Conditions: Sarcoidosis-associated Pulmonary Hypertension
Keywords: selexipag, sarcoidosis, pulmonary hypertension
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 10
Healthy volunteers: no

Brief summary:
Oral selexipag is commercially available in several countries for the treatment of a particular group of pulmonary hypertension (PH) called pulmonary arterial hypertension (PAH). The aim of the present study is to investigate whether selexipag could be helpful to treat patients with another form of PH called sarcoidosis-associated pulmonary hypertension (SAPH).

Detailed description:
Pulmonary hypertension (PH) is a pathophysiological disorder that may involve multiple clinical conditions and can complicate several cardiovascular and respiratory diseases. Sarcoidosis is a multisystemic disorder that is characterized by non-caseating granulomas which are present in multiple tissues, particularly in the lung and lymphatic system. Severe untreated pulmonary hypertension (PH) carries a poor prognosis and is associated with higher mortality in participants with interstitial lung diseases and sarcoidosis. While there is no approved treatment for SAPH, PH-specific treatments are frequently used. Selexipag is a selective, orally available and long-acting non-prostanoid agonist of the prostacyclin receptor (prostacyclin \[IP\] receptor) for the treatment of patients with PAH. The rationale for this study is based on the unmet medical need for new therapeutic options for patients with SAPH and is supported by the established efficacy and safety of selexipag in the PAH indication, the shared pathomechanism between SAPH and PAH, and the available data on the efficacy and safety of PH-specific therapies in SAPH. This study consists of screening period, main observation period and double blind extension period and safety follow-up period. The duration of individual participation in the study will be different for each individual participant (between approximately 15 months and up to approximately 3.5 years) and will depend on the time of each participant's individual date of entering the study and the total recruitment time. The efficacy assessments include right heart catheterization (RHC), assessment of exercise capacity, dyspnea, pulmonary function tests, etc. Safety and tolerability will be evaluated throughout the study and includes review of concomitant medications and adverse events (AEs), clinical laboratory tests, 12-lead electrocardiogram (ECG), vital signs, physical examination, and pregnancy testing.

Arms:
arm 1: Study intervention will be up-titrated to allow each participant to reach their individual maximum tolerated dose (iMTD), in the range of 200 μg to1600 μg (ie, 1 to 8 tablets) twice daily/once daily. Dosing frequency will be twice daily, except for participants with moderate hepatic impairment (Child-Pugh Class B) or who are concomitantly taking (a) moderate CYP2C8 inhibitor(s), who receive study intervention once daily. The dose will be up-titrated by the investigator/delegate in 200 μg twice daily/once daily increments at weekly intervals during scheduled TCs until reaching the iMTD. If the dose regimen is not well tolerated or symptoms cannot be fully managed with symptomatic treatment, the duration of the titration step can be prolonged to 2 weeks. If needed, the dose can be reduced by 200 μg twice daily/once daily. arm 2: The comparator will be administered similarly to the experimental intervention.

Interventions: intervention 1: Selexipag intervention 2: Placebo
Intervention descriptions: intervention 1: Oral tablets containing 200 µg of selexipag. Depending on the iMTD, participants will receive 1 (200 µg) to 8 (1600 µg) tablets at each administration intervention 2: Oral tablets without active compound. Participants can receive 1 to 8 tablets at each administration.

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date: 25 February 2022
Actelion Pharmaceuticals Ltd*
(a Janssen Pharmaceutical Company of Johnson & Johnson)
Clinical Protocol
Protocol Title
A Multicenter, Randomized, Double-blind, Placebo-controlled Study in Participants With
Sarcoidosis-associated Pulmonary Hypertension (SAPH) to Assess the Efficacy and Safety
of Oral Selexipag
SPHINX
Protocol AC-065D301; Phase 2
AMENDMENT 3
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).
Regulatory Agency Identifier Number(s):
IND:143208
EudraCT NUMBER: 2018-004887-74
Status: 
Approved
Date: 
25 February 2022
Prepared by: Actelion Pharmaceuticals Ltd and Janssen Research & Development, a division of
Janssen Pharmaceutica NV
EDMS number: 
EDMS-RIM-263140, 3.0
Protocol Version: 
4.0
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.
NCT03942211


JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved,  Date: 25 February 2022
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
Document 
Date
Amendment 3 
25-Feb-2022
Amendment 2 
21-Sep-2020
Amendment 1 
5-Dec-2019
Original Protocol 
28-Mar-2019
Amendment 3 (25 February 2022)
Overall Rationale for the Amendment: The overall reason for Amendment 3 is to modify some inclusion
and exclusion criteria aiming to facilitate enrollment (based on inputs from the Steering Committee [SC]
of the SPHINX study), update Coronavirus Disease 2019 (COVID-19) appendix with recent updates
pertaining to study conduct related to COVID-19 vaccine deployment for non-COVID-19 clinical trials,
and implement miscellaneous minor corrections and clarifications.
A Protocol Amendment Summary of Changes Table for the current amendment is provided below. The
updates are indicated in bold text and strike-through for the deleted text, wherever possible.
Section Number 
and Name
Description of Change 
Brief Rationale
1.1. Synopsis (Objectives and 
Endpoints); 
1.3.1. Visits and Assessments
While Taking Study
Intervention;
1.3.2. Visits and Assessments
After Premature
Discontinuation of Study
Intervention;
3. Objectives and Endpoints;
8.2.2.5. Dyspnea (Pre- and
Post-6MWT);
10.14. Appendix 14: Study
Conduct During a Natural
Disaster
Replaced Borg Dyspnea Index (BDI) with
‘Borg CR Scale® (CR10)’.
For consistency with trade name.
1.3.2. Visits and Assessments 
After Premature 
Discontinuation of Study 
Intervention 
Text updated to indicate that the survival
follow-up to be conducted ‘Yearly after
study discontinuation until death or ±1
month of Visit 6 for the last participant
(EOMOP)’.
For clarification.
4.2. Scientific Rationale for 
Study Design  
Modified the terminology
‘morbidity/mortality (M/M)’ to ‘clinical
worsening’.
To align with the terminology of
the corresponding efficacy
endpoint.
1.1. Synopsis; 
4.1. Overall Design; 
4.4.1. EOS Visit 
Sections updated and aligned with the
revised definitions of ‘end-of-study (EOS)
Visit’ under various circumstances for
participant who complete or discontinue
the treatment, before and after end-of-
main-observation-period (EOMOP) or in
case of entering the continued access
program.
To align with the latest protocol
template language.
5.1. Inclusion Criteria 
Updated the reference supporting inclusion
criterion # ‘4’
To rectify the error.
Modified criterion # ‘9’ with a note as
follows:
An upper limit of the baseline 6-
minute walk distance (6MWD)
NCT03942211


JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
3
Status: Approved,  Date: 25 February 2022
‘6MWD between ≥50 and 450 m both at 
Screening and at the time of
randomization.
NOTE: Participants can use their usual 
walking aids during the test (e.g., cane, 
crutches). The same walking aid should 
be used for all 6MWTs. Walkers are not
allowed.’
is not regarded relevant.
Added the note for clarification
regarding the use of walking
aids.
Modified criterion # ‘10’ as follows: 
‘Forced vital capacity (FVC) >50% of 
predicted at Screening FVC >50% and 
FEV1 >50% of predicted at Screening.’
Combination of the previous
inclusion criteria # 10 and 11
into one.
Modified criterion # ‘11’ as follows: 
‘FEV1/FVC ≥60%, or if FEV1/FVC <60% 
then FEV1 must be ≥60% of predicted at 
Screening DLCO ≥40% of predicted. If 
DLCO <40% of predicted, the extent of 
emphysema should not be greater than
that of fibrosis as assessed by high
resolution CT scan.’
Addition of a diffusing capacity
of the lung for carbon monoxide
(DLCO) criterion is deemed
appropriate and useful, based on
recent literature.
Modified criterion # ‘14’ as follows: 
‘A woman only using hormonal oral
contraceptives must have been using this
method for at least 1 month 30 days prior
to randomization.’
For clarification.
5.2. Exclusion Criteria 
Revised criterion # ‘8’ as follow: 
‘Implantable cardioverter defibrillator 
(ICD) for secondary prevention (current or 
planned). Participants who either are 
planning to receive an implantable
cardioverter defibrillator (ICD) or who
already have one that has delivered
shock therapy any time in the previous 1
year prior to Day 1. Participants with
ICD are eligible if no shock therapy has
been delivered in the previous 1 year
prior to Day 1.’
As it is not required to exclude
patients with an ICD if no shock
therapy has been delivered 1
year prior to enrollment.
Deleted criterion # ‘23’: ‘Received an 
investigational intervention or used an 
invasive investigational medical device
within 90 days prior to randomization.’
Content redundant with criterion
# ‘22’.
Modified criterion # ‘25’ as follows: 
‘Any acute or chronic impairment that may 
influence the ability to comply with study
requirements such as to perform RHC, a
reliable and reproducible 6MWT (eg, use
of walking aids such as cane, walker, etc.),
or lung function tests.’
To be consistent with modified
inclusion criterion # ‘9’.
6.1.3.1. Study Intervention Up- 
titration (previous)
Deleted section number and heading. 
To remove redundancy.
8. Study Assessments and 
Procedures 
Added new footnotes ‘g’ and ‘h’ to Table 
2. 
To clarify and align with Section
1.3.1.
Revised ‘Study-Specific Materials’ with 
respect to pregnancy forms. 
To update with latest available
information.
8.2.2.1. Clinical Worsening and 
Hospitalization Related to PH- 
worsening
Deleted the phrase ‘non-planned PH- 
related’ associated with ‘hospitalization’.
For accuracy.
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JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Status: Approved,  Date: 25 February 2022
10.5. Appendix 5:
Contraceptive and Barrier
Guidance
Updated the section heading and content. 
To align with latest protocol
template language.
10.14. Appendix 14: Study
Conduct During a Natural
Disaster
(previously ‘Appendix 14:
COVID-19 Appendix’)
Updated section heading and deleted the
title page.
To align with latest protocol
template.
Section is updated with new pulmonary
hypertension therapeutic area-specific
standard text by Janssen.
To align with recent updates
pertaining to study conduct
related to COVID-19 vaccine
deployment for non-COVID-19
clinical trials.
11. References 
Updated the list of references and the
citations throughout the document.
To align with organization’s
standard format of parenthetical
referencing.
Throughout the protocol 
 Replaced ‘qd’ with ‘once daily’ and
‘bid’ with ‘twice daily’.
 Corrected and updated references, as
applicable.
 Updated the abbreviations.
 Minor corrections and editorial
revisions are made.
For clarity and consistency.
NCT03942211


JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
Status: Approved,  Date: 25 February 2022
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 7
1. 
PROTOCOL SUMMARY..................................................................................................................... 8
1.1. 
Synopsis........................................................................................................................................... 8
1.2. 
Schema.......................................................................................................................................... 16
1.3. 
Schedule of Activities..................................................................................................................... 18
1.3.1. 
Visits and Assessments While Taking Study Intervention.......................................................... 18
1.3.2. 
Visits and Assessments After Premature Discontinuation of Study Intervention ....................... 21
2. 
INTRODUCTION................................................................................................................................ 24
2.1. 
Study Rationale.............................................................................................................................. 25
2.2. 
Background .................................................................................................................................... 25
2.3. 
Benefit/Risk Assessment ............................................................................................................... 25
2.3.1. 
Known Benefits........................................................................................................................... 25
2.3.2. 
Potential Benefits........................................................................................................................ 25
2.3.3. 
Known Risks............................................................................................................................... 25
2.3.4. 
Potential Risks............................................................................................................................ 26
2.3.5. 
Overall Benefit/Risk Assessment ............................................................................................... 26
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 27
4. 
STUDY DESIGN ................................................................................................................................ 30
4.1. 
Overall Design................................................................................................................................ 30
4.2. 
Scientific Rationale for Study Design............................................................................................. 33
4.2.1. 
Study-Specific Ethical Design Considerations ........................................................................... 35
4.3. 
Justification for Dose...................................................................................................................... 35
4.4. 
End-of-Study Definition .................................................................................................................. 35
4.4.1. 
EOS Visit .................................................................................................................................... 35
4.4.2. 
Participant Completion................................................................................................................ 36
4.4.3. 
Study Completion ....................................................................................................................... 36
5. 
STUDY POPULATION ...................................................................................................................... 36
5.1. 
Inclusion Criteria............................................................................................................................ 37
5.2. 
Exclusion Criteria........................................................................................................................... 39
5.3. 
Lifestyle Considerations................................................................................................................. 41
5.4. 
Screen Failures.............................................................................................................................. 41
6. 
STUDY INTERVENTION................................................................................................................... 42
6.1. 
Study Interventions Administered .................................................................................................. 42
6.1.1. 
Description of Study Interventions.............................................................................................. 42
6.1.2. 
Study Intervention Administration............................................................................................... 42
6.1.3. 
Study Intervention Up-titration.................................................................................................... 43
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 44
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 45
6.4. 
Study Intervention Compliance...................................................................................................... 46
6.5. 
Concomitant Therapy..................................................................................................................... 46
6.6. 
Dose Modification........................................................................................................................... 48
6.7. 
Intervention After the End of the Study.......................................................................................... 48
6.8. 
Treatment of Overdose .................................................................................................................. 48
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 49
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JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Status: Approved,  Date: 25 February 2022
7.1. 
Discontinuation of Study Intervention ............................................................................................ 49
7.1.1. 
Temporary Discontinuation......................................................................................................... 50
7.2. 
Participant Discontinuation/Withdrawal from the Study................................................................. 50
7.2.1. 
Withdrawal From the Use of Research Samples ....................................................................... 51
7.3. 
Lost to Follow-up............................................................................................................................ 52
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 53
8.1. 
Demographics and Baseline Characteristics ................................................................................. 55
8.2. 
Efficacy Assessments .................................................................................................................... 56
8.2.1. 
Primary Efficacy Endpoint Assessment...................................................................................... 56
8.2.1.1. 
Right Heart Catheterization ..................................................................................................... 56
8.2.2. 
Exploratory Endpoint Assessments............................................................................................ 57
8.2.2.1. 
Clinical Worsening and Hospitalization Related to PH-worsening.......................................... 57
8.2.2.2. 
Survival Follow-up ................................................................................................................... 57
8.2.2.3. 
Exercise Capacity.................................................................................................................... 57
8.2.2.4. 
Oxygen Saturation (Pre- and Post-6MWT)............................................................................. 58
8.2.2.5. 
Dyspnea (Pre- and Post-6MWT)............................................................................................. 58
8.2.2.6. 
WHO FC .................................................................................................................................. 58
8.2.2.7. 
NT-proBNP.............................................................................................................................. 58
8.2.2.8. 
Patient-reported Outcomes ..................................................................................................... 58
8.2.2.9. 
Clinician-reported Outcomes (CROs)...................................................................................... 60
8.3. 
Safety Assessments....................................................................................................................... 60
8.3.1. 
Physical Examination.................................................................................................................. 60
8.3.2. 
Vital Signs................................................................................................................................... 61
8.3.3. 
Electrocardiogram....................................................................................................................... 61
8.3.4. 
Clinical Safety Laboratory Assessments .................................................................................... 61
8.3.5. 
Pulmonary Function Tests.......................................................................................................... 62
8.3.5.1. 
Spirometry ............................................................................................................................... 62
8.3.5.2. 
Diffusing Capacity of the Lung for Carbon Monoxide (DLCO).................................................. 62
8.3.6. 
Resting Arterial Blood Gas ......................................................................................................... 62
8.4. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 62
8.4.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 63
8.4.2. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 63
8.4.3. 
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 63
8.4.4. 
Pregnancy................................................................................................................................... 64
8.5. 
Biomarkers..................................................................................................................................... 64
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 64
9.1. 
Populations for Analyses................................................................................................................ 65
9.2. 
Statistical Hypotheses.................................................................................................................... 65
9.3. 
Analysis Timepoints ....................................................................................................................... 65
9.4. 
Sample Size................................................................................................................................... 65
9.4.1. 
Sample Size Assumptions.......................................................................................................... 65
9.4.2. 
Sample Size Sensitivity .............................................................................................................. 66
9.5. 
Statistical Analyses ........................................................................................................................ 67
9.5.1. 
Efficacy Analyses........................................................................................................................ 67
9.5.1.1. 
Primary Efficacy Analysis ........................................................................................................ 67
9.5.1.2. 
Secondary Efficacy Analyses .................................................................................................. 70
9.5.1.3. 
Other Efficacy Analyses .......................................................................................................... 70
9.5.2. 
Safety Analyses.......................................................................................................................... 70
9.5.2.1. 
Study Safety Monitoring .......................................................................................................... 71
9.5.3. 
Biomarkers Analyses.................................................................................................................. 71
9.6. 
Data Monitoring Committee ........................................................................................................... 72
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 73
10.1. 
Appendix 1: Abbreviations and Trademarks.................................................................................. 73
NCT03942211


JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
7
Status: Approved,  Date: 25 February 2022
10.2. 
Appendix 2: Clinical Laboratory Tests ........................................................................................... 75
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 77
10.4. 
Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating,
Follow-up, and Reporting............................................................................................................... 89
10.5. 
Appendix 5: Contraceptive and Barrier Guidance ......................................................................... 94
10.6. 
Appendix 6: WHO Function Classification of Pulmonary Hypertension ........................................ 97
10.7. 
Appendix 7: PAH-SYMPACTTM  Questionnaire .............................................................................. 98
10.8. 
Appendix 8: SF-12 ....................................................................................................................... 104
10.9. 
Appendix 9: King’s Sarcoidosis Questionnaire ............................................................................ 108
10.10. Appendix 10: Patient Global Assessment of Disease Severity (PGA-S)..................................... 112
10.11. Appendix 11: Clinician Global Impression of Severity (CGI-S).................................................... 113
10.12. Appendix 12: Clinician Global Impression of Change (CGI-C).................................................... 114
10.13. Appendix 13: Child-Pugh Classification....................................................................................... 115
10.14. Appendix 14: Study Conduct During a Natural Disaster.............................................................. 116
10.15. Appendix 15: Protocol Amendment History................................................................................. 119
11. REFERENCES................................................................................................................................. 131
INVESTIGATOR AGREEMENT............................................................................................................... 133
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Study Intervention Up-titration Scheme.................................................................................... 43
Table 2: 
Volume of Blood to be Collected From Each Participant per Visit ........................................... 54
Table 3: 
Overview of the Different Populations for Analyses. ................................................................ 65
Table 4: 
Sample size sensitivity for the main analysis ........................................................................... 66
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 16
Figure 2: Titration Phase Design.............................................................................................................. 17
NCT03942211


JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
8
Status: Approved,  Date: 25 February 2022
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Multicenter, Randomized, Double-blind, Placebo-controlled Study in Participants With
Sarcoidosis-associated Pulmonary Hypertension (SAPH) to Assess the Efficacy and Safety
of Oral Selexipag
Selexipag (JNJ-67896049 [also known as ACT-293987]) is a selective, orally available and long-acting
non-prostanoid agonist of the prostacyclin receptor (IP receptor), approved and commercially available for
the treatment of patients with pulmonary arterial hypertension (PAH) in the United States (US), the
European Union  (EU), Japan, and other countries. Selexipag is currently being investigated for the
treatment of sarcoidosis-associated pulmonary hypertension (SAPH), chronic thromboembolic pulmonary
hypertension (CTEPH), arteriosclerosis obliterans (ASO) with intermittent claudication (IC), and lumbar
spinal stenosis (LSS) with IC (IB selexipag).
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
 
To assess the effect of selexipag versus 
placebo 
on 
pulmonary 
vascular 
resistance (PVR) in participants with
sarcoidosis 
associated 
pulmonary
hypertension (SAPH) up to Week 26.
 
PVR on study intervention up to Week 26 expressed
as percent of the baseline value.
Exploratory
 
To evaluate the effect of selexipag 
versus placebo on time to clinical 
worsening (TTCW). 
 
TTCW  up to end-of-main-observation-period
(EOMOP) defined as at least one of the following
components:
All-cause death
Unplanned pulmonary hypertension  (PH)-related
hospitalization
Increase (ie, worsening) in WHO functional class
(FC)
Lung transplantation
Atrial balloon septostomy
Initiation of parenteral or new class of PH -specific
therapy for clinical worsening
 
To evaluate the effect of selexipag 
versus placebo on exercise capacity. 
 
Change from baseline in  6-minute walk distance
(6MWD), Borg CR Scale® (CR10), oxygen
saturation, and WHO FC at Week 39 and over time.
 
Proportion of participants with oxygen desaturation
post-6-minute walk test (6MWT) at Week 39 and
over time (identified by decrease in oxygen
saturation [SpO2] by at least 5% from pre-6MWT).
NCT03942211


JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
9
Status: Approved,  Date: 25 February 2022
Objectives 
Endpoints
 
To evaluate the effect of selexipag vs
placebo on daily life physical activity 
(DLPA) and sleep parameters.
 
Change from baseline to Week 39 in actigraphy-
assessed DLPA as measured by:
 
Total DLPA in counts per minute
 
Total volume of activity (above sedentary)
 
Daily time spent (minutes) in non-sedentary
activity
 
Percentage of daily time spent in non-sedentary
activity
 
Moderate to vigorous physical activity
(MVPA)
 
Time spent in the different activity categories
 
Change from baseline to Week 39 in sleep
parameters:
 
Total sleep time (TST; minutes)
 
Wake after sleep onset (WASO; minutes)
 
Number of awakenings
 
Sleep efficiency (percentage)
 
To evaluate the effect of selexipag 
versus placebo on WHO FC. 
 
Proportion of participants with improvement,
worsening and no change from baseline in WHO FC
at Week 39 and over time.
 
To evaluate the effect of selexipag 
versus placebo on death or PH-related 
hospitalizations.
 
Rate of all-cause death or unplanned PH-related
hospitalization up to EOMOP.
 
Time to all-cause death up to EOMOP.
 
To evaluate the effect of selexipag 
versus placebo on patient-reported 
outcomes (PROs) assessed by the
12-Item Short Form Health Survey
(SF-12), 
King’s 
sarcoidosis 
questionnaire 
(KSQ), 
Pulmonary 
Arterial Hypertension-Symptoms and
Impact (PAH-SYMPACT), and Patient
Global 
Assessment 
of 
Severity
(PGA-S).
 
Change from baseline up to Week 39 in SF-12
scores.
 
Change from baseline up to Week 39 in KSQ scores.
 
Change from baseline up to Week 39 in
PAH-SYMPACT scores.
 
Change from baseline up to Week 39 in PGA-S
scores.
 
To evaluate the effect of selexipag 
versus placebo on clinician-reported 
outcomes (CROs) assessed by the
Clinician Global Impressionof Severity
(CGI-S) 
and 
Clinician 
Global
Impression of Change (CGI-C).
 
Change from baseline up to Week 39 in CGI-S
scores.
 
Change from baseline up to Week 39 as measured
by CGI-C scores.
 
To evaluate the effect of selexipag on 
the number of PH low-risk criteria. 
 
Absolute and change from baseline in the number of
low-risk criteria based on WHO FC, 6MWD, N-
NCT03942211


JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
10
Status: Approved,  Date: 25 February 2022
Objectives 
Endpoints
terminal pro B-type natriuretic peptide (NT-
proBNP), and cardiac index (CIn) up to Week 26.
 
To evaluate the effect of selexipag on 
NT-proBNP. 
 
Change from baseline in NT-proBNP serum levels
up to Week 39.
 
To evaluate the effect of selexipag on 
disease and pathway-related serum 
biomarkers. 
 
Change from baseline in serum biomarkers and
associations between serum biomarker levels and
clinical response and baseline characteristics up to
Week 39.
 
To 
evaluate 
the 
change 
in 
hemodynamic variables other than PVR  
 
Change from baseline in other hemodynamic
variables (including cardiac output [CO], CIn, mean
right atrial pressure [mRAP], mean pulmonary
arterial pressure [mPAP], and mixed venous oxygen
saturation [SVO2]) up to Week 26.
Safety
 
To assess the overall safety of 
selexipag.
 
Intervention-emergent adverse events (AEs).
 
Intervention-emergent prostacyclin-associated AEs.
 
Serious adverse events (SAEs) up to end-of-study
(EOS).
 
AEs leading to premature discontinuation of study
intervention.
 
Intervention-emergent AEs of special interest
(eg, hypotension, anemia, hyperthyroidism).
 
Change in vital signs (systolic and diastolic arterial
blood pressure and pulse rate) and body weight from
baseline to all assessed timepoints during the study.
 
Intervention-emergent 
marked 
laboratory
abnormalities.
 
Change from baseline in supplemental oxygen rate.
 
Change from baseline in forced vital capacity (FVC)
and diffusing capacity of the lung for carbon
monoxide (DLCO).
 
Change from baseline in arterial blood gas
parameters.
Hypothesis
The reduction in PVR after 26 weeks of treatment with selexipag is superior to placebo in participants with
SAPH.
OVERALL DESIGN
This is a prospective, randomized, double-blind (DB), placebo-controlled, multicenter, interventional study
in men and women ≥18and ≤75 years of age with SAPH. Study intervention will be up-titrated to allow
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JNJ-67896049 / ACT-293987 (selexipag)
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
each participant to reach their individual maximum tolerated dose (iMTD), in the range of 200 µg to
1,600 μg twice daily. For participants with moderate hepatic impairment (Child-Pugh Class B) or who are
concomitantly taking a moderate cytochrome P450 (CYP)2C8 inhibitor(s) the dosing frequency is once
daily.
The study starts with the first Informed Consent Form (ICF) signed by the first participant and ends with
the last safety follow-up telephone call (TC) or visit of the last participant. The study comprises the
following periods:
 
A screening period of up to 30 days: starts with the signature of the ICF and ends with the participant’s
randomization at Visit 2, Day 1. The screening period should last at least 14 days to allow collection
of baseline data for daily life physical activity (DLPA), sleep parameters, and Pulmonary Arterial
Hypertension-Symptoms and Impact (PAH-SYMPACT™).
 
Intervention and observation periods:
 
A main observation period (MOP) that starts with the participants’ randomization at Visit 2, Day
1 and with a titration phase of up to 12 weeks. Participants receive double-blind study intervention
(selexipag or placebo) during this period. It ends on the day of the EOMOP visit. The EOMOP
visit is the data cut-off for the primary efficacy and safety analyses. The EOMOP visit for all
participants is planned at 39 Weeks ±1 month after randomization of the last participant. The
duration of the MOP will be different for each individual participant and will depend on the time
of each participant’s individual date of randomization.
o Participants who prematurely discontinue study intervention before the EOMOP visit will
continue to perform visits and assessments as scheduled until the EOMOP visit.
o For participants who prematurely discontinue study intervention before the EOMOP visit and
who disagree to perform visits and assessments as scheduled until the EOMOP visit, long-
term follow-up information regarding their survival status will be collected yearly until death
or the time of EOMOP.
o Information on the required procedures to follow if participants discontinue the study
intervention prematurely is provided in Section 7.1.
 
A DB extension period extending intervention for participants who do not prematurely discontinue
study intervention before EOMOP: The period starts in the evening of the day of the EOMOP visit
and ends with the end-of-treatment (EOT) visit. This period will last approximately 5 months.
All participants entering the DB extension period will continue taking blinded study intervention
(selexipag or placebo) during this period. Study intervention allocation will be unblinded
approximately 1 month before the expected EOT visit.
 
A safety follow-up period starting on the day after the last dose of study intervention and ending with
the safety follow-up call at the End-of-Study (EOS) visit. For an individual participant, EOS visit is
defined as follows:
 
For participants who complete the treatment, EOS visit is defined as the safety follow-up visit
(TC) 30 (+5) days after last dose of study intervention.
 
For participants who prematurely discontinue study intervention for any reason before EOMOP
visit (except for withdrawal from the study as defined in Section 7.2) but complete the main
observation period (see Section 4.4.2), EOS visit corresponds to the last visit, which is either the
EOMOP visit or the safety follow-up TC, whichever occurs last (see Schedule of Activities).
 
For participants who prematurely discontinue study intervention for any reason before the
EOMOP visit and who decline to continue with visits and assessments up to the EOMOP visit,
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Status: Approved,  Date: 25 February 2022
but agree to the collection of long-term survival information, the EOS visit corresponds to the last
visit or TC before study discontinuation (see Schedule of Activities).
 
For participants who prematurely discontinue study intervention between the EOMOP and EOT
visits for any reason (except for withdrawal from the study as defined in Section 7.2), the EOS
visit corresponds to the safety follow-up TC (see Schedule of Activities).
 
For participants who complete the treatment and who are entering a continued access program
(ie, other open-label extension study or post-trial access), the EOS visit is defined as the EOT
visit and enrollment in the continued access program must occur on the day of the last visit in the
SPHINX study.
A sponsor Data Monitoring Committee (DMC), Clinical Event Committee (CEC), and Steering Committee
(SC) will be established.
The sponsor DMC has overall responsibility for safeguarding the interests of participants and will review
safety data throughout the study. The sponsor DMC will provide recommendations to the study team.
The CEC will be a sub-committee of the SC  that will review and adjudicate the following cases:
hospitalization, WHO FC increase (ie, worsening), and initiation of PH-specific therapy.
An  SC  is involved in the study design and will provide guidance on the study conduct and study
publications.
The EOS at study level is considered as the last visit or safety follow-up TC, whichever occurs last, for the
last participant in the study.
NUMBER OF PARTICIPANTS
Approximately 74 participants will be randomized in a 1:1 ratio to receive either selexipag or placebo.
Randomization will be stratified by PH-specific therapies at baseline (yes vsno).
INTERVENTION GROUPS AND DURATION
Study Participation Duration
The duration of individual participation in the study will be different for each individual participant
(between approximately 15 months and up to approximately 3.5 years) and will depend on the time of each
participant’s individual date of entry into the study and the total recruitment time.
Description of Interventions
Selexipag 200 μg and matching placebo, will be provided as oral tablets in childproof bottles. Study
intervention will be up-titrated to allow each participant to reach their iMTD, in the range of 200 µg to
1,600 μg (ie, 1 to 8 tablets). Dosing frequency will be twice daily, except for participants with moderate
hepatic impairment (Child-Pugh Class B), or who are concomitantly taking (a) moderate CYP2C8
inhibitor(s), who receive study intervention once daily.
Each participant will start with 1 tablet of study intervention, ie, selexipag (200 μg) or matching placebo,
in the evening of Day 1, and will continue with 200 μg twice daily on Day 2. Participants with moderate
hepatic impairment (Child-Pugh Class B) or who are concomitantly taking (a) moderate CYP2C8
inhibitor(s) will start with 200 µg once daily in the morning of Day 2. The dose will be up-titrated by the
investigator/delegate in 200 μg twice daily/once daily increments at weekly intervals during scheduled TCs
until reaching the iMTD (see table below). If the dose regimen is not well tolerated or symptoms cannot be
fully managed with symptomatic treatment, the duration of the titration step can be prolonged to 2 weeks.
If needed, the dose can be reduced by 200 μg twice daily/once daily. The decision to not further up-titrate
the dose will be based on the investigator’s medical judgment based on the occurrence and severity of
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JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
typical pharmacological effects of IP receptor agonists and the participant’s individual tolerability. At Week
12 (Visit 3), the twice daily/once daily dose reached for each participant is defined as the iMTD. This dose
must be kept stable at least until Week 39 (Visit 6) but can be adjusted for safety and tolerability reasons.
Any study intervention interruption of 3 days or more will require a new up-titration.
Study intervention interruptions exceeding 14 consecutive days must lead to permanent discontinuation of
study intervention.
Study Intervention Up-titration Scheme
Period 
Dose regimen 
Duration
First dose 
200 μg 
On Day 1 in the evening (pm) 
1 tablet
Up titration  
200 μg twice daily *, § 
From Day 2 am to Day 8 am** 
1 tablet twice daily §
400 μg twice daily*, § 
From Day 8 pm to Day 15 am** 
2 tablets twice daily §
600 μg twice daily*, § 
From Day 15 pm to Day 22 am** 
3 tablets twice daily §
800 μg twice daily*, § 
From Day 22 pm to Week 4 am** 
4 tablets twice daily §
1,000 μg twice daily*, § 
From Week 4 pm to Week 5 am** 
5 tablets twice daily §
1,200 μg twice daily*, § 
From Week 5 pm to Week 6 am** 
6 tablets twice daily §
1,400 μg twice daily*, § 
From Week 6 pm to Week 7 am** 
7 tablets twice daily §
1,600 μg twice daily*,§ 
From Week 7 pm to Week 12 am** 
8 tablets twice daily §
Maintenance 
iMTD: 
200 µg to 1,600 μg twice daily §
From Week 12 onwards 
1 8 tablets twice daily §
am  morning;; iMTD  individual maximum tolerated dose; pm  evening.
* Or the iMTD until Week 12.
** If the dose regimen is not well tolerated or symptoms cannot be fully managed with symptomatic treatment, the duration of the titration step
can be prolonged to 2 weeks.
§ For participants with moderate hepatic impairment (Child Pugh Class B) or who are concomitantly taking (a) moderate CYP2C8 inhibitor(s) the
dosing frequency is once daily. These participants must take the study intervention in the morning; hence the first dose of study intervention
should be taken in the morning of Day 2.
EFFICACY EVALUATIONS
The efficacy assessments include, but are not limited to, PVR up to Week 26, assessment of exercise
capacity, dyspnea, and WHO FC, measurement of the NT-proBNP levels, and recording PROs and CROs.
SAFETY EVALUATIONS
Safety and tolerability assessments include review of concomitant medications and AEs, clinical laboratory
tests, 12-lead electrocardiogram (ECG), vital signs, physical examination, pulmonary function tests, DLCO,
oxygen saturation and pregnancy testing.
STATISTICAL METHODS
Analysis Timepoints
There are 2 Analysis Timepoints:
 
Analysis Timepoint 1 (final analysis for the primary endpoint and all supportive efficacy endpoints):
When all participants have completed the EOMOP visit, or survival information is available (or if
participants have discontinued the study prematurely). At this timepoint, the primary analysis of the
PVR endpoint will be conducted. Data for all remaining endpoints will also be analyzed. After the
database lock for the main observation period is done, the study team will be unblinded.
 
Analysis Timepoint 2 (additional follow-up): When all participants have completed the study (EOS)
or discontinued prematurely. At this timepoint, the additional safety data collected during the DB
extension period will be reported.
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
Sample Size Calculation
The calculation of sample size was approximated by Z-test for superiority on the log-transformed ratio of
PVR to baseline at Week26 (or premature EOT if study intervention is discontinued before Week 26) using
the software package EASTTM version 6.4.0.1 for difference of means. A total sample size of 74 participants
will provide a power of 90% for the treatment effect of a 30% relative decrease (ie, improvement) in
geometric mean (GM) as compared to placebo, with a CV of 0.5 and a 2-sided significance level of 0.05.
Primary Efficacy Analysis
The derived parameter that will be used for the primary efficacy analysis is the ratio of the PVR value
postintervention initiation up to Week 26, ie, at Week 26 or at premature EOT in case of discontinuation of
study intervention before Week 26 (post) vs the PVR value pre-intervention initiation at baseline (pre),
expressed as a percentage, ie:
PVRpostto prepercent=PVRatWeek26(orpremature EOT)
PVRatbaseline
 × 100 (%)
Missing PVR assessments at baseline or post-baseline will be imputed specific to the reason for missing
data (refer to statistical analysis plan [SAP] for more details).
As a summary measure, ratio of the GM of the PVR post to pre percent between selexipag and placebo,
obtained by exponentiation of the difference in means of the natural logarithm transformed PVR post to pre
percent between selexipag and placebo will be calculated, ie:
GM(PVRpostto pre percentin selexipag)
GM(PVRpostto pre percentin placebo)
The analyses of the primary efficacy endpoint will be tested using the ANCOVA model.
From the ANCOVA model, PVR post to pre percent will be summarized by intervention group using
covariate adjusted GM  and corresponding 2-sided 95% CI. The between-group ratio of GM  with
corresponding 95% 2-sided CI and p-value will be displayed as the placebo-corrected intervention effect.
For each intervention group, the least square mean and 2-sided 95% CI of the natural logarithm of the PVR
post to pre percent will be inversely transformed using the exponential function and multiplied by 100 to
provide the GM of the PVR post to pre percent and the corresponding 2-sided 95% CI, expressed as a
percentage.
Absolute values at baseline and post-baseline as well as absolute pre-post changes from baseline to
postbaseline in PVR will be summarized using descriptive statistics.
Other Exploratory Efficacy Analysis
For continuous and categorical endpoints, where applicable, the response profiles over time (eg change
from baseline, proportions of participants by categorical endpoint categories) will be inspected graphically
and by the usual summary statistics at each visit (with 95% CI) up to the EOMOP visit by randomized
treatment group on the randomized set (RS). Two sets of profiles will be provided: one considering
assessments measured on study intervention up to the EOMOP visit, and one including all data collected
up to the EOMOP visit, regardless of treatment discontinuations.
Time-to-event endpoints will be analyzed using the Kaplan-Meier method by randomized treatment group
up to EOMOP regardless of study intervention discontinuations.
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JNJ-67896049 / ACT-293987 (selexipag)
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
Safety Analysis
For each AE, the percentage of participants who experience at least 1 occurrence of the given event will be
summarized by intervention group. In addition, comparisons between intervention groups will be provided
if appropriate.
Laboratory data will be summarized by type of laboratory test. Descriptive statistics will be calculated for
each laboratory analyte at baseline and for observed values and changes from baseline at each scheduled
timepoint by intervention group. Frequency tabulations of abnormalities will be made.
Descriptive statistics of pulse rate, systolic and diastolic blood pressure (SBP and DBP, respectively) values
and changes from baseline will be summarized at each scheduled timepoint by intervention group.
Descriptive statistics of values and changes from baseline in supplemental oxygen rate, PFTs and
blood gas analysis will be summarized by intervention group.
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Status: Approved,  Date: 25 February 2022
1.2. 
Schema
Figure 1: 
Schematic Overview of the Study
EOMOP
end of main observation period; EOS
end of study; EOT
end of treatment; iMTD
individual maximum tolerated
dose; TC
telephone call, V
visit; W
week.
*The EOMOP visit has to be performed within ±1 month of planned Visit 6/ Week 39 of the last participant and it will be announced
approximately 9 months in advance. For the last participant, the EOMOP visit will be the Visit 6/Week 39. For all other participants,
if the EOMOP visit falls within the visit window of any other scheduled visit, these visits can be combined, and assessments will
not be repeated. Survival information will be collected for participants who discontinued from study intervention and visits and
assessments.
**Intervention group allocation will be provided to study sites approximately 1 month prior to EOT.
***Study intervention will be provided until the EOT visit, which is planned approximately 5 months after the last EOMOP visit.
In case of premature discontinuation of study intervention, the premature EOT visit should be performed within 7 days after last
study intervention dose and participants should continue to perform visits and assessments up to the EOMOP visit.
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JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
Figure 2: 
Titration Phase Design
D  day; EOT  end of treatment; iMTD  individual maximum tolerated dose; V  visit; W  week.
NOTE: In general, dosing frequency will be twice daily, except for participants with moderate hepatic impairment (Child Pugh
Class B) or who are concomitantly taking (a) moderate CYP2C8 inhibitor(s), for whom the dosing frequency is to be reduced to
once daily. These participants must take the study intervention in the morning, hence the first dose of study intervention should be
taken in the morning of Day 2.
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JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
20
Status: Approved,  Date: 25 February 2022
Assessment of Severity; PH = pulmonary hypertension; RHC = right heart catheterization; SAE = serious adverse event; SF-12 = 12-Item Short Form Health Survey; SpO 2 = peripheral
capillary oxygen saturation; TC = telephone call; WHO = World Health Organization; WOCBP = woman of childbearing potential.
a. The EOMOP visit will have to be performed within ± 1 month of the planned Visit 6/Week 39 of the last participant and will be announced approximately 9 months in advance. For
the last participant the EOMOP visit will be Visit 6/Week 39. For all other participants, if the EOMOP visit falls within the visit window of any other scheduled visit, these visits can
be combined, and assessments will not be repeated.
b. Unscheduled visits may be performed at any time during the study. Assessments (other than reporting of AE/SAE and concomitant medication) are to be performed at the discretion of
the investigator and are reported in the eCRF. An unscheduled visit must be performed for reasons outlined in Section 8. Footnote c indicates which assessments are mandatory in case
an unscheduled visit is performed for reasons outlined in Section 8.
c. In case an unscheduled visit is performed for reasons outlined in Section 8, this assessment must be performed and recorded in the eCRF.
d. Must be signed before first study-related activity.
e. A serum pregnancy test must be performed at Screening or in case of a positive urine pregnancy test.
f. 
Transferred electronically by an external service provider.
g. Assessment not collected in eCRF.
h. In case of twice daily dosing, first dose to be taken in the evening of Day 1. In case of once daily dosing, the first dose of study intervention should be taken in the morning of Day 2.
Includes study intervention up-titration (see Section 6.1.3 for detailed information).
i. 
A historical RHC is allowed taking into account the restrictions provided in Section 8.2.1.1.1. If no historical results are available, an RHC must be performed during the Screening
period only if all other inclusion criteria are met and none of the exclusion criteria is met.
j. 
If the 6MWT and RHC are assessed on the same day the RHC should be performed after the 6MWT and within 2 to 5 hours post-dose.
k. To be performed within 2 to 5 hours post-dose and prior to the RHC (if applicable).
l. 
To collect baseline data, participants should wear the actigraphy device 14 days between Visit 1 (Screening) and Visit 2 (Randomization). It is recommended to start on the day
following the screening visit. If required, the baseline RHC should not be done during this time.
m. To assess baseline, the PAH-SYMPACTTM questionnaire should be completed on 7 consecutive days starting on the day following the screening visit. If required, the baseline RHC
should not be done during the 7 consecutive days of the PAH-SYMPACT completion.
n. If the results for the screening blood samples from the central laboratory are not available in time for randomization of the participant, an additional blood sample may be drawn to
verify eligibility based on a local laboratory test.
o. A historical ABG is allowed taking into account the restrictions provided in Section 8.3.6. If no historical results are available, an ABG must be performed during the Screening
period.
p. The ABG can be done during the RHC taking into account the restrictions provided in Section 8.3.6.
q. All AE and SAEs will be reported throughout the study from signing of the ICF onwards until the EOS visit (see Section 4.4.1) or death or lost to follow-up (see Section 7.3).
r. Optional assessment.
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Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
a. Participants who discontinue study intervention and have their premature EOT visit before the EOMOP visit will continue with visits and assessments until the EOMOP visit. If the
premature EOT visit falls within the visit window of any other scheduled visit, these visits can be combined, and assessments will not be repeated.
b. The EOMOP visit will have to be performed within ± 1 month of the planned Visit 6/Week 39 of the last participant and will be announced approximately 9 months in advance. For the
last participant the EOMOP Visit will be Visit 6/Week 39. For all other participants, if the EOMOP visit falls within the visit window of any other scheduled visit, these visits can be
combined, and assessments will not be repeated.
c. Unscheduled visits may be performed at any time during the study. Assessments (other than reporting of AE/SAE and concomitant medication) are to be performed at the discretion of
the investigator and are reported in the eCRF. An unscheduled visit must be performed for reasons outlined in Section 8. Footnote d indicates which assessments are mandatory in case
an unscheduled visit is performed for reasons outlined in Section 8.
d. In case an unscheduled visit is performed for reasons outlined in Section 8, this assessment must be performed and recorded in the eCRF.
e. Only for participants who prematurely discontinue from study intervention and who disagree to continue to perform visits and assessments until EOMOP, survival information will be
collected yearly (Section 8.2.2.2).
f. 
A serum pregnancy test must be performed in case of a positive urine pregnancy test.
g. Transferred electronically by an external service provider.
h. Assessment not collected in eCRF.
i. 
In case of premature discontinuation of study intervention before Visit 5/Week 26 it is recommended to perform a postbaseline RHC and within 3 days after last dose of study intervention
and before initiation of new PH-specific therapies if possible.
j. 
If the 6MWT and RHC are assessed on the same day the RHC should be performed after the 6MWT.
k. ABG is only mandatory at the premature EOT in case of premature discontinuation before Visit 5/Week 26 and can be done during the RHC taking into account the restrictions provided
in Section 8.3.6.
l. 
This assessment can only be done at the premature EOT in case of premature discontinuation of study intervention before Visit 6/Week 39.
m. All AE and SAEs will be reported throughout the study from signing of the ICF onwards until the EOS visit (see Section 4.4.1) or death or lost to follow-up (see Section 7.3)
n. Optional assessment.
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JNJ-67896049 / ACT-293987 (selexipag)
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
2. 
INTRODUCTION
Pulmonary hypertension (PH) is a pathophysiological disorder that may involve multiple clinical
conditions and can complicate several cardiovascular and respiratory diseases such as left
ventricular dysfunction and chronic obstructive pulmonary disease.
Sarcoidosis is a multisystemic disorder that is characterized by non-caseating granulomas which
are present in multiple tissues, particularly in the lung and lymphatic system. Pulmonary
hypertension (PH; defined as a mean pulmonary artery pressure [PAP] of ≥25 mm Hg at rest
measured by right heart catheterization [RHC]) is increasingly recognized as a serious
complication of pulmonary sarcoidosis and is associated with an increased morbidity and mortality
(Baughman 2010, 2011; Huitema 2016; Kirkil 2018; Shorr 2003; Shlobin 2014).The World Health
Organization (WHO) generally classifies sarcoidosis -associated PH (SAPH) as Group 5 ie, PH
with an unknown and multifactorial mechanism (Galiè 2016; Ryan 2012). Severe untreated PH
carries a poor prognosis and is associated with higher mortality in patients with interstitial lung
diseases and sarcoidosis. Early diagnosis and consideration of treatment options may be key for
improving patient outcomes (Diaz-Guzman 2008). There are no clear data regarding the true
prevalence of SAPH. The proportion of sarcoidosis patients with  PH varies from 5% to 20%
(Huitema 2016).
While there is no approved treatment for SAPH, PH-specific treatments are frequently used,
including endothelin receptor antagonists (ERA; eg, bosentan, ambrisentan, macitentan),
phosphodiesterase type-5 inhibitors (PDE5i; eg, sildenafil), guanylate cyclase agonist (eg,
riociguat), and prostacyclin analogues (eg, i.v. epoprostenol or inhaled iloprost) (Shlobin 2014).
There is evidence from small studies and case series that PH-specific therapies reduce pulmonary
vascular resistance (PVR) and impact other pulmonary hemodynamic parameters in patients with
SAPH. Some of these studies also showed an improvement in WHO functional class (FC), exercise
capacity, or Quality of Life (QoL) (Barnett 2009; Baughman 2009, 2014; FDA Guidance 2003).
Selexipag (JNJ-67896049 [also known as ACT-293987]) is a selective, orally available and long-
acting non-prostanoid agonist of the prostacyclin receptor (IP receptor), approved and
commercially available for the treatment of patients with pulmonary arterial hypertension (PAH)
in the United States (US), the European Union (EU), Japan, and other countries. Selexipag is
currently being investigated for the treatment of SAPH, chronic thromboembolic pulmonary
hypertension (CTEPH), arteriosclerosis obliterans (ASO) with intermittent claudication (IC), and
lumbar spinal stenosis (LSS) with IC (IB selexipag).
The term “study intervention” throughout the protocol, refers to study drug (selexipag or placebo).
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”.
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Status: Approved,  Date: 25 February 2022
2.1. 
Study Rationale
The rationale for this study is based on the unmet medical need for new therapeutic options for
patients with SAPH and is supported by the established efficacy and safety of selexipag in the
PAH indication, the shared pathomechanism between SAPH and PAH, and the available data on
the efficacy and safety of PH-specific therapies in SAPH.
This study will be the first global, randomized, controlled study to explore the efficacy and safety
of selexipag for the treatment of SAPH. The purpose of this study is to assess the efficacy and
safety of selexipag in the studied population.
2.2. 
Background
For the most recent comprehensive quality, nonclinical, and clinical information, refer to the latest
version of the Investigator’s Brochure for selexipag (IB selexipag).
2.3. 
Benefit/Risk Assessment
2.3.1. Known Benefits
The clinical benefits of selexipag for the treatment of SAPH have yet to be established.
2.3.2. Potential Benefits
Efficacy of selexipag in the treatment of adult patients with symptomatic PAH was demonstrated
in the AC-065A302 (GRIPHON) study, a large (N 1,156) randomized long-term, controlled
morbidity/mortality study (Noel 2017; Sitbon 2015). A highly statistically significant effect on the
primary endpoint, risk of first morbidity or mortality event during treatment, was observed: the
hazard ratio versus placebo was 0.60 (99% confidence interval [CI]: 0.46, 0.78, 1-sided unstratified
log-rank p<0.0001), corresponding to a 40% relative risk reduction versus placebo. The treatment
effect was consistent across WHO FC II III and was fully preserved in patients already treated
with an approved PAH-specific medicine at baseline (80% of the study population), as well as in
patients treated with 2 such medicines (30% of the study population). In all analyses, the effect of
selexipag was established early and was sustained over this long-term study, in which the mean
duration of treatment was nearly 1.5 years (and up to 4.2 years). GRIPHON was the first study to
demonstrate the long-term outcome benefit of an oral IP receptor agonist, in particular when added
sequentially to therapies acting on other pathological pathways in PAH (endothelin and nitric oxide
pathways). The study outcome is reflected in the current consensus guidelines for PAH, where
selexipag is the only IP receptor agonist with a Class I evidence recommendation for sequential
drug combination therapy (Galiè 2016).
Given the pathophysiological and clinical similarities between SAPH and PAH, SAPH patients
may benefit from selexipag treatment.
2.3.3. Known Risks
The safety and tolerability of selexipag in patients with SAPH has not yet been evaluated.
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Status: Approved,  Date: 25 February 2022
2.3.4. Potential Risks
The tolerability and safety profile of selexipag administered to SAPH patients is expected to be
consistent with that in adult patients with PAH.
The short- and long-term safety profile of selexipag has been established in PAH patients in the
AC-065A302 (GRIPHON) study conducted in 1,156 participants and is mainly characterized by
prostacyclin-associated adverse events (AEs) associated with the mode of action of selexipag.
Such AEs typically occur during the initial phase of individualized dose titration, and the
susceptibility varies between individuals. Adverse reactions, reflecting the mode of action of
selexipag, included headache, diarrhea, nausea and vomiting, jaw pain, myalgia, pain in extremity,
arthralgia, and flushing.
Other AEs reported more frequently on selexipag compared to placebo included hypotension,
anemia, hyperthyroidism, nasopharyngitis, nasal congestion, decreased appetite, weight decreased,
rash, urticaria, and erythema.
Hypotension was reported more frequently in the selexipag group than in the placebo group (5.0%
and 3.1%, respectively). In the selexipag group, 9.7% of patients had systolic blood pressure (SBP)
˂90 mm Hg on at least 1  occasion, compared to 6.7% in the placebo group. A decrease from
baseline of >40 mm Hg in SBP was reported for 2.3% and 3.0% of patients in the selexipag and
placebo groups, respectively.
Sinus tachycardia was reported more frequently on 12-lead electrocardiogram (ECG) with
selexipag compared to placebo.
Hyperthyroidism was reported more frequently in the selexipag group compared to the placebo
group. Corresponding laboratory changes were a small reduction in thyroid stimulating hormone
(TSH) at most post-baseline visits.
Anemia was reported more frequently in the selexipag group, and a small reduction in hemoglobin
was observed at most post-baseline visits.
2.3.5. Overall Benefit/Risk Assessment
The overall benefit/risk assessment for this clinical study is considered acceptable for the following
reasons:
 
Efficacy and safety of selexipag has been established in the PAH indication.
 
There is an unmet medical need for therapeutic options for patients with SAPH.
 
Given the pathophysiological and clinical similarities between SAPH and PAH, it is
anticipated that SAPH patients could benefit from selexipag treatment.
 
Only participants who meet all inclusion criteria and none of the exclusion criteria (specified
in Section 5) will be allowed to participate in this study. The selection criteria include adequate
provisions to minimize the risk and protect the well-being of participants in the study.
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JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
27
Status: Approved,  Date: 25 February 2022
Safety will be closely monitored throughout the study:
 
In general, safety evaluations (including but not limited to thyroid function tests, blood
pressure monitoring, hematology laboratory tests) will be performed at scheduled visits during
the study, as indicated in the Schedule of Activities.
 
The investigator or the designee will document unsolicited AEs as indicated in Section 10.4.
 
Any clinically significant abnormalities (including those persisting at the end of the
study/early withdrawal) will be followed by the investigator until resolution or until a
clinically stable condition is reached.
Safety measures are included in this protocol to minimize the potential risk to participants,
including the following:
 
Participants will discontinue study intervention for the reasons included in Section 7.1.
 
The study will be closely  monitored by a sponsor Data Monitoring Committee (DMC)
throughout its conduct.
It is the investigator’s responsibility to monitor the individual benefit/risk of study intervention
administration, as well as the degree of distress caused by study procedures at an individual
participant level, and to discontinue study intervention or the study if he/she believes that
continuation would be detrimental to the participant’s well-being.
More detailed information about the known and expected benefits and risks of selexipag may be
found in the latest version of the Investigator’s Brochure (IB selexipag) and in local Product
Information.
3. 
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
 
To assess the effect of selexipag 
versus placebo on pulmonary 
vascular 
resistance 
(PVR) 
in
participants 
with 
sarcoidosis
associated pulmonary hypertension
(SAPH) up to Week 26.
 
PVR on study intervention up to Week 26
expressed as percent of the baseline value.
Exploratory
 
To evaluate the effect of selexipag 
versus placebo on time to clinical 
worsening (TTCW). 
 
TTCW up to end-of-main-observation-period
(EOMOP) defined as at least one of the
following components:
 
All-cause death
 
Unplanned PH-related hospitalization
 
Increase (ie, worsening) in WHO functional
class (FC)
 
Lung transplantation
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JNJ-67896049 / ACT-293987 (selexipag)
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Status: Approved,  Date: 25 February 2022
Objectives 
Endpoints
 
Atrial balloon septostomy
 
Initiation of parenteral or new class of PH-
specific therapy for clinical worsening
 
To evaluate the effect of selexipag
versus placebo on exercise capacity.
 
Change from baseline in 6-minute walk distance
(6MWD), Borg CR Scale® (CR10), oxygen
saturation, and WHO FC at Week 39 and over
time.
 
Proportion 
of participants 
with 
oxygen
desaturation post 6-minute walk test (6MWT) at
Week 39 and over time (identified by decrease
in oxygen saturation [SpO2] by at least 5% from
pre-6MWT).
 
To evaluate the effect of selexipag
vs placebo on daily life physical
activity 
(DLPA) 
and 
sleep
parameters.
 
Change from baseline to Week 39 in actigraphy-
assessed DLPA as measured by:
 
Total DLPA in counts per minute
 
Total volume of activity (above sedentary)
 
Daily time spent (minutes) in non-sedentary
activity
 
Percentage of daily time spent in non-
sedentary activity
 
Moderate to vigorous physical activity
(MVPA)
 
Time spent in the different activity
categories
 
Change from baseline to Week 39 in sleep
parameters:
 
Total sleep time (TST; minutes)
 
Wake after sleep onset (WASO; minutes)
 
Number of awakenings
 
Sleep efficiency (percentage)
 
To evaluate the effect of selexipag
versus placebo on WHO FC.
 
Proportion of participants with improvement,
worsening and no change from baseline in WHO
FC at Week 39 and over time.
 
To evaluate the effect of selexipag
versus placebo on death or PH-
related hospitalizations.
 
Rate of all-cause death or unplanned PH-related
hospitalization up to EOMOP.
 
Time to all-cause death up to EOMOP.
NCT03942211


JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
Objectives 
Endpoints
 
To evaluate the effect of selexipag 
versus placebo on patient-reported 
outcomes (PROs) assessed by the
12-Item Short Form Health Survey
(SF-12), 
King’s 
sarcoidosis
questionnaire (KSQ), Pulmonary 
Arterial 
Hypertension-Symptoms 
and Impact (PAH-SYMPACT), and
Patient Global Assessment of
Severity (PGA-S).
 
Change from baseline up to Week 39 in SF-12
scores.
 
Change from baseline up to Week 39 in KSQ
scores.
 
Change from baseline up to Week 39 in
PAH-SYMPACT scores.
 
Change from baseline up to Week 39 in PGA-S
scores.
 
To evaluate the effect of selexipag 
versus placebo on clinician-reported 
outcomes (CROs) assessed by the
Clinician Global Impression of
Severity (CGI-S) and Clinician
Global Impression of Change (CGI-
C).
 
Change from baseline up to Week 39 in CGI-S
scores.
 
Change from baseline up to Week 39 as
measured by CGI-C scores.
 
To evaluate the effect of selexipag 
on the number of PH low-risk 
criteria. 
 
Absolute and change from baseline in the
number of low-risk criteria based on WHO FC,
6MWD, N-terminal pro B-type natriuretic
peptide (NT-proBNP), and Cardiac Index (CIn)
up to Week 26.
 
To evaluate the effect of selexipag 
on NT-proBNP. 
 
Change from baseline in NT-proBNP serum
levels up to Week 39.
 
To evaluate the effect of selexipag 
on disease and pathway-related 
serum biomarkers. 
 
Change from baseline in serum biomarkers and
associations between serum biomarker levels
and 
clinical 
response 
and 
baseline
characteristics up to Week 39.
 
To 
evaluate the 
change 
in 
hemodynamic variables other than 
PVR. 
 
Change from baseline in other hemodynamic
variables (including cardiac output [CO], CIn,
mean right atrial pressure [mRAP], mean
pulmonary arterial pressure [mPAP], and mixed
venous oxygen saturation [SVO2]) up to Week
26.
Safety
 
To assess the overall safety of 
selexipag. 
 
Intervention-emergent AEs.
 
Intervention-emergent prostacyclin-associated
AEs.
 
Serious adverse events (SAEs) up to end-of-
study (EOS).
 
AEs leading to premature discontinuation of
study intervention.
NCT03942211


JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
Objectives 
Endpoints
 
Intervention-emergent AEs of special interest
(eg, hypotension, anemia, hyperthyroidism).
 
Change in vital signs (systolic and diastolic
arterial blood pressure and pulse rate) and body
weight from baseline to all assessed timepoints
during the study.
 
Intervention-emergent 
marked 
laboratory
abnormalities.
 
Change from baseline in forced vital capacity
(FVC) and diffusing capacity of the lung for
carbon monoxide (DLCO).
 
Change from baseline in supplemental oxygen
rate.
 
Change from baseline in arterial blood gas
parameters.
Refer to Section 8for evaluations related to endpoints.
HYPOTHESIS
The reduction in PVR after 26 weeks of treatment with selexipag is superior to placebo in
participants with SAPH.
4. 
STUDY DESIGN
4.1. 
Overall Design
This is a prospective, randomized, double-blind (DB), placebo-controlled, multicenter,
interventional study in men and women ≥18 and ≤75 years of age with SAPH. Study intervention
will be up-titrated to allow each participant to reach their individual maximum tolerated dose
(iMTD), in the range of 200 µg to 1,600 μg twice daily. For participants with moderate hepatic
impairment (Child-Pugh Class B) or who are concomitantly taking (a) moderate cytochrome P450
(CYP)2C8 inhibitor(s) the dosing frequency is once daily. Diagrams of the study design  and
titration are provided in Figure 1 and Figure 2, respectively.
Approximately 74  participants will be randomized in a 1:1 ratio to receive either selexipag or
placebo. Randomization will be stratified by PH-specific therapies at baseline (yes vsno).
The study starts with the first informed consent form (ICF) signed by the first participant and ends
with the last safety follow-up telephone call (TC) or visit of the last participant. The study
comprises the following periods:
 
A screening period of up to 30 days: starts with the signature of the ICF and ends with the
participant’s randomization at Visit 2, Day 1. The screening period should last at least 14 days
to allow collection of baseline data for daily life physical activity (DLPA), sleep parameters
and PAH- SYMPACT™(Section 10.7).
NCT03942211


JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
 
Intervention and observation periods:
 
A main observation period (MOP) which starts with the participants randomization at
Visit 2, Day 1 and with a titration phase of up to 12 weeks. Participants receive double-
blind study intervention (selexipag or placebo) during this period. It ends on the day of
the EOMOP visit. The EOMOP visit is the data cut-off for the primaryefficacy and safety
analyses. The EOMOP visit for all participants is planned 39 Weeks ±1 month after
randomization of the last participant. The duration of the MOP will be different for each
individual participant and will depend on the time of each participant’s individual date of
randomization.
o 
Participants who prematurely discontinue study intervention before the EOMOP visit
will continue to perform visits and assessments as scheduled until the EOMOP visit
(see Section 1.3.2).
o 
For participants who prematurely discontinue study intervention before the EOMOP
visit and who disagree to perform visits and assessments as scheduled until the
EOMOP visit long-term -follow-up information regarding their survival status will
be collected yearly until death or the time of EOMOP.
o 
Information on the required procedures to follow if participants discontinue the study
intervention prematurely is provided in Section 1.3.2 and Section 7.1.
 
A DB extension period extending intervention for participants who do not prematurely
discontinue study intervention before EOMOP. The period starts in the evening of the
day of the EOMOP visit and ends with the end-of-treatment (EOT) visit. This period will
last approximately 5 months. All participants entering the DB extension period will
continue taking study intervention (selexipag or placebo) during this period. Study
intervention allocation will be unblinded approximately 1 month before the expected
EOT visit. The EOT visit may be performed at any time during the 1 month following
unblinding.
 
A safety follow-up period starting on the day after the last dose of study intervention  and
ending with the safety follow-up call at the EOS visit. For an individual participant, EOS visit
is defined as follows:
 
For participants who complete the treatment, EOS visit is defined as the safety follow-up
visit (TC) 30 (+5) days after last dose of study intervention.
 
For participants who prematurely discontinue study intervention for any reason before
EOMOP visit (except for withdrawal from the study as defined in Section 7.2) but
complete the main observation period (see Section 4.4.2), EOS visit corresponds to the
last visit, which is either the EOMOP visit or the safety follow-up TC, whichever occurs
last (see Schedule of Activities).
 
For participants who prematurely discontinue study intervention for any reason before
the EOMOP visit and who decline to continue with visits and assessments up to the
EOMOP visit, but agree to the collection of long-term survival information, the EOS visit
corresponds to the last visit or TC  before study discontinuation (see Schedule of
Activities).
NCT03942211


JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
32
Status: Approved,  Date: 25 February 2022
 
For participants who prematurely discontinue study intervention between the EOMOP
and EOT visits for any reason (except for withdrawal from the study as defined in Section
7.2), the EOS visit corresponds to the safety follow-up TC (see Schedule of Activities).
 
For participants who complete the treatment and who are entering a continued access
program (ie, other open-label extension study  or post-trial access), the EOS visit is
defined as the EOT visit and enrollment in the continued access program must occur on
the day of the last visit in the SPHINX study.
The duration of individual participation in the study will be different for each participant (between
approximately 15 months and up to approximately 3.5 years), and will depend on the time of each
participant’s individual date of entry into the study and the total recruitment time.
The visit schedule and protocol-mandated procedures are performed according to the Schedule of
Activities.
The efficacy assessments include, but are not limited to, RHC at Week 26, assessment of exercise
capacity, dyspnea, WHO FC, measurement of the NT-proBNP levels, recording PROs and CROs.
Refer to Section 8.2 for more information.
Safety and tolerability will be evaluated throughout the study from signing of the ICF onwards
until the EOS visit (see Section 4.4.1) or date of last contact (see Section 7.3). Safety and
tolerability assessments include review of concomitant medications and AEs, clinical laboratory
tests, ECG, vital signs, physical examination, pulmonary function tests, DLCO, oxygen saturation
and pregnancy testing. Refer to Section 8.3 and Section 8.3.5 for more information.
Plasma and serum samples will be collected and archived for future analysis of disease or pathway-
related biomarkers. Refer to Section 8.5 for more information.
There are two Analysis Timepoints (see Section 9.3 for detailed information):
 
Analysis Timepoint 1 (final analysis for the primary endpoint and all supportive efficacy
endpoints): When all participants have completed the EOMOP visit, or survival information
is available (or if participants have discontinued the study prematurely). At this timepoint, the
primary analysis of the PVR endpoint will be conducted. Data for all other endpoints will also
be analyzed. After the database lock for the MOP is done, the study team will be unblinded.
 
Analysis Timepoint 2 (additional follow-up): When all participants have completed the study
(EOS) or discontinued the study prematurely. At this timepoint, the additional safety data
collected during the DB extension period will be reported.
A sponsor DMC, SC and CEC will be established (see Section 10.3).
The sponsor DMC has overall responsibility for safeguarding the interests of participants and will
review safety data throughout the study (see Section 9.6). The sponsor DMC will provide
recommendations to the study team.
An SC is involved in the study design and will provide guidance on the study conduct and study
publications. Refer to Section 10.3 Appendix 3 for more information.
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JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
The CEC will be a sub-committee of the SC that will review and adjudicate the following cases:
hospitalization, WHO FC increase (ie, worsening), and initiation of PH-specific therapy. Refer to
Section 10.3 for more information. A diagram of the study design is provided in Section 1.2,
Schema.
4.2. 
Scientific Rationale for Study Design
Rationale for the Use of Placebo/Randomization/Stratification/Blinding
A placebo-controlled study conducted in a randomized and DB fashion will be used to evaluate
the efficacy of selexipag and will allow to establish the frequency and magnitude of changes in
hemodynamic and clinical endpoints that may occur in the absence of active intervention. The use
of a placebo control will also allow proper evaluation of any safety related events or abnormalities
and disease progression observed during the study and to differentiate between events potentially
related to the use of selexipag vs those related to the underlying disease.
A placebo-controlled study is considered ethically acceptable due to the lack of approved treatment
for SAPH. The use of background therapy with PH-specific therapies (excluding prostanoids,
prostacyclin analogues and non-prostanoid IP receptor agonists) is allowed. In addition, treatment
escalation of PH-specific therapies is allowed following the Week 39 visit (Visit 6). Stable
treatment for sarcoidosis is also allowed.
Randomization will be used to minimize bias in the assignment of participants to intervention
groups, to increase the likelihood that known and unknown participant attributes (eg, demographic
and baseline characteristics) are evenly balanced across intervention groups, and to enhance the
validity of statistical comparisons across intervention groups.
Blinded intervention will be used to reduce potential bias during data collection and evaluation of
clinical endpoints. Randomization will be stratified by PH-specific therapies at baseline (yes vs
no) to enhance the validity of statistical comparisons across intervention groups and to account for
a potentially different treatment effect in participants already receiving PH-specific therapies
compared to treatment-naïve participants.
Rationale for the Duration of the Study
Participants will receive DB selexipag or placebo until EOT. PVR and other hemodynamic
endpoints will be assessed by RHC at Week 26, which is considered sufficient to observe
hemodynamic changes. Other clinical endpoints, eg, exercise capacity and PROs will be assessed
up to Week 39, and TTCW and rate of hospitalization related to PH-worsening or death will be
assessed up to EOMOP.
The total duration of the study of approximately 3.5 years with variable follow-up time for
individual participants is expected to allow for an evaluation of the TTCW endpoint and the long-
term safety and tolerability endpoints in a blinded fashion.
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JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
In order to be able to estimate the effect of treatment initially assigned at baseline, regardless of
adherence to the planned course of treatment (intent-to-treat principle), participants who
prematurely discontinue the study intervention will be followed up until EOMOP.
Continued treatment with blinded study  intervention for approximately 5 months beyond the
EOMOP visit until the study results are available will allow investigators to make an informed
decision on post-study therapy based on the primary analysis results and the actual intervention
received by the study participants.
Rationale for the Study Population
There is currently no approved treatment for SAPH. SAPH is a serious complication of sarcoidosis
and is associated with increased morbidity and mortality  (clinical worsening), particularly in
precapillary SAPH. Given the evidence from small studies and case studies that PH-specific
therapies reduce PVR and impact other pulmonary hemodynamic variables in patients with
precapillary SAPH, the demonstrated efficacy of selexipag in clinical worsening risk reduction in
PAH, and the hemodynamic similarities between PAH and precapillary SAPH, selexipag may
represent a potential treatment option for this patient population.
Rationale for Right Heart Catherization
Precapillary PH is characterized by an increased resistance to blood flow in the pulmonary
vasculature quantified by PVR. PVR is determined by RHC. Since this procedure is indispensable
for the diagnosis of PH and to evaluate treatment response (Galiè2016), sites treating PH patients
are well experienced with RHC. The study will include sites that are specialized in treating PH
patients and performing RHC. The risk associated with RHC procedures is considered acceptable
for this study as it is reported to be low in centers experienced in treating PH patients and
performing RHC (Hoeper 2006). In addition, a historical RHC is allowed for all participants if it
was performed in accordance with the guidance provided in Section 8.2.1.1.
Rationale for the Primary Endpoint
The choice of PVR as the primary endpoint in this study is based on the prognostic and predictive
value of PVR for clinical outcome in PH and the similarities between precapillary SAPH and PAH.
Rationale for Optional Biomarker Collection
Optional biomarker samples will be collected for exploratory biomarker analyses to evaluate the
biology of SAPH and pulmonary fibrosis, to discover markers of disease severity, to provide a
biological assessment of the response of participants to treatment with selexipag, to analyze
differences between responders and non-responders, and to determine if markers can be used to
classify participants as potential responders prior to treatment. The samples may also be used to
develop tests/assays related to selexipag, SAPH and/or pulmonary fibrosis.
Analyses of biomarkers may be performed at the sponsor’s discretion and reported separately from
this study.
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JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
No human deoxyribonucleic acid (DNA) analyses will be performed on these samples.
4.2.1. Study-Specific Ethical Design Considerations
In the continuing search for efficacious and safe medications, thorough scientific evaluation of any
intervention is an ethical requirement before exposing the target population. This study is being
conducted to evaluate the efficacy and safety of selexipag in participants with SAPH.
Potential participants will be fully informed ofthe 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 informed 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.
There are no specific ethical concerns. The following ethical aspects have been considered: the study
is conducted in a DB fashion using a placebo control group, and PVR is assessed by an invasive
method, RHC. The rationale for these ethical aspects is addressed above.
The measures that are taken to minimize the risks for participants are described in Section 2.3.5.
The total blood volume to be collected from the population over the study period (see Table 2) is
considered to be acceptable based upon WHO recommendations (WHO Guidelines 1994).
4.3. 
Justification for Dose
Study intervention will be up-titrated (see Section 6.1.3) to allow each participant to reach their
iMTD, in the range of 200 µg to 1,600 μg twice daily; or in the range of 200 µg to 1,600 μg once
daily  for participants with  moderate hepatic impairment (Child-Pugh Class B) or who are
concomitantly taking (a) moderate CYP2C8 inhibitor(s). This is in accordance with the approved
regimen and doses per local Product Information. Depending on the iMTD, a single dose of study
intervention will consist of 1 to 8 tablets (200 µg to 1,600 μg).
4.4. 
End-of-Study Definition
4.4.1. EOS Visit
Refer to Section 4.1 for EOS visit definition for individual participants in various scenarios.
NCT03942211


JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
36
Status: Approved,  Date: 25 February 2022
4.4.2. Participant Completion
A participant will be considered to have completed the study if he or she has completed the main
observation period (ie, visits and assessments up to and including the EOMOP visit), whether or
not on study intervention. Participants who prematurely discontinue study intervention and
withdraw from the study (see Section 7.2) will be considered to have not completed the study.
4.4.3. Study Completion
Sites will be informed once the enrollment for the study is completed, ie, last planned participant
randomized.
All ongoing participants, whether or not on study intervention, should be invited to perform their
EOMOP visit (39 weeks [±1 month] after randomization of the last participant).
Final survival information will be collected for participants who prematurely discontinued from
the study except for the reason ‘withdrawal of consent’ (39 weeks [±1 month] after randomization
of the last participant).
The End-of-Study (EOS) at a study level is considered as the last visit or safety follow-up TC (see
Section 4.4.1), whichever occurs last, 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 visit/TC
at that study site, in the time frame specified in the Clinical Trial Agreement.
5. 
STUDY POPULATION
Screening for eligible participants will be performed within 30 days. The screening period should
start at least 14 days before administration of study intervention to allow for collection of baseline
DLPA, sleep parameters, and pulmonary arterial hypertension-symptoms and impact (PAH-
SYMPACT™) data.
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.
It is the responsibility of the investigator/delegate to obtain written informed consent from each
subject participating in this study after adequate face-to-face explanation of the objectives,
methods, and potential hazards of the study. The subjects who agree to participate in the study and
the investigator/delegate must sign the ICF prior to any study-related assessment or procedure. See
Section 10.3 for more information.
Participants who are in Screening when the enrollment target has been met may still be
randomized.
For a discussion of the statistical considerations of participant selection, refer to Section 9.4,
Sample Size Determination.
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. 
Must sign an ICF indicating that he or she understands the purpose of, and procedures
required for, the study and is willing to participate in the study.
2. 
Male or female.
3. 
18 (or the legal age of consent in the jurisdiction in which the study is taking place) to 75
years of age, inclusive, at Screening.
4. 
Confirmed diagnosis of sarcoidosis as per American Thoracic Society (ATS) criteria
(Crouser 2020; Statement on sarcoidosis 1999).
5. 
Sarcoidosis-associated precapillary PH, confirmed by RHC (at rest) within 90 days prior
to randomization:
a. PVR ≥320 dyn*sec/cm5 (≥4.0 Wood units)
b. Mean pulmonary arterial pressure (mPAP) ≥25 mm Hg
c. Pulmonary artery wedge pressure (PAWP) ≤15 mm Hg, or if not available or
unreliable, a left ventricular end diastolic pressure (LVEDP) ≤15 mm Hg.
Note: A historical RHC is allowed taking into account the restrictions provided in
Section 8.2.1.1. If no historical results are available, an RHC must be performed during
the Screening period, but only if all other inclusion criteria are met and none of the
exclusion criteria is met.
6. 
PH severity according to modified WHO FC II IV at Screening and randomization;
participants in WHO FC IV must be in a stable condition and able to perform a 6MWT.
7. 
Criterion modified per Amendment 2
7.1 Either not receiving PH-specific treatment, or receiving PH-specific oral monotherapy
(ie, riociguat or PDE5i or ERA); if on oral PH-specific monotherapy treatment has to be
stable (ie, no introduction of new therapies or changes in dose) for at least 90 days prior
to both the RHC qualifying for enrollment and randomization.
8. 
Criterion modified per Amendment 2
8.1 Stable sarcoidosis treatment regimen, ie, no new specific anti-inflammatory treatment
for sarcoidosis for at least 90 days, and stable dose(s) for at least 30 days prior to both the
RHC qualifying for enrollment and randomization.
9. 
Criterion modified per Amendment 3
9.1 6MWD ≥50 m both at Screening and at the time of randomization.
NOTE: Participants can use their usual walking aids during the test (eg, cane, crutches).
The same walking aid should be used for all 6MWTs. Walkers are not allowed.
NCT03942211


JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
10. 
Criterion modified per Amendment 3
10.1 FVC >50% and FEV1 >50% of predicted at Screening.
NOTE: Short-acting-beta-agonists (eg, salbutamol) and long-acting-beta-agonists must
not be taken 6 hours and 24 hours prior to spirometry testing, respectively.
11. 
Criterion modified per Amendment 3
11.1 DLCO  ≥40% of predicted. If DLCO  <40% of predicted, the extent of emphysema
should not be greater than that of fibrosis as assessed by high resolution CT scan.
NOTE: Short-acting-beta-agonists (eg, salbutamol) and long-acting-beta-agonists must
not be taken 6 hours and 24 hours prior to spirometry testing, respectively.
12. 
For patients enrolled or planned to be enrolled in a cardio-pulmonary rehabilitation
program based on exercise training, one of the following must apply:
 
In the maintenance phase of the program at the time of randomization with no plans
to stop the program until Week 39, or
 
Start of the cardio-pulmonary rehabilitation program based on exercise training is
planned after Week 39.
13. 
A woman must be (as defined in Section 10.5)
a. Not of childbearing potential
b. Of childbearing potential and
o 
Have a negative highly sensitive serum -human chorionic gonadotropin
(-hCG) at Screening and a negative urine pregnancy test at randomization.
o 
Agree to undertake monthly urine pregnancy tests during the study and up
to at least 30 days after study intervention discontinuation.
o 
Practicing an acceptable method of contraception and agreeing to remain on
an acceptable method while receiving study intervention and until 30 days
after last dose of study intervention. Examples of acceptable methods of
contraception are located in Section 10.5.
14. 
Criterion modified per Amendment 3:
14.1 A woman only using hormonal contraceptives must have been using this method for
at least 30 days prior to randomization.
15. 
Willing and able to adhere to the lifestyle restrictions specified in Section 5.3.
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JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
5.2. 
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in the study:
1. 
PH due to left heart disease (PAWP >15 mm Hg).
2. 
PH due to compression of pulmonary arteries and/or pulmonary veins.
3. 
History of left heart failure (LHF) as assessed by the investigator including
cardiomyopathies and cardiac sarcoidosis with a left ventricular ejection fraction
(LVEF) <40%.
4. 
Severe coronary heart disease (CHD) or unstable angina as assessed by the investigator.
5. 
Myocardial infarction within the last 6 months prior to or during Screening.
6. 
Criterion modified per Amendment 2
6.1 Decompensated cardiac failure not receiving optimal medical treatment according to
local guidelines.
7. 
Arrhythmias assessed as severe by the investigator.
8. 
Criterion modified per Amendment 2
8.1 Criterion modified per Amendment 3
8.2 Participants who either are planning to receive an implantable cardioverter
defibrillator (ICD) or who already have one that has delivered shock therapy any time
in the previous 1 year prior to Day 1. Participants with ICD are eligible if no shock
therapy has been delivered in the previous 1 year prior to Day 1.
9. 
Cerebrovascular events (eg, transient ischemic attack, stroke) within the last 90 days
prior to or during Screening.
10. 
Congenital or acquired valvular defects with clinically relevant myocardial function
disorders not related to PH.
11. 
Overt features of pulmonary veno-occlusive disease (PVOD).
12. 
Significant emphysema as assessed by the investigator.
13. 
Criterion modified per Amendment 2
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JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
13.1 Known and documented severe hepatic impairment, eg, Child-Pugh Class C (see
Section 10.13).a
14. 
Severe renal failure (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2
or serum creatinine >2.5 mg/dL) based on central laboratory results from the Screening
blood sample.
15. 
Criterion modified per Amendment 2
15.1 Treatment with prostacyclin, prostacyclin analogues or IP receptor agonists (ie,
selexipag) within 90 days prior to randomization and/or prior to the RHC qualifying for
enrollment, except those given at vasodilator testing during RHC.
16. 
Included on a lung transplant list or planned to be included until Visit 6 / Week 39.
17. 
Known or suspected uncontrolled thyroid disease as per investigator judgment.
18. 
Treatment with moderate inducers of CYP2C8, eg, rifampicin or strong inhibitors of
CYP2C8, eg, gemfibrozil at or within 14 days prior to randomization.
19. 
Change in dose or initiation of new diuretics and/or calcium channel blockers within
1 week prior to RHC qualifying for enrollment.
20. 
SBP <90 mmHg at Screening or at randomization.
21. 
Known allergies, hypersensitivity, or intolerance to selexipag or its excipients (refer to
IB selexipag).
22. 
Planned or current treatment with another investigational interventionup to 90 days prior
to randomization.
23. 
Criterion deleted per Amendment 3
24. 
Any condition for which, in the opinion of the investigator, participation would not be
in the best interests of the participant (eg, compromise well-being), or that could prevent,
limit, or confound the protocol-specified assessments.
25. 
Criterion modified per Amendment 3
25.1 Any acute or chronic impairment that may influence the ability to comply with
study requirements such as to perform RHC, a reliable and reproducible 6MWT, or lung
function tests.
a 
Note: The assessment of hepatic impairment (Child-Pugh Score) must be fully documented for patients who have
clinical signs and evidence (from central and/or local lab) of hepatic impairment (see Section 10.13).
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JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
41
Status: Approved,  Date: 25 February 2022
26. 
Employee of the investigator or study site, with direct involvement in the proposed study
or other studies under the direction of that investigator or study site, as well as family
members of the employees or the investigator.
27. 
Pregnant, breast-feeding, or planning to become pregnant while enrolled in this study or
within 30 days after the last dose of study intervention.
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 randomization 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, Regulatory, Ethical, and Study Oversight Considerations.
5.3. 
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions
during the course of the study to be eligible for participation:
1. 
Refer to Section 6.5, Concomitant Therapy  for details regarding prohibited and
restricted therapy during the study.
2. 
Agree to follow all requirements that must be met during the study as noted in the
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
5.4. 
Screen Failures
For participants who failed Screening, the following additional data will be recorded in the
electronic Case Report Form (eCRF) if available: reason for Screening failure, baseline data
collected until confirmation of the Screening failure.
Individuals who do not meet the criteria for participation in this study (Screening failure) may be
rescreened once, if the reason for non-eligibility was transient (eg, abnormal laboratory test,
insufficient wash-out period of a forbidden medication). All Screening assessments must be
repeated at the time of rescreening. If the Screening RHC was done as per timing requirements
indicated in Section 8.2.1.1.1, it does not need to be repeated. Rescreened participants will be
assigned a different participant number than for the initial Screening.
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.
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JNJ-67896049 / ACT-293987 (selexipag)
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
All reports and communications relating to the study will identify participants by participant
identification and age at initial informed consent. In cases where the participant is not randomized
into the study, the date seen and age at initial informed consent will be used.
6. 
STUDY INTERVENTION
6.1. 
Study Interventions Administered
Manufacturing, labeling, packaging, and supply of study intervention will be conducted according
to Good Manufacturing Practice, Good Clinical Practice (GCP) and any local or national
regulatory requirements.
Selexipag and placebo will be manufactured and provided under the responsibility of the sponsor.
Refer to the IB selexipag for a list of excipients.
All study intervention supplies are to be used only in accordance with this protocol and not for any
other purpose.
Study intervention is labeled to comply with the applicable laws and regulations of the countries
in which the study sites are located. Labels must remain affixed to the bottles.
6.1.1. Description of Study Interventions
Selexipag 200 μg andmatching placebo will be provided as identical yellow, round, non-debossed,
film-coated tablets in childproof bottles containing 120 tablets.
6.1.2. Study Intervention Administration
The tablets are administered orally and should be swallowed whole (ie, not crushed, split or
chewed) with water.
Dosing frequency will be twice daily, except for participants with moderate hepatic impairment
(Child-Pugh Class B) or who are concomitantly taking (a) moderate CYP2C8 inhibitor(s), for
whom the dosing frequency is once daily.
In case of twice daily dosing, at the beginning of each up-titration step, the first dose is to be taken
in the evening. In case of once daily dosing, participants must take the study intervention in the
morning; hence the first dose of study intervention should be taken in the morning of Day 2.
Beginning with the morning of Visit 3, and at each visit thereafter up to the EOMOP visit,
participants must take the morning study intervention dose before any visit-related procedure and
preferably at the site. Tolerability may improve when study intervention is taken with food.
For the definition of study intervention overdose, refer to Section 6.8, Treatment of Overdose.
Study intervention administration must be captured in the source documents and the eCRF. Study
site personnel will instruct participants on how to store study intervention for at home use as
indicated for this protocol.
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Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
6.1.3. Study Intervention Up-titration
Study intervention will be up-titrated to allow each participant to reach their iMTD, in the range
of 200 µg to 1,600 μg (ie, 1 to 8 tablets) twice daily/once daily. Dosing frequency will be twice
daily, except for participants with moderate hepatic impairment (Child-Pugh Class B) or who are
concomitantly taking (a) moderate CYP2C8 inhibitor(s), who receive study intervention once
daily.
Each participant will start with 1 tablet of study intervention, ie, selexipag (200 μg) or matching
placebo, in the evening of Day 1 and will continue with 200 μg twice daily on Day 2. Participants
with moderate hepatic impairment (Child-Pugh Class B) or who are concomitantly taking (a)
moderate CYP2C8 inhibitor(s) will start with 200 µg once daily in the morning of Day 2.
The dose will be up-titrated by the investigator/delegate in 200 μg twice daily/once daily
increments at weekly intervals during scheduled TCs until reaching the iMTD (see Table 1 and
Figure 2).
If the dose regimen is not well tolerated or symptoms cannot be fully managed with symptomatic
treatment (refer to Section 6.5 for information on the allowed concomitant medication), the
duration of the titration step can be prolonged to 2 weeks. If needed, the dose can be reduced by
200 μg twice daily/once daily.
The decision to not further up-titrate the dose will be based on the investigator’s medical judgment
based on the occurrence and severity of typical pharmacological effects of IP  receptor agonists
and the participant’s individual tolerability (see also Section 2.3.4 and IB selexipag). At Week 12
(Visit 3), the twice daily/once daily dose reached for each participant is defined as the iMTD. This
dose must be kept stable at least until Week 39 (Visit 6) but can be adjusted for safety and
tolerability reasons.
Any study intervention interruption of 3 days or more will require a new up-titration to avoid
tolerability-limiting side effects (see Section 7.1.1).
After Week 39, it is permitted to further up-titrate the dose for the participant, if necessary (up to
the maximum of 1,600 μg twice daily/once daily, as applicable) in 200 μg twice daily/once daily
increments at scheduled or unscheduled visits. Starting with Visit 3 and at all consecutive Visits
up to and including the EOMOP Visit, 6MWT and RHC must be performed within 2 to 5 hours
post-dose.
Table 1: 
Study Intervention Up-titration Scheme
Period 
Dose regimen 
Duration
First dose 
200 μg 
On Day 1 in the evening (pm) 
1 tablet
Up-titration  
200 μg twice daily*,§ 
From Day 2 am to Day 8 am** 
1 tablet twice daily§
400 μg twice daily*,§ 
From Day 8 pm to Day 15 am** 
2 tablets twice daily§
600 μg twice daily*,§ 
From Day 15 pm to Day 22 am** 
3 tablets twice daily§
800 μg twice daily*,§ 
From Day 22 pm to Week 4 am** 
4 tablets twice daily§
1,000 μg twice daily*,§ 
From Week 4 pm to Week 5 am** 
5 tablets twice daily§
1,200 μg twice daily*,§ 
From Week 5 pm to Week 6 am** 
6 tablets twice daily§
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JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
Period 
Dose regimen 
Duration
1,400 μg twice daily*,§ 
From Week 6 pm to Week 7 am** 
7 tablets twice daily§
1,600 μg twice daily*,§: 
From Week 7 pm to Week 12 am** 
8 tablets twice daily§
Maintenance 
iMTD: 
200 µg to 1,600 μg twice daily§
From Week 12 onwards 
1–8 tablets twice daily§
am  morning;; iMTD  individual maximum tolerated dose; pm  evening.
* Or the iMTD until Week 12.
** If the dose regimen is not well tolerated or symptoms cannot be fully managed with symptomatic treatment, the duration of
the titration step can be prolonged to 2 weeks.
§ For participants with moderate hepatic impairment (Child Pugh Class B) or who are concomitantly taking (a) moderate
CYP2C8 inhibitor(s) the dosing frequency is once daily. These participants must take the study intervention in the morning;
hence the first dose of study intervention should be taken in the morning of Day 2.
6.2. 
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
Study intervention supplies must be kept in an appropriate, secure area and stored according to the
conditions specified on the label. Refer to the pharmacy manual/study site investigational product
and procedures manual for additional guidance on study intervention preparation, handling, and
storage.
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 (number
of dispensed bottles and date dispensed/number of tablets dispensed) to the participant, and the
return of study intervention (date returned/number of tablets returned) from the participant (if
applicable), must be documented on the intervention accountability form. Participants must be
instructed to return all original containers, whether empty or containing study intervention. All
study intervention will be stored and disposed of according to the sponsor’s instructions. Study
site personnel must not combine contents of the study intervention containers. If the participant
forgets to bring the remaining study intervention to a study visit, he/she must be instructed to not
take any tablets from the remaining study intervention bottle and to return it at the next visit.
Study intervention must be handled in strict accordance with the protocol and the container label,
and must be stored at the study site in a limited-access area or in a locked cabinet under appropriate
environmental conditions. Unused study intervention, and study intervention returned by the
participant, must be available for verification by the sponsor’s study site monitor during on-site
monitoring visits. The return to the sponsor of unused study intervention, or used returned study
intervention for destruction, will be documented on the intervention return form. When the study
site is an authorized destruction unit and study intervention supplies are destroyed on-site, this
must also be documented on the intervention return form.
Potentially hazardous materials such as, but not limited to, used ampules, needles, syringes and
vials containing hazardous liquids, should be disposed of immediately in a safe manner and
therefore will not be retained for intervention accountability purposes.
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Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
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 participating in the study. The participants will receive sufficient study
intervention to cover the period up to the next scheduled visit. Returned study intervention must not
be dispensed again, even  to the same participant. Study intervention may not be relabeled or
reassigned for use by other participants. The investigator agrees neither to dispense the study
intervention from, nor store it at, any site other than the study sites agreed upon with the sponsor.
6.3. 
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Participants will be randomly assigned
to 1 of 2 intervention groups based on a computer-generated randomization schedule prepared
before the study by or under the supervision of the sponsor. The randomization will be balanced
by using randomly permuted blocks and will be stratified by PH-specific therapy at baseline (yes
vs no). The Interactive Web Response System (IWRS) will assign a unique intervention code,
which will dictate the intervention assignment and matching study intervention kit for the
participant. The requestor must use his or her own user identification and personal identification
number when contacting the IWRS, and will then give the relevant participant details to uniquely
identify the participant.
Blinding
This study will be performed in a DB fashion.
The investigator will not be provided with randomization codes. The codes will be maintained
within the IWRS, which has the functionality to allow the investigator to break the blind for an
individual participant.
Data that may potentially unblind the intervention assignment will be handled with special care to
ensure that the integrity of the blind is maintained and the potential for bias is minimized. This can
include making special provisions, such as segregating the data in question from view by the
investigators, clinical study team, or others as appropriate until after the time ofthe database lock
(see Section 9.3) and unblinding.
Under normal circumstances, the investigator and study personnel, the participants, sponsor
personnel directly involved in the conduct of the trial, and CRO personnel involved in the conduct
of the study will remain blinded to the study intervention until after completion of the first analysis
timepoint (see Section 9.3), or until the study is stopped prematurely. In order to preserve the blind
of each individual participant until the primary analysis (see Section 4.1), the randomization codes
and, if required, the translation of randomization codes into intervention and control groups will
be disclosed to those authorized and only for those participants included in the analyses for the
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Status: Approved,  Date: 25 February 2022
sponsor DMC. A statistical support group (SSG) independent from the study team will conduct
the analyses and present unblinded results to the sponsor DMC (see Section 9).
The investigator may in an emergency determine the identity of the intervention by contacting the
IWRS. While the responsibility to break the intervention  code in emergency situations resides
solely with the investigator, it is recommended that the investigator contact the sponsor or its
designee, if possible, to discuss the particular situation before breaking the blind. Telephone
contact with the sponsor or its designee will be available 24 hours per day, 7 days per week. In the
event the blind is broken, the sponsor must be informed as soon as possible. The date, time, and
reason for the unblinding must be documented in the Investigator Site file and in the appropriate
section of the eCRF, and in the source document. The documentation received from the IWRS
indicating the code break must be retained with the participant’s source documents in a secure
manner.
If a suspected unexpected serious adverse reaction (SUSAR) occurs for a participant in the study,
unblinded SUSAR information will be provided to respective health authorities and Independent
Ethics Committees (IECs) or Institutional Review Boards (IRBs) only. SUSARs will be reported
to investigators in a blinded fashion. The intervention assignment will not be communicated to site
personnel or to sponsor study team (see Section 8.4.3).
Participants who have had their intervention assignment unblinded may stay on study intervention
after unblinding provided the following conditions are met: emergency unblinding for accidental
or intentional overdose or medication error.
6.4. 
Study Intervention Compliance
Study intervention compliance is based on study intervention accountability  (see Section 6.2).
Study intervention compliance will be calculated by site personnel at each visit using the below
formula and documented in the source data:
Compliance  [(number of tablets dispensed  number of tablets returned) / total number of tablets
that should have been taken during the period] × 100.
Between visits and overall study compliance are expected to be between 80% and 120%. 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.
6.5. 
Concomitant Therapy
Prestudy therapies administered up to 30 days before first dose of study intervention  and any
previous therapies for the treatment of PH (ERA, PDE5i, riociguat) and sarcoidosis (eg, infliximab,
methotrexate, azathioprine, hydroxychloroquine, leflunomide, steroids) administered up to
90 days before the baseline RHC and 90 days before randomization, respectively, must be recorded
in the eCRF at time of Screening.
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Clinical Protocol AC-065D301 Amendment 3
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Status: Approved,  Date: 25 February 2022
Concomitant medications, except those listed below, are allowed during this study. Concomitant
therapies must be recorded in the eCRF throughout the study from signing of the ICF onwards
until the EOS visit (see Section 4.4.1) or date of last contact (see Section 7.3).
All therapies (oxygen supplementation, prescription or over-the-counter medications, including
vaccines, vitamins, herbal supplements; non-pharmacologic therapies such as electrical
stimulation, acupuncture, special diets, exercise regimens) different from the study intervention
must be recorded in the eCRF. Recorded information will include a description of the generic
name, start/end dates of administration (as well as whether it was ongoing at start of intervention
and/or EOS), route, dose, frequency and indication.
For any concomitant therapy given as a treatment for a new condition or a worsening of an existing
condition, the condition must be documented in the AE section of the eCRF.
Modification of an effective pre-existing therapy should not be made for the explicit purpose of
entering a participant into the study.
The following medications and/or therapies are not allowed to be administered concomitantly with
study intervention:
 
Prostacyclin (epoprostenol), prostacyclin analogues (eg, treprostinil, iloprost, beraprost) or
prostacyclin receptor agonists (ie, selexipag/UPTRAVI®) until study intervention
discontinuationand if possible up to the post-baseline RHC at premature EOT before Week 26
(see Section 8.2.1.1.2).
 
Strong inhibitors of CYP2C8 (eg, gemfibrozil) until study intervention discontinuation.
 
Change in dose or initiation of new diuretics and/or calcium channel blockers within 1 week
prior to RHC at Week 26.
 
Any other investigational drug up to 30 days after study intervention discontinuation.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
Medications and/or therapies allowed to be administered concomitantly with study intervention,
include, but are not limited to:
 
Stable doses of PH-specific monotherapies (ie, riociguat, PDE5i, or ERA). Change in dose or
initiation of new therapies for the treatment of PH are allowed as of Week 39 (Visit 6).
 
Short-acting-beta-agonists (eg, salbutamol) and long-acting-beta-agonists, but must not be
taken within 6 hours and 24 hours prior to spirometry testing, respectively.
 
Single administration of prostacyclin or analogues used for acute vasodilator testing during
an RHC procedure.
 
Moderate inhibitors of CYP2C8. Dosing frequency of study intervention must be reduced to
once daily if a moderate inhibitor of CYP2C8 (eg, clopidogrel, deferasirox, teriflunomide,
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Status: Approved,  Date: 25 February 2022
leflunomide) is concomitantly administered. Dosing frequency of selexipag should be
reverted to twice daily when co-administration of moderate CYP2C8 inhibitor is stopped.
 
Sarcoidosis-specific 
treatment, 
eg, 
infliximab, 
methotrexate, 
azathioprine,
hydroxychloroquine, leflunomide, steroids. Initiation of new treatment or change in dose is
allowed as of Week 39 (Visit 6).
 
Strong inhibitors of UGT1A3 and UGT2B7 (eg, valproic acid, probenecid, and fluconazole).
The effect of strong inhibitors of UGT1A3 and UGT2B7 on the exposure to selexipag and its
active metabolite has not been studied. Caution is required when administering these
medicinal products concomitantly with selexipag. A potential pharmacokinetic interaction
with strong inhibitors of UGT1A3 and UGT2B7 cannot be excluded.
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).
For participants who are unable to tolerate the protocol-specified dosing scheme, dose adjustments
must follow the down-titration instructions (see Section 6.1).
6.7. 
Intervention After the End of the Study
After the participant has completed or discontinued the study, the investigator/delegate will explain
to the participant what treatment(s)/medical care is necessary and available according to local
regulations. If considered by the investigator to be in the best interests of the participant, the
investigator can ask the sponsor to provide participants who completed the study and did not
prematurely discontinue study intervention with selexipag. In this case, selexipag can be provided
until access to commercial selexipag is possible in this indication in the participant’s country of
residence (according to local regulatory requirements), until selexipag can be accessed through
another source in the country where he/she is living, or until the sponsor terminates clinical
development of selexipag in this indication.
Investigators may re-contact the participant to obtain long-term follow-up information regarding
the participant’s safety or survival status as noted in the ICF (refer to Informed Consent in
Section 10.3).
6.8. 
Treatment of Overdose
Overdose is defined by the intake of any single dose greater than 1,600 μg or a total daily dose
greater than 3,200 μg (only in case subjects are on a twice daily regimen) (IB selexipag). For
participants with moderate hepatic impairment or who are concomitantly taking moderate
CYP2C8 inhibitor(s) the dosing frequency is once daily and overdose is defined by the intake of a
dose >1,600 μg or a total daily dose >1,600 μg.
Isolated cases of overdose up to 3,200 μg have been previously reported. Mild, transient nausea
was the only reported consequence.
In the event of an overdose, the investigator or treating physician should:
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Status: Approved,  Date: 25 February 2022
 
Contact the Medical Monitor immediately.
 
Evaluate the participant to determine, in consultation with the Medical Monitor, whether study
intervention should be interrupted or whether the dose should be reduced.
 
Closely monitor the participant for AE/SAE and laboratory abnormalities until selexipag can
no longer be detected systemically (at least 3 days).
 
Document the quantity of the excess dose as well as the duration of the overdosing in the
eCRF.
 
Institute supportive therapy as clinically indicated. Dialysis is unlikely to be effective because
selexipag and its active metabolite are highly protein bound.
For more information see Section 10.4.
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1. 
Discontinuation of Study Intervention
The decision to prematurely discontinue study intervention may be made by the participant, the
investigator or sponsor personnel. A participant has the right to prematurely discontinue study
intervention at any time, without any justification, by withdrawal from study intervention only or
by withdrawal from any further participation in the study. The investigator must discontinue study
intervention for a given participant if, on balance, he/she believes that continued administration
would be contrary to the best interests of the participant.
A participant’s study intervention must be discontinued if:
 
The investigator considers that for safety reasons or tolerability reasons (eg, AE) it is in the
best interests of the participant to discontinue study intervention.
 
The participant becomes pregnant. Refer to Section 10.5, Contraceptive Guidance and
Collection of Pregnancy Information.
 
If hepatic impairment is suspected, a clinical assessment of severity (eg, Child-Pugh score)
must be performed and fully documented. If a subject has developed severe hepatic
impairment (Child-Pugh Class C) at any time during the study, the study intervention must be
permanently discontinued (see Section 10.13).
 
Pulmonary edema due to PVOD  occurs. Should signs of pulmonary edema occur, the
possibility of associated PVOD should be considered. If confirmed, the study intervention
must be discontinued.
 
Study intervention interruptions exceeding 14 consecutive days.
 
The participant withdraws consent to receive study intervention.
If a participant discontinues study intervention prematurely before the EOMOP visit, he/she will
continue to perform the visits and assessments as scheduled until the EOMOP visit, provided the
participant’s consent for this limited participation in the study has not been withdrawn (see
Section 7.2). The participant will be asked to return for the premature EOT visit within 7 days of
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last intake of study intervention and for a safety follow-up TC 30 (+5) days after the last intake of
study intervention. If the premature EOT visit falls within the visit window of any other scheduled
visit, these visits can be combined, and assessments will not be repeated.
If a participant discontinues study intervention prematurely before the EOMOP visit and does not
agree to continue to perform the visits and assessments as scheduled until the EOMOP visit, he/she
will be asked to return for the premature EOT visit within 7 days of last intake of study intervention
and for a safety follow-up TC 30 (+5) days after the last intake of study intervention, provided the
participant’s consent for this limited participation in the study has not been withdrawn. Long-term
survival follow-up information will be collected yearly until death or the time of EOMOP (see
Section 7.2 and Section 8.2.2.2).
If a participant discontinues study intervention prematurely after EOMOP but before the study
results are available and the treatment assignment is unblinded, he/she will be asked to return for
the premature EOT visit within 7 days of last intake of study intervention and for a safety follow-
up TC 30 (+5) days after the last intake of study intervention, provided the participant’s consent
for this limited participation in the study has not been withdrawn.
If the reason for withdrawal from the study is withdrawal of consent, then no additional
assessments are allowed.
7.1.1. Temporary Discontinuation
Study intervention may be temporarily interrupted in response to an AE, a diagnostic or therapeutic
procedure, a laboratory abnormality, or for administrative reasons.
Interruptions of study intervention must be kept as short as possible. Any study intervention
interruption of 3 days or more will require a new up-titration starting with 1 tablet of study
intervention (200 μg) twice daily/once daily. For each participant, the up-titration frequency will
be up to the medical judgment of the investigator and based on his/her clinical evaluation of the
participants’ tolerability of the study drug prior to its interruption  (see Section 6.1.2). Re-
uptitration to a previously reached dose can be done at scheduled or unscheduled TCs or visits,
respectively.
Study intervention interruptions exceeding 14 consecutive days must lead to permanent
discontinuation of study intervention (see Section 7.1).
Interruptions of 1 day or more must be recorded in the eCRF.
7.2. 
Participant Discontinuation/Withdrawal from the Study
A participant will not be automatically withdrawn from the study if they have to discontinue study
intervention before EOT (see Section 7.1).
A participant will be withdrawn from the study for any of the following reasons:
 
Lost to follow-up.
 
Withdrawal of consent.
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Death.
 
Participant is poorly compliant with study procedures, visits, and assessments, preferably after
evaluation and discussion between the investigator and the sponsor.
 
The investigator considers that continued participation in the study would be contrary to the best
interests of the participant.
 
Sponsor’s decision for any reason, including, but not limited to premature termination or
suspension of the study.
If a participant discontinues study intervention and withdraws from the study before completing
the study (see Section 4.4.2) for any reason (except for death or withdrawal of consent), every
attempt should be made to schedule a last appointment/TC to assess the safety and well-being of
the participant, collect unused study intervention and discuss follow-up medical care. If the reason
for withdrawal from the study is withdrawal of consent, then no additional assessments are
allowed. The investigator must provide follow-up medical care for all participants who are
prematurely withdrawn from the study, or must refer them for appropriate ongoing care, as
described in Section 6.7.
A participant who prematurely discontinues study intervention before the EOMOP visit and
declines 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, continuing with survival follow-up, consulting with family members, contacting the
participant’s other physicians, medical records, database searches, and use of locator agencies at
study completion), as local regulations permit.
Refer to Section 7.3 for more information on the required procedure to follow if a participant is
lost to follow-up.
When a participant withdraws before completing the study, the reason for withdrawal is to be
documented in the eCRF and in the source document.
Study intervention assigned to the withdrawn participant may not be assigned to another
participant.
If participants prematurely discontinue study intervention or withdraw consent, participants will
not be replaced.
7.2.1. Withdrawal From the Use of Research Samples
A participant who withdraws from the study will have the following options regarding the optional
research samples:
 
The collected samples will be retained and used in accordance with the participant’s original
separate informed consent for optional research samples.
 
The participant may withdraw consent for optional research samples, in which case the
samples will be destroyed and no further testing will take place. To initiate the sample
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destruction process, the investigator must notify the sponsor study site contact of withdrawal
of consent for the optional research samples and to request sample destruction. The sponsor
study site contact will, in turn, contact the biomarker representative to execute sample
destruction. If requested, the investigator will receive written confirmation from the sponsor
that the samples have been destroyed.
Withdrawal From the Optional Research Samples While Remaining in the Main Study
The participant may withdraw consent for optional research samples while remaining in the study.
In such a case, the optional research samples will be destroyed. The sample destruction process
will proceed as described above.
Withdrawal From the Use of Samples in Future Research
The participant may withdraw consent for use of samples for research (refer to Long-Term
Retention of Samples for Additional Future Research in Section 10.3, Regulatory, Ethical, and
Study Oversight Considerations). In such a case, samples will be destroyed after they are no longer
needed for the clinical study. Details of the sample retention for research are presented in the main
ICF.
7.3. 
Lost to Follow-up
To reduce the chances of a participant being deemed lost to follow-up attempts should be made,
prior to randomization 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. These contact attempts should be documented in the participant’s medical
records.
 
Should the participant continue to be unreachable, they will be considered lost to follow-up,
and hence will be withdrawn from the study (see Section 7.2).
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8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities summarizes the frequency and timing of efficacy, safety, andbiomarker
measurements applicable to this study. For all visits, the participants must be seen or called on the
designated day with an allowed visit window per the Schedule of Activities. If it is not possible to
complete all assessments on the same day, a visit may extend over more than 1 day within the
allowed time window.
The following order of assessments is recommended, as applicable:
1) PROs completed at each site Visit: SF-12, King’s SQ, PGA-S
2) Investigator to complete CGI-S and CGI-C
3) Safety assessments (see Section 8.3 for the order of safety assessments)
4) Pulmonary function tests
5) WHO FC
6) 6MWT* and oxygen saturation and Borg CR Scale® (CR10) (pre- and post-6MWT)
7) Blood samples for hematology, and clinical chemistry tests, NT-proBNP, and/or biomarkers
8) Arterial Blood Gas analysis (if possible, during RHC)
9) RHC*
*Assessments to be performed within 2 to 5 hours post-dose.
Actual dates and times of assessments (where applicable) will be recorded in the eCRF.
All study assessments are performed by qualified study personnel (medical, nursing or specialist
technical personnel) and are recorded in the eCRF, unless otherwise specified.
The maximum total blood volume to be collected during the entire study from each participant will
vary depending on when the patient enters the study. The total blood volume (excluding the serum
-hCG pregnancy test and arterial blood gas) to be collected at each visit from screening to
Week 39/Visit 6 and from Week 65/Visit 7 until EOT will be approximately 21.5 mL and 9.5 mL,
respectively (see Table 2). An additional 1 mL to 3 mL of blood may be collected during RHC to
measure CO according to Fick’s method.
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Table 2: 
Volume of Blood to be Collected From Each Participant per Visit
Type of Sample 
Volume per Sample 
(mL) 
Volume per sample 
(mL) at each Visit until 
Visit 6e 
Volume per sample
(mL) at each Visit from
Visit 7 to EOTe
Safety (including
Screening and post-
intervention assessments)
- Hematology  
2 
2 
2
- Serum chemistryb 
7.5 
7.5 
7.5
- NT-proBNPg 
2.5 
2.5 
0
- Serum -hCG
pregnancy testsd
2.5 
2.5 
2.5
Exploratory biomarker
plasma samplec,h
4.5 
4.5 
0
Exploratory biomarker
serum samplec,h 
5 
5 
0
Arterial Blood Gasf 
2 
2 
0
Approximate Total per
Visita
21.5 
9.5
 hCG   human chorionic gonadotropin; EOT = end-of-treatment; NT proBNP  N terminal pro b type natriuretic
peptide.
a. The approximate total per visit does not include the required volume for the serum -hCG pregnancy test and
the arterial blood gas.
b. See Section 10.2 for more information.
c. Optional sample (see Section 8.5).
d. Only for women at screening or in case of a positive urine pregnancy test, as no serum -hCG pregnancy test
will be performed in male participants.
e. Repeated or unscheduled samples may be taken for safety reasons or technical issues with the samples.
f. Arterial blood gas only at screening, and Week 26.
g. Not collected at Screening.
h. Not collected at Screening and Week 20.
Note: An indwelling intravenous cannula may be used for blood sample collection.
Unscheduled Visits
Unscheduled visits may be performed at any time during the study. Depending on the reason for
the unscheduled visit, appropriate assessments will be performed based on the judgment of the
investigator.
An unscheduled visit including all mandatory assessments described in the Schedule of Activities
must be performed in case of the following occurring outside of a scheduled visit:
 
Any new AE suggestive of RHF or SAPH disease progression.
 
Any new evidence of a decrease in exercise capacity or increase in dyspnea.
 
Any change in dose/initiation of new PH-specific therapies and/or up-titration of study
intervention beyond the planned titration phase.
The date of the visit and the reason for the visit, as well as data related to study-specific
assessments performed at unscheduled visits, will be recorded in the eCRF.
After an unscheduled visit, the regular scheduled study visits must continue according to the
planned visit and assessment schedule.
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Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory
requisition form.
Refer to the Schedule of Activities for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, shipment of samples, and reporting of results are
found in the laboratory manual that will be provided. Collection, handling, storage, and shipment
of samples must be under the specified, and where applicable, controlled temperature conditions
as indicated in the laboratory manual.
Study-Specific Materials
The investigator will be provided with the following:
 
Investigator’s Brochure
 
Pharmacy manual/study site investigational product and procedures manual
 
Laboratory manual, requisition forms, and sampling supplies
 
IWRS Manual
 
PRO questionnaires, CRO questionnaires, completion guidelines, and electronic devices
 
Actigraphy devices and user guidelines
 
eCRF completion guidelines
 
SAE form and completion guideline
 
Pregnancy forms
 
Product quality complaint (PQC) form
 
Study participant cards
 
Pregnancy cards
 
RHC guidance document
 
6MWT guidance document
8.1. 
Demographics and Baseline Characteristics
Demographic and baseline characteristic data to be collected on all randomized participants
include: age, sex, race and ethnicity (where local regulations permit), weight and height, date of
the initial SAPH diagnosis, WHO FC, and smoking status (never, former, current).
All relevant medical history / current medical conditions based on the investigator’s judgment (eg,
chronic and ongoing acute conditions, serious past conditions) present before and/or at the time of
signing informed consent will be recorded on the medical history page. Where possible, diagnoses
and not symptoms will be recorded.
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For participants who are naïve to PH-specific therapies, the reason(s) for not prescribing
ERA/PDE-5 inhibitors/riociguat are collected in the eCRF  (not available, not reimbursed,
contraindicated, not tolerated, other).
8.2. 
Efficacy Assessments
Data obtained from the efficacy assessments listed below will be recorded in the eCRF, unless
stated otherwise.
8.2.1. Primary Efficacy Endpoint Assessment
8.2.1.1. 
Right Heart Catheterization
Guidance for the RHC assessment is provided in  the SPHINX RHC guidance document. The
following hemodynamic variables are to be collected: heart rate, peripheral systolic and diastolic
blood pressure (SBP and DBP, respectively), pulmonary artery wedge pressure (PAWP;
alternatively, LVEDP), mRAP, systolic/diastolic pulmonary artery pressures (sPAP/dPAP), CO,
and SvO2.
8.2.1.1.1. 
Baseline RHC
All participants must have a baseline RHC.
A historical RHC is allowed, if following criteria are met:
 
All required variables as per SPHINX RHC guidance document are available.
 
It is feasible to perform the Week 26 RHC as described in Section 8.2.1.1.2
 
Historical RHC was performed:
 
Within 90 days prior to randomization,
 
At least 90 days after last change in PH-specific therapies (ie, change in dose or initiation
of new class of drugs).
 
At least 90 days after starting a new specific anti-inflammatory treatment for sarcoidosis.
 
At least 30 days after last change in dose of specific anti-inflammatory treatment for
sarcoidosis.
If no historical results meeting the above criteria are available, an RHC, according to the SPHINX
RHC guidance document must be performed during the Screening periodonly if all other inclusion
criteria are met and none of the exclusion criteria is met.
8.2.1.1.2. 
Week 26 RHC
At Week 26 an RHC will be performed within 2 to 5 hours post-dose. It is recommended that any
post-baseline RHC is performed by the same operator, according to the same standards and
procedures and in the same catheterization laboratory. Guidance for the RHC assessment is
provided in the SPHINX RHC guidance document.
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If a participant prematurely discontinues study intervention between Week 12 and Week 26, it is
recommended to perform an RHC within 3 days after last study intervention dose.
An RHC performed at any unscheduled visit must be entered into the eCRF.
8.2.2. Exploratory Endpoint Assessments
8.2.2.1. 
Clinical Worsening and Hospitalization Related to PH-worsening
The following data (obtained as part of other assessments) are required to derive TTCW (see
Section 3): reporting of death, hospitalization, WHO FC, concomitant medications, AEs and SAEs.
The following cases will be adjudicated by the CEC: hospitalization, increase (ie, worsening) in
WHO FC and initiation of new PH-therapies. For all participants, assessment and reporting of any
further disease progression will continue up to the EOMOP visit (see Section 4.1).
8.2.2.2. 
Survival Follow-up
For participants who prematurely discontinue study intervention and do not agree to continue to
perform the visits and assessments up to EOMOP, long-term survival information will be collected
yearly until death or the time of EOMOP (see Sections 7.1, 7.2, and 4.1). The following
information will be collected in the eCRF: vital status (including date and cause of death).
8.2.2.3. 
Exercise Capacity
8.2.2.3.1. 
6MWT
Exercise capacity will be measured by the 6MWT  (ATS Guidelines 2002; Holland 2014). The
6MWT is a non-encouraged test that measures the distance walked in 6 minutes (6MWD).
Guidelines on execution of the 6MWT will be provided in the separate SPHINX 6MWT guidance
document.
During the entire study, the 6MWT must be performed within 2 to 5 hours post-dose and prior to
the RHC (if applicable). The time of the study intervention morning dose intake will be recorded
in the eCRF. For participants who have never performed a 6MWT previously, a training test will
be requested before the Screening 6MWT for inclusion (data from the training test are not collected
in eCRF).
If a 6MWT cannot be performed at a scheduled visit beyond Visit 2 or at an unscheduled visit, a
reason must be provided (ie, PH-related or other).
8.2.2.3.2. 
Daily Life Physical Activity (DLPA) and Sleep Parameters
DLPA and sleep parameters are assessed via an actigraphy device. The device is given to the
participant at Visit 1 (Screening Visit), and the participant is instructed to wear the actigraphy
device on the wrist for 2 weeks during the screening period and following site visits. Detailed
instructions for use of the actigraphy device and accessories are provided to participants via a
participant guide.
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The actigraphy device does not display collected data, ie, the participants do not have access to
their activity measurements, as this could influence their behavior. Data will be uploaded to the
vendor as described in the participant guide.
The data received will be monitored for compliance. Should corrective actions be necessary,
participants may be contacted from the site staff.
The data from the actigraphy device will be collected by the vendor, who will send the results to
the sponsor, but the results will not be recorded in the eCRF.
8.2.2.4. 
Oxygen Saturation (Pre- and Post-6MWT)
Oxygen saturation will be measured using pulse oximetry (performed as per standard practice at
the study site) just before starting and immediately after stopping the 6MWT.
8.2.2.5. 
Dyspnea (Pre- and Post-6MWT)
Dyspnea will be assessed by the Borg CR Scale® (CR10) (Borg 1970, 1998), a scale used to
quantify the degree of shortness of breath as per the SPHINX 6MWT guidance. Dyspnea will be
evaluated by each individual participant immediately before starting and after stopping the 6MWT.
8.2.2.6. 
WHO FC
WHO FC, as defined in Section 10.6, will be assessed.
8.2.2.7. 
NT-proBNP
A blood sample for the analysis of NT-proBNP will be drawn (see Section 10.2). Details about the
collection, sampling, storage, shipment procedures and reporting of results and abnormal findings
can be found in the central laboratory manual.
8.2.2.8. 
Patient-reported Outcomes
The following PRO instruments will not be administered to illiterate participants and will not be
administered to a participant when the instrument is not available in a language that can be easily
understood and read by the participant. It is recommended that the PROs are completed prior to
any clinical assessments.
The PROs are completed on an electronic device. As participants need to complete the
PAH-SYMPACT™at home, participants can take home the electronic device after being trained
by the site staff during Visit 1. Participants must return the mobile device to the site at Visit 7.
Data will be transferred daily to an electronic database immediately upon completion of the
questionnaire via a cellular connection to the vendor. The data received will be checked for
completion compliance. The site will be informed if the questionnaire has not been completed as
per protocol. Should corrective actions be necessary, participants may be contacted either from the
site staff or via messages onto the mobile device from the vendor. All other PROs will be
completed on an electronic device at the site.
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The data from the mobile device will be collected by the vendor, who will send the results to the
sponsor, but are not recorded in the eCRF.
8.2.2.8.1. 
PAH-SYMPACT™ questionnaire
The PAH-SYMPACT™ (Section 10.7) (Chin 2018) questionnaire is a PRO instrument that was
developed by Actelion Pharmaceuticals Ltd. (McCollister 2016). This questionnaire has been
developed and validated for use in PAH patients. Content validity of the questionnaire is being
tested with SAPH patients in a separate stand-alone qualitative interview study.
The PAH-SYMPACT™ consists of 2 parts:
 
The symptom part is completed for the 7 consecutive days following the visit at site (ie,
starting the day following the visit day).
 
The impact part is completed once, on the seventh day of the symptoms diary data collection
period, together with the symptom part (ie, in the evening).
The PAH-SYMPACT™ should be completed in the evening before bedtime.
8.2.2.8.2. 
SF-12
The SF-12v2® Healthy Survey (Section 10.8) (Gandek 1998) is a quality of life self-assessment
derived from the SF-36v2® (Health Survey© 1996, 2000 by Medical Outcomes Trust and Quality
Metric Incorporated). It has 12 items measuring 8scales, including physical functioning, physical
role limitations, bodily pain, general health, vitality, social functioning, emotional role limitations,
and mental health (Gandek 1998). The SF-12 is scored using norm-based scoring in the same way
as for the SF-36v2®.
8.2.2.8.3. 
King’s Sarcoidosis Questionnaire (KSQ)
The KSQ (Section 10.9) is a health status questionnaire developed and validated for patients with
sarcoidosis. It is brief, adaptable to individual patients and assesses general and organ-specific
health status. The KSQ consists of 5 modules: General health status (10 items), Lung (6 items),
Skin (3 items), Eye (7 items), Medications (3 items). The organ-specific modules can be combined
with the General health status module to assess overall health status for patients depending on
which organs are affected by their disease (Patel 2013). The KSQ is summarized as a number
between 1 and 100, with higher numbers indicating better health.
8.2.2.8.4. 
Patient Global Assessment of Disease Severity (PGA-S)
The PGA-S (Section 10.10) is a 6-point single item self-evaluation scale (Nikiphorou 2016; Scott
1977). Participants will be asked to rate the overall severity of their disease on the day of
administration, with responses of none, very mild, mild, moderate, severe or very severe.
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8.2.2.9. 
Clinician-reported Outcomes (CROs)
The CROs (CGI-S and CGI-C) (Busner 2007; Guy 1976) are completed on an electronic device.
The data from the mobile device will be collected by the vendor, who will send the results to the
sponsor. The results are not recorded in the eCRF.
8.2.2.9.1. 
Clinician Global Impression of Severity (CGI-S)
The CGI-S (Section 10.11) is a 6-point single-item scale. The investigator/delegate will rate the
overall severity of the participant’s disease on the day of administration with responses of none,
very mild, mild, moderate, severe or very severe.
8.2.2.9.2. 
Clinician Global Impression of Change (CGI-C)
The CGI-C (Section 10.12) is a 7-point single-item scale. The investigator/delegate will rate the
overall participant’s change of the participant’s disease since baseline with responses of very much
better, moderately better, a little better, no change, a little worse, moderately worse or very much
worse.
8.3. 
Safety Assessments
Safety and tolerability will be evaluated throughout this study from signing of the ICF onwards
until the EOS visit (see Section 4.4.1) or date of last contact (see Section 7.3).
The standard safety assessments to evaluate the safety and tolerability of selexipag in this study
include reporting and follow-up of (S)AEs, pregnancies, vital signs, physical examination, ECG,
and safety laboratory tests. In addition, pulmonary function, DLCO and arterial blood gas will be
monitored.
Details regarding the sponsor DMC and SC are provided in Committees Structure in Section 10.3,
Regulatory, Ethical, and Study Oversight Considerations.
Adverse events will be reported and followed by the investigator as specified in Section 8.4 and
Section 10.4.
Any clinically relevant changes occurring during the study must be recorded on the AE section of
the eCRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be
followed by the investigator until resolution or until a clinically stable condition is reached or until
the participant has been deemed lost to follow-up- (see Section 7.3).
The study will include the following evaluations of safety and tolerability according to the
timepoints provided in the Schedule of Activities.
8.3.1. Physical Examination
Physical examination includes the examination of the general appearance, heart, lungs, extremities,
eyes. Other exams will be performed if indicated, based on medical history and/or symptoms.
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Height will be measured without shoes.
Body weight will be measured in indoor clothing but without shoes.
Clinically relevant findings (other than those related to SAPH) that are present prior to signing of
ICF must be recorded on the Medical History eCRF page. Physical examination findings made
after signing of ICF, which meet the definition of an AE must be recorded on the AE page of the
eCRF.
8.3.2. Vital Signs
Pulse rate, SBP and DBP will be assessed in a supine or sitting position. It is recommended that
the participant is allowed to rest for at least 5 minutes before the measurement. It is also
recommended that measurements are performed on the same arm and in the same position (supine
or sitting) throughout the study for each individual participant. Vital signs are to be measured prior
to blood collection.
Vital signs data will be recorded in the eCRF.
8.3.3. Electrocardiogram
A single standard 12-lead ECG will be performed and interpreted locally.
During the collection of ECGs, participants should be in a quiet setting without distractions (eg,
television, cell phones). Participants should rest in a supine position for at least 5 minutes before
ECG collection and should refrain from talking or moving arms or legs. If blood sampling or vital
sign measurement are scheduled for the same timepoint as ECG recording, the procedures should
be performed in the following order: ECG(s), vital signs, blood draw.
Clinically relevant ECG findings that are present prior to the initiation of study intervention must
be documented in the Medical History section of the eCRF. Clinically relevant ECG findings found
after the study intervention initiation that were not present at Screening or that worsened during
the study, meet the definition of an AE and should be recorded on the Adverse Event form of the
eCRF.
8.3.4. Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology will be collected as noted in Section 10.2. The
investigator must review the laboratory results, document this review, and record any clinically
relevant changes occurring during the study in the AE section of the eCRF.
The laboratory reports from the central laboratory must be filed with the source documents. The
local laboratory results (with the corresponding normal ranges), if applicable per Section 10.2,
must be recorded in the eCRF.
Details about the collection, sampling, storage, shipment procedures and reporting of results and
abnormal findings can be found in the central laboratory manual.
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JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
62
Status: Approved,  Date: 25 February 2022
8.3.5. Pulmonary Function Tests
The pulmonary function tests (spirometry and DLCO) must be performed by experienced staff, such
as a pulmonary function technician or expert.
8.3.5.1. 
Spirometry
Spirometry tests will be conducted according to the ATS/ERS (Graham 2019; Miller 2005a,b).
It is recommended that all spirometry assessments are performed at the same time and under same
conditions throughout the study. Participants must refrain from taking short-acting-beta-agonists
(eg, salbutamol) for 6 hours and long-acting-beta-agonists for 24 hours prior to spirometry testing
(see Section 6.5). If taken, the test should be rescheduled. To perform the spirometry test,
participants will be rested for a minimum of 5 minutes prior to start.
The following variables will be collected at Screening (Visit 1) and subsequent Visits where
applicable: FEV1 and FVC.
8.3.5.2. 
Diffusing Capacity of the Lung for Carbon Monoxide (DLCO)
The diffusing capacity ofthe lungs, measured using carbon monoxide (DLCO) will be conducted
according to the ATS/ERS guidelines and will be assessed by the single-breath method (Graham
2017). DLCO efforts, up to a maximum of 5, will be performed to produce at least 2 technically
acceptable and repeatable traces (according to ATS/ERS guideline criteria). There must be a
minimal interval of at least 4 minutes between each effort performed.
8.3.6. Resting Arterial Blood Gas
Measurement of resting ABG will be performed as per site standard. It is recommended to be
performed during RHC if possible. The Week 26 ABG assessment should be performed under the
same conditions, eg, same oxygen rate (if applicable), as the ABG performed at screening. If a
historical RHC, meeting the criteria in Section 8.2.1.1.1, is available and if ABG was part of that
RHC, it is not necessary to repeat ABG during screening, and the available results can be entered
into the eCRF. Values to be recorded in the eCRF include PaCO2, PaO2, SaO2, fraction of inspired
oxygen (FiO2) and barometric pressure on the day of the assessment.
8.4. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information from clinical studies
are crucial for the protection of participants, investigators, and the sponsor, and are mandated by
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in
accordance with those procedures.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate,
or the participant’s legally acceptable representative) throughout the study from signing of the ICF
onwards until the EOS visit (see Section 4.4.1) or date of last contact (see Section 7.3).
NCT03942211


JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
63
Status: Approved,  Date: 25 February 2022
Further details on AEs, SAEs, and PQC can be found in Section 10.4 Adverse Events, Serious
Adverse Events, Product Quality Complaints, and Other Safety Reporting: Definitions and
Procedures for Recording, Evaluating, Follow-Up, and Reporting.
8.4.1. Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported on
specific AE pages of the eCRF throughout the study from signing of the ICF onwards until the
EOS visit (see Section 4.4.1) or date of last contact (see Section 7.3).
Serious Adverse Events
All SAEs, as well as PQC, occurring during the study must be reported to the appropriate sponsor
contact person by study site personnel within 24 hours of their knowledge of the event.
Serious adverse events, including those spontaneously reported to the investigator, until EOS visit,
must be reported on AE pages of the eCRF and on the SAE Form, whether or not this event is
considered by the investigator to be related to study intervention.
Information regarding SAEs will be transmitted to the sponsor using the SAE Form and Safety
Report Form of the CRF, 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 an SAE should
be transmitted electronically or by facsimile (fax). Telephone reporting should be the exception
and the reporter should be asked to complete the appropriate form(s) first.
If the participant is hospitalized in a hospital other than the study site, it is the investigator’s
responsibility to contact this hospital to obtain all SAE relevant information and documentation.
8.4.2. Follow-up of Adverse Events and Serious Adverse Events
The investigator is obligated to perform or arrange for the conduct of supplemental measurements
and evaluations as medically indicated to elucidate the nature and causality of the AE, SAE, or
PQC as fully as possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other health care professionals.
Adverse events, including pregnancy, will be followed by the investigator as specified in
Section 10.4 Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting.
8.4.3. 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 SUSARs. The investigator (or sponsor where required) must report SUSARs to the
appropriate IEC/IRB that approved the protocol unless otherwise required and documented by the
NCT03942211


JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
64
Status: Approved,  Date: 25 February 2022
IEC/IRB. A SUSAR will be reported to regulatory authorities unblinded. Participating
investigators and IEC/IRB will receive a blinded SUSAR summary unless otherwise specified.
8.4.4. Pregnancy
All initial reports of pregnancy in female participants or female 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 SAE reporting form. Any female participant who
becomes pregnant during the study must discontinue further study intervention (see Section 7.1).
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the
infant will be required. The duration of this follow-up will depend on the clinical conditions of the
newborn and may be extended until discharge from hospital, when applicable.
8.5. 
Biomarkers
Biomarker analysis is optional for each participant. A biomarker-specific ICF should be signed
prior to collection of any samples for biomarker analysis.
Plasma and serum samples for the analysis of pharmacodynamic and disease-related biomarkers
(see Section 4.2) can be collected at timepoints indicated in the Schedule of Activities and archived
for future analysis from all participants. Refer to the laboratory manual for detailed instructions
for sample collection, processing and shipment of archive samples for exploratory research.
The biomarkers included in the analysis will be specified in a biomarker plan.
Refer to Section 10.3 for more information on the long-term retention of samples collected for
biomarker analysis.
9. 
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or delegated to a Contract Research Organization
under the responsibility  of the sponsor. Unblinded analyses for the sponsor DMC will be
performed by an SSG independent from the study team to protect from unblinding. A general
description of the statistical methods to be used to analyze the efficacy and safety data is outlined
below. Specific details will be provided in the Statistical Analysis Plan (SAP).
Data collected during the study will be summarized by intervention group and, where appropriate
and applicable, compared between intervention groups with hypothesis test.
Individual listings for participant demographics, baseline characteristics, and endpoint-related data
will be provided as applicable and will be detailed in the SAP.
NCT03942211


JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
65
Status: Approved,  Date: 25 February 2022
9.1. 
Populations for Analyses
For analysis purposes, the following populations are defined:
Table 3: 
Overview of the Different Populations for Analyses.
Population 
Description
Screened Analysis Set (SCR) 
All participants who were screened and received a participant identification
number.
Randomized Set (RS) 
All participants assigned to a study intervention.
Full Analysis Set (FAS) 
All patients from the RS who took at least one dose of study intervention
and for whom the baseline pulmonary vascular resistance is non-missing.
Per-Protocol Analysis Set (PPS) 
All participants from the FAS who received the assigned study intervention
and who complied with the protocol sufficiently to be likely to exhibit the
intervention effects.
Safety Analysis Set (SAS) 
All participants who received at least one dose of study intervention.
Participants will be analyzed according to the intervention they actually
received.
PVR and all other efficacy analyses will primarily be evaluated on the Full Analysis Set (FAS).
The PVR analyses will also be performed on the Per-Protocol Analysis Set (PPS), unless the
number of subjects in the PPS and the FAS differ by less than 5%, in which case, no analyses will
be performed using the PPS. Safety endpoints will be primarily evaluated on the SAS.
9.2. 
Statistical Hypotheses
The null and alternative hypotheses are described in Section 9.5.1.1  together with the estimand
and statistical model definitions.
9.3. 
Analysis Timepoints
There are two analysis timepoints as defined in Section 4.1.
Details on the statistical analyses performed at each of the different Analysis Timepoints will be
specified in the SAP.
9.4. 
Sample Size
The calculation of sample size was approximated by Z-test for superiority on the log-transformed
PVR post- to pre- percent of baseline as defined in Section 9.5.1.1) using the software package
EASTTM version 6.4.0.1 for the difference of two means.
In order to guarantee the appropriate design characteristics (see assumptions in Section 9.4.1), a
total of 74 patients is required (ie, 37 patients per treatment arm).
9.4.1. Sample Size Assumptions
In a clinical study with bosentan in participants with SAPH (BOSAPAH-1), the observed GM ratio
for PVR post to pre percent (defined in Section 9.5.1.1) was around 0.7 in 35 participants with
SAPH at Week 16 (bosentan vs placebo) (Baughman 2014). It was also 0.7 in the NS-304/-02
study in 35 participants with PAH at Week 17 (selexipag vs placebo, with CV of PVR post to pre
percent 0.28 vs 0.08). In the CTEPH studies MERIT-1 (80 participants) and BENEFIT (157
participants) the observed CVs of PVR post to pre percent approached 0.4. The blinded interim
estimate in 79 participants of the TRITON study gives a CV of 0.5.
NCT03942211


JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
66
Status: Approved,  Date: 25 February 2022
Sample size is calculated based on the statistical requirements to detect a clinically relevant
difference between the selexipag and placebo groups using a 1:1 randomization ratio, a two-sided
Type I error of 5% and a Type II error of 10% (90% power).
The following assumptions were made:
 
A ratio of the GM of Week 26 (or premature EOT) to Baseline PVR values equal to 0.70 ie,
a 30% relative decrease (improvement) in GM as compared to placebo;
 
A coefficient of variation (CV) of the ratio of 0.50;
 
Normal distribution for the loge-transformed ratio of Week 26 (or premature EOT) to baseline
PVR values.
Based on the above assumptions, 74 subjects are required to establish the superiority of selexipag
vs placebo with 90% power to correctly reject a false null hypothesis in favor of the alternative
hypothesis.
9.4.2. Sample Size Sensitivity
With a fixed sample size of 74, the power for showing superiority of selexipag over placebo
depends on the ratio of geometric means (GMs) and the CV of the percent of baseline PVR at
Week 26 (or premature EOT). Table 4 displays power calculations for different assumptions for
these two parameters and a two-sided α
0.05.
Table 4: 
Sample size sensitivity for the main analysis
Scenario 
Ratio of GMs 
CV 
Power
Sensitivity 1 
0.65 
0.45 
99%
Sensitivity 2 
0.65 
0.50 
97%
Sensitivity 3 
0.70 
0.45 
94%
Original 
0.70 
0.50 
90%
Sensitivity 4 
0.75 
0.45 
82%
Sensitivity 5 
0.75 
0.50 
74%
CV  coefficient of variation; GM  geometric mean.
Figures in bold red correspond to the sample size calculation in the paragraph above.
NCT03942211


JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
67
Status: Approved,  Date: 25 February 2022
9.5. 
Statistical Analyses
9.5.1. Efficacy Analyses
9.5.1.1. 
Primary Efficacy Analysis
Definition of PVR Endpoint
The primary endpoint is PVR on study intervention at peak concentration up to Week 26, ie, at
Week 26 or at premature EOT in case of discontinuation of study intervention before Week 26.
Estimand
The primary PVR estimand is described according to the following four attributes:
A. Population: FAS (Full analysis set), as randomized.
B. Variable: Per each patient, the absolute change from baseline to Week 26 (or premature EOT)
visit of the natural log-transformed PVR values will be estimated.
The corresponding ratio of the PVR value post-intervention initiation at Week 26 (or premature
EOT) (post) vs the PVR value pre-intervention  initiation at baseline (pre), expressed as a
percentage will also be estimated, ie:
)*+ ,-./ /- ,01 ,10213/ = )*+ 4/ 5116 26(-0 ,0174/801 9:;)
)*+ 4/ <4.1=>31
 × 100 (%)
C. Intercurrent events (events that preclude observation of the variable or affect its
interpretation):
 
Death occurring prior to Week 26 (or premature EOT) visit,
 
Initiation of prostacyclin (epoprostenol), prostacyclin-analogs (eg, treprostinil, iloprost,
beraprost) or prostacyclin receptor agonists (ie, selexipag/UPTRAVI) for any reason prior to
post-baseline RHC,
 
Study intervention discontinuation/interruption for more than 3 days immediately prior to the
post-baseline RHC
D. Population-level summary: Ratio of the GM of the PVR post to pre percent between selexipag
and placebo, obtained by exponentiation of the difference in means of the natural logarithm
transformed PVR post to pre percent between selexipag and placebo:
?@()*+ ,-./ /- ,01 ,10213/ >3 .1=1A>,4B)
?@()*+ ,-./ /- ,01 ,10213/ >3 ,=421<-)
This estimand targets the effect of treatment initiation on the variable measurement prior to the
occurrence of death or introduction of prohibited PH-specific medication and follows a “while on
NCT03942211


JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
68
Status: Approved,  Date: 25 February 2022
treatment” strategy. For the purpose of the primary endpoint, on-treatment is defined as up to
3 days after last study intervention intake.
Intercurrent events will be handled as follows:
 
“Death occurring prior to the post-baseline RHC” will be addressed by imputing the post-
baseline PVR value using the missing data rules specified in subsequent sections.
 
Initiation of prostacyclin (epoprostenol), prostacyclin  analogs (eg, treprostinil, iloprost,
beraprost) or prostacyclin receptor agonists (ie, selexipag/UPTRAVI) for any reason prior to
post-baseline RHC” will be addressed by disregarding the post-baseline PVR assessments and
imputing them using the missing data rules specified in subsequent sections.
 
“Study intervention discontinuation/interruption for more than 3 days immediately prior to
the post-baseline RHC” will be addressed by disregarding the PVR assessments obtained more
than 3 days after study intervention discontinuation and imputing them using the missing data
rules specified in subsequent sections.
Hypotheses
The hypotheses for the primary endpoint of PVR at peak concentration at Week 26 (or premature
EOT) are formulated in terms of GM of PVR post to pre percent (as defined above) in participants
treated with selexipag (GMselexipag) versus placebo (GMplacebo):
H0: GMselexipag / GMplacebo  1
HA: GMselexipag / GMplacebo ≠ 1
Statistical Model
The null hypothesis is planned to be tested in the FAS by means of an ANCOVA model on the
natural logarithm transformed PVR post to pre percent. Model covariates will include randomized
intervention, stratification factor and the natural logarithm transformed baseline PVR value. The
results will be presented on the original scale (GM) after exponentiation of the absolute adjusted
mean changes obtained on the natural log scale:
Handling of Missing Data
By design, only one post-baseline PVR measurement will be taken at the time of the scheduled
Week 26 or at the premature EOT visit. In some instances, the Week 26 (or premature EOT)
assessment may be missing with no other post-baseline assessment available.
Imputation methods for PVR will be specific to the reason for missing data.
The baseline reference value for PVR is based on the last RHC performed prior to study
intervention initiation.
If PVR cannot be calculated due to missing PAWP, the following conventions will be applied for
the calculation at a visit at which both mPAP and CO are assessed and not missing:
NCT03942211


JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
69
Status: Approved,  Date: 25 February 2022
1. If only PAWP is missing, then the LVEDP will be used.
2. If PAWP and LVEDP are missing both at baseline and post-baseline, the missing PAWP is
imputed using the median of all values observed at the respective time point in all subjects
from the same randomized intervention group.
3. If PAWP and LVEDP are missing either at baseline or at post-baseline, the available PAWP
for the subject is used as a substitute for the missing PAWP.
If apost-baseline PVR assessmentis missing up to Week 26, the following missing data imputation
rules will be used:
 
If a participant dies without a post-baseline value, then the missing PVR post to pre foldvalue
is imputed with the largest PVR post to pre percent value for post-baseline amongst all
participants in the same analysis set. The resulting imputed post-baseline PVR is the product
of this imputed PVR post to pre percent value and the respective baseline PVR value.
 
If a participant experiences clinical worsening, with a subsequent missing PVR post to pre
fold value, the post-baseline value is imputed with the 75th  percentile of the PVR post to pre
foldvalues from all participants in the same analysis set. The resulting imputed post-baseline
PVR is the product of this imputed PVR post to pre fold value and the respective baseline
PVR value.
 
If the participant is alive and does not experience clinical worsening, then the missing PVR
post to pre fold value is imputed with the 50th  percentile of the PVR post to pre foldvalues
from all participants in the same intervention group and analysis set. The resulting imputed
post-baseline PVR is the product of this imputed PVR post to pre fold value and the respective
baseline PVR value.
Main Analysis
The analyses of the primary efficacy endpoint will be tested in the FAS using the ANCOVA model.
From the ANCOVA model, PVR post to pre percent will be summarized by intervention group
using covariate adjusted- GM and corresponding 2-sided 95% CI. The between-group ratio of GM
with corresponding 95% 2-sided CI and p-value will be displayed as the -placebo corrected
intervention effect.
For each intervention group, the least square mean and 2-sided 95% CI of the natural logarithm of
the PVR post to pre percent will be inversely transformed using the exponential function and
multiplied by 100 to provide the GM of the PVR post to pre percent and the corresponding 2-sided
95% CI, expressed as a percentage.
Absolute values at baseline and post-baseline as well as absolute pre-post changes from baseline
to post-baseline for PVR will be summarized using descriptive statistics.
Supportive/Sensitivity Analyses
Sensitivity analyses will be conducted using alternative imputation rules to assess the imputation
assumptions of the main statistical analysis for PVR at Week 26 (or premature EOT).
NCT03942211


JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
70
Status: Approved,  Date: 25 February 2022
Furthermore, a sensitivity analysis of PVR at Week 26 (or premature EOT) will be conducted in
the per-protocol analysis set to assess the robustness of the results of the main statistical analysis
against protocol deviations leading to exclusion from the PPS.
Details of the sensitivity analyses and other imputation approaches will be specified in the SAP.
9.5.1.2. 
Secondary Efficacy Analyses
There are no secondary endpoints for which confirmatory hypotheses are tested with adequate
control of type I error. All efficacy endpoints other than PVR are exploratory; a general statistical
analysis strategy is briefly discussed in Section 9.5.1.3. The full details will be provided in the
SAP.
9.5.1.3. 
Other Efficacy Analyses
For continuous and categorical endpoints, where applicable, the response profiles over time (eg,
change from baseline, proportions of participants by categorical endpoint categories) will be
inspected graphically and by the usual summary statistics at each visit (with 95% CIs) up to the
EOMOP visit by randomized treatment group on the RS. Two sets of profiles will be provided:
one considering assessments measured on study intervention up to the EOMOP visit, and one
including all data collected up to the EOMOP visit regardless of treatment discontinuations.
Time-to-event endpoints will be analyzed using the Kaplan-Meier method by randomized
treatment group up to EOMOP, regardless of study intervention discontinuations.
9.5.2. Safety Analyses
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the
Medical Dictionary for Regulatory Activities (MedDRA). Intervention-emergent adverse events
are AEs with onset during the intervention  period or that are a consequence of a pre-existing
condition that has worsened since baseline. All reported AEs will be included in the analysis. For
each AE, the percentage of participants who experience at least 1 occurrence of the given event
will be summarized by intervention group. In addition, comparisons between intervention groups
will be provided if appropriate.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue intervention due to an AE, or who experience a severe or
an SAE.
Summaries will be by intervention (selexipag or placebo) and will include all events collected
throughout the study.
The AEs of special interest will be defined in the SAP.
NCT03942211


JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
71
Status: Approved,  Date: 25 February 2022
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly
abnormal results (specified in the SAP) will be used in the summary of laboratory data. Descriptive
statistics will be calculated for each laboratory analyte at baseline and for observed values and
changes from baseline at each scheduled timepoint by intervention group. Frequency tabulations
of the abnormalities will be made.
Vital Signs
Descriptive statistics of pulse rate, SBP and DBP  values and changes from baseline will be
summarized at each scheduled timepoint by intervention group.
Supplemental Oxygen Rate
Descriptive statistics of values and changes from baseline in supplemental oxygen rate will be
summarized by intervention group.
Pulmonary Function Tests
Descriptive statistics of values and changes from baseline in DLCO  and FVC will be summarized
by intervention group.
Arterial Blood Gas
Descriptive statistics of values and changes from baseline in ABG parameters will be summarized
by intervention group.
9.5.2.1. 
Study Safety Monitoring
Study safety information (AEs, SAEs, laboratory values, PFTs, DLCO and vital signs) is monitored
and reviewed on a continuous basis by the sponsor’s clinical study team (to ensure participant’s
safety as well as data quality). In addition, a sponsor DMC monitors safety data (see Section 9.6).
The sponsor may request additional data pertaining to the diagnostic work-up of an AE or SAE
(eg, medical imaging, local laboratory values) for the purpose of safety monitoring. Such
additional data may be shared with external experts.
9.5.3. Biomarkers Analyses
Biomarker samples will be used to generate plasma and serum marker data for computational
analyses (see Section 8.5). These analyses are considered exploratory and the results will be
reported separately from this study.
Changes in plasma and serum biomarkers over time will be summarized by intervention group.
Associations between baseline levels and changes from baseline in selected markers and clinical
responses will be explored.
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JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
9.6. 
Data Monitoring Committee
A sponsor DMC will be established as noted in Committees Structure in Section 10.3.
The sponsor DMC has overall responsibility for safeguarding the interests of participants by
monitoring safety data obtained in the study and making appropriate recommendations based on
the reported data, thus ensuring the study is conducted with the highest scientific and ethical
standards.
Detailed information on the sponsor DMC is available in Section 10.3.
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JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Abbreviations and Trademarks
6MWD  
6-minute walk distance
6MWT  
6-minute walk test
AE 
adverse event
ASO  
arteriosclerosis obliterans
ATS  
American Thoracic Society
BP 
blood pressure
CGI-C 
Clinician Global impression of Change
CGI-S 
Clinician Global impression of Severity
CHD  
coronary heart disease
CI 
confidence interval
CIn  
cardiac index
CRO  
clinician-reported outcome
CO  
cardiac output
CRF  
case report form(s) (paper or electronic as appropriate for this study)
CTEPH  
chronic thromboembolic pulmonary hypertension
CV  
coefficient of variation
CYP  
cytochrome P450
DB  
double-blind
DBP  
diastolic blood pressure
DLCO  
diffusing capacity of the lung for carbon monoxide
DMC  
Data Monitoring Committee
DNA  
deoxyribonucleic acid
dPAP  
diastolic pulmonary artery pressure
ECG  
electrocardiogram
eCRF  
electronic Case Report Form
eDC  
electronic data capture
eGFR  
estimated glomerular filtration rate
EOT  
end-of-treatment
EOMOP 
end-of-main-observation-period
EOS  
end-of-study
ERA  
endothelin receptor antagonist
FAS  
Full Analysis Set
FC 
functional class
FSH  
follicle stimulating hormone
FVC  
forced vital capacity
GCP  
Good Clinical Practice
GM  
geometric mean
HRT  
hormonal replacement therapy
IC  
intermittent claudication
ICD  
implantable cardioverter defibrillator
ICF  
informed consent form
ICH  
International Council for Harmonisation
ICMJE  
International Committee of Medical Journal Editors
IEC  
Independent Ethics Committee
iMTD  
individual maximum tolerated dose
IP  
prostacyclin
IRB  
Institutional Review Board
IUD  
intrauterine device
IUS  
intrauterine hormone-releasing system
IWRS  
Interactive Web Response System
KSQ  
King’s sarcoidosis questionnaire
LHF  
left heart failure
LSS  
lumbar spinal stenosis
NCT03942211


JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
74
Status: Approved,  Date: 25 February 2022
LVEDP  
left ventricular end-diastolic pressure
LVEF  
left ventricular ejection fraction
MedDRA  
Medical Dictionary for Regulatory Activities
mPAP  
mean pulmonary arterial pressure
mRAP  
mean right atrial pressure
NT-proBNP  
N--terminal pro b-type natriuretic peptide
O 
Optional
PAH  
pulmonary arterial hypertension
PAH-SYMPACT™ 
Pulmonary Arterial Hypertension-Symptoms and Impact
PAP  
pulmonary artery pressure
PAWP  
pulmonary artery wedge pressure
PDE5i 
phosphodiesterase type-5 inhibitor
PGA-S 
Patient Global Assessment of Severity
PH 
pulmonary hypertension
PPS 
Per-Protocol Analysis Set
PQC  
product quality complaint
PRO  
patient-reported outcome
PVOD  
pulmonary veno-occlusive disease
PVR  
pulmonary vascular resistance
QoL 
quality of life
RBC  
red blood cell
RHC  
right heart catheterization
RHF  
right heart failure
RS  
randomized set
SAE 
serious adverse event
SAP  
Statistical Analysis Plan
SAPH  
sarcoidosis-associated PH
SAS  
Safety Analysis Set
SBP 
systolic blood pressure
SC 
Steering Committee
SCR  
Screened Analysis Set
SF-12 
12-Item Short Form Health Survey
sPAP  
systolic pulmonary artery pressure
SpO2 
peripheral capillary oxygen saturation
SUSAR  
suspected unexpected serious adverse reaction
SvO2 
venous oxygen saturation
T3 
free tri-iodothyronine
T4 
free thyroxin
TC 
telephone call
TSH  
thyroid stimulating hormone
TTCW  
time to clinical worsening
WHO  
World Health Organization
WOCBP 
women of childbearing potential
β-hCG  
β-human chorionic gonadotropin
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10.2. Appendix 2: Clinical Laboratory Tests
A central laboratory (see central laboratory manual for contact details) will be used for all protocol-
mandated laboratory tests, including re-tests due to laboratory abnormalities and laboratory tests
performed at unscheduled visits.
If the results from the central laboratory are not available in time for randomization of the
participant, an additional blood sample may be drawn to verify eligibility based on a local
laboratory test. The local laboratory results (with the corresponding normal ranges) must be
recorded in the eCRF.
Other exceptional circumstances that require recording of local laboratory results (with
corresponding normal ranges) include hospitalization of the participant due to a medical
emergency and missing central laboratory results from a scheduled or unscheduled visit.
If central laboratory samples are lost or cannot be analyzed for any reason, the investigator will
consider collecting an additional sample as soon as possible for repeat analysis, if deemed
medically necessary.
Central laboratory reports will be sent to the investigator.
All laboratory reports must be reviewed, signed and dated by the investigator or delegate and filed
with the source documents. The investigator/delegate must indicate on the laboratory report
whether abnormal values are considered clinically relevant or not. Clinically relevant laboratory
findings that are known at the time of signing of informed consent must be recorded on the Medical
History page of the eCRF. Any clinically relevant laboratory abnormalities detected after signing
of informed consent must be reported as an AE or SAE as appropriate (see Section 8.4 and
Section 10.4).
The participants do not need to be fasted prior to the laboratory tests.
Details about the collection, sampling, storage, shipment procedures and reporting of results and
abnormal findings can be found in the central laboratory manual.
The following tests will be performed according to the Schedule of Activities by the central
laboratory:
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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 GCP, and
applicable regulatory and country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing,
conducting, recording, and reporting studies that involve the participation of human participants.
Compliance with this standard provides public assurance that the rights, safety, and well-being of
study participants are protected, consistent with the principles that originated in the Declaration of
Helsinki, and that the study data are credible.
Protocol 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 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)
 
Investigator’s Brochure (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 Investigator’s Brochure and amendments/addenda
 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at
least annually)
 
Reports of AEs that are serious, unlisted/unexpected, and associated with the study
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
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must be submitted promptly to the IEC/IRB for review and approval before implementation of the
change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about
the study completion.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise help
ensure access to the developed product if the need for the product persists, unless explicitly
addressed as a specific ethical consideration in Section  10.3, Study-Specific Ethical Design
Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 10.3.
FINANCIAL DISCLOSURE
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial
information in accordance with local regulations to allow the sponsor to submit complete and
accurate financial certification or disclosure statements to the appropriate regulatory authorities.
Investigators are responsible for providing information on financial interests during the course of
the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) for details on financial disclosure.
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 studysite 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. 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 subject agrees to allow his or
her study physician to re-contact the participant for the purpose ofobtaining consent for additional
safety evaluations, and subsequent disease-related treatments, if needed.
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 ofthe participant’s personally dated signature. After consent has been obtained, a copy of
the ICF must be given to the participant.
Participants who are rescreened are required to sign a new ICF.
If the participant is unable to read or write, an impartial witness should be present for the entire
informed consent process (which includes reading and explaining all written information) and
should personally date and sign the ICF after the oral consent of the participant is obtained.
Note, 2 ICFs will be prepared: one main ICF and one for the optional biomarker sample collection.
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.
Exploratory biomarker research is not conducted under standards appropriate for the return of data
to participants. In addition, the sponsor cannot make decisions as to the significance of any findings
resulting from exploratory research. Therefore, exploratory research data will not be returned to
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participants or investigators, unless required by law or local regulations. Privacy and
confidentiality of data generated in the future on stored samples will be protected by the same
standards applicable to all other clinical data.
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE RESEARCH
Plasma and serum samples will be used to analyze fibrosis and disease-related biomarkers (see
Section 8.5). Samples collected in this study may be stored for up to 15 years (or according to local
regulations) for additional research. Samples will only be used to understand SAPH and pulmonary
fibrosis, to provide a biological assessment of the response of participants to treatment with
selexipag, to understand differential intervention responders, to determine if the markers can be
used to classify participants as potential responders prior to treatment, and to develop tests/assays
related to selexipag and SAPH and pulmonary fibrosis. The research may begin at any time during
the study or the post-study period.
Stored samples will be coded throughout the sample storage and analysis process and will not be
labeled with personal identifiers. Participants may withdraw their consent for their samples to be
stored for research (refer to Section 7.2.1, Withdrawal From the Use of Research Samples).
COMMITTEES STRUCTURE
Sponsor Data Monitoring Committee (DMC)
A sponsor DMC  has overall responsibility for safeguarding the interests of participants by
monitoring safety data obtained in the study and making appropriate recommendations based on
the reported data, thus ensuring the study is conducted with the highest scientific and ethical
standards.
The sponsor DMC will be fully operational prior to enrollment of the first participant into the
study.
This committee will consist of at least one medical expert in the relevant therapeutic area and at
least one statistician; committee membership responsibilities, authorities, and procedures will be
documented in its charter.
Steering Committee
A Steering Committee (SC) is involved in the study design and will provide guidance on the study
conduct and study publications. The committee is governed by a dedicated SC charter.
Clinical Event Committee
The Clinical Event Committee (CEC) is a sub-committee of the SC. The CEC is responsible for
reviewing and adjudicating potential clinical worsening events in a blinded fashion.
CEC membership and responsibilities, as well as the adjudication procedure will be described in
the CEC charter.
Participant cases will be submitted to the CEC if at least one of the following conditions is reported
by the investigator:
 Hospitalization
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 Increase (ie, worsening) in WHO FC
 Initiation of PH-specific medication.
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA
All information, including but not limited to information regarding selexipag or the sponsor’s
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior
clinical data, formulation information) supplied by the sponsor to the investigator and not
previously published, and any data, including exploratory biomarker research data, generated as a
result of this study, are considered confidential and remain the sole property of the sponsor. The
investigator agrees to maintain this information in confidence and use this information only to
accomplish this study, and will not use it for other purposes without the sponsor’s prior written
consent.
The investigator understands that the information developed in the study will be used by the
sponsor in connection with the continued development ofselexipag, and thus may be disclosed as
required to other clinical investigators or regulatory agencies. To permit the information derived
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and
will contain data from all study sites that participated in the study as per protocol. Recruitment
performance or specific expertise related to the nature and the key assessment parameters of the
study will be used to determine a coordinating investigator for the study. Results of exploratory
biomarker analyses performed after the Clinical Study Report has been issued will be reported in
a separate report and will not require a revision of the Clinical Study Report.
Study participant identifiers will not be used in 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 substudy 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
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from the individual study site until the combined results from the completed study have been
submitted for publication, within 18months 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.
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 start of the study, periodic monitoring visits by the sponsor, and
electronic transfer of clinical laboratory data (including NT-proBNP from a central laboratory),
ePRO, and data collected by actigraphy and IRT vendor to 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.
eCRF data will be captured via electronic data capture (eDC). The investigator and site personnel
will be trained to enter and edit the data via a secure network, with secure access features. A
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complete electronic audit trail will be maintained. The investigator/delegate will approve the data
using an electronic signature.
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 (eg, pain scale information or other questionnaires) 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 the 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.
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 variables as required by the
protocol; record of all AEs and follow-up of AEs; concomitant medication; intervention
receipt/dispensing/return records; study intervention administration information; and date of study
completion and reason for early discontinuation of study intervention  or withdrawal from the
study, if applicable.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be
reviewed with the investigator before the start of the study and will be described in the monitoring
guidelines (or other equivalent document).
Entries recorded through an electronic device by the participant in the PROs and by the
investigator, the actigraphy device and electronically transferred clinical laboratory data (including
NT-proBNP from a central laboratory) and data collected by IRT are considered source data.
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
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 Complete history of medical notes at the site or
 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, physical
examination, laboratory assessment) 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. These data are 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,
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 studysite 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.
Detailed information is available in the study-specific monitoring guidelines.
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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 studysite 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
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.
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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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JNJ-67896049 / ACT-293987 (selexipag)
Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
10.4. Appendix 4: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a medicinal
(investigational or non-investigational) product. An AE does not necessarily have a causal
relationship with the intervention. An AE can therefore be any unfavorable and unintended sign
(including an abnormal finding), symptom, or disease temporally associated with the use of a
medicinal (investigational or non-investigational) product, whether or not related to that medicinal
(investigational or non-investigational) product (Definition per ICH).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to Section 8.4.1 for time
of last AE recording).
Serious Adverse Event
An SAE 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.
If a serious and unexpected AE occurs for which there is evidence suggesting a causal relationship
between the study intervention  and the event, the event must be reported as a serious and
unexpected suspected adverse reaction even if it is a component of the study endpoint.
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JNJ-67896049 / ACT-293987 (selexipag)
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product
reference safety information. For selexipag, the expectedness of an AE will be determined by
whether or not it is listed in the Investigator’s Brochure (see Section 8.4).
Adverse Event Associated with the use of the Intervention
An AE is considered associated with the use of the intervention if the attribution is related by the
definitions listed below (see Attribution Definitions).
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 (see Section 6.8)
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Status: Approved,  Date: 25 February 2022
 
Suspected abuse/misuse of a sponsor study intervention
 
Accidental or occupational exposure to a sponsor study intervention
 
Unexpected therapeutic or clinical benefit from use of a sponsor study intervention
 
Medication error involving a sponsor product (with or without participant/patient exposure to
the sponsor study intervention, eg, name confusion)
 
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
SAE Form.
PROCEDURES
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study intervention, must
be recorded using medical terminology in the source document and the eCRF (see Section 8.4.1).
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 OL 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 staff only)
 
Site number
 
Participant number
 
Any other information that is required to do an emergency breaking of the blind
Serious Adverse Events
Refer to Section 8.4.1 for more information on the reporting procedures of SAEs.
All SAEs that have not resolved at time of the EOS visit (see Section 4.4.1) must be followed until
any of the following occurs:
 
The event resolves
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Status: Approved,  Date: 25 February 2022
 
The event stabilizes
 
The event returns to baseline, if a baseline value/status is available
 
The event can be attributed to agents other than the study intervention or to factors unrelated
to study conduct
 
It becomes unlikely that any additional information can be obtained (participant or health care
practitioner refusal to provide additional information, lost to follow-up [see Section 7.3])
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during
participation in the study must be reported as an SAE, except hospitalizations for the following:
 
Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as pending
placement in long-term care facility, cosmetic elective surgery).
 
Surgery or procedure planned before entry into the study (must be documented in the eCRF)
or standard monitoring of a pre-existing disease or medical condition that did not worsen, eg,
hospitalization for coronary angiography in a participant with stable angina pectoris. Note:
Hospitalizations that were planned before the signing of the ICF, and where the underlying
condition for which the hospitalization was planned has not worsened, will not be considered
SAEs. Any AE that results in a prolongation 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.
If the participant is hospitalized in a hospital other than the study site, it is the investigator’s
responsibility to contact this hospital to obtain all SAE-relevant information and documentation.
The cause of death of a participant in a study within 30 days of the last dose of study intervention,
whether or not the event is expected or associated with the study intervention, is considered an
SAE.
Information regarding SAEs will be transmitted to the sponsor using an SAE reporting form and
safety report form of the CRF, which must be completed and reviewed by a physician from the
study site andtransmitted in a secure manner to the sponsor within 24 hours. The initial and follow-
up reports of an SAE should be transmitted in a secure manner electronically or by facsimile (fax).
PRODUCT QUALITY COMPLAINT HANDLING
Definition
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, reliability, or performance of a distributed product, including its labeling, drug delivery
system, or package integrity. A PQC may have an impact on the safety and efficacy of the product.
In addition, it includes any technical complaints, defined as any complaint that indicates a potential
quality issue during manufacturing, packaging, release testing, stability monitoring, dose
preparation, storage or distribution of the product or the drug delivery system.
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Status: Approved,  Date: 25 February 2022
Procedures
All initial PQCs must be reported to the sponsor by the study site personnel within 24 hours after
being made aware of the event.
A sample of the suspected product should be maintained for further investigation if requested by
the sponsor.
Contacting Sponsor Regarding Safety, Including 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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Status: Approved,  Date: 25 February 2022
10.5. Appendix 5: Contraceptive and Barrier Guidance
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria.
Pregnancy information will be collected and reported as noted in Section 8.4.4, Pregnancy and
Appendix 5: Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and
Reporting.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Woman Not of Childbearing Potential
 
premenarchal
A premenarchal state is one in which menarche has not yet occurred.
 
postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the
postmenopausal range may be used to confirm a postmenopausal state in women not using
hormonal contraception or hormonal replacement therapy (HRT), however in the absence of
12 months 
of 
amenorrhea, 
a 
single 
FSH 
measurement 
is 
insufficient.
If there is a question about menopausal status in women on HRT, the woman will be required
to use one of the non-estrogen-containing hormonal highly effective contraceptive methods if
she wishes to continue HRT during the study.
 
permanently sterile (for the purpose of this study)
 
Permanent sterilization methods include hysterectomy, or bilateral salpingectomy, or
bilateral oophorectomy.
 
Has congenital abnormalities resulting in sterility.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually
active becomes active), a woman must begin an acceptable method of contraception, as described
throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by men or women must 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 must be
consistent with local regulations regarding the use of contraceptive methods for participants in
clinical studies.
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT
 Implantable progestogen-only hormone contraception associated with inhibition of ovulation
 Intrauterine device (IUD)
 Intrauterine hormone-releasing system (IUS)
 Tubal closure (eg, bilateral tubal occlusion, bilateral tubal ligation)
 Azoospermic partner (vasectomized or due to medical cause)
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the
sole sexual partner of the woman of childbearing potential and the absence of sperm has been
confirmed. If not, additional highly effective method of contraception must be used.
Spermatogenesis cycle is approximately 74 days.)
USER DEPENDENT
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulation
 oral
 intravaginal
 transdermal
 injectable
 Progestogen-only hormone contraception associated with inhibition of ovulation
 oral
 injectable
 Male or female condom with or without spermicideb
 Cap, diaphragm, or sponge with spermicide
 A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-
barrier methods)b
 Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from
heterosexual intercourse during the entire period of risk associated with the study intervention.
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study
and the preferred and usual lifestyle of the participant.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY
 Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary
mode of action
 Periodic abstinence (calendar, symptothermal, post-ovulation methods)
 Withdrawal (coitus-interruptus)
 Spermicides alone
 Lactational amenorrhea method (LAM)
a. Typical use failure rates may differ from those when used consistently and correctly. Use must be consistent
with local regulations regarding the use of contraceptive methods for participants in clinical studies.
b. Male condom and female condom must not be used together (due to risk of failure with friction).
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Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
Pregnancy During the Study
If a participant becomes pregnant while on study intervention, study intervention must be
discontinued and the investigator should arrange for specific therapy, as needed (Regitz-Zagrosek
2011). For reporting of pregnancies, refer to Section 8.4.4.
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Status: Approved,  Date: 25 February 2022
10.6. Appendix 6: WHO Function Classification of Pulmonary Hypertension
Class I 
Patients with pulmonary hypertension but without resulting
limitation of physical activity. Ordinary physical activity does not
cause undue dyspnea or fatigue, chest pain or near syncope.
Class II 
Patients with pulmonary hypertension resulting in slight limitation of
physical activity. They are comfortable at rest. Ordinary physical
activity causes undue dyspnea or fatigue, chest pain or near syncope.
Class III 
Patients with pulmonary hypertension resulting in marked limitation
of physical activity. They are comfortable at rest. Less than ordinary
activity causes undue dyspnea or fatigue, chest pain or near syncope.
Class IV  
Patients with pulmonary hypertension with inability to carry out any
physical activity without symptoms. These patients manifest signs of
right heart failure (RHF). Dyspnea and/or fatigue may even be
present at rest. Discomfort is increased by any physical activity.
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Clinical Protocol AC-065D301 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 February 2022
10.7. Appendix 7: PAH-SYMPACTTM  Questionnaire
Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT)
Questionnairea
Programming note: Day 1 (First day of diary completion-Symptoms items only)
INSTRUCTIONS
Each day you will answer questions about your Pulmonary Arterial Hypertension symptoms over the
PAST 24 HOURS. Please select the answer that best describes your experience with your symptoms.
On the 7th  day you will answer questions about your Pulmonary Arterial Hypertension symptoms over the
PAST 24 HOURS and additional questions about how your life was affected by Pulmonary Arterial
Hypertension in the PAST 7 DAYS.
Please do not skip any questions. There are no right or wrong answers to any of the questions.
Programming note: Days 2-6 (Subsequent days prior to last day in week-Symptoms items only)
INSTRUCTIONS
Today you will answer questions about your Pulmonary Arterial Hypertension symptoms over the PAST
24 HOURS. Please select the answer that best describes your experience with your symptoms.
Please do not skip any questions. There are no right or wrong answers to any of the questions.
Programming note: Day 7 (Last day of week-Symptoms and Impact items)
INSTRUCTIONS
Today you will answer questions about your Pulmonary Arterial Hypertension symptoms over the PAST
24 HOURS and additional questions about how your life was affected by Pulmonary Arterial Hypertension
in the PAST 7 DAYS.
Please do not skip any questions. There are no right or wrong answers to any of the questions.
a. 
a PAH-SYMPACT Version 1.0, 07June2016. PAH-SYMPACT is a registered trademark of Actelion
Pharmaceuticals Ltd.
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Status: Approved,  Date: 25 February 2022
SYMPTOMS
1. In the past 24 hours …
Did you use oxygen?
0 No
1 Yes 
If yes: How many hours? _______
Answer the questions that follow based on your experiences regardless of whether you were using
oxygen or not.
2. In the past 24 hours …
How would you rate your shortness of breath?
0 No shortness of breath at all
1 Mild
2 Moderate
3 Severe
4 Very Severe
3. In the past 24 hours …
How would you rate your fatigue?
0 No fatigue at all
1 Mild
2 Moderate
3 Severe
4 Very Severe
4. In the past 24 hours …
How would you rate your lack of energy?
0 No lack of energy at all
1 Mild
2 Moderate
3 Severe
4 Very Severe
5. In the past 24 hours …
How would you rate the swelling in your ankles or legs?
0 No swelling in ankles or legs at all
1 Mild
2 Moderate
3 Severe
4 Very Severe
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6. In the past 24 hours …
How would you rate the swelling in your stomach area?
0 No swelling in stomach area at all
1 Mild
2 Moderate
3 Severe
4 Very Severe
7. In the past 24 hours …
How would you rate your cough?
0 No cough at all
1 Mild
2 Moderate
3 Severe
4 Very Severe
8. In the past 24 hours …
How would you rate your heart palpitations (heart fluttering)?
0 No heart palpitations (heart fluttering) at all
1 Mild
2 Moderate
3 Severe
4 Very Severe
9. In the past 24 hours …
How would you rate your rapid heartbeat?
0 No rapid heartbeat at all
1 Mild
2 Moderate
3 Severe
4 Very Severe
10. In the past 24 hours …
How would you rate your chest pain?
0 No chest pain at all
1 Mild
2 Moderate
3 Severe
4 Very Severe
11. In the past 24 hours …
How would you rate your chest tightness?
0 No chest tightness at all
1 Mild
2 Moderate
3 Severe
4 Very Severe
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12. In the past 24 hours …
How would you rate your lightheadedness?
0 No lightheadedness at all
1 Mild
2 Moderate
3 Severe
4 Very Severe
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IMPACTS
For the following questions, please select the answer that best describes how your life was affected by
Pulmonary Arterial Hypertension in the PAST 7 DAYS. Answer the questions based on your experiences
regardless of whether you were using oxygen or not.
1. In the past 7 days …
Were you able to walk slowly on a flat surface?
0 Yes, with no difficulty at all
1 Yes, with a little difficulty
2 Yes, with some difficulty
3 Yes, with much difficulty
4 No, not able at all
2. In the past 7 days …
Were you able to walk quickly on a flat surface?
0 Yes, with no difficulty at all
1 Yes, with a little difficulty
2 Yes, with some difficulty
3 Yes, with much difficulty
4 No, not able at all
3. In the past 7 days …
Were you able to walk uphill?
0 Yes, with no difficulty at all
1 Yes, with a little difficulty
2 Yes, with some difficulty
3 Yes, with much difficulty
4 No, not able at all
4. In the past 7 days …
Were you able to carry things, such as bags or baskets?
0 Yes, with no difficulty at all
1 Yes, with a little difficulty
2 Yes, with some difficulty
3 Yes, with much difficulty
4 No, not able at all
5. In the past 7 days …
Were you able to do light indoor household chores, such as preparing food, cleaning surfaces, or
tidying up?
0 Yes, with no difficulty at all
1 Yes, with a little difficulty
2 Yes, with some difficulty
3 Yes, with much difficulty
4 No, not able at all
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6. In the past 7 days …
Were you able to wash or dress yourself?
0 Yes, with no difficulty at all
1 Yes, with a little difficulty
2 Yes, with some difficulty
3 Yes, with much difficulty
4 No, not able at all
7. In the past 7 days …
How much did you need help from others?
0 Not at all
1 A little bit
2 Some
3 Quite a bit
4 Very much
8. In the past 7 days …
Were you able to think clearly?
0 Yes, with no difficulty at all
1 Yes, with a little difficulty
2 Yes, with some difficulty
3 Yes, with much difficulty
4 No, not able at all
9. In the past 7 days …
How sad did you feel?
0 Not at all
1 A little bit
2 Somewhat
3 Very
4 Extremely
10. In the past 7 days …
How worried did you feel?
0 Not at all
1 A little bit
2 Somewhat
3 Very
4 Extremely
11. In the past 7 days …
How frustrated did you feel?
0 Not at all
1 A little bit
2 Somewhat
3 Very
4 Extremely
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10.8. Appendix 8: SF-12
CCI
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CCI
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CCI
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CCI
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10.9. Appendix 9: King’s Sarcoidosis Questionnaire
King’s Sarcoidosis Questionnaire
This questionnaire is designed to assess the impact of sarcoidosis on various aspects of your life.
Read each question carefully and answer by SELECTING the response that best applies to you.
Please answer ALL questions as honestly as you can. This questionnaire is confidential.
All questions relate to how SARCOIDOSIS has affected your health.
GENERAL HEALTH STATUS
In the last 2 weeks...
All of the
time
Most of
the time
A lot of
the time
Some of
the time
A little of
the time
Hardly
any of the
time
None of
the time
1 
I have felt frustrated 
1 
2 
3 
4 
5 
6 
7
2 
I have had trouble concentrating 
1 
2 
3 
4 
5 
6 
7
3 
I have lacked motivation  
1 
2 
3 
4 
5 
6 
7
4 
I have felt tired 
1 
2 
3 
4 
5 
6 
7
5 
I have felt anxious 
1 
2 
3 
4 
5 
6 
7
6 
I have felt aches and pains in my 
muscles/joints
1 
2 
3 
4 
5 
6 
7
7 
I have felt embarrassed 
1 
2 
3 
4 
5 
6 
7
8 
I have worried about my weight 
1 
2 
3 
4 
5 
6 
7
9 
I have worried about my sarcoidosis 
1 
2 
3 
4 
5 
6 
7
In the last 2 weeks...
A huge
amount
A considerable
amount
A moderate
amount
A modest
amount
A small
amount
A tiny amount
None at all
10 
Tiredness has interfered with my
normal social activities such as going
out with friends/family
1 
2 
3 
4 
5 
6 
7
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LUNGS
In the last 2 weeks...
All of the
time
Most of
the time
A lot of
the time
Some of
the time
A little of
the time
Hardly any
of the time
None of
the time
11 
My cough has caused 
pain/discomfort
1 
2 
3 
4 
5 
6 
7
12 
I have been breathless climbing stairs 
or walking up slight inclines
1 
2 
3 
4 
5 
6 
7
13 
I have had to take deep breaths, also 
known as ‘air hunger’
1 
2 
3 
4 
5 
6 
7
14 
My chest has felt tight 
1 
2 
3 
4 
5 
6 
7
15 
I have had episodes of breathlessness 1 
2 
3 
4 
5 
6 
7
16 
I have experienced chest pains 
1 
2 
3 
4 
5 
6 
7
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MEDICATION
In the last 2 weeks...
A huge
amount
A
considerable
A moderate
amount
A modest
amount
A small
amount
A tiny
amount
None at all
17 
I have worried about the side effects
of my medication for sarcoidosis
1 
2 
3 
4 
5 
6 
7
18 I have felt worse because of my
medication
1 
2 
3 
4 
5 
6 
7
19 
I have gained weight because of my
medication
1 
2 
3 
4 
5 
6 
7
SKIN
In the last 2 weeks...
A huge
amount
A considerable
amount
A moderate
amount
A modest
amount
A small
amount
A tiny amount
None at all
20 
I have been bothered by my skin
problems
1 
2 
3 
4 
5 
6 
7
21 
I have been concerned about changes
in the color of my skin lesions
1 
2 
3 
4 
5 
6 
7
In the last 2 weeks...
All of the
time
Most of
the time
A lot of
the time
Some of
the time
A little of
the time
Hardly any
of the time
None of
the time
22 
I have been embarrassed about my
skin
1 
2 
3 
4 
5 
6 
7
EYES
In the last 2 weeks...
All of the
time
Most of
the time
A lot of
the time
Some of
the time
A little of
the time
Hardly any
of the time
None of
the time
23 
I have had dry eyes 
1 
2 
3 
4 
5 
6 
7
24 
I have had difficulty with bright lights 1 
2 
3 
4 
5 
6 
7
25 
My eyes have been red 
1 
2 
3 
4 
5 
6 
7
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Status: Approved,  Date: 25 February 2022
26 
I have had pain in/or around the eyes 1 
2 
3 
4 
5 
6 
7
27 
I have had difficulty reading 
1 
2 
3 
4 
5 
6 
7
In the last 2 weeks...
A huge
amount
A
considerable
A moderate
amount
A modest
amount
A small
amount
A tiny
amount
None at all
28 I have had blurred vision 
1 
2 
3 
4 
5 
6 
7
29 
I have been worried about my 
eyesight
1 
2 
3 
4 
5 
6 
7
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Status: Approved,  Date: 25 February 2022
10.10. Appendix 10: Patient Global Assessment of Disease Severity (PGA-S)
Patient Global Assessment of Disease Severity (PGA-S)
This question refers to symptoms related to sarcoidosis and associated pulmonary hypertension.
Please choose the response that best describes the severity of your disease symptoms today.
(Check one response)
 None
 Very mild
 Mild
 Moderate
 Severe
 Very severe
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Status: Approved,  Date: 25 February 2022
10.11. Appendix 11: Clinician Global Impression of Severity (CGI-S)
Clinician Global Impression of Severity (CGI-S)
Please choose the response that best describes the severity of the patient’s sarcoidosis-associated
pulmonary hypertension (SAPH) symptoms today. (Check one response)
 None
 Very mild
 Mild
 Moderate
 Severe
 Very severe
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Status: Approved,  Date: 25 February 2022
10.12. Appendix 12: Clinician Global Impression of Change (CGI-C)
Clinician Global Impression of Change (CGI-C)
Please choose the response that best describes the severity of the patient’s sarcoidosis-associated
pulmonary hypertension (SAPH) symptoms compared to the randomization visit (Visit 2).
(Check one response)
 Very Much Better
 Moderately Better
 A Little Better
 No Change
 A Little Worse
 Moderately Worse
 Very Much Worse
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Status: Approved,  Date: 25 February 2022
10.13. Appendix 13: Child-Pugh Classification
The Child-Pugh classification will be used to assess the severity of the liver disease according to
the following table (Child-Pugh 2012; FDA Guidance 2003).
Clinical and Lab Parameters 
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 
encephalopathyINR 
 
International 
normalized ratio
*
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, 5 cycles per second waves.
• Grade 2: lethargic, time disoriented, inappropriate, asterixis, ataxia, slow triphasic waves.
• Grade 3: somnolent, stuporous, place disoriented, hyperactive reflexes, rigidity, slower waves.
• Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2 3 cycles per second delta activity.
Child Pugh class is obtained by adding score for each parameter (total points):
 
Class A: Score 5 6
 
Class B: Score 7 9
 
Class C: Score 10 15
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Status: Approved,  Date: 25 February 2022
10.14. Appendix 14: Study Conduct During a 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.
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. In any case, the following assessments and procedures will
be performed at the study site: informed consent, RHC, 6MWT / Borg CR Scale® (CR10)
/ SpO2, vital signs, weight, ECG, physical examination, arterial blood gas, DLCO, and
spirometry.
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Status: Approved,  Date: 25 February 2022
Related to protocol sections 8.3.4 - Clinical Safety Laboratory Assessments and 8.6 - Biomarkers
 When participant visits to the study site are not possible, laboratory assessments using a
suitably accredited local laboratory, or the use of home phlebotomy / home testing services
may be considered.
Related to protocol section 6.2 - Study Intervention, 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 considered.
Related to protocol section 10.3 - Regulatory and Ethical Considerations, Monitoring, On-Site
Audits
 The sponsor may apply remote monitoring and/or remote auditing if on-site visits are not
possible.
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Status: Approved,  Date: 25 February 2022
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 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.
 
Study participants do not require unblinding of the study intervention to receive a COVID-19
vaccine.
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Status: Approved,  Date: 25 February 2022
10.15. Appendix 15: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents (TOC).
Amendment 2 (21-Sep-2020)
Overall Rationale for the Amendment: The overall reason for the amendment is to clarify the Child-Pugh
assessments as needed for Exclusion Criterion #13, add a Coronavirus Disease 2019 (COVID-19) appendix,
adapt internal safety reporting processes, align with TransCelerate template, make minor corrections, and
perform editorial document formatting revisions.
Section Number
and Name
Description of Change 
Brief Rationale
Summary of Changes Table
(Amendment 1): Throughout
the protocol
Updated text in Brief Rationale: 
(deleted text as strikethrough and new 
text in bold) 
To explore safety and efficacy data 
that require a longer observation 
period such as time to clinical 
worsening (TTCW) or long-term 
safety in a controlled manner, all 
participants, whether or not on 
treatment, will continue in a double 
blind 
(DB) 
fashion 
until 
approximately 5 months after the last 
participant has completed the Week 
39 visit (time of primary analysis 
results available and unblinding). End 
of 
main 
observation 
period 
(EOMOP) 
(EOMOP 
visit 
is 
39 weeks 
[±1 
month] 
after 
randomization 
of 
the 
last 
participant). Participants who do 
not prematurely discontinue study 
intervention will continue taking
study intervention (DB) until the
results of the analysis Timepoint 1
are 
available 
(approximately
5 months).
As described in protocol Section 1.1
(Synopsis) 
and 
Section 
7.1
(Discontinuation of Study Intervention),
all participants whether or not on
treatment, will continue in a DB fashion
until EOMOP (EOMOP visit is 39
weeks [±1 month] after randomization
of the last participant). Participants who
do not prematurely discontinue study
intervention 
before 
EOMOP 
will
continue taking study intervention
(selexipag or placebo) during the DB
extension period. The DB extension
period starts in the evening of the day of
the EOMOP visit and ends with the EOT
visit. This period will last approximately
5 months until the results of the Analysis
Timepoint 1 are available. Participants
who prematurely discontinue study
treatment before EOMOP will not enter
the DB extension period.
Summary of Changes Table
(Amendment 1): Section 3
Objectives and Endpoints,
Hypothesis
Modified the following text in Brief 
Rationale: 
(deleted 
text 
as 
strikethrough and new text in bold) 
Given the limitations in sample size to 
explore TTCW in a controlled
manner, a longer observation period is
required and all participants, whether
or not on treatment, will continue in a
DB fashion until approximately 5
months after the last participant has
completed the Week 39 visit until
EOMOP (EOMOP visit is 39 weeks
[± 1 month] after randomization of
the last participant).
All participants, whether or not on
treatment, will continue in a DB fashion
until EOMOP, to explore TTCW in a
controlled 
manner 
for 
a longer
observation period.
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Status: Approved,  Date: 25 February 2022
Section Number
and Name
Description of Change 
Brief Rationale 
Section 1.3.1 Visits and 
assessments while taking 
double-blind study 
intervention  
The schedule of visits indicated that
study intervention dispensing/return
is applicable at the scheduled
telephone call Week 52 and the
6-monthly telephone calls thereafter,
which was deleted.
This 
was 
incorrect, 
no 
study
intervention dispensing/return will be
done at telephone calls.
Section 1.3.2 Visits and 
assessments after premature 
discontinuation of study
intervention  
Deleted ‘before EOMOP’ from the
title.
Footnote ‘a’ was updated: (deleted
text as strikethrough and new text in
bold)
The premature EOT visit is the first
visit after premature discontinuation
of study intervention. For Participants
who discontinue study intervention
and have their premature EOT visit
before the EOMOP visit will and
continue with visits and assessments
until the EOMOP visit. If the
premature EOT visit falls within the
visit window of any other scheduled
visit, these visits can be combined,
and assessments will not be repeated.
The change was made to footnote to
cover any premature discontinuation of
study intervention, whether before or
after EOMOP.
Section 4.2 Scientific 
Rationale for Study Design: 
Rationale for Right Heart 
Catherization
Modified the following text: (deleted
text as strikethrough and new text in
bold)
The MMrisk associated with RHC
procedures is considered acceptable
for this study as it is reported to be low
in centers experienced in treating PH
patients and performing RHC.
In addition, a historical RHC is
allowed for all participantsin the non
hemodynamic 
cohort 
and 
for
participants in the hemodynamic
cohort, if the historical RHC if it was
performed in accordance with the
guidance provided in Section 8.2.1.1
The cohorts were previously removed in
Amendment 1. This wording was
overlooked at that time and is now
deleted.
Section 5.1 Inclusion Criteria 
Criterion #7 was updated to: (deleted
text in strikethrough, and new text in
bold).
No 
treatment 
with 
PH specific
therapies 
or 
oral 
PH specific
monotherapy
Either not receiving PH-specific
treatment, or receiving treatment
with PH-specific oral monotherapy
(ie, riociguat or PDE5i or ERA); if on
oral PH-specific monotherapy then
treatment had has to be stable (ie, no
introduction of new therapies or
changes in dose) during for at least
The criterion was potentially misleading
and based on a request from the
Canadian health authority the inclusion
criterion was rephrased.
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Status: Approved,  Date: 25 February 2022
Section Number 
and Name
Description of Change 
Brief Rationale
90 days prior to both the RHC
qualifying for enrollment and
randomization 
and 
the 
RHC
qualifying for enrollment.
Section 5.1 Inclusion Criteria 
Criterion #8 was updated to: (deleted 
text in strikethrough, and new text in 
bold).
Stable sarcoidosis treatment regimen,
ie, no new specific anti-inflammatory
treatment for sarcoidosis for at least
90 days, and stable dose(s) for at least
30 days prior to both the RHC
qualifying for enrollment and
randomization 
and 
the 
RHC
qualifying for enrollment
For consistency, as the qualifying RHC
is always before randomization.
Section 5.2 Exclusion Criteria 
Criterion #6 was updated to: (deleted 
text in strikethrough, and new text in 
bold). 
Decompensated cardiac failure if not
under close supervision not receiving
optimal 
medical 
treatment
according to local guidelines.
To be more specific regarding which
participant may be eligible despite
having decompensated cardiac failure.
Section 5.2 Exclusion Criteria 
Criterion #8 was updated to: (new text 
in bold).
Implantable cardioverter defibrillator
(ICD) for secondary prevention
(current or planned).
To clarify the previous wording.
Section 5.2 Exclusion Criteria 
Updated Criterion #13: 
Added Appendix of Child-Pugh 
Classification as reference to the 
criterion. 
Added a note that: The assessment of 
hepatic impairment (Child-Pugh 
Score) must be fully documented
for patients who have clinical signs
and evidence (from central and/or
local lab) of hepatic impairment
(see Section 10.13 ).
Exclusion criterion #13 was clarified for
consistency 
in 
the 
selexipag
development program to indicate that
Child-Pugh scoring is only required in
patients with hepatic impairment and
does not apply to patients with no
hepatic impairment.
Section 
6.5 
Concomitant 
Therapy  
Deleted “qualifying for enrollment” 
and specified Week 26 for change in 
dose or initiation of new  diuretics 
and/or calcium channel blockers
within 1 week prior to RHC
:(deleted text in strikethrough, and
new text in bold).
Change in dose or initiation of new
diuretics and/or calcium channel
blockers within 1 week prior to RHC
qualifying for enrollmentat at Week
26.
To correct for an oversight and exclude
potential confounders for the efficacy
assessment.
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Status: Approved,  Date: 25 February 2022
Section Number 
and Name
Description of Change 
Brief Rationale
Section 7.1 Discontinuation of 
Study Intervention  
Added the following text: 
If a participant discontinues study 
intervention 
prematurely 
after 
EOMOP but before the study 
results are available and the 
treatment assignment is unblinded,
he/she will be asked to return for
the premature EOT visit within 7
days of last intake of study
intervention and for a safety follow-
up phone call 30 (+5) days after the
last intake of study intervention,
provided the participant’s consent
for this limited participation in the
study has not been withdrawn.
Clarification of the EOT and follow-up
process for participants who discontinue
study intervention prematurely before
the EOMOP visit and do not agree to
continue to perform the visits and
assessments as scheduled until the
EOMOP visit.
Section 7.1 Discontinuation of 
Study Intervention  
Section was updated to: (deleted text 
in strikethrough). 
Hepatic impairment occurs or is 
suspected. If hepatic impairment is 
suspected, a clinical assessment of
severity (Child Pugh score) should be
performed If hepatic impairment is
suspected, a clinical assessment of
severity (eg, Child-Pugh score)
must be performed and fully
documented. If a subject has
developed 
severe 
hepatic
impairment (Child-Pugh C) at any
time during the study, the study
intervention must be permanently
discontinued (see Section 10.13 ).
To align with the UPTRAVI label
which states that use of UPTRAVI in
severe hepatic impairment should be
avoided.
Section 5.2 Exclusion Criteria 
Criterion #15 was updated to: (deleted 
text in strikethrough and new text in
bold).
Treatment 
with 
prostacyclin,
prostacyclin analogues or IP receptor
agonists (ie, selexipag) during within
90 days prior to randomization and/or
prior to the RHC qualifying for
enrollment, except those given at
vasodilator testing during RHC.
To clarify the previous wording.
Section 6.8 
Treatment 
of 
Overdose 
Text moved from Section 8.5. 
Additional 
overdose 
definition 
included 
for 
participants 
with 
moderate hepatic impairment or
concomitantly 
taking 
moderate
CYP2C8 inhibitors which requires
dosing frequency reduction from
twice daily to once daily. Background
Location of text adjusted to match
TransCelerate template.
Text adapted to match changes with
internal safety reporting processes.
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Status: Approved,  Date: 25 February 2022
Section Number
and Name
Description of Change 
Brief Rationale
information for overdose added.
Management of overdose updated.
Deleted the text ‘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.’
Section 8 Study Assessments
and 
Procedures; 
Study-
Specific Materials
Deleted SAE Fax cover page from the 
Study-Specific Materials. 
The information previously included on
a separate fax cover sheet was integrated
into the SAE form and thus the add-on
form is not needed.
Section 8 Study Assessments
and Procedures; Overview
Revised the sentence: 
Actual dates and times of assessments 
(where applicable) will be recorded
in the eCRF.
The time is not collected for all
assessments.
Section 8.2.2.3.1 6MWT  
Added that:
Guidelines on execution of the
6MWT will be provided in the
separate SPHINX 6MWT guidance
document.
To clarify that the guidelines on
execution of the 6MWT will be a
separate document.
Section 8.2.2.3.2 Daily Life 
Physical Activity (DLPA) and 
Sleep Parameters 
Removed that participants will be
provided with a report summarizing
their individual activity levels during
the study.
Patient-specific reports will not be
available from the provider for this
study.
Section 
8.2.2.8 
Patient- 
Reported Outcomes 
Added that:
The following PRO instruments will
not be administered to illiterate
participants 
and 
will 
not 
be
administered to a participant when the
instrument is not available in a
language 
that 
can 
be 
easily
understood 
and 
read 
by 
the
participant.
The PRO instruments will not be
administered to a participant when it is
not available in a language that can be
understood and read by the participant.
Section 8.4.1 Time Period and 
Frequency 
for 
Collecting 
Adverse Event and Serious
Adverse Event Information
Updated the description for serious
adverse events.
To adapt the text to changes in internal
safety reporting processes.
Section 8.4.2 Follow-up of 
Adverse Events and Serious 
Adverse Events 
Updated the description for follow-up
of Adverse Events and Serious
Adverse Events.
Section 8.4.4 Pregnancy  
Updated 
the 
description 
for
pregnancy and included reporting
requirement for female partners of
male participants.
Section 10.4 Appendix 4: 
Adverse Events: Definitions
and Procedures for Recording, 
Evaluating, Follow-up, and 
Reporting 
Deleted the following:
Any 
failure 
of 
expected
pharmacologic action (ie, lack of
effect) 
of 
a 
sponsor 
study
intervention.
Text deleted to match the TransCelerate
template as criterion is only applicable
for marketed products used according to
the local label. As UPTRAVI is not
approved for SAPH, this is removed.
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Status: Approved,  Date: 25 February 2022
Section Number 
and Name
Description of Change 
Brief Rationale
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 8.4.1).
Section 10.13 Appendix 13: 
Child-Pugh Classification  
Added 
Child-Pugh 
Classification 
Appendix. 
To add Child-Pugh classification to
assess the severity of the liver disease.
Section 10.14 Appendix 14: 
COVID-19 Appendix  
Added COVID-19 Appendix. 
The COVID-19 appendix describes
potential measures to manage the impact
of the COVID-19 pandemic on the
study.
References 
Added new literature references: 
Holland AE, Spruit MA, Troosters T
et al. An official European R 
American Thoracic Society technical 
standard field walking tests in chronic
respiratory 
disease. 
Respir 
J.
2014;44:1428-1446.
Borg G. Borg’s Perceived Exertion
and Pain Scales. Champaign, II.
Human Kinetics. 1998.
FDA 2003. Guidance for Industry,
Pharmacokinetics in Patients with
Impaired Hepatic Function: Study
Design, Data Analysis, and Impact on
Dosing and Labeling. May 2003.
Child-Pugh. In: Vincent JL., Hall J.B.
(eds) Encyclopedia of Intensive Care
Medicine. 
Springer, 
Berlin,
Heidelberg. (2012).
Numbering for further references
were updated.
The Borg CR10 scale is newly
introduced as a tool in this study.
Added citations (literature references) to
support the respective sections.
Section 4.1 Overall Design  
Added citations (literature
references) to support the respective
sections. References to IB addendum
added.
Section 8.2.2.3.1 6MWT  
Section 8.2.2.5 Dyspnea (Pre- 
and Post-6MWT) 
Section 8.2.2.6 WHO FC
Section 8.2.2.8.1 PAH-
SYMPACT™ questionnaire
Section 8.2.2.8.2 SF-12
Section 10.1 Appendix 1: 
Abbreviations and Trademarks 
The Abbreviations list and Definition
of Terms were updated.
Throughout the protocol 
Minor 
editorial 
and 
document
formatting revisions.
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Status: Approved,  Date: 25 February 2022
Amendment 1 (5 December 2019)
Overall Rationale for the Amendment:
The sponsor has revised the study design following Health Authority  (HA) feedback that
recommended that the study should also be powered for clinical endpoints such as time to clinical
worsening, 6-minute walk distance (6MWD) and patient reported outcomes (PRO). However,
there is an absence of conclusive data for the effects of selexipag in patients with sarcoidosis-
associated pulmonary hypertension (SAPH) to guide the design of such a study. Therefore, in
agreement with the Steering Committee, the sponsor has decided to revise the scope to an
exploratory Phase 2 study to investigate the effects of selexipag on hemodynamics, other efficacy
endpoints, and on  safety in patients with SAPH. Consequently, elements of the study design,
sample size, secondary and exploratory objectives and endpoint definitions, requirements for
safety monitoring and statistical considerations have been amended.
Section number 
and Name
Description of Change 
Brief Rationale
Cover page 
Synopsis 
Section 1.3 Schedule of 
Activities 
Section 4.1 Overall Design, 
Section 4.2 Scientific Rationale 
for Study Design  
Section 4.4 EOS Definition 
Section 5 Study Population 
Section 6.1.3.1 Study 
Intervention Up-titration  
Section 7.1 Discontinuation of 
Study Intervention  
Section 8 Study Assessments and 
Procedures
The study title, study 
phase, study periods, visit 
schedule and 
assessments, and number 
of participants were 
changed. 
This is in accordance with HA feedback which
recommended that the study should be powered
for clinical endpoints such as time to clinical
worsening, 6-minute walk distance (6MWD) and
patient-reported outcome (PRO). However, as
there is an absence of conclusive data for the
effects of selexipag in patients with SAPH, in
agreement with the Steering Committee (SC) the
sponsor decided to revise the scope to an
exploratory Phase 2 study investigating the
effects of selexipag on hemodynamics, other
efficacy endpoints, and on safety in patients with
sarcoidosis-associated pulmonary hypertension
(SAPH).
Cover page and throughout the 
document 
The study acronym 
(PHASE) was changed to 
SPHINX.
The acronym has been changed due to copyright
reasons.
Throughout the protocol 
All references to double-
blind (DB) and open-
label (OL) study
intervention as well as to
the two cohorts and the
OL period have been
removed. The term ‘study
intervention’ is used to
refer to DB intervention
(placebo or selexipag).
The revised study design does not include an OL
period. To explore safety and efficacy data that
require a longer observation period such as time
to clinical worsening (TTCW) or long-term
safety in a controlled manner, all participants,
whether or not on treatment, will continue in a
DB  fashion until approximately 5 months after
the last participant has completed the Week 39
visit (time of primary analysis results available
and unblinding). Continued treatment with study-
intervention until the study results are available
will allow collection of additional safety data so
that investigators can make an informed decision
on post-study therapy based on the study results
(risk-benefit of selexipag in SAPH) and the actual
treatment received by the study participants.
Section 1.3 Schedule of
Activities
Instead of providing only
one schedule of activities
As participants who discontinue from study
intervention before the End of Main Observation
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Section number 
and Name
Description of Change 
Brief Rationale
applicable to all 
participants whether or 
not on study intervention, 
a separate schedule of 
activities for participants 
who prematurely 
discontinue study
intervention is provided
in Section 1.3. Footnotes
were changed
accordingly.
Period (EOMOP) visit should continue with all
visits and assessments up to the EOMOP,
separate schedules of activities are provided for
participants on study intervention (Section 1.3.1)
and 
for 
participants 
who 
prematurely
discontinued study intervention (Section 1.3.2.
Section 3 Objectives and 
Endpoints, Hypothesis 
Pulmonary vascular 
resistance (PVR) 
assessment and analysis 
changed from Week 20 to 
Week 26. Assessment 
and analysis of other 
clinical endpoints, 
including daily life 
physical activity and 
PROs changed from up to 
Week 52 to up to 
Week 39. TTCW will be 
analyzed up to EOMOP 
instead of up to Week 52. 
The timepoint of the assessment of the primary
endpoint PVR has been moved from Week 20 to
Week 26 for consistency with the timeframe for
repeated/follow-up right heart catheterization
(RHC) in clinical practice. Other clinical
endpoints, such as daily life physical activity and
PROs will be assessed and analyzed up to
Week 39 to explore the correlation between the
effect of study intervention on cardiopulmonary
hemodynamics (change in PVR up to Week 26)
and its translation into clinical and functional
changes over time. Given the limitations in
sample size to explore TTCW in a controlled
manner, a longer observation period is required
and all participants, whether or not on treatment,
will continue in a DB fashion until approximately
5 months after the last participant has completed
the Week 39 visit.
Section 3 Objectives and 
Endpoints 
All secondary and 
exploratory objectives are 
grouped under 
exploratory objectives, 
and the wording was 
revised as necessary to 
match the study objective 
and analysis plan. 
Assessment of daily life 
physical activity (DLPA) 
and sleep parameters up 
to Week 39 (DLPA) by
actigraphy were added.
Given the limitation in sample size in this rare
indication, no secondary endpoints are defined
for which hypotheses are tested with adequate
control of type I error. All efficacy endpoints
other than PVR are exploratory, and only a brief
general description on the planned analyses are
described in the protocol. Full details will be
provided in the Statistical Analysis Plan.
Assessment of DLPA and sleep parameters was
added to explore as a novel endpoint in SAPH
patients.
Throughout the document 
The requirement for 
collection of medical 
resource utilization data
has been removed.
In line with the revised study strategy, collection
of this information is not required.
Throughout the document 
All reference to HRCT  
(High-resolution 
computed tomography)
and cardiac MRI are
removed, including
related inclusion and
exclusion criteria.
To reduce the burden for participants, the HRCT
and cardiac MRI substudies have been removed.
Section 2.3.5 Overall 
Benefit/Risk Assessment 
Independent Data 
Monitoring Committee 
Protocol Version 2 does not include decision-
making based on interim analysis. Thus, in line
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Section number
and Name
Description of Change 
Brief Rationale 
Section 4.1 Overall Design  
Section 6.3 Measures to 
Minimize Bias –Randomization 
and Blinding 
Section 9.5.2.1 Study Safety 
Monitoring
Section 9.6 Data monitoring
Committee
Appendix 3 Committees
Structure
(IDMC) responsibilities
are now covered by the
sponsor’s Data
Monitoring Committee
(DMC).
with the company requirements for a DMC in a
non-confirmatory study, and in agreement with
the SC, an IDMC is not required. To ensure
participants’ safety as well as data quality, the
safety information will be monitored and
reviewed on a continuous basis by a sponsor
DMC not otherwise involved in the conduct of
the study, rather than by an IDMC.
Section 9 Statistical 
Considerations 
The sample size was
reduced from 150 to 74
due to the removal of the
interim analysis rules.
The primary estimand
was changed from a
treatment policy estimand
to a “while on-treatment”
estimand.
The HRCT Analysis Set
(HAS), 
Cardiac 
MRI
Analysis Set (MAS) and
Selexipag-Initiated 
Set
(SIS) analysis populations
were removed, and the
Hemodynamic Set (HS)
set was replaced by the
Full Analysis Set (FAS),
which was updated from
“All participants assigned
to study intervention” to
“All randomized patients
who took at least one dose
of study intervention and
for whom a valid baseline
PVR value could be
obtained”.
The detailed analysis plan
and 
sample 
size
considerations for the
secondary endpoints was
removed and substituted
with a high-level plan for
the analysis of the “other
efficacy endpoints”.
With the removal of the initially planned interim
analysis on PVR for futility  and with TTCW
becoming an exploratory endpoint, the required
total sample size is reduced to 74 participants; the
study will be adequately powered for analysis of
the primary efficacy endpoint (PVR) as per the
original assumptions. The analysis timepoints are
revised to match the study design modifications.
Section 8.2.2.3.1 6MWT  
Requirements 
for 
the
length of the corridor for
the 6-minute walk test
(6MWT) were removed
and will be included in the
separate 
guidance
document separate to the
protocol.
For consistency with company requirements for
the 6MWT.
Section 3 Objectives and 
Endpoints 
The endpoint: Change
from baseline in forced
As per SC recommendation.
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Section number
and Name
Description of Change 
Brief Rationale
vital capacity (FVC) and
diffusing capacity of the
lung for carbon monoxide
(DLCO) was moved from
exploratory 
to 
safety
endpoints.
Section 3 Objectives and
Endpoints
Section 8.3 Safety Assessments
Section 1.3 Schedule of
Activities
Monitoring of arterial 
blood gas (ABG) was
added 
as 
a 
safety
assessment.
As per SC recommendation.
Section 3 Objectives and 
Endpoints 
Section 8.2.2.1 Clinical 
Worsening and Hospitalization  
The definition of clinical 
worsening 
(CW) 
components is modified 
to include all-cause death, 
non-planned pulmonary 
hypertension (PH)-related
hospitalization, increase
in WHO functional class
(FC), 
lung
transplantation, 
atrial
balloon septostomy and
initiation of parenteral or
new class of PH-specific
therapy 
for 
clinical
worsening.
Following the SC recommendation, the CW
component definition has been refined to better
reflect relevant determinants of CW events in
patients with SAPH, and also requires
adjudication.
Section 4.1 Overall Design 
Section 8.2.2.1 Clinical 
Worsening and Hospitalization  
Appendix 3 Committees 
Structure 
Addition of a clinical 
event committee (CEC) 
responsible 
for 
adjudication of cases, ie, 
hospitalization, increase 
in WHO FC and initiation 
of 
new 
PH-specific
therapy.
To better reflect relevant determinants of CW in
patients with SAPH the components for the
TTCW endpoint were refined based on the
recommendation of the SC. A sub-committee of
the SC will serve as the CEC responsible for
adjudication of CW events.
Section 5.1 Inclusion criteria 
Section 6.5 Concomitant Therapy  
Inclusion 
criterion 
7 
regarding 
PH-specific 
therapy was reworded to 
clarify that only PH- 
specific monotherapy (ie, 
endothelin 
receptor 
antagonist 
or
phosphodiesterase type-5
inhibitor or riociguat) is
allowed for inclusion.
Section 6.5 concomitant
medications was modified
accordingly.
To be able to understand the treatment effect
resulting from selexipag treatment it is important
to reduce any confounding factors, ie,
concomitant PH-specific therapies. Therefore,
SAPH patients who are receiving combination
PH-specific therapy are not eligible.
Section 8 Study Assessments and 
Procedures 
The 6MWT starter kit will 
not be provided by default 
to all sites. 
Only sites experienced and equipped for
performing the 6MWT will be selected for this
study. As part of the site selection it will be
assessed if any materials/equipment needs to be
provided by the sponsor.
Appendix 6 
Appendix 7 
Appendix 8 
Information provided in 
Appendix 
6 
(RHC), 
Appendix 7 (6MWT) and
To allow for dedicated training (other than
protocol training) and documentation of these for
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Section number 
and Name
Description of Change 
Brief Rationale
References to the appendices 
throughout the protocol 
Appendix 
8 
(Borg 
Dyspnea 
Index scale) 
were removed from the
protocol and will instead
be provided as separate
guidance 
documents
outside of the protocol.
All references to these
appendices 
were
removed.
study personnel involved in performing the RHC
and 6MWT.
Section 5.1 Inclusion Criteria 
Inclusion criterion #5, 
eligibility 
requirements 
for the PVR value was 
modified 
from 
PVR
≥240 dyn*sec/cm5
(≥3 WU) to PVR ≥320
dyn*sec/cm5 (≥4 WU).
To ensure recruitment of participants with
substantially impaired pulmonary vascular
function.
Section 5.1 Inclusion Criteria 
Inclusion criteria #10 and 
#11 
regarding 
forced 
expiratory volume criteria 
were adjusted.
Following the SC recommendation to exclude
patients with moderate and severe pulmonary
obstruction and restriction.
Section 5.2 Exclusion criteria 
Addition 
of a 
new 
exclusion criterion (# 27) 
to clarify that pregnant
women are not allowed to
participate in this study.
Added for clarity at the request of the UK Ethics
Committee.
Appendix 5 Contraceptive and 
Barrier Guidance and Collection 
of Pregnancy Information 
Bilateral 
tubal 
ligation/occlusion 
was 
removed 
from 
the 
definition of a woman 
being 
of 
non-child- 
bearing 
potential.
Therefore, women who
have undergone bilateral
tubal 
ligation/occlusion
are considered to be of
childbearing potential.
Bilateral 
tubal 
ligation/occlusion 
is 
not
considered a method of permanent sterilization as
it is potentially reversible. Bilateral tubal
ligation/occlusion is included in the list of
acceptable methods of contraception.
Appendix 5 Contraceptive and 
Barrier Guidance and Collection 
of Pregnancy Information – 
Examples of Acceptable 
Contraceptives in this Study  
Bilateral 
tubal 
occlusion/ligation 
procedure was removed 
from the definition of a
woman being not of
childbearing 
potential.
Bilateral 
tubal
occlusion/ligation 
are
acceptable methods of
contraception.
Bilateral tubal occlusion/ligation procedure is
potentially reversible, therefore these women will
still be considered as of childbearing potential.
Section 5.4 Screen Failures 
Re-screened participants 
will 
be 
assigned 
a 
different 
participant 
number than for the initial
screening.
Internal 
sponsor 
decision: 
screen-failed
participants will be assigned a new participant
number in case of re-screening
Section 8 Study Assessments and 
Procedures 
Optional 
patient 
experience survey was 
removed. 
Participant feedback from different clinical trials
was gathered and used to improve the design and
conduct of future trials. Meanwhile, sufficient
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Section number
and Name
Description of Change 
Brief Rationale 
Section 1.3 Schedule of
Activities − Qualitative
Interviews
Appendix 3 Data Quality
Assurance and Source
Documents
information was collected from enough studies
for its primary purpose. The conduct of further
similar surveys for new studies is not required, as
it would increase the burden for participants.
Section 6.4 Study Intervention 
Compliance 
It was clarified that
compliance calculated by
study personnel is to be
documented in the source
documents.
Clarification of requirements for expected source
data documentation.
Section 8 Study Assessments and 
Procedures − 
Table 2 and associated text − 
Volume of Blood to be Collected 
from Each Participant per Visit 
Required amount of blood
adjusted due to removal
of 
the 
OL 
period.
Provision made for 1 mL
to 3 mL and 2 mL of
blood to be collected for
cardiac 
output 
(CO)
according 
to 
Fick’s
method 
and 
ABG,
respectively.
Removal of the OL period decreased the amount
of blood required to be collected. Some labs may
use Fick’s method for the calculation of CO
during RHC. This and ABG would require
additional collection of approximately 1 mL to
3 mL and 2 mL of blood, respectively.
Throughout the protocol 
Minor 
grammatical,
formatting, and spelling
changes were made.
Minor errors were noted and corrected.
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11. 
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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor’s Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Actelion Pharmaceuticals Ltd. (a Janssen pharmaceutical company of Johnson &
Johnson)
Signature: [electronic signature appended at the end of the protocol] 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD
NCT03942211


Signature
User 
Date 
Reason
25-Feb-2022
14:36:08
(GMT)
Document Approval
25-Feb-2022
17:41:26
(GMT)
Document Approval
PPD
PPD
NCT03942211

SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 01 December 2022
Actelion Pharmaceuticals Ltd
Statistical Analysis Plan
A multicenter, randomized, double-blind, placebo-controlled study in participants with 
sarcoidosis-associated pulmonary hypertension (SAPH) to assess the efficacy and safety of 
oral selexipag.
Protocol AC-065D301; Phase 2
JNJ-67896049  (selexipag)
Status:
Approved
Date:
01 December 2022
Prepared by:
Janssen Research & Development, LLC; Janssen Research & Development, 
a division of Janssen Pharmaceutica NV
Document No.:
905229
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.
NCT03942211


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065D301
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 01 December 2022
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
VERSION HISTORY..................................................................................................................................... 4
1.
INTRODUCTION.................................................................................................................................. 5
1.1.
Objectives and Endpoints (as per protocol)..................................................................................... 5
1.2.
Study Design.................................................................................................................................... 8
1.2.1.
Analysis Timepoints.................................................................................................................... 11
1.2.2.
DMC and Steering Committee.................................................................................................... 11
1.2.3.
Randomization and blinding ....................................................................................................... 11
2.
STATISTICAL HYPOTHESES.......................................................................................................... 12
3.
SAMPLE SIZE DETERMINATION....................................................................................................12
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS.....................................................................13
5.
STATISTICAL ANALYSES............................................................................................................... 13
5.1.
General Considerations ................................................................................................................. 13
5.1.1.
Visit Windows ............................................................................................................................. 13
5.1.2.
Study Day and Relative Day....................................................................................................... 14
5.1.3.
Baseline ...................................................................................................................................... 14
5.1.4.
Imputation Rules for Missing Date/Time of Onset/Resolution.................................................... 14
5.2.
Participant Dispositions.................................................................................................................. 16
5.3.
Primary Endpoint(s) Analysis......................................................................................................... 16
5.3.1.
Definition of Endpoint(s) ............................................................................................................. 16
5.3.2.
Analysis Methods........................................................................................................................ 17
5.4.
Secondary Endpoint(s) Analysis .................................................................................................... 17
5.5.
Tertiary/Exploratory Endpoint(s) Analysis...................................................................................... 17
5.5.1.
Time To Clinical Worsening (TTCW).......................................................................................... 17
5.5.2.
6-Minute Walk Distance (6MWD) and Borg CR Scale® (CR10)................................................ 17
5.5.3.
Proportion of participants with oxygen desaturation post 6MWT up to Week 39....................... 17
5.5.4.
Proportion of participants with improvement/no change/worsening versus baseline in 
WHO FC up to Week 39............................................................................................................. 17
5.5.5.
Daily life physical activity (DLPA) and sleep parameters up to Week 39................................... 18
5.5.6.
Time to all-cause death up to EOMOP....................................................................................... 20
5.5.7.
Rate of all-cause death or unplanned PH-related hospitalizations up to EOMOP..................... 20
5.5.8.
Change from baseline up to Week 39 in SF-12 scores..............................................................20
5.5.9.
Change from baseline up to Week 39 in the KSQ scores..........................................................20
5.5.10.
Change from baseline up to Week 39 in the PAH-SYMPACT scores ....................................... 20
5.5.11.
Change from baseline up to Week 39 in the PGA-S scores ...................................................... 20
5.5.12.
Change from baseline up to Week 39 in the CGI-S scores........................................................ 20
5.5.13.
Change from baseline up to Week 39 in the CGI-C scores ....................................................... 20
5.5.14.
Change from baseline up to Week 39 in NT-proBNP serum levels ........................................... 20
5.5.15.
Change from baseline up to Week 39 in other hemodynamic variables (including 
cardiac output [CO], CIn, mean right atrial pressure [mRAP]) ................................................... 20
5.5.16.
Change from baseline up to Week 39 in the number of low-risk criteria.................................... 20
5.6.
Safety Analyses ............................................................................................................................. 21
5.6.1.
Extent of Exposure ..................................................................................................................... 21
5.6.2.
Adverse Events........................................................................................................................... 21
5.6.3.
Additional Safety Assessments .................................................................................................. 22
5.6.3.1.
Clinical Laboratory Tests......................................................................................................... 22
5.6.3.2.
Vital Signs and Physical Examination Findings.......................................................................24
5.6.3.3.
Electrocardiogram ................................................................................................................... 25
5.6.3.4.
Other Safety Parameters......................................................................................................... 25
5.7.
Other Analyses............................................................................................................................... 25
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JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065D301
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Status: Approved, Date: 01 December 2022
5.7.1.
Pharmacokinetics ....................................................................................................................... 25
5.7.2.
Immunogenicity........................................................................................................................... 25
5.7.3.
Pharmacodynamics .................................................................................................................... 25
5.7.4.
Pharmacokinetic/Pharmacodynamic Relationships ................................................................... 25
5.7.5.
Biomarkers.................................................................................................................................. 25
5.7.6.
Health Economics....................................................................................................................... 26
5.7.7.
Other Variables and/or Parameters............................................................................................ 26
5.7.8.
Definition of Subgroups .............................................................................................................. 26
5.8.
Interim Analyses............................................................................................................................. 26
5.8.1.
Data Monitoring Committee (DMC) or Other Review Board ...................................................... 26
6.
SUPPORTING DOCUMENTATION ..................................................................................................27
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 27
6.2.
Appendix 2 Changes to Protocol-Planned Analyses ..................................................................... 28
6.3.
Appendix 3 Demographics and Baseline Characteristics.............................................................. 29
6.4.
Appendix 4 Protocol Deviations ..................................................................................................... 29
6.5.
Appendix 5 Prior and Concomitant Medications............................................................................31
6.6.
Appendix 6 Medical History ........................................................................................................... 32
6.7.
Appendix 7 Intervention Compliance ............................................................................................. 33
6.8.
Appendix 8 Adverse Events of Special Interest.............................................................................34
6.9.
Appendix 9 Medications of Special Interest................................................................................... 35
6.10.
Appendix 10 Laboratory Toxicity Grading...................................................................................... 36
7.
REFERENCES................................................................................................................................... 37
NCT03942211


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065D301
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Status: Approved, Date: 01 December 2022
VERSION HISTORY
Table 1 – SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1.0
14 May 2019
Not Applicable
Initial release. 
2.0
05 April 2022
Changes in 
primary/secondary/exploratory 
endpoints.
Update the full SAP according to 
major protocol amendments 2, 3
and 4 (full change in study 
objectives/strategy). See protocol 
version 2 (05 Dec 2019), version 
3 (21 Sep 2020) and version 4 
(25 Feb 2022) for all details.
3.0
01 December 2022
Update the SAP for a synoptic 
CSR
Update after announcement of 
study termination by the Sponsor 
(26 Sep 2022). Reporting 
simplified. All listings are kept, 
and all the analyses already 
planned and produced for DMC.
NCT03942211


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065D301
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Status: Approved, Date: 01 December 2022
1.
INTRODUCTION
This Statistical Analysis Plan (SAP) presents the planned analyses for the primary endpoint, 
pulmonary vascular resistance (PVR) up to Week 26, exploratory efficacy endpoints and safety 
endpoints. It also covers the needs for regular internal data monitoring committee (DMC) 
meetings. This current SAP presents a simplified version of the previous final SAP covering the 
analyses to be performed following the Sponsor decision to prematurely terminate the study due 
to slow enrollment (decision on 26 Sep 2022). Reporting is simplified: all listings and all the 
analyses already planned and produced for DMC are kept. For efficacy, all parameters will be 
listed only.
This SAP is referring to the documents listed in Table 2.
Table 2
Study Documents
Document
Date,
Version
Study Protocol
25 February 2022
Amendment 3 (Version 4)
Internal DMC Charter
28 January 2020
Version 1
1.1.
Objectives and Endpoints (as per protocol)
Objectives
Endpoints
Primary 
!
To assess the effect of selexipag versus 
placebo 
on 
pulmonary 
vascular 
resistance (PVR) in participants with 
sarcoidosis
associated 
pulmonary 
hypertension (SAPH) up to Week 26.
!
PVR on study intervention up to Week 26 expressed 
as percent of the baseline value. 
Exploratory
!
To evaluate the effect of selexipag 
versus placebo on time to clinical 
worsening (TTCW).
!
TTCW
up to End-of-Main-Observation-period 
(EOMOP) defined as at least one of the following 
components:
o
All-cause death
o
Unplanned
pulmonary hypertension
(PH)-
related hospitalization
o
Increase in WHO functional class (FC)
o
Lung transplantation
o
Atrial balloon septostomy
o
Initiation of parenteral or new class of PH-
specific therapy for clinical worsening
NCT03942211


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065D301
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Status: Approved, Date: 01 December 2022
Objectives
Endpoints
!
To evaluate the effect of selexipag
versus placebo on exercise capacity.
!
Change from baseline in 6MWD, Borg CR Scale®
(CR10), oxygen saturation, and WHO FC at Week 
39 and over time.
!
Proportion of participants with oxygen desaturation 
post-6-minute walk test (6MWT) at Week 39 and 
over time
(identified by decrease in oxygen 
saturation [SpO2] by at least 5% from pre-6MWT).
!
To evaluate the effect of selexipag vs 
placebo on daily life physical activity 
(DLPA) and sleep parameters
!
Change from baseline to Week 39 in actigraphy-
assessed DLPA as measured by:
o
Total DLPA in counts per minute
o
Total 
volume 
of 
activity 
(above 
sedentary)
o
Daily time spent (minutes) in non-
sedentary activity 
o
Percentage of daily time spent in non-
sedentary activity 
o
Moderate to vigorous physical activity 
(MVPA)
o
Time spent in the different activity 
categories
!
Change from baseline to Week 39 in sleep 
parameters: 
o
Total sleep time (TST; minutes)
o
Wake 
after 
sleep 
onset 
(WASO; 
minutes)
o
Number of awakenings
o
Sleep efficiency (percentage)
!
To evaluate the effect of selexipag 
versus placebo on WHO FC.
!
Proportion of participants with improvement, 
worsening and no change from baseline in WHO FC 
at Week 39 and over time.
!
To evaluate the effect of selexipag 
versus placebo on death or PH-related 
hospitalizations 
!
Rate of all-cause death or unplanned PH-related 
hospitalization up to EOMOP.
!
Time to all-cause death up to EOMOP.
NCT03942211


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065D301
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Status: Approved, Date: 01 December 2022
Objectives
Endpoints
!
To evaluate the effect of selexipag 
versus placebo on patient-reported 
outcomes (PROs) assessed by the 
12-Item Short Form Health Survey 
(SF-12), 
King’s 
sarcoidosis 
questionnaire 
(KSQ), 
Pulmonary 
Arterial Hypertension-Symptoms and 
Impact (PAH-SYMPACT), and Patient 
Global 
Assessment 
of 
Severity 
(PGA-S)
!
Change from baseline up to Week 39 in SF-12 
scores.
!
Change from baseline up to Week 39 in KSQ scores.
!
Change from baseline up to Week 39 in 
PAH-SYMPACT scores.
!
Change from baseline up to Week 39 in PGA-S 
scores.
!
To evaluate the effect of selexipag 
versus placebo on clinician-reported 
outcomes (CROs) assessed by the 
Clinician 
Global 
Impression
of 
Severity (CGI-S) and Clinician Global 
Impression of Change (CGI-C)
!
Change from baseline up to Week 39 in CGI-S 
scores.
!
Change from baseline up to Week 39 as measured by 
CGI-C scores.
!
To evaluate the effect of selexipag on 
the number of PH low-risk criteria
!
Absolute and change from baseline in the number of 
low-risk criteria based on WHO FC, 6MWD, 
N-terminal 
pro 
b-type 
natriuretic 
peptide 
(NT-proBNP), and cardiac index (CIn) up to Week 
26.
!
To evaluate the effect of selexipag on 
NT-proBNP
!
Change from baseline in NT-proBNP serum levels 
up to Week 39.
!
To evaluate the effect of selexipag on 
disease and pathway-related serum 
biomarkers 
!
Change from baseline in serum biomarkers and 
associations between serum biomarker levels and 
clinical response and baseline characteristics up to 
Week 39.
!
To 
evaluate 
the
change 
in 
hemodynamic variables other than 
PVR
!
Change from baseline in other hemodynamic 
variables (including cardiac output [CO], CIn, mean 
right atrial pressure [mRAP]) up to Week 26.
Safety
!
To assess the overall safety of selexipag
!
Intervention-emergent AEs.
!
Intervention-emergent prostacyclin-associated AEs.
!
Serious adverse events (SAEs) up to End-of-Study 
(EOS).
!
AEs leading to premature discontinuation of study 
intervention.
!
Intervention-emergent AEs of special interest 
(eg, hypotension, anemia, hyperthyroidism).
!
Change in vital signs (systolic and diastolic arterial 
blood pressure and pulse rate) and body weight from 
baseline to all assessed timepoints during the study.
NCT03942211


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065D301
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Status: Approved, Date: 01 December 2022
Objectives
Endpoints
!
Intervention-emergent 
marked 
laboratory 
abnormalities.
!
Change from baseline in supplemental oxygen rate.
!
Change from baseline in forced vital capacity (FVC) 
and diffusing capacity of the lung for carbon 
monoxide (DLCO).
!
Change from baseline in arterial blood gas 
parameters.
1.2.
Study Design
This is a prospective, randomized, double-blind (DB), placebo-controlled, multicenter, 
interventional study in men and women ≥18 and ≤75 years of age with SAPH. Study intervention 
will be up-titrated to allow each participant to reach their individual maximum tolerated dose
(iMTD), in the range of 200 μg to 1,600 μg twice daily. For participants with moderate hepatic 
impairment (Child-Pugh Class B) or who are concomitantly taking a moderate cytochrome P450 
(CYP)2C8 inhibitor(s) the dosing frequency is once daily.
The study starts with the first Informed Consent Form (ICF) signed by the first participant and 
ends with the last safety follow-up telephone call (TC) or visit of the last participant. The study 
comprises the following periods:
!
A screening period of up to 30 days: starts with the signature of the ICF and ends with the 
participant’s randomization at Visit 2, Day 1. The screening period should last at least 14 days 
to allow collection of baseline data for daily life physical activity (DLPA), sleep parameters, 
and Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT™).
!
Intervention and observation periods:
∀
A main observation period (MOP) that starts with the participants’ randomization at Visit 
2, Day 1 and with a titration phase of up to 12 weeks. Participants receive double-blind 
study intervention (selexipag or placebo) during this period. It ends on the day of the 
EOMOP visit. The EOMOP visit is the data cut-off for the primary efficacy and safety 
analyses. The EOMOP visit for all participants is planned at 39 Weeks ±1 month after 
randomization of the last participant. The duration of the MOP will be different for each 
individual participant and will depend on the time of each participant’s individual date of 
randomization.
o
Participants who prematurely discontinue study intervention before the EOMOP visit 
will continue to perform visits and assessments as scheduled until the EOMOP visit.
o
For participants who prematurely discontinue study intervention before the EOMOP 
visit and who disagree to perform visits and assessments as scheduled until the 
EOMOP visit, long-term follow-up information regarding their survival status will 
be collected yearly until death or the time of EOMOP.
NCT03942211


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065D301
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
9
Status: Approved, Date: 01 December 2022
!
A DB extension period extending intervention for participants who do not prematurely 
discontinue study intervention before EOMOP: The period starts in the evening of the day of 
the EOMOP visit and ends with the end-of-treatment (EOT) visit. This period will last 
approximately 5 months. All participants entering the DB extension period will continue
taking blinded study intervention (selexipag or placebo) during this period. Study intervention 
allocation will be unblinded approximately 1 month before the expected EOT visit.
!
A safety follow-up period starting on the day after the last dose of study intervention and 
ending with the safety follow-up call at the End-of-Study (EOS) visit. For an individual 
participant, EOS visit is defined as follows:
∀
For participants who complete the treatment, EOS visit is defined as the safety follow-up 
visit (TC) 30 (+5) days after last dose of study intervention.
∀
For participants who prematurely discontinue study intervention for any reason before 
EOMOP visit (except for withdrawal from the study) but complete the main observation 
period, EOS visit corresponds to the last visit, which is either the EOMOP visit or the 
safety follow-up TC, whichever occurs last.
∀
For participants who prematurely discontinue study intervention for any reason before 
the EOMOP visit and who decline to continue with visits and assessments up to the 
EOMOP visit, but agree to the collection of long-term survival information, the EOS visit 
corresponds to the last visit or TC before study discontinuation.
∀
For participants who prematurely discontinue study intervention between the EOMOP 
and EOT visits for any reason (except for withdrawal from the study), the EOS visit 
corresponds to the safety follow-up TC.
∀
For participants who complete the treatment and who are entering a continued access 
program (ie, other open-label extension study or post-trial access), the EOS visit is 
defined as the EOT visit and enrollment in the continued access program must occur on 
the day of the last visit in the SPHINX study.
Following the study premature termination by the sponsor, the EOMOP will refer to a premature 
EOMOP. 
NCT03942211


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065D301
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Status: Approved, Date: 01 December 2022
See figure below for the study design schematic overview.
A sponsor Data Monitoring Committee (DMC), Clinical Event Committee (CEC), and Steering 
Committee (SC) will be established.
The sponsor DMC (internal) has overall responsibility for safeguarding the interests of participants 
and will review safety data throughout the study. The sponsor DMC will provide recommendations 
to the study team.
The CEC will be a sub-committee of the SC that will review and adjudicate the following cases: 
hospitalization, WHO FC increase, and initiation of PH-specific therapy (not to be performed 
because of study premature termination). An SC is involved in the study design and will provide 
guidance on the study conduct and study publications.
The End-of-Study (EOS) at study level is considered as the last visit or safety follow-up TC, 
whichever occurs last, for the last participant in the study.
NCT03942211


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065D301
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Status: Approved, Date: 01 December 2022
1.2.1.
Analysis Timepoints
Following the study premature termination by the sponsor, the final analysis will be performed at 
the final database lock only, when all participants have completed the safety follow-up phone call 
or discontinued prematurely.
1.2.2.
DMC and Steering Committee
A sponsor Data Monitoring Committee (DMC) and a Steering Committee will be established.
The sponsor DMC (internal) has the overall responsibility for safeguarding the interests of 
participants and will review on regular basis the results of safety analyses performed by an 
unblinded statistical support group (SSG) independent from the study team. The DMC will provide 
recommendations to the study team. The committee is governed by a dedicated DMC charter.
A Steering Committee is involved in the study design and will provide guidance on the study 
conduct and study publications. The committee is governed by a dedicated Steering Committee 
charter.
1.2.3.
Randomization and blinding
Treatment Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Participants will be randomly assigned 
to 1 of 2 treatment groups based on a computer-generated randomization schedule prepared before 
the study under the supervision of the sponsor. The randomization will be stratified by PH-specific 
therapy at baseline (yes vs no). The Interactive Web Response System (IWRS) will assign a unique 
treatment code, which will dictate the treatment assignment and matching study treatment kit for 
the participant. The requestor must use his or her own user identification and personal 
identification number when contacting the IWRS and will then give the relevant participant details 
to uniquely identify the participant.
Blinding
The study period up to EOMOP will be performed in a DB fashion. Unblinding will occur after 
all patients completed EOMOP.
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual participant.
Under normal circumstances, the investigator and study personnel, the participants, sponsor 
personnel, and CRO personnel involved in the conduct of the study will remain blinded to the 
study treatment until EOMOP analysis timepoint, or until the study is stopped prematurely. In 
order to preserve the blind of each individual participant until EOMOP analysis timepoint, 
randomization codes and, if required, the translation of randomization codes into treatment and 
NCT03942211


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065D301
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Status: Approved, Date: 01 December 2022
control groups will be disclosed to those authorized and only for those participants included in the
analyses for the DMC. An internal SSG will conduct the analyses and present unblinded results to 
the DMC (see specific DMC charter).
The investigator may in an emergency determine the identity of the treatment by contacting the 
IWRS. While the responsibility to break the treatment code in emergency situations resides solely 
with the investigator, it is recommended that the investigator contact the sponsor or its designee if 
possible to discuss the particular situation, before breaking the blind. Telephone contact with the 
sponsor or its designee will be available 24 hours per day, 7 days per week. In the event the blind 
is broken, the sponsor must be informed as soon as possible. The date, time, and reason for the 
unblinding must be documented in the Investigator Site file and in the appropriate section of the 
eCRF, and in the source document. The documentation received from the IWRS indicating the 
code break must be retained with the participant’s source documents in a secure manner.
If a suspected unexpected serious adverse reaction (SUSAR) occurs for a participant in the study, 
unblinded SUSAR information will be provided to DMC and respective health authorities and 
Independent Ethics Committees (IECs) or Institutional Review Boards (IRBs) only. SUSARs will 
be reported to investigators in a blinded fashion. The treatment assignment will not be 
communicated to site personnel or to sponsor study team.
Participants who have had their treatment assignment unblinded may stay on study treatment after 
unblinding provided the following conditions are met: emergency unblinding for accidental or 
intentional overdose or medication error.
2.
STATISTICAL HYPOTHESES
The primary objective is: " To assess the effect of selexipag versus placebo on pulmonary vascular 
resistance (PVR) in participants with sarcoidosis associated pulmonary hypertension (SAPH) up 
to Week 26."
As the study is prematurely terminated, no formal hypothesis will be tested, and all efficacy 
parameters will be listed only.
3.
SAMPLE SIZE DETERMINATION
In a clinical study with bosentan in participants with SAPH (BOSAPAH-1), the observed GM ratio 
for PVR post to pre percent (defined in Section 5.3.1) was around 0.7 in 35 participants with SAPH 
at Week 16 (bosentan vs placebo). It was also 0.7 in the NS-304/-02 study in 35 participants with 
PAH at Week 17 (selexipag vs placebo, with CV of PVR post to pre percent 0.28 vs 0.08). In the 
CTEPH studies MERIT-1 (80 participants) and BENEFIT (157 participants) the observed CVs of 
PVR post to pre percent approached 0.4. The blinded interim estimate in 79 participants of the 
TRITON study gives a CV of 0.5.
Sample size is calculated based on the statistical requirements to detect a clinically relevant 
difference between the selexipag and placebo groups using a 1:1 randomization ratio, a two-sided 
Type I error of 5% and a Type II error of 10% (90% power).
NCT03942211


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065D301
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Status: Approved, Date: 01 December 2022
The following assumptions were made:
!
A ratio of the GM of Week 26 (or premature EOT) to Baseline PVR values equal to 0.70 ie, 
a 30% relative decrease (improvement) in GM as compared to placebo; 
!
A coefficient of variation of the ratio of 0.50; 
!
Normal distribution for the loge-transformed ratio of Week 26 (or premature EOT) to baseline 
PVR values.
Based on the above assumptions, 74 participants are required to establish the superiority of 
selexipag vs placebo with 90% power to correctly reject a false null hypothesis in favor of the 
alternative hypothesis.
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
Analysis sets are detailed in the Table 3 below:
Table 3
Overview of the Different Populations for Analyses
Population
Description
Screened Analysis Set (SCR)
All participants who were screened and received a participant identification 
number.
Randomized Set (RS)
All participants assigned to a study intervention.
Safety Analysis Set (SAS)
All participants who received at least one dose of study intervention. Participants 
will be analyzed according to the intervention they actually received.
All baseline characteristics and safety analyses will be performed on the SAS. Efficacy will be 
listed only using the RS.
5.
STATISTICAL ANALYSES
5.1.
General Considerations
Following the sponsor decision to prematurely terminate the study due to slow enrollment 
(decision on 26 Sep 2022), the reporting is simplified: all listings and all the analyses already 
planned and produced for the sponsor DMC are kept for the final CSR. For efficacy, all parameters 
will be listed only.
Statistical analysis will be done by the sponsor or delegated to a Contract Research Organization 
under the responsibility of the sponsor. Unblinded analyses for the sponsor DMC will be 
performed by an SSG independent from the study team to protect from unblinding.
5.1.1.
Visit Windows
As participants do not always adhere to the protocol visit schedule, the following rules are applied 
to assign actual visits to analysis visits. Listed below are the visit windows and the target days for 
each visit. The period starts with the administration of the first dose of DB study treatment. The 
reference day is Study Day 1, which is the day of randomization. If a participant has 2 or more 
actual visits in one visit window, the visit closest to the target day will be used as the protocol visit 
for that visit window. The other additional visit(s) will not be used in the summaries or analyses, 
NCT03942211


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065D301
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Status: Approved, Date: 01 December 2022
but they can be used for determination of clinically important endpoints. If 2 actual visits are 
equidistant from the target day within a visit window, the later visit is used.
All assignments will be made in chronological order. Once a visit date is assigned to a visit 
window, it will no longer be used for a later time point except for the endpoint. Listed below 
(Table 4) are the visit windows and the target days for each visit defined in the protocol.
Table 4
Visit Windows for double-blind treatment period
Parameter
Scheduled 
Visit Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point (Day)
All parameters§
1
Screening
< 1
[-30 to -1]
2
Baseline
<=1
1
RHC (including PVR)
/ DLco / Spirometry / 
Arterial blood gas
5
Week 26
2 to 280
183
All Other parameters
3
Week 12
2 to 112
85
4
Week 20
113 to 161
141
5
Week 26
162 to 228
183
6
Week 39
229 to 364
274
7
Week 65
365 to 546
456
8
Week 91
547 to 728
638
9
Week 117
729 to 910
820
10
Week 143
911 to 1092
1002
§ RHC is collected only during the screening period, not at baseline. *Relative to Study Day 1; 
DLCO = diffusing capacity for carbon monoxide; RHC = right heart catheterization.
It is likely that only few participants (or none) will have an assessment after visit 10 and therefore 
those data will not be used in summary statistics and will be listed only.
5.1.2.
Study Day and Relative Day
Study Day 1 or Day 1 refers to the day of randomization. All efficacy and safety assessments at 
all visits will be assigned a day relative to this date.
Study day or relative day for a visit is defined as:
!
Visit date - (date of Study Day 1) +1, if visit date is ≥date of Day 1
!
Visit date - Date of Day 1, if visit date <date of Day 1
There is no 'Day 0'
5.1.3.
Baseline
Baseline is defined as the last observation on or before the day of first dose of study treatment.
5.1.4.
Imputation Rules for Missing Date/Time of Onset/Resolution
Partial AE onset dates will be imputed as follows:
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!
If the onset date of an adverse event is missing day only, it will be set to:
∀
First day of the month that the AE occurred, if month/year of the onset of AE is different 
than the month/year of the first dose of study treatment.
∀
The day of first dose of study treatment, if the month/year of the onset of AE is the same 
as month/year of the first dose of study treatment and month/year of the AE resolution 
date is different
∀
The day of first dose of study treatment or day of AE resolution date, whichever is earliest, 
if month/year of the onset of AE and month/year of the first dose of study treatment date
and month/year of the AE resolution date are same
!
If the onset date of an adverse event is missing both day and month, it will be set to the earliest 
of:
∀
January 1 of the year of onset, as long as this date is on or after the first dose of study 
treatment
∀
Month and day of the first dose of study treatment, if this date is the same year that the 
AE occurred
∀
Last day of the year if the year of the AE onset is prior to the year of the first dose of 
study treatment,
∀
The AE resolution date.
!
Completely missing onset dates will not be imputed, but the event will be assumed to be 
treatment emergent unless otherwise indicated.
Partial AE resolution dates not marked as ongoing will be imputed as follows:
!
If the resolution date of an adverse event is missing day only, it will be set to the earliest of 
the last day of the month of occurrence of resolution or the day of the date of death, if the 
death occurred in that month.
!
If the resolution date of an adverse event is missing both day and month, it will be set to the 
earliest of December 31 of the year or the day and month of the date of death, if the death 
occurred in that year.
!
Completely missing resolution dates will not be imputed.
Concomitant therapy start dates will be imputed as follows:
!
If the start date is missing day only, it will be set to first day of the month.
!
If the start date has the year, but is missing the month, it will be set to January 1.
!
If the start date is completely missing, it will not be imputed
Concomitant therapy end dates will be imputed as follows:
!
If the end date is missing day only, it will be set to last day of the month.
!
If the year is supplied, but is missing the month, it will be set to December 31, or the date of 
death if this is earlier.
!
If the end date is completely missing, it will not be imputed
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For missing or partial assessment dates:
!
For scheduled visits, the date will be set to the date closest to the scheduled date, within the 
range allowed by the partial dates. (For screening assessments, use day -8 as the scheduled 
date.)
!
For unscheduled visits with partial dates:
∀
if the day of first dose of study treatment is within the period, it will be set to the day after 
first dose;
∀
otherwise, if the day of first dose of study treatment is within the period, it will be set to 
the day of first dose;
∀
otherwise, if only the day is missing, it will be set to first of the month.
otherwise, if the year is supplied, but is missing the month, it will be set to January1.
5.2.
Participant Dispositions
Screened participants and reason for screen failures will be summarized overall.
The number of participants in the following disposition categories will be summarized throughout 
the study by intervention group and overall:
!
Participants randomized
!
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
A listing of participants will be provided for the following categories:
!
Participants who discontinued study intervention
!
Participants who terminated study prematurely
!
Participants who were unblinded during the study period
!
Participants who were randomized yet did not receive study intervention.
5.3.
Primary Endpoint(s) Analysis
PVR data will be listed only.
5.3.1.
Definition of Endpoint(s)
The primary endpoint is the ratio of the PVR value post-treatment initiation up to Week 26 (post) 
vs the PVR value pre-treatment initiation at baseline (pre), expressed as a percentage, ie:
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 	
 
  
 =   
  26
 
 	  × 100 (%)
The baseline reference value for PVR is based on the last RHC performed prior to study 
intervention initiation.
At each assessment, PVR (dyn.sec/cm5) is derived as follows:
PVR = 80 × (mPAP - PAWP) / CO
where mPAP is mean pulmonary artery pressure measured in mmHg, PAWP is pulmonary artery 
wedge pressure measured in mmHg, and CO is cardiac output measured in L/min. If PAWP is 
missing, then the LVEDP will be used.
Handling of missing data
No imputation will be performed for missing PVR. 
5.3.2.
Analysis Methods
PVR data will be listed only using the Randomized Set (RS). 
5.4.
Secondary Endpoint(s) Analysis
Not applicable. For efficacy, the study has only primary and exploratory endpoints.
5.5.
Tertiary/Exploratory Endpoint(s) Analysis
All exploratory endpoints will be listed only using the Randomized Set (RS).
5.5.1.
Time To Clinical Worsening (TTCW)
No event adjudication will be performed by the Clinical Event Committee (CEC). Therefore, no 
data will be reported for this endpoint. 
5.5.2.
6-Minute Walk Distance (6MWD) and Borg CR Scale® (CR10)
6MWD and Borg Scale will be listed only using the Randomized Set (RS).
5.5.3.
Proportion of participants with oxygen desaturation post 6MWT up to 
Week 39
Oxygen desaturation will be listed only using the Randomized Set (RS).
5.5.4.
Proportion of participants with improvement/no change/worsening
versus baseline in WHO FC up to Week 39
WHO FC will be listed only using the Randomized Set (RS).
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5.5.5.
Daily life physical activity (DLPA) and sleep parameters up to 
Week 39
Actigraph data as per source transfer as documented in the data transfer agreement (instead of 
derived data) may be reported in listings (on the Randomized Set (RS) as we may not have 
sufficient data for derivation.
If derived, the following variables will be computed and listed over time on the Randomized Set 
(RS):
∀
Total DLPA in counts per minute
∀
Total volume of activity (above sedentary)
∀
Daily time spent (minutes) in non-sedentary activity 
∀
Percentage of daily time spent in non-sedentary activity 
∀
Moderate to vigorous physical activity (MVPA)
∀
Time spent in the different activity categories
All actigraphy endpoints will be aggregated into 14-day windows for analysis. Baseline will be 
the average of the last 14 days prior to first dose of study drug (Day −1 to Day −14); post baseline 
assessments will be aggregated in 14-day intervals as shown in Table 5. 
Likewise, the last 14 days prior to the last dose of study treatment will be used for determination 
of the EOT value. All patients will have an EOT value, unless patient withdrew within a week of 
treatment start or no actigraphy data available after the study day 7 (See section "Handling of 
missing data"). 
If enough valid data have been collected in a time window at an analysis visit (see 
Section Handling of missing data"), the average of the values assessed within the time window 
will be used as analysis value. Actigraphy data collected prior to Day −14 or after EOT will be 
listed only. 
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Table 5
Actigraphy assessment time windows
Analysis Visit
Start Day
End Day
Baseline
−14
−1
Week 3 
8
21
Week 5
22
35
Week 7
36
49
Week 9
50
63
Week 11
64
77
Week 13
78
91
Week 15
92
105
Week 17
106
119
Week 19
120
133
Week 21
134
147
Week 23
148
161
Week 25
162
175
Week 27
176
189
Week 29
190
203
Week 31
204
217
Week 33
218
231
Week 35
232
245
Week 37
246
259
Week 39
260
273
EOT1
Last study treatment
− 14 days*
Last study treatment
− 1 day*
1 EOT value will be computed out of the last two weeks prior to last study treatment, regardless if the last study treatment date 
was before, at, or after Day 273. 
* EOT will have a valid value. If EOT value based on the period (EOT-14, EOT-1) is missing (not valid), the EOT period will 
be rolled back by one day, i.e., (EOT-15, EOT -2), (EOT-16, EOT-3), and so on until a non-missing (valid) value is 
available. The period can be rolled back until (1, 14). 
EOT = End-of-Treatment. 
Handling of missing data
Actigraphy variables will be considered valid (non-missing) for a specific time window if the data 
are available for at least 7 complete days (consecutive or not) within that time window of 
assessment.
For DLPA actigraphy endpoints, a complete day is defined as a record of at least 7 awake hours 
of data. If less than 7 complete days are available, the value of the time window will be set to 
missing.
In case of premature discontinuation of study drug, the average of the last non-missing 14-day 
window prior to the last dose of study treatment will always be used as an EOT value. If the EOT 
value corresponding to the period (EOT-14, EOT-1) is missing (not valid), the EOT period will be 
rolled back by one day, i.e., (EOT-15, EOT-2), (EOT-16, EOT-3), until a non-missing (valid) value 
is available. This corresponds to a last observation carried forward (LOCF) up to Week 39/EOT 
approach. If no post-baseline actigraphy data have been collected for at least 7 days over a 14-day 
time window, no EOT value will be computed, and the post-baseline value will be set as missing.
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5.5.6.
Time to all-cause death up to EOMOP
Deaths will be listed only using the Randomized Set (RS).
5.5.7.
Rate of all-cause death or unplanned PH-related hospitalizations up 
to EOMOP
Unplanned PH-related hospitalizations will be listed only using the Randomized Set (RS).
5.5.8.
Change from baseline up to Week 39 in SF-12 scores
SF-12 individual questions responses will be listed only using the Randomized Set (RS). If 
available for analysis, the physical and mental component summary scores will be reported
according to the instrument’s instruction (and applying the OPTUM process). 
5.5.9.
Change from baseline up to Week 39 in the KSQ scores
KSQ individual questions responses will be listed only using the Randomized Set (RS).
5.5.10.
Change from baseline up to Week 39 in the PAH-SYMPACT scores
PAH-SYMPACT individual questions responses will be listed only using the Randomized Set 
(RS).
5.5.11.
Change from baseline up to Week 39 in the PGA-S scores
PGA-S individual questions responses will be listed only using the Randomized Set (RS). 
5.5.12.
Change from baseline up to Week 39 in the CGI-S scores
CGI-S individual questions responses will be listed only using the Randomized Set (RS).
5.5.13.
Change from baseline up to Week 39 in the CGI-C scores
CGI-C individual questions responses will be listed only using the Randomized Set (RS).
5.5.14.
Change from baseline up to Week 39 in NT-proBNP serum levels 
NT-proBNP values will be listed only using the Randomized Set (RS).
5.5.15.
Change from baseline up to Week 39 in other hemodynamic variables 
(including cardiac output [CO], CIn, mean right atrial pressure 
[mRAP])
Other hemodynamic variables (including cardiac output [CO], CIn, mean right atrial pressure 
[mRAP]) will be listed only using the Randomized Set (RS).
5.5.16.
Change from baseline up to Week 39 in the number of low-risk 
criteria
This endpoint is derived based on other endpoints and will not be computed for this study, due to
the very limited number of study participants. 
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5.6.
Safety Analyses
All safety analyses will be based on the safety analysis set based on actual intervention received, 
unless otherwise specified. Analyses will be conducted for the entire study period only.
For all continuous safety variables, descriptive statistics by intervention group will include the N, 
mean, standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized by intervention group using frequency counts and percentages.
5.6.1.
Extent of Exposure
Exposure will be summarized for the entire study period, by treatment group and overall using the 
SAS.  
The number and percentage of participants who receive study intervention will be summarized. 
The number and percentage of participants at each dose level will also be summarized by visit.
Descriptive statistics for duration of study intervention (N, mean, SD, median, and range 
(minimum, maximum)) will be summarized. Participant-[years] of intervention are calculated as 
[days of intervention/365.25]. Participant-[years] will be presented by intervention group.
Cumulative exposure will be summarized using week categories.
Study intervention duration is defined as (date of last dose of study intervention – date of first dose 
of study intervention) +1.
Total dose days of intervention is defined as the total number of days that study intervention was 
administered to the participant (excluding days off study intervention).
The number (%) of participants with a dose adjustment/dose not administered will be summarized 
by intervention group. Reasons for dose adjustments/doses not administered will also be 
summarized.
Descriptive statistics will be presented for the following parameters: Maximum Study Treatment 
Total Daily Dose and Weighted-Average Study Treatment Total Daily Dose (separately for 
titration and maintenance periods); Individual Total Daily Maintenance Dose of Study Treatment; 
Maximum Tolerated Total Daily Dose of Study.
The mean daily dose of study treatment is calculated as (sum of total daily dose)/study treatment 
duration.
5.6.2.
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after the 
initial administration of study intervention through the day of last dose plus 3 days is considered 
to be treatment emergent. If the event occurs on the day of the initial administration of study 
intervention, and either event time or time of administration are missing, then the event will be 
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assumed to be treatment emergent. If the event date is recorded as partial or completely missing, 
then the event will be considered to be treatment emergent unless it is known to be prior to the first 
administration of study intervention based on partial onset date or resolution date. All reported 
treatment-emergent adverse events will be included in the analysis. For each adverse event, the
number and percentage of participants who experience at least 1 occurrence of the given event will 
be summarized by intervention group.
Summaries will be displayed by treatment (selexipag or placebo) and will include all events up to 
3 days after the last dose of study drug or EOS, whichever occurs first.
Summary tables will be provided for treatment-emergent adverse events:
!
AEs
!
Serious AEs (SAEs)
!
AEs leading to discontinuation of study intervention
!
AEs by severity
!
AEs by relationship to study intervention
!
All SAEs up to 30 days after the last study treatment
In addition to the summary tables, listings will be provided for participants who:
!
Had AEs
!
Had SAEs
!
Had AEs leading to discontinuation of study intervention
!
Had AEs of COVID-19
!
AEs of special interest (Appendix 8)
Deaths will be displayed by actual intervention received. Frequencies for the following parameters 
will be included in the summary table:
!
Number of participants who died
!
Cause of death
!
Relationship to study intervention (yes/no)
A listing of participants who died will be provided.
5.6.3.
Additional Safety Assessments 
5.6.3.1.
Clinical Laboratory Tests
Clinical laboratory tests will be displayed for the participants included in the safety analysis set
and will be presented by study treatment for the entire study period. Local laboratory data will be 
included in listings and used only to find marked abnormalities.
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!
Treatment emergent (TE) will be concluded if the postbaseline value is worse than the baseline
value.
!
If the postbaseline value is above the upper limit and the baseline value is below the upper 
limit (eg, Normal or Low), then the postbaseline abnormality will be considered TE. The same 
applies to the postbaseline value being below the lower limit with the baseline value being 
above the lower limit (eg, Normal or High).
!
If the baseline value is missing, a postbaseline abnormality will always be considered as TE.
Treatment-emergent marked laboratory abnormalities will be summarized for each laboratory 
variable for which marked abnormalities are defined providing their incidence and frequency. 
In addition, the proportion of participants with the following treatment-emergent liver 
abnormalities will be summarized:
!
ALT ≥3# upper limit of normal (ULN), ALT ≥5#ULN, ALT ≥8#ULN
!
AST ≥3#ULN, AST ≥5#ULN, AST ≥8#ULN
!
ALT or AST ≥3#ULN, ALT or AST ≥5#ULN, ALT or AST ≥8#ULN
!
ALT or AST ≥3#ULN and concomitant (collected on the same day) bilirubin ≥2#ULN 
and both (ALT or AST and bilirubin) increased compared to baseline
!
ALT or AST ≥3#ULN and bilirubin ≥2#ULN  at any time and both (ALT or AST and 
bilirubin) increased compared to baseline
All laboratory data will be listed together with derived marked abnormality flag. A separate listing 
of marked abnormality laboratory values will be provided.
5.6.3.2.
Vital Signs and Physical Examination Findings
Vital signs will be displayed for the participants included in the safety analysis set and will be 
presented by study treatment for the entire study period.
Continuous vital sign parameters including weight, pulse, blood pressure (systolic and diastolic),
and Body Mass Index (BMI) will be summarized at each assessment time point. Body Mass Index 
will be calculated as weight (kg)/(height (m))2, at each time point that body weight is measured. 
The height measurement collected at [screening/the nearest visit] will be used in the calculation.
Change from baseline will be summarized. Descriptive statistics (mean, standard deviation, 
median, minimum and maximum) will be presented.
Abnormality criteria (based on criteria defined below in Table 6) will be applied to baseline and 
postbaseline values. For baseline values, increase or decrease criteria are not applied.
Postbaseline values will be considered treatment-emergent if they meet both value and change 
criteria in the Table 6 below. If the baseline value is missing, a postbaseline abnormality will 
always be considered as treatment-emergent.
Incidence of treatment-emergent clinically important vital signs during intervention, as defined in 
Table 6, will be summarized for participants who had a baseline assessment and at least 1
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postbaseline assessment for that vital sign. A listing of participants with treatment-emergent 
clinically important vital signs will be presented, along with a listing of all vital sign 
measurements.
Table 6
Clinically Important Vital Signs
Vital Sign
Criteria
Pulse
>120 bpm and with >30 bpm increase from baseline
<50 bpm and with >20 bpm decrease from baseline
Systolic blood pressure
>180 mm Hg and with >40 mm Hg increase from baseline
<90 mm Hg and with >30 mm Hg decrease from baseline
Diastolic blood pressure
>105 mm Hg and with >30 mm Hg increase from baseline
<50 mm Hg and with >20 mm Hg decrease from baseline
5.6.3.3.
Electrocardiogram
Listings will be produced for all ECG data including unscheduled visit data on the SAS. A listing 
of clinically relevant ECG abnormalities will also be provided.
5.6.3.4.
Other Safety Parameters
Descriptive statistics of values and changes from baseline in supplemental oxygen rate, DLCO, 
FVC and arterial blood gas will be summarized over time on the SAS by treatment group for the 
entire study period.
5.7.
Other Analyses
5.7.1.
Pharmacokinetics
Not applicable.
5.7.2.
Immunogenicity
Not applicable.
5.7.3.
Pharmacodynamics
Not applicable.
5.7.4.
Pharmacokinetic/Pharmacodynamic Relationships
Not applicable.
5.7.5.
Biomarkers
Biomarker analysis is optional for each participant. A biomarker-specific ICF should be signed 
prior to collection of any samples for biomarker analysis.
Biomarker samples will be used to generate plasma and serum marker data for computational 
analyses. These analyses are considered exploratory and the results will be reported separately 
from the CSR.
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Available biomarkers data at time of final database lock will be listed only.
5.7.6.
Health Economics
Not applicable.
5.7.7.
Other Variables and/or Parameters
Not applicable.
5.7.8.
Definition of Subgroups
No subgroup analysis will be performed. 
5.8.
Interim Analyses
Not applicable.
5.8.1.
Data Monitoring Committee (DMC) or Other Review Board
There is no formal efficacy interim analysis for this study. The sponsor DMC (internal DMC) has 
overall responsibility for safeguarding the interests of participants and will review on regular basis 
the results of analyses performed by an unblinded internal statistical support group (SSG) 
independent from the study team. The DMC will provide recommendations to the study team. 
Outputs needed for DMC meetings will be flagged in list of outputs in this SAP (DPS part 1) and 
will focus only on baseline characteristics, protocol deviations, concomitant medications and all 
safety data (adverse events and laboratory data). 
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6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
AE
adverse event
ALT/SGPT
alanine aminotransferase
ANCOVA
analysis of covariance
AST/SGOT
aspartate aminotransferase
ATC
anatomic and therapeutic class
BMI
body mass index
BSA
body surface area
CI
confidence interval
CL
total systemic clearance
CRF
case report form
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
DMC
Data Monitoring Committee
DPS
Data Presentation Specifications
ECG
electrocardiogram
eCRF
electronic case report form
EOT
End of treatment
FAS
full analysis set
FDA
Food and Drug Administration
ICH
International Conference on Harmonisation
IQ
interquartile
IVRS
interactive voice response system
IWRS
interactive web response system
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
PD
pharmacodynamic(s)
PI
principal investigator
PK
pharmacokinetic(s)
PP
per protocol
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SMQs
standardised MedDRA queries
TEAE
treatment-emergent adverse event
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
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6.2.
Appendix 2 Changes to Protocol-Planned Analyses
This current SAP presents a simplified version of the previous final SAP covering the analyses to 
be performed following the Sponsor decision to prematurely terminate the study due to slow 
enrollment (decision on 26 Sep 2022). Reporting is simplified: all listings and all the analyses 
already planned and produced for DMC are kept. For efficacy, all parameters will be listed only.
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6.3.
Appendix 3 Demographics and Baseline Characteristics
The number of participants in each analysis set will be summarized and listed by intervention 
group, and overall. 
Table 7 and Table 8 present a list of the demographic variables and baseline disease characteristics
that will be summarized by intervention group and overall for the SAS. 
Table 7
Demographic Variables
Continuous Variables:
Summary Type
Age (years)
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum], and IQ range).
Weight (kg)
Height (cm)
Body Mass Index (BMI) (kg/m2)
Categorical Variables
Age ([18-25 years, 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 (American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or other Pacific Islander, White, Multiple)
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
Region (US, Latin America, Europe)
aIf multiple race categories are indicated, the Race is recorded as 'Multiple'
Table 8
Baseline disease characteristics
Continuous Variables:
Summary Type
Time from SAPH diagnosis (months) 
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum], and IQ range).
6MWD (m)
NT-proBNP (ng/L)
Calculated PVR (dyn.sec/cm5)
Cardiac Outputs (L/min), mPAP (mmHg), mRAP (mmHg),
PAWP (mmHg), LVEDP (mmHg), sPAP (mmHg), dPAP (mmHg),
Mixed venous oxygen saturation (%),Cardiac Index (L/min/m2), 
sSAP (mmHg), dSAP (mmHg)
Total pulmonary resistance
Categorical Variables
PH therapies (ERA, PD5-inhibitors, Riociguat)
Frequency distribution with the 
number and percentage of 
participants in each category.
WHO FC (I, II, III, IV)
For each participant time since SAPH diagnosis (months) will be derived as:
o
(Date of randomization – date of diagnosis + 1) / 12
Demographics and baseline characteristics will also be listed on the SAS.
All available hemodynamic parameters should be included, as available in the clinical database.
6.4.
Appendix 4 Protocol Deviations
In general, the following list of major protocol deviations may have the potential to impact 
participants’ rights, safety or well-being, or the integrity and/or result of the clinical study. 
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Participants with major protocol deviations will be identified prior to database lock and the 
participants with major protocol deviations will be displayed by category.
!
Developed withdrawal criteria but not withdrawn
!
Entered but did not satisfy criteria
!
Received a disallowed concomitant treatment
!
Received wrong treatment or incorrect dose
!
Other
See TV-FRM-04718 "Major Protocol Deviation Criteria" for detailed definitions of major protocol 
deviations.
A separate listing for all protocol deviations related to COVID-19 will be also produced.
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6.5.
Appendix 5 Prior and Concomitant Medications
Prior and Concomitant medications will be coded using the last available version of World Health 
Organization Drug Dictionary (WHO-DD). Prior medications are defined as any therapy used 
before the day of first dose (partial or complete) of study intervention (including those ongoing at 
first dose). Concomitant medications are defined as any therapy used on or after the same day as 
the first dose of study intervention, including those that started before and continue on after the 
first dose of study intervention.
All prior and concomitant medications will be listed for the SAS.
NCT03942211


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065D301
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
32
Status: Approved, Date: 01 December 2022
6.6.
Appendix 6 Medical History
All Medical history will be listed for the SAS. 
NCT03942211


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065D301
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
33
Status: Approved, Date: 01 December 2022
6.7.
Appendix 7 Intervention Compliance
Study intervention compliance will be summarized descriptively for the SAS. 
The number and percentage of participants who have at least 80% study intervention compliance 
through the EOMOP period will be summarized by treatment group.
Study intervention compliance will be calculated as follows:
Compliance = [(number of tablets dispensed − number of tablets returned) / total number of tablets 
that should have been taken during the period] × 100.
Compliance will be also listed.
NCT03942211


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065D301
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
34
Status: Approved, Date: 01 December 2022
6.8.
Appendix 8 Adverse Events of Special Interest
The following adverse events of special interest will be used for selexipag. These are based on the 
important identified and potential risks in the latest Risk Management Plan and on-going 
discussion with Pharmacovigilance Risk Assessment Committee.  
AE Special Interest Category
Anaemia
Bleeding events
Gastrointestinal disturbances denoting intestinal intussusception (manifested as ileus or obstruction)
Hyperthyroidism
Hypotension
Light-dependent non-melanoma skin malignancies
Major adverse cardiovascular events (MACE)
Medication errors
Ophthalmological effects associated to retinal vascular system
Pregnancy
Pulmonary venoocclusive disease associated with pulmonary oedema
Renal function impairment / acute renal failure
Prostacyclin associated reactions*
*Prostacyclin associated reactions will be summarized separate from other AESIs
A specific file containing all preferred terms for each category as per last coding version will be 
maintained.
NCT03942211


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065D301
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
35
Status: Approved, Date: 01 December 2022
6.9.
Appendix 9 Medications of Special Interest
Concomitant and prior medications of special interest are defined as follows:
Concomitant/Prior Medication Special 
Interest Category
Standard ATC Name
Note
PAH-specific medications
Sildenafil
Medications with ATC name 
containing any of the listed 
standard ATC names are 
considered as PAH-specific 
medications.
PAH-specific medications
Tadalafil
PAH-specific medications
Vardenafil
PAH-specific medications
Iloprost
PAH-specific medications
Epoprostenol
PAH-specific medications
Beraprost
PAH-specific medications
Treprostinil
PAH-specific medications
Selexipag
PAH-specific medications
Riociguat
PAH-specific medications
Macitentan
PAH-specific medications
Bosentan
PAH-specific medications
Ambrisentan
NCT03942211


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065D301
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
36
Status: Approved, Date: 01 December 2022
6.10.
Appendix 10 Laboratory Toxicity Grading
The grading scale use for lab assessments is based on tables below.
Blood chemistry marked abnormalities (SI Units)
Laboratory test 
name (CDISC 
Synonym[s])
LL
LLL
HH
HHH
Alanine 
aminotransferase
NA
NA
> 3 × ULN
> 5 × ULN
Aspartate 
aminotransferase
NA
NA
> 3 × ULN
> 5 × ULN
Alkaline 
phosphatase
NA
NA
> 2.5 × ULN
> 5 × ULN
Bilirubin; Total 
bilirubin
NA
NA
> 2 × ULN
> 5 × ULN
Creatinine
NA
NA
> 1.5 × ULN
> 3 × ULN
Sodium
NA
< 130 mmol/L
> 150 mmol/L
> 155 mmol/L
Potassium
< 3.2 mmol/L
< 3.0 mmol/L
> 5.5 mmol/L
> 6.0 mmol/L
CDISC = Clinical Data Interchange Standards Consortium; NA = not applicable; ULN = upper limit of normal. 
Blood chemistry marked abnormalities (SI Units)
Laboratory test 
name (CDISC 
Synonym[s])
LL
LLL
HH
HHH
Hemoglobin
< 100 g/L
< 80 g/L
> 20 g/L above
baseline
> 40 g/L above 
baseline
Hematocrit; EVF; 
PCV (male)
< 0.32 L/L
< 0.20 L/L
> 0.60 L/L
> 0.65 L/L
Hematocrit; EVF; 
PCV (female)
< 0.28 L/L
< 0.20 L/L
> 0.55 L/L
> 0.65 L/L
Platelets 
(assuming no 
platelet cluster)
< 75 × 109/L
< 50 × 109/L
> 600 × 109/L
> 999 × 109/L
Leukocytes; white 
blood cells
< 3.0 × 109/L
< 2.0 × 109/L
> 20.0 × 109/L
> 100.0 × 109/L
Neutrophils (Abs)
< 1.5 × 109/L
< 1.0 × 109/L
NA
NA
Eosinophils (Abs)
NA
NA
> 5.0 × 109/L
NA
Lymphocytes 
(Abs)
< 0.8 × 109/L
< 0.5 × 109/L
> 4.0 × 109/L
> 20 × 109/L
CDISC = Clinical Data Interchange Standards Consortium; EVF = erythrocyte volume fraction; NA = not applicable; PCV = 
packed cell volume.
NCT03942211


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065D301
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
37
Status: Approved, Date: 01 December 2022
7.
REFERENCES
Frye BC, R. I. (2020). Safety and efficacy of abatacept in patients with treatment-resistant SARCoidosis 
(ABASARC) - protocol for a multi-center, single-arm phase IIa trial. Contemp Clin Trials Commun., 19:100575.
NCT03942211