Clinical trial NCT04565990
Conditions: Hypertension, Pulmonary
Sponsor: Actelion
Start date: 2021-05-03; Completion date: 2023-11-10
Enrollment: 43 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to assess the long-term safety of selexipag while providing continued selexipag treatment for participants who were previously enrolled in an Actelion-sponsored study with selexipag and who derived benefit from selexipag in indications for which a positive benefit-risk has been established.

Detailed description:

Arms: arm 1: Participants will receive selexipag tablets twice daily with the dose strength corresponding to their individual maximum tolerated dose (iMTD) from the parent study.
Interventions: intervention 1: Selexipag
Intervention descriptions: intervention 1: Selexipag tablets will be administered orally at all dose strengths (200, 400, 600, 800, 1000, 1200, 1400 and 1600 microgram) twice daily.

Protocol documents:
Prot_000.pdf: 
Confidential –FOIA Exemptions Apply in U.S. 
1
Status: Approved,Date: 26 October 2021
Actelion Pharmaceuticals Ltd.*
(a Janssen Pharmaceutical Company of Johnson & Johnson)
Clinical Protocol
Protocol Title
A Multicenter, Single-arm, Open-label, Long-term Follow-up Safety Study of Selexipag in
Participants who Participated in a Previous Selexipag Study
SOMBRERO
Protocol 67896049PUH3001; Phase 3b, Amendment 2
JNJ-67896049 / ACT-293987 (selexipag)
* Actelion Pharmaceuticals Ltd. (“Actelion”) is a global organization that operates through different legal
entities in various countries. Therefore, the legal entity acting as the sponsor for Actelion studies may vary,
such as, but not limited to Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; or
Janssen Research & Development, LLC. The term “sponsor” is used throughout the protocol to represent
these various legal entities; the sponsor is identified on the Contact Information page that accompanies the
protocol.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
IND:104504
EudraCT NUMBER:2020-000475-21
Status: 
Approved
Date: 
26 October 2021
Prepared by: Actelion Pharmaceuticals Ltd. and Janssen Research & Development, a division of
Janssen Pharmaceutica NV
EDMS number: 
EDMS-RIM-265923, 2.0
Protocol Version: 
3.0
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.
NCT04565990


JNJ-67896049 / ACT-293987 (selexipag) 
Clinical Protocol 67896049PUH3001, Amendment 2
Confidential –FOIA Exemptions Apply in U.S. 
2
Status: Approved,Date: 26 October 2021
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 2, Version 3 
26-Oct-2021
Amendment 1, Version 2 
08-Dec-2020
COVID-19 Appendix (EDMS-RIM-272313, 1.0) 
27-Nov-2020
Original Protocol, Version 1 
04-Mar-2020
Amendment 2 (26 October 2021)
Overall Rationale for the Amendment:  The main reason for the amendment is to clarify the definition
of end of study (EOS) and safety reporting requirements for participants who complete treatment in this
study and who will continue with selexipag treatment by rolling over into a post-trial access (PTA) program
or Study NOPRODPAPUH3001 (PLATYPUS). This is to avoid duplicate reporting of adverse events
(AEs) in the clinical databases and of serious adverse events (SAEs) in the safety database. In addition,
exploratory objectives, endpoints and analyses corresponding to World Health Organisation functional
class (WHO FC) and overall survival status were deleted to reflect the recent update in SOMBRERO study
population that the SOMBRERO study will only recruit the participants with pulmonary arterial
hypertension (PAH) from the GRIPHON OL study.
A Protocol Amendment Summary of Changes Table for the current amendment is provided below. The
updates are indicated in bold text and the deleted text in strike-through.
Section Number 
and Name
Description of Change 
Brief Rationale
1.1. Synopsis (Objectives and
Endpoints; Exploratory
Evaluation; Statistical Methods-
Exploratory Analyses);
1.3. Schedule of Activities (SoA);
3. Objectives and Endpoints;
4.1. Overall Design;
8.2. Exploratory Assessment;
9.4.3. Exploratory Endpoint and
Analyses
Exploratory objectives, endpoints
and analyses corresponding to
World Health Organisation
functional class (WHO FC) and
overall survival status were
deleted.
To reflect the recent update in study
population that the SOMBRERO
study will only recruit the participants
with PAH from the GRIPHON OL
study.
As survival and WHO FC are not
assessed in GRIPHON OL, these
endpoints will not be included in the
current study.
1.1. Synopsis (Exploratory
Evaluation, Statistical Methods-
Exploratory Analyses);
8.2. Exploratory Assessment;
8.2.1. Dose Reduction or Increase
of Selexipag;
9.4.3. Exploratory Endpoint and
Analyses
‘Selexipag dose reduction or
increase and corresponding
reasons’was included under the
heading of ‘Exploratory
Evaluation’ or ‘Exploratory
Endpoints and Analyses’ and
sections of ‘Efficacy
Evaluations/Assessments’ were
deleted.
To align with updates corresponding
to exploratory evaluations.
1.1. Synopsis (Overall Design);
1.3. Schedule of Activities (SoA):
Footnote ‘g’;
4.1. Overall Design
Following text was revised and
added at applicable instances:
‘Participants will present for the
EOT visit within 7 days of the
last dose of study intervention.
For participants rolled over to
post-trial access (PTA) or Study
NOPRODPAPUH3001
(PLATYPUS), the enrollment
To update information about the end
of treatment (EOT) Visit / EOS Visit.


JNJ-67896049 / ACT-293987 (selexipag) 
Clinical Protocol 67896049PUH3001, Amendment 2
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Status: Approved,Date: 26 October 2021
Section Number 
and Name
Description of Change 
Brief Rationale
must occur on the day of the last
visit of SOMBRERO study, ie,
EOS visit which corresponds to
EOT, to avoid selexipag
treatment interruption.’
Following text was included: ‘For 
participants who complete the 
study treatment and who are 
eligible for a post-trial access 
(PTA) or Study 
NOPRODPAPUH3001 
(PLATYPUS), the post- 
treatment follow-up period will 
be waived.’
To clarify the reporting of AEs/SAEs
after the last study drug administration
in the SOMBRERO study for
participants who will continue to be
treated with selexipag after the end of
study (EOS) Visit in a PTA program
or Study NOPRODPAPUH3001
(PLATYPUS).
1.1. Synopsis (Number of 
Participants); 
2.1. Study Rationale; 
2.3.2. Benefits for Study 
Participation; 
9.2. Sample Size Determination  
Content related to rollover of 
participants to current study from 
ongoing interventional clinical 
studies with selexipag in various
indications in other classes of
pulmonary hypertension (PH) was
deleted.
As the current study will only recruit
the participants with PAH from the
GRIPHON OL study.
1.1. Synopsis (Overall Design); 
4.1. Overall Design; 
8. Study Assessment and 
Procedures 
Text was updated (deletion of 
‘[limited] efficacy’) to indicate that 
only safety and other information
will be collected during study
visits and telephone calls.
As no efficacy assessments will be
performed.
1.1. Synopsis (Safety Analyses); 
9.4.2. Safety Analyses 
The term ‘stratified by indication’ 
was deleted. 
As the current study will only recruit
the participants with PAH from the
GRIPHPON OL study.
1.2. Schema (Figure 1) 
Abbreviations and following note 
were added under Figure 1: ‘For 
participants who are entering a 
post-trial access (PTA) program
or Study NOPRODPAPUH3001
(PLATYPUS), the enrollment
must occur on the day of the last
visit of SOMBRERO study ie,
EOS visit which corresponds to
EOT to avoid selexipag
treatment interruption. The
post-treatment follow-up period
will be waived in this case.’
To indicate that EOT = EOS for
participants rolling over to a continued
access program with selexipag.
1.3. Schedule of Activities (SoA) 
Note corresponding to 
‘Concomitant therapy’ was 
deleted.
As information about all concomitant
medications is collected.
2. Introduction 
Following statement was added: 
‘Unless specified otherwise, the 
parent study refers to 
GRIPHON OL throughout the
protocol.’
As the current study will only recruit
the participants with PAH from the
GRIPHPON OL study.
8. Study Assessments and 
Procedures 
Following statement was deleted: 
‘If multiple assessments are 
scheduled for the same timepoint,
it is recommended that procedures
be performed in the following
As no efficacy assessments will be
performed.


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Clinical Protocol 67896049PUH3001, Amendment 2
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Status: Approved,Date: 26 October 2021
Section Number 
and Name
Description of Change 
Brief Rationale
sequence: safety assessments and
WHO FC.’
8.3.1. Time Period and Frequency 
for Collecting Adverse Events 
and Serious Adverse Events 
Text updated to indicate that AEs 
and SAEs will be reported ‘up to 
EOS for participants who enter a 
continued access program on the 
same day as the EOS Visit’. 
To clarify that for participants who
enter a post-trial access program or
Study NOPRODPAPUH3001
(PLATYPUS), safety information is to
be reported up to EOS visit in this
study.
10.6. Appendix 6: World Health 
Organization (WHO) Functional 
Classification of Pulmonary 
Hypertension 
Appendix 6 was deleted and 
following appendices were 
renumbered. 
As the current study will only recruit
the participants with PAH from the
GRIPHON OL study, WHO-FC
assessment is no longer applicable.
10.7. Appendix 7: Guidance on 
Study Conduct During Natural 
Disaster 
Included updates about ‘Study 
conduct related to COVID-19 
vaccine deployment for non- 
COVID-19 clinical trials.’ 
To align with Medicines and
Healthcare products Regulatory
Agency (MHRA) vaccination
guidance to be followed during
Corona Virus Disease-2019 (COVID-
19) pandemic.
11. References 
Reference corresponding to 
selexipag investigator’s brochure 
(IB) was updated. 
To update information about latest IB
and IB-addendum (edition and
publishing date).
Throughout the protocol 
Minor grammatical, formatting, or 
spelling changes were made.
Minor errors were noted.


JNJ-67896049 / ACT-293987 (selexipag) 
Clinical Protocol 67896049PUH3001, Amendment 2
Confidential –FOIA Exemptions Apply in U.S. 
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Status: Approved,Date: 26 October 2021
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 5
LIST OF IN-TEXT FIGURES ........................................................................................................................ 6
1. 
PROTOCOL SUMMARY..................................................................................................................... 7
1.1. 
Synopsis........................................................................................................................................... 7
1.2. 
Schema.......................................................................................................................................... 10
1.3. 
Schedule of Activities (SoA)........................................................................................................... 11
2. 
INTRODUCTION................................................................................................................................ 13
2.1. 
Study Rationale.............................................................................................................................. 13
2.2. 
Background .................................................................................................................................... 13
2.3. 
Benefit-Risk Assessment............................................................................................................... 14
2.3.1. 
Risks for Study Participation....................................................................................................... 14
2.3.2. 
Benefits for Study Participation .................................................................................................. 15
2.3.3. 
Benefit-Risk Assessment for Study Participation ....................................................................... 16
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 16
4. 
STUDY DESIGN ................................................................................................................................ 16
4.1. 
Overall Design................................................................................................................................ 16
4.2. 
Scientific Rationale for Study Design............................................................................................. 17
4.2.1. 
Study-Specific Ethical Design Considerations ........................................................................... 17
4.3. 
Justification for Dose...................................................................................................................... 18
4.4. 
End of Study Definition................................................................................................................... 18
5. 
STUDY POPULATION ...................................................................................................................... 18
5.1. 
Inclusion Criteria............................................................................................................................ 18
5.2. 
Exclusion Criteria........................................................................................................................... 19
5.3. 
Screen Failures.............................................................................................................................. 20
6. 
STUDY INTERVENTION................................................................................................................... 20
6.1. 
Study Intervention(s) Administered................................................................................................ 20
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 21
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 22
6.4. 
Study Intervention Compliance...................................................................................................... 22
6.5. 
Concomitant Therapy..................................................................................................................... 23
6.6. 
Dose Modification........................................................................................................................... 23
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 24
7.1. 
Discontinuation of Study Intervention ............................................................................................ 24
7.1.1. 
Temporary Discontinuation......................................................................................................... 25
7.2. 
Participant Discontinuation/Withdrawal From the Study................................................................ 25
7.3. 
Lost to Follow-up............................................................................................................................ 26
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 26
8.1. 
Safety Assessments....................................................................................................................... 27
8.2. 
Exploratory Assessment ................................................................................................................ 28
8.2.1. 
Dose Reduction or Increase of Selexipag .................................................................................. 28
8.3. 
Adverse Events and Serious Adverse Events ............................................................................... 28
8.3.1. 
Time Period and Frequency for Collecting Adverse Events and Serious Adverse Events ........ 28
8.3.2. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 29
8.3.3. 
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 29
8.3.4. 
After the 30-day follow-up period................................................................................................ 29


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Confidential –FOIA Exemptions Apply in U.S. 
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Status: Approved,Date: 26 October 2021
8.4. 
Pregnancy...................................................................................................................................... 30
8.4.1. 
Reporting of Pregnancy.............................................................................................................. 30
8.4.2. 
Follow-up of Pregnancy.............................................................................................................. 30
8.5. 
Treatment of Overdose .................................................................................................................. 30
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 31
9.1. 
Statistical Hypotheses.................................................................................................................... 31
9.2. 
Sample Size Determination ........................................................................................................... 31
9.3. 
Populations for Analysis Sets ........................................................................................................ 31
9.4. 
Statistical Analyses ........................................................................................................................ 31
9.4.1. 
Safety Endpoints......................................................................................................................... 31
9.4.2. 
Safety Analyses.......................................................................................................................... 31
9.4.3. 
Exploratory Endpoint and Analyses............................................................................................ 32
9.5. 
Interim Analysis.............................................................................................................................. 32
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 33
10.1. 
Appendix 1: Abbreviations ............................................................................................................. 33
10.2. 
Appendix 2: Clinical Laboratory Tests ........................................................................................... 34
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 35
REGULATORY AND ETHICAL CONSIDERATIONS................................................................................. 35
FINANCIAL DISCLOSURE......................................................................................................................... 38
INFORMED CONSENT PROCESS............................................................................................................ 38
DATA PROTECTION.................................................................................................................................. 39
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA................................................. 39
DATA QUALITY ASSURANCE................................................................................................................... 41
CASE REPORT FORM COMPLETION...................................................................................................... 41
SOURCE DOCUMENTS............................................................................................................................. 42
MONITORING............................................................................................................................................. 42
ON-SITE AUDITS ....................................................................................................................................... 43
RECORD RETENTION............................................................................................................................... 43
STUDY AND SITE START AND CLOSURE .............................................................................................. 44
10.4. 
Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating,
Follow-up, and Reporting............................................................................................................... 45
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS .................................................................... 45
ATTRIBUTION DEFINITIONS .................................................................................................................... 46
SEVERITY CRITERIA................................................................................................................................. 46
SPECIAL REPORTING SITUATIONS........................................................................................................ 46
PROCEDURES........................................................................................................................................... 47
CONTACTING SPONSOR REGARDING SAFETY ................................................................................... 48
PRODUCT QUALITY COMPLAINT HANDLING ........................................................................................ 48
10.5. 
Appendix 5: Contraceptive and Barrier Guidance and Collection of Pregnancy Information........ 50
10.6. 
Appendix 6: Child-Pugh Classification........................................................................................... 52
10.7. 
Appendix 7: Guidance on Study Conduct During Natural Disaster ............................................... 53
10.8. 
Appendix 8: Protocol Amendment History..................................................................................... 55
11. REFERENCES................................................................................................................................... 58
INVESTIGATOR AGREEMENT................................................................................................................. 59
LIST OF IN-TEXT FIGURES
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 10


JNJ-67896049 / ACT-293987 (selexipag) 
Clinical Protocol 67896049PUH3001, Amendment 2
Confidential –FOIA Exemptions Apply in U.S. 
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Status: Approved,Date: 26 October 2021
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Multicenter, Single-arm, Open-label, Long-term Follow-up Safety Study of Selexipag in Participants
who Participated in a Previous Selexipag Study (SOMBRERO)
Selexipag (JNJ-67896049, also known as ACT-293987) is an oral, selective and long-acting non-prostanoid
agonist of the prostacyclin receptor (IP receptor) approved and commercially available for the treatment of
pulmonary arterial hypertension (PAH) in the United States, European Union, Japan and other countries.
The purpose of the SOMBRERO study is 1) to enable participants of selexipag clinical studies in pulmonary
hypertension who are currently treated with selexipag to continue to benefit from treatment with selexipag
after the closure of their parent study in case they have no alternative means of access to selexipag (eg,
commercially available drug, post-trial access program), and 2) to accrue long-term safety data on
selexipag,which may be used in interactions with health agencies and in aggregate study reports.
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
 To assess the long-term safety of selexipag 
while providing continued treatment for
participants who were previously enrolled in
an Actelion-sponsored study with selexipag
and who derived benefit from selexipag in 
indications for which a positive benefit-risk
has been established.
 Frequency of adverse events (AEs)
 Frequency of AEs leading to premature
discontinuation of selexipag
 Frequency of serious adverse events (SAEs)
 Frequency of deaths
 Number of pregnancies with maternal exposure to
selexipag
These 
safety 
endpoints 
will 
be 
assessed
continuously from enrollment on Day 1 up to
End-of-Study (EOS) visit.
Secondary
 Not applicable 
 Not applicable
Exploratory
 To capture the long-term dosing pattern of 
selexipag 
 Proportion of participants requiring selexipag
dose reduction or increase,by reason
Hypothesis
There will be no formal statistical hypothesis testing in this study.
OVERALL DESIGN
This is an open-label, multicenter, long-term, follow-up safety study of selexipag in participants who are
currently treated with selexipag at the end of an Actelion-sponsored interventional study and who benefit
from selexipag in indications for which a positive benefit-risk has been established.
The study includes 3 periods:


JNJ-67896049 / ACT-293987 (selexipag) 
Clinical Protocol 67896049PUH3001, Amendment 2
Confidential –FOIA Exemptions Apply in U.S. 
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Status: Approved,Date: 26 October 2021
 
a screening period starting with the signature of the informed consent form and ending with the
administration of the first dose of the study intervention (all expected to take place on Day 1, which
may correspond to EOT in their respective parent study).
 
an open-label treatment period starting with the administration of the first dose of the study
intervention and ending on the day of the last dose of study intervention (EOT). All participants
entering the study will continue with the same maintenance dose of selexipag that they were taking
during their respective parent study. Participants will present for the EOT visit within 7 days of the
last dose of study intervention. For participants rolled over to post-trial access (PTA) or Study
NOPRODPAPUH3001 (PLATYPUS), the enrollment must occur on the day of the last visit of
SOMBRERO study ie, EOS visit which corresponds to EOT, to avoid selexipag treatment interruption.
 
a post-treatment follow-up period starting on the day after the last dose of study intervention and
ending 30 days thereafter with the EOS visit. For participants who complete the study treatment and
who are eligible for a post-trial access (PTA) program or Study NOPRODPAPUH3001 (PLATYPUS),
the post-treatment follow-up period will be waived.
Following enrollment, telephone calls (TCs) or regular visits with the investigator to collect safety and other
information will be scheduled alternatingly every 6 months.
Study intervention re-supply visits will be scheduled every 6 months. For those months when a TC with the
investigator is scheduled, the participant may pick up the re-supplies at the study site without meeting with
the investigator. The TC will still be required but can be scheduled within the allowed time window.
NUMBER OF PARTICIPANTS
There is no pre-determined number of participants to be enrolled in the study; it will depend on the number
of participants who are taking selexipag at the end of their parent study and whether they have other options
to access selexipag when their parent study is completed. The maximum number of participants currently
expected to roll-over from the GRIPHON OL study is approximately 50 participants.
INTERVENTION GROUPS AND DURATION
An individual’s participation in the study will last until access to selexipag (eg, commercially available
drug, post-trial access program) has been identified. Consequently, the duration of the study will be
different for each individual participant and will depend on the time of access to selexipag. The dose of
open-label selexipag administered at the end of the parent study will be maintained in the SOMBRERO
study and can be adjusted at any time during the study if the investigator identifies a tolerability/efficacy
concern.
Description of Interventions
The study intervention, selexipag (JNJ-67896049), will be provided as round, film-coated tablets at all dose
strengths (200, 400, 600, 800,1,000, 1,200, 1,400 and 1,600 µg), to be taken orally twice daily (bid), in the
morning and in the evening (about 12 hours apart), unless the participant needs to start treatment with a
moderate cytochrome P4502C8 (CYP2C8) inhibitor concomitantly; in these cases, selexipag will be
administered once daily. Dosing frequency of selexipag should be reverted to bid when co-administration
of a moderate CYP2C8 inhibitor is stopped. If a participant is already receiving a moderate inhibitor of
CYP2C8 at the time of study enrollment, the dosing and dosing frequency of selexipag must be considered
based on medical judgment at the time of study entry and when co-administration of a moderate CYP2C8
inhibitor is stopped. If the participant develops moderate hepatic impairment (eg, Child-Pugh class B) once
daily administration must be considered. Differentiation of the tablets is based on the color and a debossing
according to the selexipag dose in hundreds of µg (eg, 4 for 400 µg, 12 for 1,200 µg).
SAFETY EVALUATIONS
Safety evaluations include monitoring of all AEs, SAEs,and pregnancy tests.


JNJ-67896049 / ACT-293987 (selexipag) 
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Confidential –FOIA Exemptions Apply in U.S. 
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Status: Approved,Date: 26 October 2021
EXPLORATORY EVALUATION
Selexipag dose reduction or increase and corresponding reasons.
STATISTICAL METHODS
Sample Size Determination
Due to the nature and scope of this study, the sample size is not based on statistical considerations. The
sample size will be driven by the number of participants still taking selexipag who do not have other options
to access selexipag when their respective parent study is completed.
Safety Analyses
Descriptive summaries for all TEAEs, AEs leading to premature discontinuation of selexipag, SAEs (up to
30 days after study intervention discontinuation), and deaths using number of participants and percentage,
as well as listing of pregnancies, will be provided.
Exploratory Analyses
Dose reduction or increase of selexipag will be summarized descriptively, by reason.
Interim Analyses
No formal interim analysis is planned. However, data from this study may be used for interactions with
health authorities and/or aggregate safety reporting. Details about such analyses will be provided in the
respective statistical analysis plan (SAP).


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Status: Approved,Date: 26 October 2021
1.2. 
Schema
Figure 1: 
Schematic Overview of the Study
EOT = end of treatment; EOS = end of study; PTA = post-trial access; OL = open-label.
Note: For participants who are entering a post-trial access (PTA) or Study NOPRODPAPUH3001 (PLATYPUS), the enrollment
must occur on the day of the last visit of SOMBRERO study ie, EOS visit which corresponds to EOT to avoid selexipag treatment
interruption. The post-treatment follow-up period will be waived in this case.




JNJ-67896049 / ACT-293987 (selexipag) 
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Confidential –FOIA Exemptions Apply in U.S. 
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Status: Approved,Date: 26 October 2021
d. 
Study intervention re-supply visits will be scheduled every 6 months. For those months when a TC with the investigator is scheduled, the participant may pick up
the re-supplies at the study site without meeting with the investigator. The TC will still be required but can be scheduled within the allowed time window.
e. 
Key safety assessments are listed. For special reporting situations, refer to Section 10.4, Appendix 4.
f. 
A urine (or serum if applicable) pregnancy test for women of childbearing potential must be performed at screening if not already performed at the last visit of the
parent study. Thereafter, urine pregnancy tests will be performed at home monthly using the urine pregnancy test kits provided by the study site. A urine (or serum
if applicable) pregnancy test will be performed at all study site visits.
g. 
For participants who complete the study treatment and who are eligible for a post-trial access (PTA) or Study NOPRODPAPUH3001 (PLATYPUS),the post-
treatment follow-up period will be waived. Participants will present for the EOT visit within 7 days of the last dose of study intervention. For participants rolled
over to PTA or Study NOPRODPAPUH3001 (PLATYPUS), the enrollment must occur on the day of the last visit of SOMBRERO study,ie, EOS visit which
corresponds to EOT, to avoid selexipag treatment interruption.


JNJ-67896049 / ACT-293987 (selexipag) 
Clinical Protocol 67896049PUH3001, Amendment 2
Confidential –FOIA Exemptions Apply in U.S. 
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Status: Approved,Date: 26 October 2021
2. 
INTRODUCTION
Selexipag (JNJ-67896049, also known as ACT-293987) is an oral, selective and long-acting
non-prostanoid agonist of the prostacyclin receptor (IP receptor) approved and commercially
available for the treatment of pulmonary arterial hypertension (PAH) in the United States,
European Union, Japan, and other countries.
Selexipag targets the prostacyclin pathway by selectively stimulating the IP receptor to promote
vasodilation and antiproliferation. Adverse effects are similar to the prostacyclin class, including
myalgia and jaw pain in addition to diarrhea. Selexipag is a substrate of CYP2C8 and is
contraindicated with concomitant gemfibrozil (Coons 2019).
For the most comprehensive nonclinical and clinical information regarding selexipag, refer to the
latest version of the Investigator’s Brochure (IB) for selexipag (Selexipag IB).
The term “study intervention” throughout the protocol, 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.
The term “participant” throughout the protocol refers to the common term “subject”.
Unless specified otherwise, the parent study refers to GRIPHON OL throughout the protocol.
2.1. 
Study Rationale
The purpose of the SOMBRERO study is two-fold.
First, SOMBRERO will enable clinical study participants with pulmonary hypertension (PH) who
are currently treated with selexipag to continue to benefit from selexipag after the closure of their
parent study in case they have no alternative means of access to selexipag (eg, commercially
available drug, post-trial access [PTA] program). SOMBRERO will only be open for indications
for which a positive benefit-risk has been established and approval for market authorization is
ongoing in the country of residence or approval was already granted in other countries. Currently,
a positive benefit/risk profile of selexipag has been established in PAH.
Second, SOMBRERO will also accrue long-term safety data on selexipag, which may be used in
interactions with health agencies or in aggregate study reports.
2.2. 
Background
Efficacy of selexipag was demonstrated during a long-term, double-blind, placebo-controlled,
event-driven Phase 3 study conducted in 1156 PAH patients (AC-065A302, GRIPHON study). A
summary of the GRIPHON study is provided below.
Participants in the GRIPHON study were randomly assigned to receive placebo or selexipag in
individualized doses (maximum dose, 1,600 μg twice daily). Participants were eligible for


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enrollment if they were not receiving treatment for PAH or if they were receiving a stable dose of
an endothelin  receptor antagonist, a phosphodiesterase type 5 (PDE-5) inhibitor, or both. The
primary endpoint was a composite of death from any cause or a complication related to PAH up
to the end of the treatment period (defined for each patient as 7 days after the date of the last intake
of selexipag or placebo) (Sitbon 2015).
A primary endpoint event occurred in 41.6% of participants in the placebo group and 27.0% of
those in the selexipag group (hazard ratio in the selexipag group compared with the placebo group,
0.60; 99% confidence interval, 0.46 to 0.78; p<0.001). Disease progression and hospitalization
accounted for 81.9% of the events. The effect of selexipag with respect to the primary endpoint
was similar in the subgroup of participants who were not receiving treatment for the disease at
baseline and in the subgroup of participants who were already receiving treatment at baseline
(including those who were receiving a combination of 2 therapies). By the end of the study,
105 participants in the placebo group and 100 participants in the selexipag group had died from
any cause. Overall, 7.1% of participants in the placebo group and 14.3% of those in the selexipag
group discontinued their assigned regimen prematurely because of adverse events (AEs). The most
common AEs in the selexipag group were consistent with the known side effects of prostacyclin,
including headache, diarrhea, nausea, and jaw pain (Sitbon 2015).
The risk of the primary composite endpoint of death or a complication related to PAH was
significantly lower with selexipag than with placebo. There was no significant difference in
mortality between the 2 study groups at the end of the study (Sitbon 2015).
2.3. 
Benefit-Risk Assessment
More detailed information about the known and expected benefits and risks of selexipag may be
found in the IB (Selexipag IB).
2.3.1. Risks for Study Participation
Potential Risks of Clinical 
Significance 
Summary of Data/
Rationale for Risk  
Mitigation Strategy
Drug-drug interactions 
Refer to the 
Selexipag IB. 
Concomitant treatment with a strong CYP 2C8
inhibitor (eg, gemfibrozil) is prohibited until
discontinuation of the study intervention (Refer
to Sections 5.2 and 7.1).
Dose adjustment is recommended in case of
co-administration with a moderate CYP2C8
inhibitor (refer to Sections 6.1 & 6.5) or with
rifampicin (Refer to Section 6.5).
Hepatic impairment 
Refer to the 
Selexipag IB. 
Exclusion of participants with severe hepatic
impairment (Refer to Sections 5.2. and 7.1).
Reduced dosing regimen is recommended in
participants with moderate hepatic impairment
(Refer to Section 6.1).
Pregnancy  
Refer to the 
Selexipag IB. 
Exclusion of pregnant and breastfeeding
female participants, or female participant


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planning to become pregnant while enrolled in
this study (Refer to Sections 5.2,and 7.1).
The study site will contact participants for
contraception counseling and as a reminder to
perform the urine pregnancy tests and record
the results as specified in Section 8.
Pulmonary veno-occlusive disease 
(PVOD) 
Refer to the 
Selexipag IB. 
Exclusion of suspected or known PVOD
(Refer to Sections 5.2 and 7.1)
Risks Due to Study Intervention (selexipag)
Prostacyclin-associated adverse 
events: headache, diarrhea, nausea, 
jaw pain, vomiting, pain in
extremity, myalgia, flushing,
arthralgia,and pain.
Refer to the 
Selexipag IB. 
Dose adjustments are allowed in case of
tolerability issues (Refer to Section 6.6).
Hyperthyroidism  
Refer to the 
Selexipag IB. 
Participants with uncontrolled thyroid disease
are excluded (Refer to Section 5.2).
Specific safety assessments may be performed
as per medical advice on a case-by-case basis
(Refer to Section 8.1).
Other AEs reported more frequently 
on selexipag compared to placebo: 
anemia, 
hypotension, 
nasopharyngitis, nasal congestion,
decreased appetite, weight decrease,
rash, urticaria, erythema
Refer to the 
Selexipag IB. 
Appropriate measures should be taken as per
local clinical practice in case of anemia and/or
hypotension suspicion or manifestation (Refer
to Section 8.1).
Dose adjustments are allowed in case of
tolerability issues (Refer to Section 6.6).
Risks Due to Study Procedures
Possible bruising and discomfort
from venipuncture if serum
pregnancy tests are obtained from
women of child-bearing potential
NA  
Minimal blood sample collection and the
option to use urine samples for pregnancy
testing
2.3.2. Benefits for Study Participation
The benefit for study participation is that this study will enable participants to continue treatment
with selexipag in indications for which a positive benefit-risk has been established when no other
means of access is available. For PAH, a positive benefit/risk assessment has been established
(Selexipag IB, Sitbon 2015). Selexipag is currently indicated for the treatment of PAH World
Health Organization functional class (WHO FC) Group I to delay disease progression and reduce
the risk of hospitalization for PAH. Effectiveness was established in a long-term study in PAH
patients with WHO FC II to III symptoms. Patients had idiopathic and heritable PAH (58%), PAH
associated with connective tissue disease (29%), and PAH associated with congenital heart disease
with repaired shunts (10%) (Sitbon 2015).


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2.3.3. Benefit-Risk Assessment for Study Participation
Taking into account the measures taken to minimize risk to participants ofthis study, the potential
risks identified in association with selexipag are justified by the anticipated benefits that may be
afforded to participants with PAH.
3. 
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
 To assess the long-term safety of selexipag 
while providing continued selexipag 
treatment for participants who were 
previously enrolled in an Actelion-sponsored
study with selexipag and who derived benefit
from selexipag in indications for which a 
positive benefit-risk has been established 
 Frequency of AEs
 Frequency of AEs leading to premature
discontinuation of selexipag
 Frequency of serious adverse events (SAEs)
 Frequency of deaths
 Number of pregnancies with maternal exposure to
selexipag
These safety endpoints will be assessed
continuously from enrollment on Day 1 up to
End-of-Study (EOS) visit.
Secondary
 Not applicable 
 
Not applicable
Exploratory
 To capture the long-term dosing pattern of 
selexipag 
 
Proportion of participants requiring selexipag
dose reduction or increase by reason
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
HYPOTHESIS
There will be no formal statistical hypothesis testing in this study.
4. 
STUDY DESIGN
4.1. 
Overall Design
This is an open-label (OL), multicenter, long-term, follow-up safety study of selexipag in
participants who are currently treated with selexipag at the end of an Actelion-sponsored,
interventional study and who benefit from selexipag in indications for which a positive benefit-
risk has been established.
The study includes 3 periods:
 a screening period starting with the signature of the informed consent form and ending with
the administration of the first dose of the study intervention (all expected to take place on
Day 1 which may correspond to EOT in their respective parent study).


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 an OL treatment period starting with the administration of the first dose of the study
intervention and ending on the day of the last dose of study intervention  (EOT). All
participants entering the study will continue with the same maintenance dose of selexipag
that they were taking during their respective parent study. Participants will present for the
EOT visit within 7 days of the last dose of study intervention. For participants rolling over
to post-trial access (PTA) or Study NOPRODPAPUH3001 (PLATYPUS), the enrollment
must occur on the day of the last visit of SOMBRERO study, ie, EOS visit which
corresponds to EOT, to avoid selexipag treatment interruption.
 a post-treatment follow-up period starting on the day after the last dose of study
intervention and ending 30 days thereafter with  the EOS visit. For participants who
complete the study treatment and who are eligible for a post-trial access (PTA) or Study
NOPRODPAPUH3001 (PLATYPUS), the post-treatment follow-up period will be waived.
Safety assessments include monitoring of AEs, SAEs,and pregnancy tests.
Following enrollment, telephone calls (TCs) or regular visits with the investigator to collect safety
and other information will be scheduled alternatingly every 6 months.
Study intervention re-supply visits will be scheduled every 6 months. For those months when a
TC with the investigator is scheduled, the participant may pick up the re-supplies at the study site
without meeting with the investigator. The TC will still be required but can be scheduled within
the allowed time window.
A diagram of the study design is provided in Section 1.2, Schema.
4.2. 
Scientific Rationale for Study Design
An open-label design is justified as the participants enrolled in this study will receive the study
intervention at the same maintenance dose that they were receiving in their parent study.
The study is designed to include both TC and study site visits alternatively every 6 months to
monitor the safety of the participants and allow for the resupply of study intervention until each
participant has access to commercially available selexipag. This safety monitoring schedule is
supported by the established safety profile of selexipag for daily doses up to 3,200 µg (1,600 µg
twice daily [bid]).
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. They will be told 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 total blood volume to be collected is expected to be none or minimal during this study,based
on assessments to be performed according to the SoA table and Section 8.


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4.3. 
Justification for Dose
All available dose strengths of selexipag will be supplied to maintain the participant’s maintenance
dose established per protocol in their parent study. The dose of selexipag may be adjusted during
the study as necessary.
4.4. 
End of Study Definition
End of Study Definition
EOS  is considered as the last scheduled study assessment shown in the Schedule of Activities
(SoA) 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 EOS Visit in the time frame specified
in the Clinical Trial Agreement.
EOS for an individual participant occurs when one of the following occurs:
 the participant decides to withdraw from the study or the treating physician determines it
is in the best interest of the participant to withdraw from study
 the study is terminated
 the participant dies.
Study Completion Definition
A participant will be considered to have completed the study if he or she has completed
assessments through the EOS.
5. 
STUDY POPULATION
Screening for eligible participants will be performed on Day 1, the same day as study intervention
intake.
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.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2,
Sample Size Determination.
5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. 
treated with selexipag at the end of a parent study and:
a) the parent study has established efficacy with a favorable benefit/risk profile for the
indication under investigation


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b) participant may continue to benefit from treatment with selexipag
c) has completed the EOT visit of the parent study
d) no alternative means of access to selexipag have been identified
2. 
women of childbearing potential must use an acceptable method of contraception
throughout the study and until at least 1 month following the last dose of study intervention.
Examples of methods of contraceptionallowedduring the study are located in Section 10.5,
Appendix  5, Contraceptive and Barrier Guidance and Collection of Pregnancy
Information.
3. 
women  of childbearing potential must have a negative urine (or serum if applicable)
pregnancy test at screening on Day 1 or at the last visit of the parent study
4. 
must sign an informed consent form (ICF) indicating that he or she understands the purpose
of, and procedures required for, the study and is willing to participate in the study.
5.2. 
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in the study:
1. 
suspected or known pulmonary veno-occlusive disease (PVOD)
2. 
known allergies, hypersensitivity, or intolerance to selexipag or its excipients
(Selexipag IB)
3. 
interruption of study intervention for more than 14 days since the last dose of study
intervention taken in the parent study
4. 
female participant being pregnant, or breastfeeding, or planning to become pregnant at
the time of screening and while enrolled in this study
5. 
uncontrolled thyroid disease
6. 
severe coronary heart disease or unstable angina, myocardial infarction within the last 6
months, decompensated cardiac failure if not under close medical supervision, severe
arrhythmia,cerebrovascular events (eg, transient ischemic attack, stroke) within the last
3 months, or congenital or acquired valvular defects with clinically relevant myocardial
function disorders not related to PH
7. 
known and documented severe hepatic impairment, eg, Child-Pugh Class C*


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8. 
taken any disallowed therapies as noted in Section 6.5, Concomitant Therapy,before the
planned first dose of study intervention:
 treatment with a strong CYP2C8 inhibitor (eg, gemfibrozil)
 treatment with oral prostacyclin analogs (eg, beraprost,treprostinil) since the last
dose of study intervention taken in the parent study
 any investigational treatment other than selexipag
9. 
Criterion modified per Amendment 1
9.1 plan to receive an investigational intervention (including investigational vaccines)
other than selexipag.
*The assessment of hepatic impairment (Child-Pugh Score, Section 10.6, Appendix 6) must be
fully documented for patients that have clinical signs and evidence (from central and/or local
laboratory) of hepatic impairment.
NOTE: 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 he or she no longer meets all eligibility criteria, then the participant should be excluded
from participation in the study. The required source documentation to support meeting the
enrollment criteria are noted in Section 10.3, Appendix 3, Regulatory, Ethical, and Study
Oversight Considerations.
5.3. 
Screen Failures
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. In cases where the participant is not enrolled into the study, the date seen at initial
informed consent will be used.
Individuals who do not meet the criteria for participation in this study (screen failure) may not be
rescreened.
6. 
STUDY INTERVENTION
6.1. 
Study Intervention(s) Administered
The study intervention, selexipag, will be provided as tablets for oral administration.


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The tablets are to be swallowed whole (ie, not crushed, split or chewed) with water, with or without
food (tolerability may be improved when it is taken with food).
When enrolling in SOMBRERO,the participants will continue with the same individual maximum
tolerated dose (iMTD) that they are taking at the end of their parent study,ie, same daily dose and
same dosing frequency (bid or qd). Tablets will be available at all dose strengths, and participants
will be instructed to take only one tablet of the required dose strength at each intake. Thus, the
number of tablets per dose and tablet appearance in this study will differ from those used in the
parent study depending on the iMTD (eg, if the iMTD in the parent study was 800 µg bid,
participants took 4 200 µg tablets bid. After enrolling in SOMBRERO,they will take one 800 µg
tablet bid). The color of the tablets will depend on the dose strength.
Description of Interventions
Study Intervention Name 
Selexipag
Type 
Drug
Dose Formulation 
Round, film-coated tablets (all dose strengths). Differentiation of
the tablets is based on the color and a debossing according to the
selexipag dose in hundreds of µg (Selexipag IB).
Unit Dose Strength(s) 
200, 400, 600, 800, 1,000, 1,200, 1,400 and 1,600 µg
Dosage Level(s) 
The dose of selexipag administered at the end of the parent study
will be maintained in the SOMBRERO study.
Route of Administration 
Oral
Use 
Investigational
Investigational Medicinal Product (IMP) 
Selexipag
Sourcing 
Provided centrally by the sponsor.
Packaging and Labeling 
Child-resistant packaging
Each bottle will contain information and be labeled as required
per country regulatory requirements.
Study intervention administration must be captured in the source documents and the electronic
case report form (eCRF). Study-site personnel will instruct participants on how to store study
intervention for at-home use as indicated for this protocol.
Selexipag will be manufactured and provided under the responsibility of the sponsor. Refer to the
IB for a list of excipients (Selexipag IB).
For a definition of study intervention overdose, refer to Section 8.5, Treatment of Overdose.
6.2. 
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
All study intervention must be stored according to the label.
Refer to the pharmacy manual/study site investigational product and procedures manual for
additional guidance on study intervention preparation, handling, and storage.


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Accountability
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 to the
participant, and the return of study intervention 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.
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.
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. 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.
6.3. 
Measures to Minimize Bias: Randomization and Blinding
Study Intervention Allocation
Randomization will not be used in this study.
Blinding
As this is an open study, blinding procedures are not applicable.
6.4. 
Study Intervention Compliance
Compliance with study intervention will be assessed at each visit by direct questioning.
Compliance will be assessed at each on-site visit by counting returned tablets and documented in
the source documents. Start and stop dates of study intervention, including dates for dose
adjustments will also be recorded in the eCRF.
Participants will receive instructions on compliance with study intervention administration at the
screening visit. 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.


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6.5. 
Concomitant Therapy
All concomitant therapies must be recorded in the eCRF throughout the study beginning with start
of the first dose of study intervention through the EOS.
The use of the following concomitant therapies is allowed in the study:
 approved PH-specific therapies including PDE-5 inhibitors, endothelin receptor
antagonists and/ or riociguat
 single administration of intravenous (IV) / inhaled prostacyclin or prostacyclin analogs
used for acute vasodilator testing during a right-heart catheterization procedure
 temporary concomitant use of inhaled, IV, and subcutaneous (SC) prostacyclin and
prostacyclin analogs (eg, epoprostenol, treprostinil, iloprost) is permitted, as deemed
medically indicated by the investigator, to stabilize a participant with worsening of PH or
to switch a participant to IV or SC treatment
 treatment with moderate inhibitors of CYP2C8 is allowed. If a moderate inhibitor of
CYP2C8 (eg, clopidogrel, deferasirox, teriflunomide, levoflunomide) is started
concomitantly with selexipag during the study, the dosing frequency of selexipag must be
reduced to qd(resulting in halving of the daily dose). Dosing frequency of selexipag should
be reverted to bid when co-administration of a moderate CYP2C8 inhibitor is stopped. If a
participant is already receiving a moderate inhibitor of CYP2C8 at the time of study
enrollment, the dose and dosing frequency of selexipag must be considered based on
medical judgment at the time of study entry and when co-administration of a moderate
CYP2C8 inhibitor is stopped.
 concomitant administration of rifampicin, an inducer of CYP2C8 and uridine 5'-
diphospho-glucuronosyltransferase (UGT) enzymes, is allowed,but due to potential drug-
drug interactions (ie, exposure to the active metabolite of selexipag reduced by half), dose
adjustment of selexipag may be required. Concomitant administration of strong inhibitors
of UGT1A3 and UGT2B7 (eg, valproic acid, probenecid, fluconazole) is allowed but
caution is required since the interactions between UGT1A3 and/or UGT2B7 inhibitors and
selexipag have not been studied, and a potential pharmacokinetic interaction cannot be
excluded.
The use of the following therapies is prohibited in this study:
 other oral IP-receptor agonists (eg, treprostinil, beraprost) until study intervention
discontinuation
 strong inhibitors of CYP2C8 (eg, gemfibrozil) until study intervention discontinuation
 any investigational treatment other than selexipag up to and including the EOS.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
6.6. 
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).


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The dose of selexipag can be adjusted at any time based on the judgment of the investigator.
If a participant needs to start treatment with a moderate CYP2C8 inhibitor at any time after entering
the study, the dosing frequency of selexipag will be reduced to once daily (qd, in the morning). If
hepatic impairment is suspected, a clinical assessment of severity (eg, Child-Pugh score) must be
performed and fully documented. If the participant develops moderate hepatic impairment
(Child-Pugh class B) once daily administration must be considered. If there is a study intervention
interruption of 3 days or more, the participant will re-initiate the study intervention starting with
200 µg bid/qd (depending on the dosing frequency before interruption). If this dose is well
tolerated, it will be up-titrated by the investigator in 200 µg increments using 200 µg tablets up to
the iMTD of study intervention before treatment was interrupted,not exceeding a total daily dose
of 3,200 µg (or 1,600 µg bid). During the up-titration period, the participant will receive 200 µg
tablets corresponding to the dose strength level. When the iMTD is reached, the corresponding
strength tablet will be administered. For each participant, the up-titration intervals will be
determined according to the investigator’s judgment.
In case of any tolerability issues or lack of efficacy, the dose of selexipag should be adjusted by
the treating physician as necessary. For this purpose, the participant will down- or up-titrate the
dose to the next possible dose using 200 µg tablets. Once a new and stable maintenance dose has
been established based on acceptable tolerability, the participant should continue treatment with
selexipag on this dose using 200 µg tablets until provided with respective tablets of the required
dose strength.
7. 
DISCONTINUATION  OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1. 
Discontinuation of Study Intervention
A participant’s study intervention must be discontinued if:
 the participant withdraws consent to receive study intervention
 the investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the
best interest of the participant to discontinue study intervention
 the female participant becomes pregnant. Refer to Section 10.5, Appendix 5, Contraceptive
Guidance and Collection of Pregnancy Information.
 non-compliance with study intervention  administration defined as study intervention
interruption exceeding 14 consecutive days
 the participant initiates treatment with a strong CYP2C8 inhibitor (ie, gemfibrozil) or oral
prostacyclin or prostacyclin analogs (eg, beraprost, treprostinil)
 there is a need for long-term use of inhaled, IV or SC prostacyclins or prostacyclin analogs
(eg,epoprostenol, treprostinil, iloprost)
 the participant initiates any other investigational treatments
 the participant develops severe hepatic impairment (Child-Pugh class C) at any time during
the study. 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


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severe hepatic impairment (Child-Pugh C) at any time during the study, the study
intervention must be permanently discontinued.
 pulmonary edema due to pulmonary veno-occlusive disease (PVOD) occurs. Should signs
of pulmonary edema occur, the possibility of associated PVOD should be considered. If
confirmed the study intervention must be discontinued.
A participant who prematurely discontinues study intervention is not considered withdrawn from
the study. A participant who prematurely discontinues study intervention and withdraws consent
to participate in any further study assessments is considered as withdrawn from the study.
If a participant discontinues study intervention for any reason before EOS, then the EOT
assessments should be obtained. Study intervention assigned to the participant who discontinued
study intervention may not be assigned to another participant.
7.1.1. Temporary Discontinuation
If a participant is scheduled for an intervention that may temporarily prevent him/her from taking
oral medications, selexipag treatment may be interrupted for not more than 14 days and the
participant may temporarily switch to another IP receptor agonist medication with a different route
of administration during that time. The participant will be allowed to restart selexipag once he/she
can take oral medications again. When re-starting selexipag, it is recommended to begin with the
lowest dose (ie, 1 tablet/200 µg bid) and to progressively increase the selexipag dose to reach the
maximum dose that was previously tolerated by the participant. The decrease of the other IP
receptor agonist dose will be done in parallel with the increase of the selexipag dose based on the
participant’s individual tolerability. If the participant experiences pharmacological side effects that
cannot be tolerated while he/she is concomitantly taking selexipag and the other IP receptor agonist
medication, a dose reduction or discontinuation of the other IP receptor agonist will be considered
before considering a dose reduction or a discontinuation of selexipag.
7.2. 
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:
 lost to follow-up
 withdrawal of consent
 death
When a participant withdraws before study  completion, the reason for withdrawal is to be
documented in the eCRF and in the source document. If the reason for withdrawal from the study
is withdrawal ofconsent then no additional assessments are allowed.
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 at study completion) as local regulations permit.


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7.3. 
Lost to Follow-up
To reduce the chances of a participant being deemed lost to follow-up, attempts should be made
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 he or she 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
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 TCs,
e-mails, fax, and, if necessary, a certified letter to the participant’s last known mailing
address, or local equivalent methods). Locator agencies may also be used as local
regulations permit. These contact attempts should be documented in the participant’s
medical records.
 Should the participant continue to be unreachable, they 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 the participant to inform them, their contact information will be transferred to another study
site.
8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
The SoA summarizes the frequency and timing of safety, and other measurements applicable to
this study.
All study assessments are performed by qualified study personnel (medical, nursing or specialist
technical personnel) and are recorded in the eCRF, unless otherwise specified. Study assessments
performed during unscheduled visits will also be recorded in the eCRF. Actual dates and times of
assessments will be recorded in the source documentation and eCRF.
Additional urine (or serum if applicable) pregnancy tests may be performed, as determined
necessary by the investigator or required by local regulation, to establish the absence of pregnancy
at any time during the participation in the study and:
 at monthly intervals (a urine pregnancy test will be performed at home by women of
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 at the end of study intervention (EOT, within 7 days of the last dose)
 30 days after the last dose of study intervention (EOS).
To ensure proper pregnancy monitoring and contraception counseling, study site staff must call
each woman of childbearing potential once per month to:
 remind the participant to perform a urine pregnancy test and
 collect the outcome of the urine pregnancy test.
During each study site visit or each TC, it must be verified whether the method of contraception
used previously is still valid, in accordance with the protocol and correctly used by the participant.
The total blood volume to be collected is expected to be none or minimal. Urine pregnancy tests
are allowed and serum pregnancy tests are not required but may be done if deemed necessary by
the investigator.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the
samples.
Demographic data (age, sex, race, height, weight), PH etiology, WHO FC will be taken from the
participant’s parent study (or the double-blind core study preceding the parent study) and not
recorded in the eCRF.
All AEs ongoing from the parent study at the time of enrollment in the SOMBRERO study will be
recorded in the eCRF and will be considered as part of the participant’s medical history.
The participant identifier from the parent study will be collected in the eCRF at enrollment in
SOMBRERO (ie, Visit 1).
Study-Specific Materials
The investigator will be provided with the following supplies:
 IB
 pharmacy manual / study site investigational product and procedures manual
 electronic data capture (eDC) manual
 Interactive Web Response System Manual
 sample ICF.
8.1. 
Safety Assessments
The study will include the following evaluations of safety and tolerability according to the
timepoints provided in the SoA:
 All AEs and special reporting situations, whether serious or non-serious,will be recorded in the
eCRF.


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 Pregnancies.
A urine (or serum if applicable) pregnancy test for women of childbearing potential must be
performed at screening if not already performed at the last visit of the parent study. Thereafter,
urine pregnancy tests will be performed at home monthly, using the urine pregnancy test kits
provided by the study site. A urine (or serum if applicable) pregnancy test will be performed at
study site visits. The results of the pregnancy tests will not be recorded in the eCRF but must
be kept in the source document. Pregnancies will be recorded on the AE page of the eCRF.
Refer to Section 8.4 for further details on reporting of pregnancies.
Assessment of Child-Pugh score (as described in Section 10.6, Appendix 6), thyroid function,
hemoglobin, vital signs may be performed for  participants as clinically indicated. The results of
these evaluations will not be recorded in the eCRF. In the event of clinical suspicion or
manifestation of hyperthyroidism, thyroid function markers including thyroid stimulating
hormone, free triiodothyronine (T3), and free thyroxine (T4) levels must be monitored by the
investigator/delegate, and appropriate measures according to local clinical practice should be
implemented.
For details on special reporting situations,refer to Section 10.4, Appendix 4.
8.2. 
Exploratory Assessment
8.2.1. Dose Reduction or Increase of Selexipag
Dose reduction or increase of selexipag and corresponding reason will be recorded in the eCRF.
8.3. 
Adverse Events and Serious Adverse Events
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.
For further details on AE and SAE reporting (Definitions and Classifications; Attribution
Definitions; Severity Criteria; Special Reporting Situations; Procedures) as well as product quality
complaints, refer to Section 10.4, Appendix 4, Adverse Events: Definitions and Procedures for
Recording, Evaluating,Follow-Up, and Reporting.
8.3.1. Time Period and Frequency for Collecting Adverse Events and Serious
Adverse Events
Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from the
time a signed and dated ICF is obtained until completion of the participant’s last study-related
procedure (up to EOS for participants who enter a continued access program on the same day as
the EOS Visit, see Section 4.1), which may include contact for follow-up of safety.


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Serious Adverse Events
SAEs, including those spontaneously reported to the investigator within 30 days after the last dose
of study intervention (up to EOS for participants who enter a continued access program on the
same day as the EOS Visit, see Section 4.1), must be reported using the Serious Adverse Event
Form. The sponsor will evaluate any safety information that is spontaneously reported by an
investigator beyond the time frame specified in the protocol.
All SAEs 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.
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 within 24 hours. The initial and follow-up reports of a SAE should be sent to Sponsor.
8.3.2. 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
product quality complaint (PQC) as fully as possible. This may include additional laboratory tests
or investigations, histopathological examinations, or consultation with other health care
professionals.
All AEs and SAEs, including pregnancy with maternal exposure to selexipag, will be followed by
the investigator as specified in Section 10.4, Appendix 4, Adverse Events: Definitions and
Procedures for Recording, Evaluating, Follow-up, and Reporting.
AE/SAEs still ongoing more than 30 days after study intervention  discontinuation must be
followed up until they are no longer considered clinically relevant or until stabilization. The
follow--up information after the participant’s EOS will not be collected by the Sponsor.
8.3.3. 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.
8.3.4. After the 30-day follow-up period
New SAEs occurring after the 30-day follow-up period must be reported to the Sponsor within
24 hours of the investigator’s knowledge of the event, only if considered by the investigator to be
causally related to previous exposure to the study intervention.


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8.4. 
Pregnancy
8.4.1. Reporting of 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 the Serious Adverse Event Form. Any participant
who becomes pregnant during the study must be promptly withdrawn from the study and
discontinue further study intervention.
8.4.2. Follow-up of Pregnancy
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the
infant will be required.
Any AE associated with the pregnancy occurring during the follow-up period after study
intervention  discontinuation must be reported on separate AE pages in the eCRF. Abnormal
pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies,
ectopic pregnancy) are considered serious adverse events and must be reported on an SAE form
as described in Section 8.3.1.
8.5. 
Treatment of Overdose
For this study, overdose is defined by the intake of a dose > 1,600 μg or a total daily dose
> 3,200 μg. For participants taking selexipag once daily (eg, moderate hepatic impairment or
concomitant administration of a moderate CYP2C8 inhibitor), overdose is defined by the intake of
a dose > 1,600 μg or a total daily dose > 1,600 μg.
Isolated cases of overdose up to 3,200 μg have been reported. Mild, transient nausea was the only
reported consequence.
In the event of an overdose, the investigator or treating physician should:
 contact the Medical Monitor immediately
 closely monitor the participant for (S)AEs and institute supportive measures as required.
Dialysis is unlikely to be effective because selexipag and its active metabolite are highly
protein bound.
 document the quantity of the excess dose as well as the duration of the overdosing in the
eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in
consultation with the Medical Monitor based on the clinical evaluation of the participant.


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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 safety and efficacy data is outlined
below. Specific details will be provided in the statistical analysis plan (SAP).
9.1. 
Statistical Hypotheses
There will be no formal statistical hypotheses due to the design of this study. Only descriptive
analyses will be performed.
9.2. 
Sample Size Determination
Due to the nature and scope of this study, the sample size is not based on statistical considerations.
The sample size will be driven by the number of participants still taking selexipag who do not have
other options to access selexipag when their respective parent study is completed and who consent
to participate in this study. The maximal number of participants currently expected to roll-over
from the GRIPHON OL study is approximately 50 participants.
9.3. 
Populations for Analysis Sets
For purposes of analysis, the following populations are defined:
Population 
Description
Enrolled 
All participants who sign the ICF
Safety  
All participants who take at least 1 dose of study intervention.
9.4. 
Statistical Analyses
9.4.1. Safety Endpoints
The primary safety endpoints are:
 frequency of AEs
 frequency of AEs leading to premature discontinuation of selexipag
 frequency of SAEs
 frequency of deaths
 number of pregnancies with maternal exposure to selexipag.
These safety endpoints will be assessed continuously from enrollment on Day 1 up to the EOS.
See definition of AEs and SAEs in Section 10.4, Appendix 4.
9.4.2. Safety Analyses
Adverse Events
All safety analyses will be made on the Safety Population.


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The verbatim terms used in the eCRF by investigators to identify AEs and SAEs will be coded
using the Medical Dictionary for Regulatory Activities (MedDRA). Any AE or SAE 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 (TEAEs). All reported TEAEs, and SAEs (up to 30 days after
study intervention discontinuation) will be included in the analysis. For each event, the percentage
of participants who experience at least 1 occurrence of the given event will be summarized.
Summaries, listings datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who prematurely discontinue study intervention due to a TEAE, or who
experience an  SAE. More specifically, descriptive summaries for all TEAEs, AEs leading to
premature discontinuation of selexipag, SAEs (up to 30 days after study intervention
discontinuation), and deaths using number of participants and percentage, as well as listing of
pregnancies, will be provided.
9.4.3. Exploratory Endpoint and Analyses
The exploratory endpoint is the proportion of participants requiring selexipag dose reduction or
increase by reason.
The proportion of participants requiring dose reduction or increase of selexipag will be
summarized descriptively, by reason.
9.5. 
Interim Analysis
No formal interim analysis is planned. However, data from this study may be used for interactions
with health authorities. Details about such analyses will be provided in the respective SAP.


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Abbreviations
AE 
adverse events
bid 
twice daily
COVID-19 
Coronavirus Disease 2019
CYP2C8 
cytochrome P₄₅₀2C8
DTP  
Direct-to-patient
eCRF  
electronic case report form(s)
eDC  
electronic data capture
EOS  
End of Study
EOT  
End of Treatment
FOIA  
Freedom of Information Act
FSH  
follicle-stimulating hormone
GCP  
Good Clinical Practice
IB  
Investigator’s Brochure
ICF  
informed consent form
ICH  
International Council for Harmonisation
ICMJE 
International Committee of Medical Journal Editors
IEC  
Independent Ethics Committee
IMP  
Investigational Medicinal Product
iMTD  
individual maximum tolerated dose
INR  
international normalized ratio
IP receptor 
prostacyclin receptor
IRB  
Institutional Review Board
IV  
Intravenous
MedDRA  
Medical Dictionary for Regulatory Activities
OL 
open-label
PAH  
pulmonary arterial hypertension
PDE-5 
phosphodiesterase type 5
PH 
pulmonary hypertension
PQC  
product quality complaint
PTA  
post-trial access
PVOD  
pulmonary veno-occlusive disease
qd 
once daily
SAE 
serious adverse event
SAP  
statistical analysis plan
SC 
Subcutaneous
SoA  
Schedule of Activities
SUSAR  
suspected unexpected serious adverse reaction
T3 
triiodothyronine
T4 
free thyroxine
TC 
telephone call
TEAE 
treatment-emergent adverse event
UGT  
uridine 5'-diphospho-glucuronosyltransferase
WHO FC  
World Health Organization functional class
Definitions of Terms
Electronic source
system
Contains data traditionally maintained in a hospital or clinic record to document medical
care or data recorded in a CRF as determined by the protocol. Data in this system may be
considered source documentation.




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10.3. Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
REGULATORY AND ETHICAL CONSIDERATIONS
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current International Council for Harmonisation  (ICH) guidelines on Good Clinical
Practice (GCP), and applicable regulatory and country-specific requirements.
GCP 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 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.
During the course of the study, in situations where a departure from the protocol is unavoidable,
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 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, 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:


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 
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
 
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)
 
IB (or equivalent information) and amendments/addenda
 
Sponsor-approved participant recruiting materials


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 
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 IB 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
intervention
 
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).


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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 (if applicable, the notification will be submitted through the head of
investigational institution).
Country Selection
This study will only be conducted in those countries where there is no intent 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.
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) and contracts for details on financial
disclosure.
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
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.


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By signing the ICF the participant is authorizing such access, which includes permission to obtain
information about his or her survival status. It also denotes that the participant agrees to allow his
or her study physician to recontact the participant for the purpose of obtaining consent for
additional safety evaluations and subsequent disease-related treatments, if needed. The physician
may also recontact the participant for the purpose of obtaining consent to collect information about
his or her survival status.
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.
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 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 consent also addresses the transfer of the data to other entities and to
other countries.
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. 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.
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 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.


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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 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 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.
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 of publications 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.


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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.
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, and periodic monitoring visits by the sponsor. 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.
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 the 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.
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.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any
such worksheets will become part of the participant’s source documents. Data must be entered into
the eCRF in English. The eCRF must be completed as soon as possible after a participant visit and
the forms should be available for review at the next scheduled monitoring visit.
All participative measurements will be completed by the same individual who made the initial
baseline determinations whenever possible.
If necessary, queries will be generated in the 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.


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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 as required by the protocol and follow-up of these AEs; concomitant
medication  as applicable; 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 following data will be recorded directly into the eCRF and will be considered source data:
 Parent study that the participant was enrolled in prior to enrolling in this study
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:
 Referral letter from treating physician or
 Complete history of medical notes at the site
 Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a
minimum by participant interview or other protocol-required assessment (eg, pregnancy tests for
women of childbearing potential) and documented in the source documents.
An eSource system may be utilized, 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 utilized, 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.
MONITORING
The sponsor will use a combination of monitoring techniques central, remote, or 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,


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the monitor will compare data entered into the eCRF with the source documents (eg,
hospital/clinic/physician’s office medical records); a sample may be reviewed. 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.
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.
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


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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.
STUDY AND SITE START AND CLOSURE
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.
Study 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: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting
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 ICH)
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition on Day 1 of this study, 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 8.3.1, Time Period and Frequency for Collecting Adverse Events and Serious
Adverse Events, for time of last AE recording).
Serious Adverse Event
A serious adverse event based on ICH and EU 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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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. The expectedness of an AE will be determined by whether or not it
is listed in the Investigator’s Brochure.
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.
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).
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
 Suspected abuse/misuse of a sponsor study intervention
 Accidental or occupational exposure to a sponsor study intervention
 Any failure of expected pharmacologic action (ie, lack of effect) of a sponsor study
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 Unexpected therapeutic or clinical benefit from use of a sponsor study intervention
 Medication error, intercepted medication error, or potential medication error involving a
Johnson & Johnson medicinal product (with or without patient exposure to the Johnson &
Johnson medicinal product, eg, product name confusion, product label confusion,
intercepted prescribing or dispensing errors)
 Exposure to a sponsor study intervention from breastfeeding
Special reporting situations should be recorded in the 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 the
SAE Form.
PROCEDURES
Adverse Events
All AEs and special reporting situations, whether serious or non-serious 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 AE to study
therapy. All measures required for AE 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
All SAEs that have not resolved by the end of the study, or that have not resolved upon
discontinuation of the participant's participation in the study, must be followed until any of the
following occurs:
 the event resolves
 the event stabilizes
 the event returns to baseline, if a baseline value/status is available


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 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 after
demonstration of due diligence with follow-up efforts).
Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE.
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the
course of a participant’s participation in a 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)
 Surgery or procedure planned before entry into the study (must be documented in the
eCRF): 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 of the 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.
 The cause of death of a participant in a study, whether or not the event is expected or
associated with the study intervention, is considered an SAE.
CONTACTING SPONSOR REGARDING SAFETY
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues or questions regarding the study are listed in the Contact Information
page(s), which will be provided as a separate document.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality,
durability, or reliability of a product, including its labeling or package integrity. A PQC may have
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and
analysis of PQC information from studies are crucial for the protection of participants,
investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor
has established procedures in conformity with regulatory requirements worldwide to ensure
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates will
be conducted in accordance with those procedures.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after
being made aware of the event.


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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 8.3.1, Time Period and Frequency for
Collecting Adverse Event and Serious Adverse Event Information). A sample of the suspected
product should be maintained for further investigation if requested by the sponsor.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding product quality issues are listed in the Contact Information page(s), which will be
provided as a separate document.


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10.5. Appendix 5: Contraceptive and Barrier Guidance and Collection of
Pregnancy Information
Participants must follow contraceptive measures as outlined in Section  5.1, Inclusion Criteria.
Pregnancy information will be collected and reported as noted in Section  8.4, Pregnancy and
Section 10.4, Appendix 4 Adverse Events: Definitions and Procedures for Recording, Evaluating,
Follow-up, and Reporting.
Definitions
Woman of Childbearing Potential
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; however, in the absence of 12 months
of amenorrhea, a single FSH measurement is insufficient.
permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral
oophorectomy.
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
below.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by men or 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:
 Oral or injectable contraceptive agents, implants or transdermal contraceptive hormoneb
 Implantable progestogen-only hormone contraception associated with inhibition of ovulationb
 Intrauterine device
 Sterilization (bilateral tubal occlusion)
 Vasectomized partner
(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.)
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulationb
 oral
 intravaginal
 transdermal
 injectable
 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.)
 Diaphragm; female condom or cervical cap; or partner’s use of a condom, and any of these used in
combination with a spermicidec.
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) Hormonal contraception may be susceptible to interaction with the study intervention, which may
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception
may interact with the study intervention.
c) Male condom and female condom should not be used together (due to risk of failure with friction).


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10.6. Appendix 6: Child-Pugh Classification
The Child-Pugh classification will be used to assess the severity of the liver disease according to
the following table (Adapted from (2012) Child-Pugh, FDA 2003):
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
INR = international normalized ratio
*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, five 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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Clinical Protocol 67896049PUH3001, Amendment 2
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53
Status: Approved,Date: 26 October 2021
10.7. Appendix 7: Guidance on Study Conduct During Natural Disaster
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants and
study-site personnel; travel restrictions/limited access to public places, including hospitals; study
site personnel being reassigned to critical tasks.
In alignment with recent health authority guidance, the sponsor is providing options for
study-related participant management in the event of disruption to the conduct of the study. This
guidance does not supersede any local or government requirements or the clinical judgement of
the investigator to protect the health and well-being of participants and site staff. If, at any time, a
participant’s safety is considered to be at risk, study intervention will be discontinued, and study
follow-up will be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each
contact, participants will be interviewed to collect safety data. Key efficacy endpoint assessments
should be performed if required and as feasible. Participants will also be questioned regarding
general health status to fulfill any physical examination requirement.
Every effort should be made to adhere to protocol-specified assessments for participants on study
intervention, including follow up. Modifications to protocol-required assessments may be
permitted via COVID-19 Appendix after consultation with the participant, investigator, and the
sponsor. Missed assessments/visits will be captured in the clinical trial management system for
protocol deviations. Discontinuations of study interventions and withdrawal from the study should
be documented with the prefix “COVID-19-related” in the case report form (CRF).
The sponsor will continue to monitor the conduct and progress of the clinical study, and any
changes will be communicated to the sites and to the health authorities according to local guidance.
If a participant has tested positive for COVID-19, the investigator should contact the sponsor’s
responsible medical officer to discuss plans for study intervention and follow-up. Modifications
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the
clinical study report.


JNJ-67896049 / ACT-293987 (selexipag) 
Clinical Protocol 67896049PUH3001, Amendment 2
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54
Status: Approved,Date: 26 October 2021
GUIDANCE SPECIFIC TO THIS PROTOCOL
Related to Protocol Section 8 - Study Assessments and Procedures
 When participant visits to the study site are not possible, assessments and procedures may
be performed remotely (eg, by phone, telemedicine) or in-person off-site (eg, at
participant’s home). The study site and the sponsor will discuss and agree on the applicable
assessments and procedures.
Related to Protocol Section 8.1 - Safety Assessments and Section 10.2 - Clinical Laboratory Tests
 When participant visits to the study site are not possible, on-site pregnancy tests for women
of childbearing potential will be performed at home for urine pregnancy tests or at a local
laboratory if a serum pregnancy test is judged necessary by the study physician.
Related to protocol section 6.2 - Preparation/Handling/Storage/Accountability
 When participant visits to the study site are not possible, shipment of study intervention
from the study site directly to participants (and vice versa for return of study intervention)
may be implemented where allowed per local regulations and if requested by the treating
study physician. When Direct-to-patient (DTP) shipments are deemed necessary, the
process should be coordinated between the site and the sponsor staff following the
"COVID-19 DTP Guidance Document".
Related to protocol section 10.3 –Regulatory, Ethical and Study Oversight Considerations
 The sponsor may apply remote monitoring and/or remote auditing if on-site visits are not
possible.
 Consenting and reconsenting of participants will be performed as applicable for the
measures taken (including remote consenting by phone or video consultation) and
according to local guidance for informed consent.
STUDY CONDUCT RELATED TO COVID-19 VACCINE DEPLOYMENT FOR NONCOVID-19
CLINICAL TRIALS
 
Study participants can undergo a COVID-19 vaccination procedure in compliance with
applicable local governmental regulations.
 
No pharmacokinetic interaction between the study intervention and currently available
COVID-19 vaccines are expected. In addition, based on the mechanism of action of the study
intervention and COVID-19 vaccines, no relevant interaction is expected.
 
Any COVID-19 vaccine administered to a study participant is considered a concomitant
medication and should be reported on the electronic case report form (eCRF).
 For serious adverse events (SAEs) reported after COVID-19 vaccination, the investigator
should provide narrative details on the SAE form to allow adequate assessment of causal
relationship between the reported SAE and vaccination. This is particularly relevant in cases
where the reported SAE is an expected event with the study intervention and the COVID-19
vaccine. If the event is serious and considered to be related to both the COVID-19 vaccine
and the study intervention, it is a serious adverse reaction and expectedness must be assessed.
Suspected unexpected serious adverse reaction (SUSAR) reporting will be performed if the
serious adverse reaction is unexpected as per applicable reference safety document.


JNJ-67896049 / ACT-293987 (selexipag) 
Clinical Protocol 67896049PUH3001, Amendment 2
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55
Status: Approved,Date: 26 October 2021
10.8. Appendix 8: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents. A summary of previous amendments is provided below.
Amendment 1, Version 2 (08 December 2020)
Overall Rationale for the Amendment: The overall reasons for this protocol amendment are to adapt
safety reporting processes as part of the full transition of Actelion into Janssen, to align with TransCelerate
Protocol Template, and to make minor corrections and editorial revisions.
Section Number and Name 
Description of Change 
Brief Rationale
Title Page 
Legal name of the organization and 
confidentiality statement are updated. 
To update administrative
changes.
1.1. Synopsis-Objectives and 
endpoints; 
3. Objectives and Endpoints; 
9.4.1. Safety Endpoints 
Primary objective is revised. 
To clarify that continued
treatment will be provided for
participants who were previously
enrolled in an Actelion-
sponsored study with selexipag
and who derived benefit from
selexipag.
A new primary endpoint is added as 
follows: 
‘• Frequency of adverse events (AEs)’ 
Consequently, the following endpoint
"frequency of AEs related to dose changes
or temporary interruption of selexipag" is
no longer needed and is deleted.
Updated as all AEs whether
serious or non-serious will be
collected to align with Janssen's
safety processes.
1.1. Synopsis-Number of 
participants; 
9.2. Sample Size Determination  
The maximum number of participants 
expected to roll-over from the GRIPHON 
OL study is revised to approximately 50 
participants (earlier 114). 
To update the number of
participants based on the current
information on the ongoing
participants of GRIPHON OL
study who will not have other
options to access selexipag.
1.1. Synopsis-Intervention 
groups and duration; 
6.5. Concomitant Therapy; 
6.6. Dose Modification 
Content related to dosing frequency of 
study intervention in presence of permitted 
moderate inhibitors of cytochrome 
P4502C8 (CYP2C8) is updated. 
To clarify dosing adjustment
with and without concomitant
administration of moderate
CYP2C8 inhibitor and under the
circumstances of hepatic
impairment.
1.1. Synopsis-Safety evaluations; 
4.1. Overall Design; 
8.1. Safety Assessments; 
9.4.2. Safety Analyses
Statement related to safety evaluations is 
revised to include all AEs. 
To align with Janssen's safety
processes requiring the
collection of all AEs.
1.3. Schedule of Activities (SoA) 
SoA updated as all AEs are to be collected
4.4. End of Study Definition  
Content is revised to avoid duplication of 
information. 
To delete the redundant
information
5.2. Exclusion Criteria 
Criterion 9 is revised as follows: 
‘plan to receive an investigational 
intervention (including investigational
vaccines) other than selexipag.’
"Other than selexipag" added to
avoid confusion.
5.3. Screen Failures 
Screening failure-description (age at initial 
informed consent) has been removed. 
Age at initial consent will not be
used for participant identification
for all study-related reports and
communications


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56
Status: Approved,Date: 26 October 2021
Section Number and Name 
Description of Change 
Brief Rationale
6.1. Study Intervention(s) 
Administered 
Content of the section is revised. 
To clarify that dose & dosing
frequency of the study
intervention at enrollment will be
the same as in the parent study;
to clarify that the color of the
tablets will depend on the dose
strength.
6.4. Study Intervention 
Compliance 
Information about assessment of study 
intervention compliance is updated. 
To provide proper information
for assessment of study
intervention compliance.
6.5. Concomitant Therapy; 
Content revised as all concomitant 
therapies must be collected now. 
To align with TransCelerate
Protocol Template and processes
that require collection of all
concomitant therapies.
7.2. Participant 
Discontinuation/Withdrawal 
From the Study  
Content related to use of locator agencies 
is deleted. 
Not applicable to SOMBRERO
and not provided as an option in
the informed consent form (ICF).
8.1 Safety Assessments 
Child-Pugh score assessment is included 
in safety assessments. 
Added because this test will be
needed for participants with
known or suspected hepatic
impairments.
8.3.1. Time Period and 
Frequency for Collecting 
Adverse Events and Serious 
Adverse Events; 
8.3.2. Follow-up of Adverse 
Events and Serious Adverse
Events;
10.4. Appendix 4: Adverse
Events: Definitions and
Procedures for Recording,
Evaluating, Follow-up, and
Reporting
Reference to AEs leading to premature 
discontinuation of study intervention (SI), 
related to dose changes or temporary 
interruption of SI has been removed from
heading and content of the sections.
To align with Janssen's processes
that require collection of all AEs
whether serious or not.
8.3.1. Time Period and 
Frequency for Collecting 
Adverse Events and Serious 
Adverse Events 
Following content is updated.
The initial and follow-up reports of a SAE
should be made by facsimile (fax) sent to
Sponsor.
8.3.3. Regulatory Reporting 
Requirements for Serious 
Adverse Events
The list of disease related events not
requiring expedited reporting is removed.
8.3.4. After the 30-day follow-up 
period 
A new section is included to provide
information about reporting of serious
adverse events (SAEs) occurring after 30-
day follow-up period.
8.4.1. Reporting of Pregnancy; 
8.4.2. Follow-up of Pregnancy  
Information about reporting and follow-up 
procedures for pregnancy is updated. 
To reflect the standard Janssen
wording and include monitoring
of pregnant partners of male
patients per Janssen safety
reporting procedures.
8.5. Treatment of Overdose 
Section of ‘Treatment of Overdose’ is 
updated to include definition of overdose 
and mandatory treatment provided by the 
investigator or treating physician in case
of overdose.
Text updated to match changes
with internal safety reporting
processes.


JNJ-67896049 / ACT-293987 (selexipag) 
Clinical Protocol 67896049PUH3001, Amendment 2
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57
Status: Approved,Date: 26 October 2021
Section Number and Name 
Description of Change 
Brief Rationale
9.2. Sample Size Determination  
Following statement is added: 
‘It is foreseen that participants enrolled 
in other parent studies with selexipag 
may be enrolled in this study if they 
meet eligibility criteria.’ 
To clarify about the possible
enrolment of participants from
other parent studies with
selexipag if eligibility criteria are
met.
9.3. Populations for Analysis 
Sets 
Heading of the section is updated 
To align with TransCelerate
Protocol Template.
9.4.2. Safety Analyses 
For analysis purpose, definition of 
maintenance dose is included.
To improve the clarity.
9.4.3. Exploratory Endpoints 
The definition of baseline for WHO FC is 
clarified as the last WHO FC value 
assessed before the first dose of selexipag 
in the parent study (or the double-blind 
core study preceding the parent study).
Note: WHO FC is not collected in
GRIPHON OL study, hence this
endpoint is not applicable to
participants from GRIPHON OL study.
To avoid any confusion in the
way baseline must be taken into
account in the assessment of
WHO FC changes over time
9.4.4.2. Overall Survival 
The statement is revised as follow: 
‘Time to death will be calculated from the 
date of first intake of selexipag in the 
parent study or the double-blind core 
study preceding the parent study’.
To specify the date of first intake
of selexipag to be taken into
account in the calculation of
"time to death" .
10.1. Appendix 1: Abbreviations 
Terms ‘COVID-19, ‘DTP’, ‘FOIA’ and 
‘INR’ are included in the list of
abbreviations.
To update new abbreviations.
10.4. Appendix 4: Adverse 
Events: Definitions and 
Procedures for Recording, 
Evaluating, Follow-up, and
Reporting
Content related to ‘Unlisted (Unexpected) 
Adverse Event/Reference Safety 
Information’ is updated.
To align with TransCelerate
Protocol Template.
10.7. Appendix 7: Child-Pugh 
Classification; 
11. References 
The Child-Pugh classification is included 
and the corresponding references are 
updated. Appendix 7 is cited throughout 
the protocol, wherever applicable.
To provide detailed information
for the assessment of severity of
liver diseases.
10.8. Appendix 8: Guidance on 
Study Conduct During Natural 
Disaster 
Guidance on study conduct during the 
COVID-19 pandemic is added. 
To describe measures to be taken
to manage the study during the
COVID-19 pandemic while
access to sites is restricted
Throughout the protocol 
 Term ‘Study treatment’ is replaced 
with ‘Study intervention’. 
 Running footer updated. 
 Minor corrections and editorial 
revisions. 
To maintain consistency
throughout.
To align with TransCelerate
Protocol Template.
To improve clarity of the
content.
COVID-19 Appendix (27 November 2020)
Overall Rationale: To provide a guidance on study conduct during the COVID-19 pandemic.


JNJ-67896049 / ACT-293987 (selexipag) 
Clinical Protocol 67896049PUH3001, Amendment 2
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58
Status: Approved,Date: 26 October 2021
11. 
REFERENCES
(2012 Child-Pugh) (2012) Child-Pugh. In: Vincent JL, Hall JB. (eds) Encyclopedia of Intensive Care Medicine.
Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-00418-6_3060.
(ClinicalTrials.gov) NCT03689244 A Study to Find Out if Selexipag is Effective and Safe in Patients With
Chronic Thromboembolic Pulmonary Hypertension When the Disease is Inoperable or Persistent/Recurrent
After Surgery (SELECT).
https://clinicaltrials.gov/ct2/show/NCT03689244?term=SELECT&cond=CTEPH&draw=2&rank=1. Accessed
3 March 2020.
(Coons 2019) Coons JC, Pogue K, Kolodziej AR, et al. Pulmonary Arterial Hypertension: a Pharmacotherapeutic
Update. Curr Cardiol Rep 2019;21:141.
(FDA 2003) Guidance for Industry, Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design,
Data Analysis, and Impact on Dosing and Labeling. May 2003. Available at :
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm072123.pdf
[accessed 24 Aug 2020].
(Selexipag IB) Investigator’s Brochure, JNJ-67896049 (selexipag), Edition 16 (02 Feb 2021) and Addendum to IB
Edition 16 (25 May 2021). Actelion Pharmaceuticals Ltd .
(Sitbon 2015) Sitbon Q, Channick R, Chin KM, et al; GRIPHON Investigators. Selexipag for the Treatment of
Pulmonary Arterial Hypertension. N Engl J Med. 2015 Dec 24;373(26):2522-2533.


JNJ-67896049 / ACT-293987 (selexipag) 
Clinical Protocol 67896049PUH3001, Amendment 2
Confidential –FOIA Exemptions Apply in U.S. 
59
Status: Approved,Date: 26 October 2021
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Actelion Pharmaceutical Ltd and Janssen Research and Development, a Division of
Janssen Pharmaceutica NV
Signature: 
[electronic signature appended at the end of the protocol] 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD


Signature
User 
Date 
Reason
26-Oct-2021
16:44:12
(GMT)
Document Approval
27-Oct-2021
07:43:59
(GMT)
Document Approval
PPD
PPD


CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date: 19 May 2022
Actelion Pharmaceuticals Ltd
(a Janssen Pharmaceutical Company of Johnson & Johnson)*
Clinical Protocol
GUIDANCE ON STUDY CONDUCT DURING A NATURAL DISASTER /MAJOR
DISRUPTION/PANDEMIC
Protocol Title
A Multicenter, Single-arm, Open-label, Long-term Follow-up Safety Study of Selexipag in
Participants who Participated in a Previous Selexipag Study
SOMBRERO
Protocol 67896049PUH3001; Phase 3b
JNJ-67896049/ACT-293987  (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 Janssen Research
& Development studies may vary, such as, but not limited to; Janssen-Cilag International NV; Janssen, Inc;
Janssen Pharmaceutica NV; Janssen Research & Development, LLC. The term “sponsor” is used
throughout the protocol to represent these various legal entities; the sponsor is identified on the Contact
Information page that accompanies the protocol.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
IND:104504
EudraCT NUMBER:2020-000475-21
Status: 
Approved
Date: 
19 May 2022
Prepared by: Actelion Pharmaceutical Ltd and Janssen Research and Development, a division of
Janssen Pharmaceutica NV
EDMS number: 
EDMS-RIM-272313, 2.0
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL
FOR IMPACTED COUNTRIES
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.
NCT04565990


Guidance on Study Conduct During Natural Disaster/Major Disruption/Pandemic
JNJ-67896049/ACT-293987 (selexipag) 
Clinical Protocol 67896049PUH3001
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved,  Date: 19 May 2022
STUDY CONDUCT DURINGA NATURAL DISASTER/MAJOR
DISRUPTION/PANDEMIC
GUIDANCE ON STUDY CONDUCT DURING NATURAL DISASTER/ MAJOR
DISRUPTION/PANDEMIC
It is recognized that the natural disaster/major disruption/pandemic may have an impact on the
conduct of this clinical study due to, for example, isolation or quarantine of participants and study
site personnel; travel restrictions/limited access to public places, including hospitals; study site
personnel being unavailable, isolated, or reassigned to critical tasks.
The sponsor is providing options for study related participant management in the event of
disruption to the conduct of the study. This guidance does not supersede any local or government
requirements or the clinical judgement of the investigator to protect the health and well-being of
participants and site staff. If, at any time, a participant’s travel to the study site is considered to be
dangerous, study participation may be interrupted, and study follow-up conducted. If it becomes
necessary to discontinue participation in the study, the procedures outlined in the protocol for
discontinuing study intervention will be followed, if the situation allows.
If, as a result of the natural disaster/major disruption/pandemic, scheduled visits cannot be
conducted in person at the study site, they will be performed to the extent possible
remotely/virtually or delayed until such time that on-site visits can be resumed. At each contact,
participants will be interviewed to collect safety data. Key efficacy endpoint assessments should
be performed if required and as feasible. Participants will also be questioned regarding general
health status to fulfill any physical examination requirement.
Every effort should be made to adhere to protocol-specified assessments for participants on study
intervention, including follow-up. Modifications to protocol-required assessments may be
permitted after consultation with the participant, investigator, and the sponsor. Missed
assessments/visits will be captured in the clinical trial management system for protocol deviations.
Discontinuations of study interventions and withdrawal from the study due to a natural disaster, a
pandemic (eg, Coronavirus Disease 2019 [COVID-19]) or a major disruption should be clearly
identified in the electronic Case Report Form (eCRF) by providing the specific prefix as instructed
by the sponsor (eg, use the prefix "COVID-19-related if a participant discontinued due to COVID-
19 pandemic").
NATURAL DISASTER/MAJOR DISRUPTION/PANDEMIC: The sponsor will continue to
monitor the conduct and progress of the clinical study, and any changes will be communicated to
the sites and to the health authorities according to local guidance. Modifications made to the study
conduct as a result of a natural disaster, major disruption, or pandemic should be summarized in
the clinical study report.


Guidance on Study Conduct During Natural Disaster/Major Disruption/Pandemic
JNJ-67896049/ACT-293987 (selexipag) 
Clinical Protocol 67896049PUH3001
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
3
Status: Approved,  Date: 19 May 2022
GUIDANCE SPECIFIC TO THE  STUDY PROTOCOL  67896049PUH3001 DURING
NATURAL DISASTER/MAJOR DISRUPTION/PANDEMIC
Scheduled Visits and Procedures (Protocol Section 1.3 & Section 8)
 
When participant visits to the study site are not possible, assessments and procedures may be
performed remotely (eg, by phone, telemedicine) or in-person off-site (eg, at participant’s
home). The study site and the sponsor will discuss and agree on the applicable assessments
and procedures.
Pregnancy tests (Protocol Section 8.1 & Section 10.2)
 
When participant visits to the study site are not possible, on-site pregnancy tests for women
of childbearing potential will be performed at home for urine pregnancy tests or where
possible, at a local laboratory if a serum pregnancy test is judged necessary by the study
physician.
Study Intervention (Protocol Section 6.2)
 
When participant visits to the study site are not possible, shipment of study intervention from
the study site directly to participants (and vice versa for return of study intervention) may be
implemented where allowed per local regulations and if requested by the treating study
physician.
Site Monitoring and Informed Consent (Protocol section 10.3)
 
The sponsor may apply remote monitoring and/or remote auditing if on-site visits are not
possible.
 
Consenting on the specific temporary changes related to Natural disaster/Major
disruption/Pandemic situations will be performed and documented according to local
guidance for informed consent as applicable (Remote reconsenting of participants, eg, by
phone or video consultation, may be considered according to local guidance).
STUDY CONDUCT RELATED TO COVID-19 VACCINE DEPLOYMENT FOR
NONCOVID-19 CLINICAL TRIALS
 
Study participants can undergo a COVID-19 vaccination procedure in compliance with
applicable local governmental regulations.
 
No pharmacokinetic interaction between the study intervention and currently available
COVID-19 vaccines are expected. In addition, based on the mechanism of action of the study
intervention and COVID-19 vaccines, no relevant interaction is expected.
 
Any COVID-19 vaccine administered to a study participant is considered a concomitant
medication and should be reported on the eCRF.
 
For serious adverse events (SAEs) reported after COVID-19 vaccination, the investigator
should provide narrative details on the SAE form to allow adequate assessment of causal
relationship between the reported SAE and vaccination. This is particularly relevant in cases
where the reported SAE is an expected event with the study intervention and the COVID-19
vaccine. If the event is serious and considered to be related to both the COVID-19 vaccine


Guidance on Study Conduct During Natural Disaster/Major Disruption/Pandemic
JNJ-67896049/ACT-293987 (selexipag) 
Clinical Protocol 67896049PUH3001
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Status: Approved,  Date: 19 May 2022
and the study intervention, it is a serious adverse reaction and expectedness must be assessed.
Suspected unexpected serious adverse reaction (SUSAR) reporting will be performed if the
serious adverse reaction is unexpected as per applicable reference safety document.


Guidance on Study Conduct During Natural Disaster/Major Disruption/Pandemic
JNJ-67896049/ACT-293987 (selexipag) 
Clinical Protocol 67896049PUH3001
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
Status: Approved,  Date: 19 May 2022
INVESTIGATOR AGREEMENT
I have read this protocol appendix and agree that it contains all necessary details for carrying out
this study. I will conduct the study as outlined herein and will complete the study within the time
designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to
me who assist in the conduct of this study. I will discuss this material with them to ensure that they
are fully informed regarding the study intervention, the conduct of the study, and the obligations
of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Actelion Pharmaceutical Ltd and Janssen Research and Development, a division of
Janssen Pharmaceutica NV
Signature: [electronic signature appended at the end of the protocol] 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD


Signature
User 
Date 
Reason
 
19-May-2022
10:29:26
(GMT)
Document Approval
 
19-May-2022
10:38:11
(GMT)
Document Approval
PPD
PPD

SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 27 October 2023
Janssen Research & Development
Statistical Analysis Plan
A Multicenter, Single-arm, Open-label, Long-term Follow-up Safety Study of Selexipag in 
Participants who Participated in a Previous Selexipag Study - SOMBRERO
Protocol 67896049PUH3001; Phase 3b
JNJ-67896049 / ACT-293987  (selexipag)
Status:
Approved
Date:
27 October 2023
Prepared by:
Actelion Pharmaceuticals Ltd., a Janssen Pharmaceutical Company of Johnson &
Johnson
Document No.: EDMS-RIM-379401, 3.0
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.
NCT04565990


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Status: Approved, Date: 27 October 2023
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
VERSION HISTORY..................................................................................................................................... 4
1.
INTRODUCTION.................................................................................................................................. 5
1.1.
Objectives and Endpoints ................................................................................................................ 5
1.2.
Study Design.................................................................................................................................... 6
2.
STATISTICAL HYPOTHESES............................................................................................................ 7
3.
SAMPLE SIZE DETERMINATION...................................................................................................... 7
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS....................................................................... 7
5.
STATISTICAL ANALYSES................................................................................................................. 7
5.1.
General Considerations ................................................................................................................... 7
5.1.1.
Visit Windows ............................................................................................................................... 8
5.1.2.
Study Day and Relative Day......................................................................................................... 8
5.1.3.
Baseline ........................................................................................................................................ 8
5.1.4.
Signed Informed Consent Date .................................................................................................... 9
5.1.5.
Study Intervention Start Date ....................................................................................................... 9
5.1.6.
Study Intervention End Date......................................................................................................... 9
5.1.7.
End of Study ................................................................................................................................. 9
5.2.
Participant Dispositions.................................................................................................................... 9
5.3.
Primary Safety Endpoints Analyses............................................................................................... 10
5.3.1.
Extent of Exposure ..................................................................................................................... 10
5.3.1.1.
Study Intervention Duration..................................................................................................... 10
5.3.1.2.
Treatment-Emergent Exposure Duration ................................................................................ 10
5.3.1.3.
At-Risk Exposure Duration ...................................................................................................... 10
5.3.2.
Definition of Endpoints................................................................................................................ 11
5.3.2.1.
Adverse Event ......................................................................................................................... 11
5.3.2.2.
Serious Adverse Event............................................................................................................ 11
5.3.2.3.
Treatment-Emergent Adverse Event....................................................................................... 11
5.3.2.4.
Adverse Events of Special Interest ......................................................................................... 11
5.3.2.5.
Adverse Events Leading to Death........................................................................................... 11
5.3.2.6.
Deaths ..................................................................................................................................... 11
5.3.3.
Attributes of Endpoints................................................................................................................ 12
5.3.4.
Analysis Methods........................................................................................................................ 12
5.3.5.
Specifications of Outputs............................................................................................................ 13
5.4.
Exploratory Endpoints Analyses .................................................................................................... 14
5.4.1.
Definition of Endpoints................................................................................................................ 14
5.4.1.1.
Selexipag dose adjustments.................................................................................................... 14
5.4.2.
Analysis Methods........................................................................................................................ 14
5.5.
Other Safety Analyses ................................................................................................................... 14
5.5.1.
Adverse events continuing from the parent study ...................................................................... 14
5.5.2.
Adverse events COVID-19 related ............................................................................................. 14
5.5.3.
Study Intervention Interruptions.................................................................................................. 14
5.6.
Additional Safety Assessments...................................................................................................... 15
5.6.1.
Clinical Laboratory Tests ............................................................................................................ 15
5.6.2.
Vital Signs and Physical Examination Findings.......................................................................... 15
5.6.3.
Electrocardiogram....................................................................................................................... 15
5.7.
Interim Analyses............................................................................................................................. 15
6.
SUPPORTING DOCUMENTATION .................................................................................................. 16
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 16


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6.2.
Appendix 2 Changes to Protocol-Planned Analyses ..................................................................... 17
6.3.
Appendix 3 Demographics and Baseline Characteristics.............................................................. 18
6.4.
Appendix 4 Protocol Deviations ..................................................................................................... 19
6.5.
Appendix 5 Concomitant Medications............................................................................................ 20
6.6.
Appendix 6 Intervention Compliance ............................................................................................. 22
6.7.
Appendix 7 Adverse Events of Special Interest............................................................................. 23
6.8.
Appendix 8 COVID-19 Medical History.......................................................................................... 24
7.
REFERENCES................................................................................................................................... 25


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VERSION HISTORY
Table 1 – SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1
9 November 2021
Not Applicable
Initial release
2
16 November 2021
Removal of a sentence under 
‘Frequency of AEs’ in 
Section 5.3.4.
Sentence not applicable
3
27 November 2023
Removal “Selexipag baseline” in 
Section 5.1.3
After Dry Run the team realized 
it is not needed


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1.
INTRODUCTION
This Statistical Analysis Plan (SAP) describes in detail the methods, conduct and content of 
statistical analyses of the safety and exploratory endpoints planned for the final Clinical Study 
Report (CSR). 
The following study documents are used for the preparation of the SAP:

Protocol 67896049PUH3001, Approved version, Amendment 2 Version 3.0, dated 26 
October 2021, EDMS-RIM-265923 version 2.0,

Electronic Case Report Form (eCRF), version 03, dated 27 January 2021,

Electronic Case Report Form (eCRF) Specifications, version 1.05, dated 05 March 2021.
Source data for the analyses will be provided as Statistical Analysis Software (SAS®) data sets 
according to Clinical Data Interchange Standards Consortium (CDISC) Study Data Tabulation 
Model (SDTM). 
Analysis Data Model (ADaM) datasets from GRIPHON / GRIPHON OL will be used as additional 
source data for specific statistical analyses where applicable.
The Data Presentation Specifications (DPS) Part 1 document will be prepared in line with this SAP 
to provide the list of outputs, layouts and all the programming details necessary to implement the 
statistical analyses.
The CSR analyses will be performed on the locked database following completion of study by all 
participants.
1.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To assess the long-term safety of selexipag while 
providing continued treatment for participants who 
were previously enrolled in an Actelion-sponsored 
study with selexipag and who derived benefit from 
selexipag in indications for which a positive benefit-
risk has been established.
Frequency of AEs
Frequency of AEs leading to premature discontinuation 
of selexipag
Frequency of serious adverse events (SAEs)
Frequency of deaths
Number of pregnancies with maternal exposure to 
selexipag
These safety endpoints will be assessed continuously 
from enrollment on Day 1 up to End-of-Study (EOS) 
visit.
Secondary

Not applicable

Not applicable
Exploratory

To capture the long-term dosing pattern of 
selexipag 

Proportion of participants requiring selexipag dose 
reduction or increase by reason


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1.2.
Study Design
This is an open-label, multicenter, long-term, follow-up safety study of selexipag in participants 
who are currently treated with selexipag at the end of an Actelion-sponsored, interventional study 
and who benefit from selexipag in indications for which a positive benefit-risk has been 
established. 
The study includes the following consecutive periods: 

Screening period: starting with the signature of the informed consent form and ending with 
the administration of the first dose of the study intervention. 

Open-label (OL) treatment period: starting with the administration of the first dose of the 
study intervention and ending on the day of the last dose of study intervention (EOT). All 
participants entering the study will continue with the same maintenance dose of selexipag that 
they were taking during their respective parent study. Participants will present for the EOT 
visit within 7 days of the last dose of study intervention. For participants rolled over to post-
trial access (PTA) or Study NOPRODPAPUH3001 (PLATYPUS), the enrollment must occur 
on the day of the last visit of SOMBRERO study ie, EOS visit which corresponds to EOT, to 
avoid selexipag treatment interruption.

Post-treatment follow-up period: starting on the day after the last dose of study intervention 
and ending 30 days thereafter with the EOS visit. For participants who complete the study 
treatment and who are eligible for a post-trial access (PTA) program or Study 
NOPRODPAPUH3001 (PLATYPUS), the post-treatment follow-up period will be waived.
Following enrollment, telephone calls (TCs) or regular visits with the investigator will be 
scheduled alternatingly every 6 months. 
Study intervention re-supply visits will be scheduled every 6 months. For those months when a 
TC with the investigator is scheduled, the participant may pick up the re-supplies at the study site 
without meeting with the investigator. The TC will still be required but can be scheduled within 
the allowed time window. 
Participants will present for the EOT visit within 7 days of the last dose of study intervention 
followed by the EOS visit 30 days after last dose (for participants who complete the study treatment 
and who are eligible for a post-trial access (PTA) program or Study NOPRODPAPUH3001 
(PLATYPUS), the EOS will occur on the same day of EOT).
The overall study design is depicted in Figure 1.


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Figure 1 – Schematic Overview of the Study
2.
STATISTICAL HYPOTHESES
The objective of the study is to assess the long-term safety of selexipag and no statistical hypothesis 
will be tested. Only descriptive analyses will be performed and the 95% confidence intervals will 
be displayed when applicable.
3.
SAMPLE SIZE DETERMINATION
Due to the nature and scope of this study, the sample size is not based on statistical considerations. 
The sample size will be driven by the number of participants still taking selexipag who do not have 
other options to access selexipag when their respective parent study is completed and who consent 
to participate in this study. The maximum number of participants currently expected to roll-over 
from the GRIPHON OL study is approximately 50 participants.
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
Analysis Sets
Description
Enrolled
All participants who signed the informed consent form 
(ICF).
Safety
The safety set includes all enrolled who received at 
least 1 dose of study intervention in SOMBRERO.
5.
STATISTICAL ANALYSES
5.1.
General Considerations
No formal hypothesis testing will be conducted. Data will be summarized using descriptive 
statistics. Continuous variables will be summarized using the number of observations, mean, SD, 
median, and range as appropriate. Categorical values will be summarized using the number of 
observations and percentages as appropriate.
The Safety Set will be used for all analyses, if not otherwise specified.


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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 analysis visit windows and the target 
days for each visit. The reference day is Study Day 1 (Section 5.1.2). If a participant has 2 or more 
actual visits in 1 analysis visit window, the visit closest to the target day will be used as the protocol 
visit for that analysis 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 an analysis visit window, the later visit is used. If 
more than one value falls on the same time point (date and time) then the one with the last 
sequential number in SDTM will be used.
All assignments will be made in chronological order. Once a visit date is assigned to an analysis
visit window, it will no longer be used for a later time point except for the endpoint. Listed below 
(Table 2) are the analysis visit windows and the target days for each visit defined in the protocol.
Assessments which fall outside of any planned analysis visit window will not be included in 
summary tables but will be included into individual participants listings.
Table 2 – Analysis Visit Windows
Parameter
Scheduled Visit 
Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time Point 
(Day)
Safety and 
exploratory 
parameters
1
Baseline
<=1
1
2
Month 6
2 to 274
183
3
Month 12
275 to 456
365
4
Month 18
457 to 638
547
...
*Relative to Study Day 1
5.1.2.
Study Day and Relative Day
Study Day 1 or Day 1 refers to the start of the first study intervention under this protocol. All safety 
and exploratory assessments at all visits will be assigned a study 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 of SOMBRERO study is defined as the last value assessed on or before the start date of 
the study intervention under this protocol. If unscheduled/re-test visits are performed on the day 
of study intervention start, the available value of the last unscheduled/re-test visit on study 
intervention start date is considered as baseline.


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5.1.4.
Signed Informed Consent Date
It is the date of the signed informed consent to this protocol and collected in the "Demographics" 
eCRF form.
5.1.5.
Study Intervention Start Date
Study intervention start date in SOMBRERO is defined as the 'Treatment start date' (the date when 
the first dose of study intervention in the SOMBRERO study was received) from the first record, 
in chronological order, recorded in the "Study Drug Administration" eCRF form. If missing, the 
signed informed consent date will be used.
Selexipag start date is the start date of selexipag from ADaM datasets of GRIPHON (for 
participants randomized to selexipag in GRIPHON) or GRIPHON OL (for participants 
randomized to placebo in GRIPHON).
5.1.6.
Study Intervention End Date
Also known as the date of study intervention discontinuation, this is the 'Treatment end date' from 
the last record (defined as the date of the last dose of study intervention intake, i.e. the time of 
permanent discontinuation of study intervention), in chronological order, recorded in the "Study 
Drug Administration [Selexipag]" eCRF form where the reason the dose was not administered is 
≠ ‘TEMPORARILY INTERRUPTED DUE TO AN AE’ or ‘TEMPORARILY INTERRUPTED 
NOT DUE TO AN AE’. If the exact date of the last dose is missing, the date of the EOT visit will 
be used. If the participant is lost to follow-up during treatment, the date of last contact ('Last date 
known to be alive' from the "Survival Data" eCRF form) will be used.
5.1.7.
End of Study
The end of study (EOS) visit is planned at the end of the 30-day post-treatment follow-up. For 
participants who will complete the study treatment and who will be eligible for a post-trial access 
(PTA) program or Study NOPRODPAPUH3001 (PLATYPUS), the post-treatment follow-up 
period will be waived and EOS visit will correspond to EOT in SOMBRERO.
This is the 'Completed date' or 'Discontinued Date' as applicable from the "Trial Disposition 
(Completion/ Discontinuation)" eCRF form.
5.2.
Participant Dispositions
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

Participants who discontinued study intervention

Reasons for discontinuation of study intervention

Participants who terminated study prematurely

Reasons for termination of study.


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Listings of participants will be provided for the following categories:

Participants who discontinued study intervention

Participants who terminated study prematurely.
5.3.
Primary Safety Endpoints Analyses
The primary objective is to assess the long-term safety of selexipag, hence the primary endpoints 
are for safety (Section 1.1). 
Additional safety analyses for non-primary endpoints are specified in Section 5.5.
5.3.1.
Extent of Exposure
The number and percentage of participants who received study intervention will be summarized
by dose level at Study Day 1. Additional analyses are specified in the following subsections.
5.3.1.1.
Study Intervention Duration
Based on the study intervention start date (Section 5.1.5) and end date (Section 5.1.6), study 
intervention duration in days for individual participants is defined as:
date of last dose of study intervention – date of first dose of study intervention +1.
The study intervention duration in months is calculated as (days of intervention / 30.4). Participant-
years of intervention are calculated as (days of intervention / 365.25).
Descriptive statistics for duration of study intervention will be summarized. Cumulative duration 
of intervention (≥3 months, ≥6 months, ≥9 months, ≥12 months, then every 12 months where 
applicable) will be summarized.
5.3.1.2.
Treatment-Emergent Exposure Duration
For estimating average annualized event rates of treatment-emergent (TE) adverse events of 
special interest (AESI, Section 5.3.2.4), the TE exposure durations (in days) for individual 
participants are required and calculated as
(date of last dose of study intervention + 3) – date of first dose of study intervention +1.
The TE exposure duration in months is calculated as (duration in days / 30.4) and in years as 
(duration in days / 365.25). The total TE exposure duration is the sum over individual participants, 
and the average TE exposure duration is the total duration divided by the number of participants.
5.3.1.3.
At-Risk Exposure Duration
For estimating exposure adjusted incidence rates (EAIR, Section 5.3.4) of treatment-emergent 
adverse events (TEAEs, Section 5.3.2.3), the at-risk exposure durations of individual participants 
are required. For a specific TEAE, the at-risk exposure duration in days of a participant is 
calculated as 


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
For participants without the specific TEAE: the at-risk exposure duration is the same as the 
TE exposure duration (Section 5.3.1.2);

For participants with the specific TEAE: the at-risk exposure duration is calculated as (first 
onset date of the specific TEAE – study intervention start date + 1).
The at-risk exposure duration in years is calculated as (duration in days / 365.25). The total at-risk
exposure duration is the sum over individual participants.
5.3.2.
Definition of Endpoints
Definitions of safety endpoints are provided in the sections below.
5.3.2.1.
Adverse Event
An Adverse Event (AE) is defined as any term reported by the investigator in the “Adverse Event” 
eCRF form. The verbatim terms used by the investigators to describe AEs are coded to preferred 
terms (PT) for classification and tabulation using the latest implemented version of the Medical 
Dictionary for Regulatory Activities (MedDRA).
5.3.2.2.
Serious Adverse Event
An AE is considered serious if the tick box ‘Yes’ for ‘Serious?’ is checked on the AE eCRF page. 
If the information on seriousness is missing, this AE will be considered Treatment-Emergent 
Adverse Event serious for the analysis.
5.3.2.3.
Treatment-Emergent Adverse Event
Treatment-emergent adverse event (TEAE) is any AE occurring at or after the initial 
administration of study intervention in SOMBRERO through the day of the last dose plus 3 days 
(see protocol Section 9.4.2). 
Note: for participants who entered a post-trial access program or Study NOPRODPAPUH3001 
(PLATYPUS), safety information will be reported up to the last dose in SOMBRERO 
(Section 5.1.6), to avoid duplicate reporting of adverse events (AEs).
5.3.2.4.
Adverse Events of Special Interest
AESIs are defined using a selection of PTs (internal MedDRA Query). The full definition is 
included in Section 6.7.
5.3.2.5.
Adverse Events Leading to Death
An AE is considered as leading to death if the tick box “Death” for “Outcome” on the eCRF 
Adverse Event page is ticked.
5.3.2.6.
Deaths
Deaths are derived from the "Death Information" eCRF form. The verbatim terms used by the 
investigators to describe the death cause are coded to PTs for classification and tabulation using 
the latest implemented version of MedDRA.


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5.3.3.
Attributes of Endpoints

Primary Trial Objective: To assess the long-term safety of selexipag in participants who 
were previously enrolled in an Actelion-sponsored study with selexipag and who derived 
benefit from selexipag in indications for which a positive benefit-risk has been established.

Population: Safety Set.

Study Intervention: selexipag, tablets for oral administration.

Outcome measures: .

TEAEs

TEAEs by relationship to study intervention (defined as ‘Related’ or ‘Unrelated’ in CRF)

TEAEs leading to death (by the tick box 'Death' for 'Outcome' in CRF)

TE serious adverse events (SAEs)

TE SAEs by relationship to study intervention

All SAEs (also including SAEs occurring more than 3 days after the last dose of study 
intervention, up to EOS)

All SAEs by relationship to study intervention

TEAEs leading to discontinuation of study intervention

TE AESI

TEAEs by severity (by ‘Maximum intensity’ in CRF)

Deaths 

Pregnancies with maternal exposure to selexipag (AE associated with the pregnancies are 
recorded on the AE/SAE page of the eCRF).

Summary method(s) for outcome measures: In addition to count and percentage for the 
AEs specified above, EAIR will be presented for TEAEs. Details are specified in 
Sections 5.3.4 and 5.3.5.
5.3.4.
Analysis Methods
The following methods are relevant for analyzing the AEs occurred during the study:

Frequency of AEs
AEs reported more than once within a participant (as qualified by the same PT(s)) are counted 
in the frequency table once.

Intensity (severity) of AEs
For AEs reported more than once within a participant (as qualified by the same PT(s)), the 
worst outcome is considered. The categories of intensity are : mild, moderate, severe, If the 
intensity is missing, the AE is considered severe. Listings of AEs will include imputed values 
with a flag to indicate the imputation.

Relationship to study intervention


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Relationship to study intervention is defined as ‘related’ or ‘not related’ (see definition in the 
protocol Section 10.4). For AEs reported more than once for the same participant (as qualified 
by the same PT(s)), the worst relationship is considered. AEs with missing relationship are 
considered as related in the analysis. Listings of AEs will include imputed values with a flag 
to indicate the imputation.

EAIR of AEs
For a specific AE (including TEAE), the EAIR per 100 participant-years is calculated as:
EAIR = 100 × (Number of participants with the specific AE at least once  / total at-risk 
exposure duration).
The total at-risk exposure duration is defined in Section 5.3.1.3.
Note: AEs continuing from the parent study will not be included in the summaries described above 
and will be analysed separately (see Section 5.5).
5.3.5.
Specifications of Outputs
For each summary table the AEs will be displayed in descending order of incidence either by SOC 
and then PT within a SOC, or by PT. Summary tables will be provided for the following categories 
of AEs.

Overall summary of specified AE categories: A summary table including average TE exposure 
duration in months as well as count and percentage of participants with at least one occurrence 
for each of the following AE categories -- TEAE, TEAE related to study intervention, TEAE 
leading to death, TE SAE, TE SAE related to study intervention, all SAE, all SAE related to 
study intervention, AE leading to discontinuation of study intervention  

TEAEs: A summary table by SOC and PT; a summary table by PT; a summary table of severe 
TEAEs by SOC and PT; a summary table of related TEAEs by SOC and PT; a summary table 
of EAIR by SOC and PT, including also total at-risk exposure duration in years

TESAEs: A summary table by SOC and PT; a summary table by PT

TEAEs leading to discontinuation of study intervention: A summary table by SOC and PT

TEAEs leading to death: A summary table by SOC and PT

TE AESIs: A summary table by PT, as well as an overview of AESIs leading to 
discontinuation of study intervention, serious AESIs, related AESIs and AESIs leading to 
death, total number of recurrent AESIs, total TE exposure duration and average annualized 
event rate.

All SAEs up to EOS: A summary table by PT

TE deaths: A summary table by PT for cause of death

All deaths up to EOS: A summary table by PT for cause of death.
Listings will be provided for specific participants who:

Had AEs


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
Had SAEs (note: information collected in the eCRF form 'Relevant Medical History' will be 
provided in the SAEs listing)

Had AEs leading to premature discontinuation of study intervention

Had AEs leading to death

Had died

Became pregnant (from the AE/SAE form).
The listings will have a flag to indicate TE events.
5.4.
Exploratory Endpoints Analyses
5.4.1.
Definition of Endpoints
5.4.1.1.
Selexipag dose adjustments
Doses and reasons for adjustments are retrieved from the "Study Drug Administration [Selexipag]" 
eCRF form ('Up-titration', 'Dose adjusted due to use of concomitant medication', 'Dose reduced 
due to an AE', 'Dose reduced not due to an AE', 'Medication error').
5.4.2.
Analysis Methods
The proportion of participants requiring selexipag dose adjustments will be summarized 
descriptively, by reason. A listing of all dosing records will be provided.
5.5.
Other Safety Analyses
In addition to the primary safety analyses described in Section 5.3, the following analyses will also 
be provided. 
5.5.1.
Adverse events continuing from the parent study
AEs continuing from the parent study (i.e. with onset date in the parent study that are still ongoing 
at Day 1 in SOMBRERO) are collected in the "Adverse Event from Parent Study Continuing" 
eCRF form. A summary table by SOC and PT as well as a listing will be provided.
5.5.2.
Adverse events COVID-19 related
COVID-19 related AEs are collected in the "COVID-19 Case of AEs" eCRF form. A summary 
table by PT on treatment emergent AEs COVID-19 related and a listing of all AEs COVID-19 
related will be provided.
5.5.3.
Study Intervention Interruptions
A participant is considered to have had a study intervention interruption if the reason for treatment 
end is either ‘Temporarily interrupted due to an AE’ or ‘Temporarily interrupted not due to an AE’ 
("Study Drug Administration " eCRF form). Study intervention interruptions will be derived from 
the listing of all dosing records as provided in Section 5.4.2.


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5.6.
Additional Safety Assessments
5.6.1.
Clinical Laboratory Tests
No laboratory assessments are performed during the study. Urine (or serum if applicable) 
pregnancy test for women of childbearing potential will be performed at screening, if not already 
performed at the last visit of the parent study, and at all study site visits; pregnancy tests will also 
be performed monthly at home for the months without on-site visits. 
The results of the pregnancy tests will not be recorded in the eCRF.
5.6.2.
Vital Signs and Physical Examination Findings
Vital signs assessment may be performed for individual participants as clinically indicated but the 
results of these evaluations will not be recorded in the eCRF.
5.6.3.
Electrocardiogram
No reporting of ECG results is planned.
5.7.
Interim Analyses
No formal interim analysis is planned. However, data from this study may be used for interactions 
with health authorities; in such cases details about the ad-hoc interim analyses will be provided in 
a separate SAP.


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6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
AE 
AESI
ATC
Adverse Events 
Adverse Events of Special Interest
Anatomic Therapeutic Chemical
DPS
Data Programming Specification
eCRF 
Electronic Case Report Form(S) 
EOS 
End of Study 
EOT 
End of Treatment 
GCP 
Good Clinical Practice 
IB
IC 
Investigator’s Brochure
Informed Consent 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ID 
Identification
IMP 
Investigational Medicinal Product 
IV
IQ range
Intravenous 
Interquartile Range
KM 
Kaplan Meier 
MedDRA
N
NA 
ND
NYHA FC
OL
OS
Medical Dictionary for Regulatory Activities 
Number
Not Available
No Date
New York Heart Association Functional Classification
Open-label treatment period
Overall Survival
PAH 
PD
Pulmonary Arterial Hypertension 
Protocol Deviation
PH 
Pulmonary Hypertension 
PT
Preferred Term
qd 
Once Daily 
SAE 
Serious Adverse Event 
SAP
SAS
Statistical Analysis Plan 
Statistical Analysis Software
SC 
SD
Subcutaneous 
Standard Deviation
SDTM
SoA 
SS
Standards Consortium Study Data Tabulation Model
Schedule of Activities 
Safety Set
TC 
Telephone Call 
TEAE 
Treatment-Emergent Adverse Event 
US
WHO 
United States
World Health Organization
WHO FC 
World Health Organization Functional Class 


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6.2.
Appendix 2 Changes to Protocol-Planned Analyses
Not applicable.


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6.3.
Appendix 3 Demographics and Baseline Characteristics
The number of participants in each analysis set (Enrolled Set and Safety Set) will be summarized 
and listed. In addition, the distribution of participants by region, country and site ID will be 
presented unless otherwise noted.
The following demographic data will be taken from the participant’s parent study (or the double-
blind core study preceding the parent study) and not recorded in the eCRF of this study: 

Sex,

Age at IC for SOMBRERO as a continuous variable and in categories (18-25 years, 26-50 
years, 51-64 years and >65 years),
Note: Age at IC for SOMBRERO will be calculated as age at parent study entry plus the time 
(in years, not rounded) from parent study IC to SOMBRERO IC

Body weight (kg),

Height (cm),

Race (where permitted),

Ethnicity (where permitted),

Country,

Geographical region (Europe, Asia).
Table 3 presents the list of demographic variables that will be summarized for the safety set.  
Table 3 - 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)
Categorical Variables:
Age (18-25 years, 26-50 years, 51-64 years, and >65 years)
Frequency distribution with the 
number 
and 
percentage 
of 
participants in each category.
Sex (male, female)
Racea
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
aIf multiple race categories are indicated, the Race is recorded as 'Multiple'.
PH etiology at baseline will be taken from the participant’s parent study (or the double-blind core 
study preceding the parent study) and is not recorded in the eCRF.
Table 4 - Baseline Disease Characteristics Variables
Categorical Variables
PH etiology
Frequency distribution with the number and percentage of participants in each category.


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6.4.
Appendix 4 Protocol Deviations
In general, the following list of major protocol deviations (PDs) 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 ones 
with major protocol deviations will be summarized by the following categories (DVDECOD).

Developed withdrawal criteria but not withdrawn 

Entered but did not satisfy criteria

Received a disallowed concomitant treatment 

Received wrong treatment or incorrect dose

Other.
Protocol deviations related to COVID-19 will be identified with the text ‘COVID-19 related’ as a
prefix of the PD description.
Protocol deviations are summarized by categories, displaying counts and percentages of 
participants with at least a major protocol deviation. Summaries will be presented on the Enrolled 
Set. The summary tables will be sorted by overall frequency, in descending order; if a tie occurs, 
the tied characteristics will be sorted alphabetically.
All major PDs will also be presented in a listing.


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6.5.
Appendix 5 Concomitant Medications
All therapies as collected in the “Concomitant Therapy” eCRF form.
The original terms used by the investigators to describe therapies will be coded to PTs for 
classification and tabulation using the latest version of the WHO Drug code and Anatomic 
Therapeutic Chemical (ATC) class code dictionaries. The version number will be specified as a 
footnote in the relevant tables and listings.
Study intervention concomitant medication is any treatment that is either ongoing at the start of 
study intervention or is initiated during the intervention period. It is identifiable in the eCRF page 
'Concomitant Therapy' with:

Start date before intervention start date and end date on or after intervention start date,
or

Start date before intervention start date and end date missing with the question 'Is the 
medication/therapy still ongoing?' answered 'Yes', 
or

Start date on or after intervention start date and before study intervention end date.
Concomitant medication at SOMBRERO baseline is any medication that is either ongoing at 
the start of study intervention or is initiated at the start date of study intervention, identified as:

Start date before or on study intervention start date and end date on or after study intervention
start date,
or

Start date before intervention start date, end date missing and 'Is the medication/therapy still 
ongoing?'= Yes, ticked by the investigator in the eCRF,
or

Start date before or on study intervention start date and end date missing with 'Is the 
medication/therapy still ongoing?' ≠ No'.
PAH-specific medications will be identified by the preferred term according to Table 5 below:


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Table 5 - PAH specific medications
Group name for the 
outputs
Category
Subcategory
Generic names
ERA
Antihypertensive 
for pulmonary 
arterial 
hypertension
ERA
ambrisentan, bosentan, sitaxentan, macitentan 
PDE5-i
PDE-5 Inhibitor
sildenafil, tadalafil, vardenafil, udenafil  
sCG stimulator
sGC stimulator
riociguat 
Prostacyclin
Prostanoids 
epoprostenol, treprostinil, iloprost, beraprost  
Categories will be identified by searching the coded WHODRUG preferred terms for occurrence of any of the 
ingredient names. E.g., 'Sildenafil' and 'Sildenafil Citrate' will be both assigned to sildenafil and thus both 
considered PDE-5 inhibitors.
Counts and percentages of participants having taken at least a concomitant medication will be 
presented, separately, by Anatomic Therapeutic Chemical (ATC) class and PT within each ATC 
class as well as by PT. The summary table will present concomitant medications in descending 
order (e.g., ATC and PT within each ATC with the highest number of occurrences appear first). 
Equal frequency of different ATC/PTs will be sorted in alphabetical order of the ATC/PT. 
Participants who took more than once the same concomitant medication (as qualified by the same 
PT) will be counted only once.
A listing of concomitant medications will be also provided.
Summaries of PAH-specific concomitant medications at baseline and during intervention will be 
presented by PT and group name. The proportion of participants who received none, 1 and at least 
2 PAH-specific concomitant medications at SOMBRERO baseline will be reported.


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6.6.
Appendix 6 Intervention Compliance
Study intervention compliance will not be assessed in this study.


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6.7.
Appendix 7 Adverse Events of Special Interest
The following adverse events of special interest will be evaluated 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 
AESI are defined in the aesi220.xlsx file available in the statistical computing environment.


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6.8.
Appendix 8 COVID-19 Medical History
All events as collected in the “COVID-19 Medical History” eCRF form.
The original terms used by the investigators will be assigned preferred terms for classification and 
tabulation using the latest implemented version of Medical Dictionary for Regulatory Activities 
(MedDRA).
COVID-19 medical history will be summarized displaying counts and percentages of participants
having been diagnosed with at least one COVID-19 related disease. Counts and percentages of 
participants having been diagnosed with at least one COVID-19 disease are presented by PT. The 
summary tables are presented in descending order according to the incidence (e.g., PT with the 
highest number of occurrences appears first). Equal frequency of different PTs is sorted in 
alphabetical order of the PT. Participants with two or more occurrences of the same disease (as 
qualified by the same PT) are counted only once.
The COVID-19 medical history will also be reported in a listing.


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7.
REFERENCES
Coons (2019) Coons, JC, Pogue K, Kolodziej, AR, et al. Pulmonary Arterial Hypertension: a 
Pharmacotherapeutic Update. Curr Cardiol Rep 2019;21:141. 
Investigator’s Brochure: JNJ-67896049 (selexipag), edition 16. Actelion Pharmaceuticals Ltd (02 
Feb 2021).