Clinical trial NCT04435782
Conditions: Pulmonary Arterial Hypertension
Keywords: Right ventricle Reverse remodeling Magnetic resonance Imaging
Sponsor: Actelion
Start date: 2021-07-07; Completion date: 2023-07-28
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to assess the effects of selexipag on right ventricular (RV) function in participants with Pulmonary arterial hypertension (PAH).

Detailed description:

Arms: arm 1: Participants will receive JNJ-67896049 tablets at a starting dose of 200 mcg on Day 1. Dose will be up-titrated from Day 1 to the end of Week 12 (Day 84) to determine individual maintenance dose (IMD). Then, participants will receive JNJ-67896049 tablets at their IMD from Week 13 to Week 52.
Interventions: intervention 1: JNJ-67896049
Intervention descriptions: intervention 1: Participants will receive tablets at a starting dose of 200 mcg on Day 1. Dose will be up-titrated from Day 1 to the end of Week 12 (Day 84) to determine individual maintenance dose (IMD). Then, participants will receive JNJ-67896049 tablets at their IMD from Week 13 to Week 52.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date: 25 March 2022
Actelion Pharmaceuticals Ltd*
(a Janssen Pharmaceutical Company of Johnson & Johnson)
Clinical Protocol
Protocol Title
A PRospective, Multicenter, Single-arm, Open-label, Phase 4 Study of the Effects of
Selexipag on RighT Ventricular RemOdeling in Pulmonary Arterial Hypertension
Assessed by Cardiac Magnetic REsonance Imaging (RESTORE)
Selexipag MRI Study
Protocol 67896049PAH4005 (Amendment 3); Phase 4
ACT-293987 / JNJ-67896049 (selexipag)
* Actelion Pharmaceuticals Ltd (“Actelion”) is a global organization that operates through different legal
entities in various countries/territories. 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.
United States sites of this study will be conducted under United States Food & Drug
Administration Investigational New Drug regulations (21 CFR Part 312).
EudraCT NUMBER: 2019-004783-22
Status: 
Approved
Date: 
25 March 2022
Prepared by: Actelion Pharmaceuticals Ltd and Janssen Research & Development, a division of
Janssen Pharmaceutica NV
EDMS number: 
EDMS-RIM-265483, 5.0
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.
NCT04435782


ACT-293987 / JNJ-67896049 (selexipag) 
Clinical Protocol 67896049PAH4005 (Amendment 3)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved,  Date: 25 March 2022
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 3 
25-Mar-2022
Guidance on Study Conduct During A Natural 
Disaster/Major Disruption/Pandemic
(EDMS-RIM-265584, 4.0)
25-Mar-2022
Amendment 2 
08-Jan-2021
COVID-19 Appendix (EDMS-RIM-265584, 3.0) 
09-Nov-2020
Amendment 1 
20-Feb-2020
Original Protocol 
18-Nov-2019
Amendment 3 (25 March 2022)
Overall Rationale for the Amendment: The overall reasons for this protocol amendment are 1) to clarify
selected inclusion and exclusion criteria to better define the target population that may benefit from the
study intervention and 2) to clarify the definition of end of study (EOS) for the participants continuing
selexipag treatment in a continued access program. In addition, small editorial revisions and corrections
were made.
A Protocol Amendment Summary of Changes Table for the current amendment is provided below. The
updates are indicated in bold text and strikethrough for the deleted text. Changes made in previous protocol
amendments are listed in Section 10.10 Appendix 10: Protocol Amendment History.
Section Number 
and Name
Description of Change 
Brief Rationale
Protocol Title; 
1.1 Synopsis 
To define the acronym “RESTORE”, the protocol 
title has been updated with capitalization of relevant 
letters and without any content change from “A
Prospective, Multicenter, Single-Arm, Open-Label,
Phase 4 Study of the Effects of Selexipag on Right
Ventricular Remodeling in Pulmonary Arterial
Hypertension Assessed by Cardiac Magnetic
Resonance Imaging (RESTORE)” to “A
PRospective, Multicenter, Single arm, Open-label,
Phase 4 Study of the Effects of Selexipag on RighT
Ventricular RemOdeling in Pulmonary Arterial
Hypertension Assessed by Cardiac Magnetic
REsonance Imaging (RESTORE)”.
To define the acronym
‘RESTORE’.
1 Protocol Summary
(1.1 Synopsis
[Exploratory
Evaluations]);
4.2 Scientific Rationale
for Study Design;
8.3.6 Biomarkers;
10.2. Appendix 2:
Clinical Laboratory
Tests; Biomarkers)
Clarified the timepoint for exploratory biomarker
evaluation by addition of text ‘at study level’.
To concise wording to
differentiate end of study (EOS)
at the study level from EOS at
the participant level.


ACT-293987 / JNJ-67896049 (selexipag) 
Clinical Protocol 67896049PAH4005 (Amendment 3)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
3
Status: Approved,  Date: 25 March 2022
Section Number 
and Name
Description of Change 
Brief Rationale
1 Protocol Summary 
(1.1 Synopsis 
[Benefit-risk 
Assessment]) 
Added a new section: 
BENEFIT-RISK ASSESSMENT  
Based on the available data and proposed safety
measures, the overall benefit/riskassessment for
this clinical study is considered acceptable for
the following reasons:
 
Efficacy and safety of selexipag have been
established in PAH.
 
Only participants who meet all inclusion
criteria and none of the exclusion criteria
(specified in this protocol) will be allowed to
participate in this study. The selection
criteria include adequate provisions to
minimize the risk and protect the
well-being of participants in the study.
 
Safety will be closely monitored throughout
the study.
 
Several safety measures are included in this
protocol to minimize the potential risk to
participants, including the following:
 
Participants will interrupt or discontinue
study intervention for the protocol-allowed
reasons.
It is the investigator’s responsibility to monitor
the individual risk-benefit ratio of study
intervention administration, as well as the degree
of distress caused by study procedures at an
individual participant level, and to discontinue
study intervention or the study if, on balance,
investigator believes that continuation would be
detrimental to the participants’ well-being.
To align with latest protocol
template guidance.
1 Protocol Summary 
(1.1 Synopsis 
[Description of 
Interventions]) 
Added text: 
Study intervention: Open-label selexipag will be 
provided as round, film-coated tablets for oral
administration.
To align with latest protocol
template guidance.
1.2 Schema; 
1.3 Schedule of 
Activities 
Added a new footnote: 
For participants who complete treatment in the 
RESTORE study and who are entering another 
open-label clinical study with selexipag, the EOS  
visit is defined as the EOT visit. The enrollment
in the other open-label clinical study with
selexipag must occur on the day of the last visit
in the RESTORE study.
To define EOS=end of
treatment (EOT) for participants
who enter into an open-label
clinical study with selexipag.
1.2. Schema 
Updated the Figure 1 Schematic Overview of the 
Study to indicate that the EOS visit as a phone call 
instead of a site visit by removal of the symbol for
site visit.
To correct an error in the figure
aligning it with Table 1.
1.3 Schedule of 
Activities 
Table was updated to include information about 
‘Target study days’ for all scheduled visits till 
EOS.
To mark the exact study day for
each visit.
1.3 Schedule of 
Activities 
(Footnote “l”) 
Changed the footnote reference "l" for study 
procedure “Participant’s Experience” to "m". 
To rectify the error from
previous approved version of
global protocol amendment.


ACT-293987 / JNJ-67896049 (selexipag) 
Clinical Protocol 67896049PAH4005 (Amendment 3)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Status: Approved,  Date: 25 March 2022
Section Number 
and Name
Description of Change 
Brief Rationale
1.3 Schedule of 
Activities 
(Footnote “r”) 
Updated the footnote ‘r’: 
In case of an epidemic situation or major 
disruptions, eg, COVID-19, the Week 26 visit may 
be delayed up to an additional 28 days (Week 26 
+6/-2 weeks). 
For consistency with the
information in Appendix
‘Guidance on Study Conduct
During Natural Disaster/Major
Disruption/Pandemic’.
2.1. Study Rationale 
Updated the text with addition of a relevant 
reference: 
The interim and final results of this study have 
emphasized the relevance of magnetic resonance
imaging (MRI) in assessing cardiac changes with
PAH treatment.25,37
Final results have been
published since the last protocol
amendment.
4.1 Overall design 
(Day 1) 
Modified the text: 
First dosing should occur in the evening of Day 1 
at the site. 
To clarify that the first dose
should be taken in the evening
to improve tolerability and to
obtain an approximate 12-hour
dosing interval consistent with
twice daily dosing on the
following days. Taking the first
dose in the evening of Day 1 is
in line with the reference label.
4.1. Overall Design 
(Safety follow-up) 
Revised the text: 
The safety follow up will start the day after the last 
study intervention dose and end with the safety 
follow up telephone call (EOS visit) at least 30 days 
after the last dose. 
 
A safety follow-up period starting on the 
day after the last dose of study intervention
and ends at the End ofStudy (EOS) visit.
For an individual participant, EOS visit is
defined as follows:
o 
For participants who complete
treatment or who prematurely
discontinue study intervention, EOS
visit is defined as the safety follow-up
telephone call at least 30 days after last
dose of study intervention.
o 
For participants who complete
treatment in the RESTORE study
and who are entering another
open-label clinical study with
selexipag, the EOS visit is defined
as the EOT visit. The enrollment in
the other open-label clinical study
with selexipag must occur on the
day of the last visit in the
RESTORE study. Safety data
collection will continue in the other
open-label clinical study with
selexipag.
To clarify the EOS definition
for participants who completed
the study and are continuing
selexipag treatment in a
continued access program, ie,
open-label study.


ACT-293987 / JNJ-67896049 (selexipag) 
Clinical Protocol 67896049PAH4005 (Amendment 3)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
Status: Approved,  Date: 25 March 2022
Section Number 
and Name
Description of Change 
Brief Rationale
4.4. End of Study 
Definition  
Updated the section title from ‘EOS Definition’ to 
‘EOS Definition at Study Level’ 
Revised the section title from “Study Completion 
Definition for an Individual Participant” to “EOS 
Definition at Participant Level” and revised the 
text:
The EOS for an individual participant is the end of
the safety follow up, which is planned at least 30
days after last study intervention intake (also
applies to participants who prematurely discontinue
study intervention). For participants lost to follow
up, the EOS is the last contact with the site. In case
of death, death is the EOS.
For participants who complete treatment or who
prematurely discontinue study intervention,
EOS visit is defined as the safety follow-up
telephone call at least 30 days after last dose of
study intervention.
For participants who complete treatment in the
RESTORE study and who are entering another
open-label clinical study with selexipag, the EOS
visit is defined as the EOT visit. The enrollment
in the other open-label clinical study must occur
on the day of the last visit in the RESTORE
study. Safety data collection will continue in the
other open-label clinical study with selexipag.
To clarify the EOS definition
for participants who completed
the study and are continuing
selexipag treatment in a
continued access program, ie,
open-label study.
5.1 Inclusion Criteria; 
5.2 Exclusion Criteria 
Added weeks and/or days as applicable for relevant 
eligibility criteria.
For consistency.
5.1 Inclusion Criteria 
Revised the inclusion criterion 4: Diagnosis of PAH 
First hemodynamic diagnosis by right heart 
catheterization (RHC) within 12 months 3 years 
prior to initiation of selexipag (Day 1), and most 
recent right heart catheterization (RHC) within 
1 year prior to initiation of selexipag (Day 1) 
showing: 
 mPAP ≥25 mmHg and 
 PA wedge pressure (PAWP) or LV end-diastolic 
pressure (LVEDP) ≤15 mmHg and 
 PVR >5 WU (400 dyn.s.cm-5) and 
 RVSV ≤60 mL as shown in RHC. (CO/HR) 
In clinical practice, the decision
of adding selexipag to other
pulmonary arterial hypertension
(PAH) treatments is often taken
at 1 year after initial diagnosis
or later. The Steering
Committee agreed to expand
time from diagnosis to 3 years.
The time point of the RHC for
assessing eligibility is changed
to "most recent" and kept at a
maximum of one year prior to
selexipag initiation.
5.1 Inclusion Criteria 
Modified the inclusion criterion 6 to add alternative 
units: 
NT-proBNP ≥300 ng/L (≥300 pg/mL; 
≥35.5 pmol/L)at screening. Note: If local 
assessment of BNP (instead of NT-proBNP) is used 
for eligibility, BNP measurement of ≥50 ng/L 
(≥50 pg/mL; 14.4 pmol/L) will be considered as 
meeting the inclusion criterion.
To provide other common units
for N-terminal-pro-hormone
brain natriuretic peptide
(NT-proBNP) and BNP as local
and central laboratories may
provide units different from
ng/L.


ACT-293987 / JNJ-67896049 (selexipag) 
Clinical Protocol 67896049PAH4005 (Amendment 3)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Status: Approved,  Date: 25 March 2022
Section Number 
and Name
Description of Change 
Brief Rationale
5.1 Inclusion Criteria 
Revised the text for inclusion criterion 8 for 
consistency: 
 Agree to use reliable acceptable methods of
contraception from Day 1 to at least 30 days
after study intervention discontinuation
(Section 10.5), and
For consistency with Section
10.5 Appendix 5.
5.2 Exclusion criteria 
Revised exclusion criterion 5: 
Decompensated cardiac failure requiring 
hospitalization, emergency room visit or 
intravenous (iv)diuretics in the 6 10 weeks 
(70 days) before informed consent Day 1, inclusive 
To clarify that the described
conditions are exclusionary not
only if present at any time
before informed consent signed
but also if present at any time
during the screening period
before or on Day 1.
5.2 Exclusion criteria 
Modified exclusion criterion 15: 
Severe renal impairment (estimated glomerular 
filtration rate by Modification of Diet in Renal 
Disease [MDRD] formula creatinine clearance 
≤30 mL/min/1.73 m2 or serum creatinine
>2.5 mg/dL at screening) or ongoing or planned
dialysis.
To correct a discrepancy with
Section 10.2 Appendix 2. The
value and the units of the
assessment remain unchanged.
5.2 Exclusion Criteria 
Text added to the footnote c of exclusion 
criterion 16: 
“Absence of hepatic impairment must be 
documented in the source data as well.”
To document the absence of
hepatic impairment in the
source data.
5.2 Exclusion criteria 
Revised the exclusion criterion 18: 
Any hospitalization within 6 10 weeks (70 days) 
prior to informed consent Day 1, inclusive (except 
elective hospitalizations for surgery or standard 
monitoring of pre-existing conditions that did not 
worsen). 
To clarify that the described
conditions are exclusionary not
only if present at any time
before informed consent signed
but also if present at any time
during the screening period
before or on Day 1.
5.2 Exclusion criteria 
Modified exclusion criteria 20 to add alternative 
units: 
Hemoglobin <80 g/L (<8 g/dL; <4.96 mmol/L) at 
screening 
To provide other common units
for hemoglobin as local and
central laboratories may provide
units different from g/L.
5.2 Exclusion criteria 
Revised exclusion criterion 27 to avoid 
disambiguation of "any other condition that would 
interfere with proper cardiac gating": 
Severe arrythmia, atrial fibrillation, multiple 
premature ventricular or atrial contractions, or any 
other condition that would interfere with proper 
cardiac gating during MRI. 
 Cardiac arrythmia assessed severe by the 
investigator 
 Conditions that could interfere with proper 
cardiac gating, eg, atrial fibrillation,
multiple premature ventricular or atrial
contractions.
To clarify that severe
arrhythmia is a contraindication
of selexipag, whereas atrial
fibrillation, multiple premature
ventricular or atrial
contractions, and other
conditions are excluded because
they may interfere with cardiac
gating and therefore with
cardiac MRI.


ACT-293987 / JNJ-67896049 (selexipag) 
Clinical Protocol 67896049PAH4005 (Amendment 3)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
7
Status: Approved,  Date: 25 March 2022
Section Number 
and Name
Description of Change 
Brief Rationale
6.6 Concomitant 
Therapy  
Modified a bullet point clarifying forbidden 
therapies from Day 1 to EOT: 
 
Prostacyclin, or prostacyclin analog, or any 
other agent acting on the prostacyclin 
pathway, except iv selexipag in the US for 
participants who are temporarily (maximum
of 14 days; see Section 7.2) unable to take
the study intervention orally
To clarify that participants who
received iv selexipag during
hospitalization do not need to be
discontinued from study
intervention.
6.8. Continued Access 
to Study Intervention 
After the End of the 
Treatment Period 
Modified the title from “Continued Access to Study 
Intervention After the End of the Study” to 
“Continued Access to Study Intervention After the 
End of the Treatment Period” and revised the text 
under this section to align with the text on
continued access program per the transcelerate
clinical protocol template:
Local regulations on continued access will
always take precedence.
At the end of their participation in the treatment
period, participants who benefit from the study
intervention as assessed by the treating physician
will be offered the opportunity to continue
receiving selexipag via the following options:
 Switch to commercial selexipag, applicable to
participants who reside in a
country/territory where selexipag is
approved, commercially available and
reimbursed for the treatment of
participant’s PAH.
 Switch to a PTA program which will be set
up for participants who reside in
countries/territories where selexipag is not
yet commercially available or not
reimbursed for the participant’s PAH, if
allowed as per local regulations.
 Switch to another open-label clinical study
with selexipag, applicable for participants
who reside in a country/territory where the
conduct of such study is approved by the
local health authorities and where the 2
options above are not applicable.
After the participant’s study completion, the
investigator/delegate will explain to the participant
what treatment(s)/medical care is necessary and
available according to local regulations. If
indicated, the sponsor will provide participants who
completed the study (and did not prematurely
discontinue study treatment with selexipag) access
to selexipag if possible in the participant’s country
of residence, according to local regulatory
requirements, until selexipag can be accessed
commercially or through another source in the
country where the participant is living, including
the option that the participant’s physician may
To describe the modalities of
continued access to selexipag
for study participants after end
of study treatment period.


ACT-293987 / JNJ-67896049 (selexipag) 
Clinical Protocol 67896049PAH4005 (Amendment 3)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
8
Status: Approved,  Date: 25 March 2022
Section Number 
and Name
Description of Change 
Brief Rationale
request post trial access to selexipag from the
sponsor, based on favorable benefit/risk ratio for
this specific participant, or until the sponsor
terminates clinical development of selexipag. If in
the best interest of the study participant,
commercial selexipag supply should start in the
evening of EOT visit (date of last study medication
dose) to avoid any unnecessary selexipag treatment
interruption.
8. Study Assessments 
and Procedures, 
Table 3 (Footnotes ‘b’
and ‘c’)
Corrected the key definitions of footnotes ‘b’ and 
‘c’ as they were mixed up. 
To rectify the references to
footnotes.
8. Study Assessments 
and Procedures, 
Study-specific 
Materials
Revised the text: 
 Pregnancy notification forms and pregnancy 
follow up forms.
To indicate that only one form
is available.
8.5.1. Time Period and 
Frequency for 
Collecting Adverse 
Event and Serious 
Adverse Event 
Information, Serious 
Adverse Events 
Updated the text: 
Information regarding SAEs will be transmitted to 
the sponsor using the Serious Adverse Event form,
which must be completed and signed by a physician
from the study site, and transmitted to the sponsor
immediately but no later than within 24 hours.
The initial and follow-up reports of a SAE should
be made by facsimile (fax) or email. Telephone
reporting should be the exception and the reporter
should be asked to complete the appropriate form(s)
first.
To align with latest protocol
template language.
10.2. Appendix 2: 
Clinical Laboratory 
Tests 
Added the text: 
The actual date of assessment and, if required, 
the actual time of the assessment of laboratory
samples will be recorded in the source
documentation and in the eCRF or laboratory
requisition form.
To align with latest protocol
template language.
10.3. Appendix 3: 
Regulatory, Ethical, 
and Study Oversight 
Considerations; 10.3.1. 
Regulatory and ethical 
considerations 
Added a new subsection “Protocol Clarification 
Communications”: 
Protocol Clarification Communications
If text within a final approved protocol requires
clarification (eg, current wording is unclear or
ambiguous) that does not change any aspect of
the current study conduct, a protocol
clarification communication (PCC) may be
prepared. The PCC Document will be
communicated to the Investigational Site, Site
Monitors, Local Trial Managers (LTMs),
Clinical Trial Managers (CTMs), and/or
Contract Research Organizations (CROs) who
will ensure that the PCC explanations are
followed by the investigators.
The PCC Document may be shared by the sites
with Independent Ethics
Committees/Institutional Review Boards
(IECs/IRBs) per local regulations.
The PCC Documents must NOT be used in place
of protocol amendments, but the content of the
To define the use of protocol
clarification communications.


ACT-293987 / JNJ-67896049 (selexipag) 
Clinical Protocol 67896049PAH4005 (Amendment 3)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
9
Status: Approved,  Date: 25 March 2022
Section Number 
and Name
Description of Change 
Brief Rationale
PCC Document must be included in any future
protocol amendments.
10.3. Appendix 3: 
Regulatory, Ethical, 
and Study Oversight 
Considerations; 10.3.1. 
Regulatory and ethical 
considerations, 
Required Prestudy 
Documentation  
Added the text: 
The following documents must be provided to 
the sponsor before enrollment of the first 
participant:
 
Completed investigator financial disclosure
forms from all subinvestigators
 
Documentation of subinvestigator
qualifications (eg, curriculum vitae)
 
Name and address of any local laboratory
conducting tests for the study, and a dated
copy of current laboratory normal ranges
for these tests, if applicable
 
Local laboratory documentation
demonstrating competence and test
reliability (eg, accreditation/license), if
applicable
Revisions made to align with
latest protocol template
language.
10.3. Appendix 3: 
Regulatory, Ethical, 
and Study Oversight 
Considerations; 10.3.4. 
Data protection 
Added text: 
The informed consent obtained from the participant 
includes information about, and where required 
per applicable regulations, explicit consent for the
processing of personal data and for the
investigator/institution to allow direct access to his
or her original medical records (source
data/documents) for study-related monitoring, audit,
IEC/IRB review, and regulatory inspection. This
informed consent also addresses provides
information to address the lawful transfer of the
data to other entities and to other
countries/territories.
The participant has the right to request through the
investigator access to his or her personal data and
the right to request rectification of any data that are
not correct or complete., or make requests
concerning his or her personal data in
accordance with applicable data protection law.
Reasonable steps will be taken to respond to such a
request, taking into consideration the nature of the
request, the conditions of the study, and the
applicable laws and regulations.
In the event of a data security breach, the
sponsor will apply measures to adequately
manage and mitigate possible adverse effects
taking into consideration the nature of the data
security breach as necessary to address other
obligations such as notifying appropriate
authorities in accordance with applicable data
protection law.
Revisions made to align with
latest protocol template
language.


ACT-293987 / JNJ-67896049 (selexipag) 
Clinical Protocol 67896049PAH4005 (Amendment 3)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
10
Status: Approved,  Date: 25 March 2022
Section Number 
and Name
Description of Change 
Brief Rationale
10.3. Appendix 3: 
Regulatory, Ethical, 
and Study Oversight 
Considerations; 
10.3.10. Source
documents
Added text to the first bullet: 
• Date of an RHC performed before initiation of 
selexipag and associated mPAP, CO, HR, and 
either PAWP or LVEDP. 
Heart rate (HR) is necessary for
the calculation of right
ventricular stroke volume
(RVSV).
10.3. Appendix 3: 
Regulatory, Ethical, 
and Study Oversight 
Considerations; 
10.3.10. Source 
documents 
Added a new bullet: 
 
Documentation confirming absence of 
hepatic impairment. If known or 
documented hepatic impairment, all 
components used for the assessment of 
Child-Pugh Class should be documented.
To document the absence of
hepatic impairment or
assessment of hepatic
impairment and its outcome in
the source data.
10.3. Appendix 3: 
Regulatory, Ethical, 
and Study Oversight 
Considerations; 
10.3.14. Study and Site 
Start and Closure 
Revised the text under the subsection “First Act of 
Recruitment” 
The first site open informed consent signed is
considered the first act of recruitment and it
becomes the study start date.
Updated the title of the subsection from ‘Study
Termination” to “Study/Site Termination”.
To align with latest protocol
template language.
10.4. Appendix 4: 
Adverse Events, 
Serious Adverse 
Events, Product 
Quality Complaints,
and Other Safety
Reporting: Definitions
and Procedures for
Recording, Evaluating,
Follow-Up, and
Reporting; 10.4.4.
Special Reporting
Situations
Added a bullet: 
• Reporting of participant pregnancy or 
participant partner pregnancy  
To align with the requirements
in Section 8.5.4 and with the
latest protocol template
language.
10.5. Appendix 5: 
Contraceptive and 
Barrier Guidance 
Updated the section heading from “Contraceptive 
and Barrier Guidance and Collection of Pregnancy 
Information” to “Contraceptive and Barrier 
Guidance” and updated the content of the appendix. 
To align with latest protocol
template language. The
collection of pregnancy
information is described in
Sections 8.5.4 and 10.4.
Guidance on Study 
Conduct During A 
Natural Disaster/Major 
Disruption/Pandemic 
(EDMS-RIM-265584, 
5.0) 
Updated the coronavirus disease-2019 
(COVID-19) Appendix title and content to include 
natural disasters and major disruptions, and to 
anticipate recent developments related to the 
Covid-19 pandemic including the availability of 
vaccines. 
To provide guidance for
conducting the study under
special circumstances not only
related to COVID-19 but also to
natural disasters, major
disruptions and pandemics. To
align with latest appendix
template and to provide
guidance on COVID-19 vaccine
deployment and its impact on
the investigational medicinal
product and study procedures.
Throughout the 
protocol 
Updated the terms ‘country’ and ‘countries’ to 
‘country/territory’ and ‘countries/territories’, 
respectively.
To align with latest protocol
template language.


ACT-293987 / JNJ-67896049 (selexipag) 
Clinical Protocol 67896049PAH4005 (Amendment 3)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
11
Status: Approved,  Date: 25 March 2022
Section Number 
and Name
Description of Change 
Brief Rationale
Throughout the 
protocol 
 
Corrected and updated references, as 
applicable.
 
Updated the abbreviations.
 
Minor corrections, editorial revisions,
grammatical, formatting, or spelling changes
are made.
For clarity and consistency.


ACT-293987 / JNJ-67896049 (selexipag) 
Clinical Protocol 67896049PAH4005 (Amendment 3)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
12
Status: Approved,  Date: 25 March 2022
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................. 12
LIST OF IN-TEXT TABLES AND FIGURES.............................................................................................. 14
1. 
PROTOCOL SUMMARY................................................................................................................... 15
1.1. 
Synopsis......................................................................................................................................... 15
1.2. 
Schema.......................................................................................................................................... 22
1.3. 
Schedule of Activities..................................................................................................................... 23
2. 
INTRODUCTION................................................................................................................................ 26
2.1. 
Study Rationale.............................................................................................................................. 26
2.2. 
Background .................................................................................................................................... 27
2.3. 
Benefit-Risk Assessment............................................................................................................... 27
2.3.1. 
Known Benefits........................................................................................................................... 27
2.3.2. 
Known and Potential Risks......................................................................................................... 27
2.3.3. 
Overall Benefit/Risk Assessment ............................................................................................... 28
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 29
4. 
STUDY DESIGN ................................................................................................................................ 31
4.1. 
Overall Design................................................................................................................................ 31
4.2. 
Scientific Rationale for Study Design............................................................................................. 32
4.2.1. 
Study-Specific Ethical Design Considerations ........................................................................... 33
4.3. 
Justification for Dose...................................................................................................................... 33
4.4. 
End of Study Definition................................................................................................................... 34
5. 
STUDY POPULATION ...................................................................................................................... 34
5.1. 
Inclusion Criteria............................................................................................................................ 35
5.2. 
Exclusion Criteria........................................................................................................................... 36
5.3. 
Lifestyle Considerations................................................................................................................. 38
5.4. 
Screen Failures.............................................................................................................................. 38
6. 
STUDY INTERVENTION................................................................................................................... 39
6.1. 
Description of Study Intervention ................................................................................................... 39
6.2. 
Study Intervention Administration .................................................................................................. 40
6.2.1. 
Study Intervention Up-Titration................................................................................................... 40
6.2.2. 
Study Intervention Maintenance................................................................................................. 41
6.3. 
Preparation/Handling/Storage/Accountability ................................................................................ 41
6.4. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 42
6.5. 
Study Intervention Compliance...................................................................................................... 42
6.6. 
Concomitant Therapy..................................................................................................................... 43
6.7. 
Study Intervention Dose Modification ............................................................................................ 43
6.8. 
Continued Access to Study Intervention After the End of the Treatment Period........................... 44
6.9. 
Overdose........................................................................................................................................ 44
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 45
7.1. 
Discontinuation of Study Intervention ............................................................................................ 45
7.2. 
Temporary Interruption of Study Intervention ................................................................................ 46
7.3. 
Participant Discontinuation/Withdrawal from the Study................................................................. 46
7.4. 
Lost to Follow-up............................................................................................................................ 47
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 48
8.1. 
Demographics and Baseline Characteristics ................................................................................. 50
8.2. 
Medical History............................................................................................................................... 50


ACT-293987 / JNJ-67896049 (selexipag) 
Clinical Protocol 67896049PAH4005 (Amendment 3)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
13
Status: Approved,  Date: 25 March 2022
8.3. 
Efficacy Assessments .................................................................................................................... 50
8.3.1. 
Imaging ....................................................................................................................................... 50
8.3.1.1. 
Expert Reviewers .................................................................................................................... 50
8.3.1.2. 
Site Qualification...................................................................................................................... 50
8.3.1.3. 
Image Acquisition .................................................................................................................... 51
8.3.1.4. 
Quality Control......................................................................................................................... 51
8.3.1.5. 
Imaging Assessment............................................................................................................... 51
8.3.2. 
6MWT ......................................................................................................................................... 51
8.3.3. 
WHO FC ..................................................................................................................................... 51
8.3.4. 
Risk Stratification........................................................................................................................ 51
8.3.5. 
NT-proBNP ................................................................................................................................. 51
8.3.6. 
Biomarkers.................................................................................................................................. 52
8.4. 
Safety Assessments....................................................................................................................... 52
8.4.1. 
Physical Examination.................................................................................................................. 52
8.4.2. 
Vital Signs................................................................................................................................... 52
8.4.3. 
Clinical Safety Laboratory Assessments .................................................................................... 53
8.5. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 53
8.5.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 54
8.5.2. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 54
8.5.3. 
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 54
8.5.4. 
Pregnancy................................................................................................................................... 55
8.6. 
Participants’ Experience................................................................................................................. 55
8.7. 
Genetics ......................................................................................................................................... 55
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 55
9.1. 
Statistical Hypotheses.................................................................................................................... 55
9.2. 
Sample Size Determination ........................................................................................................... 55
9.3. 
Populations for Analyses................................................................................................................ 56
9.4. 
Statistical Analyses ........................................................................................................................ 56
9.4.1. 
General Considerations.............................................................................................................. 57
9.4.2. 
Primary Endpoint ........................................................................................................................ 57
9.4.3. 
Secondary Endpoints.................................................................................................................. 57
9.4.4. 
Exploratory Endpoints................................................................................................................. 58
9.4.5. 
Safety Analyses.......................................................................................................................... 58
9.5. 
Interim Analysis.............................................................................................................................. 59
9.6. 
Data Monitoring Committee ........................................................................................................... 59
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 60
10.1. 
Appendix 1: Abbreviations ............................................................................................................. 60
10.2. 
Appendix 2: Clinical Laboratory Tests ........................................................................................... 62
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 64
10.3.1. 
REGULATORY AND ETHICAL CONSIDERATIONS ................................................................ 64
10.3.2. 
FINANCIAL DISCLOSURE......................................................................................................... 67
10.3.3. 
INFORMED CONSENT PROCESS ........................................................................................... 67
10.3.4. 
DATA PROTECTION.................................................................................................................. 68
10.3.5. 
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE RESEARCH............ 69
10.3.6. 
COMMITTEES STRUCTURE .................................................................................................... 69
10.3.7. 
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA................................. 70
10.3.8. 
DATA QUALITY ASSURANCE .................................................................................................. 71
10.3.9. 
CASE REPORT FORM COMPLETION ..................................................................................... 71
10.3.10. SOURCE DOCUMENTS ............................................................................................................ 72
10.3.11. MONITORING ............................................................................................................................ 73
10.3.12. ON-SITE AUDITS....................................................................................................................... 74
10.3.13. RECORD RETENTION .............................................................................................................. 74
10.3.14. STUDY AND SITE START AND CLOSURE.............................................................................. 74


ACT-293987 / JNJ-67896049 (selexipag) 
Clinical Protocol 67896049PAH4005 (Amendment 3)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
14
Status: Approved,  Date: 25 March 2022
10.4. 
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-
Up, and Reporting.......................................................................................................................... 76
10.4.1. 
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS.................................................... 76
10.4.2. 
ATTRIBUTION DEFINITIONS.................................................................................................... 77
10.4.3. 
SEVERITY CRITERIA................................................................................................................ 77
10.4.4. 
SPECIAL REPORTING SITUATIONS ....................................................................................... 77
10.4.5. 
PROCEDURES .......................................................................................................................... 78
10.4.6. 
PRODUCT QUALITY COMPLAINT HANDLING........................................................................ 79
10.4.7. 
CONTACTING SPONSOR REGARDING SAFETY, INCLUDING PRODUCT QUALITY ......... 80
10.5. 
Appendix 5: Contraceptive and Barrier Guidance ......................................................................... 81
10.6. 
Appendix 6: WHO Functional Classification of Pulmonary Hypertension...................................... 84
10.7. 
Appendix 7: EuroQol 5-Dimension Questionnaire......................................................................... 85
10.8. 
Appendix 8: Child-Pugh Classification........................................................................................... 87
10.9. 
Appendix 9: Sponsor 6-Minute Walk Test Guidance ..................................................................... 88
10.9.1. 
INSTRUCTIONS......................................................................................................................... 88
10.9.2. 
TEST REQUIREMENTS............................................................................................................. 89
10.9.3. 
PERFORMING THE 6MWT........................................................................................................ 89
10.9.4. 
6MWT WORKSHEET................................................................................................................. 91
10.9.5. 
HOW TO USE THE BORG CR 10 SCALE®.............................................................................. 91
10.10. Appendix 10: Protocol Amendment History................................................................................... 97
11. REFERENCES................................................................................................................................. 112
INVESTIGATOR AGREEMENT............................................................................................................... 114
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Schedule of Activities................................................................................................................ 23
Table 2: 
Up-Titration Guide..................................................................................................................... 41
Table 3: 
Volume of Blood to be Collected From Each Participant.......................................................... 49
Table 4: 
Sample Size Power Sensitivity................................................................................................. 56
Table 5: 
Child-Pugh classification........................................................................................................... 87
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 22


ACT-293987 / JNJ-67896049 (selexipag) 
Clinical Protocol 67896049PAH4005 (Amendment 3)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
15
Status: Approved,  Date: 25 March 2022
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A PRospective, Multicenter, Single arm, Open-label, Phase 4 Study of the Effects of Selexipag on
RighT Ventricular RemOdeling in Pulmonary Arterial Hypertension Assessed by Cardiac Magnetic
REsonance Imaging (RESTORE)
This is an open-label, multicenter, single-arm, interventional study to assess the effect of selexipag in adult
participants (≥18 to <65 years) with a diagnosis of pulmonary arterial hypertension (PAH) up to 52 weeks
on study intervention.
Selexipag is a selective prostacyclin receptor (IP) agonist indicated for the treatment of PAH to delay
disease progression and reduce the risk of hospitalization for PAH.
BENEFIT-RISK ASSESSMENT
Based on the available data and proposed safety measures, the overall benefit/risk assessment for this
clinical study is considered acceptable for the following reasons:
 
Efficacy and safety of selexipag have been established in PAH.
 
Only participants who meet all inclusion criteria and none of the exclusion criteria (specified in this
protocol) will be allowed to participate in this study. The selection criteria include adequate provisions
to minimize the risk and protect the well-being of participants in the study.
 
Safety will be closely monitored throughout the study.
 
Several safety measures are included in this protocol to minimize the potential risk to participants,
including the following:
 
Participants will interrupt or discontinue study intervention for the protocol-allowed reasons.
It is the investigator’s responsibility to monitor the individual risk-benefit ratio of study intervention
administration, as well as the degree of distress caused by study procedures at an individual participant
level, and to discontinue study intervention or the study if, on balance, investigator believes that
continuation would be detrimental to the participants’ well-being.
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
 
To assess the effects of selexipag on right 
ventricular (RV) function in participants 
with PAH. 
Change from baseline to Week 26 in RV  stroke
volume (RVSV) assessed by pulmonary artery flow
magnetic resonance imaging (MRI).
Secondary
 
To further assess the effects of selexipag 
on RV function using MRI. 
Change from baseline to Week 26 assessed by MRI:
 
RV end-diastolic volume (RVEDV)
 
RV end-systolic volume (RVESV)
 
RV ejection fraction (RVEF)
 
RV mass
 
RV global longitudinal strain (RVGLS)
 
To assess the effects of selexipag on 
disease severity and exercise capacity. 
Change from baseline to Week 26:
 
World Health Organization (WHO) Functional
Class (FC)


ACT-293987 / JNJ-67896049 (selexipag) 
Clinical Protocol 67896049PAH4005 (Amendment 3)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
16
Status: Approved,  Date: 25 March 2022
Objectives 
Endpoints
 
N-terminal-pro-hormone 
brain 
natriuretic
peptide (NT-proBNP)
 
6-minute walk distance (6MWD)
 
To evaluate the safety and tolerability of
selexipag.
 
Treatment-emergent adverse events (AEs)
 
Serious adverse events (SAEs)
 
AEs leading to premature discontinuation of
study drug
 
AEs of special interest (AESI)
 
Treatment-emergent 
marked 
laboratory
abnormalities
 
To evaluate the effects of selexipag on risk
stratification in PAH.10
Change from baseline to Week 26 in number of
non-invasive low-risk criteria among the following
8 variables:
 
Absence of clinical signs of right heart failure
 
Absence of symptoms progression
 
Absence of syncope
 
WHO FC I–II
 
6MWD >440 m
 
NT-proBNP <300 ng/L
 
Right atrial (RA) area <18 cm2, as determined by
echocardiography (Echo)
 
Absence of pericardial effusion, as determined by
Echo
Change from baseline to Week 26 in number of
non-invasive low-risk criteria among the following
3 variables:
 
WHO FC I–II
 
6MWD >440 m
 
NT-proBNP <300 ng/L
Exploratory
 
To assess the effects of selexipag on RV
function using MRI at Week 52.
Change from baseline to Week 52 assessed by MRI:
 
RVSV
 
RVEDV
 
RVESV
 
RVEF
 
RV mass
 
RVGLS
 
To further assess the effects of selexipag
on cardiac morphology.
Change from baseline to Week 26 and Week  52
assessed by MRI:
 
RV mass/LV mass
 
To further assess the effects of selexipag
on RV function using Echo.
Change from baseline to Week 26 assessed by Echo:
 
Tricuspid annular plane systolic excursion
 
Pericardial effusion size scored from 0 to 4
 
RV end-diastolic area
 
RV end-systolic area
 
RV fractional area change
 
RVSV determined from pulmonary valve
Doppler and pulmonary annulus dimension
 
RA area


ACT-293987 / JNJ-67896049 (selexipag) 
Clinical Protocol 67896049PAH4005 (Amendment 3)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
17
Status: Approved,  Date: 25 March 2022
Objectives 
Endpoints
 
To assess the effects of selexipag on left 
ventricular (LV) function. 
Change from baseline to Week 26 and Week  52
assessed by MRI:
 
LV end-diastolic volume (LVEDV)
 
LV end-systolic volume (LVESV)
 
LV ejection fraction (LVEF)
 
LV mass
 
To assess the effects of selexipag on
pulmonary artery (PA) function.
Change from baseline to Week 26 and Week 52
assessed by MRI:
 
Right main PA pulsatility
 
To explore 4-dimensional (4D) flow
imaging
In participants from sites able to provide suitable MRI
imaging, change from baseline to Week 26 and Week
52 in:
 
RVSV determined from 4D flow imaging in PA
 
LVSV determined from 4D flow imaging in aorta
 
To 
explore 
whether 
individual
maintenance 
dose 
impacts 
reverse
remodeling.
Change in RVSV from baseline to Week 26 and
Week 52
 
To further assess the effects of selexipag
on disease severity and exercise capacity.
Change from baseline to Week 52:
 
WHO FC
 
NT-proBNP
 
6-minute walking distance (6MWD)
 
To explore the effects of selexipag on 
blood biomarkers. 
Change from baseline to Week 26 and Week 52 in
blood biomarkers
 
To explore participants’ experience. 
 
EuroQol 5-dimension scale (EQ-5D-3L) on
Day 1, and at Week 26 and Week 52
 
To evaluate the effect of selexipag on 
dyspnea during the 6-minute walking test
(6MWT)
 
Change from baseline to Week 26 and Week 52
in the difference between the pre-walk and
post-walk assessed dyspnea Borg Dyspnea Index
(BDI).
Hypothesis
The primary hypothesis of the study is that 26 weeks of selexipag treatment will induce a mean increase in
RVSV by 8 mL in participants with PAH.
OVERALL DESIGN
This is an open-label, multicenter, single-arm, interventional study to assess the effect of selexipag in adult
participants (≥18 to <65 years) with a diagnosis of PAH up to 26 and 52 weeks on study intervention.
The duration of individual participation will be approximately 60 weeks. The study will be conducted in
3 phases: a 28-day screening phase, a 52-week treatment phase (which will include an initial 12-week
up-titration period), and a post-intervention safety follow-up period of at least 30 days. Primary and
secondary objectives will be evaluated up to Week 26 and exploratory objectives will be evaluated up to
Week 52.
Efficacy assessments will include MRI, Echo, 6MWT, WHO FC, NT-proBNP, and risk stratification.
Safety assessments will include the monitoring of AEs, clinical laboratory evaluations, and pregnancy
testing in female participants of childbearing potential. Exploratory assessments will include biomarkers,
the participants’ experience using a questionnaire and efficacy assessments measured at Week 52.


ACT-293987 / JNJ-67896049 (selexipag) 
Clinical Protocol 67896049PAH4005 (Amendment 3)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
18
Status: Approved,  Date: 25 March 2022
NUMBER OF PARTICIPANTS
The study will enroll approximately  80 participants in total, considering 15% of participants with
non-evaluable MRI assessments at baseline and/or Week 26. Thus, it is expected that approximately
68 participants will have evaluable MRIs both at baseline and Week 26. Additionally, it is anticipated that
95 participants will need to be screened in order to enroll 80 participants (assuming 15% screening failure
rate).
INTERVENTION GROUP AND DURATION
Eligible participants will be treated with selexipag for 52 weeks. Dosing with selexipag will start at 200 µg
twice daily (on Day 1, the participant will receive only 1 dose, and at each dose change, the first intake of
the new dose should be taken in the evening). The site will call the participant once a week from the end of
Week 1 to the end of Week 12 and decide whether to increase the dose by 200 µg twice daily if possible.
Up-titration will be flexible and can be adapted in case of adverse effects that cannot be relieved with
symptomatic treatment. In this case, the site may either postpone up-titration by 1 week or down-titrate
study drug. The dose reached at end of Week 12 will be considered the participant’s individual maintenance
dose (IMD) and will be maintained until EOT.
Description of Interventions
Study intervention: Open-label selexipag will be provided as round, film-coated tablets for oral
administration.
Comparator and/or placebo: Not applicable.
EFFICACY EVALUATIONS
 
Imaging: Imaging will be performed as described in the MRI Image Acquisition Protocol (IAP)/Echo
IAP and centrally reviewed. Expert reviewers will be blinded to the participant and timepoint and will
assess variables according to the MRI/Echo review charter. For each imaging modality(MRI or Echo),
all scans of an individual participant will be reviewed by the same reviewer at the same time, in order
to ensure consistent assessment.
 
6MWT: Tests will follow the sponsor’s guidance for 6MWT. Dyspnea will be assessedusing the Borg
CR 10 Scale® (Section 10.9).
 
WHO FC: WHO FC will be determined as per WHO definition (Section 10.6).
 
NT-proBNP: NT-proBNP will be assessed by the central laboratory.
 
Risk stratification: Clinical signs of right heart failure, progression of PAH symptoms, and syncope
will be collected.
SAFETY EVALUATIONS
 
AEs: AEs will be assessed by sites.
 
Safety laboratory analyses: Safety laboratory results will be assessed by the central laboratory and
will include basic hematology panel, basic clinical chemistry panel, and pregnancy tests for females
of childbearing potential. A serum pregnancy test will be performed at the site at screening, at
Week 26, and at Week 52 (EOT); urine pregnancy tests will be performed at the site on Day 1 and at
the participant’s home monthly between Day 1 and End of Study (EOS), except for Month 6 and
Month 12, when a serum pregnancy test is performed at the site visit (Weeks 26 and 52).


ACT-293987 / JNJ-67896049 (selexipag) 
Clinical Protocol 67896049PAH4005 (Amendment 3)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
19
Status: Approved,  Date: 25 March 2022
EXPLORATORY EVALUATIONS
 
Biomarkers: Exploratory biomarkers will be measured after the end of the study at study level based
on the latest scientific evidence regarding RV function and structure at the time of laboratory analysis.
No genetic testing of any kind will be performed.
 
EQ-5D-3L questionnaire: This will be assessed onDay 1, at Week 26, andat Week 52 (Section 10.7).
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general description
of the statistical methods to be used to analyze the efficacy and safety data is outlined below. Specific
details will be provided in the Statistical Analysis Plan (SAP).
Sample Size Determination
Sample size calculation for the primary endpoint is based on the following assumptions:
 
A 2-sided Type I error of 5% and a Type II error of 10% (90% power)
 
A change from baseline to Week 26 in RVSV of +8 mL
 
A standard deviation (SD) of 20 mL for the change from baseline to Week 26 in RVSV
 
A normal distribution for the change from baseline to Week 26 in RVSV
 
15% of participants with non-evaluable RVSV assessment at baseline and/or postbaseline
Based on the above assumptions, a total of 80 participants (68 analyzable + 12 to account for 15%
non-evaluable) must be enrolled to establish whether change from baseline to Week 26 in RVSV is different
from zero (based on paired t-test for single arm).
Populations for Analyses
For purposes of analysis, the following populations are defined:
 
Screened Analysis Set: The Screened Analysis Set will include all participants who were screened
and received a participant number.
 
Safety Set: The Safety Set (SS) will include all participants from the Screened Analysis Set who
received at least 1 dose of study intervention.
 
Full Analysis Set: The Full Analysis Set (FAS) will include all participants from the SS who had a
baseline as well as a postbaseline measurement for RVSV assessed by cardiac MRI from pulmonary
artery flow.
 
Per-Protocol Analysis Set: The Per-Protocol Analysis Set (PPS) will include all participants in the
FAS  without major protocol deviations that could affect the main analysis of the primary efficacy
variable.
Statistical Analyses
General Considerations
The overall Type I error is α=0.05. All analyses will be performed using 2-sided statistical tests.
If the primary endpoint analysis is statistically significant (ie, p-value below nominal alpha), the study will
be declared positive.
No multiplicity adjustments will be performed for secondary/exploratory endpoints, and therefore, all
associated p-values are of exploratory nature. No interim analysis will be performed.


ACT-293987 / JNJ-67896049 (selexipag) 
Clinical Protocol 67896049PAH4005 (Amendment 3)
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Status: Approved,  Date: 25 March 2022
Participants without a baseline value will be excluded from the corresponding analysis.
Subgroup analyses on primary and secondary endpoints will include WHO FC (II/III) at baseline.
Additional subgroup analyses will be specified in the SAP. All subgroup analyses will be of exploratory
nature.
Primary Endpoint
The null statistical hypothesis is that the mean change from baseline to Week 26 in RVSV is equal to zero.
The alternative statistical hypothesis is that the mean change from baseline to Week 26 in RVSV is different
from zero.
The primary efficacy analysis will be performed on the FAS. RVSV will be summarized by timepoint
(baseline and Week 26) using descriptive statistics (n, mean, SD, median, Q1 and Q3). The change from
baseline to Week 26 in RVSV will be summarized similarly.
Change from baseline in RVSV will be analyzed at α=0.05 (2-sided) using an analysis of covariance
(ANCOVA) with a factor for WHO FC (II/III) at baseline and a covariate for baseline RVSV. The mean
change from baseline and 95% confidence interval (CI) will be estimated based on the model.
A sensitivity analysis will be performed on the PPS. Another sensitivity analysis will be performed on the
SS, where participants with missing postbaseline RVSV will be imputed using their baseline value.
Secondary Endpoints
Change from baseline to Week 26 in RVEDV, RVESV, RVEF, RV mass, RVGLS, 6MWD, and number
of low-risk criteria will be summarized descriptively by timepoint and analyzed at α=0.05 (2-sided) on the
FAS using an ANCOVA with a factor for WHO FC (II/III) at baseline and a covariate for baseline value.
The mean change from baseline and 95% CI will be estimated based on the model.
WHO FC will be summarized on the FAS by timepoint using frequency tables. Changes from baseline in
WHO FC will be dichotomized as worsening (ie, change >0) versus no change or improvement (ie, change
≤0). Worsening will be analyzed at α=0.05 (2-sided) using a logistic regression model with a factor for
WHO FC (II/III) at baseline.
NT-proBNP will be summarized on the FAS by timepoint using descriptive statistics as well as geometric
means and coefficients of variation (CVs). The Week 26 versus baseline ratio will be summarized similarly.
The ratio versus baseline in NT-proBNP will be log-transformed and analyzed at α=0.05 (2-sided) using an
ANCOVA with a factor for WHO FC (II/III) at baseline and a covariate for baseline log NT-proBNP.
All analyses for secondary endpoints are of exploratory nature because there will be no adjustment for
multiplicity. Additional analyses will be performed on the SS for all secondary endpoints, where
participants with missing postbaseline values will be imputed using their baseline values.
Exploratory Endpoints
Exploratory variables will be analyzed at α=0.05 (2-sided) on the FAS and SS. Details will be specified in
the SAP.
Biomarker exploratory analyses will be specified in a separate specific SAP.
Safety Analyses
Safety analyses will be performed on the SS.


ACT-293987 / JNJ-67896049 (selexipag) 
Clinical Protocol 67896049PAH4005 (Amendment 3)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
21
Status: Approved,  Date: 25 March 2022
Adverse Events
A treatment-emergent AE is any AE from first dose up to 3 days after end of study intervention. The number
and percentage of participants experiencing at least 1 treatment-emergent AE or SAE will be tabulated by:
 
Medical Dictionary for Regulatory Activities system organ class and individual preferred term, in
descending order of incidence.
 
Frequency of participants with events coded with the same preferred term, in descending order of
incidence.
Treatment-emergent AEs and SAEs will be tabulated as described above by severity and relationship to
study intervention. SAEs will be also tabulated up to 30 days after end of study intervention.
AEs leading to premature discontinuation of study intervention, AEs with an outcome of death, and AEs of
special interest will be summarized as described above. The detailed list of AEs of special interest will be
specified in the SAP.
AEs occurring during titration period will also be summarized separately.
Listings will be provided for all reported AEs, including SAEs. In addition, separate listings will be
provided for SAEs, for AEs leading to premature discontinuation of study intervention, and for AEs with
an outcome of death.
The following AEs will be listed only:
 
AEs occurring prior to first study intervention dose
 
Non-serious AEs occurring after EOT + 3 days
 
SAEs occurring more than 30 days after discontinuation of study intervention
Clinical Laboratory Tests
Descriptive summary statistics by visit will be provided for observed values and absolute changes from
baseline, in both hematology and clinical chemistry laboratory tests. In order to minimize missing data and
to allow for out-of-window visits, all recorded assessments up to EOT + 3 days will be assigned to the most
appropriate visit timepoint according to the best fitting time window for that assessment.
The sponsor’s internal guidelines will be used for the definitions of marked abnormalities and for the
standardization of numeric values obtained from different laboratories and/or using different normal ranges.
Standard numeric laboratory variables will be transformed to standard units. All laboratory data transferred
will be taken into account regardless of whether they correspond to scheduled (per protocol) or unscheduled
assessments.
Marked laboratory abnormalities will be summarized for each laboratory variable providing the incidence
and frequency. Absolute values and changes from baseline of laboratory values during the course of the
study will also be summarized.
The number and percentage of participants with treatment-emergent laboratory abnormalities will be
tabulated.








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g. Urine pregnancy test at site.
h. Urine pregnancy test at participant’s home. The site will call female participants of childbearing potential monthly to check the pregnancy test result. A window of
±5 days for each pregnancy test/phone call will be allowed.
i. Test to be done within 30 to 37 days after EOT.
j. If MRI, Echo, 6MWT, or WHO FC assessments were done as part of routine practice in a way that fully complies with the study requirements, and within 28 days
before Day 1, these data can be used for the study.
k. Optional in case of premature EOT before end of Week 16 (Day 112).
l. Only if EOT.
m. Participant’s experience refers to the EQ-5D-3L questionnaire (Section 10.7).
n. For safety laboratory analyses (Section 8.4.2), NT-proBNP and biomarkers (Section 8.3.6).
o. If the results for the screening blood samples from the central laboratory are not available in time for Day 1 visit, an additional blood sample may be drawn to verify
eligibility based on a local laboratory test.
p. Including premature EOT. In case of premature EOT, the EOT visit should take place within 7 days after the decision to end study intervention.
q. Except for month of Week 26 and Week 52.
r. In case of an epidemic situation or major disruptions, eg, COVID-19, the Week 26 visit may be delayed up to an additional 28 days (Week 26 +6/-2 weeks).
s. For participants who complete treatment in the RESTORE study and who are entering another open-label clinical study with selexipag, the EOS visit is defined as
the EOT visit. The enrollment in the other open-label clinical study with selexipag must occur on the day of the last visit in the RESTORE study.


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2. 
INTRODUCTION
Pulmonary arterial hypertension (PAH) is a serious chronic disorder of the pulmonary circulation,
a syndrome of diverse etiology and pathogenesis characterized by a progressive increase in
pulmonary arterial pressure (PAP) and in pulmonary vascular resistance (PVR) potentially leading
to right heart failure and death.3,17,19
PAH is associated with structural changes in both pulmonary vasculature and right ventricle (RV).
The changes in vascular structure involve 3 combined elements: vasoconstriction, vascular-wall
remodeling, and thrombosis in situ.14 The changes in the RV mainly consist of hypertrophy,
dilation, altered contractility, and septal bowing.9,22,36 Collectively, these changes of the RV are
termed remodeling.
PAH is hemodynamically defined as a resting mean pulmonary arterial pressure (mPAP)
25 mmHg with normal pulmonary artery wedge pressure or left atrial pressure (≤15 mmHg) and
a PVR greater than 3 Wood units (WU).10,13
The updated clinical classification of pulmonary hypertension classifies the numerous conditions
that are known to lead or be associated with the development of PAH into 4 groups, based on their
similar clinical presentation, pathology, pathophysiology, prognosis, and, most of all, similar
therapeutic approach. PAH may occur in the absence of a demonstrable cause (idiopathic), in a
familial setting (heritable), as the result of the use of drugs and toxins, or it can be associated with
a connective tissue disease, human immunodeficiency virus (HIV) infection, portal hypertension,
congenital heart disease, or schistosomiasis.26,27
Selexipag (JNJ-67896049 [also known as ACT-293987]) is a selective, orally available, long-
acting, non-prostanoid agonist of the prostacyclin receptor (IP receptor), approved and
commercially available for the treatment of patients with PAH in the United States, the European
Union, Japan, and other countries/territories. Selexipag is currently under development for
sarcoidosis-associated 
pulmonary 
hypertension, 
chronic 
thromboembolic 
pulmonary
hypertension, arteriosclerosis obliterans with intermittent claudication, and lumbar spinal stenosis
with intermittent claudication.
Throughout the protocol, the term “study intervention” refers to study drug.
The term “sponsor”, used throughout this document, refers to the entities listed in the Contact
Information page(s), which will be provided as a separate document.
2.1. 
Study Rationale
Selexipag was approved on the basis of long-term clinical efficacy; however, short-term cardiac
imaging data on selexipag are lacking.28
In PAH, RV function is a determinant of survival. In order to compensate for the increased PVR,
the RV remodels. It dilates and hypertrophies, but may be unable to maintain a sufficient cardiac


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output. The AC-055-403 REPAIR studya evaluated the effect of macitentan, an endothelin receptor
antagonist (ERA), on the right ventricle. The interim  and final results of this study have
emphasized the relevance of magnetic resonance imaging (MRI) in assessing cardiac changes with
PAH treatment.25,37 The study has shown that RV reverse remodeling can be detected, as the RV
re-shapes to return closer to a healthy heart. Furthermore, an increase in RV stroke volume (RVSV)
by 8 mL to 12 mL is considered clinically significant.35
2.2. 
Background
For the most recent comprehensive quality, nonclinical, and clinical information regarding
selexipag, see the latest version of the Investigator’s Brochure.16
2.3. 
Benefit-Risk Assessment
2.3.1. 
Known Benefits
Efficacy of selexipag in the treatment of adult participants with symptomatic PAH was
demonstrated in study AC-065A302 (GRIPHON), the largest (N 1156) and only randomized
long-term (mean duration 1.5 years and up to 4.2 years), controlled morbidity/mortality study
conducted with an IP-receptor agonist.18,28 A highly statistically significant effect on the primary
endpoint, risk of first morbidity or mortality event during treatment, was observed: the hazard ratio
versus placebo was 0.60 (99% confidence interval [CI]: 0.46, 0.78, 1-sided unstratified log-rank
p <0.0001), corresponding to a 40% relative risk reduction versus placebo. The treatment effect
was consistent across World Health Organization (WHO) functional class (FC) II III and was fully
preserved in participants already treated with at least 1 approved PAH-specific medicine at
baseline (80% of the study population), as well as in participants treated with 2 such medicines
(30% of the study population). In all analyses, the effect of selexipag was established early and
was sustained over this long-term study. GRIPHON was the first study to demonstrate the
long-term outcome benefit of an oral IP-receptor agonist, in particular when added sequentially to
therapies acting on other pathogenic pathways in PAH (endothelin and nitric oxide pathways). The
study outcome is reflected in the current consensus guidelines for PAH, where selexipag is the
only IP-receptor agonist with a Class I evidence recommendation for sequential drug combination
therapy.10
2.3.2. 
Known and Potential Risks
The short and long-term safety profile of selexipag has been established in PAH participants in
study AC-065A302 (GRIPHON), conducted in 1156 participants, and is mainly characterized by
prostacyclin-associated adverse events (AEs) linked with the mode of action of selexipag. Such
AEs typically occur during the initial phase of individualized dose titration, and the susceptibility
varies between individuals. Adverse drug reactions reflecting the mode of action of selexipag
included: headache, diarrhea, nausea and vomiting, jaw pain, myalgia, pain in extremity,
arthralgia, and flushing.
a 
NCT02310672; EUDRACT: 2014-004066-20


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Other AEs reported more frequently in the selexipag group compared with placebo group included
hypotension, anemia, hyperthyroidism, nasopharyngitis, nasal congestion, decreased appetite,
weight decreased, rash, urticaria, and erythema.
Hypotension was reported more frequently in the selexipag group than in the placebo group (5.0%
and 3.1%, respectively). In the selexipag group, 9.7% of participants had systolic blood pressure
(SBP) ˂90 mmHg on at least 1 occasion, compared with 6.7% in the placebo group. A decrease
from baseline of >40 mmHg in SBP was reported for 2.3% and 3.0% of participants in the
selexipag and placebo groups, respectively.
Hyperthyroidism was reported more frequently in the selexipag group compared with the placebo
group. Corresponding laboratory changes were a small reduction in thyroid-stimulating hormone
at most postbaseline visits.
Anemia was reported more frequently in the selexipag group, and a small reduction in hemoglobin
was observed at most postbaseline visits.
2.3.3. 
Overall Benefit/Risk Assessment
Based on the available data and proposed safety measures, the overall benefit/risk assessment for
this clinical study is considered acceptable for the following reasons:
 
Efficacy and safety of selexipag have been established in PAH.
 
Only participants who meet all inclusion criteria and none of the exclusion criteria (specified
in Section 5.1 and Section 5.2, respectively) will be allowed to participate in this study. The
selection criteria include adequate provisions to minimize the risk and protect the well-being
of participants in the study.
 
Safety will be closely monitored throughout the study.
 
Several safety measures are included in this protocol to minimize the potential risk to
participants, including the following:
 
Participants will interrupt or discontinue study intervention for the reasons included in
Sections 7.2 and 7.1, respectively.
It is the investigator’s responsibility to monitor the individual risk-benefit ratio of study
intervention administration, as well as the degree of distress caused by study procedures at an
individual participant level, and to discontinue study intervention  or the study if, on balance,
investigator believes that continuation would be detrimental to the participants’ well-being.
More detailed information about the known and expected benefits and risks of selexipag is
available in the Investigator’s Brochure.16


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3. 
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
 
To assess the effects of selexipag on RV 
function in participants with PAH. 
Change from baseline to Week 26 in RV stroke
volume (RVSV) assessed by pulmonary artery flow
MRI.
Secondary
 
To further assess the effects of selexipag 
on RV function using MRI. 
Change from baseline to Week 26 assessed by MRI:
 
RV end-diastolic volume (RVEDV)
 
RV end-systolic volume (RVESV)
 
RV ejection fraction (RVEF)
 
RV mass
 
RV global longitudinal strain (RVGLS)
 
To assess the effects of selexipag on 
disease severity and exercise capacity. 
Change from baseline to Week 26:
 
WHO FC
 
N-terminal-pro-hormone 
brain 
natriuretic
peptide (NT-proBNP)
 
6-minute walk distance (6MWD)
 
To evaluate the safety and tolerability of 
selexipag. 
 
Treatment-emergent AEs
 
Serious adverse events (SAEs)
 
AEs leading to premature discontinuation of
study drug
 
AEs of special interest
 
Treatment-emergent 
marked 
laboratory
abnormalities
 
To evaluate the effects of selexipag on risk 
stratification in PAH.10 
Change from baseline to Week 26 in number of
non-invasive low-risk criteria among the following
8 variables:
 
Absence of clinical signs of right heart failure
 
Absence of symptoms progression
 
Absence of syncope
 
WHO FC I–II
 
6MWD >440 m
 
NT-proBNP <300 ng/L
 
Right atrial (RA) area <18 cm2, as determined by
echocardiography (Echo)
 
Absence of pericardial effusion, as determined by
Echo
Change from baseline to Week 26 in number of
non-invasive low-risk criteria among the following
3 variables:
 
WHO FC I–II
 
6MWD >440 m
 
NT-proBNP <300 ng/L
Exploratory
 
To assess the effects of selexipag on RV 
function using MRI at Week 52. 
Change from baseline to Week 52 assessed by MRI:
 
RVSV
 
RVEDV
 
RVESV


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Objectives 
Endpoints
 
RVEF
 
RV mass
 
RVGLS
 
To further assess the effects of selexipag
on cardiac morphology.
Change from baseline to Week 26 and Week 52
assessed by MRI:
 
RV mass/LV mass
 
To further assess the effects of selexipag
on RV function using Echo.
Change from baseline to Week 26 assessed by Echo:
 
Tricuspid annular plane systolic excursion
 
Pericardial effusion size scored from 0 to 4
 
RV end-diastolic area
 
RV end-systolic area
 
RV fractional area change
 
RVSV determined from pulmonary valve
Doppler and pulmonary annulus dimension
 
RA area
 
To assess the effects of selexipag on left
ventricular (LV) function.
Change from baseline to Week 26 and Week 52
assessed by MRI:
 
LV end-diastolic volume (LVEDV)
 
LV end-systolic volume (LVESV)
 
LV ejection fraction (LVEF)
 
LV mass
 
To assess the effects of selexipag on
pulmonary artery (PA) function.
Change from baseline to Week 26 and Week 52
assessed by MRI:
 
Right main PA pulsatility
 
To explore 4-dimensional (4D) flow
imaging.
In participants from sites able to provide suitable MRI
imaging, change from baseline to Week 26 and
Week 52 in:
 
RVSV determined from 4D flow imaging in PA
 
LVSV determined from 4D flow imaging in aorta
 
To 
explore 
whether 
individual
maintenance 
dose 
impacts 
reverse
remodeling.
Change in RVSV from baseline to Week 26 and
Week 52
 
To assess the effects of selexipag on
disease severity and exercise capacity.
Change from baseline to Week 52:
 
WHO FC
 
NT-proBNP
 
6MWD
 
To explore the effects of selexipag on
blood biomarkers.
Change from baseline to Week 26 and Week 52 in
blood biomarkers
 
To explore participants’ experience. 
EuroQol 5-dimension scale (EQ-5D-3L) on Day 1,
and at Week 26 and Week 52
 
To evaluate the effect of selexipag on 
dyspnea during the 6MWT  
 
Change from baseline to Week 26 and Week 52
in the difference between the pre-walk and
post-walk assessed dyspnea Borg Dyspnea Index
(BDI).
HYPOTHESIS
The primary hypothesis of the study is that treatment with selexipag for 26 weeks will induce a
mean increase in RVSV by 8 mL in participants with PAH.


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4. 
STUDY DESIGN
4.1. 
Overall Design
This is an open-label, multicenter, single-arm, interventional study to assess the effect of selexipag
in adult participants (≥18 to <65 years) with a diagnosis of PAH  up to 52 weeks on study
intervention.
The duration of individual participation will be approximately  60 weeks. The study will be
conducted in 3 phases: a 28-day screening phase, a 52-week interventionphase (which will include
an initial 12-week up-titration period), and a post-intervention safety follow-up period of at least
30 days. Primary and secondary objectives will be evaluated up to Week 26 and exploratory
objectives will be evaluated up to Week 52. Following are detailed descriptions of the study
periods:
 
Screening period: Informed consent signature marks both the start of the study and the start
of the screening period. This period serves to assess eligibility (medical history, treatments,
blood tests) and to perform baseline efficacy assessments (MRI, Echo, 6MWD, WHO FC,
NT-proBNP, and exploratory blood tests). Screening may last up to 28 days. A participant
who is temporarily ineligible may be rescreened once (Section 5.4). Note: if MRI, Echo,
6MWT, or WHO FC assessments were done as part of routine practice in a way that fully
complies with the study requirements, and within 28 days before Day 1, these data can be
used for the study.
 
Treatment period: Starts with the first dose of study drug (Day 1 of study) and ends with
EOT on the day of the last dose of study drug which is at Week 52 ± 7 days or at premature
discontinuation of study intervention.
 
Day 1: Day 1 is defined as the day when a participant receives the first dose of study
intervention. First dosing should occur in the evening of Day 1. Day 1 may occur once
screening assessments are completed, and no later than 28 days after informed consent
signature. For rescreened participants, all screening assessments must have been made
within 28 days before Day 1; only screening assessments beyond the 28-day window will
need to be repeated. The last study procedure to be performed on Day 1 will be selexipag
intake.
 
Up-titration: During this period, study intervention will be up-titrated from Day 1 to the
end of Week 12 (Day 84). Weekly phone calls from the site to participant will be
performed to guide the up-titration and collect safety information. At the end of Week 4
(+7 days) and Week 12 (+7 days) and participants will return to the site for a
return/dispensing visit; no assessments will be performed at these site visits.
 
Maintenance: During this period, participants will receive study intervention at their
individual maintenance dose (IMD) from the start at Week 13 to EOT (scheduled at the
end of Week 52, ± 7 days). Monthly phone calls (except when site visits take place) from
the site to the participant will be made to monitor participant’s safety by collecting
information on concomitant medications, AEs and SAEs. At Week 26 (Day 168 to 196),
a site visit is scheduled to assess MRI, Echo, 6MWT, WHO FC, blood draw for secondary
and exploratory endpoints. At Week 39 (+14 days), participants will return to the site for
a study drug return/dispensing visit; no assessments will be performed at this site visits.


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EOT: EOT should occur at end of Week 52 ± 7 days (Day 350 to 378). At this visit,
postbaseline assessments will be performed (MRI, 6MWT, WHO FC, blood draw). In
case of premature EOT before Week 16, postbaseline efficacy assessments will be
optional and safety assessments will be mandatory. In case of premature EOT after
Week 16, all postbaseline assessments will be performed.
 
Safety follow-up: A safety follow-up period starting on the day after the last dose of
study intervention and ends at the End ofStudy (EOS) visit. For an individual participant,
EOS visit is defined as follows:
o 
For participants who complete treatment or who prematurely discontinue study
intervention, EOS visit is defined as the safety follow-up telephone call at least
30 days after last dose of study intervention.
o 
For participants who complete treatment in the RESTORE study  and who are
entering another open-label clinical study with selexipag, the EOS visit is defined as
the EOT visit. The enrollment in the other open-label clinical study with selexipag
must occur on the day of the last visit in the RESTORE study. Safety data collection
will continue in the other open-label clinical study with selexipag.
 
Unscheduled visits: Unscheduled visits will be allowed and will not be documented in
the electronic case report form (eCRF); however, any AE/SAE reported during an
unscheduled visit should still be recorded.
Eligible participants will be treated with selexipag for 52 weeks. Dosing with selexipag will start
at 200 µg twice daily. On Day 1, the participant will receive only 1 dose, and at each dose change,
the first intake of the new dose should be taken in the evening. The site will call the participant
once a week from the end of Week 1 to the end of Week 12 and decide whether to increase the
dose by 200 µg twice daily if possible. Up-titration will be flexible and can be adapted in case of
adverse effects that cannot be relieved with symptomatic treatment. In this case, the site may either
postpone up-titration by 1 week or down-titrate study intervention. The dose reached at end of
Week 12 will be considered the participant’s IMD and will be maintained until EOT.
Efficacy assessments will include MRI, Echo, 6MWT, WHO FC, NT-proBNP, and risk
stratification. Safety assessments will include the monitoring of AEs, clinical laboratory
evaluations, and pregnancy testing in female participants of childbearing potential. Exploratory
assessment will include biomarkers and the participants’ experience using a questionnaire.
A diagram of the study design is provided in Figure 1.
4.2. 
Scientific Rationale for Study Design
The primary cause of death in PAH is right ventricular failure. Several studies have shown that
RV function has a prognostic relevance in this condition.12,29,32,34 Cardiac MRI is a safe,
non-invasive method to assess RV  geometry and function, with low between-study6,11 and
between-observer6 variability. In addition, cardiac imaging can be satisfactorily assessed without
contrast medium. Therefore, it is the method of choice for assessing RV remodeling.
Non-controlled, open-label trials are classically used in imaging studies that assess cardiac changes
in PAH.4,12,20,24,33,38 Open-label trials have a potential for bias. Bias in the assessment of imaging,
including the primary endpoint, is reduced by ensuring objectivity of assessment.


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Objectivity of imaging results is ensured by central assessment of images by assessors who are
blinded to the participant and imaging timepoint (ie, before or during treatment). Because PAH is
a progressive disease, reverse remodeling is not expected to be observed unless it is induced by a
study intervention. Therefore, participants may be used as their own control (ie, a participant’s
postbaseline values may be compared with the corresponding baseline values).
The primary endpoint will be assessedat 26 weeks as this is a sufficient study interventionduration
to enable a relevant change and also early enough to have a relatively low proportion of participants
dropping out for the primary endpoint.
This study will contain a 12-week up-titration period. The goal of the up-titration is to ensure that
each participant reaches his/her individual highest tolerated dose; ie, without unmanageable
prostacyclin-associated adverse effects. Based on the GRIPHON study, the effect of selexipag on
the composite endpoint of death from any cause or a complication related to PAH is consistent
across different IMDs following up-titration.
It is hypothesized that selexipag may have a beneficial effect on circulating biomarkers involved
in RV function and structure. Therefore, changes in such biomarkers from baseline to Week 26
and Week 52 will be explored. Biomarkers will be measured after the EOS at study level and will
be based on  the latest scientific evidence regarding RV function and structure at the time of
laboratory analysis. No genetic testing of any kind will be performed.
4.2.1. 
Study-Specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, during
the study, participants will be given any new information that may affect their decision to continue
participation. It will be explained that their consent to participate in the study is voluntary and may
be withdrawn at any time with no reason given and without penalty or loss of benefits to which they
would otherwise be entitled. Only participants who are fully able to understand the risks, benefits,
and potential AEs of the study, and provide their consent voluntarily will be enrolled.
The primary ethical concern is that PAH therapy escalation might be delayed in some participants
due to study participation. This is mitigated by assessing the primary endpoint after arelatively short
study duration and the permission to escalate PAH therapy at any time.
The total blood volume to be collected is considered to be an acceptable amount of blood to be
collected over this time period from the population in this study based upon the standard of the
American Red Cross.1
4.3. 
Justification for Dose
Study intervention will be up-titrated (see Section 6.1) to allow each participant to reach the IMD,
in the range of 200 to 1,600 µg twice daily. This is in accordance with the approved regimen and
doses as per the summary of product characteristics and United States prescribing information for
UPTRAVI®.30,31 Depending on the dose, a single dose of study intervention may consist of 1 or
more tablets.


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4.4. 
End of Study Definition
EOS Definition at Study Level
The EOS is defined as the day of the last study assessment shown in the schedule of activities
(Table 1) for the last participant in the study. The final data from the study site will be sent to the
sponsor (or designee) after completion of the final participant assessment at that study site, in the
time frame specified in the clinical trial agreement.
EOS Definition at Participant Level
For participants who complete treatment or who prematurely discontinue study intervention, EOS
visit is defined as the safety follow-up telephone call at least 30 days after last dose of study
intervention.
For participants who complete treatment in the RESTORE study and who are entering another
open-label clinical study with selexipag, the EOS visit is defined as the EOT visit. The enrollment
in the other open-label clinical study with selexipag must occur on the day of the last visit in the
RESTORE study. Safety data collection will continue in the other open-label clinical study with
selexipag.
5. 
STUDY POPULATION
Screening for eligible participants will be performed within 28 days before administration of the
study intervention. See Section 5.4 for conditions under which the repeat of any screening
procedures is allowed.
The inclusion and exclusion criteria for enrolling participants in this study are described below. If
there is a question about these criteria, the investigator must consult with the appropriate sponsor
representative and resolve any issues before enrolling a participant in the study. Waivers are not
allowed.
Investigators should ensure that all study enrollment criteria have been met at screening. If a
participant’s clinical status changes (including any available laboratory results or receipt of
additional medical records) after screening but before the first dose of study intervention is given
such that the participant no longer meets all eligibility criteria, then the participant should be
excluded from participation in the study. Section 5.4 describes options for retesting. The required
source documentation to support meeting the enrollment criteria is noted in Section 10.3.
Eligibility assessment may be made on the basis of local laboratory results assessed during
screening, in order to permit a quick decision and reduce participant burden. The local laboratory
results (with the corresponding normal ranges) must be recorded in the eCRF. Screening blood
samples are nevertheless required to be sent to the central laboratory.
For a discussion of the statistical considerations of participant selection, see Section 9.2.


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5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. 
Signed informed consent prior to any study-mandated procedure.
2. 
Criterion modified per Amendment 2
2.1 WHO FC II or III. Enrollment will be stratified by WHO FC II or III. Proportion of
participants with WHO FC II and WHO FC III are expected to be approximately 40%
and 60%, respectively.
3. 
Criterion modified per Amendment 2
3.1 PAH etiology belonging to one of the following groups according to classification27:
 Idiopathic PAH
 Heritable PAH
 Drugs or toxins induced
 PAH associated with connective tissue disease
 PAH associated with congenital heart disease, with simple systemic-to-pulmonary
shunt at least 1 year after surgical repair.
4. 
Criterion modified per Amendment 2
4.1 Criterion modified per Amendment 3
4.2 Diagnosis of PAH within 3 years prior to initiation of selexipag (Day 1), and most
recent right heart catheterization (RHC) within 1 year prior to initiation of selexipag
(Day 1) showing:
 mPAP ≥25 mmHg and
 PA wedge pressure (PAWP) or LV end-diastolic pressure (LVEDP) ≤15 mmHg
and
 PVR >5 WU (400 dyn.s.cm 5) and
 RVSV ≤60 mL as shown in RHC.
5. 
Criterion modified per Amendment 2
5.1 Patients already receiving PAH-specific oral mono or dual therapy (ie,
phosphodiesterase type 5 inhibitors (PDE-5i) or soluble guanylate cyclase stimulators
(sGCs) and/or ERA) or patients who are not candidates for these therapies. If on oral
PAH-specific therapy, treatment has to be stable (ie, no introduction of new therapies or
changes in dose) for at least 90 days prior to both ICF signature and Day 1.
6. 
Criterion modified per Amendment 2
6.1 Criterion modified per Amendment 3
6.2 NT-proBNP ≥300 ng/L (≥300 pg/mL; ≥35.5 pmol/L) at screening. Note: If local
assessment of BNP (instead of NT-proBNP) is used for eligibility, BNP measurement of
≥50 ng/L (≥50 pg/mL; 14.4 pmol/L) will be considered as meeting the inclusion criterion.
7. 
Criterion modified per Amendment 2


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7.1 Men or women ≥18 years (or the legal age of consent in the jurisdiction in which the
study is taking place if greater than 18) and <65 years.
8. 
Criterion modified per Amendment 2
8.1 Criterion modified per Amendment 3
8.2 Women of childbearing potential (Section 10.5) must meet the following criteria:
 Have a negative serum pregnancy test during screening and a negative urine
pregnancy test on Day 1, and
 Agree to use acceptable methods of contraception from Day 1 to at least 30 days
after study intervention discontinuation (Section 10.5), and
 If only using hormonal contraception, have used it for at least 1 month (30 days)
before Day 1, and
 Agree to perform monthly pregnancy tests to at least 30 days after study
intervention discontinuation.
9. 
New criterion per Amendment 2
9.1 6MWD ≥150 m during screening period.
5.2. 
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in the study:
1. 
Prior use of IP-receptor agonist, prostacyclin, or prostacyclin analog. Use of such
treatments for vasoreactivity testing is not exclusionary; intermittent use of such
treatments for digital ulcers or Raynaud’s phenomenon is not exclusionary if stopped
>6 months (180 days) prior to Day 1.
2. 
Treatment with strong inhibitors of CYP2C8 (eg, gemfibrozil) within 4 weeks (28 days)
prior to Day 1.
3. 
Treatment with another investigational drug planned or taken within 12 weeks (84 days)
prior to Day 1.
4. 
Cardiopulmonary rehabilitation programs based on exercise between informed consent
and expected Week 26 visit date.
5. 
Criterion modified per Amendment 3
5.1 Decompensated cardiac failure requiring hospitalization, emergency room visit or
intravenous (iv) diuretics in the 10 weeks (70 days) before Day 1, inclusive.
6. 
Severe coronary heart disease or unstable angina.
7. 
Cerebrovascular events (eg, transient ischemic attack, stroke) within 3 months (90 days)
prior to Day 1.


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8. 
Left atrial volume indexed for body surface area ≥43 mL/m2, assessed by Echo or
cardiac MRI.
9. 
Myocardial infarction within 6 months (180 days) prior to Day 1.
10. 
Criterion modified per Amendment 2
10.1 Body mass index >40 kg/m2 or body weight <40 kg.
11. 
Criterion modified per Amendment 2
11.1 Presence of one or more of the following signs of relevant lung disease at any time
up to Day 1 - if pulmonary function test results are missing, then exclusion 11 is
considered as met.
 
Diffusing capacity of the lung for carbon monoxide <40% of predicted
UNLESS computed tomography reveals no or mild interstitial lung disease
 
Forced vital capacity <60% of predictedb
 
Forced expiratory volume in 1 second <60% of predictedb.
12. 
Known or suspected pulmonary veno-occlusive disease (PVOD).
13. 
Congenital or acquired valvular defects with clinically relevant myocardial function
disorders not related to pulmonary hypertension.
14. 
SBP <90 mmHg at screening or on Day 1.
15. 
Criterion modified per Amendment 3
15.1 Severe renal impairment (estimated glomerular filtration rate by Modification of
Diet in Renal Disease [MDRD] formula ≤30 mL/min/1.73 m2 or serum creatinine
>2.5 mg/dL at screening) or ongoing or planned dialysis.
16. 
Criterion modified per Amendment 2
16.1 Criterion modified per Amendment 3
16.2 Known and documented severe hepatic impairment (with or without cirrhosis) at
screening, defined as Child-Pugh Class Cc.
17. 
Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism).
18. 
Criterion modified per Amendment 3
18.1 Any hospitalization within 10 weeks (70 days) prior to Day 1, inclusive (except
elective hospitalizations for surgery or standard monitoring of pre-existing conditions
that did not worsen).
b 
Pulmonary function tests may be performed either with or without the use of bronchodilators, as per local clinical
practice.
c 
The assessment of hepatic impairment (Child-Pugh Score) must be fully documented for participants who have
clinical signs and/orevidence (from central and/or local lab) of hepatic impairment. Absence of hepatic impairment
must be documented in the source data as well.


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19. 
Concomitant life-threatening disease with a life expectancy of less than 12 months.
20. 
Criterion modified per Amendment 3
20.1 Hemoglobin <80 g/L (<8 g/dL; <4.96 mmol/L) at screening.
21. 
Hypersensitivity to selexipag or any study intervention excipient (mannitol, maize
starch, hydroxypropylcellulose, magnesium stearate, hypromellose, propylene glycol,
titanium dioxide, carnauba wax, iron oxide red, iron oxide yellow, iron oxide black).
22. 
Criterion modified per Amendment 2
22.1 Pregnancy, breastfeeding, or intention to become pregnant during the study.
23. 
Any factor or condition likely to affect compliance with study intervention or visit plan,
as judged by the investigator.
24. 
Claustrophobia.
25. 
MRI-incompatible permanent cardiac pacemaker, automatic internal cardioverter.
26. 
Metallic implant (eg, defibrillator, neurostimulator, hearing aid, permanent use of
infusion device, dental brace, metal-containing tattoo ink)d.
27. 
Criterion modified per Amendment 3
27.1
 Cardiac arrythmia assessed severe by the investigator
 Conditions that could interfere with proper cardiac gating, eg, atrial fibrillation,
multiple premature ventricular or atrial contractions.
5.3. 
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions
during the course of the study to be eligible for participation:
1. 
See Section 6.6 for details regarding prohibited and restricted therapy during the study.
2. 
Agree to follow all requirements that must be met during the study as noted in the
inclusion and exclusion criteria (eg, contraceptive requirements, monthly pregnancy
testing in Section 5.1).
5.4. 
Screen Failures
For participants who failed screening, the following data will be recorded in the eCRF if available:
reason for screening failure and baseline data collected until confirmation of the screening failure.
d 
Local MRI team’s advice should be sought in case of doubt.


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Individuals who do not meet the criteria for participation in this study (screen failure) may be
rescreened once, if the reason for non-eligibility was transient (eg, abnormal laboratory test,
insufficient wash-out period of an exclusionary medication). All screening assessments must have
been made within 28 days before Day 1. Exceptional and limited retesting of abnormal screening
values that lead to exclusion are allowed only once using an unscheduled visit to reassess eligibility
during the screening period. If a participant does not meet all inclusion and exclusion criteria (is a
screen failure) but at some point in the future is expected to meet the participant eligibility criteria,
the participant may be rescreened on one occasion only. Participants who are rescreened will be
assigned a new participant number, undergo the informed consent process, and then restart a new
screening phase.
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy
identification of each participant during and after the study. This document will be reviewed by
the sponsor study-site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed
by the investigator in the study file. To ensure participant confidentiality, no copy will be made.
All reports and communications relating to the study will identify participants by participant
identification.
6. 
STUDY INTERVENTION
6.1. 
Description of Study Intervention
Manufacturing, labeling, packaging, and supply of study intervention will be conducted according
to Good Manufacturing Practice, Good Clinical Practice, and any local or national regulatory
requirements.
Selexipag will be manufactured and provided under the responsibility of the sponsor. See the
Investigator’s Brochure16 for a list of excipients.
All study intervention supplies are to be used only in accordance with this protocol and not for any
other purpose.
Study intervention is labeled to comply with the applicable laws and regulations of the
countries/territories in which the study sites are located. Labels must remain affixed to the bottles.
Open-label selexipag will be provided as round, debossed, film-coated tablets in childproof bottles.
Study intervention 
name:
Selexipag
Dosage formulation 
Round, film-coated tablets


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Unit dose strengths/ 
Dosage levels: 
200 g: light-yellow, film-coated tablets with “2” debossed on one side
400 g: red, film-coated tablets with “4” debossed on one side
600 g: light-violet, film-coated tablets with “6” debossed on one side
800 g: green, film-coated tablets with “8” debossed on one side
1000 g: orange, film-coated tablets with “10” debossed on one side
1200 g: dark-violet, film-coated tablets with “12” debossed on one side
1400 g: dark-yellow, film-coated tablets with “14” debossed on one side
1600 g: brown, film-coated tablets with “16” debossed on one side
Route of administration 
Oral
Dosing instructions 
One dose twice daily (in the morning and in the evening), with or without food.
6.2. 
Study Intervention Administration
The tablets will be administered orally and should be swallowed whole (ie, not crushed, split, or
chewed) with water.
On Day 1, the participant will receive only 1 dose, and at each dose change, the first intake of the
new  dose is to be taken in the evening to reduce the likelihood of the occurrence of
prostacyclin-associated AEs. Tolerability may improve when study interventionis taken with food.
Participants with moderate hepatic impairment (Child-Pugh Class B) or who are concomitantly
taking (a) moderate CYP2C8 inhibitor(s) will start with 200 µg qd in the morning of Day 2.
For a definition of study intervention overdose, see Section 6.9.
Study intervention  administration must be captured in the source documents and the eCRF.
Study-site personnel will instruct participants on how to store study intervention for at-home use
as indicated for this protocol.
6.2.1. 
Study Intervention Up-Titration
Based on the GRIPHON study, the effect of selexipag on the composite endpoint of death from
any cause or a complication related to PAH is consistent across different IMDs. The goal of the
up-titration is to permit each participant to reach his/her personal highest tolerated dose without
unmanageable prostacyclin-associated adverse effects.
Study intervention will be up-titrated to allow each participant to reach their IMD, in the range of
200 to 1,600 µg twice daily.
The study intervention will be up-titrated from Day 1 to the end of Week 12 (Day 84). Dosing will
start at 200 g twice daily. The site will call the participant once a week from the end of Week 1
to the end of Week 12 and decide whether to increase the dose by 200 g twice daily (Table 2) if
possible. Up-titration will be flexible and may be adapted in case of adverse effects that cannot be
relieved with symptomatic treatmente. In this case, the site may either postpone up-titration by
1 week or down-titrate study intervention.
e 
Such as headache, diarrhea, nausea and vomiting, jaw pain, myalgia, pain in extremity, arthralgia, and flushing.


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The dose reached at the end of Week 12 will be considered the participant’s IMD and will be
maintained until EOT.
Table 2: 
Up-Titration Guide
Weeks 
Days 
Target selexipag dose
(µg, twice per day)a 
Comments
1 
1-7 
200 
In case of adverse effects that cannot be relieved
with symptomatic treatment, postponement of
up-titration by 1 week or down-titration should be
considered.
2 
8-14 
400
3 
15-21 
600 
4 
22-28 
800
5 
29-35 
1000
6 
36-42 
1200
7 
43-49 
1400
8 
50-56 
1600
9-12 
57-84  
Buffer period to permit
up/down-titration to
ensure IMD is reached at
the end of Week 12.
13-52 
85-364 
IMD
IMD individual maintenance dose
a 
On Day 1, the participant will receive only 1 dose, and at each dose change the first intake of the new dose should be
taken in the evening.
6.2.2. 
Study Intervention Maintenance
The maintenance phase will consist oftreatment at the participant’s IMD from the start at Week 13
to the end of Week 52.
6.3. 
Preparation/Handling/Storage/Accountability
Study intervention supplies must be kept in an appropriate, secure area and stored according to the
conditions specified on the label. See the pharmacy manual/study-site investigational product and
procedures manual for additional guidance on study intervention preparation, handling, and
storage.
Participants will be asked to return all used, partially used, and unused study intervention bottles at
each visit. The protocol-mandated study intervention  dispensing procedures may not be altered
without prior written approval from the sponsor. The interactive web response system will allow
dispensation of study intervention outside scheduled visits. An accurate record of the date, strength,
and amount of study intervention dispensed to each participant must be available for inspection at
any time.
The investigator is responsible for ensuring that all study intervention received at the site is
inventoried and accounted for throughout the study. The dispensing of study intervention (strength


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and number of dispensed bottles and date dispensed/strength and number of tablets dispensed) to
the participant, and the return of study intervention (date returned/strength and number of tablets
returned) from the participant (if applicable), must be documented on the intervention
accountability form. Participants must be instructed to return all original containers, whether
empty or containing study intervention. All study intervention  will be stored and disposed of
according to the sponsor’s instructions. Study-site personnel must not combine contents of the
study intervention containers. If the participant forgets to bring the remaining study intervention
to a study visit, participant must be instructed to not take any tablets from the remaining study
intervention bottle and to return it at the next visit.
Study intervention must be handled in strict accordance with the protocol and the container label,
and must be stored at the study site in a limited-access area or in a locked cabinet under appropriate
environmental conditions. Unused study intervention, and study intervention  returned by the
participant, must be available for verification by the sponsor’s study-site monitor during on-site
monitoring visits. The return to the sponsor of unused study intervention, or used returned study
intervention for destruction, will be documented on the intervention return form. When the study
site is an authorized destruction unit and study intervention supplies are destroyed on-site, this
must also be documented on the intervention return form.
Potentially hazardous materials such as, but not limited to, needles, syringes and vials containing
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be
retained for accountability purposes.
Study intervention should be dispensed under the supervision of the investigator or a qualified
member of the study-site personnel, or by a hospital/clinic pharmacist. Study intervention will be
supplied only to participants enrolled in the study. The participants will receive sufficient study
intervention to cover the period up to the next scheduled visit. Returned study intervention must
not be dispensed again, even to the same participant. Study intervention may not be relabeled or
reassigned for use by other participants. The investigator agrees neither to dispense the study
intervention from, nor store it at, any site other than the study sites agreed upon with the sponsor.
Further guidance and information for the final disposition of unused study interventions will be
provided in the pharmacy manual/study-site investigational product and procedures manual.
6.4. 
Measures to Minimize Bias: Randomization and Blinding
As this is an open-label study, randomization and blinding procedures are not applicable.
6.5. 
Study Intervention Compliance
Study intervention  compliance will be based on study intervention  accountability. Study
intervention compliance will be calculated by site personnel at each  site visit using the below
formula and entered in the eCRF:


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For each strength dispensed:
Compliance [(number of tablets dispensed  number of tablets returned) /
total number of tablets that should have been taken during the periodf] × 100.
Between visits, compliance is expected to be between 80% and 120%. Compliance values outside
of this range will be considered as a protocol deviation, which will be reported in the clinical trial
management system  by the clinical research associate. During the course of the study, the
investigator or designated study-site personnel will be responsible for providing additional
instruction to reeducate any participant who is not compliant with taking the study intervention.
This discussion and its outcome must be documented in the source documents.
6.6. 
Concomitant Therapy
Aparticipantmay be enrolled only if therapies received before Day 1 comply with eligibility criteria.
From Day 1 to completion of EOT assessments, the following therapies are forbidden and will lead
to study intervention discontinuation:
 Strong inhibitors of CYP2C8 (eg, gemfibrozil)
 Prostacyclin, prostacyclin analog, or any other agent acting on the prostacyclin pathway,
except iv selexipag in the US for participants who are temporarily (maximum of 14 days; see
Section 7.2) unable to take the study intervention orally
 Any other investigational drug
From Day 1 to completion of EOT assessments, the following therapies may be initiated or
up-titrated (if applicable) ifdocumented symptoms lead to the decision to escalate PAH treatment
before Week 52 assessments:
 sGCs
 ERA
 PDE-5i
 Any other PAH-specific therapy that would become commercially available, provided it is not
acting on the prostacyclin pathway
6.7. 
Study Intervention Dose Modification
Any dose/dosage adjustment should be overseen by medically-qualified study-site personnel
(principal or sub-investigator), unless an immediate safety risk appears to be present. See
Section 6.2.1 for titration of study intervention during the first 12 weeks of treatment.
For participants with moderate hepatic impairment (Child-Pugh Class B) or using moderate
inhibitors of CYP2C8 (eg, clopidogrel, deferasirox, teriflunomide, leflunomide) concomitantly with
the study intervention, dosing frequency of study intervention must be reduced to once a day. Dosing
f 
According to the study intervention administration log


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frequency of selexipag should be reverted to twice daily  when co-administration of moderate
CYP2C8 inhibitor is stopped16.
It has been shown that, when moderate or strong inducers of CYP2C8 are used in combination with
selexipag, the exposure to selexipag active metabolite is reduced by half. Dose adjustment of
selexipag may be required with concomitant administration of inducers of CYP2C8 (eg, rifampicin,
carbamazepine, phenytoin).
The effect of strong inhibitors of UDP-glucuronosyltransferase (UGT)1A3 and UGT2B7 (eg,
valproic acid, probenecid, and fluconazole) on the exposure to selexipag or its active metabolite has
not been studied. Concomitant administration may result in an increase in exposure to the active
metabolite. Therefore, caution is required when these medicinal products are administered
concomitantly with selexipag.
6.8. 
Continued Access to Study Intervention After the End of the Treatment
Period
Local regulations on continued access will always take precedence.
At the end of their participation in the treatment period, participants who benefit from the study
intervention as assessed by the treating physician  will be offered the opportunity to continue
receiving selexipag via the following options:
 
Switch to commercial selexipag, applicable to participants who reside in a country/territory
where selexipag is approved, commercially available and reimbursed for the treatment of
participant’s PAH.
 
Switch to a PTA program which will be set up for participants who reside in
countries/territories where selexipag is not yet commercially available or not reimbursed for
the participant’s PAH, if allowed as per local regulations.
 
Switch to another open-label clinical study with selexipag, applicable for participants who
reside in a country/territory where the conduct of such study is approved by the local health
authorities and where the 2 options above are not applicable.
6.9. 
Overdose
Overdose is defined by the intake of a dose >1,600 µg or a total daily dose >3,200 µg. For
participants with moderate hepatic impairment or who are concomitantly taking moderate
CYP2C8 inhibitor(s), the dosing frequency is once daily and overdose is defined by the intake of
a dose >1,600 µg or a total daily dose >1,600 µg.16
Isolated cases of overdose up to 3,200 µg were reported. Mild, transient nausea was the only
reported consequence. In the event of overdose, supportive measures must be taken as required.
In the event of a selexipag overdose, the investigator or treating physician should:
 
Contact the Medical Monitor immediately.


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Evaluate the participant to determine, in consultation with the Medical Monitor, 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).
 
Document the quantity of the excess dose as well as the duration of the overdosing in the
eCRF.
 
Institute supportive therapy as clinically indicated. Dialysis is unlikely to be effective because
selexipag and its active metabolite are highly protein bound.
For more information see Section 10.4.
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1. 
Discontinuation of Study Intervention
The decision to prematurely discontinue study intervention may be made by the participant, the
investigator, or sponsor personnel. A participant has the right to prematurely discontinue study
intervention at any time, without any justification, by withdrawal from study intervention only or
by withdrawal from any further participation in the study. The investigator must discontinue study
intervention  for a given participant if, on balance, investigator believes that continued
administration would be contrary to the best interests of the participant.
A participant’s study intervention must be discontinued if:
 
The participant withdraws consent to receive study intervention.
 
The investigator believes that for safety or tolerability reasons, it is in the best interest of the
participant to discontinue study intervention.
 
The female participant becomes pregnant (see Section 10.5).
 
The participant develops severe hepatic impairment. If hepatic impairment is suspected, a
clinical assessment of severity (eg, Child-Pugh score) must be performed and fully
documented. If a participant has developed severe hepatic impairment (Child-Pugh Class C)
at any time during the study, the study intervention must be permanently discontinued (see
Section 10.8).
 
The participant develops pulmonary edema due to PVOD. Should signs of pulmonary edema
occur, the possibility of associated PVOD should be considered. If confirmed, the study
intervention must be discontinued.
 
Planned initiation of prohibited treatments during the treatment period.
 
Study intervention interruptions exceeding 14 consecutive days.
If a participant discontinues study intervention for any reason (except withdrawal of consent from
any further participation in the study) before scheduled EOT at Week 52, participant will continue
to attend the visits and assessments as scheduled (ie, premature EOT and EOS visits), provided
the participant’s consent for this limited participation in the study has not been withdrawn. If the


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reason for withdrawal from the study is withdrawal of consent from any further participation in
the study, then no additional assessments will be permitted.
7.2. 
Temporary Interruption of Study Intervention
Study interventionmay be temporarily interrupted in response to an AE, a diagnostic or therapeutic
procedure, a laboratory abnormality, or for administrative reasons.
Interruptions of study intervention must be kept as short as possible. In case of study intervention
interruption between 3 to 14 days, study intervention should be re-started at a lower dose at the
discretion of the investigator, and then titrated to the pre-interruption dose. For each participant,
the up-titration frequency will be up to the medical judgment of the investigator and based on
his/her clinical evaluation of the participant’s tolerability of the study intervention prior to its
interruption (see Section 6.2.1). Re-uptitration can be done at scheduled or unscheduled telephone
calls or visits.
Study intervention  interruptions exceeding 14 consecutive days must lead to permanent
discontinuation of study intervention (see Section 7.1).
Interruptions of 1 day or more must be recorded on the study intervention log in the eCRF.
7.3. 
Participant Discontinuation/Withdrawal from the Study
A participant will not be automatically withdrawn from the study if participant has to discontinue
study intervention before the end of the intervention regimen (Section 7.1).
A participant will be withdrawn from the study for any of the following reasons:
 
Lost to follow-up (Section 7.4)
 
Withdrawal of consent from any further participation in the study
 
Death
 
Participant is poorly compliant with study procedures, visits, and assessments, preferably after
evaluation and discussion between the investigator and the sponsor
 
The investigator believes that continued participation in the study would be contrary to the
best interests of the participant
 
Sponsor’s decision for any reason, including but not limited to premature termination or
suspension of the study
If a participant discontinues study intervention and withdraws from the study before the EOS visit
for any reason (except for death, loss to follow-up, or withdrawal of consent from any further
participation in the study), every attempt should be made to schedule a last appointment/telephone
call to assess the safety and well-being of the participant, collect unused study intervention, and
discuss follow-up medical care. 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 6.7.


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When a participant withdraws before study completion, the reason for withdrawal (if known) is to
be documented in the eCRF and in the source document.
Withdrawal of Consent
A participant declining to return for scheduled visits does not necessarily constitute withdrawal of
consent. Alternate follow-up mechanisms that the participant agreed to when signing the consent
form apply (eg, consult with family members, contacting the participant’s other physicians,
medical records, database searches, use of locator agencies at study completion) as local
regulations permit.
Prior to a participant withdrawing consent for follow-up, the investigator should offer the
participant an opportunity for one of the alternative reduced follow-up mechanisms described
below. Withdrawal of consent should be an infrequent occurrence in clinical studies,23 therefore,
prior to the start of the study, the sponsor and the investigator should discuss and reach a clear
understanding of what constitutes withdrawal of consent in the context of the available reduced
follow-up mechanisms listed.
Circumstances for Reduced Follow-up
Only in a situation where a participant may be at risk for withdrawal of consent and is unable to
return for scheduled visits at the protocol-defined frequency, the investigator may consider options
for reduced follow-up. These may include (as local regulations permit):
 
Less frequent clinical visits
 
Telephone, email, letter, social media, fax, or other contact with:
 
participant
 
relatives of the participant
 
participant’s physicians (general or specialist)
 
Review of any available medical records
Details regarding these contacts must be properly documented in source records including
responses by participants.
7.4. 
Lost to Follow-up
Prior to enrollment, measures should be taken to reduce the chances of a participant being deemed
lost to follow-up. These measures include attempts to obtain contact information from each
participant, eg, home, work, and mobile telephone numbers and email addresses for both the
participant as well as appropriate family members.
A participant will be considered lost to follow-up if participant repeatedly fails to return for
scheduled visits and is unable to be contacted by the study site. A participant cannot be deemed
lost to follow-up until all reasonable efforts made by the study-site personnel to contact the


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participant are deemed futile. The following actions must be taken if a participant fails to return to
the study site for a required study visit:
 
The study-site personnel must attempt to contact the participant to reschedule the missed visit
as soon as possible, to counsel the participant on the importance of maintaining the assigned
visit schedule, to ascertain whether the participant wishes to or should continue in the study.
 
Before a participant is deemed lost to follow-up, the investigator or designee must make every
reasonable effort to regain contact with the participant (where possible, 3 telephone calls,
e-mails, fax, and, if necessary, a certified letter to the participant’s last known mailing address,
or local equivalent methods). These contact attempts should be documented in the
participant’s medical records.
 
Should the participant continue to be unreachable, participant will be considered to have
withdrawn from the study.
Should a study site close, eg, for operational, financial, or other reasons, and the investigator cannot
reach participants to inform them, their contact information will be transferred to another study
site.
8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
The schedule of activities (Table 1) summarizes the frequency and timing of efficacy, safety, and
exploratory assessments applicable to this study.
For all visits, the participants must be seen or called on the designated day with an allowed visit
window indicated in the schedule of activities. Efficacy assessments at EOT must be performed at
trough (ie, morning dose NOT taken). A follow-up safety telephone call/visit must be performed
at least 30 days after intake of the last dose of study intervention. If it is not possible to complete
all assessments on the same day, a visit may extend over more than 1 day within the allowed time
window.
All study assessments will be performed by qualified study personnel (medical, nursing, or
specialist technical personnel) and will be recorded in the eCRF, unless otherwise specified. Actual
dates of assessments will be recorded in the eCRF.
The total blood volume to be collected from  each participant will be approximately 69 mL
(Table 3).


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Table 3: 
Volume of Blood to be Collected From Each Participant
Type of Sample 
Volume per 
Sample (mL) 
No. of Samples 
per Participant 
Approximate
Total Volume
of Blood (mL)a
Safety (including screening and post-intervention
assessments)
Hematology  
2 
3 
6
Clinical chemistry  
6 
3 
18
Serum -hCG pregnancy testsb 
2.5 
3 
7.5
NT-proBNP sample 
2.5 
3 
7.5
Biomarker samples 
10 
3 
30
Approximate totalc 
23 
69
a 
Calculated as number of samples multiplied by amount of blood per sample.
b 
For women of childbearing potential.
c
Repeated or unscheduled samples may be taken for safety reasons or technical issues with the samples.
hCG human chorionic gonadotropin; NT proBNP N terminal pro hormone brain natriuretic peptide.
Unscheduled Visits
Unscheduled visits may be performed at any time during the study. Depending on the reason for
the unscheduled visit, appropriate assessments may be performed based on the judgment of the
investigator.
After an unscheduled visit, the regular scheduled study visits must continue according to the
planned visit and assessment schedule.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory
requisition form.
See the schedule of activities (Table 1) for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples will be provided in the
laboratory manual. Collection, handling, storage, and shipment of samples must be under the
specified, and where applicable, controlled temperature conditions as indicated in the laboratory
manual.
Study-specific Materials
The investigator will be provided with the following supplies:
 
Investigator’s Brochure.
 
Pharmacy manual/study site investigational product and procedures manual.
 
MRI image acquisition protocol (IAP) and Echo IAP.
 
Sponsor guidance for 6MWT.
 
Laboratory manual, requisition forms, and sampling supplies.
 
Participant experience questionnaire EQ-5D-3L in local language(s).
 
Interactive web response system manual (IWRS).


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eCRF completion guidelines.
 
SAE form and completion guideline.
 
Pregnancy notification forms.
 
Product Quality Complaint (PQC) forms.
 
Study participant cards.
 
Sample ICFs.
8.1. 
Demographics and Baseline Characteristics
Demographic and baseline PAH characteristic data to be collected on all enrolled participants
include: age, sex, race and ethnicity (where local regulations permit), weight and height, date of
the initial PAH diagnosis by RHC and WHO FC at screening.
8.2. 
Medical History
All relevant medical history/current medical conditions based on the investigator’s judgment (eg,
chronic and ongoing acute conditions, serious past conditions) or for which the participantreceives
a treatment and that are ongoing before and/or at the time of signing informed consent will be
recorded on the medical history page. Where possible, diagnoses and not symptoms will be
recorded.
8.3. 
Efficacy Assessments
8.3.1. 
Imaging
8.3.1.1. 
Expert Reviewers
A team of independent expert MRI reviewers and a team of independent expert Echo reviewers
will be selected, based on their qualifications and experience. For their respective imaging
modality (MRI or Echo), they will be responsible for:
 
Reviewing and approving the IAP
 
Writing the variable assessment charter
 
Quality control of images
 
Central assessment of imaging according to the charter.
IAPs and variable assessment charters will be reviewed by the sponsor.
8.3.1.2. 
Site Qualification
Participating sites will need to be qualified for MRI and Echo before enrolling participants.
Qualification will be performed in 2 steps: first, a questionnaire describing the site’s MRI/Echo
equipment will be reviewed by one of the appropriate expert reviewers. Second, if the
questionnaire is approved, the site will submit imaging of a volunteer, performed according to the


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IAP. Sites will be qualified if an expert reviewer confirms that imaging quality is appropriate for
the study.
Sites who previously demonstrated suitable imaging quality in any other of the sponsor’s studies
will be qualified for MRI/Echo by confirming that the equipment and imaging team for this study
are those that previously proved appropriate.
8.3.1.3. 
Image Acquisition
Imaging will be performed as described in the MRI IAP/Echo IAP.
8.3.1.4. 
Quality Control
For each enrolled participant, expert reviewers will control the quality of imaging as it becomes
available.
8.3.1.5. 
Imaging Assessment
After an individual participant’s Week 26 or Week 52 imaging assessments, a single reviewer will
read all scans (MRI or Echo) of that participant at once. For this review, expert reviewers will be
blinded to the participant and timepoint and will assess variables according to the MRI/Echo
review charter.
8.3.2. 
6MWT
Exercise capacity will be measured by the 6MWT. The 6MWT is a non-encouraged test that
measures the distance walked in 6 minutes. It will be performed according to sponsor guidance
(Section 10.9).
At Week 26 and EOT visit, participants must NOT take the morning study interventiondose before
any visit-related procedure.
Dyspnea will be assessed by the Borg CR 10 Scale®, a scale used to quantify the degree of
shortness of breath before and at the end of the 6MWT (Section 10.9).
8.3.3. 
WHO FC
WHO FC will be determined as per WHO definition (Section 10.6).
8.3.4. 
Risk Stratification
Clinical signs of right heart failure, progression of PAH symptoms, and syncope will be collected
at screening and Week 26 visit; and will be used for risk stratification.
8.3.5. 
NT-proBNP
A blood sample will be drawn for the analysis of NT-proBNP. NT-proBNP results will be assessed
by the central laboratory. Details regarding blood sampling procedures, collection, and shipment
of the samples will be described in the laboratory manual.


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8.3.6. 
Biomarkers
It is hypothesized that selexipag may have a beneficial effect on circulating biomarkers involved
in RV function and structure; therefore, changes in such biomarkers from baseline to Week 26 and
Week 52 will be explored.
Serum samples will be stored. They will be used to assess additional exploratory biomarkers after
the EOS  at study level. These additional exploratory biomarkers will be based on the latest
scientific evidence regarding RV  function and structure at the time of laboratory analysis
(Section 10.2). No genetic testing of any kind will be performed.
The exploratory biomarkers may be analyzed by different laboratories; each analyte will be
analyzed by the same laboratory for all participants.
8.4. 
Safety Assessments
The standard assessments to evaluate the safety and tolerability of selexipag in this study include
reporting and follow-up of (S)AEs, pregnancies, physical examination, vital signs, and safety
laboratory tests from signing of ICF onwards until the EOS visit (see Section 4.4) (Table 1).
AEs will be reported and followed by the investigator as specified in Section 8.5 and Section 10.4.
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event
section of the eCRF.
Any clinically significant abnormalities persisting at the EOS/early withdrawal will be followed
by the investigator until resolution or until a clinically stable condition is reached or until the
participant has been deemed lost to follow-up (see Section 7.4).
8.4.1. 
Physical Examination
Physical examination will include the evaluation of the participant’s height (only at screening), the
general appearance, heart and lungs. Other examinations will be performed if indicated, based on
medical history and/or symptoms.
Height will be measured without shoes.
Physical examination findings made after signing of informed consent, which meet the definition
of an AE must be recorded on the Adverse Event page of the eCRF.
8.4.2. 
Vital Signs
Heart rate (HR), SBP, diastolic blood pressure (DBP) and body weight, will be assessed during
on-site visits.
Blood pressure and pulse/heart rate measurements will be assessed in a supine or sitting position
with an automated device. Manual techniques will be used only if an automated device is not
available. It is recommended that the participant is allowed to rest for at least 5 minutes before the
measurement. It is also recommended that measurements are performed on the same arm and in


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the same position (supine or sitting) throughout the study for each individual participant. Vital
signs are to be measured prior to blood collection.
Body weight will be measured in indoor clothing without shoes.
8.4.3. 
Clinical Safety Laboratory Assessments
Blood samples for clinical chemistry and hematology will be collected as noted in Section 10.2.
Safety laboratory results will be assessed by the central laboratory. Safety laboratory analyses will
include:
 
Basic hematology panel
 
Clinical chemistry panel including thyroid-stimulating hormone (TSH), triiodothyronine (T3),
and thyroxine (T4)
 
Pregnancy tests for females of childbearing potential. A serum pregnancy test will be
performed at the site at screening, at Week 26 and at Week 52 (EOT); urine pregnancy tests
will be performed at the site on Day 1, and at the participant’s home monthly between Day 1
and EOS, except for Month 6 and Month 12, when a serum pregnancy test is performed at the
site visit (Weeks 26 and 52). The site will call female participants of childbearing potential
monthly to check the pregnancy test result.
All laboratory reports must be reviewed, signed and dated by the investigator or delegate and filed
with the source documents. 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 signing of informed consent 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 8.5 and
Section 10.4).
8.5. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information, from clinical studies
are crucial for the protection of participants, investigators, and the sponsor, and are mandated by
regulatory agencies worldwide. The sponsor has established standard operating procedures in
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in
accordance with those procedures.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the
participant’s legally acceptable representative) for the duration of the study.
Further details on AEs, SAEs, and PQC can be found in Section 10.4.


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8.5.1. 
Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
All Adverse Events
All AEs and special reporting situations (Section 10.4), whether serious or non-serious, will be
reported on specific Adverse Event pages of the eCRF throughout the study from signing of the
ICF onwards until the EOS visit (see Section 4.4) or date of last contact (see Section 7.3).
Serious Adverse Events
All SAEs, as well as PQC, occurring during the study must be reported to the appropriate sponsor
contact person by study-site personnel within 24 hours of their knowledge of the event.
Serious adverse events, including those spontaneously reported to the investigator until EOS, must
be reported on Adverse Event pages in the eCRF and on the Serious Adverse Event form, whether
or not this event is considered by the investigator to be related to study intervention.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event
form, which must be completed and signed by a physician from the study site, and transmitted to
the sponsor immediately but no later than within 24 hours. The initial and follow-up reports of a
SAE should be made by facsimile (fax) or email. Telephone reporting should be the exception and
the reporter should be asked to complete the appropriate form(s) first.
8.5.2. 
Follow-up of Adverse Events and Serious 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.
Adverse events, including pregnancy, will be followed by the investigator as specified in
Section 10.4 Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-Up, and
Reporting.
8.5.3. 
Regulatory Reporting Requirements for Serious Adverse Events
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 suspected unexpected serious adverse reactions (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.


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8.5.4. 
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be
reported to the sponsor by the study site personnel within 24 hours of their knowledge of the event
using the appropriate Pregnancy Notification Form. Abnormal pregnancy outcomes (eg,
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are
considered SAEs and must be reported using an SAE reporting form. Any participant who becomes
pregnant during the study must discontinue further study intervention.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the
newborn will be required. The duration of this follow-up will depend on the clinical conditions of
the newborn and may be extended until discharge from hospital when applicable.
Any SAE occurring during the pregnancy must be reported as described in Section 10.4.
8.6. 
Participants’ Experience
Participants’ experience will be assessed with the 3-level version of EQ-5D (EQ-5D-3L)
questionnaire during Day 1, and at Week 26 and Week 52 (EOT) at the site.
The EQ-5D-3L questionnaire has 2 components: health state description and visual analogue scale
(EQ VAS) for participant’s self-rating. In the description part, health status is measured in
5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression  at 3
levels: no problems, some problems, and extreme problems. See Section 10.7.
If an event meeting the definition of an AE is reported by a participant in the context of a
questionnaire, it is the physician’s responsibility to report it as an AE in the eCRF form.
8.7. 
Genetics
Genetics are not evaluated in this study.
9. 
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the efficacy and safety data is outlined
below. Specific details will be provided in the SAP.
9.1. 
Statistical Hypotheses
The null statistical hypothesis is that the mean change from baseline to Week 26 in RVSV is equal
to zero. The alternative statistical hypothesis is that the mean change from baseline in RVSV is
different from zero.
9.2. 
Sample Size Determination
Sample size calculation for the primary endpoint is based on the following assumptions:
 
A 2-sided Type I error of 5% and a Type II error of 10% (90% power)
 
A mean change from baseline to Week 26 in RVSV of +8 mL
 
A standard deviation (SD) of 20 mL for the change from baseline to Week 26 in RVSV


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A normal distribution for the change from baseline to Week 26 in RVSV
 
15% of participants with non-evaluable RVSV assessment at baseline and/or postbaseline
Based on the above assumptions, a total of 80 participants (68 analyzable + 12 to account for 15%
non-evaluable) must be enrolled in order to establish whether change from baseline to Week 26 in
RVSV is different from zero (based on paired t-test for single arm).
The assumption that the change from baseline to Week 26 in RVSV is +8 mL is in line with
literature suggesting that a difference of 8 mL to 12 mL is clinically relevant.35 The associated SD
of 20 mL is justified by the REPAIR study interim analysis on 42 participants, where the observed
mean change (SD) from baseline to Week 26 was +16.6 mL (16.34).
Table 4 displays power calculations for different assumptions of treatment effect and associated
SD, given a fixed number of 68 analyzable participants (80 in total).
Table 4: 
Sample Size Power Sensitivity
Scenario 
Change from baseline
to Week 26 in RVSV (mL) 
Associated SD  
Power
Retained scenario 
8 
20 
90%
Sensitivity 1 
8 
22 
84%
Sensitivity 2 
8 
25 
74%
Sensitivity 3 
10 
20 
98%
Sensitivity 4 
10 
22 
96%
Sensitivity 5 
10 
25 
90%
9.3. 
Populations for Analyses
For purposes of analysis, the following populations are defined:
 
Screened Analysis Set: The Screened Analysis Set will include all participants who were
screened and received a participant number.
 
Safety Set: The Safety Set (SS) will include all participants from the Screened Analysis Set
who received at least 1 dose of study intervention.
 
Full Analysis Set: The Full Analysis Set (FAS) will include all participants from the SS who
had a baseline as well as a postbaseline measurement for RVSV assessed by cardiac MRI from
pulmonary artery flow.
 
Per-protocol Analysis Set: The Per-Protocol Analysis Set (PPS) will include all participants
in the FAS without major protocol deviations that could affect the main analysis of the primary
efficacy variable.
9.4. 
Statistical Analyses
The SAP will be finalized prior to database lock and it will include a more technical and detailed
description of the statistical analyses described in this section. This section is a summary of the
planned statistical analyses of the most important endpoints including primary and secondary
endpoints.


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9.4.1. 
General Considerations
The overall type I error is α 0.05. All analyses will be performed using 2-sided statistical tests.
If the primary endpoint analysis is statistically significant (ie, p-value below nominal alpha), the
study will be declared positive.
No multiplicity adjustments will be performed for secondary/exploratory endpoints, and therefore,
all associated p-values are of exploratory nature. No interim analysis will be performed.
Participants without a baseline value will be excluded from the corresponding analysis.
Subgroup analyses on primary and secondary endpoints will include WHO FC (II/III) at baseline.
Additional subgroup analyses will be specified in the SAP. All subgroup analyses will be of
exploratory nature.
9.4.2. 
Primary Endpoint
The primary efficacy analysis will be performed on the FAS. RVSV will be summarized by
timepoint (baseline and Week 26) using descriptive statistics (n, mean, SD, median, Q1 and Q3).
The change from baseline to Week 26 in RVSV will be summarized similarly.
Change from baseline in RVSV will be analyzed at α 0.05 (2-sided) using an analysis of
covariance (ANCOVA) with a factor for WHO FC (II/III) at baseline and a covariate for baseline
RVSV. The mean change from baseline and 95% CI will be estimated based on the model.
A sensitivity analysis will be performed on the PPS. Another sensitivity analysis will be performed
on the SS, where participants with missing postbaseline RVSV will be imputed using their baseline
value.
9.4.3. 
Secondary Endpoints
Change from baseline to Week 26 in RVEDV, RVESV, RVEF, RV mass, RVGLS, 6MWD, and
number of low-risk criteria will be summarized descriptively by timepoint and analyzed at α 0.05
(2-sided) on the FAS using an ANCOVA with a factor for WHO FC (II/III) at baseline and a
covariate for baseline value. The mean change from baseline and 95% CI will be estimated based
on the model.
WHO FC will be summarized on the FAS by timepoint using frequency tables. Changes from
baseline in WHO FC will be dichotomized as worsening (ie, change >0) versus no change or
improvement (ie, change ≤0). Worsening will be analyzed at α 0.05 (2-sided) using a logistic
regression model with a factor for WHO FC (II/III) at baseline.
NT-proBNP will be summarized on the FAS by timepoint using descriptive statistics as well as
geometric means and CVs. The Week 26 versus baseline ratio will be summarized similarly. The
ratio versus baseline in NT-proBNP will be log-transformed and analyzed at α 0.05 (2-sided)
using an ANCOVA with a factor for WHO FC (II/III) at baseline and a covariate for baseline log
NT-proBNP.


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As described in Section 9.4.1, all analyses for secondary endpoints are of exploratory nature
because there will be no adjustment for multiplicity. Additional analyses will be performed on the
SS for all secondary endpoints, where participants with missing postbaseline value will be imputed
using their baseline value.
9.4.4. 
Exploratory Endpoints
Exploratory variables will be analyzed at α 0.05 (2-sided) on the FAS and SS. Details will be
specified in the SAP.
Biomarker exploratory analyses (Section 8.3.6) will be specified in a separate specific SAP.
9.4.5. 
Safety Analyses
Safety analyses will be performed on the SS.
Adverse Events
A treatment-emergent AE is any AE from first dose up to 3 days after end of study intervention.
The number and percentage of participants experiencing at least 1 treatment-emergent AE or SAE
will be tabulated by:
 
Medical Dictionary for Regulatory Activities system organ class and individual preferred
term, in descending order of incidence.
 
Frequency of participants with events coded with the same preferred term, in descending order
of incidence.
Furthermore, treatment-emergent AEs and SAEs will be tabulated as described above by severity
and relationship to study intervention. SAEs will be also tabulated up to 30 days after end of study
intervention.
AEs leading to premature discontinuation of study intervention, AEs with an outcome of death,
and AEs of special interest will be summarized as described above. The detailed list of AEs of
special interest will be specified in the SAP.
AEs occurring during titration period will also be summarized separately.
Listings will be provided for all reported AEs, including SAEs. In addition, separate listings, as
well as narratives, will be provided for SAEs, for AEs leading to premature discontinuation of
study intervention, and for AEs with an outcome of death.
The following AEs will be listed only:
 
AEs occurring prior to first study intervention dose
 
Non-serious AEs occurring after EOT + 3 days
 
SAEs occurring more than 30 days after discontinuation of study intervention


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Clinical Laboratory Tests
Descriptive summary statistics by visit will be provided for observed values and absolute changes
from baseline, in both hematology and clinical chemistry laboratory tests. In order to minimize
missing data and to allow for out-of-window visits, all recorded assessments up to EOT + 3 days
will be assigned to the most appropriate visit timepoint according to the best fitting time window
for that assessment.
The sponsor’s internal guidelines will be used for the definitions of marked abnormalities and for
the standardization of numeric values obtained from different laboratories and/or using different
normal ranges. Standard numeric laboratory variables will be transformed to standard units. All
laboratory data transferred will be taken into account regardless of whether they correspond to
scheduled (per protocol) or unscheduled assessments.
Marked laboratory abnormalities will be summarized for each laboratory variable providing their
incidence and frequency. Absolute values and changes from baseline of laboratory values during
the course of the study will also be summarized.
The number and percentage of participants with treatment-emergent laboratory abnormalities will
be tabulated.
Physical Examinations
Physical examination findings will be listed.
9.5. 
Interim Analysis
Not applicable.
9.6. 
Data Monitoring Committee
Not applicable.


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Abbreviations
6MWD  
6-minute walking distance
6MWT  
6-minute walking test
AE 
Adverse event
AESI 
Adverse event of special interest
ALT  
Alanine aminotransferase
ANCOVA  
Analysis of covariance
AST  
Aspartate aminotransferase
CBC 
Complete blood count
CHF  
Congestive heart failure
CI 
Confidence interval
CV  
Coefficient of variation
4D  
4-dimensional
Echo 
Echocardiogram
eCRF  
Electronic case report form
EOS 
End of Study
EOT  
End of Treatment
EQ-5D  
EuroQol 5-Dimension scale
ERA  
Endothelin receptor antagonist
FAS  
Full Analysis Set
FC  
Functional class
HIV  
Human immunodeficiency virus
IAP  
Image Acquisition Protocol
ICF  
Informed Consent Form
ICH  
International Council for Harmonisation of Technical Requirements
IEC  
Independent Ethics Committee
IMD  
Individual maintenance dose
INR  
International normalized ratio
IP  
Prostacyclin
IRB  
Institutional Review Board
iv  
Intravenous
LV  
Left ventricle, left ventricular
LVEDV  
Left ventricular end-diastolic volume


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LVEDP  
Left ventricular end-diastolic pressure
LVEF  
Left ventricular ejection fraction
LVESV  
Left ventricular end-systolic volume
LVSV  
Left ventricular stroke volume
MCV  
Mean corpuscular volume
MDRD  
Modification of diet in renal disease
mPAP  
Mean pulmonary arterial pressure
MRI 
Magnetic resonance imaging
NT-proBNP  
N-terminal-pro-hormone brain natriuretic peptide
PA  
Pulmonary artery
PAH  
Pulmonary arterial hypertension
PAWP  
Pulmonary artery wedge pressure
PDE-5i 
Phosphodiesterase type 5 inhibitor
PPS  
Per-Protocol Set
PT  
Prothrombin time
PTA  
Post-trial access
PVR  
Pulmonary vascular resistance
RA  
Right atrium, right atrial
RBC  
Red blood cell
RHC  
Right heart catheterization
RV  
Right ventricle, right ventricular
RVEDV  
Right ventricular end-diastolic volume
RVEF  
Right ventricular ejection fraction
RVESV  
Right ventricular end-systolic volume
RVGLS  
Right ventricular global longitudinal strain
RVSV  
Right ventricular stroke volume
SAE 
Serious adverse event
SAP  
Statistical analysis plan
SBP  
Systolic blood pressure
SD  
Standard deviation
sGCs 
Soluble guanylate cyclase stimulator
SS  
Safety Set
SUSAR  
Suspected unexpected serious adverse reaction
T3 
Tri-iodothyronine






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10.3. Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
10.3.1. 
REGULATORY AND ETHICAL CONSIDERATIONS
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and
country- or territory-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing,
conducting, recording, and reporting studies that involve the participation of human participants.
Compliance with this standard provides public assurance that the rights, safety, and well-being of
study participants are protected, consistent with the principles that originated in the Declaration of
Helsinki, and that the study data are credible.
Protocol Clarification Communications
If text within a final approved protocol requires clarification (eg, current wording is unclear or
ambiguous) that does not change any aspect of the current study conduct, a protocol clarification
communication (PCC) may be prepared. The PCC Document will be communicated to the
Investigational Site, Site Monitors, Local Trial Managers (LTMs), Clinical Trial Managers
(CTMs), and/or Contract Research Organizations (CROs) who will ensure that the PCC
explanations are followed by the investigators.
The PCC Document may be shared by the sites with Independent Ethics Committees/Institutional
Review Boards (IECs/IRBs) per local regulations.
The PCC Documents must NOT be used in place of protocol amendments, but the content of the
PCC Document must be included in any future protocol amendments.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by
the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by the
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or
when the relevant competent authority has raised any grounds for non-acceptance, except when
necessary to eliminate immediate hazards to the participants, in which case the amendment must
be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the
change(s) involve only logistic or administrative aspects of the study, the IEC/IRB (where
required) only needs to be notified.
In situations where a departure from the protocol is unavoidable during the study, the investigator
or other physician in attendance will contact the appropriate sponsor representative listed in the
Contact Information page(s), which will be provided as a separate document. Except in emergency
situations, this contact should be made before implementing any departure from the protocol. In
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and


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agree on an appropriate course of action. The data recorded in the eCRF and source documents
will reflect any departure from the protocol, and the source documents will describe this departure
and the circumstances requiring it.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities
in each respective country/territory, if applicable. A study may not be initiated until all local
regulatory requirements are met.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention
to the study site:
 
Protocol and amendment(s), if any, signed and dated by the principal investigator.
 
A copy of the dated and signed (or sealed, where appropriate per local regulations), written
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if
applicable, participant compensation programs. This approval must clearly identify the
specific protocol by title and number and must be signed (or sealed, where appropriate per
local regulations) by the chairman or authorized designee.
 
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their
function, with a statement that it is organized and operates according to GCP and the
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a
member of the study-site personnel is a member of the IEC/IRB, documentation must be
obtained to state that this person did not participate in the deliberations or in the vote/opinion
of the study.
 
Regulatory authority approval or notification, if applicable.
 
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable.
 
Documentation of investigator qualifications (eg, curriculum vitae).
 
Completed investigator financial disclosure form from the principal investigator, where
required.
 
Signed and dated clinical trial agreement, which includes the financial agreement.
 
Any other documentation required by local regulations.
The following documents must be provided to the sponsor before enrollment of the first
participant:
 
Completed investigator financial disclosure forms from all subinvestigators
 
Documentation of subinvestigator qualifications (eg, curriculum vitae)
 
Name and address of any local laboratory conducting tests for the study, and a dated copy of
current laboratory normal ranges for these tests, if applicable


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Local laboratory documentation demonstrating competence and test reliability
(eg, accreditation/license), if applicable
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB
with current and complete copies of the following documents (as required by local regulations):
 
Final protocol and, if applicable, amendments
 
Sponsor-approved ICF (and any other written materials to be provided to the participants)
 
Investigator’s Brochure (or equivalent information) and amendments/addenda
 
Sponsor-approved participant recruiting materials
 
Information on compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
Investigator’s curriculum vitae or equivalent information (unless not required, as documented
by the IEC/IRB)
 
Information regarding funding, name of the sponsor, institutional affiliations, other potential
conflicts of interest, and incentives for participants
 
Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol,
amendments (if any, excluding the ones that are purely administrative, with no consequences for
participants, data or study conduct, unless required locally), the ICF, applicable recruiting
materials, and participant compensation programs, and the sponsor has received a copy of this
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the
documents being approved.
During the study the investigator (or sponsor where required) will send the following documents
and updates to the IEC/IRB for their review and approval, where appropriate:
 
Protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct)
 
Revision(s) to ICF and any other written materials to be provided to participants
 
If applicable, new or revised participant recruiting materials approved by the sponsor
 
Revisions to compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
New edition(s) of the Investigator’s Brochure and amendments/addenda
 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at
least annually)
 
Reports of AEs that are serious, unlisted/unexpected, and associated with the study
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New information that may adversely affect the safety of the participants or the conduct of the
study
 
Deviations from or changes to the protocol to eliminate immediate hazards to the participants
 
Report of deaths of participants under the investigator’s care
 
Notification if a new investigator is responsible for the study at the site
 
Development Safety Update Report and Line Listings, where applicable
 
Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct), the amendment and applicable ICF revisions
must be submitted promptly to the IEC/IRB for review and approval before implementation of the
change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about
the study completion.
Country/Territory Selection
This study will only be conducted in those countries/territories where selexipag is available or
where the intent is to launch or otherwise help ensure access to the developed product if the need
for the product persists, unless explicitly addressed as a specific ethical consideration in
Section 4.2.1, Study-Specific Ethical Design Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
10.3.2. 
FINANCIAL DISCLOSURE
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial
information in accordance with local regulations to allow the sponsor to submit complete and
accurate financial certification or disclosure statements to the appropriate regulatory authorities.
Investigators are responsible for providing information on financial interests during the course of
the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) for details on financial disclosure.
10.3.3. 
INFORMED CONSENT PROCESS
Each participant must give written consent according to local requirements after the nature of the
study has been fully explained. The ICF(s) must be signed before performance of any study-related
activity. The ICF(s) that is/are used must be approved by both the sponsor and by the reviewing
IEC/IRB and be in a language that the participant can read and understand. The informed consent


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should be in accordance with principles that originated in the Declaration of Helsinki, current ICH
and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site
personnel must explain to potential participants the aims, methods, reasonably anticipated benefits,
and potential hazards of the study, and any discomfort participation in the study may entail.
Participants will be informed that their participation is voluntary and that they may withdraw
consent to participate at any time. They will be informed that choosing not to participate will not
affect the care the participant will receive for the treatment of his or her disease. Participants will
be told that alternative treatments are available if they refuse to take part and that such refusal will
not prejudice future treatment. Finally, they will be told that the investigator will maintain a
participant identification register for the purposes of long-term follow-up if needed and that their
records may be accessed by Health Authorities and authorized sponsor personnel without violating
the confidentiality of the participant, to the extent permitted by the applicable law(s) or regulations.
By signing the ICF the participant is authorizing such access.
The participant will be given sufficient time to read the ICF and the opportunity to ask questions.
After this explanation and before entry into the study, consent should be appropriately recorded by
means of the participant’s personally dated signature. After having obtained the consent, a copy of
the ICF must be given to the participant.
A participant who is rescreened is not required to sign another ICF.
If the participant is unable to read or write, an impartial witness should be present for the entire
informed consent process (which includes reading and explaining all written information) and
should personally date and sign the ICF after the oral consent of the participant is obtained.
10.3.4. 
DATA PROTECTION
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality
and compliance with applicable data privacy protection laws and regulations. Appropriate
technical and organizational measures to protect the personal data against unauthorized disclosures
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place.
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity
of participants confidential.
The informed consent obtained from the participant includes information about, and where
required per applicable regulations, explicit consent for the processing of personal data and for the
investigator/institution to allow direct access to his or her original medical records (source
data/documents) for study-related monitoring, audit, IEC/IRB review, and regulatory inspection.


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This informed consent also provides information to address the lawful transfer of the data to other
entities and to other countries/territories.
The participant has the right to request through the investigator access to his or her personal data
and the right to request rectification of any data that are not correct or complete, or make requests
concerning his or her personal data in accordance with applicable data protection law. Reasonable
steps will be taken to respond to such a request, taking into consideration the nature of the request,
the conditions of the study, and the applicable laws and regulations.
In the event of a data security breach, the sponsor will apply measures to adequately manage and
mitigate possible adverse effects taking into consideration the nature of the data security breach as
necessary to address other obligations such as notifying appropriate authorities in accordance with
applicable data protection law.
Exploratory biomarker research is not conducted under standards appropriate for the return of data
to participants. In addition, the sponsor cannot make decisions as to the significance of any findings
resulting from exploratory research. Therefore, exploratory research data will not be returned to
participants or investigators, unless required by law or local regulations. Privacy and
confidentiality of data generated in the future on stored samples will be protected by the same
standards applicable to all other clinical data.
10.3.5. 
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE
RESEARCH
Samples collected in this study may be stored for up to 15 years (or according to local regulations)
for additional research. Samples will only be used to understand selexipag, to understand PAH, to
understand differential intervention responders, and to develop tests/assays related to selexipag
and PAH. The research may begin at any time during the study or during the post-study storage
period.
Stored samples will be coded throughout the sample storage and analysis process and will not be
labeled with personal identifiers. Participants may withdraw their consent for their samples to be
stored for research.
10.3.6. 
COMMITTEES STRUCTURE
Steering Committee
A steering committee is involved in the study design and will provide guidance on the study
conduct and study publications. The committee is governed by a dedicated Steering Committee
charter.
MRI Expert Reviewers
A committee of expert MRI reviewers will review and approve the MRI IAP, write the variable
assessment charter, perform quality control of images, and assess imaging variables according to
the charter.


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Echo Expert Reviewers
A committee of expert Echo reviewers will review and approve the Echo IAP, write the variable
assessment charter, perform quality control of images, and assess imaging variables according to
the charter.
10.3.7. 
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA
All information, including but not limited to information regarding selexipag or the sponsor’s
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior
clinical data, formulation information) supplied by the sponsor to the investigator and not
previously published, and any data, including exploratory biomarker research data, generated as a
result of this study, are considered confidential and remain the sole property of the sponsor. The
investigator agrees to maintain this information in confidence and use this information only to
accomplish this study and will not use it for other purposes without the sponsor’s prior written
consent.
The investigator understands that the information developed in the study will be used by the
sponsor in connection with the continued development ofselexipag, and thus may be disclosed as
required to other clinical investigators or regulatory agencies. To permit the information derived
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and
will contain data from all study sites that participated in the study as per protocol. Recruitment
performance or specific expertise related to the nature and the key assessment parameters of the
study will be used to determine a coordinating investigator for the study. Results of exploratory
biomarker analyses performed after the Clinical Study Report has been issued will be reported in
a separate report and will not require a revision of the Clinical Study Report.
Study participant identifiers will not be used in the publication of results. Any work created in
connection with performance of the study and contained in the data that can benefit from copyright
protection (except any publication by the investigator as provided for below) shall be the property
of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter)
data and information without approval from the investigator. The investigator has the right to
publish study site-specific data after the primary data are published. If an investigator wishes to
publish information from the study, a copy of the manuscript must be provided to the sponsor for
review at least 60 days before submission for publication or presentation. Expedited reviews will
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in
writing, the investigator will withhold such publication for up to an additional 60 days to allow for
filing of a patent application. In the event that issues arise regarding scientific integrity or
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will
not mandate modifications to scientific content and does not have the right to suppress information.


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For multicenter study designs and sub-study approaches, secondary results generally should not
be published before the primary endpoints of a study have been published. Similarly, investigators
will recognize the integrity of a multicenter study by not submitting for publication data derived
from the individual study site until the combined results from the completed study have been
submitted for publication, within 18 months after the study end date, or the sponsor confirms there
will be no multicenter study publication. Authorship ofpublications resulting from this study will
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which
state that the named authors must have made a significant contribution to the conception or design
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the
work or revised it critically for important intellectual content; and given final approval of the
version to be published; and agreed 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.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required
by law. The disclosure of the final study results will be performed after the end of study in order
to ensure the statistical analyses are relevant.
10.3.8. 
DATA QUALITY ASSURANCE
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified
investigators and appropriate study sites, review of protocol procedures with the investigator and
study-site personnel before the study, periodic monitoring visits by the sponsor, and direct
transmission of clinical laboratory data from a central laboratory into the sponsor’s data base.
Written instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before
the start of the study.
The sponsor will review eCRF for accuracy and completeness during on-site monitoring visits and
after transmission to the sponsor; any discrepancies will be resolved with the investigator or
designee, as appropriate. After upload of the data into the study database they will be verified for
accuracy and consistency with the data sources.
10.3.9. 
CASE REPORT FORM COMPLETION
Case report forms are prepared and provided by the sponsor for each participant in electronic
format. All data relating to the study must be recorded in eCRF. All eCRF entries, corrections, and
alterations must be made by the investigator or authorized study-site personnel. The investigator
must verify that all data entries in the eCRF are accurate and correct.


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The study data will be transcribed by study-site personnel from the source documents onto an
eCRF, if applicable. Study-specific data will be transmitted in a secure manner to the sponsor.
All participative measurements (eg, questionnaires) will be completed by the same individual who
made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the electronic data capture (EDC) tool. If corrections to
an eCRF are needed after the initial entry into the eCRF, this can be done in either of the following
ways:
 Investigator and study-site personnel can make corrections in the EDC tool at their own
initiative or as a response to an auto query (generated by the EDC tool).
 Sponsor or sponsor delegate can generate a query for resolution by the investigator and study-
site personnel.
10.3.10. 
SOURCE DOCUMENTS
At a minimum, source documents consistent in the type and level of detail with that commonly
recorded at the study site as a basis for standard medical care must be available for the following:
participant identification, eligibility, and study identification; study discussion and date of signed
informed consent; dates of visits; results of safety and efficacy parameters as required by the
protocol; record of all AEs and follow-up of AEs; concomitant medication; intervention
receipt/dispensing/return records; study intervention administration information; and date of study
completion and reason for early discontinuation of study intervention  or withdrawal from the
study, if applicable.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be
reviewed with the investigator before the study and will be described in the monitoring guidelines
(or other equivalent document).
The minimum source documentation requirements for Section 5.1, Inclusion Criteria and
Section 5.2, Exclusion Criteria that specify a need for documented medical history are as follows:
 Date of an RHC performed before initiation of selexipag and associated mPAP, CO, HR, and
either PAWP or LVEDP.
 Date of a pulmonary function test performed before initiation of selexipag and associated
diffusing capacity of the lung for carbon monoxide (or CT scan summary), forced vital capacity
(% predicted), and forced expiratory volume in 1 second (% predicted).
 Documentation confirming absence of hepatic impairment. If known or documented hepatic
impairment, all components used for the assessment of Child-Pugh Class should be
documented.


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Inclusion and exclusion criteria not requiring documented medical history must be verified at a
minimum by participant interview or other protocol-required assessment (eg, physical
examination, laboratory assessment) and documented in the source documents.
An eSource system may be used, which contains data traditionally maintained in a hospital or
clinic record to document medical care (eg, electronic source documents) as well as the clinical
study-specific data fields as determined by the protocol. This data is electronically extracted for
use by the sponsor. If eSource is used, references made to the eCRF in the protocol include the
eSource system but information collected through eSource may not be limited to that found in the
eCRF.
10.3.11. 
MONITORING
The sponsor will use a combination of monitoring techniques: central, remote, and on-site
monitoring to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will
record dates of the visits in a study-site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the
monitor will compare the data entered into the eCRF with the source documents (eg,
hospital/clinic/physician’s office medical records). The nature and location of all source
documents will be identified to ensure that all sources of original data required to complete the
eCRF are known to the sponsor and study-site personnel and are accessible for verification by the
sponsor study-site contact. If electronic records are maintained at the study site, the method of
verification must be discussed with the study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of verifying
that the recorded data are consistent with the original source data. Findings from this review will
be discussed with the study-site personnel. The sponsor expects that, during monitoring visits, the
relevant study-site personnel will be available, the source documents will be accessible, and a
suitable environment will be provided for review of study-related documents. The monitor will
meet with the investigator on a regular basis during the study to provide feedback on the study
conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these
remote contacts, study-site personnel will be available to provide an update on the progress of the
study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
Study Safety Monitoring
Study safety information (AEs, SAEs, laboratory values, physical examinations, as required) will
be monitored and reviewed on a continuous basis by the sponsor’s clinical trial team. 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.


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10.3.12. 
ON-SITE AUDITS
Representatives of the sponsor’s clinical quality assurance department may visit the study site at
any time during or after completion of the study to conduct an audit of the study in compliance
with regulatory guidelines and company  policy. These audits will require access to all study
records, including source documents, for inspection. Participant privacy must, however, be
respected. The investigator and study-site personnel are responsible for being present and available
for consultation during routinely scheduled study-site audit visits conducted by the sponsor or its
designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part
of a national GCP compliance program or to review the results of this study in support of a
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
10.3.13. 
RECORD RETENTION
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF
and all source documents that support the data collected from each participant, as well as all study
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical
Trial, and all study documents as specified by the applicable regulatory requirement(s). The
investigator/institution will take measures to prevent accidental or premature destruction of these
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing
application in an ICH region and until there are no pending or contemplated marketing applications
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical
development of the investigational product. These documents will be retained for a longer period
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the
responsibility of the sponsor to inform the investigator/institution as to when these documents no
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the
responsibility of keeping the study records, custody must be transferred to a person who will accept
the responsibility. The sponsor must be notified in writing of the name and address of the new
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any
documentation relating to this study, the investigator/institution must permit access to such reports.
10.3.14. 
STUDY AND SITE START AND CLOSURE
First Act of Recruitment
The first informed consent signed is considered the first act of recruitment and it becomes the study
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Study/Site Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been collected
and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not
limited to:
 Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or
local Health Authorities, the sponsor’s procedures, or GCP guidelines
 Inadequate recruitment of participants by the investigator
 Discontinuation of further study intervention development


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10.4. Appendix 4: Adverse Events, Serious Adverse Events, Product Quality
Complaints, and Other Safety Reporting: Definitions and Procedures for
Recording, Evaluating, Follow-Up, and Reporting
10.4.1. 
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study participant administered
a medicinal (investigational or non-investigational) product. An adverse event does not necessarily
have a causal relationship with the intervention. An adverse event can therefore be any unfavorable
and unintended sign (including an abnormal finding), symptom, or disease temporally associated
with the use of a medicinal (investigational or non-investigational) product, whether or not related
to that medicinal (investigational or non-investigational) product. (Definition per International
Council for Harmonisation [ICH]).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to All Adverse Events
under Section 8.5.1, Time Period and Frequency for Collecting Adverse Events and Serious
Adverse Events Information, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and European Union Guidelines on Pharmacovigilance for
Medicinal Products for Human Use is any untoward medical occurrence that at any dose:
 
Results in death
 
Is life-threatening
(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 if it were more severe.)
 
Requires inpatient hospitalization or prolongation of existing hospitalization
 
Results in persistent or significant disability/incapacity
 
Is a congenital anomaly/birth defect
 
Is a suspected transmission of any infectious agent via a medicinal product
 
Is medically important*
* Medical and scientific judgment should be exercised in deciding whether expedited reporting is
also appropriate in other situations, such as important medical events that may not be immediately
life threatening or result in death or hospitalization but may jeopardize the participant or may
require intervention to prevent one of the other outcomes listed in the definition above. These
should usually be considered serious.


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If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal
relationship between the study intervention and the event, the event must be reported as a serious
and unexpected suspected adverse reaction even if it is a component of the study endpoint.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product
reference safety information. For selexipag, the expectedness of an AE will be determined by
whether or not it is listed in the Investigator’s Brochure.16
10.4.2. 
ATTRIBUTION DEFINITIONS
Assessment of Causality
The causal relationship to study intervention is determined by the Investigator. The following
selection should be used to assess all AEs.
Related
There is a reasonable causal relationship between study intervention administration and the AE.
Not Related
There is not a reasonable causal relationship between study intervention administration and the
AE.
The term “reasonable causal relationship” means there is evidence to support a causal relationship.
10.4.3. 
SEVERITY CRITERIA
An assessment of severity grade will be made using the following general categorical descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation.
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly
experienced by the participant (eg, laboratory abnormalities).
10.4.4. 
SPECIAL REPORTING SITUATIONS
Safety events of interest on a sponsor study intervention in an interventional studythat may require
expedited reporting or safety evaluation include, but are not limited to:
 
Overdose of a sponsor study intervention (see Section 6.9).
 
Suspected abuse/misuse of a sponsor study intervention
 
Accidental or occupational exposure to a sponsor study intervention


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Any failure of expected pharmacologic action (ie, lack of effect if used according to the local
label) of a sponsor study intervention (to be reported as a PQC for marketed products)
 
Unexpected therapeutic or clinical benefit from use of a sponsor study intervention
 
Medication error, intercepted medication error, or potential medication error involving a
sponsor medicinal product (with or without participant exposure to the sponsor medicinal
product, eg, product name confusion, product label confusion, intercepted prescribing or
dispensing errors)
 
Exposure to a sponsor study intervention from breastfeeding
 
Reporting of participant pregnancy or participant partner pregnancy
Special reporting situations should be recorded in the eCRF. Any special reporting situation that
meets the criteria of an SAE should be recorded on the SAE page of the eCRF and reported on
SAE Form.
10.4.5. 
PROCEDURES
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study intervention, must
be recorded using medical terminology in the source document and the eCRF. Whenever possible,
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough,
runny nose, sneezing, sore throat, and head congestion should be reported as “upper respiratory
infection”). Investigators must record in the eCRF their opinion concerning the relationship of the
adverse event to study therapy. All measures required for adverse event management must be
recorded in the source document and reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant must be
provided with a “wallet (study) card” and instructed to carry this card with them for the duration
of the study indicating the following:
 
Study number
 
Statement, in the local language(s), that the participant is participating in a clinical study
 
Investigator’s name and 24-hour contact telephone number
 
Local sponsor’s name and 24-hour contact telephone number (for medical personnel only)
 
Site number
 
Participant number
Serious Adverse Events
 
Refer to Section 8.5 for more information on the reporting procedures of SAEs. All SAEs that
have not resolved at time of the EOS visit (see Section 4.4) must be followed until any of the
following occurs: The event resolves
 
The event stabilizes


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The event returns to baseline, if a baseline value/status is available
 
The event can be attributed to agents other than the study intervention or to factors unrelated
to study conduct
 
It becomes unlikely that any additional information can be obtained (participant or health care
practitioner refusal to provide additional information, lost to follow-up [see Section 7.4])
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during
participation in the study must be reported as an SAE, except hospitalizations for the following:
 
Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as pending
placement in long-term care facility, cosmetic elective surgery).
 
Surgery or procedure planned before entry into the study (must be documented in the eCRF)
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. Note:
Hospitalizations that were planned before the signing of the ICF, and where the underlying
condition for which the hospitalization was planned has not worsened, will not be considered
SAEs. Any AE that results in a prolongation ofthe originally planned hospitalization is to be
reported as a new SAE.
 
For convenience the investigator may choose to hospitalize the participant for the duration of
the intervention period.
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 cause of death of a participant in a study within 30 days of the last dose of study intervention,
whether or not the event is expected or associated with the study intervention, is considered an
SAE.
Information regarding SAEs will be transmitted to the sponsor using an SAE reporting form and
safety report form of the CRF, which must be completed and reviewed by a physician from the
study site and transmitted in a secure manner to the sponsor within 24 hours. The initial and
follow-up reports of an SAE should be transmitted by facsimile (fax).
10.4.6. 
PRODUCT QUALITY COMPLAINT HANDLING
Definition
A 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, reliability, or
performance of a distributed product, including its labeling, drug delivery system, or package
integrity. A PQC may have an impact on the safety and efficacy of the product. In addition, it
includes any technical complaints, defined as any complaint that indicates a potential quality issue
during manufacturing, packaging, release testing, stability monitoring, dose preparation, storage
or distribution of the product or the drug delivery system.


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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.
If the defect is combined with an SAE, the study site personnel must report the PQC to the sponsor
according to the SAE reporting timelines (refer to Section 8.5.1). A sample of the suspected
product should be maintained under the correct storage conditions until a shipment request is
received from the sponsor.
10.4.7. 
CONTACTING SPONSOR REGARDING SAFETY, INCLUDING
PRODUCT QUALITY
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues, PQC, or questions regarding the study are listed in the Contact Information
page(s), which will be provided as a separate document.


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10.5. Appendix 5: Contraceptive and Barrier Guidance
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria.
Pregnancy information will be collected and reported as noted in Section 8.5.4, Pregnancy and
Section 10.4 Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and
Reporting.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Woman Not of Childbearing Potential
 
premenarchal
A premenarchal state is one in which menarche has not yet occurred.
 
postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the
postmenopausal range may be used to confirm a postmenopausal state in women not using
hormonal contraception or hormonal replacement therapy (HRT), however in the absence of
12 months 
of 
amenorrhea, 
a 
single 
FSH 
measurement 
is 
insufficient.
If there is a question about menopausal status in women on HRT, the woman will be required
to use one of the non-estrogen-containing hormonal highly effective contraceptive methods if
she wishes to continue HRT during the study.
 
permanently sterile (for the purpose of this study)
 
Permanent sterilization methods include hysterectomy, or bilateral salpingectomy, or
bilateral oophorectomy.
 
Has congenital abnormalities resulting in sterility.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually
active becomes active), a woman must begin an acceptable method of contraception, as described
throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by women should be consistent with local regulations regarding
the acceptable methods of contraception for those participating in clinical studies.
Typical use failure rates may differ from those when used consistently and correctly. Use should
be consistent with local regulations regarding the use of contraceptive methods for participants in
clinical studies.


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Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT
 Implantable progestogen-only hormone contraception associated with inhibition of ovulation
 Intrauterine device (IUD)
 Intrauterine hormone-releasing system (IUS)
 Tubal closure (eg, bilateral tubal occlusion, bilateral tubal ligation)
 Azoospermic partner (vasectomized or due to medical cause)
(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.
Spermatogenesis cycle is approximately 74 days.)
USER DEPENDENT
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulation
 oral
 intravaginal
 transdermal
 injectable
 Progestogen-only hormone contraception associated with inhibition of ovulation
 oral
 injectable
 Male or female condom with or without spermicideb
 Cap, diaphragm, or sponge with spermicide
 A combination ofmale condom with either cap, diaphragm, or sponge with spermicide
(double-barrier methods)b
 Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from
heterosexual intercourse during the entire period of risk associated with the study intervention.
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study
and the preferred and usual lifestyle of the participant.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY
 Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary
mode of action.
 Periodic abstinence (calendar, symptothermal, post-ovulation methods)
 Withdrawal (coitus-interruptus)
 Spermicides alone
 Lactational amenorrhea method (LAM)
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent
with local regulations regarding the use of contraceptive methods for participants in clinical studies.
b Male condom and female condom should not be used together (due to risk of failure with friction).


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Pregnancy During the Study
If a female participant becomes pregnant while on study intervention, study intervention must be
discontinued and the investigator should arrange for specific therapy as needed.21 For reporting of
pregnancies, refer to Section 8.5.4.


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10.6. Appendix 6: WHO Functional Classification of Pulmonary Hypertension
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 even be present at rest.
Discomfort is increased by any physical activity.


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10.7. Appendix 7: EuroQol 5-Dimension Questionnaire
CCI


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CCI


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10.8. Appendix 8: Child-Pugh Classification
The Child-Pugh classification will be used to assess the severity of the liver disease according to
the Table 5.7,8
Table 5: 
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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10.9. Appendix 9: Sponsor 6-Minute Walk Test Guidance
This document stipulates the criteria under which study-required 6MWTs will be carried out in
Clinical Protocol 67896049PAH4005 (Amendment 3).
These criteria are, in part, derived from the recommendations included in the ATS Guidelines
issued in 2002 and the ERS/ATS Technical Standard published in 2014.2,14 As opposed to the
comprehensive published manuscripts, this guidance has been shortened and accustomed for use
in a clinical study in which a variety of different assessments may need to be performed at a given
visit. In addition, dyspnea will be assessed using the Borg CR 10 Scale®.5
10.9.1. 
INSTRUCTIONS
General
The 6-Minute Walk Test (6MWT) must be performed indoors, along a long, flat, straight, enclosed
corridor (or similar location) with a hard surface that can be blocked for traffic during the conduct
of the test. The track length for the 6MWT must be free of obstacles. The use of treadmill and a
continuous course, eg, a circuit, is not allowed.
The ideal track length used for the 6MWT is 30 meters (If the track is shorter, it must be no shorter
than 20 meters in length). The track must be marked at regular intervals to facilitate measurement
of the distance walked (markings every 3 meters are recommended). The turnaround points must
be marked with a cone. A starting line, which marks the beginning and the end of each lap (one
lap is twice the length of the track used at the site), needs to be marked on the floor.
Local safety practice regarding medical emergencies and contraindications for 6MWT must be
followed at each participating site.
The person administering the 6MWT (tester) needs to stand near the starting line during the
6MWT, must not walk with the participant, and must not get distracted during the conduct of this
6MWT (eg, by talking to someone).
Rest periods are allowed if the participant can no longer continue. If the participant needs to rest,
participant may pause, lean against the wall and continue walking whenever participant feels able.
The timer must continue to run even if the participant stops to rest. The 6MWT can be stopped at
any moment due to medical emergencies or safety issues such as chest pain, intolerable dyspnea,
leg cramps, staggering, diaphoresis, and pale or ashen appearance.
The 6MWT is a non-encouraged test. An even tone of voice must be used when using the standard
phrases. No other instructions or words of encouragement are given during the test, other than the
pre-scripted phrases. Eye contact and body language signaling the participant to speed up must be
avoided during the test.
Whenever possible, for an individual participant, repeat 6MWTs must be conducted in the same
corridor and by the same tester, and preferably at about the same time of the day (ie, within
± 2 hours of the baseline test) to minimize variability.
If a participant is oxygen dependent, the flow rate must remain constant from 30 minutes prior to
each 6MWT until the completion of all protocol-mandated assessments after the 6MWT.


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Additionally, the way oxygen is delivered (delivery device, application route, way of carrying
delivery device) must be the same for all 6MWTs, unless a change is required for documented
medical reasons.
Training Tests
For participants who have not previously performed a 6MWT, a training 6MWT must be
performed before the first protocol-mandated 6MWT is performed.
Data from the training 6MWT are not collected in the CRF but must be documented in the source
data.
Timing
Only two 6MWTs can be performed on the same day. The interval between two 6MWTs on the
same day must be at least 2 hours.
10.9.2. 
TEST REQUIREMENTS
Participant
 The participant must wear comfortable clothing and appropriate walking shoes.
 The participant must not have exercised vigorously within 2 hours of beginning the test.
 It is recommended that the participant rests for at least 15 minutes before the test starts.
 It is recommended that participants receive their concomitant therapy on the day of the test.
Study intervention must be taken after all study assessments have been performed. If the
participant is used to take bronchodilators, participant must take them at least 10 to 30 min
before the test.
 Participants can use their usual walking aids during the test (eg, cane). The same walking aid
should be used for all 6MWTs. Walkers are not allowed.
Equipment to Perform the Test
 Countdown timer
 Mechanical lap counter
 Two cones to mark the turnaround points
 A chair that can be easily moved along the track
 6MWT Worksheet
 Borg category-ratio (Borg CR 10 Scale®)
10.9.3. 
PERFORMING THE 6MWT
Assessments before the 6MWT
Before the 6MWT, the tester shows the Borg CR 10 Scale® to the participant and asks the
participant:
 “Please grade your dyspnea using this scale”.


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The tester will record the baseline-6MWT dyspnea on the 6MWT the 6MWT worksheet.
Instructions to the Participant During the 6MWT
The tester uses the following exact dialogue with the participant:
“The objective of this test is to walk as far as possible in 6 minutes. You will walk back and
forth in this hallway. Six minutes is a long time to walk, so you will be exerting yourself.
You will probably get out of breath or become exhausted. You are permitted to slow down,
to stop, and to rest as necessary. You may lean against the wall while resting, but resume
walking as soon as you are able.
You will be walking back and forth around the cones. You should pivot briskly around the
cones and continue back the other way without hesitation. Now I’m going to show you.
Please watch the way I turn without hesitation.”
(The tester demonstrates the walking and pivots around a cone briskly).
“Are you ready to do that? I am going to use this counter to keep track of the number of
laps you complete. I will click it each time you turn around at this starting line. Remember
the object is to walk AS FAR AS POSSIBLE in 6 minutes, but don’t run or jog.”
After these instructions are given to the participant, the tester says:
“Start now, or whenever you are ready.”
As soon as the participant starts to walk, the tester starts the timer and writes down start time. The
tester reminds the participant of the elapsed time by saying:
After the first minute: “You are doing well. You have 5 minutes to go”.
When the timer shows 4 minutes remaining: “Keep up the good work. You have 4 minutes
to go.”
When the timer shows 3 minutes remaining: “You are doing well. You are halfway done.”
When the timer shows 2 minutes remaining: “Keep up the good work. You have 2 minutes
to go.”
When the timer shows only 1 minute remaining: “You are doing well. You have only 1
minute to go.”
If the participant stops walking during the test and needs a rest, the tester says:
“You can lean against the wall if you would like; then continue walking whenever you feel
able.”
The tester will not stop the timer. If the participant stops before the 6 minutes are up and refuses
to continue (or the tester decides that they should not continue), the tester wheels the chair over
for the participant to sit on, discontinue the walk, and note on the worksheet the distance, the time
stopped, and the reason for stopping prematurely.


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When the timer is 15 seconds from completion, the tester says:
“In a moment I’m going to tell you to stop. When I do, just stop right where you are and I
will come to you.”
When the timer alarm rings the tester says:
“Stop!”
Assessments After the 6MWT
The tester walks over to the participant, marks the spot where the participant stopped, records the
total distance walked in the 6MWT worksheet and congratulates the participant on good effort.
After the 6MWT, the tester reminds the participant of their dyspnea and level of exertion that they
chose before the 6MWT. The tester shows the Borg CR 10 Scale® to the participant and asks the
participant:
 “Please grade your dyspnea using this scale”.
The tester will record the post-6MWT dyspnea on the 6MWT worksheet.
10.9.4. 
6MWT WORKSHEET
It is mandatory to use the 6MWT worksheet to capture documentation of each 6MWT newly
performed for the purpose of the study and report relevant data in the eCRF, as indicated.
It is not mandatory to use the study 6MWT worksheet for historical 6MWTs.
10.9.5. 
HOW TO USE THE BORG CR 10 SCALE®
Instructions
The Borg CR 10 Scale® will be explained in detail to the participants at Screening before starting
the first 6MWT (questionnaires and instructions will be provided in local language).
The tester will provide the following instruction to the participant:
“Use this rating scale to report how strong your perception of dyspnea is. First look at the verbal
expressions. Start with them and then the numbers. Of these, ten (10) or “Extremely strong”,
“Maximal” is a very important intensity level. This is the most intense perception or feeling you
have ever had.
If your experience or feeling is “Very weak”, you should say “1”, if it is “Moderate”, say “3”. Note
that “Moderate” is “3” and thus weaker than “Medium”, “Mean” or “Middle”. If the experience is
“Strong” or “Heavy” (it feels “Difficult”) say “5”. Note that “Strong” is about half of “Maximal”.
If your feeling is “Very strong”, choose a number from 6 to 8. If your perception or feeling is
stronger than “10”, - “Extremely strong”, “Maximal”
you can use a larger number, eg, 12 or still
higher (that’s why “Absolute maximum” is marked with a dot “•”).


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It’s very important that you report what you actually experience or feel, not what you think you
should report. Be as spontaneous and honest as possible and try to avoid under- or overestimating.
Look at the verbal descriptors and then choose a number.
When rating dyspnea give a number that corresponds to how hard and strenuous you perceive your
breathing to be. The perception of dyspnea is mainly the feeling that one cannot breathe well
enough.
0 - “Nothing at all”, means that you don’t feel any shortness of breath.
1 - “Very weak” means a very light shortness of breath.
3 - “Moderate” is somewhat but not especially hard. You are somewhat shorter of breath.
5 - “Strong”. Breathing is getting difficult. The effort to breathe is about half as intense as
“Maximal”.
7 - “Very strong” is quite strenuous. You can still breathe, but breathing is getting very
difficult.
10 - “Extremely strong  Maximal” is the greatest shortness of breath you have ever
experienced in your life.
“•” - Is “Absolute maximum” for example “12” or even more.
Any questions?”
Borg CR 10 Scale®
The Borg CR 10 Scale® may be administered to the participant in an electronic format, ie, on a
device such as a tablet, or in plain paper. If used in paper format, it must be printed on heavy paper
(either DIN A4 or ANSI letter size and perhaps laminated) in 20-point type size.


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Signature of the tester performing the 6MWT: 
Signature of the staff member completing the
worksheet (if different from the tester performing
the 6MWT):
Date: 
Date:


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10.10. Appendix 10: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents.
Summary of changes for Amendment 2, 08 January 2021
Overall Rationale for the Amendment:  The overall reasons for this protocol amendment are to provide
clarification for several inclusion and exclusion criteria to better define the target population that may
benefit from the study intervention, to add exploratory objectives and endpoints for long-term outcomes, to
adaptto changed internal safety language and reporting processes, to align with TransCelerate template and
to implement minor corrections and editorial revisions.
Section Number and Name 
Description of Change 
Brief Rationale
Section 1.1. Synopsis - Safety 
evaluations; 
Section 8.4.3. Clinical Laboratory 
assessments 
Serum pregnancy test (not urine 
pregnancy test) will be performed 
at End of treatment (EOT). 
“A serum pregnancy test will be 
performed at the site at screening at 
Week 26 and at Week 52 (EOT); 
urine pregnancy tests will be
performed at the site on Day 1 and
the EOT visit and at the participant’s
home monthly between Day 1 and
EOT and at End of Study (EOS),
except for Month 6 and Month 12,
when a serum pregnancy test is
performed at the site visit (Week 26
and Week 52).”
Correction 
for 
consistency:
Erroneous “urine” test at EOT.
Should be serum test which is done
by the central lab (corrected in
Schedule of activities and in Section
8.4.3).
Section 1.1. Synopsis 
(Objectives/endpoints, Overall 
design); 
Section 1.2. Schema; 
Section 1.3. Schedule of Activities; 
Section 3. Objectives and 
Endpoints; 
Section 4.1. Overall Design;
Section 6.2.2. Study Intervention
Maintenance;
Section 7.1. Discontinuation of
Study Intervention
52-week assessment: Repetition of 
Week 26 assessments for 
exploratory objectives/endpoints at 
Week 52, except for Echo and Risk 
Assessment. 
EOT Week 52
Dispense/return of study drug at
Weeks 26, 39, and 52 (return only).
Primary 
endpoint 
at 
Week 26
remains at Week 26. Exploratory
endpoints at Week 52 or premature
EOT  to assess the sustainability of
the Week 26 results.
Section 1.1. Synopsis - Exploratory 
Objectives; 
Section 3. Objectives and 
Endpoints 
Additional exploratory objectives 
and exploratory endpoints are 
added. 
Objective: To assess the effects of
selexipag on RV function using
MRI at Week 52.
Endpoint: Change from baseline to
Week 52 assessed by MRI: RVSV,
RVEDV, RVESV, RVEF, RV
mass, RVGLS
Exploratory endpoints at Week 52 or
premature EOT  to assess the
sustainability of the Week 26 results.
Section 1.1. Synopsis - Exploratory 
Objectives; 
Section 3. Objectives and 
Endpoints 
Additional exploratory objectives 
and exploratory endpoints are 
added. 
Objective: To further assess the
effects of selexipag on disease
Exploratory endpoints at Week 52 or
premature EOT  to assess the
sustainability of the Week 26 results.


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severity and exercise capacity.
Endpoint: Change from baseline to
Week 52: WHO FC, NT-proBNP,
6MWD.
Section 1.1. Synopsis - Exploratory 
Objectives; 
Section 3. Objectives and Endpoints 
Additional exploratory objectives 
and exploratory endpoints are 
added. 
Objective: To evaluate the effect of 
selexipag on dyspnea during the 
6-minute walking test (6MWT). 
Endpoint: Change from baseline in
the difference between the pre-walk
and post-walk assessed dyspnea
Borg Dyspnea Index (BDI).
Participants may experience exercise
induced dyspnea during the 6MWT.
Dyspnea is an indicator of disease
severity. The new objective and
endpoint will evaluate the extent of
dyspnea during the 6MWT.
Section 1.1. Synopsis- Exploratory 
Evaluations; 
Section 8.3.6. Biomarkers 
Deletion of “The list of biomarkers 
may include: 
• Uric acid 
• Red cell distribution width  
• Activin A  
• Cystatin C  
• Follistatin  
• Galectin-3 
• Growth differentiation factor-15 
• Cardiac troponin T  
• Lactate dehydrogenase
• Osteoprotegerin
• Tumor necrosis factor alpha”
The biomarker samples will be
analyzed based on the test results of
previous 
studies and literature
reports after the last participant has
completed the study (last participant
out). The current wording is not
binding (“may”) and therefore a
general wording without specifying
individual biomarkers is in-line with
the current protocol.
Section 1.1. Synopsis; 
Section 8.6. Participant’s 
Experience 
Additional information was added 
regarding timing of assessment 
using EQ-5D-3L questionnaire and 
how health status as measured. 
Information regarding the 
prostacyclin associated AEs 
questionnaire was deleted. 
The EQ-5D questionnaire was
specified to mean EQ-5D-3L.
Assessment at site visits was
deemed sufficient. Therefore,
EQ-5D-3L at the weekly phone calls
during the titration period were
removed.
The prostacyclin questionnaire was
removed since all AEs including
those associated with prostacyclin
are collected throughout the study at
phone calls and site visits.
Section 1.1. Synopsis- Statistical 
Analyses; 
Section 9.4.1. General 
Considerations; 
Section 9.4.2. Primary Endpoints; 
Section 9.4.3. Secondary Endpoints 
The statement was revised in 
Statistical Methods at relevant 
instances to include “World Health 
Organization (WHO) functional 
class (FC) (II/III) at baseline” 
instead of “pulmonary arterial 
hypertension (PAH) background
therapy (yes/no).”
This reflects the new change for
inclusion criteria 2 that specifies that
enrollment will be stratified by
proportion of FC II to FC III to
approximately 
40% 
and 
60%,
respectively.
Section 1.3. Schedule of Activities 
The table was updated to clarify the 
study procedures and detailed 
information on visit names and 
time phase were added. 
 Clarification related to 
timepoints and visits are added 
for study periods: Up-titration
to individual maintenance dose
(IMD), Maintenance with IMD,
Clarity on number of site visits and
adaptation to EOT at Week 52. Drug
dispense/return 
visits 
were
mentioned in the footnotes and easily
missed. 
For 
clarity 
and
completeness, drug dispense/return
visits are now visible in the table.


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and Follow-up.
 To align with the exploratory
endpoints (Week 52), columns
for site visits have been revised
for study assessments/
evaluations.
Section 1.3. Schedule of Activities 
Following footnotes were updated. 
 Footnote “b”: Participants must 
NOT take the morning study 
intervention dose before any 
visit-related procedure. In case 
of premature EOT, the EOT
visit should take place within 7
days after the decision to end
treatment.
 Footnote “h”: Urine pregnancy
test at participant’s home. The
site will call female participants
of childbearing potential
monthly to check the pregnancy
test result. A window of 5
days for each pregnancy
test/phone call will be
allowed.
Foot notes were amended to
accommodate the changes in the
Table for clarity on number of site
visits and adaptation to EOT at
Week 52.
Section 1.3. Schedule of Activities 
Footnotes “j” and “k” are deleted 
and further footnotes are 
renumbered.
Following footnotes have been 
replaced to include updated 
information. 
 Footnote “l”: A telephone call 
will be made to the participant 
to monitor AEs, assess need for 
symptomatic treatment of side 
effects, decide dose for starting 
week, and document the 
participant’s experience Only if
EOT.
 Footnote “m”: Participant’s
experience refers to the
prostacyclin associated AEs
questionnaire (Section 10.7)
and the EQ-5D questionnaire
(Section 10.78).
Footnotes are renumbered/
repurposed.
Foot notes were amended to
accommodate the changes in the
Table for clarity on number of site
visits and adaptation to EOT at
Week 52.
Footnote “m”: text referring to
prostacyclin questionnaire was
removed because the questionnaire
will not be used.
Section 1.3. Schedule of Activities 
Following new footnotes have been 
added in the table. 
 Footnote “o”: If the results for 
the screening blood samples 
from the central laboratory are 
not available in time for Day 1 
visit, an additional blood 
sample may be drawn to verify 
eligibility based on a local 
laboratory test. 
 Footnote “p”: Including 
premature EOT. In case of 
Foot notes were amended to
accommodate the changes in the
Table for clarity on number of site
visits and adaptation to EOT at
Week 52.
 Footnote “o”: To allow for
merging the screening visit and
Day 1 visit, all labs for
eligibility can be done locally.
 Footnote “p”: To specify the
assessments to be done in case
of premature study intervention


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premature EOT, the EOT visit 
should take place within 7 days 
after the decision to end study 
intervention. 
 Footnote “q”: Except for month 
of Week 26 and Week 52. 
 Footnote “r”: In case of 
epidemic situation, eg, Corona 
Virus Disease-2019 
(COVID-19), the Week 26 visit 
may be delayed up to an 
additional 28 days (Week 26 
+6/-2 weeks). 
discontinuation.
 Footnote “q”: To clarify that no
phone calls are required when
site visits are scheduled.
 Footnote “r”: The current
window of the Week 26 visit is
2 weeks. If a site- or
participant-specific situation due
to COVID-19 prevents the
conduct of the Week 26 visit
(primary efficacy endpoints)
within the defined timeframe,
the visit may be postponed by an
additional 28 days resulting in a
total time window of +6/-2
weeks. Accordingly, treatment
with study intervention can be
extended to avoid study
intervention interruptions.
Section 1.3. Schedule of Activities 
Monthly phone calls to monitor 
participant’s safety during IMD 
maintenance phase are introduced. 
Monthly phone calls from the site to
the participant are introduced to
monitor participant’s safety by
collecting 
information 
on
concomitant medications, adverse
events (AEs) and serious adverse
events (SAEs).
Section 1.3. Schedule of Activities 
Time window for telephone call 
visits was updated. 
No time window defined in the
current protocol. A window of 3
days for the weekly phone calls
during the titration phase and 5
days for the phone calls during the
IMD maintenance phase will be
permitted to account for site or
participant specific situations that
prevent the phone call on the
calculated date.
Section 1.3. Schedule of Activities 
Expanded window for pregnancy 
tests done at home and associated 
phone calls. 
No time window defined in the
current protocol. A window of 5
days for each pregnancy test/phone
call will be allowed to account for
site- or participant-specific situations
that prevent the test/call on the
calculated 
date. 
Allows 
for
reminding the participant of the due
date.
Section 4.1. Overall Design  
Information in this section has been 
rearranged. 
The flow of this section was
rearranged to match the sequence of
events.
For completeness, weekly and
monthly phone calls are described.
Section 
4.2.1. 
Study 
Specific 
Ethical Design Considerations 
Following sentence was revised. 
This is mitigated assessing the 
primary endpoint after a relatively 
short study duration and the 
permission to escalate PAH therapy 
at any time if the investigator can 
The mitigation of the primary ethical
concern of a potential delay of study
intervention escalation was modified
to i) reflect the 52-week follow-up,
and ii) to clarify that study
intervention escalation is allowed at
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justify, 
based 
on participant’s 
symptoms, 
that it 
cannot be 
postponed 
to after Week 26
assessments.
investigator 
(no 
“justification”
needed).
Section 5. Study Population  
Additional details are added. 
To 
complement 
“The 
local
laboratory 
results 
(with the
corresponding normal ranges)
must be recorded in the electronic
case report form (eCRF)”.
To 
include 
complementary
information.
Section 5.1. Inclusion Criteria 
Inclusion criterion 2 is modified. 
WHO FC II or III. Enrollment will 
be stratified by WHO FC II to 
FC III. Proportion of
participants with WHO FC II
and WHO FC III are expected to
be approximately 40% and 60%,
respectively.
The stratification by FC is to ensure
that the majority of participants is at
intermediate 
risk 
of 
disease
progression.
Section 5.1. Inclusion Criteria 
Inclusion criterion 3 is modified: 
PAH induced by drugs or toxins is 
added to the list of included PAH. 
Drugs and toxins induced PAH is an
etiology belonging to Group 1
pulmonary hypertension and has
been included in previous studies
with selexipag. Drugs and toxins
induced PAH is included in an effort
to align inclusion criteria with other
selexipag studies allowing better
comparability between them.
Section 5.1. Inclusion Criteria 
Inclusion criterion 4 is modified: 
 Pulmonary vascular resistance 
(PVR) >3 WU >5 Wood Unit 
(WU)(400 dyn.s.cm-5) 
 Right ventricular stroke 
volume (RVSV) ≤60 mL as 
shown in right heart
catheterization (Cardiac
output [CO]/heart rate [HR]).
The increase of the lower limit of
PVR from >3 to >5 WU and
introduction of RVSV threshold aim
at enrolling a participant population
with more advanced remodeling of
the right ventricle.
Section 5.1. Inclusion Criteria 
Inclusion criterion 5 is modified: 
Patients already receiving PAH- 
specific oral mono or dual therapy 
(ie, phosphodiesterase type 5
inhibitors (PDE-5i) or soluble
guanylate 
cyclase 
stimulators
(sGCs) and/or ERA) or patients
who are not candidates for these
therapies. If on oral PAH-specific
therapy, treatment has to be
stable (ie, no introduction of new
therapies or changes in dose) for
at least 90 days prior to both ICF
signature and Day 1.
To clarify selection of participants
according to the label indication of
selexipag.
Section 5.1. Inclusion Criteria 
Inclusion criterion 6 is modified: 
Correction of units for N-terminal 
pro-hormone brain natriuretic 
peptide (NT-proBNP) levels.
The erroneous unit of NT-proBNP
levels is changed to ng/L (from
ng/mL).
The range of NT-proBNP level


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NT-proBNP >≥300 ng/mL at 
screening 
Added note: If local assessment of 
BNP (instead of NT-proBNP) is
used for eligibility, BNP 
measurement of ≥50 ng/L will be 
considered as meeting inclusion 
criterion. 
required for inclusion is adjusted to
the ERS/ESC guidelines for
intermediate risk: ≥300 ng/L (from
>300 ng/L).
To allow for merging the screening
visit with the Day 1, local
assessments of NT-proBNP or BNP
(if BNP is measured routinely) are
acceptable for inclusion.
Section 5.1. Inclusion Criteria 
Inclusion criterion 7 is modified: 
Men or women ≥18 years (or the 
legal age of consent in the 
jurisdiction in which the study is 
taking place if greater than 18) 
and <65 years 
In countries where the legal age to
provide individual informed consent
is greater than 18 years (eg, SOUTH
KOREA), the participant population
is restricted to participants who have
reached this legal age.
Section 5.1. Inclusion Criteria 
Inclusion criterion 8 is modified: 
 Agree to use reliable methods of 
contraception from Day 1 for at 
least 30 days after study
intervention 
discontinuation
(Section 10.5), and
 Agree 
to perform 
monthly
pregnancy tests up to for at least
30 days after study intervention
discontinuation.
Contraception and pregnancy tests
should be performed until at least 30
days after EOT.
Section 5.1. Inclusion Criteria 
New inclusion criterion 9 is added:
6-minute walking distance (6MWD)
≥150 m during screening period.
Since FC IV participants are not
eligible for this study, a 6MWD of
<150 m may indicate a walking
impairment not due to PAH and
unlikely to improve with PAH
treatment.
Section 5.2. Exclusion Criteria 
Exclusion criterion 10 is modified.
“Body mass index >40 kg/m2 or
body weight <40 kg”
Lower body weight limit to exclude
participants with cachexia.
Section 5.2. Exclusion Criteria 
Exclusion criterion 11 is modified:
“Presence of one or more of the
following signs of relevant lung
disease at any time up to screening
Day 1 - if pulmonary function test
results are missing, then exclusion
11 is considered as met.
Pulmonary function test results to
assess the eligibility of a prospective
study participant, can be part of the
participant’s 
medical 
history
(historical data, no date restrictions)
or when not available, pulmonary
function testing can be performed
after signing informed consent form
and during the screening phase.
Section 5.2. Exclusion Criteria 
Exclusion criterion 16 is modified:
Removed 
“moderate” 
hepatic
impairment as exclusion criterion.
Known and documented moderate
or severe hepatic impairment (with
or without cirrhosis) at screening,
defined as Child-Pugh Class B or C.
Added a foot note: The assessment
of 
hepatic 
impairment
(Child-Pugh Score) must be fully
documented for participants who
Exclusion criterion aligned with the
selexipag label.
Exclusion criterion clarified to
indicate that Child-Pugh scoring is
only required in participants with
hepatic impairment and does not
apply to participants with no hepatic
impairment.


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have 
clinical 
signs 
and/or
evidence (from central and/or
local lab) of hepatic impairment.
Section 5.2. Exclusion Criteria 
Exclusion criterion 22 is modified: 
Expanded 
to 
“Pregnancy, 
breastfeeding, or intention to 
become pregnant during the
study”.
To complement the criterion with
important additional information in
alignment with other sections of the
protocol.
Section 5.4. Screen failures 
Clarification on the rescreening 
process. 
only screening assessments beyond 
the 28 day window will need to be 
repeated. Rescreened participants 
will be assigned a new participant
number. The consent process will
not be repeated when re screening
participants.
Exceptional and limited retesting
of abnormal screening values that
lead to exclusion are allowed only
once using an unscheduled visit to
reassess eligibility during the
screening period. If a participant
does not meet all inclusion and
exclusion criteria (is a screen
failure) but at some point in the
future is expected to meet the
participant eligibility criteria, the
participant may be rescreened on
one occasion only. Participants
who are rescreened will be
assigned 
a 
new 
participant
number, undergo the informed
consent process, and then restart
a new screening phase.
To adopt the wording from the
TransCelerate template, clarifying
the repetition of assessments during
the screening period and the
rescreening process.
Section 6.2. Study Intervention 
Administration 
Following text added: 
“Participants 
with 
moderate 
hepatic impairment (Child-Pugh 
B) or who are concomitantly 
taking (a) moderate cytochrome 
P450 (CYP)2C8 inhibitor(s) will
start with 200 µg qd in the
morning of Day 2”.
To complement the text including
specific 
instructions 
for 
the
administration 
of 
the 
study
intervention in case of concomitant
use of moderate CYP2C8 inhibitors
or moderate hepatic impairment.
Section 6.2.1. Study Intervention 
Up-titration  
Timing in the Table 2, Up-titration 
Guide is revised. 
Week: from 13-26 to 13-52
Days: from 85-182 to 85-364
To reflect the IMD duration now
until EOT at Week 52.
Section 6.7. Study Intervention 
Dose Modification 
Following text has been modified. 
IfFor participants with moderate 
hepatic impairment (Child-Pugh 
B) or using moderate inhibitors of 
CYP2C8 
(eg, 
clopidogrel, 
deferasirox, 
teriflunomide, 
leflunomide) 
are 
used
To complement the text including
specific 
instructions 
for 
the
administration 
of 
the 
study
intervention in case of concomitant
moderate 
hepatic 
impairment,
concomitant use of strong inducers
of CYP2C8, and concomitant use of


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concomitantly 
with the study 
intervention, dosing frequency of 
study intervention must be reduced
to once a day.
Text has been added regarding dose
modification in case of concomitant
use of strong inducers of CYP2C8
or 
strong 
inhibitors 
of
UDP-glucuronosyltransferase
(UGT)1A3 and UGT2B7.
It has been shown that, when
moderate or strong inducers of
CYP2C8 are used in combination
with selexipag, the exposure to
selexipag active metabolite is
reduced by half. Dose adjustment
of selexipag may be required with
concomitant administration of
inducers 
of 
CYP2C8 
(eg,
rifampicin, 
carbamazepine,
phenytoin).
The effect of strong inhibitors of
UGT1A3 
and 
UGT2B7 
(eg,
valproic acid, probenecid, and
fluconazole) on the exposure to
selexipag or its active metabolite
has 
not 
been 
studied.
Concomitant administration may
result in an increase in exposure
to 
the 
active 
metabolite.
Therefore, caution is required
when these medicinal products
are administered concomitantly
with selexipag.
strong inhibitors of UGT1A3 and
UGT2B7, as per selexipag label.
Section 6.8. Continued Access to 
Study Intervention After the End of 
the Study  
Title changed to “Continued Access 
to Study Intervention After the End 
of the Study” from “Intervention
after end of the study”.
Following text added:
“If in the best interest of the study 
participant, commercial selexipag 
supply should start in the evening 
of EOT visit (date of last study
medication dose) to avoid any
unnecessary study intervention
interruption.”
Heading text adjusted to match
TransCelerate template.
To complement the text including
specific 
instructions 
for 
the
administration 
of 
commercial
selexipag after EOT.
Section 6.9. Overdose 
Text moved from Section 8.6: 
Additional 
overdose 
definition
included for participants with
moderate hepatic impairment or 
concomitantly 
taking 
moderate 
CYP2C8 inhibitors which requires
dosing frequency reduction from
Location of text adjusted to match
TransCelerate template.
Text adapted to match changes in
internal safety reporting processes.


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bid to qd. Background information
for overdose added.
Section 7.1. Discontinuation of 
Study Intervention  
Section was updated to: 
The participant develops severe 
hepatic impairment. If hepatic 
impairment is suspected, a clinical
assessment of severity (eg, Child-
Pugh score) must be performed
and fully documented. If a
participant has developed severe
hepatic impairment (Child-Pugh
C) at any time during the study,
the study intervention must be
permanently discontinued (see
Section 10.8).
The 
participant 
develops
(suspected) hepatic impairment. If
hepatic impairment is suspected, a
clinical assessment of severity (eg,
Child Pugh 
score) 
should 
be
performed. If a participant develops
moderate 
or 
severe 
hepatic
impairment (Child Pugh B or C) at
any time during the study, the study
intervention must be permanently
discontinued.
Clarification to indicate that Child-
Pugh scoring must be assessed and
documented in case of hepatic
impairment suspicion
Section 8. Study Assessments and 
Procedures 
Total blood volume is revised from 
27 mL to 69 mL. 
Table 3 has been revised for the 
volume of blood to be collected 
from each participant. 
Additional study specific materials 
added to the list. 
Blood volume for Clinical
Chemistry increased for the
additional analysis of thyroid-
stimulating hormone (TSH),
tri-iodothyronine (T3), and
thyroxine (T4).
Blood volume for Biomarkers
increased from 2.5 mL to 10 mL to
allow for more comprehensive tests
as per laboratory instruction.
Total blood volume increased due to
the additional assessment at Week
52.
Section 
8.3.1.5. 
Imaging 
Assessment 
Following text was updated. 
After an individual participant’s 
EOT Week 26 or Week 52 imaging 
assessments, a single reviewer will
read all scans (MRI or Echo) of that
participant at once.
Visits were updated to add more
clarity about the timing of imaging
assessments.
Section 8.3.2. 6MWT  
Text as updated. 
Dyspnea will be assessed by the 
Borg CR 10 Scale®, a scale used to 
quantify the degree of shortness of 
breath before and at the end of the 
6MWT. 
Participants may experience exercise
induced dyspnea during the 6MWT.
Dyspnea is an indicator of disease
severity. The new objective and
endpoint will evaluate the extent of
dyspnea during the 6MWT.
Section 8.4. Safety Assessments 
New section (Section 8.4.2) is 
introduced to capture “Vital Signs”. 
Added assessment of vital signs 
(HR, systolic blood pressure [SBP], 
Vital signs are recorded for safety
assessment in general and as part of
risk mitigation strategy for adverse
event of special interest (AESI).


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diastolic blood pressure [DBP])
during on-site visits
Section 8.4.1. Physical Examination Following text was modified. 
“Physical examination will include 
the evaluation of the participant’s 
height (only at screening), weight,
the general appearance, heart and
lungs.”
Following statement was deleted
from this section.
“Body weight will be measured in
indoor clothing without shoes.”
Body weight is being assessed as part
of the newly added vital sign
assessment (Section 8.4.2), and not
as part of physical exam.
Section 8.4.2. Vital Signs 
A new section is included. 
The measurement of SBP, DBP, HR,
and body weight was introduced as a
measurement 
to 
monitor
participant’s safety during the study.
Section 8.4.3. 
Clinical Safety 
Laboratory Assessments; 
Section 10.2. Clinical Laboratory 
tests 
The following text has been 
modified. 
Clinical chemistry panel including 
TSH, T3, and T4
The following text has been 
removed from the table of 
Protocol-required Laboratory 
Assessments: 
APTT, PT, INR 
TSH, T3, and T4 included in the
clinical chemistry laboratory
assessment as part of risk mitigation
strategy for AESI hyperthyroidism.
Coagulation tests are needed to
assess Child-Pugh score only when
hepatic impairment is suspected. As
this cannot be foreseen, these
assessments will be done locally,
when applicable, as defined in the
corresponding sections.
Section 
8.5. 
Adverse 
Events, 
Serious Adverse Events, and Other 
Safety Reporting 
 The section heading was 
revised. 
 Text pertaining to safety
reporting for the duration of
study was modified.
To adapt the text to changes in
internal safety reporting processes.
Section 8.5.1. Time Period and 
Frequency for Collecting Adverse 
Event and Serious Adverse Event 
Information
Addition of Product Quality 
Complaints (PQC) to the safety 
reporting process.
General updates related to the
safety reporting process.
To adapt the text to changes in
internal safety reporting. processes.
Section 8.5.2. Follow-up of Adverse 
Events and Serious Adverse Events 
Updated information regarding the 
follow-up of adverse events. 
To adapt the text to changes in
internal safety reporting. processes.
Section 8.5.3. Regulatory Reporting 
Requirements for Serious Adverse 
Events 
Updated information regarding 
reporting of suspected unexpected 
serious adverse events.
To adapt the text to changes in
internal safety reporting processes.
Section 8.5.4. Pregnancy  
Reference to faxing serious adverse 
events/pregnancy forms was 
replaced with “send”.
The name of the pregnancy form
was updated to pregnancy
notification form.
Addition of pregnancy reporting for
partners of male study participants.
To adapt the text to changes in
internal safety reporting. processes.
Section 8.5.4. Pregnancy; 
References to “Actelion Global 
To adapt the text to changes in


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Status: Approved,  Date: 25 March 2022
Section 10.4. Adverse Events: 
Definitions and Procedures for 
Recording, Evaluating, Follow-up, 
and Reporting
Drug Safety” references (or 
similar) were replaced by
“Sponsor”.
internal safety reporting processes.
Section 
8.5.5. 
Disease-Related 
Events 
This section was deleted. 
To adapt the text to changes in
internal safety reporting processes.
Section 10.2. Clinical Laboratory 
Tests 
Following clinical chemistry 
parameter was added. 
Glomerular filtration rate, using 
the Modification of Diet in Renal 
Disease (MDRD)formula 
To include assessment of kidney
function by means of estimated
glomerular filtration rate in a
standardized way using the MDRD
formula.
Section 10.4. Adverse Events, 
Serious Adverse Events, Product 
Quality Complaints, and Other 
Safety Reporting: Definitions and 
Procedures 
for 
Recording, 
Evaluating, 
Follow-up, 
and 
Reporting 
Section heading was updated from 
“Adverse Events: Definitions and 
Procedures for Recording,
Evaluating, Follow-up, and
Reporting” to “Adverse Events,
Serious Adverse Events, Product
Quality Complaints, and Other
Safety Reporting: Definitions and
Procedures for Recording,
Evaluating, Follow-up, and
Reporting”.
Text adapted to match changes with
the TransCelerate template.
Section 10.4. Adverse Events, 
Serious Adverse Events, Product 
Quality Complaints, and Other
Safety Reporting: Definitions and
Procedures 
for 
Recording,
Evaluating, 
Follow-up, 
and
Reporting 
– 
ATTRIBUTION
DEFINITION
Text has been revised. 
Text adapted to match changes with
the TransCelerate template.
Section 10.4. Adverse Events, 
Serious Adverse Events, Product 
Quality Complaints, and Other
Safety Reporting: Definitions and
Procedures 
for 
Recording,
Evaluating, 
Follow-up, 
and
Reporting – ADVERSE EVENT
DEFINITIONS 
AND
CLASSIFICATIONS
Reference to disease-related events 
was removed. 
To adapt the text to changes in
internal safety reporting processes.
Section 10.4. Adverse Events, 
Serious Adverse Events, Product 
Quality Complaints, and Other
Safety Reporting: Definitions and
Procedures 
for 
Recording,
Evaluating, 
Follow-up, 
and
Reporting 
– 
SPECIAL
REPORTING SITUATIONS
Addition of PQC to the special 
reporting situations. 
To adapt the text to changes in
internal safety reporting processes.
Section 10.4. Adverse Events, 
Serious Adverse Events, Product 
Quality Complaints, and Other
Safety Reporting: Definitions and
Procedures 
for 
Recording,
Evaluating, 
Follow-up, 
and
Reporting –PRODUCT QUALITY
COMPLAINT HANDLING
Updated guidance on the handling 
of PQCs. 
To adapt the text to changes in
internal safety reporting processes.
Section 10.7. EuroQol 5-Dimension 
Questionnaire 
Prostacyclin-associated adverse 
events questionnaire is deleted and 
For completeness and reading
convenience, the EQ-5D-3L


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a sample EQ-5D-3L questionnaire 
has been added. 
questionnaire in English is
presented in the appendix instead of
the web-site reference only.
Section 
10.8. 
Child-Pugh 
Classification  
A new section is included. 
To add Child-Pugh classification as
reference to assess severity of liver
impairment.
Section 10.9. 6-Minute Walk Test 
Guidance 
Appendix 10.9 was replaced by the 
6MWT guidance based on 
Sponsor’s Template Version 3.3, 
dated 29 June 2020. 
This is to align with updated
Pulmonary Hypertension
Therapeutic Area guidance
document. Includes to add Borg’s
dyspnea assessment at the beginning
of the 6MWT in addition to that
assessed at the end of the 6MWT.
The use of masks is described (and
collected in the electronic case
report form).
Section 11. References 
Reference list was updated. 
Added citations (literature
references) to support the respective
sections.
Throughout the protocol 
References to “Actelion” were 
replaced by reference to “Sponsor”. 
The term “subject” or “patient” was
replaced with “participant”.
The term “study treatment” was
replaced with “study intervention”
for consistency.
To adapt the text to changes in
internal safety reporting processes.
Throughout the protocol 
New safety language 
Safety language being updated to
align with the Pulmonary
Hypertension Therapeutic Area
selexipag safety language
implemented in all protocols.
This includes the deletion of
outdated safety contact numbers.
Throughout the protocol 
Minor editorial revisions. 
Minor errors were noted, and
updates were made, wherever
applicable.
COVID-19 Appendix (9 November 2020)
Overall Rationale: To provide a guidance on study conduct during the COVID-19 pandemic.


ACT-293987 / JNJ-67896049 (selexipag) 
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Status: Approved,  Date: 25 March 2022
Summary of changes for Amendment 1, 20 February 2020
Section Number and Name 
Description of Change 
Brief Rationale
1.3 Schedule of Activities 
8.4.2 Clinical Safety Laboratory 
Assessments 
Added that the site will call female 
participants of childbearing potential 
monthly to check the pregnancy test
result.
Ensure pregnancy test result is
regularly collected.
5.1 Inclusion Criteria 
Added that females of childbearing 
potential who are only using a hormonal 
contraception method must have used it 
for at least 1 month (30 days) before
Day 1 to be eligible.
Strengthen methods to avoid
pregnancies in study
participants.
10.5 Contraceptive and Barrier 
Guidance and Collection of 
Pregnancy Information
Updated the table of examples of 
contraceptives.
Alignment with other studies.
5.3 Lifestyle Considerations 
Added monthly pregnancy testing as an 
agreed requirement.
Clarification.
5.2 Exclusion criteria 
6.6 Concomitant Therapy  
Removed moderate inhibitors of 
CYP2C8. 
Consistency with the current
label, which indicates that
moderate inhibitors of CYP2C8
are permitted.
6.6 Concomitant Therapy  
Added that for PAH therapies to be 
initiated or up-titrated, documented
symptoms resulting in the decision to
escalate PAH treatment before Week 26
assessments were to be observed.
Clarification.
6.7 Study Intervention Dose 
Modification  
Added clarification that if moderate 
inhibitors of CYP2C8 are used 
concomitantly with study intervention,
then the dosing frequency of study
intervention must be reduced to once a
day. Dosing frequency of selexipag
should be reverted to twice daily when
co-administration of moderate CYP2C8
inhibitor is stopped.
Emphasized need for dose
adjustment.
8.5.3 Regulatory Reporting 
Requirements for Serious Adverse 
Events
Deleted text referring to anticipated 
events. 
The notion of “anticipated
events” is not used.
8.3.2 6MWT  
Removed text about use of 6MWT 
corridor card. 
Changed dyspnea assessment to Borg
CR 10 Scale®.
Updated sponsor guidance for
6MWT.
10.6 Borg Dyspnea Index Scale 
Deleted section. 
Updated sponsor guidance for
6MWT.
10.9 Actelion 6MWT Guidance 
Added section. 
Updated sponsor guidance for
6MWT.
Synopsis 
Changed the assessment of participant’s 
experience (ie, prostacyclin-associated 
AEs questionnaire and the EQ-5D
questionnaire) at screening to Day 1.
Removed alternative therapies from
mitigation strategies.
Clarification of timing and
assessment.
1.2 Schema 
Changed safety follow-up from 30 to 60 
days to at least 30 days in schema for 
consistency with text.
Clarification of timing and
assessment.


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Status: Approved,  Date: 25 March 2022
Section Number and Name 
Description of Change 
Brief Rationale
1.3 Schedule of activities 
Added time window for 
return/dispensing visit. 
Clarification of timing and
assessment.
1.3 Schedule of activities 
Deleted assessments related to 
participant experience at EOS. 
Correction of timing and
assessment.
1.3 Schedule of activities 
3 Objectives and endpoints 
Added footnote that participants’ 
experience refers to the 
prostacyclin-associated AEs
questionnaire and the EQ-5D
questionnaire.
Clarification of timing and
assessment.
1.3 Schedule of activities 
Baseline participants’ experience 
changed from screening to Day 1. 
Clarification of timing and
assessment.
1.3 Schedule of activities 
Removed “of NT-proBNP” from 
footnote about eligibility based on blood 
laboratory results to make statement
more general.
Clarification of timing and
assessment.
1.3 Schedule of activities 
Added “NT-proBNP” to footnote about 
safety-related and biomarker evaluations 
using blood draws.
Clarification of timing and
assessment.
1.3 Schedule of activities 
Added a footnote that study drug 
accountability will be performed once 
study drug has been returned after
return/dispensing visits at end of Week 4
and end of Week 12.
Clarification of timing and
assessment.
1.3 Schedule of activities 
Added a footnote that participants must 
NOT take the morning study 
intervention dose before any visit-related
procedure
Clarification of timing and
assessment.
1.3 Schedule of activities 
In case of premature EOT, the EOT visit 
should take place within 7 days after 
decision to end treatment.
Clarification of timing and
assessment.
4.1 Overall Design  
Added text to clarify that only screening 
assessments beyond the 28-day window 
will need to be repeated.
Added text to clarify that the last study
procedure to be performed on Day 1 will
be selexipag intake.
Clarification of timing and
assessment.
5.2 Exclusion Criteria 
Added to criterion 18 that exceptions 
were elective hospitalizations for 
surgery or standard monitoring of
pre-existing conditions that did not
worsen.
Clarification of timing and
assessment.
6.8 Intervention After EOS  
Added the option that the participant’s 
physician may request post-trial access
to selexipag from the sponsor, based on
favorable benefit/risk ratio for this
specific participant.
Clarification.
7.3 Participant Discontinuation  
/Withdrawal from the Study  
Added the word “only” to describe the 
options for reduced follow-up.
Clarification of assessment.
8.5 Adverse Events and Serious 
Adverse Events 
Added “or last contact” to timeframe for 
duration of the study.
Clarification of timing.
8.7 Participant’s Experience 
Added that ifan event meeting the 
definition of an AE is reported by a
participant in the context of a
questionnaire, it is the physician’s
responsibility to report it as an AE in the
eCRF form.
Clarification of assessment.


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Status: Approved,  Date: 25 March 2022
Section Number and Name 
Description of Change 
Brief Rationale
Changed the assessment of participant
experience at screening to Day 1.
Removed alternative therapies as a
mitigation strategy.
10.2. Clinical Laboratory Tests 
Deleted ‘and urine’ from the pregnancy 
testing for women of childbearing
potential because it will not be assessed
by the central laboratory.
Clarification of assessment.
Protocol Title 
1.1 Synopsis
Added study acronym, RESTORE. 
Administrative.
Synopsis 
Added the word “approximately” before 
the text about 80 participants to allow
for variance.
Administrative.
5.4 Screen Failures 
Consent process will not be repeated 
when re-screening participants, and
rescreened participants should be
assigned a new participant number.
Administrative.
6.1 Description of study 
intervention  
Removed number of tablets per bottle to 
allow flexibility.
Administrative.
10.3 Regulatory, Ethical, and 
Study Oversight Considerations 
Deleted text that the following 
documents must be provided to the
sponsor before enrollment of the first
participant: completed investigator
financial disclosure forms from all
subinvestigators and documentation of
subinvestigator qualifications.
Administrative.
10.4 Adverse Events: Definitions 
and Procedures for Recording,
Evaluating, Follow-up, and
Reporting
Added text on expected SAEs. 
Administrative.
10.7 Prostacyclin-associated 
Adverse Events Questionnaire 
Added participant number, date and time 
of questionnaire administration.
Administrative.
10.8 EuroQol 5-Dimension 
Questionnaire 
Removed URL as vendor website has 
changed, and webpage no longer exists.
Administrative.
10.10 Protocol Amendment 
History  
Updated with Amendment 1 
information.
Administrative.


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Status: Approved,  Date: 25 March 2022
11. 
REFERENCES
1. 
American Red Cross. 50 Quick facts. https://www.umms.org/-/media/files/ummc/community/blood-facts.
Accessed: 12 September 2019.
2. 
American Thoracic Society. ATS Statement: Guidelines for the Six-Minute Walk Test. Am J Respir Crit Care
Med. 2002;166:111-117.
3. 
Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, Coffey CS. Predicting survival in
pulmonary arterial hypertension insights from the registry to evaluate early and long-term pulmonary arterial
hypertension disease management (REVEAL). Circulation. 2010;122:164-172.
4. 
Blalock SE, Matulevicius S, Mitchell LC, Reimold D, Warner J, Peshock R. Long-term outcomes with
ambrisentan monotherapy in pulmonary arterial hypertension. J Cardiac Fail. 2010;16:121-127.
5. 
Borg, G. Borg’s Perceived Exertion and Pain Scales. Champaign, IL:HK; 1998.
6. 
Bradlow WM, Hughes ML, Keenan NG, Bucciarelli-Ducci C, Assomull R, Gibbs JS. Measuring the heart in
pulmonary arterial hypertension (PAH): implications for trial study size. J Magn Reson Imaging.
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7. 
Child-Pugh. In: Vincent JL., Hall J.B. (eds) Encyclopedia of Intensive Care Medicine. Springer, Berlin,
Heidelberg. (2012) https://doi.org/10.1007/978-3-642-00418-6 3060.
8. 
FDA 2003. Guidance for Industry, Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design,
Data 
Analysis, 
and 
Impact 
on 
Dosing 
and 
Labeling. 
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9. 
Franco V. Right ventricular remodeling in pulmonary hypertension. Heart Failure Clin. 2012;8:403-412.
10. Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary
hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European
Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for
European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung
Transplantation (ISHLT). Eur Heart J. 2016;37:67-119.
11. Grothues F, Moon JC, Bellenger NG, Smith GS, Klein HU, Pennell DJ. Interstudy reproducibility of right
ventricular volumes, function, and mass with cardiovascular magnetic resonance. Am Heart J.
2004;147(2):218-223.
12. Hagger D, Ventricular mass index correlates with pulmonary artery pressure and predicts survival in suspected
systemic sclerosis-associated pulmonary arterial hypertension. Rheumatology (Oxford). 2009;48(9):1137-1142.
13. Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, Khanna D, Kurzyna M. Definitions and diagnosis of pulmonary
hypertension. J Am Coll Cardiol. 2013;62:D42-50.
14. Holland AE, Spruit MA, Troosters T, et al. An official European Respiratory Society/ American Thoracic Society
technical standard field walking tests in chronic respiratory disease. Eur Respir J. 2014;44:1428-1446.
15. Humbert M, Morell NW, Archer SL, et al. Cellular and Molecular Pathobiology of pulmonary Arterial
Hypertension. J Am Coll Cardiol. 2004;43:13S-24S.
16. Investigator’s Brochure: ACT-293987 (Selexipag) Edition 17. Actelion Pharmaceuticals Ltd ( 7 February 2022).
17. Kylhammar D, Persson L, Hesselstrand R, Rådegran G. Prognosis and response to first-line single- and
combination therapy in pulmonary arterial hypertension. Scand Cardiovasc J. 2014;10:1-23.
18. Noel ZE, Kido K, Macaulay TE. Selexipag for the treatment of pulmonary arterial hypertension. Am J Health
Syst Pharm. 2017;74:1135-1141.
19. Oudiz RJ. Death in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2013;188(3):269-270.
20. Peacock A, Crawley S, McLure L, Blyth K, Vizza CD, Poscia R. Changes in right ventricular function measured
by cardiac magnetic resonance imaging in patients receiving pulmonary arterial hypertension-targeted therapy
The EURO-MR study. Circ Cardiovasc. Imaging. 2014;7:107-114.


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Status: Approved,  Date: 25 March 2022
21. Regitz-Zagrosek V, Blomstrom Lundqvist C, Borghi C, et al. ESC Guidelines on the management of
cardiovascular diseases during pregnancy: the Task Force on the Management of Cardiovascular Diseases during
Pregnancy of the European Society of Cardiology (ESC). Eur Heart J. 2011;32:3147-3197.
22. Rich S. Right ventricular adaptation and maladaptation in chronic pulmonary arterial hypertension. Cardiol Clin.
2012;30(2):257-269.
23. Rodriguez F, Harrison RW, Wojdyla D, Mahaffey KW. Lost to Follow-up and Withdrawal of Consent in
Contemporary Global Cardiovascular Randomized Clinical Trials. Crit Pathways in Cardiol. 2015;14:150-153.
24. Roeleveld RJ, Vonk-Noordegraaf A, Marcus JT, Bronzwaer JG, Marques KM, Postmus PE. Effects of
epoprostenol on right ventricular hypertrophy and dilatation in pulmonary hypertension. Chest.
2004;125(2):572-579.
25. Rosenkranz S, Galiè N, Channick R, et al. Effects of macitentan on right ventricular remodeling in pulmonary
arterial hypertension: results from the REPAIR study interim analysis. J Am Coll Cardiol. 2019;73(9):1898.
26. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A. Updated clinical classification of
pulmonary hypertension. J Am Coll Cardiol. 2013;62:D34-D41.
27. Simonneau G, Montani D, Celermajer DS. Haemodynamic definitions and updated clinical classification of
pulmonary hypertension. Eur Respir J. 2019;53(1): 1801913.
28. Sitbon O, Channick R, Chin KM, Frey A, Gaine S, Galiè N, et al. Selexipag for the Treatment of Pulmonary
Arterial Hypertension. NEJM. 2015;373(26):2522-2533.
29. Swift A, Rajaram S, Campbell MJ. Prognostic value of cardiovascular magnetic resonance imaging
measurements corrected for age and sex in idiopathic pulmonary arterial hypertension. Swift A. Circ Cardiovasc
Imaging. 2014;7(1):100-106.
30. Uptravi® Prescribing Information. Beerse, Belgium: Janssen-Cilag International NV.
31. Uptravi® Summary of Product Characteristics. Beerse, Belgium: Janssen-Cilag International NV.
32. Van de Veerdonk MC, Kind T, Marcus JT. Progressive Right Ventricular Dysfunction in Patients With
Pulmonary Arterial Hypertension Responding to Therapy. J Am Coll Cardiol. 2011;58(24):2511-2519.
33. van Wolferen SA, Boonstra A, Marcus JT, Marques KM, Bronzwaer JG, Postmus PE. Right ventricular reverse
remodelling after sildenafil in pulmonary arterial hypertension. Heart. 2006;92(12):1860-1861.
34. Van Wolferen SA, Marcus JT, Boonstra A. Prognostic value of right ventricular mass, volume, and function in
idiopathic pulmonary arterial hypertension. Euro Heart J. 2007;28:1250–1257.
35. van Wolferen SA, van de Veerdonk MC, Mauritz GJ, Jacobs W, Marcus JT, Marques KMJ, et al. Clinically
significant change in stroke volume in pulmonary hypertension. Chest. 2011;139(5):1003-1009.
36. Vonk-Noordegraaf A, Galiè N. The role of the right ventricle in pulmonary arterial hypertension. Eur Respir
Rev. 2011;20(122):243-253.
37. Vonk Noordegraaf A, Channick R, Cottreel E, et al. The REPAIR Study: Effects of Macitentan on RV Structure
and Function in Pulmonary Arterial Hypertension. JACC Cardiovasc Imaging. 2022;15(2):240-253.
38. Wilkins MR, Paul GA, Strange JW, Tunariu N, Gin-Sing W, Banya WA. Sildenafil versus Endothelin Receptor
Antagonist for Pulmonary Hypertension (SERAPH) study. Am J Respir Crit Care Med.
2005;171(11):1292-1297.


ACT-293987 / JNJ-67896049 (selexipag) 
Clinical Protocol 67896049PAH4005 (Amendment 3)
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114
Status: Approved,  Date: 25 March 2022
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 Pharmaceuticals Ltd. (a Janssen Pharmaceutical Company of Johnson &
Johnson)
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 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
 
21-Apr-2022
12:15:18
(GMT)
Document Approval
 
21-Apr-2022
14:22:43
(GMT)
Document Approval
PPD
PPD

SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 11 April 2023
Janssen Research & Development
Statistical Analysis Plan
A Prospective, Multicenter, Single-Arm, Open-Label, Phase 4 Study of the Effect of 
Selexipag on Right Ventricular Remodeling in Pulmonary Arterial Hypertension Assessed 
by Cardiac Magnetic Resonance Imaging.
Protocol 67896049PAH4005; Phase 4
JNJ-67896949  (selexipag)
Status:
Approved
Date:
11 April 2023
Prepared by:
Janssen Research & Development, LLC; Janssen Research & Development, a 
division of Janssen Pharmaceutica NV
Document No.: EDMS-RIM-378063, 1.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
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.
NCT04435782


JNJ-67896949  (selexipag)
Statistical Analysis Plan 67896049PAH4005
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 11 April 2023
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
VERSION HISTORY..................................................................................................................................... 4
1.
INTRODUCTION.................................................................................................................................. 5
1.1.
Objectives and Endpoints ................................................................................................................ 5
1.2.
Study Design.................................................................................................................................... 7
1.2.1.
Analysis Timepoint(s) ................................................................................................................... 9
2.
STATISTICAL HYPOTHESES............................................................................................................ 9
3.
SAMPLE SIZE DETERMINATION...................................................................................................... 9
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS.....................................................................10
5.
STATISTICAL ANALYSES............................................................................................................... 10
5.1.
General Considerations ................................................................................................................. 10
5.1.1.
Visit Windows ............................................................................................................................. 10
5.1.2.
Study Day and Relative Day....................................................................................................... 11
5.1.3.
Baseline ...................................................................................................................................... 11
5.1.4.
Up-titration period start date ....................................................................................................... 11
5.1.5.
Up-titration period end date ........................................................................................................ 11
5.1.6.
Maintenance period start date .................................................................................................... 11
5.1.7.
Maintenance period end date ..................................................................................................... 12
5.1.8.
Imputation Rules for Missing AE Date/Time of Onset/Resolution.............................................. 12
5.2.
Participant Dispositions.................................................................................................................. 13
5.3.
Primary Endpoint(s) Analysis......................................................................................................... 14
5.3.1.
Definition of Endpoint(s) ............................................................................................................. 14
5.3.2.
Analysis Methods........................................................................................................................ 15
5.4.
Secondary Endpoint(s) Analysis .................................................................................................... 15
5.4.1.
Change from baseline to Week 26 of additional measures of RV function using MRI............... 15
5.4.2.
Change from baseline to Week 26 for 6MWD, WHO FC and NT-proBNP ................................ 15
5.4.3.
Change from baseline to Week 26 in the number of low-risk criteria......................................... 15
5.5.
Tertiary/Exploratory Endpoint(s) Analysis...................................................................................... 16
5.5.1.
Change from baseline to Week 52 on RV function assessed by MRI........................................ 16
5.5.2.
Change from baseline to Week 26 and Week 52 of RV mass/LV mass.................................... 16
5.5.3.
Change from baseline to Week 26 of RV function assessed by Echo ....................................... 16
5.5.4.
Change from baseline to Week 26 and Week 52 of LV function assessed by MRI................... 17
5.5.5.
Change from baseline to Week 26 and Week 52 of Right main PA pulsatility assessed 
by MRI......................................................................................................................................... 17
5.5.6.
Change from baseline to Week 26 and Week 52 of RV/LV function using 4D flow 
imaging ....................................................................................................................................... 17
5.5.7.
Impact of individual maintenance dose ...................................................................................... 17
5.5.8.
Change from baseline to Week 52 for 6MWD, WHO FC and NT-proBNP ................................ 17
5.5.9.
EuroQol 5-dimension scale (EQ-5D-3L).....................................................................................17
5.5.10.
Change from baseline to Week 26 and Week 52 in the difference between the pre-walk 
and post-walk assessed Borg Dyspnea Index (BDI) ..................................................................17
5.6.
Safety Analyses ............................................................................................................................. 17
5.6.1.
Extent of Exposure ..................................................................................................................... 18
5.6.2.
Adverse Events........................................................................................................................... 19
5.6.3.
Deaths......................................................................................................................................... 20
5.6.4.
Additional Safety Assessments .................................................................................................. 20
5.6.4.1.
Clinical Laboratory Tests......................................................................................................... 20
5.6.4.2.
Vital Signs and Physical Examination Findings.......................................................................21
5.6.4.3.
Electrocardiogram ................................................................................................................... 21


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5.6.4.4.
Other Safety Parameters......................................................................................................... 21
5.7.
Other Analyses............................................................................................................................... 21
5.7.1.
Pharmacokinetics ....................................................................................................................... 21
5.7.2.
Immunogenicity........................................................................................................................... 21
5.7.3.
Pharmacodynamics .................................................................................................................... 21
5.7.4.
Pharmacokinetic/Pharmacodynamic Relationships ................................................................... 21
5.7.5.
Biomarkers.................................................................................................................................. 22
5.7.6.
Health Economics....................................................................................................................... 22
5.7.7.
Other Variables and/or Parameters............................................................................................ 22
5.7.8.
Definition of Subgroups .............................................................................................................. 22
5.8.
Interim Analyses............................................................................................................................. 22
5.8.1.
Data Monitoring Committee (DMC) or Other Review Board ...................................................... 22
6.
SUPPORTING DOCUMENTATION ..................................................................................................23
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 23
6.2.
Appendix 2 Changes to Protocol-Planned Analyses ..................................................................... 25
6.3.
Appendix 3 Demographics and Baseline Characteristics..............................................................26
6.4.
Appendix 4 Protocol Deviations ..................................................................................................... 27
6.5.
Appendix 5 Prior and Concomitant Medications............................................................................28
6.6.
Appendix 6 Medical History ........................................................................................................... 29
6.7.
Appendix 7 Intervention Compliance ............................................................................................. 30
6.8.
Appendix 8 Adverse Events of Special Interest.............................................................................31
6.9.
Appendix 9 Medications of Special Interest................................................................................... 32
6.10.
Appendix 10 Laboratory Toxicity Grading...................................................................................... 33
7.
REFERENCES................................................................................................................................... 34


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VERSION HISTORY
Table 1 – SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1
11-Apr-23
Not Applicable
Initial release


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1.
INTRODUCTION
This Statistical Analysis Plan (SAP) presents the planned analysis for the primary endpoint  
(change from baseline to Week 26 in right ventricular stroke volume (RVSV) assessed by 
pulmonary artery flow magnetic resonance imaging (MRI)), secondary efficacy endpoints, 
exploratory efficacy endpoints and safety endpoints.
This SAP is referring to the Global Study Protocol document version 5.0, dated 25 March 2022
[Document number: EDMS-RIM-265483, 5.0].
Following premature study termination, only descriptive statistics will be performed for all 
collected safety and efficacy data (no inferential statistics). 
1.1.
Objectives and Endpoints
Objectives 
Endpoints 
Primary 
!
To assess the effects of selexipag on 
right ventricular (RV) function in 
subjects with PAH. 
!
Change from baseline to Week 26 in RV stroke 
volume (RVSV) assessed by pulmonary artery flow 
magnetic resonance imaging (MRI). 
Secondary 
!
To further assess the effects of 
selexipag on RV function using MRI. 
!
Change from baseline to Week 26 assessed by MRI: 
o
RV end-diastolic volume (RVEDV) 
o
RV end-systolic volume (RVESV) 
o
RV ejection fraction (RVEF) 
o
RV mass 
o
RV global longitudinal strain (RVGLS) 
!
To assess the effects of selexipag on 
disease severity and exercise capacity. 
!
Change from baseline to Week 26: 
o
World Health Organization (WHO) Functional 
Class (FC) 
o
N-terminal-pro-hormone brain natriuretic peptide 
(NT-proBNP) 
o
6-minute walk distance (6MWD) 
!
To evaluate the safety and tolerability 
of selexipag. 
!
Treatment-emergent adverse events (AEs)
!
Serious adverse events (SAEs) 
!
AEs leading to premature discontinuation of study 
drug 
!
AEs of special interest 
!
Treatment-emergent marked laboratory abnormalities 
!
To evaluate the effects of selexipag on 
risk stratification in PAH.
!
Change from baseline to Week 26 in number of non-
invasive low-risk criteria among the following 8 
variables:
o
Absence of clinical signs of right heart failure
o
Absence of symptoms progression
o
Absence of syncope
o
WHO FC I-II
o
6MWD >440 m


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o
NT-proBNP < 300 ng/L
o
Right atrial (RA) area < 18 cm2, as determined 
by echocardiography (Echo)
o
Absence of pericardial effusion, as determined 
by Echo
!
Change from baseline to Week 26 in number of non-
invasive low-risk criteria among the following 3
variables:
o
WHO FC I-II
o
6MWD >440 m
o
NT-proBNP <300 ng/L
Exploratory
!
To assess the effects of selexipag on 
RV function using MRI at Week 52
!
Change from baseline to Week 52 assess by MRI:
o
RVSV
o
RVEDV
o
RVESV
o
RVEF
o
RV mass
o
RVGLS
!
To further assess the effects of 
selexipag on cardiac morphology.
!
Change from baseline to Week 26 and Week 52 
assessed by MRI:
o
RV mass/LV mass
!
To further assess the effects of 
selexipag on RV function using Echo.
!
Change from baseline to Week 26 assessed by Echo:
o
Tricuspid annular plane systolic excursion
o
Pericardial effusion size scored from 0 to 4
o
RV end-diastolic area
o
RV end-systolic area
o
RV fractional area change
o
RVSV determined from pulmonary valve 
Doppler and pulmonary annulus dimension
o
RA area
!
To assess the effects of selexipag on 
left ventricular (LV) function.
!
Change from baseline to Week 26 and Week 52 
assessed by MRI:
o
LV end-diastolic volume (LVEDV)
o
LV end-systolic volume (LVESV)
o
LV ejection fraction (LVEF)
o
LV mass
!
To assess the effects of selexipag on 
pulmonary artery (PA) function.
!
Change from baseline to Week 26 and Week 52 
assessed by MRI:
o
Right main PA pulsatility
!
To explore 4-dimensional (4D) flow 
imaging
!
In participants from sites able to provide suitable 
MRI imaging, change from baseline to Week 26 and 
Week 52 in:
o
RVSV determined from 4D flow imaging in PA


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o
LVSV determined from 4D flow imaging in 
aorta
!
To explore whether individual 
maintenance dose impacts reverse 
remodeling.
!
Change in RVSV from baseline to Week 26 and 
Week 52
!
To assess the effects of selexipag on 
disease severity and exercise capacity
!
Change from baseline to Week 52:
o
WHO FC
o
NT-proBNP
o
6MWD
!
To explore the effects of selexipag on 
blood biomarkers.
!
Change from baseline to Week 26 and Week 52 in 
blood biomarkers
!
To explore subject's experience.
!
EuroQOL 5-dimension scale (EQ-5D-3L) on Day 1, 
and at Week 26 and Week 52 
!
To evaluate the effect of selexipag on 
dyspnea during the 6MWT
!
Change from baseline to Week 26 and Week 52 in 
the difference between the pre-walk and post-walk 
assess dyspnea Borg Dyspnea Index (BDI)
1.2.
Study Design
This is an open-label, multicenter, single-arm, interventional study to assess the effect of selexipag 
in adult participants (≥18 to <65 years) with a diagnosis of PAH up to 52 weeks on study 
intervention.
The duration of individual participation will be approximately 60 weeks.  The study will be 
conducted in 3 phases: a 28-day screening phase, a 52-week intervention phase (which will include 
an initial 12-week up-titration period), and a post-intervention safety follow-up period of at least 
30 days.  Primary and secondary objectives will be evaluated up to Week 26 and exploratory 
objectives will be evaluated up to Week 52.
The study comprises the following periods:
!
Screening period: Informed consent signature marks both the start of the study and the start 
of the screening period.
This period serves to assess eligibility (medical history, treatments, blood tests) and to perform 
baseline efficacy assessments (MRI, Echo, 6MWD, WHO FC, NT-proBNP, and exploratory 
blood tests). Screening may last up to 28 days.  A participant who is temporarily ineligible may 
be re-screened.  Note: in case MRI, Echo, 6MWT or WHO FC assessment was made as part 
of routine practice in a way that fully complies with the study requirements, and within 28 days 
before Day 1, these data can be used for the study.


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!
Treatment period: Starts with the first dose of study drug (Day 1 of study) and ends with 
EOT on the day of the last dose of the study drug which is at Week 52 ± 7 days or at premature 
discontinuation of study intervention. This period includes:
o
Day 1: Day 1 is defined as the day when a participant receives the first dose of 
study intervention. First dosing should occur at the site.  Day 1 may occur once 
screening assessments are completed, and no later than 28 days after informed 
consent signature.  For re-screened participants, all screening assessments must 
have been made (or repeated) within 28 days before Day 1.
o
Up-titration: During this period, study intervention will be up-titrated from Day 1 
to the end of Week 12 (Day 84).  Weekly phone calls from the site to participant 
will be performed to guide the up-titration and collect safety information.  At the 
end of Week 4 (+ 7 days) and Week 12 (+ 7 days) and participants will return to 
the site for a return/dispensing visit; no assessments will be performed at these site 
visits.
o
Maintenance: During this period, participants will receive study intervention at 
their individual maintenance dose (IMD) from the start at Week 13 to EOT 
(scheduled at the end of Week 52, ± 7 days). Monthly phone calls (except when site 
visits take place) from the site to the participant will be made to monitor 
participant's safety by collecting information on concomitant medications, AEs and 
SAEs.  At Week 26 (Day 168 to 196), a site visit is scheduled to assess MRI, Echo, 
6MWT, WHO FC, blood draw for secondary and exploratory endpoints.  At Week 
39 (+ 14 days), participants will return to the site for a study drug return/dispensing 
visit: no assessments will be performed at this site visit.
!
EOT: EOT should occur at end of Week 52 ± 7 days (Day 350 to 378). At this visit, 
postbaseline assessments will be performed (MRI, 6MWT, WHO FC, blood draw). In case of 
premature EOT before Week 16, postbaseline efficacy assessments will be optional and safety 
assessments will be mandatory. In case of premature EOT after Week 16, all postbaseline 
assessments will be performed.
!
Safety follow-up: The safety follow-up will start the day after the last study intervention dose 
and end with the safety follow-up telephone call (EOS visit).
!
EOS: for an individual participant, EOS visit is defined as follows:
o For participants who complete treatment or who prematurely discontinue study
intervention, EOS visit is defined as the safety follow-up telephone call at least 30 days 
after last dose of study intervention.
o For participants who complete treatment in the RESTORE study and who are entering 
another open-label clinical study with selexipag, the EOS visit is defined as the EOT visit. 


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!
Unscheduled visits: Unscheduled visits will be allowed and will not be documented in the 
electronic case report form (eCRF); however, any AE/SAE reported during an unscheduled 
visit should still be recorded.
Eligible participants will be treated with selexipag for 52 weeks. Dosing with selexipag will start 
at 200 μg twice daily. On Day 1, the participant will receive only 1 dose, and at each dose change, 
the first intake of the new dose should be taken in the evening. The site will call the participant
once a week from the end of Week 1 to the end of Week 12 and decide whether to increase the 
dose by 200 μg twice daily if possible. Up-titration will be flexible and can be adapted in case of 
adverse effects that cannot be relieved with symptomatic treatment. In this case, the site may either 
postpone up-titration by 1 week or down-titrate study intervention. The dose reached at end of 
Week 12 will be considered the subject’s IMD and will be maintained until EOT.
Efficacy assessments will include MRI, Echo, 6MWD, WHO FC, NT-proBNP, and risk 
stratification. Safety assessments will include the monitoring of AEs, clinical laboratory 
evaluations, and pregnancy testing in female participants of childbearing potential. Exploratory 
assessment will include biomarkers and the participants’ experience using a questionnaire.
Imaging will be performed as described in the MRI Image Acquisition Protocol (IAP)/Echo IAP 
and centrally reviewed. Expert reviewers will be blinded to the participant and timepoint and will 
assess variables according to the MRI/Echo review charter. For each imaging modality (MRI or 
Echo), all scans of an individual participant will be reviewed by the same reviewer at the same 
time, in order to ensure consistent assessment.
1.2.1.
Analysis Timepoint(s)
Following premature study termination, there will be only 1 Analysis Timepoint:
!
Analysis Timepoint 1 (final analysis all data up to EOS): EOS.
2.
STATISTICAL HYPOTHESES
Following premature study termination, there is no formal statistical hypothesis. Only descriptive 
statistics will be reported. 
3.
SAMPLE SIZE DETERMINATION
Initial sample size calculation for the primary endpoint was based on the following assumptions:
!
A 2-sided Type I error of 5% and a Type II error of 10% (90% power)
!
A mean change from baseline to Week 26 in RVSV of +8 mL
!
A standard deviation (SD) of 20 mL for the change from baseline to Week 26 in RVSV
!
A normal distribution for the change from baseline to Week 26 in RVSV
!
15% of participants with non-valuable RVSV assessment at baseline and/or postbaseline


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Based on the above assumptions, a total of 80 participants (68 analyzable + 12 to account for 15% 
non-evaluable) must be enrolled in order to establish whether change from baseline to Week 26 in 
RVSV is different from zero (based on paired t-test for single arm).
The assumption that the change from baseline to Week 26 in RVSV is +8 mL is in line with 
literature suggesting that a difference of 8 mL to 12 mL is clinically relevant1.  The associated SD 
of 20 mL is justified by the REPAIR study interim analysis on 42 subjects, where the observed 
mean change (SD) from baseline to Week 26 was +16.6 mL (16.34).
After the decision to prematurely terminate the study, this sample size calculation was no longer 
relevant.
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
Analysis sets are detailed in table 2 below:
Table 2:
Overview of the Different Populations for Analyses
Analysis Sets
Description
Screened Analysis Set (SCR)
The screened analysis set (SCR) includes all participants 
who were screened and received a participant number.
Safety Set (SS)
The safety set (SS) includes all participants from the SCR 
who received at least 1 dose of study intervention.
Due to premature study termination, only the SCR and the SS will be kept.  
5.
STATISTICAL ANALYSES
5.1.
General Considerations
Following premature study termination, all analyses will be performed using descriptive statistics 
only. No subgroup analysis will be performed. For efficacy, only listings will be produced. For 
baseline characteristics and safety, the usual standard tables/listings will be produced. 
5.1.1.
Visit Windows
As participants do not always adhere to the protocol visit schedule, the following rules are applied 
to assign actual visits to analysis visits. Listed below are the visit windows and the target days for 
each visit. The reference day is Study Day 1. If a participant has 2 or more actual visits in 1 visit 
window, the visit closest to the target day will be used as the protocol visit for that visit window.
The other additional visit(s) will not be used in the summaries or analyses but they can be used for 
determination of clinically important endpoints. If 2 actual visits are equidistant from the target 
day within a visit window, the later visit is used.
All assignments will be made in chronological order. Once a visit date is assigned to a visit 
window, it will no longer be used for a later time point except for the endpoint. Listed below (Table
3) are the analysis visit windows and the target days for each visit defined in the protocol.


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Table 3:
Visit Windows
Parameter
Time Interval
(label on output)
Time Interval
(Day)*
Target Time Point 
(Day)
Screening, Efficacy, and 
Safety 
Screening
< 1
[-28 to 1]
Baseline visit
Baseline
<= 1
1
MRI, Echo, 6MWT, 
WHO FC, Risk 
stratification 
Week 26
113 to 254
180
Week 52
255 to 400
360
All other parameters
Week 12
2 to 112
84
Week 26
113 to 210
180
Week 52
211 to 400
360
*Relative to Study Day 1
5.1.2.
Study Day and Relative Day
Study Day 1 or Day 1 refers to the day when a participant receives the first dose of study 
intervention. All efficacy and safety assessments at all visits will be assigned a day relative to this 
date.
Study day or relative day for a visit is defined as:
!
Visit date - (date of Study Day 1) +1, if visit date is ≥date of Day 1
!
Visit date - Date of Day 1, if visit date <date of Day 1
There is no 'Day 0'.
5.1.3.
Baseline
Baseline is defined as the last observation on or before the day of the first dose of study 
intervention.  Participants without a baseline value will be excluded from the corresponding 
analysis.
5.1.4.
Up-titration period start date 
It is the first day of selexipag administration. It is derived as the first treatment start date (in
chronological order) in the "Study Drug Administration" eCRF.
5.1.5.
Up-titration period end date 
It is the date of Week 12 visit from the "Medication Kit Dispensation/ Accountability [IWRS or 
Balance]" eCRF form. In case of premature discontinuation or death prior to Week 12, the 'End of 
Treatment Date' in the "End of Treatment" eCRF form or the date of death will be considered. If 
both dates are missing and the subject discontinued from the study prior to Week 12, the 'End of 
Trial Date' from the "End of Trial" form will be used.
5.1.6.
Maintenance period start date
It is derived for subjects who did not discontinue the study prior to Week 12, as the day after the 
Week 12 visit date.


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5.1.7.
Maintenance period end date
It is derived for subjects with maintenance period start date available.
It is the 'End of Treatment Date' in the "End of Treatment" eCRF form or the date of death (when 
applicable). If both dates are missing the 'End of Trial Date' from the "End of Trial" form will be 
used.
5.1.8.
Imputation Rules for Missing AE Date/Time of Onset/Resolution
Partial AE onset dates will be imputed as follows:
!
If the onset date of an adverse event is missing day only, it will be set to:
∀
First day of the month that the AE occurred, if month/year of the onset of AE is different 
than the month/year of the first dose of study treatment.
∀
The day of first dose of study treatment, if the month/year of the onset of AE is the same 
as month/year of the first dose of study treatment and month/year of the AE resolution 
date is different
∀
The day of first dose of study treatment or day of AE resolution date, whichever is earliest, 
if month/year of the onset of AE and month/year of the first dose of study treatment date
and month/year of the AE resolution date are same.
!
If the onset date of an adverse event is missing both day and month, it will be set to the earliest 
of:
∀
January 1 of the year of onset, as long as this date is on or after the first dose of study 
treatment
∀
Month and day of the first dose of study treatment, if this date is the same year that the 
AE occurred
∀
Last day of the year if the year of the AE onset is prior to the year of the first dose of 
study treatment,
∀
The AE resolution date.
!
Completely missing onset dates will not be imputed, but the event will be assumed to be 
treatment emergent unless otherwise indicated.
Partial AE resolution dates not marked as ongoing will be imputed as follows:
!
If the resolution date of an adverse event is missing day only, it will be set to the earliest of 
the last day of the month of occurrence of resolution or the day of the date of death, if the 
death occurred in that month.
!
If the resolution date of an adverse event is missing both day and month, it will be set to the 
earliest of December 31 of the year or the day and month of the date of death, if the death 
occurred in that year.
!
Completely missing resolution dates will not be imputed.
Concomitant therapy start dates will be imputed as follows:


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!
If the start date is missing day only, it will be set to first day of the month.
!
If the start date has the year, but is missing the month, it will be set to January 1.
!
If the start date is completely missing, it will not be imputed.
Concomitant therapy end dates will be imputed as follows:
!
If the start date is missing day only, it will be set to last day of the month.
!
If the year is supplied, but is missing the month, it will be set to December 31, or the date 
of death if this is earlier.
!
If the start date is completely missing, it will not be imputed.
For missing or partial assessment dates:
!
For scheduled visits, the date will be set to the date closest to the scheduled date, within 
the range allowed by the partial dates.  (For screening assessments, use day -8 as the 
scheduled date.)
!
For unscheduled visits with partial dates:
!
if the day after first dose of study treatment is within the period, it will be set to the 
day after first dose;
!
otherwise, if the day after first dose of study treatment is within the period, it will be 
set to the day of first dose;
!
otherwise, if only the day is missing, it will be set to first of the month.
otherwise, if the year is supplied, but is missing the month, it will be set to January 1.
5.2.
Participant Dispositions
It is permitted to re-screen subjects once, if the reason for non-eligibility was transient (e.g., 
abnormal laboratory test, insufficient wash-out period of a forbidden medication). All screening 
assessments should then be repeated at the time of re-screening.
If a subject is screened twice and then enrolled, the first screening attempt is not considered in the 
evaluation of screening failures. 
A subject is considered a screening failure as identified from the answer ‘Screen Failure’ to the 
eCRF question ‘What was the subject's status?’ in the “End of Trial” form and the reason provided 
in the same form is used as the primary reason for screening failure.
Screened participants and reason for screen failures will be summarized overall.
A subject listing (including the inclusion criteria not met or the exclusion criteria met as collected 
in the " Inclusion/Exclusion Criteria Not Met" eCRF form) will be also provided for screening 
failures.


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The number of participants in the following disposition categories will be summarized throughout 
the study:
!
Participants who received study intervention
!
Participants who completed the study (including EOS visit)
!
Participants who terminated study prematurely
!
Reasons for premature termination of study
!
Participants who discontinued study intervention
!
Reasons for discontinuation of study intervention
A listing will be provided for the following categories:
!
Participants who discontinued study intervention prematurely
!
Participants who terminated study prematurely
The number of subjects in each analysis set (i.e., SCR, SS) will be summarized. 
A listing will be provided displaying the subject membership in the SS. This listing will be run on 
the SCR.
5.3.
Primary Endpoint(s) Analysis
Change in RVSV from baseline to Week 26 will be reported descriptively only (listing).
5.3.1.
Definition of Endpoint(s)
The primary endpoint is the change in RVSV from baseline to Week 26 as assessed by pulmonary 
artery flow MRI:
RVSV at Week 26 - RVSV at baseline
The baseline reference values for RVSV is based on the RVSV as determined from the screening 
MRI.
Handling of missing data
By design, only one post-baseline RVSV measurement will be taken at the time of the scheduled 
Week 26 or at the premature EOT visit. 
In some instances, the Week 26 (or premature EOT) assessment may be missing with no other 
post-baseline assessment available.
No imputation methods will be used for the primary endpoint analysis.


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5.3.2.
Analysis Methods
Due to very limited number of subjects, the absolute values at baseline and post-baseline as well 
as the absolute changes from baseline to post-baseline in RVSV will be reported in an individual 
subjects’ listing on the SS. No imputation will be performed.
5.4.
Secondary Endpoint(s) Analysis
Due to the small sample size, only listings will be provided for all secondary endpoints on the SS.
No imputation of missing data will be performed.
5.4.1.
Change from baseline to Week 26 of additional measures of RV 
function using MRI
Change from baseline to Week 26 assessed by MRI for:
!
RV end-diastolic volume (RVEDV)
!
RV end-systolic volume (RVESV)
!
RV ejection fraction (RVEF)
!
RV mass
!
RV global longitudinal strain (RVGLS).
The change from baseline to Week 26 for these additional measures of RV function assessed by 
MRI will be listed by timepoint on the SS.
5.4.2.
Change from baseline to Week 26 for 6MWD, WHO FC and NT-proBNP
Absolute values as well as the change from baseline to Week 26 in 6MWD will be reported in 
individual subjects’ listing on the SS. 
WHO FC will be listed on the SS by timepoint. Changes from baseline in WHO FC will be 
dichotomized as worsening (i.e., change >0) versus no change or improvement (ie, change ≤0) and 
reported in the listing. 
NT-proBNP will be listed on the SS by timepoint on the SS
5.4.3.
Change from baseline to Week 26 in the number of low-risk criteria
The change from baseline to Week 26 in the number of low-risk criteria based on the following 8 
variables in accordance with the 2015 ESC/ERS Guidelines for the diagnosis and treatment of 
pulmonary hypertension2:
!
Absence of clinical signs of right heart failure (“Does the patient have clinical signs of right 
heart failure?” = ‘No’ in the ‘Risk Stratification’ eCRF form)
!
Absence of symptoms of PAH progression (“Progression of PAH symptoms” = ‘No’ in the 
‘Risk Stratification’ eCRF form)


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!
Absence of syncope (“Did the patient experience syncope?” = ‘No’ in the ‘Risk 
Stratification’ eCRF form)
!
WHO FC I-II
!
6MWD >440m
!
NT-proBNP < 300 ng/L
!
Right atrial (RA) area <18 cm2, as determined by Echo
!
Absence of pericardial effusion, as determined by Echo
will be calculated for each participant in the SS, and reported in a listing. The number of low-risk 
criteria at baseline and Week 26 constitutes the risk score and will be derived for each subject by 
adding ‘1’ for each of the above criteria met. The number of low-risk criteria for each subject can 
vary from 0 (worse subjects) to 8 (healthier subjects).
Note: the risk score will be assessed
excluding subjects with even a single missing value at baseline and/or endpoint visit.
5.5.
Tertiary/Exploratory Endpoint(s) Analysis
Due to the small sample size, only listings will be provided for all exploratory endpoints.
5.5.1.
Change from baseline to Week 52 on RV function assessed by MRI
The absolute values as well as the change from baseline to Week 52 in RVSV, RVEDV, RVESV, 
RVEF, RV mass and RVGLS assessed by MRI will be listed on the SS.  
The number and percent of participants who achieve normalized RVSV at Week 26 and Week 52 
will be displayed in the above listing. Patients with a RVSV >60mL will be considered as normal 
(Kawel-Boehm, 2015)3, this is consistent with Protocol inclusion criterion 4.2.
5.5.2.
Change from baseline to Week 26 and Week 52 of RV mass/LV mass
The absolute values as well as the change from baseline to Week 26 and Week 52 in RV mass/LV 
mass assessed by MRI will be listed on the SS.
5.5.3.
Change from baseline to Week 26 of RV function assessed by Echo
The absolute value as well as the change from baseline to Week 26 of RV function assessed by 
Echo for the parameters listed below, will be listed on the SS:
!
Tricuspid annular plane systolic excursion (TAPSE)
!
Pericardial effusion size scored from 0 to 4
!
RV end-diastolic area
!
RV end-systolic area
!
RV fractional area change
!
RVSV determined from pulmonary valve Doppler and pulmonary annulus dimension


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RA area.
5.5.4.
Change from baseline to Week 26 and Week 52 of LV function 
assessed by MRI
The absolute values as well as the change from baseline to Week 26 and Week 52 of LVEDV, 
LVESV, LV ejection fraction and LV mass assessed by MRI will be listed on the SS.
5.5.5.
Change from baseline to Week 26 and Week 52 of Right main PA 
pulsatility assessed by MRI
The absolute values as well as the change from baseline to Week 26 and Week 52 of right main 
PA pulsatility assessed by MRI will be listed on the SS. 
5.5.6.
Change from baseline to Week 26 and Week 52 of RV/LV function using 
4D flow imaging
The absolute values as well as the change from baseline to Week 26 and Week 52 of RVSV 
determined from 4D flow imaging in PA and LVSV determined from 4D flow imaging in aorta, 
in participants from sites able to provide suitable MRI imaging, will be reported in individual 
subjects’ listing on the SS.
5.5.7.
Impact of individual maintenance dose
Due to the very limited number of patients, RVSV will not be analyzed by maintenance dose
subgroup. 
5.5.8.
Change from baseline to Week 52 for 6MWD, WHO FC and NT-proBNP
The change from baseline to Week 52 for 6MWD, WHO FC and NT-proBNP will be analyzed 
similarly as the change from baseline to Week 26 in Section 5.4.2.
5.5.9.
EuroQol 5-dimension scale (EQ-5D-3L)
The health profile and health state index score will be derived according to the instrument's 
instruction for each individual and visit. The absolute values as well as the change from baseline 
to Week 26 and Week 52 in the health profile, in the health state index score and in the EQ VAS 
will be reported in a listing on the SS. 
5.5.10.
Change from baseline to Week 26 and Week 52 in the difference 
between the pre-walk and post-walk assessed Borg Dyspnea Index 
(BDI)
The pre-walk assessed BDI and post-walk assessed BDI at Week 26 and Week 52 as well as the 
difference between the pre-walk and post-walk assessed BDI at both visits and from baseline will 
be listed on the SS.
5.6.
Safety Analyses
All safety analyses will be conducted on the safety analysis set.


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For all continuous safety variables, descriptive statistics will include the N, mean, standard 
deviation, median, minimum, and maximum. Categorical variables will be summarized using 
frequency counts and percentages.
5.6.1.
Extent of Exposure
Exposure will be summarized up to EOT. 
The number and percentage of participants who received study intervention will be summarized.
Descriptive statistics for duration of study intervention (N, mean, SD, median, and range 
(minimum, maximum)) will be summarized. Participant-years of intervention are calculated as
[days of intervention/365.25].
Duration of exposure will be summarized in the following duration categories: <1 week, 1-<4 
weeks, 4-<12 weeks, 12-<26 weeks, ≥ 26 weeks.
Cumulative duration of intervention ≥ 1 week, ≥ 4 weeks, ≥ 12 weeks, ≥ 26 weeks will be 
summarized.
Study intervention duration is defined as (date of last dose of study intervention – date of first dose 
of study intervention) +1.
Total dose days of intervention is defined as the total number of days that study intervention was 
administered to the participant (excluding days off study intervention).
The number (%) of participants with a dose adjustment/dose not administered will be summarized. 
Reasons for dose adjustments/doses not administered will also be summarized.
Descriptive statistics will be presented for the following parameters during the dose maintenance 
period:
!
The number (%) of participants with a dose adjustment after the 12-week up-titration period.  
Reasons for dose adjustments will also be summarized.
!
Cumulative total dose per participants
!
Mean daily dose per participant (after the 12-week up-titration period)
!
IMD at end of Week 12 (Day 84).
The mean daily dose of study intervention is calculated as (sum of total daily dose)/study treatment 
duration.
The total daily dose is calculated according to frequency and dose (μg).


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Frequency 
(coded)a
Total daily dose (μg / day)
Once a day
dose
Twice a day 
2 × dose
Twice weekly 
2 × dose / 7
Monthly
dose / 30.5
Every other 
day
dose / 2
<X> times 
<X> × dose
<X> times 
<X> × dose / 7
Weekly 
dose / 7
Every <X> 
dose /(7 × <X>)
Twice per 
month
2 x dose / 30.5
Missing, other 
codes 
0
a:  values coded to CONTINUOUS, ONCE, AS NECESSARY, INFREQUENT, UNKNOWN
cannot be used to determine the total daily dose and therefore the total daily dose will be set to 
zero. 
The cumulative total dose per participant is calculated as the sum of total daily dose over the whole 
treatment period.
5.6.2.
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after the 
initial administration of study intervention through the day of last dose plus 3 days is considered 
to be treatment-emergent. If the event occurs on the day of the initial administration of study 
intervention, and either event time or time of administration are missing, then the event will be 
assumed to be treatment emergent. If the event date is recorded as partial or completely missing, 
then the event will be considered to be treatment emergent unless it is known to be prior to the first 
administration of study intervention based on partial onset date or resolution date. All reported 
treatment-emergent adverse events will be included in the analysis. For each adverse event, the 
number and percentage of participants who experience at least 1 occurrence of the given event will 
be summarized.
Note: for participants who are entering another open-label clinical study with selexipag, safety 
information will be reported up to the last dose in RESTORE as the EOT visit will be combined 
with EOS visit. This is intended to avoid duplicate reporting of adverse events (AEs).
Summary tables will be provided for treatment-emergent adverse events by System Organ Class 
(SOC) and Preferred Term (PT):
!
AEs
!
Serious AEs (SAEs)


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AEs leading to discontinuation of study intervention
!
AEs of COVID-19
!
AEs by severity 
!
AEs by relationship to study intervention
SAEs will also be tabulated up to 30 days after end of study intervention or EOS whichever is first.
In addition to the summary tables, listings will be provided for participants who:
!
Had AEs
!
Had SAEs
!
Had AEs leading to discontinuation of study intervention
!
Had AEs of special interest (AESI) (see Appendix 8)
5.6.3.
Deaths
Deaths will be displayed. Frequencies for the following parameters will be included in the 
summary table:
!
Number of participants who died
!
Cause of death.
!
Relationship to study intervention (yes/no).
A listing of participants who died will be provided.
5.6.4.
Additional Safety Assessments
5.6.4.1.
Clinical Laboratory Tests
Clinical laboratory tests will be displayed for the participants included in the safety analysis set.
Descriptive statistics (observed values and absolute changes from baseline) will be presented for
all chemistry and hematology laboratory tests at scheduled time points.  All recorded assessments 
up to EOT + 3 days will be assigned to the most appropriate visit time point according to the best 
fitting time window for that assessment.
Scatter plots (eDISH plot) of maximum treatment-emergent ALT and AST versus maximum 
treatment-emergent total bilirubin up to EOT + 3 days will be presented.
An abnormality (abnormality based on criteria defined in tables in Appendix 10, Section 6.10) will 
be attributed to the baseline and post baseline values.
Post baseline abnormalities will be compared with their corresponding baseline result:


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Treatment-emergent (TE) will be concluded if the post baseline value is worse than the 
baseline value.
!
If the post baseline value is above the upper limit and the baseline value is below the upper 
limit (e.g., Normal or Low), then the post baseline abnormality will be considered TE. The 
same applies to the post baseline value being below the lower limit with the baseline value 
being above the lower limit (e.g., Normal or High).
!
If the baseline value is missing, a post baseline abnormality will always be considered as TE.
Treatment-emergent marked laboratory abnormalities (see Section 6.10) will be summarized for 
each laboratory variable for which marked abnormalities are defined providing their incidence and 
frequency. 
All laboratory data will be listed together with derived marked abnormality flag.  A separate listing 
of all laboratory data for the subjects with at least one marked abnormality value will be provided.
5.6.4.2.
Vital Signs and Physical Examination Findings
Physical examination findings will be listed. Vital signs include height (cm), weight (kg), BMI 
(kg/m2), pulse (beats/min), systolic blood pressure (mmHg) and diastolic blood pressure (mmHg). 
Observed values and absolute change from baseline will be summarized descriptively by 
timepoint.
5.6.4.3.
Electrocardiogram
Not applicable.
5.6.4.4.
Other Safety Parameters
Not applicable.
5.7.
Other Analyses
5.7.1.
Pharmacokinetics
Not applicable.
5.7.2.
Immunogenicity
Not applicable.
5.7.3.
Pharmacodynamics
Not applicable.
5.7.4.
Pharmacokinetic/Pharmacodynamic Relationships
Not applicable.


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5.7.5.
Biomarkers
Biomarker samples will be used to generate circulating marker data for computational analyses. 
These analyses are considered exploratory and the results will be reported separately from the 
CSR.
5.7.6.
Health Economics
Not applicable.
5.7.7.
Other Variables and/or Parameters
Not applicable.
5.7.8.
Definition of Subgroups
Following study premature termination, no subgroup analysis will be performed.
5.8.
Interim Analyses
Not applicable.
5.8.1.
Data Monitoring Committee (DMC) or Other Review Board
Not applicable.


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6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
4D
4-dimensional
6MWD
6-minute walking distance
6MWT
6-minute walking test
AE
adverse event
AESI
adverse event of special interest
ALT/SGPT
alanine aminotransferase
ANCOVA
analysis of covariance
AST/SGOT
aspartate aminotransferase
ATC
anatomic and therapeutic class
BDI
Borg dyspnea index
BMI
body mass index
CI
confidence interval
CRF
case report form
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
DPS
Data Presentation Specifications
Echo
Echocardiogram
ECG
electrocardiogram
eCRF
electronic case report form
EOS
end of study
EOT
end of treatment
EQ-5D
EuroQol 5-Dimension scale
FDA
Food and Drug Administration
IAP
image acquisition protocol
ICF
informed consent form
ICH
International Conference on Harmonisation
IMD
individual maintenance dose
IQ
interquartile
LV
left ventricle, left ventricular
LVEDV
left ventricular end diastolic volume
LVEF
left ventricular ejection fraction
LVESV
left ventricular end systolic volume
MedDRA
Medical Dictionary for Regulatory Activities
mPAP
mean pulmonary arterial pressure
MRI
magnetic resonance imaging
NT-proBNP
N-terminal-pro-hormone brain natriuretic peptide
PA
pulmonary artery
PAH
pulmonary arterial hypertension
PAWP
pulmonary artery wedge pressure
PI
principal investigator
PT
prothrombin time
PVR
pulmonary vascular resistance
RA
right atrium, right atrial
RHC
right heart catheterization
RV
right ventricle, right ventricular
RVEDV
right ventricular end diastolic volume
RVEF
right ventricular ejection fraction
RVESV
right ventricular end systolic volume
RVGLS
right ventricular global longitudinal strain
RVSV
right ventricular stroke volume
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBP
systolic blood pressure


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SD
standard deviation
SMQs
standardised MedDRA queries
SS
Safety set
TEAE
treatment-emergent adverse event
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary


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6.2.
Appendix 2 Changes to Protocol-Planned Analyses
!
The number and percent (%) of patients achieving a normalized RVSV assessed by MRI 
at Week 26 and Week 52 was added as an exploratory endpoint.
!
Following premature study termination, it is clarified that only descriptive statistics will be 
reported, no analysis will be performed using FAS/PP and no subgroup analysis will be 
performed. 


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6.3.
Appendix 3 Demographics and Baseline Characteristics
The number of participants in each analysis set will be summarized and listed overall.
Tables 4 and 5 present a list of the demographic variables and baseline disease characteristics that 
will be summarized overall for the SS analysis set.
Table 4:
Demographic Variables
Continuous Variables:
Summary Type
Age (years)
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum], and IQ range).
Weight (kg)
Height (cm)
Body Mass Index (BMI) (kg/m2)
Categorical Variables
Age (18-<25 years, 25-<51 years, 51-<65 years and >=65 years)
Frequency distribution with the 
number and percentage of 
participants in each category.
Sex (male, female, undifferentiated)
Racea (American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or other Pacific Islander, White, Multiple)
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
a
If multiple race categories are indicated, the Race is recorded as 'Multiple'
Table 5:
Baseline disease characteristics
Continuous Variables:
Summary Type
Time since PAH diagnosis (months)
Descriptive statistics (N, mean, 
standard deviation [SD], median and 
range [minimum and maximum], and 
IQ range).
6MWD (m)
BDI score (pre-walk, post-walk and difference pre-post)
NT-proBNP (ng/L)
Categorical Variables
PAH Etiology
Frequency distribution with the 
number and percentage of participants
in each category.
WHO FC (II, III)
Naïve to PH therapies (yes, no)*
* Naive to PH therapies participants are participants without any of the PAH-specific therapies listed in Section 6.9 (Appendix 9) taken as 
concomitant at baseline (see Section 6.5 for definition of concomitant medication at baseline)
For each subject time since PAH diagnosis (months) will be derived as:
(Date of Day 1 - date of diagnosis +1) / 30.4375.
Demographics and baseline characteristics will also be listed on the SS.


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6.4.
Appendix 4 Protocol Deviations
In general, major protocol deviations may have the potential to impact participants’ rights, safety 
or well-being, or the integrity and/or result of the clinical study. Participants with major protocol 
deviations will be identified prior to database lock and the participants with major protocol 
deviations will be summarized by category.
See TV-FRM-04718 "Major Protocol Deviation Criteria" for detailed definitions of major protocol 
deviations.
A specific listing will be provided for major protocol deviations by region and site.


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6.5.
Appendix 5 Prior and Concomitant Medications
Prior and Concomitant medications will be coded using the last available version of World Health 
Organization Drug Dictionary (WHO-DD). Prior medications are defined as any therapy used 
before the day of first dose (partial or complete) of study intervention. 
Concomitant medications are defined as any therapy used on or after the same day as the first 
dose of study intervention, including those that started before the first dose of study intervention.
Concomitant medication at baseline is any medication taken at the same day of the first dose of 
study intervention (see Section 5.1.3).
Summaries of concomitant medications will be presented by ATC class and PT on the SS. The 
proportion of participants who receive each concomitant medication will be summarized as well 
as the proportion of participants who receive at least 1 concomitant medication. 
In addition, concomitant medications of special interest (PAH-specific) will be presented on the 
SS. See Appendix 9 (Section 6.9) for list of medications in PAH-specific category.
In addition, summaries of concomitant medications of special interest at baseline will be presented 
by ATC class and PT on the SS in the same way.
Prior medications will be summarized by ATC term (highest available level) on the SS.
All prior and concomitant medications will also be listed, with flags for PAH-specific ones and for 
concomitant at baseline ones.


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6.6.
Appendix 6 Medical History
Medical history by System Organ Class (SOC) and Preferred Term (PT) will be summarized on 
the SS. A separate table will be created for Medical history ongoing at baseline (“Is the medical 
history disease/condition or event still ongoing?” = ‘Yes’ in the ‘General Medical History eCRF 
form). All Medical history will also be listed. 


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6.7.
Appendix 7 Intervention Compliance
Compliance through EOT will be summarized descriptively, including in the summary the 
following compliance categorization: < 80%, 80–120% and > 120%.
Compliance will be calculated as follows, for each strength dispensed:
Compliance = [(number of tablets dispensed - number of tablets returned)/2 x total duration of 
treatment period] x 100.
Compliance will be calculated only if the answer to the question “Was drug accountability 
performed for returned study treatment?” is ‘Yes’.
Compliance will also be listed.


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6.8.
Appendix 8 Adverse Events of Special Interest
The following adverse events of special interest will be used for selexipag. These are based on the 
important identified and potential risks in the latest Risk Management Plan and on-going 
discussion with Pharmacovigilance Risk Assessment Committee.  
AE Special Interest Category
Anaemia
Bleeding events
Gastrointestinal disturbances denoting intestinal intussusception (manifested as ileus or obstruction)
Hyperthyroidism
Hypotension
Light-dependent non-melanoma skin malignancies
Major adverse cardiovascular events (MACE)
Medication errors
Ophthalmological effects associated to retinal vascular system
Pregnancy
Pulmonary venoocclusive disease associated with pulmonary oedema
Renal function impairment / acute renal failure
Prostacyclin associated reactions*
*Prostacyclin associated reactions will be summarized separate from other AESIs
A specific file containing all preferred terms for each category as per last coding version will be 
maintained.


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6.9.
Appendix 9 Medications of Special Interest
Concomitant medications of special interest are defined as follows:
Concomitant/Prior Medication Special 
Interest Category
Standard ATC Name
Note
PAH-specific medications
Sildenafil
Medications with ATC name 
containing any of the listed 
standard ATC names are 
considered as PAH-specific 
medications.
PAH-specific medications
Tadalafil
PAH-specific medications
Vardenafil
PAH-specific medications
Iloprost
PAH-specific medications
Epoprostenol
PAH-specific medications
Beraprost
PAH-specific medications
Treprostinil
PAH-specific medications
Selexipag
PAH-specific medications
Riociguat
PAH-specific medications
Macitentan
PAH-specific medications
Bosentan
PAH-specific medications
Ambrisentan


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6.10.
Appendix 10 Laboratory Toxicity Grading
The grading scale use for lab assessments is based on the tables below.
Blood chemistry marked abnormalities (SI Units)
Laboratory test 
name (CDISC 
Synonym[s])
LL
LLL
HH
HHH
Alanine 
aminotransferase
NA
NA
> 3 × ULN
> 5 × ULN
Aspartate 
aminotransferase
NA
NA
> 3 × ULN
> 5 × ULN
Alkaline 
phosphatase
NA
NA
> 2.5 × ULN
> 5 × ULN
Bilirubin; Total 
bilirubin
NA
NA
> 2 × ULN
> 5 × ULN
Creatinine
NA
NA
> 1.5 × ULN
> 3 × ULN
Sodium
NA
< 130 mmol/L
> 150 mmol/L
> 155 mmol/L
Potassium
< 3.2 mmol/L
< 3.0 mmol/L
> 5.5 mmol/L
> 6.0 mmol/L
CDISC=Clinical Data Interchange Standards Consortium; NA = not applicable; ULN = upper limit of normal. 
Blood chemistry marked abnormalities (SI Units)
Laboratory test 
name (CDISC 
Synonym[s])
LL
LLL
HH
HHH
Hemoglobin
< 100 g/L
< 80 g/L
> 20 g/L above 
baseline
> 40 g/L above 
baseline
Hematocrit; EVF; 
PCV (male)
< 0.32 L/L
< 0.20 L/L
> 0.60 L/L
> 0.65 L/L
Hematocrit; EVF; 
PCV (female)
< 0.28 L/L
< 0.20 L/L
> 0.55 L/L
> 0.65 L/L
Platelets 
(assuming no 
platelet cluster)
< 75 × 109/L
< 50 × 109/L
> 600 × 109/L
> 999 × 109/L
Leukocytes; white 
blood cells
< 3.0 × 109/L
< 2.0 × 109/L
> 20.0 × 109/L
> 100.0 × 109/L
Neutrophils (Abs)
< 1.5 × 109/L
< 1.0 × 109/L
NA
NA
Eosinophils (Abs)
NA
NA
> 5.0 × 109/L
NA
Lymphocytes 
(Abs)
< 0.8 × 109/L
< 0.5 × 109/L
> 4.0 × 109/L
> 20 × 109/L
CDISC= Clinical Data Interchange Standards Consortium; EVF = erythrocyte volume fraction; NA = not applicable; PCV = packed 
cell volume.


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7.
REFERENCES
1. van Wolferen SA, van de Veerdonk MC, Mauritz GJ, Jacobs W, Marcus JT, Marques KMJ, et al. Clinically
significant change in stroke volume in pulmonary hypertension. Chest. 2011;139(5):1003-1009.
2. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for 
the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the 
European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital 
Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016 Jan 
1;37(1):67-119. doi: 10.1093/eurheartj/ehv317. Epub 2015 Aug 29. PMID: 26320113. 
3. Kawel-Boehm N, et al.  Normal values for cardiovascular magnetic resonance in adults and children. Journal of 
Cardiovascular Magnetic Resonance. 2015; 17:29.