A Multicenter, Open-label, Randomized, Study With Single-arm Extension Period to Assess the Pharmacokinetics, Safety and Efficacy of Macitentan Versus Standard of Care in Children With Pulmonary Arterial Hypertension
Phase: PHASE3
Conditions: Pulmonary Arterial Hypertension
Sponsor: Actelion

Actelion Pharmaceuticals Ltd*
(a Janssen Pharmaceutical Company of Johnson & Johnson)
CONFIDENTIAL -FOIA Exemptions Apply in U.S.
Macitentan / ACT-064992/ JNJ-67896062
Pediatric PAH
Protocol AC-055-312
TOMORROW: pediaTric use OfMacitentan tO delay disease pRogRessiOn in
PAHWorldwide
A multicenter, open-label, randomized study with single-arm extension period to assess
the pharmacokinetics, safety and efficacy of macitentan versus standard of care in
children with pulmonary arterial hypertension
Study Phase: 
3
EudraCT Number: 
2016-001062-28
Status and version: 
Final Version 9
Date: 
23 November 2021
Document type: 
Amended Global Protocol
EDMS no & version: 
EDMS-RIM-264221, 4.0
*Actelion Pharmaceuticals Ltd (“Actelion”) is a global organization that operates through different legal
entities in various countries. Therefore, the legal entity acting as the Sponsor for Actelion studies may vary,
such as, but not limited to Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; or
Janssen Research & Development, LLC. The term “Sponsor” is used throughout the protocol to represent
these various legal entities; the Sponsor is identified on the Contact Information page that accompanies the
protocol.
Confidentiality statement
The information provided herein contains Company trade secrets, commercial or financial information that
the Company customarily holds close and treats as confidential. The information is being provided under the
assurance that the recipient will maintain the confidentiality of the information under applicable statutes,
regulations, rules, protective orders or otherwise.
NCT02932410

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SPONSOR CONTACT DETAILS
SPONSOR  
Actelion Pharmaceuticals Ltd*
Gewerbestrasse 16
CH-4123 Allschwil
Switzerland
+41 61 565 65 65
Clinical Trial Physician 
Contact details of the Clinical Trial Physician can
be found in the Investigator Site File
Medical Emergency Hotline 
Toll phone number: [number]
Site-specific toll telephone numbers and toll-free
numbers for the Medical Emergency Hotline can be
found in the Investigator Site File
* Actelion Pharmaceuticals Ltd. is a Janssen pharmaceutical company of Johnson &
Johnson and is hereafter referred to as the Sponsor of the study
CONTRIBUTORS TO THE PROTOCOL
Study Responsible Scientist 
Statistician -QS SDS  
Director CTSL -QS SDS  
Study Responsible Physician  
Associate 
Scientific 
Director 
Clinical Pharmacology
Director Medical Safety Officer 
PPD
PPD
PPD
PPD
PPD
PPD

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CONTRACT RESEARCH ORGANIZATIONS INFORMATION
CRO OUTSOURCED STUDY 
CONDUCT  
Pharmaceutical Product Development (PPD)
Global Ltd
Granta Park, Great Abington, Cambridge,
CB21 6GQ, United Kingdom
LABORATORY FOR 
PHARMACOKINETICS 
PRA Health Sciences, Amerikaweg 18, 9407 TK
Assen, Netherlands
STATISTICAL ANALYSIS  
Frontier Science (Scotland) Ltd, Grampian
View, Kincraig Inverness-shire, PH21 1NA,
Scotland
CENTRAL LABORATORY  
PPD Laboratories, Kleine Kloosterstraat 19,
B-1932 Zaventem, Belgium
CENTRAL RANDOMIZATION  Almac Clinical Technologies, 20 Seagoe
Industrial Estate Craigavon BT63 5UA, United
Kingdom
CENTRAL 
ECHOCARDIOGRAPHY 
PROCESSING
Perceptive Informatics, 2 Federal Street,
Billerica, MA 01821, USA
ACCELEROMETRY  
ActiGraph LLC, 49 East Chase Street,
Pensacola, FL 32502, USA
STUDY BRANDING  
Acurian, 2 Walnut Grove Dr., Suite 375,
Horsham, PA 19044, USA
SUBJECT RETENTION  
Exco InTouch, Unit 6, Wheatcroft Business
Park, Landmere Lane, Nottingham, NG12 4DG,
United Kingdom
COORDINATION OF 
BASELINE
CHARACTERISTICS
ADJUDICATION COMMITTEE
Refer to the Investigator Site File.
LAB SAMPLE COLLECTION 
AT SUBJECT’S HOME
Refer to the Investigator Site File.
A list of site-specific contact details for Contract Research Organizations (CROs) can be
found in the Investigator Site File.

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INVESTIGATOR SIGNATURE PAGE
Treatment name / number
Macitentan / ACT-064992 / JNJ-67896062
Indication
Pediatric pulmonary arterial hypertension
Protocol number, study acronym, study title
AC-055-312, TOMORROW; A multicenter, open-label, randomized, study with single-
arm extension period to assess the pharmacokinetics, safety and efficacy of macitentan
versus standard of care in children with pulmonary arterial hypertension
I agree to the terms and conditions relating to this study as defined in this protocol, the
electronic Case Report Form (eCRF), and any other protocol-related documents. I fully
understand that any changes instituted by the investigator(s) without previous agreement
with the Sponsor would constitute a protocol deviation, including any ancillary studies or
procedures performed on study subjects (other than those procedures necessary for the
wellbeing of the subjects).
I agree to conduct this study in accordance with the Declaration of Helsinki principles,
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines,
and applicable regulations and laws. I will obtain approval by an Independent Ethics
Committee or institutional review board(IEC/IRB) prior to study start and signed informed
consent from parent(s) / legally designated representative of all subjects included in this
study. Furthermore, I will obtain assent from developmentally capable children before
entering them into this study. For subjects who come of age during their participation in
this study I will obtain a separate consent. If an amendment to the protocol is necessary, I
will obtain approval by an IEC/IRB and ensure approval by regulatory authorities has been
obtained before the implementation of changes described in the amendment. If a protocol
amendment leads to a change to the ICF I will re-consent the parent(s) / legally designated
representative. I will allow direct access to source documents and study facilities to
Sponsor representative(s), particularly Clinical Research Associate(s) (CRA[s]) and
auditor(s), and agree to inspection by regulatory authorities or IEC/IRB representative(s).
I will ensure that the study treatment supplied by the Sponsor is being used only as
described in this protocol. I will ensure that all parents or legally designated representatives
have understood the nature, objectives, benefits, implications, risks and inconveniences for
participating in this study. During the conduct of the study, I will constantly monitor the
risk/benefit balance for an individual subject. I confirm herewith that the Sponsor is

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allowed to enter and utilize my professional contact details and function in an electronic
database for internal purposes and for submission to Health Authorities worldwide.
I participate in the Pharmacokinetics (PK) substudy:
I do not participate in the PK substudy:
Initial the option that applies.
Country  
Site 
number
Town 
Date 
Signature
Principal
Investigator

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 8, Version 9 
23-Nov-2021
COVID-19 Appendix (EDMS-RIM-265698, 5.0) 
16-Nov-2021
Amendment 7, Version 8 
25-Jan-2021
Amendment 6, Version 7** 
16-Sep-2020
COVID-19 Appendix (EDMS-RIM-265698, 4.0) 
17-Jun-2020
Amendment 3.1, Version 4.1 
17-Jul-2020
Amendment 5, Version 6* 
10-Jun-2020
Amendment 4, Version 5* 
20-Mar-2020
Amendment 3, Version 4 
13-Mar-2018
Amendment 2, Version 3 
25-Apr-2017
Amendment 1, Version 2 
13-Oct-2016
Original Protocol, Version 1 
01-Jul-2016
*Protocol Versions 5 and 6 were only submitted to US FDA as they were superseded by Version 4.1, which
was an urgent safety measure.
**Protocol Amendment 6 Version 7 submission was halted after submission to Health Authorities in Austria,
Canada, Portugal, and United States of America (USA), as it was superseded by Version 8.
Amendment 8 Version 9 (23 November 2021)
Overall Rationale for the Amendment:
The TOMORROW study was designed to enroll a sufficient number of children to observe at least
187 primary disease progression events. Given recruitment challenges and number of events
observed, the study design has been amended from an event-driven study to a pharmacokinetics
(PK), safety and efficacy study with a fixed study duration (calendar-driven analysis timepoints).
Furthermore, an open-label (OL) single-arm extension period (SAEP) which was planned as a
separate study protocol has been integrated into the present study protocol to allow seamless
transition of all subjects to macitentan treatment if this is considered in their best interest after the
last efficacy analysis (in 2024).
For these reasons, the following elements of the study have been amended:
 
The Core Period will continue until first quarter 2024 and study duration will therefore be
up to 7 years (considering first subject randomized in November 2017 as study started).
Based on current recruitment, it is anticipated to have approximately 200 subjects enrolled
by that time.

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 
The single-arm extension period (SAEP) will start seamlessly after the Core Period.
 The primary objective of the TOMORROW study will be to describe PK of macitentan in
pediatric patients with PAH.
 
The secondary objectives of the TOMORROW study will be the evaluation of safety and
efficacy of macitentan in pediatric pulmonary arterial hypertension (PAH) patients.
o Consequently, previous primary endpoint has been changed to a secondary
endpoint.
o In addition, exploratory efficacy endpoints related to World Health Organization
functional class (WHO FC), N-terminal-pro-brain natriuretic peptide (NT-
proBNP), echocardiography and physical activity have been changed to secondary
endpoints as described in the summary of changes table below.
o The totality of the secondary endpoints will be used to evaluate the efficacy of
macitentan in pediatric PAH.
In addition, the enrollment of the TOMORROW study has been extended to pediatric patients <
2 y.o. (i.e., age 1 month and older). The PK information collected in children ≥ 2 y.o. and adults
enabled the dose selection for children < 2 y.o. Due to the rarity of this population, only few subjects
< 2 y.o. are likely to be enrolled. Therefore, in order to assess macitentan in this population, they
will be enrolled as a cohort in the macitentan arm without randomization. The endothelin receptor
antagonist (ERA) cap and the exclusion criterion related to prior/concomitant use of macitentan at
Visit 2 will not apply to them either.
The continuation of the TOMORROW study will allow the evaluation of safety and efficacy of
macitentan in pediatric patients with PAH, and to characterize the pharmacokinetics of macitentan
in the pediatric population.
In addition, to the clinical formulation of the study drug macitentan (0.5 mg, 2.5 mg and 5 mg
dispersible tablets), the to-be-marketed image (1 mg and 2.5 mg dispersible tablets) has been
introduced. This formulation (called ‘final market image’or ‘FMI’) is also dispersible in water. A
change in the tablet image is necessary for future commercial use to ensure that the different dose
strengths of the pediatric dispersible formulation are easily distinguishable in order to minimize the
risk for future dosing errors. The FMI will replace the clinical formulation once sufficient stability
data is available and local approval, if applicable, has been obtained.
The summary of changes table for current amendment is provided below. The updates are indicated
in bold and deletions in strikethrough, wherever possible.

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Section Number 
and Name
Description of Change 
Brief Rationale
Title Page; 
Investigator Signature 
Page; 
Protocol Synopsis AC- 
055-312 (Design) 
Study title was revised as: 
‘A multicenter, open-label, 
randomized, event driven study with
single-arm extension period to assess
efficacy, safety and the
pharmacokinetics, safety and efficacy
of macitentan versus standard of care
in children with pulmonary arterial
hypertension’.
To align with modified study
design.
1.3. Purpose and Rationale 
of the Study ; 
3.2 Study Design
Rationale
Study rationale was revised. 
To align with modified study
design.
Protocol Synopsis AC- 
055-312 (Objectives); 
2.1 Primary Objective;
2.2 Secondary Objectives
Primary and secondary objectives were 
revised. 
To align with modified study
design.
Protocol Synopsis AC- 
055-312 (Design); 
3.1 Study Design  
 Text was added to indicate that the 
new cohort of children <2 y.o. will 
be assigned to macitentan group
without randomization.
 Information about two important 
milestones and 3 timepoints of 
study analysis which will be 
triggered by them was added.
 Text added to indicate that the
Cohort of children <2 y.o. may
additionally be analyzed.
 Additional information about study 
duration, safety follow-up and 
probable continuation in open-
label single-arm extension period
(SAEP) for each participating
subject was added.
 Text related to study conduct-
related activities outsourced to 
Contract Research Organizations
(CROs) was revised.
To assess macitentan in this
rare population.
To comply with different
requirements from Health
Authorities.
To align with modified study
design.

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Section Number 
and Name
Description of Change 
Brief Rationale
Protocol Synopsis AC- 
055-312 (Periods); 
3.1. Study Design  
 Text was added to indicate that for 
the cohort of children < 2 y.o., the 
screening period ends with 
confirmation of eligibility (i.e., 
age at Visit 2 is less than 2 years) 
and assignment of macitentan kit
at Visit 2, or with screening
failure.
 Content related to study period was 
revised as ‘Core Period’ which 
commences with Visit 2  and
continues until the end of Core
Period (EOCP) visit.
 Information about ‘Survival
Follow-up’ was revised.
 Definition of EOCP visit was
added.
 Definition of ‘Survival Follow-up’
was revised.
 Details for additional ‘ Single-arm
Extension Period (SAEP)’ were
added.
 Text corresponding to ‘Study
closure announcement’ was
deleted, wherever applicable.
 End of study (EOS) was redefined
to indicate that EOS will happen
at the end of SAEP.
 Also, information was updated to
include the eligibility of a subject
to participate in a post-trial access
(PTA) or long-term extension
(LTE) study and to clarify that
subjects entering PTA or LTE
study will not have a safety
follow-up call in TOMORROW
since their safety follow-up
continues in the respective PTA
or LTE study.
As the subjects < 2 y.o will not
be randomized and will be
assigned to macitentan arm to
assess macitentan in this rare
population.
To align with modified study
design.
To clarify the post-trial access
of macitentan and to clarify the
reporting of AEs/SAEs after
transitioning to post-trial access
program.
Protocol Synopsis AC- 
055-312 (Planned 
Duration); 
3.1. Study Design  
 Text was updated to indicate that 
the current study is a calendar- 
driven study and study duration 
depends on dates to meet
To indicate change in study
duration per modified study
design.

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Section Number 
and Name
Description of Change 
Brief Rationale
regulatory commitment and
individual study duration will be
based on the time of enrollment.
 Also, it was clarified that the
overall study duration (including
the Core Period and extension
period) will be a minimum of 7
years (from first subject screened
until last subject last EOS visit).
Protocol Synopsis AC-
055-312
(Subjects/Groups);
3.1. Study Design
 
Previous information related to
study sample size in terms of
number of subjects to observe 187
primary endpoint events (i.e., 300
subjects) was deleted and updated
with ‘Approximately 200
subjects and no more than 300
subjects will be enrolled in this
study based on feasibility.’
 
Cohort of children < 2 y.o. will not
be randomized but will directly
enter into the macitentan arm and
ERA cap does not apply to this
cohort.
To adjust as per new study
design.
To ensure that the data on
macitentan (and not on standard
of care [SOC]) is generated in
this rare subpopulation.
Protocol Synopsis AC-
055-312 (Inclusion
Criteria);
4.3. Inclusion Criteria
 
Inclusion criterion # 2 was updated
to include lower age limit as ≥1
month (instead of ≥2 years).
 
Inclusion criterion # 3 was updated
to include lower weight limit as ≥
3.5 kg (instead of ≥10 kg).
To enroll children <2 y.o. for
whom the daily macitentan dose
has been determined.
Protocol Synopsis AC-
055-312 (Exclusion
Criteria);
4.4. Exclusion Criteria
 
New exclusion criterion # 5 was
added to indicate that subjects with
known diagnosis of
bronchopulmonary dysplasia will
be excluded.
 
Following criteria were
renumbered.
 
Exclusion criterion # 8 is
applicable to only children with ≥
2 y.o.
To ensure that the infants
entering in current study are not
premature.
To clarify that children <2 y.o.
are allowed to enter on
macitentan.
Protocol Synopsis AC-
055-312 (Study
Treatments);
 
Text was updated to introduce the
FMI and clarify how it will replace
the clinical formulation.
To account for the new tablet
image and dose strengths
introduced. As the current

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Section Number 
and Name
Description of Change 
Brief Rationale
5.1.1. Investigational 
treatment: Macitentan- 
description and rationale; 
5.1.5. Macitentan 
administration 
 
A new table of number oftablets to 
be dispersed to attain a daily dose 
for the cohort ofchildren <2 y.o. 
was added. 
 
In addition to body weight, age of 
the subject will be verified every 
12 weeks and this information will
also be used for potential dose
adjustment.
 
Following statement was added:
‘In subjects < 2 years of age,
oral/ inhaled prostanoid 
treatment are also allowed as 
PAH-specific background
therapy in all study periods.’
clinical formulation does not
provide differentiation across
dose strengths a "to be
marketed image" (different size,
shape and deboss across dose
strengths) has been introduced.
To account for the dosing
regimen in children <2 y.o.
Protocol Synopsis AC- 
055-312 (Concomitant 
Therapy); 
5.2.4. Allowed 
concomitant therapy; 
5.2.5. Forbidden 
concomitant therapy; 
5.2.6. PAH treatment 
escalation  
 
Information about permitted 
concomitant medications during 
SAEP was added. 
 
Following statement was added: 
‘Concomitant use ofan ERA 
(e.g., bosentan, ambrisentan) 
with macitentan is forbidden
during entire study duration.’
 
Text added to indicate that that the 
use of macitentan is allowed only 
for participant of <2 y.o. during 
Screening and before study entry.
 
Forbidden concomitant 
medications to be prohibited to 
avoid drug-drug interactions (DDI) 
‘in the SAEP until EOS.’ This 
update was made, wherever 
applicable. 
 
Systemic administration of
moderate dual CYP3A4/CYP2C9
inhibitors alone or in combination
is additionally forbidden in the
SoC arm from 4 weeks before
crossing over to macitentan and
until EOM and in the SAEP until
EOS.
 
PAH treatment escalation to be
employed only in the presence of
To update information  and new
rules applicable to SAEP per
modified study design.
To clarify that concomitant
administration of 2 ERA
treatments is forbidden.
To clarify which medications
are allowed in the cohort <2
y.o.
To allow continued
administration of macitentan in
the presence of strong CYP3A4
inducers since low exposure to
macitentan is better than no
exposure.

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Section Number 
and Name
Description of Change 
Brief Rationale
disease progression defined per
protocol as per judgment of the
investigator.
 
Also, it is specified that ‘During
the SAEP, PAH treatment can be
escalated as per local practice.’
Protocol Synopsis AC-
055-312 (Endpoints);
6.1. Efficacy endpoints;
6.2. Safety endpoints
Primary, secondary and exploratory
efficacy endpoints were revised as
follows:
 
The pharmacokinetic (PK)
endpoints (same definition of PK
endpoints defined since Protocol
V1) have been updated as the
primary endpoints.
 
In addition to other secondary
endpoints, previous primary
endpoint (i.e., the time to Clinical
Event Committee [CEC]-
confirmed disease progression
events) has become a secondary
efficacy endpoint and retains the
same definition since Protocol V1.
 
The previous exploratory efficacy
endpoints N-terminal pro-brain
natriuretic peptide (NT-proBNP),
WHO FC, echocardiography,
accelerometry as well as the
quality of life (QoL) endpoint
related to Short Form (SF)-15 have
become secondary efficacy
endpoints.
 
Exploratory efficacy endpoints
were revised.
 
Additional safety endpoint of
‘AEs of special interest’ was
added in the existing list of the
safety endpoints. Also, it was
stated that ‘These endpoints are
assessed up to EOS.’(previously
mentioned as ‘up to randomized
macitentan or SOC + 30 days).
To align with modified study
design.

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Section Number 
and Name
Description of Change 
Brief Rationale
Protocol Synopsis AC- 
055-312 (Assessments) 
A reference to new tables (Table 2 and 
3 corresponding to ‘Visit and 
assessment schedule during Core 
Period for cohort of children <2 y.o.’
and ‘Visit and assessment schedule
during single-arm extension period’,
respectively) was added.
To align with modified study
design.(cohort of children <2
y.o. and SAEP).
Protocol Synopsis AC- 
055-312 (Statistical 
Methodology) 
 Analysis sets and statistical 
analyses for primary and 
secondary efficacy endpoints as
well as exploratory and
pharmacokinetic endpoints were
revised.
 New information about additional
PK sets was included.
 Text was added to indicate that the 
safety endpoints for the cohort of
children <2 y.o. will be
summarized separately.
To align with modified study
design.
Protocol Synopsis AC- 
055-312 (Study 
Committee); 
3.4. Study committees 
 Content corresponding to 
Independent Statistical Analysis 
Center (ISAC) was revised to
indicate that ISAC will no more
perform the formal analysis for
early efficacy or futility.
 Also, other statements were
updated as follows:
o ISAC will monitor, in
collaboration with the IDMC,
the number of primary
efficacy endpoint disease
progression events occurring
over time, in order to make
appropriate predictions for
Study Closure announcement
date.
o A Clinical Event Committee
(CEC), an independent
committee of PAH experts
(including pediatricians), will
review and adjudicate in a
blinded fashion the primary
secondary endpoints related
To align with modified study
design.

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Section Number 
and Name
Description of Change 
Brief Rationale
to disease progression of the
study according to the CEC
Charter.
o An independent BCAC will
centrally review and confirm
eligibility of subjects with co-
incidental congenital heart
disease before their
randomization (before
macitentan start for children
< 2 y.o.)as described in the
BCAC Charter.
Protocol Synopsis AC-
055-312 (PK Substudy)
It was clarified that the modeling and
simulation were performed based on
the PK data from pediatric subjects
older than 2 years and adults to
select the appropriate daily dose in
subjects below 2 years of age.
To provide background
information used for selection
of appropriate daily dose for
subjects <2 y.o.
Protocol Synopsis AC-
055-312 (Study
Extension);
3.1. Study Design
Study extension-related content was
deleted.
As the study design has been
revised to include SAEP, this
content is not applicable
anymore.
Protocol Synopsis AC-
055-312 (Table 1)
 
Table 1’s heading was revised as:
‘Visit and assessment schedule
during Core Period for subjects
≥ 2 years of age’.
 
Content of the table was revised to
include new details of EOCP and
analysis 1 and 2 cut-off dates.
To align with modified study
design.
Protocol Synopsis AC-
055-312 (Table 2 and 3)
New tables (Table 2 and 3)
corresponding to visit and assessment
schedule for cohort of children < 2 y.o.
during Core Period and SAEP were
added.  Also, accordingly subsequent
table numbers were updated.
To include information about
visit and assessment schedule
per modified study design.
1.2.2. Benefit-risk
Assessment for
Participation in This
Clinical Trial
 
Following statement was deleted: ‘
Children of at least 2 years of age
and adolescents are at a more
advanced developmental stage
compared to suckling juvenile
rats.’
Since study has been amended
to allow enrollment of children
<2 y.o.

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Section Number 
and Name
Description of Change 
Brief Rationale
 
Section was updated with
information corresponding to
background and rationale for
including pediatric population < 2
years of age and proposed
macitentan dosing regimen to be
used in these pediatric subjects.
3.1. Study Design  
(PK assessment for 
Subjects < 2 y.o.) 
New content was added to indicate that  
all subjects <2 y.o. receiving 
macitentan will have PK assessments 
and this subpopulation PK analysis 
will be reported separately. Additional
information about sampling and data
analysis is also included.
To allow adequate
characterization of macitentan
PK and dose regimen in this age
cohort.
3.1. Study Design  
(Figure 1) 
Figure 1 and underlying abbreviations 
and footnotes were revised to 
implement information about Core
Period, EOCP, SAEP and EOS-related
updates.
To align with modified study
design.
3.2. Study Design 
Rationale 
Added information about rationales for 
revisions made to previous study 
design. 
To provide appropriate
justifications for implemented
revisions.
Added information about Sponsor 
representatives who are completely or 
partially blinded to study results.
To provide brief details about
the content of Firewall Charter.
4.1. Subject Population 
Description; 
 Study population age range was 
revised as ≥1 month to < 18 
years (from previous range of ≥2
years to <18 years).
 Following statement was added:
‘Cohort < 2 y.o. is allowed to enter
on macitentan.’
To allow enrollment of children
<2 y.o.
4.5.2. Acceptable Methods 
of Contraception  
Following statement was added: 
‘Subjects in the SoC group who 
initiate macitentan study treatment 
(i.e., at Cross-over or at EOCP) 
must use either Option 1, 2 or 3.’
To clarify methods of
contraceptions, the female
subjects from SoC group must
opt for after cross-over/EOCP.
5.1.1. Investigational 
Treatment: Macitentan - 
Description and Rationale 
 Added information about PK 
profile assessment in the cohort of 
children <2 y.o.
 Added following statement:
To provide instructions for the
new cohort of children <2 y.o.

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‘After EOCP (i.e., during SAEP)
those medications can be
initiated at any time.’
To indicate that the forbidden
PAH medications (PDE5i,
ERA, prostanoid) can be
initiated during SAEP for the
new cohort of children < 2 y.o.
5.1.3.Treatment
Assignment
Added information about treatment
assignment for the cohort of children <
2 y.o.
To provide instructions for the
new cohort of children < 2 y.o.
5.1.5. Macitentan
Administration
It was clarified that the macitentan will
be administered after dispersion of
tablets in water for all subjects.
To update information based on
new dispersible tablet
formulation.
Following text was added:
‘For cohort of children < 2 y.o., the
parent(s) / legally designated
representative is instructed not to
administer macitentan at Week 4
and Week 8 visits until the pre-dose
PK sample has been collected.’
For appropriate collection of
pre-dose PK sample in this
study population.
5.1.6.3. Macitentan
Dispensing
Statement was revised as follows:
‘The subjects will receive enough
macitentan to cover the period up to
the next scheduled 12-weekly visit
(i.e., excluding Visit 3 for PK) during
Core Period, or 24-weekly visit
during SAEP, respectively.’
To ensure that subject receives
enough macitentan till EOT.
5.1.8. Macitentan dose
adjustments and
interruptions
Statement was revised as follows:
‘Macitentan dose adjustments other
than for change in age category for
subjects of < 2 y.o. and for weight
category for subjects at least 2 y.o.
are not permitted.’
To provide instructions for the
new cohort of children < 2 y.o.
5.1.9. Macitentan:
Premature Discontinuation
of Study Treatment
Section was updated to include
information about ‘premature
discontinuation during Core Period’
and to indicate that the vital status will
be collected  at least yearly (i.e.,
survival FU) until the cutoff date for
Analysis 2.
To align with modified study
design.
6.3. Quality of Life
endpoints
 
Quality of life endpoints will be
assessed only in English-speaking
To align with modified study
design.

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Section Number 
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Brief Rationale
subjects in the USA, up to end of
randomized macitentan or SoC+
7 days.
 
Assessment using PedsQLTM4.0 
Generic Core Scale Short Form 
(SF15), was deleted from this 
section. 
 
Following text was added: 
‘For the cohort of children < 2 y.o., 
this questionnaire is not available.’
Per revised study design, this
endpoint is considered as a
secondary endpoint and
included in respective section.
Not applicable to this specific
study population.
6.4. Other 
Pharmacokinetic 
Endpoints 
Content of the section was updated. 
To align with modified study
design. Trough PK has become
primary endpoint.
7.3. Efficacy Assessments 
Statement referring to Sections 6.1.1 
and 6.1.2 was deleted. 
No longer applicable due to
revision of primary and
secondary endpoints.
7.3.5. 6-minute Walk Test 
Following statement was revised as: 
‘The 6-minute walk distance (6MWD) 
will be assessed in subjects ≥6 years of 
age who understand and are able to 
perform the test correctly [Douwes
2015, Takatsuki 2013b] and who can
perform the test per protocol at
randomization.’
To clarify that this test will only
be done if baseline
(Randomization/ Visit 2)
6MWD can be done.
7.4.3. Physical 
Examination 
Following statement was added to 
existing text: ‘During SAEP, the 
physical examination will only be 
documented in the subject's medical 
chart and not in the eCRF.
Abnormal observations must be
reported in the AE pages of the
eCRF.’
To provide appropriate
guidance for documentation of
information related to physical
examination during SAEP.
7.4.5.1. Type of 
Laboratory  
Following statement was added to 
existing text: ‘For monthly liver and 
hemoglobin/hematocrit tests, a local 
laboratory may be used if normal 
ranges are available for the given
age group of the subject. Respective
local laboratory results, will be
entered into the eCRF together with
the respective normal ranges.’
To allow for use of local
laboratory for monthly liver and
hemoglobin/hematocrit tests
under specific circumstances.

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Section Number 
and Name
Description of Change 
Brief Rationale
7.4.5.2. Laboratory Tests 
 Following statement was added to 
existing text: ‘In subjects < 2 
y.o., liver tests must be
monitored monthly for the first
12 months of study period and
at each scheduled visit (every
12 weeks) thereafter until
EOS.’
 Statement was revised to indicate 
that hemoglobin and hematocrit 
and liver aminotransferase 
s(AST/ALT) levels must be
monitored monthly for the first 6
months of macitentan treatment
and every 12 weeks thereafter.
To align with JNJ requirements
for liver safety assessment.
To aid in deciding the
interruption of macitentan study
treatment.
7.5. Palatability and 
Acceptability of 
Macitentan Drug 
Formulation  
Following statement was revised as: 
‘The site study personnel will record 
the score and the method of 
administration (e.g., spoon) in the
eCRF.’
To capture additional data about
method of study intervention
administration.
7.6. Quality of Life 
Assessments 
Following statement was added to 
existing text: ‘Below that age the 
selected questionnaires are 
developmentally not appropriate
and are thus not collected.’
To indicate why QoL
questionnaires are not collected
for subjects < 2 years of age.
7.7.1. Timing for PK 
Sampling 
Text was updated as follows:
‘In all subjects who are 2 y.o. and 
older randomized to macitentan and 
receiving macitentan, a trough sample 
(i.e., pre-dose) will be drawn on Visit 4
(Week 12) for PK assessments.’
‘In subjects younger than 2 y.o., 
samples will be drawn at 2h, 5h, and 
24h after the first macitentan dose at 
Visit 2. Trough samples (i.e., pre-
dose) will be drawn on Week 4 and 8
(refer to 7.7.2 Procedures for
sampling for details).’
To specify that the substudy
only applies to subjects at least
2 years-old.
To introduce age-appropriate
PK sampling for children < 2
y.o.

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Section Number 
and Name
Description of Change 
Brief Rationale
7.7.2. Procedures for 
Sampling 
New instructions for PK sampling in
age cohort < 2 years of age were
introduced.
Detailed instructions on sample 
manipulation were deleted.
To introduce age-appropriate
PK sampling for children < 2
y.o.
To avoid duplicating
instructions available in the
laboratory manual.
7.7.3. Labeling; 
7.7.5. Shipping procedures 
(previous sections) 
These subsections were deleted and 
other subsections were renumbered 
accordingly. 
As the information will be
updated in central lab document
and not in the protocol, to allow
more flexible information
recording.
7.7.3. Bioanalysis 
Section was revised. 
To update information.
7.7.4. Total blood volume 
Section was revised. 
To update information.
8. Schedule of Visits 
Following text was added: ‘During 
the SAEP unscheduled visits are not 
recorded in the eCRF but (S)AE are
reported, if applicable.’
To indicate that SAEs must be
reported in SAEP.
8.1. Screening / Visit 1 
Following text was added: ‘ For the 
cohort of children < 2 y.o. screening 
ends with confirmation of eligibility 
and assignment of macitentan kit at
Visit 2, or with screening failure.’
To provide information about
screening completion for the
cohort of children < 2 y.o.
8.2. Randomization / Visit 
2 (Day 1) 
A new assessment was added: ‘ for 
children < 2 y.o.: PK samples at 2h, 
5h, and 24h after the first
macitentan dose’.
To provide information about
the cohort of children < 2 y.o.
Following text was added: ‘For
subjects < 2 y.o. age will be used by
IRT system to calculate the daily
dose of macitentan.’
Following text was added:
‘For subjects < 2 years of age at
Visit 2:
For PK assessment, approximately
1.7 mL of blood (including dried
blood samples via Neoteryx MitraTM
device where the use of this sampler
is allowed per local requirements)
are collected at 3 timepoints after

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Brief Rationale
the first dose of macitentan as
described in Section 7.7.1.’
8.3. PK Visits at Week 4 
and Week 8 for Subjects < 
2 Years of Age 
New section added. Following 
subsections were renumbered 
To account for the extra visits
in children <2 y.o. for PK
sample collection.
8.10. Cross-over Visit 
A new eligibility criteria for severe 
liver injury and severe renal 
impairment was added to determine 
eligibility of a subject to cross-over to
macitentan treatment.
To account for all safety
eligibility criteria relevant for
macitentan treatment.
8.11. Unscheduled Visits 
Following text was added: ‘During 
SAEP, the only data collected and 
reported as part of an unscheduled 
visit are (S)AEs and if applicable 
laboratory re-tests as requested in
Section 5.1.10.’
To indicate that only AE-SAE-
related safety data will be
collected on unscheduled visit
in SAEP.
8.13. End of Core Period 
(EOCP); 
8.14. Single-arm Extension 
Period (SAEP) 
New sections were added to include 
relevant information about 
corresponding study visits.
Following subsections were
renumbered.
To align with modified study
design.
8.15. End of Study  
Section was revised. 
To align with modified study
design.
8.16. Safety Follow-up; 
9.4. 
Medical Care of 
Subjects After Study 
Completion/Withdrawal 
from Study
Section was revised to clarify about 
safety follow-up procedure in case of
subjects who will be transitioned to
PTA or LTE study by Janssen.
For clarification.
8.17. Survival Follow-up 
Timepoints for collection of survival 
follow-up data before Analysis 1 and 2 
was clarified.
To account for modified study
design.
9.1. Study Completion 
Content was revised as follows: 
‘The clinical database, the CEC 
database, and the central laboratory
databases are is locked after all data
collected up to last subject last
visit/contact have been collected and
are considered accurate.
Subjects who are already in screening
at announcement of Study Closure will
be handled as screening failure.’
To align with modified study
design.

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Section Number 
and Name
Description of Change 
Brief Rationale
9.2. Premature withdrawal 
from study, premature 
study visit discontinuation
The term ‘study closure’ was replaced 
with ‘EOCP’, wherever applicable. 
New content about ‘ Premature study
discontinuation during Single-Arm
Extension Period’ was added. 
To align with modified study
design.
To give instructions for the new
study period.
10.1.4. Reporting of 
Adverse Events; 
10.2.2. Reporting of 
Serious Adverse Events; 
10.3.1. Reporting of 
Pregnancy  
Following statement was added: 
‘Subjects who enter a PTA or LTE 
study at EOS will be waived from 
the safety follow-up call since they 
will be monitored in the respective
PTA or LTE study.’
To avoid double safety
reporting for subjects who will
be transitioned to continued
access program.
10.1.4. Reporting of 
Adverse Events 
Following statement was added: 
‘Single-Arm Extension Period: 
During SAEP all exacerbations of
underlying disease will be reported
on the AE form.’
To give instructions for the new
study period.
10.2.2. Reporting of 
Serious Adverse Events 
Following statement was added: 
‘During the SAEP disease 
progression events will be reported
in the AE section of the eCRF and, if
classified as "serious," on an SAE
form.’
To give instructions for the new
study period.
10.2.3. Follow-up of 
Serious Adverse Events; 
10.2.4. After the Study 
Period and Safety Follow- 
up Period; 
10.2.5. Reporting
Procedures
Content was added to indicate that 
during SAEP the investigator will 
report all SAEs directly to the
Sponsor within 24 hours of their
knowledge.
To give instructions for the new
study period.
10.2.5. Reporting 
Procedures 
Content was amended as follows:
 ‘The SAE forms must be sent to
the CRO during Core Period
(contact details are provided on
the SAE form), while they will
be sent directly to the Sponsor
during SAEP.’
 ‘The CRO personnel (or Sponsor
personnel during SAEP) may
contact the investigator to obtain
further information as instructed
by the Sponsor.’
To give instructions for the
new study period.

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Brief Rationale
10.3.1. Reporting of 
Pregnancy; 
10.3.2. Follow-up of 
Pregnancy  
Content was updated with following 
details: 
 ‘Any pregnancy must be followed
up to its conclusion and the
outcome must be reported to the
CRO on the applicable
pregnancy notification form.
 During SAEP the pregnancy is 
reported directly to the 
Sponsor.’
To account for new pregnancy
forms used by the Sponsor.
To give instructions for the new
study period.
11. Statistical Methods 
Content was deleted from here and 
moved to Section 3.2: 
‘The Sponsor representatives preparing
and reviewing the Statistical Analysis
Plan (SAP) for the Randomized Period
will remain blinded until the Analysis
1 results are available.’
To align with modified study
design.
11.1.2. Full Analysis Set 
Information about FAS2 and FAS3
was included.
11.1.3. Per Protocol Set 
Section was deleted and following
sections were renumbered.
11.1.4. Pharmacokinetic 
Analysis Sets 
New PK analysis sets were added. 
To cover the age cohort of
children < 2 y.o.
11.1.5. Usage of the 
Analysis Sets 
Use of analysis sets were further 
specified. 
Statement related to per protocol set 
(PPS) was deleted. 
To cover analysis of cohort of
children < 2 y.o. and new study
periods.
To align with modified study
design.
11.2.1. Primary Efficacy 
Variable 
Section was renamed (previously 
‘Primary efficacy variable’) and 
updated with relevant information
about new primary variable.
To align with modified study
design.
11.2.2. Secondary Efficacy 
Variables 
A new secondary efficacy variable 
‘Time to first CEC-confirmed disease 
progression’ was added. Also, few
exploratory variables which are now
considered as secondary variables per
modified study design, were moved in
this section.
To align with modified study
design.

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Brief Rationale
11.2.3. Exploratory 
Variables; 
11.2.4. Safety Variables;
11.2.5. Quality of Life at
Each Timepoint of
Assessment;
11.2.6. Pharmacokinetic
Variables
Sections were updated. 
To align with modified study
design.
11.3. Description of 
Statistical Analyses 
Subsection on overall testing strategy 
was deleted and next subsection was 
renumbered.
To align with modified study
design.
11.3.1. Analysis of the 
Primary Variable 
Section was revised to include updates 
of new primary variable. 
To align with modified study
design.
11.3.2. Analysis of the 
Time to Event Secondary 
Efficacy Variables 
A new Section 11.3.2 was added to
include information about main,
supportive and subgroup analyses and
handling of missing data for ‘time to
event secondary efficacy variables.’
11.3.3. Other Secondary 
Efficacy Variables 
A new section was added to include 
additional revised secondary efficacy 
variables.
To align with modified study
design.
11.3.4. Analysis of the 
Exploratory Variables 
Subsections 11.3.4.1 (WHO FC I or
II), 11.3.4.2 (Percent of Baseline in
plasma NT-proBNP), 11.3.4.4
(Physical activity) and 11.3.4.5
(Echocardiography variables) were
moved to Section 11.3.3 (Other
secondary efficacy variables) and
remaining subsections were
renumbered.
11.3.5.1. Adverse Events ; 
11.3.5.2. Laboratory 
Variables
Updated information about analysis of
safety variables for SAEP.
11.4. Interim Analysis 
Section was revised to include new
timepoints of study analysis and
content related to ‘group sequential
design’ and Table 5 was deleted.
11.5. Sample Size 
All subsections (Section 11.5.1 to
11.5.5, including Tables 6 to 9) were
deleted and following statement was
added:

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Section Number 
and Name
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Brief Rationale
‘The sample size of approximately
200 subjects and not more than 300
subjects is driven by feasibility and
no formal sample size calculations
are provided. The study recruitment
will be closed by Q4 2023 to allow at
least 12 weeks study follow-up for
Analysis 2 in Q1 2024. Analysis 1
and 2 are driven by the regulatory
timelines.’
12.1. Data Collection 
Content was updated to indicate that
the third party (CRO) will carry out the
data management and the Sponsor will
work with the CRO following a
detailed oversight plan to ensure that
oversight of quality is maintained.
To avoid repetition in the
protocol document.
12.3. Database 
Management and Quality 
Control
Unnecessary information was deleted
and the text was revised.
Since data hand over is
governed by contractual
agreement between Sponsor
and CRO and not by the
protocol; to improve the clarity.
13.3. Informed Consent 
Following statement was added:
‘If the female partner of a male
participant becomes pregnant, an
informed consent will be obtained
prior collecting the information on
pregnancy. For pregnant partners
who are not yet of legal age, the
consent will be obtained from
parent(s)/ legally designated
representative and assent will be
obtained from the partner.’
To provide information about
obtaining an informed
consent/assent form in case of
pregnancy.
14. References 
List of references was updated with 2
new references and corresponding
references are cited in main protocol,
wherever applicable.
To provide supporting
information.
Throughout the protocol 
 
The term ‘event-driven’ was either
deleted or replaced with ‘calendar-
driven,’ wherever applicable.
 
‘previous EOS was replaced with
‘EOCP (last visit with efficacy
assessment),’ wherever applicable
For clarity and consistency;
minor errors were noted.

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Section Number 
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Brief Rationale
and new EOS was introduced (last
visit of SAEP).
 
‘Primary Endpoint Event’ was
replaced with ‘per protocol disease
progression’.
 
Minor corrections and editorial
revisions were made.

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TABLE OF CONTENTS
SPONSOR CONTACT DETAILS......................................................................................2
CONTRIBUTORS TO THE PROTOCOL..........................................................................2
CONTRACT RESEARCH ORGANIZATIONS INFORMATION ...................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE................................6
TABLE OF CONTENTS...................................................................................................26
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................34
PROTOCOL SYNOPSIS AC-055-312 .............................................................................38
1 BACKGROUND.........................................................................................................69
1.1 
Indication......................................................................................................69
1.1.1 
Definition and Diagnosis ..................................................................69
1.1.2 
Classification ....................................................................................69
1.1.3 
Epidemiology....................................................................................70
1.1.4 
Current Treatment and Unmet Clinical Need...................................70
1.2 
Study Treatment(s) .......................................................................................71
1.2.1 
Macitentan ........................................................................................71
Mechanism of Action..............................................................71
Pharmacokinetics and Metabolism..........................................72
Efficacy in Adult Patients With Pulmonary Arterial
Hypertension ...........................................................................73
Nonclinical Safety Data...........................................................73
Clinical Safety in Adults .........................................................74
1.2.2 
Benefit-risk Assessment for Participation in This Clinical Trial......75
1.2.3 
Standard of Care ...............................................................................77
Endothelin Receptor Antagonists............................................77
Phosphodiesterase-5 Inhibitors................................................79
Prostanoids ..............................................................................80
1.3 
Purpose and Rationale of the Study..............................................................80
2 STUDY OBJECTIVES...............................................................................................81
2.1 
Primary Objective.........................................................................................81

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2.2 
Secondary Objectives ...................................................................................81
3 
OVERALL STUDY DESIGN AND PLAN ...............................................................81
3.1 
Study Design.................................................................................................81
3.2 
Study Design Rationale ................................................................................88
3.3 
Site Personnel and Their Roles.....................................................................89
3.4 
Study Committees.........................................................................................90
4 SUBJECT POPULATION..........................................................................................91
4.1 
Subject Population Description....................................................................91
4.2 
Rationale for the Selection of the Study Population.....................................91
4.3 
Inclusion Criteria..........................................................................................92
4.4 
Exclusion Criteria.........................................................................................93
4.5 
Criteria for Female Subjects of Childbearing Potential................................94
4.5.1 
Definition of Childbearing Potential.................................................94
4.5.2 
Acceptable Methods of Contraception .............................................95
4.6 
Medical History............................................................................................97
5 TREATMENTS ..........................................................................................................97
5.1 
Study Treatment ...........................................................................................97
5.1.1 
Investigational Treatment: Macitentan -Description and
Rationale...........................................................................................97
5.1.2 
Comparator: Standard of Care -Description and Rationale.............99
5.1.3 
Treatment Assignment....................................................................100
5.1.4 
Blinding ..........................................................................................100
5.1.5 
Macitentan Administration.............................................................101
5.1.6 
Macitentan Supply..........................................................................102
Macitentan Packaging and Labeling .....................................102
Macitentan Distribution and Storage.....................................102
Macitentan Dispensing..........................................................102
Macitentan Return and Destruction.......................................103
5.1.7 
Macitentan Accountability and Compliance With Macitentan
Study Treatment..............................................................................103
Macitentan Drug Accountability...........................................103
Macitentan Compliance.........................................................103
5.1.8 
Macitentan Dose Adjustments and Interruptions............................104
5.1.9 
Macitentan: Premature Discontinuation of Study Treatment.........104

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5.1.10 
Study-specific Criteria for Interruption / Premature
Discontinuation of Macitentan Study Treatment............................105
5.2 
Previous and Concomitant Therapy ...........................................................108
5.2.1 
Definitions ......................................................................................108
5.2.2 
Reporting of Previous/Concomitant Therapy in the ECRF............108
5.2.3 
Mandatory Concomitant Therapy...................................................109
5.2.4 
Allowed Concomitant Therapy.......................................................109
5.2.5 
Forbidden concomitant therapy......................................................110
5.2.6 
PAH Treatment Escalation .............................................................112
6 STUDY ENDPOINTS ..............................................................................................112
6.1 
Efficacy Endpoints .....................................................................................112
6.1.1 
Primary Endpoint............................................................................112
6.1.2 
Secondary efficacy endpoints.........................................................112
Time to First CEC-confirmed Disease Progression..............112
Other Secondary Endpoints...................................................113
6.1.3 
Exploratory Endpoints....................................................................114
6.2 
Safety Endpoints.........................................................................................114
6.3 
Other Quality of Life Endpoints.................................................................115
6.4 
Other Pharmacokinetic Endpoints..............................................................115
6.5 
Drug formulation endpoint.........................................................................116
7 STUDY ASSESSMENTS.........................................................................................116
7.1 
Screening/Baseline Assessments................................................................117
7.1.1 
Baseline Demographics ..................................................................118
7.1.2 
Baseline Disease Characteristics ....................................................118
7.2 
Previous/Concomitant Therapy..................................................................118
7.3 
Efficacy assessments ..................................................................................118
7.3.1 
Monitoring of Disease Progression.................................................119
Signs and Symptoms of PAH................................................119
Functional Class ....................................................................119
7.3.2 
NT-proBNP.....................................................................................119
7.3.3 
Echocardiography...........................................................................120
7.3.4 
Physical Activity.............................................................................120
7.3.5 
6-minute walk test...........................................................................121
7.4 
Safety Assessments.....................................................................................121
7.4.1 
Vital Signs.......................................................................................122
7.4.2 
Weight and Height/Length..............................................................122

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7.4.3 
Physical Examination .....................................................................122
7.4.4 
Tanner Stage ...................................................................................123
7.4.5 
Laboratory Assessments .................................................................123
Type of Laboratory................................................................123
Laboratory Tests....................................................................125
7.5 
Palatability and Acceptability of Macitentan Drug Formulation ...............127
7.6 
Quality of Life Assessments.......................................................................127
7.7 
Pharmacokinetic Assessments....................................................................129
7.7.1 
Timing for PK Sampling.................................................................129
7.7.2 
Procedures for Sampling.................................................................129
7.7.3 
Bioanalysis......................................................................................129
7.7.4 
3-Total Blood Volume....................................................................130
8 SCHEDULE OF VISITS ..........................................................................................130
8.1 
Screening / Visit 1 ......................................................................................130
8.2 
Randomization / Visit 2 (Day 1).................................................................132
8.3 
PK Visits at Week 4 and Week 8 for Subjects < 2 y.o...............................134
8.4 
PK Substudy / Visit 3 for Subjects ≥2 y.o. on Macitentan/ Visit 3 ...........134
8.5 
Treatment Visits / Visit 4 (Week 12)..........................................................135
8.6 
Treatment Visits / Visit 5 (Week 24)..........................................................137
8.7 
Treatment Visits / Visit 6 (Week 36), Visit 7 (Week 48)...........................138
8.8 
Treatment Visits / Visit 8 (Week 60), Visit 9 (Week 72), etc. ...................139
8.9 
Visit for a Disease Progression Event ........................................................140
8.10 
Cross-over Visit..........................................................................................142
8.11 
Unscheduled Visits.....................................................................................143
8.12 
End of Macitentan (EOM)..........................................................................144
8.13 
End of Core Period (EOCP) .......................................................................145
8.14 
Single-arm Extension Period (SAEP).........................................................147
8.15 
End of Study...............................................................................................147
8.16 
Safety follow-up .........................................................................................148
8.17 
Survival Follow-up.....................................................................................148
9 STUDY COMPLETION AND POST-STUDY TREATMENT/MEDICAL
CARE ........................................................................................................................149
9.1 
Study Completion.......................................................................................149
9.2 
Premature Withdrawal from Study, Premature Study Visit
Discontinuation...........................................................................................149
9.3 
Premature Termination or Suspension of the Study...................................150

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9.4 
Medical Care of Subjects After Study Completion/Withdrawal from
Study...........................................................................................................151
10 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS.........................152
10.1 
Adverse Events...........................................................................................152
10.1.1 
Definition of Adverse Events .........................................................152
10.1.2 
Intensity of Adverse Events............................................................153
10.1.3 
Relationship to Study Treatment ....................................................154
10.1.4 
Reporting of Adverse Events..........................................................154
10.1.5 
Follow-up of Adverse Events .........................................................154
10.2 
Serious Adverse Events..............................................................................155
10.2.1 
Definitions of Serious Adverse Events...........................................155
10.2.2 
Reporting of Serious Adverse Events.............................................155
10.2.3 
Follow-up of Serious Adverse Events ............................................156
10.2.4 
After the Study Period and Safety Follow-up Period.....................156
10.2.5 
Reporting Procedures......................................................................156
10.3 
Pregnancy ...................................................................................................157
10.3.1 
Reporting of Pregnancy..................................................................157
10.3.2 
Follow-up of Pregnancy..................................................................158
10.4 
Study Safety Monitoring ............................................................................158
10.5 
Product Quality Complaint Handling.........................................................158
10.5.1 
Procedures.......................................................................................158
10.5.2 
Contacting Sponsor Regarding Product Quality.............................159
10.6 
Special Reporting Situations ......................................................................159
11 STATISTICAL METHODS .....................................................................................159
11.1 
Analysis Sets...............................................................................................159
11.1.1 
Screened Analysis Set.....................................................................159
11.1.2 
Full Analysis Set.............................................................................159
11.1.3 
Safety Set........................................................................................160
11.1.4 
Pharmacokinetic Analysis Sets.......................................................160
11.1.5 
Usage of the Analysis Sets..............................................................160
11.2 
Variables.....................................................................................................161
11.2.1 
Primary Variable.............................................................................161
11.2.2 
Secondary efficacy variables ..........................................................161
Time to First CEC-confirmed Disease Progression..............161
Time to First CEC-confirmed Hospitalization for PAH .......162
Time to CEC-confirmed Death Due to PAH.........................162

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Time to Death (All Causes)...................................................162
WHO FC I or II (Yes/no) at Week 24...................................163
Percent of Baseline in Plasma NT-proBNP at Week 24 .......163
Mean Daily Time Spent in Moderate to Vigorous
Physical Activity as Measured by Accelerometry at
Week 48.................................................................................163
Echocardiography Variables at Week 24..............................164
Quality of Life As Measured by the PedsQLTM 4.0
Generic Core Scales Short Form (SF15) At Week 24...........164
11.2.3 
Exploratory Variables.....................................................................164
Panama FC I or II (yes/no) at Week 24.................................164
Additional Physical Activity (Accelerometry) at Weeks
12, 24 and 48.........................................................................164
Six-minute Walk Distance at all Time Points .......................165
11.2.4 
Safety Variables..............................................................................165
11.2.5 
Quality of Life at Each Timepoint of Assessment..........................166
11.2.6 
Pharmacokinetic Variables .............................................................166
11.2.7 
Palatability and Acceptability of Macitentan..................................166
11.3 
Description of Statistical Analyses.............................................................166
11.3.1 
Analysis of the Primary Variable....................................................166
11.3.2 
Analysis of the Time to Event Secondary Efficacy Variables........167
Main Analysis........................................................................167
Supportive/sensitivity Analyses ............................................167
Supportive/sensitivity analyses will be described in the
SAP. Subgroup Analyses ......................................................167
Handling of Missing Data .....................................................168
11.3.3 
Other Secondary Efficacy Variables...............................................170
Percent of Baseline in Plasma NT-proBNP at Week 24 .......170
WHO FC I or II (Yes/no) at Week 24...................................171
Mean Daily Time Spent in Moderate to Vigorous
Physical Activity as Measured by Accelerometry at
Week 48.................................................................................171
Echocardiography Variables at Week24 ...............................171
Quality of Life As Measured by the PedsQLTM 4.0
Generic Core Scales Short Form (SF15) at Week 24............172
11.3.4 
Analysis of the Exploratory Variables............................................172
Panama FC I or II (Yes/no) at Week 24................................172
Other Physical activity variables (accelerometry) at
Weeks 12, 24 and 48.............................................................172

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Six-minute Walk Distance at Weeks 12, 24 and 48..............173
11.3.5 
Analysis of the Safety Variables.....................................................173
Adverse Events......................................................................173
Laboratory Variables.............................................................175
Vital Signs.............................................................................177
Growth...................................................................................177
Sexual Maturation (Tanner Stage) ........................................177
11.3.6 
Quality of Life ................................................................................177
11.3.7 
Analysis of pharmacokinetic variable(s) ........................................178
11.3.8 
Palatability and Acceptability.........................................................179
11.4 
Interim Analysis .........................................................................................179
11.5 
Sample Size ................................................................................................179
12 DATA HANDLING..................................................................................................179
12.1 
Data Collection...........................................................................................179
12.2 
Maintenance of Data Confidentiality .........................................................180
12.3 
Database Management and Quality Control...............................................180
13 PROCEDURES AND GOOD CLINICAL PRACTICE...........................................181
13.1 
Ethics and Good Clinical Practice..............................................................181
13.2 
Independent Ethics Committee / Institutional Review Board ....................181
13.3 
Informed Consent.......................................................................................182
13.4 
Compensation to Subjects and Investigators..............................................184
13.5 
Protocol Adherence/Compliance................................................................184
13.6 
Protocol Amendments ................................................................................184
13.7 
Essential Documents and Retention of Documents....................................185
13.8 
Monitoring..................................................................................................186
13.9 
Investigator Site File...................................................................................188
13.10 Audit...........................................................................................................188
13.11 Inspections..................................................................................................188
13.12 
Publication Policy / Dissemination of Clinical Study Data........................189
14 REFERENCES..........................................................................................................191
15 APPENDICES...........................................................................................................200
15.1 
Appendix 1: Child Pugh Classification......................................................200
15.2 
Appendix 2: Instructions on Switch in ERA Treatment.............................201
15.3 
Appendix 3: WHO Functional Class..........................................................202

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15.4 
Appendix 4: Panama Functional Class for Pediatrics ................................203
15.5 
Appendix 5: Tanner Scale ..........................................................................208
15.6 
Appendix 6: Palatability and Acceptability of Macitentan ........................209
15.7 
Appendix 7 : Short Form (SF)-15 Questionnaires......................................212
15.8 
Appendix 8: Cardiac Module Questionnaires ............................................228
15.9 
Appendix 9: Multidimensional Fatigue Scale Questionnaires ...................244
15.10 Appendix 10 : Protocol Amendment History.............................................260
INVESTIGATOR AGREEMENT...................................................................................268
LIST OF TABLES
Table 1: 
Visit and Assessment Schedule During Core Period for Subjects ≥ 2 y.o..60
Table 2: 
Visit and Assessment Schedule During Core Period for Cohort of Children
< 2 y.o..........................................................................................................64
Table 3: 
Visit and Assessment Schedule During Single-arm Extension Period .......67
Table 4: 
Clinical Trials Studying Bosentan in Pediatric PAH ..................................78
Table 5: 
Sildenafil Doses Administered 3 Times Daily in STARTS-1.....................79
Table 6: 
Dosing Scheme for Clinical Formulation..................................................101
Table 7: 
Dosing Scheme for Final Market Image ...................................................102
Table 8: 
Child Pugh Classification..........................................................................200
LIST OF FIGURES
Figure 1 
Study Design ...............................................................................................86

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LIST OF ABBREVIATIONS AND ACRONYMS
6MWD  
6-minute walk distance
6MWT  
6-minute walk test
AE 
Adverse event
ALT  
Alanine aminotransferase
ANCOVA  
Analysis of covariance
AST  
Aspartate aminotransferase
AUC  
Area under the curve
AUCτ 
Area under the plasma concentration-time curve during one
dosing interval
BCAC  
Baseline Characteristics Adjudication Committee
BP 
Blood pressure
CEC  
Clinical Event Committee
CFR  
Code of Federal Regulations (US)
CHD  
Congenital heart disease
CHMP  
Committee for Medicinal Products for Human Use
CI 
Confidence interval
CL 
Confidence limits
Cmax  
Maximum plasma concentration
CRA  
Clinical Research Associate
CRO  
Contract Research Organization
CSR  
Clinical Study Report
CYP  
Cytochrome P450
ECG  
Electrocardiogram
eCRF  
Electronic Case Report Form
EEA  
European economic area
EMA  
European Medicines Agency
EOM  
End of macitentan
EOCP  
End of core period

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EOS  
End of study
ERA  
Endothelin receptor antagonist
ET  
Endothelin
FAS  
Full Analysis Set
FC  
Functional class
FDA  
Food and Drug Administration
GCP  
Good Clinical Practice
GMP  
Good Manufacturing Practice
HIV  
Human immunodeficiency virus
hPAH  
Heritable pulmonary arterial hypertension
HR  
Hazard ratio
IV  
Intravenous
IB  
Investigator’s Brochure
ICF  
Informed Consent Form
ICH  
International Council for Harmonisation
ICMJE 
International Committee of Medical Journal Editors
IDMC  
Independent Data Monitoring Committee
IEC  
Independent Ethics Committee
ILSDRB  
Independent Liver Safety Data Review Board
IP receptor 
Prostacyclin receptor
iPAH  
Idiopathic pulmonary arterial hypertension
IRB  
Institutional Review Board
IRT  
Interactive Response Technology
ISAC  
Independent Statistical Analysis Center
ISF  
Investigator site file
LAP  
Left atrium pressure
LLN  
Lower limit of normal range
LOQ  
Limit of quantification
LTE 
Long-term extension
LVEDP  
Left ventricular end diastolic pressure

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MAR  
Missing at random
MedDRA  
Medical Dictionary for Regulatory Activities
mPAP  
Mean pulmonary artery pressure
MRI 
Magnetic resonance imaging
MVPA  
Moderate to vigorous physical activity
NT-proBNP  
N-terminal pro-brain natriuretic peptide
o.d. 
Once daily
p.p. 
Post-partum
PAH  
Pulmonary arterial hypertension
PAH-aCTD  
PAH associated with connective tissue disease
PAWP  
Pulmonary artery wedge pressure
PDE-5 
Phosphodiesterase Type 5
PH  
Pulmonary hypertension
PI 
Principal investigator
PK  
Pharmacokinetics
PTA  
Post-trial Access
PVO2 
Peak oxygen consumption
PVR  
Pulmonary vascular resistance
PVRi 
Pulmonary vascular resistance index
QoL 
Quality of Life
REVEAL 
Registry to Evaluate Early and Long-Term PAH Disease
Management
RHC  
Right heart catheterization
RSI 
Reference safety information
SC 
Subcutaneous
SAE 
Serious adverse event
SAP  
Statistical Analysis Plan
SD 
Standard deviation
SAEP  
Single-arm extension period
SE 
Standard error

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SIV  
Site initiation visit
SoC  
Standard of Care
SOCBP  
Subject of childbearing potential
SOP  
Standard operating procedure
SUSAR  
Suspected unexpected serious adverse reaction
SP 
Study phase
t½ 
Terminal half-life
TAPSE 
Tricuspid annular plane systolic excursion
TBIL 
Total bilirubin
tmax  
Time to reach maximum plasma concentration
TOPP  
Tracking Outcomes in Pediatric Pulmonary Hypertension
Registry
ULN  
Upper limit of the normal range
WHO  
World Health Organization

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PROTOCOL SYNOPSIS AC-055-312
TITLE
A multicenter, open-label, randomized study with single-arm
extension period to assess the pharmacokinetics, safety and
efficacy of macitentan versus standard of care in children with
pulmonary arterial hypertension.
ACRONYM
TOMORROW: pediaTric use OfMacitentan tO delay disease
pRogRessiOn in PAH Worldwide
OBJECTIVES
Primary objective
To evaluate the pharmacokinetics (PK) of macitentan in
children with pulmonary arterial hypertension (PAH).
Secondary objectives
To assess safety and tolerability of macitentan in children with
PAH.
To assess efficacy of macitentan in children with PAH.
DESIGN
This is a prospective, multicenter, open-label, randomized,
controlled, parallel group, Phase 3 study with  an open-label
single-arm extension period to evaluate PK safety and efficacy
of macitentan in children with PAH. Children < 2 years old
(y.o.) will be assigned as a cohort to the macitentan group
without randomization.
In consideration of the different requirements from Health
Authorities, two important milestones (ie, fourth quarter of
2022 (Analysis 1), and first quarter of 2024 (Analysis 2),
respectively) will trigger the analysis timepoints.
There will be three time points of study analysis:
 Analysis 1 of Core Period: with cutoff date in the fourth
quarter of 2022.
 Analysis 2 of Core Period: with cutoff date in the first
quarter of 2024.
 Analysis 3 final analyses including the core and the
single-arm extension periods.

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The sponsor will determine the cutoff date for the first two
analyses three months prior to this date and will document the
decision accordingly in the Trial Master File.
The cohort < 2 y.o. may be analyzed at additional timepoints
in order to allow ongoing evaluation of benefit-risk in this
vulnerable population.
Study duration  for each individual subject will be based on
their time of enrollment. All subjects are planned to remain in
the study  until the database lock  in 2024 (Analysis 2).
Thereafter, if it is considered in the best interest of the subject,
continuation in the open-label single-arm  extension period
with macitentan will be offered.
In order to minimize potential bias related to the open-label
design some aspects of the study conduct have been outsourced
to Contract Research Organizations (CROs). The firewalls put
in place between blinded and unblinded study team members
are described in a dedicated Firewall Charter.
PERIODS
Screening Period: Starts from signed informed consent and
ends with randomization or confirmation of screening failure
(up to 6 weeks after signed informed consent).
Cohort of children < 2 y.o.: The Screening Period ends with
confirmation of eligibility (i.e., age at Visit 2 is less than 2
years) and assignment of macitentan kit at Visit 2, or with
screening failure.
Core Period: Commences with Visit 2 and continues until the
End of Core Period (EOCP) visit.
Pre-Event Study Phase (Pre-Event SP): Starts from Visit 2
until disease progression event confirmed by the CEC or
until EOCP visit, whichever comes first.
Post-Event Study Phase (Post-Event SP): Begins with
CEC-confirmed event and continues until EOCP  visit.
During Post-Event SP PAH-specific background treatment
may be escalated in both treatment arms as per local
practice. Any additional treatment, including intravenous

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(IV) or subcutaneous (SC) prostanoids may be used in both
treatment arms. Subjects in the macitentan arm can continue
receiving macitentan. Subjects in the SoC arm are offered
to cross-over to macitentan treatment, if this is in their best
interest per investigator judgment.
End of Macitentan (EOM): All subjects treated with
macitentan who prematurely discontinue macitentan will have
an EOM visit within 1 week after the last dose of macitentan.
Survival Follow-up: Applies to subjects who prematurely
discontinue regular study visits during Core Period. Survival
data will be collected at least yearly after the last regular study
visit and until EOCP for Analysis 2 . In these subjects the last
survival follow-up contact constitutes their EOS.
End of Core Period (EOCP) Visit: This visit will occur in first
quarter 2024 and before the cutoff date for Analysis 2 which
will be announced by the sponsor. For subjects who don’t enter
the Single-Arm Extension Period (SAEP), the EOCP Visit
constitutes their End-of-Study (EOS) Visit.
Safety Follow-up Period: Applies to subjects who
prematurely discontinue macitentan or SoC treatment during
Core Period or during the SAEP. In addition, it applies to
subjects at EOS who do not enter the SAEP or who do not go
into a post-trial access (PTA) or long-term extension (LTE)
study. It begins immediately after premature end of treatment
or after EOCP/EOS and ends at least 30 days later with a safety
follow-up telephone call.
Subjects prematurely discontinuing treatment during Core
Period are encouraged to continue participation in the study
according to the regular study visit schedule or at least agree to
Survival Follow-up until EOCP. Only for subjects whose
parent(s) / legal representative withdraw consent to further
study participation is the safety follow-up telephone call EOS.
Single-arm Extension Period (SAEP): This period starts at
EOCP  visit and ends at EOS  visit. Subjects who are in the
12-weekly regular visits at EOCP visit, and for whom the

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investigator judges that macitentan treatment could be
beneficial and who fulfill the safety criteria to initiate or
continue macitentan treatment are eligible to enter the
open-label single-arm extension period.
End of Study (EOS) Visit: At the end of the SAEP each subject
will come for an EOS visit within 12 weeks of the Sponsor
announcing the end of the study. For subjects who discontinue
the study prematurely the last visit or last survival FU contact
constitutes their EOS visit.
For subjects who cannot access macitentan, a continued access
program will be put in place (e.g., PTA, LTE study) to allow
treatment continuation, if assessed beneficial by the
investigator and within local regulations.
For subjects rolling over to a PTA or LTE study  after the
SAEP, the enrollment must occur on the day of the last visit of
this study i.e., EOS  visit, to avoid macitentan  treatment
interruption. These subjects will not have a safety follow-up
call in TOMORROW since their safety follow-up continues in
the respective PTA or LTE study.
The study is considered completed when the last subject
completes the study (i.e., last EOS visit).
PLANNED DURATION
The study starts from first subject, first visit, defined as
screening (i.e., ICF signed), and ends with last subject, last
visit, defined as the last EOS visit.
This is a calendar-driven study  and time points of analysis
depend on dates to meet regulatory commitment.
Study duration for each individual subject will be based on
their time of enrollment. All subjects are planned to remain in
the study until the cutoff date for Analysis 2 in 2024.
Thereafter, if it is considered in the best interest of the subject,
continuation in the open-label single-arm extension period
with macitentan will be offered.

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Subject participation in the Core Period at timepoint of
Analysis 2 will be up to 7 years. Participation in the SAEP will
be at least 24 weeks.
Overall study duration (including Core Period and extension
period) will be a minimum of 7 years (from first subject
screened until last subject last EOS visit).
SITE(S)
/ COUNTRY(IES)
Approximately 90 sites in about 30 countries (planned).
SUBJECTS / GROUPS
Approximately 200 subjects and no more than 300 subjects
will be enrolled in this study based on current feasibility.
Subjects ≥ 2 y.o. at Visit 2 will be randomized in a 1:1 ratio to
either receive macitentan or continue SoC. Randomization is
stratified by  ongoing/planned endothelin receptor antagonist
(ERA) treatment (yes vs no) and by WHO Functional Class
(FC; FC I/II vs FC III) at randomization. In the central
randomization system, the proportion of subjects with ERA
treatment will be limited to a maximum of 40% of the overall
number of randomized subjects.
Cohort of children < 2 y.o. will not be randomized but will
enter directly into the macitentan arm. The ERA cap does not
apply to this cohort.
INCLUSION CRITERIA
1. Signed informed consent by the parent(s) or legally
designated 
representative 
AND 
assent 
from
developmentally capable children prior to initiation of any
study-mandated procedure.
2. Criterion modified per Amendment 8 Version 9:
Males or females between ≥1 month  and <18years of
age.
3. Criterion modified per Amendment 8 Version 9:
Subjects with body weight ≥ 3.5 kg at randomization
4. Criterion modified per Amendment 6 Version 7: 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

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resistance index (PVRi) >3 Wood Units x m2), where in
the absence of pulmonary vein obstruction and/or
significant lung disease PAWP can be replaced by LAP or
LVEDP (in absence of mitral stenosis) assessed by heart
catheterization.
5. PAH belonging to the Nice 2013 Updated Classification
Group 1 (including Down Syndrome) and of the following
etiologies:
 Idiopathic PAH (iPAH)
 Heritable PAH (hPAH)
 PAH associated with congenital heart disease (CHD):
 PAH with co-incidental CHD (confirmed by the
Baseline Characteristics Adjudication Committee
[BCAC])
 Post-operative 
PAH 
(persisting/ 
recurring/
developing ≥6 months after repair of CHD)
 Drug or toxin-induced PAH
 PAH associated with HIV
 PAH associated with connective tissue disease
(PAH-aCTD)
6. WHO FC I to III
7. PAH-specific treatment-naïve subjects or subjects on
PAH-specific treatment (monotherapy or combination of
two therapies)
8. Females of childbearing potential must have a negative
pregnancy test at Screening and at Baseline, and must
agree to undertake monthly pregnancy tests, and to use
reliable method of contraception (if sexually active) up to
EOS.
EXCLUSION CRITERIA
Etiology
1. Subjects with PAH due to portal hypertension,
schistosomiasis, pulmonary veno-occlusive disease and/or
pulmonary capillary hemangiomatosis, and persistent
pulmonary hypertension of the newborn.
2. Subjects with PAH associated with open shunts, as
specified below:
a. Eisenmenger syndrome

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b. Moderate to large left-to-right shunts.
3. Subjects 
with 
the 
following 
congenital 
cardiac
abnormalities:
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 subjects with Fontan-
palliation.
4. Subjects with pulmonary hypertension due to lung disease
(e.g., bronchopulmonary dysplasia).
5. Criterion added per Amendment 8 Version 9:
Subjects with known diagnosis of bronchopulmonary
dysplasia.
Treatment and intervention
6. Subjects receiving a combination of >2 PAH-specific
treatments at randomization.
7. Treatment with IV  or SC prostanoids within 4 weeks
before randomization unless given for vasoreactivity
testing.
8. Criterion modified per Amendment 8 Version 9: 
In children ≥ 2 y.o.:Previous treatment with macitentan at
any time.
9. Treatment with another investigational drug within
4 weeks prior to randomization.
10. Any PAH-related surgical intervention planned, or
subjects listed for organ transplantation related to PAH.
11. Treatment with strong inducers of cytochrome P450 3A
(CYP3A4) such as rifabutin, rifampicin, rifapentin,
carbamazepine, phenobarbital, phenytoin, St. John’s wort
(hypericum perforatum), within 4 weeks prior to
randomization.
12. Systemic treatment with strong inhibitors of CYP3A4
such as boceprevir, clarithromycin, conivaptan, indinavir,
itraconazole, 
ketoconazole, 
nefazodone, 
nelfinavir,
posaconazole, 
ritonavir, 
saquinavir, 
telaprevir,

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telithromycin, and voriconazole within 4 weeks prior to
randomization.
13. Criterion modified per Amendment 3.1 Version 4.1:
Systemic treatment with moderate dual CYP3A4/CYP2C9
inhibitor (e.g., fluconazole and amiodarone), or
administration of a combination of a moderate CYP3A4
(e.g., 
ciprofloxacin, 
cyclosporine, 
diltiazem,
erythromycin, verapamil) together with a moderate
CYP2C9 inhibitor (e.g., miconazole, piperine) within 4
weeks prior to randomization.
Baseline abnormalities
14. Subjects with pulmonary vein stenosis.
15. Known concomitant life-threatening disease with a life
expectancy < 12 months.
16. Hemoglobin or hematocrit < 75% of the lower limit of
normal range.
17. Serum 
aspartate 
aminotransferase 
and/or 
alanine
aminotransferase > 3 ×upper limit of normal range.
18. Criterion modified per Amendment 6 Version 7: Severe
hepatic impairment, e.g., Child-Pugh Class C.
19. Clinical signs of hypotension which in the investigator’s
judgment would preclude initiation of a PAH-specific
therapy.
20. Criterion added per Amendment 6 Version 7: Severe renal
insufficiency (estimated creatinine clearance < 30 mL/min
or serum creatinine >221 µmol/L).
Pregnancy and breastfeeding
21. Pregnancy (including family planning) or breastfeeding.
Other categories
22. Known hypersensitivity to ERAs, or any of the excipients.
Drug or substance abuse, or any condition that, in the opinion
of the investigator, may prevent compliance with the protocol
or adherence to study treatment.
STUDY TREATMENTS
Macitentan arm
Macitentan, open-label, is administered once daily via oral
route in dispersed form.

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Clinical Formulation: Macitentan is provided as a dispersible
tablet of following dosage strengths: 0.5 mg, 2.5 mg, and 5 mg.
This formulation is only used in subjects of at least 6 months
of age and will be controlled via IRT.
Clinical Formulation:
Age 
[Months] 
Body Weight [kg] 
Daily 
dose 
Number of tablets to
be dispersed
≥ 1 and < 6 
not applicable (NA) 
NA  
NA
≥ 6 and < 24 
not applicable 
2.5 mg 
1×2.5 mg
≥ 24
≥10 kg and < 15 kg 
3.5 mg 
2×0.5 mg & 1×2.5
mg
≥15 kg and < 25 kg 
5.0 mg 
1×5.0 mg
≥25 kg and < 50 kg 
7.5 mg 
1×2.5 mg & 1×5.0
mg
≥ 50 kg 
10.0 mg 
2×5.0 mg
Final Market Image (FMI): Macitentan dispersible tablet will
be available in new dose strengths of 1 mg and 2.5 mg with
different shape and debossing. The FMI will replace the
Clinical Formulation once sufficient stability data is available
and local approval, if applicable, has been obtained. This
formulation will be used in all subjects (≥1 month of age).
Final Market Image:
Age 
[Months] 
Body Weight [kg] 
Daily 
dose 
Number of tablets to
be dispersed
≥ 1 and < 6 
not applicable 
1.0 mg 
1×1.0 mg
≥ 6 and < 24 
not applicable 
2.5 mg 
1×2.5 mg
≥ 24 
≥10 kg and < 15 kg 
3.5 mg 
1×1.0 mg & 1×2.5
mg
≥15 kg and < 25 kg 
5.0 mg 
2×2.5 mg
≥25 kg and < 50 kg 
7.5 mg 
3×2.5 mg
≥50 kg 
10.0 mg 
4×2.5 mg
For subjects ≥ 2 y.o. the daily doses depend on the body weight
category of the subjects and doses will be adjusted for change
to body weight during the study as needed.
For subjects <2 y.o., the daily doses depend on the age of the
subject and will be adjusted during the study.

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Body weight or age for potential dose adjustment will be
verified every 12 weeks at scheduled study visits.
In subjects ≥ 2 y.o., phosphodiesterase Type 5 (PDE-5)
inhibitor is the only allowed PAH-specific background
medication until disease progression.
In subjects < 2 y.o., oral/ inhaled prostanoid treatment are also
allowed as PAH-specific background therapy in all study
periods.
Control arm / Standard of Care (SoC)
SoC (including PAH non-specific treatment and/or up to two
PAH-specific medications as per local practice) is the control
group.
Children treated with a PDE-5 inhibitor and/or other
PAH-specific treatment (such as an ERA or inhaled/oral
prostanoids) at Baseline continue their medications. Additional
PAH-specific therapy (excluding macitentan and IV/SC
prostanoids) prescribed as SoC prior to randomization can be
initiated.
Dose adjustments to reach the targeted dose or sequential
introduction of combination therapy are allowed as prescribed
by the investigator in Interactive Response Technology (IRT)
prior to randomization. After randomization, change in a
PAH-specific medication is allowed, if remaining within the
same drug class.
CONCOMITANT
THERAPY
Mandatory concomitant therapy
In both treatment arms female subjects of childbearing
potential who are sexually active must use reliable
contraceptive methods until EOS or until the last safety follow-
up (FU) call (whichever occurs latest). If hormonal
contraceptives are used those must be initiated at least 4 weeks
before randomization.
For subjects who become sexually active any time after
randomization and who are of childbearing potential,

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contraceptive method(s) that are immediately effective must be
applied.
Allowed concomitant therapy
Supportive PAH non-specific therapies (e.g., diuretics,
anticoagulants, oxygen, calcium channel blockers) and
changes to such medications are allowed during all study
periods in both treatment arms. For IV diuretics and continuous
oxygen therapy, refer also to ‘PAH treatment escalation.’
Screening Period: Any PAH-specific therapy (excluding
macitentan and IV./SC prostanoids) can be given or initiated as
mono- or combination therapy with a maximum of two
treatments.
Cohort of children <2 y.o.: is allowed to use macitentan during
Screening.
Core Period:
Macitentan group
 Pre-Event SP: PDE-5 inhibitor treatment ongoing at
randomization can continue.
 Post-Event 
SP: Any PAH-specific 
medication
(including IV/SC  prostanoids), except ERA, can be
administered in addition to macitentan.
SoC group
 Pre-Event SP: Any PAH-specific treatment (other than
macitentan and IV/SC prostanoids) as either mono- or
double combination therapy identified as planned SoC
before randomization can be administered.
 Post-Event 
SP: 
Any  PAH-specific 
medication
(including IV/SC  prostanoids) can be administered.
Macitentan treatment will be offered after CEC
confirms disease progression, if this is in the best
interest of the subject per their investigator’s judgment.
Single-arm Extension Period:

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 Any PAH-specific medication except an ERA can be
administered in addition to macitentan.
Use of IV prostanoids for vasoreactivity testing is allowed in
all study subjects and during all study periods.
Forbidden concomitant therapy
To avoid confounding effects, the following treatments are
forbidden as specified:
 
Use of any investigational drug is forbidden from
4 weeks before randomization/Visit 2 and up to EOS in
all subjects.
 
I.V./S.C. prostanoids are forbidden from 4 weeks
before randomization/Visit 2 and during Pre-Event SP
in all subjects (except if given for vasoreactivity
testing).
 
Use of macitentan is forbidden in all subjects ≥ 2 y.o.
at any time before study entry. In the SoC group,
macitentan is forbidden during the Pre-Event SP.
 
In subjects ≥ 2 y.o. in the macitentan arm, the use of
any PAH-specific background therapy other than PDE-
5 inhibitor is forbidden during the Pre-Event SP.
Concomitant use of an ERA (e.g., bosentan, ambrisentan) with
macitentan is forbidden during entire study duration.
Cohort of children < 2 y.o.: use of macitentan is allowed at any
time before study entry  and oral/inhaled prostanoids are
allowed as PAH-specific background therapy.
To avoid drug-drug interactions with macitentan the following
treatments are forbidden as specified:
 
Strong inducers of CYP3A4 such as rifabutin,
rifampicin, rifapentin, carbamazepine, phenobarbital,
phenytoin, and St. John’s wort (hypericum perforatum)
are forbidden from 4 weeks prior to and until
randomization/ Visit 2 because the efficacy of
macitentan could be reduced. After randomization/
Visit 2 these medications should be avoided as follows:
 in the macitentan arm until EOM.

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 in the SoC arm from 4 weeks before crossing
over to macitentan and until EOM.
 in the SAEP until EOS.
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 
such 
as 
boceprevir, 
clarithromycin,
conivaptan, indinavir, itraconazole, ketoconazole,
nefazodone, 
nelfinavir, 
posaconazole, 
ritonavir,
saquinavir, telaprevir, telithromycin, and voriconazole
is forbidden from 4 weeks prior to and until
randomization/ Visit 2. After randomization/ Visit 2
systemic administration of these medications is
forbidden as follows:
 in the macitentan arm until EOM.
 in the SoC arm from 4 weeks before crossing
over to macitentan and until EOM.
 in the SAEP until EOS.
 Systemic 
administration 
of 
moderate 
dual
CYP3A4/CYP2C9 inhibitor such as fluconazole and
amiodarone, or combination of a moderate CYP3A4
inhibitors (e.g., ciprofloxacin, cyclosporine, diltiazem,
erythromycin, verapamil) together with a moderate
CYP2C9inhibitor (e.g., miconazole, piperine) is forbidden
from 4 weeks prior to and until randomization/ Visit 2.
After randomization/ Visit 2 systemic administration of
these medications is forbidden as follows:
 in the macitentan arm until EOM.
 in the SoC arm from 4 weeks before crossing
over to macitentan and until EOM.
 in the SAEP until EOS.
In case such treatments are needed during study participation
(except CYP3A4 inducers), macitentan treatment must be
interrupted. To avoid any drug-drug interactions with  SoC

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treatments the investigator should consult respective
medication label(s).
PAH Treatment Escalation
In the presence of PAH worsening, any PAH-specific
treatment can be initiated per investigator’s judgment. It is
strongly recommended however to initiate PAH-specific
medications, and/or continuous oxygen and/or IV  diuretics,
only in the presence of disease progression defined per
protocol as per judgment of the investigator.
Subjects in the SoC group will be offered macitentan if the
CEC confirms disease progression, and if this is considered in
the best interest of the subject per their investigator’s
judgement. Subjects in the macitentan group will continue
receiving macitentan after a CEC-confirmed disease
progression event.
During the SAEP, PAH treatment can be escalated as per local
practice.
ENDPOINTS
Primary endpoint(s)
In subjects ≥ 2 y.o. in the macitentan arm:
 Trough (pre-dose) plasma concentrations of macitentan
and its active metabolite (ACT-132577) at Week 12
(steady-state conditions)
In subjects < 2 y.o. on macitentan:
 Trough concentrations of macitentan and its active
metabolite (ACT-132577) at Week 4 (steady-state
conditions)
PK data will be listed by subject number and PK endpoints will
be analyzed descriptively by body weight and age group in
subjects ≥ 2 y.o. and <2 y.o., respectively.
Secondary efficacy endpoints
The secondary endpoints are:

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 Time to the first of the following CEC-confirmed
disease 
progression 
events occurring 
between
randomization/Visit 2 and EOCP:
o Death (all causes)
o Atrial septostomy or Potts’ anastomosis, or
registration on lung transplant list
o Hospitalization due to worsening PAH§
o Clinical worsening* of PAH defined as:
o 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 (i.e., 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 (e.g., pneumonia).
* Worsening from baseline.
# E.g., ERA, PDE-5 inhibitor, prostanoids, prostacyclin receptor
(IP receptor) agonist, soluble guanylate cyclase stimulator.
 Time to first CEC-confirmed hospitalization for PAH
occurring between randomization/Visit 2 and EOCP.
 Time to CEC-confirmed death due to PAH occurring
between randomization/Visit 2 and EOCP.
 Time to death (all causes) occurring between
randomization/Visit 2 and Study Closure.
Following secondary endpoints are analyzed up to end of
randomized macitentan or SoC + 7 days. Baseline is the last
non-missing value observed before or on the day of
randomization/ Visit 2.

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 WHO FC status (I or II vs III or IV) at Week 24 .
 Percent of Baseline plasma NT-proBNP at Week 24.
 Change from baseline to Week 48 in mean daily time
spent in moderate to vigorous physical activity  as
measured by accelerometry.
 Change from Baseline to Week 24 in tricuspid annular
plane systolic excursion (TAPSE), and left ventricular
eccentricity index measured by echocardiography
(centrally assessed).
 Change from Baseline to Week 24 in Quality of Life as
measured by the PedsQLTM  4.0 Generic Core Scales
Short Form (SF15).
Exploratory endpoints
 Panama FC status (I or II vs FC III or IV) at Week 24
 Change from Baseline up to Weeks 12, 24 and 48 in
exercise capacity as measured by the 6MWT in
children ≥6 years of age who are developmentally able
to understand and perform the test.
Exploratory endpoints are analyzed up to end of randomized
macitentan or SoC + 7 days. Further exploratory endpoints are
described in the body text of the protocol.
Safety endpoints
Safety endpoints are assessed up to EOS and include:
 Adverse events (AEs)
 Serious adverse events (SAEs)
 AEs leading to premature discontinuation of
macitentan or SoC
 AEs of special interest
 Marked laboratory abnormalities
 Change from Baseline in selected laboratory
parameters to all timepoints of assessments
 Change from Baseline in vital signs (blood pressure,
heart rate) to all timepoints of assessments

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 Growth from Baseline to all timepoints of scheduled
assessments
 Sexual maturation (Tanner stage) change from Baseline
to all timepoints of scheduled assessments
Baseline is the last non-missing value observed before or on
the day of randomization/ Visit 2.
Other endpoints
Other endpoints are described in the body text of the protocol.
ASSESSMENTS
Refer to the schedule of assessments in Table 1,Table 2 and
Table 3.
STATISTICAL
METHODOLOGY
Analysis sets
The Full Analysis Set 1 (FAS1, all randomized subjects ≥ 2
y.o. at randomization) is used for the analyses of all the efficacy
and exploratory variables.
The Full Analysis Set 2 (FAS2, subjects < 2 y.o. at Visit 2) is
used for the descriptive analyses of all efficacy and exploratory
variables.
The Full Analysis Set 3 (FAS3, includes both FAS1 and FAS2)
is used for the description of the study population at Baseline.
The Safety Set is used for the analyses of the safety variables.
The Screened Analysis Set is used for the description of subject
disposition.
The PK Set 1 includes all subjects randomized to and treated
with macitentan, for whom a PK blood sample at trough has
been taken and who do not deviate from the protocol in a way
that might affect the evaluation of the PK trough endpoints.
The PK Set 2 includes all subjects ≥ 2 y.o. randomized to and
treated with macitentan or crossing over to macitentan and part
of the PK substudy, who have evaluable PK profiles and who
do not deviate from the protocol in a way that might affect the
evaluation of the PK substudy endpoints.

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The PK Set 3 includes all subjects < 2 y.o. treated with
macitentan, for whom a PK blood sample has been taken and
who do not deviate from the protocol in a way that might affect
the evaluation of the PK endpoints.
Primary variable
In subjects who are ≥ 2 y.o. in the macitentan arm:
 
Trough plasma concentrations of macitentan and its
active metabolite ACT-132577 at Week 12 (steady-
state conditions)
In subjects <2 y.o.:
 
Trough concentrations of macitentan and ACT-132577
at Week 4 (steady-state conditions)
PK data will be listed by subject number and PK endpoints will
be analyzed descriptively by body weight (≥2 y.o.) and age (<
2 y.o.) groups.
Primary statistical analysis
For macitentan and ACT-132577 trough concentration
analysis, the PK Set 1 will be used.
PK data will be listed by subject number and PK endpoints will
be analyzed descriptively by body weight group. For children
<2 y.o. the analysis will be descriptive by age group.
Plasma and blood concentrations of macitentan and ACT-
132577 per timepoint will be summarized by body weight
groups and age groups in ≥2 y.o. and <2 y.o., respectively,
using arithmetic mean, geometric mean, minimum, median,
maximum, standard deviation (SD), standard error (SE), and 2-
sided 95% confidence interval (CI) of the mean.
Secondary efficacy endpoints
At Analysis 1 cutoff date, treatment effect estimates and 95%
CLs will be provided for exploratory purposes only. No
multiplicity adjustment will be applied. Analysis 2 cutoff date
will be the primary analyses for these endpoints; p-values will

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be provided in addition to treatment effect estimates and 95%
CLs. Further details will be described in the statistical analysis
plan (SAP). The analysis of the time to event variables will
only be descriptive for subjects of the FAS2 (<2 y.o. receiving
macitentan) at Analysis 1 and 2 cutoff dates.
Exploratory endpoints
Due to the nature of these analyses, at Analysis 1 cutoff date,
treatment effect estimates and 95% CLs will be provided for
exploratory purposes only.  At Analysis 2 cutoff date 2-sided
p-values will be provided in addition to the treatment effect
estimates and 95% CLs for exploratory purpose.
Safety endpoints
The number and percentage of subjects with at least one AE up
to EOS, number and percentage of subjects with at least one
SAE up to EOS, number and percentage of subjects with at
least one AE leading to premature discontinuation of
macitentan or SoC, and number and percentage of subjects
with at least one AE up to EOS  with fatal outcome will be
tabulated by randomized treatment group and by:
 
System organ class and individual preferred term
within each system organ class, in descending order of
incidence within the macitentan treatment group.
 
Preferred term, in descending order of incidence in the
macitentan treatment group.
Furthermore, for subjects exposed to macitentan, the number
and percentage of subjects with at least one AE up to EOT +
30 days according to intensity, number and percentage of
subjects with at least one AE up to EOT + 30 days according
to relationship to macitentan, and number and percentage of
subjects with at least one SAE up to EOT + 30 days according
to relationship to macitentan will be tabulated by:
 
System organ class and individual preferred term
within each system organ class, in descending order of
incidence within macitentan treatment group.

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 
Preferred term, in descending order of incidence in the
macitentan treatment group.
Cohort of children <2 y.o. will be summarized separately.
Pharmacokinetic endpoints
For PK profiles in subjects who are 2 years or older, the PK Set
2 will be used and PK Set 3 will be for PK assessment in
children < 2 y.o.PK data will be listed by subject number and
PK endpoints will be analyzed descriptively by body weight
group (≥2 y.o.) and age (<2 y.o.) groups.
Plasma or blood concentrations of macitentan and ACT-
132577 per timepoint will be summarized by body weight
group or age group, respectively, using arithmetic mean,
geometric mean, minimum, median, maximum, standard
deviation (SD), standard error (SE), and 2-sided 95% CI of the
mean.
Maximum plasma or blood concentration (Cmax), the area under
the plasma/ blood concentration-time curve during one dosing
interval (AUCτ), and the time to reach maximum plasma/ blood
concentration (tmax)* will be summarized with arithmetic
mean, geometric mean, minimum, median, maximum, SD, SE,
coefficient of variation inter-subject in %, and 95% CI of the
arithmetic and geometric means.
* For tmax  the geometric mean and its 95% CI will not be calculated.
STUDY COMMITTEES
An Independent Data Monitoring Committee (IDMC) will
review data at regular intervals according to the IDMC Charter.
The IDMC has overall responsibility for safeguarding the
interests of subjects by monitoring safety, tolerability  and
efficacy data obtained in the study and making appropriate
recommendations based on the reported data.
An Independent Statistical Analysis Center (ISAC) will
support the IDMC for their review and recommendation over
the entire course of the study.

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In addition, the ISAC will monitor, in collaboration with the
IDMC, the number of disease progression  events occurring
over time, in order to make appropriate predictions for number
of events anticipated by timepoint of Analysis 1 and Analysis
2.
A Clinical Event Committee (CEC), an independent
committee of PAH experts (including pediatricians), will
review and adjudicate in a blinded fashion the secondary
endpoints related to disease progression according to the CEC
Charter. If there is any change to key data, as defined in the
CEC Charter, or new key data become available after a first
submission of a subject case has been submitted to the CEC,
the CEC Coordinator re-submits the case for re-adjudication.
An independent BCAC  will centrally review and confirm
eligibility of subjects with co-incidental congenital heart
disease before their randomization (before macitentan start for
children <2 y.o.) as described in the BCAC Charter.
An Independent Liver Safety Data Review Board
(ILSDRB), a non-study-specific external expert committee of
hepatologists, will receive cases of serious hepatic events of
special interest from the Sponsor. This board provides ongoing
assessment and advice regarding cases that may require further
evaluation during the study.
PK SUBSTUDY
For up to 40 subjects ≥ 2 years of age receiving macitentan
participation to the PK substudy is optional and will be
controlled via IRT.
At steady-state conditions a PK profile will be collected over
24 hours from subjects ≥ 2 y.o. treated with macitentan.
Collected PK data (both PK profiles and trough concentrations)
will be regularly assessed using non-linear mixed effects PK
modeling during the course of the study to confirm the
appropriateness of the selected dosing regimen in subjects
older than  2 years. A formal sample size calculation will
determine the amount of PK data (full PK profile plus trough
samples collected) required to ensure at least 80% power to

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conclude that exposure in pediatric subjects is as targeted from
the knowledge available from adults.
Modeling and simulation have been performed based on the
PK data from pediatric subjects older than 2 years and adults
to select the appropriate daily dose in subjects below 2 years of
age. The modeling and PK data will be reported separately (i.e.,
not included in the Clinical Study Report).

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6 
Both Panama FC and classical WHO FC are assessed. Panama FC is assessed in subjects until the age of 16 years.
7 
Relevant data denoting disease progression are submitted to the CEC.
8 
Only mandated for subjects eligible to start macitentan crossover treatment.
9 
Data is collected in subjects ≥ 2 y.o. via accelerometer carried by the subject for 10 14 days.
10 6MWT in subjects ≥6 years of age who are able to understand and perform the test correctly. Only for subjects for whom 6MWT can be done at randomization.
11 Assessed at Central Laboratory. If data is missing, routine local laboratory data (if available) is recorded in the eCRF.
12 Only mandated for subjects eligible to start macitentan crossover treatment.
13 The investigator may decide to continue monthly liver tests via central laboratory. This is not mandated per protocol, but tests are mandatory every 12 weeks. In the SoC
group monthly tests are only mandatory for subjects receiving an ERA for which the label instruction requests monthly tests. In other subjects in the SoC group those
tests are done at the regular study visits (i.e., every 12 weeks).
14 Subjects of childbearing potential who are sexually active should be receiving at least 4 weeks of contraception before the urine pregnancy test at randomization. The
pregnancy test is done locally.
15 Monthly pregnancy tests can be done at home under parental supervision. In this case the investigator will verify via phone that the test was done and will verify the
results.
16 A PK profile is collected over a period of 24 hours (pre dose and then 1 h, 2 h, 4 h, 8h, 12 h, and 24 h post dose) in up to 40 subjects as part ofthe PK substudy.
17 Scheduled study medication dispensing/return procedures may be adapted according to the site practice.
18 Parent(s)/caregiver(s) and subjects are instructed that macitentan should not be administered on days of study visits 3 (Day 14 PK) and 4 (Week 12) until instructed by
site personnel.
19 All AEs and SAEs that occur after signing the Informed Consent Form and up to EOS or up to Safety FU (whichever is last) must be reported.

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23 Applicable for subjects who prematurely discontinue regular study visits. Data are collected at least yearly and additionallywithin 6 weeks before the cutoff date for Analysis
1 and Analysis 2. Data can be obtained via visit, telephone or in writing (e.g., letter).
24 Both Panama FC and classical WHO FC are assessed.
25 Relevant data denoting disease progression are submitted to the CEC.
26 Assessed at Central Laboratory. If data is missing, routine local laboratory data (if available) is recorded in the eCRF.
27 Use of local laboratory is allowed, if normal range for applicable age group is available.  Monthly tests will continue until 48 weeks after the first dose of macitentan study
treatment even if this falls into the Extension Period (refer to Table 3).
28 PK samples will be drawn at 2h, 5h, and 24h after the first dose.
29 Scheduled study medication dispensing/return procedures may be adapted according to the site practice.
30 Parent(s)/caregiver(s) and subjects are instructed that macitentan should not be administered on days of study visits Week 4 and Week 8 until instructed by site personnel.
31 All AEs and SAEs that occur after signing the Informed Consent Form and up to EOS or up to Safety FU (whichever is last) must be reported.

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PROTOCOL
1 
BACKGROUND
1.1 Indication
Treatment of pulmonary arterial hypertension (PAH) in children.
1.1.1 Definition and Diagnosis
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
[Widlitz 2003, 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 (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 Wood units
(WU) x m2 [Ivy 2013, Abman 2015, Hansmann 2016].
PVRi [WU x m2]  mPAP [mm Hg] -PAWP [mm Hg] / Cardiac index [(L/min) / m2]
Cardiac index [(L/min) / m2]  Cardiac output [L/min]/ body surface area [m2]
PAH diagnosis can be confirmed only if elevated left heart pressures are excluded as a
reason for pulmonary hypertension. PAWP is used for this purpose as a surrogate of a
directly measured pressure in the left atrium [Galiè2015]. In the absence of mitral stenosis,
left ventricular end diastolic pressure (LVEDP) can also be used as an alternative surrogate
for left atrial pressure (LAP) [Grignola 2011, Takala 2003].
1.1.2 Classification
According to the revised clinical classification of pulmonary hypertension
[Simonneau 2013] PAH comprises: idiopathic PAH (iPAH); heritable PAH (hPAH);
drug-and toxin-induced PAH; and PAH associated with connective tissue diseases
(PAH-aCTD), HIV infection, portal hypertension, congenital heart diseases (CHD),
schistosomiasis; it also includes the subcategories pulmonary veno-occlusive disease
and/or pulmonary capillary hemangiomatosis as well as persistent pulmonary hypertension
of the newborn [Ivy 2013].

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This protocol addresses iPAH, hPAH, and PAH associated with CHD which account for
the majority of pediatric PAH patients [refer to Section 1.1.3]. PAH associated with HIV,
PAH associated with CTD, as well as drug or toxin-induced PAH are also included in this
trial even though they represent only a minor proportion of the pediatric PAH population
[D-16.012].
Within the subgroup of PAH associated with CHD, the protocol excludes patients with
Eisenmenger syndrome as well as patients with open left-to-right shunts. In those patients,
there is not sufficient adult data available to support efficacy of macitentan.
1.1.3 Epidemiology
Knowledge about incidence and prevalence of PAH in children is limited to a few national
registries. A retrospective, nationwide registry-based study performed in the Netherlands
during 1991-2005 revealed an annual incidence and point prevalence of 0.7 and 4.4 cases
per million children for iPAH, and 2.2 and 15.6 cases per million children for PAH
associated with CHD, respectively [van Loon 2011]. In France in 2005, the estimated
annual prevalence per million children was 2.2 cases of iPAH [Fraisse 2010]. Data from
the UK National Pulmonary Hypertension Service between 2001 and 2007 showed that the
incidence of iPAH was 0.48 cases per million children per year, and the prevalence 2.1
cases per million children [Moledina 2010].
In the majority of pediatric patients, PAH presents as iPAH or PAH associated with CHD
[Ivy 2013]. Data from various PAH pediatric registries have shown that iPAH accounts for
35% to 60% of cases in children, whereas CHD is also a common cause of PAH accounting
for 24% to 52% of pediatric patients (UK PH service [Moledina 2010]; the French PH
registry [Fraisse 2010]; the Netherlands PH registry [van Loon 2011]; the TOPP registry
[Berger 2012]; the US REVEAL registry [Barst 2012a]).
Diagnosis of PAH in children occurs at all ages and with an almost equal gender
distribution. These results are based on a systematic review of four prospective
observational registries [D-16.012].
1.1.4 Current Treatment and Unmet Clinical Need
At the time the study was designed, there was no PAH-specific therapy approved globally
for use in children. In Europe, sildenafil and bosentan were approved for pediatric use.
Bosentan was also approved for pediatric use in Japan. No PAH-specific therapies were
approved for children in the US. In the meantime, bosentan received approval for pediatric
use in some countries, such as China and the US.
The current management of pediatric PAH is based primarily on results from studies in
adult patients, together with expert recommendations, such as those from the 5th  World
Symposium for PH [Ivy 2013]. Results from different cohorts suggest that survival has

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improved in pediatric patients with the use of these therapies [Haworth 2009, Barst 2012a,
Moledina 2010, 
van Loon 2010, 
Zijlstra 2014]. 
However, 
treatment 
remains
unsatisfactory, with 5-year survival rates ranging from 71% to 75% [Ivy 2013].
Hence 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.
1.2 Study Treatment(s)
1.2.1 Macitentan
Macitentan (Opsumit®; macitentan 10 mg film-coated tablets) monotherapy or in
combination is indicated for the long-term treatment of PAH in adult patients of WHO
Functional Class (FC) II to III to delay disease progression. Macitentan has been approved
for PAH in multiple countries worldwide including the US, the European Economic Area
(EEA), Switzerland, Canada, Australia, and Japan.
Macitentan has been selected for further clinical development in pediatrics due to its long-
term effectiveness and good safety profile in adult PAH.
Mechanism of Action
Macitentan is an orally active, nonpeptide, potent dual endothelin (ET) ETA and ETB
receptor antagonist (ERA).
The endothelin system comprises a family of proteins originally described for their
vasoconstrictive activity [Levin 1995, Masaki 2000]. ET-1, a 21-amino acid peptide
produced by endothelial and other cells, is considered one of the most potent
vasoconstrictors known. Additionally, endothelins such as ET-1 and their receptors act as
paracrine and autocrine tissue factors to regulate biological processes such as tissue
remodeling and repair, smooth muscle cell proliferation and inflammation [Teder 2000,
Clozel 2003].
ET-1 is over-expressed in several forms of pulmonary vascular disease. It is likely a major
player in the vasodilator and vasoconstrictor imbalance, as well as in the abnormal
pulmonary vascular remodeling present in the development and progression of pulmonary
hypertension of various etiologies [Stewart 1991, Giaid 1993]. Plasma levels of ET-1
correlate with pulmonary hemodynamics [Giaid 1993], PAH severity and prognosis
[Rubens 2001].
Macitentan showed a dose-dependent efficacy similar to that observed with bosentan
(Tracleer®, the first ERA registered for the treatment of patients with PAH) in nonclinical
models of hypertension and PAH, but macitentan was approximately 10 times more potent
than bosentan.

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Pharmacokinetics and Metabolism
For details provided in this section and further information refer to the Investigator’s
Brochure (IB) ACT-064922 [Macitentan IB].
Macitentan has a pharmacologically active metabolite, aprocitentan (ACT-132577), in
humans.
In healthy subjects maximum plasma concentrations are generally achieved about 8h after
oral administration of macitentan. Thereafter, plasma concentrations decrease slowly with
anapparent terminal half-life (t1/2) of approximately 16 h (and 48 h for ACT-132577). After
multiple-dose administration steady-state conditions of macitentan are obtained after
3 days (and 7 days for ACT-132577). Macitentan accumulates only minimally (about
1.5-fold), whereas the active metabolite ACT-132577 accumulates substantially (about
8.5-fold). For plasma concentrations and other pharmacokinetic (PK) parameters measured
in Phase 1 studies, refer to the [Macitentan IB].
Bioavailability of macitentan and exposure to ACT-132577 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 PAH treatment at Baseline on plasma
concentrations of macitentan and ACT-132577.
Macitentan clearance is mediated by several human P450 enzymes including CYP3A4 and
CYP2C9 and is mainly eliminated via the urine (49.7% ± 3.9%).
ACT-132577 is approximately 5-fold less potent than macitentan in vitro. However, in
humans systemic exposure to ACT-132577 is about 3-fold higher as compared to
macitentan, and ACT-132577 contributes to the overall pharmacological effect. Formation
of ACT-132577 is mainly catalyzed by CYP3A4. At the maximum dose of 10 mg planned
in this clinical trial, macitentan and ACT-132577 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 ACT-132577. Conversely,
macitentan’s effect on sildenafil exposure is modest and can also be ignored.
In the presence of strong inhibitors of CYP3A4 (e.g., ketoconazole) and moderate dual
inhibitors of CYP3A4 and CYP2C9 (e.g., 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.

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Efficacy in Adult Patients With Pulmonary Arterial Hypertension
In 
SERAPHIN 
(AC-055-302), 
a 
multicenter, 
double-blind, 
randomized,
placebo-controlled, parallel group, event-driven, Phase 3 study in adult patients with
symptomatic PAH, 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 event with
a hazard ratio (HR) of 0.547 versus placebo (97.5% confidence limits [CL] 0.392-0.762,
log-rank p < 0.0001). The HR in the macitentan 3 mg group versus placebo was 0.704
(97.5% CL 0.516-0.960, log-rank 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, log-rank p < 0.0001). The respective HR in the
macitentan 
3 
mg 
group 
versus 
placebo 
was 
0.669 
(97.5% 
CL
0.462-0.970, log-rank 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].
Nonclinical Safety Data
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. Nonclinical safety pharmacology studies did not indicate
treatment-related effects, except for a decrease in arterial blood pressure (BP) in
cardiovascular studies in dogs.
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,

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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 [D-12.346], corresponding to 1.7-fold the human
therapeutic exposure.
Available data indicate that nonclinical pharmacology, PK and available toxicity data
support a pediatric development program and sNDA.
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 (i.e., 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 (i.e., 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] / aspartate
aminotransferase [AST] > 3 × upper limit of normal range [ULN] was 3.4% on macitentan
10 mg and 4.5% on placebo, ALT/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 leukocyte 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 (o.d.) or higher (maximum 300 mg o.d.), generating
exposures 6-10 times higher than those observed with 10 mg o.d., have been used over
several months in combination with temozolomide in patients with glioblastoma
[D-16.563]. These doses were well-tolerated, and in particular were not associated with a
different safety profile, or with an increased incidence or severity of known adverse drug
reactions for macitentan such as headache, hypotension, liver enzyme elevations, or
anemia, compared to 10 mg o.d. doses.

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During the post-marketing 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 Investigator’s Brochure
[Macitentan IB].
1.2.2 Benefit-risk Assessment for Participation in This Clinical Trial
Macitentan Group
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. 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.
To support the use of macitentan in the pediatric population in children with PAH
(TOMORROW, AC-055-312), a population PK model was developed to establish
macitentan doses with the aim of achieving similar systemic exposures to those observed
in  adults with  PAH, treated with  macitentan  10 mg o.d. doses. Exposures for children
≥2 to <18years ofage were predicted based on allometric scaling of an adult population
PK macitentan model, derived using PK profiles obtained in patients with PAH in a PK
substudy  of the SERAPHIN open-label extension  study. To cover the age range
≥2 to <18years with associated body weights (and volumes of distribution, i.e., blood),
an optimization approach was used to determine the dosing for specific body weight
ranges. Thereafter, simulations were performed to anticipate the distribution of exposure
for the selected dosing strategy in relation to the adult exposure. The selected doses and
their expected exposures in children are aimed at limiting under-dosing and insufficient
therapeutic effect.
The data used to develop the macitentan adult population PK model consisted of plasma
concentration samples collected over a 24-hour period at steady-state from  20 patients
with PAH  who participated in  the SERAPHIN  PK substudy (AC-055-303). This adult
population PK model for macitentan was updated through allometric scaling. Age factors
were not included in the model update as the metabolic pathways relevant for macitentan,

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i.e., primarily cytochrome P450 3A4 (CYP3A4), are fully  mature by 2 years of age
[Johnson 2006].
The proposed macitentan dosing regimen to be used in pediatric subjects < 2 years old
(y.o.) is as follows: 1 mg macitentan for subjects in the age range from 1 to <6 months;
and 2.5 mg macitentan for subjects in the age range from 6 months to <2 y.o.
The dosing regimen in pediatric subjects < 2 y.o. was proposed based on a population PK
modeling complemented with physiologically-based PK (PBPK) approach. A PK model
previously developed in adults was updated with the data from pediatric subjects ≥2 y.o.
The PK model was further incorporated with time course functions describing the
development of cytochrome P450 (CYP) enzymes to account for the development of the
elimination pathways in pediatric population < 2 y.o. (maturation functions). Simulations
with different doses were performed to establish the appropriate dosing regimens to
provide the predefined target systemic exposure range (i.e. AUCss) in subjects < 2 y.o.
similar to those observed in adult subjects receiving the 10mg once daily clinical dose.
Ongoing review of safety data in pediatric population (off-label use) as part of the periodic
safety update reports, did not raise any new safety concern including the population <24
months of age. In the TOMORROW population currently enrolled (i.e., ≥ 2 y.o.) did not
reveal any new safety concern, either. There is no need for additional safety monitoring in
children < 2 y.o. as compared to the safety monitoring done in children ≥ 2 y.o. As
described in Section 10.1.1 investigators will instruct parents/ care givers of study subjects
on how to report specific and unspecific symptoms (including vomiting, diarrhea,
sleepiness, change in pattern of crying, etc.) in order to reduce the risk for under- or mis-
reporting.
Taking into account the following factors, it is justified to include  pediatric participants ≥
1 month to < 18 years of age: no new safety concern from the currently enrolled population
(i.e., ≥ 2 y.o.) in TOMORROW study, no new safety concern coming from the periodic
safety reports in the population < 24 months, the lack of organ-specific toxicity or specific
developmental concerns in juvenile animals; the safety profile corresponding to that of
adult patients in adolescents on 10 mg doses showing no indication of different or more
severe AEs in earlier studies and post-marketing; and the good tolerance for high doses
and exposures of macitentan in adult patients with glioblastoma.
Macitentan is approved for treatment in adult PAH as a 10 mg o.d. dose based on a
favorable benefit-risk ratio [see Sections 1.2.1.3 and 1.2.1.5 on efficacy and safety in
adults]. 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
receiving a 10 mg dose, will also result in a favorable benefit-risk ratio.

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Comparator Group
In the comparator group, subjects will receive best available care which may include an
ERA (other than macitentan). Thus subjects will not be deprived of any treatment.
Additional Benefits and Safety Measures:
Subjects in both treatment groups will receive additional attention by being in a clinical
trial including close monitoring every 12 weeks at a PAH expert center. In addition, if
disease progresses, treatment can be escalated by the investigator immediately and without
any restrictions, as per best local practice. Macitentan treatment will be offered to subjects
in the SoC group after a CEC-confirmed disease progression event, if this is considered in
their best interests per their investigator’s judgment.
It is the investigator’s responsibility to monitor the risk-benefit ratio of study treatment
administration, as well as the degree of distress caused by study procedures on an
individual subject level, and to discontinue study treatment or the study procedures if, on
balance, he/she believes that continuation would be detrimental to the subjects’ well-being.
Safety surveillance for patients participating in study AC-055-312 will additionally be
ensured by  an independent data safety  monitoring committee (IDMC) which  will
periodically review unblinded safety and efficacy data [see Section 3.4].
1.2.3 Standard of Care
Although clinical studies have been performed in children with PAH (e.g., 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.
As per recent guidelines children with negative acute vasoreactivity response should be
treated with an ERA or a phosphodiesterase Type 5 (PDE-5) inhibitor. If despite such
treatment there is PAH deterioration, combination therapy should be given which can also
include inhaled prostanoids. In children who are at higher risk of death
(e.g., signs/symptoms of right heart failure, progression of PAH symptoms and/or WHO
FC, syncope) it is strongly advised to initiate intravenous (IV) or subcutaneous (SC)
prostanoids [Ivy 2013, Galiè2015, Abman 2015].
Endothelin Receptor Antagonists
ET-1 is over-expressed in several forms of pulmonary vascular disease. The mechanism of
action of ERAs is described in Section 1.2.1.1.
Bosentan has been studied in children with PAH in five prospective, open-label trials:
BREATHE-3, FUTURE 1, 2, 3 and 3 extension study [refer to Table 4].

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Table 4: 
Clinical Trials Studying Bosentan in Pediatric PAH
Study  
Study 
Objectives
Design 
Study Population 
Sample
enrolled (n) 
Treatment dose/
duration
Exploratory Efficacy Results
BREATHE-3
[B-02.003]
PK,
tolerability,
safety of adult
formulation
Prospective,
multicenter, OL,
non-controlled,
parallel group,
single-and
multiple-dose
Age: 3-15 years
Etiology: primary PAH
or aPAH-CHD
Severity: WHO FC II/III
19 
Dose: ~2 mg/kg b.i.d.
> 40 kg: 125 mg b.i.d.
> 20-40 kg: 62.5 mg
b.i.d.
10-20 kg: 31.25 mg
b.i.d.
Median Exposure:
23.9 weeks
Mean changes from Baseline in hemodynamic
variables:
mPAP: −8 mm Hg (p < 0.01),
PVRi: −300 dyn×sec×m2/cm5 (p < 0.05),
CO: +0.61 L/min (p < 0.05)
FUTURE 1
[D-07.041]
and its
extension
study
FUTURE 2
[D-12.790]
PK, safety,
tolerability,
efficacy of
pediatric
formulation
Prospective,
multicenter, OL,
single-arm, non-
controlled
Age: 2-11 years
Etiology: iPAH, hPAH
Severity: WHO FC II/III
36 
(Extension
study: 33) 
Dose: 2 to 4 mg/kg
b.i.d.
Median Exposure:
120 weeks
(8-258weeks)
Disease progression (death, transplantation,
hospitalization for PAH worsening, new PAH therapy
or new/worsening RHF): KM event-free estimates at
Month 12 was 65.8% (95% CL: 47.7, 78.9%), at
Month 24 was 56.2% (95% CL: 38.0, 71.0%), at
Month 36 was 51.9% (95% CL: 33.4, 67.5%).
FUTURE 3
and its
extension
study
[D-13.335]
[D-14.491]
PK,
tolerability,
safety and
efficacy of
pediatric
formulation
Prospective,
multicenter, OL,
randomized,
multiple-dose
Age: 3 months-11 years
Etiology: iPAH/hPAH,
aPAH-CHD (including
Eisenmenger)
Severity: WHO FC I-III
64
(Extension
study: 58)
Dose: 2 mg/kg b.i.d. vs
2 mg/kg t.i.d.
Median Exposure:
72 weeks (0.4-90
weeks)
WHO FC: worsening from Baseline
At Month 12: 10.9% (12.1% in b.i.d., 9.7% in t.i.d.)
At Month 18: 12.5% (15.2% in b.i.d., 9.7% in t.i.d.)
Disease progression (death, lung transplant,
hospitalization for PAH worsening, new PAH therapy
or new/worsening RHF): KM event-free estimate at
Month 12 was 81.4% (95% CL: 69.0, 89.3%)and at
Month 18 was 74.1% (95% CL: 60.8, 83.6%)%).
aPAH CHD  PAH associated with congenital heart disease, b.i.d.  twice a day, CO  Cardiac Output, CL  confidence limits, hPAH  heritable PAH, iPAH  idiopathic PAH, KM
Kaplan
Meier, mPAP  mean pulmonary artery pressure, OL  open label, PAH  pulmonary arterial hypertension; PK  pharmacokinetics, PVRi  pulmonary vascular resistance index, RHF 
right heart failure, t.i.d.  three times a day; WHO FC  World Health Organization Functional Class. Sources [B 02.003; D 07.041; D 12.790; D 13.335; D 14.491].

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For ambrisentan, another ERA, only limited data are available in children. In a
retrospective cohort study, effects of ambrisentan were studied in 38 patients (aged 2 to 18
years). After a median treatment duration of 21 months there was a significant
improvement in mPAP as compared to patients on alternative PAH-specific treatment.
There was no effect on other hemodynamic variables (such as cardiac index, PVR index
[PVRi]) [Takatsuki 2013a].
Phosphodiesterase-5 Inhibitors
PDE-5 inhibitors prevent enzymatic degradation of cyclic guanine monophosphate and
thereby lead to vasodilation. In addition they have some antiproliferative effects
[MacKenzie 2015].
The effect of sildenafil was assessed in STARTS-1, a multicenter, randomized,
double-blind, placebo-controlled dose-ranging study in treatment-naïve children with PAH
(aged 1 to 17 years). Patients were randomized to either receive low-dose (n 
 42),
medium-dose (n
55), high dose (n  77) sildenafil or placebo (n  60), see Table 5. After
16 weeks of treatment exercise capacity as measured by cardiopulmonary exercise testing
(peak oxygen consumption, i.e., PVO2) did not meet the primary endpoint (p
0.056).
However, PVO2 improved in the medium and high dose groups compared to placebo. In
addition, there was improvement in mPAP and PVRi in the medium- and high dose
sildenafil groups as compared to placebo [Barst 2012b]. Long-term treatment with
sildenafil was assessed in the extension study, STARTS-2. Kaplan-Meier estimates for
survival at 3 years were 93% for the low-dose, 91% for the medium-dose, and 87% for the
high dose group [Barst 2014]. The EMA approved use of sildenafil in children with PAH
but warned against use of the high dose. Sildenafil is not approved for pediatric use in the
US nor is it recommended by the FDA for use in children [Revatio® USPI] and can only
be considered for prescription on an individual basis.
Table 5: 
Sildenafil Doses Administered 3 Times Daily in STARTS-1
Sildenafil dose [mg]
Body weight [kg] 
Low  
Medium  
High
≥ 8 to 20 
Not applicable 
10 
20
> 20 to 45 
10 
20 
40
> 45 
10 
40 
80
Derived from [Barst 2012b].
For tadalafil, retrospective data in 33 PAH patients (aged 4 to 18 years) have been
published. In 4 patients tadalafil was given as initial therapy, in 29 patients sildenafil

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treatment was switched to tadalafil mainly to allow once daily dosing. In 14 of those
patients a repeat catheterization was performed and showed statistically significant
improvement in mPAP and PVRi [Takatsuki 2012].
For vardenafil, there are no pediatric data. In treatment-naïve adults with PAH vardenafil
increased exercise capacity, 6-minute walk distance (6MWD), and reduced clinical
worsening as compared to placebo [Wardle 2013, Jing 2011].
Prostanoids
Prostacyclin, an endogenous prostaglandin primarily produced by endothelial cells, is a
potent inducer of vasodilation. In addition, it inhibits platelet aggregation and appears to
have both cytoprotective and antiproliferative activities. In patients with PAH prostacyclin
synthesis is reduced. Administration of prostacyclin or analogs can improve PAH
symptoms, exercise capacity and hemodynamics [Galiè2013].
In a cohort of 22 PAH patients (aged 4.5 to 17.7 years) inhaled iloprost lowered mPAP and
caused sustained functional improvement. The need for 6 to 9 inhalations daily negatively
impacting compliance and side effects such as bronchoconstriction may however limit
chronic treatment in children [Ivy 2008].
A retrospective analysis performed in 29 PAH patients (aged 3.2 to 19 years) indicated that
inhaled treprostinil as add-on to PAH-specific background therapy was associated with
improved exercise capacity (6MWD and PVO2) and WHO FC [Krishnan 2012]. The
efficacy of IV and SC treprostinil seems to be comparable to the one of epoprostenol. This
is based on a retrospective cohort of 77 patients with PAH (aged 0.04 to 13.3 years)
evaluating hemodynamics and long-term transplant-free survival in patients receiving
either of these medications [Siehr 2013]. Subcutaneous administration of treprostinil is
however often painful and difficult to tolerate. In adults infusion site pain was reported in
92% of patients and 23% of patients discontinued treatment because of site pain and/or
reaction [Barst 2006].
Retrospective data of using IV epoprostenol in children with severe PAH (WHO FC III/IV)
suggest improvement in survival, WHO FC, and exercise capacity. In this retrospective
cohort of 39 patients (aged 4 months to 17 years) IV epoprostenol was initiated if the
children failed to appropriately respond to oral PAH-specific therapy or were severely
symptomatic. Epoprostenol alone was insufficient to maintain clinical improvement in 14
children who needed additional treatment with either bosentan or sildenafil. Complications
related to IV administration included infections and leaking lines [Lammers 2007].
1.3 Purpose and Rationale of the Study
The purpose of the study is to establish the PK, safety and efficacy of macitentan in children
with PAH treated with a dispersible formulation using a clinical composite primary

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endpoint and targeting a similar exposure as seen in adults with macitentan 10 mg [refer to
Section 1.2.1.3].
The overall rationale is based on the positive Phase 3 study of macitentan in adults with
PAH (AC-055-302) which showed significant clinical benefit and a good overall safety
profile [refer to Sections 1.2.1.3 and 1.2.1.5].
2 STUDY OBJECTIVES
2.1 Primary Objective
The primary objective of the study is to evaluate the PK of macitentan in children with
PAH.
2.2 Secondary Objectives
To assess safety and tolerability of macitentan in children with PAH.
To assess efficacy of macitentan in children with PAH.
3 
OVERALL STUDY DESIGN AND PLAN
3.1 Study Design
This is a prospective, multicenter, open-label, randomized, controlled, parallel group,
Phase 3 study with an open-label single-arm extension period to evaluate PK, safety and
efficacy of macitentan in children with PAH.
Children < 2 y.o. will be assigned as a cohort to the macitentan group without
randomization.
Approximately 200 subjects and no more than 300 subjects will be enrolled in this study
based on current feasibility. Subjects ≥ 2 y.o. at Visit 2 will be randomized in a 1:1 ratio to
either receive macitentan or continue SoC. Randomization is stratified by ongoing/planned
ERA treatment at randomization (yes vs no) and by WHO FC at randomization (FC I/II vs
FC III). The proportion of subjects with ERA treatment, as a component of the planned
SoC, is limited to a maximum of40% of the overall number of subjects randomized.
Cohort of children <2 y.o. will not be randomized but will enter directly into the macitentan
arm. The ERA cap does not apply to this cohort.
In consideration of the different requirements from Health Authorities, two important
milestones (i.e., fourth quarter of 2022 (Analysis 1), and first quarter of 2024 (Analysis 2),
respectively) will trigger the analysis timepoints.
There will be three time points of study analysis:
 Analysis 1 of Core Period: with cutoff date in the fourth quarter of 2022

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 Analysis 2 of Core Period: with cutoff date in the first quarter of 2024
 Analysis 3 final analyses including the core and single-arm extension periods.
The sponsor will determine the cutoff date for the first two analyses three months prior to
this date and will document the decision accordingly in the Trial Master File.
The cohort <2 y.o. may be analyzed at additional timepoints in order to allow ongoing
evaluation of benefit-risk in this vulnerable population.
Study duration for each individual subject will be based on their time of enrollment. All
subjects are planned to remain in the study until the database lock in 2024 (Analysis 2).
Thereafter, if it is considered in the best interest of the subject, continuation in the open-
label single-arm extension period with macitentan will be offered.
The study will be conducted at approximately 90 sites in about 30 countries. Sites with no
screening activities or subject enrollment may be replaced.
The study consists of the following periods:
Screening Period: Starts from signed informed consent and ends with randomization or
confirmation of screening failure (up to 6 weeks after signed informed consent).
Cohort of children <2 y.o.: The screening period ends with confirmation of eligibility (i.e.,
age at Visit 2 is less than 2 years) and assignment of macitentan kit at Visit 2, or with
screening failure.
Core Period: Commences with Visit 2 and continues until the End of Core Period (EOCP)
visit. 
Pre-Event Study Phase (Pre-Event SP): Starts from Visit 2 until disease progression
event confirmed by the CEC or until EOCP visit, whichever comes first.
Post-Event Study Phase (Post-Event SP): Begins with CEC-confirmed disease
progression event and continues until EOCP visit. During Post-Event SP PAH-specific
background treatment may be escalated in both treatment arms as per local practice.
Any additional treatment, including IV  or SC prostanoids may be used in both
treatment arms. Subjects in the macitentan arm can continue receiving macitentan.
Subjects in the SoC arm are offered to cross-over to macitentan treatment, if this is in
their best interests per their investigator’s judgment.
End of Macitentan (EOM): All subjects treated with macitentan who prematurely
discontinue macitentan will have an EOM visit within 1 week after the last dose of
macitentan.

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Survival Follow-up: Applies to subjects who prematurely discontinue regular study visits
during Core Period. Survival data will be collected at least yearlyafter the last regular study
visit and until EOCP for Analysis 2 . In these subjects the last survival follow-up contact
constitutes their EOS.
End of Core Period (EOCP) Visit: This visit will occur in first quarter of2024 and before
the cutoff date for Analysis 2 which will be announced by the sponsor. For subjects who
don’t enter the Single-Arm Extension Period the EOCP visit constitutes their End-of-Study
visit.
Safety Follow-up Period: Applies to subjects who prematurely discontinue macitentan or
SoC treatment during Core Period or during the single-arm extension period (SAEP). In
addition, it applies to subjects at EOS who do not enter the SAEP or who do not go into a
PTA or LTE study. It begins immediately after premature end of treatment or after
EOCP/EOS and ends at least 30 days later with a safety follow-up telephone call.
Subjects prematurely discontinuing treatment during the Core Period are encouraged to
continue participation in the study according to the regular study visit schedule or at least
agree to Survival Follow-up until EOCP. Only for subjects whose parent(s) / legal
representative withdraw consent to further study participation the safety follow-up
telephone call is EOS.
In addition, and as per local practice, unscheduled visits may also take place, in which case
study-related information as specified in Section 8.11 will be collected and recorded in the
electronic Case Report Form (eCRF).
Single-arm Extension Period (SAEP): This period starts at EOCP visit and ends at EOS
visit. Subjects who are in the 12-weekly regular visits at EOCP visit, and for whom the
investigator judges that macitentan treatment could be beneficial and who fulfill the safety
criteria to initiate or continue macitentan treatment are eligible to enter the open-label
single-arm extension period.
End of Study (EOS) Visit: At the end of the SAEP each subject will come for an EOS Visit
within 12 weeks of the Sponsor announcing the end of the study. For subjects who
discontinue the study prematurely the last visit or last survival FU contact constitutes their
EOS visit.
For subjects who cannot access macitentan, acontinued access program will be put in place
(e.g., post-trial access [PTA], long-term extension study  [LTE]) to allow treatment
continuation, if assessed beneficial by the investigator and within local regulations.
For subjects rolling over to PTA or LTE study after the SAEP, the enrollment must occur
on the day of the last visit of this study ie, EOS Visit to avoid macitentan treatment

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interruption. These subjects will not have a Safety FU call in TOMORROW since their
safety follow-up continues in the respective PTA or LTE study.
Pharmacokinetic (PK) Substudy for Subjects ≥ 2y.o.
Participation in the PK substudy is optional for up to 40 subjects ≥ 2 y.o. receiving
macitentan.
At steady-state conditions, a PK profile will be collected over 24 hours from subjects ≥ 2
y.o. treated with macitentan. Collected PK data (both PK profiles and trough
concentrations) will be regularly assessed using non-linear mixed effects pharmacokinetic
modeling during the course of the study to confirm the appropriateness of the selected
dosing regimen in subjects older than 2 years. A formal sample size calculation will
determine the amount of PK data (full PK profile plus trough samples collected) required
to ensure at least 80% power to conclude that exposure in pediatric subjects is as targeted
from the knowledge available from adults.
Modeling and simulation have  been performed based on the  PK data from pediatric
subjects older than 2 years and adults to select the appropriate daily dose in subjects below
2 years of age. The modeling and PK data will be reported separately (i.e., not included in
the Clinical Study Report [CSR]).
The participation in the PK substudy will be controlled via Interactive Response
Technology (IRT) system.
A separate informed consent will be obtained for participation to the PK substudy. Subjects
who prematurely discontinue macitentan treatment before the scheduled Visit 3 are
excluded from the PK substudy.
PK Assessment for Subjects < 2 y.o.
All subjects < 2 y.o. will have PK assessments (refer to Section 7.7) to allow adequate
characterization of macitentan PK and dose regimen in this age cohort.
Sparse and patient-centric sampling will be utilized to reduce the burden of extensive blood
collections in young children. Samples over 24 hours after the first dose and two trough
samples at steady-state will be collected. Collected PK data will be regularly assessed using
non-linear mixed effects pharmacokinetic modeling during the course ofthe study to
confirm the appropriateness of the selected dosing regimen in these subjects.
Macitentan and ACT-132577 (aprocitentan) concentrations will be summarized
descriptively and reported in the CSR. The population PK analysis will be reported
separately. 

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Study Duration
The study starts with the first act of recruitment (i.e., Informed Consent Form [ICF] signed)
and ends with the last visit/contact of the last subject. The study is considered completed
when the last subject completes the study (i.e., last EOS visit).
This is a calendar-driven study and time points of analysis depend on dates to meet
regulatory commitment.
Study duration for each individual subject will be based on their time of enrollment. All
subjects are planned to remain in the study until the cutoff date for Analysis 2 in 2024.
Thereafter, if it is considered in the best interest of the subject, continuation in the open-
label single-arm extension period with macitentan will be offered.
Subject participation in the Core Period at timepoint of Analysis 2 will be up to 7 years.
Participation in the SAEP will be at least 24 weeks.
Overall study duration (including Core Period and extension period) will be a minimum of
7 years (from first subject screened until last subject last EOS visit).
The overall study design is depicted in Figure 1.

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Figure 1: 
Study Design
  EOS 
 end of study; FU 
 follow up; IV  
 intravenous; PAH 
 pulmonary arterial hypertension; PDE
5i
phosphodiesterase Type 5 inhibitor; PK  pharmacokinetics; SC
 subcutaneous.
1 
The PK Visit will occur under steady state conditions (i.e., ≥ 10 days of same macitentan dose), as described in
Section 8.4.
2 
After disease progression confirmed by the CEC, the subject enters the Post Event Study Phase. In the macitentan
group, the study treatment will continue during this Post Event Study Phase until EOS. Subjects in the SoC group
will be offered cross-over to macitentan, if this is considered in the best interests of the subject per their
investigator’s judgement. The Cross over Visit is described in Section 8.10.
3 
Subjects discontinuing macitentan or SoC treatment prematurely have a Safety FU call 30 days (+ 1 week) after the
treatment stop. End of standard of care will be declared, if a planned PAH specific drug class is discontinued, or if
any additional PAH specific drug class is added, or if subjects cross over to macitentan after CEC confirmed disease
progression.
4 
Subjects discontinuing site visits during the Core Period will have Survival FU contacts at least yearly to collect vital
status.
5 
Subjects still in the 12 weekly visit schedule at Analysis 2 will come for the EOCP Visit before the cutoff date
announced by the Sponsor, and will be offered to enter the single arm extension period. The eligibility to
continue/start macitentan in the single arm extension period (SAEP) must be confirmed as described in Section 8.13.

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For subjects who continue macitentan or SoC treatment until EOCP but do not enter the SAEP, the EOCP will
constitute their EOS Visit and they will have a Safety FU call 30 days (+ 1 week) after EOS.
Note: For subjects who after EOS in the SAEP cannot access macitentan continued access program will be put in place
(e.g., post trial access [PTA] or long term extension [LTE] study) to allow treatment continuation as per local
regulations. For subjects who complete the study treatment and who are eligible for a continued access program (PTA
or LTE study), enrollment into the continued access program should occur on the same day as the EOS Visit to avoid
macitentan treatment interruption and the Safety FU period will be waived.

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3.2 Study Design Rationale
As per ICH [ICH E11 Guidelines] the efficacy of medications approved in adults can be
assumed to be comparable for the same indication in children if the disease process is
similar in the two populations, which is the case for PAH [Barst 2011]. A long-term, open-
label controlled trial investigating the PK, safety and evaluating the totality of efficacy of
macitentan in children is deemed appropriate.
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 and mortality as the most clinically meaningful outcomes in PAH [Ivy 2013,
Chakinala 2013]. Successful use of such endpoints in adult studies [Pulido 2013,
Sitbon 2015] suggests that it is worthwhile to also consider similar endpoints and
assessments in the pediatric population. However, based on disease rarity hampering
recruitment, and current management of pediatric PAH patients leading to slow disease
progression powering a pediatric study to show delay in disease progression can take more
than 10 years and is not considered feasible.
It is deemed necessary to establish the PK of macitentan in children to allow correct dosing
and to evaluate efficacy of macitentan considering the totality of evidence including all
efficacy endpoints.
The open-label design with SoC as a comparator arm has considerable ethical and scientific
merit: (i) it does not impose specific therapies as comparator in the absence of well
documented effectiveness of any PAH-specific therapy in children and approval of these
globally, (ii) it allows all children to be treated with either best SoC according to
investigator’s judgment or with macitentan, a compound that has demonstrated efficacy on
delaying disease progression in adults, and (iii) it allows inclusion of a wide population
representative of the overall pediatric PAH patients regardless of their previous PAH-
specific therapy.
In order to minimize potential bias related to the open-label design, some aspects of the
study conduct have been  outsourced to Contract Research Organizations (CROs). The
firewalls put in place between blinded and unblinded study team members are described in
a dedicated Firewall Charter. The Sponsor representatives preparing and reviewing the
Statistical Analysis Plan (SAP) for the Core Period will remain blinded until the Analysis
1 results are available. Sponsor representatives accountable for Safety Monitoring will
review the SAP sections related to safety analysis and will have partial access to unblinding
information as described in the Firewall Charter.
Medical treatment guidelines for pediatric PAH recommend the use of PAH-specific
combination therapy for children who have progression of PAH symptoms or clinical

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evidence of right heart failure [Rosenzweig 2019]. However, not all study subjects have
access to an ERA treatment. Therefore, after CEC-confirmed disease progression
macitentan is offered to those subjects who may benefit from such treatment per their
investigator’s judgment. It is expected that this will improve subject retention. In order to
reduce potential reporting bias for disease progression in the SoC group, macitentan will
only be offered after the event has been confirmed by the blinded CEC.
Enrollment of children < 2 y.o. can only be initiated with Protocol V9 since sufficient PK
data was needed in older children in the TOMORROW study to determine the daily
macitentan doses necessary to reach similar exposure in the youngest age cohort as
described in Section 1.2.2. Consequently, the recruitment period for children < 2 y.o. is
marginally shorter as compared to the recruitment period of the older age groups. In
addition, the age cohort < 2 y.o. is rare and PAH diagnosis is lengthy since transient PH
must be excluded and PAH after shunt repair cannot be reliably diagnosed within the first
few months after surgery delaying the diagnosis [Haarman 2020, Ivy 2013, Kwiatkowska
2020]. Aiming to establish the PK and safety of macitentan also in patients <2 y.o. those
will be directly enrolled into the macitentan arm without randomization. This will ensure
that data are generated on macitentan and not on standard of care. Efficacy assessments
will still be performed as applicable in this age cohort.
The single-arm open-label extension period allows seamless continuation of treatment and
access to the study drug for all subjects if this is considered in their best interest and trial
results do not reveal any harmful effect in the pediatric population.
3.3 Site Personnel and Their Roles
The following tasks must be carried out by a physician as delegated by the principal
investigator (PI):
 
Informed consent process (study physician must be involved in the process)
 
Specific protocol procedures including:
o decision on subject eligibility,
o macitentan prescription (decision on start and discontinuation),
o reporting of SAEs,
o reporting of disease progression,
 
eCRF sign off.
Note: in some regions an Advanced Practice Role (or an equivalent), such as a registered
nurse practitioner, can perform the consent interview and sign the ICF without a second
signature of a physician. However, there must be documented acceptance by the respective
Independent Ethics Committee (IEC) / Institutional Review Board (IRB), and Delegation
of Authority must be given by the PI. A physician must be available to answer any medical

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questions or questions regarding alternative therapies and this must be documented in the
source data of the subject.
3.4 Study Committees
An IDMC has overall responsibility for safeguarding the interests of subjects by
monitoring safety, tolerability and efficacy data obtained in the study and making
appropriate recommendations based on the reported data, thus ensuring that the study is
being conducted with the highest scientific and ethical standards. The IDMC will be fully
operational prior to enrolment of the first subject into the study. The composition and
operation of the IDMC is described in the IDMC Charter.
The IDMC may recommend modifications of the protocol (to enhance subject safety) or
recommend early termination of the study if major concerns arise about subject safety at
any time during the course of the study or during any other study with the same
investigational drug.
An Independent Statistical Analysis Center (ISAC, not otherwise involved with study
conduct or statistical analysis) will have access to the randomization list and will generate
the monitoring reports exclusively for review by the IDMC.
The ISAC will also be in charge of monitoring, in collaboration with the IDMC, the number
of disease progression events occurring over time, in order to make appropriate predictions
for number of events anticipated by timepoint of Analysis 1 and Analysis 2.
A CEC consisting of independent PAH experts also including pediatricians has been
appointed to review and adjudicate in a blinded fashion the secondary endpoints related to
disease progression [see Section 6.1.2]. The composition and operation of the CEC is
described in the CEC Charter. The CEC Coordinator will provide feedback on the
adjudication decisions of the events to the investigators. In order to ensure exhaustive and
systematic adjudication, in addition to disease progression events reported by the
investigator [refer to Section 8.9], subject cases will be submitted to the CEC if at least one
of the following conditions is reported by the investigator: death, (S)AEs denoting PAH
worsening/ right heart failure (pre-specified list of MedDRA terms in CEC Charter),
interventions such as lung transplantation, atrial septostomy and Pott’s anastomosis, new
administration of at least one PAH-specific medication, initiation of IV diuretics or chronic
use of oxygen. Generic/brand names of PAH-specific medications will be blinded to the
CEC to reduce assessment bias. If there is any change to key data (defined in the CEC
Charter) or new key data become available after a first submission of a subject case to the
CEC, the CEC Coordinator re-submits the case for re-adjudication.
An independent Baseline Characteristics Adjudication Committee (BCAC) will review and
approve the randomization  before macitentan start for children < 2 y.o. / eligibility of

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subjects with PAH with co-incidental CHD i.e., small atrial septal defect, ventricular septal
defect or patent ductus arteriosus which themselves do not account for the development of
elevated PVR. This independent review is governed by a Charter.
An Independent Liver Safety Data Review Board (ILSDRB), a non-study-specific external
expert committee of hepatologists, will receive cases of serious hepatic events of special
interest from the Sponsor. This board provides ongoing assessment and advice regarding
cases that may require further evaluation during the study.
4 
SUBJECT POPULATION
4.1 Subject Population Description
Study AC-055-312 includes male and female pediatric subjects aged ≥ 1 month to <18
years.
Subjects with iPAH or hPAH, as well as PAH associated with CHD, drug or toxin-induced
PAH, or CTD and PAH associated with HIV are enrolled if they are of WHO FC I, II, or
III.
Eligible subjects are PAH-specific treatment-naïve, or already treated with PAH-specific
monotherapy or double combination therapy excluding macitentan and IV/SC prostanoids.
Cohort of children < 2 y.o. is allowed to enter on macitentan.
Subject randomization will be stratified according to clinical variables outlined in
Section 3.1.
4.2 Rationale for the Selection of the Study Population
Pediatric subjects with PAH across all age groups and of all etiologies relevant in children
[refer to Section 4.1] are enrolled to cover a generalizable pediatric PAH population.
Within the subgroup of PAH associated with CHD, the protocol excludes patients with
Eisenmenger syndrome as well as patients with open left-to-right shunts due to lack of
sufficient adult data supporting efficacy of macitentan in children. Subjects with Down
Syndrome, representing an important subset of subjects with CHD, will also be included.
This provides an opportunity to assess the efficacy and safety of a targeted PAH therapy in
this subgroup rarely evaluated in randomized clinical trials.
Macitentan has shown benefit in both treatment-naïve adults as well as in adults previously
treated with PAH-specific therapies. A similar benefit is anticipated in children. Subjects
on triple combination therapy are excluded because treatment escalation is part of the
clinical worsening component of the secondary efficacy endpoint and the possibility for
further escalation in such subjects would otherwise be very limited.

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WHO FC I, II, or III subjects are targeted since they classify for monotherapy or double
combination therapy with a PAH-specific drug. Inclusion of WHO FC I and II subjects will
allow for the investigation of occurrence of disease progression in less advanced disease.
In children, PAH is associated with rapid disease course justifying early targeted therapy
[Lammers 2007].
4.3 Inclusion Criteria
For inclusion in the study, all of the following inclusion criteria must be fulfilled. It is not
permitted to waive any of the criteria for any subject:
1. Signed informed consent by the parent(s) or legally designated representative AND
assent from developmentally capable children prior to initiation of any study-mandated
procedure.
2. Criterion modified per Amendment 8 Version 9:
Males or females between ≥1 month and <18years of age.
3. Criterion modified per Amendment 8 Version 9:
Subjects with body weight ≥3.5 kg at randomization.
4. Criterion modified per Amendment 6: PAH diagnosis confirmed by historical RHC
(mPAP ≥25 mm Hg, and PAWP ≤15 mm Hg, and PVRi > 3 WU x m2), where in the
absence of pulmonary vein obstruction and/or significant lung disease PAWP can be
replaced by LAP or LVEDP (in absence of mitral stenosis) assessed by heart
catheterization.
5. PAH belonging to the Nice 2013 Updated Classification Group 1 (including subjects
with Down Syndrome) and of following etiologies:
 iPAH
 hPAH
 PAH associated with CHD:
 PAH with co-incidental CHD (confirmed by BCAC)
 Post-operative PAH (persisting/recurring/developing ≥6 months after repair of
CHD)
 Drug or toxin-induced PAH
 PAH associated with HIV
 PAH-aCTD
6. WHO FC I to III.
7. PAH-specific treatment-naïve subjects or subjects on PAH-specific treatment
(mono-therapy or combination of two therapies)*.
8. Females of childbearing potential must have a negative pregnancy test at Screening and
at Baseline, and must agree to undertake monthly pregnancy tests, and to use a reliable
method of contraception (if sexually active) up to EOS .

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*Note to inclusion criterion 7: Treatments other than PDE-5 inhibitors, such as
prostanoids, cannot be continued in the macitentan arm, and therefore will have to be
stopped [see Section 5.1.1] if the patient is randomized into the macitentan arm. The
appropriateness of stopping such treatment must be assessed by the investigator before
screening the patient for the study and should not be done for the sole objective of selecting
a patient for the study.
4.4 Exclusion Criteria
Subjects must not fulfill any of the following exclusion criteria. It is not permitted to waive
any of the criteria for any subject:
Etiology
1. Subjects with PAH due to portal hypertension, schistosomiasis, pulmonary
veno-occlusive disease and/or pulmonary capillary hemangiomatosis, and persistent
pulmonary hypertension of the newborn.
2. Subjects with PAH associated with open shunts, as specified below:
a. Eisenmenger syndrome
b. Moderate to large left-to-right shunts.
3. Subjects with the following congenital cardiac abnormalities:
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 subjects with Fontan-palliation.
4. Subjects with pulmonary hypertension due to lung disease (e.g., bronchopulmonary
dysplasia).
5. Criterion added per Amendment 8 Version 9:
Subjects with known diagnosis of bronchopulmonary dysplasia.
Treatment and intervention
6. Subjects receiving a combination of > 2 PAH-specific treatments at randomization.
7. Treatment with IV or SC prostanoids within 4 weeks before randomization, unless
given for vasoreactivity testing.
8. Criterion added per Amendment 8 Version 9: 
In children ≥ 2 y.o.: Previous treatment with macitentan at any time.
9. Treatment with another investigational drug within 4 weeks prior to randomization.
10. Any PAH-related surgical intervention planned, or subjects listed for organ
transplantation related to PAH.
11. Treatment with strong inducers of CYP3A4 such as rifabutin, rifampicin, rifapentin,
carbamazepine, phenobarbital, phenytoin, St. John’s wort (hypericum perforatum),
within 4 weeks prior to randomization.
12. Systemic treatment with strong inhibitors of CYP3A4 such as boceprevir,
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nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and
voriconazole within 4 weeks prior to randomization.
13. Criterion modified per Amendment 3.1 Version 4.1:
Systemic treatment with moderate dual CYP3A4/ CYP2C9 inhibitor (e.g., fluconazole
and amiodarone), or administration of a combination of a moderate CYP3A4 (e.g.,
ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) together with a
moderate CYP2C9 inhibitor (e.g., miconazole, piperine) within 4 weeks prior to
randomization.
Baseline abnormalities
14. Subjects with pulmonary vein stenosis.
15. Known concomitant life-threatening disease with a life expectancy < 12 months.
16. Hemoglobin or hematocrit < 75% of the lower limit of normal range (LLN).
17. Serum AST and/or ALT > 3 ×ULN.
18. Criterion modified per Amendment 6 Version 7: Severe hepatic impairment, e.g.,
Child-Pugh Class C [see Appendix 1].
19. Clinical signs of hypotension which in the investigator’s judgment would preclude
initiation of a PAH-specific therapy.
20. Criterion added per Amendment 6 Version 7: Severe renal insufficiency (estimated
creatinine clearance <30 mL/min or serum creatinine >221 µmol/L)
Pregnancy and breastfeeding
21. Pregnancy (including family planning) or breastfeeding.
Other categories
22. Known hypersensitivity to ERAs, or any of the excipients.
23. Drug or substance abuse, or any condition that, in the opinion of the investigator, may
prevent compliance with the protocol or adherence to study treatment.
Note: The assessment for hepatic impairment at Screening (Child Pugh Score) must be
fully documented for patients with hepatic impairment as part of their medical history
and/or clinical signs and evidence (from the local lab) of hepatic impairment.
4.5 Criteria for Female Subjects of Childbearing Potential
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 subjects of childbearing
potential who are sexually active must use a reliable method of contraception.
4.5.1 
Definition of Childbearing Potential
A female subject is considered to be of childbearing potential unless she meets at least one
of the following criteria:

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 
Prepubescence*
 
Previous 
bilateral 
salpingectomy, 
bilateral 
salpingo-oophorectomy 
or
hysterectomy.
 
Tubal sterilization#
 
Premature ovarian failure confirmed by a specialist.
 
XY genotype or any other genetic disorder associated with permanent sterility,
uterine agenesis.
* Childbearing potential status will be assessed at each visit and recorded in the eCRF. For females who are
not considered to be of childbearing potential due to pre-pubescence, the pubertal status must be reassessed
at each visit.
# Tubal sterilization may not fully protect against pregnancy [Bouillon 2018]. Therefore, subjects who had a
tubal sterilization will have monthly pregnancy tests but are exempted from use of contraceptives.
The reason for not being of childbearing potential will be recorded in the eCRF.
4.5.2 
Acceptable Methods of Contraception
In both treatment arms for female subjects of childbearing potential [definition in
Section 4.5.1] and who are sexually active the use of contraception is mandatory during
Screening and up to EOS.

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In the macitentan group, one of the following options for contraception must be used:
* Option 1 and Option 2 are classified as highly effective methods (<1% failure rate).
In the SoC group, reliable methods of contraception are defined as per local medical
practice. Subjects in the SoC group who initiate macitentan study treatment (i.e., at Cross-
over or at EOCP) must use either Option 1, 2 or 3.
If hormonal contraception is one of the methods used, then it must have been initiated at
least 4 weeks prior to Randomization (Visit 2).
In subjects who become sexually active any time after randomization and who are of
childbearing potential, contraceptive method(s) that are immediately effective must be used
initially (e.g., Option 3 in macitentan group). This method(s) can be replaced but must
continue until the new method of contraception becomes effective.
The methods of contraception used (including non-pharmacological methods) must be
recorded in the eCRF.

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4.6 Medical History
The study indication, i.e., PAH, and related signs and symptoms, are not recorded as
medical history but on dedicated eCRF pages. Relevant medical history other than PAH,
as defined below, must be recorded in the eCRF:
 
Any condition that is currently treated (i.e., on therapy at enrollment)
 
Any serious medical conditions in the past 6 months
 
Chronic medical conditions (e.g., diabetes, seizure, asthma)
 
Any life-threatening condition in the past (e.g., sepsis)
 
Any condition in the past that resolved with sequelae
5 TREATMENTS
5.1 Study Treatment
5.1.1 Investigational Treatment: Macitentan - Description and Rationale
Macitentan, open-label, is administered once daily via oral route in dispersed form. Daily
doses are given according to the body weight category for subjects of ≥ 2 y.o. and
according to age in the subjects of <2 y.o. [refer to Section 5.1.5].
Clinical Formulation: Macitentan is provided as a dispersible tablet of following dose
strengths: 0.5 mg, 2.5 mg, and 5 mg. This formulation is only used in subjects of at least 6
months of age and will be controlled via IRT.
Final Market Image (FMI): Macitentan dispersible tablet will be available in new dose
strengths of 1 mg and 2.5 mg with different shape and debossing. The FMI will replace the
clinical formulation once sufficient stability data is available and local approval, if
applicable, has been obtained. This formulation will be used in all subjects (≥1 month of
age).
The pediatric macitentan doses for children above 2 years were determined using
population pharmacokinetic modeling that considered allometric scaling and maturation of
clearance [D-14.468]. The resulting doses, to be given according to body weight category,
were selected to achieve systemic exposure observed in adults with PAH treated with
macitentan 10 mg once daily in a majority of the pediatric population. The study has been
started with children above 2 years of age as they have more mature hepatic and renal
function and, therefore, the metabolism and clearance of drugs can be better predicted.
In a substudy of up to 40 subjects distributed over the different age ranges between 2 and
< 18 years (across age categories: 2 to < 7 years, 7 to < 12 years, and 12 to < 18 years), PK
profiles will be assessed over a period of 24 hours at steady-state conditions.

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Dosing regimen for children below 2 y.o. was proposed using population and PBPK
approach that considered maturation of CYP enzyme functions in infants and young
children between 1 month and 2 y.o. Exposure to macitentan was simulated following
administration of different potential doses, and doses, to be given according to age, were
selected to provide similar exposure to that of adult subjects receiving 10 mg once daily.
PK assessment will be performed in all children under 2 y.o. For this cohort of subjects,
sparse and patient-centric sampling will be used to lower the burden of extensive blood
collection in young children. Blood concentrations after a single dose of macitentan over
the first 24 hours and two trough concentrations at steady-state will be collected.
Macitentan and ACT-132577 (aprocitentan) concentrations will be summarized
descriptively per timepoint and a population PK analysis will be done separately.
Scales used to assess the body weight of subjects must be calibrated and respective
calibration certificates must be available prior to the first subject being randomized at the
site. Scales must be calibrated annually.
Subjects randomized to macitentan are treated as follows:
 
Subjects with no PAH-specific therapy at randomization will receive macitentan
monotherapy.
 
Subjects on PDE-5 inhibitor monotherapy at randomization will receive macitentan
as add-on therapy.
 
Subjects on ERA or oral/inhaled prostanoid monotherapy at randomization will
receive macitentan monotherapy instead.
 
Subjects on PDE-5 inhibitor in combination with another PAH-specific therapy at
randomization will receive the combination of macitentan and the PDE-5 inhibitor.
In subjects ≥ 2 y.o., a PDE-5 inhibitor is the only allowed PAH-specific background
medication until disease progression in the macitentan arm. All other PAH-specific
medications must be stopped. If the subject is on an ERA treatment, refer to instructions in
Appendix 2 for transition to macitentan. If the patient is on a prostanoid treatment during
Screening, this treatment must be discontinued if they are randomized to macitentan. In
order to avoid any rebound effect of pulmonary hypertension, prostanoids should be
cautiously downtitrated after randomization until complete discontinuation, as per local
practice. After randomization, new PAH-specific medications, and/or continuous oxygen
and/or IV diuretics are recommended to be initiated only if the condition of the secondary
efficacy endpoint (PAH disease progression) is met per investigator’s judgment. However,
non-adherence to these recommendations does not constitute per se a reason for premature
study discontinuation. All efforts should be made to keep the patients in the study according
to the original schedule of assessments.

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After EOCP (i.e., during the SAEP) those medications can be initiated at any time.
In subjects < 2 y.o., oral/ inhaled prostanoid treatment are also allowed as PAH-specific
background therapy in all study periods.
5.1.2 Comparator: Standard of Care - Description and Rationale
The study protocol does not impose any predefined comparator drug. Subjects randomized
to the control arm are treated with SoC as per site’s clinical practice which may comprise
treatment with PAH non-specific treatment and/or up to two PAH-specific medications
excluding macitentan and IV/SC prostanoids.
Subjects randomized to the SoC arm will be treated as follows:
 
Subjects only on PAH non-specific medications at randomization will continue on
their medications.
 
Subjects on PDE-5 inhibitor and/or on other PAH-specific treatment (such as ERA,
or inhaled/oral prostanoids) at randomization will continue on their medications.
 
For all subjects, additional PAH-specific therapy (excluding macitentan and IV/SC
prostanoids), if prescribed during the screening period, can be initiated.
The investigator documents the SoC in the IRT system before randomization.
Dose adjustment to reach the targeted dose or sequential introduction of combination
therapy is allowed as prescribed by the investigator in IRT prior to randomization. Once
the target maintenance dose is achieved, the regimen should be stable except in the
presence of AEs or change to the subject’s body weight. In these cases dose adjustments,
interruptions and permanent discontinuation follow local practice.
After randomization, new PAH-specific medications (not prescribed as part of the SoC
regimen), and/or continuous oxygen and/or IV diuretics are recommended to be initiated
only if the condition of the secondary efficacy endpoint (PAH disease progression) is met
as per judgment of the investigator. Changes within the same drug class are allowed.
However, non-adherence to these recommendations does not constitute per se a reason for
premature study discontinuation. All efforts should be made to keep the patients in the
study according to the original schedule of assessments. End of SoC will be declared if a
planned PAH-specific drug class is discontinued or if any additional PAH-specific drug
class is added.
In the presence of a CEC-confirmed disease progression event, the subjects in the SoC arm
will be offered to start macitentan treatment, if this is in their best interest per their
investigator’s judgment [refer to Section 8.10]. Cross-over to macitentan study treatment
will be offered at the EOCP visit as per best interest of the subject. If the subject is on an

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ERA treatment at the time of cross-over to macitentan, refer to instructions in Appendix 2
for transition to macitentan.
PAH-specific medications are reported in the eCRF as described in Section 5.2.2.
Current PAH-specific treatments for children with PAH are described in Section 1.2.3. The
rationale for the use of SoC as comparator is provided in Section 3.2.
5.1.3 Treatment Assignment
After having obtained informed consent and assent (if applicable) at Visit 1, the
investigator/delegate contacts the IRT system and obtains a subject number from the IRT
system which will identify the subject throughout the study. After having verified that the
subject meets all inclusion criteria and none of the exclusion criteria, the
investigator/delegate contacts the IRT at Visit 2 to document the SoC and to subsequently
randomize the subject ≥ 2 y.o. The IRT assigns a randomization number to the subject. If
the subject is randomized to the macitentan group the IRT also assigns the treatment
pack(s) number(s) assigned by the randomization list to the randomization number. If
applicable, damaged blister packs are recorded by the investigator/delegate in the IRT
system and are not allocated to any study subject. If the subject is randomized to the SoC
group, standard of care treatment is continued or initiated as documented by the
investigator. For subjects in the SoC group who receive macitentan after disease
progression is confirmed by the CEC or during the SAEP, the IRT assigns the treatment
pack(s) number(s) according to the subject’s body weight group.
Subjects ≥ 2 y.o. are assigned in a 1:1 ratio to the macitentan or the SoC group.
Randomization is stratified according to ongoing/planned ERA treatment at randomization
(yes vs no) and WHO FC at randomization (I/II vs III).
The enrollment of subjects with SoC in a control group containing ERAs is limited to
maximum of 40% using IRT system.
The randomization list is generated by the Central Randomization CRO.
The cohort of children < 2 y.o. at Visit 2 will enter the macitentan arm without
randomization. No ERA cap will be set for this cohort. The investigator/ delegate contacts
the IRT at Visit 2 after eligibility has been confirmed, and IRT assigns the treatment pack
number according to the subject's age. At 12-weekly visits when the subject is at least 2
years old the IRT will assign the macitentan pack number as per subject's body weight
group.
5.1.4 Blinding
Not applicable. Measures taken to reduce the bias inherent to open-label design are
described in Section 3.2.

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5.1.5 Macitentan Administration
Macitentan is administered after dispersion of tablet(s) in water even to subjects who can
swallow tablets. The dose is adjusted to the subject’s age (for those < 2 y.o.) or to the
subject's body weight (for those ≥ 2 y.o.) at treatment assignment as described in Table 6
and Table 7.
At each 12-weekly study visit (i.e., excluding Visit 3) the subject’s age or body weight (as
applicable) must be verified for potential dose adjustment. Change in age or weight
category is entered into the IRT system which will provide new macitentan study treatment
pack(s).
The dispersion must be reconstituted by the caregiver (e.g., parent) prior to administration.
Subjects who are developmentally capable may prepare the drug dispersion themselves.
Whole tablet(s) are dispersed in water and administered orally (e.g., via spoon). The full
daily dose is taken at a single occasion (refer to the Pharmacy Manual for TOMORROW
study).
The first dose in the macitentan group is administered at Visit 2 (i.e., within 24 hours after
macitentan treatment pack has been assigned to the subject) and under the guidance of the
investigator or delegate. Thereafter, macitentan is administered once daily and irrespective
of time of food intake but at approximately the same time of the day.
Parent(s) / legally designated representative and subjects are instructed that macitentan
should not be administered on days of study Visits 3 (at steady-state) and 4 (Week 12) until
the pre-dose PK sample has been collected and as instructed by the study-site person.
For cohort of children < 2 y.o., the parent(s) / legally designated representative is instructed
not to administer macitentan at Week 4 and Week 8 visits until the pre-dose PK sample has
been collected.
Instructions regarding dose adjustment and the need for interruption or discontinuation of
macitentan are provided in Sections 5.1.8, 5.1.9, and 5.1.10.
Table 6: 
Dosing Scheme for Clinical Formulation
Age [month] 
Body Weight [kg] 
Daily dose 
Number of tablets to be dispersed
≥ 1 and < 6 
not applicable (NA) 
NA  
NA
≥ 6 and < 24 
not applicable 
2.5 mg 
1 x 2.5 mg
≥ 24
≥10 kg and < 15 kg 
3.5 mg 
2×0.5 mg & 1×2.5 mg
≥ 15 kg and < 25 kg 
5.0 mg 
1 x 5.0 mg
≥ 25 kg and < 50 kg 
7.5 mg 
1×2.5 mg & 1x5.0mg
≥ 50 kg 
10.0 mg 
2×5.0 mg

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Table 7: 
Dosing Scheme for Final Market Image
Age [month] 
Body Weight [kg] 
Daily dose 
Number of tablets to be dispersed
≥ 1 and < 6 
not applicable 
1.0 mg 
1 x 1.0 mg
≥ 6 and < 24 
not applicable 
2.5 mg 
1 x 2.5 mg
≥ 24
≥10 kg and < 15 kg 
3.5 mg 
1 × 1.0 mg and 1×2.5 mg
≥15 kg and < 25 kg 
5.0 mg 
2 x 2.5 mg
≥25 kg and < 50 kg 
7.5 mg 
3×2.5 mg
≥50 kg 
10.0 mg 
4 × 2.5 mg
5.1.6 Macitentan Supply
Manufacture, labeling, packaging, and supply of macitentan will be conducted according
to Good Manufacturing Practice, Good Clinical Practice (GCP), and any local or national
regulatory requirements.
All macitentan supplies are to be used only in accordance with this protocol, and not for
any other purpose.
The following sections are only applicable for subjects who receive macitentan study
treatment.
Macitentan Packaging and Labeling
5.1.6.1.1 Macitentan packaging
Macitentan is provided as dispersible tablets and supplied in childproof blister packs.
5.1.6.1.2 Macitentan labeling
Macitentan is labeled to comply with the applicable laws and regulations of the countries
in which the study sites are located.
Macitentan Distribution and Storage
Macitentan supplies must be kept in an appropriate, secure area and stored according to the
conditions specified on the label.
Macitentan Dispensing
The subjects will receive enough macitentan to cover the period up to the next scheduled
12-weekly visit (i.e., excluding Visit 3 for PK). Subject’s parent(s) / legal representative
are asked to return all used, partially used, and unused study treatment blister packs at each
scheduled visit (except Visit 3). The protocol-mandated study treatment dispensing/return
procedures may not be altered without prior written approval from the Sponsor. An
accurate record of the date and amount of macitentan dispensed to each subject must be
available for inspection at any time.

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Macitentan Return and Destruction
On an ongoing basis and on termination of the study, the monitor, i.e., Clinical Research
Associate (CRA) will collect used and unused treatment packs, which will be sent to the
warehouse for reconciliation. In certain circumstances, used and unused macitentan
containers may be destroyed at the site once study treatment accountability is finalized and
has been checked, and written permission for destruction has been obtained.
5.1.7 Macitentan Accountability and Compliance With Macitentan Study
Treatment
Sections 5.1.7.1 and 5.1.7.2 are only applicable for subjects who receive macitentan study
treatment.
Macitentan Drug Accountability
The inventory of macitentan dispensed to and returned by the subject (i.e., study treatment
accountability) must be performed by the site personnel on the day of the visit and before
dispensing further macitentan in order to ensure that the subject is compliant with study
requirements. The site personnel records this inventory on the study treatment dispensing
and accountability log and in the eCRF. The CRA checks these entries during monitoring
visits and at the end of the study. The study treatment accountability log in the eCRF will
include at least the following information for each macitentan unit (blister) dispensed to
the subject:
 
Unique blister-card identifying number of the dispensed blisters
 
Date dispensed / number of tablets dispensed
 
Date returned / number of tablets returned
All macitentan supplies, including partially used or empty blister packs must be retained at
the site for review by the CRA.
If the parent/ legally designated representative of the subject forgets to bring the remaining
macitentan to a study visit, he/she must be instructed that the subject should not receive
any tablet from the remaining study treatment blister pack(s) and to return it/them at the
next visit.
Macitentan 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

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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
subject (if developmentally capable) and re-educate them on correct administration of
study treatment. Details of such discussion must be documented in the subject’s file.
If the compliance with study treatment 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 subject
(if developmentally capable), the reasons for this non-compliance and discuss actions to be
taken to avoid re-occurrence. This discussion and its outcome must be documented in the
source documents.
5.1.8 Macitentan Dose Adjustments and Interruptions
Macitentan dose adjustments other than for change in age category for subjects < 2 y.o.
and for weight category for subjects at least 2 y.o. are not permitted.
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 5.1.10.
If macitentan is interrupted by the subject 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.
Dose adjustments of other PAH-specific medications needed due to the subjects’ change
in body weight or due to an AE are performed as per local practice.
For macitentan study treatment interruptions, dose adjustments and the reason for
interruption must be recorded in the eCRF.
5.1.9 Macitentan: Premature Discontinuation of Study Treatment
The decision to prematurely discontinue macitentan before EOS may be made by the
parent(s) / legally designated representative of the subject, the subject (who is
developmentally capable to assent or who comes of age), the investigator, or the Sponsor
personnel. The main reason and whether discontinuation of macitentan is the decision of
the subject (i.e., parent[s] / legally designated representative, e.g., for tolerability or
efficacy reasons), the investigator (e.g., due to pre-specified macitentan discontinuation

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criteria, an AE or lack of efficacy), or the Sponsor (e.g., 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 during the Core Period does not constitute per se a reason to withdraw from
the study. In case of premature discontinuation of macitentan during the Core Period, every
attempt should be made to keep subjects in the study according to the original schedule of
assessment until the cutoff date for Analysis 2 (EOCP visit). 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 9.2), vital status will be
collected at least yearly (i.e., survival FU) until the cutoff date for Analysis 2 [see
Section 8.17], 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
subject’s rights.
The investigator must discontinue macitentan for a given subject if, on balance, he/she
believes that continued administration would be contrary to the best interests of the subject.
Study treatment (macitentan) may be discontinued in response to an AE, a protocol
deviation (including eligibility failure, non-compliance with study requirements), a
diagnostic or therapeutic procedure, for lack of efficacy, for a laboratory abnormality, or
for administrative reasons.
Study-specific criteria for discontinuation of macitentan are described in Section 5.1.10.
Withdrawal from the study and medical care of subjects withdrawn from the study are
described in Sections 9.2 and 9.4, respectively.
5.1.10 Study-specific Criteria for Interruption / Premature Discontinuation of
Macitentan Study Treatment
A) Pregnancy
If a female subject becomes pregnant while on macitentan, study treatment must be
discontinued immediately, and a Pregnancy Form must be completed [see Section 10.3].
The investigator will discuss with the subject and her parent(s) / legally designated
representative the appropriate follow-up medical care.
B) Liver aminotransferases abnormalities
Interruption of study treatment

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Macitentan study treatment must be interrupted in the following cases:
 
Aminotransferases (i.e., ALT and/or AST) ≥3 and <8 x 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 x ULN
 
Aminotransferases ≥3 x ULN and associated clinical symptoms of liver injury,
e.g., nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy or fatigue,
flu like syndrome (arthralgia, myalgia, fever)
 
Aminotransferases ≥3 x ULN and associated increase in total bilirubin ≥2 x 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.
Other diagnoses (e.g., viral hepatitis, mononucleosis, toxoplasmosis, cytomegalovirus)
and/or etiologies (e.g., 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]. 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 an SAE. If these abnormalities
are serious hepatic events of special interest they will be reviewed by an ILSDRB.

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C) Hemoglobin abnormalities
If there is a decrease in hemoglobin from Baseline* of >20 g/L during treatment with
macitentan, a re-test 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 (<4.9mmol/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.
* Baseline hemoglobin: refers to the last hemoglobin value obtained prior to first intake of macitentan study
treatment.
D) Start of an ERA / strong CYP3A4 inducer / strong CYP3A4 inhibitor / investigational
product
Interruption of study treatment
If any strong inhibitors of CYP3A4 are given, macitentan must be interrupted from first
dose ofCYP3A4 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 and a moderate CYP2C9 inhibitor are given,
macitentan must be interrupted as follows:
 
For dual CYP3A4/CYP2C9 inhibitors: from first dose of dual CYP3A4/CYP2C9
inhibitor and until 4 weeks after the last dose of dual CYP3A4/CYP2C9 inhibitor.
 
For co-administration of a combination of a CYP3A4 and a 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.
Permanent discontinuation of study treatment
Macitentan must be permanently discontinued if an ERA is administered and/or another
investigational product is started during study period.

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All re-tests (refer to points B, C and D in this section) are sent for analysis to the Central
Laboratory and results are transferred electronically to the clinical database. If, however,
re-tests are done in the local laboratory, values available before EOS are recorded by the
site in the eCRF.
5.2 Previous and Concomitant Therapy
5.2.1 Definitions
A previous therapy is any treatment for which the end date is prior to signing of informed
consent.
A therapy that is study-concomitant is any treatment that is ongoing or initiated after
signing of informed consent, or initiated up to EOS.
A therapy comprises medications as well as therapeutic medical interventions such as
radiotherapy.
5.2.2 Reporting of Previous/Concomitant Therapy in the ECRF
The use of all study-concomitant therapy (including oxygen, blood transfusions,
electrolytes, contraceptives and traditional and alternative medicines, i.e., plant-, animal-,
or mineral-based medicines as well as radiotherapy and diagnostic agents such as contrast
media) are recorded in the eCRF.
The generic name, start/end dates of administration (as well as whether it was ongoing at
randomization/Visit 2 and/or EOS), route and indication are recorded in the eCRF.
Previous therapy must be recorded in the eCRF if discontinued less than 4 weeks prior to
signing the informed consent.
PAH-related treatments and interventions
Previous medications and interventions related to PAH treatment (i.e., PAH-specific
medications such as ERAs, PAH non-specific treatment such as inotropes, diuretics,
anticoagulants, oxygen, etc) are reported in the eCRF if stopped less than 48 weeks prior
to signing informed consent.
For PAH-specific treatment, and for oxygen and diuretics it is mandatory to also record the
dose in the eCRF.
PAH-specific medications prescribed as planned SoC will be identified in the eCRF. PAH-
related non-pharmacological interventions such as atrial septostomy, Potts’ anastomosis,
and registration on the list for lung transplantation are recorded on dedicated pages for
disease progression in the eCRF with date of the intervention/registration.

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Survival Follow-up: In addition for subjects who prematurely discontinue study visits,
PAH-specific treatments administered up to EOS (i.e., last survival follow-up contact) are
recorded in the eCRF.
5.2.3 Mandatory Concomitant Therapy
In both treatment arms female subjects of childbearing potential who are sexually active
[refer to Section 4.5.1] must use reliable contraceptive methods as specified in
Section 4.5.2 until EOS or until last Safety FU phone call (whichever is last). If hormonal
contraceptives are used, those must be initiated at least 4 weeks before Visit 2
(Randomization).
For subjects who become sexually active any time after randomization and who are of
childbearing potential, contraceptive method(s) that are immediately effective must be
applied as specified in Section 4.5.2.
5.2.4 Allowed Concomitant Therapy
PAH non-specific therapies (e.g., diuretics, anticoagulants, oxygen, calcium channel
blockers) and changes to such medications are allowed during all study periods in both
treatment arms. For IV diuretics and continuous oxygen therapy refer also to Section 5.2.6
‘PAH treatment escalation’.
Use of IV prostanoids for vasoreactivity testing is allowed in all study subjects and during
all study periods.
Screening Period: Any PAH-specific therapy (excluding macitentan and IV/SC
prostanoids) can be given or initiated as mono- or combination therapy with a maximum
of two treatments.
Cohort of children <2 y.o.: is allowed to use macitentan during Screening.
Core Period:
Macitentan group
 Pre-Event SP: PDE-5 inhibitor treatment ongoing at randomization can continue.
 Post-Event SP: Any PAH-specific medication (including IV/SC  prostanoids),
except ERA, can be administered in addition to macitentan.
Cohort of children <2 y.o.: is allowed to use oral/ inhaled prostanoids concomitantly
with macitentan.
SoC group

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 Pre-Event SP: Any  PAH-specific treatment (other than macitentan and IV/SC
prostanoids) as either mono- or double combination therapy prescribed as SoC
before randomization can be administered.
 Post-Event SP: Any PAH-specific medication (including IV/SC prostanoids) can
be administered. Macitentan treatment will be offered after CEC confirms disease
progression, if this is in the best interest of the subject per their investigator’s
judgment [refer to Section 8.10].
Single-arm Extension Period:
 Any PAH-specific medication except an ERA can be administered in addition to
macitentan.
5.2.5 Forbidden concomitant therapy
To avoid confounding effects, the following treatments are forbidden as specified:
 
Use of any investigational drug is forbidden from 4 weeks before
randomization/Visit 2 and up to EOS in all subjects.
 
IV/SC prostanoids are forbidden from 4 weeks before randomization/Visit 2 and
during Pre-Event SP in all subjects, except if given for vasoreactivity testing.
 
Use of macitentan is forbidden in subjects ≥ 2 y.o. at any time before study entry.
In the SoC group, macitentan is forbidden during the Pre-Event SP.
 
In subjects ≥ 2 y.o in the macitentan arm, use of any PAH-specific background
therapy other than PDE-5 inhibitor is forbidden during the Pre-Event SP. In order
to safely stop prostanoids, these medications should be cautiously downtitrated
after randomization, as per local practice.
Concomitant use of an ERA (e.g., bosentan, ambrisentan) with macitentan is forbidden
during entire study duration.
Cohort of children < 2 y.o.: use of macitentan is allowed at any time before study entry and
oral/inhaled prostanoids are allowed as PAH-specific background therapy.
To avoid drug-drug interactions with macitentan the following treatments are forbidden as
specified [Macitentan IB].
 
Strong inducers of CYP3A4 such as rifabutin, rifampicin, rifapentin,
carbamazepine, phenobarbital, phenytoin, and St. John’s wort (hypericum
perforatum) are forbidden from 4 weeks prior to and until randomization/Visit 2,
because the efficacy of macitentan could be reduced. After randomization/Visit 2
these medications should be avoided as follows:
 in the macitentan arm until EOM.
 in the SoC arm from 4 weeks before crossing over to macitentan and until
EOM

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 in the SAEP until EOS.
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 such as boceprevir,
clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, nefazodone,
nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and
voriconazole is forbidden from 4 weeks prior to and until randomization/Visit 2.
After randomization/Visit 2 systemic administration of these medications is
forbidden as follows:
 in the macitentan arm until EOM.
 in the SoC arm from 4 weeks before crossing over to macitentan and until
EOM.
 in the SAEP until EOS.
 
Systemic administration of moderate dual CYP3A4/CYP2C9 inhibitor such as
fluconazole and amiodarone, or combination of a moderate CYP3A4 (e.g.,
ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) together with a
moderate CYP2C9 inhibitor (e.g., miconazole, piperine) is forbidden from 4 weeks
prior to and until randomization/Visit 2. After randomization/Visit 2 systemic
administration of these medications is forbidden as follows:
 in the macitentan arm until EOM.
 in the SoC arm from 4 weeks before crossing over to macitentan and until
EOM.
 in the SAEP until EOS.
Note: Subjects who at the time Protocol V4.1 became effective were stable on a moderate
dual CYP3A4/CYP2C9 inhibitor (e.g., fluconazole, amiodarone) or co-administration of a
combination of a moderate CYP3A4 (e.g., ciprofloxacin, cyclosporine, diltiazem,
erythromycin, verapamil) and moderate CYP2C9 inhibitor (e.g., miconazole, piperine)
were allowed to remain on macitentan treatment if per the investigator’s clinical judgment
this was in the best interest of the subject, refer to Food and Drug Administration website
[FDA 2020].
To avoid any drug-drug interactions with SoC treatments, the investigator should consult
respective medication label(s).
The administration of an ERA and/or of any investigational drug must lead to permanent
discontinuation of macitentan as described in Section 5.1.10. The systemic administration
of a strong CYP3A4 inhibitor as well as administration of moderate dual CYP3A4/

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CYP2C9 inhibitor or a combination of a moderate CYP3A4 and moderate CYP2C9
inhibitor must lead to interruption of macitentan as described in Section 5.1.10.
5.2.6 PAH Treatment Escalation
In the presence of PAH worsening, any PAH-specific treatment can be initiated per
investigator’s judgment. It is strongly recommended, however, to initiate PAH-specific
medications, and/or continuous oxygen and/or iv diuretics only in the presence of disease
progression defined per protocol as per judgment of the investigator.
Subjects in the SoC group will be offered macitentan if the CEC confirms disease
progression and if this is considered in the best interests of the subject per their
investigator’s judgment [refer to Section 8.10]. Subjects in the macitentan group will
continue receiving macitentan after a CEC-confirmed disease progression event.
During the SAEP, PAH treatment can be escalated as per local practice.
6 STUDY ENDPOINTS
6.1 Efficacy Endpoints
6.1.1 Primary Endpoint
In subjects ≥ 2 years of age in the macitentan arm:
 
Trough (pre-dose) plasma concentrations of macitentan and its active metabolite
(ACT-132577) at Week 12 (steady-state)
In subjects less than 2 years of age on macitentan:
 
Trough concentrations of macitentan and its active metabolite (ACT-132577) at
Week 4 (steady-state)
PK data will be listed by subject number and PK endpoints will be analyzed descriptively
by body weight and age group in subjects ≥ 2 y.o. and <2 y.o., respectively.
6.1.2 Secondary efficacy endpoints
The secondary endpoints are described in Sections 6.1.2.1 and 6.1.2.2.
Time to First CEC-confirmed Disease Progression
Time to the first of the following CEC-confirmed disease progression events occurring
between randomization/Visit 2 and EOCP:
 Death (all causes)
 Atrial septostomy or Potts’ anastomosis, or registration on lung transplant list
 Hospitalization due to worsening PAH§

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 Clinical worsening* of PAH defined as:
Need for, or initiation ofnew 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 (i.e., 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 (e.g., pneumonia).
* Worsening from Baseline.
# E.g., ERA, PDE-5 inhibitor, prostanoid, IP receptor agonist, soluble guanylate cyclase stimulator.
Investigators will be requested to describe the condition of the subject at Baseline in a
Baseline narrative. In the presence of disease progression the investigator must prepare a
narrative of the subject’s condition and perform an echocardiography and test the level of
n-terminal pro-brain natriuretic peptide (NT-proBNP). These data together with any other
relevant supportive routine assessment (e.g., RHC, magnetic resonance imaging [MRI],
uric acid, etc) and potential hospital discharge summary (if applicable) will be provided to
the CEC for adjudication [refer to Sections 3.4 and 8.9].
An independent CEC will adjudicate in a blinded fashion all potential disease progression
events reported by investigators (as defined in the CEC Charter; see also Section 3.4),
determining the components of the event, the relationship of death or hospitalization with
PAH as well as the event onset date. The date of the first CEC-confirmed disease
progression event will be used for derivation of the disease progression efficacy variable.
Other Secondary Endpoints
 
Time to first CEC-confirmed hospitalization for PAH occurring between
randomization/Visit 2 and EOCP.
 
Time to CEC-confirmed death due to PAH occurring between randomization/Visit
2 and EOCP.
 
Time to death (all causes) occurring between randomization/Visit 2 and Study
Closure.
Following secondary endpoints are analyzed up to end of randomized macitentan or SoC
+ 7 days. Baseline is the last non-missing value observed before or on the day of
randomization/ Visit 2

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 
WHO FC status (I or II vs III or IV) at Week 24.
 
Percent of Baseline plasma NT-proBNP at Week 24.
 
Change from Baseline to Week 48 in in mean daily time spent in moderate to
vigorous physical activity as measured by accelerometry.
 
Change from Baseline to Week 24 in tricuspid annular plane systolic excursion
(TAPSE), and left ventricular eccentricity index measured by echocardiography
(centrally assessed).
 
Change from Baseline to Week 24 in Quality of Life as measured by the PedsQLTM
4.0 Generic Core Scales Short Form (SF15)1.
6.1.3 Exploratory Endpoints
Exploratory endpoints are analyzed up to end of randomized macitentan or SoC + 7 days.
 
Panama FC status (I or II vs III or IV) at Week 24.
 
Change from Baseline to Weeks 12, 24 and 48 in exercise capacity as measured by
the 6MWT in children ≥6 years of age who are developmentally able to understand
and perform the test.
 
Percent of Baseline plasma NT-proBNP up to Week 48.
 
Change from Baseline to Week 48 in number of hours of daytime activity assessed
by accelerometry.
 
Change from Baseline to Week 48 in mean count per minute of daily activity
assessed by accelerometry.
 
Change from Baseline to Week 48 in mean daily time spent in light physical activity
based on a threshold from 800 to 3199 activity counts per minute assessed by
accelerometry.
Baseline is the last non-missing value observed before or on the day of randomization/Visit
2.
6.2 Safety Endpoints
Safety endpoints are assessed until EOS and include:
 
AEs and SAEs
 
AEs leading to premature discontinuation of macitentan or SoC
 
AEs of special interest
 
Marked laboratory abnormalities
1 This endpoint will be assessed by subjects and as assessed by a caregiver (e.g., parent) as described in Section 6.3.

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 
Change from Baseline in selected laboratory parameters [refer to Section 11.3.5.2]
to all timepoints of assessments
 
Change from Baseline in vital signs (BP, heart rate) to all timepoints of assessments
 
Growth from Baseline to all timepoints of scheduled assessments
 
Sexual maturation (Tanner stage) change from Baseline to all timepoints of
scheduled assessments
Baseline is the last non-missing value observed before or on the day of randomization/
Visit 2.
Cohort of children <2 y.o. will be summarized separately.
6.3 Other Quality of Life Endpoints
In English-speaking subjects in the USA, change from Baseline to all timepoints of
assessments up to end of randomized macitentan or SoC + 7 days in:
 
QoL as measured by the disease-specific PedsQL™ 3.0 Cardiac Module using the
“heart problems and treatment” component only.
 
QoL as measured by the PedsQL™Multidimensional Fatigue Scale standard
version using the “general fatigue” component only.
Each of these endpoints will be analyzed as assessed by subjects and as assessed by a
caregiver (e.g., parent). Questionnaires are adapted for following age categories:
 
Toddlers: 2 to 4 years of age
 
Young children: 5 to 7 years of age
 
Children: 8 to 12 years of age
 
Adolescents: 13 to 18 years of age
For the youngest age category (toddlers) the questionnaire exists only for parent/caregiver
(i.e., Parent Report). For all other age categories separate questionnaires exist for
parent/caregiver and for subjects (i.e., Child report) and address the same items. For the
cohort of children < 2 y.o., this questionnaire is not available.
6.4 Other Pharmacokinetic Endpoints
In a subpopulation of the macitentan arm or of those subjects in SoC who crossover to
macitentan (up to 40 subjects ≥ 2 y.o. distributed over the different age groups) at steady-
state for both macitentan and ACT-132577:
 
PK profile over 24 hours at pre-dose and following administration of macitentan
during steady-state conditions.

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 
The time to reach maximum plasma concentration (tmax) during a dosing interval.
 
Maximum plasma concentration (Cmax) during a dosing interval.
 
The area under the plasma concentration-time curve during one dosing interval
(AUCτ).
Plasma PK parameters of macitentan and ACT-132577 will be derived by
noncompartmental analysis or population PK analysis of the plasma or blood
concentration-time profiles.
The following assumptions have been made:
 
Cmax, AUC, and t½ values are assumed to be log-normally distributed
[Julious 2000].
 
No period or carry-over effects.
The measured individual plasma concentrations of macitentan and ACT-132577 will be
used to directly obtain Cmax and tmax.
AUCτ will be calculated according to the linear trapezoidal rule using the measured
concentration-time values above the limit of quantification (LOQ) during one dosing
interval.
In subjects < 2 y.o. who are on macitentan, concentration of macitentan and ACT-132577
(aprocitentan) will be summarized per time point:
 
PK assessment of single dose macitentan after the first dose (2, 5, and 24h) and
trough concentrations at steady state.
 
Collected PK data will be regularly assessed using non-linear mixed effects
pharmacokinetic modeling during the course of the study to confirm the
appropriateness of the selected dosing regimen in subjects < 2 y.o.
6.5 Drug formulation endpoint
The palatability and acceptability of the macitentan dispersible formulation after the first
dose on Day 1 and at Week 12 (Visit 4) in subjects randomized to the macitentan arm.
7 STUDY ASSESSMENTS
All study assessments are performed by a qualified study personnel member: medical,
nursing, or specialist technical personnel, and are recorded in the eCRF, unless otherwise
specified. Assessments to be performed by a physician are specified in Section 3.3. If
permitted by local legislation, physicians may delegate to an Advanced Practice Role (or
an equivalent) specific tasks normally performed by a physician such as the consent

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interview and the signature of the ICF without a second signature of a physician. Study
assessments performed during unscheduled visits will also be recorded in the eCRF.
Vital signs must be done before collection of blood sample. The study personnel is noting
the time of those assessments in the source document. On days of PK sampling macitentan
must not be administered to the subject before the pre-dose PK sample has been collected.
The timing of PK sample collection is described in Section 7.7.1. At Visit 2
(Randomization) palatability and acceptability of macitentan is assessed after the subject
has taken the first dose of macitentan. The order of the other assessments is not specified.
If the PI delegates any study procedure/assessment for a subject, e.g., echocardiography,
blood sampling to an external facility, he/she must inform the Sponsor (or delegate) to
whom these tasks are delegated. The set-up and oversight will be agreed upon with the
Sponsor (or delegate). The supervision of any external facilities remains the responsibility
of the PI.
Calibration certificates for the following equipment used to perform study assessments
must be available prior to the screening of the first subject:
 
Body weight scale
 
Thermometers for study drug storage and blood sample storage (e.g., PK)
 
Local laboratory certification and reference ranges
 
Echocardiography machine
The calibration certificates must be filed in the Investigator Site File (ISF).
The ICF must be signed and dated before performing any study-mandated procedure. If
the signing of ICF and performance of the first study-specific procedures or assessments
take place on the same day, it must be clear from the source documents that informed
consent was obtained prior to any study-specific procedures being performed (i.e., time of
signatures and time of procedures will be documented). If a study-specific procedure or
assessment has been performed as part of routine assessments and the results are available
prior to the signing ofthe ICF, they may  be used to assess eligibility  and do not have to
be repeated. In such cases, it must be clear from the source document when and for which
reason the assessment was done prior to the signing ofthe informed consent.
The schedule of study assessments is provided in Table 1, Table 2, and Table 3 and in
Section 8.
7.1 Screening/Baseline Assessments
For subjects with PAH with co-incidental CHD, i.e., small atrial septal defect, ventricular
septal defect or patent ductus arteriosus which themselves do not account for the
development of elevated PVR, the investigator submits relevant clinical, RHC and

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echocardiography data to the BCAC for review and approval [see Section 3.4]. Only after
BCAC confirms the diagnosis of PAH associated with co-incidental CHD will the subjects
be randomized, provided all other entry criteria are confirmed.
7.1.1 Baseline Demographics
Baseline demographics include sex, ethnicity/race, age and weight/height (or length) and
are recorded in the eCRF.
Clinically relevant medical history as defined in Section 4.6 is documented and recorded
in the eCRF. The presence/absence of Down Syndrome is recorded for all subjects in the
eCRF.
7.1.2 Baseline Disease Characteristics
Disease characteristics such as PAH etiology, PAH diagnosis (mPAP, PAWP [or LAP, or
LVEDP], PVRi values assessed by RHC and date of diagnosis), and date of first
observed/assumed PAH symptoms are documented and reported in the eCRF.
7.2 Previous/Concomitant Therapy
For reporting of medications and of PAH-related non-pharmacological interventions refer
to Section 5.2.2.
7.3 Efficacy assessments
In order to assess endpoints related to disease progression, 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
[refer to Section 5.2.2].
 
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 5.2.2].
 
For hospitalizations, the admission/discharge date together with the reason for
hospitalization is recorded on either the AE eCRF page or on the dedicated clinical
worsening eCRF page (if cause is related to PAH) as indicated in Section 8.9.
 
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 7.3.1.
The investigator (or delegate) will describe the condition of the subject at Baseline (i.e. 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 subject’s condition.
Narratives and local echocardiography reports [refer to Section 7.3.3] are sent to the CEC

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Coordinator who will upload them into the Adjudication system [refer to Section 8.9].
Narratives and locally read echocardiography data are not collected in the eCRF.
7.3.1 Monitoring of Disease Progression
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.
The occurrence of a new or worsening sign/symptom is not reported as AEs in the eCRF.
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 [refer to Section 8.9].
Functional Class
The WHO FC [see Appendix 3] and the Panama FC [Appendix 4] are recorded in the
eCRF. The Panama FC is tailored for children up to 16 years of age [Lammers 2011] and
thus its assessment will discontinue in children > 16 years of age.
If there is worsening in the WHO FC refer to Section 8.9 for reporting of disease
progression. Worsening in Panama FC does not classify for disease progression but the
data will be provided to the CEC as supportive data.
7.3.2 NT-proBNP
The quantification  of NT-proBNP plasma levels will be performed by the Central
Laboratory [see contact details, page 3]. Central laboratory data will be automatically
transferred from the Central Laboratory database to the clinical database.
The blood volume to be taken at each timepoint will be approximately 1.2 mL.
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.

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7.3.3 Echocardiography
Central Reading: At least the following parameters will be assessed as described in the
TOMORROW image acquisition guidelines: left ventricular eccentricity index and
tricuspid annular plane systolic excursion (TAPSE). These data are analyzed centrally as
per Independent Review Charter and transferred electronically to the clinical database. The
investigator (or delegate) submits generated echocardiography data in digital format,
together with a Data Transmittal Form to the Central Echocardiography CRO [see contact
details, page 3] as instructed in the TOMORROW Site Operations Manual. The CRO
conducting the central reading will also receive the clinical data necessary for the
interpretation of the images such as body weight/height and heart rate.
Local Reading: An echocardiography (and/or Doppler) to document the severity of PAH
(assessing, e.g., pericardial effusion, right ventricular pressure, inferior vena cava size) is
performed as per local practice during Screening. The data are analyzed locally. In the
presence of suspected disease progression, the same parameters are assessed as a follow-up
echocardiography (and/or Doppler) in order to document whether there is any change since
Baseline. The report of the Baseline and of the follow-up echocardiography at disease
progression is sent to the CEC Coordinator who provides this as supportive data to the CEC
[refer to Section 8.9].
In addition, for subjects with PAH with co-incidental shunts, the local echocardiography
used to confirm eligibility must be submitted to the BCAC [see Sections 3.4 and 7.1].
7.3.4 Physical Activity
In subjects of at least 2 years of age, 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
[Cliff2009, 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.
The physical activity [counts/min] of the subject is assessed via accelerometer in subjects
of at least 2 years of age. The subject collects data wearing the accelerometer for 10-14
consecutive days before respective visits [refer to Table 1 or Section 8]. If, for any reason,

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data are not collected before respective study visits, the subject will collect the data during
the 10-14 days following the visit. This does not apply for the assessment during Screening.
For Screening, the physical activity must be collected any time during Screening and before
Visit 2. This will allow collecting data during week days and weekend days and will
provide a reliable estimate of the usual physical activity of the subject.
At Visit 1 the investigator (or delegate) instructs parent(s) / legally designated
representative and developmentally capable subjects on how and when to wear the
accelerometer (refer to TOMORROW Accelerometry Guidelines). The accelerometer is
worn during the waking hours of the subject. The device may be removed during the night
rest and during activities when the device could get wet (e.g., showering, bathing,
swimming).
The parent(s) / legally designated representative or subject bring the device to the study-
site at site visits and the investigator (or delegate) transfers the data to the accelerometry
Central Laboratory  as instructed in the TOMORROW Accelerometry Guidelines. For
subjects who are not eligible to participate in the study, data (if collected during Screening)
is transferred to the central lab. At Visit 7 the accelerometer will not be returned to the
subject. After successful data transfer the device is re-set and can be re-used by another
study subject.
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 CRO.
Accelerometer devices will be provided to the investigational site before the start of the
study.
7.3.5 6-minute walk test
The 6-minute walk  test (6MWT) is a non-encouraged test that measures the distance
covered by the subject during a 6-minute walk. Guidelines are provided in  the
TOMMOROW 6-Minute Walk Test Guidelines.
The 6-minute walk distance (6MWD) will be assessed in subjects ≥6 years of age who
understand and are able to perform the test correctly [Douwes 2015, Takatsuki 2013b] and
who can perform the test per protocol at randomization. Test results and the date and time
of assessment will be recorded in the eCRF. If a subject wears a mask during the 6MWT
this will be entered in the source document but not in the eCRF.
7.4 Safety Assessments
The definitions, reporting and follow-up of AEs, SAEs, and pregnancies are described in
Section 10.

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7.4.1 Vital Signs
Vital signs include systolic and diastolic BP and heart rate. Vital signs are measured
non-invasively.
It is recommended that vital signs are measured after the subject has rested at least
5 minutes (e.g., sitting). If applicable, vital signs are measured before any invasive
assessment (such as blood draw).
The same type of device is used throughout the study for an individual subject. In addition,
throughout the study BP is measured on the same arm for an individual subject.
Vital signs are recorded in the eCRF.
7.4.2 Weight and Height/Length
Body weight and height/length are measured and recorded in the eCRF.
 
For children less than 2 years of age length is measured while the child is lying
down.
 
For children above 2 years of age, height will be measured using a stadiometer.
7.4.3 Physical Examination
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. The observations should be reported according to body system in the eCRF
as either normal or abnormal. If an abnormality is found it should be specified on the
corresponding eCRF page (except for abnormalities related to PAH worsening), describing
the signs related to the abnormality (e.g., fever, coughing, dyspnea) and not the diagnosis
(e.g., pneumonia). 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 10.1.1], must be recorded on the AE page of
the eCRF.
During the SAEP, the physical examination will only be documented in the subject's
medical chart and not in the eCRF. Abnormal observations must be reported in the AE
pages of the eCRF.

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Signs and symptoms related to PAH  are not reported together with the physical
examination findings but on dedicated eCRF pages [refer to Section 7.3.1.1].
7.4.4 Tanner Stage
As per CHMP Paediatric addendum to the PAH guidelines [EMA/CHMP/213972/2010]
sexual maturation of pediatric patients in long-term studies is of particular importance.
Therefore the Tanner stage [refer to Appendix 5] is assessed at regular timepoints during
the study.
Tanner stage is assessed in female subjects ≥ 8 years of age and in male subjects ≥ 9 years
of age (i.e., examination is started once they are 8 and 9 years old, respectively). For
subjects who enter the study below these ages sexual maturity assessments will start once
they reach the ages of 8 or 9 years (for girls and boys, respectively). Tanner stage
assessment is stopped once full sexual maturation is reached (if applicable before EOS).
(Self-)Assessment of pubertal Tanner stage by parents or subjects may be allowed by the
study investigator. In this case, the investigator instructs and assists parents / subjects on
how this should be assessed at each time of scheduled assessment.
The Tanner stages of puberty in girls are based on breast size and shape and pubic hair
distribution. The Tanner stages of puberty in boys are based on the development of the
genitalia and pubic hair distribution  [Blondell 1999, Marshall 1969, Marshall 1970].
Actual age at milestone attainment may vary among individuals and among different study
populations.
In female subjects the investigator verifies at each study visit (including unscheduled visits)
the childbearing potential of the subject [refer to Section 4.5.1].
The site study personnel will record the Tanner stage and the childbearing potential in the
eCRF. For subjects with childbearing potential the study personnel will verify at each visit
whether the subject has or plans to become sexually active. If confirmed the study
personnel will counsel the subject on the appropriate methods of contraception [refer to
Section 4.5.2].
7.4.5 Laboratory Assessments
Type of Laboratory
A Central Laboratory (see Central Laboratory manual for contact details) will be used for
all protocol-mandated laboratory tests, including re-tests due to laboratory abnormalities
and laboratory tests performed at unscheduled visits.
Laboratory parameters at Visits 1 and 2 (Randomization) are assessed by  the Central
Laboratory.

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Under specific circumstances (e.g., if the subject lives far from the site and cannot return
every month), laboratory samples may be collected at a laboratory close to where the
subject lives (local laboratory) and sent to the Central Laboratory for analysis.
Alternatively and if allowed per local regulations, a study nurse (or study person qualified
to collect blood samples) or a CRO can collect samples at subject’s home and send them
to the Central Laboratory for analysis.
In exceptional cases (e.g., subject is hospitalized in a different hospital from the study
center due to a medical emergency, or missing Central Laboratory values) valid local
laboratory results, if available, will be entered into the clinical database together with the
respective normal ranges via dedicated eCRF pages. For monthly liver and
hemoglobin/hematocrit tests, a local laboratory may be used if normal ranges are available
for the given age group of the subject. Respective local laboratory results will be entered
into the eCRF together with the respective normal ranges.
In case a Central Laboratory sample is lost or cannot be analyzed for whatever reason, the
investigator will collect an additional sample as soon as possible for repeat analysis, unless
a local laboratory sample was collected within the same time-window and these test results
are available.
Central laboratory reports will be sent to the investigator. In case of specific (predefined)
laboratory abnormalities, the Central Laboratory will alert the CRO and the concerned site.
Alert flags that will trigger such notifications are displayed in the Laboratory Manual.
All laboratory reports must be reviewed, signed and dated by the investigator or delegate
within 10 working days of receipt and filed with the source documentation. The
investigator/delegate must indicate on the laboratory report whether abnormal values are
considered clinically relevant or not. Clinically relevant laboratory findings (local
laboratory report) that are known at the time of signature of informed consent must be
recorded on the medical history page of the eCRF. Any clinically relevant laboratory
abnormalities (Central Laboratory or local laboratory) detected after signature of informed
consent must be reported as an AE or SAE as appropriate [see Section 10], and must be
followed until the value returns to within the normal range, or until the change is no longer
clinically relevant. Further laboratory analyses should be performed as indicated and
according to the judgment of the investigator.
Details about the collection, sampling, storage, shipment procedures, and reporting of
results and abnormal findings can be found in the Laboratory Manual. Material required
for sampling will be provided to the investigational site before the start of the study.

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Laboratory Tests
Assessment of plasma NT-proBNP is described in Section 7.3.2. For PK assessments refer
to Section 7.7.
For the complete list of laboratory tests and their normal ranges refer to Laboratory Manual.
Hematology
Hemoglobin and hematocrit are assessed to confirm eligibility. Values must be available
within 6 weeks prior to Visit 2 (Randomization). Local laboratory values may be used and
recorded in the eCRF, if normal ranges applicable for the age category of the subject are
available.
Complete hematology tests include:
 
Hemoglobin,
 
Hematocrit,
 
Erythrocyte count,
 
Leukocyte count with differential counts,
 
Platelet count.
Hemoglobin must be monitored monthly in all subjects in the macitentan group for the first
6 months of study period and subsequently at each scheduled visit (every 12 weeks) until
EOS. In the SoC group monthly tests are only mandatory for subjects receiving an ERA
for which respective label instruction requests monthly tests. In all other subjects in the
SoC group those tests are done at the regular study visits (i.e., every 12 weeks).
Subjects in the SoC group who cross over to macitentan after CEC-confirmed disease
progression event or at entry into single arm extension period must have their hemoglobin
and hematocrit levels assessed before macitentan is initiated, to confirm hemoglobin and/or
hematocrit are ≥ 75% of the LLN [refer to Section 8.10 and Section 8.13]. If levels are
lower, macitentan treatment start must be delayed until re-tests show hemoglobin and
hematocrit levels are ≥ 75% of the LLN. These values must be monitored monthly for the
first 6 months of macitentan treatment and every 12 weeks thereafter.
In the presence of decreased hemoglobin values refer to Section 5.1.10 for instructions
regarding interruption of macitentan study treatment.
Clinical chemistry
Liver aminotransferases (AST and ALT), creatinine and creatinine clearance are assessed
to confirm eligibility. Values must be available within 6 weeks prior to Visit 2
(Randomization). Local laboratory values may be used and recorded in the eCRF, if normal
ranges applicable for the age category of the subject are available.

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Complete blood chemistry tests include:
 Liver tests: aminotransferases (AST/ALT), alkaline phosphatase, total and direct
bilirubin,
 Creatinine and creatinine clearance,
 Blood urea nitrogen,
 Glucose,
 Sodium,
 Potassium,
 Calcium.
In all subjects ≥ 2 y.o. in the macitentan group, liver tests must be monitored monthly for
the first 6 months of study period and at each scheduled visit (every 12 weeks) until EOS.
In subjects of < 2 y.o., liver tests must be monitored monthly for the first 12 months of
study period and at each scheduled visit (every 12 weeks) thereafter until EOS.
The investigator may decide to continue monthly liver test monitoring via central lab. This
is not mandated per protocol; however liver tests are mandatory every 12 weeks. In the
SoC group monthly liver tests are only mandatory for subjects receiving an ERA for which
the respective label instructionrequests monthly tests. In all other subjects in the SoC group
those tests are done at the regular study visits (i.e., every 12 weeks).
Subjects in the SoC group who cross-over to macitentan after CEC-confirmed disease
progression  event or at entry into single arm extension period must have liver
aminotransferase levels assessed before macitentan is initiated to confirm ALT and AST
are ≤ 3 ×ULN [refer to Section 8.10]. If levels are higher, macitentan treatment start must
be delayed until re-tests show ALT and AST levels ≤ 3 × ULN. These values must be
monitored monthly for the first 6 months of macitentan treatment and every 12 weeks
thereafter.
In the presence of elevated AST/ALT values, refer to Section 5.1.10 for instructions
regarding interruption of macitentan study treatment.
Pregnancy test
In both treatment arms female subjects of childbearing potential are monitored for
pregnancy during Screening and until EOS or safety follow-up telephone call (whichever
is last).
During screening, a serum pregnancy test will be done. At randomization, a urine
pregnancy test will be performed and is verified by the investigator (or delegate).

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Subjects who are sexually active and use hormonal contraception must have been receiving
those medications at least 4 weeks before the pregnancy test at Visit 2 [refer to
Section 5.2.3].
Macitentan study treatment must not start in female subjects of childbearing potential
before results of the pregnancy test are available and negative.
Monthly monitoring of pregnancy is performed using urine pregnancy tests. The urine
pregnancy test can be done via urine dipstick by the subject at home and under supervision
of her parent(s)/caregiver/guardian until reaching legal age. Pregnancy tests approved as
per local requirements will be provided to the respective subjects. The investigator (or
delegate) will confirm via phone call that the test was done and will verify the results. If a
urine pregnancy test is inconclusive a serum pregnancy test must be done.
If pregnancy is suspected during the study, a serum pregnancy test must be performed. If
pregnancy is confirmed, macitentan must be stopped as per Section 5.1.10.
7.5 Palatability and Acceptability of Macitentan Drug Formulation
Subjects randomized to the macitentan group report the palatability and acceptability
(separately) of the pediatric formulation.
Subjects aged 4 years and more will be instructed to rate the palatability and acceptability
of the daily dose of dispersed macitentan by marking the appropriate face on a 5-point
facial hedonic scale via a circle or a cross. For younger children the caregiver will be
instructed to rate the ease to administer the daily dose of dispersed macitentan to the subject
using the same 5-point facial hedonic scale [refer to Appendix 6]. For subjects who are
developmentally not capable of reporting palatability and acceptability (e.g., subjects with
Down Syndrome), the caregiver will complete the questionnaire. The investigator will
judge whether a subject is capable to complete the palatability and acceptability
questionnaire.
The site study personnel will record the score and the method of administration (e.g.,
spoon) in the eCRF.
7.6 Quality of Life Assessments
The QoL will be assessed for subjects of at least 2 years of age. Below that age the selected
questionnaires are developmentally not appropriate and are thus not collected.
The PedsQLTM  Pediatric Quality of Life Inventory version 4.0 short form (SF15) will
assess the general physical, emotional, social and school functioning (15 questions) [refer
to Appendix 7 :]. The “heart problems and treatment” component of the PedsQLTM Cardiac
Module version 3.0 and the “general fatigue” component of the PedsQLTM
Multidimensional Fatigue Scale standard version paper questionnaires assess:

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 
Heart problems and problems with treatment (7 questions) [Appendix 8], and
 
Problems with general fatigue (6 questions) [Appendix 8]
The questionnaires are adapted for different age groups: toddlers (2-4 years of age), young
children (5-7 years of age), children (8-12 years of age) and adolescents
(13-18 years of age).
For toddlers a parent or caregiver completes the QoL questionnaire and rates each item
using a 5-point Likert scale per item. For young children (excluding toddlers) a site study
person reads the questions to the subject and asks the child to point to a 3-scale smiley
score (Young Child Report). This score is then marked by the site study person. In older
age groups subjects complete their age-adapted QoL questionnaire using a 5-point Likert
scale for each item. A parent/caregiver additionally completes the QoL questionnaire
(Parent Report) adapted to rate their young child, child or adolescent also using a 5-point
Likert scale per item. For subjects growing into adults (reaching legal age) Parent Reports
will not be collected. For subjects with Down Syndrome only Parent Reports are collected.
Subjects and parent(s)/caregiver(s) are asked to rate the QoL considering the 1-month
period preceding the completion of the questionnaire.
The QoL paper questionnaire is completed by parent(s)/caregiver(s) and by subjects. The
cardiac and fatigue components will only be assessed for English-speaking subjects in the
USA, since these questionnaires have only been validated for the USA.
 
The Parent Report (QoL questionnaire) will preferably be completed by the same
parent/caregiver at all timepoints for an individual subject. If the parent cannot visit
the site at the time when the QoL questionnaire must be completed, the parent can
complete it at home within a planned period of the scheduled visit, sign and date
the original form and return it to the site.
 
If the subject changes age group during the conduct of the study, the same
questionnaire as at Visit 2 will be continued.
 
Parent(s)/caregiver(s) and subjects who complete the questionnaire sign the paper
questionnaire.
 
For young children the study person who (together with the subject) completed the
Young Child Report signs the questionnaire.
The site study personnel will record the QoL scores from  parent(s)/caregiver(s) and
subjects into the eCRF. The reason for missing data are recorded by the investigator or
delegate in the eCRF.
For the data analysis the 5-point Likert scale (from 0 [never] to 4 [almost always]) will be
reversed, scored, and linearly transformed to a 0 100 scale as follows:
0  100, 1
 75, 2
 50, 3
 25, 4
0.

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All items have the same weight. If more than 50% of the items in the scale are missing, the
scale scores will not be computed.
7.7 Pharmacokinetic Assessments
Macitentan and its active metabolite ACT-132577 will be determined in plasma and blood
samples. Samples will not be used for any genomic screening.
7.7.1 Timing for PK Sampling
In all subjects who are 2 y.o. and older randomized to macitentan and receiving macitentan,
a trough sample (i.e., pre-dose) will be drawn on Visit 4 (Week 12) for PK assessments. 
In addition, up to 40 subjects (distributed over the different age groups) receiving
macitentan study treatment (randomized or after cross-over), a PK profile will be collected.
At Visit 3, the blood samples for the PK profiling must be drawn at the following
timepoints: Immediately before administration of the dose of macitentan study treatment
(pre-dose) and then 1 h, 2 h, 4 h, 8h, 12 h, and 24 h (before macitentan intake the next day)
post-dose.
In subjects younger than 2 y.o., samples will be drawn at 2h, 5h, and 24h after the first
macitentan dose at Visit 2. Trough samples (i.e., pre-dose) will be drawn on Week 4 and 8
(refer to Section 7.7.2).
7.7.2 Procedures for Sampling
Approximately 0.5 mL of blood per time point will be collected in tubes containing
ethylene diamine K3 tetra-acetic acid.
For children < 2 y.o., in addition, a volume of approximately 40 µL of blood  will be
collected at each timepoint using Neoteryx MitraTM  samplers (resulting in dried blood
samples) where the use of this sampler is allowed per local requirements. Based on
emerging data, method for PK sampling in children < 2 years of age may be switched to
0.5 mL blood sampling per time point only or dried blood sampling via Neoteryx MitraTM
samplers only.
Details for sample collection, labeling and shipping will be described in the laboratory
manual. The date and exact actual clock time of each blood sample draw will be entered
into the eCRF. In addition, the last dosing date and time of macitentan intake before and
after blood PK sampling will be collected in the eCRF.
7.7.3 Bioanalysis
The concentrations of macitentan and its metabolite ACT-132577 in plasma from PK
samples and in dried blood (for children <2 y.o.) will be determined using validated liquid
chromatography coupled to mass spectrometry methods, by or under supervision of the
sponsor.

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7.7.4 3-Total Blood Volume
For subjects ≥ 2 y.o., the total blood volume drawn  for the PK assessments will be
approximately0.5 mL at steady state with an additional 7×0.5 mL  3.5 mL for the subjects
that participate in the PK substudy.
For subjects < 2 y.o., the total volume drawn for PK assessments will be approximately 1.7
mL at Visit 2 and approximately 0.6 mL at steady state (Week 4 and Week 8) .
8 SCHEDULE OF VISITS
To ensure compliance, at each visit, the study personnel must verify with female subjects
of childbearing potential whether they are sexually active and must remind those who are
sexually active to use the methods of contraception defined for this study. The reminders
must be documented in the subject chart.
Unscheduled visits may be performed at any time during the study. During an unscheduled
visit, assessments to verify worsening of PAH (until EOCP) and presence of AEs/SAEs
must be performed [see Table 1, Table 2, Table 3 and Section 8.11]. In addition, depending
on the reason for the unscheduled visit (e.g., an AE), appropriate assessments will be
performed based on the judgment of the investigator and the results 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. During the SAEP, unscheduled
visits are not recorded in the eCRF but (S)AE are reported, if applicable.
To minimize pain and distress an anesthetic cream (e.g., EMLA® cream containing
lidocaine 2.5% and prilocaine 2.5%) may be applied prior to any venipuncture as per
preference of the subject or parent(s)/caregiver. Local anesthetics will be recorded as
concomitant medications in the eCRF.
8.1 Screening / Visit 1
The screening period can take up to 6 weeks and ends with randomization or screening
failure. It can comprise several site visits. However, for simplicity this will be referred to
as Visit 1 for all subjects.
For the cohort of children < 2 y.o., screening ends with confirmation of eligibility and
assignment of macitentan kit at Visit 2, or with screening failure.
Once the subject’s parent(s) / legally designated representative have signed the ICF and
assent has been obtained from developmentally capable subjects the investigator enrolls
the subject into the study through the IRT system which will provide a unique subject
number. The investigator documents the planned SoC in the IRT system  for
subjects ≥2 y.o.

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For subjects with co-incidental CHD the investigator submits data to the BCAC [refer to
Sections 3.4 and 7.1]. Only after BCAC  confirms the eligibility, the investigator
randomizes the subject given all other entry criteria are confirmed.
If eligibility of a subject cannot be confirmed within the 6-weeks Screening period, it is
permitted to re-screen the subject once, if the reason for non-eligibility was transient (e.g.,
abnormal laboratory test, insufficient washout period of a forbidden medication). All
screening assessments should then be repeated at the time of re-screening and are used to
randomize the subject in IRT (if eligible) using the same subject number.
Visit 1 includes:
 
Informed consent from parent(s) / legally designated representative and assent
from developmentally capable subjects
 
Verification PAH diagnosis
And assessment of:
 
Demography and medical history
 
Baseline disease characteristics (co-incidental CHD  requires approval through
BCAC)
 
Previous and concomitant medications (including contraceptives)
 
PAH-related non-pharmacological interventions
 
Signs and symptoms of PAH
 
WHO FC and Panama FC
 
Echocardiography
 
Physical activity (collected anytime during Screening and before Visit 2)
 
6MWT
 
Vital signs (BP, heart rate)
 
Weight and height/length
 
Physical examination
 
Laboratory tests (complete hematology and clinical chemistry)
 
Tanner stage
 
Serum pregnancy test in subject of childbearing potential (SOCBP)
 
AE/SAE
Some of these assessments depend on the age of the subject, please refer to Section 7 and
to Table 1 and Table 2. Study assessments can be distributed over the entire screening
period. At Visit 1 the investigator (or delegate) instructs parent(s) / legally designated
representative and developmentally capable subjects on how and when to wear the
accelerometer [refer to Section 7.3.4]. Furthermore, for female subjects of childbearing
potential and who are sexually active, the investigator discusses methods of contraception.

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At Visit 1, 3 mL of blood is collected for hematology and clinical chemistry. In addition,
in SOCBP (and including those subjects who had tubal sterilization), 1 mL of blood is
collected to exclude pregnancy. Routine test results may be used as specified in
Section 7.4.5.
8.2 Randomization / Visit 2(Day 1)
The investigator will verify all inclusion and exclusion criteria assessed during Screening
and will decide on the final eligibility of the subject. The investigator marks the source data
used to assess subject’s eligibility. For potential re-screening refer to Section 8.1.
Visit 2 includes assessment of:
 
Vital signs (BP, heart rate) #
 
Previous and concomitant medications (including contraceptives)
 
PAH-related non-pharmacological interventions
 
Signs and symptoms of PAH
 
WHO FC and Panama FC
 
6MWT
 
Plasma NT-proBNP#
 
Weight# and height/length
 
Physical examination#
 
Laboratory tests (complete hematology and clinical chemistry) # unless blood
sample at Visit 1 (Central Laboratory) was collected within 1 week before Visit 2
 
For children <2 y.o.: PK samples at 2h, 5h, and 24h after the first macitentan dose
 
Urine pregnancy test in SOCBP#*
 
QoL
 
AE/SAE
Some of these assessments depend on the age of the subject, please refer to Section 7 and
to Table 1 and Table 2. All assessments will be done on the same calendar day. The QoL
questionnaire may be reported within ±5 calendar days of the visit. The investigator, based
on the assessments above and any other relevant information in the medical chart, will
write a Subject Narrative, which will help as a reference at the time of a disease
progression.
# These assessments must be done before randomization (and for children < 2 y.o. before first dose
of macitentan study drug).
* Subjects who are sexually active and who use hormonal contraceptives must have initiated those
medications at least 4 weeks prior to the test at Visit 2 [refer to Section 4.5.2].
At Visit 2, 4.2 mL of blood is collected to assess plasma NT-proBNP, hematology and
clinical chemistry. For subjects <2 y.o., approximately 1.7 mL is additionally taken for

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PK. In addition in SOCBP (and including those subjects who had tubal sterilization) urine
is collected to exclude pregnancy. Routine test results may be used as specified in
Section 7.4.5.
If a subject is not eligible, the reason for screening failure will be entered in the eCRF.
Baseline data collected until confirmation of Screening failure are also recorded in the
eCRF. If Baseline data are available from any Central Laboratory (e.g., physical activity)
those will be transferred to the clinical database.
For subjects ≥2 y.o. at Visit 2: If the eligibility of the subject is confirmed, the investigator
performs or oversees:
 
Documentation of SoC (including ERA: yes vs no) and WHO FC (FC I/II vs FC
III) in the IRT system
 
Randomization through IRT (subjects taking ERAs are limited up to 40% of the
overall number of randomized subjects).
In subjects randomized to macitentan, and in subjects <2 y.o., Visit 2 also includes:
 
Macitentan study treatment dispensing
 
Palatability and acceptability of macitentan
In subjects randomized to SoC, the investigator
 
Prescribes SoC as documented in the IRT
For subjects randomized to the macitentan group, the subject’s body weight recorded at
Visit 2 will be used by the IRT system to calculate the daily dose of macitentan [refer to
Table 6 and Table 7] and to assign the respective study treatment kit. For subjects <2 y.o.,
age will be used by IRT system to calculate the daily dose of macitentan.
The study personnel instructs parent(s) / legally designated representative and
developmentally capable subjects on macitentan administration [refer to Section 5.1.5]. In
SOCBP  (and including those subjects who had tubal sterilization) macitentan study
treatment can only be started in the presence of a negative pregnancy test. For subjects
randomized to SoC PAH-specific medications are continued or newly initiated as
instructed in Section 5.1.2.
For subjects <2 years of age at Visit 2:
For PK assessment, approximately 1.7 mL of blood (including dried blood samples via
Neoteryx MitraTM device where the use of this sampler is allowed per local requirements)
are collected at 3 timepoints after the first dose of macitentan as described in Section 7.7.1.

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8.3 PK Visits at Week 4 and Week 8 for Subjects < 2 y.o.
This visits apply only to cohort < 2 years of age at first dose of macitentan study treatment.
The visit will take place at steady-state conditions for macitentan and its active metabolite
(ACT-132577), i.e., subjects must have received at least 10 days of continuous
administration of the same dose of macitentan. For subjects who prematurely discontinue
macitentan treatment before the planned visit(s), the respective visit(s) will be cancelled.
Parent(s) / legally designated representative must be reminded before Week 4 and before
Week 8 visits not to administer macitentan before blood has been collected for the PK
sampling and for laboratory safety tests on the day of the Visits but to bring the macitentan
to the site for administration.
During these visits the following is collected and reported:
 
Vital signs (BP, heart rate)
 
Concomitant medications (including contraceptives)
 
PAH-related non-pharmacological interventions
 
Signs and Symptoms of PAH#
 
Weight and height/length
 
Physical examination
 
Laboratory tests (hemoglobin, hematocrit and liver tests)
 
PK sample
 
AE/SAE
The assessments are done on the same calendar day. Approximately 0.5 mL of blood and
a dried blood sample via Neoteryx MitraTM device (where allowed) are collected to assess
trough  (pre-dose) PK. In addition, 2 mL of blood is collected to assess hemoglobin/
hematocrit and liver tests.
The daily macitentan dose is taken at site after the collection of the PK samples.
The investigator (or delegate) will document the date, time, and dose of macitentan before
and after PK sample collection as well as the date and time of the PK sample (blood
collection).
# In the presence of clinical worsening, refer to Section 8.9.
8.4 PK Substudy / Visit 3 for Subjects ≥2 y.o. on Macitentan/ Visit 3
This visit applies only  to subjects ≥ 2 y.o. receiving macitentan  and who signed the
informed consent for the PK substudy [refer to PK substudy in Section 3.1] or to subjects
randomized to SoC and crossing over to macitentan and providing informed consent for
the PK substudy during the Cross-over visit. The visit will take place at steady-state
conditions for macitentan and its active metabolite (ACT-132577), i.e., subjects must have

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received at least 10 days of continuous administration of the same dose of macitentan. To
collect the PK profile, it is recommended that the subjects stay overnight in the
investigational site. This is, however, not mandated. The investigator will instruct subjects
who leave the hospital that some medications are forbidden due to drug-drug interactions
with macitentan, and not to take the next macitentan dose until after the last PK sample is
taken the next morning. For subjects who prematurely discontinue macitentan treatment
before the planned Visit 3, the visit is cancelled.
Parent(s) / legally designated representative must be reminded before Visit 3 not to
administer macitentan before blood has been collected for the pre-dose PK sampling on the
day of Visit 3, and not to administer macitentan the next morning before the last PK sample
is drawn.
Visit 3 includes collection and reporting of:
 
Vital signs (BP, heart rate)
 
Concomitant medications (including contraceptives)
 
PAH-related non-pharmacological interventions
 
Signs and Symptoms of PAH#
 
Weight and height/length
 
Physical examination
 
Laboratory tests (complete hematology and clinical chemistry)
 
PK samples for PK profile
 
AE/SAE
The assessments are done on the same calendar day the first PK sample is collected. At
Visit 3, 3.5 mL of blood is collected to assess PK profile. In addition, 3 mL of blood is
collected to assess hematology and clinical chemistry.
# In the presence of clinical worsening, refer to Section 8.9.
8.5 Treatment Visits / Visit 4 (Week 12)
Visit 4 occurs 12 weeks (± 2 weeks) after randomization. Parent(s) / legally designated
representative of subjects ≥ 2 y.o. must be reminded before Visit 4 that macitentan study
treatment should not be administered at the day of Visit 4 until after blood has been
collected for PK sampling. The subject’s body weight is verified by the investigator to
adjust the study treatment dose of macitentan as appropriate [refer to Section 5.1.5]. For
subject < 2 y.o. the age is verified for correct macitentan dose.
The investigator discusses monthly hemoglobin, livertest results with the parent(s) / legally
designated representative as appropriate and verifies that monthly urine pregnancy tests, if
applicable, have been performed and were negative. The investigator also assesses whether

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a subject has reached childbearing potential and, if confirmed, whether the subject is
sexually active to ensure counseling for appropriate contraception.
Visit 4 includes assessment and reporting of:
 
Vital signs (BP, heart rate)
 
Concomitant medications (including contraceptives)
 
PAH-related non-pharmacological interventions
 
Signs and symptoms of PAH#
 
WHO FC and Panama FC#
 
Plasma NT-proBNP
 
Echocardiography
 
Physical activity
 
6MWT (for subjects who performed this test at Visit 2)
 
Weight and height/length
 
Physical examination
 
Laboratory tests (complete hematology and clinical chemistry)
 
Urine pregnancy test (in SOCBP)
 
Palatability and acceptability of macitentan§
 
QoL
 
PK trough sample§
 
AE/SAE
Visit 4 also includes:
 
Macitentan study treatment dispensing/return
Some of these assessments depend on the age of the subject, please refer to Section 7 and
to Table 1 and Table 2. The blood samples for NT-proBNP and PK trough are collected on
the same calendar day. The other assessments should preferably be done on the same
calendar day but if necessary can be done within ±5 calendar days. The physical activity is
not assessed at site but is collected by the subject via accelerometry device. At Visit 4, 4.2
mL of blood is collected to assess plasma NT-proBNP, hematology and clinical chemistry.
In subjects ≥ 2 y.o. treated with macitentan, 0.5 mL of blood is collected for PK. In
addition in SOCBP (including subjects with tubal sterilization) urine is collected to
exclude pregnancy.
# In the presence of clinical worsening, refer to Section 8.9.
§ In subjects treated with macitentan.

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8.6 Treatment Visits / Visit 5 (Week 24)
Visit 5 occurs 24 weeks (± 2 weeks) after randomization. The investigator discusses
monthly hemoglobin, liver test results with the parent(s) / legally designated representative
as appropriate and verifies that monthly urine pregnancy tests if applicable have been
performed and were negative. The investigator also assesses whether a subject has reached
childbearing potential and if confirmed whether the subject is sexually active to ensure
counseling for appropriate contraception. Furthermore the investigator reminds parent(s)/
legally designated representative that monthly monitoring of hemoglobin and AST/ALT is
discontinued and that monthly urine pregnancy tests if applicable would continue.
Visit 5 includes assessment and reporting of:
 
Vital signs (BP, heart rate)
 
Concomitant medications (including contraceptives)
 
PAH-related non-pharmacological interventions
 
Signs and symptoms of PAH#
 
WHO FC and Panama FC#
 
Plasma NT-proBNP
 
Echocardiography
 
Physical activity
 
6MWT (for subjects who performed this test at Visit 2)
 
Weight and height/length
 
Physical examination
 
Tanner stage
 
Laboratory tests (complete hematology and clinical chemistry)
 
Urine pregnancy test in SOCBP
 
QoL
 
AE/SAE
Visit 5 also includes:
 
Macitentan study treatment dispensing/return
Some of these assessments depend on the age of the subject, please refer to Section 7 and
to Table 1 and Table 2. Assessments should preferably be done on the same calendar day
but if necessary can be done within ±5 calendar days of the visit day. The physical activity
is not assessed at site but is collected by the subject via accelerometry device. The subject’s
body weight (or age for children <2 y.o.) is verified by the investigator to adjust the study
treatment dose of macitentan as appropriate [refer to Section 5.1.5].

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At Visit 5, 4.2 mL of blood is collected to assess plasma NT-proBNP, hematology and
clinical chemistry. In addition in SOCBP (including subjects with tubal sterilization) urine
is collected to exclude pregnancy.
# In the presence of clinical worsening, refer to Section 8.9.
8.7 Treatment Visits / Visit 6 (Week 36), Visit 7 (Week 48)
Visits 6 and 7 occur 36 and 48 weeks (± 2 weeks) after randomization, respectively. The
investigator verifies that monthly urine pregnancy tests, if applicable, have been performed
and were negative. The investigator also assesses whether a subject has reached
childbearing potential and, if confirmed, whether the subject is sexually active to ensure
counseling for appropriate contraception.
Visits 6 and 7 include assessment and reporting of:
 
Vital signs (BP, heart rate)
 
Concomitant medications (including contraceptives)
 
PAH-related non-pharmacological interventions
 
Signs and symptoms of PAH#
 
WHO FC and Panama FC#
 
Plasma NT-proBNP
 
Physical activity (before Visit 7)
 
6MWT (at Visit 7 for subjects who performed this test at Visit 2)
 
Weight and height/length
 
Physical examination
 
Tanner stage (at Visit 7)
 
Laboratory tests (complete hematology and clinical chemistry)
 
Urine pregnancy test in SOCBP
 
QoL (at Visit 7)
 
AE/SAE
Visits 6 and 7 also include:
 
Macitentan study treatment dispensing/return
Some of these assessments depend on the age of the subject, please refer to Section 7 and
to Table 1 and Table 2. Assessments should preferably be done on the same calendar day
but if necessary can be done within ±5 calendar days of the visit day. The physical activity
is not assessed at site but is collected by the subject via accelerometry device. The subject’s
body weight (or age for children <2 y.o.) is verified by the investigator to adjust the study
treatment dose of macitentan as appropriate [refer to Section 5.1.5].

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At Visits 6 and 7, 4.2 mL of blood is collected to assess plasma NT-proBNP, hematology
and clinical chemistry. In addition in SOCBP (including subjects with tubal sterilization)
urine is collected to exclude pregnancy.
# In the presence of clinical worsening, refer to Section 8.9.
8.8 Treatment Visits / Visit 8 (Week 60), Visit 9 (Week 72), etc.
Visits 8, 9 and subsequent treatment visits occur every 12 weeks (± 2 weeks), yearly visits
(i.e., Visit 11, Visit 15, Visit 19, etc) every 48weeks (± 2 weeks). The investigator verifies
at each visit that monthly urine pregnancy tests if applicable have been performed and were
negative. The investigator also assesses whether a subject has reached childbearing
potential and, if confirmed, whether the subject is sexually active to ensure counseling for
appropriate contraception.
Visits 8, 9, etc, include assessment and reporting of:
 
Vital signs (BP, heart rate)
 
Concomitant medications (including contraceptives)
 
PAH-related non-pharmacological interventions
 
Signs and symptoms of PAH#
 
WHO FC and Panama FC#
 
Plasma NT-proBNP
 
Weight and height/length
 
Physical examination
 
Tanner stage (only every 6 months at Visits 9, 11, 13, etc)
 
Laboratory tests (complete hematology and clinical chemistry)
 
Urine pregnancy test in SOCBP
 
QoL (only yearly, i.e., at Visits 11, 15, 19, etc)
 
AE/SAE
Visits 8, 9, etc, also include:
 
Macitentan study treatment dispensing/return
Assessments should preferably be done on the same calendar day but if necessary can be
done within ±5 calendar days of the visit day. The subject’s body weight is verified by the
investigator to adjust the study treatment dose of macitentan as appropriate [refer to
Section 5.1.5].
At Visits 8, 9, etc, 4.2 mL of blood is collected to assess plasma NT-proBNP, hematology
and clinical chemistry. In addition in SOCBP (including subjects with tubal sterilization)
urine is collected to exclude pregnancy.

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# In the presence of clinical worsening, refer to Section 8.9.
8.9 Visit for a Disease Progression Event
Worsening of the clinical condition of a subject can occur at any time during study
participation. Parent(s)/caregiver(s) are instructed to contact the investigator immediately
if the subject deteriorates to arrange for a visit if needed.
During the Core Period, in the presence of suspected disease progression  event (e.g.,
signs/symptoms denoting PAH worsening or deterioration of WHO FC [refer to
Sections 7.3.1.1 and 7.3.1.2]), the investigator determines the main and contributing causes
for worsening as per local practice. If applicable, the investigator reports which
components of the disease progression 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”). The disease progression event (i.e., 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 (e.g., 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
form.
Contributing causes other than PAH are also reported as AE or SAE, as appropriate.
The following assessments are performed and reported by the investigator in the eCRF:
 
Vital signs
 
Concomitant medications (including contraceptives)
 
PAH-related non-pharmacological intervention
 
Signs/symptoms of PAH
 
WHO FC and Panama FC
 
6MWT (for subjects who performed this test at Visit 2)
 
Main and contributing cause(s) of worsening
 
Plasma NT-proBNP
 
Physical examination
 
QoL
 
AE/SAE
In addition the following assessments/reports are done and provided by the investigator for
uploading in the CEC adjudication system:
 
Echocardiography report (locally read).

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 
Subject narrative describing the suspected disease progression event based on the
assessments above and any additional relevant information in the medical chart to
help the CEC committee to confirm the suspected event as a per protocol disease
progression. In this endeavor, the investigator will use as Baseline reference the
Subject Narrative written at Visit 2.
Assessments should preferably be done on the same calendar day but, if necessary, can be
done within ±5 calendar days of the visit day. At disease progression, 1.2 mL of blood is
collected to assess plasma NT-proBNP.
In case the subject is hospitalized at another center than the investigational site, the
investigator collects above data as available by contacting the treating center and requests
the hospital discharge summary and the autopsy report (if applicable) and reports disease
progression in the eCRF as best as possible, e.g., QoL, may in this case not be collected.
The investigator or delegate sends narratives (subject condition at Baseline and at disease
progression) and a copy of the Baseline and follow-up echocardiography report as well as
other relevant reports (such as hospital discharge letter, RHC  report, etc) that support
disease progression via email to the CEC Coordinator (see contact details in the ISF). The
CEC Coordinator provides reports and narratives to the CEC as supportive data to assess
disease progression. The CEC Coordinator ensures these are translated into English if
provided in another language. The CEC Coordinator must ensure that narratives and copies
of source data are blinded for subject identifiers (such as initials, birth dates, address,
telephone numbers, etc [refer to Section 12.2]), and do not reveal the study treatment
(macitentan versus SoC), the investigational site or country.
If the CEC requests further data or clarification  (e.g., follow-up narrative), the CEC
Coordinator will contact the respective investigator and forward the additional information
to the CEC, if available. For further details regarding the role of the CEC refer to
Sections 3.4 and 6.1.1 and to the CEC Charter.
If the CEC confirms the disease progression event, macitentan treatment will continue for
subjects randomized to macitentan. For subjects randomized to SoC, macitentan will be
offered if the investigator considers this to be in the best interest of the subject, and if the
subject meets the qualifications to start macitentan treatment [refer to Section 8.10].
In all study subjects, assessment and reporting of any further disease progression continues
until EOCP. All disease progression events reported until EOCP are adjudicated by the
CEC.

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8.10 Cross-over Visit
This visit applies only to subjects in the SoC group who have CEC-confirmed disease
progression and who wish to cross-over to macitentan treatment. It is the investigator’s
responsibility to assess whether it is in the subject’s best interest to cross over to
macitentan, in particular for those subjects who are already on an alternative ERA
treatment. Before macitentan treatment is started, the investigator must confirm the
following to ensure the subject is eligible to start macitentan treatment:
1. Informed consent from subjects of legal age or informed consent to cross over is
available from parent(s) / legally designated representative (assent from
developmentally capable subjects ≥12 years of age)
2. Serum AST and/or ALT must be ≤ 3 ×ULN (assessed by local or Central Laboratory
within 6 weeks before or at the Cross-over Visit)
3. Severe hepatic impairment, e.g., Child-Pugh Class C [see Appendix 1] Note: Child
Pugh Score must be fully documented for subjects with hepatic impairment as part of
their medical history and/or clinical signs and evidence of hepatic impairment.
4. Hemoglobin or hematocrit must be ≥ 75% of the LLN (assessed by local or Central
Laboratory within 6 weeks before or at the Cross-over Visit)
5. Renal function must not be severely impaired (i.e. estimated creatinine clearance ≥30
mL/min or serum creatinine ≤221 µmol/L)
6. In SOCBPs, pregnancy must be excluded via urine test
7. SOCBPs who are sexually active must use a reliable method of contraception (refer to
Section 4.5.2)
8. No treatment with strong inducers of CYP3A4 within 4 weeks before Cross-over Visit
(for list of medications, refer to exclusion criterion #11 in Section 4.4).
9. No systemic treatment with strong inhibitors of CYP3A4 nor with moderate dual
CYP3A4/CYP2C9 inhibitors, or combination of a moderate CYP3A4 and a moderate
CYP2C9 inhibitor within 4 weeks before Cross-over Visit (for list of medications, refer
to exclusion criterion #12 and #13 in Section 4.4).
In addition, the following assessments are mandated during the same Cross-over visit and
recorded in the eCRF:
 
Vital signs (BP, heart rate)
 
Weight and height/length
 
Physical examination

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 
AE/SAE
 
Concomitant medications (including contraceptives)
 
PAH-related non-pharmacological interventions
 
Signs and symptoms of PAH
 
WHO FC and Panama FC
 
Plasma NT-proBNP (assessed by the Central Laboratory)*
 
Laboratory tests (complete hematology and clinical chemistry assessed by the
Central Laboratory)*
* Not mandated for subjects who are not eligible to start macitentan treatment.
Assessments should preferably be done on the same calendar day but if necessary can be
done within ±5 calendar days of the visit day.
If the subject is not eligible to start macitentan treatment the reason needs to be documented
in the eCRF and the subject can be re-tested once for eligibility to start macitentan. In this
case a new Cross-over Visit has to be scheduled and all eligibility criteria and assessments
have to be reported again.
If the subject is eligible to start macitentan, the subject’s body weight is entered by the
investigator in IRT to calculate the daily dose of macitentan [refer to Table 6 and Table 7]
and to assign  the appropriate macitentan treatment kit [refer to Section 5.1.3]. The
investigator (or delegate) dispenses the macitentan treatment and instructs parent(s) /
legally designated representative and developmentally capable subjects on macitentan
administration [refer to Section 5.1.5].
The investigator may also discuss potential participation of the subject in the PK substudy.
A new optional informed consent/ assent is needed for subjects who cross-over to
macitentan and who would like to participate in the PK substudy.
For subjects who cross-over to macitentan treatment, “end of standard of care” must be
reported in the eCRF.
For subjects who cross-over to macitentan and who discontinue macitentan before End of
Study the EOM visit and the safety follow-up call must be performed [refer to
Sections 8.12 and 8.16].
8.11 Unscheduled Visits
Unscheduled Visits may occur at any time during study participation. During the Core
Period, the investigator verifies that monthly urine pregnancy tests, if applicable, have been
performed and were negative. The investigator also assesses whether a subject has reached
childbearing potential and, if confirmed, whether the subject is sexually active to ensure
counseling for appropriate contraception.

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At an unscheduled visit during Core Period, the following assessments are mandated and
recorded in the eCRF:
 
Concomitant medications (including contraceptives)
 
PAH-related non-pharmacological interventions
 
Signs and symptoms of PAH#
 
WHO FC and Panama FC#
 
Physical examination
 
Laboratory re-tests if applicable
 
AE/SAE
Assessments should preferably be done on the same calendar day but, if necessary, can be
done within ±5 calendar days of the visit day. Any other efficacy assessment [Section 7.3]
or any safety assessment [Section 7.4] if collected are also recorded in the eCRF.
During the SAEP, the only data collected and reported as part of an unscheduled visit are
(S)AEs and if applicable laboratory re-tests as requested in Section 5.1.10.
# In the presence of clinical worsening, refer to Section 8.9.
8.12 End of Macitentan (EOM)
If macitentan is prematurely discontinued, the subject must come for a site visit within 1
week after the last dose.
The investigator verifies that monthly urine pregnancy tests if applicable have been
performed and were negative. The investigator also assesses whether a subject has reached
childbearing potential and if confirmed whether the subject is sexually active to ensure
counseling for appropriate contraception  (which must continue until EOS), refer to
Section 9.4.
The EOM visit includes:
 
Vital signs (BP, heart rate)
 
Concomitant medications (including contraceptives)
 
PAH-related non-pharmacological interventions
 
Signs and symptoms of PAH#
 
WHO FC and Panama FC#
 
Plasma NT-proBNP
 
Weight and height/length
 
Physical examination
 
Tanner stage
 
Laboratory tests (complete hematology and clinical chemistry)

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 
AE/SAE
 
Macitentan study treatment return
Assessments should preferably be done on the same calendar day but, if necessary, can be
done within ±5 calendar days of the visit day. Any other efficacy assessment [Section 7.3]
or any safety assessment [Section 7.4] if collected are also recorded in the eCRF.
At EOM, 4.2 mL of blood is collected to assess plasma NT-proBNP, hematology, and
clinical chemistry.
# In the presence of clinical worsening, refer to Section 8.9.
8.13 End ofCore Period (EOCP)
Once clinical cut-off date for Analysis 2 is announced, individual EOCP visits are
scheduled within 12 weeks.
The EOCP Visit includes:
 
Vital signs (BP, heart rate)
 
Concomitant medications (including contraceptives)
 
PAH-related non-pharmacological interventions
 
Signs and symptoms of PAH#
 
WHO FC and Panama FC#
 
Plasma NT-proBNP
 
Weight and height/length
 
Physical examination
 
Tanner stage
 
Laboratory tests (complete hematology and clinical chemistry)
 
Urine pregnancy test in SOCBP
 
QoL
 
AE/SAE
The EOCP Visit also includes:
 
Macitentan study treatment dispensing/ return
Some of these assessments depend on the age of the subject, please refer to Section 7 and
to Table 1 and Table 2. Assessments should preferably be done on the same calendar day
but, if necessary, can be done within ±5 calendar days of the visit day. At EOCP, 4.2 mL
of blood is collected to assess plasma NT-proBNP, hematology and clinical chemistry. In
addition in SOCBP (including subjects with tubal sterilization) urine is collected to
exclude pregnancy.

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At EOCP, participation to the SAEP will be proposed to eligible subjects.
For definition of EOCP  for subjects who withdraw from the study or prematurely
discontinue study visits, refer to Sections 8.17 and 9.2.
Eligibility for entering the SAEP with macitentan:
Before macitentan treatment is continued/started, the investigator must confirm the
following to ensure the subject is eligible to enter the SAEP and continue/receive
macitentan treatment:
1. Informed consent from subjects of legal age or informed consent to enter the SAEP
is available from parent(s) / legally designated representative (assent from
developmentally capable subjects ≥12 years of age)
2. Serum AST and/or ALT must be ≤ 3 ×ULN (assessed by local or Central Laboratory
within 6 weeks before or at the EOCP Visit)
3. Severe hepatic impairment, e.g., Child-Pugh Class C [see Appendix 1] Note: Child
Pugh Score must be fully documented for subjects with hepatic impairment as part of
their medical history and/or clinical signs and evidence of hepatic impairment
4. Hemoglobin or hematocrit must be ≥ 75% of the LLN (assessed by local or Central
Laboratory within 6 weeks before or at the EOCP Visit)
5. Renal function must not be severely impaired (i.e. estimated creatinine clearance ≥30
mL/min or serum creatinine ≤221 µmol/L) (assessed by local or Central Laboratory
within 6 weeks before or at the EOCP Visit)
6. In SOCBPs, pregnancy must be excluded via urine test
7. SOCBPs who are sexually active must use a reliable method of contraception (refer to
Section 4.5.2) and agree to continue monthly urine pregnancy tests
8. No treatment with strong inducers of CYP3A4 within 4 weeks before EOCP Visit (for
list of medications, refer to exclusion criterion #11 in Section 4.4).
9. No systemic treatment with strong inhibitors of CYP3A4 nor with moderate dual
CYP3A4/CYP2C9 inhibitors, or combination of a moderate CYP3A4 and a moderate
CYP2C9 inhibitor within 4 weeks before Cross-over Visit (for list of medications,
refer to exclusion criterion #12 and #13 in Section 4.4).
# In the presence of clinical worsening refer to Section 8.9.

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8.14 Single-arm Extension Period (SAEP)
Once subject is enrolled in the SAEP, individual Extension Visits are scheduled every
24 weeks (±2 weeks).
The Extension Visit includes:
 
Vital signs (BP, heart rate)
 
Concomitant medications (including contraceptives)
 
Weight and height/length
 
Physical examination
 
Tanner stage
 
Laboratory tests (complete hematology and clinical chemistry)
 
Urine pregnancy test in SOCBP
 
AE/SAE
The Extension Visit also includes:
 
Macitentan study treatment dispensing/ return
8.15 
End of Study
Once Study Closure is announced, individual EOS visits are scheduled within
approximately 12 weeks.
The EOS Visit includes:
 
Vital signs (BP, heart rate)
 
Concomitant medications (including contraceptives)
 
Weight and height/length
 
Physical examination
 
Tanner stage
 
Laboratory tests (complete hematology and clinical chemistry)
 
Urine pregnancy test in SOCBP
 
AE/SAE
The EOS visit also includes:
 
Macitentan study treatment return
Assessments should preferably be done on the same calendar day but, if necessary, can be
done within ±5 calendar days of the visit day. At EOS, 3 mL of blood is collected to assess
hematology and clinical chemistry. In addition in SOCBP (including subjects with tubal
sterilization) urine is collected to exclude pregnancy.

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At EOS (Study Closure) participation to a PTA or LTE study will be offered to subjects
who otherwise have no access to macitentan or alternative treatment [refer to Section 3.1].
For definition of EOS for subjects who withdraw from the study or prematurely discontinue
study visits, refer to Section 3.1.
8.16 
Safety follow-up
For subjects who prematurely discontinue macitentan or SoC treatment the investigator
will do the Safety FU 30 days (+ 1 week) after end of treatment. End of SoC  will be
declared, if a planned PAH-specific drug class is discontinued or if any additional PAH-
specific drug class is added, or if the subject crosses over to macitentan after a
CEC-confirmed disease progression event.
For subjects who continue study treatment until EOS and who do not enter any PTA or
LTE studyby Janssen, the investigator will do the Safety FU 30 days (+ 1 week) after EOS.
Subjects who continue study treatment until EOS and enter a Janssen PTA or LTE study
will have no Safety FU call since they will be continuously followed in the Janssen PTA
or LTE study.
The safety follow-up is conducted by the investigator through a telephone contact with the
subject’s parent(s) / legally designated representative or with subjects who came of legal
age and includes assessment of:
 
Information regarding urine pregnancy test in female subjects of childbearing
potential (including subjects with tubal sterilization)
 
AE/SAE
8.17 
Survival Follow-up
Subjects for whom parent(s) / legal representative have withdrawn the consent to continue
the planned schedule of assessments (regular study visits) but who are not withdrawn from
the study [see Section 9.2] are contacted at least yearly by the study investigator and within
6 weeks before cutoff date for Analysis 1 and Analysis 2.
The last survival follow-up contact is performed for Analysis 2 and is considered EOS.
The survival follow-up contact includes assessment of:
 
PAH-specific medications
 
Vital status (including date/ cause of death)
The investigator can collect these data through direct contact with parent(s) / legally
assigned representative or subjects as well as indirectly via the treating physician. Data can
be collected via telephone call, site visit or through written communication (e.g., letter).

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The investigator reports these data in the eCRF. Fatal events are additionally reported using
an SAE form.
9 STUDY COMPLETION AND POST-STUDY TREATMENT/MEDICAL
CARE
9.1 Study Completion
For an individual subject study completion is reached when the EOS visit or the safety
follow-up telephone call (if applicable) is completed.
The study is considered completed when the last subject completes the study (i.e., last EOS
visit or last safety follow-up telephone call, whichever occurs last). The clinical database
is locked after all data collected up to last subject last visit/contact have been collected and
are considered accurate.
9.2 Premature Withdrawal from Study, Premature Study Visit
Discontinuation
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
subject from the study (without regard to the subject’s consent) if, on balance, he/she
believes that continued participation in the study would be contrary to the best interests of
the subject. 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 subject 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 or change in/ discontinuation of SoC(other than
what is allowed according to protocol [see Sections 5.1.2 and 5.1.9] do not per se constitute
premature withdrawal from the study. Every effort should be made to keep subjects in the
study as per original schedule of assessments and hence allowing full data collection as per
protocol until EOCP in order to reduce missing data. .
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 EOCP. As a consequence, the subject enters the survival follow-up [refer to
Section 8.17]. The date and reason for this premature study visit discontinuation will be
reported in the eCRF. Efforts should be made so that the subject returns for a last site visit

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before the survival follow-up starts (e.g., EOM for macitentan group, unscheduled visit for
SoC group). The last survival follow-up contact will be used as the EOS.
Subjects are considered as lost to follow-up if all reasonable attempts by the investigator
to communicate with the individual and/or respective parent(s) / legally designated
representative failed. The site must take preventive measures to avoid a subject being lost
to follow-up (e.g., document at least three ways of contact such as telephone number, home
address, email address, person to be contacted in case the subject and/or parent(s) / legally
designated representative cannot be reached). If the subject/parent(s) / legally designated
representative cannot be reached, the site must make a reasonable effort to contact them,
document all attempts, and enter the loss of follow-up information into the eCRF. The
following methods must be used: at least three telephone calls must be placed to the last
available telephone number and one registered letter must be sent by post to the last
available home address. Additional methods may be acceptable if they are compliant with
local rules/regulations (e.g., a visit by site personnel to the subject’s home), respecting the
subject’s right to privacy. If the parent(s) / legally designated representative or subject is
still unreachable after all contact attempts listed above, he/she will be considered to be lost
to follow-up.
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 subject, 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 subject is withdrawn from the
study, the investigator should make efforts to schedule a last appointment/telephone call to
assess the safety and wellbeing of the subject, collect unused study treatment and discuss
follow-up medical care. Data obtained during this last appointment/telephone call will be
recorded in the subjects’ medical records but it will not be collected in the eCRF. The
investigator must provide follow-up medical care for all subjects who are prematurely
withdrawn from the study, or must refer them for appropriate ongoing care, as described
in Section 9.4.
Premature study discontinuation during Single-Arm Extension Period: Premature
discontinuation of macitentan during the SAEP or withdrawal from the SAEP will trigger
an EOS visit. The same instruction provided for lost to follow-up and medical care after
study withdrawal as described earlier will also apply during the SAEP.
9.3 Premature Termination or Suspension of the Study
The Sponsor reserves the right to terminate the study at any time globally or locally.
Investigators can terminate the participation of their site in the study at any time.

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If the study is prematurely suspended or terminated, the investigators, the IECs/IRBs, and
Health Authorities will be promptly informed as appropriate, and the reasons for the
suspension or termination will be provided.
If the study is suspended or prematurely terminated for any reason, the investigator in
agreement with the Sponsor must promptly inform all enrolled subjects, and ensure their
appropriate treatment and follow-up, as described in Section 9.2. The Sponsor (or delegate)
may inform the investigator of additional procedures to be followed in order to ensure that
adequate consideration is given to the protection of the subjects’interests.
In addition, if the investigator suspends or terminates the study, the investigator must
promptly inform the CRO personnel and the IEC/IRB, and provide both with a detailed
written explanation of the termination or suspension.
If the IEC/IRB  suspends or terminates its approval/favorable opinion of the study, the
investigator must promptly notify the CRO and provide a detailed written explanation of
the termination or suspension.
The Sponsor must discuss any suspension or premature termination of the study with the
IDMC.
9.4 Medical Care of Subjects After Study Completion/Withdrawal from
Study
After the subject’s study completion or premature withdrawal from study visits or from the
study, whichever applies, the investigator/delegate will explain to subject’s parent(s) /
legally designated representative and to subjects who have come of age what treatment(s) /
medical care is necessary and available according to local regulations. Such care may
include:
 
Continuation of SoC or of PAH background therapy.
 
Recommendation to initiate any PAH-specific treatment, per investigator’s
judgment.
 
Female subjects of childbearing potential and parent(s) / legally designated
representative must be reminded that pregnancy must be prevented until EOS or
until 30 days after last intake of macitentan and about acceptable methods of
contraception if sexually active. Appropriate counseling regarding risks of
pregnancy and reliable methods of contraception must be ensured.
 
Participation to a PTA or LTE study for continuous macitentan access under a
separate study protocol will be offered at EOS if available[refer to Section 3.1].
Subjects entering a Janssen PTA or LTE study will not have a Safety FU call in
TOMORROW since their safety will be followed as part of the respective study.

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10 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS
10.1 Adverse Events
10.1.1 Definition of Adverse Events
An AE is any untoward medical occurrence, i.e., any unfavorable and unintended sign,
including an abnormal laboratory finding, symptom, or disease that occurs in a subject
during the course of the study, whether or not considered by the investigator as related to
study treatment.
AEs include:
 
Exacerbation of a pre-existing disease with the exception of efficacy endpoints
(i.e., PAH disease progression) and associated symptoms.
 
Increase in frequency or intensity of a pre-existing episodic disease or medical
condition.
 
Disease or medical condition detected or diagnosed during the course of the study
even though it may have been present prior to the start of the study.
 
Continuous persistent disease or symptoms present at study start that worsen
following the signing of informed consent.
 
Abnormal assessments, e.g., change in physical examination, ECG findings, if they
represent a clinically significant finding that was not present at study start or
worsened during the course of the study.
 
Laboratory test abnormalities if they represent a clinically significant finding,
symptomatic or not, which was not present at study start or worsened during the
course of the study or led to dose reduction, interruption or permanent
discontinuation of study treatment.
Overdose, misuse, abuse and macitentan study treatment errors will be reported as an AE.
Overdose is defined as any dose that is higher than in described in Table 6 and Table 7 of
Section 5.1.5. In adults macitentan has been administered as a single dose of up to 600 mg
to healthy subjects. Adverse reactions of headache, nausea and vomiting were observed. In
the event of overdose, standard supportive measures must be taken, as required. Due to the
high degree of protein binding of macitentan, dialysis is unlikely to be effective. The
investigator or treating physician should:
i. 
Immediately contact the Study Responsible Physician
ii. 
Evaluate the participant to determine, in consultation with the Study
Responsible Physician, whether study intervention should be interrupted or
whether the dose should be reduced

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iii. 
Closely monitor the subject for AE/SAE and laboratory abnormalities for at
least 14 days (by that time it is anticipated that the levels of macitentan and
its active metabolite have returned to normal values)
iv. 
If requested by the Sponsor Medical Safety Physician (determined on a
case-by-case basis) a plasma sample for PK analysis can be obtained within
3 days from the date of the last overdose of study intervention
v. 
Document the overdose as well as the duration of the overdosing in the
eCRF.
Moreover, symptoms that are dependent on participant communication ability (e.g.,
nausea, pain, mood alterations) in younger or mentally disabled children could potentially
be at risk for under- or mis-reporting. Study-site staff should instruct the legal guardians
and caregivers on how to report signs and symptoms (e.g., crying and pain) in the individual
pediatric participant. They will be instructed to report both specific and non-specific
symptoms (including vomiting, diarrhea, sleepiness, variation in the intensity and pattern
of crying, etc). These non-specific symptoms may be the only manifestations of some
adverse reaction observed in infants and toddlers. Care should be taken that the clinical
presentation of adverse reactions is not misinterpreted as the manifestation of a pre-existing
or unrelated condition.
10.1.2 Intensity of Adverse Events
The intensity of clinical AEs is graded on a three-point scale -mild, moderate, severe -and
is reported on specific AE pages of the eCRF.
If the intensity of an AE worsens between randomization and EOS  a new AE must be
reported (including AEs ongoing at randomization). If the AE lessens in intensity, no
change in the severity is required to be reported.
The three categories of intensity are defined as follows:
 Mild
The event may be noticeable to the subject. It does not usually influence daily activities,
and normally does not require intervention.
 Moderate
The event may make the subject uncomfortable. Performance of daily activities may be
influenced, and intervention may be needed.
 Severe
The event may cause noticeable discomfort, and usually interferes with daily activities.
The subject may not be able to continue in the study, and treatment or intervention is
usually needed.

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A mild, moderate, or severe AE may or may not be serious [see Section 10.2.1]. These
terms are used to describe the intensity of a specific event. Medical judgment should be
used on a case-by-case basis.
Seriousness, rather than intensity  assessment, determines the regulatory reporting
obligations.
10.1.3 Relationship to Study Treatment
For subjects in the macitentan group, each AE must be assessed by the investigator as to
whether or not there is a reasonable possibility of causal relationship to macitentan, and
reported as either related or unrelated. The determination of the likelihood that the study
treatment caused the AE will be provided by the investigator.
10.1.4 Reporting of Adverse Events
All AEs with onset date after signing of informed consent and up to EOS or up to the safety
follow-up telephone call (whichever is last) must be recorded on specific AE pages of the
eCRF. Subjects who enter a PTA or LTE study at EOS will be waived from the safety
follow-up call since they will be monitored in the respective PTA or LTE study. Exception:
Events of exacerbation of underlying disease occurring until EOCP (see below).
Reporting of efficacy endpoint events:
 
Core Period: All exacerbations of underlying disease during the Core Period must be
reported on specific pages of the eCRF  capturing disease progression  where the
information reported is similar to that captured for AEs (e.g., relationship to
macitentan, action taken with macitentan). Such disease progression events and
associated symptoms are not to be entered on the AE form of the eCRF.
 
Single-Arm Extension Period: During the SAEP, all exacerbations of underlying
disease will be reported on the AE form.
10.1.5 Follow-up of Adverse Events
AEs still ongoing after EOS  or after safety follow-up telephone call (whichever is last)
must be followed up until they are no longer considered clinically relevant (e.g., until
symptom resolution) or until stabilization.
The investigator is obligated to perform or arrange for the conduct of supplemental
measurements and evaluations as medically indicated to elucidate the nature and causality
of the AE, SAE, or PQC as fully as possible. This may include additional laboratory tests
or investigations, histopathological examinations, or consultation with other health care
professionals.

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The follow-up information obtained after subjects’EOS / safety follow-up telephone call
is recorded in the medical chart of the subject (source data), but is not recorded in the eCRF.
10.2 Serious Adverse Events
10.2.1 Definitions of Serious Adverse Events
An SAE is defined by the ICH guidelines as any AE fulfilling at least one of the following
criteria:
 
Fatal.
 
Life-threatening: Refers to an event in which the subject was at risk of death at the
time of the event. It does not refer to an event that hypothetically might have caused
death had it been more severe.
 
Requiring in-patient hospitalization, or prolongation of existing hospitalization.
 
Resulting in persistent or significant disability or incapacity.
 
Suspected transmission of any infectious agent via a medicinal product.
 
Congenital anomaly or birth defect.
 
Medically significant: Refers to important medical events that may not immediately
result in death, be life-threatening, or require hospitalization but may be considered
to be SAEs when, based upon appropriate medical judgment, they may jeopardize
the subject, and may require medical or surgical intervention to prevent one of the
outcomes listed in the definitions above.
The following reasons for hospitalization are not considered as SAEs:
 
Hospitalization for cosmetic elective surgery, or social and/or convenience reasons.
 
Hospitalization for pre-planned (i.e., planned prior to signing informed consent)
surgery or standard monitoring of a pre-existing disease or medical condition that
did not worsen.
However, complications that occur during hospitalization are AEs or SAEs (e.g., if a
complication prolongs hospitalization).
10.2.2 Reporting of Serious Adverse Events
All SAEs, occurring after signing of informed consent and up to EOS or up to the safety
follow-up telephone call (whichever is last) as well as product quality complaints (PQC)
occurring during the study must be reported on AE pages in the eCRF (including the reason
for seriousness) and on an SAE form, regardless of the investigator-attributed causal
relationship with study treatment or study-mandated procedures. Subjects who enter a PTA
or LTE study at EOS will be waived from the safety follow-up call since they will be
monitored in the respective PTA or LTE study.

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An SAE is defined as related to protocol-mandated procedures if it appears to have a
reasonable possibility of a causal relationship to either the study design or to
protocol-mandated procedures (e.g., discontinuation of a subject’s previous treatment
during a washout period, leading to exacerbation of underlying disease).
PAH  disease progression events that occur during the Core Period are recorded on
dedicated eCRF pages (“Disease Progression Event Summary,” “Disease Progression
Event page,” and if applicable “clinical worsening”) but not in the AE section of the eCRF.
However, serious events of PAH disease progression must be reported additionally using
an SAE form. During the SAEP, disease progression events will be reported in the AE
section of the eCRF and, if classified as "serious," on an SAE form.
10.2.3 Follow-up of Serious Adverse Events
SAEs still ongoing after the EOS  visit or after the safety follow-up telephone call
(whichever is last) must be followed up until resolution or stabilization, or until the event
outcome is provided. The follow-up information obtained after the subject’s EOS/ safety
follow-up telephone call must be reported to the CRO, but it is not recorded in the eCRF.
During the SAEP, the investigator will report all SAEs directly to the Sponsor.
10.2.4 After the Study Period and Safety Follow-up Period
New SAEs occurring after EOS or after the safety follow-up telephone call (whichever is
last) must be reported to the CRO within 24 hours of the investigator’s knowledge of the
event, only if considered by the investigator to be causally related to previous exposure to
the study treatment.
During the SAEP, the investigator will report these events directly to the Sponsor within
24 hours of their knowledge.
10.2.5 Reporting Procedures
All SAEs must be reported by the investigator to the CRO  within 24 hours of the
investigator’s first knowledge of the event. The CRO will forward the SAE forms, blinded
for treatment arm, to the Sponsor. During the SAEP, the SAEs will be directly reported to
the Sponsor.
All SAEs must be recorded on an SAE form, irrespective of the study treatment received
by the subject, and whether or not this event is considered by the investigator to be related
to study treatment.
The SAE forms must be sent to the CRO  during the Core Period (contact details are
provided on the SAE form), while they will be sent directly to the Sponsor during the
SAEP. The investigator must complete the SAE form in English, and must assess the
event’s causal relationship to the study treatment for subjects in the macitentan group.

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Any relevant information from source documents regarding the SAE, e.g., hospital notes
or discharge summaries, etc, must be summarized on the SAE form.
Follow-up information about a previously reported SAE must also be reported within
24 hours of receiving it. The CRO personnel (or Sponsor personnel during the SAEP) may
contact the investigator to obtain further information as instructed by the Sponsor.
If the subject is hospitalized in a hospital other than the study-site, it is the investigator’s
responsibility to contact this hospital to obtain all SAE relevant information and
documentation.
The expectedness of an adverse reaction is determined by the Sponsor in the reference
safety information (RSI) section provided in the most recent version of the Investigator’s
Brochure. Any SAE that is assessed as related and unexpected against the RSI is known as
a suspected unexpected serious adverse reaction and must be reported by the Sponsor to
concerned Health Authorities (including the EudraVigilance database if the study is
conducted in Europe), IECs/IRBs and investigators.
The Sponsor assumes responsibility for appropriate reporting of AEs to the regulatory
authorities. The Sponsor will also report to the investigator (and the head of the
investigational institute where required) all suspected unexpected serious adverse reactions
(SUSARs). The investigator (or Sponsor where required) must report SUSARs to the
appropriate IEC/IRB that approved the protocol unless otherwise required and documented
by the IEC/IRB.
10.3 Pregnancy
If a female subject becomes pregnant while on study treatment with macitentan, study
treatment must be discontinued [refer to Section 5.1.10]. The investigator must counsel the
subject 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.
10.3.1 Reporting of Pregnancy
Irrespective of the treatment received by the subject, any pregnancy occurring in female
participants or partners of male participants after study start (i.e., 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 applicable pregnancy notification form, which is sent
to the CRO (see contact details provided on the respective Pregnancy form) during the Core
Period, 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). Subjects who enter a PTA or LTE study at EOS will

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be waived from the safety follow-up call since they will be monitored in the respective
PTA or LTE study. The CRO will provide blinded pregnancy forms to the Sponsor. During
the SAEP, the investigator will report the pregnancy directly to the Sponsor.
10.3.2 Follow-up of Pregnancy
Any pregnancy must be followed up to its conclusion and the outcome must be reported to
the CRO on the applicable pregnancy notification form. During the SAEP, the pregnancy
is reported directly to the Sponsor.
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 form as described
in Section 10.2.5.
10.4 Study Safety Monitoring
Study safety information (AEs, SAEs, laboratory values, vital signs, Tanner stage and
growth) is monitored and reviewed on a continuous basis by the responsible Clinical Team
(in charge of ensuring subjects’ safety as well as data quality). In addition, an IDMC is
monitoring safety data [see Section 3.4].
10.5 Product Quality Complaint Handling
A product quality complaint (PQC) is defined as any suspicion of a product defect related
to manufacturing, labeling, or packaging, i.e., any dissatisfaction relative to the identity,
quality, durability, or reliability of a product, including its labeling or package integrity. A
PQC may have an impact on the safety and efficacy of the product. Timely, accurate, and
complete reporting and analysis of PQC information from studies are crucial for the
protection of participants, investigators, and the Sponsor, and are mandated by regulatory
agencies worldwide. The Sponsor has established procedures in conformity with regulatory
requirements worldwide to ensure appropriate reporting of PQC information; all studies
conducted by the Sponsor or its affiliates will be conducted in accordance with those
procedures.
10.5.1 Procedures
All initial PQCs must be reported to the Sponsor by the study-site personnel within 24
hours after being made aware of the event.
A sample of the suspected product should be maintained under the correct storage
conditions until a shipment request is received from the Sponsor.

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10.5.2 Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be
contacted regarding product quality issues are listed in the Contact Information page(s),
which will be provided as a separate document.
10.6 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
 
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, e.g., 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.
11 STATISTICAL METHODS
All statistical analyses will be conducted by a designated CRO supervised by the Sponsor.
The firewalls put in place between blinded and unblinded study team members are
described in a dedicated Firewall Charter.
A SAP will provide full details of the analyses, data displays, and algorithms to be used
for data derivations.
11.1 Analysis Sets
11.1.1 Screened Analysis Set
The Screened Analysis Set includes all subjects who were screened and have a subject
identification number.
11.1.2 Full Analysis Set
The Full Analysis Set 1 (FAS1) includes all subjects assigned to a study treatment via IRT
(all randomized subjects ≥2 y.o. at randomization).
In order to adhere to the intention-to-treat principle as much as possible:

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 
Subjects are evaluated according to the study treatment they have been assigned to
via IRT  (which may be different from the study  treatment they have actually
received),
 
All available data are taken into account.
FAS2 includes all subjects less than 2 y.o. at Visit 2 who are assigned to macitentanwithout
randomization.
FAS3 includes all subjects (subjects ≥2 y.o.) assigned to a study treatment via IRT (FAS1)
and all subjects less than 2 y.o. assigned to macitentan without randomization (FAS2).
11.1.3 Safety Set
The Safety Set includes all subjects who received at least one dose of macitentan or who
were randomized to continue the planned SoC. Subjects will be analyzed based on actual
treatment received pre-event SP (which may be different to the study treatment arm they
have been randomized to).
Subjects <2 y.o. at Visit 2 will be summarized separately.
11.1.4 Pharmacokinetic Analysis Sets
The PK Set 1 includes all subjects randomized to and treated with macitentan, for whom a
PK blood sample at trough has been taken and who do not deviate from the protocol in a
way that might affect the evaluation of the PK trough endpoints.
The PK Set 2 includes all subjects ≥ 2 y.o. randomized to and treated with macitentan or
crossing over to macitentan and part of the PK substudy, who have evaluable PK profiles
and who do not deviate from the protocol in a way that might affect the evaluation of the
PK substudy endpoints.
The PK Set 3 includes all subjects < 2 y.o. treated with macitentan, for whom a PK blood
sample has been taken and who do not deviate from the protocol in a way that might affect
the evaluation of the PK endpoints.
11.1.5 Usage of the Analysis Sets
The FAS1 is used for the main  analyses of all the secondary efficacy and exploratory
variables.
The FAS2 is used for descriptive analyses of all secondary efficacy and exploratory
variables.
The FAS3 is used for the description of the study population at Baseline. Unless specified
otherwise, individual listings are prepared on the FAS3. 
The Safety Set is used for the analyses of the safety variables.

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The Screened Analysis Set is used for the description of subject disposition.
For macitentan and ACT-132577 trough concentration analysis, the PK Set 1 (≥2 y.o.) and
PK Set 3 (< 2 y.o.) will be used. For PK substudy analysis, the PK Set 2 (≥2 y.o.) and PK
Set 3 will be used.
11.2 Variables
All variables described thereafter are related to the endpoints defined in Section 6.
11.2.1 Primary Variable
In  subjects who are ≥ 2 y.o.: in the macitentan arm:
 
Trough plasma concentrations of macitentan and its active metabolite ACT-132577
at Week 12 (steady-state conditions)
In subjects < 2 y.o.:
 
Trough concentrations of macitentan and ACT-132577 at Week 4 (steady-state
conditions)
PK data will be listed by subject number and PK endpoints will be analyzed descriptively
by body weight (≥2 y.o.) and age (< 2 y.o.) groups.
11.2.2 Secondary efficacy variables
Secondary efficacy variables described here below are related to the secondary efficacy
endpoints described in Section 6.1.2.
Time to First CEC-confirmed Disease Progression
All disease progressions occurring from randomization (or Visit 2 for subjects < 2 y.o.)
until EOCP are considered, irrespective of subjects compliance to assigned therapies.
Subjects who do not experience any CEC-confirmed disease progression before the end of
the Core Period have their time to first disease progression right-censored at the time of
EOCP visit or cutoff date for the respective analysis, whichever occurs first. For subjects
who discontinue prematurely regular study visits the last survival follow-up contact will
be used as the EOCP  visit. Time to first disease progression is expressed in days and
calculated as the onset date of the first CEC-confirmed disease progression minus date of
randomization (or Visit 2 for subjects < 2 y.o.) plus 1 or, for censored subjects, as censoring
date minus date of randomization (or Visit 2 for subjects < 2 y.o.) plus 1.
The events to be considered for the first CEC-confirmed disease progression are described
in Section 6.1.1.

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Time to First CEC-confirmed Hospitalization for PAH
All hospitalizations occurring from randomization (or Visit 2 for subjects < 2 y.o.) until
EOCP are considered, irrespective of subjects’compliance to assigned therapies.
Subjects who do not experience any CEC-confirmed hospitalization for PAH before the
end of the Core Period, have their time to first hospitalization right-censored at the time of
EOCP visit or cutoff date for the respective analysis, whichever occurs first. Subjects who
discontinue prematurely regular study visits are censored at the time of the last study visit
performed (end of adjudication).
Time to first hospitalization is expressed in days and calculated as the onset date of the first
CEC-confirmed hospitalization minus date of randomization (or Visit 2 for subjects < 2
y.o.) plus 1 or, for censored subjects, as censoring date minus date of randomization (or
enrolment for subjects < 2 y.o.) plus 1.
Time to CEC-confirmed Death Due to PAH
All deaths occurring from randomization (or Visit 2 for subjects < 2 y.o.) until EOCP are
considered, irrespective of subjects’compliance to assigned therapies.
Subjects who have not died due to PAH before study completion have their time to death
right-censored at the time of EOCP  visit or cutoff date for the respective analysis,
whichever occurs first. Subjects who discontinue prematurely regular study visits are
censored at the time of the last study visit performed (end of adjudication).
Time to death is expressed in days and calculated as the onset date of the CEC-confirmed
death for PAH minus date of randomization (or Visit 2 for subjects < 2 y.o.) plus 1 or, for
censored subjects, as censoring date minus date of randomization (or Visit 2 for subjects <
2 y.o.) plus 1.
Time to Death (All Causes)
All deaths occurring from randomization (or Visit 2 for subjects < 2 y.o.) until EOS are
considered, irrespective of subjects’compliance to assigned therapies.
Subjects still alive at study closure have their time to death right-censored at the time of
EOS or cutoff date for the respective analysis , whichever occurs first. For subjects who
discontinue prematurely regular study visits, the last survival follow-up contact will be
used as the EOS.
Time to death is expressed in days and calculated as the date of death minus date of
randomization (or Visit 2 for subjects < 2 y.o.) plus 1 or, for censored subjects, as censoring
date minus date of randomization (or Visit 2 for subjects < 2 y.o.) plus 1.

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WHO FC I or II (Yes/no) at Week 24
It is the WHO FC value categorized as I/II versus III/IV at 24 weeks.  The WHO FC value
will also be categorized at every timepoint of assessment. The proportion of subjects with
WHO FC equal to I or II is described for every timepoint of assessment based on the
number of subjects with available data (i.e., those having a reported value of I through IV)
and only considering values collected up to end of randomized macitentan or SoC + 7 days.
For subjects < 2 y.o. who enter macitentan arm without randomization values collected
until end of macitentan study treatment + 7 days are considered.
Percent of Baseline in Plasma NT-proBNP at Week 24
It is the percent of Baseline at 24 weeks in plasma NT pro-BNP, defined as:
   −      
   −        × 100
The percent of baseline in plasma NT pro-BNP will also be calculated at every timepoint
of assessment and only considering values collected up to end of randomized macitentan
or SoC + 7 days.
For subjects < 2 y.o. who enter macitentan arm without randomization values collected
until end of macitentan study treatment + 7 days are considered.
Mean Daily Time Spent in Moderate to Vigorous Physical Activity as
Measured by Accelerometry at Week 48
It is the change from baseline to Week 48 in mean daily time spent in moderate to vigorous
physical activity as measured by accelerometry.
The change from baseline to Weeks 12 and 24 will also be presented.  All accelerometry
variables will only consider values collected up to end of randomized macitentan or SOC
+ 7 days.
These additional variables will be expressed as change from Baseline as well. All
accelerometry variables will also be presented as change from Baseline to Week 12 and 24
and only considering values collected up to end of randomized macitentan or SoC + 7 days.
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].

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Echocardiography Variables at Week 24
The echocardiographic variables of interest are TAPSE and left ventricular eccentricity
index expressed as change from Baseline to Week 24.  The echocardiographic variables
will also be expressed as change from Baseline to Week 12 and only considering values
collected up to end of randomized macitentan or SoC + 7 days.
For subjects < 2 y.o. who enter macitentan arm without randomization values collected
until end of macitentan study treatment + 7 days are considered.
Quality of Life As Measured by the PedsQLTM 4.0 Generic Core Scales
Short Form (SF15) At Week 24
Expressed as change from Baseline to 24 weeks.  The change from Baseline to each post-
Baseline timepoint of assessment will also be presented and only considering values
collected up to end of randomized macitentan or SoC + 7 days.
The quality of life variables are further defined in Section 11.2.5.
11.2.3 Exploratory Variables
This section contains definitions of the variables related to the exploratory  endpoints
outlined in Section 6.1.3.
Panama FC I or II(yes/no) at Week 24
It is the Panama FC value categorized as I/II versus III/IV at Week 24.  The Panama FC
values is also categorized at every timepoint. The proportion of subjects with Panama FC
equal to I or II is described for every timepoint of assessment based on the number of
subjects with available data (i.e., those having a reported value of I through IV) and only
considering values collected up to end of randomized macitentan or SoC + 7 days.
For subjects < 2 y.o. who enter macitentan arm without randomization values collected
until end of macitentan study treatment + 7 days are considered.
Additional Physical Activity (Accelerometry) at Weeks 12, 24 and 48
The additional 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.
Expressed as change from Baseline to Weeks 12, 24, and 48 and only considering values
collected up to end of randomized macitentan or SoC + 7 days.

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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].
Six-minute Walk Distance at all Time Points
The variable of interest is 6-minute walk distance expressed as change from Baseline to
all timepoints, and only considering values collected up to end of randomized macitentan
or SoC + 7 days.
11.2.4 Safety Variables
Safety variables described here below are related to the safety endpoints described in
Section 6.2.
The safety variables are the following:
 
AEs from randomization up to EOS
AEs leading to premature discontinuation of randomized macitentan or SoC
AEs with fatal outcome
AEs of special interest (as defined in the SAP)
 
Treatment-emergent AEs up to end of randomized macitentan or SoC + 30 days
 
SAEs up to EOS
 
Marked laboratory abnormalities up to EOS
 
Change from Baseline in selected laboratory variables [refer to Section 11.3.5.2] to
all timepoints of assessments up to EOS
 
Change from Baseline in vital signs (BP, heart rate) to all timepoints up to EOS
 
Growth from Baseline to all timepoints of assessments up to end of randomized
macitentan or SoC + 30 days
 
Sexual maturation (Tanner stage) change from Baseline to all timepoints of
assessments up to end of randomized macitentan or SoC + 30 days
Baseline is the last non-missing value observed before or on the day of randomization.
For subjects < 2 y.o. who enter macitentan arm without randomization the day of
randomization equals the day of Visit 2 and end of randomized macitentan refers to end of
macitentan study treatment.
Treatment emergent AEs are defined as any AEs occurring after randomization up to end
of randomized macitentan or SoC + 30 days.

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11.2.5 Quality of Life at Each Timepoint of Assessment
The Pediatric Quality of Life Inventory™ (PedsQL™) questionnaire is used and the QoL
variables of interest are:
 
PedsQL™3.0 Cardiac Module score (English-speaking US subjects)
 
PedsQL™Multidimensional Fatigue Scale score (English-speaking US subjects)
Expressed as change from Baseline to each post-Baseline timepoint of assessment and only
considering values collected up to end of randomized macitentan or SoC + 7 days. The
mean score for each scale is calculated according to the algorithm in the scoring manual
[Peds QL™2014]. Where applicable the total score is used in calculation of the mean.
QoL variables will be analyzed separately depending on subjects or caregivers report.
11.2.6 Pharmacokinetic Variables
In a subpopulation of subjects ≥ 2 y.o. receiving macitentan treatment as randomized or
after crossover (up to 40 subjects distributed over the different age groups) for both
macitentan and ACT-132577 at steady-state conditions:
 
PK profile over 24 hours at pre-dose and following administration of macitentan
during steady-state conditions
 
AUCτ
 
Cmax during a dosing interval
 
tmax during a dosing interval
In subjects younger than 2 y.o.:
 
Concentrations after the first dose of macitentan within 24 hours (2, 5, 24h post-
dose) and trough concentrations at steady state
 
Concentrations will be summarized descriptively per timepoint.
11.2.7 Palatability and Acceptability of Macitentan
Palatability and acceptability of macitentan dispersible formulation on Day 1 and at Week
12 are assessed on 5-point facial hedonics (refer to Appendix 6).
11.3 Description of Statistical Analyses
11.3.1 Analysis of the Primary Variable
For PK trough analysis in all subjects, the PK Set 1 will be used.
PK data will be listed by subject number, and PK endpoints will be analyzed descriptively
by body weight group  for those who are 2 years or older or by age group for those who
are <2 y.o.

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Plasma and blood concentrations of macitentan and ACT-132577 per timepoint will be
summarized by body weight or age group in ≥2 y.o. and < 2 y.o., respectively, using
arithmetic mean and geometric mean, minimum, median, maximum, standard deviation
(SD), standard error (SE), and 2-sided 95% CI of the mean.
Subgroup analyses will be described in the SAP.
11.3.2 Analysis of the Time to Event Secondary Efficacy Variables
The analysis of the time to event variables will be performed on subjects of the FAS1
(subjects ≥ 2 y.o.), according to the intent-to-treat principle.
At Analysis 1 cutoff date, treatment effect estimates and 95% CLs will be provided for
exploratory purposes only. No multiplicity adjustment will be applied.   Analysis 2 cutoff
date will be the primary analyses for these endpoints; p-values will be provided in addition
to the treatment effect estimates and 95% CLs. Further details will be described in the SAP.
The analysis of the time to event variables will only be descriptive for subjects of the FAS2
(less than 2 y.o. receiving macitentan) at Analysis 1 and 2 cutoff dates.
Main Analysis
The main analysis of the time to event efficacy variables will be carried out using a 2-sided
stratified log-rank test with stratification factors: ongoing/planned ERA treatment (yes vs
no) and WHO FC (FC I/II vs FC III) at randomization as documented in the IRT. The
resulting 2-sided p-value will be provided.
The treatment effect will be estimated based on a proportional hazards Cox model adjusting
for the same stratification factors. Estimates of each HR and its associated 95% CL will be
displayed.
Kaplan-Meier estimates will be calculated with 2-sided 95% CLs at relevant time-points
for each treatment group and displayed in both a graphical (where the number of subjects
at risk is at least 10% of the total number of subjects in the analysis set) and a tabular form.
In addition, the number of subjects at risk, the number of subjects censored and the number
of subjects with event will be computed at each timepoint and for each treatment group.
Supportive/sensitivity Analyses
Supportive/sensitivity analyses will be described in the SAP. Subgroup
Analyses
In order to assess the consistency of the treatment effect across different subject subgroups
for the time to event secondary efficacy variables, subgroup analyses are performed
according to the demographic and Baseline disease characteristics at randomization:
 
WHO FC (FC I/II vs FC III),

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 
Ongoing/planned ERA treatment at randomization (yes vs no),
 
Ongoing/planned PDE-5i treatment at randomization (yes vs no),
 
PAH etiology ([iPAH, hPAH, HIV, drug or toxin induced]vs [PAH with co-
incidental CHD, CHD post-operative] vs [PAH-aCTD]),
 
Geographical region (North America vs Europe/Israel vs Asia/Australia vs Other),
 
Age (≥ 2 to < 6 years / ≥ 6 to < 12 years / ≥ 12 to < 18 years),
 
Sex (male vs female).
Subgroup analyses will be described in the SAP.
Further subgroups will be added for analysis if deemed appropriate.
Handling of Missing Data
Due to the nature of the time to event secondary efficacy variables, subjects with no CEC-
confirmed disease progression have their time to disease progression right-censored at the
time of EOCP, or cutoff date for the respective analysis , whichever comes first. No
additional imputation method will be used.
The nature of the censoring process will be investigated by plotting the survival distribution
of the time to censoring (where censored data for main analysis  event, and event for main
analysis  censored data) for both treatment groups using the Kaplan-Meier product-limit
method.

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The following table illustrates different possible cases and the outcome for time to CEC-
disease progression analysis:
Compliance to
study
Follow-up
Situation* 
Date of disease 
progression or
Censoring
Outcome 
Subject
completes
regular study
visits up to
EOCP
Disease progression or death 
documented during a regular study visit 
up to EOS  
Date of first
documented disease
progression or death
Event
No disease progression up to EOS  
Earliest between EOS
date and cutoff date for
the respective analysis
Censored
Reason:Study
completed
Subject
prematurely
discontinues
regular study
visits
AND
completes
survival follow-
up until EOCP
Disease progression documented during
a regular study visit
Date of first
documented disease
progression
Event
No disease progression during regular
study visits
AND death
Date of death  
Event
No disease progression during regular
study visits
AND no death
Earliest between last
survival follow-up
contact date and cutoff
date for the respective
analysis
Censored
Reason:Study
completed
Subject
prematurely
discontinues
regular study
visits and/or
survival follow-
up before
EOCP
Disease progression documented during
a regular study visit
Date of first 
documented disease
progression
Event
No disease progression during regular
study visits AND death
Date of death  
Event
No disease progression during regular
study visits
AND no death
Earliest between last
regular study visit and
last survival follow-up
contact date
Censored
Reason:as
reported on
‘End of study’
eCRF page
* All disease progressions have to be CEC confirmed
CEC  Clinical Event Committee; eCRF  electronic case report form; EOCP  end of core period; EOS  end of
study.

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Missing data handling and the censoring rules for the other time to event variables will be
described in the SAP.
11.3.3 Other Secondary Efficacy Variables
The analysis of other secondary efficacy variables will be carried out on the FAS1 (subjects
≥ 2 y.o.) and will only consider values collected up to end of randomized macitentan or
SoC + 7 days.
At Analysis 1 cutoff date, treatment effect estimates and 95% CLs will be provided for
exploratory purposes only.  Analysis 2 cutoff date will be the primary analyses for these
endpoints; p-values will be provided in addition to the treatment effect estimates and 95%
CLs.
The analysis of the other secondary efficacy variables will only be descriptive for subjects
of the FAS2 (less than 2 y.o. receiving macitentan) at Analysis 1 and 2 cutoff dates.
Percent of Baseline in Plasma NT-proBNP at Week 24
Only values collected up to end of randomized macitentan or SoC + 7 days will be
considered for this analysis. 
The percent of Baseline at each timepoint of assessment will be evaluated with the use of
a repeated measures mixed model on the log-transformed NT-proBNP values (including
Baseline). The model will include randomized treatment, visit, treatment by visit
interaction, the 2 randomization stratification factors as fixed effects and log transformed
Baseline NT-proBNP as a fixed covariate, while subject will be included as a random
effect.  Each timepoint of assessment will be assessed with the comparison at Week 24
being the most relevant.
The treatment effect expressed as geometric means ratio and its associated 95% 2-sided
CIs will be then estimated at each post-Baseline timepoint of assessment by inversely
transforming, using the exponential function, the difference in change from Baseline
between treatment groups and the associated 95% CIs, both estimated via the above model
in log scale.
Adjusted geometric means within each treatment group and ratios of adjusted geometric
means of percent of baseline between treatment groups will be displayed for each visit
along with their corresponding 2-sided 95% CIs and p-values.
If the treatment by visit interaction is not significant at the 0.01 level then the model will
be re-run without the interaction term and the overall averaged treatment effect will be
presented with 2-sided 95% CI and p-value.

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Plot ofNT-proBNP profile over time will be provided considering observed NT-proBNP
values (original scale).
WHO FC I or II (Yes/no) at Week 24
Only values collected up to end of randomized macitentan or SoC + 7 days will be
considered for this analysis.
The proportion of subjects having WHO FC I or II will be calculated at each timepoint of
assessment, and compared between the two treatment groups by means of a stratified
logistic regression. The two stratification factors will be ongoing/planned ERA treatment
(yes vs no) and WHO FC (FC I/II vs FC III) at randomization as documented in the IRT.
The odds ratio (macitentan/SoC) will be displayed with 2-sided 95% CLs.  Each timepoint
of assessment will be assessed with the comparison at Week 24 being the most relevant.
In addition to the stratified analysis, an unstratified logistic regression will be performed.
Plot of WHO FC profile over time will be provided.
Mean Daily Time Spent in Moderate to Vigorous Physical Activity as
Measured by Accelerometry at Week 48
Only values collected up to end of randomized macitentan or SoC + 7 days will be
considered for this analysis.
Changes from Baseline in mean daily time spent in moderate to vigorous physical activity
as measure by accelerometry defined in Section 11.2.2.7 will be analyzed over time by
means of a repeated measures mixed model on values at each visit (including Baseline).
The model will include randomized treatment, visit, treatment by visit interaction, the 2
randomization stratification factors as fixed effects and the baseline value as fixed
covariate, while subject will be included as a random effect. Each timepoint of assessment
will be assessed with the comparison at Week 24 being the most relevant.
Adjusted least squares means within each treatment group and adjusted estimates of the
differences in change from Baseline between treatment groups will be displayed for each
visit along with their corresponding 2-sided 95% CIs and p-values.
If the treatment by visit interaction is not significant at the 0.01 level then the model will
be re-run without the interaction term and the overall averaged treatment effect will be
presented with 2-sided 95% CI and p-value.
Plots of physical activity profiles over time will be provided.
Echocardiography Variables at Week24
Only values collected up to end of randomized macitentan or SoC + 7 days will be
considered for this analysis.

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The change from Baseline to Weeks 12 and 24 in echocardiography variables defined in
Section 11.2.2.8will be described over time by means of repeated measures mixed models
as described for physical activity variables in Section 11.3.4.2. Each timepoint of
assessment will be assessed with the comparison at Week 24 being the most relevant.
Plots of echocardiography variables profiles over time will be provided.
Quality of Life As Measured by the PedsQLTM 4.0 Generic Core Scales
Short Form (SF15) at Week 24
The analysis of QoL variables as measured by the PedsQLTM 4.0 Generic Core Scales Short
Form (SF15) are described in the QoL Section 11.3.6. Each timepoint of assessment will
be assessed with the comparison at Week 24 being the most relevant.
11.3.4 Analysis of the Exploratory Variables
The analysis of exploratory variables will be carried out on the FAS1 (subjects ≥ 2 y.o.)
and will only consider values collected up to end of randomized macitentan or SoC +
7 days.
Due to the nature of these analyses, at Analysis 1 cutoff date, treatment effect estimates
and 95% CLs will be provided for exploratory purposes only.  At Analysis 2 cutoff date,
two-sided p-values will be provided in addition to the treatment effect estimates and 95%
CLs for exploratory purposes only.
The analysis of these efficacy variables will only be descriptive for subjects of the FAS2
(<2 y.o. receiving macitentan) at Analysis 1 and 2 cutoff dates.
Panama FC I or II (Yes/no) at Week 24
Only values collected up to end of randomized macitentan or SoC + 7 days will be
considered for this analysis.
The proportion of subjects will be analyzed at each timepoint of assessment using the same
methods outlined in Section 11.3.3.2 for the WHO FC endpoint.
Plot of Panama FC profile over time will be provided.
Other Physical activity variables (accelerometry) at Weeks 12, 24 and 48
Only values collected up to end of randomized macitentan or SoC + 7 days will be
considered for this analysis.
Changes from Baseline in accelerometry variables defined in Section 11.2.3.2will be
analyzed over time by means of a repeated measures mixed model on values at each visit.
The model will include randomized treatment, visit, treatment by visit interaction, the 2

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randomization stratification factors and baseline value as fixed effects, while subject will
be included as a random effect.
Adjusted least squares means within each treatment group and adjusted estimates of the
differences in Change from Baseline between treatment groups will be displayed for each
visit along with their corresponding 2-sided 95% CIs and p-values.
If the treatment by visit interaction is not significant at the 0.01 level then the model will
be re-run without the interaction term and the overall averaged treatment effect will be
presented with 2-sided 95% CI and p-value.
Plots of physical activity profiles over time will be provided.
Six-minute Walk Distance at Weeks 12, 24 and 48
Only values collected up to end of randomized macitentan  or SoC + 7 days will be
considered for this analysis.
The change from Baseline to Weeks 12, 24 and 48 in 6-minute walk distance will be
described over time by means of repeated measures mixed models as described for physical
activity variables in Section 11.3.3.3.
Plots of 6-minute walk distance profile over time will be provided.
11.3.5 Analysis of the Safety Variables
Analysis of the safety variables will be from randomization (or Visit 2 for subjects less
than 2 y.o.) until EOS. AEs will be summarized during the Core Period and open label
extension period. The time periods of interest for the analyses of the safety variables will
be defined in the SAP.
Adverse Events
All AEs are coded with MedDRA and will be analyzed on the Safety Set by treatment arm.
The number and percentage of subjects with at least one AE, number and percentage of
subjects with at least one SAE, number and percentage of subjects with at least one AE
leading to premature discontinuation of randomized macitentan or SoC, and number and
percentage of subjects with at least one AE with fatal outcome up to EOS will be tabulated
by randomized treatment group and by:
 
System organ class and individual preferred term within each system organ class,
in descending order of incidence within the macitentan treatment group,
 
Preferred term, in descending order of incidence in the macitentan treatment group.
Furthermore, for subjects exposed to macitentan, the number and percentage of subjects
with at least one AE according to intensity, number and percentage of subjects with at least

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one AE according to relationship to macitentan, and number and percentage of subjects
with at least one SAE according to relationship to macitentan up to EOT + 30 days will be
tabulated by:
 
System organ class and individual preferred term within each system organ class,
in descending order of incidence within macitentan treatment group,
 
Preferred term, in descending order of incidence in the macitentan treatment group.
The worst intensity among ‘mild’‘moderate and ‘severe’during the studied period will be
considered if the same AE is reported more than once for the same subject. AEs with
missing intensity will be counted as ‘severe.’
The worst relationship among ‘not related’and ‘related’during the studied period will be
considered if the same AE is reported more than once for the same subject. AEs with
missing relationship will be counted as ‘related.’
For subjects randomized to the SoC arm and who received macitentan after
CEC-confirmed disease progression, the number and percentage of subjects with at least
one AE; number and percentage of subjects with at least one SAE; number and percentage
of subjects with at least one AE leading to premature discontinuation of macitentan
(initiated at cross-over); number and percentage of subjects with at least one AE with fatal
outcome; number and percentage of subjects with at least one AE according to intensity;
number and percentage of subjects with at least one AE according to relationship to
macitentan; and number and percentage of subjects with at least one SAE according to
relationship to macitentan will be tabulated by:
 
System organ class and individual preferred term within each system organ class,
in descending order of incidence within the macitentan treatment group,
 
Preferred term, in descending order of incidence in the macitentan treatment group
For adverse events of special interest, the following analyses will be performed:
 
Number and percentage of subjects with at least one AE of special interest by
treatment group and preferred term in the overall Safety set population as well as
by age categories (≥ 2 to <6 years / ≥ 6 to < 12 years / ≥ 12 to < 18 years) and sex
(female vs male).
 
Kaplan-Meier estimates of the time to first of each AESI will be calculated with 2-
sided 95% CIs at relevant timepoints for each treatment group and displayed in both
a graphical form (where the number of subjects at risk is at least 10% of the total
number of subjects in the analysis set) and a tabular form. In addition, the number
of subjects at risk, the number of subjects censored and the number of subjects with
event will be computed at each timepoint and for each treatment group.

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For subjects enrolled in the single-arm extension period, the number and percentage of
subjects with at least one AE; number and percentage of subjects with at least one SAE;
number and percentage of subjects with at least one AE leading to premature
discontinuation of macitentan (during the SAEP); number and percentage of subjects with
at least one AE with fatal outcome; number and percentage of subjects with at least one
AE according to intensity; number and percentage of subjects with at least one AE
according to relationship to macitentan; and number and percentage of subjects with at
least one SAE according to relationship to macitentan will be tabulated bytreatment group
and by:
 
System organ class and individual preferred term within each system organ class,
in descending order of incidence within the macitentan treatment group,
 
Preferred term, in descending order of incidence in the macitentan treatment group.
Listings will be provided for all reported AEs, including SAEs. In addition, separate
listings will be provided for all AEs leading to premature discontinuation of randomized
macitentan treatment, for all AEs leading to death, for all AEs occurring in the SoC arm
after cross-over to macitentan, for all AEs occurring in the SAEP and for all AEs leading
to premature discontinuation of macitentan at any time.
Laboratory Variables
All Central Laboratory data transferred to the clinical database will be taken into account
regardless of whether they correspond to scheduled (per protocol) or unscheduled
assessments. All recorded assessments will be assigned to the most appropriate visit
timepoints according to the best fitting time-window for that assessment using the usual
location and scale summary statistics by treatment group.
Treatment-emergent marked laboratory abnormalities will be analyzed on the Safety Set
by treatment arm.
A dictionary listing of definitions of marked laboratory abnormality (LL, LLL, HH, HHH)
will be provided for each variable.
For each category (i.e., LL, LLL, HH, HHH, HHHH), treatment-emergent marked
laboratory abnormalities are summarized for each laboratory variable by treatment group
displaying counts and percentages of subjects with at least a treatment-emergent marked
laboratory abnormality. Percentages are calculated as number of subjects with at least once
the abnormality for the variable under consideration divided by the number of subjects with
any post-Baseline laboratory measurement (and for hemoglobin and creatinine, also with
a valid Baseline value based on the definition of the abnormality).
Specifically for erythrocytes, hemoglobin, hematocrit, AST, ALT, total bilirubin, and
alkaline phosphatase, the following analyses will be performed:

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 
Absolute values and changes from Baseline will be summarized over time up to
EOS.
 
Plots of profiles over time will also be provided.
 
Kaplan-Meier estimates of the time to first marked abnormalities will be calculated
with 2-sided 95% CIs at relevant timepoints for each treatment group and displayed
in both a graphical form (where the number of subjects at risk is at least 10% of the
total number of subjects in the analysis set) and a tabular form. In addition, the
number of subjects at risk, the number of subjects censored and the number of
subjects with event will be computed at each timepoint and for each treatment
group.
In addition, scatter plots of the worst post-Baseline value (vertical axis) versus Baseline
value (horizontal axis) will be displayed for each laboratory variable, once transformed as
follows:
Transformed value  (Worst post-Baseline value  LLN) / (ULN  LLN)
Vertical and horizontal lines representing the transformed references ranges (0 for lower
limit and 1 for upper limit) will be added to the plot. For laboratory variables that could
worsen toward either low or high value, two separate plots will be performed, one for each
worsening direction.
Finally, the emergence of potential Hy’s Law cases will be explored by providing, for each
of the following conditions, the number and frequency of subjects meeting the condition
for at least one post-Baseline visit, provided the condition was not already present at
Baseline:
 
ALT > 3 × ULN at any time,
 
ALT and/or AST > 3 × ULN at any time,
 
ALT > 5 × ULN at any time,
 
ALT and/or AST > 5 × ULN at any time,
 
ALT > 8 × ULN at any time,
 
ALT and/or AST > 8 × ULN at any time,
 
ALT and/or AST > 3 × ULN + total bilirubin (TBIL) > 2 × ULN at any time,
 
ALT or AST > 3 × ULN + TBIL > 2 × ULN at the same time,
 
ALT or AST > 3 × ULN + TBIL > 2 × ULN + AP < 2 × ULN at the same time,
 
TBIL > 2 × ULN at any time.
eDISH plots will also be provided to facilitate exploration [Watkins 2011].
For subjects who received macitentan after CEC-confirmed disease progression, all
the above analyses will be reproduced.

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For subjects who enroll in the single-arm extension period, all the above analyses will
be reproduced.
All available local laboratory data will be listed by subject.
Vital Signs
BP (i.e., diastolic BP and systolic BP) and heart rate will be described over time by means
of repeated measures mixed models as described for physical activity variables in
Section 11.3.4.2.  Mixed models will be used to handle missing data under missing at
random (MAR) assumption.
Plots of vital signs profiles over time will be provided.
Growth
Growth variables body mass index, height and weight, will be analyzed over time by means
of repeated measures mixed models as described for physical activity variables in
Section 11.3.4.2.  Mixed models will be used to handle missing data under MAR
assumption.
In addition, body weight (kg) and body length/height (cm) will be plotted over time as
individual curves per subject. The x-axis will display age in months. The y-axis will display
the growth variable of interest, weight (kg) or length/height (cm). Separate figures will be
created for male and female subjects with/without Down Syndrome, with overlays of
sex-specific standard WHO growth percentiles by age for the 5th, 25th, 50th, 75th, and 95th
percentiles. All collected values of weight and length/height will be used.
A different symbol will be used for each treatment group.
Sexual Maturation (Tanner Stage)
Sexual maturation changes from baseline as measured by the Tanner stage will be
summarized at each scheduled time point by intervention group.
In addition, summary tables will be provided by treatment group for childbearing potential
at each timepoint of assessment.
11.3.6 Quality of Life
The analysis of QoL variables will be carried out on the FAS1 and will only consider values
collected up to end of randomized macitentan or SoC + 7 days.
QoL variables will be analyzed separately depending on subjects’or caregivers’reports.
Changes from Baseline in QoL scores defined in Section 11.2.5 will be analyzed over time
by means of a repeated measures mixed model on values at each visit . The model will
include randomized treatment, visit, treatment by visit interaction, the 2 randomization

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stratification factors as fixed effect and Baseline value as fixed covariate, while subject
will be included as a random effect.
Adjusted least squares means within each treatment group and adjusted estimates of the
differences in change from Baseline between treatment groups will be displayed for each
visit along with their corresponding 2-sided 95% CIs and p-values.
If the treatment by visit interaction is not significant at the 0.01 level then the model will
be re-run without the interaction term and the overall averaged treatment effect will be
presented with 2-sided 95% CI and p-value.
Plots of QoL variables profiles over time will be provided.
Spider plots displaying for every problem, the percentage of subjects with the problem will
also be generated at Week 12, Week 24, Week 48 and Week 96.
11.3.7 Analysis of pharmacokinetic variable(s)
For PK profiles in children > 2 y.o., the PK  Set 2 will be used, and PK Set 3 will be used
for PK assessment in children < 2 y.o
PK data will be listed by subject number and PK endpoints will be analyzed descriptively
by body weight (≥2 y.o.) and age (<2 y.o.) groups.
Plasma or blood concentrations of macitentan and ACT-132577 per timepoint will be
summarized by body weight group or age group, respectively, using arithmetic mean,
geometric mean, minimum, median, maximum, standard deviation (SD), standard error
(SE), and 2-sided 95% CI of the mean.
Maximum plasma or blood concentration (Cmax), the area under the plasma/ blood
concentration-time curve during one dosing interval (AUCτ) and the time to reach
maximum plasma/ blood concentration (tmax)* will be summarized with arithmetic mean,
geometric mean, minimum, median, maximum, SD, SE, coefficient of variation inter-
subject in %, and 95% CI of the arithmetic and geometric means.
* For tmax the geometric mean and its 95% CI will not be calculated.
Population pharmacokinetic analysis maybe undertaken as deemed appropriate. If
undertaken, the analysis details will be described separately.
The following assumptions have been made:
 
Cmax, AUC, and t½ values are assumed to be log-normally distributed
[Julious 2000].
 
No period or carry-over effects.

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The measured individual concentrations of macitentan and ACT-132577 will be used to
directly obtain Cmax and tmax.
AUCτ will be calculated according to the linear trapezoidal rule using the measured
concentration-time values above the LOQ during one dosing interval.
11.3.8 Palatability and Acceptability
Palatability and acceptability  of macitentan dispersible formulation on Day 1 and at
Week 12 assessed on a hedonic facial scale, will be summarized separately with counts and
percentages using the safety analysis set.
11.4 Interim Analysis
Interim analyses are planned to allow assessment of emerging PK, efficacy and safety data
and support regulatory interactions.  Three analysis time points are considered
(Section 3.1).
There will be three time points of study analysis:
 Analysis 1 (interim analysis for Core Period): with cutoff date in the fourth quarter
of 2022
 Analysis 2 (final analysis for Core Period): with cutoff date in the first quarter of
2024
 Analysis 3 (final analyses including the core and the single-arm extension periods):
11.5 Sample Size
The sample size of approximately 200 subjects and not more than 300 subjects is driven
by feasibility and no formal sample size calculations are provided. The study recruitment
will be closed by fourth quarter of 2023 to allow at least 12 weeks study follow-up for
Analysis 2 in first quarter of2024. Analysis 1 and 2 cutoff dates are driven bythe regulatory
timelines.
12 DATA HANDLING
12.1 Data Collection
The investigator/delegate is responsible for ensuring the accuracy, completeness, and
timeliness of the data reported. All source documents should be completed in a neat, legible
manner to ensure accurate interpretation of the data. Data reported in the eCRF derived
from source documents must be consistent with the source documents.
Electronic Case Report Form (eCRF) data will be captured via electronic data capture (
using the Rave system provided by Medidata Solutions, Inc., a web-based tool). The
investigator and site personnel will be trained to enter and edit the data via a secure
network, with secure access features (username, password, and identification - an

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electronic password system). A complete electronic audit trail will be maintained. The
investigator/delegate will approve the data (i.e., confirm the accuracy of the data recorded)
using an electronic signature (ref. to US 21 CFR Part 11).Subject screening and enrollment
data will be completed for all subjects (i.e., eligible and non-eligible) through the IRT
system and eCRF.
For each subject screened, regardless of study treatment initiation, an  eCRF must be
completed and signed by the investigator/delegate. This also applies to those subjects who
fail to complete the study. If a subject is withdrawn from the study, the reason must be
noted on  the eCRF. For screening failures the eCRF is only completed for Baseline
assessments collected before confirmation of non-eligibility of the subject.
A third party (CRO) will carry out the data management. The Sponsor will work with the
CRO following a detailed oversight plan which will ensure that oversight of quality is
maintained.
12.2 Maintenance of Data Confidentiality
The investigator/delegate must ensure that data confidentiality is maintained. On
documents (e.g., documents attached to SAE forms / Pregnancy forms) submitted to the
Sponsor, the CRO and any other external service providers, subjects must be identified
only by number, and never by their name or initials, hospital numbers, or any other
identifier. The investigator/delegate must keep a subject identification code list, at the site,
showing the screening/randomization number, the subject’s name, date of birth, and
address or any other locally accepted identifiers. Documents identifying the subjects (e.g.,
signed ICF) must not be sent to the CRO nor to the Sponsor, and must be kept in strict
confidence by the investigator/delegate.
12.3 Database Management and Quality Control
The investigators will have access to the site eCRF data until the database is closed.
Thereafter, they will have read-only access. The eCRF must be kept current to reflect
subject status at any timepoint during the course of the study.
While entering the data, the investigator/delegate will be instantly alerted to data queries
by validated programmed checks. Additional data review (including medical review) will
be performed by the sponsor/CRO personnel on an ongoing basis to look for discrepancies
or unexpected patterns in data and for study monitoring. If discrepant data are detected or
clarification is required, a query specifying the problem or question will be issued and
visible to the investigator/delegate via the eCRF. All electronic queries visible in the
system either require a data correction (when applicable) and a response from the
investigator/delegate to clarify the queried data directly in the eCRF, or simply a data
correction in the eCRF. This process will continue until database closure.

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The investigator/delegate must, on request, supply the CRO with any required background
data from the study documentation or clinical records. This is particularly important when
errors in data transcription are suspected. In the case of health authority queries, it is also
necessary to have access to the complete study records, provided that subject
confidentiality is protected.
For data processed by central readers/laboratories (e.g., Laboratory) the results will be sent
electronically to the CRO.
After the database has been declared complete and accurate, the database will be closed.
Any changes to the database after that time may only be made as described in the
appropriate Standard Operating Procedure (SOP). After database closure, the investigator
will receive the eCRFs of the subjects of his/her site (including all data changes made) on
electronic media or as a paper copy.
13 PROCEDURES AND GOOD CLINICAL PRACTICE
13.1 Ethics and Good Clinical Practice
Sponsor personnel, CRO  personnel, and the investigators will ensure that the study is
conducted in full compliance with ICH-GCP Guidelines, the principles of the “Declaration
of Helsinki,” and with the laws and regulations of the country in which the study  is
conducted.
13.2 Independent Ethics Committee / Institutional Review Board
The investigator will submit this protocol and any related document(s) provided to the
parent(s) / legally designated representative and the subject (such as the ICF and the assent
form) to an IEC/IRB. Approval from the committee/board must be obtained before starting
the study, and must be documented in a dated letter to the investigator, clearly identifying
the study, the documents reviewed, and the date of approval.
Modifications made to the protocol or ICF  after receipt of the approval must also be
submitted as amendments by the investigator to the IEC/IRB  in accordance with local
procedures and regulations [see Section 13.6].
A list of members participating in the IEC/IRB meetings must be provided, including the
names, qualifications, and functions of these members. If that is not possible, the attempts
made to obtain this information along with an explanation as to why it cannot be obtained
or disclosed must be documented in the study documentation.
If a member of the study personnel was present during an IEC/IRB meeting, it must be
clear that this person did not vote.

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13.3 Informed Consent
Pediatric subjects are legally unable to provide informed consent. Therefore, fully informed
consent must be obtained from parent(s) or legally designated representative prior to
enrolling the child into the study. The ICF(s) must be signed before performance of any
study-related procedure/activity.
It is the responsibility of the investigator/delegate to obtain informed consent according to
ICH-GCP and Declaration of Helsinki guidelines and local regulations from the parent(s)
/ legally designated representative of each individual participating in this study. Assent
must be obtained from study participants who are developmentally capable. The criteria
for developmental capability to give assent follows local requirements.
The ICF(s) and Assent(s) used must be approved by both the Sponsor (or delegate) and by
the reviewing IEC/IRB and be in a language that the parent(s) or legally designated
representative and the potential subject can read and/or understand.
The investigator/delegate must explain to parent(s) / legally designated representative that
they are completely free to refuse to enter their child into the study, or to withdraw him/her
from it at any time for any reason without having to provide any justification.
Before enrollment in the study, the investigator or an authorized member of the study-site
personnel must explain to the parent(s) or legally designated representative of potential
subjects the aims, methods, reasonably anticipated benefits, and potential hazards of the
study, and any discomfort participation in the study may entail. They will be informed that
choosing not to participate will not affect the care the potential subject will receive. Finally,
they will be told that the investigator will maintain a subject 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 and its partners personnel without violating the
confidentiality of the subject, to the extent permitted by the applicable law(s) or
regulations. By signing the ICF the parent(s) or legally designated representative of the
subject is authorizing such access.
Special attention shall be paid to the information needs of individuals, as well as to the
methods used to give the information. Adequate time shall be given for the parent(s) or
legally designated representative to consider their decision for their child to participate in
the study and it shall be verified that they have understood the information (e.g., by asking
them to explain what is going to happen).
Subjects who come of age during their study participation must be consented to continue
their participation in the study. The age when subjects are considered capable to give
informed consent must follow local regulations.

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The ICF for parent(s) / legally designated representative, for subjects who come of age and
the Assent Form for developmentally capable subjects will be provided in the country local
language(s). Distinct assent forms are provided per age categories as per local practice.
If a female partner of a male participant becomes pregnant, an informed consent will be
obtained prior collecting the information on pregnancy. For pregnant partners who are not
yet of legal age, the consent will be obtained from parent(s)/ legally designated
representative and assent will be obtained from the partner.
Site personnel authorized to participate in  the consent/ assent process and/or to obtain
consent/assent from the parent(s) / legally designated representative and subject will be
listed on the Delegation of Authority form. A study physician must be available to answer
medical questions or questions regarding alternative therapies.
The parent(s) / legally designated representative and/or subject who come of age must sign,
personally date, and time (if the first study-mandated procedure is to be performed on the
same day informed consent is obtained) the ICF before any study-related procedures (i.e.,
any procedures required by the protocol) begin. The ICF must also be signed, personally
dated, and timed (if the first study-mandated procedure is to be performed on the same day
informed consent is obtained) by the authorized site personnel listed on the Delegation of
Authority form.
A copy of the signed and dated ICF is given to the parent(s) / legally designated
representative; the original is filed in the site documentation. Subjects who were assented
receive a copy of the assent form; the original is filed in the site documentation. The
informed consent process as well as the assent process must be fully documented in the
subject’s medical records. This must include the study reference, the subject number, the
date and, if applicable, time when the subject’s parent(s) / legally designated representative
was first introduced to the Sponsor clinical study, the date and, if applicable, time of
consent, who participated in the consent discussion, who consented the subject’s parent(s)
/ legally designated representative, and any additional person present during the consent
process (e.g., subject, any other family member), statement that a copy of the signed ICF
has been given to the subject’s parent(s) / legally designated representative. For subject(s)
who come of age during study conduct the date the subject was first approached to consent
to continue participation must be documented. In addition, all other information indicated
for parent(s) /legally designated representative is also documented and the subject receives
a copy of the signed and dated ICF.
In the case that the site would like to recruit subjects 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 subject’s rights are respected
and the consent obtained is legally valid. If the subject is unable to read or write, an

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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 subject is obtained. The CRO, the regulatory authorities (if
applicable), and the IEC/IRB  must be informed prior to the recruitment. The consent
process (e.g., involvement of an impartial witness) must be fully described, submitted to,
and approved by the IEC/IRB, according to procedures and before such subjects are
recruited.
A subject who is scheduled for re-screening is not required to sign another ICF if the
re-screening occurs within 90 days from the previous ICF signature date.
13.4 Compensation to Subjects and Investigators
The Sponsor provides insurance in order to indemnify (with both legal and financial
coverage) the investigator/site against claims arising from the study, except for claims that
arise from malpractice and/or negligence.
The compensation of the subject’s parent(s) / legally designated representative in the event
of study-related injuries will comply with applicable regulations.
13.5 Protocol Adherence/Compliance
The investigator must conduct the study in compliance with the IEC/IRB and/or the
regulatory authority  approved version of the protocol and must not implement any
deviation/change from the protocol, except when deviation is necessary to eliminate an
immediate hazard to the subject.
If a protocol deviation occurs, the investigator/delegate will inform the CRO  or its
representative, in a timely manner. The investigator/delegate must document and explain
any deviation from the approved protocol. Deviations considered to be a violation of ICH-
GCP must be reported to the IEC/IRB and regulatory authorities according to Sponsor or
(overruling) local requirements.
All relevant protocol deviations will be reported in the CSR. IECs/IRBs will be provided
with listings of protocol deviations as per local requirements.
13.6 Protocol Amendments
Any change to the protocol can only be made through a written protocol amendment. A
protocol amendment must be submitted to IEC/IRB and regulatory authorities, according
to their requirements.

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13.7 Essential Documents and Retention of Documents
The investigator/delegate must maintain adequate records necessary for the reconstruction
and evaluation of the study. A number of attributes are considered of universal importance
to source data and the records that hold those data. These include that the data and records
are accurate, legible, contemporaneous, original (or certified copy), attributable, complete,
consistent, enduring, and available when needed.
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.
These records are to be classified into two different categories of documents: ISF  and
subjects’source documents.
These records must be kept by the investigator for as long as is necessary to comply with
the Sponsor's requirements (i.e., as specified in the clinical study agreement), and national
and/or international regulations, whichever would be the longest period. 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 investigator cannot guarantee this archiving
requirement at the site for any or all of the documents, special arrangements, respecting the
data confidentiality, must be made between the investigator and the CRO to store these
documents outside the site, so that they can be retrieved in case of a regulatory inspection.
No study document should be destroyed without prior written approval from the CRO. The
investigator/institution will take measures to prevent accidental or premature destruction
of these documents. Should the investigator wish to assign the study records to another
party, or move them to another location, the CRO  must be notified in advance. At a
minimum, source documents consistent in the type and level of detail with that commonly
recorded at the study-site as a basis for standard medical care must be available for the
following: participant identification, eligibility, and study identification; study discussion
and date of signed informed consent; dates of visits; results of safety and efficacy
parameters as required by the protocol; record of all AEs and follow-up of AEs;
concomitant medication; intervention receipt/dispensing/return records; study intervention
administration information; and date of study completion and reason for early

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discontinuation of study intervention or withdrawal from the study, if applicable. The
author of an entry in the source documents should be identifiable.
If the site is using an electronic/computerized system to store subject medical records, it
can be used for the purpose of the clinical study if it is validated (as per 21 CFR Part 11 or
equivalent standard) and if the CRA has been provided personal and restricted access to
study subjects only, to verify consistency between electronic source data and the eCRF
during monitoring visits.
If the site is using an electronic/computerized system to store subject medical records but
it could not be confirmed that the system is validated or if the CRA could not be provided
access to the system, the site is requested to print the complete set of source data needed
for verification by the CRA. The printouts must be numbered, stapled together with a
coversheet, signed and dated by the investigator/delegate to confirm that these certified
copies are exact copies having the same information as the original source data. The
printouts will be considered as the official clinical study records and must be filed either
with the subject’s medical records or with the subject’s eCRF.
In order to verify that the process the site uses to prepare certified copies is reliable, the
CRA must be able to observe this process and confirm that the comparison of the source
documents and the certified copy did not reveal inconsistencies. The CRA does not need
to verify this process for all data of all subjects but at least for some of them (e.g., first
subject; regular check during the study of critical data like inclusion/exclusion criteria,
endpoints for some subjects) as per the CRO’s instructions. If it was not possible for the
CRA to observe this process, it would not be possible to rely on the site’s certified copies
and therefore the site cannot be selected for the clinical study.
13.8 Monitoring
Prior to study start, a site initiation visit (SIV) will be performed after the required essential
study documents are approved by the CRO. The study treatment will be shipped to the site
upon approval of the required essential documents.
The PI must ensure that all site personnel involved in the study are present during the SIV
and will dedicate enough time to it. Site Information Technology support, if applicable,
should also be available during the SIV.
The SIV must be completed before the site can start the screening of study subjects.
Following the SIV, a copy of the completed initiation visit report and follow-up letter will
be provided to the PI and filed in the ISF.
The Sponsor will use a combination of monitoring techniques (central, remote, or on-site
monitoring) to monitor this study. During the study, the CRA will contact and visit the site

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regularly and must be permitted, on request, to have access to study facilities and all source
documents needed to verify adherence to the protocol and the completeness, consistency,
and accuracy of the data being entered in the eCRFs and other protocol-related documents.
The Sponsor monitoring standards require full verification that informed consent has been
provided, verification of adherence to the inclusion/exclusion criteria, documentation of
SAEs, and the recording of the main efficacy, safety, and tolerability endpoints. Additional
checks of the consistency of the source data with the eCRFs will be performed according
to the study-specific monitoring guidelines. The frequency of the monitoring visits will be
based on subject recruitment rate and critical data collection times.
The PI must ensure that the eCRF is completed after a subject’s visit (site visit or telephone
call), and that all requested subject files (e.g., ICFs, medical notes/charts, other
documentation verifying the activities conducted for the study) are available for review by
the CRA. The investigator and required site personnel must be available during monitoring
visits and allow adequate time to meet with the CRA to discuss study-related issues.
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.
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.
The investigator agrees to cooperate with the CRA(s) to ensure that any issues detected in
the course of these monitoring visits are resolved. If the subject is hospitalized or dies in a
hospital other than the study-site, the investigator is responsible for contacting that hospital
in order to document the SAE, in accordance with local regulations.
A close-out visit will be performed for any initiated site when there are no more active
subjects and all follow-up issues have been resolved. In case a site does not enroll any

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subjects, the close-out visit may be performed prior to study database closure at the
discretion of the Sponsor.
13.9 Investigator Site File
Each site will be provided with an ISF prior to the SIV. It will contain all the essential
documents that are required to be up-to-date and filed at site as per ICH-GCP Section 8.
The ISF will include a table of content listing the essential documents. All study-related
documentation must be maintained in the ISF.
In some cases, exceptions can be discussed with the CRA regarding the filing of the study
documents outside the ISF. It should be clearly documented where each document is filed.
This note to file should be present in the specific tab of the document in the ISF.
The ISF must be stored in a secure and access-restricted area during and after the study. It
must be kept by the site for as long as needed to comply with any applicable rules and
regulations, ICH-GCP, as well as instructions from the CRO. If the site needs to transfer
the ISF to another location and/or if site facility can no longer store the ISF, the PI must
immediately inform the CRO during the course of the study, or the Sponsor if this applies
after the end of the study.
If the PI will change, or if the site will relocate, the CRA must be notified as soon as
possible.
13.10 Audit
The Sponsor’s or the CRO’s Global Quality Management (GQM) representatives may
audit the investigator site (during the study or after its completion). The purpose of this
visit will be to determine the investigator’s adherence to ICH-GCP, the protocol, and
applicable regulations; adherence to the CRO’s requirements (e.g., SOPs) will also be
verified. Prior to initiating this audit, the investigator will be contacted to arrange a time
for the audit.
The investigator and site personnel must cooperate with the auditor(s) and allow access to
all study documentation (e.g., subject records) and facilities. Subject privacy must,
however, be respected.
13.11 Inspections
Health authorities and/or IEC/IRB may also conduct an inspection of this study (during the
study or after its completion) at the site.
Should an inspection be announced by a health authority and/or IEC/IRB, the investigator
must immediately inform the CRO (usually via the CRA) that such a request has been
made.

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The investigator and site personnel must cooperate with inspector(s) and allow access to
all study documentation (e.g., subject records) and study facilities.
13.12 Publication Policy / Dissemination of Clinical Study Data
All information, including but not limited to information regarding macitentan  or the
Sponsor’s operations (e.g., 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/assent.
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 CSR 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 CSRhas been issued will be reported in a separate
report and will not require a revision of the CSR.
Study subject 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

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not mandate modifications to scientific content and does not have the right to suppress
information. For multicenter study designs and substudy approaches, secondary results
generally should not be published before the primary endpoints of a study have been
published. Similarly, investigators will recognize the integrity of a multicenter study by
not submitting for publication data derived from the individual study-site until the
combined results from the completed study have been submitted for publication, within
18months after the study end date, or the Sponsor confirms there will be no multicenter
study publication. Authorship of publications resulting from this study will be based on the
guidelines on authorship, such as those described in the ICMJE Recommendations for the
Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which
state that the named authors must have made a significant contribution to the conception
or design of the work; or the acquisition, analysis, or interpretation of the data for the work;
and drafted the work or revised it critically for important intellectual content; and given
final approval of the version to be published; and agreed to be accountable for all aspects
of the work in ensuring that questions related to the accuracy or integrity of any part of the
work are appropriately investigated and resolved.

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Netherlands: epidemiology and characterization during the period 1991 to 2005.
Circulation. 2011 Oct 18;124(16):1755-64.
[Watkins 2011] Watkins PB, Desai M, Berkowitz SD, Peters G, Horsmans Y, Larrey D,
et al. Evaluation of drug-induced serious hepatotoxicity (eDISH): application of this
data organization approach to phase III clinical trials of rivaroxaban after total hip or
knee replacement surgery. Drug Saf. 2011;34(3):243-52.
[Widlitz 2003] Widlitz A, Barst RJ. Pulmonary arterial hypertension in children. Eur
Respir J. 2003;21:155-76.
[Wardle 2013] Wardle AJ, Tulloh RMR. Evolving Management of Pediatric Pulmonary
Arterial Hypertension: Impact of Phosphodiesterase Inhibitors. Pediatr Cardiol.
2013;34:213-9.
[Zijlstra 2014] Zijlstra WM, Douwes JM, Rosenzweig EB, Schokker S, Krishnan U,

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Roofthooft MT, 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):2159-69.

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15 APPENDICES
15.1 Appendix 1: Child Pugh Classification
The Child-Pugh classification will be used to assess the severity of the liver disease
according to the following table [FDA 2003]:
Table 8: 
Child Pugh Classification
Score
1 
2 
3
Total bilirubin (mg/dL) 
<2.0 
2.0-3.0 
>3.0
Serum albumin (g/dL) 
>3.5 
2.8-3.5 
<2.8
Ascites 
Absent 
Slight 
Moderate
Hepatic encephalopathy* 
Grade 0 
Grade 1-2 
Grade 3-4
Prothrombin time (seconds prolonged) 
<4 
4-6 
> 6
*Hepatic encephalopathy scoring will be based on the following criteria:
• Grade 0: normal consciousness, personality, neurological examination, and electroencephalogram
• Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cycles per second waves
• Grade 2: lethargic, time disoriented, inappropriate, asterixis, ataxia, slow triphasic waves
• Grade 3: somnolent, stuporous, place disoriented, hyperactive reflexes, rigidity, slower waves
• Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2 3 cycles per second delta activity
 Class A: Score 5-6
 Class B: Score 7-9
 Class C: Score 10-15

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15.2 Appendix 2: Instructions on Switch in ERA Treatment
Transition from bosentan to macitentan:
 
Switching PAH treatment from bosentan to macitentan when a patient’s clinical
condition is unstable or undergoing continuous deterioration is not recommended.
 
To ensure continuous ERA-based PAH therapy when switching patients from
bosentan to macitentan, it is recommended to initiate macitentan  on  the day
following the last dose of bosentan.
 
Continued adherence to the Tracleer product label with respect to the potential for
drug-drug interactions is recommended for a period of up to 7 days after the
permanent discontinuation of bosentan.

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15.3 Appendix 3: WHO Functional Class
Class I 
Patients with pulmonary hypertension but without resulting limitation of
physical activity. Ordinary physical activity does not cause undue dyspnea or
fatigue, chest pain or near syncope.
Class II 
Patients with pulmonary hypertension resulting in slight limitation of physical
activity. They are comfortable at rest. Ordinary physical activity causes undue
dyspnea or fatigue, chest pain, or near syncope.
Class III 
Patients with pulmonary hypertension resulting in marked limitation of
physical activity. They are comfortable at rest. Less than ordinary activity
causes undue dyspnea or fatigue, chest pain, or near syncope.
Class IV 
Patients with pulmonary hypertension with inability to carry out any physical
activity without symptoms. These patients manifest signs of right heart failure.
Dyspnea and/or fatigue may be present even at rest. Discomfort is increased by
any physical activity.

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15.4 Appendix 4: Panama Functional Class for Pediatrics
For children aged 0-0.5 years
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.

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For children aged 0.5-1 years
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.

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For children aged 1-2years
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.

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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 (e.g., 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.

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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 (e.g., 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.

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15.5 Appendix 5: Tanner Scale
Illustrated by Michal Komorniczak (Poland)

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15.6 Appendix 6: Palatability and Acceptability of Macitentan
ACCEPTABILITY AND PALATABILITY QUESTIONNAIRE FOR PARTICIPANTS
1.
How much do
you like the taste
of this medicine?
Dislike
very
much
Dislike
a
little
Not
sure
Like
a
little
Like
very
much
2.
How easily can
you swallow this
medicine?
Very
difficult
Difficult 
OK  
Easy  
Very easy
3.
How much do
you like that this
medicine is taken
once every day? 
Dislike
very
much
Dislike
a
little
Not
sure
Like
a
little
Like
very
much
4.
How easily can
you disperse the
medicine?
Very
difficult
Difficult 
OK  
Easy  
Very easy

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5.
How easy is it to
remove the
medicine from
the packaging?
Very difficult 
Difficult 
OK  
Easy  
Very easy
ACCEPTABILITY AND PALATABILITY QUESTIONNAIRE FOR CAREGIVERS
1.
On the basis of
reaction/ facial
expression of
your child, how
much do you
believe your child
likes the taste of
this medicine?
Dislike
very
much
Dislike
a
little
Not
sure
Like
a
little
Like
very
much
2.
On the basis of
reaction/ facial
expression of
your child, how
easily can your
child swallow this
medicine?
Very difficult 
Difficult 
OK  
Easy  
Very easy
3.
How much do
you like that this
medicine is given
once every day? 
Dislike
very
much
Dislike
a
little
Not
sure
Like
a
little
Like
very
much
4.
How easily can
you disperse the
medicine?
Very difficult 
Difficult 
OK  
Easy  
Very easy

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5.
How easy is it to
remove the
medicine from the
packaging?
Very difficult 
Difficult 
OK  
Easy  
Very easy

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15.7 Appendix 7 :Short Form (SF)-15 Questionnaires

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15.8 Appendix 8: Cardiac Module Questionnaires

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15.9 Appendix 9: Multidimensional Fatigue Scale Questionnaires

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15.10 Appendix 10 : 
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is
located directly before the Table of Contents. A Summary of previous amendments is
provided below:
Amendment 
Date 
Main reason(s)
Amendment 
7, 
Version 8 
25 Jan 2021 
It has been clarified which sponsor team members are
blinded to treatment assignment in this open-label study.
Reference has been made to the Firewall Charter which is
in place since study start and which governs the flow of
blinded and unblinded data.
The background information on macitentan safety data has
been updated to match the Investigator's Brochure (IB).
Language for the definitions and the reporting of serious
adverse events (SAE) has been updated.
COVID-19 
Appendix, Version 1 
17 Jun 2020 
To provide a guidance on study conduct during the
COVID-19 pandemic.
Amendment 
3.1, 
Version 4.1 
17 Jul 2020 
This amendment constitutes an urgent safety measure and
will be implemented with immediate effect.
The rationale for this urgent safety measure is a newly
identified 
drug-drug 
interaction 
(DDI) 
between
macitentan and fluconazole (a dual moderate inhibitor of
CYP3A4 & CYP2C9). Per Physiologically Based
Pharmacokinetic (PBPK) model, fluconazole (400 mg
daily) co-administration could result in a 3.8-fold increase
in macitentan exposure due to the dual inhibition of the
two most important metabolic pathways.
Amendment 
5, 
Version 6 
10 Jun 2020 
The synopsis of the global protocol Version 5 (dated 20
March 2020) was inconsistent with the core text in Section
4.4 Exclusion Criteria (numbers 16 and 18), and the
Extension study was accidentally deleted in protocol
Section 3.1. Therefore a new protocol version 6 (dated 10
June 2020) is issued to correct these inconsistencies. The
rationale for changes from Protocol Version 4 are copied
in this section since Protocol Version 5 will not be
submitted for approval by Health Authorities and
independent Ethics Committees / Review Boards.

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Changes introduced in protocol Version 5 dated 20 March
2020:
 In order to improve subject retention in this long-term
controlled study especially for subjects without
endothelin receptor antagonist in their background
therapy  the following changes are applied to the
protocol:
 
Macitentan will be offered to all subjects after
Clinical Event Committee (CEC)-confirmed
disease progression, including the subjects in the
standard of care (SoC) group, if this is in the
subject’s best interests per their investigator’s
judgment. In order to reduce potential reporting
bias for disease progression in the SoC group,
macitentan will only be offered after the event
has been confirmed by the blinded CEC.
 
The information regarding the option to cross
over to macitentan has also been added to the
informed consent forms and to the assent form
for adolescents.
 
The planned statistical analysis has been
modified 
for 
key 
secondary 
variables,
exploratory variables and safety variables, to
account for cross-over to macitentan in the SoC
arm, after CEC-confirmed disease progression.
The analysis of recurrent events (e.g.,
CEC-confirmed 
disease 
progressions 
and
hospitalizations for PAH) as well as the
description of the number of days hospitalized
have been deleted due to the cross-over to
macitentan in the SoC arm, which makes the
interpretation of results too difficult.
 In addition, the study population will be extended to
patients 
diagnosed 
with 
pulmonary 
arterial
hypertension (PAH) more than 5 years before
randomization (i.e., there will be no limitation with
regard to time since diagnosis) since it is assumed that
these patients are at similar risk of developing disease
progression as patients diagnosed within 5 years of
study entry.
 The 6-minute walk distance (6MWD) will be added as
an exploratory endpoint in children ≥ 6 years of age,

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who are able to understand and perform the test, in
order to enrich the collected data with exercise
capacity.
 A clarification to the Exclusion criterion No.16 has
been added in order to clarify for which patients the
Child Pugh Score must be fully documented.
 An 
additional 
exclusion 
criterion 
for 
renal
insufficiency has been included in the protocol in order
to be consistent across macitentan trials.
 Clarifications and minor corrections have been added
to the protocol.
Non-substantial changes introduced in Protocol Version
6 dated 10 June 2020:
 
Exclusion criterion No. 16 and No. 18 have been
adjusted in the protocol synopsis to match Section 4.4
of the core protocol text.
 
The paragraph regarding the planned Extension
study, which was accidentally deleted in Section 3.1
of Protocol Version 5, has been reinserted.
 
Publications not referred to have been removed from
Section 14.
Amendment 
4,
Version 5
20 Mar 2020 
This document was only submitted to the US FDA.
Subsequently inconsistencies were detected between the
protocol synopsis and the protocol core text. It was
decided to correct those inconsistencies and release
Protocol V6 for submissions.
The changes are summarized in Amendment 5, Protocol
Version 6.
Amendment 
3,
Version 4
13 Mar 2018 
Feedback received from study investigators during the site
initiation visits has been taken into account to improve the
feasibility of the study protocol.
 
The overnight hospitalization during the
pharmacokinetic (PK) substudy visit has been
changed to a recommendation since it poses an
unnecessary burden to pediatric participants.
 
PK substudy visit can occur any time during
steady-state conditions to improve enrollment in

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the PK substudy and potentially allow earlier
completion.
 
Monthly pregnancy tests can be taken at home
under supervision of parents/caregiver/guardian
in order to reduce the burden to study
participants. The investigator must confirm via
phone that test was performed and verify the
results.
 
Collection of accelerometry data has been
reduced from two weeks to 10-14 days in order
to ease the burden on participants while keeping
the risk of missing data low. The data can be
collected after study visit if they could not be
collected before the visit in order to reduce the
risk of missing data.
It has been clarified that analysis of PK data will be done
regularly in order to confirm the appropriateness of the
selected dosing regimen.
The safety follow-up call has also been added for subjects
in the Standard of Care (SoC) group in order to collect the
same level of safety data in both treatment arms. In
addition, the definition of end of SoC has been added to
define start of safety follow-up period.
Instructions have been appended [Appendix 2] for the
switch of an endothelin receptor antagonist to macitentan
after randomization in order to standardize procedures
across all sites.
Monthly pregnancy tests also apply to participants with
tubal sterilization since this method cannot completely
prevent occurrence of pregnancy.
The study endpoints and statistical analysis sections have
been aligned with the Statistical Analysis Plan (Final
Version 1, 9 August 2017), which was finalized before the
randomization of the first subject.
The PK bioanalysis has been delegated to PRA Health
Sciences and respective corrections have been made to the
protocol.

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Minor clarifications and corrections have been added to
the protocol.
Some of the above changes have also affected the
informed consent/assent forms. In addition, the assent
form documents for children have been merged as listed
below in order to reduce the administrative burden:
 
Assent forms for children aged 7–9 years and
10–12 years merged into one assent for children
aged 7–12 years
 
Assent forms for adolescents aged 13–15 years
and 16–17 years merged into one assent for
adolescents aged 13–17 years
Amendment 
2,
Version 3
25 Apr 2017 
In January 2017, the FDA raised concerns regarding the
protocol, which were addressed in the Type A meeting
held on 21 March 2017. This meeting led to enhancements
of the study protocol as follows.
 
In order to render the study population more
homogeneous (etiology-wise), and similar to the
adult population evaluated in the SERAPHIN
adult study, the subjects with pulmonary arterial
hypertension 
(PAH) 
associated 
with
Eisenmenger syndrome or with inoperable left-
to-right shunts will be excluded.
 
Patients with PAH associated with congenital
heart disease who have co-incidental shunts are
eligible. Their hemodynamic data will be
centrally 
reviewed 
for 
eligibility 
before
randomization.
 
The rationale for a target treatment effect of
hazard ratio (HR) =0.65 for macitentan vs
Standard of Care (SoC), used in the sample size
assumptions, is clarified. A HR =0.65 was
chosen to account for 50% on planned/ongoing
ERA at randomization.
 
In order to increase the interpretability of a study
comparing macitentan vs a SoC control group
containing other ERAs:
o 
The enrollment of subjects with an SoC
control group, containing other ERAs,
is limited to 40% of the overall number
of 
randomized 
subjects 
as 
per

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Interactive Response Technology. The
choice of a cap to 40%, as compared to
the original sample size assumptions
(50%), will allow having a higher power
and, as such, the ability of the study to
deliver interpretable results.
o 
The randomization and the primary
analysis 
are 
stratified, 
by
ongoing/planned ERA treatment (yes vs
no) and WHO FC (FC I/II vs FC III) at
randomization.
 
The rule for futility recommendation has been
modified to increase the likelihood of the study
conclusiveness. In addition to the current futility
boundary (HR >0.80), the Independent Data
Monitoring Committee will consider stopping for
futility, if the lower boundary of the 95% (2-
sided) confidence interval (CI) of the observed
HR exceeds 0.65.
o 
This additional rule does not affect the
type I error spending and also allows for
the exclusion of an overall treatment
effect of HR =0.65 for macitentan vs
SoC at the interim analysis.
o 
The probability of stopping early for
futility is decreased by the additional
rule and is changed accordingly in
Table 8of the sample size section.
In addition, the Sponsor, through the Voluntary
Harmonization Procedure (VHP) assessment number 983
(VHP2016117), was advised to extend the current benefit-
risk analysis to contain further information on the long-
term safety of macitentan in children and adolescents.
Furthermore, the Sponsor, was advised by the Portuguese
Health Authorities (INFARMED) to ensure collection of
adverse events leading to discontinuation of treatment in
both treatment groups.
To account for a pediatric population, it is considered
more appropriate to use pulmonary vascular resistance
index instead of pulmonary vascular resistance for PAH
definition, since it takes into account the body surface area

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as recognized by the most recent pediatric guidelines
[Ivy 2013, Abman 2015, Hansmann 2016].
Feedback received from study investigators during the
investigator meeting has also been taken into account,
mostly to improve the feasibility of the study protocol.
This feedback lead to the following:
 
Change of entry criterion time since diagnosis of
PAH from 12 months to 5 years before
randomization
 
Downtitration of prostanoids as per local practice
in subjects randomized to macitentan instead of
requesting their immediate stop
 
Allowing removal of the accelerometer device
during night rest
 
Allowing self-assessment of pubertal Tanner
stage by parents or subjects
 
Allowing Contract Research Organizations
(CROs) to collect monthly blood/urine samples
at subject’s home
 
Allowing that quality of life questionnaires are
answered at home by the parent
 
Requesting 
serious 
adverse 
events 
and
Pregnancy forms to be sent to CROs for
treatment blinding
 
Clarifications to several sections
In addition, contact details of contracted CROs have been
added 
to 
the 
Contract 
Research 
Organizations
Information.
Amendment 
1,
Version 2
13 Oct 2016 
The sponsor, through the Voluntary Harmonization
Procedure (VHP) assessment number 2016117, was
advised to clarify that pharmacokinetic (PK) substudy data
will be used to update the PK model, and which methods
of contraception are highly effective. For this reason the
protocol has been amended.
In addition, the following clarifications and corrections
have been made:
 For the diagnosis of pulmonary arterial hypertension
(PAH), pulmonary artery wedge pressure (PAWP) is
requested to exclude increased left heart pressures as

Macitentan / ACT-064992
Pediatric PAH
Protocol AC-055-312, TOMORROW
Amendment 8 Version 9
23 November 2021, page 267/268
EDMS-RIM-264221
CONFIDENTIAL -FOIA Exemptions Apply in U.S.
the cause of pulmonary hypertension. Since PAWP
and left ventricular end diastolic pressure (LVEDP)
are both surrogates for left atrial pressure (LAP),
LVEDP or LAP can replace PAWP for the diagnosis
of PAH, refer also to Section 1.1.1 of the protocol.
 The assessment of cardiac and fatigue components of
quality of life will only be assessed in English-
speaking subjects in the USA, since they have not
been validated for other countries and languages.
 Only events denoting disease progressions will be
exempted from expedited reporting to health
authorities, IECs/IRBs and investigators.
 Adverse events leading to study drug discontinuation
will be only described for the macitentan arm since no
study drug is administered in the control arm.
Furthermore, for completeness the acceptability and
palatability forms as well as the quality of life
questionnaires have been appended to the protocol.

Macitentan / ACT-064992
Pediatric PAH
Protocol AC-055-312, TOMORROW
Amendment 8 Version 9
23 November 2021, page 268/268
EDMS-RIM-264221
CONFIDENTIAL -FOIA Exemptions Apply in U.S.
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study.
I will conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to
me who assist in the conduct of this study. I will discuss this material with them to ensure that they
are fully informed regarding the study intervention, the conduct of the study, and the obligations of
confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or 
printed):
Institution: 
Actelion Pharmaceutical Ltd and Janssen Research and Development, a
Division of Janssen Pharmaceutica NV
Signature: [electronic signature appended at the end of the protocol] 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the 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
 
 
24-Nov-2021 
14:58:48
(GMT)
Document Approval
PPD

CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved,Date: 16 November 2021
Actelion Pharmaceutical Ltd
Janssen Research & Development*
Clinical Protocol
COVID-19 Appendix
Protocol Title
A Multicenter, Open-label, Randomized Study with Single-arm Extension Period to Assess the
Pharmacokinetics, Safety and Efficacy of Macitentan Versus Standard of Care in Children With
Pulmonary Arterial Hypertension
TOMORROW
TOMORROW: pediaTric use OfMacitentan tO delay disease pRogRessiOn in
PAHWorldwide
Protocol AC-055-312; Phase 3
ACT-064992 (JNJ-67896062)macitentan
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen Biologics,
BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen Sciences Ireland
UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC; or Actelion Pharmaceuticals Ltd.
The term “sponsor”is used throughout the protocol to represent these various legal entities; the sponsor is
identified on the Contact Information page that accompanies the protocol.
United States (US)sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
EudraCT NUMBER: 
2016-001062-28
Status: 
Approved
Date: 
16 November 2021
Prepared by: Actelion Pharmaceuticals Ltd (a Janssen Pharmaceutical company of Johnson &
Johnson)
EDMS number: 
EDMS-RIM-265698,5.0
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or otherwise.
NCT02932410

COVID-19 Appendix
ACT-064992 (JNJ-67896062) macitentan  
Clinical Protocol AC-055-312
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved,  Date: 16 November 2021
COVID-19 APPENDIX
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on
the conduct of this clinical study due to, for example, self-isolation/quarantine by subjects and
study-site personnel; travel restrictions/limited access to public places, including hospitals; study
site personnel being reassigned to critical tasks.
In alignment with recent health authority guidance, the sponsor is providing options for study
related subject 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 subjects and site staff. If, at any time, a subject’s
safety is considered to be at risk, study treatment will be discontinued, and study follow-up will
be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each
contact, subjects will be interviewed to collect safety data. Key efficacy endpoint assessments
should be performed if required and as feasible. Subjects 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 subjects on study
intervention, including follow up. Modifications to protocol-required assessments may be
permitted via COVID-19 Appendix after consultation with the subject, 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 electronic case report form (eCRF).
The sponsor will continue to monitor the conduct and progress of the clinical study, and any
changes will be communicated to the sites and to the health authorities according to local guidance.
If a subject has tested positive for COVID-19, the investigator should contact the sponsor’s
responsible medical officer to discuss plans for study intervention and follow-up. Modifications
made to the study conduct as a result of the COVID-19 pandemic will be summarized in the clinical
study report.

COVID-19 Appendix
ACT-064992 (JNJ-67896062) macitentan  
Clinical Protocol AC-055-312
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
3
Status: Approved,  Date: 16 November 2021
CHANGES TO STUDY CONDUCT DURING THE COVID-19 PANDEMIC
The sponsor evaluates the benefit-risk of study continuation for study subjects with planned
upcoming study interventions (eg, onsite visits, investigational product dispensing). The available
safety information for the respective subject will be considered. If needed (eg, in case of missing
safety information), the sponsor will discuss individual cases directly with the responsible
investigator.
Screening of New Subjects
 
Screening ofnew subjects is only allowed if, in the investigator’s judgment, study visits can
occur onsite and approval is provided by the sponsor.
 
Subjects who are in Screening and for whom onsite visits per protocol cannot occur due to
COVID-19 restrictions must be considered screen-failed. Subsequent care for screen-failed
subjects remains the investigator’s responsibility following local guidelines.
 
Re-screening of screen-failed subjects is allowed if TOMORROW entry criteria are met after
COVID-19 restrictions are lifted and onsite visits can resume safely.
Scheduled Visits
 
When scheduled onsite visits can take place, all assessments per protocol will be performed,
unless in the investigator’s judgment the assessment is not safe either for the subject or for the
site staff. If blood samples (hematology and/or clinical chemistry) cannot be analyzed at the
central laboratory due to COVID-19-related impact, the samples will be tested locally.
 
When COVID-19-related local restrictions do not allow onsite visits, investigators will
schedule virtual visits (ie, via phone or video call) within the requested visit window per
protocol (ie,every 12 weeks ±2 weeks) in order to collect the following data for entering into
the eCRF:
 
Pulmonary arterial hypertension (PAH) signs and symptoms (to check for disease
progression)
 
WHO & PANAMA Functional Class (FC) (to check for disease progression)
 
Adverse events
 
Concomitant therapies
 
Childbearing potential (where applicable)
 
Counseling for contraception (where applicable)
 
Monthly pregnancy tests (where applicable)
 
Quality of Life questionnaire (if applicable)
 
Study treatment compliance
 
Palatability and acceptability of macitentan (if applicable).
In addition, the investigator will remind study subjects to wear the accelerometry device (if
applicable for a visit) per protocol.

COVID-19 Appendix
ACT-064992 (JNJ-67896062) macitentan  
Clinical Protocol AC-055-312
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Status: Approved,  Date: 16 November 2021
The investigator will record in the source document how the above-mentioned data have been
obtained (eg, in-person, via video call, via phone call).
If any of the above-mentioned assessments are missing for a visit where the assessments are
planned per protocol, or if a visit is performed outside the protocol-specified time window, a
protocol deviation will be assigned using the prefix “COVID-19-related”. Visits performed
virtually will also be documented in the clinical trial management system (CTMS) as a
protocol deviation using the prefix “COVID-19-related”.
 If an onsite visit is not feasible due to COVID-19 restrictions, blood samples can be collected
locally (ie, by flying nurse [contract research organization], site personnel, or by a local
healthcare professional,including local laboratory).
 If any blood samples are analyzed locally, a copy of the local laboratory certification and the
respective reference ranges must be obtained and stored in the Investigator Site File (refer to
Section 7 of the protocol).
 If the subject is visiting a local healthcare professional, the investigator will ask the local
healthcare professional to share the following data (if available) for eCRF data entry:
 
Hematology and clinical chemistry blood test results with normal ranges (including re-
tests as per Section 5.1.10 of the protocol)
 
NT-proBNP test results with normal ranges
 
Vital signs (blood pressure/heart rate)
 
Monthly pregnancy test
 
Weight and height
 
Physical examination
 
Tanner staging.
The investigator will collect a copy of the respective local report(s) including above-
mentioned assessments and will sign and date the report(s) to confirm the content was
reviewed and assessed for potential adverse events. These reports will serve as source
documents for the TOMORROW study.
Collection of data via local healthcare professionals will be documented in the CTMS as a
protocol deviation using the prefix “COVID-19-related”.
If applicable, the home pregnancy test kit will be provided by the site (eg, shipped directly to
the subject’s family), or the subject’s family may purchase the home pregnancy test locally,
if shipment is not feasible.
Investigational Product (IP)
 
Where COVID-19-related local restrictions do not allow onsite visits, the investigator will
consult the sponsor to discuss the possibility of direct-to-patient (DTP) shipment of study
treatment (macitentan and Standard of Care [SoC]) via courier. Available safety data (assessed
by the investigator and/or local health care professional) will be reviewed to verify that no
treatment interruption/discontinuation criteria have been met (refer to Section 5.1.10 of the
protocol). Local regulations for DTP shipment will be followed.

COVID-19 Appendix
ACT-064992 (JNJ-67896062) macitentan  
Clinical Protocol AC-055-312
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
Status: Approved,  Date: 16 November 2021
 
The investigator may also ask the sponsor to support DTP shipment of SoC medication and
of phosphodiesterase type 5 inhibitor (eg,sildenafil, tadalafil).
 
In case of DTP  shipment of IP, the investigator will use the latest available body weight
assessment by a healthcare professional to assign the macitentan kit in Interactive Response
Technology (IRT).
 
If needed, it will be discussed on a case-by-case basis between the investigator and the sponsor
whether the number of IP kit packages to be shipped to the subject will cover the 12-week
interval between scheduled visits (as per protocol) or less or more.
 
An investigator’s site (not the sponsor) will ship the IP or SoC to the subject. The investigator
will contact the subject’s family for consent to provide their name and address to the courier
as per local COVID-19 guidance.
 
The IP shipment should be made in a manner that allows tracking of transport, delivery, receipt
and temperature control (refer to Janssen COVID-19 DTP Process). When IP is shipped by
study sites, the receipt and return of IP must be documented in order to assess compliance and
accountability, per protocol.
Study treatment interruption or discontinuation due to COVID-19 will be reported as protocol
deviations using the prefix “COVID-19-related”.
Informed Consent
 Where required, informed consent for COVID-19-related changes in study conduct must be
obtained per local COVID-19 guidance (eg, retrospective written consent may apply). Assent
from children/adolescents will not be requested for these changes unless specifically requested
by local regulations related to COVID-19.
 The investigator will inform families of subjects with planned site visits or scheduled
assessments during COVID-19 restrictions about changes and alternatives to standard visit
procedures (eg, virtual visits, assessment through local healthcare professionals, DTP  drug
shipment). The date,means of communication (eg,via email, or virtually via phone/video call),
and consent received will be documented by the investigator in the source data. The options
discussed and the agreed solution as well as questions and concerns addressed will also be
documented by the investigator.
 In case of DTP shipment (eg, IP, pregnancy tests), parent/legal guardian (or subject who came
of legal age) must consent to having their personal data shared with the courier company. 
 All attempts made by the study site staff to reach the subject’s family during COVID-19
restrictions must be documented.
Site Monitoring
 
If onsite monitoring is not possible due to COVID-19 restrictions, monitoring will be done
remotely to the extent possible. Changes to the monitoring process will be documented in the
monitoring plan. Onsite monitoring will be delayed until after COVID-19 restrictions are
lifted.
 
In order to catch up with source data verification and resolution of potential pending issues,
onsite monitoring visit frequency and/or duration  may be increased after COVID-19
restrictions are lifted.

COVID-19 Appendix
ACT-064992 (JNJ-67896062) macitentan  
Clinical Protocol AC-055-312
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Status: Approved,  Date: 16 November 2021
Audits
 
During the COVID-19 pandemic at the impacted sites, clinical site Good Clinical Practice
audits with direct impact/engagement with the clinical investigator team will not be conducted
to comply with national, local and/or organizational social distancing restrictions. Additional
quality assurance activities such as remote audits or focused review of study related
documents may take place with limited impact/engagement,if possible.
STUDY CONDUCT RELATED TO COVID-19 VACCINE DEPLOYMENT FOR
NONCOVID-19 CLINICAL TRIALS
 
Study participants can undergo a COVID-19 vaccination procedure in compliance with
applicable local governmental regulations.
 
No pharmacokinetic interactions between the study intervention and currently available
COVID-19 vaccines are expected. In addition, based on the mechanism of action of the study
intervention and COVID-19 vaccines, no relevant interaction is expected.
 
Any COVID-19 vaccine administered to a study participant is considered a concomitant
medication and should be reported on the electronic case report form (eCRF).
 
For serious adverse events (SAEs) reported after COVID-19 vaccination, the investigator
should provide narrative details on the SAE form to allow adequate assessment of causal
relationship between the reported SAE and vaccination. This is particularly relevant in cases
where the reported SAE is an expected event with the study intervention and the COVID-19
vaccine. If the event is serious and considered to be related to both the COVID-19 vaccine
and the study intervention, it is a serious adverse reaction and expectedness must be assessed.
Suspected unexpected serious adverse reaction (SUSAR) reporting will be performed if the
serious adverse reaction is unexpected as per applicable reference safety document.
 
Study participants do not require unblinding of the study intervention to receive a COVID-19
vaccine.

COVID-19 Appendix
ACT-064992 (JNJ-67896062) macitentan  
Clinical Protocol AC-055-312
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
7
Status: Approved,  Date: 16 November 2021
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Actelion Pharmaceutical Ltd and Janssen Research and Development, a Division of
Janssen Pharmaceutica NV
Signature: 
[electronic signature appended at the end of the protocol] 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the 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
 
 
16-Nov-2021 
12:46:04
(GMT)
Document Approval
 
17-Nov-2021 
08:37:22
(GMT)
Document Approval
PPD
PPD