A Multicenter, Open-label, Phase III Study to Assess the Efficacy, Safety, and Pharmacokinetics of Macitentan in Japanese Pediatric Patients (>=3 Months to <15 Years) With Pulmonary Arterial Hypertension
Phase: PHASE3
Conditions: Pulmonary Arterial Hypertension
Sponsor: Janssen Pharmaceutical K.K.

CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date:  7 August 2023
Janssen Pharmaceutical K.K.*
Clinical Protocol
Protocol Title
A Multicenter, Open-label, Phase III Study to Assess the Efficacy, Safety, and
Pharmacokinetics of Macitentan in Japanese Pediatric Patients (≥3 months to <15 years)
with Pulmonary Arterial Hypertension
Protocol 67896062PAH3001; Phase 3
Amendment 5
JNJ-67896062 Macitentan
*This study is being conducted by Janssen Pharmaceutical K.K. in Japan. The term “sponsor” is used
throughout the protocol to represent Janssen Pharmaceutical K.K.; the sponsor is identified on the
Protocol Supplementary Information page that accompanies the protocol.
Status: 
Approved
Date: 
7 August 2023
Prepared by: Janssen Pharmaceutical K.K.
EDMS number: 
EDMS-RIM-454995, 6.0
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.
NCT05167825

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
2
Status: Approved,  Date:  7 August 2023
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 5 
7 August 2023
Amendment 4 
9 March 2023
Amendment 3 
9 March 2022
Amendment 2 
25 November 2021
Amendment 1 
2 November 2021
Original Protocol 
15 October 2021
Amendment 5 (7 August 2023)
Overall Rationale for the Amendment: The main reason for this protocol amendment is to add a database
lock (DBL) for Foreign Health Authority interaction.
The updates are indicated in bold for new text and strike-through for deleted text in the following table.
Section number 
and Name
Description of Change 
Brief Rationale
9.4. Statistical Analyses 
The sentence is changed as follows: 
 
The SAP for Foreign Health Authority interactions will 
be finalized prior to the first database lock (DBL) (see 
Section 9.5). The SAP will be finalized prior to first second
DBL and it will include a more technical and detailed
description of the statistical analyses described in this
section. This section is a summary of the planned statistical
analyses of the most important endpoints including primary
and secondar y endpoints.
To include data from
2 participants < 2
years in the PIP and
CHMP submission.
9.5. Interim Analysis 
The sentence is changed as follows: 
 
This study plans 2 3 database locks (DBLs). 
 
1. The first DBL will occur when 2 participants < 2
years of age have completed evaluations at Week 24. The
dataset at first DBL 24 will be used to support Foreign
Health Authority interactions and will be summarized in
a separate report.
2. The first second DBL will occur at Week 24 when all
participants complete evaluations at Week 24 and both PVRI
measurements at baseline and at Week 24 are available with
at least 5 participants. The dataset at second DBL cutoff
dataset at Week 24 will be used for the submission in Japan.
3. The second third DBL will occur at the end of study
when all participants complete evaluations at Week 52 and
consecutive safety follow-up. The dataset at second third
DBL will be provided for the long-term safety evaluation
during new drug application (NDA) review by PMDA. The
SAP will describe the planned interim analyses in greater
detail
To include data from
2 participants < 2
years in the PIP and
CHMP submission.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
3
Status: Approved,  Date:  7 August 2023
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................. 2
TABLE OF CONTENTS .......................................................................................................................... 3
LIST OF IN-TEXT TABLES AND FIGURES ............................................................................................ 6
1. 
PROTOCOL SUMMARY ................................................................................................................ 7
1.1. 
Synopsis ..................................................................................................................................... 7
1.2. 
Schema .................................................................................................................................... 12
1.3. 
Schedule of Activities (SoA) ...................................................................................................... 13
2. 
INTRODUCTION .......................................................................................................................... 16
2.1. 
Study Rationale......................................................................................................................... 17
2.2. 
Background............................................................................................................................... 17
2.3. 
Benefit-Risk Assessment .......................................................................................................... 21
2.3.1. 
Risks for Study Participation .................................................................................................. 22
2.3.2. 
Benefits for Study Participation .............................................................................................. 23
2.3.3. 
Benefit-Risk Assessment for Study Participation .................................................................... 23
3. 
OBJECTIVES AND ENDPOINTS ................................................................................................. 23
4. 
STUDY DESIGN ........................................................................................................................... 25
4.1. 
Overall Design .......................................................................................................................... 25
4.2. 
Scientific Rationale for Study Design ......................................................................................... 26
4.2.1. 
Study-Specific Ethical Design Considerations ........................................................................ 28
4.3. 
Justification for Dose ................................................................................................................. 29
4.4. 
End of Study Definition .............................................................................................................. 31
5. 
STUDY POPULATION ................................................................................................................. 31
5.1. 
Inclusion Criteria ....................................................................................................................... 31
5.2. 
Exclusion Criteria ...................................................................................................................... 33
5.3. 
Lifestyle Considerations ............................................................................................................ 36
5.3.1. 
Activity ................................................................................................................................... 36
5.4. 
Screen Failures ......................................................................................................................... 37
5.5. 
Criteria for Temporarily Delaying Enrollment or Administration of Study Intervention .................. 37
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY ......................................................... 37
6.1. 
Study Intervention Administered ................................................................................................ 37
6.2. 
Preparation/Handling/Storage/Accountability ............................................................................. 39
6.3. 
Measures to Minimize Bias: Randomization and Blinding .......................................................... 40
6.4. 
Study Intervention Compliance .................................................................................................. 40
6.5. 
Dose Modification ..................................................................................................................... 40
6.6. 
Continued Access to Study Intervention After the End of the Study............................................ 40
6.7. 
Treatment of Overdose ............................................................................................................. 41
6.8. 
Concomitant Therapy ................................................................................................................ 41
6.8.1. 
Rescue Medication ................................................................................................................ 43
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL ........................................................................................... 43
7.1. 
Discontinuation of Study Intervention ........................................................................................ 43
7.1.1. 
Permanent Discontinuation .................................................................................................... 43
7.1.2. 
Temporary Discontinuation .................................................................................................... 44
7.1.3. 
Liver Chemistry Stopping Criteria ........................................................................................... 45
7.1.4. 
Hemoglobin Abnormalities ..................................................................................................... 46
7.1.5. 
Start of a Strong CYP3A4 Inhibitor / Moderate Dual CYP3A4/CYP2C9 Inhibitors ................... 46
7.2. 
Participant Discontinuation/Withdrawal From the Study ............................................................. 47
7.3. 
Lost to Follow-up ....................................................................................................................... 48

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
4
Status: Approved,  Date:  7 August 2023
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................ 49
8.1. 
Demographics and Baseline Characteristics .............................................................................. 51
8.2. 
Efficacy Assessments ............................................................................................................... 52
8.2.1. 
Hemodynamic Assessments .................................................................................................. 52
8.2.2. 
Monitoring of disease progression .......................................................................................... 53
8.2.2.1. 
Signs and Symptoms of PAH .............................................................................................. 53
8.2.2.2. 
Functional Class ................................................................................................................. 54
8.2.3. 
6-Minute Walk Test ................................................................................................................ 54
8.2.4. 
NT-proBNP ............................................................................................................................ 54
8.2.5. 
Echocardiography .................................................................................................................. 55
8.2.6. 
Physical activity ..................................................................................................................... 55
8.2.7. 
Borg CR10 Scale® ................................................................................................................ 56
8.3. 
Safety Assessments .................................................................................................................. 56
8.3.1. 
Physical Examinations ........................................................................................................... 57
8.3.2. 
Vital Signs ............................................................................................................................. 57
8.3.3. 
Electrocardiograms ................................................................................................................ 58
8.3.4. 
Clinical Safety Laboratory Assessments ................................................................................. 58
8.3.5. 
Pregnancy Testing ................................................................................................................. 58
8.4. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting...................................... 59
8.4.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information ............................................................................................................................ 60
8.4.2. 
Method of Detecting Adverse Events and Serious Adverse Events ......................................... 60
8.4.3. 
Follow-up of Adverse Events and Serious Adverse Events ..................................................... 60
8.4.4. 
Regulatory Reporting Requirements for Serious Adverse Events ........................................... 60
8.4.5. 
Pregnancy ............................................................................................................................. 61
8.4.6. 
Adverse Events of Special Interest ......................................................................................... 61
8.5. 
Quality of Life Assessments ...................................................................................................... 61
8.6. 
Pharmacokinetics ...................................................................................................................... 63
8.6.1. 
Evaluations ............................................................................................................................ 63
8.6.2. 
Analytical Procedures ............................................................................................................ 63
8.6.3. 
Pharmacokinetic Parameters and Evaluations........................................................................ 64
8.7. 
Genetics and Pharmacogenomics ............................................................................................. 64
8.8. 
Immunogenicity Assessments ................................................................................................... 64
8.9. 
Health Economics OR Medical Resource Utilization and Health Economics .............................. 64
9. 
STATISTICAL CONSIDERATIONS .............................................................................................. 65
9.1. 
Statistical Hypotheses ............................................................................................................... 65
9.2. 
Sample Size Determination ....................................................................................................... 65
9.3. 
Populations for Analysis Sets .................................................................................................... 68
9.4. 
Statistical Analyses ................................................................................................................... 68
9.4.1. 
General Considerations ......................................................................................................... 68
9.4.2. 
Primary Endpoint ................................................................................................................... 68
9.4.3. 
Secondary Endpoints ............................................................................................................. 70
9.4.3.1. 
Hemodynamic Parameters/Right Heart Catheterization ....................................................... 70
9.4.3.2. 
WHO FC I or II (Yes/No) ..................................................................................................... 70
9.4.3.3. 
Panama FC I or II (Yes/No) ................................................................................................. 70
9.4.3.4. 
6-minute Walk Test ............................................................................................................. 70
9.4.3.5. 
Percent of Baseline in Plasma NT-proBNP .......................................................................... 70
9.4.3.6. 
Echocardiography Variables ............................................................................................... 71
9.4.3.7. 
Quality of Life ...................................................................................................................... 71
9.4.3.8. 
Physical Activity (Accelerometry)......................................................................................... 71
9.4.4. 
Exploratory Endpoints ............................................................................................................ 71
9.4.5. 
Safety Analyses ..................................................................................................................... 72
9.4.6. 
Pharmacokinetic Analyses ..................................................................................................... 73
9.5. 
Interim Analysis......................................................................................................................... 74
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................... 75
10.1. 
Appendix 1: Abbreviations and Definitions ................................................................................. 75

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
5
Status: Approved,  Date:  7 August 2023
10.2. 
Appendix 2: Clinical Laboratory Tests........................................................................................ 77
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations ....................................... 78
10.3.1. 
Regulatory and Ethical Considerations ................................................................................... 78
10.3.2. 
Financial Disclosure ............................................................................................................... 81
10.3.3. 
Informed Consent Process and Assent Form ......................................................................... 81
10.3.4. 
Data Protection ...................................................................................................................... 82
10.3.5. 
Committees Structure ............................................................................................................ 83
10.3.6. 
Publication Policy/Dissemination of Clinical Study Data .......................................................... 83
10.3.7. 
Data Quality Assurance ......................................................................................................... 84
10.3.8. 
Case Report Form Completion ............................................................................................... 85
10.3.9. 
Source Documents ................................................................................................................ 85
10.3.10. Monitoring.............................................................................................................................. 86
10.3.11. On-Site Audits ....................................................................................................................... 87
10.3.12. Record Retention ................................................................................................................... 87
10.3.13. Study and Site Start and Closure ........................................................................................... 88
10.4. 
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting ........................................................................................................................... 89
10.4.1. 
Adverse Event Definitions and Classifications ........................................................................ 89
10.4.2. 
Attribution Definitions ............................................................................................................. 90
10.4.3. 
Severity Criteria ..................................................................................................................... 90
10.4.4. 
Special Reporting Situations .................................................................................................. 90
10.4.5. 
Procedures ............................................................................................................................ 91
10.4.6. 
Product Quality Complaint Handling ....................................................................................... 92
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality ........................................... 93
10.5. 
Appendix 5: Contraceptive and Barrier Guidance ...................................................................... 94
10.6. 
Appendix 6: Sponsor Heart Catheterization Guidance ............................................................... 96
10.7. 
Appendix 7: WHO Functional Class ........................................................................................... 99
10.8. 
Appendix 8: Panama Functional Class for Pediatrics ............................................................... 100
10.9. 
Appendix 9: Quality of Life assessments ................................................................................. 103
10.10. Appendix 10: Sponsor 6-minute Walk Test Guidance .............................................................. 118
10.11. Appendix 11: Borg CR10 Scale® ............................................................................................ 122
10.12. Appendix 12: Study Conduct During a Natural Disaster ........................................................... 124
10.13. Appendix 13: Protocol Amendment History .............................................................................. 127
11. REFERENCES ........................................................................................................................... 134
INVESTIGATOR AGREEMENT .......................................................................................................... 137

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
6
Status: Approved,  Date:  7 August 2023
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Description of Interventions .................................................................................................. 38
Table 2: 
Volume of Blood to be Collected From Each Participant ....................................................... 50
Table 3: 
PVRI Fold Change of Week 24 to Baseline (AC-055-302) .................................................... 66
Table 4: 
PVRI Fold Change from Baseline to Week 24 (PPS/pseudo-pediatric population)- AC-
055-307 ............................................................................................................................... 67
Table 5: 
Sample Size and Probability of Success (%) ........................................................................ 67
FIGURES
Figure 1: Schematic Overview of the Study ......................................................................................... 12
Figure 2: Relationship between MM event and PVR/PVRI ................................................................... 28

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
7
Status: Approved,  Date:  7 August 2023
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Multicenter, Open-label, Phase III Study to Assess the Efficacy, Safety, and Pharmacokinetics of
Macitentan in Japanese Pediatric Patients (≥3 months to <15 years) with Pulmonary Arterial Hypertension
Macitentan was approved for the treatment of adult patients with pulmonary arterial hypertension (PAH)
in 2015 in Japan, however, is not indicated for pediatric PAH patients in the world. Pediatric indication of
macitentan is highly desired because macitentan is the commonly prescribed endothelin receptor
antagonists (ERAs) for adult PAH in Japan.
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints*
Primary 
To evaluate the effect of macitentan on hemodynamic 
measures at Week 24 
Fold change at Week 24 in pulmonary vascular
resistance index (PVRI)
Secondary 
To evaluate the effect of macitentan on pulmonary 
hemodynamic parameters other than PVRI at Week 24 
Change from baseline to Week 24 in the following
hemodynamic variables: pulmonary vascular resistance
(PVR), mean right atrial pressure (mRAP), mean
pulmonary arterial pressure (mPAP), cardiac index
(CI), cardiac output (CO), total pulmonary resistance
(TPR) and mixed venous oxygen saturation (SvO2) at
rest
To evaluate the effect of macitentan on World Health 
Organization (WHO) Functional Class (FC) at 
Week 24 (For patients whose age is >4 years of age
when initial informed consent)
Improvement in WHO FC from baseline to Week 24
(yes/no).
To evaluate the effect of macitentan on Panama FC at 
Week 24  
Improvement in Panama FC from baseline to Week 24
(yes/no).
To evaluate the effect of macitentan on exercise 
capacity at Week 24 (For patients who are 
developmentally able to understand and perform 6- 
minute walk test [6MWT] and whose age is ≥6 years of
age when initial informed consent)
Change from baseline to Week 24 in exercise capacity
(6-minute walk distance [6MWD], as measured by the
6MWT).
To evaluate the effect of macitentan on N-terminal pro- 
brain natriuretic peptide (NT-proBNP) at Week 24
Change from baseline to Week 24 in NT-proBNP
To evaluate the effect of macitentan on 
Echocardiography at Week 24 
Change from baseline to Weeks 24 in tricuspid annular
plane systolic excursion (TAPSE) and left ventricular
eccentricit y index measured b y echocardiography.
To evaluate the effect of macitentan on quality of life
at Week 24
Change from baseline to Week 24 in: PedsQL™ 4.0
Generic Core Scales Short Form (SF-15).
To evaluate the effect of macitentan on physical
activity at Week 24 (For patients whose age is ≥2 years
of age when initial informed consent)
Change from baseline to Week 24 in physical activity
as measured by accelerometry
To assess pharmacokinetics (PK) of macitentan and its
active metabolite (aprocitentan) in pediatric
participants with PAH.
Macitentan and aprocitentan concentrations in plasma
or blood at all assessed timepoints
To evaluate the long-term effect of macitentan on
exercise capacity in PAH children (For patients who
are developmentally able to understand and perform
6MWT and whose age is ≥6 years of age when initial
informed consent )
Changes from baseline to all assessed timepoints in
exercise capacity (6MWD, as measured by the
6MWT).

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
8
Status: Approved,  Date:  7 August 2023
Objectives 
Endpoints*
To evaluate the long-term effect of macitentan on 
dyspnea on exertion (For patients who perform 
6MWT) 
Change from baseline to all assessed timepoints in
dyspnea on exertion assessed by the Borg CR10
Scale®
To evaluate the effect of macitentan on physical 
activity (For patients whose age is ≥2 years of age 
when initial informed consent)
Change from baseline to all assessed timepoints in
physical activity as measured by accelerometry
To evaluate the long-term effect of macitentan on 
WHO FC  
Improvement in WHO FC from baseline to all assessed
timepoints
To evaluate the long-term effect of macitentan on 
Panama FC  
Improvement in Panama FC from baseline to all
assessed timepoints
To evaluate the long-term effect of macitentan on 
NT-proBNP 
Percent of Baseline plasma NT-proBNP at each
timepoint of assessment.
To evaluate the long-term effect of macitentan on 
Echocardiography  
Percent of Baseline in TAPSE, and left ventricular
eccentricity index measured by echocardiography to all
assessed timepoints
To evaluate the effect of macitentan on quality of life 
Change from baseline to all assessed timepoints in:
PedsQL™ 4.0 Generic Core Scales Short Form
(SF-15).
To evaluate the safety and tolerability of macitentan in 
pediatric participants with PAH. 
Safety endpoints are assessed up to 30 days after study
intervention discontinuation
 Adverse events (AEs)
 Serious adverse events (SAEs)
 AEs leading to premature discontinuation of
macitentan
 AEs of special interest
 Markedly laboratory abnormalities
 Change from baseline in laboratory parameters to
all timepoints of assessments
 Change from baseline in vital signs (diastolic blood
pressure [DBP], systolic blood pressure [SBP], and
pulse rate [PR]), height and body weight to all
timepoints of assessments
 Change from baseline in electrocardiogram (ECG)
parameters
* Throughout the document, baseline is defined as the last observed value before the first study intervention intake.
OVERALL DESIGN
This is a multi-center, open-label, single-arm, Phase 3 study in Japanese pediatric participants (aged
between ≥ 3 months and < 15 years), with PAH, to evaluate the efficacy, safety, and pharmacokinetics of
macitentan. The study will consist of a screening period of 30 days (Day -30 to Day -1, beginning with the
signing of the informed consent/assent form [ICF]), a treatment period until Week 52 (from Day 1), and a
post-treatment follow-up period (end of study) of 30 days after end of treatment. The end of study is
considered as the last visit/assessment for the last participant in the study.
An Independent Liver Safety Data Review Board (ILSDRB), a non-study specific external expert
committee of hepatologists, will be commissioned for this study to review serious hepatic events of special
interest.
NUMBER OF PARTICIPANTS
A target of 6 Japanese participants (aged ≥3 months and <15 years) will be enrolled in this study

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
9
Status: Approved,  Date:  7 August 2023
INTERVENTION GROUPS AND DURATION
Description of Interventions
Intervention Name 
Macitentan
Type 
Drug
Dose Formulation 
Dispersible Tablet
Unit Dose Strength(s) 
Final market image (FMI) 1.0 mg and 2.5 mg
Dosage Level(s) 
If a participant is 2 years old,
Body weight 
Daily dose
Combination of tablets
(FMI)
<15 kg 
3.5 mg
1 tablet 1.0 mg
+ 1 tablet 2.5 mg
15 kg and <25 kg 
5.0 mg 
2 tablets 2.5 mg
25 kg and <50 kg 
7.5 mg 
3 tablets 2.5 mg
50 kg 
10.0 mg 
4 tablets 2.5 mg
 
If a participant is under 2 years old,
Age 
Daily dose
Combination of tablets
(FMI)
3 months and <6 months 
1.0 mg 
1 tablet 1.0 mg
6 months and <2 years 
2.5 mg 
1 tablet 2.5 mg
Route of Administration 
Oral
Use 
Experimental
Investigational Medicinal Product 
(IMP)
Yes
Non-Investigational Medicinal 
Product/Auxiliary Medicinal
Product (NIMP/AxMP)
No
Sourcing 
Provided centrall y b y the sponsor
Packaging and Labeling 
(Labels will contain information to
meet the applicable regulatory
requirements.)
Child resistant blister packs
Delivery Instructions 
Whole tablet(s) are dispersed in water and administered orally (eg, via
spoon, glass, syringe). The full daily dose is taken at a single occasion.
Macitentan is administered once daily and irrespective of time of food
intake but at approximately the same time of the day. The same
administration method should be used as far as possible.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
10
Status: Approved,  Date:  7 August 2023
EFFICACY EVALUATIONS
The following efficacy assessments will be performed during the study:
 
Hemodynamic assessments
 
Monitoring of disease progression
 
Monitoring of signs and symptoms of disease progression
 
WHO and Panama functional class
 
6-minute walk test
 
NT-proBNP
 
Echocardiography
 
PedsQL™ 4.0 Generic Core Scales Short Form (SF-15)
 
Physical daily activity
 
Borg CR10 scale®
PHARMACOKINETIC EVALUATIONS
Venous blood samples of approximately 0.5 mL will be drawn for plasma concentrations of macitentan and
aprocitentan. After the macitentan and aprocitentan analysis method for
 microsampling is validated,
 microsampling device can be used for blood sample collection. If
 microsampling device is used
for PK sample collection, 0.02 mL or 0.04 mL is needed for blood volume per sample. For individual
participants, all points of blood collection should be done using the same sampling method. The timepoints
of blood collection will be determined by the age at the start of administration.
For participants ≥2 years old, Visit 3 will take place at steady-state conditions for macitentan and
aprocitentan, ie, participants must have received at least 10 days of continuous administration of the same
dose of macitentan. The blood samples will be drawn at the following timepoints at Visit 3: predose
(immediately before administration of the dose of macitentan study intervention), and at 1, 2, 4, 8, 12, and
24 hours (before macitentan intake the next day) postdose. A trough sample (ie, predose) will be drawn on
Week 12 (Visit 6).
For participants <2 years old, the blood samples will be drawn at the following timepoints: 2, 5, and 24
hours (before macitentan intake the next day) postdose on Day 1. A trough sample will be drawn at steady
state (Visit 4 and Visit 5).
SAFETY EVALUATIONS
The following safety assessments will be performed during the study:
 
AEs
 
Physical examination and weight
 
Vital signs
 
Electrocardiogram
 
Hematology, including hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell (WBC)
count with automated differential, platelet count
CCI
CCI
CCI

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
11
Status: Approved,  Date:  7 August 2023
 
Serum chemistry, including sodium, potassium, glucose, aspartate aminotransferase (AST), alanine
aminotransferase (ALT), blood urea nitrogen (BUN), total and direct bilirubin, alkaline phosphatase
(AP), creatinine, and calcium
 
Routine urinalysis
 
Pregnancy testing
STATISTICAL METHODS
Sample Size Determination
Assuming the true PVRI fold change at Week 24 is 70% and the standard deviation of logarithmic PVRI
fold change is 0.50, 5 participants demonstrate 75.4% probability to achieve success criterion. PVRI fold
change at Week 24 can be calculated when both measurements, baseline and Week 24, are available.
Considering discontinuation of one participant without PVRI assessment of Week 24 during the study, total
6 participants will be defined as the sample size for this study.
Statistical Analysis
For purposes of analysis, the following populations are defined:
Population 
Description
Efficac y Analysis Set 
All participants who take at least 1 dose of stud y intervention.
PK Analysis Set 
All participants who received at least 1 administration of macitentan and whose
measured plasma or blood concentration after macitentan administration for
pharmacokinetic analysis is available.
Safet y Analysis Set 
All participants who take at least 1 dose of stud y intervention.
PK: pharmacokinetic
 
Efficacy endpoints will be summarized over time by descriptive statistics. Descriptive summary statistics,
such as n, mean, standard deviation (SD), median, geometric mean, inter quantile range, minimum, and
maximum for continuous variables, and counts and proportions for discrete variables, will be used to
summarize data. No statistical test will be performed due to the small sample size and insufficient statistical
power. Unless otherwise specified, no imputation will be applied to the analysis. The efficacy endpoints
will be analyzed using efficacy analysis set. The detailed methods of analysis and the data-handling rules
will be provided in the statistical analysis plan.
The safety analysis set is used for the analyses of the safety variables. Adverse events, SAEs, related AEs,
AEs by severity and treatment-emergent AEs will be summarized by system organ class (SOC) and
preferred term (PT). Descriptive statistics would be provided for all other safety assessments (clinical
laboratory parameters, vital signs and ECG parameters).
The PK analysis set will be used for the analyses of macitentan and aprocitentan concentrations.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
12
Status: Approved,  Date:  7 August 2023
1.2. 
Schema
Figure 1: 
Schematic Overview of the Study
Abbreviations: EOS=end of study; EOT=end of treatment; PE=primary endpoint; PVRI=pulmonary vascular
resistance index; Wk=week.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
15
Status: Approved,  Date:  7 August 2023
h. 
Serum Pregnancy Testing (for women of childbearing potential only) at the time of screening. Subjects of childbearing potential who are sexually active should be
receiving at least 4 weeks of contraception before the urine pregnancy test at Day 1. Monthly urine pregnancy tests for women of child bearing potential to be done
at home under parental supervision. In this case the investigator or designee will verify via phone that the test was done and will verify the results. The pregnancy
test is done locally.
i. 
A trough sample (ie, predose) will be drawn on Visit 6 (Week 12). At Visit 3, the blood samples for the PK profiling must be drawn at the following timepoints:
Immediately before administration of macitentan (predose) and then 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h (before macitentan intake the next day) postdose. Samples for
PK assessment should be collected within 20% deviation from the nominal sampling time.
j. 
At Day 1, the blood samples for the PK profiling must be drawn at the following timepoints: 2 h, 5 h, and 24 h (before macitentan intake the next day) postdose. A
trough sample (ie, predose) will be drawn on Visit 4 and Visit 5. Samples for PK assessment should be collected within 20% deviation from the nominal sampling
time.
k. 
Visit 3 will take place at steady-state conditions for macitentan and its active metabolite (aprocitentan), ie, patients must have received at least 10 days of
continuous administration of the same dose of macitentan (patients should take the same dose level and time of day for 11 days prior to Visit 3 including the day of
visit). After completion of the 24 hour PK collection, macitentan treatment will begin at the dose determined at Visit 3.
l. 
Data available within 14 days prior to Day 1
m. For patients of < 2 years, liver tests must be monitored monthly until EOS
n. 
If there is no change in clinical conditions, data available within 14 days prior to Day1. Not required on Day 1 if screening assessment is performed within 14 days
prior to Day1.
o. 
If there is no change in clinical conditions, data available within 7 days prior to Day1. Not required on Day 1 if screening assessment is performed within 7 days
prior to Day1.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
16
Status: Approved,  Date:  7 August 2023
2. 
INTRODUCTION
Pulmonary arterial hypertension (PAH) is a rare and complex disease characterized by
vasoconstriction and progressive remodeling of the pulmonary arterial wall. Resulting permanent
increase in pulmonary vascular resistance (PVR) eventually leads to right ventricular failure and
death. The pathological features are similar in children and adults, but the spectrum of associated
conditions, clinical presentation, and factors influencing survival may differ (Ivy 2013).
The definition of PAH in adults and children is the same and is based on pulmonary hemodynamics
measured by right heart catheterization (RHC): a mean pulmonary artery pressure (mPAP)
≥25 mm Hg at rest demonstrates pulmonary hypertension. In patients with PAH, the pulmonary
hypertension is pre-capillary and thus they have a normal pulmonary artery wedge pressure
(PAWP) ≤15 mm Hg and an elevated PVR > 3 Wood units (WU) (mm Hg/L⋅min) (Hoeper 2013).
In children, PVR index (PVRI) instead of PVR is used in order to account for growth, and PAH is
defined as PVRI > 3 WU × m2 (Ivy 2013; Abman 2015; Hansmann 2016).
There are few epidemiological studies on pediatric PAH in Japan, but according to a nationwide
survey on idiopathic PAH/hereditary PAH, the annual incidence is approximately 1 in 1 million
people, and it is estimated that children account for approximately 25% of all patients with PAH
including adults (Saji 2000). At the end of fiscal 2019, there were 29 PAH patients aged 0 to
19 years who received the intractable disease medical care certificate.
Macitentan (JNJ-67896062) is an orally active, nonpeptide, potent dual endothelin (ET) ET  A and
ETB receptor antagonist characterized by high receptor affinity and a slow receptor dissociation
rate. In vitro, macitentan selectively inhibits the binding of ET-1 to ET  A and ET  
B receptors as well
as the effects mediated by these receptors in functional assays in cells and isolated organs. In vivo,
macitentan increases ET-1 plasma concentrations. Macitentan has one active circulating
metabolite, aprocitentan, which is also a dual ETA/ETB receptor antagonist. In functional in vitro
assays (inhibition of contraction of isolated rat aorta and trachea), aprocitentan is, on average,
5-fold less potent than macitentan. However, aprocitentan systemic exposure in humans is about
3-fold higher than macitentan, and aprocitentan contributes to the overall pharmacological effect
of macitentan.
Macitentan (OPSUMIT in the United States [US] and the European Union [EU] and ZEPENDO
in other regions; 10 mg film coated tablets, once daily) was granted a marketing authorization for
the treatment of patients with PAH in the US, European Economic Area (EEA), Canada, Australia,
Switzerland, Japan, and additional countries in the Middle East, Asia, and Latin America.
For the most comprehensive nonclinical and clinical information regarding macitentan, refer to the
latest version of the Investigator's Brochure (IB) and Addenda for macitentan.
The term “study intervention” throughout the protocol, refers to macitentan as defined in Section
6.1, Study Intervention Administered.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
17
Status: Approved,  Date:  7 August 2023
The term "sponsor" used throughout this document refers to the entities listed in the Protocol
Supplementary Information, which will be provided as a separate document.
2.1. 
Study Rationale
Macitentan was approved for the treatment of adult patients with PAH in 2015 in Japan; however,
is not indicated for pediatric PAH patients in the world. Pediatric indication of macitentan is highly
desired because macitentan is the commonly prescribed endothelin receptor antagonist (ERA) for
adult PAH in Japan.
The current management of pediatric PAH by physicians is based primarily on results from studies
in adult patients, together with expert recommendations, such as those from the 5th World
Symposium for pulmonary hypertension (Ivy 2013). Results from different cohort studies
demonstrate that survival rate has been improved in pediatric patients by the use of therapies
approved for adult PAH patients (Haworth 2009; Barst 2012; Moledina 2010; Van Loon 2010;
Zijlstra 2014). However, treatment remains unsatisfactory, with 5-year survival rates ranging from
71% to 75% (Ivy 2013). These cohort studies before the launch of macitentan indicate that the
management of PAH in young patients remains sub-optimal. It is important to address this medical
need by making available an efficacious and well-tolerated therapy with an age-appropriate
formulation for children with PAH.
The current treatment algorithm for pediatric PAH in Japan is similar to those in the US and Europe.
In Japan, various kind of drugs for the treatment of PAH have been approved for children compare
to other countries. As of July 2021, 4 drugs (bosentan, sildenafil, ambrisentan, epoprostenol) have
been approved for pediatric, and 2 of those 4 drugs (bosentan and ambrisentan) have a same mode
of action as macitentan (endothelin receptor antagonist). However, ambrisentan is indicated only
for patients aged ≥8 years and not for children aged <8 years. In addition, although bosentan was
the first drug approved for pediatric patients in Japan, it has been reported that macitentan tablet
for adult is preferred even for pediatric over bosentan pediatric formulation (eg, macitentan does
not need monthly liver tests), and number of pediatric PAH patients receiving macitentan as an
off-label use exceeds those receiving bosentan (Medical Data Vision [MDV] database).
In order to provide a seamless treatment from pediatric to adult patients also in Japan, it is of
significance to develop macitentan, which is commonly prescribed for adults, in pediatric patients
in this country.
This study is designed to describe the efficacy, safety, and pharmacokinetics (PK) of macitentan
in Japanese pediatric participants with PAH and is being planned to enable pediatric PAH patients
to use macitentan in Japan in the future.
2.2. 
Background
Nonclinical Studies
Available data indicate that nonclinical pharmacology, PK, and available toxicity data support a
pediatric development program and supplemental New Drug Application (sNDA).

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
18
Status: Approved,  Date:  7 August 2023
Safety Pharmacology
Nonclinical safety pharmacology studies did not indicate treatment-related effects, except for a
decrease in arterial blood pressure (BP) in cardiovascular studies in dogs.
Toxicology
In repeated-dose toxicity studies, the heart (dog), liver (mouse, rat, dog), and testes (rat, dog) were
identified as the main organs affected by treatment with macitentan. Minor or secondary changes
were observed in red blood cells, the hemostatic system, thyroid, uterus, and nasal cavities.
Macitentan was embryotoxic and teratogenic in developmental and reproductive toxicity studies.
It was not genotoxic or phototoxic. Macitentan was not carcinogenic in mice and rats.
In juvenile rats, target organs were not different from those in adult animals. In the pivotal rat
juvenile toxicity study at the high dose of 30 mg/kg/day (corresponding to 7-fold the human
exposure at 10 mg per day), reduced body-weight gain and low food consumption were noted.
Effects on development, such as slight delay of descensus testis, reversible reduction of long-bone
length, prolonged estrous cycle, slightly increased pre- and postimplantation loss, decreased mean
number of pups, and decreased testis and epididymis weights are considered to be largely
secondary to low food consumption and retarded body-weight development. This conclusion was
based on literature data showing the correlation between pre- and post-weaning food restriction
and delayed onset of puberty and impaired reproductive performance (Almeida 2000;
Engelbregt 2002; McGuire 1995). The mean number of sperms with malformed hook was
increased in high dose group males, whereas sperm count and motility were unchanged. In two
high dose males, testicular tubular atrophy was noted after treatment for 66 days. The no observed
adverse effect level was 3 mg/kg/day (TWS Macitentan 2012), corresponding to 1.7-fold the
human therapeutic exposure.
Clinical Studies
Pharmacokinetics and Metabolism
For details provided in this section and further information refer to the IB ACT-064922
(Macitentan IB).
Macitentan has a pharmacologically active metabolite (aprocitentan) in humans. In healthy
subjects maximum plasma concentrations are generally achieved about 8 h after oral
administration of macitentan. Thereafter, plasma concentrations decrease slowly with an apparent
terminal half-life (t1/2) of approximately 16 h (and 48 h for aprocitentan). After multiple-dose
administration steady-state conditions of macitentan are obtained after 3 days (and 7 days for
aprocitentan). Macitentan accumulates only minimally (about 1.5-fold), whereas aprocitentan
accumulates substantially (about 8.5-fold). For plasma concentrations and other PK parameters
measured in Phase 1 studies, refer to the IB (Macitentan IB).
Bioavailability of macitentan and exposure to aprocitentan are unchanged in the presence of food.
Thus, macitentan can be taken irrespective of food intake. In adult PAH patients there was no
clinically relevant influence of different demographic variables, disease severity, or concomitant

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
19
Status: Approved,  Date:  7 August 2023
PAH treatment at Baseline on plasma concentrations of macitentan and aprocitentan. Macitentan
clearance is mediated by several human P450 enzymes including CYP3A4 and CYP2C9 and is
mainly eliminated via the urine (49.7% ± 3.9%). Aprocitentan is approximately 5-fold less potent
than macitentan in vitro. However, in humans, systemic exposure to aprocitentan is about 3-fold
higher as compared to macitentan, and aprocitentan contributes to the overall pharmacological
effect. Formation of aprocitentan is mainly catalyzed by CYP3A4. At the maximum dose of 10 mg
planned in this clinical trial, macitentan and aprocitentan are not expected to inhibit cytochrome
P450 enzymes or drug transport proteins in the liver or kidney. Neither is it expected that there
will be a relevant induction of hepatic CYP3A4. There was no drug-drug interaction between
warfarin and macitentan. Concomitant administration of sildenafil has no clinically relevant effect
on the PK of macitentan or aprocitentan. Conversely, macitentan’s effect on sildenafil exposure is
modest and can also be ignored. In the presence of strong inhibitors of CYP3A4 (eg, ketoconazole)
and moderate dual inhibitors of CYP3A4 and CYP2C9 (eg, fluconazole, amiodarone) or during
co-administration of moderate CYP3A4 inhibitors and moderate CYP2C9 inhibitors, exposure of
macitentan increases whereas potent inducers of CYP3A4 reduce exposure to macitentan.
Therefore, these agents should not be used concomitantly with macitentan.
Clinical Safety in Adults
The safety of macitentan was evaluated in the long-term placebo-controlled trial SERAPHIN
(AC-055-302) in 742 subjects with symptomatic PAH. The mean treatment duration was
103.9 weeks in the macitentan 10 mg group and 85.3 weeks in the placebo group. Adverse
reactions that occurred in at least 10% of the patients (ie, very common) included bronchitis,
nasopharyngitis, headache, and anemia. Macitentan 10 mg was associated with a decrease from
Baseline hemoglobin levels to below 10 g/dL in 8.7% of patients (as compared to 3.4% in placebo).
Common adverse reactions (ie, incidence at least 1% and below 10%) included hypotension,
pharyngitis, influenza, and urinary tract infection. Edema and fluid retention, which have been
associated with the use of ERAs and are also a clinical manifestation of right heart failure and
PAH, had similar frequencies in macitentan 10 mg and placebo groups: 21.9% and 20.5%,
respectively (this corresponded to 11.0 events/100 patient-years on macitentan 10 mg vs
12.5 events/100 patient-years on placebo). The incidence of aminotransferase elevations was
similar in patients treated with macitentan and with placebo (alanine aminotransferase [ALT]
and/or aspartate aminotransferase [AST] >3 × upper limit of normal range [ULN] was 3.4% on
macitentan 10 mg and 4.5% on placebo, ALT and/or AST >5 × ULN was 2.5% on macitentan
10 mg and 2% on placebo). Macitentan 10 mg was associated with a decrease in mean count of
leukocytes and platelets: incidence on macitentan 10 mg and placebo was 2.5% and 1.6%,
respectively, for leukopenia; and 5.0% and 2.8%, respectively, for thrombocytopenia. In the same
study, macitentan 10 mg was associated with a decrease in mean leucocyte count from baseline of
0.7×109 /L versus no change in placebo-treated patients, and with a decrease in mean platelet count
of 17×109/L, versus a mean decrease of 11×109/L in placebo-treated patients.
Macitentan doses of 150 mg once daily or higher (maximum 300 mg once daily), generating
exposures 6 to 10 times higher than those observed with 10 mg once daily, have been used over
several months in combination with temozolomide in patients with glioblastoma. These doses were
well tolerated, and in particular were not associated with a different safety profile, or with an

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
20
Status: Approved,  Date:  7 August 2023
increased incidence or severity of known adverse drug reactions for macitentan such as headache,
hypotension, liver enzyme elevations, or anemia, compared to 10 mg once daily doses
(CSR AC-055-115 2017).
The safety, and tolerability of macitentan in Japanese PAH patients were evaluated in a Phase 2/3
open-label, multicenter study (AC-055-307). Macitentan at a dose of 10 mg per day was
well-tolerated in Japanese subjects with PAH. The median (range) duration of study treatment in
the Safety set (n = 30) was 839 days (range: 229 to 1037). 100% (30 subjects) had at least one
adverse event (AE). Serious adverse events (SAEs) were reported in 30.0% (9 subjects). One
subject discontinued study drug due to an AE and eventually died (worsening of pulmonary
embolism). The most frequently reported AEs included nasopharyngitis (reported by 21 subjects),
headache (14 subjects), diarrhea (10 subjects), epistaxis (9 subjects), flushing (8 subjects), anemia
(7 subjects) and contusion (7 subjects).
During the postmarketing experience edema/fluid retention (very common), nasal congestion
(common), and hypersensitivity reactions (angioedema, pruritus, rash) (uncommon) have been
reported. Cases of pulmonary edema have been reported with vasodilators (mainly prostacyclins)
when used in patients with pulmonary veno-occlusive disease. Consequently, if signs of
pulmonary edema occur when macitentan is administered in patients with PAH, the possibility of
pulmonary veno-occlusive disease should be considered.
More comprehensive safety data are provided in the IB (Macitentan IB).
Clinical Efficacy in Adults
The efficacy of macitentan in adult patients with symptomatic PAH was evaluated in SERAPHIN
(AC-055-302), a multicenter, double-blind, randomized, placebo-controlled, parallel-group,
event-driven, Phase 3 study. In this study, macitentan significantly reduced the risk of the
occurrence of morbidity and mortality event. This study was conducted between May 2008 and
March 2012 and enrolled 742 subjects randomized in a 1:1:1 ratio to either receive macitentan
10 mg, macitentan 3 mg or placebo allowing the use of PAH-specific background therapy.
Macitentan 10 mg reduced the risk for the occurrence of a morbidity/mortality (MM) event with a
hazard ratio (HR) of 0.547 versus placebo (97.5% confidence limits [CL] 0.392-0.762, logrank p
<0.0001). The HR in the macitentan 3 mg group versus placebo was 0.704 (97.5% CL 0.516-0.960,
logrank p=0.0108). Thus the 10 mg dose showed a stronger treatment effect than the 3 mg dose.
The treatment effect with macitentan was established early and was sustained for the duration of
the study (median duration of treatment of >2 years). Macitentan 10 mg also reduced risk of
hospitalization for PAH or PAH-related deaths; HR 0.500 (97.5% CL 0.335-0.747, logrank
p<0.0001). The respective HR in the macitentan 3 mg group versus placebo was 0.669 (97.5% CL:
0.462-0.970, logrank p=0.0146). Treatment with macitentan reduced also the number of days in
hospital: The mean number of hospitalization days per year (all causes) was 7.5 days in the
macitentan 3 mg group and 5.7 days in the macitentan 10 mg group, compared to 12.2 days in the
placebo group (Pulido 2013; Macitentan IB).

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
21
Status: Approved,  Date:  7 August 2023
The efficacy of macitentan 10 mg administered once daily for 24 weeks was evaluated in Japanese
PAH patients in a Phase 2/3 open-label, multicenter study (AC-055-307). A total of 30 Japanese
patients with PAH were enrolled and received the study drug (macitentan 10 mg). The geometric
mean PVR at Week 24 in the per-protocol set (PPS; n = 28) decreased to 60.5% of the baseline
level (95% CL: 52.4, 69.9) and the difference from baseline was significant (p<0.0001 by the
Wilcoxon signed-rank test). The median decrease from baseline to Week 24 was 178 dyn∙s/cm5
(95% CL: −294, −136). At Week 48, mean 6-minute walk distance (6MWD) in the PPS had
increased by 62 meters (95% CL: 38, 87) compared to baseline. An increase in Borg dyspnea index
was observed at Week 48 (mean of 1.0 [95% CL: 0.4, 1.5] compared to baseline). None of the
patients had deterioration in World Health Organization (WHO) functional class (FC) at Week 48.
Improvement of WHO FC was observed in 9 (40.9%) out of 22 patients in the PPS at Week 48.
Six out of 7 patients with FC III PAH at baseline had improvement to FC II. The geometric mean
NT-proBNP at Week 48 in the PPS was 100 pg/mL (95% CL: 54, 183), representing a decrease to
87.7% of the baseline level (95% CL: 62.0, 123.9). At study completion, improvement of 6MWD
and WHO FC were maintained in each patient. No patients had deterioration in WHO FC at the
end of the study (Macitentan IB).
2.3. 
Benefit-Risk Assessment
Studies in juvenile rats showed effects mainly during the suckling period (Days 4–21): macitentan
exposure was associated with lower food intake, which appeared to be the cause for all other
observed differences regarding weight gain and developmental indices. Compared to the toxicity
profile known in adult animals, no change in target organ toxicity was identified. Children of at
least 2 years of age and adolescents are at a more advanced developmental stage compared to
suckling juvenile rats. Adverse event (AE) reports received so far on adolescents and children
receiving off-label macitentan have not indicated reduced food intake or delays in general growth
or development.
The dose regimens in this study are the same as those in TOMORROW study, which is an ongoing
global study in non-Japanese pediatric participants with PAH. Results from the previous clinical
studies showed that there was no difference in the efficacy and safety of macitentan between
Japanese adults and non-Japanese adults. Also, since there was no ethnic PK difference between
Japanese adults and non-Japanese adults up to 10 mg and it is considered that there is no PK
difference between Japanese pediatrics and non-Japanese pediatrics, dose regimen rationale for
the non-Japanese pediatrics patients is applicable to Japanese pediatric patients (for additional
details regarding the justification of dose, see Section 4.3).
Although clinical studies have been performed in children with PAH (eg, bosentan, sildenafil) and
other studies are ongoing, current treatment of PAH in children is mostly based on data from
clinical trials in adults with PAH.
More detailed information about the known and expected benefits and risks of macitentan may be
found in the IB.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
22
Status: Approved,  Date:  7 August 2023
2.3.1. 
Risks for Study Participation
Potential Risks of Clinical 
Significance 
Summary of Data/
Rationale for Risk
Mitigation Strategy
Clinical worsening of PAH 
The benefit-risk of macitentan in
the treatment of PAH has not been
established.
Participants will discontinue study
intervention if it is not in their best
interest or if they need to initiate
protocol-prohibited medications
including certain biologics
(Section 6.8 and Section 7.1). In the
presence of PAH-worsening, any
PAH specific treatment (PDE5
inhibitor, riociguat, prostanoid) can
be initiated per investigator’s
judgment (Section 6.8.1).
Risks Due to Study Intervention
Teratogenicity 
Teratogenicity was seen in rats and
rabbits and is a known class-effect
among ERAs. Nonclinical studies
in rats revealed that macitentan and
its metabolites were excreted into
milk during lactation.
Women of childbearing potential
who are not using reliable
contraception will not be enrolled in
the study (Section 5.1 and
Section 5.2). Monthly pregnancy
tests during treatment with
macitentan are recommended to
allow the early detection of
pregnancy. Women who are
pregnant, or breast-feeding, or
planning to become pregnant while
enrolled in this study or within
4 weeks after the last dose of study
intervention will not be enrolled in
the study. If a female participant
becomes pregnant while on study
treatment with macitentan, study
treatment must be discontinued
(Section 7.1).
Elevations of liver
aminotransferases (AST and/or
ALT)
Elevations of liver
aminotransferases (AST, ALT)
have been associated with PAH and
with other ERAs. However, in a
long-term placebo-controlled study,
in PAH, macitentan 10 mg was not
associated with increased
incidences of treatment-emergent
elevations of AST and/or ALT
versus placebo.
If unexplained aminotransferase
elevations occur and are deemed
clinically relevant, or if elevations
are accompanied by an increase in
bilirubin 2×ULN, or by clinical
symptoms of liver injury,
macitentan treatment will be
discontinued. Reinitiation of
macitentan may be considered
following the return of hepatic
enzyme levels to within the normal
range in patients who have not had
clinical symptoms of liver injury
(Section 7.1.3).

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
23
Status: Approved,  Date:  7 August 2023
Risks Due to Study Procedures
Right heart catherization (RHC) 
Potential risks associated with RHC
include bruising or hematoma,
swelling and infection. irritating
sensation, heart rhythm
abnormalities, low blood pressure,
bleeding, general infection,
collapsed lung, or clotting of the
blood, mortality.
To minimize the risks that may be
associated with RHC, the procedure
will only be performed at sites
experienced with the procedure and
complying with specific RHC
guidelines.
2.3.2. 
Benefits for Study Participation
Macitentan is approved for treatment in adult PAH as a 10 mg once daily dose based on a favorable
benefit-risk ratio from above stated studies in adults (AC-055-302, AC-055-115, and AC-055-307).
Given the similarity of the PAH pathophysiology in adults and children, it is anticipated that
treating pediatric patients with PAH with a macitentan dose according to their body weight,
targeting a systemic exposure similar to that in adult patients with PAH, will also result in a
favorable benefit/risk ratio.
2.3.3. 
Benefit-Risk Assessment for Study Participation
Taking into account the measures taken to minimize risk to participants of this study, the potential
risks identified in association with macitentan are justified by the anticipated benefits that may be
afforded to participants with PAH.
3. 
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints*
Primary 
To evaluate the effect of macitentan on hemodynamic 
measures at Week 24 
Fold change at Week 24 in pulmonary vascular
resistance index (PVRI)
Secondary 
To evaluate the effect of macitentan on pulmonary 
hemodynamic parameters other than PVRI at Week 24 
Change from baseline to Week 24 in the following
hemodynamic variables: pulmonary vascular resistance
(PVR), mean right atrial pressure (mRAP), mean
pulmonary arterial pressure (mPAP), cardiac index
(CI), cardiac output (CO), total pulmonary resistance
(TPR) and mixed venous oxygen saturation (SvO2) at
rest
To evaluate the effect of macitentan on World Health 
Organization (WHO) Functional Class (FC) at 
Week 24 (For patients whose age is >4 years of age
when initial informed consent)
Improvement in WHO FC from baseline to Week 24
(yes/no).
To evaluate the effect of macitentan on Panama FC at 
Week 24 
Improvement in Panama FC from baseline to Week 24
(yes/no).
To evaluate the effect of macitentan on exercise 
capacity at Week 24 (For patients who are 
developmentally able to understand and perform the 6- 
minute walk test [6MWT] and whose age is ≥6 years of
age when initial informed consent)
Change from baseline to Week 24 in exercise capacity
(6-minute walk distance [6MWD], as measured by the
6MWT).
To evaluate the effect of macitentan on NT-proBNP at 
Week 24
Change from baseline to Week 24 in NT-proBNP

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
24
Status: Approved,  Date:  7 August 2023
Objectives 
Endpoints*
To evaluate the effect of macitentan on 
Echocardiography at Week 24 
Change from baseline to Weeks 24 in tricuspid annular
plane systolic excursion (TAPSE) and left ventricular
eccentricit y index measured b y echocardiography.
To evaluate the effect of macitentan on quality of life 
at Week 24 
Change from baseline to Week 24 in: PedsQL™ 4.0
Generic Core Scales Short Form (SF-15).
To evaluate the effect of macitentan on physical 
activity at Week 24 (For patients whose age is ≥2 years 
of age when initial informed consent)
Change from baseline to Week 24 in physical activity
as measured by accelerometry
To assess pharmacokinetics (PK) of macitentan and its 
active metabolite (aprocitentan) in pediatric 
participants with PAH.
Macitentan and aprocitentan concentrations in plasma
or blood at all assessed timepoints
To evaluate the long-term effect of macitentan on 
exercise capacity in PAH children 
(For patients who are developmentally able to 
understand and perform 6MWT and whose age is ≥6
years of age when initial informed consent)
Changes from baseline to all assessed timepoints in
exercise capacity (6MWD, as measured by the
6MWT).
To evaluate the long-term effect of macitentan on 
dyspnea on exertion (For patients who perform 
6MWT) 
Change from baseline to all assessed timepoints in
dyspnea on exertion assessed by the Borg CR10
Scale®
To evaluate the effect of macitentan on physical 
activity (For patients whose age is ≥2 years of age 
when initial informed consent)
Change from baseline to all assessed timepoints in
physical activity as measured by accelerometry
To evaluate the long-term effect of macitentan on 
WHO FC  
Improvement in WHO FC from baseline to all assessed
timepoints
To evaluate the long-term effect of macitentan on 
Panama FC  
Improvement in Panama FC from baseline to all
assessed timepoints
To evaluate the long-term effect of macitentan on NT- 
proBNP 
Percent of Baseline plasma NT-proBNP at each
timepoint of assessment.
To evaluate the long-term effect of macitentan on 
Echocardiography  
Percent of Baseline in TAPSE, and left ventricular
eccentricity index measured by echocardiography to all
assessed timepoints
To evaluate the effect of macitentan on quality of life 
Change from baseline to all assessed timepoints in:
PedsQL™ 4.0 Generic Core Scales Short Form
(SF-15).
To evaluate the safety and tolerability of macitentan in 
pediatric participants with PAH. 
Safety endpoints are assessed up to 30 days after study
intervention discontinuation
 Adverse events (AEs)
 Serious adverse events (SAEs)
 AEs leading to premature discontinuation of
macitentan
 AEs of special interest
 Markedly laboratory abnormalities
 Change from baseline in laboratory parameters to
all timepoints of assessments
 Change from baseline in vital signs (diastolic blood
pressure [DBP], systolic blood pressure [SBP], and
pulse rate [PR]), height and body weight to all
timepoints of assessments
 Change from baseline in electrocardiogram (ECG)
parameters

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
25
Status: Approved,  Date:  7 August 2023
Objectives 
Endpoints*
Exploratory 
To confirm the time to occurrence of the 
morbidity/mortality event. 
Time to occurrence of any of the following events from
the start of Treatment phase as defined below:
 Death (all causes)
 Atrial septostomy or Potts’ anastomosis, or
registration on lung transplant list
 Hospitalization due to worsening PAH§
 Clinical worsening* of PAH defined as:
Need for, or initiation of new PAH-specific
therapy# or IV diuretics or continuous oxygen use
AND at least one of the following:
 Worsening in WHO FC, or
 New occurrence or worsening of syncope (in
frequency or severity as per medical judgment),
or
 New occurrence or worsening of at least two
PAH symptoms (ie, shortness of
breath/dyspnea, chest pain, cyanosis, dizziness/
near syncope, or fatigue), or
 New occurrence or worsening of signs of right
heart failure not responding to oral diuretics
§ Excluding hospitalizations that are elective, routine or
clearly attributable to appearance/worsening of
comorbidities (eg, pneumonia).
* Worsening from baseline.
# Eg, ERA, phosphodiesterase type 5 (PDE-5)
inhibitor, prostanoids, prostacyclin receptor (IP
receptor) agonist, soluble guanylate cyclase stimulator
To evaluate the effect of macitentan on PAH-related 
deaths and hospitalizations 
Time to hospitalization or death due to PAH occurring
between the first administration of study intervention
and end of stud y (EOS).
To evaluate the effect of macitentan on PAH-related 
hospitalizations 
Time to hospitalization due to PAH occurring between
the first administration of stud y intervention and EOS.
To evaluate the effect of macitentan on PAH-related 
deaths  
Time to death due to PAH occurring between the first
administration of stud y intervention and EOS.
To evaluate the effect of macitentan on death (of all 
causes) 
Time to death (all causes) occurring between the first
administration of stud y intervention and Stud y Closure.
* Throughout the document, baseline is defined as the last observed value before the first study intervention intake.
Refer to Section 8, STUDY ASSESSMENTS AND PROCEDURES for evaluations related to
endpoints.
4. 
STUDY DESIGN
4.1. 
Overall Design
This is a multi-center, open-label, single-arm, Phase 3 study in Japanese pediatric participants
(aged between ≥ 3 months and < 15 years) with PAH, to evaluate the efficacy, safety, and PK of
macitentan. Patients with idiopathic PAH or hereditary PAH as well as PAH associated with
congenital heart disease (CHD), drug or toxin induced PAH, or connective tissue disorder (CTD)
and PAH associated with human immunodeficiency virus (HIV) will be enrolled if they are of

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
26
Status: Approved,  Date:  7 August 2023
WHO FC I, II, III, or IV. Eligible patients are PAH-specific treatment-naïve or already treated
with PAH-specific treatment.
A target of 6 participants will be enrolled in this study. For dosing details, refer to Section 6,
STUDY INTERVENTION AND CONCOMITANT THERAPY.
The study will consist of a screening period of 30 days (Day -30 to Day -1, beginning with the
signing of the informed consent/assent form [ICF]), a treatment period until Week 52 (from Day 1),
and a posttreatment follow-up period (end-of-study) of 30 days after end-of-treatment. The end-
of-study is considered as the last visit/assessment for the last participant in the study.
An Independent Liver Safety Data Review Board (ILSDRB) will review serious hepatic events of
special interest.
A diagram of the study design is provided in Section 1.2, Schema.
4.2. 
Scientific Rationale for Study Design
According to International Council for Harmonisation (ICH) E11 (R1) guidelines “Addendum to
Guidance on Clinical Trials of Medicinal Products in the Pediatric Population 5.1.1 Use of
Extrapolation in Pediatric Development" (ICH E11 Guidelines), clinical data from drugs approved
in adults can provide evidence to support their effective and safe use in children for the same
indication if the disease course and expected response to the drug can be assumed to be similar
between the pediatric and adult populations. In adults, the efficacy and safety of Macitentan in
Japanese patients with PAH have already been demonstrated, and PVR and PVRI obtained in the
Japanese adult study (AC-055-307) showed improvement similar to that in the non-Japanese adult
study (AC-055-302/SERAPHIN).
Similarity of Disease in Adults and Children
PAH in children has been shown to share many similarities with the disease in adults. PAH has a
broad spectrum of clinical features in both children and adults that are manifestations of similar
processes (Barst 2011; Ollivier 2019). The current management of pediatric PAH is based
primarily on results from studies in adult patients, together with expert recommendations, such as
those from the 5th and 6th World Symposium for Pulmonary Hypertension (Galiè 2013; Ivy 2013;
Rosenzweig 2019). Pediatric consensus treatment guidelines recommend therapeutic algorithms
in children based on expert opinion and several studies in children and adults (evidence-based)
(Ivy 2013; Abman 2015; Hansmann 2016). Available adult PAH treatments are routinely used in
children with PAH according to consensus guidelines. the pathology of PAH are similar between
adults and children, and there is no difference in the diagnostic criteria or treatment of PAH
between adults and children. Therefore, if the same exposure as that in adults was confirmed in
Japanese children in PAH3001 and PVRI tended to improve as in AC-055-307, the results of
AC-055-307 could be extrapolated to Japanese children and the efficacy and safety in Japanese
children with PAH could be evaluated by reference to the results of the SERAPHIN.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
27
Status: Approved,  Date:  7 August 2023
Blinding, Randomization, and Control Group
There will be no blinding, randomization, or control in this study.
Efficacy Measures
Currently, there are no validated surrogate biomarker endpoints available for PAH in children.
Recent treatment guidelines for pediatric PAH patients highlight the need for clinical endpoints
measuring long-term outcomes (Ivy 2013). Clinical experts recognize morbidity/mortality event
(MM event) as the most clinically meaningful outcomes in PAH (Ivy 2013; Chakinala 2013). A
global phase 3 study (AC-055-302, SERAPHIN) in adult PAH patients with macitentan was
conducted with the MM event as the primary endpoint (Pulido 2013). As PAH is a progressive
disease, MM events are considered to be a more accurate and appropriate endpoint of disease status
compared to patient symptom-based endpoints such as 6MWD. At the 4th PAH World Symposium,
the MM event was recommended as a clinically meaningful and robust primary endpoint
(McLaughlin 2009). On the other hand, in many studies in adult PAH patients, 6-minute walking
distance has been defined as the primary efficacy endpoint in clinical trials with short-term follow-
up duration of 3 to 6 months (Galiè 2009; Ollivier 2019). Study AC-055-302 (SERAPHIN) is the
first clinical study to evaluate long-term outcomes of PAH treatment with MM events as the
primary endpoint (Pulido 2013).
PAH is a disease in which the lumen of pulmonary blood vessels is narrowed due to contraction
of pulmonary microarteries, thickening of vascular smooth muscle, and proliferation of intima,
and PVR is significantly increased. PVR is an objective parameter that reflects right heart load and
has been reported to correlate with the prognosis of PAH patients (D'Alonzo 1991; Sitbon 2002).
It is used for clinical assessment (D'Alonzo 1991; Barst 2010; Peacock 2009). In addition, a
reduction in the risk of MM event occurrence and PVR at 6 months after administration of
macitentan was observed in the AC-055-302 (SERAPHIN) study. These results suggest a possible
correlation between MM event and PVR (Pulido 2013). The AC-055-307 study with Japanese
adult PAH patients defined PVR as the primary endpoint (Tahara 2016). In Japan, it is difficult to
conduct a study to evaluate the treatment effect using the MM event from the viewpoint of sample
size. The population of Japanese PAH is very small while event-driven study requires a large
number of patients.
In assessment of the treatment effect in pediatric PAH patients with PVR, PVRI is usually applied.
PVRI is the PVR corrected by the body surface area (Del Cerro 2011; Hansmann 2017). As large
individual differences in physique in children, PVRI is generally used for children. In the Japanese
pediatric study of bosentan (AC-052-377) (Saji 2018a) and epoprostenol (AC-066A308)
(Saji 2018b), the change from baseline in PVRI at 12 weeks after administration was defined as
the primary endpoint. Additionally, in the Japanese pediatric study of sildenafil (AC1481298),
change from baseline in PVRI at 16 weeks after administration was defined as the primary
endpoint.
Figure 2 summarizes the relationship between MM events and PVR/PVRI in the studies of
macitentan.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
28
Status: Approved,  Date:  7 August 2023
Figure 2: 
Relationship between MM event and PVR/PVRI
Abbreviations: MM= morbidity/mortality; PE= primary endpoint; PVR= pulmonary vascular resistance;
PVRI=pulmonary vascular resistance index
The AC-055-302 (SERAPHIN) study suggests a correlation between MM events and PVR. That
is, a decrease in MM events and a decrease in PVR were observed in the macitentan treated group.
The correlation between MM events and PVR can be fully explained by the disease mechanism.
Therefore, PVRI is selected as the primary endpoint in this study. Given the lack of previous
research data describing a clinically meaningful change in PVRI, an exploratory analysis was
performed to quantitate clinically meaningful change in PVRI using the clinical study data with
macitentan. Based on this exploratory analysis, it was estimated that it would be clinically
meaningful if the point estimate of PVRI fold change (Week 24 to baseline) is equal to or less than
81.6%. For additional details regarding the discussion of clinically meaningful PVRI fold change
and the success criterion for this study, please refer to Section 9.2.
4.2.1. 
Study-Specific Ethical Design Considerations
Potential participants or their legal guardian or legally acceptable representative(s) will be fully
informed of the risks and requirements of the study and, during the study, participants will be given
any new information that may affect their decision to continue participation. They will be told that
their consent to participate in the study is voluntary and may be withdrawn at any time with no reason
given and without penalty or loss of benefits to which they would otherwise be entitled. Only
participants who are fully able to understand the risks, benefits, and potential AEs of the study, and
provide their consent voluntarily will be enrolled.
When referring to the signing of the informed consent/assent form (ICF), the terms legal guardian
and legally acceptable representative refer to the legally appointed guardian of the child with
authority to authorize participation in research. For each participant, his or her parent(s) (preferably
both parents, if available) or legally acceptable representative(s), as required by local regulations,
must give written consent (permission) according to local requirements after the nature of the study
has been fully explained and before the performance of any study-related assessments. Assent must
be obtained from children (minors) capable of understanding the nature of the study, typically
participants 7 years of age and older, depending on the institutional policies. For the purposes of this

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
29
Status: Approved,  Date:  7 August 2023
study, all references to participants who have provided consent (and assent as applicable) refers to
the participants and his or her parent(s) or the participant's legal guardian(s) or legally acceptable
representative(s) who have provided consent according to this process. Minors who assent to a study
and later withdraw that assent should not be maintained in the study against their will, even if their
parent(s) still want them to participate.
In the case that the site would like to recruit participants whose parent(s)/legally designated
representative cannot read or write, or do not speak or understand the ICF language, additional
measures must be implemented in order to ensure participant’s rights are respected and the consent
obtained is legally valid. 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. The Contract Research Organization (CRO), the regulatory authorities (if applicable), and
the IEC/IRB must be informed prior to the recruitment. The consent process (eg, involvement of an
impartial witness) must be fully described, submitted to, and approved by the Independent Ethics
Committee (IEC)/ Institutional Review Board (IRB), according to procedures and before such
subjects are recruited.
The total blood volume (approximately 65 mL per participant will be collected through Week 52)
to be collected.
4.3. 
Justification for Dose
Dose regimen rationale
Given the similarity of the PAH pathophysiology in adults and children, it is anticipated that
treating pediatric patients with PAH with a macitentan dose according to their body weight,
targeting a systemic exposure similar to that in adult patients with PAH, will also show efficacy in
pediatric patients with PAH. The dose regimens in this study are the same as those in
TOMORROW study. TOMORROW study is an ongoing global study in non-Japanese pediatrics
with PAH. When multiple doses of macitentan 10 mg once daily were administered to Japanese
and non-Japanese healthy adult subjects, there were no major ethnic differences in the PK of
macitentan and aprocitentan. There were no major differences in the steady-state trough
concentration of macitentan following multiple doses of 10 mg once daily between non-Japanese
PAH patients and Japanese PAH patients. Also, it was concluded that there were no major
differences in the PK between healthy adult subjects and PAH patients. Therefore, it was
considered that even when macitentan was administered to Japanese and non-Japanese pediatric
PAH patients at the same dosage and administration, there were no major ethnic differences in the
PK. In addition, it was confirmed that the efficacy and safety profiles of macitentan in Japanese
PAH patients are not markedly different from those in non-Japanese PAH patients Therefore, the
dosage regimen used in this study is identical to that used in TOMORROW study.
Dose regimen rationale for pediatric patients between ≥ 2 years to < 15 years
In order to determine the dosage and administration in pediatric PAH patients, the effect of body
weight on clearance and distribution volume was included in a population pharmacokinetic

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
30
Status: Approved,  Date:  7 August 2023
analysis (PPK) model constructed based on data from adult PAH patients (SERAPHIN study)
using allometric scaling factors of 0.75 and 1, respectively, and used as a pediatric PPK model.
Since macitentan is mainly metabolized by CYP3A4 and CYP2C9, the metabolic pathway of
macitentan is considered to be mature to the same level as that in adults by 2 years of age
(Salem F 2014; Koukoulitaki SB 2004), and thus age was not included in the pediatric PPK model.
To determine the dosing regimen by body-weight category using the pediatric PPK model,
simulations were performed to predict the distribution of macitentan exposure by dosing regimen
and body-weight category. For each weight category, dosage was selected to achieve pediatric
exposures similar to those in adults following multiple 10 mg once daily doses of macitentan.
When the steady state PK data of 24 pediatric PAH patients in TOMORROW study and the steady-
state PK data of 20 adult PAH patients in SERAPHIN study were compared, the mean exposure
of macitentan in children was slightly lower than that in adults. Aprocitentan showed similar mean
exposures in children and adults. Using the PK data obtained from TOMORROW study, the
pediatric PPK model was updated to estimate the steady state AUC at the planned dose in each
body-weight category. As the estimated steady state area under the concentration time curve
(AUC) was similar to the mean steady state AUC in adults, it was determined that there is no need
to change the dosage and administration in TOMORROW study.
AC-055-307 study confirmed the safety and tolerability of the same dosage and administration as
in SERAPHIN study (macitentan 10 mg once daily) in Japanese adult PAH patients, and confirmed
the efficacy was similar to that in SERAPHIN study. Furthermore, 67896062PAH1005 study, in
which Japanese healthy adult participants were treated with multiple doses of macitentan at 75 mg
once daily, demonstrated the safety and tolerability at doses up to 75 mg. Therefore, it was
considered that the dosage regimen used in TOMORROW Study is acceptable for Japanese as well.
Based on the above, the dosage and administration selected in TOMORROW study in children
aged ≥2 years can be applied to this study.
Dose regimen rationale for under 2 years pediatric patients
Using the updated pediatric PPK model with the PK data from TOMORROW study, the allometric
scaling and clearance in children < 2 years of age was refined. The dose regimen for children
below 2 years of age was selected based on the PPK model with a conservative maturation function
from Salem et al (Salem 2014) and the body weight from WHO growth chart to avoid excessive
systemic exposures. Simulated area under the concentration time curve (AUC) at steady state for
the 2 age groups (1 to <6 months and 6 months to <2 years) and for each dose strength (0.5, 1, 2,
2.5, 3 and 3.5 mg) was compared to observed AUC in adults from SERAPHIN-OL and percent of
pediatric patients with AUC in [10th, 90th] percentile of adult AUC was assessed. If patients are
1 month to <6 months of age and receive 1 mg, 59.0% of patients can reach [10th, 90th] percentile
of adult AUC. If patients are 6 months <2 years of age and receive 2.5 mg, 64.7% of patients can
reach (10th, 90th) percentile of adult AUC.
Dose transfer scenario
If a patient becomes 2 years old, he or she will receive macitentan at higher dose (≥3.5 mg) based
on the body-weight category (see Table 1).

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
31
Status: Approved,  Date:  7 August 2023
4.4. 
End of Study Definition
End of Study Definition
The end of study is considered as the last visit/study assessment shown in the Schedule of
Activities 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/study assessment at that study
site, in the time frame specified in the Clinical Trial Agreement.
Study Completion Definition
A participant will be considered to have completed the study if the participant has completed
assessments at safety follow-up for up to 30 days after last dose of study intervention.
Participants who prematurely discontinue study intervention for any reason before completion of
all study visits can be considered to have completed the study if they have completed follow-up.
5. 
STUDY POPULATION
Screening for eligible participants will be performed within 30 days before administration of the
study intervention. Refer to Section 5.4, Screen Failures for conditions under which the repeat of
any screening procedures are allowed.
The inclusion and exclusion criteria for enrolling participants in this study are described below. If
there is a question about these criteria, the investigator must consult with the appropriate sponsor
representative and resolve any issues before enrolling a participant in the study. Waivers are not
allowed.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2,
Sample Size Determination.
5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
Age
1. 
Japanese1   males or females between ≥ 3 months and < 15 years of age at the first
administration of study intervention.
Type of Participant and Disease Characteristic
2. 
PAH belonging to the Nice 2013 Updated Classification Group 1 (including Down
syndrome) and of the following etiologies:
1 Patient whose parents are Japanese (excluding naturalized Japanese) as verbally reported by the participant or his or
her parent(s)/legally designated representative

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
32
Status: Approved,  Date:  7 August 2023
a. Idiopathic PAH (iPAH)
b. Heritable PAH (hPAH)
c. PAH associated with CHD:
i. 
PAH with co-incidental CHD
ii. 
Post-operative PAH (persisting/ recurring/ developing ≥ 6 months after
repair of CHD)
d. Drug or toxin induced PAH
e. PAH associated with HIV
f. PAH associated with connective tissue disease (PAH-aCTD)
3. 
PAH diagnosis confirmed by historical right heart catheterization (RHC; characterized
by mean pulmonary arterial pressure ≥25 mm Hg, and pulmonary arterial wedge
pressure ≤15 mm Hg, and pulmonary vascular resistance index (PVRi) >4 Wood
Units × m2), where in the absence of pulmonary vein obstruction and/or significant lung
disease PAWP can be replaced by left atrium pressure (LAP) or left ventricular end
diastolic pressure (LVEDP) (in absence of mitral stenosis) assessed by heart
catheterization.
4. 
WHO FC I to IV.
5. 
PAH-specific treatment-naïve patients or patients on PAH-specific treatment
Weight
Sex and Contraceptive/Barrier Requirements
6. 
A woman of childbearing potential must have a negative highly sensitive serum
-human chorionic gonadotropin [-hCG] test at Screening and a negative urine
pregnancy test at the first administration of study intervention.
7. 
Criterion modified per Amendment 3
7.1 A woman must be (as defined in Appendix 5: Contraceptive and Barrier Guidance)
a. Not of childbearing potential
b. Of childbearing potential and
o 
Practicing a highly effective, preferably user-independent method of
contraception (failure rate of <1% per year when used consistently and
correctly) and agrees to remain on a highly effective method while
receiving study intervention and until 30 days after last dose - the end of

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
33
Status: Approved,  Date:  7 August 2023
relevant systemic exposure. The investigator should evaluate the potential
for contraceptive method failure (eg, noncompliance, recently initiated) in
relationship to the first dose of study intervention. Examples of highly
effective methods of contraception are located in Appendix 5:
Contraceptive and Barrier Guidance.
8. 
A woman must agree not to donate eggs (ova, oocytes) or freeze for future use for the
purposes of assisted reproduction during the study and for a period of up to 4 weeks
following the EOS.
9. 
Criterion deleted per Amendment 3.
10. 
Criterion deleted per Amendment 3.
11. 
Criterion deleted per Amendment 3.
Informed Consent
12. 
Parent(s) (preferably both if available or as per local requirements) (or their legally
acceptable representative) must sign an ICF indicating that they understand the purpose
of, and procedures required for, the study and is/are willing to allow the child to
participate in the study. Assent is also required of children capable of understanding the
nature of the study (typically 7 years of age and older) as described in Informed Consent
Process in Appendix 3: Regulatory, Ethical, and Study Oversight Considerations.
13. 
Willing and able to adhere to the lifestyle restrictions specified in this protocol.
5.2. 
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in the study:
Medical Conditions
Pulmonary Hypertension related
1. 
Patients with PAH due to portal hypertension, schistosomiasis, pulmonary
veno-occlusive disease, and/or pulmonary capillary hemangiomatosis, and persistent
pulmonary hypertension of the newborn.
2. 
Patients with PAH associated with open shunts, as specified below:
a. Eisenmenger syndrome
b. Moderate to large left-to-right shunts as judged by the investigator
3. 
Patients with the following congenital cardiac abnormalities:

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
34
Status: Approved,  Date:  7 August 2023
a. Cyanotic congenital cardiac lesions such as transposition of the great arteries,
truncus arteriosus, pulmonary atresia with ventricular septal defect, unless
operatively repaired and with no residual shunt
b. Univentricular heart and/or patients with Fontan-palliation
4. 
Patients with pulmonary hypertension due to lung disease (eg, bronchopulmonary
dysplasia)
Comorbidities related
5. 
Criterion modified per Amendment 3
5.1 Patients with the following diseases:
a. Patients with pulmonary vein stenosis
b. Patients with bronchopulmonary dysplasia
6. 
Hemoglobin or hematocrit <75% of the lower limit of normal range (LLN) at Screening.
7. 
Serum AST and/or ALT >3 × ULN at Screening.
8. 
Severe hepatic impairment, eg, Child-Pugh Class C, at Screening.
9. 
Clinical signs of hypotension which in the investigator’s judgment would preclude
initiation of a PAH-specific therapy at Screening.
10. 
Severe renal dysfunction with an estimated Glomerular Filtration Rate (eGFR) 2
<30 mL/min/1.73 m2 at Screening.
11. 
Known concomitant life-threatening disease with a life expectancy <12 months.
Prior/Concomitant Therapy
12. 
Patients receiving PAH-specific treatments (excluding PDE-5 inhibitor) at the first
administration of study intervention.
2 ≥ 2 years and < 15 years ; eGFR = 110.2 x [reference serum Cr (mg/dL) / patient’s serum Cr (mg/dL)] + 2.93
  ≥ 3 months and < 2 years ; eGFR = [110.2 x (reference serum Cr / patient’s serum Cr) + 2.93] x R  
Reference serum Cr: 
Males  = -1.259Ht5 + 7.815 Ht 4 – 18.57 Ht 3 +21.39 Ht 2 – 11.71 Ht + 2.628
    
 
Females = - 4.536 Ht 5 + 27.16 Ht 4 – 63.47 Ht 3 +72.43 Ht 2 – 40.06 Ht + 8.778
R = 0.107 x In (age (months)) + 0.656, Ht = body height (m), (Editorial Committee for pediatric CKD 2019)

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
35
Status: Approved,  Date:  7 August 2023
13. 
Start or change of dose* with PDE-5 inhibitor within 90 days before RHC at Screening
(* Dose adjustments are permitted based on patient body-weight change).
14. 
Start or change of dose* of Calcium channel blockers and/or diuretics within 7 days
before RHC (* Dose adjustments are permitted based on patient body-weight change).
15. 
Criterion modified per Amendment 4
15.1 Previous treatment* with macitentan at any time.
* It is not considered treatment if it does not affect the evaluation of efficacy and safety
of this study. In such cases (eg, medical history of short-term macitentan
administration), the investigator must contact the sponsor’s responsible medical officer
to confirm the interpretation is applicable.
16. 
Any PAH-related surgical intervention planned, or patients listed for organ
transplantation related to PAH.
17. 
Treatment with strong inducers of CYP3A4 (eg, rifabutin, rifampicin, carbamazepine,
phenobarbital, phenytoin, St. John’s wort), within 4 weeks prior to the first
administration of study intervention.
18. 
Systemic treatment with strong inhibitors of CYP3A4 (eg, clarithromycin, itraconazole,
ketoconazole, nelfinavir, posaconazole, ritonavir, and voriconazole) within 4 weeks
prior to the first administration of study intervention.
19. 
Systemic treatment with moderate dual CYP3A4/CYP2C9 inhibitor (eg, fluconazole
and amiodarone), or administration of a combination of a moderate CYP3A4 inhibitor
(eg, ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) together with a
moderate CYP2C9 inhibitor (eg, miconazole) within 4 weeks prior to the first
administration of study intervention.
20. 
Taken any disallowed therapies as noted in Section 6.8, Concomitant Therapy before
the planned first dose of study intervention.
Prior/Concurrent Clinical Study Experience
21. 
Received an investigational intervention (including investigational vaccines) or used an
invasive investigational medical device within 4 weeks before the planned first dose of
study intervention or is currently enrolled in an investigational study.
22. 
Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study
or within 4 weeks after the last dose of study intervention.
23. 
Criterion deleted per Amendment 3.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
36
Status: Approved,  Date:  7 August 2023
24. 
Any condition for which, in the opinion of the investigator, participation would not be
in the best interest of the participant (eg, compromise the well-being) or that could
prevent, limit, or confound the protocol-specified assessments.
Diagnostic Assessments
25. 
Known allergies, hypersensitivity, or intolerance to macitentan or its excipients.
26. 
Drug or substance abuse, or any condition that, in the opinion of the investigator, may
prevent compliance with the protocol or adherence to study intervention.
27. 
Previous RHC assessments associated with serious complications, such as (but not
limited to) cardiac arrest, arrhythmia requiring intervention, pulmonary hemorrhage,
stroke, thromboembolic event, and pulmonary hypertensive crisis.
28. 
 Criterion deleted per Amendment 3.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening.
If a participant's clinical status changes (including any available laboratory results or receipt of
additional medical records) after screening but before the first dose of study intervention is given
such that the participant no longer meets all eligibility criteria, then the participant should be
excluded from participation in the study. Section 5.4, Screen Failures, describes options for
retesting. The required source documentation to support meeting the enrollment criteria are noted
in Appendix 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 study to be eligible for participation:
1. 
Refer to Section 6.8, 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).
5.3.1. 
Activity
1. 
Strenuous exercise may affect study specified assessments and safety laboratory results;
for this reason, strenuous exercise should be avoided within 2 hours before all planned
study visits and during stays in the study site.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
37
Status: Approved,  Date:  7 August 2023
5.4. 
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy
identification of each participant during and after the study. This document will be reviewed by
the sponsor study site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed
by the investigator in the study file. To ensure participant confidentiality, no copy will be made.
All reports and communications relating to the study will identify participants by participant
identification and age at initial informed consent. In cases where the participant is not enrolled into
the study, the date seen and age at initial informed consent will be used.
Individuals who do not meet the criteria for participation in this study (screen failure) may be
rescreened if the reason for non-eligibility was transient (eg, abnormal laboratory test, insufficient
wash-out period of a forbidden medication). All screening assessments should then be repeated at
the time of re-screening. If all re-screening assessments can't be conducted within original
screening period, IC should be obtained again and a new patient number should be assigned.
5.5. 
Criteria for Temporarily Delaying Enrollment or Administration of Study
Intervention
Not applicable
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY
6.1. 
Study Intervention Administered
Study intervention administration must be captured in the source documents and the case report
form (CRF). Study site personnel will instruct participants on how to store study intervention for
at-home use as indicated for this protocol.
Macitentan will be manufactured and provided under the responsibility of the sponsor. Refer to
the IB for a list of excipients.
For details on treatment in the presence of PAH-worsening, refer to Section 6.8.1, Rescue
Medication. For a definition of study intervention overdose, refer to Section 6.7, Treatment of
Overdose.
The method of administration (eg, spoon) must be recorded in the eCRF.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
38
Status: Approved,  Date:  7 August 2023
Table 1: 
Description of Interventions
Intervention Name 
Macitentan
Type 
Drug
Dose Formulation 
Dispersible Tablet
Unit Dose Strength(s) 
Final market image (FMI)* 1.0 m  g and 2.5 mg
Dosage Level(s) 
 
If a participant is 2 years old,
Body weight 
Daily dose
Combination of tablets
(FMI)
<15 kg 
3.5 mg
1 tablet 1.0 mg
+ 1 tablet 2.5 mg
15 kg and <25 kg 
5.0 mg 
2 tablets 2.5 mg
25 kg and <50 kg 
7.5 mg 
3 tablets 2.5 mg
50 kg 
10.0 mg 
4 tablets 2.5 mg
 
If a participant is under 2 years old,
Age 
Daily dose
Combination of tablets
(FMI)
3 months and <6 months 
1.0 mg 
1 tablet 1.0 mg
6 months and <2 years 
2.5 mg 
1 tablet 2.5 mg
Route of Administration 
oral
Use 
Experimental
Investigational Medicinal 
Product (IMP)
Yes
Non-Investigational Medicinal 
Product/Auxiliary Medicinal
Product (NIMP/AxMP)
No
Sourcing 
Provided centrall y b y the sponsor
Packaging and Labeling 
(Labels will contain information
to meet the applicable regulatory
requirements.)
Child resistant blister packs
Delivery Instructions 
Whole tablet(s) are dispersed in water and administered orally (eg, via
spoon, glass, syringe). The full daily dose is taken at a single occasion.
Macitentan is administered once daily and irrespective of time of food
intake but at approximately the same time of the day. The same
administration method should be used as far as possible.
* CSF (clinical service form) ma y be used dependin  g on the results of the FMI stabilit y study 

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
39
Status: Approved,  Date:  7 August 2023
6.2. 
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
All study intervention must be stored in an appropriate, secure area and stored according to the
conditions specified on the label.
Refer to the Investigational Product Procedures Manual (IPPM) 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 to the
participant, and the return of study intervention from the participant, must be documented on the
intervention accountability form. Participants, or their legally acceptable representatives where
applicable, must be instructed to return all original containers, whether empty or containing study
intervention. All study intervention will be stored and disposed of according to the sponsor's
instructions. Study site personnel must not combine contents of the study intervention containers.
Study intervention must be handled in strict accordance with the protocol and the container label,
and must be stored at the study site in a limited-access area or in a locked cabinet under appropriate
environmental conditions. Unused study intervention, and study intervention returned by the
participant, must be available for verification by the sponsor's study site monitor during on-site
monitoring visits. The return to the sponsor of unused study intervention, or used returned study
intervention for destruction, will be documented on the intervention return form. When the study
site is an authorized destruction unit and study intervention supplies are destroyed on-site, this
must also be documented on the intervention return form.
Participants will be provided with a patient diary to record intake at home. Site personnel are to
instruct the participant (parent(s)/legally designated representative) to bring the patient diary and
any unused macitentan, as applicable, to the site at the beginning of each treatment cycle to check
macitentan dosing compliance.
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. Returned study intervention must not be
dispensed again, even to the same participant. Whenever a participant brings his or her study
intervention to the study site for tablet count, this is not seen as a return of supplies. Study
intervention may not be relabeled or reassigned for use by other participants. The investigator
agrees neither to dispense the study intervention from, nor store it at, any site other than the study
sites agreed upon with the sponsor. Further guidance and information for the final disposition of
unused study interventions are provided in the IPPM.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
40
Status: Approved,  Date:  7 August 2023
6.3. 
Measures to Minimize Bias: Randomization and Blinding
As this is an open-label study with a single treatment arm, randomization and blinding procedures
are not applicable.
6.4. 
Study Intervention Compliance
Prior to each new dispensation of macitentan, the treatment compliance with macitentan must be
evaluated by the site personnel, based on drug accountability, using below formula:
Compliance = [(number of tablets dispensed − number of tablets returned)/Total number
of tablets that should have been taken during the visit interval] × 100,
where the visit interval [days], is defined as: current visit date - previous visit date + 1
Treatment interruptions requested by the study investigator are not accounted for in the above
formula.
The site personnel must discuss any compliance issue with the parent(s)/caregiver(s) and
participant (if developmentally capable) and re-educate them on correct administration of study
intervention. Details of such discussion must be documented in the source documents.
If the compliance with study intervention intake is <80% or >120%, it will be considered as a
protocol deviation unless it is due to interruption for AE or due to anticipated drug-drug
interactions or due to laboratory abnormalities as defined per protocol. Furthermore, the
investigator must identify, with the parent(s)/legally designated representative and participant (if
developmentally capable), the reasons for this noncompliance and discuss actions to be taken to
avoid re-occurrence. This discussion and its outcome must be documented in the source documents.
6.5. 
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).
Macitentan dose adjustments other than for change in age/weight category are not permitted.
Dose adjustments of other PAH-specific medications (see Section 6.8.1) needed due to the
participants’ change in body weight or due to an AE are performed as per local practice.
6.6. 
Continued Access to Study Intervention After the End of the Study
This protocol is designed to provide participants with up to approximately 52 weeks of treatment.
No continued access will be proposed for this study as there are 4 approved products in Japan, for
the treatment of PAH in pediatric patients. At the end of their participation in the study, the
participants will be instructed that they should return to their primary physician to determine
standard of care, if applicable.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
41
Status: Approved,  Date:  7 August 2023
6.7. 
Treatment of Overdose
For this study, any dose of macitentan greater than assigned dose as per the body weight within a
24-hour time period will be considered an overdose. The sponsor does not recommend specific
treatment for an overdose. Report to the sponsor in accordance with Section 10.4.4 Special
Reporting Situations.
In the event of an overdose, the investigator or treating physician should:
 
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 macitentan can
no longer be detected systemically (at least 14 days).
 
Obtain a plasma sample for PK analysis within 3 days from the date of the last dose of study
intervention if requested by the Medical Monitor (determined on a case-by-case basis).
 
Document the quantity of the excess dose as well as the duration of the overdosing in the
electronic case report form (eCRF).
6.8. 
Concomitant Therapy
Prestudy therapies administered up to 30 days before signing the ICF and PH-specific therapies
(ongoing, initiated, or stopped) taken within 90 days of RHC at Screening must be recorded at
screening.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special
diets, exercise regimens, or other specific categories of interest) different from the study
intervention must be recorded in the eCRF. Recorded information will include 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. Non-therapeutic medications (Drug solution and
heparin used for PK blood sampling or right heart catheterization, etc.) do not need to be recorded
in the eCRF.
Modification of an effective preexisting therapy should not be made for the explicit purpose of
entering a participant into the study.
Mandatory Concomitant Therapy
Female patients of childbearing potential who are sexually active must use reliable contraceptive
methods until EOS or until the last safety follow-up (whichever occurs latest). If hormonal
contraceptives are used, those must be initiated at least 4 weeks before the first administration of
study intervention.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
42
Status: Approved,  Date:  7 August 2023
For patients who become sexually active any time after the first administration of study
intervention and who are of childbearing potential, contraceptive method(s) that are immediately
effective must be applied until hormonal contraceptives become effective.
Permitted Concomitant Therapy
Supportive PAH non-specific therapies (eg, diuretics, anticoagulants, oxygen, calcium channel
blockers) and changes to such medications are allowed during all study periods. However, the
same dose calcium channel blockers and/or diuretics is given for 7 days before RHC (dose
adjustments are permitted based on patient body-weight change).
Phosphodiesterase type 5 (PDE-5) inhibitor is the only allowed PAH-specific background
medication in this study. If PDE-5 inhibitor is used concomitantly, PDE-5 inhibitor should have
been initiated 90 days before RHC in Visit 1 (screening) and the same dose should be maintained
until end-of-treatment (EOT). Dose adjustments for PDE-5 inhibitor are permitted based on patient
body-weight change.
Use of IV prostanoids for vasoreactivity testing is allowed in all study patients and during all study
periods.
Prohibited Concomitant Therapy
To avoid confounding effects, the following treatments are prohibited as specified:
 
Use of any investigational drug is prohibited from 4 weeks before the first administration of
study intervention and up to EOS.
 
Any PAH specific therapy other than PDE-5 inhibitor are prohibited from the first
administration of study intervention. Use of macitentan is forbidden in all patients at any time
before study entry.
 
Use of any PAH-specific background therapy (excluding PDE-5 inhibitor) for the purpose
other than PAH worsening.
To avoid drug-drug interactions with macitentan, the following treatments are prohibited as
specified:
 
Strong inducers of CYP3A4 (eg, rifabutin, rifampicin, carbamazepine, phenobarbital,
phenytoin, and St. John’s wort) are prohibited from 4 weeks prior to the first administration
of study intervention and until EOT
If they cannot be avoided, their administration should be delayed to after the visits where PK
samples are collected and limited to not more than 4 consecutive weeks.
 
Systemic administration of strong inhibitors of CYP3A4 (eg, clarithromycin, itraconazole,
ketoconazole, nelfinavir, posaconazole, ritonavir, and voriconazole) is prohibited from 4
weeks prior to the first administration of study intervention and until EOT
 
Systemic administration of moderate dual CYP3A4/CYP2C9 inhibitor (eg, fluconazole and
amiodarone), or combination of a moderate CYP3A4 (eg, ciprofloxacin, cyclosporine,
diltiazem, erythromycin, verapamil) together with a moderate CYP2C9 inhibitor (eg,

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
43
Status: Approved,  Date:  7 August 2023
miconazole) is prohibited from 4 weeks prior to the first administration of study intervention
and until EOT.
The administration of ERAs and/or of any investigational drug after the first administration of
study intervention must lead to permanent discontinuation of macitentan. The systemic
administration of a strong CYP3A4 inhibitor as well as administration of moderate dual CYP3A4/
CYP2C9 inhibitor or a combination of a moderate CYP3A4 and moderate CYP2C9 inhibitor must
lead to interruption of macitentan.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
6.8.1. 
Rescue Medication
In the presence of PAH-worsening, any PAH specific treatment can be initiated per investigator’s
judgment. If a participant initiates treatment with ERAs, study intervention (macitentan) must be
discontinued (refer to Section 7.1). Clinical PAH worsening defined as:
 
Worsening in WHO FC, or
 
New occurrence or worsening of syncope (in frequency or severity as per medical judgment),
or
 
New occurrence or worsening of at least two PAH symptoms (ie, shortness of breath/dyspnea,
chest pain, cyanosis, dizziness/near syncope, or fatigue), or
 
New occurrence or worsening of signs of right heart failure not responding to oral diuretics
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1. 
Discontinuation of Study Intervention
7.1.1. 
Permanent Discontinuation
A participant's study intervention must be permanently discontinued if:
 
The participant withdraws consent or assent to receive study intervention
 
The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the
best interest of the participant to discontinue study intervention
 
The participant becomes pregnant (Refer to Section 8.3.5). The investigator will discuss with
the participant and her parent(s)/legally designated representative the appropriate follow-up
medical care.
 
Noncompliance with study intervention administration defined as compliance rate below 80%
in two consecutive visits.
 
If a participant initiates treatment with ERAs and/or of any investigational drug (see Section
6.8).

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
44
Status: Approved,  Date:  7 August 2023
The decision to prematurely discontinue macitentan may be made by the parent(s)/legally
designated representative of the participant, the participant (who is developmentally capable to
assent), the investigator, or the sponsor personnel. The main reason and whether discontinuation
of macitentan is the decision of the participant (ie, parent[s]/legally designated representative, eg,
for tolerability or efficacy reasons), the investigator (eg, due to pre-specified macitentan
discontinuation criteria, an AE or lack of efficacy), or the sponsor (eg, study terminated) must be
documented in the eCRF.
Parent(s)/legally designated representative have the right to prematurely discontinue treatment
with macitentan at any time, without any justification. Premature discontinuation of macitentan
does not constitute per se a reason to withdraw from the study. In case of premature discontinuation
of macitentan, every attempt should be made to keep participants in the study according to the
original schedule of assessment. If the parent(s)/legal representative also withdraws the consent to
follow the original schedule of assessment as per protocol (premature study visit withdrawal; see
Section 7.2), the participant enters the safety follow-up period (see Section 1.3), unless consent is
fully withdrawn.
Although parent(s)/legally designated representative do not have to give their reason for
prematurely withdrawing their child from the treatment, it is recommended that the investigator
makes a reasonable effort to ascertain the reason(s), while fully respecting the participant’s rights.
The investigator must discontinue macitentan for a given participant if, on balance, he/she believes
that continued administration would be contrary to the best interests of the participant.
Study treatment (macitentan) may be discontinued in response to an AE, a protocol deviation
(including eligibility failure, non-compliance with study requirements), for lack of efficacy, for a
laboratory abnormality, or for administrative reasons.
Study-specific criteria for discontinuation of macitentan are described Section 7.1.3, Section 7.1.4,
and Section 7.1.5, respectively.
Study intervention assigned to the participant who discontinued study intervention may not be
assigned to another participant. Additional participants will be entered to ensure the protocol-
specified number of participants complete the study.
7.1.2. 
Temporary Discontinuation
Macitentan may be temporarily interrupted in response to an AE, or a laboratory abnormality, or
due to anticipated drug-drug interaction. Study-specific criteria for interruption of study treatment
are described in Section 7.1.3, Section 7.1.4, and Section 7.1.5, respectively.
If macitentan is interrupted by the participant for any reason, the parent(s)/legally designated
representative must immediately inform the investigator.
Interruptions of macitentan must be kept as short as possible and should not exceed 4 consecutive
weeks.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
45
Status: Approved,  Date:  7 August 2023
For macitentan study treatment interruptions, dose adjustments and the reason for interruption
must be recorded in the eCRF.
7.1.3. 
Liver Chemistry Stopping Criteria
Stopping of study intervention for abnormal liver tests is required by the investigator when a
participant meets one of the conditions outlined below or in the presence of abnormal liver
chemistries not meeting protocol-specified stopping rules if the investigator believes that it is in
best interest of the participant.
Interruption of Study Treatment
Macitentan study treatment must be interrupted in the following cases:
 
Aminotransferases (ie, ALT and/or AST) 3 and <8  ULN
Perform a re-test of aminotransferases (ALT and AST), total and direct bilirubin, and alkaline
phosphatase within 10 days. If AST and/or ALT elevation is confirmed, continue to weekly
monitor aminotransferases, total and direct bilirubin, and alkaline phosphatase levels until values
return to pre-treatment levels or within normal ranges. If the aminotransferase values return to pre-
treatment levels or within normal ranges, re-introduction of macitentan study treatment can be
considered.
Re-introduction of macitentan after treatment interruption should only be considered if the
potential benefits of treatment with macitentan outweigh the potential risks and when liver
aminotransferase values are within pre-treatment levels or within normal ranges. The advice of a
hepatologist is recommended.
Liver aminotransferase levels must then be checked within 3 days after re-introduction, then again
after a further 2 weeks, at 4-weekly intervals during the first 6 months of study treatment, and
12-weekly thereafter.
Permanent Discontinuation of Study Treatment
Macitentan study treatment must be stopped and its re-introduction is not to be considered in the
following cases:
 
Aminotransferases 8  ULN
 
Aminotransferases 3  ULN and associated clinical symptoms of liver injury, eg, nausea,
vomiting, fever, abdominal pain, jaundice, unusual lethargy or fatigue, flu like syndrome
(arthralgia, myalgia, fever)
 
Aminotransferases 3  ULN and associated increase in total bilirubin 2  ULN
Perform a re-test of aminotransferases (ALT and AST), total and direct bilirubin, and alkaline
phosphatase. Aminotransferases, total and direct bilirubin, and alkaline phosphatase levels must
be monitored weekly after study treatment discontinuation until values return to pre-treatment
levels or within normal ranges.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
46
Status: Approved,  Date:  7 August 2023
Other diagnoses (eg, viral hepatitis, mononucleosis, toxoplasmosis, cytomegalovirus) and/or
etiologies (eg, hepatic toxicity of concomitant medication[s] or other substances) should be
considered and ruled out by performing the appropriate tests.
All liver aminotransferases abnormalities leading to study treatment interruption or
discontinuation must be recorded as AEs (see Section 10.4). All events of aminotransferase
≥3 × ULN and total bilirubin ≥2 × ULN (>35% direct bilirubin), which may indicate severe liver
injury (possible Hy’s Law), must be reported as a SAE. If these abnormalities are serious hepatic
events of special interest, they will be reviewed by an ILSDRB.
7.1.4. 
Hemoglobin Abnormalities
If there is a decrease in hemoglobin from baseline* of >20 g/L during treatment with macitentan,
a retest must be performed within 10 days, with additional laboratory evaluations that may include,
but are not limited to, any of the following:
 
Red blood cell cellular indices (mean corpuscular volume, mean corpuscular hemoglobin,
mean corpuscular hemoglobin concentration), peripheral blood smear, reticulocyte count, iron
status (iron level, serum ferritin, total iron binding capacity, transferrin saturation), lactate
dehydrogenase, indirect bilirubin.
Macitentan must be temporarily interrupted if clinically mandated based on the investigator’s
judgment, or in any of the following situations:
 
A decrease in hemoglobin to ≤80 g/L (≤4.9 mmol/L),
 
A decrease in hemoglobin from baseline* of ≥50 g/L,
 
The need for transfusion.
Re-introduction of macitentan may be considered by the investigator if hemoglobin recovery,
defined as a return of hemoglobin above the LLN or to baseline, is achieved.
A decrease in hemoglobin from baseline* of >20 g/L must be recorded as AEs. All hemoglobin
abnormalities leading to study treatment interruption or discontinuation must be recorded as AEs.
* Baseline hemoglobin: refers to the last hemoglobin value obtained prior to first intake of macitentan study
intervention.
7.1.5. 
Start of a Strong CYP3A4 Inhibitor / Moderate Dual CYP3A4/CYP2C9
Inhibitors
If any strong inhibitors of CYP3A4 are given, macitentan must be interrupted from first dose of
strong CYP3A4 inhibitor and until 4 weeks after the last dose of strong CYP3A4 inhibitor.
If any moderate dual CYP3A4/CYP2C9 inhibitors and/or any co-administration of a combination
of a moderate CYP3A4 inhibitor and a moderate CYP2C9 inhibitor are given, macitentan must be
interrupted as follows:

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
47
Status: Approved,  Date:  7 August 2023
 
For moderate dual CYP3A4/CYP2C9 inhibitors: from first dose of moderate dual
CYP3A4/CYP2C9 inhibitor and until 4 weeks after the last dose of moderate dual
CYP3A4/CYP2C9 inhibitor.
 
For co-administration of a combination of a moderate CYP3A4 and a moderate CYP2C9
inhibitor: from the first dose of the second co-administered inhibitor and until 4 weeks after
last dose of any of the co-administered inhibitors.
7.2. 
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:
 
Lost to follow-up
 
Withdrawal of consent or assent
 
Death
Parent(s)/legally designated representative may voluntarily withdraw their child from the study
without justification for any reason at any time. The investigator may withdraw a participant from
the study (without regard to the participant’s consent) if, on balance, he/she believes that continued
participation in the study would be contrary to the best interests of the participant. Withdrawal
from the study may also result from a decision by the sponsor for any reason, including premature
termination or suspension of the study.
Premature withdrawal from the study happens when parent(s)/legally designated representative
and/or participant withdraw the consent to continue the study according to the original schedule of
assessments and at the same time prohibit any further data collection. In this case the last visit
before full withdrawal of consent constitutes the EOS visit.
Premature discontinuation of macitentan do not per se constitute premature withdrawal from the
study. Every effort should be made to keep participants in the study as per original schedule of
assessments and hence allowing full data collection as per protocol in order to reduce missing data.
For these participants the EOS visit will happen 30 days after the last dose.
Premature study visit discontinuation happens if the parent(s)/legally designated representative
withdraw the consent to continue the study according to the original schedule of assessments but
do not withdraw the consent to provide limited information until the study closure. As a
consequence, the participant enters the safety follow-up (See Section 1.3). The date and reason for
this premature study visit discontinuation will be reported in the eCRF. The last survival follow-up
contact will be used as the EOS.
If premature withdrawal from the study or if premature study visit discontinuation occurs, the
reason (if known), along with who made the decision (parent(s)/legally designated representative
or participant, investigator, or the sponsor personnel) must be recorded in the eCRF, if known.
If for whatever reason (except death or loss-to-follow-up) a participant is withdrawn from the study,
the investigator should make efforts to schedule a last appointment/telephone call to assess the
safety and well-being of the participant, collect unused study treatment and discuss follow-up

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
48
Status: Approved,  Date:  7 August 2023
medical care. Data obtained during this last appointment/telephone call will be recorded in the
participants’ medical records, but it will not be collected in the eCRF.
When a participant withdraws before study completion, the reason for withdrawal is to be
documented in the eCRF and in the source document. If the reason for withdrawal from the study
is withdrawal of consent (or assent) then no additional assessments are allowed.
Withdrawal of Consent
A participant declining to return for scheduled visits does not necessarily constitute withdrawal of
consent. Alternate follow-up mechanisms that the participant agreed to when signing the consent
form apply (eg, consult with family members, contacting the participant’s other physicians,
medical records, database searches) as local regulations permit.
Prior to a participant withdrawing consent for follow-up, the investigator should offer the
participant an opportunity for one of the alternative reduced follow-up mechanisms described
below. Withdrawal of consent should be an infrequent occurrence in clinical studies
(Rodriguez 2015), therefore, prior to the start of the study the sponsor and the investigator should
discuss and reach a clear understanding of what constitutes withdrawal of consent in the context
of the available reduced follow-up mechanisms listed.
Circumstances for Reduced Follow-up
In the situation where a participant may be at risk for withdrawal of consent and is unable to return
for scheduled visits at the protocol-defined frequency, the investigator may consider options for
reduced follow-up. These may include (as local regulations permit):
 
Less frequent clinical visits
 
Telephone, email, letter, social media, fax, or other contact with:
 
participant
 
relatives of the participant
 
participant’s physicians (general or specialist)
 
Review of any available medical records
Details regarding these contacts must be properly documented in source records including
responses by participants.
7.3. 
Lost to Follow-up
To reduce the chances of a participant being deemed lost to follow-up, prior to the first dose of the
study intervention attempts should be made to obtain contact information from each participant,
eg, home, work, and mobile telephone numbers and email addresses for both the participant as
well as appropriate family members.
A participant will be considered lost to follow-up if the participant repeatedly fails to return for
scheduled visits and is unable to be contacted by the study site. A participant cannot be deemed

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
49
Status: Approved,  Date:  7 August 2023
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 telephone calls,
emails, 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 to have withdrawn
from the study.
 
Site personnel, or an independent third party, will attempt to collect the vital status of the
participant within legal and ethical boundaries for all participants randomized, including those
who did not get study intervention. Public sources may be searched for vital status information.
If vital status is determined as deceased, this will be documented, and the participant will not
be considered lost to follow-up. Sponsor personnel will not be involved in any attempts to
collect vital status information.
Should a study site close, eg, for operational, financial, or other reasons, and the investigator cannot
reach the participant to inform them, their contact information will be transferred to another study
site.
8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities summarizes the frequency and timing of efficacy, PK, quality of life,
and safety measurements applicable to this study.
If multiple assessments are scheduled for the same timepoint, it is recommended that procedures
be performed in the following sequence: physical and vital sign assessment, blood sample
collections for PK and biomarker assessment, blood sample collections for laboratory assessments,
efficacy assessment, and study intervention administration. Blood collections for PK and PD
assessments should be kept as close to the specified time as possible. Other measurements may be
done earlier than specified timepoints if needed. Actual dates and times of assessments will be
recorded in the source documentation and/or the eCRF.
For each participant, the maximum amount of blood drawn from each participant in this study will
not exceed 65 mL (Table 2).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the
samples.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
50
Status: Approved,  Date:  7 August 2023
Table 2: 
Volume of Blood to be Collected From Each Participant
Type of Sample 
Volume per 
Sample (mL) 
No. of Samples 
per Participant 
Approximate
Total Volume of Blood (mL)a
Safety (including screening and post-
intervention assessments)
  
 
 - Hematology 
1.2 
13 (for ≥ 2 years) 15.6
12 (for < 2 years) 14.4
 - Serum Chemistryb 
1.2 
13 (for ≥ 2 years) 15.6
16 (for < 2 years) 19.2
Pharmacokinetic samples (if the regular 
venous blood samplin  g is used) 
0.5 
8 (for ≥ 2 years) 
4.0
5 (for < 2 years) 
2.5
Pharmacodynamic/Biomarker samples 
1.1 
6 
6.6
Loss by use of indwelling intravenous 
cannula
1.0 
19 
19.0
Approximate Totalc 
 
 
60.8 (for participants aged ≥2
years)
61.7 (for participants aged <2
years)
Abbreviations: -hCG=-human chorionic gonadotropin; PK=pharmacokinetic.
a. Calculated as number of samples multiplied by amount of blood per sample.
b. Serum chemistry includes serum -hCG pregnancy tests (for women of childbearing potential only).
c. Repeat or unscheduled samples may be taken for safety reasons or technical issues with the samples.
Note: After the macitentan and aprocitentan analysis method for
 microsampling is validated,
microsampling device can be used for blood sample collection. For individual participants, all points of blood
collection should be done using the same sampling method. If
 microsampling device is used for PK
sample collection, 0.02 mL or 0.04 mL is needed for blood volume per sample and total volume of blood is
the following:
 
 sampler 
Participant 
Age 
Volume per 
Sample (mL) 
No. of 
Samples per 
Participant 
Approximate Total 
volume of blood for 
Pharmacokinetic
samples (mL)
Approximate
total (mL)
10 μL sampler 
≥ 2 years 
0.02 
8 
0.16 
50.96
< 2 years 
0.02 
5 
0.10 
56.30
20 μL sampler 
≥ 2 years 
0.04 
8 
0.32 
51.12
< 2 years 
0.04 
5 
0.20 
56.40
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory
requisition form. If blood samples are collected via an indwelling cannula, an appropriate amount
(1 mL) of serosanguineous fluid slightly greater than the dead space volume of the lock will be
removed from the cannula and discarded before each blood sample is taken. After blood sample
collection, the cannula will be flushed with 0.9% sodium chloride, or sodium heparin of 10 U/mL
and charged with a volume equal to the dead space volume of the lock.
Refer to the Schedule of Activities for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples 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.
CCI
CCI
CCI
CCI

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
51
Status: Approved,  Date:  7 August 2023
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 must be performed in case of suspected clinical worsening or initiation/dose
escalation of PH-specific therapy outside of a regular visit. At unscheduled visits performed due
suspected clinical worsening, physical examination, vital signs (blood pressure/pulse rate), weight,
laboratory assessments, and WHO FC must be done. Other assessments are done per investigator’s
discretion. 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.
Study-Specific Materials
The investigator will be provided with the following supplies:
 
Investigator Site File (includes protocol and IB)
 
IPPM
 
Laboratory manual
 
Quality of life (QoL) questionnaires and QoL completion guidelines
 
Electronic data capture (eDC) Manual
 
Accelerometer
 
Sample ICF
 
Sample patient diary
 
Additional equipment and information, as needed.
8.1. 
Demographics and Baseline Characteristics
Demographic and baseline characteristic data to be collected on all participants include: age, sex,
race and ethnicity (where local regulations permit), date of the initial PAH diagnosis, PAH disease
characteristics, hemodynamic (mPAP, PAWP, PVRI), WHO FC, and Child Pugh Score for
participants with known hepatic impairment.
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.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
52
Status: Approved,  Date:  7 August 2023
8.2. 
Efficacy Assessments
8.2.1. 
Hemodynamic Assessments
The primary efficacy endpoint as well as the secondary endpoints related to hemodynamic
parameters are described in Section 3, OBJECTIVES AND ENDPOINTS.
Pulmonary arterial catheters will be placed in all participants enrolled. Participants will consent to
have the catheter inserted for the purposes of the study. Catheter placement may be confirmed by
chest X-ray or fluoroscopy, as clinically indicated. All effort will be made to minimize radiation
exposure time.
If an RHC was performed in the 60-day period prior to the first administration of study intervention,
and the criteria for historical RHCs defined in Appendix 6: Sponsor Heart Catheterization
Guidance are met, the RHC does not need to be repeated at Screening. If PDE-5 inhibitor is used
concomitantly, PDE-5 inhibitor must be stable for at least 90 days prior to the baseline RHC.
It is to keep the dose of calcium channel blockers and/or diuretics stable for 7 consecutive days
prior to the Screening- and Week 24 RHC.
Hemodynamic parameters measured and collected in the eCRF include heart rate, PAWP (or
LVEDP), mRAP, systolic/diastolic pulmonary artery pressures (sPAP/dPAP), systolic/diastolic
systemic arterial pressure (s-, d-SAP), SvO2 and CO.
Calculated hemodynamic parameters:
Parameter 
Definition
PVRI  
(pulmonary vascular resistance index) 
ܸܴܲܫሺܹ݋݋݀ ݉ଶሻ = ݉ܲܲܣ−ܹܲܲܣ
ܫܥ 
 
ܸܴܲܫሺ݀ ݉ ܿ݁ݏ ݊ݕଶܿ݉ହ
⁄
ሻ = ൬ ݉ܲܲܣ−ܹܲܲܣ
 ܫܥ൰× 80
PVR
(pulmonary vascular resistance) 
ܸܴܲሺܹ݋݋݀ሻ = ݉ܲܲܣ−ܹܲܲܣ
ܱܥ 
 
ܸܴܲሺ݀݉ ܿ ܿ݁ݏ ݊ݕହ
⁄ 
ሻ= ൬ ݉ܲܲܣ−ܹܲܲܣ
 ܱܥ൰× 80
CO
(cardiac output)ܱܥሺ ݊݅݉ܮ
⁄ሻ
mRAP
(mean right atrial pressure)
ܴ݉ܲܣሺ݉݉݃ܪሻ
mPAP 
(mean pulmonary artery pressure)
݉ܲܲܣሺ݉݉݃ܪሻ=
ሺ2 × ݀ܲܲܣ+ܲܣܲݏሻ
3
 
sPAP
(systolic pulmonar y arterial pressure)ܲܣܲݏሺ݉݉݃ܪሻ
dPAP
(diastolic pulmonar y arterial pressure)
݀ܲܲܣሺ݉݉݃ܪሻ
dSAP
(diastolic systemic arterial pressure)
݀ܵܲܣሺ݉݉݃ܪሻ
sSAP
(systolic systemic arterial pressure)ܲܣܵݏሺ݉݉݃ܪሻ

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
53
Status: Approved,  Date:  7 August 2023
Parameter 
Definition
SvO2 
(mixed venous oxygen saturation)
ܱܵݒଶሺ%ሻ
TPR 
(total pulmonary vascular resistance) 
ܴܶܲሺܹ݋݋݀ሻ = ൬ ݉ܲܲܣ
 ܱܥ൰
 
ܴܶܲሺ݀݉ ܿܿ݁ݏ ݊ݕହ
⁄ 
ሻ = ൬ ݉ܲܲܣ
 ܱܥ൰× 80
CI 
(cardiac index) ܫܥሺ ݊݅݉ܮ
⁄
݉ଶ
⁄ 
ሻ= ܱܥ
ܣܵܤ 
BSA
(bod y surface area)ܣܵܤሺ݉ଶሻ = 0.007184× ሺܹ݁݅݃ℎݐሾ݇݃ሿሻ଴.ସଶହ× ሺ݃݅݁ܪℎݐሾܿ݉ሿሻ଴.଻ଶହ
PAWP
(pulmonar y arter y wedge pressure)
ܹܲܲܣሺ݉݉݃ܪሻ
LVEDP
(left ventricular end-diastolic pressure)ܲܦܧܸܮሺ݉݉݃ܪሻ
 
The clinical sites will use their local operating procedures for the insertion, maintenance, and
removal of the catheter. The participant will then be monitored for a minimum of 20 hours or until
discharge.
8.2.2. 
Monitoring of disease progression
The secondary endpoints are related to disease progression and are described in Section 3. In order
to assess these endpoints, the following data are collected:
 
Death, primary cause and date of death will be collected on a dedicated eCRF page.
 
PAH-related non-pharmacological interventions (such as atrial septostomy, etc.) and the date
and reason for the intervention are reported on a dedicated eCRF page.
 
Medications related to PAH (such as PAH-specific medications, diuretics, and oxygen) are
recorded on the eCRF page for previous/concomitant medications (refer to Section 6.8).
 
For hospitalizations, the admission/discharge date together with the reason for hospitalization
is recorded on either the AE eCRF page or on the dedicated eCRF page (if cause is related to
PAH).
 
Signs/symptoms denoting PAH worsening together with their onset/resolution date as well as
WHO FC are recorded on dedicated eCRF pages and as specified in Section 8.2.2.
The investigator (or delegate) will describe the condition of the participant at baseline (ie, at
Visit 2) in a narrative. In the presence of disease progression, the investigator (or delegate) will
provide an additional narrative to document worsening in the participant’s condition.
8.2.2.1. 
Signs and Symptoms of PAH
In order to standardize assessment of disease progression, investigators will verify the
presence/absence of predefined signs and symptoms denoting clinical worsening of PAH.
The presence and absence of signs/symptoms is recorded on a dedicated eCRF page. The date of
new onset or worsening is also recorded in the eCRF.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
54
Status: Approved,  Date:  7 August 2023
If there is syncope or at least 2 new or worsening signs/symptoms the investigator reports disease
progression on a dedicated eCRF page and performs further exams to determine the cause
8.2.2.2. 
Functional Class
The WHO FC (Appendix 7: WHO Functional Class) and the Panama FC (Appendix 8: Panama
Functional Class for Pediatrics) are recorded in the eCRF. The Panama FC is tailored for children
up to 16 years of age (Lammers 2011). When applicable, WHO FC and the Panama FC must be
performed before the 6MWT.
Worsening of the clinical condition of a participant can occur at any time during study participation.
Parent(s)/caregiver(s) will be instructed to contact the investigator immediately if the participant
deteriorates to arrange for a visit if needed.
In the presence of suspected disease progression event (eg, signs/symptoms denoting PAH
worsening or deterioration of WHO FC, the investigator will determine the main and contributing
causes for worsening as per local practice. If applicable, the investigator reports which components
of the primary efficacy endpoint are met. The onset date of worsening, the main and contributing
cause(s) for worsening are recorded on dedicated eCRF pages (“Disease Progression Event
Summary”, “Disease Progression Event page”, and if applicable “Clinical Worsening”). If the
disease progression fulfills the seriousness criteria (eg, needs hospitalization), the event must also
be reported as an SAE within 24 hours of the investigator’s knowledge that the event is serious
using an SAE reporting form.
Contributing causes other than PAH are also reported as AE or SAE, as appropriate.
8.2.3. 
6-Minute Walk Test
The 6MWT is a non-encouraged test that measures the distance covered by the participant during
a 6-minute walk. Guidelines are provided in Appendix 10: Sponsor 6-minute Walk Test Guidance.
The 6MWD will be assessed in participants ≥ 6 years of age when initial informed consent and
who understand and are able to perform the test correctly (Douwes 2016; Takatsuki 2013). Test
results and the date and time of assessment will be recorded in the eCRF. If a participant wears a
mask during the 6MWT this will be entered in the source document but not in the eCRF.
8.2.4. 
NT-proBNP
Venous blood samples of approximately 1.1 mL will be collected for measurement of NT-proBNP
at baseline (predose), and at Weeks 12, 24, 28, 40, and 52.
The quantification of NT-proBNP plasma levels will be performed by the central laboratory.
The material required for NT-proBNP sampling will be provided to the investigational site before
the start of the study. The procedure for collection and analysis of NT-proBNP is described in the
respective Laboratory Manual. Plasma samples are stored in an upright position at −18°C or at
cooler temperature.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
55
Status: Approved,  Date:  7 August 2023
8.2.5. 
Echocardiography
Left ventricular eccentricity index and TAPSE will be assessed.
Left Ventricular Eccentricity Index (LVEI): For this index the independent reviewer will measure,
and record in mm with up to one decimal place, the following LV internal diameters, using the
parasternal short axis view at the level of the papillary muscles.
 
D1: LV internal diameter perpendicular to interventricular septum at end-diastole
 
D2: LV internal diameter parallel to interventricular septum, and at right angle from D1, at
end-diastole
 
S1: LV internal diameter perpendicular to interventricular septum at end-systole
 
S2: LV internal diameter parallel to interventricular septum, and at a right angle from S1, at
end-systole
The LVEI is a ratio that will be calculated by Sponsor as follows:
 
LVEIdiastole = D2/D1
 
LVEIsystole = S2/S1
Tricuspid Annular Plane Systolic Excursion (TAPSE): TAPSE is a dimension used to evaluate
Right Ventricle (RV) longitudinal systolic function; it measures the extent of systolic motion of
the lateral portion of the tricuspid ring towards the apex. To obtain an appropriate M-Mode
recording to be used for TAPSE measurement, 2D imaging of the apical four-chamber view will
allow for correct placement of the M-Mode cursor through the tricuspid lateral annulus. TAPSE,
recorded in mm with up to one decimal place, is the linear dimension between the positions of the
tricuspid valve annulus at end-diastole and endsystole.
The investigator (or delegate) will submit generated echocardiography data (TAPSE, D1, D2, S1,
and S2) in eCRF.
8.2.6. 
Physical activity
Physical daily activity assessed by accelerometry has been shown to correlate with 6MWD in adult
PAH patients and is significantly lower in patients with WHO FC III/IV as compared to WHO FC
I/II. Furthermore, PAH patients with daytime activity <15 h/day had shorter transplant-free
survival (Kaplan-Meier estimate) as compared to patients with longer daytime activity. Thus,
physical activity measured by accelerometry may be used as a tool to assess functional capacity,
disease severity, and prognosis in patients with pulmonary hypertension (Pugh 2012; Ulrich 2013).
Accelerometry is being used in children excluding infants for indications other than PAH
(Cliff 2009; Robertson 2011; Van Cauwenberghe 2001). Since 6-minute walk test cannot reliably
be assessed in children with PAH (Adatia 2013), physical activity by accelerometry may be a
potential tool to assess functional capacity in this population. No data exist so far in children with
PAH and thus change in physical activity will be assessed as an exploratory endpoint in this study.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
56
Status: Approved,  Date:  7 August 2023
The physical activity [counts/min] of the participant is assessed via accelerometer. The participant
collects data wearing the accelerometer for 10 to 14 consecutive days before respective visits [refer
to Schedule of Activity]. If, for any reason, data are not collected before respective study visits,
the participant will collect the data during the 10 to 14 days following the visit. For Screening, the
physical activity must be collected any time during Screening and before Visit 2. This will allow
collecting data during weekdays and weekend days and will provide a reliable estimate of the usual
physical activity of the participant.
At Visit 1 (screening), participants, whose age is ≥2 years of age when initial informed consent,
will be provided with an accelerometer to be able to capture a baseline profile, and the investigator
(or delegate) instructs parent(s)/legally designated representative and developmentally capable
participants on how and when to wear the accelerometer (refer to Sponsor Accelerometry
Guidelines). Participants will be asked to continuously wear the device on the non-dominant wrist
or hip worn or ankle worn. The accelerometer is worn during the waking hours of the participant.
The device may be removed during the night rest and during activities when the device could get
wet (eg, showering, bathing, swimming).
The data is transferred to the accelerometry central laboratory as instructed in the Sponsor
Accelerometry Guidelines. Participants who will not prove eligible will return their accelerometer
to the study site, but whose data (if collected during Screening) are transferred to the central lab.
At Visit 12 the accelerometer will not be returned to the participant. After successful data transfer
the device is re-set and can be re-used by another study participant.
The central laboratory will read daily counts/min and will analyze duration of daytime activity and
time [minutes] spent in moderate-to-vigorous physical activity (MVPA) as compared to time spent
in sedentary, light, moderate, vigorous physical activity. These data are transferred to the sponsor.
Sites and participants will not have access to data generated from the use of the device during the
study. All devices will be collected at the final visit and inventoried.
8.2.7. 
Borg CR10 Scale®
8.3. 
Safety Assessments
Adverse events will be reported and followed by the investigator as specified in Section 8.4,
Adverse Events, Serious Adverse Events, and Other Safety Reporting, and Appendix 4: Adverse
Events, Serious Adverse Events, Product Quality Complaints, and Other Safety Reporting:
Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting.
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event
section of the eCRF.
CCI

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
57
Status: Approved,  Date:  7 August 2023
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.
The study will include the following evaluations of safety and tolerability according to the time
points provided in the Schedule of Activities.
8.3.1. 
Physical Examinations
Weight and height of the participants will be measured at each visits until the end of the treatment.
The dose of macitentan should be adjusted as per the body weight as referred in Section 6.
Physical examination at screening includes the examination of the general appearance,
cardiovascular, respiratory, gastrointestinal, skin, eyes, ears, nose, throat, lymph nodes, nervous
system. At subsequent visits, physical examination includes the examination of general appearance,
cardiovascular, and respiratory system.
Other exams will be performed if indicated, based on medical history and/or signs and symptoms.
Information for all physical examinations must be included in the source documentation at the
study site. If an abnormality is found, it should be specified on the corresponding eCRF page
(except for abnormalities related to PAH worsening), describing the diagnosis (eg, pneumonia)
and not the signs related to the abnormality (eg, fever, coughing, dyspnea). Clinically relevant
findings (other than those related to PAH worsening) that are present prior to signing of informed
consent must be recorded on the Medical History eCRF page. Physical examination findings made
after signing of informed consent, which meet the definition of an AE (Section 10.4.1), must be
recorded on the AE page of the eCRF.
Signs and symptoms related to PAH are not reported together with the physical examination
findings but on dedicated eCRF pages.
8.3.2. 
Vital Signs
Systolic and diastolic Blood pressure (BP) and heart rate will be assessed. Vital signs are measured
non-invasively.
Blood pressure and heart rate measurements will be assessed in supine, sitting or standing positions
with a completely automated device. Manual techniques will be used only if an automated device
is not available. In addition, throughout the study BP is tried to be measured on the same arm and
in the same position (supine, sitting or standing), using the same device by the same operator
throughout the study for an individual participant.
Blood pressure and heart rate measurements should be preceded by at least 5 minutes of rest in a
quiet setting without distractions (eg, television, cell phones).
Vital signs are recorded in the eCRF.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
58
Status: Approved,  Date:  7 August 2023
8.3.3. 
Electrocardiograms
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 is scheduled for the same time point as ECG recording, the procedures should
be performed in the following order: ECG(s), vital signs, blood draw.
The ECG variables that will be analyzed are heart rate, PR interval, QRS interval, QT interval, and
corrected QT (QTc) interval using the following correction methods: QT corrected according to
Bazett’s formula (QTcB), QT corrected according to Fridericia’s formula (QTcF).
ܳܶܿ=ܤ
ܶܳሺ݉ܿ݁ݏሻ
ሺܴܴሺ݉ܿ݁ݏሻ1000
⁄
ሻଵଶ
⁄  
ܳܶܿ=ܨ
ܶܳሺ݉ܿ݁ݏሻ
ሺܴܴሺ݉ܿ݁ݏሻ1000
⁄
ሻ ଵଷ
⁄
8.3.4. 
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology and a random urine sample for urinalysis will
be collected as noted in Appendix 2: Clinical Laboratory Tests . 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 must be filed with the
source documents.
A central laboratory 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 enrollment of the participant, the results from
the local laboratory may be used for eligibility verification. The results with the corresponding
normal ranges must be recorded in the eCRF.
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.
In all patients, laboratory tests must be monitored monthly for the first 6 months of study period
and at each scheduled visit (every 12 weeks) until EOS. In addition, for patients of < 2 years, liver
tests must be monitored monthly until EOS.
8.3.5. 
Pregnancy Testing
Urine pregnancy tests for women of childbearing potential can be done at home under parental
supervision at every month. The investigator (or delegate) will verify via phone that the test was
done and will verify the results.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
59
Status: Approved,  Date:  7 August 2023
Additional serum or urine pregnancy tests may be performed, as determined necessary by the
investigator or required by local regulation, to establish the absence of pregnancy at any time
during the participation in the study.
If a female participant becomes pregnant while on study intervention with macitentan, study
intervention must be discontinued (refer to Section 7.1). The investigator must counsel the
participant and the parent(s)/legally designated representative and discuss the risks of continuing
with the pregnancy and the possible effects on the fetus. This counseling comprises all medications
administered at that time and follows instructions of the respective approved drug labels.
Any pregnancy occurring in female participants or partners of male participants after study start
(ie, signing of informed consent) up to 4 weeks following EOS must be reported within 24 hours
of the investigator’s knowledge of the event.
Pregnancies must be reported on the Pregnancy Notification form, which is sent to the CRO (see
contact details provided on the respective Pregnancy form), and on an AE page in the eCRF, if
occurring up to EOS or up to the safety follow-up telephone call (whichever is last). The CRO will
provide Pregnancy forms to the sponsor.
Any pregnancy must be followed up to its conclusion and the outcome must be reported to the
CRO on the End of Pregnancy – Collection Form B and on the Product Exposure During
Pregnancy – Collection Form A.
Any AE associated with the pregnancy and occurring up to EOS or up to the safety follow-up
telephone call (whichever is last) must be reported on a separate AE page in the eCRF. Any SAE
occurring during the pregnancy must be reported on an SAE reporting form.
8.4. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information, including AEs, SAEs,
and product quality complaints (PQCs), 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) for the duration of the study.
Further details on AEs, SAEs, and PQCs can be found in Appendix 4: Adverse Events, Serious
Adverse Events, Product Quality Complaints, and Other Safety Reporting: Definitions and
Procedures for Recording, Evaluating, Follow-up, and Reporting.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
60
Status: Approved,  Date:  7 August 2023
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 from the
time a signed and dated ICF is obtained until completion of the participant’s last study-related
procedure, which may include contact for follow-up of safety.
Serious Adverse Events
All SAEs, as well as PQCs, 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 within 30 days
after the last dose of study intervention, must be reported. The sponsor will evaluate any safety
information that is spontaneously reported by an investigator beyond the time frame specified in
the protocol.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event
Form and Safety Report Form of the eCRF, which must be completed and reviewed 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.
8.4.2. 
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and nonleading
verbal questioning of the participant is the preferred method to inquire about AE occurrence.
Solicited Adverse Events
Solicited AEs are predefined local and systemic events for which the participant is specifically
questioned.
Unsolicited Adverse Events
Unsolicited AEs are all AEs for which the participant is not specifically questioned.
8.4.3. 
Follow-up of Adverse Events and Serious Adverse Events
Adverse events, including pregnancy, will be followed by the investigator as specified in
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and
Reporting.
8.4.4. 
Regulatory Reporting Requirements for Serious Adverse Events
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities.
The sponsor will also report to the investigator (and the head of the investigational institute where
required) all suspected unexpected serious adverse reactions (SUSARs). The investigator (or

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
61
Status: Approved,  Date:  7 August 2023
sponsor where required) must report SUSARs to the appropriate IEC/IRB that approved the
protocol unless otherwise required and documented by the IEC/IRB.
8.4.5. 
Pregnancy
Pregnancy is associated with maternal mortality in patients with PAH (Bédard 2009) and may
hence confound the efficacy and safety of macitentan. Furthermore, a teratogenic effect of
macitentan cannot be excluded. Therefore, female participants of childbearing potential who are
sexually active must use a reliable method of contraception (refer to Appendix 5: Contraceptive
and Barrier Guidance).
All initial reports of pregnancy in female participants or partners of male participants must be
reported to the sponsor by the study site personnel within 24 hours of their knowledge of the event
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg,
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are
considered SAEs and must be reported using an SAE reporting form. Any participant who becomes
pregnant during the study must be promptly withdrawn from the study and discontinue further
study intervention.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the
infant will be required.
8.4.6. 
Adverse Events of Special Interest
Adverse events of special interest in this study are:
 
Anemia/Decreased hemoglobin level
 
Edema/Fluid retention
 
Hepatic impairment/ ALT and/or AST increase
 
Hypotension
A possible Hy’s law case is defined by the occurrence of ALT and/or AST ≥3 x ULN, alkaline
phosphatase <2 x ULN together with total bilirubin ≥2 x ULN or INR >1.5 (if measured). Any
possible Hy’s Law case is considered an important medical event and should be reported to the
sponsor in an expedited manner using the SAE reporting form, even before all other possible
causes of liver injury have been excluded (FDA 2009).
A confirmed Hy’s law case must be reported as a SAE.
Refer to Section 7.1 for the management of liver aminotransferases and/or hemoglobin
abnormalities.
8.5. 
Quality of Life Assessments
CCI

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
62
Status: Approved,  Date:  7 August 2023
 
 
 
 
 
 
CCI

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
63
Status: Approved,  Date:  7 August 2023
8.6. 
Pharmacokinetics
Plasma or blood samples will be used to evaluate the PK of macitentan and aprocitentan. Plasma
or blood collected for PK may additionally be used to evaluate safety or efficacy aspects that
address concerns arising during or after the study period. Genetic analyses will not be performed
on these plasma or blood samples. Participant confidentiality will be maintained.
8.6.1. 
Evaluations
Venous blood samples of approximately 0.5 mL is needed for plasma concentrations of macitentan
and aprocitentan. After the macitentan and aprocitentan analysis method for 
 microsampling
is validated, 
 microsampling device can be used for blood sample collection. For individual
participants, all points of blood collection should be done using the same sampling method. If
 microsampling device 
 is used, peripheral blood samples of approximately
0.02 mL or 0.04 mL is needed for blood concentrations of macitentan and aprocitentan. The total
of volume of blood samples drawn for PK assessments would be 0.16 mL to 4.0 mL for
participants aged ≥2 years and 0.10 mL to 2.5 mL for participants aged <2 years (Refer to Section
8). The timepoints of blood collection will be determined by the age at the start of administration.
For participants 2 years old, Visit 3 will take place at steady-state conditions for macitentan and
aprocitentan, ie, participants must have received at least 10 days of continuous administration of
the same dose of macitentan. The blood samples will be drawn at the following timepoints at
Visit 3: predose (immediately before administration of the dose of macitentan study intervention),
and at 1, 2, 4, 8, 12, and 24 hours (before macitentan intake the next day) postdose. A trough
sample (ie, predose) will be drawn on Week 12 (Visit 6).
For participants <2 years old, the blood samples will be drawn at the following timepoints: 2, 5,
and 24 hours (before macitentan intake the next day) postdose on Day 1. A trough sample will be
drawn at steady state (Visit 4 and Visit 5).
The date and exact actual clock time of each blood sample draw will be collected. In addition, the
last dosing date and time of macitentan intake before and after blood PK sampling will be collected
in the eCRF.
8.6.2. 
Analytical Procedures
Pharmacokinetics
Plasma or blood samples will be analyzed to determine concentrations of macitentan and
aprocitentan using a validated, specific, and sensitive liquid chromatography coupled to mass
spectrometry method by or under the supervision of the sponsor. If the regular venous blood
sampling method is used, plasma samples will be analyzed. If 
 microsampling device is used,
blood samples will be analyzed. The foreseen limit of quantification (LOQ) in plasma and blood
for macitentan and aprocitentan is 1 ng/mL. Details of LOQ will be provided in the SAP.
If required, some plasma or blood samples may be analyzed to document the presence of
circulating metabolites using a qualified research method. In addition, plasma PK samples may be
CCI
CCI
CCI
CCI
CCI

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
64
Status: Approved,  Date:  7 August 2023
stored for future analysis of other co-administered treatments and protein binding, and the
metabolite profile.
8.6.3. 
Pharmacokinetic Parameters and Evaluations
Based on the individual plasma or blood concentration-time data, using the actual dose taken and
the actual sampling times, PK parameters and exposure information of macitentan and aprocitentan
will be derived using population PK modelling. Baseline covariates (eg, body weight, age, sex,
creatinine clearance, race) may be included in the model, if relevant.
Plasma or blood PK parameters of macitentan and aprocitentan will be derived by
noncompartmental analysis of the plasma or blood concentration-time profiles (for participants
aged ≥2 years only).
Subjects ≥2 years of age:
 
Trough concentrations of Macitentan and aprocitentan at Week 12
 
Macitentan and aprocitentan concentration at predose, postdose 1, 2, 4, 8, 12, and 24 hours at
steady state (after at least 10 days of dosing at the same dose), (PK profile over 24 hours at
predose and following administration of macitentan during steady-state conditions)
 
Maximum concentration (Cmax), time to reach maximum concentration (tmax), and AUCτ of
Macitentan and aprocitentan at steady state, These PK parameters will be derived
noncompartmental analysis of the plasma or blood concentration- time profile.
AUCτ will be calculated according to the linear trapezoidal rule using the measured
concentration-time values above the LOQ during one dosing interval.
Subjects <2 years of age:
 
First day of dosing: Macitentan and aprocitentan concentration at 2, 5, and 24 hours postdose.
 
At Week 4 and Week 8 (steady state): Predose Macitentan and Aprocitentan concentrations
 
Apparent clearance and volume of distribution from PPK.
The PPK plan and the PPK report will be prepared separately from this study protocol.
8.7. 
Genetics and Pharmacogenomics
Pharmacogenomics or genetics are not evaluated in this study.
8.8. 
Immunogenicity Assessments
Not Applicable.
8.9. 
Health Economics OR Medical Resource Utilization and Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are not
evaluated in this study.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
65
Status: Approved,  Date:  7 August 2023
9. 
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the efficacy and safety data is outlined
below. Specific details will be provided in the SAP.
9.1. 
Statistical Hypotheses
Formal statistical hypotheses testing is not planned for this study. Primary objective of this study
is to assess the effect of macitentan on hemodynamic measures in Japanese pediatric participants
with PAH in terms of geometric mean of fold change in PVRI. Refer to Section 4.2 for additional
details.
9.2. 
Sample Size Determination
In order to calculate sample size, success criterion in this study was defined. The success criterion
is closely related to the sample size. Therefore, in this section, discussion on the success criterion
is provided prior to the discussions on sample size and probability of success.
Clinically Meaningful PVRI Fold Change and Success Criterion
PVRI is selected as the primary endpoint in this study, in which macitentan is administered to
Japanese pediatric PAH patients. A literature survey was conducted to identify if there were any
previous research describing clinically meaningful fold change in PVRI. However, no relevant
literature could be found. With the pre-definition of clinically meaningful fold change in PVRI, it
would be straightforward to interpret the study results of PAH3001. Thus, an exploratory analysis
was performed to quantitate clinically meaningful changes in PVRI using the clinical study data
with macitentan.
Macitentan 10 mg is currently approved for adult PAH patients both in Japan and global. An
exploratory analysis of PVRI was performed using the placebo and macitentan 3 mg and 10 mg
groups data in the global Phase 3 study (AC-055-302 study, SERAPHIN) (Pulido 2013). The
analysis results suggested the clinically meaningful fold change in PVRI because PVRI was found
to correlate with MM events. Table 3 shows the analysis results of fold change in PVRI at 24 weeks
after administration. From the individual patient data of 187 subjects who participated in the
PK/pharmacodynamic (PD) study of AC-055-302, the analysis was conducted with 145 patients
excluding the patients who have imputation for missing values.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
66
Status: Approved,  Date:  7 August 2023
Table 3: 
PVRI Fold Change of Week 24 to Baseline (AC-055-302)
PVRI (Wood m2)
Placebo 
(n=68) 
Macitentan 3mg 
(n=62) 
Macitentan 10mg
(n=57)
Analysis set1) 
50 
47 
48
Baseline 
 
 
Mean (SD) 
19.8 (12.48) 
21.4 (11.75) 
19.8 (11.39)
 
Median 
17.1 
19.2 
18.6
 
Min, Max 
6.0, 65.6 
6.0, 50.0 
6.2, 51.3
Week 24 
 
 
Mean (SD) 
23.1 (13.85) 
16.8 (9.73) 
14.7 (9.96)
 
Median 
22.0 
14.8 
12.0
 
Min, Max 
4.4, 65.7 
1.7, 54.7 
3.2, 54.0
Change from baseline at Week 24 
 
 
Mean (SD) 
3.4 (7.64) 
-4.6 (6.29) 
-5.1 (8.34)
 
Median 
1.2 
-3.3 
-3.9
 
Min, Max 
-7.1, 24.8 
-25.2, 4.6 
-30.5, 13.9
 
[95%CI] 
[1.18, 5.52] 
[-6.48, -2.79] 
[-7.50, -2.65]
Fold change (%)2)
 
Geometric mean [95%CI] 
115.7 [104.6, 127.8] 
77.0 [69.9, 84.7] 
71.4 [62.5, 81.6]
1) Patient who participated in the PK/PD study (All randomized set) and excluded the patient who have
imputation for missing values; 2) (Postdose value/predose value) x 100
Abbreviations: CI=confidence interval; max=maximum; min=minimum; PVRI=pulmonary vascular resistance
index; SD=standard deviation
The original unit “dyn sec m2/cm5” was converted to “Wood m2” and analyzed. The 95% confidence interval of
change from baseline is calculated from the mean and standard deviation.
 
In the macitentan 10 mg group, the geometric mean of fold change and its 95% confidence interval
were 71.4% (62.5%, 81.6%). Given that the MM event was shown to be effective in the macitentan
10 mg group, it would be clinically meaningful if the point estimate of PVRI fold change (Week 24
to baseline) was equal to or less than 81.6%.
Pharmaceuticals and Medical Devices Agency (PMDA) published review report and application
material for pediatric PAH patients with sildenafil. As a posthoc analysis, the results of the fold
change in PVRI for sildenafil was described in the application material. The maximal oxygen
uptake was defined as the primary endpoint in a pediatric global study of sildenafil (A1481131).
The exploratory analysis was performed to investigate correlation between fold change in the
maximal oxygen uptake and PVRI. The analysis results revealed that a 20% decrease of fold
change in PVRI corresponds to the ≥10% fold change in exercise tolerance. Thus, a ≥20% decrease
was defined as “improvement”.
In macitentan 10 mg group of AC-055-302, equal to or less than 81.6% fold change can be
interpreted as clinically meaningful fold change. This result in AC-055-302 of macitentan was
consistent with the post-hoc analysis results in sildenafil.
Therefore, success criterion is defined as below:
݃݁݋݉݁ܿ ݈݀݋݂ ݂݋ ݊ܽ݁݉ ܿ݅ݎݐℎܽ݊݃݁ ݅ ݊ ܸܴܲ ݇ ܹ݁݁ ݐܽ ܫ24≤81.6%

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
67
Status: Approved,  Date:  7 August 2023
Sample Size and Probability of Success
The primary endpoint is the fold change in PVRI at Week 24. It is assumed that treatment effect
in the Japanese pediatric PAH patients is similar with that in the Japanese adult PAH patients. The
treatment effect in the Japanese pediatric PAH patients was estimated based on the results from a
clinical study (AC-055-307), conducted in Japanese adult PAH patients. The pediatric PAH
patients are mainly consisted of idiopathic PAH, hereditary PAH, and congenital heart disease
PAH who receive PAH medication. Using AC-055-307 study data, an analysis was performed on
the subgroup who had idiopathic PAH, hereditary PAH, or congenital heart disease PAH (Table 4).
Table 4: 
PVRI Fold Change from Baseline to Week 24 (PPS/pseudo-pediatric population)- AC-055-307
 
PP Set 
Pseudo-pediatric
N 
28 
9
Geometric mean 
60.6% 
55.2%
[95%CI] 
[52.5%, 70.1%] 
[39.2%, 77.8%]
Abbreviations: CI=confidence interval; PPS=per protocol set; PVRI= pulmonar y vascular resistance index.
It is assumed that the PVRI fold change at Week 24 follows log-normal distribution. The estimated
mean and standard deviation were -0.594 and 0.4459, respectively, after the PVRI fold change
converted to natural logarithm.
The success criterion for the study is defined as ≤81.6% of the geometric mean of fold change in
PVRI at Week 24. The probability to achieve success criterion was calculated, assuming that the
PVRI fold change is log-normally distributed.
The true PVRI fold change was assumed to be 60%, 70%, and 80%. Standard deviation of
logarithmic PVRI fold change was assumed to be 0.40, 0.50, and 0.60. Based on these assumptions,
probability to achieve success criterion was calculated with sample size ranging from 4 to 6
patients (Table 5).
Table 5: 
Sample Size and Probability of Success (%)
Assumption 
Sample size
True fold
change
SD 
4 
 5 
 6
60% 
0.40 
93.8 
95.7 
97.0
0.50 
89.1 
91.5 
93.4
0.60 
84.7 
87.4 
89.5
70% 
0.40 
77.8 
80.4 
82.6
0.50 
73.0 
75.4 
77.4
0.60 
69.5 
71.6 
73.4
80% 
0.40 
53.9 
54.4 
54.8
0.50 
53.2 
53.5 
53.9
0.60 
52.6 
52.9 
53.2
SD: standard deviation of logarithmic PVRI fold change
Assuming the true PVRI fold change at Week 24 is 70% and the standard deviation of logarithmic
PVRI fold change is 0.50, 5 participants demonstrate 75.4% probability to achieve success
criterion.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
68
Status: Approved,  Date:  7 August 2023
PVRI fold change at Week 24 can be calculated when both measurements, baseline and Week 24,
are available. Considering potential discontinuation of one participant without PVRI assessment
of Week 24 during the study, total 6 participants was defined as sample size of this study.
9.3. 
Populations for Analysis Sets
For purposes of analysis, the following populations are defined:
Population 
Description
Efficac y Analysis Set 
All participants who receive at least 1 dose of stud y intervention.
PK Analysis Set 
All participants who have received at least 1 administration of macitentan and whose
measured plasma or blood concentration after macitentan administration for
pharmacokinetic analysis is available.
Safet y Analysis Set 
All participants who receive at least 1 dose of stud y intervention.
PK: pharmacokinetic
9.4. 
Statistical Analyses
The SAP for Foreign Health Authority interactions will be finalized prior to the first database lock
(DBL) (see Section 9.5). The SAP for the submission in Japan will be finalized prior to second
DBL and it will include a more technical and detailed description of the statistical analyses
described in this section. This section is a summary of the planned statistical analyses of the most
important endpoints including primary and secondary endpoints.
9.4.1. 
General Considerations
Efficacy endpoints will be summarized over time by descriptive statistics. Descriptive summary
statistics, such as n, mean, standard deviation (SD), median, geometric mean, inter quantile range,
minimum, and maximum for continuous variables, and counts and proportions for discrete
variables will be used to summarize data. No statistical test will be performed due to the small
sample size and insufficient statistical power. Unless otherwise specified, no imputation will be
applied to the analysis. The efficacy endpoints will be analyzed using efficacy analysis set. The
detailed methods of analysis and the data-handling rules will be provided in SAP.
The safety analysis set is used for the analyses of the safety variables. Adverse events, SAEs,
related AEs, AEs by severity and treatment-emergent AEs will be summarized by system organ
class (SOC) and preferred term (PT). Descriptive statistics would be provided for all other safety
assessments (clinical laboratory parameters, vital signs and ECG parameters).
The PK analysis set will be used for the analyses of macitentan and aprocitentan concentrations.
Although there are 4 dosage defined by the body weight, participants will be analyzed as treated
with macitentan (ie, analysis by dosage will not be applied, if not specified). In this study, a patient
under 2 years old can be enrolled. However, it is not essential to enroll a patient under 2 years old.
A patient under 2 years old will be included in the primary endpoint analysis when enrolled.
9.4.2. 
Primary Endpoint
Primary endpoint is the fold change in PVRI at Week 24. The geometric mean of PVRI fold change
at Week 24 will be estimated with observed values. The success criterion is defined as the

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
69
Status: Approved,  Date:  7 August 2023
geometric mean of PVRI fold change at Week 24 ≤ 81.6%. The success criterion will be evaluated
using the calculated numerical geometric mean of PVRI fold change before rounding.
PVRI fold change at Week 24 is defined as below.
ܸܴܲܿ ݈݀݋݂ ܫℎܽ݊݃݁ ܽ ݇ ܹ݁݁ ݐ24= 100× ൬ ܸܴܲ ܹ݇݁݁ ݐܽܫ24
ܸܴ݈ܲ݁݊݅݁ݏܾܽ ݐܽܫ൰
Estimand
The primary estimand is described according to the following 4 attributes:
1. Population: Participants between ≥ 3 months and < 15 years old with a diagnosis of PAH.
2. Variable: PVRI fold change at Week 24.
3. Intercurrent events: The following intercurrent events to be considered:
Intercurrent events 
Strategy
Death 
A while on treatment strategy will be used for deaths occurring up to 7 days
after study intervention discontinuation. All assessments prior to the death will
be considered in the analysis as observed.
Premature discontinuation 
(study intervention 
discontinuation/study 
participant discontinuation) 
A while on treatment strategy will be used for premature discontinuation of
study intervention. Premature discontinuation might occur due to the several
reasons that are possibly treatment related (eg, clinical worsening, lack of
efficacy, adverse events, informed consent withdrawal due to tolerability issues).
Values after the premature discontinuation will be affected with these reasons
and interpretation of the estimate will be of difficulty. All assessments prior to
the premature discontinuation will be considered in the analysis as observed.
Administration of rescue 
therapy 
(initiation or change in PAH 
medication) 
A while on treatment strategy will be used for administration of rescue therapy.
All assessments after administration of rescue therapy will be ignored in the
primary analysis. In the usual medical practice with infant/children in PAH,
rescue therapy is easily added with the naïve patients comparing with the
patients with PAH concomitant medications.
 
4. Population-level summary (estimator): Geometric mean of PVRI fold change at Week 24
with observed values prior to intercurrent events based on the efficacy analysis set.
Primary analysis
With efficacy analysis set, summary statistics and 95% confidence interval will be calculated with
the PVRI fold change at Week 24. This study is considered as positive if the geometric mean of
PVRI fold change at Week 24 is equal to or less than 81.6%. Thus, we will confirm the
establishment of the following formula:
݃݁݋݉݁ܿ ݈݀݋݂ ܫܴܸܲ ݂ ݋ ݊ܽ݁݉ ܿ݅ݎݐℎܽ݊݃݁ ܽ ݇ ܹ݁݁ ݐ24≤81.6 [%]
The 95% confidence interval will be prepared only to show the precision of the fold change
estimate and will not be used for the decision to declare the study as positive.
In the primary analysis, missing value will not be imputed. Only the observed value is used for the
analysis.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
70
Status: Approved,  Date:  7 August 2023
9.4.3. 
Secondary Endpoints
The secondary endpoints include:
Hemodynamic parameters/ 
Right heart catheterization 
PVR (Wood), mRAP (mm Hg), mPAP (mm Hg), CI (L/min/m2),
CO (L/min), TPR (dyn sec/cm5 ), SvO2 (%)
Functional classification 
WHO FC (I, II, III, IV)
Panama WHO FC (I, II, IIIa, IIIb, IV)
Exercise capacity 
6MWD, Borg dyspnea index (BDI)
Biomarker 
NT-proBNP
Echocardiography 
Tricuspid annular plane systolic excursion (TAPSE), left ventricular
eccentricity index (LVEI)
QOL 
PedsQLTM 4.0 Generic Core Scales Short Form (SF-15)
Physical activity 
Accelerometry
9.4.3.1. 
Hemodynamic Parameters/Right Heart Catheterization
The following pulmonary hemodynamic parameters will be measured by right heart
catheterization: Summary statistics will be calculated for baseline measurements, measurements
at Week 24, fold change, and change from baseline. For fold change, geometric mean and
geometric CV% will be calculated. The definitions of change and fold change will be the same as
those used for the analysis of PVRI. Time point: Baseline, Week 24. Pulmonary hemodynamic
parameters: PVR (Wood), CO (L/min), mRAP (mmHg), mPAP (mmHg), SvO2 (%), TPR (dyn
sec/cm5), CI (L/min/m2).
9.4.3.2. 
WHO FC I or II (Yes/No)
The proportion of subjects having WHO FC I or II will be calculated at each timepoint of
assessment. The proportion of subjects whose WHO FC value is categorized as I/II or III/IV will
also be calculated at every timepoint.
9.4.3.3. 
Panama FC I or II (Yes/No)
The proportion of subjects having Panama FC I or II will be calculated at each timepoint of
assessment.
9.4.3.4. 
6-minute Walk Test
6MWT will be conducted in children ≥6 years of age when initial informed consent and who are
able to understand and perform the test correctly. The variable of interest is 6MWD expressed as
change from baseline to Weeks 24 and 52.
9.4.3.5. 
Percent of Baseline in Plasma NT-proBNP
The percent of baseline in plasma NT-proBNP is defined as following formula:
100× ൬ܰܶ-݌ݐ݊݅݋݌݁݉݅ݐ ݐܽ ܲܰܤ݋ݎ
ܶܰ-݌ ݈݁݊݅݁ݏܾܽ ݐܽ ܲܰܤ݋ݎ൰

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
71
Status: Approved,  Date:  7 August 2023
9.4.3.6. 
Echocardiography Variables
The echocardiographic variables of interest are TAPSE and left ventricular eccentricity index
expressed as change from baseline to Weeks 12, 24, and 52.
9.4.3.7. 
Quality of Life
The Pediatric Quality of Life Inventory™ (PedsQL™) questionnaire is used:
 
PedsQL™ 4.0 SF-15 Short Form Generic Core Scales score
Expressed as change from Baseline to each post-baseline timepoint of assessments. The mean
score for each scale is calculated according to the algorithm in the scoring manual (see Appendix 9:
Quality of Life assessments). Where applicable the total score is used in calculation of the mean.
QoL variables will be analyzed separately depending on subjects or caregivers report.
9.4.3.8. 
Physical Activity (Accelerometry)
The accelerometry variables of interest are:
 
Number of hours of daytime activity,
 
Mean count per minute of daily activity,
 
Mean daily time spent in light physical activity based on a threshold from 800 to 3199 activity
counts per minute,
 
Mean daily time spent in moderate to vigorous physical activity.
Expressed as change from Baseline to Weeks 12, 24, and 52.
To be considered evaluable, physical activity should have been measured for at least 4 complete
days at a specific timepoint of assessment. A complete day is defined as a record of at least 7 hours
of data (after excluding the periods when the device was apparently not worn). These limitations
allow for obtaining reliable results (Robertson 2011).
Secondary efficacy endpoints will be summarized over time by descriptive statistics. The detailed
methods of analysis and the data-handling rules will be provided in the SAP.
9.4.4. 
Exploratory Endpoints
Exploratory endpoints (morbidity/mortality) are listed below:
 
Time to morbidity/mortality
 
Time to hospitalization or death due to PAH
 
Time to hospitalization due to PAH
 
Time to death due to PAH
 
Time to death

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
72
Status: Approved,  Date:  7 August 2023
The detailed methods of analysis and the data-handling rules for the exploratory endpoints will be
provided in the SAP.
9.4.5. 
Safety Analyses
All safety analyses will be made on the Safety Population.
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). All treatment-emergent AEs will be
summarized by SOC and PT. Any AE occurring at or after the initial administration of study
intervention through the day of last dose plus 30 days is considered to be treatment-emergent. All
reported treatment-emergent 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.
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.
Adverse events of special interest (see Section 8.4.6) will also summarized by SOC and PT. More
specification of other special interesting events will be defined in the SAP. A summary table will
not be provided if the number of events is too few to provide meaningful summary.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of
laboratory data. Descriptive statistics will be calculated for all laboratory analyte at baseline and
for observed values and changes from baseline at each scheduled time point. Changes from
baseline results will be presented in pre- versus post-intervention cross-tabulations (with classes
for below, within, and above normal ranges). A listing of participants with any laboratory results
outside the reference ranges will be provided. A listing of participants with any markedly abnormal
laboratory results will also be provided. Frequency tabulations of the laboratory abnormalities will
be provided. Detailed specification of the laboratory abnormalities will be defined in the SAP.
Electrocardiogram
The effects on cardiovascular variables will be evaluated by means of descriptive statistics and
frequency tabulations. These tables will include observed values and changes from baseline values
(the predose ECG will be used as baseline).
Electrocardiogram data will be summarized by ECG parameter. Descriptive statistics will be
calculated at baseline and for observed values and changes from baseline at each scheduled time
point. Frequency tabulations of the abnormalities will be made.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
73
Status: Approved,  Date:  7 August 2023
The ECG variables that will be analyzed are heart rate, PR interval, QRS interval, QT interval, and
corrected QT (QTc) interval using the following correction methods: QTcB and QTcF.
Descriptive statistics of QTc intervals and changes from baseline will be summarized at each
scheduled time point. The percentage of participants with QTc interval >450 milliseconds,
>480 milliseconds, or >500 milliseconds will be summarized, as will the percentage of participants
with QTc interval increases from baseline >30 milliseconds or >60 milliseconds.
All clinically relevant abnormalities in ECG waveform that are changes from the baseline readings
will be reported (eg, changes in T-wave morphology or the occurrence of U-waves.
Vital Signs
Vital signs including pulse/heart rate, and blood pressure (systolic and diastolic) (supine, sitting or
standing) will be summarized over time, using descriptive statistics and/or graphically. The
percentage of participants with values beyond clinically important limits will be summarized.
Abnormality criteria will be applied to baseline and postbaseline values. Incidence of vital signs
abnormalities will be summarized. Definition of abnormality criteria will be provided in the SAP.
9.4.6. 
Pharmacokinetic Analyses
Unless otherwise specified, PK analyses will be based on the PK analysis set. Pharmacokinetic
analysis will be performed by or under the responsibility of the sponsor.
All plasma or blood concentrations below the lowest quantifiable concentration or missing data
will be labeled as such in the concentration data presentations or SAS dataset. Concentrations
below the lower quantifiable concentration will be treated as zero in the summary statistics. All
participants and samples excluded from the analysis will be clearly documented in the Clinical
Study Report.
Descriptive statistics will be used to summarize macitentan and aprocitentan plasma or blood
concentrations at each sampling time point and PK parameters of macitentan and aprocitentan:
AUCτ, Cmax, and tmax. Detailed rules for the analysis including exclusion from PK analyses will be
specified in the SAP.
If deemed appropriate, the data from other studies of macitentan may be combined for the
population analysis. If population analysis is performed, the detail and results will be provided in
separate analysis plan and report. If sufficient data are available, population PK analysis of plasma
or blood concentration-time data of macitentan  and aprocitentan will be performed using nonlinear
mixed effects modeling. If the population PK analysis is conducted, details will be given in a
population PK analysis plan and the results of the analysis will be presented in a separate report.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
74
Status: Approved,  Date:  7 August 2023
9.5. 
Interim Analysis
This study plans 3 database locks (DBLs).
1. The first DBL will occur when 2 participants < 2 years of age have completed evaluations at
Week 24. The dataset at first DBL will be used to support Foreign Health Authority
interactions and will be summarized in a separate report.
2. The second DBL will occur at Week 24 when all participants complete evaluations at Week
24 and both PVRI measurements at baseline and at Week 24 are available with at least 5
participants. The dataset at second DBL will be used for the submission in Japan.
3. The third DBL will occur at the end of study when all participants complete evaluations at
Week 52 and consecutive safety follow-up. The dataset at third DBL will be provided for the
long-term safety evaluation during new drug application (NDA) review by PMDA. The SAP
will describe the planned interim analyses in greater detail.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
75
Status: Approved,  Date:  7 August 2023
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. 
Appendix 1: Abbreviations and Definitions
6MWD 
6-minute walk distance
6MWT 
6-minute walk test
AE 
adverse event
ALT 
alanine aminotransferase
AST 
aspartate aminotransferase
ATS 
American Thoracic Society 
AUC 
area under the concentration time curve
AUCτ 
area under the concentration-time curve durin  g one dosin  g interval
BP 
blood pressure
CHD 
congenital heart disease
CI 
cardiac index
CL 
confidence limits
Cmax  
maximum concentration
CO 
cardiac output
COVID-19 
Coronavirus Disease 2019
CRO 
Contract Research Organization
CTD 
connective tissue disorder
CYP 
cytochrome P450
DBL 
database lock
dPAP 
diastolic pulmonar y arter y pressures
dSAP 
diastolic systemic arterial pressure
ECG 
electrocardiogram
eCRF 
electronic case report form
eDC 
electronic data capture
EOS 
end of study 
EOT 
end of treatment
ERA 
endothelin receptor antagonist
ET 
endothelin
EU 
European Union
FC 
functional class
FDA 
Food and Dru  g Administration
FOIA 
Freedom of Information Act
FSH 
follicle stimulatin  g hormone
GCP 
Good Clinical Practice
HIV 
human immunodeficienc y virus
HR 
hazard ratio
HRT 
hormone replacement therapy 
IB 
investigator’s brochure
ICF 
informed consent form
ICH 
International Council for Harmonisation
IEC 
Independent Ethics Committee
ILSDRB 
Independent Liver Safet y Data Review Board
INR 
international normalized ratio
IPPI 
Investigational Product Procedure Instructions
IPPM 
Investigational Product Procedure Manual
IRB 
Institutional Review Board
IV 
intravenous
LVEDP 
left ventricular end diastolic pressure
LLN 
lower limit of normal range
LOQ 
limit of quantification
MM 
morbidity/mortality 
mPAP 
mean pulmonar y arter y pressure
mRAP 
mean right atrial pressure

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
76
Status: Approved,  Date:  7 August 2023
NT-proBNP 
N-terminal pro–brain natriuretic peptide
PAH 
pulmonar y arterial hypertension
PAWP 
pulmonar y arter y wedge pressure
PCC 
protocol clarification communication
PD 
pharmacodynamic
PDE-5 
phosphodiesterase-5
PedsQL™ 
Pediatric Qualit y of Life Inventory™
PK 
pharmacokinetic
PMDA 
Pharmaceuticals and Medical Devices Agency 
PPK 
population pharmacokinetic analysis
PPS 
per-protocol set
PQC 
product qualit y complaint
PRO 
patient-reported outcome
PT 
preferred term
PVR 
pulmonar y vascular resistance
PVRI 
pulmonar y vascular resistance index
QoL 
qualit y of life
QTcB 
QT corrected accordin  g to Bazett’s formula
QTcF 
QT corrected accordin  g to Fridericia’s formula
RHC 
right heart catheterization
SAE 
serious adverse event
SAP 
statistical analysis plan
SC 
subcutaneous
SD 
standard deviation
SF 
short form
SOC 
system organ class
sPAP 
systolic pulmonar y arter y pressures
sSAP 
systolic systemic arterial pressure
SUSAR 
suspected unexpected serious adverse reactions
SvO2 
mixed venous oxygen saturation
TAPSE 
tricuspid annular plane systolic excursion
tmax  
time to reach maximum concentration
TPR 
tota l pulmonar y resistance
ULN 
upper limit of normal range
US 
United States
WHO 
World Health Organization
WOCBP 
Woman of Childbearin  g Potential
WU 
wood unit
-hCG 
-human chorionic gonadotropin
Definitions of Terms
Electronic source
system
Contains data traditionally maintained in a hospital or clinic record to document medical
care or data recorded in a CRF as determined by the protocol. Data in this system may be
considered source documentation.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
78
Status: Approved,  Date:  7 August 2023
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
10.3.1. 
Regulatory and Ethical Considerations
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing,
conducting, recording, and reporting studies that involve the participation of human participants.
Compliance with this standard provides public assurance that the rights, safety, and well-being of
study participants are protected, consistent with the principles that originated in the Declaration of
Helsinki, and that the study data are credible.
Protocol Clarification Communications
If text within a final approved protocol requires clarification (eg, current wording is unclear or
ambiguous) that does not change any aspect of the current study conduct, a protocol clarification
communication (PCC) may be prepared. The PCC Document will be communicated to the
Investigational Site, Site Monitors, Local Trial Managers (LTMs), Clinical Trial Managers
(CTMs), and/or Contract Research Organizations (CROs) who will ensure that the PCC
explanations are followed by the investigators.
The PCC Document may be shared by the sites with Independent Ethics Committees/Institutional
Review Boards (IECs/IRBs) per local regulations.
The PCC Documents must NOT be used in place of protocol amendments, but the content of the
PCC Document must be included in any future protocol amendments.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by
the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by the
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or
when the relevant competent authority has raised any grounds for non-acceptance, except when
necessary to eliminate immediate hazards to the participants, in which case the amendment must
be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the
change(s) involve only logistic or administrative aspects of the study, the IEC/IRB (where
required) only needs to be notified.
In situations where a departure from the protocol is unavoidable during the study, the investigator
or other physician in attendance will contact the appropriate sponsor representative listed in the
Protocol Supplementary Information, 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

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
79
Status: Approved,  Date:  7 August 2023
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:
 
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

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
80
Status: Approved,  Date:  7 August 2023
 
Local laboratory documentation demonstrating competence and test reliability
(eg, accreditation/license), if applicable
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB
with current and complete copies of the following documents (as required by local regulations):
 
Final protocol and, if applicable, amendments
 
Sponsor-approved ICF (and any other written materials to be provided to the participants)
 
IB (or equivalent information) and amendments/addenda
 
Sponsor-approved participant recruiting materials
 
Information on compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
Investigator's curriculum vitae or equivalent information (unless not required, as documented
by the IEC/IRB)
 
Information regarding funding, name of the sponsor, institutional affiliations, other potential
conflicts of interest, and incentives for participants
 
Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol,
amendments (if any, excluding the ones that are purely administrative, with no consequences for
participants, data or study conduct, unless required locally), the ICF, applicable recruiting materials,
and participant compensation programs, and the sponsor has received a copy of this approval. This
approval letter must be dated and must clearly identify the IEC/IRB and the documents being
approved.
During the study the investigator (or sponsor where required) will send the following documents
and updates to the IEC/IRB for their review and approval, where appropriate:
 
Protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct)
 
Revision(s) to ICF and any other written materials to be provided to participants
 
If applicable, new or revised participant recruiting materials approved by the sponsor
 
Revisions to compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
New edition(s) of the IB and amendments/addenda
 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at
least annually)
 
Reports of AEs that are serious, unlisted/unexpected, and associated with the study
intervention

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
81
Status: Approved,  Date:  7 August 2023
 
New information that may adversely affect the safety of the participants or the conduct of the
study
 
Deviations from or changes to the protocol to eliminate immediate hazards to the participants
 
Report of deaths of participants under the investigator's care
 
Notification if a new investigator is responsible for the study at the site
 
Development Safety Update Report and Line Listings, where applicable
 
Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct), the amendment and applicable ICF revisions
must be submitted promptly to the IEC/IRB for review and approval before implementation of the
change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about
the study completion (if applicable, the notification will be submitted through the head of
investigational institution).
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
10.3.2. 
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial
information in accordance with local regulations to allow the sponsor to submit complete and
accurate financial certification or disclosure statements to the appropriate regulatory authorities.
Investigators are responsible for providing information on financial interests during the study and
for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) for details on financial disclosure.
10.3.3. 
Informed Consent Process and Assent Form
Each participant (or a legally acceptable representative) must give written consent/assent
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) and assent form 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/assent should be in
accordance with principles that originated in the Declaration of Helsinki, current ICH and GCP
guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study site personnel
must explain to potential participants or their legally acceptable representatives the aims, methods,
reasonably anticipated benefits, and potential hazards of the study, and any discomfort

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
82
Status: Approved,  Date:  7 August 2023
participation in the study may entail. Participants will be informed that their participation is
voluntary and that they may withdraw consent/assent to participate at any time. They will be
informed that choosing not to participate will not affect the care the participant will receive for the
treatment of his or her disease. Participants will be told that alternative treatments are available if
they refuse to take part and that such refusal will not prejudice future treatment. Finally, they will
be told that the investigator will maintain a participant identification register for the purposes of
long-term follow up if needed and that their records may be accessed by health authorities and
authorized sponsor personnel without violating the confidentiality of the participant, to the extent
permitted by the applicable law(s) or regulations. By signing the ICF the participant or legally
acceptable representative is authorizing such access, which includes permission to obtain
information about his or her survival status. It also denotes that the participant agrees to allow his
or her study physician to recontact the participant for the purpose of obtaining consent/assent for
additional safety evaluations, and subsequent disease-related treatments, if needed.
The participant or legally acceptable representative 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/assent should be appropriately recorded by means of either the participant's or his or her
legally acceptable representative's personally dated signature. After having obtained the
consent/assent, a copy of the ICF must be given to the participant.
A participant who is rescreened is not required to sign another ICF if the rescreening occurs within
30 days from the previous ICF signature date.
If the participant or legally acceptable representative is unable to read or write, an impartial witness
should be present for the entire informed consent/assent process (which includes reading and
explaining all written information) and should personally date and sign the ICF after the oral
consent/assent of the participant or legally acceptable representative is obtained.
Children (minors) or participants who are unable to comprehend the information provided can be
enrolled only after obtaining consent of a legally acceptable representative. Assent must be
obtained from children (minors) capable of understanding the nature of the study, typically
participants 7 years of age and older, depending on the institutional policies. Written assent should
be obtained from participants who are able to write. A separate assent form written in language the
participant can understand should be developed for adolescents. After having obtained the assent,
a copy of the assent form must be given to the participant, and to the participant's parent(s) or if
applicable legally acceptable representative.
10.3.4. 
Data Protection
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality
and compliance with applicable data privacy protection laws and regulations. Appropriate

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
83
Status: Approved,  Date:  7 August 2023
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 (or his or her legally acceptable representative)
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.
10.3.5. 
Committees Structure
An Independent Liver Safety Data Review Board (ILSDRB), a non-study specific external expert
committee of hepatologists, will be established to review serious hepatic events. The ILSDRB will
receive cases of serious hepatic events of special interest from the sponsor and provides ongoing
assessment and advice regarding cases that may require further evaluation during the study.
10.3.6. 
Publication Policy/Dissemination of Clinical Study Data
All information, including but not limited to information regarding macitentan 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 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 of macitentan, 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
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.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
84
Status: Approved,  Date:  7 August 2023
Study participant identifiers will not be used in publication of results. Any work created in
connection with performance of the study and contained in the data that can benefit from copyright
protection (except any publication by the investigator as provided for below) shall be the property
of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter)
data and information without approval from the investigator. The investigator has the right to
publish study site-specific data after the primary data are published. If an investigator wishes to
publish information from the study, a copy of the manuscript must be provided to the sponsor for
review at least 60 days before submission for publication or presentation. Expedited reviews will
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in
writing, the investigator will withhold such publication for up to an additional 60 days to allow for
filing of a patent application. In the event that issues arise regarding scientific integrity or
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will
not mandate modifications to scientific content and does not have the right to suppress information.
For multicenter study designs and sub-study approaches, secondary results generally should not
be published before the primary endpoints of a study have been published. Similarly, investigators
will recognize the integrity of a multicenter study by not submitting for publication data derived
from the individual study site until the combined results from the completed study have been
submitted for publication, within 18 months after the study end date, or the sponsor confirms there
will be no multicenter study publication. Authorship of publications resulting from this study will
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which
state that the named authors must have made a significant contribution to the conception or design
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the
work or revised it critically for important intellectual content; and given final approval of the
version to be published; and agreed to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work are appropriately investigated
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required
by law. The disclosure of the final study results will be performed after the end of study in order
to ensure the statistical analyses are relevant.
10.3.7. 
Data Quality Assurance
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified
investigators and appropriate study sites, review of protocol procedures with the investigator and
study site personnel before the study, and periodic monitoring visits by the sponsor, and direct
transmission of ECG, possibly 6MWT data, as well as clinical laboratory data from a central

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
85
Status: Approved,  Date:  7 August 2023
laboratory into the sponsor's data base. Written instructions will be provided for collection,
handling, storage, and shipment of samples.
Guidelines for eCRF completion will be provided and reviewed with study site personnel before
the start of the study.
The sponsor may review the eCRF for accuracy and completeness during on-site monitoring visits
and after transmission to the sponsor; any discrepancies will be resolved with the investigator or
designee, as appropriate. After upload of the data into the study database they will be verified for
accuracy and consistency with the data sources.
10.3.8. 
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 CRF. All CRF 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 CRF are accurate and correct.
The study data will be transcribed by study site personnel from the source documents onto an
electronic CRF, 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 CRF. Any
such worksheets will become part of the participant's source documents. Data must be entered into
the CRF in English. The CRF 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 a CRF are needed after
the initial entry into the CRF, this can be done in either of the following ways:
 Investigator and study site personnel can make corrections in the eDC tool at their own
initiative or as a response to an auto query (generated by the eDC tool).
 Sponsor or sponsor delegate can generate a query for resolution by the investigator and study
site personnel.
10.3.9. 
Source Documents
At a minimum, source documents consistent in the type and level of detail with that commonly
recorded at the study site as a basis for standard medical care must be available for the following:
participant identification, eligibility, and study identification; study discussion and date of signed
informed consent; dates of visits; results of safety and efficacy parameters as required by the
protocol; record of all AEs and follow-up of AEs; concomitant medication; intervention
receipt/dispensing/return records; study intervention administration information/patient diary; and

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
86
Status: Approved,  Date:  7 August 2023
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. Given that patient-reported
outcomes (PROs) are reports of a patient's health condition that come directly from the patient,
without interpretation by a clinician or anyone else, the responses to PRO measures entered by
study participants into source records cannot be overridden by site staff or investigators.
Specific details required as source data for the study and source data collection methods will be
reviewed with the investigator before the study and will be described in the monitoring guidelines
(or other equivalent document).
The minimum source documentation requirements for Section 5.1, Inclusion Criteria and
Section 5.2, Exclusion Criteria that specify a need for documented medical history are as follows:
 Referral letter from treating physician or
 Complete history of medical notes at the site
 Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a
minimum by participant interview or other protocol required assessment (eg, physical examination,
laboratory assessment) and documented in the source documents.
10.3.10. 
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 the data entered into the eCRF with the source documents
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source
documents will be identified to ensure that all sources of original data required to complete the
eCRF are known to the sponsor and study site personnel and are accessible for verification by the
sponsor study site contact. If electronic records are maintained at the study site, the method of
verification must be discussed with the study site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of verifying
that the recorded data are consistent with the original source data. Findings from this review will
be discussed with the study site personnel. The sponsor expects that, during monitoring visits, the
relevant study site personnel will be available, the source documents will be accessible, and a
suitable environment will be provided for review of study-related documents. The monitor will
meet with the investigator on a regular basis during the study to provide feedback on the study
conduct.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
87
Status: Approved,  Date:  7 August 2023
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.
10.3.11. 
On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at
any time during or after completion of the study to conduct an audit of the study in compliance
with regulatory guidelines and company policy. These audits will require access to all study
records, including source documents, for inspection. Participant privacy must, however, be
respected. The investigator and study site personnel are responsible for being present and available
for consultation during routinely scheduled study site audit visits conducted by the sponsor or its
designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part
of a national GCP compliance program or to review the results of this study in support of a
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
10.3.12. 
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRF 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.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
88
Status: Approved,  Date:  7 August 2023
10.3.13. 
Study and Site Start and Closure
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.
Study/Site Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been collected
and a study site closure visit has been performed.
The investigator may initiate study site closure at any time, provided there is reasonable cause and
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not
limited to:
 Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or
local health authorities, the sponsor's procedures, or GCP guidelines
 Inadequate recruitment of participants by the investigator
 Discontinuation of further study intervention development

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
89
Status: Approved,  Date:  7 August 2023
10.4. 
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality
Complaints, and Other Safety Reporting: Definitions and Procedures for
Recording, Evaluating, Follow-up, and Reporting
10.4.1. 
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a
pharmaceutical (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 All Adverse Events
under Section 8.4.1, Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information, for time of last AE recording).
Serious Adverse Event
A 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 (eg, death from anaphylaxis), the event must be

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
90
Status: Approved,  Date:  7 August 2023
reported as a serious and unexpected suspected adverse reaction even if it is a component of the
study endpoint (eg, all-cause mortality).
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 macitentan, the expectedness of an AE will be determined by
whether or not it is listed in the IB.
10.4.2. 
Attribution Definitions
Assessment of Causality
The causal relationship to study intervention is determined by the Investigator. The following
selection should be used to assess all AEs.
Related
There is a reasonable causal relationship between study intervention administration and the AE.
Not Related
There is not a reasonable causal relationship between study intervention administration and the
AE.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
10.4.3. 
Severity Criteria
An assessment of severity grade will be made using the following general categorical descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation.
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly
experienced by the participant (eg, laboratory abnormalities).
10.4.4. 
Special Reporting Situations
Safety events of interest on a sponsor study intervention in an interventional study that may require
expedited reporting or safety evaluation include, but are not limited to:
 
Overdose of a sponsor study intervention
 
Suspected abuse/misuse of a sponsor study intervention
 
Accidental or occupational exposure to a sponsor study intervention

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
91
Status: Approved,  Date:  7 August 2023
 
Medication error, intercepted medication error, or potential medication error involving a
Johnson & Johnson medicinal product (with or without patient exposure to the Johnson &
Johnson medicinal product, eg, product name confusion, product label confusion, intercepted
prescribing or dispensing errors)
 
Exposure to a sponsor study intervention from breastfeeding
Special reporting situations should be recorded in the eCRF. Any special reporting situation that
meets the criteria of an SAE should be recorded on the SAE page of the eCRF.
10.4.5. 
Procedures
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study intervention, must
be recorded using medical terminology in the source document and the eCRF. Whenever possible,
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough,
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory
infection"). Investigators must record in the eCRF their opinion concerning the relationship of the
AE to study therapy. All measures required for AE management must be recorded in the source
document and reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant must be
provided with a "wallet (study) card" and instructed to carry this card with them for the duration
of the study indicating the following:
 
Study number
 
Statement, in the local language(s), that the participant is participating in a clinical study
 
Investigator's name and 24-hour contact telephone number
 
Local sponsor's name and 24-hour contact telephone number (for medical personnel only)
 
Site number
 
Participant number
 
Any other information that is required to do an emergency breaking of the blind
Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon the
participant's discontinuation from the study, must be followed until any of the following occurs:
 
The event resolves
 
The event stabilizes
 
The event returns to baseline, if a baseline value/status is available
 
The event can be attributed to agents other than the study intervention or to factors unrelated
to study conduct

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
92
Status: Approved,  Date:  7 August 2023
 
It becomes unlikely that any additional information can be obtained (participant or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration of
due diligence with follow-up efforts)
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)
 
Surgery or procedure planned before entry into the study (must be documented in the eCRF).
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.
 
Hospitalization for cosmetic elective surgery, or social and/or convenience reasons.
 
Hospitalization for standard monitoring of a pre-existing disease or medical condition that did
not worsen.
 
For convenience the investigator may choose to hospitalize the participant for the duration of
the intervention period.
The cause of death of a participant in a study 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, which
must be completed and signed by a physician from the study site, and transmitted in a secure
manner to the sponsor within 24 hours. The initial and follow-up reports of an SAE should be
made by facsimile (fax). Telephone reporting should be the exception and the reporter should be
asked to complete the appropriate form(s) first.
10.4.6. 
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.
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.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
93
Status: Approved,  Date:  7 August 2023
A sample of the suspected product should be maintained under the correct storage conditions until
a shipment request is received from the sponsor.
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues, PQC, or questions regarding the study are listed in the Protocol
Supplementary Information, which will be provided as a separate document.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
94
Status: Approved,  Date:  7 August 2023
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 8.4.5, Pregnancy and
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and
Reporting.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Woman Not of Childbearing Potential
 
premenarchal
A premenarchal state is one in which menarche has not yet occurred.
 
postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the
postmenopausal range may be used to confirm a postmenopausal state in women not using
hormonal contraception or hormonal replacement therapy (HRT), however in the absence of
12 months of amenorrhea, a single FSH measurement is insufficient. If there is a question
about menopausal status in women on HRT, the woman will be required to use one of the
non-estrogen-containing hormonal highly effective contraceptive methods if she wishes to
continue HRT during the study.
 
permanently sterile (for the purpose of this study)
Permanent sterilization methods include hysterectomy, or bilateral salpingectomy, or bilateral
oophorectomy. In addition, the following cases will be considered as permanent sterilization
for this study: a premature ovarian failure confirmed by a specialist, a XY genotype, a Turner
syndrome or participant born without a uterus.
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 a highly effective method of contraception, as
described throughout the inclusion criteria.
Contraceptive (birth control) use by men or women should be consistent with local regulations
regarding the acceptable methods of contraception for those participating in clinical studies.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
95
Status: Approved,  Date:  7 August 2023
Typical use failure rates may differ from those when used consistently and correctly.
Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used
consistently and correctly.
 Intrauterine device (IUD)
 Intrauterine hormone-releasing system (IUS)
 Bilateral tubal occlusion/ligation
 Vasectomized partner
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the
sole sexual partner of the woman of childbearing potential and the absence of sperm has been
confirmed.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used
consistently and correctly.
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulationb
 oral
 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 (not
considered to be highly effective - failure rate of 1% per year)
 Vasectomized partner
 Hormonal contraception
 Male condom with or without spermicide
 Periodic abstinence (calendar, symptothermal, post-ovulation methods)
 Withdrawal (coitus-interruptus)
 Lactational amenorrhea method (LAM)
a) Typical use failure rates may differ from those when used consistently and correctly.
b) Hormonal contraception may be susceptible to interaction with the study intervention, which may
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception
may interact with the study intervention.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
96
Status: Approved,  Date:  7 August 2023
10.6. 
Appendix 6: Sponsor Heart Catheterization Guidance
SPONSOR HEART CATHETERIZATION GUIDANCE WHEN HEMODYNAMIC
VARIABLES ARE ENDPOINTS
 
This guidance only applies to participants who will require a baseline and a post-baseline right
heart catheterization (RHC) with/without a left heart catherization (LHC) (if needed). This
guidance does not apply to RHC/LHC used only for participant eligibility.
 
Hemodynamic evaluations will be carried out according to this guidance for those conditions
and hemodynamic parameters that are described below. Further hemodynamic evaluations
will be carried out according to the catheterization laboratory’s local practice.
1. HEART CATHETERIZATION PROCEDURES
1.1 Conditions
Participants will undergo RHC/LHC at the study site (or other institution in case no suitable
catheterization laboratory is available at the study site) in an appropriate care setting
(eg, catheterization laboratory or medical procedures unit). If the assessment is performed at an
external catheterization laboratory, the Primary Investigator is responsible to provide this guidance
document to the external institution and to ensure that the catherization lab is sufficiently qualified.
Whenever possible, it is recommended that baseline and any post-baseline RHC/LHC are
performed by the same operator, according to the same standards and procedures and in the same
catheterization laboratory to ensure data consistency.
Where historical RHC/LHC is used for baseline measurements, then this guidance requirements
for zeroing (Section 1.2) and heart catheterization measurement (Section 2) must have been
followed and documented in the source notes. Otherwise a new RHC/LHC assessment will have
to be performed for baseline measurements.
1.2 ‘Zeroing’
 
‘Zeroing’ must be done prior to any RHC/LHC measurements. The participant needs to be in
a supine position and the pressure transducer is to be set to zero level at the mid-thoracic line.
 
This must be documented in the heart catherization worksheet.
1.3 Oxygen
If the participant requires supplemental oxygen during baseline RHC/LHC, oxygen should also be
given during the follow-up RHC/LHC, if needed.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
97
Status: Approved,  Date:  7 August 2023
2. HEART CATHETERIZATION MEASUREMENTS
2.1 Right Heart Catheterization measurements
 
Pulmonary Artery Pressure (PAP)
The participant will be asked to breath normally during the procedure. The operator will assess
the appropriate systolic PAP (sPAP) and diastolic PAP (dPAP) readings based on the
respiratory cycle and the pressure tracings.
The sPAP and dPAP must be measured with 2 measurements documented in the source notes
that are assessed by the operator as the most representative and reliable.
If more than 2 values are recorded, all values must be documented on the source notes.
 
Pulmonary Artery Wedge Pressure (PAWP)
The participant will be asked to breath normally during the procedure. The operator will assess
the appropriate pulmonary artery wedge pressure (PAWP) reading based on the respiratory
cycle and the pressure tracing.
If multiple measurements are performed, all PAWP values must be documented in the heart
catherization worksheet.
The operator must identify the most accurate PAWP on the heart catherization worksheet,
based on their decision of which waveform to use.
 
Cardiac Output
The same method for CO measurement must be used for both the baseline and any post-baseline
RHC to ensure consistency.
If thermodilution method is used:
 
The CO must be measured with at least 3 measurements documented in the heart
catherization worksheet.
 
The 3 measurements must be within 10% of each other, ie, the lowest of the 3 CO values
must not be lower than 10% of the middle value AND the highest value must not be
higher than 10% of the middle value.
 
If the 3 values are not within 10% of each other (as per above), additional measurements
can be performed until 3 measurements are obtained that are within 10% of each other.
 
If more than 3 measurements are taken, the largest and/or smallest outlying values in the
opinion of the operator should be discarded until at least 3 values are within 10% of each
other
 
If more than 3 values are recorded, all values must be documented in the heart
catherization worksheet.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
98
Status: Approved,  Date:  7 August 2023
If Fick method (indirect or direct) is used:
 
Only 1 value is required and must be documented in the source notes.
 
If multiple values are performed, all CO values must be documented in the source notes.
In addition, the operator must identify the most representative and reliable CO value.
2.2 Left Heart Catheterization Measurement
 
Left Ventricular end Diastolic Pressure (LVEDP)
 
LVEDP is to be recorded only when PAWP is not available or not reliable.
 
The participant will be asked to breath normally during the procedure. The operator will
assess the appropriate LVEDP reading based on the respiratory cycle and the pressure
tracing.
 
If multiple measurements are performed, all LVEDP values must be documented in the
heart catherization worksheet.
 
The operator must identify the most representative and reliable LVEDP value on the heart
catherization worksheet.
2.3 Other Measurements
HR, RAP, dSAP, sSAP, SvO2 are measured as per local practice.
3. DOCUMENTATION
3.1 Tracings
All relevant tracings are to be recorded and saved/printed for each pressure measurement and filed
as the participants’ source notes (electronic or paper).
3.2 Heart Catheterization Worksheet
It is mandatory to use the study heart catheterization worksheet to capture documentation of each
RHC with/without LHC assessments newly performed for the purpose of the study and report
relevant data in the eCRF, as indicated.
It is not mandatory to use the study heart catheterization worksheet for historical RHC/LHC
assessments.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
99
Status: Approved,  Date:  7 August 2023
10.7. 
Appendix 7: WHO Functional Class
Class I  
Patients with pulmonary hypertension but without resulting limitation of physical
activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain
or near syncope.
Class II  
Patients with pulmonary hypertension resulting in slight limitation of physical activity.
They are comfortable at rest. Ordinary physical activity causes undue dyspnea or
fatigue, chest pain, or near syncope.
Class III  Patients with pulmonary hypertension resulting in marked limitation of physical
activity. They are comfortable at rest. Less than ordinary activity causes undue
dyspnea or fatigue, chest pain, or near syncope.
Class IV  Patients with pulmonary hypertension with inability to carry out any physical activity
without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or
fatigue may be present even at rest. Discomfort is increased by any physical activity.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
100
Status: Approved,  Date:  7 August 2023
10.8. 
Appendix 8: Panama Functional Class for Pediatrics
For children aged 0–0.5 year
Class I  
Asymptomatic, growing and developing normally, no limitation of physical activity.
Gains head control and increases body tone from 0 to 3 months, then rolls over and
has no head lag. Sitting with support.
Class II  
Slight limitation of physical activity, unduly dyspnoeic and fatigued. Falling behind
physical developmental milestones. Comfortable at rest. Continues to grow along own
centiles.
Class IIIa  Marked limitation of physical activity, unduly fatigued. Regression of learned physical
activities. Quiet and needs frequent naps. Comfortable at rest. Less than ordinary
activity causes undue fatigue or syncope and/or presyncope. Growth compromised.
Poor appetite. Requires excessive medical attention.
Class IIIb Growth severely compromised. Poor appetite. Supplemental feeding. Less than
ordinary activity causes undue fatigue or syncope. Plus features of Class IIIa.
Class IV  Unable to carry out any physical activity without undue dyspnea, fatigue or syncope,
not interacting with family. Syncope and/or right heart failure. Plus features of Class
III.
For children aged 0.5–1 year
Class I  
Asymptomatic, growing along own centiles, no limitation of physical activity. Mobile,
sitting, grasping, starting to stand, crawling, playing.
Class II  
Slight limitation of physical activity, unduly dyspnoeic and fatigued when playing.
Delayed physical development. Comfortable at rest. Continues to grow along own
centiles.
Class IIIa  Marked limitation of physical activity. Regression of learned physical activities. Stops
crawling. Quiet and needs frequent naps. Hesitant and unadventurous. Comfortable at
rest. Less than ordinary activity causes undue fatigue or syncope and/or presyncope.
Growth compromised. Poor appetite. Requires excessive medical attention.
Class IIIb Growth severely compromised. Poor appetite. Supplemental feeding. Less than
ordinary activity causes undue fatigue or syncope. Plus features of Class IIIa.
Class IV  Unable to carry out any physical activity without undue dyspnea, fatigue or syncope,
not interacting with family. Syncope and/or right heart failure. Plus features of Class
III.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
101
Status: Approved,  Date:  7 August 2023
For children aged 1–2 years
Class I  
Asymptomatic, growing along own centiles, no limitation of physical activity.
Standing, starting to walk/walking, climbing.
Class II  
Slight limitation of physical activity, unduly dyspnoeic and fatigued when playing.
Delayed physical development. Comfortable at rest. Continues to grow along own
centiles.
Class IIIa  Marked limitation of physical activity. Regression of learned physical activities.
Reluctant to play. Quiet and needs frequent naps. Hesitant and unadventurous.
Comfortable at rest. Less than ordinary activity causes undue dyspnea, fatigue or
syncope and/or presyncope. Growth compromised. Poor appetite.
Class IIIb Growth severely compromised. Poor appetite. Supplemental feeding. Less than
ordinary activity causes undue fatigue or syncope. Plus features of Class IIIa.
Class IV  Unable to carry out any physical activity without undue dyspnea, fatigue or syncope,
not interacting with family. Syncope and/or right heart failure. Plus features of Class
III.
For children aged 2–5 years
Class I  
Asymptomatic, growing normally, attending nursery/school regularly, no limitation of
physical activity, playing sports with his/her classmates.
Class II  
Slight limitation of physical activity, unduly dyspnoeic and fatigued when playing with
his/her classmates. Comfortable at rest. Continues to grow along own centiles.
Nursery/school attendance 75% normal. No chest pain.
Class IIIa  Marked limitation of physical activity. Regression of learned physical activities. Not
climbing stairs, reluctant to play with friends. Hesitant and unadventurous.
Comfortable at rest. Less than ordinary activity (eg, dressing) causes undue dyspnea,
fatigue, syncope and/or presyncope or chest pain. Nursery/schooling compromised
< 50% normal attendance.
Class IIIb Unable to attend nursery/school, but mobile at home. Wheelchair needed outside home.
Growth compromised. Poor appetite. Supplemental feeding. Less than ordinary
activity causes undue fatigue, syncope or chest pain. Plus features of Class IIIa.
Class IV  Unable to carry out any physical activity without undue dyspnea, fatigue, syncope, or
chest pain, unable to attend school, wheelchair dependent, not interacting with friends.
Syncope and/or right heart failure. Plus features of Class III.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
102
Status: Approved,  Date:  7 August 2023
For children aged 5–16 years
Class I  
Asymptomatic, growing along own centiles, attending school regularly, no limitation
of physical activity, playing sports with his/her classmates.
Class II  
Slight limitation of physical activity, unduly dyspnoeic and fatigued when playing with
his/her classmates. Comfortable at rest. Continues to grow along own centiles. School
attendance 75% normal. No chest pain.
Class IIIa  Marked limitation of physical activity. No attempt at sports. Comfortable at rest. Less
than ordinary activity causes undue dyspnea, fatigue, syncope or chest pain. Schooling
compromised < 50% normal attendance.
Class IIIb Unable to attend school, but mobile at home and interacting with friends. Wheelchair
needed outside the home. Growth compromised. Poor appetite. Supplemental feeding.
Less than ordinary activity (eg, dressing) causes undue dyspnea, fatigue, syncope
and/or presyncope or chest pain. Plus features of Class IIIa.
Class IV  Unable to carry out any physical activity without undue dyspnea, fatigue, syncope, or
chest pain, unable to attend school, wheelchair dependent, not interacting with friends.
Syncope and/or right heart failure. Plus features of Class III.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
103
Status: Approved,  Date:  7 August 2023
10.9. 
Appendix 9: Quality of Life assessments
CCI

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
117
Status: Approved,  Date:  7 August 2023
CCI

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
118
Status: Approved,  Date:  7 August 2023
10.10. Appendix 10: Sponsor 6-minute Walk Test Guidance
This document stipulates the criteria under which study-required 6MWTs will be carried out in
Clinical Protocol 67896062PAH3001.
These criteria are, in part, derived from the recommendations included in the American Thoracic
Society (ATS) Guidelines issued in 2002 and the ERS/ ATS Technical Standard published in 2014
(ATS Statement 2002). As opposed to the comprehensive published manuscripts, this guidance
has been shortened and accustomed for use in a clinical study in which a variety of different
assessments may need to be performed at a given visit.
1. INSTRUCTIONS
General
 
The 6-Minute Walk Test (6MWT) must be performed indoors, along a long, flat, straight,
enclosed corridor (or similar location) with a hard surface that can be blocked for traffic during
the conduct of the test. The track length for the 6MWT must be free of obstacles. The use of
treadmill and a continuous course, eg, a circuit, is not allowed.
 
The ideal track length used for the 6MWT is 30 meters (If the track is shorter, it must be no
shorter than 20 meters in length). The track must be marked at regular intervals to facilitate
measurement of the distance walked (markings every 3 meters are recommended). The
turnaround points must be marked with a cone. A starting line, which marks the beginning
and the end of each lap (one lap is twice the length of the track used at the site), needs to be
marked on the floor.
 
Local safety practice regarding medical emergencies and contraindications for 6MWT must
be followed at each participating site.
 
The person administering the 6MWT (tester) needs to stand near the starting line during the
6MWT and must not walk with the participant, and not get distracted during the conduct of
this 6MWT (eg, by talking to someone).
 
Rest periods are allowed if the participant can no longer continue. If the participant needs to
rest, he/she may pause, lean against the wall and continue walking whenever he/she feels able.
The timer must continue to run even if the participant stops to rest. The 6MWT can be stopped
at any moment as due to medical emergencies or safety issues such as chest pain, intolerable
dyspnea, leg cramps, staggering, diaphoresis, and pale or ashen appearance
 
The 6MWT is a non-encouraged test. An even tone of voice must be used when using the
standard phrases. No other instructions or words of encouragement are given during the test,
other than the pre-scripted phrases (see instructions to participant). Eye contact and body
language signaling the participant to speed up must be avoided during the test.
 
Whenever possible, for an individual participant, repeat 6MWTs must be conducted in the
same corridor and by the same tester, and preferably at about the same time of the day
(ie, within ± 2 hours of the baseline test) to minimize variability.
 
If a participant is oxygen dependent, the flow rate must remain constant from 30 minutes prior
to each 6MWT, until the completion of all protocol-mandated assessments after the 6MWT.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
119
Status: Approved,  Date:  7 August 2023
Additionally, the way oxygen is delivered (delivery device, application route, way of carrying
delivery device) must be the same for all 6MWTs, unless a change is required for documented
medical reasons.
Training tests
For participants who have not previously performed a 6MWT, a training 6MWT must be
performed before the first protocol-mandated 6MWT is performed.
Data from the training 6MWT are not collected in the eCRF but must be documented in the source
data.
Timing
Only two 6MWTs can be performed on the same day. The interval between two 6MWTs on the
same day must be at least 2 hours.
2. TEST REQUIREMENTS
Participant
 
The participant must wear comfortable clothing and appropriate walking shoes.
 
The participant must not have exercised vigorously within 2 hours of beginning the test.
 
It is recommended that the participant rests for at least 15 minutes before the test starts.
 
It is recommended that participants receive their concomitant therapy on the day of the test.
If the participant is used to taking bronchodilators, he/she must take them at least 10 to 30 min
before the test.
 
Participants can use their usual walking aids during the test (eg, cane). The same walking aid
should be used for all 6MWTs. Walkers are not allowed.
Equipment to perform the test
 
Countdown timer
 
Mechanical lap counter
 
Two cones to mark the turnaround points
 
A chair that can be easily moved along the track
 
6MWT Worksheet
 
Borg category-ratio (CR) 10 scale®

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
120
Status: Approved,  Date:  7 August 2023
3. PERFORMING THE 6MWT
Assessments before the 6MWT
Before the 6MWT, the tester shows the Borg CR10 Scale® to the participant and asks the
participant:
 
&Please grade your dyspnea using this scale'.
Record the baseline-6MWT dyspnea using the Borg CR10 scale® on the 6MWT worksheet.
Instructions to the participant during the 6MWT
The tester uses the following exact dialogue with the participant:
&The objective of this test is to walk as far as possible in 6 minutes. You will walk back and
forth in this hallway. Six minutes is a long time to walk, so you will be exerting yourself. You
will probably get out of breath or become exhausted. You are permitted to slow down, to stop,
and to rest as necessary. You may lean against the wall while resting, but resume walking as
soon as you are able.
You will be walking back and forth around the cones. You should pivot briskly around the
cones and continue back the other way without hesitation. Now I.m going to show you. Please
watch the way I turn without hesitation'.
(The tester demonstrates the walking and pivots around a cone briskly).
 &Are you ready to do that? I am going to use this counter to keep track of the number of laps
you complete. I will click it each time you turn around at this starting line. Remember the
object is to walk AS FAR AS POSSIBLE in 6 minutes, but don.t run or jog.'
After these instructions are given to the participant, the tester says:
 &Start now, or whenever you are ready'
As soon as the participant starts to walk, the tester starts the timer and writes down start time. The
tester reminds the participant of the elapsed time by saying:
After the first minute: &You are doing well. You have 5 minutes to go'.
When the timer shows 4 minutes remaining: &Keep up the good work. You have 4 minutes to
go.'
When the timer shows 3 minutes remaining: &You are doing well. You are halfway done.'
When the timer shows 2 minutes remaining: &Keep up the good work. You have 2 minutes to
go.'
When the timer shows only 1 minute remaining: &You are doing well. You have only 1 minute
to go.'
If the participant stops walking during the test and needs a rest, the tester says:

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
121
Status: Approved,  Date:  7 August 2023
&You can lean against the wall if you would like; then continue walking whenever you feel
able.'
The tester will not stop the timer. If the participant stops before the 6 minutes are up and refuses
to continue (or the tester decides that they should not continue), the tester wheels the chair over
for the participant to sit on, discontinue the walk, and note on the worksheet the distance, the time
stopped, and the reason for stopping prematurely.
When the timer is 15 seconds from completion, the tester says:
&In a moment I.m going to tell you to stop. When I do, just stop right where you are and I will
come to you'.
When the timer alarm rings the tester says:
&Stop!'
Assessments after the 6MWT
The tester walks over to the participant, marks the spot where the participant stopped, records the
total distance walked in the 6MWT worksheet and congratulates the participant on good effort.
After the 6MWT, the tester reminds the participant of their dyspnea that they chose before the
6MWT. The tester shows the Borg CR10 Scale® to the participant and asks the participant:
 
&Please grade your dyspnea using this scale'.
The tester will record the post-6MWT dyspnea on the 6MWT worksheet.
4. 6MWT WORKSHEET
It is mandatory to use the 6MWT worksheet to capture documentation of each 6MWT newly
performed for the purpose of the study and report relevant data in the eCRF, as indicated.
It is not mandatory to use the study 6MWT worksheet for historical 6MWTs.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
122
Status: Approved,  Date:  7 August 2023
10.11. Appendix 11: Borg CR10 Scale®
CCI

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
123
Status: Approved,  Date:  7 August 2023
Borg CR10 Scale®:
CCI

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
124
Status: Approved,  Date:  7 August 2023
10.12. Appendix 12: Study Conduct During a Natural Disaster
GUIDANCE ON STUDY CONDUCT DURING CORONAVIRUS DISEASE 2019
 
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, isolation or quarantine of participants and
study site personnel; travel restrictions/limited access to public places, including hospitals; study
site personnel being unavailable, isolated, or reassigned to critical tasks.
The sponsor is providing options for study related participant management in the event of
disruption to the conduct of the study. This guidance does not supersede any local or government
requirements or the clinical judgement of the investigator to protect the health and well-being of
participants and site staff. If, at any time, a participant’s travel to the study site is considered to be
dangerous, study participation may be interrupted, and study follow-up conducted. If it becomes
necessary to discontinue participation in the study, the procedures outlined in the protocol for
discontinuing study intervention will be followed.
If, as a result of the COVID-19 scheduled visits cannot be conducted in person at the study site,
they will be performed to the extent possible remotely/virtually or delayed until such time that on-
site visits can be resumed. At each contact, participants will be interviewed to collect safety data.
Key efficacy endpoint assessments should be performed if required and as feasible. Participants
will also be questioned regarding general health status to fulfill any physical examination
requirement.
Every effort should be made to adhere to protocol-specified assessments for participants on study
intervention, including follow up. Modifications to protocol-required assessments may be
permitted using the examples contained in this 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 eCRF.
If the participant has tested positive for the COVID-19, the investigator should contact the
sponsor’s responsible medical officer to discuss plans for administration of study intervention,
performing. study assessments, and follow-up. Modifications made to the study conduct as a result
of the COVID-19 should be summarized in the clinical study report.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
125
Status: Approved,  Date:  7 August 2023
GUIDANCE SPECIFIC TO THIS PROTOCOL
STUDY VISITS
 
Missed visits, missed assessments or assessments performed out of window due to COVID-
19 will be captured in the clinical trial management system for protocol deviations with the
prefix “COVID-19-related”, with the actual visit date documented or reason for withdrawal
specified. Other relevant study elements impacted by the pandemic should also be
documented/labeled as “COVID-19 related” in the clinical trial management system for
protocol deviations or other study system, as applicable.
 
Discontinuations of study interventions and withdrawal from the study due to COVID-19 will
be captured with the prefix “COVID-19-related” in the eCRF.
 
Participants entering in screening who are not able to complete all screening assessments on
site due to COVID-19 restrictions (eg, no on-site visit possible) would be considered screening
failures.
 
Scheduled visits that cannot be conducted in person at the study site will be performed to the
extent possible by remote/virtually/home visits. This applies to all visits except Visit
1/Screening which must be conducted in person at the study site.
For scheduled visits that cannot be conducted on-site options may include (as local regulations
permit):
 
Involvement of a local registered nurse, or any other properly trained person, site study
nurse or the participant’s physician to collect required blood samples and/or perform
physical examinations, as indicated per protocol (see Section 1.3 Schedule of Activities of
the Protocol) for planned remote visits.
 
Blood sampling with central laboratory kits may be performed locally and shipped to the
central laboratory. Alternatively, a local laboratory may be considered, in case the central
laboratory kits cannot be used for the scheduled blood tests.
 
Telephone calls at scheduled visits or monthly at a minimum, if the window for scheduled
visits is wider, with participant and their primary care physician, local nurse, etc if
applicable.
 
Telemedicine consultation, if permitted by local regulation and if part of the local clinical
practice.
 
Review of any available medical records.
Details regarding these contacts (date, time, contact person) must be properly documented in
source records including a detailed content of the discussion points (eg, responses from
participants and/or results of physical evaluation performed by the trained person or treating
physician).
Participants will be asked to return to the site as soon as possible once restrictions are lifted to
perform all assessments that would have been missed.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
126
Status: Approved,  Date:  7 August 2023
LABORATORY ASSESSMENTS
 
For participants not able to perform their regular on-site scheduled visits due to COVID-19
pandemic (eg, due to self-isolation/quarantine, travel restrictions, limited access to
hospitals, …), at least the planned safety assessments must be performed remotely, including
safety laboratory assessments (eg, hematology, liver function test, and urine pregnancy test
for women of childbearing potential) and physical examination.
 
The investigator must review all safety assessments to confirm the participant can pursue
his/her study intervention. If the safety assessments cannot be performed and reviewed by the
investigator in a timely manner, the investigator may decide to interrupt or discontinue
permanently study intervention, if it is in the best interest of the participant.
TREATMENT
 If the participant cannot come to the site for his visits, his/her study intervention may be
provided, via direct-to-participant shipment, to the participant’s home or a participant’s
relative/caregiver may pick up study drug on behalf of the participant, in accordance with local
regulations.
 The participant will be asked to save and return unused tablets (study drug) at their next on-
site visit. Treatment compliance will meanwhile be assessed via monthly phone calls.
 This distribution and shipment of study intervention will be done if the treating physician can
ensure that they can maintain participant safety oversight (based on clinical evaluation, results
of laboratory tests and pregnancy test, if applicable).
HANDLING OF SAFETY AND EFFICACY DATA INTEGRITY
The sponsor will monitor the COVID-19 related protocol deviations and evaluate their impact on
study safety and efficacy outcomes.
The statistical analysis plan will specify details on addressing impact of COVID-19 related aspects
on the analyses. This includes the following planned analyses (not limited to):
 
Sensitivity analyses for primary and secondary efficacy endpoints to address intercurrent
events caused by COVID-19, as well as handling of missing values caused by the limits from
the COVID-19 pandemic.
 
Summary of safety analyses (eg, AEs, SAEs) by COVID-19 (yes or no).
 
Summary/listings of protocol deviations related to COVID-19.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
127
Status: Approved,  Date:  7 August 2023
10.13. Appendix 13: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents.
Amendment 4 (9 March 2023)
Overall Rationale for the Amendment: The main reason for this protocol amendment is to add allowance
for Day1 and to add interpretation of exclusion criteria, and to also allow for the use of local laboratory data
for eligibility assessment. Minor corrections and editorial revisions are also being implemented.
The updates are indicated in bold for new text and strike-through for deleted text in the following table.
Section number 
and Name
Description of Change 
Brief Rationale
1.1. 
Synopsis
3. OBJECTIVES AND
ENDPOINTS
8.2.7. Borg CR10
Scale®
The following words were corrected:
 
Dyspnea and on exertion
For clarity and
consistency
1.3. 
Schedule of
Activities (SoA)
ECG, Hematology,
chemistry
Added allowance in footnote for Day 1:
 
ECG
n. If there is no change in clinical conditions, data
available within 14 days prior to Day1. Not required on
Day 1 if screening assessment is performed within 14
days prior to Day1.
 
Hematology, chemistry
o. If there is no change in clinical conditions, data
available within 7 days prior to Day1. Not required on
Day 1 if screening assessment is performed within 7 days
prior to Day1.
To avoid short term
invasive tests or
restraint for exam,
Day 1 assessments
are not required if
screening
assessments are close
to Day1
5.2. 
Exclusion
Criteria
Criterion 15 is modified as follows:
 
Previous treatment * with macitentan at any time.
 
*It is not considered treatment if it does not affect the
evaluation of efficacy and safety of this study. In such
cases (eg, medical history of short-term macitentan
administration), the investigator must contact the
sponsor’s responsible medical officer to confirm the
interpretation is applicable.
To clarify that the
sponsor should be
consulted to avoid
discrepancies in the
interpretation of
‘ treatment ’.
6.8. 
Concomitant
Therapy
The following sentence is added:
 
Non-therapeutic medications (Drug solution and heparin
used for PK blood sampling or right heart
catheterization, etc.) do not need to be recorded in the
eCRF.
For clarity and
consistency.
The purpose is to
collect treatments
that may affect the
evaluation of efficacy
and safety of
macitentan.
8.2.2.2. 
Functional
Class
The following sentence is deleted:
 
The disease progression event (ie, worsening of clinical
condition related to PAH) must be reported in the eCRF
within 24 hours of the investigator’s knowledge of the event.
If the disease progression fulfills the seriousness criteria (eg,
For clarity and
consistency

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
128
Status: Approved,  Date:  7 August 2023
Section number 
and Name
Description of Change 
Brief Rationale
needs hospitalization), the event must also be reported as an
SAE within 24 hours of the investigator’s knowledge that the
event is serious usin  g an SAE reportin  g form.
8.3.1. Physical 
Examinations 
The following sentence is deleted: 
 
Weight and height of the participants will be measured at
each visits until the end of the treatment except for Visit 3
where onl y weight will be measured.
For clarity and
consistency
 
8.3.4. Clinical Safety 
Laboratory Assessments 
The following sentence is added: 
 
A central laboratory 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 enrollment of the participant, the
results from the local laboratory may be used for
eligibility verification. The results with the corresponding
normal ranges must be recorded in the eCRF.
Conditions for use of
local laboratory
results at enrollment
are clarified.
10.10. Appendix 10: 
Sponsor 6-minute Walk 
Test Guidance
10.11. Appendix 11:
Bor g CR10 Scale®
Deletion of description about exertion. 
For clarity and
consistency
 
Throughout the protocol 
Minor grammatical, formatting, or spelling changes were 
made. 
Minor errors were
noted.
Amendment 3 (9 March 2022)
Overall Rationale for the Amendment: The main reason for this protocol amendment is to change the
inclusion/exclusion criteria, to update the method of administration and to modify the definition prohibited
concomitant therapy. Minor corrections and editorial revisions are also being implemented.
The updates are indicated in bold for new text and strike-through for deleted text in the following table.
Section number 
and Name
Description of Change 
Brief Rationale
1.1. 
Synopsis 
Description of 
Interventions 
6.1. 
Study 
Intervention 
Administered
The sentence is changed as follows: 
Whole tablet(s) are dispersed in water and administered 
orally (eg, via spoon, glass, syringe). 
The same administration method should be used as far as 
possible. 
To update
information based on
dispersible tablet
formulation (not
limited to spoons)
1.1. 
Synopsis 
SAFETY 
EVALUATIONS 
 
1.3. 
Schedule of
Activities (SoA)
 
10.2. Appendix 2:
Clinical Laboratory
Tests
The following items are deleted 
Serology (hepatitis B surface antigen [HBsAg] and hepatitis 
C virus antibody)
To align with
exclusion criteria
1.3. 
Schedule of 
Activities (SoA) 
Weight and height 
Removed "weight only" and added "X" 
For clarity and
consistency
(height is required to

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
129
Status: Approved,  Date:  7 August 2023
Section number 
and Name
Description of Change 
Brief Rationale
assess eGFR)
1.3. 
Schedule of 
Activities (SoA) 
Pregnanc y test
Added “urine” at Visit 12 and FU. 
For clarity and
consistency
 
1.3. 
Schedule of 
Activities (SoA) 
Echocardiography
(TAPSE, LVEI)
Added allowance in footnote for Day 1: 
l. Data available within 14 days prior to Day 1 
For clarity and
consistency
 
1.3. 
Schedule of 
Activities (SoA) 
Visit 3 
The following sentence is added in footnote k: 
k. Visit 3 will take place at steady-state conditions for 
macitentan and its active metabolite (aprocitentan), ie, 
patients must have received at least 10 days of continuous 
administration of the same dose of macitentan (patients 
should take at the same dose level and time of day for 11
days prior to Visit 3 including the day of visit). After
completion of the 24-hour PK collection, macitentan
treatment will begin at the dose determined at Visit 3.
Specification of
points to be complied
with in
administration before
PK measurement
5.1. 
Inclusion Criteria 
Criterion 7 is modified the following: 
b. Of childbearing potential and  
  o Practicing a highly effective, preferably user- 
independent method of contraception… 
 
 
 
Criteria 9, 10 and 11 were deleted. 
 
To align with latest
JNJ risk language
(Clarified
contraception
requirements for
pediatric study)
 
Contraception is not
required for male
participant
5.2. 
Exclusion 
Criteria 
Patients diagnosed with bronchopulmonary dysplasia were 
added to exclusion criterion 5. 
 
 
 
Criterion 23 was deleted. 
 
 
 
Criterion 28 was deleted. 
 
 
 
 
 
Added subtitles “Pulmonary hypertension related” and 
“Comorbidities related” to medical condition 
To ensure that the
infants entering in
current study are not
premature.
 
Contraception is not
required for male
participant.
 
This is a criterion for
administration of
immunosuppressants
and is not appropriate
for this study.
 
For clarity and
consistency 
6.1. 
Study 
Intervention 
Administered 
The following sentence is added: 
The method of administration (eg, spoon) must be 
recorded in the eCRF. 
To update
information based on
dispersible tablet
formulation (not
limited to spoons).
6.8. 
Concomitant 
Therapy 
Prohibited Concomitant 
Therapy 
The following sentence is added in strong inducers of 
CYP3A4 section: 
If they cannot be avoided, their administration should be 
delayed to after the visits where PK samples are collected 
and limited to not more than 4 consecutive weeks. 
To allow continued
administration of
macitentan in the
presence of strong
CYP3A4 inducers
but to avoid affecting

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
130
Status: Approved,  Date:  7 August 2023
Section number 
and Name
Description of Change 
Brief Rationale
PK measurements
6.8. 
Concomitant 
Therapy 
Prohibited Concomitant 
Therapy 
The sentence is changed as follows: 
The administration of ERAs and/or of any investigational 
drug after the first administration of study intervention must 
lead to permanent discontinuation of macitentan. The 
administration of any strong CYP3A4 inducer and/or any 
systemic administration of a strong CYP3A4 inhibitor as 
well as administration of moderate dual CYP3A4/ CYP2C9 
inhibitor or a combination of a moderate CYP3A4 and 
moderate CYP2C9 inhibitor must lead to interruption of 
macitentan 
To clarify the action
to be taken when any
investigational drug
is administered.
To allow continued
administration of
macitentan in the
presence of strong
CYP3A4 inducers
since low exposure to
macitentan is better
than no exposure.
7.1.1 Permanent 
Discontinuation 
The sentence is changed as follows: 
If a participant initiates treatment with ERAs and/or of any 
investigational drug 
For consistency with
the prohibited
concomitant therapy 
7.1.4. Hemoglobin 
Abnormalities 
The sentence is changed as follows: 
• A decrease in hemoglobin to < ≤80 g/L (< ≤4.9 mmol/L), 
• A decrease in hemoglobin from baseline* of > ≥50 g/L,
For clarity and
consistency
 
7.1.5. Start of a Strong 
CYP3A4 Inducer/Strong 
CYP3A4 Inhibitor 
The section title is changed: 
Start of a Strong CYP3A4 Inducer/Strong CYP3A4 Inhibitor 
/ Moderate Dual CYP3A4/CYP2C9 Inhibitors 
 
Removed description of a strong CYP3A4 inducers and the 
sentence is changed as follows: 
If any strong inhibitors of CYP3A4 are given, macitentan 
must be interrupted from first dose of strong CYP3A4 
inhibitor and until 4 weeks after the last dose of strong
CYP3A4 inhibitor.
To allow continued
administration of
macitentan in the
presence of strong
CYP3A4 inducers
since low exposure to
macitentan is better
than no exposure.
8. STUDY 
ASSESSMENTS AND 
PROCEDURES 
Table 2 
The frequency and volume of blood are changed as follows: 
 
No. of Samples per 
Participant 
Approximate 
Total Volume of 
Blood (mL) 
Hematology 
13 (for ≥ 2 years)  
12 (for < 2 years) 
15.6 
15.6 to 14.4
Serum 
Chemistry 
13 (for ≥ 2 years)  
16 (for < 2 years)  
15.6
19.2
Serum β hCG 
pregnancy 
tests 
1.8  
1.8
Loss by use of
indwelling
intra venous
cannula
20 to 19 (for < 2 years)
17 to 19 (for < 2 years)
20.0 to 19.0
17.0 to 19.0
Total blood volume is changed as follows:
63.6 to 60.8 (for participants aged ≥2 years)
59.1 to 61.7 (for participants aged <2 years)
 
10 μL sampler / ≥ 2 years: 53.76 to 50.96
10 μL sampler / < 2 years: 53.70 to 56.30
20 μL sampler / ≥ 2 years: 53.92 to 51.12
20 μL sampler / < 2 years: 53.80 to 56.40
To align with
exclusion criteria
To align with JNJ
requirements for liver
safety assessment.
(For children < 2
years, liver function
tests will be
performed monthly
during the study.)
8. STUDY
ASSESSMENTS AND
PROCEDURES
The sentence is changed as follows:
Sample patient diary
For clarity and
consistency

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
131
Status: Approved,  Date:  7 August 2023
Section number 
and Name
Description of Change 
Brief Rationale
Study-Specific Materials
8.3.4. Clinical Safety 
Laboratory Assessments 
 
(1.3. Schedule of 
Activities (SoA) Clinical 
Laborator y Tests) 
The following sentence is added: 
In all patients, laboratory tests must be monitored 
monthly for the first 6 months of study period and at 
each scheduled visit (every 12 weeks) until EOS. In
addition, for patients of < 2 years, liver tests must be
monitored monthly until EOS.
To align with JNJ
requirements for liver
safety assessment.
Amendment 2 (25 November 2021)
Overall Rationale for the Amendment: The main reason for this protocol amendment is to modify the
amount of blood collected and to add time points for blood collection in pediatric patients < 2 years. Minor
corrections and editorial revisions are also being implemented.
The updates are indicated in bold for new text and strike-through for deleted text in the following table.
Section number 
and Name
Description of Change 
Brief Rationale
1.1. Synopsis  
PHARMACOKINETIC 
EVALUATIONS 
SAFETY
EVALUATIONS 
 
The following sentence is added: 
The timepoints of blood collection will be determined by 
the age at the start of administration.
 
PK sampling time points for trough concentrations are 
changed as follows: 
For participants <2 years old, the blood samples will be 
drawn at the following timepoints: 2, 5, and 24 hours 
(before macitentan intake the next day) postdose on Day 1. A 
trough sample will be drawn at steady state (Visit 34 and
Visit 5).
 
The sentence is changed as follows: 
Serum chemistry, including sodium, potassium, chloride, 
glucose, aspartate aminotransferase (AST), alanine
aminotransferase (ALT), blood urea nitrogen (BUN), total
and direct bilirubin, alkaline phosphatase (AP), creatinine,
and calcium
For clarity and
consistency
 
 
To assess the intra-
subject variability of
trough concentrations
for participants <2
years old.
 
 
 
For clarity and
consistency
 
1.3. Schedule of 
Activities 
PK sampling time points for trough concentrations are 
changed as follows: 
j. At Day 1, the blood samples for the PK profiling must be 
drawn at the following timepoints: 2 h, 5 h, and 24 h 
(before macitentan intake the next day) postdose. A trough 
sample (ie, predose) will be drawn on Visit 34 and Visit 5.
Samples for PK assessment should be collected within 20%
deviation from the nominal sampling time.
 
The following abbreviations is deleted: 
 DNA=deoxyribose nucleic acid; 
To assess the intra
variability of trough
concentrations
for participants <2
years old.
 
 
 
 
For clarity and
consistency 
4.2.1. Study-Specific 
Ethical Design 
Considerations 
The sentence is changed as follows: 
The total blood volume (approximately 45 65 mL per 
participant will be collected through Week 52) to be 
collected. is considered to be an acceptable amount of blood
to be collected over this time period from the population in 
this study based upon the standard of the blood donation rule 
b y the Japanese Red Cross Society.
To align with revises
the amount of blood
volume
 
For clarity and
consistency
6.1. Stud y Intervention 
The followin  g sentence is added to footnote: 
Minor updates to

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
132
Status: Approved,  Date:  7 August 2023
Section number 
and Name
Description of Change 
Brief Rationale
Administered 
CSF (clinical service form) may be used depending on the 
results of the FMI stability study 
incorporate latest
information
8 STUDY 
ASSESSMENTS AND 
PROCEDURES 
Overview 
Sample Collection and
Handling
The sentence is changed as follows: 
 For each participant, the maximum amount of blood 
drawn from each participant in this study will not exceed 
133 65 mL.
 After blood sample collection, the cannula will be
flushed with 0.9% sodium chloride, United States
Pharmacopeia (USP) or sodium heparin of 10 U/mL and
charged with a volume equal to the dead space volume of
the lock.
To align with revises
the amount of blood
volume
 
For clarity and
consistency
Table 2 
The sentence is changed as follows: 
 Pharmacokinetic samples (if an indwelling intravenous 
cannula the regular venous blood sampling is used)
 
The following No. of Samples per Participant are changed 
 PK samples (<2 years); 4 to 5
 Loss by use of indwelling intravenous cannula; 1 to 20 
(≥2 years), 1 to 17 (<2 years)
 
Total blood volume is changed as follows: 
44.6 to 63.6 (for participants aged ≥2 years) 
42.6 to 59.1 (for participants aged <2 years) 
 
10 μL sampler / ≥ 2 years: 40.76 to 53.76 
10 μL sampler / < 2 years: 40.68 to 53.70
20 μL sampler / ≥ 2 years: 40.92 to 53.92
20 μL sampler / < 2 years: 40.76 to 53.80
For clarity and
consistency
 
 
Blood sampling time
points were added to
confirm intra-subject
variability.
 
 
Since an indwelling
intravenous cannula
is used for laboratory
tests, the amount of
blood lost was added.
8.3.2. Vital signs 
Blood pressure and heart rate measurements will be assessed 
in supine, sitting or standing positions with a completely 
automated device. Manual techniques will be used only if an
automated device is not available. In addition, throughout the
study BP is tried to be measured on the same arm and in the
same position (supine, sitting or standing sitting or supine),
using the same device by the same operator throughout the
stud y for an individual participant.
For clarity and
consistency
 
8.5. Quality of Life 
Assessments 
The following word is added: 
The QoL will be assessed for participants of ≥2 years of age 
at Day 1 (Visit 2).
For clarity and
consistency
 
8.6.1. Evaluations 
The following sentence is deleted: 
If 
 microsampling device
 is used, peripheral 
blood samples of approximately 0.02 mL or 0.04 mL is 
needed for blood concentrations of macitentan and 
aprocitentan. Peripheral blood samples will be collected via
patients’ finger.
 
The total of volume of blood samples are changed as 
follows: 
The total of volume of blood samples drawn for PK 
assessments would be 0.16 mL to 4.0 mL for participants 
aged ≥2 years and 0.080.10 mL to 2.02.5 mL for participants
aged <2 years (Refer to Section 8).
 
The followin  g sentence is added: 
To allow blood
collection
from other site than
fingers
 
 
 
To align the total
blood volume with
the PK sampling
point change
 
 
 
For clarit y and
CCI
CCI

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
133
Status: Approved,  Date:  7 August 2023
Section number 
and Name
Description of Change 
Brief Rationale
The timepoints of blood collection will be determined by 
the age at the start of administration.
 
PK sampling time points for trough concentrations are 
changed as follows: 
For participants <2 years old, the blood samples will be 
drawn at the following timepoints: 2, 5, and 24 hours 
(before macitentan intake the next day) postdose on Day 1. A 
trough sample will be drawn at steady state (Visit 34 and 
Visit 5).
consistency
 
 
To assess the intra-
subject variability
of trough
concentrations
for participants <2
years old.
8.6.2. Analytical 
Procedures  
Pharmacokinetics 
The sentence is changed as follows: 
If an indwelling intravenous cannula the regular venous 
blood sampling method is used, plasma samples will be
analyzed.
For clarity and
consistency
8.6.3. Pharmacokinetic 
Parameters and 
Evaluations 
PK sampling time points for trough concentrations are 
changed as follows: 
Subjects <2 years of age: 
 Steady StateAt Week 4 and Week 8 (steady state): 
Predose Macitentan and Aprocitentan concentrations 
To assess the intra-
subject variability of
trough concentrations
for participants <2
years old.
9.4.5. Safety Analyses 
Vital Signs 
The sentence is changed as follows: 
Vital signs including temperature, pulse/heart rate, 
respiratory rate, and blood pressure (systolic and diastolic)
(supine, sitting and or standing) will be summarized over
time, usin  g descriptive statistics and/or graphically.
For clarity and
consistency
10.12. Appendix 12: 
Study Conduct During a 
Natural Disaster 
STUDY VISITS 
The sentence is changed as follows: 
 Scheduled visits that cannot be conducted in person at the 
study site will be performed to the extent possible by
remote/virtually/flying nurse service/home visits.
Home nurse is not
allowed at this study
Amendment 1 (2 November 2021)
Overall Rationale for the Amendment: The reason for this protocol amendment is to clarify that the
treatment of PAH worsening is not limited to a specific drug, but within the scope of routine clinical practice.
The updates are indicated in bold for new text and strike-through for deleted text in the following table.
Section number 
and Name
Description of Change 
Brief Rationale
6.8.1. Rescue
Medication
Following text was modified:
 
‘In the presence of PAH-worsening, any PAH
specific treatment can be initiated per investigator’s
judgment. If a participant initiates treatment
with ERAs, study intervention (macitentan)
must be discontinued (refer to Section 7.1).’
 
‘In the presence of PAH worsening, any PAH
specific treatment (PDE5 inhibitor, riociguat,
prostanoid) can be initiated per investigator’s
judgment.’
The specific drug name was deleted
to clarify that it is within the scope
of usual care.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
134
Status: Approved,  Date:  7 August 2023
11. 
REFERENCES
Abman SH, Hansmann G, Archer SL, et al. Pediatric Pulmonary Hypertension: Guidelines From the American
Heart Association and American Thoracic Society. Circulation. 2015;132(21):2037-2099.
Adatia I Haworth SG, Wegner M, et al. Clinical trials in neonates and children: Report of the pulmonary
hypertension academic research consortium pediatric advisory committee. Pulm Circ. 2013;3(1):252-66.
Addendum to ICH E11: Clinical Investigation Of Medicinal Products In The Pediatric Population (R1) 2017.
Available from: https://database.ich.org/sites/default/files/E11 R1 Addendum.pdf. Accessed 14 July 2021.
Almeida SA, Kempinas WG, Lamano Carvalho TL. Sexual behavior and fertility of male rats submitted to
prolonged immobilization-induced stress. Braz J Med Biol Res 2000;33:1105-9.
ATS Statement: Guidelines for the Six-Minute Walk Test. Am J Respir Crit Care Med 2002;166:111-117.
Barst R. How has epoprostenol changed the outcome for patients with pulmonary arterial hypertension?
International Journal of Clinical Practice 2010;64:23-32.
Barst RJ, Ertel SI, Beghetti M, Ivy DD. Pulmonary arterial hypertension: a comparison between children and adults.
Eur Respir J. 2011;37(3):665-677.
Barst RJ, McGoon MD, Elliott CG, et al. Survival in Childhood Pulmonary Arterial Hypertension: Insights From the
Registry to Evaluate Early and Long-term PAH Disease Management. Circulation. 2012;125(1):113-122.
Bédard E, Dimopoulos K, Gatzoulis MA. Has there been any progress made on pregnancy outcomes among women
with pulmonary arterial hypertension? Eur Heart J. 2009;30(3):256-65.
Borg G. Psychophysical basis of perceived exertion. Medicine and Science in Sports and exercise. 1982;14(5):377-
381.
Borg G. Borg’s Perceived Exertion and Pain Scales. Champaign, IL: Human Kinetics, 1998.
Chakinala MM, Barst R. From short-term benefits to long-term outcomes: the evolution of clinical trials in
pulmonary arterial hypertension. Pulm Circ. 2013;3(3):507-522.
Cliff DP, Reilly JJ, Okely AD. Methodological considerations in using accelerometers to assess habitual physical
activity in children aged 0-5 years. J Sci Med Sport. 2009;12(5):557-67.
Clinical Study Report AC-055-115. A phase 1/1B, open-label study in patients with recurrent glioblastoma to assess
the safety and tolerability of macitentan in combination with dose-dense temozolomide. Actelion Pharmaceuticals
Ltd.4 (January 2017).
D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: results from a
national prospective registry. Annals of internal medicine 1991;115:343-9.
Del Cerro MJ, Abman S, Diaz G, et al. A consensus approach to the classification of pediatric pulmonary
hypertensive vascular disease: Report from the PVRI Pediatric Taskforce, Panama 2011. Pulmonary circulation
2011;1:286-98.
Douwes JM, Hegeman AK, van der Krieke MB, Roofthooft MT, Hillege HL, Berger RM. Six-Minute Walking
Distance and decrease in oxygen saturation during the six-minute walk test in pediatric pulmonary arterial
hypertension. Int J Cardiol. 2016 Jan 1;202:34-9. doi: 10.1016/j.ijcard.2015.08.155. Epub 2015 Aug 28.
Editorial Committee for Chronic Kidney Disease in Children Guide to the Diagnosis of Renal Impairment and
Assessment of Renal Function in Children (Editorial Committee for pediatric CKD). Chronic kidney disease in
children Guide to the Diagnosis of Renal Impairment and Assessment of Renal Function in Children. 2019.
Available from: http://www.jspn.jp/guideline/pdf/20191003 01.pdf . Accessed 13 October 2021.
EMA/CHMP/213972/2010. Paediatric addendum to CHMP guideline on the clinical investigations of medicinal
products for the treatment of pulmonary arterial hypertension. 5 December 2011.
Engelbregt MJ, van Weissenbruch MM, Popp-Snijders C, Delemarre-van de Waal HA. Delayed first cycle in
intrauterine growth-retarded and postnatally undernourished female rats: follicular growth and ovulation after
stimulation with pregnant mare serum gonadotropin at first cycle. J Endocrinol. 2002;173:297-304.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
135
Status: Approved,  Date:  7 August 2023
Food and Drug Administration Center for Drugs Evaluation Research, Center for Biologics Evaluation and
Research. Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 2009
Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the
Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology
(ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung
Transplantation (ISHLT). European heart journal 2009;30:2493-537.
Galiè N, Corris PA, Frost A, et al. Updated Treatment Algorithm of Pulmonary Arterial Hypertension. J Am Coll
Cardiol. 2013;62:D60-72.
Hansmann G, Arpitz C Abdul-Khaliq H, et al. Executive summary. Expert consensus statement on the diagnosis and
treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network,
endorsed by ISHLT and DGPK. Heart 2016;102 Suppl 2:ii86–100.
Hansmann G. Pulmonary hypertension in infants, children, and young adults. Journal of the American College of
Cardiology 2017;69:2551-2569.
Haworth SG, Hislop AA. Treatment and survival in children with pulmonary arterial hypertension: the UK
Pulmonary Hypertension Service for Children 2001–2006. Heart. 2009;95(4):312–317.
Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, Khanna D, et al. Definitions and diagnosis of pulmonary
hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D42-50.
Ivy DD, Abman SH, Barst RJ, Berger RM, Bonnet D, Fleming TR, et al. Pediatric pulmonary hypertension. J Am
Coll Cardiol. 2013;62(25 Suppl):D117-126.
Koukoulitaki SB, Manro JR, Marsh SA, et al. Developmental Expression of Human Hepatic CYP2C9 and
CYP2C19. J Pharmacol Exp Ther. 2004;308(3):965-74.
Lammers AE, Adatia I, del Cerro MJ, Diaz G, et al. Functional classification of pulmonary hypertension in children:
Report from the PVRI pediatric taskforce, Panama. 2011.
Macitentan IB Macitentan (ACT-064992) Investigator’s Brochure, Endothelin Receptor Antagonist, Non-oncology
Indications. Version 18, December 2020, and as updated.
McGuire MK, Littleton AW, Schulze KJ, Rasmussen KM. Pre- and postweaning food restrictions interact to
determine reproductive success and milk volume in rats. J Nutr. 1995;125:2400-2406.
McLaughlin VV, Badesch DB, Delcroix M, et al. End points and clinical trial design in pulmonary arterial
hypertension. Journal of the American College of Cardiology 2009;54:S97-S107.
Moledina S, Hislop AA, Foster H, Schulze-Neick I, Haworth SG. Childhood idiopathic pulmonary arterial
hypertension: a national cohort study. Heart. 2010;96:1401-1406.
Ollivier C, Sun H, Amchin W, et al. New strategies for the conduct of clinical trials in pediatric pulmonary arterial
hypertension: Outcome of a multistakeholder meeting with patients, academia, industry, and regulators, held at the
European Medicines Agency on Monday, June 12, 2017. Journal of the American Heart Association
2019;8:e011306.
Peacock AJ, Naeije R, Galiè N, Rubin L. End-points and clinical trial design in pulmonary arterial hypertension:
have we made progress? European Respiratory Journal 2009;34:231-242.
Peds QL™. Mapi Research Trust. Version 14; 2014 [updated March 2014; accessed on 1 July 2016]. Available
from: http://www.pedsql.org/PedsQL-Scoring.pdf.
Pugh ME, Buchowski MS, Robbins IM, Newman JH, Hemnes AR. Physical Activity Limitation as Measured by
Accelerometry in Pulmonary Hypertension. Chest. 2012;142(6):1391-1398.
Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial
hypertension. N engl j med 2013;369:809-818.
Robertson W, Stewart-Brown S, Wilcock E, Oldfield M, Thorogood M. Utility of Accelerometers to Measure
Physical Activity in Children Attending an Obesity Treatment Intervention. J Obes. 2011:1-8
Rodriguez F, Harrison RW, Wojdyla D, Mahaffey KW. Lost to Follow-up and Withdrawal of Consent in
Contemporary Global Cardiovascular Randomized Clinical Trials. Crit Pathways in Cardiol. 2015;14:150-153.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
136
Status: Approved,  Date:  7 August 2023
Rosenzweig EB, Abman SH, Adatia I, et al. Paediatric pulmonary arterial hypertension: updates on definition,
classification, diagnostics and management. Eur Respir J. 2019;53(1):pii:1801916.
Saji T (2018a), Nakanishi T, Yamada O, et al. Clinical Use of Pediatric Bosentan in Japanese Children with
Pulmonary Arterial Hypertension: Investigation of Efficacy, Pharmacokinetics, Safety, and Tolerability. Pediatric
Cardiology and Cardiac Surgery 2018;34(1):22-29.
Saji T (2018b), Yamada O, Doi S, Yamagishi H, Hatta M, Yokoyama Y. Results of a Clinical Trial to Determine the
Efficacy, Safety, and Tolerability of Intravenous Drip Infusion Therapy of a New Epoprostenol Formulation in
Japanese Children with Pulmonary Arterial Hypertension. Pediatric Cardiology and Cardiac Surgery
2018;34(1):30-38.
Saji T, Kadoma K, Shibata T, et al. Results of a nationwide survey on primary pulmonary hypertension in
childhood: A survey of patients eligible for lung transplantation (1st Report). (in Japanese) Journal of the Japanese
Circulation. 2000;16:230-237.
Salem F, Johnson TN, Abduljalil K, Tucker GT, Rostami-Hodjegan A. A re-evaluation and validation of ontogeny
functions for cytochrome P450 1A2 and 3A4 based on in vivo data. Clin Pharmacokinet. 2014;53:625-636.
Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary
hypertension: prognostic factors and survival. Journal of the American College of Cardiology 2002;40:780-788.
Tahara N, Dobashi H, Fukuda K, et al. Efficacy and safety of a novel endothelin receptor antagonist, macitentan, in
Japanese patients with pulmonary arterial hypertension. Circulation Journal 2016:CJ-15-1305.
Takatsuki S, Ivy DD. Current challenges in pediatric pulmonary hypertension. Semin Respir Crit Care Med.
2013;34(5):627-644.
Toxicology Written Summary Macitentan (ACT-064992). Actelion Pharmaceuticals Ltd. (14 September 2012).
Ulrich S, Fischler M, Speich R, Block KE. Wrist actigraphy predicts outcome in patients with pulmonary
hypertension. Respiration. 2013;86(1):45-51.
Van Cauwenberghe E, Gubbels J, De Bourdeaudhuij I, Cardon G. Feasibility and validity of accelerometer
measurements to assess physical activity in toddlers. Int J Behav Nutr Phys Act. 2011;8:67.
Van Loon RL, Van Loon RL, Roofthooft MT, et al. Outcome of pediatric patients with pulmonary arterial
hypertension in the era of new medical therapies. Am J Cardiol. 2010;106:117-124.
Zijlstra WM, Douwes JM, Rosenzweig EB, et al. Survival differences in pediatric pulmonary arterial hypertension:
clues to a better understanding of outcome and optimal treatment strategies. J Am Coll Cardiol. 2014;63(20):2159-
2169.

JNJ-67896062  Macitentan  
Clinical Protocol 67896062PAH3001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
137
Status: Approved,  Date:  7 August 2023
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: 
Janssen Pharmaceutical K.K.
Signature: 
electronic signature appended at the end of the protocol 
Date:
  
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the study, written notification will be
provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD

Signature
User 
Date 
Reason
07-Aug-2023
03:42:44
(GMT)
Document Approval
PPD