A Prospective, Randomized, Double-blind, Multicenter, Placebo-controlled, Parallel Group, Adaptive Phase 3 Study With Open-label Extension to Evaluate Efficacy and Safety of Macitentan 75 mg in Inoperable or Persistent/Recurrent Chronic Thromboembolic Pulmonary Hypertension
Phase: PHASE3
Conditions: Chronic Thromboembolic Pulmonary Hypertension
Sponsor: Actelion

Confidential – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 16 December 2020
Actelion Pharmaceuticals Ltd*
(a Janssen Pharmaceutical Company of Johnson & Johnson)
Clinical Protocol
Protocol Title
A prospective, randomized, double-blind, multicenter, placebo-controlled, parallel group, 
adaptive Phase 3 study with open-label extension to evaluate efficacy and safety of 
macitentan 75 mg in inoperable or persistent/recurrent chronic thromboembolic 
pulmonary hypertension.
Macitentan in inoperAble or persistent/reCurrent chronIc ThromboEmbolic Pulmonary 
Hypertension (MACiTEPH)
Protocol 67896062CTP3001 (Amendment 4); Phase 3
JNJ-67896062 / ACT-064992 macitentan
*Actelion Pharmaceuticals Ltd (“Actelion”) is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Actelion studies may vary, such as, but not
limited to Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; or Janssen Research &
Development, LLC. The term “sponsor” is used throughout the protocol to represent these various legal entities; the
sponsor is identified on the Contact Information page that accompanies the protocol.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
Regulatory Agency Identifier Number(s):
IND: 77258
EudraCT NUMBER: 2019-004131-24
Status:
Approved  
Date:
16 December 2020
Prepared by:
Actelion Pharmaceuticals Ltd and Janssen Research & Development, a division of 
Janssen Pharmaceutica NV  
EDMS number:
EDMS-RIM-265157, 5.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential. The information is being provided under the assurance that the recipient will 
maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or otherwise.
NCT04271475

JNJ-67896062 / ACT-064992 macitentan
Clinical Protocol 67896062CTP3001 (Amendment 4)
Confidential – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 16 December 2020
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 4, Version 6
16-Dec-2020
Amendment 3, Version 5
05-Aug-2020
Amendment 2, Version 4 
13-Jul-2020
Amendment 1, Version 3
22-Apr-2020
Original Protocol Version 2 (issued)
20-Jan-2020
Original Protocol Version 1
19-Dec-2019
A Protocol Amendment Summary of Changes Table for the current amendment is provided below:
Amendment 4 (16-December-2020)
Overall Rationale for the Amendment: The overall reason for this protocol amendment is to modify the 
study design for increasing the double-blind (DB) follow-up time. This increase in the DB follow-up time
improves the statistical power for the key secondary endpoint (time to clinical worsening). Also, a new 
substudy is added to provide additional safety data of chronic treatment with macitentan on testicular function
in patients with PAH or CTEPH. Specific requirements for Japanese sites were added. Minor corrections and 
editorial revisions are also being implemented.
The updates are indicated in bold for new text and strike-through for deleted text in the following table.
Section number
and Name
Description of Change
Brief Rationale
Title Page
Legal name of the organization is clarified. 
Logistical update
1.1 Synopsis
Changes made to main body text were 
reflected in the corresponding sections of 
Section 1.1.
To align the content of synopsis 
and main body.
1.2 Schedule of Activities (SoA);
4.1 Overall Design; 
6.1 Study Intervention (s) 
Administered

Details 
about 
components 
of 
maintenance phase were updated.

Minimum duration of the (DB) period 
for an individual participant is revised 
as 28 weeks.

Post-treatment observation period 
(PTOP) was revised to up to Week 28 
(earlier Week 52).
To modify the study design to 
increase double-blind follow-up 
time. 
1.2 Schedule of Activities (SoA)-
Table 1, Table 2, Table 3
Tables were updated for following details:
Table 1 (Schedule of Activities (SoA)):

Maintenance phase was divided into 
fixed duration and variable duration 
parts.

Revised electrocardiogram (ECG) 
schedule.

Revised liver function test (LFT) 
schedule to monthly until Week 52 
and every 12 weeks thereafter.

Right heart catheterization (RHC) 
substudy row was shifted to end under 
the heading ‘Optional Substudies’
To align with modified study 
design.

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
Addition 
of 
optional 
male 
reproductive system safety substudy.

Footnote 
‘9’
corresponding 
to 
periodic aspartate aminotransferase 
(AST)/ 
alanine 
aminotransferase 
(ALT) monitoring. was updated and 
Japan-specific requirements during 
monthly LFTs were added.

Footnote ‘13’ was revised to indicate 
that RHC sub-study is mandatory for 
all Japanese participants based on an 
agreement with Pharmaceuticals and 
Medical Devices Agency (PMDA).
Table 2 (Visit and assessment schedule 
during the open-label extension period):

Revised ECG assessment schedule to 
match the ECG schedule during the 
OL Maintenance Phase.

Deletion of EQ-5D-5L©, PAH-
SYMPACT®, PHQ-8, WPAI, and
SF36® v2 Acute.

Addition 
of 
optional 
male 
reproductive 
system 
safety 
sub-study.

Footnotes 1, 3, and 5 were revised.

A new footnote 7 was added to 
obtain information about vital status 
and hospitalization via phone calls.
Table 
3
(Visit 
and 
assessment 
schedule for participants entering the 
post-treatment observation period 
(PTOP)):

Footnote 5 was revised.

A new footnote 6 was added to 
clarify that PTOP 7 and 8 visits are 
not applicable to current protocol
version 6
and participants who 
consented to an earlier version of the 
protocol will be given the choice to 
maintain the previous visit schedule 
and enter the OL period at Week 52. 
PTOP 7 and 8 visits may still be 
performed for such participants if 
they prematurely discontinued study 
intervention.
1.3 Schema
Figures 1 and 2 were revised.
To align with modified study 
design.
2.1 Study Rationale; 
6.5 Concomitant Therapy
The word ‘inhaled’ associated with 
prostacyclins/ prostacyclin analogs was 
deleted. 
To 
clarify 
that 
inhaled
prostacyclins/ 
prostacyclin 
analogs will now be allowed as 
background 
pulmonary 

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Clinical Protocol 67896062CTP3001 (Amendment 4)
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Status: Approved, Date: 16 December 2020
hypertension 
(PH)-specific 
therapy.
2.2 Background
Results of the recently completed Part A of 
study 
67896062PAH1003 (Effect 
of 
macitentan 75 mg on pharmacokinetics 
[PK] of riociguat and sildenafil in healthy 
subjects) were added. 
The results of this study provide 
justification for allowing co-
administration of macitentan 
with riociguat or sildenafil.
3 Objectives and Endpoints; 
6.1 Study Interventions (s) 
Administered; 
9.4.2.1 Time to first clinical 
worsening up to EODBT; 
10.18 Appendix 18: COVID-19 
Appendix (Study visits)
The wording of the secondary objective 
and the corresponding endpoint of DB 
treatment period was revised. 
Secondary objective pertaining to time to 
clinical worsening was revised as ‘up to 
End-of-double-blind 
treatment 
(EODBT)’ from earlier ‘up to Week 52’.
DB treatment will no longer end 
at Week 52 for all participants. 
For an individual participant, 
EODBT will occur when the last 
participant completed Week 28 
or as soon as a Clinical Event 
Committee 
(CEC)-confirmed 
clinical 
worsening 
event 
occurred during the variable 
duration part of the DB period. 
3 Objectives and Endpoints: Double-
blind treatment period-Secondary; 
Open-label treatment extension 
period-Exploratory; 
8.2.3 Clinical worsening

The definition of clinical worsening 
was revised by removing the below 
component: 
‘Initiation or dose escalation of PH
specific therapy due to worsening of PH 
based 
on 
additional 
assessments 
performed at the discretion of the 
investigator and confirmed by the CEC’

A new heading was added to the 
criteria 
denoting 
PH-related 
deterioration: 
‘PH-related 
deterioration 
from 
baseline 
identified by at least one of the 
following:’
Two notes were added:
For CEC-confirmed CW up to EODBT8*:
* Including events occurring up to 7 
days after last dose of DB study 
intervention.
For All-cause death**:
**Including deaths occurring within 30 
days of last dose of study intervention 
caused by an AE that occurs within 7 
days of intake of last dose of DB study 
intervention.
Initiation and dose escalation of 
PH-specific therapy is difficult 
to measure objectively and was 
therefore removed from the 
definition of clinical worsening 
following a recommendation 
from 
European 
Medicines 
Agency 
(EMA)
Scientific 
advice.
In addition, the heading 'PH-
related deterioration identified 
by' was added to emphasize the 
specific criteria for identifying a 
PH-related deterioration as a 
clinical worsening event.
For clarification.
3 Objectives and Endpoints: Double-
blind treatment period- Exploratory; 
Open-label treatment extension 
period-Exploratory efficacy

A new exploratory objective (to 
evaluate the effect of macitentan 75 
mg 
on 
PH-related 
deaths 
and 
hospitalizations) and corresponding 
endpoint to evaluate time to first 
occurrence of CEC-confirmed PH-
related death or unplanned PH-related 
To evaluate effect of macitentan 
on hard components (ie., PH-
related 
deaths
and 
hospitalizations 
of 
the 
key 
secondary endpoint.

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Status: Approved, Date: 16 December 2020
hospitalization up to 7 days after the 
last dose of DB study intervention 
were added.

Apart from hospitalizations related to 
PH 
worsening, 
all-cause 
hospitalizations were included 

A new exploratory objective (to 
evaluate the effect of macitentan 75 
mg on low risk criteria and non-
invasive risk group defined from 
WHO FC, 6MWD and NT-proBNP 
thresholds) and the corresponding 
endpoints were updated.
To
assess 
the 
effect 
of 
macitentan on hospitalizations 
up to EODBT.
To 
evaluate 
the 
effect 
of 
macitentan 75 mg on low risk 
criteria and non-invasive risk 
group.
3 Objectives and Endpoints; 
8.6.3 Pharmacokinetic Parameters 
and Evaluations;
9.4.3 Safety Analyses;
9.4.4 Other Analyses
The term ‘Intervention-emergent’ was 
replaced with ‘Treatment-emergent’ in 
endpoints 
corresponding 
to 
safety 
objectives.
For 
wording 
consistency 
throughout the document.
3 Objectives and Endpoints: OL 
treatment extension period-
Exploratory efficacy
Two 
exploratory 
objectives 
and 
corresponding endpoints were added.
To evaluate effect of macitentan
75 mg on PH-related deaths and 
hospitalizations
and 
overall 
survival and hospitalizations. 
4.1 Overall Design
An optional male reproductive system 
safety sub-study was added.
To provide additional safety data 
of 
chronic 
treatment 
with 
macitentan on testicular function 
in patients with pulmonary 
arterial hypertension (PAH) or 
chronic 
thromboembolic 
pulmonary 
hypertension 
(CTEPH), as requested by EMA 
Scientific advice.
4.1 Overall Design

Detailed information about duration 
of the DB treatment period was added, 
keeping the sample size unchanged 
(n=144) as a possible outcome of the 
interim analysis.

Eligibility criteria for participants who 
completed PTOP up to Week 28 to 
enter the open-label (OL) extension 
period were specified.

Duration of the DB period was revised 
as minimum 28 weeks and maximum 
approximately 3.5 years.

After completion of the DB treatment 
period, eligible participants will enter 
the OL treatment period, which will 
last until 2 years after the last 
participant completed the fixed 
duration part of the DB period.
To describe the changes to the 
study periods triggered by the 
revised study design.
4.2 Scientific Rationale for Study 
Design
Following text was modified:
‘Participants who are on Riociguat, PDE-
5 inhibitors or oral or SC prostanoids at 
To 
allow 
participants 
with 
riociguat background therapy 
based on results of drug-drug 
interaction (DDI) study.

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Status: Approved, Date: 16 December 2020
baseline are allowed to remain on these 
medications.’
Riociguat will be allowed as background 
therapy once absence of a clinically 
meaningful DDI interaction has been 
confirmed in a separate study.
A new measure to minimize the risks of 
prolonged 
DB 
treatment 
for 
the 
participants was added as follows:
‘After Week 28 (timepoint of assessing 
the primary endpoint), transition to OL 
macitentan 75 mg is possible in case of a 
CEC-confirmed 
clinical 
worsening 
event.’
The possibility of crossing-over 
to OL study intervention in case 
of a CEC-confirmed clinical 
worsening event after Week 28 
ensures that participants have 
access to active treatment when 
they need it. 
Rationale for implementing a DB period of 
variable duration was added and rationale 
for the OL extension period was updated
to state that the earliest possible 
timepoint of entering the OL extension 
is Week 28.
To provide justification for 
revised study design.
4.4 End of Study Definition

Table 4 (EOS visits definition) was 
deleted and status of participants were 
specified to aid in defining EOS visit 
for an individual participant.

Definition of study completion was 
revised.

Definition of completion of OL 
Treatment Extension period was 
revised.
Content of the section updated 
based on revised study design.
5.1 Inclusion Criteria
Updated a reference to criteria
for 
inclusion in the male reproductive system 
safety 
(spermatogenesis) 
sub-study 
(Appendix 17).
To update information about 
new optional sub-study
5.1.1 Inclusion Criteria for OL 
extension period
Inclusion criteria for OL extension period 
were deleted.
To rearrange the information in 
Section 5.3.
5.2 Exclusion Criteria

Exclusion criteria 1 and 2 related to 
the disease were updated.

Exclusion criterion 5 related to 
comorbidities was updated.

Exclusion criterion 11 related to 
macitentan use was updated. 

Exclusion criterion 12 related to 
macitentan use was removed.

Exclusion criterion 13 related to 
macitentan use was updated.

Exclusion criterion 24 related to 
general criteria was updated.
Exclusion criteria 2, 5, 13, and 
24: Time windows were updated 
to reflect the revised duration of 
the DB period.
Exclusion 
criterion 
1: 
The 
acceptable time window for 
acute pulmonary embolism (PE)
prior to Screening was reduced 
from 6 to 3 months, since most 
of the recovery after a true 
incident PE is expected to 
happen within 3 months.
Exclusion criterion 11 and 13 
were revised to allow use of 
inhaled 
prostacyclins/prostacyclin 
analogues, given that oral- and 

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Status: Approved, Date: 16 December 2020
subcutaneous 
routes 
of 
administration are allowed.
Exclusion criterion 12 was 
removed since use of riociguat 
as background therapy is now 
permitted. 
5.3 Qualifying Criteria for 
Transitioning to the OL Extension
Sections 5.1.1 and 5.2.1 mentioning 
inclusion 
and 
exclusion 
criteria 
respectively, to qualify for enrolment in 
OL extension were deleted and combined 
under a new Section 5.3. Section 4.1 
revised with corresponding update.
To 
retain 
the 
information 
essential from operational point 
of view in one common section.
6.1 Study Intervention (s) 
Administered

Table 4 was updated to include 
information 
about 
dosage 
levels 
during revised maintenance phase. 

Following text added:
Extra bottles can be requested via 
interactive web response system 
(IWRS) if needed (eg, if a visit 
cannot be scheduled within the visit
window).

Tables 5 and 6 were updated to 
include information about revised 
study 
intervention 
dispensation 
schedule.
To align with revised study 
design.
6.5 Concomitant Therapy
Soluble guanylate cyclase stimulators (eg, 
riociguat) and corresponding note deleted 
from the list of prohibited concomitant 
medications.
To 
allow 
participants 
with 
riociguat background therapy 
based on results of DDI study.
6.5.1 Rescue Medication
Content of this section was revised to 
permit the use of riociguat as a rescue
medication.
To allow rescue treatment with 
riociguat based on results of DDI 
study.
6.7 Continued Access to Study 
Intervention After the End of the 
Study

Heading of the section was revised 
(Earlier- ‘Intervention After the End 
of the Study’).

Information regarding collection of 
vital status and hospitalization will be 
collected approximately every 6 
months until completion of the study
for all participants who had their EOS 
visit before the completion of the 
study. Options for post-trial access to 
study intervention were added.
To align with revised study 
design.
7.1.1 Permanent Discontinuation
New text updated as follows:
The safety follow-up visit will be waived 
in case the participant moves to a 
continued access program and in that 
case EOLT will be the last visit in the 
study.
To clarify that the requirement to 
have an end of study (EOS) visit 
30 days after last intake of study 
intervention does not apply to 
participants who will move to a 
continued access program.
7.1.2 Temporary Discontinuation
The requirement to limit the total allowed 
study intervention interruption time to 28 
days was removed.
To align the requirements for 
study 
intervention 
discontinuation with the revised 

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Status: Approved, Date: 16 December 2020
Rules for interrupting and re-introducing 
study 
invention 
when 
a 
forbidden 
medication (except endothelin receptor 
antagonists [ERAs]) is administered were 
added.
study design: with the variable 
duration of the DB treatment 
period, the need to restrict the 
allowed interruption time to 28 
days does not apply any longer. 
The need to administer a 
forbidden medication does not 
necessarily need to result in 
permanent 
treatment 
discontinuation. 
Study 
intervention can be re-started 
under certain conditions.
7.3 Lost to Follow-up
Information about collection of vital status 
of the participant was updated.
To align with the standard 
protocol template language.
8 Study Assessment and Procedures

Maximum amount of blood drawn 
from each participant will not exceed 
260 mL per year (earlier 250 mL).

The range of volume of blood 
collected during each visit was 
updated as 15 to 25 mL (earlier 6.3 to 
20 mL).

Volume of blood collected per visit 
during OL extension period will not 
exceed 15 mL (earlier 6.3 mL).

The amount of blood to be withdrawn 
for optional sub-study of male 
reproductive 
system 
safety 
is 
mentioned in Appendix 17.
To update the volume of blood 
withdrawn to align with revised 
study design.
To provide information about 
volume of blood withdrawn in 
new sub-study.
8.1.1 Eligibility Adjudication 
procedure
Heading of the section updated from 
‘Adjudication Procedure’ to ‘Eligibility 
Adjudication Procedure’.
To 
align 
with 
Janssen 
TransCelerate template.
8.1.2 Clinical Events Adjudication 
Procedure
A new section was added to describe the
process 
for 
adjudicating 
clinical 
worsening events to be eligible to enter the 
OL extension period.
The revised study design allows 
transition 
to 
OL 
study 
intervention in case of a CEC-
confirmed clinical worsening 
event.
8.2.1 6-minute Walk Test
Following text was added:
‘If a 6MWT cannot be performed at a 
scheduled visit beyond Visit 2 or at an 
unscheduled visit, a reason must be 
provided (ie, PAH-related or other).’ 
To document the reason for not 
performing the
6MWT at a 
scheduled visit beyond Visit 2 or 
at an unscheduled visit.
8.2.3 Clinical Worsening
Following text was added:
‘If 
a 
repeat 
6MWT 
cannot 
be 
performed 
due 
to 
PH-related 
deterioration, 
this 
needs 
to 
be 
documented in the eCRF.’
To 
document 
the 
related 
information in electronic case 
report form (eCRF).
8.2.4 Risk Categories for Clinical 
Worsening and Death
A new section was added to describe the 
risk categories.
A new Table 8 (An outline of risk 
stratification strategy) was added.
Number of risk criteria and 
proportion of participants in 
each risk category were added as 
an exploratory endpoint.

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8.2.7.1 PAH SYMPACT®
The 
use 
of 
a 
paper-based 
PAH-SYMPACT®
questionnaire 
is 
permitted 
under 
exceptional 
circumstances.
To give participants who are 
unable to use the mobile device 
despite adequate training the 
option 
to 
complete 
the 
questionnaire on paper. This 
back-up solution is intended to 
limit the risk of missing data.
8.2.8 Right Heart Catheterization

For participants who underwent PEA
or BPA, the time between the 
procedure and the RHC was revised to 
be at least 12 weeks (earlier 24 
weeks).

A new footnote ‘a’ was added to 
indicate 
that 
RHC 
substudy 
is 
mandatory for all participants enrolled 
in Japan based on an agreement with 
Pharmaceuticals and Medical Devices 
Agency (PMDA).
To align with revises study 
design.
To avoid a local amendment for 
Japan, 
the 
requirement 
for 
Japanese sites to include all 
participants in the substudy was 
added as a footnote.
8.3.5 Clinical Safety Laboratory 
Assessments

AST/ALT 
monitoring 
will 
be 
performed 3-monthly after 52 weeks 
exposure in the DB or OL periods, 
unless 
continued 
monthly 
monitoring is mandated based on 
local regulatory requirements.

Updated a requirement for Japanese 
participants for additional assessments 
to be conducted on monthly visit for 
liver 
function 
tests 
and 
their 
documentation in source notes and if 
assessments are related to adverse 
events (AEs), they must be recorded in 
eCRF.
For clarification.
To update the requirements for 
Japanese sites.
8.5 Treatment of Overdose
Content of the section was updated to 
provide information about treatment of 
overdose to investigator or treating 
physician.
To 
align 
with 
Janssen 
TransCelerate template; to align 
with safety reporting processes.
8.9 Medical Resource Utilization
Medical resource utilization data will 
include 
all 
PH-related 
events 
and 
hospitalizations (CTEPH was updated as 
PH).
To 
capture 
all 
available 
information.
9 Statistical Consideration
Details about statistical analysis plans
(SAPs) were updated.
To clarify the types of SAPs that 
will be developed during the 
course of the study.
9.1 Statistical Hypotheses

Section of statistical hypotheses was 
subdivided 
into 
Sections 
9.1.1 
(Primary 
Hypothesis)
and 
9.1.2 
(Secondary Hypotheses).

Primary end point ‘change in 6MWD 
from baseline to Week 28’ was 
mentioned in the section of primary 
hypothesis.

The 
new 
section 
of 
secondary 
hypotheses was also updated with 
To provide clarification on the a 
priory
order 
of 
hypothesis 
testing for secondary endpoints. 

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Table 9 (Secondary endpoints and 
associated hypotheses).
9.1.3 Overall Testing Strategy
A new Section 9.1.3 was added to include 
information about overall testing strategy. 
For clarification.
9.2 Sample Size Determination

A new subsection 9.2.1 (Estimated 
Power for Key Secondary Endpoint: 
Time to Clinical Worsening) was 
added.

A new table (Table 10) was included 
to provide information about expected 
clinical worsening (CW) events and 
associated power.
To provide information 
on 
increased power for the key 
secondary endpoint time to 
clinical worsening (TTCW) due 
to revised study design.
9.3 Populations for Analyses

Table 11 and 12 were updated for 
pharmacokinetic/pharmacodynamic
(PK/PD) and patient reported outcome 
(PRO) 
analysis 
sets 
and 
corresponding timepoints to include 
new information. 

A new analysis timepoint was updated 
in text as follow:
‘Interim analysis of OL extension 
period: Timing is determined by the 
data cutoff date of the final analysis (DB 
period).

For consistency with the 
SAP.

To clarify that an IA will be 
performed using data from 
DB period and OL period at 
the 
time 
of 
DB 
final 
analysis.
9.4 Statistical Analyses

SAP-Part 1 and 2 details were 
updated.

Information about unblinded interim 
analysis (IA) and control for type I 
error inflation was included.

Supporting 
literature 
publications
were updated in Section 11. 

For clarification.

Previous version of the 
protocol indicated that the 
details on type I error 
control due to unblinded 
SSRE will be provided in 
the SAP. However, to 
address a question from an 
Ethics Committee (EC), 
these details are now added 
to the protocol.
9.4.1 primary Efficacy Analysis

Population-related 
estimand 
describing attribute was revised as: 
‘Participants 
diagnosed 
with 
CTEPH, 
meeting 
the 
study 
eligibility criteria’.

Content of intercurrent events (IEs) 
was revised to clarify about the 
applicable imputation rules.

Content corresponding to Handling of 
missing data, Main analysis and 
Sensitivity analyses was updated.

Table 13 was updated to include 
above-mentioned changes.
Minor modifications to clarify 
estimand population, imputation 
rules 
and 
handling 
of 
implausible values.
9.4.2 Secondary Efficacy Endpoint 
Analyses

Section was revised to include 
information about combination tests 
Previous version of the protocol 
indicated that the details will be 

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which will be applied to each of the 
secondary efficacy endpoints in order 
to account for type I error inflation due 
to unblinded sample size re-estimation 
(SSRE).
provided in the SAP. To address 
a question from an (EC), this 
information is now added to the 
protocol.
9.4.2.1 Time to first clinical 
worsening up to EODBT

Population 
related 
estimand 
describing attribute was revised as: 
‘Participants 
diagnosed 
with 
CTEPH, 
meeting 
the 
study 
eligibility criteria’.

Content of the section was updated to 
align with revised study design.

Supportive 
exploratory/sensitivity
analyses were updated.

For 
alignment 
due 
to 
revised study design.

Minor 
clarifications 
to 
some 
details 
of 
the 
previously 
planned 
analyses.
9.4.2.2 Improvement in WHO FC 
from baseline to last value while on 
treatment up to Week 28 (yes/no); 
9.4.2.3 Change from baseline to last 
value while on treatment up to Week 
28 in PAH-SYMPACT®; 
9.4.2.5 Change from baseline to 
Week 28 in accelerometer-assessed 
proportion of time spent in moderate 
to vigorous physical activity
Imputation rules were updated for IEs 
corresponding 
to 
premature 
discontinuation/administration of rescue 
therapy.
Minor modification to clarify 
imputation rules. 
9.4.4 Other Analyses: Exploratory 
Analyses
Following statement was added:
‘Descriptive /sensitivity analyses will be 
performed to evaluate the impact of 
COVID-19 pandemic on the efficacy 
and safety endpoints. Details will be 
provided in the SAP-Part 1.’
For clarification.
9.4.5 Interim Analysis
Section was updated to include further 
details of the IA-SAP.
Minor modifications based on 
the 
Independent 
Data 
Monitoring Committee (IDMC) 
charter for clarification.
10.3 Appendix 3: Regulatory, 
Ethical, and Study Oversight 
Considerations
Information regarding provision of a case 
narrative or other relevant information to 
CEC was updated.
For clarification.
10.4. Appendix 4: Adverse Events: 
Definitions and Procedures for 
Recording, Evaluating, Follow-up, 
and Reporting
Information regarding Product Quality 
Complaint (PQC) Handling was updated.
To 
align 
with 
Janssen 
TransCelerate Template.
10.5 Appendix 5: Contraceptive and 
Barrier Guidance and Collection of 
Pregnancy Information

Table of ‘Acceptable methods of 
contraception’ 
was 
updated:
Intrauterine 
devices 
(IUDs) 
and 
implantable hormonal contraceptives 
moved to option 1 (standalone 
methods) and following text was 
added: ‘If a hormonal contraceptive 
is chosen, it must be taken for at 
least 
28 
days 
prior 
to 
randomization’.

Information 
regarding 
use 
of 
consistent and approved contraceptive 
To align with the contraceptive 
requirements of the Janssen 
TransCelerate template
To provide information about

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methods per local regulations was 
updated and table footnote revised. A 
new footnote is added to indicate 
contraceptive methods approved in 
Japan.
approved 
contraception 
methods.
10.7 Appendix 7: Sponsor 6-minute 
Walk Test Guidance
Heading of the section was updated
(earlier: Appendix 7: Actelion 6-minute 
walk test guidance).
To 
align 
with 
Janssen 
TransCelerate template.
10.8 Appendix 8: Borg CR10 Scale®
A new footnote ‘a’ was added:
‘The instructions for rating dyspnea have 
been customized by the sponsor based on 
the instructions for rating exertion. These 
modifications have not been validated by 
Borg Perception AB.’
For clarification.
10.11 Appendix 11: 5-level EuroQol 
5-Dimension Questionnaire (EQ-5D-
5L©)
A new image for EQ-5D-5L© visual 
analog scale (VAS) scale was added.
To 
provide 
additional 
information.
10.17 Appendix 17: Guidance on 
Male Reproductive System Safety 
Sub-study
A new appendix was added to provide 
information about background, design, 
rationale, 
objectives 
and 
endpoints, 
population, assessments and analyses.
Corresponding references were updated in 
Section 11.
To provide requisite information 
for conduct of male reproductive 
system safety sub-study. 
10.18 Appendix 18: Study Conduct 
During a Natural Disaster
Section was renumbered and heading of 
the section was revised to ‘Study Conduct 
During a Natural Disaster’ (earlier: 
COVID-19 Appendix)
To 
align 
with 
Janssen 
TransCelerate template.
Throughout the protocol

Interactive 
randomization 
system 
(IRS) updated to IWRS.

New abbreviations were updated in 
Section 10.1.

Minor 
corrections 
and 
editorial 
revisions were made.
For clarity and consistency; 
minor errors were noted.

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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE................................................................2
TABLE OF CONTENTS..............................................................................................................................13
LIST OF IN-TEXT TABLES AND FIGURES...............................................................................................16
1
PROTOCOL SUMMARY....................................................................................................................17
1.1
Synopsis .........................................................................................................................................17
1.2
Schedule of Activities (SoA) ...........................................................................................................25
1.3
Schema...........................................................................................................................................32
2
INTRODUCTION................................................................................................................................34
2.1
Study Rationale ..............................................................................................................................35
2.2
Background.....................................................................................................................................35
2.3
Benefit-Risk Assessment................................................................................................................39
2.3.1
Known Benefits ...........................................................................................................................39
2.3.2
Potential Benefits ........................................................................................................................39
2.3.3
Known Risks................................................................................................................................39
2.3.4
Potential Risks.............................................................................................................................40
2.3.5
Benefit-Risk Assessment for Study Participation........................................................................40
3
OBJECTIVES AND ENDPOINTS......................................................................................................42
4
STUDY DESIGN.................................................................................................................................47
4.1
Overall Design ................................................................................................................................47
4.2
Scientific Rationale for Study Design .............................................................................................50
4.2.1
Study-Specific Ethical Design Considerations ............................................................................53
4.3
Justification for Dose ......................................................................................................................53
4.4
End of Study Definition ...................................................................................................................54
5
STUDY POPULATION.......................................................................................................................55
5.1
Inclusion Criteria.............................................................................................................................55
5.2
Exclusion Criteria............................................................................................................................57
5.3
Qualifying Criteria for Transitioning to the OL Extension ...............................................................59
5.4
Lifestyle Considerations .................................................................................................................59
5.5
Screen Failures...............................................................................................................................59
6
STUDY INTERVENTION....................................................................................................................60
6.1
Study Intervention(s) Administered ................................................................................................60
6.2
Preparation/Handling/Storage/Accountability.................................................................................62
6.3
Measures to Minimize Bias: Randomization and Blinding..............................................................63
6.4
Study Intervention Compliance.......................................................................................................64
6.5
Concomitant Therapy .....................................................................................................................64
6.5.1
Rescue Medication......................................................................................................................65
6.6
Dose Modification ...........................................................................................................................66
6.7
Continued Access to Study Intervention After the End of the Study..............................................66
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL................................................................................................66
7.1
Discontinuation of Study Intervention.............................................................................................66
7.1.1
Permanent Discontinuation .........................................................................................................66
7.1.2
Temporary Discontinuation .........................................................................................................68
7.2
Participant Discontinuation/Withdrawal From the Study ................................................................69
7.2.1
Withdrawal from the Use of Research Samples .........................................................................70
7.3
Lost to Follow-up ............................................................................................................................70

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8
STUDY ASSESSMENTS AND PROCEDURES................................................................................71
8.1
Demographics and Baseline Characteristics..................................................................................72
8.1.1
Eligibility Adjudication Procedure................................................................................................73
8.1.2
Clinical Events Adjudication Procedure ......................................................................................74
8.2
Efficacy Assessments.....................................................................................................................74
8.2.1
6-minute Walk Test .....................................................................................................................74
8.2.2
Borg CR10 Scale®.......................................................................................................................75
8.2.3
Clinical Worsening.......................................................................................................................75
8.2.4
Risk Categories for Clinical Worsening and Death .....................................................................76
8.2.5
WHO Functional Class................................................................................................................76
8.2.6
Accelerometry .............................................................................................................................76
8.2.7
Patient Reported Outcomes........................................................................................................77
8.2.7.1
PAH SYMPACT®......................................................................................................................77
8.2.7.2
EQ-5D-5L© Questionnaire........................................................................................................78
8.2.7.3
Work Productivity and Activity Impairment Questionnaire: General Health (WPAI©: GH) 
V2.0..........................................................................................................................................78
8.2.7.4
SF-36® v2 Acute Questionnaire ...............................................................................................78
8.2.7.5
Patient Health Questionnaire-8 (PHQ-8) .................................................................................79
8.2.7.6
Patient Global Assessment of Severity....................................................................................79
8.2.8
Right Heart Catheterization.........................................................................................................79
8.3
Safety Assessments .......................................................................................................................80
8.3.1
Physical Examination ..................................................................................................................80
8.3.2
Vital Signs ...................................................................................................................................81
8.3.3
Pulmonary Function Tests ..........................................................................................................81
8.3.4
Electrocardiograms .....................................................................................................................81
8.3.5
Clinical Safety Laboratory Assessments.....................................................................................82
8.4
Adverse Events and Serious Adverse Events................................................................................83
8.4.1
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information ..................................................................................................................................83
8.4.2
Follow-up of Adverse Events and Serious Adverse Events........................................................84
8.4.3
Regulatory Reporting Requirements for Serious Adverse Events..............................................84
8.4.4
Pregnancy ...................................................................................................................................84
8.4.5
Adverse Events of Special Interest .............................................................................................84
8.5
Treatment of Overdose...................................................................................................................85
8.6
Pharmacokinetics ...........................................................................................................................85
8.6.1
Evaluations..................................................................................................................................86
8.6.2
Analytical Procedures..................................................................................................................86
8.6.3
Pharmacokinetic Parameters and Evaluations ...........................................................................86
8.7
Pharmacodynamics ........................................................................................................................86
8.8
Biomarkers......................................................................................................................................86
8.9
Medical Resource Utilization ..........................................................................................................87
9
STATISTICAL CONSIDERATIONS ..................................................................................................87
9.1
Statistical Hypotheses ....................................................................................................................88
9.1.1
Primary Hypothesis .....................................................................................................................88
9.1.2
Secondary Hypotheses ...............................................................................................................88
9.1.3
Overall Testing Strategy..............................................................................................................89
9.2
Sample Size Determination ............................................................................................................89
9.2.1
Estimated Power for Key Secondary Endpoint: Time to Clinical Worsening..............................89
9.3
Populations for Analyses ................................................................................................................91
9.4
Statistical Analyses.........................................................................................................................92
9.4.1
Primary Efficacy Analysis............................................................................................................93
9.4.2
Secondary Efficacy Endpoint Analyses.......................................................................................98
9.4.2.1
Time to first clinical worsening up to end of double-blind treatment........................................98
9.4.2.2
Improvement in WHO FC from baseline to last value while on treatment up to Week 28 
(yes/no) ..................................................................................................................................100

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9.4.2.3
Change from baseline to last value while on treatment up to Week 28 in PAH-
SYMPACT® ............................................................................................................................101
9.4.2.4
Change from baseline to last value while on treatment up to Week 28 in EQ-5D-5L©
utility score .............................................................................................................................102
9.4.2.5
Change from baseline to Week 28 in accelerometer-assessed proportion of time spent in 
moderate to vigorous physical activity ...................................................................................102
9.4.3
Safety Analyses.........................................................................................................................103
9.4.4
Other Analyses..........................................................................................................................104
9.4.5
Interim Analysis.........................................................................................................................105
9.5
Data Monitoring Committee..........................................................................................................105
10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS...........................107
10.1
Appendix 1: Abbreviations............................................................................................................107
10.2
Appendix 2: Clinical Laboratory Tests..........................................................................................110
10.3
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations .......................................111
REGULATORY AND ETHICAL CONSIDERATIONS ...............................................................................111
FINANCIAL DISCLOSURE........................................................................................................................114
INFORMED CONSENT PROCESS ..........................................................................................................114
DATA PROTECTION.................................................................................................................................115
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE RESEARCH...........................116
COMMITTEES STRUCTURE ...................................................................................................................116
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA................................................117
DATA QUALITY ASSURANCE .................................................................................................................118
CASE REPORT FORM COMPLETION ....................................................................................................118
SOURCE DOCUMENTS ...........................................................................................................................119
MONITORING ...........................................................................................................................................120
ON-SITE AUDITS......................................................................................................................................120
RECORD RETENTION .............................................................................................................................121
STUDY AND SITE START AND CLOSURE.............................................................................................121
10.4
Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting .........................................................................................................................122
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS...................................................................122
ATTRIBUTION DEFINITIONS...................................................................................................................123
SEVERITY CRITERIA ...............................................................................................................................123
SPECIAL REPORTING SITUATIONS ......................................................................................................124
PROCEDURES .........................................................................................................................................124
CONTACTING SPONSOR REGARDING SAFETY..................................................................................125
PRODUCT QUALITY COMPLAINT HANDLING.......................................................................................126
10.5
Appendix 5: Contraceptive and Barrier Guidance and Collection of Pregnancy Information.......127
10.6
Appendix 6: Child-Pugh Score .....................................................................................................129
10.7
Appendix 7: Sponsor 6-minute Walk Test Guidance....................................................................130
10.8
Appendix 8: Borg CR10 Scale® ....................................................................................................134
10.9
Appendix 9: WHO Function Classification of Pulmonary Hypertension.......................................137
10.10
Appendix 10: PAH-SYMPACT® Questionnaire ............................................................................138
10.11
Appendix 11: 5-level EuroQol 5-Dimension Questionnaire (EQ-5D-5L©) ....................................145
10.12
Appendix 12: Work Productivity and Activity Impairment Questionnaire: ....................................147
10.13
Appendix 13: SF-36®v2 Health Survey Single-Item Presentation Text Acute, United States 
(English)........................................................................................................................................149
10.14
Appendix 14: Patient Health Questionnaire (PHQ-8)...................................................................153
10.15
Appendix 15: Patient Global Assessment of Severity (PGA-S) ...................................................154
10.16
Appendix 16: Actelion Heart Catheterization Guidance ...............................................................155
10.17
Appendix 17: Guidance on Male Reproductive System Safety Sub-study ..................................158
10.18
Appendix 18: : Study Conduct During a Natural Disaster ............................................................165
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC............................................165
GUIDANCE SPECIFIC TO THIS PROTOCOL..........................................................................................166
STUDY VISITS ..........................................................................................................................................166
LABORATORY ASSESSMENTS..............................................................................................................167

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PHARMACOKINETIC, EFFICACY, AND SAFETY ASSESSMENTS.......................................................167
TREATMENT.............................................................................................................................................167
HANDLING OF SAFETY AND EFFICACY DATA INTEGRITY.................................................................167
10.19
Appendix 19: Protocol Amendment History..................................................................................168
11
REFERENCES .................................................................................................................................181
INVESTIGATOR AGREEMENT................................................................................................................185
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Schedule of Activities (SoA)......................................................................................................25
Table 2:
Visit and assessment schedule during the open-label extension period ..................................28
Table 3:
Visit and assessment schedule for participants entering the post-treatment observation 
period (PTOP) ...........................................................................................................................30
Table 4:
Treatment Overview ..................................................................................................................61
Table 5:
Study intervention dispensation schedule during the double-blind treatment period................62
Table 6:
Study intervention dispensation schedule during the open label extension period ..................62
Table 7:
Data required for adjudication procedure..................................................................................73
Table 8:
An outline of risk stratification strategy......................................................................................76
Table 9: 
Secondary endpoints and associated hypotheses....................................................................88
Table 10:
Time to clinical worsening .........................................................................................................90
Table 11:
Overview of the different populations for analyses ...................................................................91
Table 12:
Analysis Sets and Their Usage at Each Analysis Timepoint ....................................................92
Table 13:
Supplementary Estimands of the Primary Endpoint..................................................................96
FIGURES
Figure 1:
Schematic Overview of the Study – participants who complete the DB treatment period as 
per protocol................................................................................................................................32
Figure 2:
Participants who prematurely discontinue DB study intervention (example of a premature 
discontinuation at Week 18)......................................................................................................32
Figure 3:
Open-label extension (eligible participants only).......................................................................33

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1
PROTOCOL SUMMARY
1.1
Synopsis
A prospective, randomized, double-blind, multicenter, placebo-controlled, parallel group, adaptive 
Phase 3 study with open-label extension to evaluate efficacy and safety of macitentan 75 mg in 
inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension.   
Macitentan in inoperAble or persistent/reCurrent chronIc ThromboEmbolic Pulmonary Hypertension 
(MACiTEPH)
Macitentan (ACT-064992, Opsumit®) is an orally active, non-peptide, potent dual endothelin receptor 
(ETA and ETB) antagonist (ERA) approved at a dose of 10 mg for the treatment of pulmonary arterial 
hypertension (PAH). Macitentan offers a new mode of action for the treatment of inoperable and 
persistent/recurrent CTEPH and addresses an important unmet medical need for an alternative 
treatment in this indication. MACiTEPH will assess the role of macitentan as a first-line, as well as 
an add-on treatment for CTEPH population.
OBJECTIVES AND ENDPOINTS
Double-blind treatment period
Objectives
Endpoints
Primary
To evaluate the effect of macitentan 75 mg versus 
placebo on exercise capacity at Week 28 in 
participants with chronic thromboembolic pulmonary 
hypertension (CTEPH).
Change from baseline to Week 28 in exercise capacity (6-minute 
walk distance [6MWD], as measured by the 6-minute walk test 
[6MWT]).
Secondary
To evaluate the effect of macitentan 75 mg versus 
placebo on time to clinical worsening up to EODBT.
Time to first Clinical event committee (CEC) confirmed clinical 
worsening up to EODBT*. Clinical worsening is defined as the 
occurrence of at least one of the following events: 

All-cause death**

Heart and/or lung transplantation

Unplanned pulmonary hypertension (PH)-related 
hospitalization 

PH-related deterioration from baseline identified by at least 
one of the following: 

Persistenta increase in World Health Organization 
functional class (WHO FC) that cannot be explained 
by another cause (eg, viral infection)

Persistenta deterioration by at least 15% in exercise 
capacity, as measured by the 6MWD

Newor worsening signs or symptoms of right heart 
failure

Rescue pulmonary endarterectomy (PEA) and/or balloon 
pulmonary angioplasty (BPA) procedure due to worsening 
of PH.
* Including events occurring up to 7 days after last dose of DB 
study intervention

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**Including deaths occurring within 30 days of last dose of study 
intervention caused by an AE that occurs within 7 days of intake of 
last dose of DB study intervention.
a Confirmed by a second measurement performed on a different day within 2 
weeks
To evaluate the effect of macitentan 75 mg versus 
placebo on WHO FC at Week 28.
Improvement in WHO FC from baseline to Week 28 (yes/no).
To evaluate the effect of macitentan 75 mg versus 
placebo on quality of life at Week 28
Change from baseline to Week 28 in 

Pulmonary Arterial Hypertension – Symptoms and 
Impact (PAH-SYMPACT®)
o
Cardiopulmonary symptom domain score
o
Cardiovascular symptom domain score

Euro Quality of life-5-Dimension-5-Level (EQ-5D-5L©) 
utility score.
To evaluate the effect of macitentan 75 mg on daily 
physical activity
Change from baseline to Week 28 in accelerometer-assessed 
proportion of time spent in moderate to vigorous physical activity.
Safety

To evaluate the safety and tolerability of 
macitentan 75 mg in participants with CTEPH.

All-cause death up to 30 days after study intervention 
discontinuation

Treatment-emergent adverse events (AEs) up to 30 days after 
study intervention discontinuation

AEs leading to premature discontinuation of study 
intervention

Treatment-emergent AEs of special interest (AESI) up to 
30 days after study intervention discontinuation

Treatment-emergent serious adverse events (SAEs) up to 
30 days after study intervention discontinuation

Treatment-emergent ECG abnormalities up to 30 days after 
study intervention discontinuation

Treatment-emergent marked laboratory abnormalities up to 
30 days after study intervention discontinuation 

Change in laboratory variables from baseline to all assessed 
timepoints during the study 

Change in vital signs (diastolic blood pressure [DBP], 
systolic blood pressure [SBP], and pulse rate [PR]) and body 
weight from baseline to all assessed timepoints during the 
study
Open-label treatment extension period
Objectives
Endpoints
Efficacy
To evaluate the long-term effect of macitentan 75 mg 
on overall survival and hospitalizations.

All-cause death 

All-cause hospitalization
Safety
To evaluate the long-term safety and tolerability of 
macitentan 75 mg in participants with CTEPH.

All-cause death up to 30 days after study intervention 
discontinuation

Treatment-emergent AEs up to 30 days after study 
intervention discontinuation

Treatment-emergent AESI up to 30 days after study 
intervention discontinuation

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
AEs leading to premature discontinuation of study 
intervention

Treatment-emergent SAEs up to 30 days after study 
intervention discontinuation

Treatment-emergent marked laboratory abnormalities up to 
30 days after study intervention discontinuation 

Change in laboratory variables from baseline to all assessed 
timepoints

Change in vital signs (DBP, SBP, and PR) and body weight 
from baseline to all assessed timepoints 
Hypothesis
The null and alternative hypotheses are formulated in terms of the difference between intervention 
groups at Week 28, as estimated from a Mixed Model Repeated Measures (MMRM) approach 
utilizing all post-baseline values (Weeks 4, 8, 12, 16, 20, 24 and 28) of 6MWD changes from baseline.
OVERALL DESIGN
This is a randomized, double-blind (DB), placebo-controlled, multicenter, two-stage, group 
sequential, adaptive study of macitentan 75 mg in men and women between 18 and 80 years of age, 
with a diagnosis of inoperable or persistent/recurrent CTEPH.
The study includes 2 optional sub-studies: 

A hemodynamic sub-study which will be conducted at centers that are able to comply with 
study-specific RHC guidelines (Appendix 16)

A male reproductive system safety sub-study which will be conducted in centers having access 
to adequate facilities. The aim of the sub-study is to provide additional safety data of chronic 
treatment with macitentan on testicular function in patients with PAH or CTEPH, and it will 
thus be offered to male patients participating in MACiTEPH or UNISUS (AC-055-315; 
macitentan 75 mg in PAH). The data from this sub-study will be pooled with the data from 
UNISUS and analyzed independently (ie., it will not be included in the MACiTEPH CSR). 
(Appendix 17) 
NUMBER OF PARTICIPANTS
At least 144 participants will be randomized in a 1:1 ratio to macitentan 75 mg or placebo.
INTERVENTION GROUPS AND DURATION
The study comprises the following periods: 

A screening period of at least 14- and up to 60 days

A DB treatment period, which starts on Day 1 (Randomization, baseline) and ends on the day of 
last DB study intervention intake. The DB period consists of an 8-week uptitration phase and a 
maintenance phase. The maintenance phase is divided into a fixed duration part, at the end of 
which the primary endpoint is assessed, and a variable duration part. Participants will remain on 
DB treatment until the all participants have completed the 28-week fixed duration part, or until 

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they experience a CEC-confirmed clinical worsening event and transitioning to OL macitentan 75 
mg is considered to be in the participant’s best interest. The minimum duration of the DB period 
for an individual participant is 28 weeks.

A post-treatment observation period (PTOP) up to Week 28 for participants who prematurely 
discontinue DB study intervention but do not withdraw consent.

An open-label (OL) extension period, which starts on the day of the EODBT visit and ends with 
the ‘End of open-label treatment’ (EOLT) visit. The OL extension period will end 104 weeks after 
the last participant has completed the DB treatment period.

A safety follow-up period, which starts on the day after the last dose of study intervention and 
ends with a post-treatment safety follow-up visit (30 [+5] days thereafter, to collect any AEs since 
the last study visit).
The entire study is expected to last approximately 6 years.
Description of Interventions
An overview of the doses of macitentan and matching placebo is shown below:
Study intervention 
name:
Macitentan 
Placebo
Dose formulation
Film-coated tablets and matching placebo
Unit dose strength(s)
10 mg
37.5 mg 
75 mg 
Placebo
Dosage levels
Double-blind treatment period: 
Titration (8 weeks)
Day 1 to Week 4 (day before visit): 10 mg od or matching placebo
Week 4 to Week 8 (day before visit): 37.5 mg od or matching placebo
Maintenance:
Fixed duration part:
Week 8 to Week 28 (day before the visit): 75 mg od or matching placebo
Variable duration part: 
Week 28 to EODBT of last participant or CEC-confirmed CW event of the 
individual participant, whichever occurs first.: 75 mg od or matching placebo
Open label extension period 
Double-dummy uptitration (8 weeks):
Ex-placebo arm: 
Day 1 to Week 4 (day before visit): 10 mg tablet + Placebo-matching 75 mg tablet
Week 4 to Week 8 (day before visit): 37.5 mg tablet + Placebo matching 75 mg 
tablet
Ex-macitentan arm: 
Day 1 to Week 4 (day before visit): 75 mg tablet + Placebo-matching 10 mg tablet
Week 4 to Week 8 (day before visit): 75 mg tablet + Placebo-matching 37.5 mg 
tablet
Maintenance:
Week 8 to EOLT: 75 mg od
Route of administration
Oral
Dosing instructions
Study intervention administration:
One tablet once a day, preferably in the morning. 
Packaging and labeling
Study intervention will be provided in childproof bottles containing 36 tablets each.

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Each bottle will contain information and be labeled as required per country 
regulatory requirements. Labels must remain affixed to the bottle.
CEC = clinical event committee; CW = clinical worsening; EODBT = end of double-blind treatment; EOLT = end of 
open-label treatment.
No dose modification is allowed during the course of the study for the study intervention. Study 
treatment must be interrupted or permanently discontinued if any of the criteria described in 
Section 7.1 are met. For details on rescue medication, refer to Section 6.5.1.
EFFICACY EVALUATIONS
Key efficacy assessments include 6MWD and clinical worsening, as well as WHO FC, the PAH 
SYMPACT® and EQ-5D-5L© questionnaires and accelerometry.
SAFETY EVALUATIONS
Key safety assessments will include the monitoring of AEs, physical examinations, measurement of 
body weight, vital signs measurements, pulmonary function tests, electrocardiograms and clinical 
laboratory tests.
STATISTICAL METHODS
Sample size calculation
Sample size determination relies on the following assumptions:

Targeted treatment effect (difference in changes from baseline to Week 28) = 33 m,

Common standard deviation of change from baseline to Week 28 = 70 m
Under these assumptions, a fixed sample size of 2 × 72 participants has a power of 80% using a 
one-sided type I error rate of 2.5% (based on an ANOVA model without interim analysis). 
This study implements an adaptive group sequential design with one interim analysis (see 
Section 9.4.5) to reassess the required sample size to maintain study power as well as to potentially 
prematurely stop the study for futility. A maximum of 230 participants is considered for this study 
based on practical considerations. 
Incorporating the interim analysis and above adaptations, the global power is 89% (based on an 
ANOVA model).
Statistical Hypotheses
The null and alternative hypotheses are formulated in terms of the difference between intervention 
groups at Week 28, as estimated from an MMRM.
If MACI,28 and PBO,28 denote the mean changes from baseline in 6MWD at Week 28 for the 
participants treated with macitentan and placebo, respectively, then the following hypotheses can be 
considered:
H0: = MACI,28 – PBO,28 0
H1: = MACI,28 – PBO,28 > 0
The null hypothesis will be tested at a study-wise 1-sided significance level of 0.025.
The MMRM used for the primary analysis is specified in Section 9.4.1.

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Primary Efficacy Analysis
The primary efficacy endpoint is change in 6MWD from baseline to Week 28.
Estimand
The estimand is described according to the following four attributes:
A. Population: Participants diagnosed with CTEPH meeting the study eligibility criteria.
B. Variable: 6MWD changes from baseline at Weeks 4, 8, 12, 16, 20, 24 and 28.
C. Intercurrent events:
The following intercurrent events (IE) are considered:

Death: A composite strategy will be used for deaths occurring up to 7 days after study intervention 
discontinuation without administration of rescue CTEPH therapy. All scheduled assessments 
following the date of death will be replaced by a ‘worst-case’ imputation, ie, the sum of the 
participant’s baseline value and the lowest observed value of 6MWD change from baseline across 
both treatment groups and over all assessments up to Week 28. All assessments prior to the death, 
as well as all imputed assessments, thereafter, will be considered in the analysis 

Premature discontinuation/Administration of rescue therapy: A composite strategy will be 
employed for premature discontinuation of study intervention that are possibly treatment related 
(eg, clinical worsening, lack of response, adverse events, informed consent withdrawal due to 
tolerability issues) and/or administration of rescue CTEPH therapy (ie, associated. PH-specific
therapy, PEA and/or BPA procedures). All 6MWD assessments performed after end of 
intervention (possibly treatment related ) plus 7 days or after administration of  rescue therapy
will be ignored in the analysis and for each visit occurring after the IE, participant’s baseline 
6MWD value plus the minimum of the following values: (1) the last observed value (observed 
6MWD change from baseline) prior to intercurrent event at the participant level and (2) the 25th
percentile of observed 6MWD change from baseline values (both treatment groups pooled and 
over all assessments up to Week 28), will be considered instead.
D. Population-level summary:
Difference in mean 6MWD change from baseline at Week 28 between macitentan and placebo as 
estimated from the MMRM in the Full analysis set (FAS; as randomized).
Statistical model
The model will include treatment (via an indicator variable for randomized intervention), time (via a 
categorical variable for visit), treatment-by-time interaction, one indicator variable for each 
stratification factor as fixed effects and baseline 6MWD as a covariable. An unstructured variance-
covariance matrix will initially be specified. If convergence issues arise from the latter, a 
heterogeneous first-order autogressive (ARH(1)) covariance structure will be considered.
Main analysis
The main analysis refers to the primary analysis performed when all participants have completed the 
28-week DB period or prematurely discontinued the study. This analysis will be performed on the 

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FAS. The treatment effect () estimate, as well as the associated p-value for the statistical hypothesis 
of interest will be obtained from the MMRM and the latter will be compared to the nominal 1-sided 
type I error of 0.025 (See Section 9.4.1 for details). 
In addition, the treatment effect will be estimated at 4-weekly intervals from baseline to Week 28 
based on the same model along with their associated 95% CIs.
Secondary Efficacy Analysis
Time to first clinical worsening up to EODBT
The first secondary efficacy endpoint is time to clinical worsening up to EODBT (See definition in 
Section 9.4.2.1). 
Analysis
A log-rank test stratified by intervention group and randomization stratification factors will be 
performed in the FAS. The resulting 1-sided p-value will be provided and compared to the nominal 
1-sided type I error of 0.025.
The treatment effect will be estimated based on a proportional hazards Cox model adjusting for the 
same randomization stratification factors. Estimate of HR and its associated 95% CI will be displayed.
Improvement in WHO FC from baseline to last value while on treatment up to Week 28 
(yes/no)
Improvement (decrease) in WHO FC from baseline to Week 28 will be calculated for each participant.
Analysis
The data in the FAS will be analyzed by a Cochran-Mantel-Haenszel test adjusted by WHO FC at 
baseline, intervention group, and randomization stratification factors. The resulting p-value will be 
compared to the nominal 1-sided type I error of 0.025.
Change from baseline to last value while on treatment up to Week 28 in PAH-SYMPACT®
The change from baseline to last value while on treatment up to Week 28 will be calculated for each 
participant and for each domain (cardiopulmonary symptoms and cardiovascular symptom). Separate 
tests will be conducted for each domain according to the above hierarchical order.
Analysis
The change from baseline to last value while on treatment up to Week 28 will be analyzed by means 
of non-parametric Mann-Whitney U test in the FAS. A point estimate for the placebo corrected 
location shift will be displayed along with associated 95% CI and p-value using the Hodges-Lehmann 
method. The resulting p-value from the U statistic will be compared to the nominal 1-sided type I 
error of 0.025.
Change from baseline to last value while on treatment up to Week 28 in EQ-5D-5L© utility 
score

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Endpoint definition
The change from baseline to last value while on treatment up to Week 28 will be calculated for each 
participant. Utilities will be calculated according to the crosswalk algorithm developed by the 
EuroQoL group (Van Hout 2012) in order to follow the NICE position paper (NICE 2018), ie, 
EQ-5D-5L© values will be mapped into the 3L values for analysis.
Analysis
The analysis will follow the same principles as for the PAH-SYMPACT® in the FAS. 
Change from baseline to Week 28 in accelerometer-assessed proportion of time spent in 
moderate to vigorous physical activity 
Endpoint definition 
For each scheduled visit, the 14 days prior to the visit will be considered as the assessment period for 
physical activity. 
At each visit, the proportion of time spent in moderate to vigorous activity will be estimated.
Analysis
The data in the FAS will be analyzed by an ANCOVA adjusting for baseline actigraphy value and 
randomization stratification factors. The resulting p-value will be compared to the nominal 1-sided 
type I error of 0.025.
Safety Analysis
All safety analyses will be made on the Safety Population.
Adverse Events
Treatment-emergent adverse events are AEs with onset during the intervention period or that are a 
consequence of a pre-existing condition that has worsened since baseline. All reported AEs will be 
included in the analysis. For each AE, the percentage of participants who experience at least 
1 occurrence of the given event will be summarized by intervention group.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Descriptive statistics will be calculated 
for each laboratory analyte at baseline and for observed values and changes from baseline at each 
scheduled timepoint by intervention group. Frequency tabulations of the abnormalities will be made.
Vital signs
Descriptive statistics of pulse rate, SBP and DBP values and changes from baseline will be 
summarized at each scheduled timepoint by intervention group.

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12 The participant will receive the mobile device at Screening and will be trained on its use. Completion of the PAH-SYMPACT® will start 7 days prior to Visit 2
(Randomization).
13 PK and ET-1 samples to be drawn pre-dose and 2-10 hours post-dose. 
14 Participation in RHC sub-study is optional, except for Japan, where the participation in the sub-study is mandatory based on an agreement with PMDA. A historical 
RHC performed within 60 days of Randomization can be used as the baseline RHC, provided the criteria for historical RHCs described in the RHC guidelines 
(Appendix 16) are met.

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Footnotes: 
1The OL Day 1 visit (and associated assessments) will be combined with the EODBT visit for participants who remained on study intervention, or with PTOP 6 for participants 
who prematurely discontinued study intervention before Week 28 and completed the PTOP, had a CEC-confirmed CW event 28 and didn’t meet any study-specific criterion for 
permanent discontinuation of study treatment. 
2 During the open-label extension period, an unscheduled visit must be performed in case of a suspected clinical worsening or initiation/dose escalation of PH-specific therapy. 
The assessments performed at the unscheduled visit include, but are not limited to: concomitant therapy, physical examination, vital signs (BP/PR) weight, post-dose 6MWT/Borg 
CR10 Scale® and WHO FC.
3 EOLT will take place 2 years after the last participant has completed the fixed duration part of the DB period. In case of premature discontinuation of open-label study 
intervention, the EOLT visit must be performed within 7 days of taking the decision to stop study intervention.
4 For women of childbearing potential. Additional serum pregnancy test to be performed in case of a positive urine pregnancy test. 
5 AST/ALT monitoring required monthly until Week 52 if interval between 2 regular site visits exceeds 4 weeks. After 52 weeks exposure in the OL period AST/ALT monitoring 
required every 12 weeks if interval between 2 regular site visits exceeds 12 weeks unless continued monthly monitoring is mandated based on local regulatory requirements . 
Local laboratory can be used. Requirement for Japan: Monthly AST/ALT monitoring is required. Whenever participants have monthly liver function tests, the following 
assessments should be conducted and reported in source notes: physical examination, body weight, blood pressure/pulse rate, and hematology (hemoglobin, hematocrit, and 
RBC count). These assessments must be recorded in the eCRF only if they are related to AEs.
6 Women of childbearing potential only. To be performed monthly (at site or at home if the interval between 2 regular site visit exceeds 4 weeks).
7 Phone calls to obtain information about vital status and hospitalization will be done approximately every 6 months until completion of the study for all participants who 
prematurely discontinued DB or OL study intervention.

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6MWT = 6-minute walk test; AE = Adverse Event; ALT = Alanine aminotransferase; AST = Serum aspartate aminotransferase; BP = Blood pressure; CTPA = computed 
tomography pulmonary angiogram; D = Day; ECG = Electrocardiogram; EODBT = End of double-blind treatment; EQ-5D-5L© = Euro Quality of life-5-Dimension-5-
Level; FU = Follow-up; OL = open-label; MRA = magnetic resonance angiography; NT-proBNP = N-terminal prohormone of Brain natriuretic peptide or N-terminal pro 
B-type natriuretic peptide; PA = pulmonary angiography; PAH-SYMPACT® = Pulmonary Arterial Hypertension Symptoms and Impact; PFT = pulmonary function test; 
PHQ-8 = Patient Heath Questionnaire; PGA-S = Patient Global Assessment of Severity; PK = pharmacokinetic; PMDA = Pharmaceuticals and Medical Devices Agency; 
PR = Pulse rate; PTOP = Post-treatment Observation Period; RHC = right heart catheterization; SF36 = 36-item Short Form survey; SAE = Serious adverse event; V/Q =
Ventilation / Perfusion; W = Week; WHO FC = World Health Organization functional class; WPAI = Work Productivity and Activity Impairment Questionnaire.

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1.3
Schema
Figure 1:
Schematic Overview of the Study – participants who complete the DB treatment period 
as per protocol
6MWD = 6-minute walk distance; EODBT = End of double-blind treatment; EOS = End of study; FU = follow-up; OL = open-
label.
Figure 2:
Participants who prematurely discontinue DB study intervention (example of a 
premature discontinuation at Week 18)
DB = double-blind; EODBT = End of double-blind treatment; EOS = End of study; FU = follow-up; PTOP = post-treatment 
observation period.

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Figure 3:
Open-label extension (eligible participants only)
DB = double-blind; EOLT = End of open label treatment; EOS = End of study; FU = follow-up; OL-open-label.

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2
INTRODUCTION
Macitentan (ACT-064992, Opsumit®) is an orally active, non-peptide, potent dual endothelin 
receptor (ETA and ETB) antagonist (ERA) approved at a dose of 10 mg for the treatment of 
pulmonary arterial hypertension (PAH). 
Chronic thromboembolic pulmonary hypertension (CTEPH) is one of the leading causes of severe
pulmonary hypertension (PH), classified within World Health Organization (WHO) group 4 PH 
(Simonneau 2019). It is a rare, progressive pulmonary vascular disease that if left untreated, leads 
to progressively increasing pulmonary vascular resistance (PVR) and eventually right ventricle 
failure and death (Lang 2016, Jenkins 2013). The precise underlying pathogenesis of CTEPH is 
not completely understood, but it appears to be a consequence of a prior acute pulmonary embolism
subsequent to deep vein thrombosis. The pathophysiological mechanisms that prevent the
complete resolution of the embolic material in CTEPH are thought to be a misguided vascular 
remodeling process, which involves a combination of defective angiogenesis, impaired fibrinolysis 
and endothelial dysfunction (Lang 2013). CTEPH is technically a dual vascular disorder, involving 
not only persistent obstruction (stenoses, web and occlusions) of proximal pulmonary arteries
(main, lobar and segmental) at sites of previous emboli (Simonneau 2017), but also a secondary 
microscopic vasculopathy affecting small resistance vessels resembling the histopathology 
described in idiopathic PAH (Lang 2016).
CTEPH is defined as precapillary PH (resting mean pulmonary arterial pressure [mPAP]
25 mmHg, mean pulmonary arterial wedge pressure [mPAWP] 15 mmHg) in the presence of 
non-resolving organized thromboemboli that are located proximally or more distally in the 
pulmonary arterial tree (main, lobar, segmental, subsegmental pulmonary arteries) and that persist 
at least 3 months after the onset of anticoagulant therapy (Gopalan 2016) At the 6th World 
Symposium on Pulmonary Hypertension, the mPAP threshold to define PH was lowered to 
20 mmHg. The new threshold for mPAP is used in the hemodynamic confirmation of CTEPH in 
the present study.
Pulmonary endarterectomy (PEA) surgery is the treatment of choice for patients with symptomatic, 
operable CTEPH, which means CTEPH is a potentially curable form of PH. However, the extent 
and burden of small vessel arteriopathy constitutes the main limit to hemodynamic improvement 
after PEA and offers the rationale for pulmonary vasodilator therapy in some CTEPH patients with 
prevalent distal disease. The more pronounced the distal vascular changes, the higher the risk of 
surgery and the less likely the hemodynamic improvement after surgery. In addition to medical 
therapy, balloon pulmonary angioplasty (BPA) is an emerging therapeutic option for CTEPH 
patients who are technically inoperable or have been judged to have an unacceptable risk/benefit 
ratio for PEA. Although BPA is not yet extensively applied, it is used with increasing frequency 
in specialist centers worldwide and thus patients who have persistent/recurrent PH after BPA, are 
allowed to participate in this study (Galiè 2016).
For the most comprehensive nonclinical and clinical information regarding macitentan, refer to the 
latest version of the Investigator’s Brochure (IB) macitentan (Macitentan IB).

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The term “study intervention” throughout the protocol, refers to study drug.
The term “sponsor” used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
The term “participant” throughout the protocol refers to the common term “subject”.
2.1
Study Rationale
MACiTEPH is a randomized, placebo-controlled, group-sequential, adaptive trial in inoperable or 
persistent/recurrent CTEPH.
Macitentan 75 mg is expected to provide significant clinical benefit to CTEPH patients, including 
those treated with background PH-specific therapy, except ERAs and intravenous
prostacyclins/prostacyclin analogs. Combination treatment with riociguat is allowed as the drug-
drug interaction (DDI) data confirmed concomitant use with macitentan 75 mg is safe. 
MACiTEPH will include patients with persistent/recurrent CTEPH following PEA and/or post-
BPA procedure, thus covering all subgroups of CTEPH populations for which medical treatment 
with PH-specific therapy is recommended (Kim 2019). Macitentan offers a new mode of action 
for the treatment of inoperable and persistent/recurrent CTEPH and addresses an important unmet 
medical need for an alternative treatment in this indication. 
Histopathologic findings including endothelial cell dysfunction and distal pulmonary arterial 
remodeling are shared between PAH and CTEPH (Humbert 2010). PH-specific therapies, such as 
riociguat (currently the only approved therapy in inoperable and persistent/recurrent CTEPH) have 
shown efficacy in CTEPH, further supporting the rationale for this study
MACiTEPH will assess the effect of macitentan 75 mg on exercise capacity and is expected to 
confirm the role of macitentan as a first-line, as well as add-on treatment for CTEPH.
2.2
Background
For the most comprehensive non-clinical and clinical information regarding macitentan, refer to 
the latest version of the IB (Macitentan IB) for macitentan.
Nonclinical Studies
Pharmacology and Nonclinical Pharmacokinetics
Macitentan and its only active metabolite ACT-132577 are both potent ETA and ETB antagonists. 
ACT-132577 is approximately 5-fold less potent than macitentan in vitro. However, ACT-132577 
systemic exposure in humans is about 3-fold higher than macitentan, and ACT-132577 contributes 
to the overall pharmacological effect of macitentan. Formation of ACT-132577 is mainly catalyzed 
by CYP3A4, with minor contributions of CYP2C8, CYP2C9, and CYP2C19.
Macitentan showed dose-dependent efficacy in nonclinical models of hypertension, PH, PAH, and 
pulmonary fibrosis. In particular, data from nonclinical in vivo experiments indicate 
dose-dependent increases in efficacy at higher doses, including a human equivalent dose of 

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approximately 100 mg daily (~30 mg/kg/day in rats) that showed improved hemodynamics and 
right ventricular hypertrophy (Iglarz 2008, Kunita-Takanezawa 2014). Two-week treatment with 
the same 30 mg/kg/day dose of macitentan in rats significantly improved pulmonary 
hemodynamics, pulmonary artery vascular remodeling, and right ventricle function and 
hypertrophy compared to vehicle-treated animals in the Sugen/hypoxia model (Kunita-
Takanezawa 2014).
Toxicology 
In repeated-dose toxicity studies, the heart, liver, and testes were identified as the main organs 
affected by treatment with macitentan. The findings were considered to be of minimal severity and 
reversible. Furthermore, they are considered to be either clinically manageable with appropriate 
patient counseling (ie, testicular findings) or not relevant to humans (ie, dog heart vascular findings)
(Macitentan IB).
Exposures (based on a combination of the areas under the curve [AUCs] for macitentan and the 
major active metabolite) at the lowest-observed-adverse-effect levels (LOAEL) are similar to 
anticipated human exposures at steady state for 75 mg macitentan per day. The toxicities observed 
at the LOAEL were of minimal severity and reversible. 
The main finding in the dog heart was coronary arterial intimal thickening, characterized by 
proliferation of the intimal layer. The severity of intimal thickening was generally minimal, and the 
incidence or severity did not increase with treatment duration. Partial to complete reversibility was 
noted in 16-week recovery in chronic dog studies. Similar lesions were not observed in mice or rats. 
The dog is a species particularly sensitive to hemodynamic changes and related coronary vascular 
and myocardial effects (Dogterom 1992). Coronary arterial lesions have often been described for 
ERAs and other marketed vasodilating drugs in dogs but not in humans (Albassam 2001,
Louden 2001, Mcduffie 2006). These findings are considered a species-specific sensitivity and not 
relevant for humans.
Changes in the liver were largely reversible and are considered non-adverse adaptations (increased 
weight, hepatocellular hypertrophy) of the liver to increased metabolic demand.
Dilation of seminiferous tubules noted in rats and dogs was of low incidence and severity, often at 
the border of detection and was reversible in 8-16 weeks. There was no effect noted on male fertility 
in rats.
Macitentan was embryotoxic and teratogenic in developmental and reproductive toxicity studies, 
which is a known effect for this class of molecules. Macitentan was not genotoxic or phototoxic. It 
was not carcinogenic in mice or rats. In juvenile toxicity studies in rats, the target organs were not 
different from those in adult animals (Macitentan IB).

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Clinical Studies
Efficacy in PAH 
Efficacy was established in the SERAPHIN study, a long-term study in 742 PAH patients with 
predominantly WHO functional class (FC) II-III symptoms treated for an average of 2 years. 
Patients had idiopathic or heritable PAH (57%), PAH associated with connective tissue disorders 
(31%), and PAH associated with congenital heart disease with repaired shunts (8%), and were 
treated with macitentan monotherapy or in combination with phosphodiesterase type-5 (PDE-5) 
inhibitors or inhaled prostanoids (Pulido 2013).
The trial demonstrated that macitentan 10 mg reduces the risk of morbidity/mortality in patients 
with symptomatic PAH, with a hazard ratio (HR) vs placebo of 0.55, 97.5% confidence limits 
(CLs): 0.39, 0.76, p <0.0001. This represents a risk reduction of 45%. The effect of macitentan 
was observed regardless of whether the patient was receiving another therapy, including a PDE-5 
inhibitor, for PAH (Pulido 2013).
The placebo-corrected mean change in 6MWD from baseline to Month 6 (24-26 weeks) showed 
an increase of 22.0 m (97.5% CLs: 3.2, 40.8, p = 0.008) with macitentan 10 mg. The WHO FC 
improved from baseline to Month 6 in 13% of the patients in the placebo group, compared to 22% 
of those in the group that received 10 mg of macitentan (p = 0.006) (Pulido 2013).
A hemodynamic sub-study in 187 subjects showed a placebo-corrected mean reduction of PVR 
from baseline (mean PVR at baseline for the overall SERAPHIN population was 
1026 dyn∙sec∙cm−5) to Month 6 of 38.5% (97.5% CLs: 25.7%, 49.0%) with macitentan 10 mg
(Pulido 2013).
Efficacy in CTEPH
The efficacy and safety of macitentan 10 mg was evaluated in a Phase 2 study of macitentan in 
inoperable CTEPH (AC-055E201/MERIT-1). Results of the MERIT-1 pre-specified primary and 
main secondary endpoint analyses showed clinically and statistically significant beneficial effects 
of macitentan 10 mg od versus placebo on hemodynamics at Week 16 (PVR: geometric mean ratio 
= 0.84, p = 0.041) and on 6MWD at Week 24 (34 m versus placebo, p = 0.0326). The treatment 
effects on PVR and on 6MWD at the 10 mg od dose were consistent regardless of whether patients 
were receiving treatment with PH-specific therapies at baseline (Ghofrani 2017).
Human Pharmacokinetics 
Based on clinical pharmacology studies conducted in healthy subjects the plasma concentration-
time profile of macitentan can be described by a slow absorption with peak plasma concentrations 
occurring about 8 h after dosing. The apparent half-life (t½) was approximately 16 h. The active 
metabolite ACT-132577 was slowly formed and had an apparent t½ of about 48 hours. At steady
state, ACT-132577 was present at 74% of total drug exposure. The accumulation indices for 
macitentan and ACT-132577 were approximately 1.5 and 8.5, respectively. After multiple-dose 
administration, the pharmacokinetics (PK) of both macitentan and ACT-132577 were dose 

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proportional over the tested dose range of 1 to 30 mg macitentan. Dose-proportional PK is also 
expected with the 75 mg dose based on the data collected in glioblastoma patients. 
Urine represented a more important elimination route for macitentan and its metabolite than feces. 
Macitentan and ACT-132577 were highly bound (>99%) to plasma proteins.
No dose adjustments are required to correct for ethnicity or sex.
Concomitant use of macitentan with strong inhibitors or inducers of CYP3A4 or moderate dual 
CYP3A4/CYP2C9 inhibitors or co-administration of a combination of moderate CYP3A4 and moderate 
CYP2C9 inhibitors should be avoided.
Macitentan 75 mg should be administered with food.
Drug-Drug Interactions
A single-center, open-label, single sequence, 2-part, Phase 1 study (67896062PAH1003) to 
investigate the effect of 75 mg macitentan once daily at steady state on the PK of riociguat, 
sildenafil, rosuvastatin and tadalafil in healthy subjects was initiated to support the registration of 
macitentan 75 mg. Part A of the study was completed and showed that co-administration of 
macitentan 75 mg in healthy subjects with riociguat decreased riociguat AUC by approximately 
25% and Cmax by approximately 20%. Similar reductions in riociguat exposure are observed with 
bosentan (27% in AUC) and omeprazole (26% in AUC). Consistent with riociguat label, these 
small effects are considered of limited clinical relevance and will not require riociguat dose 
adjustment beyond the individual dose-adjustment scheme.
In addition, the co-administration of macitentan 75 mg in healthy subjects with sildenafil did not 
result in a significant change in sildenafil AUC and Cmax. Part B of the study assessing effect on 
rosuvastatin is currently ongoing.
Safety
The safety of macitentan 10 mg has been evaluated in a long-term placebo-controlled trial of 
742 patients with symptomatic PAH, the SERAPHIN study. The mean treatment duration was 
103.9 weeks in the macitentan 10 mg group and 85.3 weeks in the placebo group. The most 
commonly reported adverse drug reactions were nasopharyngitis (14.0%), headache (13.6%), and 
anemia (13.2%). The majority of adverse reactions were mild to moderate in intensity. The 
incidence of aminotransferases (ALT/AST) >3 × ULN was 3.4% on macitentan 10 mg and 4.5% 
on placebo. 2.1% of patients on macitentan 10 mg and 0.4% of patients on placebo had 
aminotransferase elevations >8 × ULN. The overall incidence of treatment discontinuations 
because of adverse events was similar across macitentan 10 mg and placebo treatment groups 
(approximately 11%) (Pulido 2013).
The MERIT-1 safety findings were consistent with the known safety profile of macitentan 
(Ghofrani 2017).

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In the two Phase 1 glioblastoma studies (AC-055-115 and AC-055-118), a total of 44 patients were 
treated with escalating macitentan doses of up to 300 mg in combination with temozolomide. In 
study AC-055-115, the median dose was 150 mg daily (range 30-300 mg daily, 29 patients 
received doses >100 mg), and the median duration of treatment was 61 days. In study AC-055-
118, a total of 6 subjects were treated with macitentan doses of either 90 mg or 150 mg for a 
median duration of 123 days. No unexpected adverse events (AEs) were observed in either study 
and in both studies, the majority of AEs were associated with glioblastoma disease progression, 
including those that were serious or resulted in discontinuation of treatment. No dose-limiting 
toxicities occurred, and no maximum tolerated dose was identified (D-16.563, D-17.238).
Since initial approval (18 October 2013), an estimated 62,819 patients had been exposed to 
commercial macitentan worldwide by the end of September 2019. The nature and severity of the 
reported events from all sources were consistent with the known safety profile of macitentan and 
the high morbidity and/or mortality of the underlying PAH disease and did not indicate any 
changes to the safety profile (Macitentan IB).
2.3
Benefit-Risk Assessment
2.3.1 Known Benefits
The clinical benefits of macitentan 75 mg od for the treatment of patients with CTEPH have yet to 
be established.
2.3.2 Potential Benefits
The results from the MERIT-1 study (macitentan 10 mg in inoperable CTEPH) were encouraging 
in terms of efficacy and safety. If the hypothesis that increased ETB inhibition with a dose of 75 mg 
od further improves clinical outcomes is confirmed, macitentan 75 mg may improve exercise 
capacity and possibly delay time to clinical worsening in CTEPH patients (see Section 4.3).
2.3.3 Known Risks
Reproductive toxicity studies showed that macitentan is teratogenic, which is also known to be an 
ERA class effect. For this reason, the study will only enroll non-pregnant women (see Section 5.1) 
and contraception requirements are in place for women of childbearing potential. These elements 
are included in the protocol (see Appendix 5) and will be indicated in the Informed Consent Form
(ICF).
AEs of special interest identified for macitentan 10 mg include edema/fluid retention, hypotension, 
liver events, anemia/hemoglobin decrease including anemia requiring blood transfusions without 
confounding factors (see Section 8.4.5). 

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2.3.4 Potential Risks
The safety and tolerability of macitentan 75 mg od for the treatment of patients with CTEPH have
yet to be confirmed since doses higher than 10 mg have not been tested in patients with CTEPH. 
However, as indicated in Section 4.3, human safety data in healthy subjects (up to 30 mg daily) 
and glioblastoma patients (up to 300 mg daily in combination with temozolomide) did not identify 
any safety signal that would preclude studying daily doses of macitentan higher than 10 mg in 
patients with CTEPH.
To ensure the safety of the participants, several measures are in place:

Conservative uptitration scheme: Participants randomized to the 75 mg macitentan arm will 
receive macitentan 10 mg for 4 weeks, followed by macitentan 37.5 mg for 4 weeks prior to 
reaching the target dose of 75 mg. 

Safety will be closely monitored throughout the study: 
Safety evaluations (see Section 8.3) will be performed at each scheduled visit during the study, 
as indicated in Table 1 to Table 3. 

During the uptitration phase, bi-weekly safety visits and additional phone calls ensure 
early detection of signs or symptoms of potential adverse events. 

Bi-weekly liver functions tests between Weeks 4 and 12, monthly until Week 52 and 3-
monthly thereafter.

The investigator or the designee will document AEs as indicated in Section 8.4.

Any clinically significant abnormalities (including those persisting at the end of the 
study/early withdrawal) will be followed by the investigator until resolution or until a 
clinically stable condition is reached. 

Specific criteria for interruption or permanent discontinuation of study intervention are 
specified in Section 7.1

An Independent Data Monitoring Committee (IDMC) will monitor the safety of the 
participants by reviewing unblinded data. 

Hepatic Adverse Events of Special Interest (HAESIs) will be reviewed by an International 
Liver Safety Data Review Board (ILSDRB). 
During the optional hemodynamic sub-study (see Section 8.2.8), participants will undergo a right 
heart catherization (RHC), which may be associated with side effects (bruising or hematoma, 
swelling and infection, irritating sensation, heart rhythm abnormalities, low blood pressure,
bleeding, general infection, collapsed lung, or clotting of the blood, mortality). The RHC will only 
be performed at sites able to comply with the protocol-specific RHC guidelines (Appendix 16).
2.3.5 Benefit-Risk Assessment for Study Participation
The overall benefit/risk assessment for this clinical study is considered acceptable for the following 
reasons: 

There is a clear unmet need for additional medical therapy in CTEPH.

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
Only patients who meet all inclusion criteria and none of the exclusion criteria (specified in 
Section 5) will be allowed to participate in this study. The selection criteria include adequate 
provisions to minimize the risk and protect the well-being of participants in the study.

Appropriate safety measures are put in place to ensure the safety of the participants 
(see Section 2.3.4)
It is the investigator’s responsibility to monitor the individual benefit/risk of study intervention 
administration, as well as the degree of distress caused by study procedures at an individual 
participant level, and to discontinue study intervention or the study if he/she considers that 
continuation would be detrimental to the participant’s well-being. 
More detailed information about the known and expected benefits and risks of macitentan may be 
found in the IB (Macitentan IB) and local Prescribing Information.

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3
OBJECTIVES AND ENDPOINTS
Double-blind treatment period
Objectives
Endpoints
Primary
To evaluate the effect of macitentan 75 mg 
versus placebo on exercise capacity at Week 
28 in participants with chronic 
thromboembolic pulmonary hypertension 
(CTEPH).
Change from baseline to Week 28 in exercise capacity 
(6-minute walk distance [6MWD], as measured by the 
6-minute walk test [6MWT]).
Secondary
To evaluate the effect of macitentan 75 mg 
versus placebo on clinical worsening up to 
end-of double-blind-treatment (EODBT).
Time to first Clinical Event Committee (CEC) 
confirmed clinical worsening up to EODBT*. Clinical 
worsening is defined as the occurrence of at least one of 
the following events: 

All-cause death**

Heart and/or lung transplantation

Unplanned pulmonary hypertension (PH)-related 
hospitalization 

PH-related deterioration from baseline identified
by at least one of the following:

Persistenta increase in World Health 
Organization functional class (WHO FC) 
that cannot be explained by another cause 
(eg, viral infection)

Persistenta deterioration by at least 15% in 
exercise capacity, as measured by the 
6MWD; 

New or worsening signs or symptoms of 
right heart failure

Rescue pulmonary endarterectomy (PEA) and/or 
balloon pulmonary angioplasty (BPA) procedure 
due to worsening of PH.
* Including events occurring up to 7 days after last dose of DB 
study intervention.
**Including deaths occurring within 30 days of last dose of study 
intervention caused by an AE that occurs within 7 days of intake 
of last dose of DB study intervention.
To evaluate the effect of macitentan 75 mg 
versus placebo on WHO FC at Week 28.
Improvement in WHO FC from baseline to Week 28 
(yes/no).
To evaluate the effect of macitentan 75 mg 
versus placebo on quality of life at Week 28
Change from baseline to Week 28 in 

Pulmonary Arterial Hypertension – Symptoms and 
Impact (PAH-SYMPACT®)

Cardiopulmonary symptom domain score

Cardiovascular symptom domain score
                                                
a Confirmed by a second measurement performed on a different day within 2 weeks

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Double-blind treatment period

Euro Quality of life-5-Dimension-5-Level (EQ-5D-
5L©) utility score.
To evaluate the effect of macitentan 75 mg 
on daily physical activity
Change from baseline to Week 28 in accelerometer-
assessed proportion of time spent in moderate to 
vigorous physical activity.
Exploratory
To evaluate the effect of macitentan 75 mg 
versus placebo on exercise capacity in 
participants with CTEPH.
Change from baseline to all assessed timepoints in 
exercise capacity (6MWD, as measured by the 6MWT).
To evaluate the effect of macitentan 75 mg 
on PH-related deaths and hospitalizations
Time to first occurrence of CEC-confirmed PH-related 
death* or unplanned PH-related hospitalization up to 7 
days after the last dose of DB study intervention 
*including deaths occurring within 30 days of last dose of study 
intervention caused by an AE that occurs within 7 days of intake of 
last dose of DB study intervention.
To evaluate the effect of macitentan 75 mg 
versus placebo on hospitalization up to 
EODBT
Number of recurrent hospitalizations (all cause and 
related to PH worsening) up to EODBT. 
To evaluate the effect of macitentan 75 mg 
versus placebo on low risk criteria and non-
invasive risk group defined from WHO FC, 
6MWD and NT-proBNP thresholds

The proportion of participants with a total number 
of low-risk criteria (0, 1, 2 or 3) present at baseline 
and at all follow-up assessments up to EODBT

The number and % of participants within each of the 
noninvasive risk group (low-, intermediate- or high-
risk) at baseline and at all assessment timepoints up 
to EODBT

The number and % of participants who’s non-
invasive risk improved, remained stable or 
worsened from baseline. 
To evaluate the effect of macitentan 75 mg 
versus placebo on dyspnea and exertion
Change from baseline to all assessed timepoints in 

Dyspnea 

Exertion
assessed by the Borg CR10 Scale® 
To evaluate the effect of macitentan 75 mg 
versus placebo on NT-proBNP. 
Percent of baseline NT-proBNP over time.
To evaluate the effect of macitentan 75 mg 
versus placebo on quality of life 
Change from baseline to all assessed timepoints in: 
1. PAH-SYMPACT®

Cardiopulmonary symptom domain score

Cardiovascular symptom domain score

Physical Impact Score

Cognitive/Emotional Impact Score
2. Euro Quality of life-5-Dimension-5-Level (EQ-5D-
5L©) utility 
3. Euro Quality of life-5-Dimension-5-Level (EQ-5D-
5L©) VAS score 
4. SF-36© 

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Double-blind treatment period
5. PGA-S 
To evaluate the effect of macitentan 75 mg 
versus placebo on participants’ depression 
symptoms
Change from baseline to all assessed timepoints in 
Patient Heath Questionnaire (PHQ-8)
To evaluate the effect of macitentan 75 mg 
versus placebo on participants’ work and 
productivity 
Change from baseline to all assessed timepoints in work 
productivity and activity impairment, assessed by the 
Work 
Productivity 
and 
Activity 
Impairment 
Questionnaire©: General Health (WPAI©: GH) 
To evaluate the effect of macitentan 75 mg 
on daily physical activity
Change from baseline to all assessed timepoints in 
accelerometry parameters 
To evaluate the pharmacokinetics (PK) of 
macitentan and its metabolite ACT-132577 
in participants with CTEPH
Macitentan and ACT-132577 concentrations at all 
assessed timepoints
To evaluate the effect of macitentan 75 mg 
on ET-1 concentrations 
Change from baseline to all assessed timepoints in ET-
1 concentrations
To evaluate the effect of macitentan 75 mg 
on medical resource utilization compared to 
placebo
Medical resource utilization used from baseline to all 
assessed timepoints, as defined hereafter:
Number per year of all-cause and PH-related 
hospitalizations
Number per year of in-patient hospital days for all 
causes and PH-related causes
Number per year of emergency room (ER) visits for 
all causes and PH-related causes that do not result in 
hospital admittance
To evaluate effect of macitentan 75 mg on 
hemodynamic measures compared to placebo 
(subset of participants)
Hemodynamic Sub-study:

Ratio of Week 28 PVR over baseline PVR as 
assessed through RHC 

Changes from baseline to Week 28 in the following 
hemodynamic variables: mean right atrial pressure 
(mRAP), mPAP, cardiac index (CI), cardiac output 
(CO), total pulmonary resistance (TPR) and mixed 
venous oxygen saturation (SvO2) at rest. 
Safety
To evaluate the safety and tolerability of 
macitentan 75 mg in participants with 
CTEPH.

All-cause death up to 30 days after study 
intervention discontinuation

Treatment-emergent adverse events (AEs) up to 
30 days after study intervention discontinuation

AEs leading to premature discontinuation of 
study intervention

Treatment-emergent AEs of special interest 
(AESI) up to 30 days after study intervention 
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Double-blind treatment period

Treatment-emergent serious adverse events 
(SAEs) up to 30 days after study intervention 
discontinuation

Treatment-emergent ECG abnormalities up to 
30 days after study intervention discontinuation

Treatment-emergent 
marked 
laboratory 
abnormalities up to 30 days after study 
intervention discontinuation 

Change in laboratory variables from baseline to 
all assessed timepoints during the study 

Change in vital signs (diastolic blood pressure 
[DBP], systolic blood pressure [SBP], and pulse 
rate [PR]) and body weight from baseline to all 
assessed timepoints during the study
Open-label treatment extension period
Objectives
Endpoints
Safety
To evaluate the long-term safety and 
tolerability of macitentan 75 mg in
participants with CTEPH.

All-cause death up to 30 days after study 
intervention discontinuation

Treatment-emergent AEs up to 30 days after study 
intervention discontinuation

Treatment-emergent AESI up to 30 days after 
study intervention discontinuation

AEs leading to premature discontinuation of study 
intervention

Treatment-emergent SAEs up to 30 days after 
study intervention discontinuation

Treatment-emergent 
marked 
laboratory 
abnormalities up to 30 days after study intervention
discontinuation 

Change in laboratory variables from baseline to all 
assessed timepoints

Change in vital signs (DBP, SBP, and PR) and 
body weight from baseline to all assessed 
timepoints 
Exploratory efficacy
To evaluate the long-term effect of 
macitentan 75 mg on exercise capacity in 
participants with CTEPH.
Changes from baseline to all assessed timepoints in 
exercise capacity (6MWD, as measured by the 6MWT).
To evaluate the effect of macitentan 75 mg 
on time to clinical worsening up to end-of 
open-label treatment (EOLT).
CEC-confirmed clinical worsening up to EOLT*. 
Clinical worsening is defined as the occurrence of at 
least one of the following events: 

All-cause death 

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Open-label treatment extension period

Heart and/or lung transplantation

Unplanned PH-related hospitalization 

PH-related deterioration from baseline identified 
by at least one of the following:

Persistenta increase in WHO FC that cannot 
be explained by another cause (eg, viral 
infection); 

Persistenta deterioration by at least 15% in 
exercise capacity, as measured by the 
6MWD; 

New or worsening signs or symptoms of 
right heart failure

Rescue PEA and/or BPA procedure due to 
worsening of PH.
* Including events occurring up to 7 days after last dose of 
study intervention. 
To evaluate the effect of macitentan 75 mg 
on WHO FC up to EOLT 
Improvement in WHO FC from baseline to all assessed 
timepoints 
To evaluate the effect of macitentan 75 mg 
on hospitalization up to EOLT.
Number of recurrent hospitalizations related to PH 
worsening up to EOLT 
To evaluate the effect of macitentan 75 mg 
on dyspnea up to EOLT.
Change from baseline to all assessed timepoints 

Dyspnea 

Exertion
assessed by the Borg CR10 Scale®
To evaluate the effect of macitentan 75 mg 
on medical resource utilization 
Medical resource utilization used from baseline to all 
assessed timepoints, as defined hereafter:
Number per year of all-cause and PH-related 
hospitalizations
Number per year of in-patient hospital days for all 
causes and PH-related causes
Number per year of ER visits for all causes and PH-
related causes that do not result in hospital 
admittance
                                                
a Confirmed by a second measurement performed on a different day within 2 weeks

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Open-label treatment extension period

To evaluate the long term effect of 
macitentan 75 mg on low-risk non-
invasive criteria based on WHO FC, 
6MWD and NT-proBNP 

The proportion of participants with a total number 
of low-risk criteria (0, 1, 2 or 3) present at baseline 
and at all follow-up assessments up to EODBT

The number and % of participants within each of the 
noninvasive risk group (low-, intermediate- or high-
risk) at baseline and at all assessment timepoints up 
to EODBT

The number and % of participants who’s non-
invasive risk improved, remained stable or 
worsened from baseline.

To evaluate the effect of macitentan 75 
mg 
on 
PH-related 
deaths 
and 
hospitalizations
Time to first occurrence of CEC-confirmed PH-related 
deaths* or unplanned PH-related hospitalization** up 
to 7 days after the last dose of study intervention.  
*including deaths occurring within 30 days of last dose of 
study intervention caused by an AE that occurs within 7 days 
of intake of last dose of study intervention
** including hospitalizations for procedure due to clinical 
worsening (PEA/BPA) and lung transplantation.

To evaluate the effect of macitentan 75 
mg on overall survival and 
hospitalizations
Time to first occurrence of 

All-cause death 

All-cause hospitalization.
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
PRIMARY HYPOTHESIS
The null and alternative hypotheses are formulated in terms of the difference between intervention 
groups at Week 28, as estimated from a Mixed Model Repeated Measures (MMRM) approach 
utilizing all post-baseline values (Weeks 4, 8, 12, 16, 20, 24 and 28) of 6MWD changes from 
baseline. Refer to Section 9.1 for further details.
4
STUDY DESIGN
4.1
Overall Design
This is a randomized, double-blind (DB), placebo-controlled, multicenter, two-stage, group 
sequential, adaptive study of macitentan 75 mg in men and women between 18 and 80 years of 
age, with a diagnosis of inoperable or persistent/recurrent CTEPH.
The study includes 2 optional sub-studies: 

al hemodynamic sub-study which will be conducted at centers who are able to comply 
with study-specific RHC guidelines (Appendix 16).

a male reproductive system safety sub-study which will be conducted in centers who have 
access to adequate facilities. The aim of the sub-study is to provide additional safety data 

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of chronic treatment with macitentan on testicular function in patients with PAH or 
CTEPH, and it will thus be offered to male participants participating in MACiTEPH or 
UNISUS (AC-055-315; macitentan 75 mg in PAH) (see Appendix 17). The data from this 
sub-study will be pooled with the data from UNISUS and analyzed independently (ie, it 
will not be included in the MACiTEPH CSR).
At least 144 participants will be randomized in a 1:1 ratio to macitentan 75 mg or placebo.
Treatment allocation will be stratified by 

Inoperable (with or without BPA) vs persistent/recurrent after PEA surgery (with or 
without BPA)

Use of PH-specific therapies (riociguat, other PH-specific therapy, none) at baseline. 
The duration of the double-blind treatment period is variable. It will last until:

all participants either completed or prematurely discontinued the 28-Week fixed duration 
part. After completion of the DB period of the study, all eligible participants have the 
possibility of entering the OL extension. 

a CEC-confirmed clinical worsening event occurs and, in the opinion of the investigator, 
switching to OL macitentan 75 mg is in the best interest of the participant. 
Key efficacy assessments include 6MWD and clinical worsening, as well as WHO FC, the PAH 
SYMPACT® and EQ-5D-5L© questionnaires and accelerometry (refer to Section 8.2). Key safety 
assessments will include the monitoring of adverse events, physical examinations, measurement 
of body weight, vital signs measurements, pulmonary function tests, electrocardiograms and 
clinical laboratory tests.
The study uses an adaptive design with one interim analysis. At the interim analysis, the following 
decisions may be taken:

Stop the study early for futility

Keep the sample size unchanged at 144 participants 

Increase the sample size for the second stage of the study up to a maximum of 
230 participants. 
The proposed sample size reassessment procedures can help mitigate the risk of misspecification 
of the treatment effect assumptions in any of the subgroups.
The interim analysis will be conducted by an Independent Statistical Support Group (ISSG) and 
the results will be reviewed by an IDMC. The interim analysis aims at futility assessment and 
sample size reassessment. Based on the interim analysis, sample size can increase up to a 
maximum of 230 participants. Details of the interim analysis are given in Section 9.4.5.

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Study periods:
The study comprises the following periods: 

A screening period of at least 14- and up to 60 days

A DB treatment period, which starts on Day 1 (Randomization, baseline) and ends on the day 
of last DB study intervention intake. The DB period consists of an 8-week uptitration phase 
and a maintenance phase. During the uptitration phase, participants will receive macitentan at 
a dose of 10 mg for 4 weeks followed by a dose of 37.5 mg for 4 weeks before receiving the 
target dose of 75 mg. The maintenance phase is divided into a 28-week fixed duration part, at 
the end of which the primary endpoint is assessed, and a variable duration part. Participants 
assigned to the placebo arm will receive matching placebo tablets during the uptitration and 
maintenance phase (Figure 1).

A post-treatment observation period (PTOP) up to Week 28 for participants who prematurely 
discontinued DB study intervention and didn’t withdraw consent. In case of premature 
discontinuation, the DB treatment period ends on the day of intake of the last dose and the 
EODBT visit is performed within 7 days of intake of the last dose of study intervention. These 
participants will enter the PTOP and continue to perform the visits and assessments as 
scheduled until Week 28 (see schedule of activities in Section 1.2). The PTOP visits to be 
performed depend on the timepoint of discontinuation. The PTOP1 visit corresponds to the 
post-treatment safety follow-up visit and may be combined with any of the subsequent PTOP 
visits if it falls within the same time window (Figure 2). Participants who completed PTOP up 
to Week 28 are eligible to enter the open-label (OL) extension period if the eligibility criteria 
listed in Section 5.3 are met. Participants who prematurely discontinued study intervention 
and chose not to enter or complete PTOP will be contacted by phone at Week 28 and their vital 
status will be recorded in the case report form (CRF), provided their consent was not 
withdrawn.

An open-label (OL) extension period, which starts on the day of the EODBT visit and ends 
with the ‘End of open-label treatment’ (EOLT) visit. The OL period will end for all participants
104 weeks after the last participant has completed the DB treatment period. Participants who 
have reached the target dose of 75 mg and either completed the DB period as per protocol or 
experienced a CEC-confirmed clinical worsening and remained in the study at minimum up to 
Week 28 (either on treatment or in PTOP) are eligible for transitioning into the OL extension 
period, unless an exclusion criterion defined in Section 5.3 is met. Participants randomized to 
macitentan will continue to receive macitentan 75 mg daily. Participants randomized to 
placebo will receive macitentan at a dose of 10 mg for 4 weeks followed by a dose of 37.5 mg 
for 4 weeks prior to receiving the target dose of 75 mg. To preserve the blind of the DB
treatment period, a double-dummy uptitration is performed. Both participants and sites will 
remain blinded to the previous DB treatment allocations during the OL extension (Figure 3).

A safety follow-up period, which starts on the day after the last dose of study intervention and 
ends with a post-treatment safety follow-up visit (30 [+5] days thereafter, to collect any AEs 
since the last study visit).  
The end of the OL extension period of the study will be announced once all participants have 
performed their EOLT visit or left the study.

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The study results will be reported in 2 steps: 

The analysis of the DB study period will be performed when 144 participants (if there is no 
sample size increase at interim) have completed the fixed duration part of the DB period or 
prematurely discontinued the study. 

The final analysis for the study, including combined DB and OL extension, will be performed 
after closure of the OL extension period.
Diagrams of the study design are provided in Figure 1 to Figure 3.
Duration of the study 
For an individual participant, the duration of the DB period of the study is variable, depending on 
the timepoint of entry into the study and whether a CEC-confirmed clinical worsening event
occurred. The minimum duration is 28 weeks, and the maximum duration is estimated to be 
approximately 3.5 years. After completion of the DB treatment period, participants may be eligible 
to enter the OL treatment period, which will last until 2 years after the last participant completed 
the fixed duration part of the DB period. The entire study is expected to last approximately 6 years.
A diagram of the study design is provided in Section 1.3.
4.2
Scientific Rationale for Study Design
Rationale for the use of placebo
A placebo-controlled study conducted in a randomized and DB fashion provides the most 
definitive and rigorous method of evaluating treatment efficacy of a medical intervention. A 
placebo-controlled study is considered ethically acceptable due to the eligibility criteria restricting 
enrollment to stable CTEPH participants who may benefit from pharmacotherapy. Participants 
who are on Riociguat, PDE-5 inhibitors or oral or SC prostanoids at baseline are allowed to remain 
on these medications. The initiation and escalation of any PH-specific therapies (other than ERAs, 
the initiation of which requires discontinuation of study intervention) is allowed at any time during 
the study.
Additional measures to minimize the risks of prolonged DB treatment for the participants include: 

Exclusion of participants with unstable PH or who have a change in dose or initiation of 
PH-specific therapy less than 90 days prior to Randomization (see Section 5.2).

Exclusion of participants with any condition for which, in the opinion of the investigator, 
participation would not be in the best interest of the participant (see Section 5.2).

After Week 28 (timepoint of assessing the primary endpoint), transition to OL macitentan 
75 mg is possible in case of a CEC-confirmed clinical worsening event.

Close monitoring by an external IDMC throughout the study. 
Rationale for 2-step uptitration, each for 4 weeks
Macitentan at any dose is currently not approved in CTEPH. 40 inoperable CTEPH patients 
received macitentan 10 mg in a Phase 2 study (MERIT-1) which showed a safety profile that is 
consistent with the experience in PAH in trials and real-world data. However, macitentan has not 

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been studied in post-BPA or post-PEA CTEPH patients at any dose, and it has not been studied in 
any CTEPH patients including inoperable CTEPH at doses higher than 10 mg daily. In addition, 
doses of macitentan higher than 10 mg daily have not been studied in any other PH population at 
this time.
Therefore, to establish safety of these doses in the different CTEPH subgroups, a 2-step uptitration 
scheme has been implemented in this study design, first at 10 mg daily for 4 weeks, and then at 
37.5 mg daily for another 4 weeks, before achieving the target dose of 75 mg daily (8 weeks from 
the time of Randomization). This will give the target dose a period of 20 weeks to exert its effect 
before measuring the primary endpoint at Week 28. 
Down-titration to a lower dose of macitentan is not permitted. Participants who are unable to reach 
the target dose of 75 mg will be required to discontinue study intervention and enter the PTOP.
Rationale for implementing a DB period of variable duration:
The main reason for implementing a DB period of variable duration is to increase the statistical 
power for the time to clinical worsening (TTCW) endpoint. 
Time to Clinical Worsening (TTCW) is the key secondary endpoint of the MACiTEPH study. It 
is considered to represent a highly clinically relevant endpoint for participants with a progressive 
disease such as CTEPH. Because of the relatively small sample size (a larger study is not 
considered to be feasible), and the anticipated low incidence of clinical worsening events, the 
duration of follow-up on DB treatment is critical for obtaining a sufficient number of events and 
thus sufficient power for the TTCW endpoint. 
To increase follow-up time on DB treatment, the following modifications were made to the study 
design: 

The fixed duration part of the study is reduced from 52 to 28 weeks. After Week 28, the 
duration of the DB period will be variable, depending on the timepoint of randomization and 
the occurrence of a clinical worsening event (see section 4.1). The aim of the 28-week fixed 
duration part is to secure the primary endpoint of the study (6MWD), ie, without confounding 
the expected treatment effect by crossing over to OL macitentan 75mg. 

The variable duration part of the DB period is expected to result in a mean DB follow-up time 
of 24 months, which is twice as much compared to the previous study design (52 weeks). 
Furthermore, the reduction of the fixed DB duration from 52 to 28 weeks will reduce the overall 
duration of the DB period by 6 months. The end of the DB period of the study will be announced 
once all participants have completed the 28-week fixed duration period. Participants who were 
randomized under protocol versions 2-5 will be given the option to transition to the OL extension 
at the timepoint mentioned in the consent form they initially signed (ie, Week 52).

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Rationale for the open-label extension period
As CTEPH is a chronic and devastating disease in which long-term maintenance of treatment is 
recommended by current guidelines (Kim 2019), the aim of the open-label extension is to assess 
the long-term safety and tolerability, as well as the maintenance of long-term efficacy of 
macitentan 75mg in this disease. This is particularly relevant, as to date, the safety of macitentan 
has not been studied at doses higher than 10 mg od in any PH population. Furthermore, this OL 
extension study will give eligible participants who have completed the DB period of the study as 
per protocol (either on treatment or in PTOP) an opportunity to continue or to start receiving 
macitentan 75 mg. The earliest possible timepoint of entering the OL extension is Week 28 for an 
individual participant.
Rationale for 6MWD
Assessment of change in exercise capacity using the 6MWD has been used as the primary endpoint 
in most clinical trials involving patients with PAH and CTEPH (Rubin 2002, Galie 2005, 
Provencher 2006, Galie 2008, Ghofrani 2013a, Ghofrani 2013b).
In addition to pulmonary vasodilation, macitentan 75 mg is anticipated to improve vascular and 
right ventricular (RV) remodeling by achieving maximal ETB inhibition, thereby improving RV 
function and delaying progression of RV failure (Jasmin 2001, Iglarz 2008, Iglarz 2015, Kunita-
Takanezawa 2014, Nadeau 2017). The expected improvement in remodeling and cardiac 
performance at the higher doses is expected to translate into persistent functional gains 
(ie, improvement in 6MWD). 
In previous studies using the 6MWD as a primary endpoint, the time to assessment after start of 
treatment ranged from 12 to 24 weeks (Rubin 2002, Galie 2008, Ghofrani 2013b, Ghofrani 2017). 
In this planned study, the 6MWD will be assessed monthly up to Week 28. At the timepoint of 
assessing the primary endpoint, the participants will have been exposed to the target dose of 75 mg 
for 20 weeks, which is deemed adequate to detect a clinically significant treatment effect.
Medical Resource Utilization Data Collection
Treatment of CTEPH with macitentan 75 mg versus placebo may result in lower utilization of 
medical resources; therefore, comparison will be done across intervention groups.
Rationale for Optional Hemodynamic Sub-study
CTEPH is characterized by an increased resistance to blood flow in the pulmonary vasculature 
quantified by PVR. In addition, PVR has strong prognostic and predictive value for clinical 
outcome in CTEPH (Mayer 2011, Suda 2012, Kato 2014, Ramos 2016, Richter 2017). A previous 
study of macitentan 10 mg in inoperable CTEPH has shown a significant reduction in PVR (see 
Section 2.2, efficacy in CTEPH). The aim of this sub-study is to confirm the effect of macitentan 
75 mg on PVR in participants with inoperable or persistent/recurrent CTEPH. PVR and other 
hemodynamic variables (including but not limited to: mean right atrial pressure (mRAP), mPAP, 
cardiac index (CI), cardiac output (CO), total pulmonary resistance (TPR) and mixed venous 
oxygen saturation (SvO2) at rest) will be measured. 

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4.2.1 Study-Specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, during 
the study, participants will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may 
be withdrawn at any time with no reason given and without penalty or loss of benefits to which 
they would otherwise be entitled. Only participants who are fully able to understand the risks, 
benefits, and potential adverse events of the study, and provide their consent voluntarily will be 
enrolled.
The primary ethical concerns are the administration of a dose of 75 mg macitentan which exceeds
the dose of macitentan previously tested in CTEPH and approved in PAH. A justification for this 
dose is provided in Section 4.3. 
The total blood volume to be collected (see Section 8) is considered acceptable over this time 
period and for this study population, based on the standard of the WHO recommendations
(WHO Report).
4.3
Justification for Dose
Macitentan is approved for the treatment of PAH at a dose of 10 mg od, and the same dose (10 mg) 
was used in a Phase 2 study of macitentan in inoperable CTEPH (AC-055E201/MERIT-1). 
ET-1 is one of the most potent vasoconstrictors known and it exerts its effects via 2 receptor 
subtypes: ETA and ETB. In physiological conditions, ETA receptors are expressed on vascular 
smooth muscle cells and mediate vasoconstriction. ETB receptors are expressed on endothelial and 
smooth muscle cells; endothelial ETB receptors mediate vasodilation via nitric oxide release, while 
smooth muscle ETB mediates vasoconstriction. Certain pathological conditions, including PH, lead 
to endothelial dysfunction with impaired NO production (Girgis 2005) and upregulation of smooth 
muscle ETB receptors in the media of pulmonary blood vessels (Bauer 2002). As a consequence, 
endothelial mediated relaxation is lost and both ETA and ETB receptors mediate vasoconstriction 
and contribute to the detrimental effects of ET-1 (Kakoki 1999, Clozel 2006, Iglarz 2014, 
Iglarz 2010), suggesting superior efficacy of dual ET receptor antagonists.
Data from in vitro ETB receptor radioligand binding assays suggest that ETB is only partially 
blocked at a macitentan dose of 10 mg. Exposure-response analysis of human ET-1 levels 
measured in healthy subjects (AC-055-102) and glioblastoma patients (AC-055-115 & 
AC-055-118) suggest that inhibition of ETB receptors can be increased by increasing the dose of 
macitentan above 10 mg (D-16.563, D-17.238). Based on the results of this analysis, up to 60-75% 
ETB inhibition could be achieved with doses of macitentan up to 75 mg compared to the 15-20% 
ETB inhibition expected with the 10 mg dose. 
Human safety data in healthy subjects did not show any safety signal that would preclude studying 
daily doses of macitentan higher than 10 mg in patients with CTEPH. Based on the glioblastoma 
studies, no unexpected AEs were observed, and no dose-limiting toxicities occurred with 
escalating macitentan doses up of to 300 mg/day (including 14 subjects exposed to doses >100 mg 

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for more than 12 weeks) in combination with temozolomide. A macitentan dose of 75 mg od is 
expected to achieve close to maximal ETB inhibition while having a sufficient safety margin.
In summary, macitentan at a dose of 10 mg daily showed improvements in PVR and 6MWD in 
patients with inoperable CTEPH. Based on animal and translational data, a dose of 75 mg od is 
expected to further improve clinical outcomes due to the increased inhibition of the ETB receptor. 
A detailed description of the rationale for the use of macitentan 75 mg is provided in the IB 
(Macitentan IB) for macitentan.
4.4
End of Study Definition
End of Study Definition
The end of study (EOS) is considered as the last visit for the last participant in the study. The final 
data from the study site will be sent to the sponsor (or designee) after completion of the final 
participant visit at that study site, in the time frame specified in the Clinical Trial Agreement.
EOS visit
The definition of the EOS visit for an individual participant depends on the status of the participant:
Participants who didn’t enter the OL treatment extension phase:

Participants who completed the DB treatment per protocol: EOS corresponds to the Safety 
FU visit.

Participants who discontinued DB treatment during the fixed duration part and entered 
PTOP: EOS corresponds to the PTOP 6 visit

Participants who discontinued DB treatment during the fixed duration part and didn’t enter 
PTOP: EOS corresponds to the Safety FU visit 30 (+5) days after the last intake of DB 
study treatment

Participants who discontinued DB treatment at the end of the fixed duration part, or during 
the variable duration part of the DB treatment period: EOS corresponds to the Safety FU 
visit 30 (+5) days after the last intake of DB study treatment
Participants who entered the OL extension: 

Participants who either discontinue OL treatment prematurely or complete it per protocol: 
EOS corresponds to the Safety FU visit 30 (+5) days after the last intake of OL study 
treatment

Participants who transition to a post-trial access option (post-trial access program, other 
OL study): EOS corresponds to the EOLT visit

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Withdrawal of consent: 

EOS will be the last visit performed
Study Completion Definition
A participant will be considered to have completed the entire double-blind period if he or she has 
remained in the DB period until the end of the DB period is announced and either entered the OL 
extension period or had a safety follow-up (EOS) visit. 
Participants who prematurely discontinue study intervention for any reason before completion of 
the double-blind phase will not be considered to have completed the study.
A participant will be considered to have completed the OL Treatment Extension Period if he or 
she remained in the study until the end of the OL period is announced and has completed the safety 
follow-up / EOS visit or entered a continued access program.
5
STUDY POPULATION
Screening for eligible participants will be performed within 60 days before administration of the 
DB study intervention and includes confirmation of CTEPH diagnosis by the adjudication 
committee. The minimum duration of the screening period is 14 days. Refer to Section 5.5, Screen 
Failures, for conditions under which the repeat of any screening procedures is allowed.
The inclusion and exclusion criteria for enrolling participants in this study are described below. If 
there is a question about these criteria, the investigator must consult with the appropriate sponsor 
representative and resolve any issues before enrolling a participant in the study. Waivers are not 
allowed. 
For a discussion of the statistical considerations of participant selection, refer to Section 9.2, 
Sample Size Determination.
5.1
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled into the study:
1. Sign an ICF indicating that he or she understands the purpose of, and procedures required for, 
the study and is willing to participate in the study. 
2. Male or female 18 (or the legal age of consent in the jurisdiction in which the study is taking 
place) and 80 years of age.
3. CTEPH (WHO Group 4) fulfilling one of the following criteria: 
a.
Inoperable due to the localization of the obstruction being surgically inaccessible (ie, distal 
disease) as confirmed by the adjudication committee (AC), and diagnosed based on 

At least 2 of the following assessments in the 14 month-period prior to Randomization: 
Ventilation / Perfusion (V/Q) scan, pulmonary angiography (PA), computed 
tomography pulmonary angiogram (CTPA), magnetic resonance angiography (MRA). 

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
RHC at least 12 weeks after full anticoagulationa showing the following (at Screening 
or in the 24-week period prior to Randomization):
o
mPAP >20 mmHg
o
Pulmonary artery wedge pressure (PAWP) ≤15 mmHg or, if not available 
or unreliable, a left ventricular end diastolic pressure (LVEDP) ≤15 mmHg 
o
PVR at rest 240 dynsec/cm5
b. Persistent/recurrent CTEPH after BPA, and deemed inoperable due to the localization of 
the obstruction being surgically inaccessible (ie, distal disease) as confirmed by the AC, 
diagnosed based on:

At least one of the following assessments performed after the latest BPA in the 
14-month period prior to Randomization: V/Q scan, PA, CTPA or MRA 

RHC at least 12 weeks after BPA and full anticoagulationa showing the following (at 
Screening or in the 24-week period prior to Randomization):
o
mPAP > 20 mmHg
o
PAWP ≤15 mmHg or, if not available or unreliable, a LVEDP ≤15 mmHg 
o
PVR 240 dynsec/cm5
c.
Persistent/recurrent CTEPH after PEA (including PEA followed by BPA), diagnosed based 
on:

At least one of the following assessments performed after the PEA (and latest BPA
following PEA, if applicable) in the 14-month period prior to Randomization: V/Q 
scan, PA, CTPA or MRA 

RHC performed at least 12 weeks after PEA (or latest BPA, if applicable) and full 
anticoagulationa showing the following (at Screening or in the 24-week period prior to 
Randomization):
o
mPAP >20 mmHg
o
PAWP ≤15 mmHg or, if not available or unreliable, a LVEDP ≤15 mmHg 
o
PVR 240 dynsec/cm5,
4. 6MWD ≥100 m AND ≤450 m, documented by an eligibility and a baseline 6MWT. The 
baseline 6MWD must not differ by more than 15% from the eligibility test. 
5. WHO FC ≥II
6. Participants are to receive riociguat as per local standard of care, unless it is contraindicated or 
unavailable
7. A woman must be (as defined in Appendix 5)

Not of childbearing potential, or

Of childbearing potential and 
o
have a negative highly sensitive serum pregnancy test (-human chorionic 
gonadotropin) at Screening and a negative urine pregnancy test at 
Randomization.
o
practice a highly effective method of contraception (failure rate of <1% per 
year when used consistently and correctly) from Screening up to at least 
30 days after last dose of study intervention.
                                                
a Defined as treated with either vitamin K antagonists or new oral anticoagulants (eg, factor IIa inhibitors, factor Xa 
inhibitors), or treated with unfractionated heparin or low molecular weight heparin.

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Examples of highly effective methods of contraception are located in Appendix 5.
The criteria for inclusion in the male reproductive system safety (spermatogenesis) sub-study are 
detailed in Appendix 17.
5.2
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from 
participating in the study:
Exclusion criteria related to the disease
1.
Criterion modified per Amendment 4
1.1 Acute pulmonary embolism within 3 months prior to or during Screening.
2.
Criterion modified per Amendment 4
2.1 Planned BPA during the fixed duration part of the double-blind period
Exclusion criteria related to comorbidities
3.
Significant obstructive and restrictive lung disease fulfilling any of the following: 
a.
Forced expiratory volume in 1 second / forced vital capacity (FEV1/FVC) <0.7, 
associated with FEV1 <60% of predicted value after bronchodilator administration in 
participants with a known or suspected history of significant lung diseases.
b.
Known moderate or severe restrictive lung disease, eg, total lung capacity or FVC 
<60% of predicted.
c.
Clinical suspicion of diffuse interstitial fibrosis or alveolitis, unless excluded by high 
resolution computed tomography.
4.
Acute or chronic conditions (other than dyspnea) that limit the ability to comply with study 
requirements, in particular with 6MWT (eg, intermittent claudication).
5.
Criterion modified per Amendment 4
5.1 Symptomatic coronary artery disease requiring an intervention (eg, Percutaneous 
Coronary Intervention, Coronary Artery Bypass Graft) within 3 months prior to or during 
Screening or anticipated during the fixed duration part of the study.
6.
Decompensated cardiac failure if not under close supervision. 
7.
Known and documented life-threatening cardiac arrhythmias.
8.
Acute myocardial infarction within 6 months prior to, or during Screening.
9.
Cerebrovascular events (including transient ischemic attack) within 3 months prior to, or 
during Screening.
10. Known or suspicion of pulmonary veno-occlusive disease (PVOD). 
Exclusion criteria related to macitentan use
11. Criterion modified per Amendment 4
11.1 Administration of ERAs, intravenous prostacyclins / prostacyclin analogs, or
investigational treatment within 90 days prior to Randomization.
12. Criterion deleted per Amendment 4

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13. Criterion modified per Amendment 4
13.1 Change in dose or initiation of PDE-5 inhibitors, oral, inhaled or SC prostacyclins / 
prostacyclin analogues, prostacyclin receptor agonists or riociguat
a.
within 90 days prior to Randomization, or
b.
anticipated during the fixed duration part of the DB period .
14. Hypotension, ie, systolic blood pressure (SBP) <90 mmHg or diastolic blood pressure (DBP)
<50 mmHg at Screening. 
15. Severe renal dysfunction with an estimated Glomerular Filtration Rate <30 mL/min/1.73 m2 
using the Chronic Kidney Disease Epidemiology Collaboration formula at Screening. 
16. Known moderate to severe hepatic impairment, defined as Child-Pugh Class B or C (see 
Appendix 6), based on records that confirm documented medical historya
17. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≥1.5 the 
upper limit of normal (ULN) at Screening
18. Hemoglobin 100 g/L (<10 g/dL) at Screening
19. Pregnant, or breast-feeding, or planning to become pregnant, while enrolled in this study or 
within 30 days after the last dose of study intervention. 
20. Treatment with strong CYP3A4 inducers such as rifabutin, rifampin, rifampicin, rifapentin, 
carbamazepine, phenobarbital, phenytoin, or St. John’s wort within 30 days prior to 
Randomization.
21. Treatment with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, voriconazole, 
clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) or a moderate dual 
CYP3A4/CYP2C9 inhibitor (eg, fluconazole, amiodarone) or co-administration of a 
combination of moderate CYP3A4 (eg, ciprofloxacin, cyclosporine, diltiazem, erythromycin, 
verapamil) and moderate CYP2C9 inhibitors (eg, miconazole, piperine), within 30 days prior 
to Randomization.
22. Known hypersensitivity to macitentan or drugs of the same class, or any of the excipients 
(eg, soy lecithin, lactose).
General criteria
23. Any condition for which, in the opinion of the investigator, participation would not be in the 
best interest of the participant (eg, compromise well-being) or that could prevent, limit, or 
confound the protocol-specified assessments.
24. Criterion modified per Amendment 4
24.1 Planned or ongoingb exercise training program for cardiopulmonary rehabilitation during 
the fixed duration part of the study.
25. Known concomitant life-threatening disease with a life expectancy <12 months.
26. RHC sub-study only: Previous RHC with serious complications, such as (but not limited to) 
cardiac arrest, arrhythmia requiring intervention, pulmonary hemorrhage, stroke, 
thromboembolic event and pulmonary hypertensive crisis
                                                
a The assessment for hepatic impairment must be fully documented in the medical history for participants that have 
clinical signs and evidence (from central and local labs) of hepatic impairments at screening
b Stable, long-term exercise programs that have been ongoing for more than 6 months at the time of Screening may 
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NOTE: Investigators should ensure that all study enrollment criteria have been met at Screening. 
If a participant’s clinical status changes (including any available laboratory results or receipt of 
additional medical records) after Screening but before the first dose of study intervention is given 
such that he or she no longer meets all eligibility criteria, then the participant should be excluded 
from participation in the study. Section 5.5 - Screen Failures, describes options for ret–sting. The 
required source documentation to support meeting the enrollment criteria is noted in Appendix 3.
5.3
Qualifying Criteria for Transitioning to the OL Extension
1. Successful uptitration of DB study intervention to target dose of 75 mg 
2. Participant completed the DB period as per protocol up to Week 28 (either on treatment or 
in PTOP) at minimum
3. No pre-defined criterion for permanently discontinuing study intervention met during 
double-blind period (Section 7.1.1).
4. No significant decrease in hemoglobin (ie, <80 g/L (<4.9 mmol/L) or decrease >50 g/L 
from baseline) observed during the DB period that does not return to baseline value or 
within normal range, or the need for transfusion in the absence of confounding factors.
5.4
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions 
during the course of the study to be eligible for participation:
1.
Refer to Section 6.5 - Concomitant Therapy for details regarding prohibited and 
restricted therapy during the study.
2.
Agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
3.
Strenuous exercise may affect study specified assessments and safety laboratory results; 
for this reason, it is recommended to avoid strenuous exercise within 2 hours before all 
planned study visits and during stays at the study site.
5.5
Screen Failures
For participants who failed Screening, the following data will be recorded in the eCRF if available:

Date/Time of ICF signature

Demographics (age, sex, race and ethnicity)

Reason for screen failure and associated assessments, if applicable (eg, pulmonary function 
test (PFT) data in case exclusion criterion 3a is met).
Individuals who do not meet the criteria for participation in this study (Screening failure) may be 
rescreened twice, if the reason for non-eligibility is transient (eg, abnormal laboratory test, 
insufficient washout period of a forbidden medication). Assessments which are mandatory at 
Screening (eg, if historical data are not accepted) must be repeated at the time of rescreening. 

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Individuals who fail screening should discuss with their primary physician to determine their 
standard of care.
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy 
identification of each participant during and after the study. This document will be reviewed by 
the sponsor study-site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed 
by the investigator in the study file. To ensure participant confidentiality, no copy will be made. 
All reports and communications relating to the study will identify participants by participant 
identification and age at initial informed consent. In cases where the participant is not randomized 
into the study, the date seen and age at initial informed consent will be used.
6
STUDY INTERVENTION
6.1
Study Intervention(s) Administered
Macitentan and matching placebo will be provided as film-coated tablets at dose strengths of 
10 mg, 37.5 mg and 75 mg in childproof bottles. The tablets are administered orally and should be 
swallowed whole (ie, not crushed, split or chewed). Dosing frequency will be once a day.
The first intake of study intervention will take place at the randomization visit, after successful 
completion of all assessments. Thereafter, the study intervention should be administered orally 
once daily with food (ie, during a meal) at the same time each day, preferably in the morning. 
The participants must be instructed to withhold study treatment in the morning of study visit days
until all study assessments (except post-dose PK sampling, as applicable) have been performed. 
At uptitration visits (DB visits 3 and 6, OL visits 2 and 5), a tablet from the newly dispensed bottle
must be taken.
An overview of the treatments and doses of macitentan and matching placebo is provided in
Table 4.

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Table 4:
Treatment Overview
Study intervention 
name:
Macitentan 
Placebo
Dose formulation
Film-coated tablets and matching placebo
Unit dose strength(s)
10 mg
37.5 mg 
75 mg 
Placebo
Dosage levels
Double-blind treatment period: 
Titration (8 weeks)
Day 1 to Week 4 (day before the visit): 10 mg od or matching placebo
Week 4 to Week 8 (day before the visit): 37.5 mg od or matching placebo
Maintenance:
Fixed duration part:
Week 8 to Week 28 (day before the visit): 75 mg od or matching placebo
Variable duration part:
Week 28 to EODBT of last participant or CEC-confirmed CW event of the 
individual participant, whichever occurs first: : 75 mg od or matching placebo
Open label extension period 
Double-dummy uptitration (8 weeks):
Ex-placebo arm: 
Day 1 to Week 4 (day before visit): 10 mg tablet + Placebo-matching 75 mg tablet
Week 4 - Week 8 (day before visit): 37.5 mg tablet + Placebo matching 75 mg tablet
Ex-macitentan arm: 
Day 1 to Week 4 (day before visit): 75 mg tablet + Placebo-matching 10 mg tablet
Week 4 - Week 8 (day before visit): 75 mg tablet + Placebo-matching 37.5 mg 
tablet
Maintenance:
Week 8 to EOLT: 75 mg od.
Route of administration
Oral
Dosing instructions
Study intervention administration:
One tablet once a day with food, preferably in the morning. 
Packaging and labeling
Study intervention will be provided in childproof bottles containing 36 tablets each.
Each bottle will contain information and be labeled as required per country 
regulatory requirements. Labels must remain affixed to the bottle.
EOLT ꞊ end of open-label treatment; od ꞊ once daily.
Study intervention administration must be captured in the source documents and the eCRF.
Study-site personnel will instruct participants on how to store study intervention for at-home use 
as indicated for this protocol. 
Macitentan and placebo will be manufactured and provided under the responsibility of the sponsor.
Refer to the IB for a list of excipients (Macitentan IB).
Manufacturing, labeling, packaging, and supply of study intervention will be conducted according 
to Good Manufacturing Practice, Good Clinical Practice (GCP) and any local or national 
regulatory requirements. 
All study intervention supplies are to be used only in accordance with this protocol and not for any 
other purpose. Study intervention will be packed in medication kits containing the number of 
bottles required to supply enough medication until the next dispensation visit, as described in 

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Study intervention must be handled in strict accordance with the protocol and the container label and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study intervention, and study intervention returned by the 
participant, must be available for verification by the sponsor’s study site monitor during on-site 
monitoring visits. The return to the sponsor of unused study intervention, or used returned study 
intervention for destruction, will be documented on the intervention return form. When the study site 
is an authorized destruction unit and study intervention supplies are destroyed on-site, this must also 
be documented on the intervention return form.
Study intervention should be dispensed under the supervision of the investigator or a qualified 
member of the study-site personnel, or by a hospital/clinic pharmacist. Study intervention will be 
supplied only to participants participating in the study. Returned study intervention must not be 
dispensed again, even to the same participant. Study intervention may not be relabeled or reassigned 
for use by other participants. The investigator agrees neither to dispense the study intervention from, 
nor store it at, any site other than the study sites agreed upon with the sponsor.
6.3
Measures to Minimize Bias: Randomization and Blinding
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. 
Participants will be randomly assigned 1:1 to 1 of 2 intervention groups at the beginning of the DB 
period, based on a computer-generated randomization schedule prepared before the study by or under 
the supervision of the sponsor. 
The randomization will be balanced by using permutation blocks and will be stratified by 
PH-specific therapy (riociguat / other PH-specific therapy / none) and inoperable (with or without 
BPA) vs persistent/recurrent after PEA surgery (with or without BPA)
The interactive web response system (IWRS) will assign a unique intervention code, which will 
dictate the intervention assignment and matching study intervention kit for the participant. The 
requestor must use his or her own user identification and personal identification number when 
contacting the IWRS, and will then give the relevant participant details to uniquely identify the 
participant.
Blinding
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual participant.
Data that may potentially unblind the intervention assignment will be handled with special care to 
ensure that the integrity of the blind is maintained and the potential for bias is minimized. This can 
include making special provisions, such as segregating the data in question from view by the 
investigators, clinical team, or others as appropriate until the time of database lock and unblinding.

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Randomization codes will be disclosed fully only if the double-blind period of the study is 
completed and the clinical database is closed. To preserve the blind of each individual participant 
during IDMC reviews and the planned interim analysis, the randomization codes and, if required, 
the translation of randomization codes into intervention and control groups will be disclosed to 
those authorized, but only for those participants included in the analysis. An ISSG will conduct 
the analyses and present unblinded results to the IDMC (see Section 9.5).
Under normal circumstances, the blind should not be broken until all participants have completed 
the double-blind part of the study and the database is closed. The investigator may in an emergency 
determine the identity of the intervention by contacting the IWRS. While the responsibility to 
break the intervention code in emergency situations resides solely with the investigator, it is 
recommended that the investigator contacts the sponsor or its designee if possible, to discuss the 
particular situation, before breaking the blind. Telephone contact with the sponsor or its designee 
will be available 24 hours per day, 7 days per week. In the event the blind is broken, the sponsor 
must be informed as soon as possible. The date and reason for the unblinding must be documented 
in the eCRF, the Investigator Site File, and in the source document. The documentation received 
from the IWRS indicating the code break must be retained with the participant’s source documents 
in a secure manner.
Participants who have had their intervention assignment unblinded should continue the scheduled 
evaluations and are allowed to continue study intervention.
6.4
Study Intervention Compliance
Study intervention compliance is based on study intervention accountability (see Section 6.2). 
Participants will receive instructions on compliance with study intervention administration at 
Screening. During the course of the study, the investigator or designated study site-personnel will 
be responsible for providing additional instruction to reeducate any participant who is not 
compliant with taking the study intervention.
6.5
Concomitant Therapy
Pre-study therapies administered up to 30 days before signing the ICF and PH-specific therapies 
(ongoing, initiated, or stopped) taken within 90 days of Randomization must be recorded in the 
eCRF at Screening.
Concomitant therapies must be recorded throughout the study from signing of the ICF onwards 
until the EOS visit (see Section 4.4) or date of last contact (see Section 7.3).
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, exercise regimens, or other specific categories of interest) different from the study 
intervention must be recorded in the eCRF. Recorded information will include the generic name, 
start/end dates of administration (as well as whether it was ongoing at start of intervention and/or 
EOS), route, dose, frequency and indication. 

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Modification of an effective preexisting therapy should not be made for the explicit purpose of 
entering a participant into the study.
All participants are to receive riociguat as per local standard of care, unless it is contraindicated 
(eg, due to co-morbidities, interaction with other essential concomitant medications, tolerability 
issues) or unavailable (eg, treatment not approved or reimbursed). The reason for not receiving
riociguat must be documented in the participant’s chart.
Participants on background PH-specific therapies at baseline should remain on the same dose 
throughout the study unless a change is clinically mandated based on the medical assessment 
performed during the corresponding visit.
The following medications are not allowed to be administered concomitantly with study 
intervention:
ERAs (eg, bosentan, ambrisentan)
Intravenous prostacyclins/prostacyclin analogs, unless used as rescue therapy (see Rescue 
Medication section below)
Strong CYP3A4 inducers (eg, carbamazepine, phenytoin, phenobarbital, rifampin/rifampicin, 
rifabutin, rifapentin, St. John’s wort)
Strong CYP3A4 inhibitors (eg, itraconazole, ketoconazole, voriconazole, clarithromycin, 
telithromycin, nefazodone, ritonavir, and saquinavir) or moderate dual CYP3A4/CYP2C9 
inhibitors (eg, fluconazole, amiodarone) or co-administration of a combination of moderate 
CYP3A4 (eg, ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) and moderate 
CYP2C9 inhibitors (eg, miconazole, piperine) (FDA 2020)
Any other investigational drug.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
6.5.1 Rescue Medication
The initiation or dose escalation of PH-specific therapy (as defined below) is considered rescue 
pharmacotherapy. If rescue pharmacotherapy needs to be initiated outside of a regular visit, the 
participant must return to the site for an unscheduled visit to perform a medical assessment.
ERAs (eg, ambrisentan, bosentan): their administration must lead to immediate discontinuation 
of study intervention
Riociguat, PDE-5 inhibitors, prostacyclin, prostacyclin analogs, prostacyclin receptor agonist
(Their administration will not require study intervention discontinuation and participants can 
remain in the study).
Rescue medication will be obtained locally as per local practice.

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Rescue procedures
BPA and PEA, if performed during the study due to PH worsening, are considered rescue 
procedures. Participants who underwent a BPA or PEA may remain on study treatment. 
The type of rescue procedure as well as the date must be recorded in the eCRF.
6.6
Dose Modification
No dose modification of the study intervention is allowed during the study. See Section 7.1 for 
guidance on interruption / premature discontinuation of study intervention.
6.7
Continued Access to Study Intervention After the End of the Study
Participants who have had their EOS visit before the completion of the study will be contacted by 
telephone to determine vital status and whether the hospitalization was required (including date, 
duration and reason of hospitalization [(PH-related or other], if available) approximately every 6 
monthsa until completion of the study (see Section 4.4 ) , unless the participant has died, is lost to 
follow-up, or has withdrawn consent. If the information on vital status and hospitalization is 
obtained via telephone contact, written documentation of the communication must be available for 
review in the source documents. If the participant has died, the date and cause of death will be 
collected and documented on the CRF.
Local regulations on continued access will always take precedence. Plans for continued access 
stated in this protocol may change if new information on the benefit-risk profile of macitentan
becomes available during the study or program.
At the end of their participation in the study, participants who have completed the study and are 
benefiting from the study intervention, as determined by their investigator, will be able to receive 
continued access via an another open-label extension study or via post-study independent requests 
from their investigators. 
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
7.1.1 Permanent Discontinuation
A participant’s study intervention must be permanently discontinued if:

The participant withdraws consent to receive study intervention.

The investigator believes that for safety or tolerability reasons (eg, AE), it is in the best interest 
of the participant to discontinue study intervention.
                                                
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
The participant is unable to reach the target dose of 75 mg (for both DB and OL study 
intervention).

The participant becomes pregnant. Refer to Appendix 5, Contraceptive Guidance and 
Collection of Pregnancy Information.

Initiation of treatment with an ERA (eg, macitentan 10 mg, bosentan, ambrisentan).

Liver aminotransferase abnormalities:

Aminotransferase ≥8 × ULN.

Aminotransferase ≥3 × ULN and associated clinical symptoms of liver injury; Eg, nausea, 
vomiting, fever, abdominal pain, dark urine, anorexia, itching, jaundice, unusual lethargy 
or fatigue, or flu-like syndrome (arthralgia, myalgia, fever).

Aminotransferase ≥3 × ULN and associated increase in total bilirubin ≥2 × ULN. 
Aminotransferases, total and direct bilirubin, and alkaline phosphatase levels must be monitored 
weekly after study intervention discontinuation until values return to pre-treatment levels or within 
normal ranges.
The ILSDRB provides ongoing assessment and advice regarding hepatic events that require further 
evaluation during the study.
A participant who prematurely discontinues DB study treatment during the fixed duration part is 
not considered as withdrawn from the study and will be asked to enter the PTOP which lasts until 
Week 28, provided that the subject’s consent for this limited participation in the study has not been 
withdrawn.
The participant will be asked to return for an end-of treatment visit (EODBT) within 7 days after 
taking the decision to stop DB study intervention and for a safety follow-up visit 30 (+5) days after 
the last intake of dose of DB study intervention (PTOP1). At the premature EODBT visit, the 
assessments described in the Table 1 for the regular EODBT visit are to be performed. If the 
premature EODBT- or safety follow-up visit falls within the time-window of any of the PTOP 
visits, the visits can be combined. 
Participants who prematurely discontinue OL study intervention during the OL extension period 
will return for an end-of treatment visit (EOLT) within 7 days after taking the decision to stop OL 
study intervention and for a safety follow-up visit 30 (+5) days after the last intake of OL study 
intervention. At the premature EOLT visit, the assessments described in the Table 2 for the regular 
EOLT visit are to be performed.
The safety follow-up visit will be waived in case the participant moves to a continued access 
program and in that case EOLT will be the last visit in the study.
If the decision to stop study intervention is taken at a regular or unscheduled site visit, this visit 
may become the premature EODBT/EOLT visit.
Study intervention assigned to the participant who discontinued study intervention may not be
assigned to another participant. Additional participants will not be entered.

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7.1.2 Temporary Discontinuation
Participants experiencing an adverse event that precludes further dosing during uptitration will be 
allowed to interrupt study intervention temporarily for up to 5 consecutive days per uptitration step 
until their AE has resolved. During the DB maintenance- and OL period, interruption for up to 
14 consecutive days is allowed. Study intervention will be reinitiated at the dose it was interrupted 
unless the interruption was more than 5 or 14 consecutive days, respectively. If after study 
intervention re-introduction, the AE appears again and is not explained by another medical 
condition, the study intervention should be discontinued. More than one episode of study 
intervention interruption is allowed.. Longer interruptions (ie, > 5 consecutive days during each 
DB up-titration step, > 14 consecutive days during the DB maintenance- and OL period) must lead 
to permanent study intervention discontinuation. 
Study intervention interruption is mandatory in case of:

Liver aminotransferase abnormalities:

Liver aminotransferases (ie, ALT and/or AST) ≥3 and <8 × ULN.
Perform a re-test of aminotransferases (ALT and AST), total and direct bilirubin, and 
alkaline phosphatase within 1 week. If AST and/or ALT elevation is confirmed, continue 
to monitor aminotransferases, total and direct bilirubin, and alkaline phosphatase levels 
weekly until values return to pre-treatment levels or within normal ranges. If the 
aminotransferase values return to pre-treatment levels or within normal ranges, and if the 
potential benefits outweigh the risks, reintroduction of study intervention can be 
considered. The advice of a hepatologist is recommended.
Liver aminotransferase levels must be checked within 3 days after re-introduction, then 
again after a further 10 to 14 days and thereafter, if results remain within normal levels, 
per the normal assessment schedule described in Section 8.3.5.
All liver aminotransferase abnormalities leading to study intervention interruption or 
discontinuation must be recorded as AEs (see Section 8.4.5).

Hemoglobin abnormalities
In the case of a hemoglobin decrease from baseline of >20 g/L during the study, a re-test must 
be performed within 10 days; additional laboratory evaluations 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; and

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
Indirect bilirubin.
If hemoglobin remains >20 g/L below baseline value at subsequent visits, further re-tests are to be 
performed as per investigator’s judgment.
This work-up should not result in study intervention interruption or discontinuation, unless 
clinically mandated based on the investigator’s judgment, or in the following situation (unless 
clearly unrelated to study intervention, eg, hemoglobin decrease due to a bleeding event):

A decrease in hemoglobin to <80 g/L (<4.9 mmol/L).

A decrease in hemoglobin from baseline of >50 g/L.

The need for transfusion in the absence of confounding factors.
Re-introduction of study medication can be considered if hemoglobin recovery, defined as a 
return of hemoglobin to within 20 g/L of the baseline value or within normal range, is achieved. 

Administration of a forbidden medication (except ERAs)
Study treatment must be interrupted if the participant requires treatment with a forbidden 
medication (see Section 6.5). Study treatment can be re-introduced if the forbidden treatment is 
discontinued and the time window defined above is not exceeded. Initiation of an ERA will require 
study intervention to be discontinued permanently.
7.2
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

Death
When a participant withdraws before study completion, the reason for withdrawal is to be 
documented in the CRF and in the source document. If the reason for withdrawal from the study 
is withdrawal of consent, then no additional assessments are allowed.
When participants are withdrawn from the main study, they are also withdrawn from the 
hemodynamic sub-study. Participants can be withdrawn from the sub-study while continuing the 
main study.
Withdrawal of Consent
A participant declining to return for scheduled visits does not necessarily constitute withdrawal of 
consent. Alternate follow-up mechanisms (ie, telephone call at Week 28) that the participant 
agreed to when signing the consent form apply as local regulations permit.
If for whatever reason (except death or loss-to-follow-up) a participant is withdrawn from the 
study, the investigator should make efforts to schedule a last appointment / telephone call to assess 
the safety and well-being of the participant, collect unused study intervention and discuss follow-

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up medical care. Data obtained during this last appointment / telephone call will be recorded in the 
participants’ medical records but it will not be collected in the CRF.
7.2.1 Withdrawal from the Use of Research Samples
A participant who withdraws from the study or who withdraws consent for optional research 
samples while remaining in the study will have the following options regarding the optional 
biomarker research samples:

The collected samples will be retained and used in accordance with the participant’s original 
separate informed consent for optional research samples.

The participant may withdraw consent for the use of optional research samples, in which case 
the samples will be destroyed. To initiate the sample destruction process, the investigator must 
notify the sponsor study site contact of withdrawal of consent for the optional research 
samples and to request sample destruction. The sponsor study site contact will, in turn, contact 
the biomarker representative to execute sample destruction. If requested, the investigator will 
receive written confirmation from the sponsor that the samples have been destroyed.
7.3
Lost to Follow-up
To reduce the chances of a participant being deemed lost to follow-up, prior to randomization 
attempts should be made to obtain contact information from each participant, eg, home, work, and 
mobile telephone numbers and e-mail addresses for both the participant as well as appropriate 
family members.
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. A participant cannot be deemed 
lost to follow-up until all reasonable efforts made by the study site personnel to contact the 
participant are deemed futile. The following actions must be taken if a participant fails to return to 
the study site for a required study visit:

The study site personnel must attempt to contact the participant to reschedule the missed visit 
as soon as possible, to counsel the participant on the importance of maintaining the assigned 
visit schedule, to ascertain whether the participant wishes to or should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee must make every 
reasonable effort to regain contact with the participant (where possible, 3 telephone calls, 
emails, fax, and, if necessary, a certified letter to the participant’s last known mailing address, 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical records.

Should the participant continue to be unreachable, they will be considered to have withdrawn 
from the study.

Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including those 
who did not get study intervention. Public sources may be searched for vital status 
information. If vital status is determined as deceased, this will be documented, and the 

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participant will not be considered lost to follow-up. Sponsor personnel will not be involved in 
any attempts to collect vital status information.
8
STUDY ASSESSMENTS AND PROCEDURES
The Schedule of Activities (SoA) summarizes the frequency and timing of efficacy, PK, biomarker
and safety measurements applicable to this study. For all visits, the participants must be seen or 
called on the designated day with an allowed visit window per the Schedule of Activities (SoA). 
If it is not possible to complete all assessments on the same day, a visit may extend to more than 
1 day within the allowed time-window.
DB Visits 5 (Week 6) and 8 (Week 10), and OL Visits 4 (week 6) and 7 (Week 10), can be 
conducted either at site or by a local registered nurse, or any other appropriately trained person, 
followed by a site telephone call. 
The following order of assessments is recommended, as applicable:
1)
PAH-SYMPACT® completed at participant’s home, 7 consecutive days prior to visit (when 
applicable).
2)
EQ-5D-5L©, followed by PHQ-8, SF-36®, WPAI:GH (any order)
3)
ECG
4)
Vital signs, body weight, and physical examination
5)
WHO FC
6)
6MWT and Borg CR10 Scale® (; pre- and post-6MWT)
7)
Blood samples (PK, hematology and clinical chemistry tests, NT-proBNP, +/- biomarkers)
8)
RHC (if applicable)*
9)
Study intervention intake 
10) Blood samples for post-dose PK (2-10 hours post-dose)
*If RHC is performed, it must be done after the 6MWT
It is recommended to complete/conduct patient-reported outcome (PRO) assessments before any 
tests, procedures, or other consultations to prevent influencing participant perceptions.
Blood collections for PK assessments should be kept as close to the specified time as possible. 
Other measurements may be done earlier than specified timepoints if needed. 
Unscheduled Visits
Unscheduled visits may be performed at any time during the study. Depending on the reason for 
the unscheduled visit, appropriate assessments will be performed based on the judgment of the 
investigator.
An unscheduled visit must be performed in case of suspected clinical worsening or initiation/dose 
escalation of PH-specific therapy outside of a regular visit. At unscheduled visits performed due 

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suspected clinical worsening, physical examination, vital signs (blood pressure/pulse rate), weight, 
laboratory assessments, 6MWT/Borg CR10 Scale® and WHO FC must be done. Other assessments 
are done per investigator’s discretion.
The date of the visit and the reason for the visit, as well as data related to study-specific 
assessments performed at unscheduled visits, will be recorded in the eCRF.
After an unscheduled visit, the regular scheduled study visits must continue according to the 
planned visit and assessment schedule.
For each participant, the maximum amount of blood drawn from each participant in this study will 
not exceed 260 mL per year. The amount of blood collected during each visit ranges from 
approximately 15 mL (visits with safety labs only) to 25 mL (visits with safety labs, PK and 
biomarker samples). During the OL extension period, the amount of blood collected per visit will 
not exceed 15 mL. These estimates are without considering the amount of blood to be withdrawn 
for the optional male reproductive system safety sub-study (refer Appendix 17 for corresponding 
details).
Study-Specific Materials
The investigator will be provided with the following supplies:

Investigator’s Brochure

Laboratory manual, requisition forms, and sampling supplies

IWRS Manual

PRO questionnaires, PRO completion guidelines, and electronic devices 

eCRF completion guidelines

ECG device and manual, as required

SAE Form, SAE completion guidelines, and SAE fax cover page

Pregnancy notification form and pregnancy form completion guidelines

Study participant card

6MWT starter kit

ICF template

Accelerometer

Additional equipment and information, as needed.
8.1
Demographics and Baseline Characteristics
Demographic and baseline characteristic data to be collected on all randomized participants 
include: age, sex, race and ethnicity (where local regulations permit), date of the initial CTEPH 
diagnosis, 6MWD, WHO FC, date of most recent CTEPH hospitalization, number of previous 

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hospitalization for CTEPH within 6 months prior to Screening, Child Pugh Score for participants 
with known hepatic impairment, and signs and symptoms of right heart failure.
All relevant medical history / current medical conditions based on the investigator’s judgment 
(eg, chronic and ongoing acute conditions, serious past conditions) present before and/or at the 
time of signing informed consent will be recorded on the medical history page. Where possible, 
diagnoses and not symptoms will be recorded.
The following specific medical history will be captured in the CRF at Screening:

Pulmonary embolism

Deep vein thrombosis

Thrombophilic risk factors (eg, Lupus anticoagulant, anticardiolipin antibody, deficiency 
of natural anticoagulants (protein C, protein S, antithrombin), high concentration of factor 
VIII

Right heart failure

Splenectomy

Ventriculoatrial shunt 

Inflammatory bowel disease

Osteomyelitits

Indwelling catheters and leads (Pacemaker, automated implantable cardiac defibrillator, 
dialysis catheters, permanent intravenous lines and catheters)
8.1.1 Eligibility Adjudication Procedure
Following the Screening visit, anonymized data (listed in Table 7) of all participants judged by the 
investigator to have technically inoperable or persistent/recurrent CTEPH, and fulfilling all other 
eligibility criteria, will be submitted to the adjudication committee for confirmation of eligibility
and a scientific and medical plausibility check.
Table 7:
Data required for adjudication procedure
Inoperable
CTEPH
Persistent/recurrent 
CTEPH after BPA
Persistent/recurrent 
CTEPH after PEA**
RHC*
X
X
X
Imaging assessments
≥ 2†
≥ 1‡
≥ 1‡
Historical surgery & 
intervention report

X
X
Medical history form
X
X
X
BPA = balloon pulmonary angioplasty; CTEPH = chronic thromboembolic pulmonary hypertension; PEA = pulmonary 
endarterectomy; RHC = right heart catheterization.

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* RHC must be performed at least 12 weeks after start of full anticoagulation and at least 12 weeks after last surgical (PEA) or 
interventional (BPA) treatment for participants with persistent/recurrent CTEPH. If no historical RHC results are available, a 
RHC must be performed during the Screening period (submission of RHC tracing is optional).
** Includes PEA followed by BPA.
† Ventilation/perfusion (V/Q) scan, pulmonary angiography (PA), computed tomography pulmonary angiogram (CTPA), 
magnetic resonance angiography (MRA) performed in the 14-month period prior to Randomization  
‡ V/Q scan, PA, CTPA, MRA performed in the 14-month period prior to Randomization after PEA and/or BPA
The imaging assessments will be performed as per local routine practice, and the data will be 
transferred from the investigational site to the AC via a central image processing center. 
The investigator will await the eligibility assessment from the AC before informing the participant 
and performing the randomization visit. 
A separate manual is provided to the investigational sites for guidance on the adjudication 
procedure (eg, requested data, transfer of data to the central image processing center, etc.).
8.1.2 Clinical Events Adjudication Procedure
All clinical worsening events will be adjudicated in a blinded manner by a CEC. Participants who 
experienced a CEC-confirmed clinical worsening event during the variable duration part of the DB 
period will be eligible to enter the OL extension period, provided that the criteria listed in Section 
5.3 are met and switching to OL macitentan 75 mg is considered to be the best treatment option 
for the participant. 
Participants who experienced a CEC-confirmed clinical worsening event during the fixed duration 
part will be eligible to enter the OL phase after having completed the assessments up to Week 28  
(Visit 13/PTOP 6), provided the criteria listed above are met.
Transitioning to OL study intervention in case of a CEC-confirmed clinical worsening event is not 
mandatory; participants may remain on DB study intervention.
The investigator is requested to prepare a narrative of the participant's condition at baseline (eg, 
intensity/severity of the symptoms and their impact on daily life) and how it changed during the 
clinical worsening event. The narrative and any other relevant supportive data (eg, routine 
assessments such as NT-proBNP, RHC, MRI; hospital discharge summaries, as applicable) will 
be made available to the CEC to facilitate the adjudication. Full details for this procedure, as well 
as the composition and operation of the CEC, are provided in the CEC charter.
8.2
Efficacy Assessments
8.2.1 6-minute Walk Test
The 6MWT is a standardized test that measures the distance walked in 6 minutes 
(ATS Statement 2002). It will be performed at the timepoints indicated in the schedule of activities 
(see Section 1.2).

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During the Screening period, an eligibility 6MWT, followed by a baseline 6MWT must be 
performed. The baseline test must be performed in the 1-week period prior to Randomization or at 
Randomization. For the participant to be eligible for randomization into the study, the distances 
walked during the eligibility and the baseline test must be ≥100 and ≤450 m, and the relative 
difference (ie, the absolute difference divided by the mean × 100) between the two tests must be 
≤15%. In case the relative difference is >15%, a third test can be performed (including Borg CR10 
Scale®). If the relative difference between the third and the second 6MWT is ≤15%, the participant 
is eligible and the third test (including Borg CR10 Scale®) will be considered as the baseline test. 
If 2 6MWTs are performed on the same day, the interval between them must be at least 2 hours. 
For participants who have not previously performed a 6MWT, a training test will be performed in 
addition (and prior) to the eligibility and the baseline 6MWT. Data from the training test are not 
collected.
If a 6MWT cannot be performed at a scheduled visit beyond Visit 2 or at an unscheduled visit, a 
reason must be provided (ie, PAH-related or other). 
If the participant wears a mask during the 6MWT, this will be documented in the eCRF.
Detailed guidelines on correct execution of the 6MWT are provided in Appendix 7.
8.2.2 Borg CR10 Scale®
Dyspnea and exertion will be assessed by the Borg CR10 scale® (Borg 1982, Borg 1998). The 
instructions on how to use the scale (Section 10.8) must be provided to the participant at Screening, 
prior to performing the first 6MWT. Dyspnea and exertion will be evaluated just before and after 
the 6MWT.
8.2.3 Clinical Worsening
Presence of clinical worsening must be assessed as indicated in the schedule of activities 
(Section 1.2). Clinical worsening is defined as the occurrence of at least one of the following 
events:

All-cause death**

Heart and/or lung transplantation

Unplanneda PH-related hospitalization

PH-related deterioration identified by at least one of the following: 

Persistentb increase in WHO FC that cannot be explained by another cause (eg, viral 
infection);

Persistentb deterioration by at least 15% in exercise capacity, as measured by 6MWD 

New or worsening signs or symptoms of right heart failure 

Rescue PEA and/or BPA procedure due to worsening of PH 
                                                
a Not planned at study entry
b Confirmed by a second measurement performed on a different day within 2 weeks

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**Including deaths occurring within 30 days of last dose of study intervention caused by an AE that occurs within 7 
days of intake of last dose of DB study intervention.
The participant must be assessed for progression of PH-related symptoms including clinical signs 
of right ventricular failure. Any assessment deemed necessary by the investigator to assess 
worsening of PH (eg, Imaging and/or cardiac catherization, NT-proBNP) may be performed.
For clinical worsening, the investigator must carefully assess if the deterioration of the 
participant’s condition (eg, worsening in exercise capacity or functional class) is related to the 
underlying PH or can be explained by an alternative cause, such as the exacerbation of concomitant 
illness or lack of adherence to medication intake.
If a repeat 6MWT cannot be performed due to PH-related deterioration, this needs to be 
documented in the eCRF.
An unscheduled visit must be performed in case of suspected clinical worsening or initiation/dose 
escalation of PH-specific therapy outside of a regular visit (see Section 8). 
8.2.4 Risk Categories for Clinical Worsening and Death
This study will include endpoints looking at changes in the non-invasive risk criteria (WHO FC, 
6MWD, NT-pro-BNP), to assess treatment effect on the number of low-risk criteria or on changes 
in risk category throughout the study and the correlation between baseline risk category and 
prediction of clinical worsening and death.(Boucly 2017; Hoeper 2017) 
Table 8:
An outline of risk stratification strategy 
Variable
Low risk category
Intermediate-risk category
High-risk category
WHO FC
I, II
III
IV
6MWD (m)
>440
165-440
<165
NT-proBNP (ng/L)
<300
300-1400
>1400
6MWD = 6-minute walk distance; NT-proBNP = N-terminal pro B-type natriuretic peptide; WHO FC = World Health 
Organization Functional Class.
Based on the thresholds defined in Table 8 for each of the variables, a participant's risk at a given 
assessment timepoint is graded as 1to 3 (1: low risk, 2: intermediate risk and 3: high risk) and the 
sum of the grades is divided by the number of available variables and rounded to the next integer 
to define the non-invasive risk group (Hoeper 2017).
8.2.5 WHO Functional Class
WHO FC will be assessed at all visits (see Appendix 9) When applicable, WHO FC must be 
performed before the 6MWT.
8.2.6 Accelerometry
The daily life physical activity of the participant is assessed using an accelerometer. The 
accelerometer is given to the participant at Screening and is to be worn daily on the wrist of the 

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non-dominant hand (ambidextrous participants may wear it on either wrist) during waking hours 
until Week 28. The minimum wear time duration during Screening is 14 days. 
Sites are able to access the participants’ wear time compliance data through a web portal. Should 
corrective actions be necessary, the participant may be contacted by the site staff (eg, by telephone 
call, text message). 
The actigraphy device does not display collected data, ie, the participants do not have access to 
their activity measurements, as this could influence their behavior. 
The vendor will derive activity counts and will provide daytime activity and time (minutes) spent 
in sedentary, light, moderate and vigorous physical activity based on these activity counts. These 
data are transferred to Actelion.
Participants must return the actigraphy device to the site at Week 28/Visit 13. The devices will be 
returned to the vendor. Upon request, participants will be provided with a report summarizing their
individual activity levels after database closure.
8.2.7 Patient Reported Outcomes
The following PRO instruments will not be administered to illiterate participants and will not be 
administered to a participant when the instrument is not available in a language that can be easily 
understood and read by the participant. It is recommended that the PROs are completed prior to 
any clinical assessments. Preferably, participants should complete the PROs while waiting for their 
appointment before any interaction with health care providers to avoid any potential bias in their 
responses. 
All PROs will be completed by the participant on an electronic device either at home 
(PAH-SYMPACT®) or at the site on the day of the visits (all other PROs). Participants will be 
trained in the use of the electronic devices by site staff. 
Refer to the schedule of activities for the timing and frequency of completion of the PROs.
8.2.7.1 PAH SYMPACT®
The PAH-SYMPACT® (Appendix 10) is a PRO instrument that was developed by Actelion 
Pharmaceuticals Ltd (Chin 2018). This questionnaire has been developed and validated for use in 
PAH patients. It is now being tested in CTEPH patients. 
The PAH-SYMPACT® consists of two parts:

The symptom part is completed for the 7 consecutive days prior to the visit at site (ie, 
starting 7 days before the scheduled visit date).

The impact part is completed once, on the seventh day of the symptom’s diary data 
collection period, together with the symptom part (ie, in the evening).

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The PAH-SYMPACT® will be administered as indicated in the schedule of activities (see 
Section 1.2). The participant will be instructed to complete the PAH-SYMPACT® questionnaire
in the evening before bedtime.
The PAH-SYMPACT® will be administered via a hand-held mobile device that participants take 
home. Participants will be trained on the use of the mobile device by the site staff during Screening. 
Data will be transferred to an electronic database upon completion of the questionnaire. Under 
exceptional circumstances (eg, participant is not comfortable with using the mobile device despite 
adequate training, technical problems) and upon prior approval from the sponsor, the paper-based 
PAH-SYMPACT® questionnaire can be provided to participants. The answers provided by the 
participants will be entered into the Sponsor's database by site staff. 
To ensure compliance, the site will receive a notification approximately 10 days prior to the 
corresponding scheduled visits. The site will contact the participants (eg, via phone or text 
messages; as agreed with the participants) to remind them to charge the device and start completion 
of the PAH-SYMPACT®. The site will be notified in case the questionnaire hasn’t been completed 
as per protocol and will implement appropriate corrective actions (contacting/re-training 
participants). If the PAH-SYMPACT® was not completed (ie, less than 4 days of data available) 
prior to a visit, the participant will be instructed to complete the PAH-SYMPACT® for the 
7 consecutive days following a visit (except randomization and Week 28).
The data from the mobile device will be collected by the vendor, who will send the results to 
Actelion.
8.2.7.2 EQ-5D-5L© Questionnaire
The EQ-5D-5L© is a standardized instrument for use as a measure of health outcomes 
(Janssen 2013). The EQ-5D-5L© (Appendix 11) will be administered as indicated in the schedule 
of activities (see Section 1.2). Each participant will enter his/her scores on an electronic device.
8.2.7.3 Work Productivity and Activity Impairment Questionnaire: General Health 
(WPAI©: GH) V2.0
The WPAI©:GH (Appendix 12) is a patient-reported quantitative assessment of the amount of 
absenteeism, presenteeism, and daily activity impairment attributable to general health. It has a 
recall period of 1 week (Reilly 1993).
8.2.7.4 SF-36® v2 Acute Questionnaire
The SF-36®v2 Acute Questionnaire (SF-36®v2 Health Survey© 1992, 2000, 2010, 2012 by 
Medical Outcomes Trust and Quality Metric Incorporated) is a 36-item short form survey used to 
assess the participant’s quality of life (Appendix 13).
In the SF-36®v2 Acute Questionnaire, participants are instructed to rate their health and capacity 
to perform activities of daily living in eight domains including physical functioning, physical role 
limitations, bodily pain, general health, vitality, social functioning, emotional role limitations, and 
mental health during the last week. Raw domain scores are determined and transformed to a 
0-100 scale as described in the SF-36®v2 manual. Individual domain scores are used to determine 

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the physical and mental component summary scores as described in the SF-36®v2 manual 
(Maruish 2011). 
8.2.7.5 Patient Health Questionnaire-8 (PHQ-8)
The Patient Health Questionnaire-8 (PHQ-8, Appendix 14) is a questionnaire containing 8 items 
to measure the presence and severity of depression a participant is experiencing (Kroenke 2001).
8.2.7.6 Patient Global Assessment of Severity
The PGA-S (Appendix 15) is a 6-point single item self-evaluation scale. Participants will be asked to 
rate the overall severity of their disease on the day of administration, with responses of none, very 
mild, mild, moderate, severe or very severe. 
8.2.8 Right Heart Catheterization 
The diagnostic RHC must be performed at least 12 weeks after full anticoagulation. For 
participants who underwent PEA or BPA, the time between the procedure and the RHC must be 
at least 12 weeks.
The diagnostic RHC is performed at Screening according to the site’s own standard procedures. If 
the RHC was performed in the 24-week period prior to Randomization, the RHC does not need to 
be repeated at Screening. 
Optional RHC sub-study:
Participants who consent to participate in the hemodynamic sub-study are required to have an RHC 
at Screening and at Week 28, following the RHC guidelines provided in Appendix 16. No 
minimum or maximum number of participants is pre-specified due to the optional nature of the 
sub-studya. If an RHC was performed in the 60-day period prior to Randomization, and the criteria
for historical RHCs defined in Appendix 16 are met, the RHC does not need to be repeated at 
Screening. PH-specific therapy must be stable for at least 90 days prior to the baseline RHC. 
It is recommended to keep the dose of diuretics stable for 7 consecutive days prior to the Screening-
and Week 28 RHC.
Hemodynamic parameters measured and collected in the eCRF include HR, PAWP (or LVEDP), 
mRAP, systolic / diastolic pulmonary artery pressures (sPAP / dPAP), systolic/diastolic systemic 
arterial pressure (s-, d-SAP), SvO2 and CO.
Calculated hemodynamic parameters:

Pulmonary vascular resistance (dyn∙sec/cm5) 
80
X
CO
PAWP
mPAP
PVR



Total pulmonary vascular resistance (dyn∙sec/cm5)
80
X
CO
mPAP
TPR 
                                                
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
SVR (dyn∙sec/cm5) = [(mSAP -mRAP)/CO] X80

mSAP (mmHg) = (2 × dSAP + sSAP)/3

CI (liters/min/m2)
BSA
CO
CI 

Diastolic pulmonary vascular pressure gradient (mmHg) = diastolic PAP – PAWP 

Transpulmonary gradient (mmHg) (TPG): mPAP-PAWP

CO: refer to Appendix 16

Body surface area (m2) = 0.007184*(weight0.425)*(height0.725) with weight expressed in kg 
and height in cm.
8.3
Safety Assessments 
Safety and tolerability will be evaluated throughout this study from signing of the ICF onwards 
until the EOS visit (see Section 4.4) or date of last contact (see Section 7.3).
The standard safety assessments to evaluate the safety and tolerability of macitentan in this study 
include reporting and follow-up of (S)AEs, pregnancies, vital signs, physical examination, ECG, 
and safety laboratory tests.
Details regarding the IDMC and the ILSDRB are provided in Section 9.5 and Section 8.4.5, 
respectively.
Adverse events will be reported and followed by the investigator as specified in Section 8.4, 
Adverse Events and Serious Adverse Events and Appendix 4.
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event 
section of the eCRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be 
followed by the investigator until resolution or until a clinically stable condition is reached or until 
the participant has been deemed lost to follow-up (see Section 7.3).
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the schedule of activities (see Section 1.2).
8.3.1 Physical Examination
Physical examination at Screening, EODBT and EOLT includes the examination of general 
appearance, heart (including signs of right ventricular failure), lungs, abdomen, skin, 
extremities/peripheral vascular assessment, eyes, ears, nose, throat, neck (including thyroid),
lymph nodes. At interim visits, a more focused/shorter physical exam will include the examination 
of general appearance, heart (including signs of right ventricular failure), lungs, abdomen and 
extremities. If indicated, based on medical history and/or symptoms, additional exams may be 
performed as per investigator’s discretion.

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Height will be measured without shoes at Screening.
Body weight will be measured at all visits in indoor clothing and without shoes, using the same 
scale. It is recommended to measure body weight at approximately same time (with respect to last 
meal) at all visits.
Participants will be instructed to monitor their body weight at home at least once per week from 
Randomization up to Week 12, and to contact the study site if they notice a weight increase of 
≥5 kg / 11 lbs after the start of treatment. It is recommended that the participants always weigh 
themselves under similar conditions, eg, every morning before breakfast. The participants will 
receive a weight card on which body weight measurements can be recorded manually and must be 
instructed to bring the card along at each visit. 
An unscheduled visit may be considered in case of significant weight increase or clinically relevant 
signs and symptoms of edema and/or fluid retention.
8.3.2 Vital Signs
SBP and DBP and radial pulse measurements will be assessed in triplicate, in a supine or sitting 
position, at all visits. It is recommended that the participant is allowed to rest for at least 5 minutes 
prior to the first reading, and to perform the triplicate measurements at least 2 minutes apart. It is 
also recommended that measurements are performed on the same arm and in the same position 
(sitting or supine), using the same device by the same operator throughout the study for an 
individual participant.
8.3.3 Pulmonary Function Tests
Post-bronchodilator pulmonary function tests (PFTs; FEV1 and FVC) will be performed at 
Screening for participants with a known or suspected history of significant lung disease. Historical 
PFT data obtained within 12 months prior to Screening are accepted, provided there is evidence in 
the source documentation that the participant’s pulmonary status has been stable/unchanged during 
this time and the results are considered to be reliable by the investigator. Predicted normal values 
for FEV1 and FVC will be used to determine eligibility. 
8.3.4 Electrocardiograms
A single standard 12-lead ECG will be performed at timepoints indicated in the schedule of 
activities (see Section 1.2). ECG traces will be sent to a central reader for interpretation. Results 
will be communicated back to the site and sent electronically to the sponsor.
It is recommended to perform the ECGs in a quiet setting without distractions (eg, television, cell 
phones), to allow the participant to rest in a supine position for at least 5 minutes before ECG 
collection. As much as possible, participants should refrain from talking or moving their arms and
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Clinically relevant ECG findings that are known at the time of signing of informed consent must 
be recorded on the Medical History page of the eCRF. Any clinically relevant ECG abnormalities 
detected after signing of informed consent must be reported as an AE or SAE, as appropriate.
8.3.5 Clinical Safety Laboratory Assessments
Details about the collection, sampling, storage, shipment procedures and reporting of results and 
abnormal findings can be found in the central laboratory manual. The actual dates of sample 
collection must be recorded in the eCRF and laboratory requisition form. 
Blood samples for serum chemistry and hematology will be collected as noted in Appendix 2 at 
timepoints indicated in the schedule of activities (see Section 1.2). The investigator must review 
the laboratory results, document this review, and record any clinically relevant changes occurring 
during the study in the adverse event section of the eCRF. The laboratory reports must be filed 
with the source documents.
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. 
For monthly (3-monthly after 52 weeks exposure in the DB or OL periods, unless continued 
monthly monitoring is mandated based on local regulatory requirements) AST/ALT monitoring in 
between visits, a local laboratory can be used. If the local laboratory results show an increase in 
AST/ALT ≥3ULN, the participant must return to the site and the AST/ALT re-test must be 
performed centrally. Only abnormal local laboratory results must be recorded in the eCRF.
Requirement for Japan: Monthly AST/ALT monitoring is required. Whenever participants have 
monthly visit for liver function tests, the following assessments should be conducted and reported 
in source notes: physical examination, body weight, blood pressure/pulse rate, and hematology 
(hemoglobin, hematocrit, and RBC count). These assessments must be recorded in the eCRF only 
if they are related to AEs.
Exceptional circumstances that will require recording of local laboratory results of the parameters 
listed in Appendix 2 (with corresponding normal ranges) include hospitalization of the participant
due to a medical emergency and missing central laboratory results from a scheduled or 
unscheduled visit.
If two or more consecutive central laboratory samples are 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.
Clinically relevant laboratory findings that are known at the time of signing of informed consent 
must be recorded on the Medical History page of the eCRF. Any clinically relevant laboratory 
abnormalities detected after signing of informed consent must be reported as an AE or SAE, as 
appropriate.

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Pregnancy tests:
For women of childbearing potential, a serum pregnancy tests will be performed at the frequency 
defined in the schedule of activities. At randomization and if the interval between site visits 
exceeds 1 month, a urine pregnancy test must be performed at home on a monthly basis. The
investigator/delegate will follow-up on the results of the urine pregnancy test during the monthly 
telephone call and record the result of the test in the eCRF. If pregnancy is suspected during the 
study, a serum pregnancy test must be performed immediately, and the study intervention must be 
discontinued until pregnancy is ruled out.
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the participation in the study.
8.4
Adverse Events and Serious Adverse Events
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of participants, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally acceptable representative) for the duration of the study.
For further details on adverse events and serious adverse events (Definitions and Classifications; 
Attribution Definitions; Severity Criteria; Special Reporting Situations; Procedures) as well as 
product quality complaints, refer to Appendix 4.
8.4.1 Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be reported 
from the time a signed and dated ICF is obtained until the EOS visit (see Section 4.4) or date of 
last contact (see Section 7.3). Serious adverse events, including those spontaneously reported to 
the investigator until the EOS visit (see Section 4.4) or date of last contact (see Section 7.3) must 
be reported using the Serious Adverse Event Form. The sponsor will evaluate any safety 
information that is spontaneously reported by an investigator beyond the time frame specified in 
the protocol.
Serious Adverse Events
All serious adverse events, including deaths, occurring during the study must be reported to the 
appropriate sponsor contact person by study-site personnel immediately, without undue delay, and 
under no circumstances later than 24 hours following knowledge of the event.

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Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form (contact details are provided on the SAE form), which must be completed 
and signed by a physician from the study site and transmitted to the sponsor within 24 hours. The 
initial and follow-up reports of a serious adverse event should be made by facsimile (fax) or sent 
via e-mail.
New SAEs occurring after the EOS or last contact must be reported to Global Medical Safety 
within 24 hours of the investigator’s knowledge of the event, only if considered by the investigator 
to be causally related to previous exposure to the study intervention.
8.4.2 Follow-up of Adverse Events and Serious Adverse Events
Adverse events, including pregnancy, will be followed by the investigator as specified in 
Appendix 4.
8.4.3 Regulatory Reporting Requirements for Serious Adverse Events
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The 
investigator (or sponsor where required) must report SUSARs to the appropriate Independent 
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless 
otherwise required and documented by the IEC/IRB. A SUSAR will be reported to regulatory 
authorities unblinded. Participating investigators and IEC/IRB will receive a blinded SUSAR 
summary, unless otherwise specified.
8.4.4 Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be 
reported to the sponsor by the study-site personnel within 24 hours of their knowledge of the event 
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, 
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are 
considered serious adverse events and must be reported using the Serious Adverse Event Form. 
For more information on the action that should be taken towards study intervention in case a 
participant becomes pregnant during the study, please refer to Section 7.1.1.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required. 
Pregnancies must be reported as an AE in the eCRF and any AE associated with the pregnancy 
occurring until the EOS visit (see Section 4.4) or date of last contact (see Section 7.3) must be 
reported as a separate AE in the eCRF.
Any SAE occurring during the pregnancy must be reported as an SAE as described in Section 8.4.1.
8.4.5 Adverse Events of Special Interest
Adverse events of special interest include:

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
Hypotension: symptomatic hypotension or potentially clinically meaningful decrease in blood 
pressure, not explained otherwise by any potential confounding factor 

Edema/fluid retention: clinically relevant signs and symptoms of edema and/or fluid 
retention (see Section 8.3.1) 

Hemoglobin decrease/anemia: events of hemoglobin decrease from baseline of >20 g/L
should be reported in the hemoglobin level abnormalities eCRF page for identification of 
confounding factors.

Liver events: liver aminotransferase abnormalities (ie, ALT and/or AST) ≥3 × ULN) should 
be reported in the liver abnormalities eCRF page for identification of confounding factors. All
events of ALT (or AST) ≥3 × upper limit of normal (ULN) and total bilirubin ≥2 × ULN
(>35% direct bilirubin), which may indicate severe liver injury (possible Hy’s Law), must be
reported as a serious adverse event.
Refer to Section 7.1 for the management of liver aminotransferases and/or hemoglobin 
abnormalities.
An ILSDRB, an external expert committee of hepatologists, has been appointed to monitor all 
sponsor’s studies with macitentan, and to provide ongoing assessment and advice regarding 
hepatic AEs of special interest that require further evaluation during the study.
8.5
Treatment of Overdose
For this study, any dose of macitentan greater than 75 mg within a 24-hour time period will be 
considered an overdose. In the event of an overdose, standard supportive measures must be taken, 
as required, and the investigator or treating physician should:

Contact the Medical Monitor immediately.

Evaluate the participant to determine, in consultation with the Medical Monitor, whether study 
intervention should be interrupted.

Closely monitor the participant for AE/SAE and laboratory abnormalities as clinically 
indicated

Obtain a plasma sample for PK analysis within 3 days from the date of the overdose of study 
intervention if requested by the Medical Monitor (determined on a case-by-case basis).

Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
8.6
Pharmacokinetics
Plasma samples will be used to evaluate the PK of macitentan. Plasma collected for PK may 
additionally be used to evaluate safety or efficacy aspects that address concerns arising during or 
after the study period. Genetic analyses will not be performed on these plasma samples. Participant 
confidentiality will be maintained.

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All participants will undergo sparse PK sampling in the study; sparse sampling consists of a 
pre-dose and a 2-10 hours post-dose PK sample.
8.6.1 Evaluations
Venous blood samples will be collected for measurement of plasma concentrations of macitentan
and ACT-132577 at timepoints specified in the schedule of activities, see Section 1.2. Samples for 
sparse sampling are to be collected pre-dose and 2-10 hours post-dose.
Information about the collection, handling, and shipment of biological samples can be found in the 
Laboratory Manual.
8.6.2 Analytical Procedures 
Pharmacokinetics
Plasma samples will be analyzed to determine concentrations of macitentan and ACT-132577 
using a validated, specific, and sensitive Liquid Chromatography-Mass Spectrometry/Mass 
Spectrometry (LC-MS/MS) method by or under the supervision of the sponsor.
8.6.3 Pharmacokinetic Parameters and Evaluations
Parameters
Based on the individual plasma concentration-time data, using the actual sampling times (see the 
schedule of activities, Section 1.2), the observed analyte concentration just prior to the beginning 
or at the end of a dosing interval (Ctrough) will be derived for macitentan and ACT-132577.
Based on the individual plasma concentration-time data, using the actual dose taken and the actual 
sampling times, PK parameters and exposure information of macitentan and ACT-132577 will be 
derived using population PK modeling. Baseline covariates (eg, body weight, age, sex, Creatinine 
Clearance, race) may be included in the model, if relevant.
Pharmacokinetic/Pharmacodynamic Evaluations
Relationships between plasma concentrations or metrics of systemic exposure and markers of 
pharmacological activities (ET-1 concentrations), efficacy or treatment-emergent AEs could also 
be explored as data allow using population approaches (eg, non-linear mixed-effects approaches).
8.7
Pharmacodynamics
Sparse venous blood samples will be collected from all participants for measurement of ET-1 
at timepoints specified in the schedule of activities (see Section 1.2). Sparse sampling consists of 
a pre-dose and a 2-10 hours post-dose ET-1 sample.
8.8
Biomarkers
Biomarker analysis is optional for each participant. A biomarker-specific ICF should be signed 
prior to collection of any samples for biomarker analysis. 

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Blood samples for the analysis of pharmacodynamic and disease-related biomarkers can be
collected at timepoints indicated in the Schedule of Activities (see Section 1.2) and archived for 
future analysis from all participants. No human DNA analyses will be performed on these samples.
Refer to the laboratory manual for detailed instructions for sample collection, processing and 
shipment of archive samples for exploratory research. 
The aim of this analysis is to investigate the effect of macitentan on biomarkers involved in the 
pathophysiology of CTEPH. The biomarkers included in the analysis will be specified in a 
biomarker plan. 
Refer to Appendix 3 for more information on the long-term retention of samples collected for 
biomarker analysis.
8.9
Medical Resource Utilization 
Medical resource utilization data, associated with medical encounters, will be collected in the 
eCRF by the investigator and study site personnel for all participants throughout the study. 
Protocol-mandated procedures, tests, and encounters and unscheduled visits are excluded. The data 
collected may be used to conduct exploratory economic analyses and will include the below data, 
collected from baseline up to EOS:

Number of hospitalizations for all-cause and PH-related events.

Number of hospital days (including duration by wards; eg, intensive care unit) for all-cause 
and for PH-related hospitalization.

Number of ER visits and reason.

Number of medical visits by specialty.
9
STATISTICAL CONSIDERATIONS
Statistical analysis will be performed by the sponsor or delegated to a Contract Research 
Organization under the responsibility of the sponsor. Unblinded analyses for IDMC will be 
performed by an independent statistician at the ISSG to prevent unblinding the sponsor (Refer to 
Sections 9.4.5 and 9.5). A general description of the statistical methods to be used to analyze the 
efficacy and safety data is outlined below. Specific details will be provided in the Statistical 
Analysis Plans (SAP) focusing on analyses performed during a specific period (ie, IA SAP, CSR 
SAP part 1: DB period, CSR SAP part 2: OL period) or on individual sub-studies.
Data collected during the DB period will be summarized by intervention group and, where 
appropriate and applicable, compared between intervention groups with hypothesis testing. Data 
collected during both DB and OL extension period will be summarized overall and by intervention 
group assigned at the start of the DB period.
Individual listings for participant demographics, baseline characteristics and endpoint-related data 
will be provided as applicable and will be detailed in the SAP.

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9.1
Statistical Hypotheses
9.1.1 Primary Hypothesis
The primary efficacy endpoint is the change in 6MWD from baseline to Week 28. The null and 
alternative hypotheses are formulated in terms of the difference between intervention groups at 
Week 28, as estimated from an MMRM approach utilizing all post-baseline values (Weeks 4, 8, 
12, 16, 20, 24, and 28) of 6MWD changes from baseline. An MMRM model adjusted for covariates
has comparable power to an ANCOVA model and intrinsically handles missing data that are not 
study intervention-related.
If MACI,28 and PBO,28 denote the mean changes from baseline in 6MWD at Week 28 for the 
participants treated with macitentan and placebo, respectively, then the following hypotheses can 
be considered:
H0: = MACI,28 – PBO,28 0 
H1: = MACI,28 – PBO,28 > 0
The null hypothesis will be tested at a study-wise 1-sided significance level of 0.025.
The MMRM used for the primary analysis is specified in Section 9.4.1.
9.1.2 Secondary Hypotheses
The secondary endpoints will be analyzed at alpha-level governed by a predefined hierarchical 
testing procedure in order to maintain an overall family-wise one-sided 2.5% alpha level (Table 9).
Table 9: 
Secondary endpoints and associated hypotheses
Order 
of 
Secondary 
Endpoints
Hypotheses
1.
Time to first clinical 
worsening (CEC
confirmed) up to 
EODBT
The null hypothesis (H01) is that there is no difference between the macitentan 75 
mg and placebo survival distributions i.e., S(t) or that the difference favors 
placebo [H01: SMACI(t) ≤ SPBO(t), t≥0]. The alternative hypothesis (H11) is that 
there is a difference between study intervention groups in favor of macitentan 75 
mg [H11: SMACI(t) > SPBO(t), t≥0].
2.
Improvement 
(decrease) in WHO 
FC from baseline to 
Week 28 (yes/no)
The null hypothesis (H02) is that the proportion of participants who improve is 
the same for macitentan 75 mg and placebo or is higher for placebo [H02: PMACI,28
≤ PPBO,28]. The alternative hypothesis (H12) is that the proportion of participants
who improve is higher for macitentan 75 mg [H12: PMACI,28 > PPBO,28].
3.
Change from baseline 
to Week 28 in 
PAH-SYMPACT® 
symptom domains 
scores:
1.
Cardiopulmonary
2.
Cardiovascular
Separate tests will be conducted for each of the symptom domains according to 
the specified hierarchical order i.e., 1) Cardiopulmonary and 2) Cardiovascular.
The null hypotheses (H03 & H04) are that there is no difference between 
macitentan 75 mg and placebo distributions of the change from baseline to last 
value while on treatment up to Week 28 or that the difference is in favor of 
placebo [H03/H04: δ = mMACI,28 – mPBO,28 ≤0]. The alternative hypotheses (H13 & 
H14) are that there is a difference between intervention groups in favor of 
macitentan 75 mg [H13/ H14: δ = mMACI,28 – mPBO,28 > 0]. 

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4.
Change from baseline 
to Week 28 in EQ-
5D-5L© utility score
The null hypothesis (H05) is that there is no difference between macitentan 75 mg 
and placebo distributions of the change from baseline to last value while on 
treatment up to Week 28 or that the difference is in favor of placebo [H05: δ = 
mMACI,28 – mPBO,28 ≤0]. The alternative hypothesis (H15) is that there is a difference 
between intervention groups in favor of macitentan 75 mg [H15: δ = mMACI,28 –
mPBO,28 > 0].
5.
Change from baseline 
to Week 28 in 
accelerometer-
assessed proportion 
of time spent in 
moderate to vigorous 
physical activity 
The null hypothesis (H06) is that there is no difference between macitentan 75 mg 
and placebo in the proportion of time spent in moderate or vigorous physical 
activity or that the difference is in favor of placebo [H06: δ = mMACI,28 – mPBO,28 
≤0]. The alternative hypothesis (H16) is that there is a difference between 
intervention groups in favor of macitentan 75 mg [H16: δ = mMACI,28 – mPBO,28 > 
0].
CEC = Clinical Event Committee ; EODBT = end of double-blind treatment; EQ-5D-5L = Euro Quality of life-5-
Dimension-5-Level; PAH-SYMPACT® = Pulmonary Arterial hypertension Symptoms and Impact, WHO-FC = 
World health Organization Functional Class.
9.1.3 Overall Testing Strategy
This study implements a two-stage, group sequential adaptive design with one IA conducted for 
futility and sample size re-estimation (SSRE), with hypotheses tested at a study-wise 1-sided 
significance level of 0.025. 
Conditional on first applying technics for controlling for type I error inflation due to performing 
an unblinded IA (See Section 0) and then rejecting the null hypothesis for the primary efficacy 
endpoint (See Section 9.1.1), the secondary efficacy endpoints are formally evaluated according 
to the a priori hierarchical testing order described in Section 9.1.2.
No type I error rate will be spent for the option of an early efficacy stop for futility.
9.2
Sample Size Determination
Sample size determination relies on the following assumptions:

Targeted treatment effect (difference in changes from baseline to Week 28) = 33 m,

Common standard deviation of change from baseline to Week 28 = 70 m
Under these assumptions, a fixed sample size of 2 × 72 participants has a power of 80% using a 
one-sided type I error rate of 2.5% (based on ANOVA without interim analysis). 
This study implements an adaptive group sequential design with one interim analysis (see 
Section 9.4.5) to reassess the required sample size to maintain study power as well as to potentially 
prematurely stop the study for futility. A maximum of 230 participants is considered for this study 
based on practical considerations. 
Incorporating the interim analysis and above adaptations, the global power is 89% (based on 
ANOVA).
9.2.1 Estimated Power for Key Secondary Endpoint: Time to Clinical Worsening
The estimated number of confirmed CW events based on different scenarios used ie, the planned
number of participants (144 vs 230), accrual duration (36 m vs 57.5 m) and underlying assumption 
on true HR (0.4, 0.5 and 0.6) is given in Table 10. The estimated power for the key secondary 

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endpoint (TTCW) is presented by assuming success in primary endpoint in the hierarchical testing
(HT) strategy, as well as by ignoring the HT strategy. Furthermore, the median time to CW in 
placebo is assumed to be 20 months and the power for the primary endpoint is assumed to be 89%
(global power).
Table 10:
Time to clinical worsening
True HR
Number of
Participants
Accrual 
duration*
(months)
Power HT **
(Power ***)
Number 
of
Events
Critical value 
(HR)
0.60
144
36 
48.1%
(54.0% )
65
0.61
230 
57.5 
73.8%
(82.9%)
130
0.71
0.50
144
36
69.3%
(77.9%)
62
0.61
230
57.5
86.3%
(97.0%)
123
0.70
0.40
144
36 
83.4%
(93.7%)
58
0.60
230
57.5 
88.9%
(99.9%)
116
0.69
HR=Hazard Ratio, TTCW=Time to first Clinical Worsening (CEC confirmed events), HT =Hierarchical testing
* assuming a constant rate of randomization (4 participants /month). Total duration of DB period =Accrual duration 
+ 28 weeks for the last randomized participant.
** Estimated power for the secondary endpoint (TTCW) conditional on rejecting the null hypothesis of the primary 
endpoint and assuming independence between primary and the secondary endpoints (i.e., Power HT= Power*89%).
*** Estimated power for TTCW, without considering HT strategy.

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9.3
Populations for Analyses
For the purpose of analyses, the following populations are defined as described in Table 11.
Table 11:
Overview of the different populations for analyses
Population
Description
Screened Analysis Set (SCR)
All screened participants who are assigned a participant 
identification number.
Full Analysis Set (FAS)
All randomized participants assigned to a study intervention.
Participants will be analyzed according to the intervention they 
have been assigned to via IWRS.
Per-Protocol Analysis Set (PPS)
All participants included in the FAS who receive at least one dose 
of study intervention and who comply adequately with the 
protocol to be likely to exhibit the intervention effects.
Criteria for sufficient compliance include exposure to treatment, 
availability of measurements and absence of major protocol 
deviations that have an impact on the treatment effect. The 
comprehensive list of criteria will be detailed in the SAP.
Participants will be analyzed according to the intervention they 
are assigned to via IWRS.
Safety Analysis Set (SAS)
All participants who receive at least one dose of study 
intervention.
Participants will be analyzed according to the intervention they 
actually received
(which may be different to the study 
intervention arm they are assigned to via IWRS).
Safety Initiated Set (SIS)
All participants who initiate macitentan at any time during the DB 
or OL periods.
Pharmacokinetics/Pharmacodynamic (PK/PD)
Analysis Set
The PK/PD analysis set is defined as participants who received at 
least 1 dose of study intervention and have at least 1 valid blood 
sample drawn for PK and/or ET-1 analysis.
PRO Analysis Sets (per PRO)
All literate participants included in the FAS for whom a suitable 
translation of each specific questionnaire exists. Where different 
from the FAS each PRO set will be defined separately.
DB = double-blind; IWRS = Interactive web response system; OL = open-label; PRO = Patient- reported outcome
The specific usage of all analysis sets is described in Table 12 and is applicable to all analysis 
timepoints:

Interim analysis: when 72 participants have completed Week 28 or prematurely 
discontinued the study,

Final analysis of DB period: when all participants have completed Week 28 or 
prematurely discontinued the study,

Interim analysis of OL extension period: Timing is determined by the data cutoff date 
of the final analysis (DB period).

Final analysis of the entire study: when all participants have completed the OL 
extension period.

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Table 12:
Analysis Sets and Their Usage at Each Analysis Timepoint
Analysis
Analysis Set
SCR
FAS
PPS
SAS
SIS
PK/PD
Participant disposition
X
X
X
Description of study 
population
X
Primary and secondary ** 
efficacy endpoints
X
X
PK/PD endpoints
X
Exploratory efficacy 
endpoints**
X
Safety endpoints
X
X*
* For Study Closure analysis at the end of OL extension period only. ** If appropriate PRO related endpoints may use PRO 
Analysis Set
FAS = Full Analysis Set; OL = open-label; PPS = Per-protocol Analysis Set; SAS = Safety Analysis Set; SIS = Safety-initiated 
Set, PK/PD = Pharmacokinetics/Pharmacodynamic
9.4
Statistical Analyses
The statistical analysis plan (SAP-Part 1) will be based on DB treatment period. It will be finalized 
prior to un-blinding and  will include a more technical and detailed description of the statistical 
analyses described in this section. SAP-Part 2 will focus on both combined DB and OL extension 
periods. This section is a summary of the planned statistical analyses of the most important 
endpoints including primary and key secondary endpoints.
Unblinded IA and controlling for type I error inflation:
As the IA is planned to be performed in an unblinded manner, a statistical adjustment using inverse 
normal combination test will be applied to control for type I error inflation as indicated below. 
For the primary endpoint analysis, two separate test statistics will be calculated. The first test 
statistic will be computed on all participants who already provided data for the interim analysis
(Stage 1). Those who did not provide data for the interim analysis will contribute to the second 
test statistics irrespective of whether they were enrolled before or after the interim analysis (Stage 
2). Then the two test statistics obtained from both groups of participants will be combined using 
the inverse normal combination method (Lehmacher 1999) with equal weights. This separation of 
participants in two non-overlapping groups, and the combination of the respective test statistics 
using prespecified equal weights ensures protection of the type I error rate. 
For the key secondary endpoint time to clinical worsening (TTCW), as well as all subsequently 
tested secondary endpoints, the weighted combination test will be applied to control for the type I 
error rate inflation in context of the unblinded interim look. In addition, further protection for type 
I error will be envisaged by the application of an a priori hierarchical ordering. 
In addition to the hypothesis testing, median-unbiased point and interval estimates for the primary 
and secondary endpoints will be provided based on an ordering of the sample space (Tsiatis 1987).

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Further details on multiplicity testing and control for the type I error will be provided in the SAP-
Part 1.
9.4.1 Primary Efficacy Analysis
The primary efficacy endpoint is change in 6MWD from baseline to Week 28. 
An MMRM-based model is proposed for the primary efficacy analysis in order to use all observed 
values over time up to Week 28 during DB study intervention period and before rescue therapy 
administration. This MMRM, proposed as the primary approach, will take advantage of the 
longitudinal efficacy values while applying a ‘penalty’ to relevant intercurrent events (see attribute 
C for the estimand). No other penalty is imposed on discontinuations for other reasons and the 
values are assumed to be missing at random, as they are implicitly handled by the model. Several 
sensitivity and supplementary analyses will provide different perspectives and will allow the 
assessment of the consistency of the results. 
Estimand
The estimand is described according to the following four attributes:
A. Population: Participants diagnosed with CTEPH, meeting the study eligibility criteria. 
B. Variable: 6MWD changes from baseline at Weeks 4, 8, 12, 16, 20, 24, and 28.
C. Intercurrent events:
The following intercurrent events are considered:

Death: A composite strategy will be used for deaths occurring up to 7 days after study 
intervention discontinuation without administration of rescue CTEPH therapy. All scheduled 
assessments following the date of death will be replaced by a ‘worst-case’ imputation, i.e., the 
sum of the participant's baseline value and the lowest observed value of 6MWD change from 
baseline across both treatment groups and over all assessments up to Week 28. All assessments 
prior to the death, as well as all imputed assessments thereafter, will be considered in the 
analysis

Premature discontinuation/Administration of rescue therapy: A composite strategy will 
be employed for premature discontinuation of study intervention that are possibly treatment 
related (eg, clinical worsening, lack of response, adverse events, informed consent withdrawal 
due to tolerability issues) and/or administration of rescue CTEPH therapy (ie, associated. PH 
specific therapy, PEA and/or BPA procedures). All 6MWD assessment performed after end of 
intervention (possibly treatment related) plus 7 days or after administration of  rescue therapy 
will be ignored in the analysis and for each visit occurring after the IE, the sum of the 
participant's baseline 6MWD value and the minimum of the following values: (1) the last 
observed value (observed 6MWD change from baseline) prior to intercurrent event at the 
participant level and (2) the 25th percentile of observed 6MWD change from baseline values 
(both treatment groups pooled and over all assessments up to Week 28), will be considered
instead.

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D. Population-level summary:
Difference in mean 6MWD change from baseline at Week 28 between macitentan and placebo as 
estimated from the MMRM in the FAS (as randomized).
Statistical model
The null hypothesis will be tested by means of an MMRM. The model will include treatment (via 
an indicator variable for randomized intervention), time (via a categorical variable for visit), 
treatment-by-time interaction, one indicator variable for each stratification factor as fixed effects 
and baseline 6MWD as a covariable. An unstructured variance-covariance matrix will initially be 
specified. If convergence issues arise from the latter, a heterogeneous first-order autogressive 
(ARH(1)) covariance structure will be considered.
Handling of missing data
Handling of missing data arising from intercurrent events of death, premature discontinuation of 
study intervention, and administration of CTEPH rescue therapy are described under attribute C 
(above). For a given assessment, if the imputed 6MWD value results in an implausible value (ie, 
6MWD <0) then the imputation of change from baseline will be capped at minus the participant's
baseline value so that the imputed 6MWD value will result in a zero. .. 
Missing data arising from events that are clearly not treatment-related (eg, life events such as 
relocation, scheduling of transportation, inadequate reimbursement of associated expenses) are 
assumed to be missing at random (MAR), and as such, will require no further pre-processing 
(ie, imputation), since the MMRM approach will implicitly impute these values. 
Main analysis
The main analysis refers to the primary endpoint analysis performed when all participants have 
completed the 28-week DB period or prematurely discontinued the study beforehand. This analysis 
will be performed on the FAS. 
As described in Section 0, two separate MMRMs will be computed using 6MWD data accumulated 
up to Week 28 from the two groups of participants: Group 1: those who participated at the IA and 
Group 2: those who did not participate at the IA. The resulting test statistics from the models 
corresponding to the two groups, denoted Z1 and Z2, are then combined to obtain the main test 
statistic ZC by using inverse normal method (i.e., weighted Z-test) with pre specified equal weights 
as such  = √0.5 ×  + √0.5 × . Resulting ZC will be compared to the standard critical value 
corresponding to the type I error rate of 0.025 to determine the statistical significance of the main 
analysis. The median-unbiased estimate of the treatment effect and the corresponding confidence 
interval will also be calculated. Further details will be provided in the SAP (Part 1).
In addition, the treatment effect will be estimated at 4-weekly intervals from baseline to Week 28 
based on the same model along with their associated 95% CIs.

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Sensitivity analyses
The following sensitivity analyses will be performed to assess the robustness of the main analysis 
results (normality of residuals and MAR):

To assess the robustness of the main results regarding the underlying normality assumption 
of the density distribution, a rank-based analysis of covariance will be performed on 
6MWD change from baseline at Week 28, using the Wilcoxon rank-based pseudo-norm 
(Hettmansperger 2011).

To assess the robustness of the results of the main analysis to deviations from the MAR 
assumption, a tipping point analysis will be performed. For the macitentan intervention 
group, the missing data handled by the MMRM (see section on handling of missing data) 
are replaced iteratively with a range of decreasing values until the primary treatment 
comparison loses statistical significance. This allows quantification of the extent to which 
6MWD values observed in the macitentan intervention group would have to be decreased 
for the results of the study to become statistically non-significant. 

Reference based analyses approaches such as Jump to reference (J2R) and Copy reference 
(CR) will be used to further investigate worst plausible departures from MAR for handling 
missing data.

An analysis will be conducted to assess the robustness of the results of the main analysis  
in handling deaths occurring on/off rescue therapy in the same way so that if a participant 
dies while on rescue therapy the imputation rules for death will be applied.
Supplementary Analyses
In support of the primary efficacy analysis, supplementary analyses will be performed for the 
following supplementary estimands (see Table 13 for full definition of the estimands):

Supplementary Estimand 1 is identical to the primary estimand but utilizes a potentially 
more efficient analytical approach, ie, parametric longitudinal modelling considering
quadratic pattern over time.

Supplementary Estimand 2a aims to provide results using an ANCOVA analysis on 
6MWD change from baseline at Week 28, facilitating comparison of results of this study 
with those of the CTEPH study with macitentan 10mg (MERIT-1 study), as well as to 
other randomized studies with PH-approved drugs (eg, CHEST-1 for CTEPH).

Supplementary Estimand 2b aims to provide results using MMRM as in the primary 
estimand while implementing a treatment policy strategy with respect to treatment 
discontinuations and rescue medication with a reference-based multiple imputation   
method for missing data. Non-parametric (Gould-type) approach will also be 
considered using time-to death for participants who die being ranked below all 
surviving participants.

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
Supplementary Estimand 3 aims to provide an inferentially valid per protocol analysis 
to allow assessment of the treatment effect in the stratum of participants who complete 
the full 28-week treatment regimen without additional rescue CTEPH therapy.
Table 13:
Supplementary Estimands of the Primary Endpoint
Component
Supplementary Estimand 1
Supplementary 
Estimand 2a
Supplementary 
Estimand 2b
Supplementary Estimand 
3
Population
Participants diagnosed with 
CTEPH meeting the study 
eligibility criteria as 
randomized
Participants 
diagnosed with 
CTEPH meeting 
the study eligibility 
criteria as 
randomized
Participants diagnosed 
with CTEPH meeting 
the study eligibility 
criteria as randomized
Participants diagnosed with 
CTEPH meeting the study 
eligibility criteria who 
would not require rescue 
CTEPH therapy and who 
are able to complete 28 
weeks of treatment 
Variable
6MWD changes from 
baseline at Weeks 4, 8, 12, 
16, 20, 24 and 28
6MWD changes 
from baseline at 
Week 28
6MWD changes from 
baseline at Weeks 4, 8, 
12, 16, 20, 24 and 28
6MWD changes from 
baseline at Week 28
Intercurrent 
events
Deaths occurring 
up to 7 days after 
study intervention 
discontinuation 
without 
administration of a 
rescue CTEPH 
therapy
Composite strategy – ‘worst-
case’ imputation† for all 
post-death assessments (same 
as MMRM)
Composite strategy 
– ‘0’ imputation for 
Week 28 
assessment only
Composite strategy –
‘0’ imputation up to 
Week 28 assessment
Treatment policy –
with rescue therapy 
Not Applicable
Premature 
discontinuation of 
study intervention 
possibly treatment 
related
Composite: The values after 
premature discontinuation of 
study intervention plus 7 
days will be imputed by the 
sum of the participant's 
baseline 6MWD value and
minimum between:
’ the last observed value
(change from baseline) prior 
to intercurrent event
- the 25th percentile of  
observed change from 
baseline value up to week 28 
over all assessments and both
treatment groups pooled
Last observation 
carried forward in 
case of missing 
data, values after 
EOT are included . 
Treatment policy –
values after treatment 
discontinuation 
included 
Incorporated in the 
population definition
Administration of 
rescue CTEPH 
therapy
The values after 
administration of rescue  
therapy  will be imputed by 
the sum of the participant's 
baseline 6MWD value and 
minimum between:
’ the last observed value
(change from baseline) prior 
to intercurrent event
- the 25th percentile of  
observed change from 
baseline value up to Week 28
over all assessments and both
treatment groups pooled
Treatment policy –
values after rescue 
included
Treatment policy –
values after rescue 
included
Incorporated in the 
population definition
Population-level 
Summary 
Measure 
Difference in 6MWD mean 
change from baseline to 
Week 28 between macitentan 
and placebo as estimated 
from a parametric 
longitudinal model
Difference in 
6MWD least-
square mean 
change from 
baseline to Week 
28 between 
Difference in 6MWD 
mean change from 
baseline to Week 28 
between macitentan 
and placebo as 
estimated from MMRM
Difference in 6MWD mean 
change from baseline to 
Week 28 between 
macitentan and placebo 

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Component
Supplementary Estimand 1
Supplementary 
Estimand 2a
Supplementary 
Estimand 2b
Supplementary Estimand 
3
macitentan and 
placebo as 
estimated from an 
ANCOVA model
Analyses
A 
parametric 
longitudinal 
mixed-effects model, with a 
(fixed-effects) mean structure 
that is quadratic over time, 
and with a random intercept 
and a random slope will be 
considered 
for 
6MWD 
changes from baseline at 4-
weekly intervals up to Week 
28. The model will include
time, 
time-by-intervention 
interaction 
term, 
time-by-
time-by-intervention 
quadratic interaction term, an 
indicator variable for each of 
the 
randomization 
stratification factors and the 
baseline 
6MWD 
value. 
Random intercept and slope at 
the level of the participant 
will be considered. 
An ANCOVA 
model, with 
intervention group, 
stratification 
factors and baseline 
6MWD value as 
covariates, will be 
considered for 
6MWD changes 
from baseline at 
Week 28.
(full detail in the 
SAP)
MMRM model as for 
primary estimand.
Non-parametric 
(Gould-type analysis)
Causal inference methods
(full detail in the SAP)
Handling of 
missing data under 
MAR: missing data 
arising from events 
that are clearly not 
treatment-related 
(eg, life events such 
as relocation, 
scheduling of 
transportation, 
inadequate 
reimbursement of 
associated 
expenses)
Handled by the model  
Treatment policy – as not IE, 
values 
after 
end 
of  
intervention plus 7 days are 
included
LOCF for missing 
values
Treatment policy –
values after end of 
intervention are 
included
Referenced-based 
multiple imputation 
method such as copy 
reference 
Treatment policy –
values after end of 
intervention plus 7 days
are included
LOCF
†Worst-case’ imputation: the sum of the participant's baseline value and the lowest observed va’ue of 6MWD change from baseline 
across both treatment groups and over all assessments.
6MWD ꞊ 6-minute walk distance; ANCOVA ꞊ Analysis of covariance; CTEPH ꞊ Chronic thromboembolic pulmonary 
hypertension; EOT = End-of-Treatment; LOCF ꞊Last observation carried forward; MAR ꞊ Missing at random; MMRM ꞊ Mixed 
Model Repeated Measures; SAP ꞊ Statistical Analysis Plan.
Subgroups Analyses
In order to assess the consistency of the treatment effect across different participant subgroups for 
the primary efficacy variable, subgroup analyses will be performed according to the following 
demographic and baseline disease characteristics at randomization:

Operability: Inoperable [including post-BPA procedure] vs persistent/recurrent after PEA 
surgery, 

Use of PH specific therapies at randomization: Riociguat vs other PH specific therapy vs none
No multiplicity adjustment will be introduced; the subgroup analysis is descriptive in nature.
Further subgroups will be provided in the SAP-Part 1.

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9.4.2 Secondary Efficacy Endpoint Analyses
To control for multiplicity across the primary and secondary efficacy endpoints, the secondary 
endpoints will be analyzed hierarchically using a fixed sequence testing (see order of objectives 
and endpoints), at the pre-defined overall 1-sided alpha = 0.025 level of significance.
Furthermore, combination tests will be applied to each of the secondary efficacy endpoints in order 
to account for type I error inflation due to unblinded SSRE (See Section 0). For each of the key 
secondary endpoint, corresponding analysis described under "Main Analysis" will be performed 
separately for the two-independent group of participants (i.e., those who participated at the IA and 
those who did not) and resulting p values and point and interval estimates will be combined to 
determine the statistical significance and treatment effect.
9.4.2.1 Time to first clinical worsening up to end of double-blind treatment
The first secondary efficacy endpoint is time to first CEC-confirmed clinical worsening up to 
EODBT (see definition in Section 3). 
Estimand
The secondary efficacy endpoint estimand follows a ‘while on treatment’ strategy. An event will 
be considered ‘while on treatment’ if it occurs up to 7 days after study intervention discontinuation. 
7 days corresponds to the time window in which an effect can still be attributed to macitentan, 
based on its half-life.  
The estimand is described according to the following attributes:
A. Population
Participants diagnosed with CTEPH meeting the study eligibility criteria.
B. Variable
Time (days) from randomization to first occurrence of CEC-confirmed clinical worsening up to 
EODBT. Only events occurring up to 7 days after study intervention discontinuation are 
considered.
Participants who do not experience any clinical worsening will have their time to clinical
worsening right-censored at earliest among the following times and prior to first dose of OL 
extension intervention:

Study intervention discontinuation (EODBT) + 7 days. 

EODBT +7 days for DB intervention completers.
C. Intercurrent events

Not applicable
D. Population-level summary
Median time to CW and Hazard ratio of macitentan versus placebo in the FAS (as randomized).

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Hypotheses:
The null hypothesis is that there is no difference between macitentan and placebo survival 
distributions or that the difference favors placebo. The alternative hypothesis is that there is a 
difference between intervention groups in favor of macitentan.
Main Analysis:
A log-rank test stratified by intervention group and randomization stratification factors will be 
performed in the FAS. The resulting 1-sided p-value (based on the combination test) will be 
compared to the nominal 1-sided type I error of 0.025.
The treatment effect will be estimated based on a proportional hazards Cox model adjusting for 
the same randomization stratification factors. Estimate of HR and its associated 95% CI will be 
displayed.
T. Time to first CEC confirmed CW event (n & % by intervention group, HR, 95% CI and p value) 
and its components i.e., a decomposition of the first CW event (n & % by intervention group) and
the first occurrence of each individual component of the CW event (n & % by intervention group, 
HR, 95% CI), will be presented side by side.
Stratified log rank test, Cox proportional hazards model and Kaplan Meier estimates will be used 
for the following exploratory analyses as appropriate. Details will be provided in SAP part 1.
Sensitivity analysis:
Time to first CEC confirmed CW event stratified by intervention group, randomization 
stratification factors and baseline noninvasive risk  group (i.e., low, intermediate, or high).
Supportive exploratory/sensitivity analyses:
1. Time to first CEC-confirmed CW event component  where each event component will be 
analyzed separately. Participants who do not have the relevant CEC-confirmed clinical 
worsening event component will have their time to clinical worsening right-censored at earliest 
among the following times:

First occurrence of any other CEC-confirmed clinical worsening event component

Study intervention discontinuation (EODBT)+ 7 days / prior to first dose of OL 
extension intervention.

EODBT +7 days for completers / prior to first dose of OL extension intervention.
2. Time to first "suspected clinical worsening" (SCW) with same definition as for the CEC 
confirmed CW endpoint but based on investigator judgment. 
3. Time to first occurrence of SCW event components based on investigator judgment where each 
event component will be analyzed separately. Participants who do not have the relevant SCW 
event component will have their time to SCW right-censored at earliest among the following 
times: 

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
First occurrence of any other SCW event component 

Study intervention discontinuation (EODBT)+ 7 days / prior to first dose of OL
extension intervention. 

EODBT +7 days for completers / prior to first dose of OL extension intervention.
4. Time to first occurrence of either CEC-confirmed PH-related deaths (occurring up to EODBT 
+7 days) or deaths occurring up to EODBT +30 days, if caused by an AE occurring up to 
EODBT +7 days) or unplanned PH-related hospitalization including hospitalizations for 
procedure due to clinical worsening (PEA/BPA) and heart/lung transplantation (up to EODBT 
+7 days).  
5. Further exploratory analysis will be performed on CW hard endpoints such as all cause death 
and all cause hospitalization occurring over the combined DB and OL periods. In case of 
heterogeneity in the treatment effect due to informative censoring caused by competing risk 
between components and the subsequent switch to OL macitentan 75 mg from DB placebo 
group, the SAP (Part 2) will describe methods such as rank preserving structural failure time 
models, marginal structural models and indirect comparisons to external control arms, to 
estimate the unbiased treatment effect.
9.4.2.2 Improvement in WHO FC from baseline to last value while on treatment up 
to Week 28 (yes/no)
Endpoint definition
Improvement (decrease) in WHO FC from baseline to Week 28 will be calculated for each 
participant.
For consistency with the primary 6MWD estimand:

For deaths occurring up to 7 days after study intervention discontinuation without 
administration of rescue CTEPH therapy, all scheduled assessments following the date of 
death will be imputed by a ‘worst-case’ imputation (WHO FC=IV). All assessments prior to 
the death, as well as all imputed assessments thereafter, will be considered in the analysis. 

Assessments that are after (possibly treatment related) discontinuation of study intervention + 
7 days and/or administration of rescue CTEPH therapy are excluded from the analysis. The 
sum of the participant's baseline WHO FC score and the 75th percentile (from observed WHO 
FC change from baseline across both treatment groups and over all assessments) will be 
imputed to Week 28 following these intercurrent events.
Missing values at Week 28 (for reasons other than described above) will be imputed by carrying 
forward the last assessment before discontinuation of study intervention + 7 days and/or 
administration of rescue CTEPH therapy. 
Hypotheses
The null hypothesis is that the proportion of participants who improve is the same for macitentan 
and placebo or is higher for placebo. The alternative hypothesis is that the proportion of 
participants who improve is higher for macitentan.

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Main Analysis
The data in the FAS will be analyzed by a Cochran-Mantel-Haenszel test adjusted by WHO FC at 
baseline, intervention group, and randomization stratification factors. The resulting p-value will 
be compared to the nominal 1-sided type I error of 0.025.
9.4.2.3 Change from baseline to last value while on treatment up to Week 28 in 
PAH-SYMPACT®
Endpoint definition 
The change from baseline to last value while on treatment up to Week 28 will be calculated for 
each participant and for each domain (cardiopulmonary symptoms and cardiovascular symptom). 
Separate tests will be conducted for each domain according to the above hierarchical order.
Hypothesis
The null hypothesis is there is no difference between macitentan and placebo distributions of the 
change from baseline to last value while on treatment up to Week 28 or that the difference is in 
favor of placebo. The alternative hypothesis is that there is a difference between intervention 
groups in favor of macitentan.
Main Analysis
The change from baseline to last value while on treatment up to Week 28 will be analyzed by 
means of non-parametric Mann-Whitney U test in the FAS. A point estimate for the placebo 
corrected location shift will be displayed along with associated 95% CI and p-value using the 
Hodges-Lehmann method. The resulting p-value from the U statistic will be compared to the 
nominal 1-sided type I error of 0.025.
For consistency with the primary 6MWD estimand:

For deaths occurring up to 7 days after study intervention discontinuation and without 
administration of a rescue CTEPH therapy, all scheduled assessments following the date of 
death will be imputed by a ‘worst-case’ imputation, ie, the sum of participant's baseline value 
and the highest observed value of change from baseline across both treatment groups and over 
all assessments. All assessments prior to the death, as well as all imputed assessments 
thereafter, will be considered in the analysis.

Assessments that are after possible treatment related discontinuation of study intervention + 
7 days and/or administration of rescue CTEPH therapy are excluded from the analysis. The 
sum of the participant's baseline value and the maximum of the following values: (1) the last
observed value (change from baseline) prior to intercurrent event at the participant level and 
(2) the 75th percentile of observed change from baseline values (both treatment groups pooled 
and over all assessments) will be imputed to Week 28 following these intercurrent events.
For Week 28 assessments that are missing for other reasons, assessments will be imputed by 
LOCF.

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9.4.2.4 Change from baseline to last value while on treatment up to Week 28 in 
EQ-5D-5L© utility score
Endpoint definition
The change from baseline to last value while on treatment up to Week 28 will be calculated for 
each participant. Utilities will be calculated according to the crosswalk algorithm developed by 
the EuroQoL group (Van Hout 2012) in order to follow the NICE position paper (NICE 2018), 
ie, EQ-5D-5L© values will be mapped into the 3L values for analysis.
Hypotheses
The null hypothesis is there is no difference between macitentan and placebo distributions of the 
change from baseline to last value while on treatment up to Week 28 or that the difference is in 
favor of placebo. The alternative hypothesis is that there is a difference between intervention 
groups in favor of macitentan.
Main Analysis
The analysis will follow the same principles as for the PAH-SYMPACT® in the FAS.
9.4.2.5 Change from baseline to Week 28 in accelerometer-assessed proportion 
of time spent in moderate to vigorous physical activity 
Endpoint definition 
For each scheduled visit, the 14 days prior to the visit will be considered as the assessment period 
for physical activity. To be considered evaluable for a given time, actigraphy variables should have 
been measured for at least 7 complete days (consecutive or not) at a specific time period of 
assessment (baseline, and 4-weekly intervals up to Week 28). A complete day is defined as a record 
of at least 7 waking hours of data. During these periods, the time spent in different level of activity: 
sedentary/light/moderate/vigorous will be determined based on activity counts per minutes and 
expressed as proportion relative to the period duration. The categories moderate and vigorous will 
be combined for the analysis and will represent the proportion of time spent in moderate to 
vigorous physical activity.
At each visit, the proportion of time spent in moderate to vigorous activity will be estimated.
For consistency with the primary 6MWD estimand:

For deaths occurring up to 7 days after study intervention discontinuation without 
administration of rescue CTEPH therapy, all scheduled assessments following the date of 
death will be imputed by a ‘worst-case’ imputation (proportion of time spent equal to 0). All 
assessments prior to the death, as well as all imputed assessments thereafter, will be 
considered in the analysis. 

Assessments that are after (possibly treatment related) discontinuation of study intervention + 
7 days and/or administration of rescue CTEPH therapy are excluded from the analysis. The 
sum of the participant's baseline value and the minimum of the following values: (1) the last 
observed value (change form baseline) prior to intercurrent event at the participant level and 

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(2) the 25th percentile of observed change from baseline values (both treatment groups pooled 
and over all assessments) will be imputed to Week 28 following these intercurrent events.
Week 28 assessments that are missing for other reasons will be imputed by carrying forward the 
last observed value before discontinuation of study intervention + 7 days and/or administration of 
rescue CTEPH therapy (LOCF).
The change from baseline to last value while on treatment up to Week 28 will be calculated for 
each participant for the accelerometry-assessed proportion of time spent in moderate to vigorous 
physical activity. Each physical activity level will be determined based on activity counts per 
minutes.
Hypothesis
The null hypothesis is there is no difference between macitentan and placebo in the proportion of 
time spent in moderate to vigorous physical activity or that the difference is in favor of placebo. 
The alternative hypothesis is that there is a difference between intervention groups in favor of 
macitentan.
Main Analysis
The data in the FAS will be analyzed by an ANCOVA adjusting for baseline actigraphy value and 
randomization stratification factors. The resulting p-value will be compared to the nominal 1-sided 
type I error of 0.025.
The above approach assumes that the proposed actigraphy endpoint will be approximately 
normally distributed. The residuals from the ANCOVA will be tested for normality using the 
Shapiro-Wilk test. Should this be significant at the 5% level, a non-parametric approach will be 
used (stratified Wilcoxon test).
9.4.3 Safety Analyses
All safety analyses will be made on the Safety Population.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse events are 
AEs with onset during the intervention period or that are a consequence of a pre-existing condition 
that has worsened since baseline. All reported AEs will be included in the analysis. For each AE, 
the percentage of participants who experience at least 1 occurrence of the given event will be 
summarized by intervention group.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those 
participants who die, who discontinue study intervention due to an AE, or who experience a severe 
AE or an SAE.

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Summaries for the DB period will be by study intervention (macitentan or placebo) and will 
include all events up to the start of OL period, or up to 30 days after study intervention 
discontinuation, whichever occurs first.
The AEs of special interest will be defined in the SAP.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the SAP) will be used in the summary of laboratory data. Descriptive 
statistics will be calculated for each laboratory analyte at baseline and for observed values and 
changes from baseline at each scheduled timepoint by intervention group. Frequency tabulations 
of the abnormalities will be made.
Vital Signs
Descriptive statistics of pulse rate, SBP and DBP values and changes from baseline will be 
summarized at each scheduled timepoint by intervention group.
9.4.4 Other Analyses
Pharmacokinetic Analyses 
If feasible, population PK analysis of plasma concentration-time data of macitentan may be 
performed using nonlinear mixed-effects modeling. Data may be combined with other selected 
studies to support a relevant structural model. Available baseline participant characteristics 
(demographics, laboratory variables, genotypes, race, etc.) will be tested as potential covariates 
affecting PK parameters. Details will be given in a population PK analysis plan and the results of 
the population PK analysis will be presented in a separate report. 
Relationships between plasma concentrations or metrics of systemic exposure and markers of 
pharmacological activities, efficacy or treatment-emergent adverse events could also be explored 
as data allow using population approaches (eg, non-linear mixed effects approaches). For example, 
Pharmacokinetic-ET-1 relationships will be explored.
A snapshot date for PK samples to be analyzed will be defined, if required. Samples collected 
before this date will be analyzed for macitentan and its active metabolite ACT-132577 and 
included in the population PK analysis. Samples collected after the snapshot date will be analyzed 
at a later date and may be included in a population PK re-analysis when they become available 
after database lock.
Data will be listed for all participants with available plasma concentrations of macitentan and 
ACT-132577 per intervention group. Participants will be excluded from the PK analysis if their 
data do not allow for accurate assessment of the PK (eg, incomplete administration of the study 
intervention; missing information of dosing and sampling times; concentration data not sufficient 
for PK parameter calculation).

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All concentrations below the lowest quantifiable concentration or missing data will be labeled as 
such in the concentration database. All participants and samples excluded from the analysis will 
be clearly documented in the study report.
For each intervention group, descriptive statistics, including arithmetic mean, SD, coefficient of 
variation, median, minimum, and maximum will be calculated for all individual derived PK 
parameters including exposure information of macitentan and ACT-132577.
Exploratory Analyses
Analysis of the exploratory variables will be described in the SAP.
Descriptive /sensitivity analyses will be performed to evaluate the impact of COVID-19 pandemic
on the efficacy and safety endpoints. Details will be provided in the SAP -Part 1.
9.4.5 Interim Analysis
The proposed study design consists of a two-stage, group sequential, adaptive design. The 
“adaptive” aspect of this study focusses either on the early termination of the study for futility or 
performing an unblinded SSRE. One unblinded interim analysis is planned once a total of 72
sequentially randomized participants have completed Week 28 or prematurely discontinued the 
study.. This gives an information fraction of 
 = 72 144

= 0.50
At the time of the IA data cut-off, all available data including those from ongoing participants not 
having yet completed Week 28 but are having at least one 6MWD assessment on 75 mg 
maintenance dose will be considered to perform the SSRE. Based on the details provided in the 
IDMC charter, ISSG will develop an IA SAP before performing any unblinding for the futility 
analysis and SSRE.
At the interim analysis, the following decisions may be taken:

Prematurely stop the study for futility

Maintain the sample size ie, 144 participants 

Increase the sample size for the second stage of the study up to a maximum of 
230 participants.
An IDMC will be established as described in Section 9.5.
The IDMC will review the results of the interim analysis and periodic safety analyses performed 
by the ISSG and will provide corresponding recommendations to the sponsor in line with the 
IDMC charter. The sponsor will decide whether to take these recommendations into account.
The IDMC may recommend continuing the trial to its planned end, even if an interim stopping 
criterion is statistically met. This applies to futility stopping criterion.
9.5
Data Monitoring Committee
An Independent Data Monitoring Committee (IDMC) has overall responsibility for 
safeguarding the interests of participants by monitoring safety and efficacy data obtained during 

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the study and for reviewing the results of the interim analysis. The IDMC will make appropriate 
recommendations based on all the reported data and statistical analysis prepared by an independent 
statistician at the Independent Statistical Support Group (ISSG), thereby ensuring that the study is 
conducted in accordance with the highest scientific and ethical standards. All communication 
between the IDMC and the Sponsor will be directed through the Sponsor Committee, which 
includes senior medical and statistical members. Due to the adaptive nature of the trial, clear and 
protected communication flows will be established. Details on IDMC roles, responsibilities and 
operating procedures are provided in the IDMC Charter. The IDMC will be fully operational prior 
to enrollment of the first participant into the study. 

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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1 Appendix 1: Abbreviations
6MWD
6-minute walk distance
6MWT
6-minute walk test
AC
Adjudication committee
AE
Adverse event
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
ARH(1)
Heterogeneous first-order autogressive
AST
Serum aspartate aminotransferase
AUC
Area under the curve
BPA
Balloon pulmonary angioplasty
CEC
Clinical event committee
CI
Cardiac index
CL
Confidence limit
Cmax
Maximum plasma concentration
CO
Cardiac output
CRF
Case report form(s) (paper or electronic as appropriate for this study)
CTEPH
Chronic thromboembolic pulmonary hypertension
CTPA
Computed tomography pulmonary angiogram
CYP
Cytochrome 
DB
Double-blind
DBP
Diastolic blood pressure
DDI
Drug-drug interaction
DHT
Dihydrotestosterone 
dPAP
Diastolic pulmonary artery pressure
dSAP
Diastolic systemic arterial pressure
ECG
Electrocardiogram
eDC
Electronic data capture
EMA
European Medicines Agency
EODBT
End-of-DB treatment
EOLT
End of open-label treatment
EOS
End of study
EQ-5D-5L©
Euro Quality of life-5-Dimension-5-Level
ER
Emergency room
ERA
Endothelin receptor antagonist
ET
Endothelin receptor
FC
Functional class
FEV1/FVC
Forced expiratory volume in 1 second / forced vital capacity
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
HAESI
Serious hepatic adverse events of special interest
HR
Hazard ratio
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference for Harmonisation
IDMC
Independent Data Monitoring Committee
IE
Intercurrent events
IEC
Independent Ethics Committee
ILSDRB
International Liver Safety Data Review Board
IND
Investigational New Drug
IRB
Institutional Review Board
ISSG
Independent Statistical Support Group
IWRS
Interactive web response system
LC-MS/MS
Liquid Chromatography-Mass Spectrometry/Mass Spectrometry

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LH
Luteinizing hormone
LLN
Lower limits of normal
LOAEL
Lowest-observed-adverse-effect level
LVEDP
Left ventricular end diastolic pressure
MAR
Missing at random
MCT
Monocrotaline
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Model Repeated Measures
mPAP
Mean pulmonary arterial pressure
mPAWP
Mean pulmonary arterial wedge pressure
MRA
Magnetic resonance angiography
mRAP
Mean right atrial pressure
mSAP
Mean systemic arterial pressure
NT-proBNP
N-terminal prohormone of Brain natriuretic peptide or N-terminal pro B-type natriuretic 
peptide
Od
Once daily
OL
Open-label
PA
Pulmonary angiography
PAH
Pulmonary arterial hypertension
PAH-SYMPACT®
Pulmonary Arterial Hypertension - Symptoms and Impact
PAWP
Pulmonary artery–wedge pressure
PD
pharmacodynamic(s)
PDE-5
Phosphodiesterase type-5
PEA
Rescue pulmonary endarterectomy
PFT
Pulmonary function test
PGA-S
Patient Global Assessment of Severity
PH
Pulmonary hypertension
PHQ-8
Patient Heath Questionnaire
PK
Pharmacokinetic(s)
PMDA
Pharmaceuticals and Medical Devices Agency
PQC
Product Quality Complaint
PR
Pulse rate
PRO
Patient-reported outcome(s) (paper or electronic as appropriate for this study)
PTOP
Post-treatment observation period
PVOD
Pulmonary veno-occlusive disease
PVR
Pulmonary vascular resistance
RHC
Right heart catheterization
RV
Right ventricular
RVSP
Right ventricular systolic pressure
SAE
Serious adverse event
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SCW
Suspected clinical worsening
SF36
36-item Short Form survey
SoA
Schedule of Activities
sPAP
Systolic pulmonary artery pressure
sSAP
Systolic systemic arterial pressure
SSRE
Sample size re-estimation
SUSAR
Suspected unexpected serious adverse reaction
SvO2
Mixed venous oxygen saturation
t½
Half-life
TPR
Total pulmonary resistance
ULN
Upper limit of normal
V/Q
Ventilation / Perfusion
WHO
World Health Organization
WPAI
Work Productivity and Activity Impairment Questionnaire
WPAI©: GH
Work Productivity and Activity Impairment Questionnaire©: General Health

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Definitions of Terms
Electronic source 
system
Contains data traditionally maintained in a hospital or clinic record to document medical 
care or data recorded in a CRF as determined by the protocol. Data in this system may be 
considered source documentation.

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10.3 Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
REGULATORY AND ETHICAL CONSIDERATIONS
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human participants. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study participants are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by 
the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by the 
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or 
when the relevant competent authority has raised any grounds for non-acceptance, except when 
necessary to eliminate immediate hazards to the participants, in which case the amendment must 
be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the 
change(s) involve only logistic or administrative aspects of the study, the IEC/IRB (where 
required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor representative 
listed in the Contact Information page(s), which will be provided as a separate document. Except 
in emergency situations, this contact should be made before implementing any departure from the 
protocol. In all cases, contact with the sponsor must be made as soon as possible to discuss the 
situation and agree on an appropriate course of action. The data recorded in the CRF and source 
documents will reflect any departure from the protocol, and the source documents will describe 
this departure and the circumstances requiring it.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.

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Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention
to the study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, participant compensation programs. This approval must clearly identify the 
specific protocol by title and number and must be signed (or sealed, where appropriate per 
local regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their 
function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from 
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a member 
of the study-site personnel is a member of the IEC/IRB, documentation must be obtained to 
state that this person did not participate in the deliberations or in the vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first 
participant:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB 
with current and complete copies of the following documents (as required by local regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the participants)

IB (or equivalent information) and amendments/addenda

Sponsor-approved participant recruiting materials

Information on compensation for study-related injuries or payment to participants for 
participation in the study, if applicable

Investigator’s curriculum vitae or equivalent information (unless not required, as documented 
by the IEC/IRB)

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
Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for participants

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol, 
amendments (if any, excluding the ones that are purely administrative, with no consequences for 
participants, data or study conduct, unless required locally), the ICF, applicable recruiting 
materials, and participant compensation programs, and the sponsor has received a copy of this 
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
Approval for the collection of optional samples for research and for the corresponding ICF must 
be obtained from the IEC/IRB. Approval for the protocol can be obtained independent of this 
optional research component.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to participants

If applicable, new or revised participant recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to participants for 
participation in the study, if applicable

New edition(s) of the IB and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the study 
intervention

New information that may adversely affect the safety of the participants or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the participants

Report of deaths of participants under the investigator’s care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of the 
change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about 
the study completion.

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Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise help 
ensure access to the developed product if the need for the product persists, unless explicitly 
addressed as a specific ethical consideration in Section 4.2.1, Study-Specific Ethical Design 
Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
FINANCIAL DISCLOSURE
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) and contracts for details on financial 
disclosure.
INFORMED CONSENT PROCESS 
Each participant must give written consent according to local requirements after the nature of the 
study has been fully explained. The ICF(s) must be signed before performance of any study-related 
activity. The ICF(s) that is/are used must be approved by both the sponsor and by the reviewing 
IEC/IRB and be in a language that the participant can read and understand. The informed consent 
should be in accordance with principles that originated in the Declaration of Helsinki, current ICH 
and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential participants the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Participants will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time. They will be informed that choosing not to participate will not 
affect the care the participant will receive for the treatment of his or her disease. Participants will 
be told that alternative treatments are available if they refuse to take part and that such refusal will 
not prejudice future treatment. Finally, they will be told that the investigator will maintain a 
participant identification register for the purposes of long-term follow up if needed and that their 
records may be accessed by health authorities and authorized sponsor personnel without violating 
the confidentiality of the participant, to the extent permitted by the applicable law(s) or regulations. 
By signing the ICF the participant is authorizing such access which includes permission to obtain 
information about his or her survival status. It also denotes that the participant agrees to allow his 
or her study physician to recontact the participant for the purpose of obtaining consent for 
additional safety evaluations, and subsequent disease-related treatments, if needed.

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The participant will be given sufficient time to read the ICF and the opportunity to ask questions. 
After this explanation and before entry into the study, consent should be appropriately recorded 
by means of either the participant’s personally dated signature. After having obtained the consent, 
a copy of the ICF must be given to the participant.
A participant who is rescreened is not required to sign another ICF if the rescreening occurs within 
90 days from the previous ICF signature date.
If the participant is unable to read or write, an impartial witness should be present for the entire 
informed consent process (which includes reading and explaining all written information) and 
should personally date and sign the ICF after the oral consent of the participant is obtained.
DATA PROTECTION
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized disclosures 
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place. 
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity 
of participants confidential.
The informed consent obtained from the participant includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original medical 
records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and 
regulatory inspection. This consent also addresses the transfer of the data to other entities and to 
other countries.
The participant has the right to request through the investigator access to his or her personal data 
and the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory PK, pharmacodynamic and biomarker research is not conducted under standards 
appropriate for the return of data to participants. In addition, the sponsor cannot make decisions as 
to the significance of any findings resulting from exploratory research. Therefore, exploratory 
research data will not be returned to participants or investigators, unless required by law or local 
regulations. Privacy and confidentiality of data generated in the future on stored samples will be 
protected by the same standards applicable to all other clinical data.

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LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE RESEARCH 
Samples collected in this study may be stored for up to 15 years (or according to local regulations) 
for additional research. Samples will only be used to understand macitentan, to understand 
CTEPH, to understand differential intervention responders, and to develop tests/assays related to 
macitentan and CTEPH. The research may begin at any time during the study or the post-study 
storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Participants may withdraw their consent for their samples to be 
stored for research (refer to Section 7.2.1, Withdrawal from the Use of Research Samples).
COMMITTEES STRUCTURE
Data Monitoring Committee
Refer to Section 9.5
Adjudication Committee (AC)
An Adjudication Committee, which is composed of CTEPH experts, will assess operability of 
participants and confirm their eligibility for participation in the study. The committee will review 
predefined data for all participants during the screening period and assess whether the participants
are technically inoperable or have persistent/recurrent CTEPH. The composition and functioning 
of the AC is described in the AC charter. 
Clinical Event Committee (CEC)
A Clinical Event Committee (CEC) will review and adjudicate in a blinded fashion each clinical 
worsening event and the time of its first occurrence. In addition, primary reason for hospitalization 
and mode of death, will be adjudicated. A case narrative any other relevant supporting information 
(hospital discharge summaries, local laboratory or imaging data, etc.) must be provided to the 
CEC. Full details for this procedure, as well as the composition and operation of the CEC is 
described in the CEC charter.
Steering Committee (SC)
A Steering Committee is involved in the study design and will be consulted prior to and during the 
study for relevant medical issues and study publications.
Independent Liver Safety Data Review Board (ILSDRB)
An Independent Liver Safety Data Review Board (ILSDRB, an external expert committee of 
hepatologists) has been appointed to provide ongoing assessment and advice regarding hepatic 
AEs of special interest that require further evaluation during the study as per the ILSDRB charter.

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

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submitted for publication, within 18 months after the study end date, or the sponsor confirms there 
will be no multicenter study publication. Authorship of publications resulting from this study will 
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations 
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which 
state that the named authors must have made a significant contribution to the conception or design 
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the 
work or revised it critically for important intellectual content; and given final approval of the 
version to be published; and agreed to be accountable for all aspects of the work in ensuring that 
questions related to the accuracy or integrity of any part of the work are appropriately investigated 
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required 
by law. The disclosure of the final study results will be performed after the end of study in order 
to ensure the statistical analyses are relevant.
DATA QUALITY ASSURANCE
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, and periodic monitoring visits by the sponsor, and direct 
transmission of ECG and PRO - and possibly 6MWT data, as well as clinical laboratory data from 
a central laboratory, into the sponsor’s data base. Written instructions will be provided for 
collection, handling, storage, and shipment of samples. 
Guidelines for CRF completion will be provided and reviewed with study-site personnel before 
the start of the study.  
The sponsor will review CRF for accuracy and completeness during on-site monitoring visits and 
after transmission to the sponsor; any discrepancies will be resolved with the investigator or 
designee, as appropriate. After upload of the data into the study database they will be verified for 
accuracy and consistency with the data sources. 
CASE REPORT FORM COMPLETION
Case report forms are prepared and provided by the sponsor for each participant in electronic 
format. All data relating to the study must be recorded in CRF. All CRF entries, corrections, and 
alterations must be made by the investigator or authorized study-site personnel. The investigator 
must verify that all data entries in the CRF are accurate and correct.
The study data will be transcribed by study-site personnel from the source documents onto an 
electronic CRF, if applicable. Study-specific data will be transmitted in a secure manner to the 
sponsor.

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Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the participant’s source documents. Data must be entered into 
CRF in English. The CRF must be completed as soon as possible after a participant visit and the 
forms should be available for review at the next scheduled monitoring visit.
All participative measurements (eg, WHO FC assessment or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the eDC tool. If corrections to a CRF are needed after 
the initial entry into the CRF, this can be done in either of the following ways:

Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and study-
site personnel.
SOURCE DOCUMENTS
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
participant identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all adverse events and follow-up of adverse events; concomitant medication; 
intervention receipt/dispensing/return records; study intervention administration information; and 
date of study completion and reason for early discontinuation of study intervention or withdrawal 
from the study, if applicable. 
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring guidelines 
(or other equivalent document).
The minimum source documentation requirements for Section 5.1, Inclusion Criteria and 
Section 5.2, Exclusion Criteria that specify a need for documented medical history are as follows:

Referral letter from treating physician or

Complete history of medical notes at the site

Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by participant interview or other protocol required assessment (eg, physical 
examination, laboratory assessment) and documented in the source documents.
An eSource system may be utilized, which contains data traditionally maintained in a hospital or 
clinic record to document medical care (eg, electronic source documents) as well as the clinical 
study-specific data fields as determined by the protocol. This data is electronically extracted for 

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use by the sponsor. If eSource is utilized, references made to the CRF in the protocol include the 
eSource system but information collected through eSource may not be limited to that found in the 
CRF.
MONITORING
The sponsor will use a combination of monitoring techniques (central, remote, or on-site 
monitoring) to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first 
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare data entered into the CRF with the source documents 
(eg, hospital/clinic/physician’s office medical records); a sample may be reviewed. The nature and 
location of all source documents will be identified to ensure that all sources of original data 
required to complete the CRF are known to the sponsor and study-site personnel and are accessible 
for verification by the sponsor study-site contact. If electronic records are maintained at the study 
site, the method of verification must be discussed with the study-site personnel. 
Direct access to source documents (medical records) must be allowed for the purpose of verifying 
that the recorded data are consistent with the original source data. Findings from this review will 
be discussed with the study-site personnel. The sponsor expects that, during monitoring visits, the 
relevant study-site personnel will be available, the source documents will be accessible, and a 
suitable environment will be provided for review of study-related documents. The monitor will 
meet with the investigator on a regular basis during the study to provide feedback on the study 
conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these 
remote contacts, study-site personnel will be available to provide an update on the progress of the 
study at the site. 
Central monitoring will take place for data identified by the sponsor as requiring central review.
ON-SITE AUDITS
Representatives of the sponsor’s clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Participant privacy must, however, be 
respected. The investigator and study-site personnel are responsible for being present and available 
for consultation during routinely scheduled study-site audit visits conducted by the sponsor or its 
designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part 
of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection.

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RECORD RETENTION
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRF and 
all source documents that support the data collected from each participant, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical 
Trial, and all study documents as specified by the applicable regulatory requirement(s). The 
investigator/institution will take measures to prevent accidental or premature destruction of these 
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents will be retained for a longer period 
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will accept 
the responsibility. The sponsor must be notified in writing of the name and address of the new 
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents 
before having obtained written approval from the sponsor.
STUDY AND SITE START AND CLOSURE
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been collected 
and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor’s procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development

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10.4 Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study participant administered 
a medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the intervention. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not related 
to that medicinal (investigational or non-investigational) product. (Definition per International 
Conference on Harmonisation [ICH]).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to All Adverse 
Events under Section 8.4.1, Time Period and Frequency for Collecting Adverse Events and Serious 
Adverse Events Information, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be immediately 
life threatening or result in death or hospitalization but may jeopardize the participant or may 
require intervention to prevent one of the other outcomes listed in the definition above. These 
should usually be considered serious.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study intervention and the event (eg, death from anaphylaxis), the event 

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must be reported as a serious and unexpected suspected adverse reaction even if it is a component 
of the study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For macitentan, the expectedness of an AE will be 
determined by whether or not it is listed in the IB (Macitentan IB).
Adverse Event Associated with the Use of the Intervention
An adverse event is considered associated with the use of the intervention if the attribution is 
related by the definitions listed below (see Attribution Definitions).
ATTRIBUTION DEFINITIONS
Assessment of Causality
The causal relationship to study treatment is determined by the Investigator based on medical 
judgment. The following selection should be used to assess all adverse events (AE).
Each AE must be assessed by the investigator as to whether or not there is a reasonable 
possibility of causal relationship to the study intervention administered and reported as either 
related or not related. The determination of the likelihood that the study intervention caused the 
AE will be provided by the investigator.
Related
There is a reasonable causal relationship between study treatment administration and the AE.
Not Related
There is not a reasonable causal relationship between study treatment administration and the AE.
SEVERITY CRITERIA 
An assessment of severity grade will be made using the following general categorical descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the participant (eg, laboratory abnormalities).

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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

Any failure of expected pharmacologic action (ie, lack of effect) of a sponsor study 
intervention

Unexpected therapeutic or clinical benefit from use of a sponsor study intervention

Medication error involving a sponsor product (with or without participant/patient exposure to 
the sponsor study intervention, eg, name confusion)

Exposure to a sponsor study intervention from breastfeeding
Special reporting situations should be recorded in the CRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the CRF.
PROCEDURES
All Adverse Events
All adverse events, regardless of seriousness, severity, or presumed relationship to study 
intervention, must be recorded using medical terminology in the source document and the CRF. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as 
“upper respiratory infection”). Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
For all studies with an outpatient phase, including open-label studies, the participant must be 
provided with a “wallet (study) card” and instructed to carry this card with them for the duration 
of the study indicating the following: 

Study number

Statement, in the local language(s), that the participant is participating in a clinical study

Investigator’s name and 24-hour contact telephone number

Local sponsor’s name and 24-hour contact telephone number (for medical personnel only)

Site number

Participant number

Any other information that is required to do an emergency breaking of the blind

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Serious Adverse Events
All serious adverse events that have not resolved by the end of the study, or that have not resolved 
upon discontinuation of the participant’s participation in the study, must be followed until any of 
the following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study intervention or to factors unrelated 
to study conduct

It becomes unlikely that any additional information can be obtained (participant or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts)
Follow-up information about a previously reported SAE must also be reported to the sponsor 
within 24 hours of receiving it. Sponsor personnel may contact the investigator to obtain further 
information. The follow-up information obtained after the participant’s EOS visit (see Section 4.4) 
must be reported to the sponsor but is not recorded in the eCRF.
Suspected transmission of an infectious agent by a medicinal product will be reported as a serious 
adverse event. 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a participant’s participation in a study must be reported as a serious adverse event, except 
hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons such 
as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the CRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not be 
considered serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event.

For convenience the investigator may choose to hospitalize the participant for a part of the 
intervention period. 
The cause of death of a participant in a study within 4 weeks of the last dose of study intervention, 
whether or not the event is expected or associated with the study intervention, is considered a 
serious adverse event.
CONTACTING SPONSOR REGARDING SAFETY
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.

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PRODUCT QUALITY COMPLAINT HANDLING
Product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, reliability, or performance of a distributed product, including its labeling, drug delivery 
system, or package integrity. A PQC may have an impact on the safety and efficacy of the product. 
In addition, it includes any technical complaints, defined as any complaint that indicates a potential 
quality issue during manufacturing, packaging, release testing, stability monitoring, dose 
preparation, storage or distribution of the product or the drug delivery system.
Procedures
All initial PQCs must be reported to the sponsor by the study site personnel within 24 hours after 
being made aware of the event.
A sample of the suspected product should be maintained under the correct storage conditions until 
a shipment request is received from the sponsor.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document.

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10.5 Appendix 5: Contraceptive and Barrier Guidance and Collection of 
Pregnancy Information
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria. 
Pregnancy information will be collected and reported as noted in Section 8.4.4, Pregnancy and 
Appendix 4 Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Woman Not of Childbearing Potential

premenarchal
A premenarchal state is one in which menarche has not yet occurred.

postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the 
postmenopausal range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT), however in the absence of 
12 months 
of 
amenorrhea, 
a 
single 
FSH 
measurement 
is 
insufficient.
If there is a question about menopausal status in women on HRT, the woman will be required 
to use one of the non-estrogen-containing hormonal highly effective contraceptive methods if 
she wishes to continue HRT during the study.

permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman 
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually 
active becomes active), a woman must begin a highly effective method of contraception, as 
described in the inclusion criteria.
Contraceptive (birth control) use by men or women should be consistent with local regulations 
regarding the acceptable methods of contraception for those participating in clinical studies.
Typical use failure rates may differ from those when used consistently and correctly. Use should 
be consistent with local regulations regarding the use of contraceptive methods for participants in 
clinical studies.

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Acceptable methods of contraception:
Option 1
One method from 
this list
OR
Option 2
One method from 
this list
OR
Option 3
OR
Option 4
Tubal sterilization 
(occlusion or 
ligation of tubes 
at least 6 weeks 
prior to 
screening),
Implantable#
hormonal 
contraceptives
Intrauterine
devices
Oral,
Transdermal#, or
Injectable#
hormonal 
contraceptives
Sterilization of the 
male partner with 
documented post-
vasectomy 
confirmation of the 
absence of sperm in 
the ejaculate 
True abstinence 
from intercourse 
with a male partner 
only when this is in 
line with the 
preferred lifestyle of 
the participant.
PLUS one method 
from this list
PLUS one method 
from this list
Diaphragm*#,
female condom*#
cervical cap*#, 
partner’s use of a 
condom*
Oral,
Implantable#,
Transdermal#, or
Injectable# hormonal 
contraceptives
Intrauterine devices
Diaphragm*#,
female condom*#
cervical cap*#, 
partner’s use of a 
condom*
*used in combination with a spermicide, unless unavailable locally. 
#methods that are not approved/certified for use in Japan.

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10.6 Appendix 6:
Child-Pugh Score
Clinical and Lab Criteria
Points
1
2
3
Encephalopathy
None
Mild to moderate 
(grade 1 or 2)
Severe 
(grade 3 or 4)
Ascites
None
Mild to moderate 
(diuretic responsive)
Severe (diuretic 
refractory)
Bilirubin (mg/dL)
<2
2-3
>3
Albumin (g/dL)
>3.5
2.8–3.5
<2.8
Prothrombin time
Seconds prolonged
International 
normalized 
ratio
<4
<1.7
4-6
1.7-2.3
>6
>2.3
Child-Pugh class obtained by adding score for each parameter (total points):
Class A = 5 to 6 points (least severe liver disease)
Class B = 7 to 9 points (moderately severe liver disease
Class C = 10 to 15 points (most severe liver disease)

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10.7 Appendix 7: Sponsor 6-minute Walk Test Guidance
This document stipulates the criteria under which study-required 6MWTs will be carried out in 
Clinical Protocol 67896062CTP3001 (Amendment 4).
These criteria are, in part, derived from the recommendations included in the ATS Guidelines 
issued in 2002 and the ERS/ ATS Technical Standard published in 2014 (ATS Statement 2002).
As opposed to the comprehensive published manuscripts, this guidance has been shortened and 
accustomed for use in a clinical study in which a variety of different assessments may need to be 
performed at a given visit.
1. INSTRUCTIONS
General

The 6-Minute Walk Test (6MWT) must be performed indoors, along a long, flat, straight, 
enclosed corridor (or similar location) with a hard surface that can be blocked for traffic during 
the conduct of the test. The track length for the 6MWT must be free of obstacles. The use of 
treadmill and a continuous course, eg, a circuit, is not allowed. 

The ideal track length used for the 6MWT is 30 meters (If the track is shorter, it must be no 
shorter than 20 meters in length). The track must be marked at regular intervals to facilitate 
measurement of the distance walked (markings every 3 meters are recommended). The 
turnaround points must be marked with a cone. A starting line, which marks the beginning and 
the end of each lap (one lap is twice the length of the track used at the site), needs to be marked 
on the floor. 

Local safety practice regarding medical emergencies and contraindications for 6MWT must be 
followed at each participating site. 

The person administering the 6MWT (tester) needs to stand near the starting line during the 
6MWT and must not walk with the participant, and not get distracted during the conduct of 
this 6MWT (eg, by talking to someone). 

Rest periods are allowed if the participant can no longer continue. If the participant needs to 
rest, he/she may pause, lean against the wall and continue walking whenever he/she feels able. 
The timer must continue to run even if the participant stops to rest. The 6MWT can be stopped 
at any moment as due to medical emergencies or safety issues such as chest pain, intolerable 
dyspnea, leg cramps, staggering, diaphoresis, and pale or ashen appearance

The 6MWT is a non-encouraged test. An even tone of voice must be used when using the 
standard phrases. No other instructions or words of encouragement are given during the test, 
other than the pre-scripted phrases (see instructions to participant). Eye contact and body 
language signaling the participant to speed up must be avoided during the test.  

Whenever possible, for an individual participant, repeat 6MWTs must be conducted in the 
same corridor and by the same tester, and preferably at about the same time of the day 
(ie, within ± 2 hours of the baseline test) to minimize variability.

If a participant is oxygen dependent, the flow rate must remain constant from 30 minutes prior 
to each 6MWT, until the completion of all protocol-mandated assessments after the 6MWT. 
Additionally, the way oxygen is delivered (delivery device, application route, way of carrying 

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delivery device) must be the same for all 6MWTs, unless a change is required for documented 
medical reasons.
Training tests
For participants who have not previously performed a 6MWT, a training 6MWT must be 
performed before the first protocol-mandated 6MWT is performed. 
Data from the training 6MWT are not collected in the CRF but must be documented in the source
data.
Timing
Only two 6MWTs can be performed on the same day. The interval between two 6MWTs on the 
same day must be at least 2 hours. 
2. TEST REQUIREMENTS
Participant

The participant must wear comfortable clothing and appropriate walking shoes. 

The participant must not have exercised vigorously within 2 hours of beginning the test. 

It is recommended that the participant rests for at least 15 minutes before the test starts.

It is recommended that participants receive their concomitant therapy on the day of the test. If 
the participant is used to taking bronchodilators, he/she must take them at least 10 to 30 min 
before the test. 

Participants can use their usual walking aids during the test (eg, cane). The same walking aid 
should be used for all 6MWTs. Walkers are not allowed. 
Equipment to perform the test

Countdown timer

Mechanical lap counter

Two cones to mark the turnaround points 

A chair that can be easily moved along the track 

6MWT Worksheet

Borg category-ratio (CR) 10 scale®
3. PERFORMING THE 6MWT
Assessments before the 6MWT
Before the 6MWT, the tester shows the Borg CR10 Scale® to the participant and asks the 
participant: 

“Please grade your dyspnea using this scale”.
Then, the tester will ask:

“Please grade your level of exertion using this scale.

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Record the baseline-6MWT dyspnea and level of exertion using the Borg CR10 scale® on the 
6MWT worksheet.
Instructions to the participant during the 6MWT
The tester uses the following exact dialogue with the participant:
“The objective of this test is to walk as far as possible in 6 minutes. You will walk back and 
forth in this hallway. Six minutes is a long time to walk, so you will be exerting yourself. You 
will probably get out of breath or become exhausted. You are permitted to slow down, to stop, 
and to rest as necessary. You may lean against the wall while resting, but resume walking as 
soon as you are able. 
You will be walking back and forth around the cones. You should pivot briskly around the 
cones and continue back the other way without hesitation. Now I’m going to show you. Please 
watch the way I turn without hesitation”. 
(The tester demonstrates the walking and pivots around a cone briskly). 
“Are you ready to do that? I am going to use this counter to keep track of the number of laps 
you complete. I will click it each time you turn around at this starting line. Remember the 
object is to walk AS FAR AS POSSIBLE in 6 minutes, but don’t run or jog.”
After these instructions are given to the participant, the tester says: 
“Start now, or whenever you are ready”
As soon as the participant starts to walk, the tester starts the timer and writes down start time. The 
tester reminds the participant of the elapsed time by saying: 
After the first minute: “You are doing well. You have 5 minutes to go”.
When the timer shows 4 minutes remaining: “Keep up the good work. You have 4 minutes to 
go.”
When the timer shows 3 minutes remaining: “You are doing well. You are halfway done.”
When the timer shows 2 minutes remaining: “Keep up the good work. You have 2 minutes to 
go.”
When the timer shows only 1 minute remaining: “You are doing well. You have only 1 minute 
to go.”
If the participant stops walking during the test and needs a rest, the tester says:
“You can lean against the wall if you would like; then continue walking whenever you feel 
able.”
The tester will not stop the timer. If the participant stops before the 6 minutes are up and refuses 
to continue (or the tester decides that they should not continue), the tester wheels the chair over 
for the participant to sit on, discontinue the walk, and note on the worksheet the distance, the time 
stopped, and the reason for stopping prematurely.
When the timer is 15 seconds from completion, the tester says: 
“In a moment I’m going to tell you to stop. When I do, just stop right where you are and I will 
come to you”. 

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When the timer alarm rings the tester says: 
“Stop!”
Assessments after the 6MWT
The tester walks over to the participant, marks the spot where the participant stopped, records the
total distance walked in the 6MWT worksheet and congratulates the participant on good effort.
After the 6MWT, the tester reminds the participant of their dyspnea and level of exertion that they 
chose before the 6MWT. The tester shows the Borg CR10 Scale® to the participant and asks the 
participant:

“Please grade your dyspnea using this scale”.
Then, the tester will ask:

“Please grade your level of exertion using this scale.
The tester will record the post-6MWT dyspnea and level of exertion on the 6MWT worksheet.
4. 6MWT WORKSHEET
It is mandatory to use the 6MWT worksheet to capture documentation of each 6MWT newly 
performed for the purpose of the study and report relevant data in the eCRF, as indicated. 
It is not mandatory to use the study 6MWT worksheet for historical 6MWTs.

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10.8 Appendix 8: Borg CR10 Scale®
Instructions for use of the Borg CR10 Scale®
The Borg CR10 Scale® will be explained in detail to the participants at Screening before starting 
the first 6MWT (questionnaires and instructions will be provided in local language). 
The tester will provide the following instruction to the participant:
“Use this rating scale to report how strong your perception of dyspnea and level of exertion is. 
First look at the verbal expressions. Start with them and then the numbers. Of these ten (10) or 
“Extremely strong”, “Maximal” is a very important intensity level. This is the most intense 
perception or feeling you have ever had.
If your experience or feeling is “Very weak”, you should say “1”, if it is “Moderate”, say “3”. Note 
that “Moderate” is “3” and thus weaker than “Medium”, “Mean” or “Middle”. If the experience is 
“Strong” or “Heavy” (it feels “Difficult”) say “5”. Note that “Strong” is about half of “Maximal”. 
If your feeling is “Very strong”, choose a number from 6 to 8. If your perception or feeling is 
stronger than “10”, - “Extremely strong”, “Maximal” – you can use a larger number, eg, 12 or still 
higher (that’s why “Absolute maximum” is marked with a dot “•”). 
It’s very important that you report what you actually experience or feel, not what you think you 
should report. Be as spontaneous and honest as possible and try to avoid under- or overestimating. 
Look at the verbal descriptors and then choose a number.
When rating dyspneaa give a number that corresponds to how hard and strenuous you perceive 
your breathing to be. The perception of dyspnea is mainly the feeling that one cannot breathe well 
enough.
0 - “Nothing at all”, means that you don’t feel any shortness of breath. 
1 - “Very weak” means a very light shortness of breath.
3 - “Moderate” is somewhat but not especially hard. You are somewhat shorter of breath. 
5 - “Strong”. Breathing is getting difficult. The effort to breathe is about half as intense as 
“Maximal”. 
7 - “Very strong” is quite strenuous. You can still breathe, but breathing is getting very 
difficult.
10 - “Extremely strong – Maximal” is the greatest shortness of breath you have ever 
experienced in your life.
“•” - Is “Absolute maximum” for example “12” or even more.
                                                
a The instructions for rating dyspnea have been customized by the sponsor based on the instructions for rating exertion. 
These modifications have not been validated by Borg Perception AB.

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When rating exertion give a number that corresponds to how hard and strenuous you perceive the 
work to be. The perception of exertion is mainly felt as strain and fatigue in your muscles and as 
breathlessness or any aches.  
0 - “Nothing at all”, means that you don’t feel any exertion whatsoever, no muscle fatigue, 
no breathlessness or difficulties breathing.
1 - “Very weak” means a very light exertion. As taking a shorter walk at your own pace. 
3 - “Moderate” is somewhat but not especially hard. It feels good and not difficult to go 
on.
5 - “Strong”. The work is hard and tiring, but continuing isn’t terribly difficult. The effort 
and exertion is about half as intense as “Maximal”.
7 - “Very strong” is quite strenuous. You can still go on, but you really have to push 
yourself and you are very tired. 
10 - “Extremely strong – Maximal” is an extremely strenuous level. For most people this 
is the most strenuous exertion they have ever experienced previously in their lives.
“•” - Is “Absolute maximum” for example “12” or even more.
Any questions?”

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Borg CR10 Scale®:

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10.9 Appendix 9: WHO Function Classification of Pulmonary Hypertension
Class I
Patients with pulmonary hypertension but without resulting 
limitation of physical activity. Ordinary physical activity does not 
cause undue dyspnea or fatigue, chest pain or near syncope. 
Class II
Patients with pulmonary hypertension resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary physical 
activity causes undue dyspnea or fatigue, chest pain or near syncope. 
Class III
Patients with pulmonary hypertension resulting in marked limitation 
of physical activity. They are comfortable at rest. Less than ordinary 
activity causes undue dyspnea or fatigue, chest pain or near syncope. 
Class IV
Patients with pulmonary hypertension with inability to carry out any 
physical activity without symptoms. These patients manifest signs of 
right heart failure. Dyspnea and/or fatigue may even be present at 
rest. Discomfort is increased by any physical activity.

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10.10 Appendix 10: PAH-SYMPACT® Questionnaire
1. 
Administration and Scoring
1.1 
Administration
The PAH-SYMPACT® is composed of two parts: the Symptoms part, which is administered daily 
for seven days, and the Impacts part, which is administered once at the end of the seven-day 
administration period. The PAH-SYMPACT® has been used in both an electronic patient-reported 
outcome and a paper-pencil format.
The Symptoms part contains 11 symptom items across two domains plus one question about 
oxygen use. There is no total symptom score; the two domains are: Cardiopulmonary Symptoms 
and Cardiovascular Symptoms. The question on oxygen use stands on its own and is not used as 
part of the domain scores. Symptoms items have a recall period of “today,” and it is recommended 
that the questions be completed in the evening. As symptoms vary by day, the Symptoms part 
should be completed daily over seven consecutive days.
The Impact part contains 11 items across two domains: Physical Impacts and Cognitive/Emotional 
Impacts. Impact items have a recall period of the last week; hence, the questions should be 
completed on the seventh day of the seven-day administration period of the Symptoms part.
1.2 
Scoring
Items have a five-point Likert response scale; responses are transcribed to numerical values for 
further analyses. 

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Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT®
Questionnaire
Programming note: Day 1 (First day of diary completion- Symptoms items only)
INSTRUCTIONS
Each day you will answer questions about your Pulmonary Arterial Hypertension symptoms over the 
PAST 24 HOURS. Please select the answer that best describes your experience with your symptoms.
On the 7th day you will answer questions about your Pulmonary Arterial Hypertension symptoms over the 
PAST 24 HOURS and additional questions about how your life was affected by Pulmonary Arterial 
Hypertension in the PAST 7 DAYS.
Please do not skip any questions. There are no right or wrong answers to any of the questions. 
Programming note: Days 2-6 (Subsequent days prior to last day in week- Symptoms items only)
INSTRUCTIONS
Today you will answer questions about your Pulmonary Arterial Hypertension symptoms over the PAST 
24 HOURS. Please select the answer that best describes your experience with your symptoms.
Please do not skip any questions. There are no right or wrong answers to any of the questions. 
Programming note: Day 7 (Last day of week- Symptoms and Impact items)
INSTRUCTIONS
Today you will answer questions about your Pulmonary Arterial Hypertension symptoms over the PAST 
24 HOURS and additional questions about how your life was affected by Pulmonary Arterial Hypertension 
in the PAST 7 DAYS.
Please do not skip any questions. There are no right or wrong answers to any of the questions.

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SYMPTOMS
1.
In the past 24 hours …
Did you use oxygen? 
0  No
1  Yes
If yes: How many hours? _______
Answer the questions that follow based on your experiences regardless of whether you were using 
oxygen or not.
2.
In the past 24 hours …
How would you rate your shortness of breath?
0  No shortness of breath at all
1  Mild
2  Moderate
3  Severe
4  Very Severe
3.
In the past 24 hours …
How would you rate your fatigue?
0  No fatigue at all
1  Mild
2  Moderate
3  Severe
4  Very Severe
4.
In the past 24 hours …
How would you rate your lack of energy?
0  No lack of energy at all
1  Mild
2  Moderate
3  Severe
4  Very Severe
5.
In the past 24 hours …
How would you rate the swelling in your ankles or legs?
0  No swelling in ankles or legs at all
1  Mild
2  Moderate
3  Severe
4  Very Severe

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6.
In the past 24 hours …
How would you rate the swelling in your stomach area?
0  No swelling in stomach area at all
1  Mild
2  Moderate
3  Severe
4  Very Severe
7.
In the past 24 hours …
How would you rate your cough?
0  No cough at all
1  Mild
2  Moderate
3  Severe
4  Very Severe
8.
In the past 24 hours …
How would you rate your heart palpitations (heart fluttering)?
0  No heart palpitations (heart fluttering) at all
1  Mild
2  Moderate
3  Severe
4  Very Severe
9.
In the past 24 hours …
How would you rate your rapid heartbeat?
0  No rapid heartbeat at all
1  Mild
2  Moderate
3  Severe
4  Very Severe
10. In the past 24 hours …
How would you rate your chest pain?
0  No chest pain at all 
1  Mild
2  Moderate
3  Severe
4  Very Severe
11. In the past 24 hours …
How would you rate your chest tightness?
0  No chest tightness at all 
1  Mild
2  Moderate
3  Severe
4  Very Severe

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12. In the past 24 hours …
How would you rate your lightheadedness?
0  No lightheadedness at all
1  Mild
2  Moderate
3  Severe
4  Very Severe

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IMPACTS
For the following questions, please select the answer that best describes how your life was affected by 
Pulmonary Arterial Hypertension in the PAST 7 DAYS. Answer the questions based on your experiences 
regardless of whether you were using oxygen or not.
1. In the past 7 days …
Were you able to walk slowly on a flat surface?
0  Yes, with no difficulty at all
1  Yes, with a little difficulty 
2  Yes, with some difficulty
3  Yes, with much difficulty
4  No, not able at all
2. In the past 7 days …
Were you able to walk quickly on a flat surface?
0  Yes, with no difficulty at all
1  Yes, with a little difficulty 
2  Yes, with some difficulty
3  Yes, with much difficulty
4  No, not able at all
3. In the past 7 days …
Were you able to walk uphill?
0  Yes, with no difficulty at all
1  Yes, with a little difficulty 
2  Yes, with some difficulty
3  Yes, with much difficulty
4  No, not able at all
4. In the past 7 days …
Were you able to carry things, such as bags or baskets?
0  Yes, with no difficulty at all
1  Yes, with a little difficulty 
2  Yes, with some difficulty
3  Yes, with much difficulty
4  No, not able at all
5. In the past 7 days …
Were you able to do light indoor household chores, such as preparing food, cleaning surfaces, or 
tidying up?
0  Yes, with no difficulty at all
1  Yes, with a little difficulty 
2  Yes, with some difficulty
3  Yes, with much difficulty
4  No, not able at all

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6. In the past 7 days …
Were you able to wash or dress yourself?
0  Yes, with no difficulty at all
1  Yes, with a little difficulty 
2  Yes, with some difficulty
3  Yes, with much difficulty
4  No, not able at all
7. In the past 7 days …
How much did you need help from others?
0  Not at all
1  A little bit
2  Some
3  Quite a bit
4  Very much
8. In the past 7 days …
Were you able to think clearly?
0 Yes, with no difficulty at all
1  Yes, with a little difficulty 
2  Yes, with some difficulty
3  Yes, with much difficulty
4  No, not able at all
9. In the past 7 days …
How sad did you feel?
0  Not at all
1  A little bit
2  Somewhat
3  Very
4  Extremely
10.In the past 7 days …
How worried did you feel?
0  Not at all
1  A little bit
2  Somewhat
3  Very
4  Extremely
11.In the past 7 days …
How frustrated did you feel?
0  Not at all
1  A little bit
2  Somewhat
3  Very
4  Extremely

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10.12 Appendix 12: Work Productivity and Activity Impairment Questionnaire:
General Health V2.0 (WPAI:GH)
The following questions ask about the effect of your health problems on your ability to 
work and perform regular activities. By health problems we mean any physical or 
emotional problem or symptom. Please fill in the blanks or circle a number, as indicated.
1.
Are you currently employed (working for pay)? 
____  NO
____  YES
If NO, check “NO” and skip to question 6.
The next questions are about the past seven days, not including today.
2.
During the past seven days, how many hours did you miss from work because of
your health problems? Include hours you missed on sick days, times you went in 
late, left early, etc., because of your health problems. Do not include time you 
missed to participate in this study.
_____HOURS
3.
During the past seven days, how many hours did you miss from work because of 
any other reason, such as vacation, holidays, time off to participate in this study?
_____HOURS
4.
During the past seven days, how many hours did you actually work?
_____HOURS (If “0”, skip to question 6.)

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5.
During the past seven days, how much did your health problems affect your 
productivity while you were working? 
Think about days you were limited in the amount or kind of work you could do, 
days you accomplished less than you would like, or days you could not do your 
work as carefully as usual. If health problems affected your work only a little, 
choose a low number. Choose a high number if health problems affected your 
work a great deal. 
Consider only how much health problems affected 
productivity while you were working.
Health 
problems had 
no effect on my 
work
Health problems 
completely 
prevented me 
from working
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER
6.
During the past seven days, how much did your health problems affect your ability 
to do your regular daily activities, other than work at a job? 
By regular activities, we mean the usual activities you do, such as work around the 
house, shopping, childcare, exercising, studying, etc. Think about times you were 
limited in the amount or kind of activities you could do and times you accomplished 
less than you would like. If health problems affected your activities only a little, 
choose a low number. Choose a high number if health problems affected your 
activities a great deal. 
Consider only how much health problems affected your ability 
to do your regular daily activities, other than work at a job.
Health problems 
had no effect on 
my daily 
activities
Health problems 
completely 
prevented me 
from doing my 
daily activities
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER

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10.13 Appendix 13: SF-36®v2 Health Survey Single-Item Presentation Text Acute, United States (English) 
CCI

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CCI

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CCI

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SF-36v2® Health Survey1992, 2000, 2010, 2012 Medical Outcomes Trust and QualityMetric Incorporated. All rights reserved.
SF-36® is a registered trademark of Medical Outcomes Trust.
(SF-36v2® Health Survey Acute, United States (English)
CCI

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10.14 Appendix 14: Patient Health Questionnaire (PHQ-8)
PHQ-8
Copyright © Pfizer Inc. All rights reserved.  Developed by Drs. Robert L. Spitzer, Janet B 
Williams, and Kurt Kroenke.1999.
CCI

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10.15 Appendix 15: Patient Global Assessment of Severity (PGA-S)
Patient Global Assessment of Disease Severity (PGA-S)
This question refers to symptoms related to chronic thromboembolic pulmonary hypertension. 
Please choose the response that best describes the severity of your symptoms today. (Check one 
response)
None
Very mild
Mild
Moderate
Severe
Very severe

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10.16 Appendix 16: Actelion Heart Catheterization Guidance
ACTELION HEART CATHETERIZATION GUIDANCE WHEN 
HEMODYNAMIC VARIABLES ARE ENDPOINTS

This guidance only applies to participants who will require a baseline and a post-baseline right 
heart catheterization (RHC) with/without a left heart catherization (LHC) (if needed). This 
guidance does not apply to RHC/LHC used only for participant eligibility. 

Hemodynamic evaluations will be carried out according to this guidance for those conditions 
and hemodynamic parameters that are described below. Further hemodynamic evaluations will 
be carried out according to the catheterization laboratory’s local practice. 
1. HEART CATHETERIZATION PROCEDURES
1.1 Conditions
Participants will undergo RHC/LHC at the study site (or other institution in case no suitable 
catheterization laboratory is available at the study site) in an appropriate care setting 
(eg, catheterization laboratory or medical procedures unit). If the assessment is performed at an 
external catheterization laboratory, the Primary Investigator is responsible to provide this guidance 
document to the external institution and to ensure that the catherization lab is sufficiently qualified. 
Whenever possible, it is recommended that baseline and any post-baseline RHC/LHC are
performed by the same operator, according to the same standards and procedures and in the same 
catheterization laboratory to ensure data consistency.
Where historical RHC/LHC is used for baseline measurements, then this guidance requirements 
for zeroing (Section 1.2) and heart catheterization measurement (Section 2) must have been 
followed and documented in the source notes. Otherwise a new RHC/LHC assessment will have 
to be performed for baseline measurements.
1.2 ‘Zeroing’

‘Zeroing’ must be done prior to any RHC/LHC measurements. The participant needs to be in 
a supine position and the pressure transducer is to be set to zero level at the mid-thoracic line. 

This must be documented in the heart catherization worksheet.
1.3 Oxygen 
If the participant requires supplemental oxygen during baseline RHC/LHC, oxygen should also be 
given during the follow-up RHC/LHC, if needed.

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2. HEART CATHETERIZATION MEASUREMENTS
2.1 Right Heart Catheterization measurements

Pulmonary Artery pressure (PAP)
The participant will be asked to breath normally during the procedure. The operator will assess 
the appropriate systolic PAP (sPAP) and diastolic PAP (dPAP) readings based on the 
respiratory cycle and the pressure tracings.
The sPAP and dPAP must be measured with 2 measurements documented in the source notes 
that are assessed by the operator as the most representative and reliable.
If more than 2 values are recorded, all values must be documented on the source notes. 

Pulmonary artery wedge pressure (PAWP)
The participant will be asked to breath normally during the procedure. The operator will assess 
the appropriate pulmonary artery wedge pressure (PAWP) reading based on the respiratory 
cycle and the pressure tracing.
If multiple measurements are performed, all PAWP values must be documented in the heart 
catherization worksheet. 
The operator must identify the most accurate PAWP on the heart catherization worksheet, 
based on their decision of which waveform to use.

Cardiac Output 
The same method for CO measurement must be used for both the baseline and any post-baseline 
RHC to ensure consistency.
If thermodilution method is used:

The CO must be measured with at least 3 measurements documented in the heart catherization 
worksheet. 

The 3 measurements must be within 10% of each other, ie, the lowest of the 3 CO values must 
not be lower than 10% of the middle value AND the highest value must not be higher than 10% 
of the middle value.

If the 3 values are not within 10% of each other (as per above), additional measurements can be 
performed until 3 measurements are obtained that are within 10% of each other.

If more than 3 measurements are taken, the largest and/or smallest outlying values in the opinion 
of the operator should be discarded until at least 3 values are within 10% of each other 

If more than 3 values are recorded, all values must be documented in the heart catherization 
worksheet. 
If Fick method (indirect or direct) is used,

Only 1 value is required and must be documented in the source notes. 

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
If multiple values are performed, all CO values must be documented in the source notes. In 
addition, the operator must identify the most representative and reliable CO value. 
2.2 Left Heart Catheterization measurement

Left ventricular end diastolic pressure (LVEDP)

LVEDP is to be recorded only when PAWP is not available or not reliable.

The participant will be asked to breath normally during the procedure. The operator will assess 
the appropriate LVEDP reading based on the respiratory cycle and the pressure tracing.

If multiple measurements are performed, all LVEDP values must be documented in the heart 
catherization worksheet.

The operator must identify the most representative and reliable LVEDP value on the heart 
catherization worksheet.
2.3 Other measurements
RAP, dSAP, sSAP, SVO2 are measured as per local practice. 
3. DOCUMENTATION
3.1 Tracings
All relevant tracings are to be recorded and saved/printed for each pressure measurement and filed 
as the participants’ source notes (electronic or paper).
3.2 Heart catheterization worksheet
It is mandatory to use the study heart catheterization worksheet to capture documentation of each 
RHC with/without LHC assessments newly performed for the purpose of the study and report 
relevant data in the eCRF, as indicated. 
It is not mandatory to use the study heart catheterization worksheet for historical RHC/LHC 
assessments.

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10.17 Appendix 17: Guidance on Male Reproductive System Safety Sub-study
1. BACKGROUND AND RATIONALE
Animal data on macitentan indicate a risk on the male reproductive system, structure and function. 
These findings consist mainly of morphological changes in the testes including tubular dilatation 
and, at higher doses, tubular degeneration and hypospermatogenesis. These effects were reversible 
and did not impact reproductive variables such as mating, fertility and fecundity. The relevance of
these findings to humans is unknown (Macitentan IB).
Macitentan, like other endothelin receptor antagonists (ERAs), may have an adverse effect on 
spermatogenesis, and decrease in sperm count in humans cannot be excluded.
This sub-study is conducted to provide additional safety data of chronic treatment with macitentan 
75 mg on testicular function in patients with PAH and CTEPH.
2. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Exploratory
To evaluate the effect of chronic administration of 
macitentan 75 mg on semen parameters in male 
participants
Percent changes from baseline to Week 24* in:
semen volume
sperm concentration
sperm motility
sperm morphology 
To evaluate the effect of chronic administration of 
macitentan 75 mg on sperm concentration in male 
participants
Percentage of participants who experience a ≥ 50% 
decline vs baseline in sperm concentration after Week 
24*
Percentage of participants reaching the lower limits of 
normal (LLN) (15 million spermatozoa per mL) in 
sperm concentration at Week 24*
To evaluate the effect of chronic administration of 
macitentan 75 mg on reproductive hormones in male 
participants
Percent changes from baseline to Week 24* in 
reproductive hormones (follicle stimulating hormone 
[FSH], luteinizing hormone (LH), testosterone, 
dihyrotestosterone [DHT], inhibin B, prolactin, 
estradiol) 
To evaluate the reversibility of the effects of 
macitentan on semen parameters in male participants
Percent change from Week 24* to 12 Weeks after 
treatment discontinuation in:
semen volume
sperm concentration
sperm motility
sperm morphology 
To evaluate the reversibility of the effects of 
macitentan on sperm concentration in male 
participants
Percentage of participants who experience a ≥ 50% 
decline vs Week 24* in sperm concentration 12 
weeks after treatment discontinuation
Percentage of participants reaching the LLN (15 
million spermatozoa per mL) in sperm concentration 
12 weeks after treatment discontinuation
To evaluate the reversibility of the effects of 
macitentan on reproductive hormones in male 
participants
Percent change from Week 24* to 12 weeks after 
treatment discontinuation in reproductive hormones
*Analyses to be repeated with week 24 OL data

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3. STUDY DESIGN
3.1 Overall design
This sub-study will be conducted in selected sites to enroll male participants from UNISUS (AC-
055-315) and MACiTEPH (67896062CTP3001) studies. Therefore, visits for the present study are 
planned to coincide with UNISUS and MACiTEPH study scheduled visits. However, participants 
who discontinue study treatment will have an extra visit 12 weeks after their treatment 
discontinuation for blood and semen samples collection (see Section 4). 
This is an optional sub-study opened to male participants willing to participate, conducted in 
selected sites. Male participants who refuse to participate in this sub-study could still participate 
to the main study. In addition, a participant may withdraw from this sub-study at any time with no 
impact on his participation to the main study. 
This sub-study includes the following periods (see Figure 1):

Prior to study intervention exposure
Male participants enrolled in either UNISUS or MACiTEPH and willing to take part to the 
testicular function sub-study will sign a separate informed consent form (ICF) at screening and 
will have their participation recorded in the interactive web response system (IWRS) system.
At baseline, blood and semen samples will be collected prior to the first study intervention dose.
During study intervention exposure
Follow-up samples will be collected at 2 timepoints corresponding to at least one spermatogenesis 
cycle with macitentan 75 mg treatment:

Week 24 after initiating study intervention (i.e. macitentan 75 mg or placebo)

Week 24 after entering into the treatment extension period with an open-label treatment 
with macitentan 75 mg.

After study intervention exposure
Participants discontinuing their study intervention either prematurely or at the end of the study will 
have samples collected at approximately 12 weeks after their last dose of study intervention.

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Figure 1
Schematic overview of the study
3.2 Scientific rationale
The duration of a spermatogenesis cycle lasts approximately 74 days (ie, 10 weeks) (Heller 1963). 
The time points of this sub-study have been chosen to assess the effect of macitentan 75 mg on 
testicular function after exposure for at least one full spermatogenesis cycle. Hence, Week 24 in
the double-blind treatment period corresponds to an exposure of 16 and 20 weeks to macitentan 
75mg in MACiTEPH and UNISUS, respectively, taking into account their different up-titration 
scheme.
Since participants will be exposed to either macitentan 10 mg or macitentan 75 mg or placebo 
during the double-blind treatment period, a second sample will be collected during the open-label 
treatment extension in order to optimize the number of participants exposed to macitentan 75 mg. 
The study endpoints will therefore be tested again at this second follow-up timepoint.
The study objectives and endpoints have been defined in line with the guidance provided by the 
FDA regarding the assessment of testicular function toxicity during drug development 
(FDA 2018).

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4. SCHEDULE OF ACTIVITIES
d = days; OL: open-label; ICF: informed consent form; IWRS: interactive web response system.
a.
Must be signed before first study-related activity.
b.
Semen samples to be collected and analyzed in a specialized local laboratory. Semen analyses (volume, 
concentration, motility and preparation of smears for morphology) to be conducted within 1-hour of 
sample collection. Morphology assessment to be conducted after fixing and staining of smears. 
Restrictions to be observed prior to each semen sample collection: Hot tub/jacuzzi/sauna use within the 
last 2 weeks, sexual abstinence for at least 2 days, extensive exercise (e.g. biking, horse riding…) for at 
least 2 days.
c.
Blood sample to be collected at the site, preferably in the morning and at the same time of the day for 
each visit and shipped to the study central laboratory.
d.
Participants who prematurely discontinue DB study intervention prior to Week 24 should have a semen-
and blood sample collected as soon as possible after the intake of the last dose 
e.
Participants who prematurely discontinue OL study intervention prior to OL Week 24 should have a 
semen- and blood sample collected as soon as possible after the intake of the last dose.
5. STUDY POPULATION
5.1 Inclusion criteria
1.
Must sign an ICF indicating that he understands the purpose of, and procedures required 
for, the sub-study and is willing to participate in the sub-study.
2.
Male participants enrolled in UNISUS or MACiTEPH studies. 
3.
Participants ≥18 (or the legal age consent in the jurisdiction in which the study is taking 
place) and ≤65 (inclusive) years of age.
5.2 Exclusion criteria
1.
Participant who has undergone a vasectomy.
2.
Treatment with hormone-suppressive agents, including androgens, estrogens, anabolic 
steroids or glucocorticoids within 6 months prior to baseline or planned during the study.
Period
Screening
Double-blind (DB) 
treatment period
Open-label 
(OL) treatment 
extension 
period
Post-Treatment 
Follow-up period
Visit number/name 
(MACiTEPH)
1
2
12
OL9
Week 12 post-
treatment Follow-
up
Timing
Day 1 
Week 24 (±5d)d
OL Week 24 
(±5d)e
12 weeks after 
treatment 
discontinuation
(+2 weeks)
Study Procedure
Informed consent (ICF)a
X
Inclusion/exclusion 
criteria
X
Sub-study participation 
record in IWRS
X
Semen analysesb
X
X
X
X
Reproductive hormonesc
X
X
X
X

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3.
Participants who refuse to abstain from the following prohibited lifestyle choices or 
activities prior to each semen sample collection:
a.
Hot tub/jacuzzi/sauna use for at least 2 weeks, 
b. Sexual abstinence for at least 2 days,
c.
Extensive exercise (e.g. biking, horse riding…) for at least 2 days.
6. CONCOMITANT THERAPY
The following medications and/or therapies are not allowed to be administered concomitantly with 
study intervention for participants enrolled in this sub-study:

Treatment with hormone-suppressive agents, including androgens, estrogens, anabolic 
steroids or glucocorticoids within 6 months prior to baseline and/or planned to be taken during 
the study.
7. SUB-STUDY ASSESSMENTS AND PROCEDURES
7.1 Semen parameters
The following non-invasive semen parameters will be assessed in this sub-study and are 
appropriate surrogate markers for evaluation of testicular toxicity: sperm concentration, semen 
volume, sperm motility and sperm morphology.
All semen analyses will be performed in accordance with the WHO Guidance (5th edition; WHO 
Guidance 2010). Instructions for the collection, handling and analyses of semen samples will be 
provided in the study laboratory manual. 
7.2 Blood 
A central laboratory will be used for all mandated blood tests. The following blood biomarkers 
will be assessed in this sub-study and are considered appropriate markers of testicular injury: 
serum concentrations of total testosterone, DHT, FSH, LH, inhibin B, prolactin, estradiol. 
If possible, blood samples for hormones assessment should be conducted preferably in the morning 
hours due to the diurnal nature of hormones secretion. If this is not possible, the sampling should 
be done consistently at the same time of the day throughout the sub-study to minimize intra-
variability. A total of approximately 11mL of blood will be drawn for the purpose of this sub-
study. 
Instructions for the collection, handling, storage, and shipment of samples will be described in the 
laboratory manual.
8. STATISTICAL CONSIDERATIONS
This is a descriptive study to evaluate: the change from baseline at Week 24, i.e. after at least one 
spermatogenesis cycle with macitentan 75mg in:

semen parameters 

reproductive hormones,

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
percentage of participants who experience a ≥50% decline vs baseline in sperm 
concentration 
In addition, the reversibility of effects on semen and reproductive hormone parameters will be 
assessed after 12 weeks of discontinuation of macitentan 75 mg treatment. 
No statistical hypothesis will be tested. Only descriptive analyses of data will be performed. Thus, 
the sample size for the study is based on estimating the percent change from baseline in the 
endpoints after 24 weeks of dosing. Limits of the precision estimates are provided as percentage 
of the true mean of the percentage of change. The sample size calculation is not based on the 
proportion of subjects falling within threshold limits. However, these proportions may be 
estimated from the data during analysis.  
8.1 Sample size
The percentage of change from baseline (BL) at post-dose time T is defined as:
Percent change = 100*(XT- XBL)/XBL  
Based on Amory et al. (Amory 2017), an intra-subject coefficient of variation (CV) of 30 and 40% 
were selected for this sample size determination. 
Assuming the sub-study can enroll a sample size ranging between 20 and 50 completers, the lower 
and upper limits of the precision estimates with a 95% confidence interval, expressed as percentage 
of the true mean value are given in table 1 when the true percent change is -50%. The 
corresponding ranges for the percent change are also provided. 
Table 1 Percentage change from baseline = -50%
Intra-subject 
CV (%)
Sample Size 
- Completers 
(N)
Precision Estimate Range 
(as % of true mean) with 
95% confidence
Corresponding range for 
percentage of change with 
95% confidence
Lower Limit 
(%)
Upper Limit 
(%)
Lower Limit 
(%)
Upper Limit 
(%)
0.3
20
85
113
-42.5
-56.5
0.3
30
88
110
-44.0
-55.0
0.3
40
90
109
-45.0
-54.5
0.3
50
91
108
-45.5
-54.0
0.4
20
80
116
-40.0
-58.0
0.4
30
85
113
-42.5
-56.5
0.4
40
87
112
-43.5
-56.0
0.4
50
88
110
-44.0
-55.0
Assuming an intra-subject CV of 40% and true percent change (decrease) from baseline equal to 
-50%, the precision estimates ranges (when expressed as the %of true mean value) will be 80 to 
116% for N= 20 completers and 88 to 110% for N= 50 completers, with 95% confidence.  
Correspondingly, the estimated ranges for the percent change will be -40 to -58% for N= 20 
completers and -44 to -55% for N= 50 completers.

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8.2 Statistical Methods
The percent change from baseline in semen parameters and reproductive hormones at Week 24, 
and the reversibility of these parameters will be presented along with 95% confidence intervals. 
The percentage of participants who experience a ≥50% decline vs baseline in sperm concentration 
after week 24 will be estimated along with 95% confidence intervals. 
8.3 Analyses timepoints
This sub-study will include the following analysis timepoints (AT):

AT1: once all sub-study participants have reached their week 24 visit during the double-blind 
treatment period;

AT2: once all sub-study participants have reached their week 24 visit during the open-label 
treatment extension period;

AT3: once all sub-study participants have either completed or prematurely discontinued the 
sub-study. This analysis timepoint may be skipped if no participant discontinue treatment after 
AT 2, e.g. all participants continue into a post-trial treatment access program or switch to 
commercially available treatment with macitentan 75 mg after the end of the study.

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10.18 Appendix 18: : Study Conduct During a Natural Disaster
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants and 
study-site personnel; travel restrictions/limited access to public places, including hospitals; study 
site personnel being reassigned to critical tasks. 
In alignment with recent health authority guidance, the sponsor is providing options for study 
related participant management in the event of disruption to the conduct of the study. This guidance 
does not supersede any local or government requirements or the clinical judgement of the 
investigator to protect the health and well-being of participants and site staff. If, at any time, a 
participant’s safety is considered to be at risk, study intervention will be discontinued, and study 
follow-up will be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent 
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each 
contact, participants will be interviewed to collect safety data. Key efficacy endpoint assessments 
should be performed if required and as feasible. Participants will also be questioned regarding 
general health status to fulfill any physical examination requirement. 
Every effort should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow-up. Modifications to protocol-required assessments may be 
permitted via COVID-19 Appendix after consultation with the participant, investigator, and the 
sponsor.
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance. 
If a participant has tested positive for COVID-19, the investigator should contact the sponsor’s 
responsible medical officer to discuss plans for study intervention and follow-up. Modifications 
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the 
clinical study report.

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GUIDANCE SPECIFIC TO THIS PROTOCOL
STUDY VISITS

Missed visits, missed assessments or assessments performed out of window due to COVID-
19 will be captured in the clinical trial management system for protocol deviations with the 
prefix “COVID-19-related”, with the actual visit date documented or reason for withdrawal 
specified. Other relevant study elements impacted by the pandemic should also be 
documented / labeled as “COVID-19 related” in the clinical trial management system for 
protocol deviations or other study system, as applicable.

Discontinuations of study interventions and withdrawal from the study due to COVID-19 will 
be captured with the prefix “COVID-19-related” in the eCRF. 

Participants entering in screening who are not able to complete all screening and 
randomization assessments on site due to COVID-19 restrictions (eg, no on-site visit possible) 
would be considered screening failures. Up to 2 re-screening assessments are permitted in 
case participant cannot attend randomization visit. 

Scheduled visits that cannot be conducted in person at the study site will be performed to the 
extent possible by remote/virtually/flying nurse service/home visits. This applies to all visits 
except Visit 1/Screening and Visit 2 (randomization) which must be conducted in person at 
the study site. Additionally, Visit 3 (Week 4), Visit 5 (Week 6), Visit 6 (Week 8), Visit 13 
(Week 28) and EODBT/OL1, should be done on-site, if possible.
For scheduled visits that cannot be conducted on-site options may include (as local regulations 
permit):

Involvement of a local registered nurse, or any other properly trained person, site study 
nurse or the participant’s physician to collect required blood samples and/or perform 
physical examinations, as indicated per protocol (see section 1.2 Schedule of Activities 
of the Protocol) for planned remote visits. 

Blood sampling with central laboratory kits may be performed locally and shipped to the 
central laboratory. Alternatively, a local laboratory may be considered, in case the central 
laboratory kits cannot be used for the scheduled blood tests.

Telephone calls at scheduled visits or monthly at a minimum, if the window for scheduled 
visits is wider, with participant and their primary care physician, local nurse, etc if 
applicable.

Telemedicine consultation, if permitted by local regulation and if part of the local clinical 
practice.

Review of any available medical records.
Details regarding these contacts (date, time, contact person) must be properly documented in 
source records including a detailed content of the discussion points (eg, responses from 
participants and/or results of physical evaluation performed by the trained person or treating 
physician).
Participants will be asked to return to the site as soon as possible once restrictions are lifted to 
perform all assessments that would have been missed.

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LABORATORY ASSESSMENTS

For participants not able to perform their regular on-site scheduled visits due to COVID-19 
pandemic (eg, due to self-isolation/quarantine, travel restrictions, limited access to 
hospitals, …), at least the planned safety assessments must be performed remotely, including 
safety laboratory assessments (eg, hematology, liver function test, and urine pregnancy test 
for women of childbearing potential) and physical examination. 

The investigator must review all safety assessments to confirm the participant can pursue 
his/her study treatment. If the safety assessments cannot be performed and reviewed by the 
investigator in a timely manner, the investigator may decide to interrupt or discontinue 
permanently study intervention, if it is in the best interest of the participant.
PHARMACOKINETIC, EFFICACY, AND SAFETY ASSESSMENTS

Enrollment in the hemodynamic sub-studies may be stopped or put on-hold in certain sites or 
countries if necessary, depending on the status of the pandemic situation or site 
recommendation.

The study IDMC will be provided with listings of COVID-19 related protocol deviations and 
will be asked to evaluate their impact on study safety and efficacy measurements.
TREATMENT 

If the participant cannot come to the site for his visits, his/her study intervention may be 
provided, via direct-to-participant shipment, to the participant’s home or distributed to a 
participant’s relative/caregiver, in accordance with local regulations. 

The participant will be asked to save and return empty study medication bottles/unused tablets 
at their next on-site visit. Treatment compliance will meanwhile be assessed via monthly phone 
calls. 

This distribution and shipment of study treatment will be done if the treating physician can 
ensure that they can maintain participant safety oversight (based on clinical evaluation, results 
of laboratory tests and pregnancy test, if applicable).
HANDLING OF SAFETY AND EFFICACY DATA INTEGRITY 
The sponsor will monitor the COVID-19 related protocol deviations and evaluate their impact on 
study safety and efficacy outcomes. 
The statistical analysis plan will specify details on addressing impact of COVID-19 related aspects 
on the analyses. This includes the following planned analyses (not limited to): 

Sensitivity analyses for primary and secondary efficacy endpoints to address intercurrent 
events caused by COVID-19, as well as handling of missing values caused by the limits from 
the COVID-19 pandemic. 

Summary of safety analyses (eg, AEs, SAEs) by COVID-19 (yes or no). 

Summary/listings of protocol deviations related to COVID-19. 

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10.19 Appendix 19: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents.
Amendment 3 (05-August-2020)
Overall Rationale for the Amendment is: 
1.
to merge global protocol version 2 and the local VHP version 3 into a new global version to 
include the changes related to the use of riociguat and the DDI study that were mandated by 
VHP
2.
to implement changes due to an USM (ie, exclusion of patients treated with dual moderate 
CYP3A4/CYP2C9 inhibitors) 
3.
to allow the use of SC treprostinil as background PH-specific therapy, since it has received 
marketing authorization in the EU in April 2020 
4.
to update the statistical section based on EMA Scientific Advice as well as to make minor 
updates and corrections and perform editorial document formatting revisions. 
The updates are indicated in bold for new text and strike-through for deleted text in the following 
table. 
Section number
and Name
Description of Change
Brief Rationale
1.2 Schedule of Activities 
(SoA): Table 1;
8.2.7 Right Heart 
Catheterization
Footnote 7 was added: ‘Physical 
examination at Screening will include 
assessment of the Child Pugh score for 
participants 
with 
known 
hepatic 
impairment’
Further numbering of the remaining 
footnotes is changed due to addition of 
new footnote 7.
Footnote 13: ‘A historical RHC 
performed within 30
60
days of 
Randomization can be used as the 
baseline RHC, provided the criteria for 
historical RHCs described in the RHC 
guidelines (Appendix 16) are met.’
Footnote 7: To
mandate the proper 
documentation of hepatic impairment at 
screening.
Footnote 13: To update the extended period 
for historical RHC which can be used as a 
baseline RHC for the RHC sub-study.
1.2 Schedule of Activities 
(SoA): Table 2 Liver 
Function Tests
Liver function test assessment interval 
was updated as ‘monthly until 52 weeks 
exposure; every 3-months after 52 
weeks 
exposure’. 
Also, 
the 
corresponding footnote 5 was updated: 
‘AST/ALT 
monitoring 
required 
monthly until week 52 if interval 
between 2 regular site visits exceeds 4 
weeks. After 52 weeks exposure in the 
OL period AST/ALT monitoring 
required every 3 monthsly if interval 
between 2 regular site visits exceeds 12
weeks. Local laboratory can be used.
To update the revised information about 
liver function test.

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Section number
and Name
Description of Change
Brief Rationale
2.3.4 Potential Risks
The sentences were revised as:
Serious 
and 
non serious 
Hhepatic adverse events of special 
interest (HAESIs) will be reviewed by 
an International Liver Safety Data 
Review Board (ILSDRB).
Minor revision to improve the clarity of the 
matter.
1.1. Synopsis, and 
3. Objectives and 
Endpoints: Exploratory 
(Double-Blind Treatment 
Period)
Assessment timepoint specified as 
‘Week 28’ was deleted.
Minor update to incorporate all visit 
assessments for all exploratory PROs 
assessed up to 52 weeks.
Two Impact domains were added for 
capturing 
cardiovascular 
symptom 
domain score as physical impact score 
and cognitive/emotional impact score.
To update missing information.
1.1. Synopsis, and 
3. Objectives and 
Endpoints: Safety 
(Double-Blind Treatment 
Period)
The sentences were revised as:

All-cause death up to 30 days 
after 
study 
intervention 
discontinuation up to Week 52
Minor update to specify all-cause-death 
period 
post-treatment 
discontinuation 
consistently with other safety parameters.
4.1 Overall Design
The sentences were revised as:
In case of premature discontinuation, 
the DB treatment period ends on the day 
of intake of the last dose and the 
EODBT visit is performed within 7 
days of taking the decision to stop
intake of the last dose of study 
intervention.
The reporting of study results is updated 
as:
•
The primary final analysis of 
the double-blind (DB) study period
will 
be 
performed 
when 
144 
participants (if there is no sample size 
increase at interim) have completed the 
DB period or prematurely discontinued 
the study. 
•
The final analysis for the 
study, including combined DB and 
OL extension will be performed after 
closure of the OL extension period.
To update information about conducting 
EODBT visit in case of premature 
discontinuation.
To clarify the planned reporting of the 
study results and remove the potentially 
misleading text in context to primary 
analysis.
4.4 End of Study 
Definition: Table 4

DB treatment period was specified 
as ‘52-week’

Footnote ‘a’ revised as: ‘Except 
withdrawal of consent, where 
EOS will be the last visit 
performed’
Minor updates to improve the clarity of the 
matter.
5.1 Inclusion Criteria
Criterion 2 was revised as: ‘Male or 
female ≥18 (or the legal age of consent 
in the jurisdiction in which the study 
is taking place) and ≤80 years of age.’
To specify the age range accepted in 
particular jurisdiction.

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Section number
and Name
Description of Change
Brief Rationale
5.2 Exclusion Criteria
A footnote was added for criterion 16 
related to hepatic impairment as 
follows: ‘The assessment for hepatic 
impairment must be fully documented 
in the medical history for participants 
that have clinical signs and evidence 
(from central and local labs) of hepatic 
impairments at screening’
To mandate the proper documentation of 
hepatic impairment at screening.
5.1 Inclusion criteria
Participants are to receive riociguat as 
per local standard of care, unless 
riociguat 
is 
contraindicated 
or 
unavailable
To ensure that all participants, for whom 
standard 
of 
care 
with 
riociguat 
is 
appropriate, receive riociguat (update 
previously captured in Version 3.VHP)
6.5 Concomitant therapy
Clarification added that participants 
should receive riociguat as per local 
standard of care, unless riociguat is 
contraindicated or unavailable. The 
reasons for a participant not receiving 
riociguat must be documented. 
To ensure that all participants, for whom 
standard 
of 
care 
with 
riociguat 
is 
appropriate, receive riociguat and that the 
reasons for riociguat treatment being 
considered inappropriate are documented
(update previously captured in Version 
3.VHP).
6.5 Concomitant therapy
Changes in exposure which would 
necessitate 
a 
dose 
adaptation 
of 
riociguat were pre-specified.
Criteria for a potential clinically significant 
DDI between macitentan 75 mg and 
riociguat have been pre-defined to allow 
co-administration of riociguat as soon as 
the DDI results are available, and without 
the need for a substantial amendment
(update previously captured in Version 
3.VHP).
6.5.1. Rescue Medication
The sentences were revised as:
PDE-5 
inhibitors, 
prostacyclin, 
prostacyclin 
analogs, 
prostacyclin 
receptor agonist (Their administration 
will not require study intervention 
discontinuation and participants can 
remain in the study).
Wordings added for clarification
7.1.2 Temporary 
Discontinuation
Study 
interruption/treatment 
discontinuation period after which 
treatment 
to 
be 
reinitiated 
was 
corrected.
The sentences were revised as:
Longer interruptions (ie>5 consecutive 
days during each DB up-titration 
step, >14 consecutive days during the 
DB maintenance- and OL period, or 
> 28 days in total) must lead to 
permanent
study 
intervention 
discontinuation.
To rectify the error; to state that longer 
interruptions will lead to permanent study 
discontinuation.

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Section number
and Name
Description of Change
Brief Rationale
8.1 Demographics and 
Baseline Characteristics
The sentences were revised as:
Demographic 
and 
baseline 
characteristic data to be collected on all 
randomized participants include: age, 
sex, race and ethnicity (where local 
regulations permit), date of the initial 
CTEPH diagnosis, 6MWD, WHO FC, 
date 
of 
most 
recent 
CTEPH 
hospitalization, number of previous 
hospitalizations for CTEPH within 6 
months prior to Screening, Child 
Pugh Score for participants with 
known hepatic  impairment.
To describe additional baseline data to be 
captured for all randomized participants.
8.2.1 6-minute walk test
The sentence was updated as:
If the participant wears a mask 
during the 6MWT, this will be 
documented in the eCRF
To state that this information should be 
captured during the conduct of 6-MWT 
during COVID-19
8.2.5 Accelerometry
The sentences were revised as:
The 
vendor 
will 
read 
daily 
counts/minute and will analyze derive 
activity counts and will provide
duration of daytime activity and time 
(minutes) spent in sedentary, light, 
moderate and vigorous physical activity 
based on these activity counts.
To specify the exact procedure for vendor 
to capture the accelerometry assessment 
data.
8.2.7 Right Heart 
Catheterization
The sentences were revised as:
For participants who underwent PEA or 
BPA, the time between the procedure 
and the RHC must be at least 24 and 12
weeks, respectively.
PH-specific therapy must be stable 
for at least 90 days prior to the 
baseline RHC.
To correct error and align with inclusion 
criteria
To indicate PH-specific therapy stability 
requirement prior to baseline RHC in the 
RHC sub-study.
8.3.5 Clinical Safety 
Laboratory Assessments
The sentences were revised as:
For monthly (3-monthly after 52 
weeks exposure in the OL period)
AST/ALT monitoring in between visits, 
a local laboratory can be used. If the 
local laboratory results show an 
increase in AST/ALT ≥3x ULN, the 
participant must return to the site and 
the AST/ALT re-test must be performed 
centrally. 
Only 
abnormal 
local 
laboratory results must be recorded 
in the eCRF.
To specify additional safety related 
information to be captured from local 
laboratory AST/ALT assessments.
8.3.5 Clinical Safety 
Pregnancy tests
The sentence was revised as:
For women of childbearing potential, a 
serum pregnancy test will be performed 
at each regular site visit
at the 
To update information about frequency and 
timepoints to conduct serum pregnancy 
test.

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Section number
and Name
Description of Change
Brief Rationale
frequency defined in the schedule of 
activities.
8.4.1 Time Period and 
Frequency for Collecting 
Adverse Event and 
Serious Adverse Event 
Information
The requirement for reporting SAEs 
was updated: 
[…] within 24 hours of their 
knowledge of the event
was replaced by 
[…] immediately, without undue delay, 
and under no circumstances later than 
24 hours following knowledge of the 
event.
To address the comment that the protocol 
wording was not aligned with the detailed 
2011/C 172/01 (EU) CT-3 guidance on the 
collection, verification and presentation of 
adverse event/reaction reports arising from 
clinical trials on medicinal products for 
human use (update previously captured in 
Version 3.VHP). 
8.4.3. Regulatory 
Reporting Requirements 
for Serious Adverse 
Events
Text removed from protocol:
The SAEs listed below that
are 
expected to occur in participants with 
PAH will be considered as ‘disease-
related’ and ‘expected’ for regulatory 
reporting purposes in this population, 
unless fatal or life-threatening.
Signs 
and 
symptoms 
of 
PH 
worsening/exacerbation/progression 
and, in particular, abdominal pain, 
anorexia, 
chest 
pain, 
cyanosis, 
diaphoresis, dizziness, pre-syncope, 
dyspnea, 
orthopnea, 
fatigue, 
hemoptysis, heart failure, hypoxia, 
palpitations, 
syncope, 
collapse, 
systemic arterial hypotension, and 
tachycardia.
The investigator must report these in the 
AE section of the eCRF and on an SAE 
form. For expedited reporting purposes, 
these SAEs will be treated as ‘disease-
related’ and expected and will therefore 
not require systematic unblinding and 
will not require expedited reporting to 
Health Authorities, IECs/IRBs, and 
investigators.
Due to Actelion integration in Janssen 
Pharmaceutical and in application to its 
operating procedures, these serious 
adverse events will be reported 
as any other SAE.
8.4.4. Pregnancy
The sentences were revised as:
All initial reports of pregnancy in 
female participants or partners of male 
participants must be reported to the 
sponsor by the study-site personnel 
within 24 hours of their knowledge of 
the 
event 
using 
the 
appropriate 
pregnancy notification form. Abnormal 
To 
capture 
reproduction-related 
information in case of all study participants 
and to comply with internal procedures.
Cross-reference to Section 7 corrected to 
relevant subsection.

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Section number
and Name
Description of Change
Brief Rationale
pregnancy outcomes (eg, spontaneous 
abortion, 
fetal 
death, 
stillbirth, 
congenital 
anomalies, 
ectopic 
pregnancy) are considered serious 
adverse events and must be reported 
using the Serious Adverse Event Form. 
For more information on the action that 
should 
be 
taken 
towards 
study 
intervention in case a participant 
becomes pregnant during the study, 
please refer to Section 7.1.2. 7.1.1.
8.4.5
Adverse Events 
of Special Interest
Information in Liver event updated to 
specify a particular SAE.
All events of ALT (or AST) ≥ 3 × 
upper limit of normal (ULN) and 
total bilirubin ≥ 2 × ULN (>35% 
direct bilirubin), which may indicate 
severe liver injury (possible Hy’s 
Law), must be reported as a serious 
adverse event.
To 
update 
information 
about 
SAE 
reporting in case of elevated ALT, AST 
and total bilirubin levels, indicating sever 
liver injury.
8.7 Pharmacodynamics
The sentence was revised as:
Sparse sampling consists of a pre 
dose and a 2-10 hours post-dose ET-1 
sample.
To state additional information about 
sparse sampling.
9.3 Population of 
Analyses
Following points related to analysis set 
were revised as:
2.
Final analysis of DB study 
period when all participants have 
completed Week 52 or prematurely 
discontinued the study,
3.
Final analysis of study: when 
all participants have completed the OL 
extension period.
Safety analysis set (SAS): Participants 
will be analyzed according to the 
intervention they actually received at 
randomization (which may be different 
to the study intervention arm they are 
assigned to via IRS)
To clarify the planned reporting of the 
study results and remove the potentially 
misleading text in context to primary 
analysis.
Synopsis; 
9.4.1. Primary Efficacy 
Analysis: Estimand-C: 
Intercurrent events
The sentences were revised as:
All scheduled assessments following 
the date of death will be replaced by a 
‘worst-case’ imputation, ie, the lowest 
observed value of 6MWD change from 
baseline across both treatment groups 
and over all assessments up to Week 
28.
To clarify the assessments used in 
imputation

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Status: Approved, Date: 16 December 2020
Section number
and Name
Description of Change
Brief Rationale
The sentences were revised as:
All 6MWD assessment performed after 
end 
of 
intervention 
(possibly 
treatment related ) plus 7 days or 
after administration of  rescue 
therapy these intercurrent events will 
be ignored in the analysis and for each 
visit occurring after the IE, the 
minimum of the following values: (1) 
the last observed value (observed 
6MWD change from baseline) prior to 
intercurrent event at the participant 
level and (2) the 25th percentile of 
observed 6MWD change from baseline 
values (both treatment groups pooled 
and over all assessments up to Week 
28), will be considered instead.
To correct the error in the intercurrent 
event with respect to end of intervention 
adding plus 7 days  
9.4.1. Primary Efficacy 
Analysis: Handling of 
missing data
The sentences were updated as:
The imputation of change from 
baseline will be bound by the baseline 
value so that any worsening cannot 
be greater than baseline value and no 
improvement from baseline will be 
imputed for missing or replacement 
of 
assessments 
following 
these 
intercurrent events.
To 
prevent 
impossible 
values 
or 
implausible 
improvement 
following 
imputation of intercurrent events.
9.4.1. Primary Efficacy 
Analysis: Main analysis
The sentences were revised as:
Type I error control with respect to 
conducting an unblinded sample size 
re-estimation will be detailed in the 
SAP.
To clarify that a two-stage testing 
procedure will be detailed in the SAP 
9.4.1. Primary Efficacy 
Analysis: Sensitivity 
analyses
The sentences were revised as:

An 
analysis 
will 
be 
conducted 
to 
assess 
the 
robustness of the results of 
the main analysis handling 
deaths before / after rescue 
therapy in the same way so 
that if a participant dies 
while on rescue therapy the 
imputation rules for death 
will be applied.
To assess robustness of handling deaths 
before / after rescue therapy
9.4.1. Primary Efficacy 
Analysis: Supplementary  
Analyses; 
Table 13 Supplementary 
Estimands of the Primary 
Endpoint
Contents of the table modified as per 
study needs.
Supplementary 
Estimand 
1: 
clarification of handling missing 
Treatment policy – as not IE, values 
after end of intervention plus 7 days 
are included
Supplementary 
estimand 
1-
Similar 
clarification were done to the intercurrent 
events as per the primary endpoint 
estimand. Text added to clarify handling of 
missing data under MMRM.
Clarification added to type of data used and 
imputations in supplementary estimand 2a 
IE (possibly treatment related) and to 

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Section number
and Name
Description of Change
Brief Rationale
Supplementary Estimand 2a:
Last observation carried forward in 
case of missing data, values after 
EOT are included
LOCF for missing values
Treatment policy – values after end
of intervention are included
Supplementary 
Estimand 
2b 
was 
updated as:
•
Supplementary Estimand 2b 
aims to provide results using MMRM as 
in 
the 
primary 
estimand 
while 
implementing 
a 
treatment 
policy 
strategy with respect to treatment 
discontinuations and rescue medication 
with 
a 
reference-based 
multiple 
imputation   method for missing data. 
Non-parametric (Gould-type) approach 
will also be considered using time-to 
death for participants who die being 
ranked below all surviving participants.
Whole column under Supplementary 
Estimand 2b is added.
indicate that missing data will be handled 
based on the treatment policy strategy
Supplementary Estimand 2b is newly 
added to first provide results using MMRM 
as 
in 
the 
primary 
estimand 
while 
implementing a treatment policy strategy 
with respect to treatment discontinuations 
and rescue medication with a reference-
based multiple imputation   method for 
missing data. 
In addition, a non-parametric (Gould-type) 
approach will also be considered using 
time-to death for participants who die 
being 
ranked 
below 
all 
surviving 
participants.

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Section number
and Name
Description of Change
Brief Rationale
9.4.2.1
Time to first 
clinical worsening up to 
Week 52
Previous information about population-
based analyses, exploratory analyses 
and sensitivity analyses was updated.
The sentences were revised as:
The first secondary efficacy endpoint is 
time 
to 
CEC-confirmed
clinical 
worsening up to Week 52 (see 
definition in Section 3). 
The number of participants with a 
CEC-confirmed clinical worsening 
by first event type (eg, all-cause 
death) will be presented.
Exploratory analyses will be 
conducted for time to first 
CEC-confirmed event for each event 
type separately. Participants who do 
not have a CEC-confirmed clinical 
worsening event type will have their 
time to clinical worsening right-
censored at earliest among the 
following times:

CEC-confirmed 
clinical 
worsening event (any other 
event type)

Study 
intervention 
discontinuation + 7 days. 

Week 52.
Sensitivity analyses will be 
conducted for time to first 
CEC-confirmed clinical worsening 
using a modified definition of clinical 
worsening to exclude the following:
1.
Initiation or dose escalation 
of PH-specific therapy due 
to worsening of PH based on 
additional assessments 
performed at the discretion 
of the investigator and 
confirmed by the CEC
2.
In addition, exploratory 
analyses will be conducted 
for time to first "suspected 
clinical worsening" with 
same definition as for the 
secondary endpoint but 
based on investigator 
judgment. 
Addition of sensitivity and exploratory 
analyses for the first secondary endpoint 
9.4.2.2
Improvement in 
WHO FC from baseline 
to last value while on 
The sentences were revised as:
Assessments that are after (possibly 
treatment related) discontinuation of 
study intervention +7 days and/or 
To clarify handling of intercurrent events 
and missing data due to other reasons 

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Section number
and Name
Description of Change
Brief Rationale
treatment up to Week 28 
(yes/no)
administration 
of 
rescue 
CTEPH 
therapy are excluded from the analysis. 
The 75th percentile (from lowest
observed WHO FC change from 
baseline across both treatment groups 
and over all assessments) will be 
imputed to Week 28 following these 
intercurrent events.
Missing values at Week 28 (for reasons 
other than described above) will be 
imputed by carrying forward the last 
assessment before discontinuation of 
study intervention +7 days and/or 
administration 
of 
rescue 
CTEPH 
therapy.
9.4.2.3
Change from 
baseline to last value 
while on treatment up to 
Week 28 in PAH-
SYMPACT®: Analysis
The sentences were revised as:
Assessments that are after possible 
treatment related discontinuation of 
study intervention +7 days and/or 
administration 
of 
rescue 
CTEPH 
therapy are excluded from the analysis. 
The maximuminimum of the following 
values: (1) the last observed value 
(change from baseline)
prior to 
intercurrent event at the participant 
level and (2) the 725th percentile of 
observed change from baseline values 
(both treatment groups pooled and over 
all assessments) will be imputed to 
Week 28 following these intercurrent 
events.
To clarify handling of intercurrent events 
and missing data due to other reasons
9.4.2.5
Change from 
baseline to Week 28 in 
accelerometer-assessed 
proportion of time spent 
in moderate to vigorous 
physical activity
The sentences were revised to update 
minor clarification.

Assessments that are after 
(possibly treatment related)
discontinuation 
of 
study 
intervention +7 days and/or 
administration 
of 
rescue 
CTEPH therapy are excluded 
from 
the 
analysis. 
The 
minimum of the following 
values: (1) the last observed 
value (change form baseline)
prior to intercurrent event at 
the participant level and (2) the 
25th percentile of observed 
change from baseline values 
(both treatment groups pooled 
and over all assessments) will 
be imputed to Week 28 
following these intercurrent 
events.
To clarify handling of intercurrent events 
and missing data due to other reasons

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Status: Approved, Date: 16 December 2020
Section number
and Name
Description of Change
Brief Rationale
Synopsis; 
9.4.3
Safety Analyses:
Pulmonary Function Tests was deleted:
Pulmonary Function Tests
Descriptive statistics of PFTs (FEV1 
and FVC) values and changes from 
baseline 
will be summarized by 
intervention group.
PFT data not to be collected post baseline.
Table 8 footnote
Footnote related to RHC was updated 
stating that the submission of RHC 
tracing is optional.
To clarify that the RHC tracing submission 
is optional.
Appendix 4: Adverse 
Events: Definitions and 
Procedures for 
Recording, Evaluating, 
Follow-up, and Reporting
Removal of reference to disease-related
SAEs in Section 8.4.4.
Due to Actelion integration in Janssen 
Pharmaceutical and in application to its 
operating procedures, these serious 
adverse events will be reported 
as any other SAE.
Appendix 14: Patient 
Health Questionnaire 
(PHQ-8)
A revised PHQ-8 questionnaire is 
included.
To correct formatting of the PHQ-8.
Appendix 16: Actelion 
Heart catheterization 
guidance
Following statement was deleted at all 
instances in Appendix 16:‘Values must 
be recorded as they were consecutively 
measured.’
To 
align 
with 
Actelion 
Heart 
Catheterization guidelines 
Appendix 17: COVID-19 
Appendix
Study-specific COVID-19 appendix is 
included.
New appendix added to provide guidance 
during the COVID-19 pandemic.
Throughout the protocol

The term ‘Subcutaneous OR 
SC’ 
in 
connection 
with 
prostanoids was deleted to 
indicate that the participants 
with background PH-specific 
therapy with SC prostacycins 
can be benefitted from current 
study intervention. 

Minor 
grammatical, 
formatting 
and 
spelling 
changes were made.
Updates were made to correct minor errors 
noted during the authoring of this 
amendment.
Amendment 2 (13 July 2020)
Overall Rationale for the Amendment: The purpose of this amendment was to update the 
exclusion criteria and concomitant therapy sections pertaining to new information regarding a 
drug-drug-interaction of macitentan 75 mg with moderate dual CYP3A4 and CYP2C9 inhibitors 
or co-administration of a combination of moderate CYP3A4 inhibitors and moderate CYP2C9 
inhibitors.
A Protocol Amendment Summary of Changes Table for the current amendment is provided below.

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Status: Approved, Date: 16 December 2020
Section number
and Name
Description of Change
Brief Rationale
5.2 Exclusion criteria -
Exclusion criteria related 
to macitentan use
The exclusion criterion 21 was updated.
1. Treatment with strong CYP3A4 inhibitors, (eg, 
ketoconazole, 
itraconazole, 
voriconazole, 
clarithromycin, 
telithromycin, 
nefazodone, 
ritonavir, and saquinavir) or moderate dual 
CYP3A4/CYP2C9 
inhibitors 
(eg, 
fluconazole, 
amiodarone) 
or 
co-
administration 
of 
a 
combination 
of 
moderate 
CYP3A4 
(eg, 
ciprofloxacin, 
cyclosporine, 
diltiazem, 
erythromycin, 
verapamil) 
and 
moderate 
CYP2C9 
inhibitors (eg, miconazole, piperine), within 
30 days prior to Randomization.
To exclude participants who, 
within 
30 
days 
of 
Randomization, 
received 
treatment with a moderate dual 
CYP3A4/CYP2C9 inhibitor or 
who received a combination of 
moderate 
CYP3A4-
and 
moderate CYP2C9 inhibitors.
2.2 Background (Clinical 
Studies 
-
Human 
Pharmacokinetics)
New information on concomitant administration of 
CYP34A and CYP2C9 inhibitors was added as 
follows.
2. Concomitant use of macitentan with strong 
inhibitors or inducers of CYP3A4 or moderate 
dual CYP3A4/CYP2C9 inhibitors or co-
administration 
of 
a 
combination 
of 
moderate CYP3A4 and moderate CYP2C9 
inhibitors should be avoided.
To 
add 
moderate 
dual 
CYP3A4/CYP2C9 inhibitors or 
co-administration 
of 
a 
combination 
of 
moderate 
CYP3A4-
and 
moderate 
CYP2C9 inhibitors to the list of 
forbidden medications.
6.5 Concomitant therapy
New information on concomitant administration of 
CYP34A and CYP2C9 inhibitors was added.
3. Strong CYP3A4 inhibitors (eg, itraconazole, 
ketoconazole, voriconazole, clarithromycin, 
telithromycin, nefazodone, ritonavir, and 
saquinavir) 
or 
moderate 
dual 
CYP3A4/CYP2C9 
inhibitors 
(eg, 
fluconazole, 
amiodarone) 
or 
co-
administration 
of 
a 
combination 
of 
moderate 
CYP3A4 
(eg, 
ciprofloxacin, 
cyclosporine, 
diltiazem, 
erythromycin, 
verapamil) 
and 
moderate 
CYP2C9 
inhibitors (eg, miconazole, piperine).
6.5 
Concomitant 
Medication;
11 References
A new reference was added to Section 6.5 and to 
the reference list.
To provide investigators with 
some examples of CYP3A4 and 
CYP2C9 inhibitors
Amendment 1 (22 April 2020)
Overall Rationale for the Amendment: The protocol was amended to ensure that all participants, for 
whom standard of care with riociguat is appropriate, receive riociguat in the study. Furthermore, 
information on the ongoing drug-drug interaction (DDI) study with riociguat is provided, and the criteria 
for concomitant riociguat therapy (in the absence of a clinically relevant DDI) to be permitted without the 
need for a substantial amendment are defined. 

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Section number
and Name
Description of Change
Brief Rationale
5.1 Inclusion criteria
Participants are to receive riociguat as per local 
standard 
of 
care, 
unless 
riociguat 
is 
contraindicated or unavailable
To ensure that all participants, for 
whom standard of care with riociguat 
is appropriate, receive riociguat
6.5 
Concomitant 
therapy
Clarification added that participants should 
receive riociguat as per local standard of care, 
unless riociguat is contraindicated or unavailable. 
The reasons for a participant not receiving 
riociguat must be documented. 
To ensure that all participants, for 
whom standard of care with riociguat 
is appropriate, receive riociguat and 
that the reasons for riociguat treatment 
being considered inappropriate are 
documented. 
2.2 Background
The ongoing DDI study with riociguat is described 
in the ‘clinical studies’ section. 
To provide information on the 
ongoing DDI study with riociguat. 
6.5 
Concomitant 
therapy
Changes in exposure which would necessitate a 
dose adaptation of riociguat were pre-specified.
Criteria for a potential clinically 
significant DDI between macitentan 
75 mg and riociguat have been pre-
defined to allow co-administration of 
riociguat as soon as the DDI results 
are available, and without the need for 
a substantial amendment.
8.4.1
Time Period 
and Frequency for 
Collecting Adverse 
Event and Serious 
Adverse 
Event 
Information
The requirement for reporting SAEs was updated: 
[…] within 24 hours of their knowledge of the 
event
was replaced by 
[…] immediately, without undue delay, and under 
no circumstances later than 24 hours following 
knowledge of the event.
To address the comment that the 
protocol wording was not aligned with 
the detailed 2011/C 172/01 (EU) CT-
3 
guidance 
on 
the 
collection, 
verification 
and 
presentation 
of 
adverse event/reaction reports arising 
from clinical trials on medicinal 
products for human use.

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JNJ-67896062 / ACT-064992 macitentan
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Confidential – FOIA Exemptions Apply in U.S.
184
Status: Approved, Date: 16 December 2020
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plasma 
derivatives, 
WHO 
Technical 
report 
series. 
(accessed 
on 
16-July-2019). 
Available 
at: 
http://www.who.int/bloodproducts/publications/WHO_TRS_840_A2.pdf.

      CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
1 
Status: Final, Date: 3 August 2020 
Actelion Pharmaceuticals Ltd 
Janssen Research & Development * 
Clinical Protocol 
COVID-19 Appendix 
Protocol Title 
A prospective, randomized, double-blind, multicenter, placebo-controlled, parallel group, 
adaptive Phase 3 study with open-label extension to evaluate efficacy and safety of 
macitentan 75 mg in inoperable or persistent/recurrent chronic thromboembolic 
pulmonary hypertension. 
 MACiTEPH 
Macitentan in inoperAble or persistent/reCurrent chronIc ThromboEmbolic Pulmonary 
Hypertension 
Protocol 67896062CTP3001; Phase 3    
 JNJ-67896062 / ACT-064992 (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 Actelion Pharmaceuticals Ltd; 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.
The term “sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is
identified on the Contact Information page that accompanies the protocol.
United States (US) sites of this study will be conducted under US Food & Drug Administration 
Investigational New Drug (IND) regulations (21 CFR Part 312). 
IND: 77258 
EudraCT NUMBER: 2019-004131-24
Status: 
Final 
Date: 
3 August 2020 
Prepared by: Actelion Pharmaceuticals Ltd and Janssen Research & Development, a division of 
Janssen Pharmaceutica NV  
Document number: 
D-20.277 
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. 
NCT04271475

COVID-19 Appendix  
 
JNJ-67896062 / ACT-064992  (macitentan)  
Clinical Protocol 67896062CTP3001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
2 
Status: Final, Date: 3 August 2020 
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 participants and 
study-site personnel; travel restrictions/limited access to public places, including hospitals; study 
site personnel being reassigned to critical tasks.  
In alignment with recent health authority guidance, the sponsor is providing options for study 
related participant management in the event of disruption to the conduct of the study. This guidance 
does not supersede any local or government requirements or the clinical judgement of the 
investigator to protect the health and well-being of participants and site staff. If, at any time, a 
participant’s safety is considered to be at risk, study intervention will be discontinued, and study 
follow-up will be conducted. 
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent 
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each 
contact, participants will be interviewed to collect safety data. Key efficacy endpoint assessments 
should be performed if required and as feasible. Participants will also be questioned regarding 
general health status to fulfill any physical examination requirement.  
Every effort should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow-up. Modifications to protocol-required assessments may be 
permitted via COVID-19 Appendix after consultation with the participant, investigator, and the 
sponsor.  
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance. 
If a participant has tested positive for COVID-19, the investigator should contact the sponsor’s 
responsible medical officer to discuss plans for study intervention and follow-up. Modifications 
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the 
clinical study report. 
 
 

COVID-19 Appendix  
 
JNJ-67896062 / ACT-064992  (macitentan)  
Clinical Protocol 67896062CTP3001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
3 
Status: Final, Date: 3 August 2020 
GUIDANCE SPECIFIC TO THIS PROTOCOL 
STUDY VISITS 
• 
Missed visits, missed assessments or assessments performed out of window due to COVID-
19 will be captured in the clinical trial management system for protocol deviations with the 
prefix “COVID-19-related”, with the actual visit date documented or reason for withdrawal 
specified. Other relevant study elements impacted by the pandemic should also be 
documented / labeled as “COVID-19 related” in the clinical trial management system for 
protocol deviations or other study system, as applicable. 
• 
Discontinuations of study interventions and withdrawal from the study due to COVID-19 will 
be captured with the prefix “COVID-19-related” in the eCRF.  
• 
Participants entering in screening who are not able to complete all screening and 
randomization assessments on site due to COVID-19 restrictions (eg, no on-site visit possible) 
would be considered screening failures. Up to 2 re-screening assessments are permitted in 
case participant cannot attend randomization visit.  
• 
Scheduled visits that cannot be conducted in person at the study site will be performed to the 
extent possible by remote/virtually/flying nurse service/home visits. This applies to all visits 
except Visit 1/Screening and Visit 2 (randomization) which must be conducted in person at 
the study site. Additionally, Visit 3 (Week 4), Visit 5 (Week 6), Visit 6 (Week 8), Visit 13 
(Week 28) and Visit 15 (EODBT/OL1/Week 52), should be done on-site, if possible.  
For scheduled visits that cannot be conducted on-site options may include (as local regulations 
permit): 
− 
Involvement of a local registered nurse, or any other properly trained person, site study 
nurse or the participant’s physician to collect required blood samples and/or perform 
physical examinations, as indicated per protocol (see section 1.2 Schedule of Activities 
of the Protocol) for planned remote visits.  
− 
Blood sampling with central laboratory kits may be performed locally and shipped to the 
central laboratory. Alternatively, a local laboratory may be considered, in case the central 
laboratory kits cannot be used for the scheduled blood tests. 
− 
Telephone calls at scheduled visits or monthly at a minimum, if the window for scheduled 
visits is wider, with participant and their primary care physician, local nurse, etc if 
applicable.  
− 
Telemedicine consultation, if permitted by local regulation and if part of the local clinical 
practice. 
− 
Review of any available medical records. 
Details regarding these contacts (date, time, contact person) must be properly documented in 
source records including a detailed content of the discussion points (eg, responses from 
participants and/or results of physical evaluation performed by the trained person or treating 
physician). 
Participants will be asked to return to the site as soon as possible once restrictions are lifted to 
perform all assessments that would have been missed. 

COVID-19 Appendix  
 
JNJ-67896062 / ACT-064992  (macitentan)  
Clinical Protocol 67896062CTP3001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
4 
Status: Final, Date: 3 August 2020 
LABORATORY ASSESSMENTS 
• 
For participants not able to perform their regular on-site scheduled visits due to COVID-19 
pandemic (eg, due to self-isolation/quarantine, travel restrictions, limited access to 
hospitals, …), at least the planned safety assessments must be performed remotely, including 
safety laboratory assessments (eg, hematology, liver function test, and urine pregnancy test 
for women of childbearing potential) and physical examination.  
• 
The investigator must review all safety assessments to confirm the participant can pursue 
his/her study treatment. If the safety assessments cannot be performed and reviewed by the 
investigator in a timely manner, the investigator may decide to interrupt or discontinue 
permanently study intervention, if it is in the best interest of the participant. 
PHARMACOKINETIC, EFFICACY, AND SAFETY ASSESSMENTS 
• Enrollment in the hemodynamic sub-studies may be stopped or put on-hold in certain sites or 
countries if necessary, depending on the status of the pandemic situation or site 
recommendation. 
• The study IDMC will be provided with listings of COVID-19 related protocol deviations and 
will be asked to evaluate their impact on study safety and efficacy measurements. 
TREATMENT  
• If the participant cannot come to the site for his visits, his/her study intervention may be 
provided, via direct-to-participant shipment, to the participant’s home or distributed to a 
participant’s relative/caregiver, in accordance with local regulations.  
• The participant will be asked to save and return empty study medication bottles/unused tablets 
at their next on-site visit. Treatment compliance will meanwhile be assessed via monthly phone 
calls.  
• This distribution and shipment of study treatment will be done if the treating physician can 
ensure that they can maintain participant safety oversight (based on clinical evaluation, results 
of laboratory tests and pregnancy test, if applicable). 
 
HANDLING OF SAFETY AND EFFICACY DATA INTEGRITY  
The sponsor will monitor the COVID-19 related protocol deviations and evaluate their impact on 
study safety and efficacy outcomes.  
The statistical analysis plan will specify details on addressing impact of COVID-19 related aspects 
on the analyses. This includes the following planned analyses (not limited to):  
• 
Sensitivity analyses for primary and secondary efficacy endpoints to address intercurrent events 
caused by COVID-19, as well as handling of missing values caused by the limits from the 
COVID-19 pandemic.  
• 
Summary of safety analyses (eg, AEs, SAEs) by COVID-19 (yes or no).  
• 
Summary/listings of protocol deviations related to COVID-19.