptable method of contraception.
In female participants of childbearing potential who become heterosexually active at any
time after enrollment, contraceptive method(s) that are immediately effective must be
initiated. This method(s) can be replaced but must continue until the new method of
contraception becomes effective. The contraceptive methods used (including non-
pharmacological methods) must be recorded in the eCRF.
If the female participant or her parent(s)/LAR(s) decide that they want to change the form
of birth control used, they need to talk with the treating physician to be sure that another
acceptable form of birth control is chosen.
To ensure compliance, the study personnel must remind female participants of childbearing
potential who are heterosexually active and their parent(s)/LAR(s) at each visit to use the
methods of contraception defined for this study. These reminders must be documented in
the source documents.
5 TREATMENTS
5.1 Study treatment
Investigational treatment: description and rationale
Selexipag is supplied by the sponsor as child-proof bottles containing tablets with the
following dosage strengths:
 Bottles of 120 film-coated tablets containing 200 g of selexipag.
 Bottles of 280 film-coated mini-tablets containing 50 g of selexipag.

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Study treatment administration
Selexipag is administered orally b.i.d. with an interval of approximately 12 hours.
Tablets can be administered via 1 of 3 options:
 
Swallowing the tablets/ mini-tablets whole with water.
 
Swallowing tablets/ mini-tablets with soft food.
 
Dispersing mini-tablets in apple or orange juice.
Tablets or mini-tablets should not be crushed, split or chewed.
Administration of tablets with soft-food
Participants can take 200 g tablets and 50 g mini-tablets (refer to Table 3) with soft food
(i.e., yoghurt, apple sauce/puree/mousse or mashed banana) according to the following
instructions:
a) .Take the instructed number of tablets (200 µg tablets and/or 50 µg mini-tablets) as
shown in the respective protocol uptitration scheme.
i. 
For 50 µg mini-tablets: place the instructed number of tablets as shown
in uptitration scheme on a spoon.
ii. 
For 200 µg tablet: place up to 4 tablets at a time on a spoon.
b) Place enough soft food onto the spoon to completely cover the tablet(s). Multiple
spoons of tablets and soft food may be used, if required.
c) All the soft food with the tablets should be consumed by the participant to ensure
administration of the complete dose.
d) After the soft food is consumed, check the spoon to ensure all tablets have been
taken (add more soft food, if necessary).
Administration of mini-tablets with juices
The 50 g mini-tablets can also be administered by dispersing in apple- or orange-juice:
a) Place the instructed number of mini-tablets as shown in uptitration scheme in a
beverage recipient made of glass or porcelain. The minimal volume of beverage to
disperse the mini-tablet, must be 1 mL per mini-tablet.

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b) Disperse the mini-tablets by adding apple- or orange-juice to the mini-tablets and
subsequently gently swirling the juice manually.
c) After the liquid is consumed, check the recipient to ensure all mini-tablets have
been taken (add more beverage, if necessary).
As the study drug starting dose is based on  body weight, calibration certificates or
maintenance records for the body weight scale should be available prior to the first
participant being enrolled at the site. The calibration should be performed according to the
manufacturer’s specification.
At the beginning of each up-titration phase, participants will be recommended to take the
first dose in the evening in order to reduce the likelihood of the occurrence of headache,
jaw pain, flushing, and nausea. The study drug can be taken with or without food (ie a
meal), although tolerability may improve when selexipag is taken with food.
On visits when PK samples are scheduled (Visit 3 or 7; Visits 4, 5, and 6), the selexipag
dose must be taken at the site under investigator / site staff supervision to ensure exact
recording of dose intake time and compliance with the blood samples time schedule:
 Visit 3 or 7 (PK sampling over 12 h): the morning and evening doses should be taken
at the site:
 The morning dose after pre-dose PK sample.
 The evening dose after the 12 hours post-dose PK sample.
 Visits 4, 5, and 6:
 The morning dose should be taken at the site after the trough PK sample.
The investigator / site staff must ensure that all PK samples are collected after 3 days at the
same dose and using the same mode of treatment administration. Exact date and time of
the treatment intakes preceding and following all PK samples, as well as the mode of
treatment administration, must be recorded in the source documents and the eCRF.
See also instructions regarding meals on the PK visit days in Section 7.2.5.2.
Treatment assignment
After having verified that the participant meets all inclusion criteria and none of the
exclusion criteria, the investigator/delegate contacts the Interactive Response Technology
(IRT) system at the Baseline/Enrollment visit to enroll the participant. The IRT assigns an
enrollment number to the participant and assigns the treatment bottle numbers, based on
the participant’s body weight category.

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Study drug starting dose and up-titration
At the Baseline/Enrollment visit, based on the participant’s body weight, the body weight
category, starting dose, and up-titration scheme will be determined.
Study medication administration will start in the evening of Day 1 and continue thereafter
with b.i.d. dosing, i.e., in the morning and in the evening. During the up-titration period of
12 weeks, it is recommended that the doses are increased weekly in increments equal to
the starting dose until the participants reach their iMTD or until a maximum dose
corresponding to their baseline body weight category is achieved.
To improve tolerability, it is recommended that the study drug, selexipag, is taken with
food and, at the beginning of each up-titration phase, that the first increased dose is taken
in the evening. The maximum dose allowed to be administered will be 8-fold the
corresponding starting dose:
 Body weight category ≥ 50 kg: starting dose of 200 µg titrated up to the iMTD of
1,600 µg b.i.d. Participants in this category will receive 200 g tablets only [Table 1].
 Body weight category ≥ 25 to < 50 kg: starting dose of 150 µg titrated up to the iMTD
of 1,200 µg b.i.d. Participants in this category will receive a combination of 50 g mini-
tablets and 200 g tablets [Table 2].
 Body weight category ≥ 9 to < 25 kg: starting dose of 100 µg titrated up to the iMTD
of 800 µg b.i.d. Participants in this category will receive either a combination of
50 g mini-tablets and 200 g tablets, or 50 g mini-tablets only, if requested by the
investigator [Table 3].
Two study-treatment supply options are available:
 Option 1 will supply participants able to swallow tablets whole with water
with a combination of 200 g tablets and 50 g mini-tablets to minimize
the overall number of tablets per intake and will be provided via IRT by
default, and
 Option 2 will supply participants with 50 g mini-tablets only upon
request by investigator, ifstudy treatment is to be taken with soft food or
dispersed in apple/ orange juice.
The up-titration will be agreed upon during scheduled telephone calls or visits.
At Week 12 the iMTD for each participant will be determined. This dose should be kept
unchanged until Week 16.

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The body  weight category, starting dose, and up-titration scheme determined at
Baseline/Enrollment will be kept unchanged until Week 16. After Week 16, if the body
weight category  of the participant changes, study drug can be up-titrated further or
down-titrated to the corresponding dose level of the next body weight category, as deemed
appropriate by the investigator (ifdose levels overlap between body weight categories, the
dose level may also remain stable).
In addition, irrespective of whether the bodyweight categorychanges or not, after Week 16
the investigators will be allowed to change the participant’s study medication dose further
if needed (up to the maximum allowed dose based on body weight category).
Ifa participant has tolerability issues and experiences adverse reactions reflecting the mode
of action for selexipag [see Section 5.1.10], the dose can remain the same without further
up-titration (pause in up-titration). Up-titration can be resumed after the pause, or the dose
can be reduced to the previous dose level. The decision to pause up-titration, to up-titrate
or down-titrate study drug, or to permanently discontinue study drug treatment will be
based on the investigator’s medical judgment [see Section 5.1.10].
If a dose of selexipag is missed, participants should take a dose as soon as possible unless
the next dose is within the next 6 h. During the up-titration period, the investigator / site
staff must ensure that PK samples are collected after 3 days at the same dose and using the
same mode of administration.
At any time during study treatment, study drug interruptions (eg, missed doses for any
reason) of 3 days or more will require a new up-titration according to the scheme from Day
1.
All selexipag dose changes and reasons for dose interruptions must be documented in the
eCRF.

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Table 1 
Up-titration dosing scheme for body weight category ≥ 50 kg
Period  
Duration 
Dose 
regimen 
Number of 
200 g 
tablets 
(b.i.d.) 
Number of
50 g
mini-
tablets
(b.i.d.)
First dose 
Day 1 p.m. 
200 µg 
1 
-
Up-titration  
Day 2 a.m. to Day 8 a.m. 
200 µg b.i.d. 
1 
-
Day 8 p.m. to Day 15 a.m. 
400 µg 
b.i.d.*
2 
-
Day 15 p.m. to Day 22 a.m. 600 µg 
b.i.d.*
3 
-
Day 22 p.m. to Week 4 a.m. 800 µg 
b.i.d.*
4 
-
Week 4 p.m. to Week 5 a.m. 1000 µg 
b.i.d.*
5 
-
Week 5 p.m. to Week 6 a.m. 1200 µg 
b.i.d.*
6 
-
Week 6 p.m. to Week 7 a.m. 1400 µg 
b.i.d.*
7 
-
Week 7 p.m. to Week 8 a.m. 1600 µg 
b.i.d.*
8 
-
Maintenance From Week 12 throughout 
the study
iMTD: 
200 1600 µg
b.i.d.
1 8 
-
b.i.d.  twice daily; iMTD  individual maximum tolerated dose.
* Or the highest tolerated dose until Week 12.

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Table 2 
Up-titration dosing scheme for body weight category ≥ 25 to < 50 kg
Period  
Duration 
Dose regimen Number 
of 
200 g 
tablets 
(b.i.d.) 
Number of
50 g mini-
tablets
(b.i.d.)
First dose 
Day 1 p.m. 
150 µg 
- 
3
Up-titration  Day 2 a.m. to Day 8 a.m. 150 µg b.i.d. 
- 
3
Day 8 p.m. to Day 15 
a.m.
300 µg b.i.d.* 1 
2
Day 15 p.m. to Day 22 
a.m.
450 µg b.i.d.* 2 
1
Day 22 p.m. to Week 4 
a.m.
600 µg b.i.d.* 3 
-
Week 4 p.m. to Week 5 
a.m.
750 µg b.i.d.* 3 
3
Week 5 p.m. to Week 6 
a.m.
900 µg b.i.d.* 4 
2
Week 6 p.m. to Week 7 
a.m. 
1050 µg 
b.i.d.*
5 
1
Week 7 p.m. to Week 8 
a.m. 
1200 µg 
b.i.d.*
6 
-
Maintenance From Week 12 
throughout the study
iMTD: 
150 1200 µg
b.i.d.
1 6 
0 3
b.i.d.  twice daily; iMTD  individual maximum tolerated dose.
* Or the highest tolerated dose until Week 12.

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Table 3 
Up-titration dosing scheme for body weight category ≥ 9 to < 25 kg
Option 1 
Option 2
Period  
Duration 
Dose 
regimen 
Number 
of200 g 
tablets 
(b.i.d.) 
Number 
of 50 g 
mini- 
tablets 
(b.i.d.) 
Number
of 50 g
mini-
tablets
(b.i.d.)
First dose 
Day 1 in the evening 
(p.m.)
100 µg 
- 
2 
2
Up-titration  Day 2 a.m. to Day 8 
a.m. 
100 µg 
b.i.d.
- 
2 
2
Day 8 p.m. to Day 15 
a.m. 
200 µg 
b.i.d.*
1 
- 
4
Day 15 p.m. to Day 22 
a.m. 
300 µg 
b.i.d.*
1 
2 
6
Day 22 p.m. to Week 4 
a.m. 
400 µg 
b.i.d.*
2 
- 
8
Week 4 p.m. to Week 5 
a.m. 
500 µg 
b.i.d.*
2 
2 
10
Week 5 p.m. to Week 6 
a.m. 
600 µg 
b.i.d.*
3 
- 
12
Week 6 p.m. to Week 7 
a.m. 
700 µg 
b.i.d.*
3 
2 
14
Week 7 p.m. to Week 8 
a.m. 
800 µg 
b.i.d.*
4 
- 
16
Maintenance From Week 12 
throughout the study
iMTD: 
100 800
µg b.i.d.
1 4 
0 or 2 
2 16
b.i.d.  twice daily; iMTD  individual maximum tolerated dose.
* Or the highest tolerated dose until Week 12.

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Blinding
Not applicable.
Study treatment supply
Selexipag 200 µg tablets and 50 µg mini-tablets are supplied by the Sponsor.
Manufacture, labeling, packaging, and supply of study treatment will be conducted
according to Good Manufacturing Practice, Good Clinical Practice (GCP), and any local
or national regulatory requirements.
All study treatment supplies are to be used only in accordance with this protocol, and not
for any other purpose.
5.1.6.1 Study treatment packaging and labeling
Study treatment is provided as tablets and supplied in childproof bottles:
 Selexipag 200 µg: bottles of 120 tablets.
 Selexipag 50 µg: bottles of 280 mini-tablets.
Study treatment is labeled to comply with the applicable laws and regulations of the
countries in which the study sites are located.
5.1.6.2 Study treatment distribution and storage
The sponsor will supply all study drug(s) to the site according to local regulations.
Study treatment supplies must be kept in an appropriate, secure area and stored according
to the conditions specified on the label.
The site must maintain an accurate record of the shipment and dispensing of study drug(s)
on an accountability form, which must be given to the monitor at the end of the study.
5.1.6.3 Study treatment dispensing
At each dispensation visit, the IRT will be used to assign study treatment bottles.
The participants will receive sufficient study treatment to cover the period until the next
treatment dispensation visit.
Participants are asked to return all used, partially used, and unused study treatment bottles
at each treatment dispensation visit from Visit 2. The protocol-mandated study treatment
dispensing procedures may not be altered without prior written approval from the Sponsor.
The IRT will allow dispensation of study drug outside ofthe scheduled visits. An accurate
record of the date and amount of study treatment dispensed to each participant must be
available for inspection at any time.

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5.1.6.4 Study treatment return and destruction
The protocol-mandated study treatment return procedures may not be altered without prior
written approval from the Sponsor. On an ongoing basis and/or on termination of the study,
the clinical research associate (CRA) will collect used and unused treatment kits, which
will be sent to the warehouse where the Sponsor personnel or a deputy will check treatment
reconciliation. In certain circumstances, used and unused study treatment containers may
be destroyed at the site once study treatment accountability  is finalized and has been
checked by the Sponsor personnel or the deputy and written permission for destruction has
been obtained from the Sponsor.
Study treatment accountability and compliance with study treatment
5.1.7.1 Study treatment accountability
The inventory of study treatment dispensed to and returned by the participant’s
parent(s)/LAR(s) (i.e., study-treatment accountability) must be performed by site personnel
at visits, indicated in the assessment schedule [Table 4 and Table 5], when the
investigational medicinal product is to be brought back to the site and before dispensing
further study treatment. It is to be recorded by site personnel on the study  treatment
dispensing and accountability log and in the eCRF, and checked by the CRA during site
visits and at the end of the study. The study treatment accountability log in the eCRF will
include at least the following information for each study treatment unit (i.e., bottle)
dispensed to the participant:
 Dispensed bottles number.
 Dispensed bottles dose.
 Date dispensed / number of tablets dispensed.
 Date returned / number of tablets returned.
Site staff will ensure study drug is accounted for by trained personnel under controlled
conditions following the study instructions.
At the dispensing visits and at the EOT visit, all study treatment supplies, including
partially used and/or empty bottles, must be returned and retained at the site for review by
the CRA during the monitoring visits.
If the participant’s parent(s)/LAR(s) forgets to bring the remaining study treatment to a
study dispensing or EOT visit, they must be instructed not to provide the participant with
any tablets from the remaining study treatment bottles and to return them at the next visit.

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5.1.7.2 Study treatment compliance
A Study Drug Diary is provided to the participant’s parent(s)/LAR(s) to record each study
drug intake.
Study treatment compliance is based on study treatment accountability. Study treatment
compliance will be calculated by site personnel at visits as indicated in the assessment
schedule using the below formula and entered in the eCRF:
Compliance  (number of tablets dispensed number of tablets returned) / Total number
of tablets that should have been taken during the period* 100
*The period is defined as the number of days of treatment from the date of
dispensation / start of study treatment until the next accountability visit. The number of
tablets that should have been taken should be calculated on a participant basis, based on
the investigator’s prescription.
Between visits, compliance is expected to be between 80% and 120%. Compliance values
outside of this range will be considered as protocol deviations. The investigator must
discuss the non-compliance with the parent(s)/LAR(s) or the participant to clarify the
reasons for non-compliance and to take appropriate actions to avoid reoccurrence. This
discussion and its outcome must be documented in the source documents. Reasons for non-
compliance will also be reported in the eCRF.
Study treatment dose adjustments and interruptions
For participants who are unable to tolerate the protocol-specified dosing scheme, dose
adjustments should follow the instructions in the up-titration scheme [Section 5.1.4]. Study
treatment may be temporarily interrupted in response to an AE, a diagnostic or therapeutic
procedure, a laboratory abnormality, or for administrative reasons. Study-specific criteria
for interruptions of study treatment are described in Section 5.1.10.
If, at any time during the study treatment, the participant experiences an AE (other than
criteria B, C, D, or E in Section 5.1.10) in response to which their dose is reduced,
re-titration to the iMTD may be resumed, per the investigator’s medical judgment. See
Section 5.1.4 for up-titration or down-titration.
If study treatment is interrupted by the participant / participant’s parent(s)/LAR(s) for any
reason, they must immediately inform the investigator.
If a dose of selexipag is missed, participants should take a dose as soon as possible unless
the next dose is within the next 6 h. During the up-titration period, the investigator / site
staff must ensure that PK samples are collected after 3 days of the same dose and using the
same mode of administration.

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From Day 1 to Week 16, any dose interruptions (morning and/or evening) must be recorded
in the study drug log in the source documents and the eCRF.
After Week 16, interruptions of 1 day or more must be recorded on the study drug log in
the source documents and in the eCRF.
In case of permanent discontinuation from study treatment, the EOT visit must occur within
7 days of the discontinuation criterion being met.
Study treatment dose adjustments / interruptions and permanent discontinuation must be
recorded in the eCRF.
Premature discontinuation of study treatment
The decision to prematurely discontinue study treatment may be made by the participant’s
parent(s)/LAR(s), the investigator, the participant (who is developmentally capable to
assent or who comes of age), or Sponsor personnel. The main reason for discontinuation
of study treatment and whether discontinuation is the decision of the participant’s
parent(s)/LAR(s) (eg, tolerability- or efficacy-related), the investigator (eg, due to
pre-specified study treatment discontinuation criteria, an AE or lack of efficacy), or the
Sponsor (eg, study terminated) must be documented in the eCRF.
A participant’s parent(s)/LAR(s) and the participant (who is developmentally capable to
assent or who comes of age) has the right to prematurely discontinue study treatment at
any time, without any justification, by withdrawal from study treatment only or by
withdrawal from any further participation in the study (i.e., premature withdrawal from the
study [see Section 8.2]). Although the participant / participant’s parent(s)/LAR(s) is not
obliged to give their reason for prematurely withdrawing from the treatment or the study,
it is recommended that the investigator makes a reasonable effort to ascertain the reason(s)
while fully respecting the participant’s / participant’s parent(s)/LAR(s)’s rights.
The investigator must discontinue study treatment for a given participant if, on balance,
they believe that continued administration would be contrary to the best interests of the
participant.
Study-specific criteria requiring discontinuation of study treatment are described in
Section 5.1.10.
A participant who prematurely discontinues study treatment is NOT considered to be
withdrawn from the study and will be followed up for safety purposes until 30 days after
the last dose of study treatment.
A participant who prematurely discontinues study treatment and withdraws consent to
participate in any further study assessments is considered to be withdrawn from the study.

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Participants who die or are lost to follow-up are also considered to be withdrawn from the
study.
Withdrawal from the study and follow-up medical care of participants withdrawn from the
study are described in Sections 8.2 and 8.4, respectively.
Study-specific criteria for pause in up-titration / interruption / premature
discontinuation of study treatment
A) Tolerability issues / AEs
Adverse reactions associated with the mode of action of selexipag have been observed
frequently, in particular during the phase of individualized dose titration. These include:
headache, diarrhea, nausea and vomiting, jaw pain, myalgia, pain in extremity, arthralgia,
and flushing. In adult participants with PAH, these effects were usually transient or
manageable with symptomatic treatment. Gastrointestinal events have been observed to
respond to antidiarrheal, antiemetic, and anti-nausea medicinal products and/or medicinal
products for functional gastrointestinal disorders. Pain-associated events have frequently
been treated with analgesics (such as paracetamol).
However, if a participant reaches a dose that cannot be tolerated, the investigator should
follow the instructions given in Section 5.1.4.
B) Gastrointestinal ileus or obstruction
In selexipag preclinical studies in juvenile dogs, intestinal intussusception due to
prostacyclin-related effects on intestinal motility was observed sporadically. The finding
did not occur in mouse or rat toxicity studies. Because of the species-specific propensity
of dogs to develop intussusception, this finding is not considered relevant for adult humans.
The clinical relevance of these findings for the pediatric population < 18 years is unknown.
The investigator is asked to inform the parents and participants and provide guidance that
they should seek immediate medical evaluation if, at any time during study treatment, the
participant experiences clinical signs compatible with gastrointestinal ileus or obstruction
(eg, sudden severe persisting abdominal pain with episodes re-appearing in shorter
intervals, stool mixed with blood and mucus [also referred as red currant jelly stool],
extensive diarrhea and/or vomiting, lump in abdomen, fever, anorexia, and lethargy).
If the diagnosis of intussusception is confirmed, the study drug must be permanently
discontinued.

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C) Hyperthyroidism
Hyperthyroidism has been observed in 1% of the participants treated with selexipag in the
GRIPHON study [Uptravi® USPI, Uptravi® SmPC].
The investigator is asked to inform the participants and the parents and provide guidance
that they should be proactive and report if, at any time during study treatment, the
participant experiences clinical signs of hyperthyroidism (eg, sudden weight loss even if
appetite and the amount and type of food remain the same or even increased), tachycardia,
arrhythmia or palpitations, nervousness, anxiety and irritability, tremor, sweating, an
enlarged thyroid gland, difficulty sleeping).
Ifthe participant experiences new or worsening of pre-existing hyperthyroidism during the
course of treatment with study medication that, in the opinion of the investigator, cannot
be adequately controlled with anti-thyroid medications, the study drug must be
permanently discontinued and the participant monitored until resolution of this condition.
D) Hepatic impairment
If the investigator becomes aware that a participant has developed moderate or severe
hepatic impairment (Child-Pugh B or C) at any time during the study, study drug must be
permanently discontinued. For participants who develop hepatic impairment at any time
during the study, the assessment for hepatic impairment (Child Pugh score, see Section
14.4 Appendix 4) must be done and fully documented.
E) Pulmonary edema due to PVOD
If a participant develops pulmonary edema due to previously undiagnosed PVOD, the study
drug must be permanently discontinued.
F) Treatment with prostacyclin / prostacyclin analogs
If treatment with prostacyclin (epoprostenol) or prostacyclin  analogs (i.e., treprostinil,
iloprost, beraprost) is initiated at any time during the study (except for acute vasodilator
testing during RHC procedure, see also Section 5.2.3), the study drug must be permanently
discontinued.
5.2 Previous and concomitant therapy
The use of all study-concomitant therapy (including contraceptives and traditional and
alternative medicines, eg, plant-, animal-, or mineral-based medicines) will be recorded in
the eCRF. Previous therapy must be recorded in the eCRF if discontinued less than 42 days
prior to the signing of the ICF. The generic name, start/end dates of administration (as well
as whether it was ongoing at start of treatment and/or EOS), route, dose, and indication
will be recorded in the eCRF.

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Mandatory treatment
The use ofcontraceptives is mandated in female subjects of childbearing potential who are
heterosexually active because pregnancy increases the risk of disease progression
[Bédard 2009] and because there are limited data on the use of selexipag in pregnant
women. Although animal studies do not indicate direct or indirect harmful effects with
respect to reproductive toxicity, pregnant women were excluded from clinical trials with
selexipag.
If hormonal contraceptives are used, they must be initiated at least 30 days before
enrollment.
For female subjects who become heterosexually active any time after enrollment and who
are of childbearing potential, contraceptives that are immediately effective must be applied
as specified in Section 4.5.2.
Contraceptives must be reported in the eCRF.
Allowed concomitant therapy
The PAH-specific therapies allowed as background therapies are ERAs and PDE-5
inhibitors. The dose must have been stable for at least 3 months prior to the first dose of
study treatment. For diuretic therapy, the dose must have been stable for at least 1 month
prior to the first dose of study treatment.
Single administration of medications used for acute vasodilator testing during RHC
procedure is allowed (eg, i.v./inhaled prostacyclin or inhaled nitric oxide or oral sildenafil).
Any change in concomitant therapy or its dose must be recorded in the eCRF.
Forbidden concomitant therapy
Strong and moderate inhibitors of CYP2C8 (eg, gemfibrozil, clopidogrel, deferasirox,
teriflunomide) and inhibitors of UGT1A3 and UGT2B7 (valproic acid, probenecid, and
fluconazole) are prohibited from 2 weeks prior to enrollment and until the last dose of
selexipag + 3 days.
As selexipag and its active metabolite ACT-333679 are IP-receptor agonists, prostacyclin
(epoprostenol) and prostacyclin analogs (i.e., treprostinil, iloprost, beraprost except for
acute vasodilator testing during RHC procedure) are prohibited from 2 months prior to
enrollment until the last dose of selexipag + 3 days or PAH worsening.

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5.3 Treatment of Overdose
For this study, an overdose is defined by the intake:
 
of any single study intervention dose greater than 1,600 μg or a total daily dose greater
than 3,200 μg (a child with body weight category ≥50 kg);
 
of any single study intervention dose greater than 1,200 μg or a total daily dose greater
than 2,400 μg (a child with body weight category ≥25 <50 kg);
 
of any single study intervention selexipag dose greater than 800 μg or a total daily
dose greater than 1,600 μg (a child with body weight category ≥9 <25 kg).
Isolated cases of overdose up to 3,200 μg were reported in adults. Mild, transient nausea
was the only reported consequence. In the event of overdose, supportive measures must be
taken as required. Dialysis is unlikely to be effective because selexipag and its active
metabolite are highly protein bound.
In the event of an overdose, the investigator or treating physician should:
 
Contact the Sponsor immediately.
 
Evaluate the participant to determine, in consultation with the Sponsor, whether study
intervention should be interrupted or whether the dose should be reduced.
 
Closely monitor the participant for AE/SAE and laboratory abnormalities until
selexipag can no longer be detected systemically (at least 3 days).
 
Obtain a plasma sample for PK analysis within 3 days from the date of the last dose of
study intervention if requested by the sponsor (determined on a case-by-case basis).
 
Document the quantity of the excess dose as well as the duration of the overdosing in
the CRF.
6 STUDY ENDPOINTS
6.1 Pharmacokinetic endpoints
Primary pharmacokinetic endpoint(s)
The primary endpoint is model-based exposure (AUCτ,ss,combined) of selexipag and
ACT-333679 corrected for their potency, determined during the 12-week up-titration
period. It is compared to the model-based exposure for participants with PAH in
GRIPHON. The GRIPHON population PK model will be used and updated based on the
acquired pediatric PK data. The model will describe the body weight dependence of the
dose-exposure relationship for pediatric participants with PAH [Modeling and Simulation
Report, Pediatric dose selection 2016].

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Secondary pharmacokinetic endpoints:
 Area under the plasma concentration-time curve over one dosing interval at steady state
(AUCτ,ss), maximum plasma concentration at steady state (Cmax,ss), and the time at
which Cmax,ss is observed (tmax,ss) for selexipag and ACT-333679 based on
non-compartmental analysis (NCA).
 Trough concentration at steady state (Ctrough,ss) on Day 15 /Visit 4, and at Week 4 / Visit
5 and Week 6 / Visit 6 for selexipag and ACT-333679.
6.2 Safety endpoints
 Treatment-emergent AEs (TEAEs) occurring up to EOT + 3 days.
 Treatment-emergent SAEs (TESAEs) occurring up to EOT + 3 days.
 AEs leading to permanent discontinuation of study drug.
 Treatment-emergent deaths (all causes) occurring up to EOT + 3 days.
 Treatment-emergent marked laboratory abnormalities (hematology and blood
chemistry tests) over time occurring up to EOT + 3 days.
 Change from baseline in selected hematology and blood chemistry laboratory variables
over time up to EOT + 3 days.
 Treatment-emergent ECG abnormalities over time occurring up to EOT + 3 days.
 Change from baseline in TSH over time up to EOT + 3 days.
 Change from baseline in vital signs (blood pressure, heart rate) over time up to EOT + 3
days.
 Change from baseline in height and body mass index over time up to EOT + 3 days.
 Change from baseline in sexual maturation (Tanner stage) over time up to
EOT + 3 days.
6.3 Exploratory endpoints
 Change from Baseline/Enrollment up to each time point of assessment in modified New
York Heart Association (NYHA) / WHO FC.
 Change from baseline up to each time point of assessment in exercise capacity as
measured by 6MWD.
 Change from baseline in Panama FC up to each time point of assessment.
 Percent of baseline in plasma NT pro-BNP at each time point of assessment.

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 Change from baseline to each time point assessment in Echo variables (imaging and
Doppler evaluation):
 Right ventricular systolic pressure.
 Tricuspid annular plane systolic excursion.
 Pulmonary artery acceleration time.
 Left ventricular eccentricity index.
 Right atrial area index (from apical 4 chamber view).
 Tricuspid annular diameter (from apical 4 chamber view).
 Time to the first of the following disease progression events occurring between first
study drug dose and EOT + 7 days:
 Death (all causes)
 Atrial septostomy or Potts’ anastomosis, or registration on lung transplant list
 Hospitalization due to worsening PAH§
 Clinical worsening* of PAH defined as:
Need for, or initiation of new PAH-specific therapy# or i.v. diuretics or
continuous oxygen use AND at least one of the following:
o Worsening in WHO FC, or
o New occurrence or worsening of syncope (in frequency or severity as per
medical judgment), or
o New occurrence or worsening of at least two PAH symptoms (i.e., shortness of
breath/dyspnea, chest pain, cyanosis, dizziness/ near syncope, or fatigue), or
o New occurrence or worsening of signs of right heart failure not responding to
oral diuretics
§excluding hospitalizations that are elective, routine or clearly attributable to
appearance/worsening of comorbidities (eg, pneumonia).
*worsening from baseline.
#eg, ERA, PDE-5 inhibitor, prostanoids, prostacyclin receptor (IP receptor) agonist, soluble
guanylate cyclase stimulator.
6.4 Other endpoints
 Palatability of selexipag formulation at Day 1, Week 12, and EOT, assessed using a
5-point facial hedonic scale.

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 Acceptability of selexipag formulation at Day 1, Week 12, and EOT, as assessed
through a 3-point categorical scale as to whether the child swallowed the medication.
7 VISIT SCHEDULE AND STUDY ASSESSMENTS
7.1 Study visits
The study visits are listed in Table 4 and Table 5. For all visits, the participants must be
seen on the designated day with an allowed visit window indicated in the tables. An EOT
visit must be performed within 7 days of intake of the last dose of study treatment. A safety
follow-up call should follow 30 days after this visit, and will be considered the EOS for an
individual participant.
All assessments pertaining to a visit should be performed on the same day. If this is not
possible, the visit may extend over more than 1 day within the allowed time window.
If study treatment is prematurely discontinued, the EOT visit must take place as soon as
possible and no later than 7 days after the last dose of study treatment. A safety follow-up
call should follow 30 days after this visit.
Participants who prematurely discontinue study treatment / study participation for any
reason before contributing to PK sampling, or for whom PK samples are missing / have
been mishandled, may be replaced.
Screening/re-screening
Screening starts with the signature of the ICF. The date on which the first screening
assessment is performed corresponds to the date of the Screening visit.
It is the responsibility of the investigator/delegate to obtain written informed consent from
the parent(s)/LAR(s) of each participant participating in this study after adequate face-to-
face explanation of the objectives, methods, and potential hazards of the study. The
participant’s parent(s)/LAR(s) who agree that their child will participate in the study and
the investigator/delegate must sign the ICF (and, if applicable, the participant’s assent
form) prior to any study-related assessment or procedure.
Participants whose parent(s)/LAR(s) have already signed the ICF (and, if applicable, the
participant’s assent form) when the enrollment target has been met may still be enrolled.
It is permitted to re-screen participants once, if the reason for non-eligibility was transient
(eg, abnormal laboratory test, insufficient wash-out period of a forbidden medication). If a
participant is re-screened, only the safety laboratory assessments must be repeated.
Re-consent is needed if the initial consent signature is more than 42 days old.

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Unscheduled visits
Unscheduled visits can be performed for any reason including (but not limited to) safety
issues, PAH worsening, and study drug dispensation. Depending on the reason for the
unscheduled visit (eg, AE), appropriate assessments will be performed based on the
judgment of the investigator and the results will be recorded in the eCRF.
If the reason for an unscheduled visit is suspected PAH worsening / PAH disease
progression (eg, signs/symptoms denoting PAH worsening or deterioration of WHO FC
[refer to Sections 7.2.2.1 and 7.2.2.2]), the investigator determines the main and
contributing causes for worsening as per local practice, preferably including the following
assessments (these are also recommended even if PAH progression is assessed at a
scheduled visit and in case these assessments are not planned for that particular visit):
 Vital signs
 Concomitant medications (including contraceptives)
 PAH-related non-pharmacological intervention
 Signs/symptoms of PAH
 WHO FC and Panama FC
 Main and contributing cause(s) of worsening
 Central laboratory tests including plasma NT-proBNP
 Physical examination
 Echocardiography (central)
The onset date of worsening, the main and contributing cause(s) for worsening are recorded
in the eCRF.
The event itself as well as contributing causes unrelated to PAH are reported as AE/SAE.
If RHCs are performed during the study for any medical reason, as judged by the
investigator, these results should be recorded in the eCRF.
After an unscheduled visit, the regular scheduled study visits must continue according to
the planned visit and assessment schedule [Table 4, Table 5].

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Table 4 
Visit and assessment schedule until Week 16
Period
Screen-
ing
Base-
line/
Enroll-
ment
Treatment
Up-titration 
Maintenance
Name
Screening
visit /
Visit 1
Visit 2
Visit 3b
or Tel
Visit 4
Tel.a
W3
Visit 5
Tel.a
W5
Visit 6
Tel.a
W7
Tel.a
W8
Tel.a
W9
Tel.a
W10
Tel.a
W11
Visit 7
Tel.a
W14
Visit 8
Time
42 days
before
Day 1
Day 1
Week
1
Day 5
1 / + 2
d
Week
2
Day 15
± 3 d
Week
3
Day 22
± 3 d
Week
4
± 3 d
Week
5
± 3 d
Week
6
± 3 d
Week
7
± 3 d
Week
8
± 3 d
Week
9
± 3 d
Week
10
± 3 d
Week
11
± 3 d
Week
12
± 3 d
Week
14
± 3 d
Week 16
/ M4
± 3 d
Written informed
consent
X
Inclusion/exclusion
criteria (incl. 
hemodynamics)
X
Med. History incl. PAH
diagnosis
X
Previous/Concomitant 
medications
X 
X 
X 
X 
X
X
Mod. NYHA/WHO FC  
X 
X 
X
Panama FC  
X 
X 
X
PAH signs/symptoms 
X 
X 
X
PAH-related non-
pharmacological 
interventions
If applicable
Physical examination 
X l 
Xk 
Xk 
Xk 
Xk
Growth: Weight and
height
Xm 
X 
X 
Xm
Vital signs (blood 
pressure, heart rate)
X 
X 
X 
X
X
ECG 
X 
Xg 
X 
Xg 
X
Echon 
X 
X
6MWD testh 
X i 
X

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Period
Screen-
ing
Base-
line/
Enroll-
ment
Treatment
Up-titration 
Maintenance
Name 
Screening
visit /
Visit 1
Visit 2
Visit 3b
or Tel 
Visit 4
Tel.a
W3 
Visit 5
Tel.a
W5 
Visit 6
Tel.a 
W7 
Tel.a 
W8 
Tel.a 
W9 
Tel.a 
W10 
Tel.a
W11 Visit 7
Tel.a
W14
Visit 8
Time
42 days
before
Day 1
Day 1
Week
1 
Day 5 
1 / + 2 
d
Week  
2 
Day 15 
± 3 d 
Week
3
Day 22
± 3 d
Week  
4 
± 3 d 
Week  
5 
± 3 d 
Week  
6 
± 3 d 
Week  
7 
± 3 d 
Week  
8 
± 3 d 
Week  
9 
± 3 d 
Week 
10 
± 3 d 
Week  
11 
± 3 d 
Week  
12 
± 3 d 
Week  
14 
± 3 d 
Week 16
/ M4
± 3 d
Tanner stage 
X 
X
Childbearing potential 
X 
X 
X 
X 
X 
X 
X 
X 
X
Pregnancy test
(if appl.)e 
X 
X 
X 
X 
X 
X
Laboratory test, 
Hematology/Chemistryf
X 
X 
X 
X
X
TSH  
X 
X 
X 
X
Thyroid antibodies 
X 
X when medically indicated
T3 and T4 
X when TSH is abnormal or when medically indicated
Plasma NT pro-BNP  
X 
X
Palatability and 
acceptability of 
selexipag
X
X
PK sampling 
Xb 
Xc 
Xc 
Xc 
Xd
Study drug dispensing 
X 
X
X
First dose of study drug 
X (p.m.)
Dose titration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X j
Drug accountability  
X 
X 
X
(Serious) adverse 
events
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X

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a. 
Tel.  Scheduled telephone call.
b. PK samples will be taken at pre dose, 1, 2, 4, 6, 8 h and 12 h post morning dose of selexipag in the first 5 participants of Cohorts 1 3 (participant should have been
at least 3 days on the same dose and mode of administration to reach steady state). The PK sample at 12 h post morning dose must be before the evening dose of
selexipag. For the rest of the participants, a phone call will be done instead of a visit.
c. 
Trough morning PK samples to be collected from all participants prior to dose escalation at Visits 4, 5, and 6 (participant should have been on the same dose and
mode of administration for at least 3 days to reach steady state).
d. For all participants ofeach cohort who did not provide the starting dose profiles: PK samples to be collected at pre dose, 1, 2, 4, 6, 8 h and 12 h post morning dose
of selexipag at highest tolerated dose at Week 12 (at least 3 days on the same dose level and mode of administration to reach steady state). The PK sample of 12 h
must be before the evening dose of selexipag.
e. 
Serum pregnancy test to be performed at screening and urine pregnancy tests every 4 weeks until 30 days after study drug discontinuation. 
f. 
Laboratory test (hematology and blood chemistry) will be repeated at Baseline/Enrollment to confirm eligibility only if the last test is available 2 weeks from
Baseline/Enrollment. 
g. 
At Week 1 or at Week 12, an ECG will be performed before drug intake, and two additional ECGs will be performed 2 and 4 h (±15 min) after study drug intake.
The ECG should be recorded before the corresponding PK sample is collected.
h. 6MWD in participants of ≥ 6 to < 18 years of age able to understand and perform the test correctly.
i. 
Conducted within 14 days before Day 1 (Visit 2).
j. 
Confirmation of iMTD.
k. Physical exam only for areas of interest (general appearance, cardiovascular, and respiratory system).
l. 
Complete examination.
m. Height required at Screening and Week 16 only.
n. Echocardiography should be performed prior to physical exertion (eg, 6MWT).
6MWD  6 minute walk distance; 6MWT  6 minute walk test; d  day(s); appl.  applicable; ECG  electrocardiogram; h  hour(s); iMTD  individual maximum tolerated
dose; M
month; Mod.  modified; NT pro BNP  N terminal pro b type natriuretic peptide; NYHA  New York Heart Association; PK
pharmacokinetic(s); Tel. 
telephone call; TSH
thyroid stimulating hormone; W  week; WHO FC
World Health Organization functional class.

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Table 5 
Visit and assessment schedule after Week 16
Period  
Site visits for
participants during the
first 12 months following
Week 16 (M4)
Site visits for
participants after 12
months
Phone calls for
participants after 12
months
Unscheduled visit
End-of-
Treatment 
Safety follow-up Tel.
Name 
Visit 9, 10, 11, 12 
Visit 13, 14, 15 …  
Tel. 
Unscheduled visit 
EOT  
EOS
Timee 
Site visits every 3 
months 
(M7, M10, M13, M16) 
± 15 days 
Site visits every 6 
months 
(M22, M28, M34…) 
± 15 days 
Phone call: every 6 months 
(M19, M25, M31, M37…) 
alternating with visits 
± 15 days 
If medically indicated
or recommended for
assessing PAH
progression
Last dose of 
study drug 
+ up to 7 days 
Phone call: 30 days after
last dose of study drug
+ up to 7 days
Previous/Concomitant
medications for PAH
X 
X 
X 
X
Mod. NYHA/WHO FC  
X 
X 
X 
X
Panama FC  
X 
X 
X 
X
PAH signs/symptoms 
X 
X 
X 
X
PAH-related non-
pharmacological 
interventions
If applicable
Physical examination 
Xc 
Xc 
X 
Xc
Growth: Weight and
height
X 
X 
X 
X
Vital signs (blood
pressure, heart rate,)
X 
X 
X 
X
Echo 
Xd 
X 
X
6MWD test 
Xb 
X 
X 
X
Tanner stage 
X 
X
Childbearing potential 
X 
X 
X 
X 
X
Pregnancy test (if appl.) 
X 
X 
Xa 
X 
X 
X
Laboratory test
(Hematology/Chemistry)
X 
X 
X 
X
TSH  
X 
X 
X 
X
Thyroid antibodies 
X when medically indicated
T3 and T4 
X when TSH is abnormal or when medically indicated
Plasma NT pro-BNP  
X 
X 
X 
X
ECG 
X 
X 
X
Study drug dispensing 
X 
X 
X
Drug accountability  
X 
X 
X 
X

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Period  
Site visits for
participants during the
first 12 months following
Week 16 (M4)
Site visits for
participants after 12
months
Phone calls for
participants after 12
months
Unscheduled visit
End-of-
Treatment 
Safety follow-up Tel.
Name 
Visit 9, 10, 11, 12 
Visit 13, 14, 15 …  
Tel. 
Unscheduled visit 
EOT  
EOS
Timee 
Site visits every 3 
months 
(M7, M10, M13, M16) 
± 15 days 
Site visits every 6 
months 
(M22, M28, M34…) 
± 15 days 
Phone call: every 6 months 
(M19, M25, M31, M37…) 
alternating with visits 
± 15 days 
If medically indicated
or recommended for
assessing PAH
progression
Last dose of 
study drug 
+ up to 7 days 
Phone call: 30 days after
last dose of study drug
+ up to 7 days
Palatability and
acceptability of 
selexipag
X
(Serious) adverse events 
X 
X 
X. 
X 
X 
X
Vital status 
X
a. 
Urine pregnancy tests to be performed monthly, and results to be communicated to site staff by telephone.
b. Only at Month 7 / Visit 9.
c. 
Physical exam only for areas of interest (general appearance, cardiovascular, and respiratory system).
d. Echo to be done at Month 7 only.
e. 
One month corresponds to 4 weeks/28 days.
6MWD  6 minute walk distance; appl.  applicable; ECG electrocardiogram; EOS  End of Study; EOT  End of Treatment; FC  functional class; M  month; Mod.
 modified; NT pro BNP
N terminal pro b type natriuretic peptide; NYHA  New York Heart Association; PAH  pulmonary arterial hypertension; Tel. telephone
call; TSH
thyroid stimulating hormone; WHO FC  World Health Organization functional class.

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7.2 Study assessments
The study assessments are listed in Table 4 and Table 5. The assessments to be performed
during each visit are marked with an ‘X’.
All study assessments are performed by qualified study personnel (medical, nursing, or
specialist technical personnel) and are recorded in the eCRF, unless otherwise specified.
Study assessments performed during unscheduled visits will also be recorded in the eCRF.
The following order of assessments is recommended: PK samples, safety assessments,
efficacy assessments, other assessments (unless otherwise specified in Table 4 and Table 5
and in the assessment descriptions below).
If the principal investigator (PI) delegates any study procedure/assessment for a participant,
eg, blood sampling to an external facility, they should inform the Sponsor to whom these
tasks are delegated. The set-up and oversight will be agreed upon with the Sponsor. The
supervision of any external facilities remains the responsibility of the PI.
Calibration certificates / evidence of equipment maintenance for the below-listed
equipment used to perform study assessments must be available prior to the screening of
the first participant:
 Body weight scale
 Temperature measurement devices for study treatment storage area and freezer.
Calibration certificates / evidence of equipment maintenance of other equipment should be
available as per local requirements.
Demographics / baseline characteristics
Demographic and baseline characteristic data to be collected on all participants include:
age, sex, race, and ethnicity. Relevant medical history / current medical conditions (eg,
chronic and ongoing acute conditions, serious past conditions) present before signing the
ICF  will be recorded on the medical history page. Where possible, diagnoses and not
symptoms will be recorded. The presence/absence of Down syndrome is recorded for all
participants in the eCRF.
Medical history of special interest will be captured on the specific Medical History eCRF
page and includes:
 Disease characteristics such as PAH etiology, PAH diagnosis (mPAP, PAWP [or LAP,
or LVEDP], PVRi values assessed by RHC, and date of diagnosis), date of first
observed / assumed PAH symptoms, and signs and symptoms of PAH.
 Medical history (previous and ongoing clinically significant diseases).

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For participants who failed screening, the following data will be recorded in the eCRF if
available:
 Reason for screening failure.
 Baseline data collected until confirmation of screening failure.
 If baseline data are available from any central laboratory (eg, physical activity) they
will be transferred to the clinical database.
Exploratory assessments
7.2.2.1 Monitoring of disease progression –signs and symptoms of PAH
To standardize assessment of disease progression, investigators will verify the
presence/absence of predefined signs and symptoms denoting clinical worsening of PAH.
The presence and absence ofsigns/symptoms as well as date of new onset or worsening is
recorded in the eCRF.
If there is syncope or at least 2 new or worsening signs/symptoms the investigator reports
disease progression in the eCRF and performs further exams to determine the cause [refer
to Section 7.1.2]. In addition, the occurrence of a new or worsening sign/symptom is
reported as Adverse Event in the eCRF.
7.2.2.2 WHO functional class
The WHO FC [see Section 14.1 Appendix 1] and the Panama FC [Section 14.2 Appendix
2] are recorded in the eCRF. The Panama FC is tailored for children up to 16 years of age
[Lammers 2011] and thus its assessment will discontinue in children > 16 years of age.
7.2.2.3 NT-proBNP
The quantification of NT pro-BNP plasma levels will be performed by the central
laboratory [see contact details on page 2]. Central laboratory data will be automatically
transferred from the central laboratory database to the clinical database.
The materials required for NT pro-BNP sampling will be provided to the investigational
site before the start of the study.
The procedure for the collection and analysis of NT pro-BNP is described in the respective
Laboratory Manual.
The actual date and clock time of withdrawal of each blood sample is to be entered in the
eCRF.
NT pro-BNP central laboratory reports will be sent to the investigator.

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7.2.2.4 6-minute walk distance test
The 6MWD test will be performed in children from ≥ 6 to < 18 years able to understand
and perform the test correctly [Takatsuki 2013, Douwes 2015].
The 6MWD test is performed and recorded in the eCRF, as indicated in the assessment
schedule. The time of the assessment will be recorded in the eCRF.
The 6MWD is a non-encouraged test that measures the distance covered by the participant
during a 6-minute walk.
7.2.2.5 Echo/Doppler
Echo/Doppler will be performed at the visits indicated in the assessment schedule and as
described in the guidelines and the central reader manual provided separately from this
protocol.
The following Echo/Doppler parameters will be measured:
 Right ventricular systolic pressure.
 Tricuspid annular plane systolic excursion.
 Pulmonary artery acceleration time.
 Left ventricular eccentricity index.
 Right atrial area index (from apical 4 chamber view).
 Tricuspid annular diameter (from apical 4 chamber view).
Echo/Doppler data are analyzed centrally and will not be recorded in the eCRF.
7.2.2.6 Palatability and acceptability
The palatability of the selexipag formulation will be assessed at the visits indicated in the
assessment schedule using a 5-point facial hedonic scale.
For children not able to comply with the instructions of the test, palatability will be
indirectly assessed by the participant’s parent(s) or LAR(s) or study site personnel
[see Section 14.3 Appendix 3].
The site study personnel will record the palatability score corresponding to the smiley face
pointed to by the participant or the response provided by participant’s parent(s) or LAR(s)
or study site personnel in the eCRF.
The acceptability of the selexipag formulation will be assessed through a 3-point
categorical scale as to whether the child swallowed the medication at the visits indicated
in the assessment schedule.

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For all participants, parent(s) or LAR(s) or study site personnel will be asked, following
the study drug intake, whether the child swallowed the medication:
a. fully,
b. partially,
c. not at all.
The site study personnel will record the acceptability score corresponding to the response
provided by participant’s parent(s) or LAR(s) or study site personnel in the eCRF and
source documents.
Safety assessments
The definitions, reporting, and follow-up of AEs, SAEs, and pregnancies are described in
Section 9.
7.2.3.1 Physical examination
Complete physical examination at screening includes the examination of:
 General appearance.
 Head, ears, eyes, nose, throat.
 Cardiovascular.
 Respiratory.
 Gastrointestinal.
 Lymphatic.
 Genitourinary.
 Skin.
 Extremities.
 Nervous system.
At subsequent visits, physical examination includes the examination of general
appearance and cardiovascular and respiratory systems.
Other exams will be performed if indicated, based on medical history and/or symptoms.
Information for all physical examinations must be included in the source documentation at
the study site. The observations should be reported according to body system in the eCRF
as either normal or abnormal. If an abnormality is found it should be specified on the
corresponding eCRF page.
Clinically relevant findings that are present prior to the signing of the ICF must be recorded
on the Medical History eCRF page.

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Physical examination findings made after the signing ofthe ICF that meet the definition of
an AE [Section 9.1.1] must be recorded on the AE page of the eCRF.
7.2.3.2 Vital signs
Vital signs include systolic and diastolic BP and heart rate. Vital signs are measured
non-invasively. It is recommended that vital signs are measured after the participant has
rested at least 5 minutes (eg, sitting). If applicable, vital signs are measured before any
invasive assessment (such as blood draw).
Systolic and diastolic BP will be measured in a supine or sitting position. It is
recommended to allow the participant to rest for at least 5 minutes, and to use the same
position (supine or sitting) throughout the study for an individual participant.
It is recommended that the same type of device is used throughout the study for an
individual participant. In addition, blood pressure is measured on the same arm for an
individual participant throughout the study.
Vital signs are recorded in the eCRF.
7.2.3.3 ECG
A standard 12-lead ECG is performed at Baseline/Enrollment, Visit 3 (only for participants
who have PK sampling), Visit 5, Visit 7 (only for subjects who have PK sampling), Visit 8,
Visits 9, 10, 11, 12, 13, 14, 15, etc., and EOT. The participant should rest for at least
5 minutes prior to the recording, and should be in a supine position during the recording.
The ECG should be performed before the morning dose of study drug is taken.
At Visit 3 or Visit 7, participants will have two additional ECGs 2 and 4 hours (±15 min)
after study drug morning dose intake.
Clinically relevant ECG findings that are present prior to the initiation of study drug must
be documented in the Medical History section of the eCRF.
Clinically relevant ECG findings observed after study drug initiation that were not present
at Screening or that worsened during the study must be reported as AEs as appropriate
[see Section 9.1.1].
A central ECG service [see contact details on page 2] will be used for ECG evaluation.
Details about the collection of ECG data and the reporting of results and abnormalities can
be found in the ECG manual provided to the investigator.
7.2.3.4 Weight and height
Height will be measured using a stadiometer at Screening and at Week 16, every 3 months
for 1 year following Week 16, then every 6 months. Body weight will be measured in
indoor clothing but without shoes.

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Body weight and height are measured and recorded in the eCRF.
7.2.3.5 Tanner stage
Per CHMP Paediatric addendum to the PAH guidelines [EMA/CHMP/213972/2010], the
sexual maturation of pediatric participants in long-term studies is of particular importance.
Therefore, the Tanner stage [refer to Section 14.5 Appendix 5] is assessed at regular time
points during the study.
Tanner stage is assessed in female participants ≥ 8 years of age and in male participants
≥9years of age (i.e., examination is started once they are 8 and 9 years old, respectively).
For participants who enter the study below these ages, sexual maturity assessments will
start once they reach the ages of 8 or 9 years (for girls and boys, respectively). Tanner stage
assessment is stopped once full sexual maturation is reached (if applicable before EOT).
(Self-)Assessment of pubertal Tanner stage by parents or participants may be allowed by
the study investigator. In this case, the investigator instructs and assists parents /
participants on how this should be assessed at each time of the scheduled assessment.
The Tanner stages of puberty in girls are based on breast size and shape and pubic hair
distribution. The Tanner stages of puberty in boys are based on the development of the
genitalia and pubic hair distribution [Blondell 1999, Marshall 1969, Marshall 1970].
Actual age at milestone attainment may vary among individuals and among different study
populations.
The site study personnel will record the Tanner stage in the eCRF.
For frequency of Tanner stage assessments, see schedule of assessments in Table 4 and
Table 5.
7.2.3.6 Childbearing potential
Childbearing potential will be assessed at each visit and recorded in the eCRF.
For female participants of childbearing potential, the study personnel will verify at each
visit whether the participant has or plans to become heterosexually active. If confirmed,
the study personnel will counsel the participant on the appropriate methods of
contraception [refer to Section 4.5.2].
The reason for not being of childbearing potential will be recorded in the eCRF.
Laboratory assessments
7.2.4.1 Type of laboratory
A central laboratory [see central laboratory manual for contact details, page 2] will be used
for all protocol-mandated laboratory tests, including re-tests due to laboratory
abnormalities and laboratory tests performed at unscheduled visits.

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If the results from the central laboratory are not available in time for enrollment of the
participant, an additional blood sample may be drawn to verify eligibility based on a local
laboratory test. The local laboratory results (with the corresponding normal ranges) must
be recorded in the eCRF.
Other exceptional circumstances that require the recording of local laboratory results of the
parameters are described in Section 7.2.4.2 (with corresponding normal ranges), including
hospitalization of the participant due to a medical emergency and missing central
laboratory results from a scheduled or unscheduled visit.
If one or more central laboratory samples are lost or cannot be analyzed for whatever
reason, the investigator will collect an additional sample as soon as possible to repeat the
analysis, unless a local laboratory sample was collected within the same time-window and
these test results are available.
After Week 16, under specific circumstances (eg, if the participant lives far from the site
and cannot return to the site), laboratory samples may be collected at a laboratory close to
where the participant lives (satellite laboratory) and sent to the central laboratory for
analysis. In such cases, the satellite laboratory must be provided with the central laboratory
sampling kits. Shipment of the samples will be organized by the satellite laboratory. If this
process is implemented, the satellite laboratory must be identified prior to enrollment of
the participant in the study. The supervision of the satellite laboratory remains the
responsibility of the PI.
Central laboratory reports will be sent to the investigator. In the case of specific
(pre-defined) laboratory abnormalities, the central laboratory will alert the Sponsor
personnel and the concerned site personnel. Alert flags that will trigger such notifications
are displayed in the central laboratory manual, provided separately.
All laboratory reports must be reviewed, signed, and dated by the investigator or delegate
within 10 working days of receipt and filed with the source documentation. The
investigator/delegate must indicate on the laboratory report whether abnormal values are
considered clinically relevant or not. Clinically relevant laboratory findings that are known
at the time of the signing of the ICF must be recorded on the Medical History page of the
eCRF. Any clinically relevant laboratory abnormalities detected after signing of informed
consent must be reported as an AE or SAE as appropriate [see Section 9], and must be
followed until the value returns to within the normal range or is stable, or until the change
is no longer clinically relevant.
Details about the collection, sampling, storage, shipment procedures, and reporting of
results and abnormal findings can be found in the laboratory manual.

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7.2.4.2 Laboratory tests
Hematology
 Hemoglobin (g/L)
 Hematocrit (L/L)
 Erythrocyte count (109/L)
 Leukocyte count with differential counts (109/L)
 Platelet count (109/L)
Clinical chemistry
 Alanine aminotransferase (U/L)
 Aspartate aminotransferase (U/L)
 Alkaline phosphatase (U/L)
 Total and direct bilirubin (μmol/L)
 Creatinine (μmol/L)
 Creatinine clearance (mL/min)
 Blood urea nitrogen (mmol/L)
 Uric acid (μmol/L)
 Glucose (mmol/L)
 Cholesterol, triglycerides (mmol/L)
 Sodium, potassium, chloride, calcium (mmol/L)
 Albumin (g/L)
 NT-pro BNP (pmol/L)
 TSH (mU/L)
 Thyroid antibodies (U/mL): Measured at Baseline/Enrollment and at subsequent visits
only if TSH is abnormal or when medically indicated
 Free T3 and free T4: Measured only ifTSH is abnormal or when medically indicated
Up to Week 16, a total of approximately 24 mL of blood are required for hematology and
clinical chemistry testing. After Week 16, approximately 4.8 mL of blood are required per
visit.
Pregnancy test
A serum pregnancy test for females of childbearing potential will be performed at
Screening and a urine test will be performed on Day 1 (Baseline/Enrollment) before dosing
and monthly thereafter. If pregnancy is suspected during the study, a serum pregnancy test

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must be performed immediately. Results of the urine pregnancy tests performed after Day
1 are not collected in the eCRF.
Pharmacokinetic assessments
7.2.5.1 Pharmacokinetic assessments
PK blood sampling will be done:
 During the first week of study treatment (PK samples will be collected in the first
5 participants treated in Cohorts 1 to 3 at the following time points: pre-dose, 1, 2, 4,
6, 8, and 12 hours post-morning dose of selexipag (participants should have been on
the same dose and mode of administration for at least 3 days in order to reach steady
state).
 During the up-titration period, Ctrough,ss PK samples will be collected in all participants
prior to dose escalation at Day 15, and Weeks 4 and 6 (participants should have been
on the same dose and mode of administration for at least 3 days in order to reach steady
state).
 In each cohort, for participants who did not provide samples during the first week of
study treatment, PK samples will be collected at Week 12 at steady state at the
following time points: pre-dose, 1, 2, 4, 6, 8, and 12 hours post-morning dose of
selexipag (participants should have been on the same dose and mode of administration
for at least 3 days in order to reach steady state).
For the participant’s convenience, an overnight stay at the site may be required before
and/or after the PK profile sampling visit.
In total, 10 PK samples (1.2 mL blood/sample) will be collected per participant. The total
amount of blood collected from each participant will be 12 mL. This is in accordance with
general recommendations that the total blood volume collected within 24 hours for the
purpose of a trial in children should not be more than 1% 5% of total body blood volume.
Children are assumed to have 75 80 mL blood / kg body weight; i.e., a 9 kg infant is
considered to have approximately 720 mL of total blood volume.
Blood sampling will take approximately 1 minute. Table 4 displays the time points at which
the PK samples will be taken.
7.2.5.2 Instructions regarding meals
On the day of the PK samples collection (at Visit 3 or Visit 7 and at Visits 4, 5, and 6), the
participant’s parent(s)/LAR(s) will be instructed that the meal preceding the morning and
evening dose should be light.
Dates and time of meals preceding PK samples will be recorded in the eCRF.

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7.2.5.3 Procedure for sampling
To prevent the degradation of selexipag and its metabolites in plasma samples, exposure
of the plasma to light should be minimized and the whole sample preparation should be
conducted under yellow light.
Blood samples of 1.2 mL will be collected by direct venipuncture or via an i.v. catheter in
spray-dried lithium heparin-containing Greiner Vacuettes®. Immediately following
collection, the tube will be slowly tilted backwards and forwards (no shaking) to bring the
anti-coagulant into solution and immediately cooled on ice. Within 30 minutes of
collection, 
the 
blood 
samples 
will 
be 
centrifuged 
at 
approximately
1500 × g / 3000 revolutions per min for 10 minutes, preferably at 4 °C (39.2 °F).
The resulting plasma (approximately 0.5 mL plasma) will be transferred into a single,
labeled, opaque polypropylene tube to avoid carryover of erythrocytes.
All samples will be stored in an upright position at ≤ 18 °C ( 0.4 °F).
The date and exact actual clock time of collection of each blood sample will be entered in
the eCRF.
For additional details, refer to the laboratory manual.
7.2.5.4 Labeling
The tubes and labels will be provided by the central laboratory. The tubes for PK
assessments will be pre-labeled and will carry the following information:
 Actelion Pharmaceuticals Ltd
 Study number: AC-065A203
 Selexipag and ACT-333679
 Type of sample: plasma
 Visit number (eg, Visit 3, Visit 7)
 Scheduled time point (eg, pre-dose, 1 hour post-dose)
 Participant number (eg, 2001 001)
7.2.5.5 Bioanalysis
The concentrations of selexipag (ACT-293987) and ACT-333679 will be determined using
a validated liquid chromatography-tandem mass spectrometry assay. The foreseen limit of
quantification for both analytes is 0.01 ng/mL. Concentrations will be calculated by
interpolation from a calibration curve.

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Quality control samples will be used to determine between-run and overall precision and
accuracy of the analysis.
7.2.5.6 Shipping procedures
The site staff will be responsible for the shipment of the samples. Samples must be sent to
the central laboratory  [see contact details on page 2] at time intervals defined in the
laboratory manual. The samples, together with the completed shipment forms, must be
packed securely in polystyrene insulated shipping containers containing enough dry ice to
last for 48 hours.
8 STUDY COMPLETION AND POST-STUDY TREATMENT /
MEDICAL CARE
8.1 Study completion as per protocol
For an individual participant, study completion is reached when the EOS follow-up
telephone call is completed.
8.2 Premature withdrawal from study
Participant’s parent(s)/LAR(s) may voluntarily withdraw their child from the study without
justification for any reason at any time. Upon reaching his/her legal majority, the
participant may also voluntarily withdraw from the study. Participants are considered to be
withdrawn if they state an intention to withdraw further participation in all components of
the study (i.e., withdrawal of consent), die, or are lost to follow-up. If a participant
withdraws consent, no further data will be collected in the eCRF from the date of
withdrawal onward. The investigator may withdraw a participant from the study (without
regard to the participant’s consent) if, on balance, they believe that continued participation
in the study would be contrary to the best interests of the participant. Withdrawal from the
study may also result from a decision by the Sponsor for any reason, including premature
termination or suspension of the study.
Participants are considered to be lost to follow-up if all reasonable attempts by the
investigator to communicate with the individual and/or their parent(s)/LAR(s) fail. The site
must take preventive measures to avoid a participant being lost to follow-up (eg, document
different ways of contact such as telephone number, home address, email address, person
to be contacted if the participant cannot be reached). If the participant cannot be reached,
the site must make a reasonable effort to contact the participant or their parent(s)/LAR(s),
document all attempts in the source documents, and enter the loss of follow-up information
into the eCRF. The following methods must be used: at least three telephone calls must be
placed to the last available telephone number and one registered letter must be sent by post
to the last available home address. Additional methods may be acceptable if they are
compliant with local rules/regulations (eg, a visit by site personnel to the participant’s

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home), respecting the participant’s right to privacy. If the participant is still unreachable
after all contact attempts listed above, they will be considered to be lost to follow-up.
If premature withdrawal occurs for any reason, the reason (if known) for premature
withdrawal from the study, along with who made the decision (participant, investigator, or
Sponsor personnel) must be recorded in the eCRF, if known.
If, for whatever reason (except death or loss-to-follow-up), a participant is withdrawn from
the study, the investigator should make efforts to schedule a last appointment / telephone
call to assess the safety and well-being of the participant, collect unused study treatment,
and discuss follow-up medical care. Data obtained during this last appointment / telephone
call will be recorded in the participant’s medical records but will not be collected in the
eCRF. The investigator must provide follow-up medical care for all participants who are
prematurely withdrawn from the study, or must refer them for appropriate ongoing care, as
described in Section 8.4.
8.3 Premature termination or suspension of the study
The Sponsor reserves the right to terminate the study at any time globally or locally.
Investigators can terminate the participation of their site in the study at any time.
If the study is prematurely suspended or terminated, the Sponsor will promptly inform the
investigators, the Independent Ethics Committee / Institutional Review Board (IEC/IRB),
and health authorities, as appropriate, and provide the reasons for the suspension or
termination.
If the study is suspended or prematurely terminated for any reason, the investigator 
in
agreement with the Sponsor
must promptly inform all enrolled participants and ensure
their appropriate treatment and follow-up, as described in Section 8.4. The Sponsor may
inform the investigator of additional procedures to be followed in order to ensure that
adequate consideration is given to the protection of the participants’ interests.
In addition, if the investigator suspends or terminates the study without prior agreement
from the Sponsor, the investigator must promptly inform the Sponsor personnel and the
IEC/IRB, and provide both with a detailed written explanation of the termination or
suspension.
If the IEC/IRB suspends or terminates its approval / favorable opinion of the study, the
investigator must promptly notify the Sponsor personnel and provide a detailed written
explanation of the termination or suspension.
Any suspension or premature termination of the study must be communicated to the IDMC.

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8.4 Medical care of subjects after study completion / withdrawal from study
After the participant’s study completion or premature withdrawal from  the study,
whichever applies, the investigator/delegate will explain to the participant’s
parent(s)/LAR(s) and to participants who have come of age, what treatment(s) / medical
care is necessary and available according to local regulations.
Such care may include:
 Switching to selexipag (Uptravi) ifcommercially available.
 Recommendation to initiate any PAH-specific treatment, as per investigator’s
judgment.
Female participants of childbearing potential must use reliable contraceptive methods until
30 days after last intake of selexipag, if heterosexually active. Appropriate counseling
regarding the risks of pregnancy and reliable methods of contraception must be ensured.
9 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS
Timely, accurate, and complete reporting and analysis of safety information, including
AEs, SAEs, and product quality complaint (PQC), from clinical studies are crucial for the
protection of participants, investigators, and the sponsor, and are mandated by regulatory
agencies worldwide.
The investigator is obligated to perform or arrange for the conduct of supplemental
measurements and evaluations as medically indicated to elucidate the nature and causality
of the AE, SAE, or PQC as fully as possible.
9.1 Adverse events
Definition of adverse events
An AE is any untoward medical occurrence, i.e., any unfavorable and unintended sign,
including an abnormal laboratory finding, symptom, or disease that occurs in a participant
during the course of the study, whether or not considered by the investigator to be related
to study treatment.
A TEAE is any AE temporally associated with the use of study treatment (from study
treatment initiation until 3 days after study treatment discontinuation) whether or not
considered by the investigator to be related to study treatment.
AEs include:
 Exacerbation of a pre-existing disease.

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 Increase in frequency or intensity of a pre-existing episodic disease or medical
condition.
 Disease or medical condition detected or diagnosed during the course of the study even
though it may have been present prior to the start of the study.
 Continuous persistent disease or symptoms present at study start that worsen following
the signing of informed consent.
 Abnormal assessments, eg, change on physical examination, ECG findings, if they
represent a clinically significant finding that was not present at study start or worsened
during the course of the study.
 Laboratory test abnormalities if they represent a clinically significant finding,
symptomatic or not, that was not present at study start, or worsened during the course
of the study or led to dose reduction, interruption, or permanent discontinuation of
study treatment.
Overdose, misuse, and/or abuse of selexipag and study treatment errors will be reported as
an AE.
Study-site staff should instruct the caregivers / legal representatives on how to report signs
and symptoms (eg, crying and pain) in the individual pediatric participant. They will be
instructed to report both specific and non-specific symptoms (including vomiting, diarrhea,
sleepiness, variation in the intensity and pattern of crying, etc.). These non-specific
symptoms may be the only manifestations of some adverse reactions observed in toddlers.
Care should be taken that the clinical presentation of adverse reactions is not misinterpreted
as the manifestation of a pre-existing or unrelated condition.
Moreover, symptoms that are dependent on participant communication ability (eg, nausea,
pain, mood alterations) in younger or mentally disabled children could potentially be at
risk for under- or mis-reporting.
Intensity of adverse events
The intensity of clinical AEs is graded on a three-point scale mild, moderate, severe 
and is reported on specific AE pages of the eCRF.
If the intensity of an AE worsens during study treatment administration, only the worst
intensity should be reported on the AE page. If the AE lessens in intensity, no change in
the severity is required to be reported.

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For AEs ongoing at the start of study treatment, if the intensity worsens after the start of
study treatment, a new AE page must be completed. The onset date of this new AE
corresponds to the date of worsening in intensity.
The three categories of intensity are defined as follows:
 Mild
The event may be noticeable to the participant. It does not usually influence daily activities,
and normally does not require intervention.
 Moderate
The event may make the participant uncomfortable. Performance of daily activities may be
influenced, and intervention may be needed.
 Severe
The event may cause noticeable discomfort and usually interferes with daily activities. The
participant may not be able to continue in the study, and treatment or intervention is usually
needed.
A mild, moderate, or severe AE may or may not be serious [see Section 9.2.1]. These terms
are used to describe the intensity of a specific event. Medical judgment should be used on
a case-by-case basis.
Seriousness, rather than intensity assessment, determines the regulatory reporting
obligations.
Relationship to study treatment
Each AE must be assessed by the investigator as to whether or not there is a reasonable
possibility of a causal relationship to selexipag, and reported as either related or unrelated.
The determination of the likelihood that the study treatment caused the AE will be provided
by the investigator.
Reporting of adverse events
All AEs with an onset date after the signing of the ICF and up to EOS must be recorded on
specific AE pages of the eCRF.
Follow-up of adverse events
The investigator is obligated to perform or arrange for the conduct of supplemental
measurements and evaluations as medically indicated to elucidate the nature and causality
of the AE, SAE, or PQC as fully as possible. This may include additional laboratory tests
or investigations, histopathological examinations, or consultation with other health care
professionals.

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AEs still ongoing after EOS must be followed up until they are no longer considered
clinically relevant (eg, until symptom resolution) or until stabilization. The follow-up
information obtained after aparticipant’s EOS is recorded in the participant’s medical chart
(source data), but is not recorded in the eCRF.
9.2 Serious adverse events
Definitions of serious adverse events
An SAE is defined by the ICH guidelines as any AE fulfilling at least one of the following
criteria:
 Fatal.
 Life-threatening: Refers to an event in which the participant was at risk of death at the
time of the event. It does not refer to an event that hypothetically might have caused
death had it been more severe.
 Requiring in-patient hospitalization or prolongation of existing hospitalization.
 Resulting in persistent or significant disability or incapacity.
 Congenital anomaly or birth defect.
 Suspected transmission of any infectious agent via a medicinal product
 Medically significant: Refers to important medical events that may not immediately
result in death, be life-threatening, or require hospitalization but may be considered to
be SAEs when, based upon appropriate medical judgment, they may jeopardize the
participant, and may require medical or surgical intervention to prevent one of the
outcomes listed in the definitions above.
The following reasons for hospitalization are not considered SAEs:
 Hospitalization for cosmetic elective surgery, or social and/or convenience reasons.
 Hospitalization for pre-planned (i.e., planned prior to signing informed consent)
surgery or standard monitoring of a pre-existing disease or medical condition that did
not worsen, eg, hospitalization for coronary angiography in a participant with stable
angina pectoris.
However, complications that occur during hospitalization are AEs or SAEs (eg, if a
complication prolongs hospitalization).
Reporting of serious adverse events
All SAEs occurring after the signing of the ICF  up to 30 days after study treatment
discontinuation must be reported on AE pages in the eCRF and on an SAE notification

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form, regardless of the investigator-attributed causal relationship with study treatment or
study-mandated procedures.
An SAE is defined as related to protocol-mandated procedures if it appears to have a
reasonable possibility of a causal relationship to either the study design or to
protocol-mandated procedures (eg, discontinuation of a participant’s previous treatment
during a washout period, leading to exacerbation of underlying disease).
Follow-up of serious adverse events
SAEs still ongoing more than 30 days after study treatment discontinuation  must be
followed up until resolution or stabilization, or until the event outcome is provided. The
follow-up information obtained after the participant’s EOS telephone call must be reported
to the Sponsor, but is not recorded in the eCRF.
After the 30-day follow-up period
New SAEs occurring after the 30-day follow-up period must be reported to the Sponsor
within 24 hours of the investigator’s knowledge of the event, only if considered by the
investigator to be causally related to previous exposure to the study treatment.
Reporting procedures
All SAEs, including PQC, must be reported by the investigator to the Sponsor within
24 hours of the investigator’s first knowledge of the event.
All SAEs must be recorded on an SAE notification form, irrespective of the study treatment
received by the participant, and whether or not this event is considered by the investigator
to be related to study treatment.
The SAE notification forms must be sent to the Sponsor (contact details are provided on
the SAE notification form). The investigator must complete the SAE notification form in
English, and must assess the event’s causal relationship to the study treatment.
Any relevant information from source documents regarding the SAE, eg, hospital notes or
discharge summaries, etc., must be summarized on the SAE notification form.
Follow-up information about a previously reported SAE must also be reported within
24 hours of receiving it. The Sponsor personnel may contact the investigator to obtain
further information.
If the participant is hospitalized in a hospital other than the study site, it is the investigator’s
responsibility to contact this hospital to obtain all SAE-relevant information and
documentation.
The expectedness of an adverse reaction is determined by the Sponsor in the reference
safety information (RSI) section provided in the most recent version of the selexipag IB.

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Any SAE that is assessed as related and unexpected against the RSI is known as a suspected
unexpected serious adverse reaction (SUSAR) and the sponsor assumes responsibility for
appropriate reporting of AEs to the regulatory authorities. The sponsor will also report to
the investigator (and the head of the investigational institute where required) all SUSARs.
The investigator (or sponsor where required) must report SUSARs to the appropriate
Independent Ethics Committee/Institutional Review Board (IEC/IRB) that approved the
protocol unless otherwise required and documented by the IEC/IRB. A SUSAR will be
reported to regulatory authorities unblinded. Participating investigators and IEC/IRB will
receive a blinded SUSAR summary, unless otherwise specified.
9.3 Pregnancy
If a female participant becomes pregnant while on study treatment, study treatment must
be discontinued. The investigator must counsel the participant and discuss the risks of
continuing with the pregnancy and the possible effects on the fetus. This counseling
comprises all medications administered at that time and follows the instructions of the
respective approved drug labels.
Reporting of pregnancy
Any pregnancy occurring after study start (i.e., signing of the ICF) in female participants
or partners of male participants up to 30 days following study treatment discontinuation
must be reported within 24 hours of the investigator’s knowledge of the event.
Pregnancies of female participants and partners of male participants must be reported on
the Pregnancy notification and follow-up forms, which are sent to the Sponsor, and on an
AE page in the eCRF.
Follow-up of pregnancy
Any pregnancies must be followed-up to their conclusion and the outcome must be reported
to the Sponsor.
Any AE associated with the pregnancy occurring during the follow-up period after study
treatment discontinuation must be reported on separate AE pages in the eCRF. Any SAE
occurring during the pregnancy must be reported on an SAE notification form as described
in Section 9.3.1.
9.4 Special Reporting Situations
Safety events of interest on a sponsor study treatment in an interventional study that may
require expedited reporting or safety evaluation include, but are not limited to:
 Overdose of a sponsor study treatment (see Section 5.3)
 Suspected abuse/misuse of a sponsor study treatment

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 Accidental or occupational exposure to a sponsor study treatment
 Medication error, intercepted medication error, or potential medication error involving
a Johnson & Johnson medicinal product (with or without participant exposure to the
Johnson & Johnson medicinal product, eg, product name confusion, product label
confusion, intercepted prescribing or dispensing errors)
 Exposure to a sponsor study intervention from breastfeeding
Special reporting situations should be recorded in the CRF. Any special reporting situation
that meets the criteria of a serious adverse event should be recorded on the serious adverse
event page of the CRF.
9.5 Study safety monitoring
Study safety information (AEs, SAEs, laboratory values, ECGs, vital signs, Tanner stage,
growth, and study-specific examinations as required) is monitored and reviewed on a
continuous basis by the responsible Sponsor Clinical Team (in charge of ensuring
participants’safety as well as data quality). In addition, an IDMC monitors safety data [see
Section 3.3]. The sponsor may request additional data pertaining to the diagnostic work-up
of an AE or SAE (eg, medical imaging, local laboratory values) for the purpose of safety
monitoring. Such additional data may be shared with external experts appointed by the
Sponsor of this study.
9.6 Product quality complaint handling
A product quality complaint (PQC) is defined as any suspicion of a product defect related
to manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity,
quality, durability, or reliability of a product, including its labeling or package integrity. A
PQC may have an impact on the safety and efficacy of the product. Timely, accurate, and
complete reporting and analysis of PQC information from studies are crucial for the
protection of participants, investigators, and the sponsor, and are mandated by regulatory
agencies worldwide. The Sponsor has established procedures in conformity with regulatory
requirements worldwide to ensure appropriate reporting of PQC information; all studies
conducted by the sponsor or its affiliates will be conducted in accordance with those
procedures.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours
after being made aware of the event.
A sample of the suspected product should be maintained under the correct storage
conditions until a shipment request is received from the sponsor.

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Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be
contacted regarding product quality issues are listed in the Contact Information page(s),
which will be provided as a separate document.
10 STATISTICAL METHODS
All statistical analyses will be conducted by the Sponsor or by designated contract research
organizations (CROs) supervised by the Sponsor.
A Statistical Analysis Plan (SAP) will provide full details of the analyses, data displays,
and algorithms to be used for data derivations. All statistical analyses will be performed by
age cohort and overall.
10.1 Analysis Sets
Screened Analysis Set
The Screened Analysis Set includes all participants who are screened and have a participant
identification number.
Full Analysis Set
The Full Analysis Set (FAS) includes all enrolled participants who were eligible to receive
the study drug.
Pharmacokinetic Analysis Set
The PK Analysis Set (PKS) comprises all participants included in the Safety Set who
complied with the protocol sufficiently and did not deviate from the protocol in a way that
might affect the PK outcome of the study. The criteria for sufficient compliance include
exposure to treatment, availability of PK measurements, and absence of major protocol
deviations that have an impact on the PK. The full list of criteria will be detailed in the
modeling data analysis plan and the SAP.
Safety Analysis Set
The Safety Analysis Set includes all participants who received at least one dose of study
treatment.
Usage of the analysis sets
The FAS is used for the analyses of exploratory efficacy variables as well as for the
description of the study population at baseline. Unless otherwise specified, individual
listings are prepared on the FAS.
The PKS is used for the analysis of the primary and secondary PK variables.

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The Safety Analysis Set is used for the analysis of the safety variables and other variables.
The Screened Analysis Set is used for the description of participant disposition.
10.2 Variables
Primary pharmacokinetic variable(s)
10.2.1.1 PK analysis and modeling
The primary endpoint is model-based exposure (AUCτ,ss,combined) of selexipag and
ACT-333679 weighted by their potency determined during the 12-week up-titration period
[Modeling and Simulation Report, Pediatric dose selection  2016]. The population PK
model in the GRIPHON study will be updated with observed data in this study during
interim and final PK analyses in order to determine the model-based exposure
(AUCτ,ss,combined) [Modeling and Simulation Report AC-065A302 (GRIPHON) 2014].
For each interim analysis and the final analysis, the available pediatric data will be pooled
and the population PK model re-estimated to properly describe the dose-exposure
relationship in dependence with body weight. PK information from the adult population
will be incorporated by pooling the data or using current parameter estimates as priors
when updating the model.
More detail will be described in the modeling data analysis plan, which will be finalized
before the PK interim analysis 1 and any update thereof.
Secondary pharmacokinetic variables
 Plasma concentrations at trough at Visits 4, 5, and 6.
 AUCτ,ss, Cmax,ss, and tmax,ss for selexipag and ACT-333679 based on NCA.
Exploratory pharmacokinetic / pharmacodynamic analysis
The PK/pharmacodynamic (PD) relationships will be investigated by population PK/PD
modeling. Details will be in the modeling data analysis plan.
Safety variables
The safety variables described below are related to the safety endpoints described in
Section 6.2. Baseline is defined as the last non-missing value observed before or on the day
of the first study drug intake.
The safety variables are the following:
 TEAEs occurring up to EOT + 3 days.
 TESAEs occurring up to EOT + 3 days.

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 AEs leading to permanent discontinuation of study drug.
 Treatment-emergent deaths (all causes) occurring up to EOT + 3 days.
 Treatment-emergent marked laboratory abnormalities (hematology and blood
chemistry tests) over time occurring up to EOT + 3 days.
 Change from baseline in selected hematology and blood chemistry laboratory variables
over time up to EOT + 3 days.
 Treatment-emergent ECG abnormalities over time occurring up to EOT + 3 days.
 Change from baseline in TSH over time up to EOT + 3 days.
 Change from baseline in vital signs (blood pressure, heart rate) over time up to EOT + 3
days.
 Change from baseline in height and body mass index over time up to EOT + 3 days
 Change from baseline in sexual maturation (Tanner stage) over time up to
EOT + 3 days.
Exploratory efficacy variables
Exploratory variables described below are related to the exploratory endpoints described
in Section 6.3.
The exploratory variables are the following:
 Time to disease progression / clinical worsening from first study drug dose up to EOT
+ 7 days.
 Change from Baseline/Enrollment up to each time point of assessment in modified
NYHA/WHO FC, classified as worsened (> baseline value), unchanged (  baseline
value), or improved (< baseline value).
 Change from baseline over time up to each time point of assessment in exercise
capacity as measured by 6MWD.
 Change from baseline in Panama FC up to each time point of assessment, classified as
worsened (> baseline value), unchanged (  baseline value), or improved (< baseline
value).
 Percent of baseline in plasma NT pro-BNP at each time point of assessment.
 Change from baseline up to each time point of assessment in Echo variables (imaging
and Doppler evaluation):
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 Tricuspid annular plane systolic excursion.
 Pulmonary artery acceleration time.
 Left ventricular eccentricity index.
 Right atrial area index (from apical 4 chamber view).
 Tricuspid annular diameter (from apical 4 chamber view).
Other variables
Other variables are related to the other endpoints described in Section 6.4.
The other variables are:
 Palatability of selexipag formulation at Day 1, Week 12, and EOT, assessed using a 5-
point facial hedonic scale.
 Acceptability on selexipag formulation at Day 1, Week 12, and EOT, as assessed
through a 3-point categorical scale as to whether the child swallowed the medication.
10.3 Description of statistical analyses
Overall testing strategy
Not applicable.
Analysis of the primary pharmacokinetic variable(s)
10.3.2.1 Hypotheses and statistical model
Not applicable.
10.3.2.2 Handling of missing data
Not applicable.
10.3.2.3 Main analysis
The observed PK data will be described by a population PK model using the same model
structure as for the adult participants with PAH in the GRIPHON study [Modeling and
Simulation Report AC-065A302 (GRIPHON) 2014, Modeling and Simulation Report,
Pediatric dose selection 2016]. This population PK model describes the PK of selexipag
and ACT-333679 by 2-compartmental distribution models with linear elimination.
Selexipag is absorbed by a first order process and part of the elimination from the central
compartment is a metabolic transformation to form ACT-333679 [Modeling and
Simulation Report AC-065A302 (GRIPHON) 2014].
The analyses will be performed to confirm or potentially revise the starting doses and
up-titration increments for the next age cohort and the starting dose of the Phase 3 study.

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10.3.2.4 Supportive/sensitivity analyses
Not applicable.
Analysis of secondary pharmacokinetic variable(s)
Plasma concentrations will be summarized per time point, by dose and body weight cohort
using arithmetic mean, geometric mean, minimum, median, maximum, standard deviation
(SD), standard error (SE), and two-sided 95% CI of the mean.
AUCτ,ss, Cmax,ss, Ctrough,ss, and tmax,ss9 for selexipag and ACT-333679 based on NCA for
selexipag and ACT-333679 will be listed and summarized by dose and body weight cohort,
with arithmetic mean, geometric mean, minimum, median, maximum, SD, SE, coefficient
of variation in %, and 95% CI of the arithmetic and geometric means.
Dose proportionality for AUCτ,ss and Cmax,ss of selexipag and ACT-333679 will be explored
by the power model as described by [Gough 1995].
Exploratory pharmacokinetic / pharmacodynamic analysis
The population PK/PD model will be built based on individual predictions of steady-state
exposure for iMTD based on the final population PK models for both selexipag and
ACT-333679. More details on PK and PD analyses will be in the modeling data analysis
plan.
Analysis of the safety variable(s)
All analyses of safety variables will be carried out descriptively using the Safety Analysis
Set and will be performed as follows:
 In the overall population.
 By iMTD dose groups.
 By age cohort.
The iMTD is defined as the last dose received before the Week 12 visit (for participants
who prematurely discontinued study drug) or the dose received on the day of the Week 12
visit (for participants who completed the 12-week up-titration period).
Safety data will also be explored by age cohort and by iMTD dose groups if a sufficient
number of participants allows.
10.3.5.1 Treatment-emergent adverse events
The number and percentage of participants with at least one TEAE / TESAE / AE leading
to study treatment discontinuation will be described by system organ class (SOC) and
9 The geometric mean of tmax and its 95% CI will not be calculated.

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preferred term (PT) up to EOT + 3 days, and separately for the up-titration period (up to
Week 12) and the maintenance phase (> Week 12 up to EOT + 3 days).
The same analysis will be performed according to the maximum intensity of reported AEs
and according to the relationship to the study drug.
Listings will be provided for all reported AEs, including SAEs. In addition, separate
listings will be provided for all AEs leading to premature discontinuation of study drug,
and for all AEs leading to death.
10.3.5.2 Treatment-emergent death
The number and percentage of treatment-emergent deaths will be described by SOC and
PT up to EOT + 3 days.
In addition, all deaths reported during the study will be listed.
10.3.5.3 Laboratory variables
All laboratory data transferred are taken into account regardless of whether they correspond
to scheduled (per protocol) or unscheduled assessments. All recorded assessments will be
assigned to the most appropriate visit time points according to the best fitting time-window
for that assessment using the usual location and scale summary statistics.
For each laboratory variable, the number and percentage of participants with at least one
treatment-emergent marked abnormality will be summarized up to EOT + 3 days.
The change in selected laboratory values and the change in TSH will also be summarized
over time up to EOT + 3 days, using the same descriptive statistics for continuous variables.
10.3.5.4 ECG
For each ECG variable, the number and percentage of participants with at least one
treatment-emergent marked abnormality will be summarized up to EOT + 3 days.
10.3.5.5 Vital signs
Absolute values and changes from baseline will be summarized over time up to
EOT + 3 days, using descriptive statistics for continuous variables.
10.3.5.6 Height and Weight
Absolute values and changes from baseline will be summarized over time up to
EOT + 3 days, using descriptive statistics for continuous variables.
10.3.5.7 Sexual maturation
Absolute values and changes from baseline will be summarized over time up to
EOT + 3 days, using descriptive statistics for continuous variables.

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Analysis of the exploratory efficacy variables
All analyses of exploratory variables will be carried out descriptively using the FAS and
will be performed as follows:
 In the overall population.
 By iMTD dose groups.
 By age cohort.
The main exploratory analysis will be based on observed data, with no imputation rules.
Sensitivity analyses will be performed by imputing missing values as appropriate and will
be described in the SAP.
10.3.6.1 Time to disease progression / clinical worsening
Event time is defined as the time elapsed from the first study drug administration to the
day of the occurrence of the event. Time to event endpoints will be presented as Kaplan
Meier estimates with two-sided 95% CLs at relevant time points and displayed in both a
graphical (where the number of participants at risk is at least 10% of the total number of
participants in the Analysis Sets) and a tabular form. Participants who did not experience
an event will have their event time censored at EOT + 7 days. The number of participants
at risk, the number of participants censored and the number of participants with event will
be displayed.
10.3.6.2 NYHA / WHO FC
The proportion of participants having worsened, remained unchanged, or improved will be
calculated at each time point of assessment and up to the timepoint with at least 10
participants in the cohort. Two-sided 95% CIs of the proportions will be presented. 
10.3.6.3 6MWD
The change from baseline will be summarized at each time point of assessment up to the
timepoint with at least 10 participants in the cohort, using descriptive statistics for
continuous variables. Two-sided 95% CIs of the mean and median will also be provided.
10.3.6.4 Panama FC
The proportion of participants having worsened, remained unchanged, or improved will be
calculated at each time point of assessment up to the timepoint with at least 10 participants
in the cohort. Two-sided 95% CIs of the proportions will be presented. 
10.3.6.5 NT-proBNP
The percent of baseline will be summarized at each time point of assessment and up to the
timepoint with at least 10 participants in the cohort, using descriptive statistics for
continuous variables on the log-transformed data. The resulting mean and two-sided 95%

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CIs will be inversely transformed using the exponential function to provide the geometric
mean and corresponding two-sided 95% CIs.
10.3.6.6 Echo/Doppler
The change from baseline to each time point of assessment for each Echo/Doppler variable
will be summarized at each point of assessment up to the timepoint with at least 10
participants in the cohort, using descriptive statistics for continuous variables. The two-
sided 95% CIs of the means will also be provided.
Analysis of the other variables
All analyses of other variables will be carried out descriptively using SAS  (Statistical
Analysis System) and will be performed as follows:
 In the overall population.
 By iMTD dose groups.
 By age cohort.
The iMTD is defined as the last dose received before the Week 12 visit (for participants
who prematurely discontinued study drug) or the dose received the day of the Week 12
visit (for participants who completed the 12-week up-titration period).
10.3.7.1 Palatability and acceptability
The palatability and acceptability of selexipag will be summarized separately with counts
and percentages.
10.4 Interim analyses
An IDMC will be involved in the study to periodically review safety data and, if requested,
PK data [see Section 3.3].
As described in Section 3.1, two interim PK analyses will be performed. They will be
detailed in the modeling data analysis plan.
Additional assessments of PK profiles and interim analyses may be performed, as deemed
appropriate by the sponsor.
10.5 Sample size
Based on clinical trial simulations using the population PK model of the GRIPHON study,
at least 15 participants between ≥ 12 and < 18 years of age (Cohort 1), at least
15 participants between ≥ 6 and < 12 years of age (Cohort 2), and 10 participants between
≥2 and < 6 years of age (Cohort 3) with evaluable PK profiles are necessary to obtain a
90% confidence interval of the AUCτ,ss,combined within a 1.4-fold range above or below the
predicted median [see Section 14.7 Appendix 7].

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PK data of pediatric participants with PAH in the planned clinical trial were simulated
using the GRIPHON population PK model by appropriate assumptions of body weights.
The body weight impact on PK model parameters was used as determined based on adult
data. PK parameters were re-estimated 100 times and AUCτ,ss,combined was simulated
1,000 times, taking the parameter estimation uncertainty into account to determine
AUCτ,ss,combined prediction uncertainty. This assessment of the AUCτ,ss,combined prediction
uncertainty was performed for each planned interim analysis and the final analysis to check
that at each stage the AUCτ,ss,combined for the respective cohort could be determined with
sufficient accuracy.
The sample size is determined based on the assumption that the PK characteristics have the
same inter-individual variability in pediatric as in adult participants with PAH.
Furthermore, it is assumed that pediatric participants with PAH of the same weight as adult
participants with PAH have the same PK, as relevant metabolic and elimination pathways
are assumed to be mature and thus the PK modeling can partly be built on results from the
GRIPHON study. At the interim analyses and the final PKanalysis, all available PK data
will be used to update the PK model and to confirm or adjust the dose selection. The
emerging results will also be used to reconsider the sample size, with the aim of minimizing
it. However, if the quality of the data collected does not allow for a sufficiently precise
confirmation of body weight-based doses, additional participants may need to be enrolled
in the study. More details oninterim analyses will be provided in the modeling data analysis
plan.
Based on the pediatric PK data available at the second interim analysis, the planned sample
size for Cohort 3 (N 10) was assessed using a simulation/estimation approach. Pediatric
datasets were simulated with fold-deviations of exposures (AUCτ,ss,combined) of 0.5, 0.7, 1,
1.3, and 1.5-fold compared to the adult reference model [PK Interim Analysis Report-2
AC-065A203 2020]. Based on this analysis, the power of recognizing a pediatric to adult
ratio of 0.5, 0.7, 1.3, and 1.5 as significantly different from 1, is predicted to be >99%,
82.8%, 56.4%, and 83.2%, respectively. Type 1 error (i.e., when the AUC ratio is 1) is
estimated to be 11.8%. If the sample size of Cohort 3 is increased to 15, the estimated
values of the power are predicted to be >99%, 91.6%, 71.2% and 96.2% for the exposure
ratios of 0.5, 0.7, 1.3, and 1.5, respectively, and the Type 1 error is estimated to be 11.0%
[PK Interim Analysis Report-2 AC-065A203 2020]. Based on this assessment, the planned
sample size for Cohort 3 has been increased to at least 15 PK evaluable participants in
order to ensure a power of at least 70% for all potential outcomes.

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11 DATA HANDLING
11.1 Data collection
The investigator/delegate is responsible for ensuring the accuracy, completeness, and
timelines of the data reported. All source documents should be completed in a neat, legible
manner to ensure accurate interpretation of the data. Data reported in the eCRF derived
from source documents must be consistent with the source documents.
eCRF data will be captured via EDC  (using the Rave system provided by Medidata
Solutions, Inc., a web-based tool). The investigator and site personnel will be trained to
enter and edit the data via a secure network, with secure access features (username,
password, and identification an electronic password system). A complete electronic audit
trail will be maintained. The investigator/delegate will approve the data (i.e., confirm the
accuracy of the data recorded) using an electronic signature (ref. to US 21 CFR Part 11).
Entries recorded by the participant or by the participant’s parent(s)/LAR(s) in the Study
Drug Diary are considered source data. Site personnel will review and ensure completeness
and readability of the participants’ entries.
Participant screening and enrollment data will be completed for all participants (i.e.,
eligible and non-eligible) through the IRT system and eCRF.
For each participant screened, regardless of study treatment initiation, an eCRF must be
completed and signed by the investigator/delegate. This also applies to those participants
who fail to complete the study. If a participant is withdrawn from the study, the reason
must be noted on the eCRF.
11.2 Maintenance of data confidentiality
The investigator/delegate must ensure that data confidentiality is maintained. On eCRFs or
other documents (eg, documents attached to SAE notification forms / Pregnancy
notification and follow-up forms) submitted to the Sponsor and any CROs, participants
must be identified only by number and never by their name or initials, date of birth, hospital
numbers, or any other identifier. The investigator/delegate must keep a participant
identification code list at the site, showing the screening/randomization number, the
participant’s name, date of birth, and address or any other locally accepted identifiers.
Documents identifying the participants (eg, signed ICFs) must not be sent to the Sponsor,
and must be kept in strict confidence by the investigator/delegate.
11.3 Database management and quality control
eCRFs will be used for all participants. The investigators will have access to the site eCRF
data until the database is closed. Thereafter, they will have read-only access. The eCRF

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must be kept current to reflect participant status at any time point during the course of the
study.
While entering the data, the investigator/delegate will be instantly alerted to data queries
by validated programmed checks. Additional data review will be performed by the Sponsor
personnel on an ongoing basis to look for unexpected patterns in data and for study
monitoring. If discrepant data are detected, a query specifying the problem and requesting
clarification will be issued and visible to the investigator/delegate via the eCRF. All
electronic queries visible in the system either require a data correction (when applicable)
and a response from the investigator/delegate to clarify the queried data directly in the
eCRF, or simply a data correction in the eCRF. The investigator/delegate must, on request,
supply the Sponsor with any required background data from the study documentation or
clinical records. This is particularly important when errors in data transcription are
suspected. In the case of health authority queries, it is also necessary to have access to the
complete study records, provided that participant confidentiality is protected. This process
will continue until database closure.
Laboratory samples will be processed through a central laboratory and the results will be
electronically sent to the Sponsor.
ECGs and Echos will be read centrally by a central reader and the results will be sent
electronically to the Sponsor.
AEs are coded according to the latest Medical Dictionary for Regulatory Activities
(MedDRA) used by the Sponsor.
After the database has been declared complete and accurate, the database will be closed.
Any changes to the database after that time may only be made as described in the Sponsor’s
appropriate Quality System documents. After database closure, the investigator will
receive the eCRFs of the participants of their site (including all data changes made) on
electronic media or as paper copies.
12 PROCEDURES AND GOOD CLINICAL PRACTICE
12.1 Ethics and Good Clinical Practice
The Sponsor personnel and the investigators will ensure that the study is conducted in full
compliance with ICH-GCP Guidelines, the principles of the “Declaration of Helsinki”, and
with the laws and regulations of the country in which the study is conducted.
12.2 Independent Ethics Committee / Institutional Review Board
The investigator will submit this protocol and any related document(s) provided to the
parent(s)/LAR(s) and the participant (such as the ICF, the Assent, the scales, the study drug
diary) to an IEC/IRB. Approval from the committee/board must be obtained before starting

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the study, and must be documented in a dated letter to the investigator, clearly identifying
the study, the documents reviewed, and the date of approval.
Modifications made to the protocol or the ICF after receipt of the approval must also be
submitted as amendments by the investigator to the IEC/IRB in accordance with local
procedures and regulations [see Section 12.6].
A list of members participating in the IEC/IRB meetings must be provided, including the
names, qualifications, and functions of these members. If this is not possible, the attempts
made to obtain this information along with an explanation as to why it cannot be obtained
or disclosed must be documented in the study documentation.
If a member of the study personnel was present during an IEC/IRB meeting, it must be
clear that this person did not vote.
12.3 Informed consent
Pediatric participants are legally unable to provide informed consent. Therefore, full
informed consent must be obtained from parent(s) or an LAR.
It is the responsibility of the investigator/delegate to obtain informed consent from the
participant’s parent(s)/LAR(s) and the assent by the child according to ICH-GCP and
Declaration of Helsinki guidelines and local regulations. The investigator/delegate must
explain to the parent(s)/LAR(s) and the child that they are completely free to refuse to enter
the study or to voluntarily withdraw from the study at any time for any reason without
having to provide any justification. Special attention shall be paid to the information needs
of specific participant populations and of individual participants, as well as to the methods
used to give the information. Adequate time shall be given for the participant, the parent(s)
and/or LAR(s) to consider their decision to participate in the study and it shall be verified
that the participant has understood the information (eg, by asking the participant and/or the
parent(s)/LAR(s) to explain what is going to happen).
Assent must be obtained from study participants who are developmentally capable. The
criteria for developmental capability to give assent follows local requirements. Distinct
assent forms are provided per age category according to local practice. Participants who
come of age during their study participation must consent to continuing their participation
in the study. The age when participants are considered capable of giving informed consent
must follow local regulations.
The ICF will be provided in the country local language(s).
Site personnel (according to local regulation) authorized to participate in the consent
process and/or to obtain consent from the participant’s parent(s)/LAR(s) and/or participant

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will be listed on the Delegation of Authority form supplied by the Sponsor. A study
physician must always be involved in the consent process.
The participant’s parent(s)/LAR(s) and authorized site personnel listed on the Delegation
of Authority form supplied by the Sponsor must sign, personally date, and time (if the first
study-mandated procedure is to be performed on the same day informed consent is
obtained) the ICF before any study-related procedures (i.e., any procedures required by the
protocol) begin.
A second original or copy of the signed and dated ICF is given to the participant’s
parent(s)/LAR(s); one original is filed in the site documentation. The informed consent
process and the assent process must be fully documented in the participant’s medical
records. This must include at minimum the study reference, the participant number, the
date and, if applicable, the time when the parent(s)/LAR(s) (and participant if applicable)
was first introduced to the study, the date and, if applicable, the time of consent, who
participated in the consent discussion, who consented the participant / participant’s
parent(s)/LAR(s), and any additional person present during the consent process (eg,
participant’s family member[s]), and the information that a copy of the signed ICF was
given to the participant’s parent(s)/LAR(s).
12.4 Indemnification, compensation, and refund of expenses to subjects’
parent(s)/LAR(s) and investigators
The Sponsor provides insurance in order to indemnify (with both legal and financial
coverage) the investigator/site against claims arising from the study, except for claims that
arise from malpractice and/or negligence.
The indemnification of the participant’s parent(s)/LAR(s) in the event of study-related
injuries will comply with applicable regulations.
Participant’s parent(s)/LAR(s) will be reimbursed for the study-related expenses (eg, travel
costs, meals, hotels) and may be offered financial compensation for their participation in
the study only to the extent permitted by applicable local regulations.
12.5 Protocol adherence/compliance
The investigator must conduct the study in compliance with the IEC/IRB and/or the
regulatory authority-approved version of the protocol and must not implement any
deviation/change from the protocol, except when deviation is necessary to eliminate an
immediate hazard to the participant.
If a protocol deviation occurs, the investigator/delegate will inform the Sponsor or its
representative in a timely manner. The investigator/delegate must document and explain
any deviation from the approved protocol. Deviations considered to be a violation of

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ICH-GCP must be reported to the IEC/IRB and regulatory authorities according to the
Sponsor’s or (overruling) local requirements.
All protocol deviations will be reported by the CRA into the Clinical Trial Management
System (CTMS). Major protocol deviations will be reported in the CSR. IECs/IRBs will
be provided with listings of protocol deviations as per local requirements.
12.6 Protocol amendments
Any change to the protocol can only be made through a written protocol amendment. An
amended protocol must be submitted to the IEC/IRB and regulatory authorities, according
to their requirements.
12.7 Essential documents and retention of documents
The investigator/delegate must maintain adequate records necessary for the reconstruction
and evaluation of the study. A number of attributes are considered of universal importance
to source data and the records that hold those data. These include that the data and records
are accurate, legible, contemporaneous, original (or certified copy), attributable, complete,
consistent, enduring, and available when needed.
These records are to be classified into two different categories of documents: Investigator
Site File (ISF) and participants’ source documents.
These records must be kept by the investigator for as long as is necessary to comply with
Sponsor’s requirements (i.e., as specified in the clinical study agreement), and national
and/or international regulations, whichever would be the longest period. If the investigator
cannot guarantee this archiving requirement at the site for any or all of the documents,
special arrangements, respecting the data confidentiality, must be made between the
investigator and the Sponsor to store these documents outside the site, so that they can be
retrieved in case of a regulatory inspection. No study document should be destroyed
without prior written approval from the Sponsor. Should the investigator wish to assign the
study records to another party, or move them to another location, the Sponsor must be
notified in advance.
If the site is using an electronic/computerized system to store participant medical records,
it can be used for the purpose of the clinical study if it is validated (as per 21 CFR Part 11
or equivalent standard) and if the CRA has been provided personal and restricted access to
study participants only, to verify consistency between electronic source data and the eCRF
during monitoring visits.
If the site is using an electronic/computerized system to store participant medical records
but it could not be confirmed that the system is validated or if the CRA could not be
provided access to the system, the site is requested to print the complete set of source data

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needed for verification by the CRA. The printouts must be numbered, stapled together with
a coversheet, signed, and dated by the investigator/delegate to confirm that these certified
copies are exact copies having the same information as the original source data. The
printouts will be considered as the official clinical study records and must be filed either
with the participant’s medical records or with the participant’s eCRF.
In order to verify that the process the site uses to prepare certified copies is reliable, the
CRA must be able to observe this process and confirm that the comparison of the source
documents and the certified copy did not reveal inconsistencies. The CRA does not need
to verify this process for all data of all participants but at least for some of them (eg, first
participant; regular check during the study of critical data like inclusion/exclusion criteria,
endpoints for some participants) as per the Sponsor’s instructions. If it were not possible
for the CRA to observe this process, it would not be possible to rely on the site’s certified
copies and therefore the site cannot be selected for the clinical study.
12.8 Monitoring
Prior to study start, a site initiation visit (SIV) will be performed after the required essential
study documents are approved by the Sponsor. The study treatment will be shipped to the
site upon approval of the required essential documents.
The PI must ensure that all site personnel involved in the study are present during the SIV
and will dedicate enough time to it. Site Information Technology support should also be
available during the SIV.
The SIV must be completed before the site can start the screening of study participants.
Following the SIV, a copy of the completed initiation visit report and follow-up letter will
be provided to the PI and filed in the ISF.
During the study, the CRA will contact and visit the site regularly and must be permitted,
on request, to have access to study facilities and all source documents needed to verify
adherence to the protocol and the completeness, consistency, and accuracy of the data being
entered in the eCRFs and other protocol-related documents. The Sponsor’s monitoring
standards require full verification that informed consent has been provided, verification of
adherence to the inclusion/exclusion criteria, documentation of SAEs, and the recording of
the main efficacy, safety, and tolerability endpoints. Additional checks of the consistency
of the source data with the eCRFs will be performed according to the study-specific
monitoring guidelines. The frequency of the monitoring visits will be based on participant
recruitment rate and critical data-collection times.
The PI must ensure that the eCRF is completed after a participant’s visit (site visit or
telephone call), and that all requested participant files (eg, ICFs, medical notes/charts, other
documentation verifying the activities conducted for the study) are available for review by

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the CRA. The required site personnel must be available during monitoring visits and allow
adequate time to meet with the CRA to discuss study-related issues.
The investigator agrees to cooperate with the CRA(s) to ensure that any issues detected in
the course of these monitoring visits are resolved. If the participant is hospitalized or dies
in a hospital other than the study site, the investigator is responsible for contacting that
hospital in order to document the SAE, in accordance with local regulations.
A close-out visit will be performed for any initiated site when there are no more active
participants and all follow-up issues have been resolved. If a site does not enroll any
participants, the close-out visit may be performed prior to study database closure at the
discretion of the Sponsor.
12.9 Investigator Site File
Each site will be provided with an ISF prior to the SIV. It will contain all the essential
documents that are required to be up-to-date and filed at site as per ICH-GCP Section 8.
The ISF will include a table of contents listing the essential documents. All study-related
documentation must be maintained in the ISF.
In some cases, exceptions can be discussed with the CRA regarding the filing of the study
documents outside the ISF. It should be clearly documented where each document is filed.
This note to file should be present in the specific tab of the document in the ISF.
The ISF must be stored in a secure and access-restricted area during and after the study. It
must be kept by the site for as long as needed to comply with any applicable rules and
regulations, ICH-GCP, as well as instructions from the Sponsor. If the site needs to transfer
the ISF to another location and/or if site facility can no longer store the ISF, the PI must
immediately inform the Sponsor.
If the PI will change, or if the site will relocate, the CRA must be notified as soon as
possible.
12.10 Audit
The Sponsor’s Global Quality Management representatives may audit the investigator site
(during the study or after its completion). The purpose of this visit will be to determine the
investigator’s adherence to ICH-GCP, the protocol, and applicable regulations; adherence
to the Sponsor’s requirements (eg, standard operating procedures) will also be verified.
Prior to initiating this audit, the investigator will be contacted by the Sponsor to arrange a
time for the audit.
The investigator and site personnel must cooperate with the auditor(s) and allow access to
all study documentation (eg, participant records) and facilities.

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12.11 Inspections
Health authorities and/or IEC/IRBs may also conduct an inspection of this study (during
the study or after its completion) at the site.
Should an inspection be announced by a health authority and/or IEC/IRB, the investigator
must immediately inform the Sponsor (usually via the CRA) that such a request has been
made.
The investigator and site personnel must cooperate with inspector(s) and allow access to
all study documentation (eg, participant records) and study facilities.
12.12 Reporting of study results and publication
The Sponsor will post the key elements of this protocol and the summary of results on the
Sponsor’s Clinical Trial Register and, within the required timelines, on publicly accessible
databases (eg, clinicaltrials.gov, EU database), as required by law and regulation.
Study results will be documented in a CSR that will be signed by the Sponsor
representatives and the Coordinating Investigator (or PI for single-center studies).
In accordance with the Good Publication Practices and ethical practice, the results of the
study will be submitted for publication in a peer-reviewed journal. Study results can be
submitted for presentation at a congress before submission to a peer-reviewed journal.
The Coordinating Investigator and the Steering Committee, if any, will have the
opportunity to review the analysis of the data and to discuss the interpretation of the study
results with Sponsor personnel prior to submission  to a peer-reviewed journal or
presentation at a congress.
Authorship will be determined in accordance with the International Committee of Journal
Editors criteria, and be based on:
 Substantial contributions to the conception or design of the study, or the acquisition,
analysis, or interpretation of data; and
 Drafting of the publication or critical review for important intellectual content; and
 Providing final approval of the version to be published; and
 Agreement to be accountable for all aspects of the work in ensuring that questions
related to the accuracy or integrity of any part of the work are appropriately investigated
and resolved.
The list of authors of any publication of study results may include representatives of the
Sponsor and will be determined by mutual agreement.

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Any study-related publication written independently by investigators must be submitted to
the Sponsor for review at least 30 days prior to submission for publication or presentation
at a congress. Upon review, the Sponsor may provide comments, and may also request
alterations and/or deletions for the sole purpose of protecting its confidential information
and/or patent rights. Neither the institution nor the investigator should permit publication
during such a review period.

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13 REFERENCES
[Abman 2015] Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK, et al.
Pediatric Pulmonary Hypertension: Guidelines From the American Heart
Association and American Thoracic Society. Circulation. 2015;132(21):2037-2099.
[ATS 2002] ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care
Med 2002;166:111-117.
[Barst 1996] Barst RJ. Diagnosis and treatment of pulmonary artery hypertension. Curr
Opin Pediatr. 1996;8(5):512-519.
[Barst 1999] Barst RJ. Recent advances in  the treatment of pediatric pulmonary artery
hypertension. Pediatr Clin North Am. 1999;46(2):331-345.
[Barst 2010] Barst R. How has epoprostenol changed the outcome for patients with
pulmonary arterial hypertension? International Journal of Clinical Practice
Supplement. 2010;(168):23-32.
[Barst 2011] Barst RJ, Ertel SI, Beghetti M, Ivy DD. Pulmonary arterial hypertension: a
comparison between children and adults. Eur Respir J. 2011;37(3):665-677.
[Bédard 2009] Bédard E, Dimopoulos K, Gatzoulis MA. Has there been any progress made
on pregnancy outcomes among women with pulmonary arterial hypertension? Eur
Heart J 2009;30(3):256-265.
[Blondell 1999] Blondell RB, Foster MB, Dave KC. Disorders of puberty. Am Fam
Physician 1999;60:209-224.
[Chadha 2009] Chadha C, Pritzker M, Mariash CN. Effect of epoprostenol on the thyroid
gland: enlargement and secretion of thyroid hormone. Endocr Pract. 2009;15(2):116-
121.
[Clinical Study Report AC-065-101 2012] A single-center, randomized, placebo-
controlled, double-blind, multiple period, multiple-ascending dose study to assess the
safety, tolerability, pharmacokinetics, and pharmacodynamics of oral ACT-293987
in healthy male subjects (D-12.471). Actelion Pharmaceuticals Ltd;, 19July 2012.
[Clinical Study Report AC-065A302 (GRIPHON) 2014] A multi-center, double-blind,
placebo-controlled Phase 3 study assessing the efficacy and safety of selexipag
(ACT-293987) on morbidity and mortality in patients with pulmonary arterial
hypertension (PAH) (D-13.361). Actelion Pharmaceuticals Ltd, 2 October 2014.

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endorsed by ISHLT and DGPK. Heart 2016;102 Suppl 2:ii86-100.
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proteins and plasma/blood cell partitioning (Covance study no. 8203016) (B-09.318).
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girls. ArchDis Child. 1969;44(235):291-303.

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[Marshall 1970] Marshall WA, Tanner JM. Variations in Pattern of Pubertal Changes in
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pulmonary hypertension. What’s the link? Panminerva Medica. 2013;55(1):93-97.
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change in pulmonary arterial smooth muscle cells using impedance technology.(B-
14.046). Actelion Pharmaceuticals Ltd, 25 March 2014.
[Modeling and Simulation Report AC-065A302 (GRIPHON) 2014] Modeling and
Simulation Report: Population pharmacokinetics and pharmacodynamics of
Selexipag (D-14.470). Actelion Pharmaceuticals Ltd; 27 December 2014.
[Modeling and Simulation Report, Pediatric dose selection  2016] Exposure-based dose
selection for pediatric studies with selexipag based on the GRIPHON population
pharmacokinetic model (D-16.138). Actelion Pharmaceuticals Ltd, 29 April 2016.
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[Research Report ACT-333679 2014] Efficacy of ACT-333679 in the cAMP pathway
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16 September 2014.

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carboxylesterase 1 during the post-neonatal stage enables a rapid gain of the capacity
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product-information_en.pdf

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[van Loon 2011] van Loon RL, Roofthooft MT, Hillege HL, ten Harkel AD,
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Dispos. 2009;37(9):1819-1825.

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14 APPENDICES
14.1 Appendix 1 
WHO Functional Class
Class I 
Patients with pulmonary hypertension but without resulting limitation of
physical activity. Ordinary physical activity does not cause undue dyspnea or
fatigue, chest pain, or near syncope.
Class II 
Patients with pulmonary hypertension resulting in slight limitation of physical
activity. They are comfortable at rest. Ordinary physical activity causes undue
dyspnea or fatigue, chest pain, or near syncope.
Class III 
Patients with pulmonary hypertension resulting in marked limitation of
physical activity. They are comfortable at rest. Less than ordinary activity
causes undue dyspnea or fatigue, chest pain, or near syncope.
Class IV  Patients with pulmonary hypertension with inability to carry out any physical
activity without symptoms. These patients manifest signs of right heart failure.
Dyspnea and/or fatigue may be present even at rest. Discomfort is increased by
any physical activity.

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14.2 Appendix 2 
Panama Functional Class For Pediatrics
For children aged 2 5 years
Class I 
Asymptomatic, growing normally, attending nursery/school regularly, no
limitation of physical activity, playing sports with his/her classmates.
Class II 
Slight limitation of physical activity, unduly dyspnoeic and fatigued when
playing with his/her classmates. Comfortable at rest. Continues to grow along
own centiles. Nursery/school attendance 75% normal. No chest pain.
Class IIIa Marked limitation of physical activity. Regression of learned physical
activities. Not climbing stairs, reluctant to play with friends. Hesitant and
unadventurous. Comfortable at rest. Less than ordinary activity (eg, dressing)
causes undue dyspnea, fatigue, syncope and/or presyncope, or chest pain.
Nursery/schooling compromised < 50% normal attendance.
Class IIIb Unable to attend nursery/school, but mobile at home. Wheelchair needed
outside home. Growth compromised. Poor appetite. Supplemental feeding.
Less than ordinary activity causes undue fatigue, syncope or chest pain. Plus
features of Class IIIa.
Class IV  Unable to carry out any physical activity without undue dyspnea, fatigue,
syncope, or chest pain, unable to attend school, wheelchair dependent, not
interacting with friends. Syncope and/or right heart failure. Plus features of
Class III.
For children aged 5 16 years
Class I 
Asymptomatic, growing along own centiles, attending school regularly, no
limitation of physical activity, playing sports with his/her classmates.
Class II 
Slight limitation of physical activity, unduly dyspnoeic and fatigued when
playing with his/her classmates. Comfortable at rest. Continues to grow along
own centiles. School attendance 75% normal. No chest pain.
Class IIIa Marked limitation of physical activity. No attempt at sports. Comfortable at
rest. Less than ordinary activity causes undue dyspnea, fatigue, syncope, or
chest pain. Schooling compromised < 50% normal attendance.
Class IIIb Unable to attend school, but mobile at home and interacting with friends.
Wheelchair needed outside the home. Growth compromised. Poor appetite.
Supplemental feeding. Less than ordinary activity (eg, dressing) causes undue

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dyspnea, fatigue, syncope and/or presyncope, or chest pain. Plus features of
Class IIIa.
Class IV  Unable to carry out any physical activity without undue dyspnea, fatigue,
syncope, or chest pain, unable to attend school, wheelchair dependent, not
interacting with friends. Syncope and/or right heart failure. Plus features of
Class III.

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14.3 Appendix 3 
Palatability And Acceptability Of Selexipag
PALATABILITY QUESTIONNAIRE FOR SUBJECTS
1.
How much do you
like the taste of
this medicine?
Dislike
very
much
Dislike
a
little
Not
sure
Like
a
little
Like
very
much
2.
How easily can
you swallow this
medicine?
Very
difficult
Difficult 
OK 
Easy  
Very easy
3.
How much do you
like that this
medicine is taken
twice every day? 
Dislike
very
much
Dislike
a
little
Not
sure
Like
a
little
Like
very
much
4.
How easy is it to
remove the
medicine from the
packaging?
Very difficult 
Difficult 
OK 
Easy  
Very easy

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PALATABILITY QUESTIONNAIRE FOR CAREGIVERS/SITE PERSONNEL
1.
On the basis of
reaction/ facial
expression of
your child, how
much do you
believe your child
likes the taste of
this medicine?
Dislike
very
much
Dislike
a
little
Not
sure
Like
a
little
Like
very
much
2.
On the basis of
reaction/ facial
expression of
your child, how
easily can your
child swallow this
medicine?
Very difficult 
Difficult 
OK 
Easy  
Very easy
3.
How much do
you like that this
medicine is given
twice every day? 
Dislike
very
much
Dislike
a
little
Not
sure
Like
a
little
Like
very
much
4.
How easy is it to
remove the
medicine from the
packaging?
Very difficult 
Difficult 
OK 
Easy  
Very easy

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14.4 Appendix 4 
Child-Pugh Classification
The Child-Pugh classification will be used to assess the severity of the liver disease
according to the following table [adapted from FDA 2003 and Vincent 2012]:
Table 6 
Child Pugh Classification
Score
1 
2 
3
Total bilirubin (mg/dL) 
< 2.0 
2.0–3.0 
> 3.0
Serum albumin (g/dL) 
> 3.5 
2.8–3.5 
< 2.8
Ascites 
Absent 
Slight 
Moderate
Hepatic encephalopathy* 
Grade 0 
Grade 1–2 
Grade 3–4
Prothrombin time (seconds prolonged) 
< 4 
4–6 
> 6
Or
INR  
<1.7 
1.7 –2.2 
>2.2
*Hepatic encephalopathy scoring will be based on the following criteria:
• Grade 0: normal consciousness, personality, neurological examination, and electroencephalogram
• Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cycles per second waves
• Grade 2: lethargic, time disoriented, inappropriate, asterixis, ataxia, slow triphasic waves
• Grade 3: somnolent, stuporous, place disoriented, hyperactive reflexes, rigidity, slower waves
• Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2 3 cycles per second delta activity
 Class A: Score 5 6
 Class B: Score 7 9
 Class C: Score 10 15

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14.5 Appendix 5 
Tanner Scale
Illustrated by Michal Komorniczak (Poland)

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14.6 Appendix 6 
Echo/Doppler
The parameters will be assessed as per Echo image acquisition guidelines.

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14.7 Appendix 7 Sample Size Calculation Related To Dosing Scheme
Confirmation In Pediatric PK Study
TABLE OF CONTENTS
1 INTRODUCTION.....................................................................................................140
2 ANALYSIS ...............................................................................................................141
2.1 
Sample size calculations based on observed AUCτ,ss,combined (NCA
analysis)......................................................................................................141
2.2 
Sample size calculations based on clinical trial simulations (model-
based analysis)............................................................................................142
2.2.1 
Preparatory assessments based on the Fisher information
matrix..............................................................................................142
2.2.2 
Simulations .....................................................................................143
2.2.3 
Parameter estimation and assessment of exposure estimation
precision..........................................................................................144
3 DISCUSSION AND CONCLUSIONS.....................................................................147
4 REFERENCES..........................................................................................................149
5 ADDITIONAL TABLES..........................................................................................150

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LIST OF TABLES
Table 1 
Sample sizes for each age cohort based on a t-distribution for
log-transformed AUCτ,ss,combined..................................................................141
Table 2 
Assumed body weight ranges by age cohort..............................................143
Table 3 
Simulated doses for PK datasets.................................................................144
Table 4 
Prediction uncertainty of AUCτ,ss,combined based on simulated data for
children in Cohort 1 (≥ 12 to < 18 years) ...................................................146
Table 5 
Prediction uncertainty of AUCτ,ss,combined based on simulated data for
children in Cohort 1 (≥ 12 to < 18 years) and Cohort 2 (≥ 6 to < 12 years)
....................................................................................................................146
Table 6 
Prediction uncertainty of AUCτ,ss,combined based on simulated data for
children ≥ 1 to < 18 years of age (Cohorts 1, 2, and 3)..............................147
Table 7 
Relative standard error of parameter estimates based on simulated data for
children ≥ 12 of age (Cohort 1) ..................................................................150
Table 8 
Relative standard error of parameter estimates based on simulated data for
children ≥ 6 of age (Cohorts 1 and 2).........................................................151
Table 9 
Relative standard error of parameter estimates based on simulated data for
children ≥2 to < 18 years of age (Cohorts 1, 2, and 3)..............................152
LIST OF FIGURES
Figure 1 
Correlation of parameter estimates without body weight as covariate.......143

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LIST OF ABBREVIATIONS
AUCτ,ss 
Area under the plasma concentration vs time curve over one
dosing interval at steady-state
AUCτ,ss,combined 
Combined exposure over one dosing interval at steady-state
CL 
Clearance (selexipag)
df 
Degree of freedom
FIM  
Fisher information matrix
GRIPHON  
Prostacyclin (PGI2) Receptor agonist In Pulmonary arterial
HypertensiON (study acronym)
IIV  
Inter-individual variability
k12 
Transfer rate constant central to peripheral volume selexipag
k21 
Transfer rate constant peripheral to central volume selexipag
k34 
Transfer rate constant central to peripheral volume ACT-333679
k43 
Transfer rate constant peripheral to central volume ACT-333679
ka 
Absorption rate constant
km 
Elimination rate (ACT-333679)
kmet 
Metabolism rate constant selexipag to ACT-333679
N 
Sample size
NCA  
Non-compartmental analysis
PAH  
Pulmonary arterial hypertension
PK 
Pharmacokinetic(s)
RSE 
Relative standard error
Tlag 
Absorption lag time
Vm 
Volume of the central compartment for ACT-333679
Vp 
Volume of the central compartment for selexipag
α 
Significance level

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β 
Power
Δ 
Log-transformed fold-difference
σ 
Population standard deviation

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INTRODUCTION
In the revised Pediatric Investigation Plan, Actelion proposes to conduct a global Phase 3
pediatric study to demonstrate the safety and effectiveness of selexipag to treat pulmonary
arterial hypertension (PAH) in children from 2 years to less than 18 years of age. Dose
selection for this future study will be based on data from a pharmacokinetic (PK) study in
pediatric PAH patients. The analyses documented here aim to establish the sample size for
the PK study to provide sufficient confidence in the selection doses for the future study.
The selection of the starting dose for the first study of selexipag in children is aimed to
provide the same overall drug exposure in pediatrics than in adults, with gradual
up-titration according to individual tolerability. Starting doses have been calculated based
on body weight, using the adult population PK model obtained from the GRIPHON study
[Modeling and Simulation Report AC-065A302 (GRIPHON) 2014, Modeling and
Simulation Report, Pediatric dose selection 2016], to achieve the same exposure as the
starting selexipag dose for adults. Exposure is defined as the combined steady-state
exposure to selexipag and its ACT-333679 metabolite over one dosing interval
(AUCτ,ss,combined). The AUCτ,ss,combined is the sum of the selexipag and ACT-333679
exposures weighted by their potency ratio. The data collected in the pediatric study phase
2 will be used to confirm or adjust the selection of the selexipag starting dose for the Phase
3 study.
The participants will be enrolled in the PK study in three age cohorts starting with
participants of 6 years and older, i.e., with Cohort 1. After an interim analysis of the data
from Cohorts 1 and 2, the children of Cohort 3 (≥2 to < 6 years of age) will be included in
the study. The model-based interim analysis will confirm or potentially adjust the selection
of the starting doses for the last cohort.
For each pediatric participant, a PK profile (pre-dose, 1, 2, 4, 6, 8, and 12 hours after
dosing) will be assessed either at the starting dose or at Week 12 at which the individual
maximum tolerated dose for each participant must be finally determined. In addition,
3 trough samples will be taken at intermediate doses at steady state.
The sample size per cohort of pediatric participants (≥ 12 to < 18 years, ≥ 6 to < 12 years,
≥2 to < 6 years) is evaluated based on the precision to predict the AUCτ,ss,combined expressed
as -fold over the median. Two approaches of sample size calculations were performed
depending on the method used to analyze the PK data obtained. First, the sample size per
age cohort was calculated based on a t-distribution of the log-transformed observed
AUCτ,ss,combined values, obtained by the non-compartmental analysis (NCA) method.
Second, clinical trial simulations using the GRIPHON population PK model [Modeling
and Simulation Report AC-065A302 (GRIPHON) 2014] were performed and the
uncertainty to estimate the model parameters and predict the AUCτ,ss,combined was

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determined. These trial simulations were performed for planned interim analyses and the
final analysis using the pooled data from all age cohorts.
Analysis
14.7.2.1 Sample size calculations based on observed AUCτ,ss,combined  (NCA analysis)
Based on each patient’s profile, the AUCτ,ss,combined can be derived by NCA and normalized
to the dose the patient received when the profile was assessed. The sample size should be
large enough to determine the mean exposure of an age cohort with sufficient precision.
Assuming a t-distribution for the log-transformed AUCτ,ss,combined values, sample sizes can
be calculated as the minimal number N for which the following equation holds true:
 ≥  ∙     ,
⁄
+     ,
⁄

 
Δ 
where t is the quantile of the t-distribution [Bock 1998] with a  =  −1 as the degree
of freedom. The significance level α and the power β are set to 5% and 80%, respectively.
The population standard deviation σ is assumed to be equal to the standard deviation of the
log-transformed AUCτ,ss,combined for the adult PAH patients in GRIPHON study, i.e., 0.6,
and the difference Δ to be detected is the log-transformed fold difference. Table 1 shows
the sample sizes for different fold differences. To detect a 1.4 fold-difference as suggested
by a draft FDA guideline [FDA 2014], the required sample size of 30 participants is
infeasible for a PK study considering the rareness of pediatric PAH. However, a sample
size of 10 participants per age group would still be able to detect a 2-fold difference.
Table 1 
Sample sizes for each age cohort based on a t-distribution for
log-transformed AUCτ,ss,combined
Fold difference 
Sample size based on Bock 1998
1.4 
30
1.75 
15
2 
10

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14.7.2.2 Sample size calculations based on clinical trial simulations (model-based
analysis)
A PK study with 15 patients in Cohort 1 and Cohort 2, respectively, and 10 patients in
Cohort 3 was evaluated in a model-based approach by clinical trial simulations. According
to the analysis based on observed AUCτ,ss,combined described above, prediction uncertainties
would be limited to 1.75- to 2-fold. Considering the rareness of pediatric PAH higher
participant numbers do not seem reasonable. Using a model-based approach that pools data
from all cohorts and adds PK information from adult PAH participants, the acquired PK
data can be utilized better.
14.7.2.2.1Preparatory assessments based on the Fisher information matrix
Before performing clinical trial simulations, the identifiability of the model parameters and
an estimate on required sample sizes were assessed based on the Fisher information matrix
(FIM). The FIM was derived using PFIM, an R-based software to assess the FIM for
population PK models [Bazzoli 2010].
Model parameters were set to the estimates obtained in the GRIPHON population PK
analysis. The absorption time lag (Tlag) was not included in order to simplify the model
implementation in PFIM. This has no effect on the results regarding the identifiability of
parameters that impact the AUC, since the time lag only constitutes a time shift.
Up-titration to the third dose level with predicted equivalent exposure to 600 μg b.i.d. in
adults was assumed. A PK sampling scenario was evaluated, which considered trough
samples on steady state of the first and second dose level and a PK profile (pre-dose and 1,
2, 4, 6, and 8 hours after dosing) on the third level. Although this scenario does not exactly
mimic the planned sampling strategy, it is similar enough to generally assess parameter
identifiability of the model.
Parameter identifiability was assessed based on a sample size of 25 subjects. When
estimating all parameters (typical values and inter-individual variability [IIV]), the
parameter correlation matrix showed high correlations between some parameters: k34 and
km, Vm and kmet, k21 and Vm, k21 and kmet, CL and k21, CL and Vm, and CL and kmet.
Consequently, CL, k21, Vm, and kmet have high estimation errors (> 400%). Since highly
correlated parameters are mutually non-identifiable, it was decided to fix k21, kmet, and k34.
The choice was based on the principle of not fixing parameters with body weight as
covariate in the GRIPHON model.

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Figure 1 
Correlation of parameter estimates without body weight as covariate
Left: estimated correlation matrix of population parameters; right: estimated correlation matrix of inter individual
variability.
14.7.2.2.2Simulations
PK datasets (N
100) for pediatric patients were simulated based on the GRIPHON
population PK model. Body weight ranges for each age cohort were derived from the
5th and 95th  percentile of body weights observed in the corresponding age cohorts in
registries of pediatric PAH patients [Table 2] [Ploegstra 2016]. Body weights were sampled
from a beta distribution with shape factor 2. Starting and maximum allowed doses were
defined based on the body weight as planned for the study [Table 3].
Table 2 
Assumed body weight ranges by age cohort
Age cohort 
Body weight range
≥ 2 to < 6 years 
10 24 kg
≥ 6 to < 12 years 
15 55 kg
≥ 12 to < 18 years 
28 90 kg
Steady-state PK profile concentrations (pre-dose, 1, 2, 4, 6, 8, and 12 hours post-dose) were
simulated for half of the patients within an age cohort at a low dose and for the other at a
high dose. The low dose was the next dose level after the starting dose and the high dose

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was the maximum allowed dose. In the study, steady-state profiles will be assessed at the
starting dose and the individual maximum tolerated dose at Week 12. Hence, profiles will
be obtained at a range of doses that is not pre-defined, but a result of the up-titration.
However, since the PK is dose-proportional, a PK profile contains the same amount of
information irrespective of the dose given (as long as the PK is in the quantifiable range of
the PK assay). The simulated data was therefore considered representative of the data that
will be generated in the study.
Table 3 
Simulated doses for PK datasets
Body weight 
Starting dose 
Low dose simulated  
High dose simulated
≥ 9 to < 25 kg 
100 μg 
200 μg 
800 μg
≥ 25 to < 50 kg 150 μg 
300 μg 
1200 μg
≥ 50 kg 
200 μg 
400 μg 
1600 μg
PK  pharmacokinetic.
14.7.2.2.3Parameter estimation and assessment of exposure estimation precision
To assess exposure estimation, precision evaluations of 3 scenarios have been performed,
which are a first PK interim analysis including data from Cohort 1, a second PK interim
analysis including data from Cohort 1 and Cohort 2, and a final analysis including data
from all cohorts.
Based on simulated datasets for each scenario, model parameters were estimated and
relative standard errors were obtained using standard pharmacometric software (Monolix).
AUCτ,ss,combined values were predicted by simulations with sampling from the parameter
estimate covariance matrix. Subjects with body weights of 17, 35, and 59 kg were
simulated 1000 times respectively to assess how well the AUCτ,ss,combined can be predicted
for patients with different body weights, i.e., ages. These body weights corresponded to the
middle weight of the range assumed for each age category. The ratio of the 95th percentile
to the median and of the median to the 5th  percentile is reported as the AUCτ,ss,combined
prediction uncertainty.
As in the GRIPHON population PK model, body weight was included as covariate on CL,
Vp, and Vm. In all estimations, k21, k34, and kmet were kept fixed to the GRIPHON parameter
values. When estimating the IIV for all parameters, the IIV for Vp, k12, k21, Vm, kmet, k34,
and k43 tended to zero and were fixed at 10% in all estimations.

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14.7.2.2.3.1 
First and second PK interim analysis
The two PK interim analyses were evaluated using simulated PK data for Cohort 1 and for
Cohort 1 and Cohort 2 respectively. Since drug absorption and metabolism is comparable
to adults and the body weight ranges of both cohorts overlap with the range of patients in
the GRIPHON study (i.e., 40 148 kg), it was considered acceptable to fix CL, Vm, and Vp
to the values estimated based on the GRIPHON data. Nevertheless, the body weight effects
on these parameters would be re-estimated during the first PK interim analysis. Using this
estimation approach, parameters were estimated for the 100 simulated datasets.
For the first interim analysis, estimation errors for population parameters are limited
(median RSEs below 50%), but are high for the covariate effects on CL, Vm, and Vp
(median RSEs up to 100%) [Table 7]. Note that the analysis of this first PK analysis was
performed with a different version of Monolix and using different analysis post-processing
tools. This led to a different implementation of the IIV of Tlag, which was fixed in the new
analysis. As Tlag has no impact on the AUCτ,ss,combined this was judged acceptable.
For the second interim analysis, the median estimation error for the model parameters was
not exceeding 60% and often below 30% [Table 8]. However, for some simulated datasets,
the estimation errors were very high for the IIV on the absorption rate constant ka and the
elimination rate constant of the metabolite km and the effect of body weight on clearance
CL.
Based on the parameter estimation uncertainty, the resulting uncertainty of AUCτ,ss,combined
predictions was assessed. For the first interim analysis only body weights of 35 and 59 kg
were assessed as children in the first cohort have body weight considerably higher than
17 kg. Although estimation errors for some parameters were high, the uncertainty of the
AUC prediction was well below 1.4-fold on average [Table 4]. At the second interim
analysis, for children at body weights of 35 and 59 kg, the prediction uncertainty of
AUCτ,ss,combined was on average 1.2 1.3-fold across all simulated datasets [Table 5]. The
uncertainty is higher for lower body weight, but still limited on average. The high
estimation error for the body weight effect on the clearance is probably the reason why the
maximal uncertainty for lower body weights is high (3.34 for a body weight of 17 kg).

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Table 4 
Prediction uncertainty of AUCτ,ss,combined  based on simulated data for
children in Cohort 1 (≥ 12 to < 18 years)
Body weight (kg) 
AUCτ,ss,combined prediction uncertainty (fold)
median  
mean  
min  
max
35 
1.22 
1.22 
1.11 
1.42
59 
1.22 
1.23 
1.11 
1.42
AUCτ,ss,combined  Combined exposure over one dosing interval at steady state.
Table 5 
Prediction uncertainty of AUCτ,ss,combined  based on simulated data for
children in Cohort 1 (≥ 12 to < 18 years) and Cohort 2 (≥ 6 to < 12
years)
Body weight (kg) 
AUCτ,ss,combined prediction uncertainty (fold)
median  
mean  
min  
max
17 
1.84 
1.9 
1.54 
3.34
35 
1.33 
1.35 
1.21 
1.65
59 
1.19 
1.20 
1.13 
1.53
AUCτ,ss,combined  Combined exposure over one dosing interval at steady state.
14.7.2.2.3.2 Final PK analysis
In the final analysis, model parameters were estimated using the pooled data from all age
cohorts. Compared to the second interim analysis, the youngest age cohort (≥ 1 to
< 2 years) was added to the analysis dataset and all parameters besides the non-identifiable
ones were estimated.
Parameters could be estimated well when pooling data from all age cohorts. The median
estimation errors were < 45% for all parameters [Table 9]. For some simulated datasets,
the estimation error for the IIV on Km and the body weight effect on the clearance were
high. The resulting AUCτ,ss,combined prediction uncertainty was on average below 1.4-fold
for subjects of 17, 35 and 59 kg [Table 6]. Although the body weight effect on the clearance
had high estimation error in some runs, the maximal prediction uncertainty was only 1.6.

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Table 6 
Prediction uncertainty of AUCτ,ss,combined  based on simulated data for
children ≥ 1 to < 18 years of age (Cohorts 1, 2, and 3)
Body weight (kg) 
AUCτ,ss,combined prediction uncertainty (fold)
median  
mean  
min  
max
17 
1.38 
1.39 
1.23 
1.60
35 
1.23 
1.23 
1.14 
1.34
59 
1.34 
1.34 
1.19 
1.61
AUCτ,ss,combined  Combined exposure over one dosing interval at steady state.
DISCUSSION AND CONCLUSIONS
The sample size for a PK study in pediatric PAH patients was assessed based on two
approaches. First, a number of subjects per age group was suggested considering exposure
determination using NCA. Second, the suggested sample size was evaluated based on
clinical trial simulations and model-based analysis as planned for dose
selection/confirmation for the following Phase 3 study.
The first analysis suggested that 10 and 15 patients per age group are sufficient to determine
the exposure up to a precision of a 2-fold and 1.75-fold difference respectively.
Considering the rareness of pediatric PAH and that the final dose will be determined based
on up-titration this sample size seems reasonable. It should also be noted that the main
objective of the pediatric program is to demonstrate safety and efficacy of PAH treatment
with selexipag in the Phase 3 study.
In the second analysis, the GRIPHON population PK model was used to perform clinical
trial simulations for the planned pediatric study. PK parameters were re-estimated based
on the simulated data. The prediction uncertainty for AUCτ,ss,combined was used to evaluate
with which precision the exposure can be predicted based on a model-based analysis of the
PK data obtained from the PK study.
Two PK interim analyses in the study will be performed considering the PK data when all
children older than 12 years (i.e., Cohort 1) and older than 6 years (i.e., Cohorts 1 and 2)
concluded the study. According to the analysis described above, data from 15 patients in
each cohort will provide a good estimate of the AUCτ,ss,combined when accounting for the
information in adults.
At the first interim analysis, it will allow for confirming the doses for Cohort 1 with 1.4-fold
precision. However, as the modeling of simulated datasets showed high estimation errors

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for some of the parameters depending on the acquired data quality, additional patients may
need to be enrolled into Cohort 1.
The data at the second interim analysis are estimated to be sufficient for confirming the
doses for Cohort 2 with approx. 1.4-fold precision and for Cohort 3 with approx. 2-fold
precision.
For the final analysis, the data across all age cohorts will be pooled. All identifiable
parameters will be estimated. Data from 10 patients from Cohort 3 (≥ 2 to < 6 years) in
addition to the 2 older age cohorts limit the fold change from the 95th percentile to median
and the median to the 5th percentile to 1.4 on average.
The PK analyses performed during and after the study will also use the trough samples of
intermediate dose levels, which were not considered in the sample size calculations.
The estimated uncertainty to determine the exposure is lower for the model-based analysis
as compared to assessing the exposure by NCA. A sample size of 15 participants per age
group as suggested by the first sample size assessment is, hence, reinforced based on
clinical trial simulations. Data from the currently planned PK study with 40 participants in
total will most likely provide a solid basis for staggered dose selection for each age cohort
for the Phase 3 study.
At interim analyses, the sample size calculation will also be revised based on the obtained
pediatric PK data and using adult data in a Bayesian approach. Confidence on the sample
size calculation is increased at that stage as pediatric PK information will be available
potentially giving the possibility to even reduce the sample size. As pediatric PAH is a rare
disease, limiting the sample size is crucial for a feasible pediatric development program.

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REFERENCES
[Bazzoli 2010] Bazzoli, C., S. Retout, and F. Mentre, Design evaluation and optimisation
in multiple response nonlinear mixed effect models: PFIM 3.0. Comput Methods
Programs Biomed. 2010;98(1);55-65.
[Bock 1998] Bock, J., Bestimmung des Stichprobenumfangs für biologische Experimente
und kontrollierte klinische Studien. 1998: R. Oldenbourg Verlag.
[Driscoll 1999] Driscoll DJ. Left-to-right shunt lesions. Pediatr Clin North Am. 1999
Apr;46(2):355-368.
[FDA 2014] General clinical pharmacology considerations for pediatric studies for drugs
and biological products. Guidance for Industry (draft), U.S. Food and Drug
Administration. 2014. available at: http://www.fda.gov/ucm/groups/fdagov-
public/@fdagov-drugs-gen/documents/document/ucm425885.pdf
[Modeling and Simulation Report AC-065A302 (GRIPHON) 2014] Modeling and
simulation report. Population pharmacokinetics and pharmacodynamics of Selexipag
(D-14.470). Actelion Pharmaceuticals Ltd; 27 December 2014.
[Modeling and Simulation Report, Pediatric dose selection 2016 ] Exposure-based dose
selection for pediatric studies with selexipag based on the GRIPHON population
pharmacokinetic model (D-16.138). Actelion Pharmaceuticals Ltd; 29 April 2016.
[Ploegstra 2016] Ploegstra, M.J., et al. Growth in children with pulmonary arterial
hypertension: a longitudinal retrospective multiregistry study. Lancet Respir Med.
2016 Apr;4(4):281-901.

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ADDITIONAL TABLES
Table 7 
Relative standard error of parameter estimates based on simulated
data for children ≥ 12 of age (Cohort 1)
Parameter 
Relative standard error (%)
Mean  
Median  
Min  
Max
Tlag 
10.51 
10.10 
8.07 
16.86
ka 
12.68 
13.06 
8.17 
22.71
k12 
27.43 
27.57 
19.83 
36.15
k43 
43.14 
37.29 
18.73 
112.39
km 
11.78 
11.78 
6.91 
16.16
Body weight on CL 
420.62 
97.84 
34.02 
7280.03
Body weight on Vm 
131.62 
68.50 
22.82 
853.12
Body weight on Vp 
103.53 
66.18 
19.64 
473.75
ω(CL) 
25.03 
23.55 
16.24 
54.26
ω(ka) 
28.27 
26.42 
17.03 
49.94
ω(km) 
71.33 
32.26 
20.71 
467.92
Proportional residual error selexipag 
7.38 
7.32 
6.31 
8.87
Proportional residual error ACT-333679 
7.34 
7.30 
6.52 
8.61

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Table 8 
Relative standard error of parameter estimates based on simulated
data for children ≥ 6 of age (Cohorts 1 and 2)
Parameter 
Relative standard error (%)
Mean  
Median  
Min  
Max
Tlag 
40.59 
34.98 
15.27 
122.28
ka 
10.04 
10.24 
6.00 
13.70
k12 
29.35 
29.27 
16.99 
41.73
k43 
44.20 
40.47 
22.67 
123.20
km 
12.31 
12.24 
8.75 
17.36
Body weight on CL 
139.95 
58.67 
26.21 
2742.56
Body weight on Vm 
60.76 
51.34 
21.65 
341.43
Body weight on Vp 
54.83 
47.80 
22.86 
224.99
ω(CL) 
18.49 
17.09 
13.28 
77.67
ω(ka) 
>1000 
23.81 
15.03 
>1000
ω(km) 
>1000 
25.72 
18.39 
>1000
ω(Tlag) 
24.16 
23.24 
16.18 
36.99
Proportional residual error selexipag 
6.28 
6.32 
3.86 
7.12
Proportional residual error ACT-333679 
6.58 
6.58 
5.75 
7.27

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Table 9 
Relative standard error of parameter estimates based on simulated
data for children ≥2 to < 18 years of age (Cohorts 1, 2, and 3)
Parameter 
Relative standard error (%)
Mean  
Median  
Min  
Max
Tlag 
38.31 
34.20 
17.17 
149.85
ka 
8.98 
9.06 
6.19 
11.26
CL 
32.01 
31.35 
23.57 
46.65
Vm 
43.27 
42.50 
28.62 
73.04
Vp 
43.80 
43.43 
27.40 
71.80
k12 
40.50 
40.67 
26.01 
63.93
k43 
35.76 
34.47 
23.90 
60.84
km 
14.41 
14.52 
12.05 
17.19
Body weight on CL 
82.68 
41.76 
20.44 
1417.01
Body weight on Vm 
39.00 
35.03 
20.86 
108.16
Body weight on Vp 
33.69 
31.94 
19.72 
78.48
ω(CL) 
14.38 
14.03 
12.17 
20.86
ω(ka) 
20.01 
18.17 
12.97 
50.27
ω(km) 
>1000 
22.72 
15.70 
>1000
ω(Tlag) 
19.12 
18.86 
13.04 
29.09
Proportional residual error selexipag 
5.20 
5.22 
3.92 
5.69
Proportional residual error ACT-333679 
5.42 
5.45 
4.95 
5.73

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14.8 Appendix 8 
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is
located directly before the Table of Contents. A summary of previous amendments is
provided below.
Amendment 
Date 
Main reason(s)
1 
17 September 
2018 
Various 
clarifications 
on 
eligibility 
and
discontinuation criteria, and corrections of mistakes.
2 
1 March 2019 
 Addition of the option to dispense 50 g tablets
only.
 Addition of the systematic collection of signs and
symptoms of right heart failure and events of
disease progression.
 Correction of mistakes.
3 
6 May 2019 
 Dispersion of tablets in water was prohibited.
Only patients able to swallow tablets whole with
water can be enrolled.
4 
18 March 2020 
 Additional treatment administration option with
soft food.
 Sample size increase in Cohort 3.
COVID-19 
Appendix 
Version 1
16 June 2020 
To provide a guidance on study conduct during the
COVID-19 pandemic
5 
05 October 2020 
To reflect updates in safety reporting process.
6 
19 May 2021 
The main reason for the amendment was to add
alternative options for administration of study
intervention and implement other minor corrections.
COVID-19 
Appendix 
Version 2 
19 May 2021 
To implement updates about ‘Study conduct related to
COVID-19 vaccine deployment for non-COVID-19
clinical trials’ per Medicines and Healthcare products
Regulatory Agency (MHRA) vaccination guidance.

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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where
required):
Name (typed or
printed):
Institution and
Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical
Officer:
Name (typed or printed): 
Institution: 
Actelion Pharmaceutical Ltd and Janssen Research and Development,
a Division of Janssen Pharmaceutica NV
Signature: 
[electronic signature appended at the end of the protocol] 
Date:
(Day Month Year)
Note: 
If the address or telephone number of the investigator changes during the course of the study, written
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be
required.
PPD

Signature
User 
Date 
Reason
 
05-Oct-2021 
15:58:12
(GMT)
Document Approval
PPD

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1
Status: Approved, Date: 19 May 2021
Actelion Pharmaceuticals Ltd
Janssen Research & Development*
Clinical Protocol
COVID-19 Appendix
Protocol Title
A prospective, multicenter, open-label, single-arm, Phase 2 study to investigate the safety, 
tolerability and pharmacokinetics of selexipag in children with pulmonary arterial hypertension
Protocol AC-065A203; Phase 2
JNJ-67896049 / ACT-293987 (selexipag)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Actelion Pharmaceuticals Ltd ; Janssen Biotech, Inc.; Janssen
Products, LP; Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica
NV; Janssen Sciences Ireland UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC,.
The term “sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is
identified on the Contact Information page that accompanies the protocol.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).]
EudraCT NUMBER:
2018-000145-39
Status:
Approved
Date:
19 May 2021
Prepared by:
Actelion Pharmaceuticals Ltd, a division of Janssen Research & Development
EDMS number:
EDMS-RIM-263660, 5.0
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or otherwise.
NCT03492177

COVID-19 Appendix
JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065A203
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 19 May 2021
COVID-19 APPENDIX
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants and 
study-site personnel; travel restrictions/limited access to public places, including hospitals; study 
site personnel being reassigned to critical tasks. 
In alignment with recent health authority guidance, the sponsor is providing options for study 
related participant management in the event of disruption to the conduct of the study. This guidance 
does not supersede any local or government requirements or the clinical judgement of the 
investigator to protect the health and well-being of participants and site staff. If, at any time, a 
participant’s safety is considered to be at risk, study intervention will be discontinued, and study 
follow-up will be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent 
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each 
contact, participants will be interviewed to collect safety data. Key efficacy endpoint assessments 
should be performed if required and as feasible. Participants will also be questioned regarding 
general health status to fulfill any physical examination requirement. 
Every effort should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow up. Modifications to protocol-required assessments may be 
permitted via COVID-19 Appendix after consultation with the participant, investigator, and the 
sponsor. Missed assessments/visits will be captured in the clinical trial management system for 
protocol deviations. Discontinuations of study interventions and withdrawal from the study should 
be documented with the prefix “COVID-19-related” in the case report form (CRF). 
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance.  
If a participant has tested positive for COVID-19, the investigator should contact the sponsor’s 
responsible medical officer to discuss plans for study intervention and follow-up. Modifications 
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the 
clinical study report.
GUIDANCE SPECIFIC TO THIS PROTOCOL
In relation to Protocol Section 4.3 (Inclusion criterion #7), urine pregnancy tests for females of 
childbearing potential may be shipped from the site to the subjects’ home, in case a re-supply via 
site-visit is not possible.
In relation to Protocol Section 5.1.6 (Study treatment supply), for subjects unable to visit the 
clinic/hospital, direct-to-patient (DTP) shipment of study drugs may be implemented, where 
allowed per local regulations and if requested by the treating study physician. Where DTP 

COVID-19 Appendix
JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065A203
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved, Date: 19 May 2021
shipments are deemed necessary, the process should be coordinated between the site and sponsor 
staff following the “COVID-19 DTP Guidance Document”.
In relation to Protocol Section 12.3 “Informed Consent”, consenting and re-consenting of subjects 
will be performed as applicable for the measures taken (including remote consenting by phone or 
video consultation) and according to local guidance for informed consent as applicable.  
STUDY CONDUCT RELATED TO COVID-19 VACCINE DEPLOYMENT FOR 
NONCOVID-19 CLINICAL TRIALS

Study participants can undergo a COVID-19 vaccination procedure in compliance with 
applicable local governmental regulations. 

No pharmacokinetic interaction between the study intervention and currently available 
COVID-19 vaccines are expected. In addition, based on the mechanism of action of the study 
intervention and COVID-19 vaccines, no relevant interaction is expected. 

Any COVID-19 vaccine administered to a study participant is considered a concomitant 
medication and should be reported on the electronic case report form (eCRF). 

For serious adverse events (SAEs) reported after COVID-19 vaccination, the investigator 
should provide narrative details on the SAE form to allow adequate assessment of causality
relationship between the reported SAE and vaccination. This is particularly relevant in cases 
where the reported SAE is an expected event with the study intervention and the COVID-19 
vaccine. If the event is serious and considered to be related to both the COVID-19 vaccine 
and the study intervention, it is a serious adverse reaction and expectedness must be assessed. 
Suspected unexpected serious adverse reaction (SUSAR) reporting will be performed if the 
serious adverse reaction is unexpected as per applicable reference safety document.