Conditions: Chronic Thromboembolic Pulmonary Hypertension
Keywords: Chronic thromboembolic pulmonary hypertension (CTEPH)
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 76
Healthy volunteers: no

Brief summary:
Long-term study to evaluate if macitentan is safe, tolerable and efficient enough to be used for treatment of inoperable chronic thromboembolic pulmonary hypertension (CTEPH)

Detailed description:

Arms:
arm 1: Macitentan 10mg, oral tablet, once daily

Interventions: intervention 1: Macitentan
Intervention descriptions: intervention 1: Macitentan 10mg, oral tablet, once daily

Protocol document:
Prot_000.pdf: 
Actelion Pharmaceuticals Ltd
(a Janssen Pharmaceutical Company of 
Johnson & Johnson)*
Confidential – FOIA Exemptions Apply in U.S.
Macitentan / ACT-064992
Chronic Thromboembolic Pulmonary Hypertension
Protocol AC-055E202
MERIT-2: Macitentan in thE tReatment of Inoperable chronic Thromboembolic 
pulmonary hypertension (Open-Label)
Long term, multicenter, single-arm, open-label extension study of the MERIT-1 
study, to assess the safety, tolerability and efficacy of macitentan in subjects with 
inoperable chronic thromboembolic pulmonary hypertension (CTEPH)
Study Phase:
2
EudraCT Number:
2013-003457-25
Status and version:
Final Version 4
Date:
22 June 2021
EDMS number:
EDMS-RIM-263288, 3.0
*Actelion Pharmaceuticals Ltd (“Actelion”) is a global organization that operates through different
legal entities in various countries. Therefore, the legal entity acting as the sponsor for Actelion
studies may vary, such as, but not limited to Janssen-Cilag International NV; Janssen, Inc; Janssen
Pharmaceutica NV; or Janssen Research & Development, LLC. The term “sponsor” is used
throughout the protocol to represent these various legal entities; the sponsor is identified on the
Contact Information page that accompanies the protocol.
Confidentiality statement
The information provided herein contains Company trade secrets, commercial or financial information that 
the Company customarily holds close and treats as confidential. The information is being provided under the 
assurance that the recipient will maintain the confidentiality of the information under applicable statutes, 
regulations, rules, protective orders or otherwise.
NCT02060721


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 2/90
EDMS-RIM-263288, 3.0
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
SPONSOR CONTACT DETAILS
SPONSOR
ACTELION Pharmaceuticals Ltd*
Gewerbestrasse 16
CH-4123 Allschwil
Switzerland
Clinical Trial Physician 
Contact details of the Clinical Trial Physician can 
be found in the Investigator Site File
MEDICAL HOTLINE
Site-specific toll telephone numbers and toll-free 
numbers for the Medical Hotline can be found in 
the Investigator Site File.
* Actelion Pharmaceuticals Ltd. (“Actelion”) is a Janssen pharmaceutical company of Johnson & Johnson 
and is hereafter referred to as the sponsor of the study.


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 3/90
EDMS-RIM-263288, 3.0
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
CONTRACT RESEARCH ORGANIZATIONS INFORMATION
CENTRAL LABORATORY
Eurofins Global Central Laboratory
Bergschot 71
4817 PA Breda
The Netherlands
Contact person
Please refer to the Central Laboratory Manual.
CENTRAL STUDY DRUG 
RE-SUPPLY
Almac Clinical Technologies
20 Seagoe Industrial Estate
Craigavon BT63 5UA
United Kingdom
Contact person
Please refer to the Investigator Site File.
CENTRAL STUDY DRUG 
RE-SUPPLY
WDC Beerse
Turnhoutseweg 30
Beerse
2340
Belgium
Contact person
Please refer to the Investigator Site File.
A list of site-specific contact details for Clinical Research Organizations (CROs) can 
be found in the Investigator Site File.


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 4/90
EDMS-RIM-263288, 3.0
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
Document
Date
Amendment 3, Version 4
22-Jun-2021
Amendment 2, Version 3
28-Sep-2020
Amendment 1, Version 2
15-Jul-2020
Original Protocol, Version 1
29-Oct-2013
Amendment 3 (22-Jun-2021)
Overall Rationale for the Amendment: The reason for the amendment is to clarify how to manage 
the roll-over of MERIT-2 patients into a continued access program (post-trial access program or 
other open-label extension study). In addition, the forbidden concomitant medications section was 
updated to clarify that macitentan 10 mg is not considered as an investigational treatment.
A Protocol Amendment Summary of Changes Table for the current amendment is provided below 
and the updates are indicated in bold text.
Section Number
and Name
Description of Change
Brief Rationale
Signature For Actelion 
Pharmaceuticals Ltd; 
Investigator Signature 
Page
Signature pages
were deleted and 
replaced with ‘Investigator  Agreement' 
at the end of the document.
To 
align 
with 
Janssen 
TransCelerate protocol template.
Protocol Synopsis AC-
055E202 (Concomitant 
medications);
5.2.3 Forbidden 
concomitant medications
List 
of 
forbidden
concomitant 
medications was updated with ‘Another 
investigational 
drug 
(other 
than 
macitentan 10 mg)’.
The list of forbidden medications 
was updated to clarify that 
macitentan 
10 
mg 
is 
not 
considered to be a forbidden 
investigational drug, to allow 
seamless transition of patients to 
a continued access program.
Protocol Synopsis AC-
055E202 (Study 
Periods);
Table 1 (Visit and 
assessment schedule);
3.1 Study design;
Figure 1 (Study design);
8.1.5 EOT visit;   
8.2 Safety follow-up 
period 
It was clarified that for patients who are 
entering a continued access program, the 
enrollment into the continued access 
program (post-trial access program or 
other open-label study) must occur on the 
day of the last visit of the MERIT-2 study 
(end-of-study [EOS], which corresponds 
to end-of-treatment [EOT] in this case). 
The purpose of the 30 day safety 
follow-up period is to monitor the 
subjects after intake of their last 
dose of study treatment for 
potential 
safety 
issues. 
For 
subjects 
who 
seamlessly 
transition to a continued access 
program with the same treatment, 
the safety follow-up period is not 
applicable since these subjects do
not stop treatment.  Therefore, for 
subjects who enter a continued 
access program, their EOT visit 
will be the EOS visit at the same 
time.  
10.1.4 Reporting of 
adverse events;
10.2.2.2
During 
treatment and follow-up 
periods; 
10.3.1 Reporting of 
pregnancy
Text corresponding to reporting of 
adverse event (AE), serious adverse event 
(SAE) and pregnancy up to 30 days after 
study drug distinuation was revised as: 
‘(up to EOS for participants who enter 
a continued access program on the 
same day as the EOS visit, see Section 


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 5/90
EDMS-RIM-263288, 3.0
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Section Number
and Name
Description of Change
Brief Rationale
8.2.1)’.
Protocol Synopsis AC-
055E202 (Study 
periods);
8.1.5 EOT visit 
EOT visit definition was updated as 
follows:
‘End of treatment (EOT): The end of 
all study treatment for an individual 
participant.’
It is clarified in the safety 
reporting requirements that for 
participants who enter a post-trial 
access program or another open 
label trial, safety information is to 
be reported up to EOS visit in this 
study. 
Protocol Synopsis AC-
055E202 (Study 
periods);
8.2.1 EOS visit 
Following content was added to define 
EOS for individual participants:
For an individual participant, EOS 
visit is defined as follows:
−For participants that complete 
treatment, EOS visit is 
defined as the safety follow-
up visit 30–35 days after last 
study treatment intake. 
−For participants that 
prematurely discontinue 
study treatment, EOS visit is 
defined as the safety follow up 
visit 30–35 days after last 
study treatment intake.
−For participants who complete 
treatment and who are 
entering a continued access 
program (post-trial access or 
other open-label extension 
study) the EOS visit is defined 
as the EOT visit.
9 Study Completion
End of current OL study was redefined as 
‘EOS visit’. 
For consistency.
9.2 End of the trial
End of trial was redefined as: ‘The end of 
the trial is reached when all the subjects 
have either completed their EOS visit, 
died or are lost to follow-up.’
For clarification.
9.4 Medical care of 
subjects after End-of-
Study
Following statement was added:
‘Local regulations on continued access 
will always take precedence.’
For clarification.
Throughout the protocol
Minor 
grammatical, 
formatting, 
or 
spelling changes have been made.
Minor errors were noted.


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 6/90
EDMS-RIM-263288, 3.0
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
TABLE OF CONTENTS
SPONSOR CONTACT DETAILS......................................................................................2
CONTRACT RESEARCH ORGANIZATIONS INFORMATION ...................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE................................4
TABLE OF CONTENTS.....................................................................................................6
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................11
PROTOCOL SYNOPSIS AC-055E202 ............................................................................13
CORE PROTOCOL...........................................................................................................21
1
BACKGROUND.........................................................................................................21
1.1
Indication......................................................................................................21
1.2
Macitentan ....................................................................................................22
1.2.1
Macitentan – Summary of risks and safety measures.......................22
1.3
Purpose and rationale of the study................................................................24
2
STUDY OBJECTIVES...............................................................................................25
3
OVERALL STUDY DESIGN AND PLAN ...............................................................25
3.1
Study design .................................................................................................25
3.2
Study committees .........................................................................................26
4
SUBJECT POPULATION..........................................................................................26
4.1
Subject population description and rationale................................................26
4.2
Inclusion criteria...........................................................................................27
4.3
Exclusion criteria..........................................................................................28
5
TREATMENTS ..........................................................................................................28
5.1
Study treatments ...........................................................................................28
5.1.1
Study drugs .......................................................................................28
5.1.2
Dose rationale ...................................................................................28
5.1.3
Investigational drug ..........................................................................29
5.1.4
Treatment assignment.......................................................................29


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 7/90
EDMS-RIM-263288, 3.0
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5.1.5
Blinding ............................................................................................29
5.1.6
Study drug supply.............................................................................29
5.1.7
Compliance with study treatment .....................................................31
5.1.8
Study drug interruption and premature discontinuation of study 
drug...................................................................................................32
5.2
Concomitant medications .............................................................................35
5.2.1
Definition..........................................................................................35
5.2.2
Reporting of concomitant medications in the eCRF.........................35
5.2.3
Forbidden concomitant medications.................................................35
6
STUDY ENDPOINTS ................................................................................................36
6.1
Exploratory efficacy endpoints.....................................................................36
6.2
Safety and tolerability endpoints ..................................................................36
7
STUDY ASSESSMENTS...........................................................................................36
7.1
Baseline parameters......................................................................................36
7.1.1
Baseline demographics and disease characteristics..........................36
7.2
Efficacy assessments ....................................................................................37
7.2.1
Six-minute walk test and Borg dyspnea index..................................37
7.2.2
WHO functional class.......................................................................37
7.3
Safety and tolerability assessments ..............................................................38
7.3.1
Vital signs .........................................................................................38
7.3.2
Weight...............................................................................................38
7.3.3
Physical examination........................................................................38
7.3.4
Laboratory assessments ....................................................................38
8
SCHEDULE OF VISITS ............................................................................................42
8.1
Treatment period...........................................................................................42
8.1.1
Enrollment visit (Visit 1)..................................................................42
8.1.2
Month 1 visit (Visit 2) ......................................................................43
8.1.3
Monthly laboratory and safety monitoring (Months 2, 3, 4, 5, 7, 
8, 9….)..............................................................................................44
8.1.4
Visits at 6-monthly intervals (Visits 3, 4 etc.)..................................44
8.1.5
EOT visit...........................................................................................45
8.2
Safety follow-up period................................................................................46
8.2.1
EOS visit...........................................................................................46
8.3
Unscheduled visits........................................................................................46
9
STUDY COMPLETION.............................................................................................47
9.1
Withdrawal from study.................................................................................47


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 8/90
EDMS-RIM-263288, 3.0
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
9.2
End of the trial ..............................................................................................48
9.3
Premature termination or suspension of the study........................................48
9.4
Medical care of subjects after End-of-Study................................................49
10 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS...........................49
10.1
Adverse events..............................................................................................49
10.1.1
Definitions of adverse events............................................................49
10.1.2
Intensity of adverse events................................................................50
10.1.3
Relationship to study drug ................................................................50
10.1.4
Reporting of adverse events..............................................................50
10.1.5
Follow-up of adverse events.............................................................51
10.2
Definitions of serious adverse events ...........................................................51
10.2.1
Serious adverse events......................................................................51
10.2.2
Reporting of serious adverse events .................................................52
10.2.3
After the 30-day follow-up period....................................................52
10.2.4
Reporting procedures........................................................................52
10.3
Pregnancy .....................................................................................................53
10.3.1
Reporting of pregnancy ....................................................................54
10.3.2
Follow-up of pregnancy....................................................................54
10.4
Study safety monitoring................................................................................54
10.5
Product quality complaint handling..............................................................54
10.5.1
Procedures.........................................................................................55
10.5.2
Contacting sponsor regarding product quality..................................55
10.6
Special reporting situations ..........................................................................55
11 STATISTICAL METHODS .......................................................................................55
11.1
Variables.......................................................................................................56
11.1.1
Time windows...................................................................................56
11.1.2
Exploratory variables........................................................................57
11.1.3
Safety variables(s).............................................................................57
11.2
Analysis Sets.................................................................................................58
11.2.1
Full Analysis Set (FAS)....................................................................58
11.2.2
Open-Label Analysis Set (OLAS) ....................................................58
11.2.3
Restricted Analysis Set (RAS)..........................................................58
11.2.4
Open-Label Safety Set (OLSS).........................................................58
11.2.5
Role of the different analysis sets.....................................................58
11.2.6
Randomization and stratification......................................................59
11.3
Description of statistical analyses.................................................................59
11.3.1
General considerations......................................................................59
11.3.2
Analysis 
of 
subject 
disposition 
and 
study 
completion/withdrawal .....................................................................60


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 9/90
EDMS-RIM-263288, 3.0
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
11.3.3
Analysis of the exploratory variables ...............................................61
11.3.4
Exposure to study drug .....................................................................62
11.3.5
Demographic and baseline characteristics........................................62
11.3.6
Analysis of the safety variables ........................................................62
11.4
Sample size...................................................................................................63
12 DATA HANDLING....................................................................................................63
12.1
Data collection..............................................................................................63
12.2
Maintenance of data confidentiality .............................................................64
12.3
Database management and quality control...................................................64
13 PROCEDURES AND GOOD CLINICAL PRACTICE.............................................65
13.1
Ethics and Good Clinical Practice................................................................65
13.2
Independent Ethics Committee / Institutional Review Board ......................65
13.3
Informed consent ..........................................................................................66
13.4
Compensation to subjects and investigators.................................................67
13.5
Protocol adherence/compliance....................................................................67
13.6
Protocol amendment.....................................................................................67
13.7
Essential documents and retention of documents.........................................67
13.8
Monitoring....................................................................................................69
13.9
Audit .............................................................................................................69
13.10
Inspections....................................................................................................69
13.11
Reporting of study results and publication...................................................70
14 REFERENCES............................................................................................................71
15 APPENDICES.............................................................................................................72
INVESTIGATOR AGREEMENT.....................................................................................90
LIST OF TABLES
Table 1
Visit and assessment schedule...................................................................19
Table 2
Use of analysis sets for analysis of efficacy and safety variables.............59
LIST OF FIGURES
Figure 1
Study design ..............................................................................................26


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 10/90
EDMS-RIM-263288, 3.0
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
LIST OF APPENDICES
Appendix 1
Sponsor Guidelines for 6MWT .................................................................72
Appendix 2
Borg Dyspnea Index (Perceived Breathlessness / Borg Scale) .................75
Appendix 3
WHO Functional Classification of Pulmonary Hypertension...................76
Appendix 4
Laboratory Abnormalities .........................................................................77
Appendix 5
Central Laboratory Alert Flags..................................................................79
Appendix 6
Central Laboratory Normal Ranges ..........................................................80
Appendix 7
Protocol Amendment History....................................................................84


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 11/90
EDMS-RIM-263288, 3.0
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
LIST OF ABBREVIATIONS AND ACRONYMS
6MWD
6-minute walk distance
6MWT
6-minute walk test
AE
Adverse event
ALT
Alanine aminotransferase
AP
Alkaline phosphatase
AST
Aspartate aminotransferase
BMI
Body mass index
BP
Blood pressure
BUN
Blood urea nitrogen
CL
Confidence limits
CRO
Clinical Research Organization
CRP
C-reactive protein
CS
Clinically significant
CTEPH
Chronic thromboembolic pulmonary hypertension
CV
Curriculum vitae
CYP
Cytochrome P-450
DB
Double-blind
DBP
Diastolic blood pressure
DoA
Delegation of authority
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture 
EOS
End-of-Study
EOT
End-of-Treatment
ERA
Endothelin receptor antagonist
ET
Endothelin 
ETA
Endothelin receptor A
ETB
Endothelin receptor B
FAS
Full Analysis Set
FC
Functional class
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HR
Heart rate
IB
Investigator’s Brochure
ICH
International Council on Harmonisation
ICF
Informed Consent Form
IEC
Independent Ethics Committee
ILSB
International Liver Safety Board
IMP
Investigational Medicinal Product


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 12/90
EDMS-RIM-263288, 3.0
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
INR
International normalized ratio
IRB
Institutional Review Board
ISF
Investigator Site File
IXRS
Interactive voice/web recognition system
LT
Liver test
MedDRA
Medical Dictionary for Regulatory Activities
MERIT
Macitentan 
in 
thE 
tReatment 
of 
Inoperable 
chronic 
Thromboembolic pulmonary hypertension
NCS
Not clinically significant
OL
Open-label
OLAS
Open-Label Analysis Set
OLSS
Open-Label Safety Set
PE
Pulmonary embolism
PEA
Pulmonary endarterectomy
PAH
Pulmonary arterial hypertension
PH
Pulmonary hypertension
PQC
Product quality complaint
PVR
Pulmonary vascular resistance
RAS
Restricted Analysis Set
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SBP
Systolic blood pressure
SC
Steering committee
SOC
System organ class
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reaction
ULN
Upper limit of the normal range
WHO
World Health Organization


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 13/90
EDMS-RIM-263288, 3.0
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
PROTOCOL SYNOPSIS AC-055E202
TITLE
Long term, multicenter, single-arm, open-label extension 
study of the MERIT-1 study, to assess the safety, tolerability 
and efficacy of macitentan in subjects with inoperable 
chronic thromboembolic pulmonary hypertension (CTEPH)
ACRONYM
MERIT-2: Macitentan in thE tReatment of Inoperable 
chronic Thromboembolic 
pulmonary 
hypertension 
(Open-Label)
OBJECTIVES
Safety objective:
To evaluate the long-term safety and tolerability of 
macitentan 10 mg in subjects with inoperable CTEPH.
Efficacy objective:
To evaluate the long term effects of macitentan 10 mg on
exercise capacity and functional class (FC).
DESIGN 
Multicenter, open-label (OL) extension, single-arm, Phase 2 
study
STUDY 
PLANNED 
DURATION
First 
subject
First visit
Q3 
2014
Last 
subject
First visit
Q4
2015
Last 
subject
Last visit
Open
SITES / COUNTRIES 
Approximately 60 centers in approximately 15 countries
(planned).
SUBJECTS / GROUPS
Up to 78 subjects in 1 group treated with macitentan 10 mg.
INCLUSION 
CRITERIA
1. Written informed consent to participate in the study 
obtained from the subject, according to local regulations, 
prior to initiation of any study mandated procedure.
2. Subject with CTEPH having completed the double-blind
(DB) AC-055E201 / MERIT-1 study as scheduled (i.e., 
who remained in the DB study up to Week 24).
3. Females of childbearing potential must have a negative 
pre-treatment serum pregnancy test, be advised on 
appropriate methods of contraception, and agree to use 
2 reliable methods of contraception concurrently during 
study treatment and for at least 30 days after study 
treatment discontinuation


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 14/90
EDMS-RIM-263288, 3.0
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
EXCLUSION 
CRITERIA
1. Permanent discontinuation of DB study treatment due to 
an hepatic adverse event or liver aminotransferase 
abnormalities.
2. Hemoglobin < 100g/L.
3. Serum aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) > 3 × the upper limit of normal 
(ULN).
4. Systolic blood pressure (SBP) < 90 mmHg.
5. Treatment with strong cytochrome P-450 3A4 (CYP3A4) 
inducers such as rifabutin, rifampin, rifampicin, 
rifapentin, carbamazepine, phenobarbital, phenytoin, St. 
John’s wort.
6. Treatment with another endothelin receptor antagonist 
(ERA [e.g., bosentan, ambrisentan]).
7. Any known factor (e.g., drug or substance abuse) or 
disease (e.g., unstable psychiatric illness) that, in the 
opinion of the investigator, may interfere with treatment 
compliance or interpretation of the results, or that may 
influence the ability to comply with any of the study 
requirements.
8. Known hypersensitivity to drugs of the same class as 
macitentan, or to any of the study drug excipients. 
9. Females who are pregnant or plan to become pregnant 
during the study, or are lactating.
CONCOMITANT 
MEDICATIONS
Prohibited

Strong 
CYP3A4
inducers 
(e.g., 
carbamazepine, 
phenytoin, phenobarbital, rifampin/rifampicin, rifabutin, 
rifapentin, St. John’s wort). 

Strong CYP3A4 inhibitors (e.g., ketoconazole, 
itraconazole, voriconazole, clarithromycin, 
telithromycin, nefazodone, ritonavir, and saquinavir) or 
moderate dual CYP3A4/CYP2C9 inhibitors (e.g.,
fluconazole, amiodarone) or co-administration of a 
combination of moderate CYP3A4 (e.g., ciprofloxacin, 
cyclosporine, diltiazem, erythromycin, verapamil) and 
moderate CYP2C9 inhibitors (e.g., miconazole, 
piperine) until study intervention discontinuation. 


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 15/90
EDMS-RIM-263288, 3.0
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
* If patients are currently stable on a strong CYP3A4 
inhibitors (e.g., ketoconazole, itraconazole, voriconazole, 
clarithromycin, telithromycin, nefazodone, ritonavir, and 
saquinavir), moderate dual CYP3A4/CYP2C9 inhibitors 
(e.g., fluconazole, amiodarone) or co-administration of a 
combination of moderate CYP3A4 (e.g., ciprofloxacin, 
cyclosporine, diltiazem, erythromycin, verapamil) and 
moderate CYP2C9 inhibitors (e.g., miconazole, piperine), 
the patient may remain on current treatment per the 
investigator’s discretion based on his/her clinical 
judgement and risk-benefit assessment.

Another ERA (e.g., bosentan, ambrisentan).

Another investigational drug (other than macitentan 
10 mg)
STUDY PERIODS
Treatment period: for each subject, the OL treatment 
duration will last from his/her enrollment (Visit 1) up to the 
End-of-Treatment, i.e., until whichever of the following 
occurs first: 

Commercial availability of macitentan in this indication 
in the subject’s country,

Actelion decides to stop this study (AC-055E202 / 
MERIT-2 OL extension),

The subject or the investigator decides to discontinue the 
study drug.
End of treatment (EOT): The end of all study treatment for 
an individual participant.
Safety follow-up: For an individual subject, the end of this 
OL study corresponds to the 30-day safety follow-up, which 
should be performed 30 days after the permanent 
discontinuation of study drug.
For patients who are entering a continued access program, the 
enrollment into the continued access program (post-trial 
access program or other open-label study) must occur on the 
day of the last visit of the MERIT-2 study (EOS, which 
corresponds to EOT in this case).
End of Study (EOS): For an individual participant, EOS visit 
is defined as follows:


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
For participants that complete treatment, EOS visit is 
defined as the safety follow-up visit 30–35 days after last 
study treatment intake. 

For participants that prematurely discontinue study 
treatment, EOS visit is defined as the safety follow-up 
visit 30–35 days after last study treatment intake.

For participants who complete treatment and who are 
entering a continued access program (post-trial access or 
other open-label extension study) the EOS visit is defined 
as the EOT visit.
INVESTIGATIONAL 
DRUG
Macitentan 10 mg, oral tablet, to be taken once daily.
COMPARATOR 
DRUG 
Not applicable
EFFICACY 
ENDPOINTS
Exploratory:

Change from baseline to each scheduled time point in 
exercise capacity, as measured by the 6-minute walk 
distance (6MWD)

Change from baseline to each scheduled time point in 
Borg dyspnea index collected at the end of the 6-minute 
walk test 

Proportion of subjects with worsening of WHO FC from 
baseline to each scheduled time point.
TOLERABILITY 
/ 
SAFETY ENDPOINTS

Treatment-emergent adverse events (AEs) up to 30 days 
after study drug discontinuation.

AEs leading to premature discontinuation of study drug.

Treatment-emergent serious adverse events up to 30 days 
after study drug discontinuation.

Treatment-emergent marked laboratory abnormalities up 
to 30 days after study drug discontinuation.

Change in vital signs (arterial blood pressure [BP], heart 
rate [HR]) and body weight from baseline to all assessed 
time points during the study.
STATISTICAL 
METHODOLOGY 
This study will not be analyzed individually, but in 
combination with data from the DB AC-055E201 / MERIT-1
study.
Sample Size


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STATISTICAL 
METHODOLOGY 
cont. 
The sample size for the OL extension study will be up to 
78 randomized 
subjects 
from 
the 
DB
study 
(AC-055E201 / MERIT-1), who are eligible for and consent 
to enter the OL extension.
Analysis sets
The Full Analysis Set (FAS), used for analysis in the DB 
study only, and reported here for completeness, comprises 
subjects from the DB AC-055E201 / MERIT-1 study who 
were randomized to either placebo or macitentan 10 mg.
The OL analysis set (OLAS), comprises all data from subjects
who enrolled into the OL extension study, from the time they 
enter the OL extension study.  
The restricted analysis set (RAS), comprises all data from
subjects enrolled in the OL extension study who received 
macitentan 10 mg during the AC-055E201 / MERIT-1, from 
the time they enter the DB study.
The OL Safety Set (OLSS), comprises all core and OL study 
subject data from subjects exposed to macitentan at least 
once, during either the DB or OL extension study for the 
period they are exposed to macitentan 10 mg.
Statistical Methods
Analysis of the exploratory efficacy endpoint variables will 
be conducted on the OLAS and RAS:
1. On the OLAS, as change from baseline of the OL 
extension study, by randomized treatment group in the 
DB core study, 
2. On the RAS, as change from baseline of the DB core 
study (single arm)
For the analysis of the exploratory endpoint variables in the 
OL extension no imputation of data will be performed. 
However, in order to maximize the use of collected data and 
to analyze the data at relevant time points, a time-windowing 
approach will be employed to include data from all study 
assessments up to EOS. 
The following analyses will be performed on all available 
data:

A repeated measures analysis of the change from baseline 
in 6MWD.


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
A repeated measures analysis of the change from baseline 
in Borg dyspnea index.
An analysis using shift tables to display change from baseline 
to all window-based time points in WHO FC on the 
dichotomized yes/no worsening variable.
Safety and tolerability endpoints
The statistical evaluation of the safety and tolerability 
endpoint variables will be performed
on the OLSS,
summarizing values and changes at each study visit time 
point from baseline of the DB study for subjects originally 
randomized to macitentan in the DB core study and as 
changes from baseline of the OL study for subjects originally 
randomized to placebo in the DB study. 
Statistical inference
No multiplicity adjustments will be made on exploratory 
efficacy endpoints. Any two-sided p-value ≤0.05 will be 
identified as statistically significant but will be considered as 
exploratory result.
STUDY 
COMMITTEES
A Steering Committee is involved in the design of the 
study and may be consulted prior to and during the study 
for any relevant medical issues and protocol-related 
questions.
An independent International Liver Safety Board (ILSB; 
an external expert committee of hepatologists) provides 
ongoing assessment and advice regarding any serious 
hepatic events that may require further evaluation during 
the study.
A Publication Committee is involved in the preparation of 
potential
manuscript(s) and will be consulted for 
authorship criteria (if applicable).




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g.
Study drug dispensing according to investigational site practice (e.g., every 6 months, or every month). 
h.
AE reporting: all AEs occurring from study drug initiation and up to 30 days after study drug discontinuation. 
i.
SAE reporting: all SAEs occurring from signature of informed consent and up to 30 days after study drug discontinuation.
j.
If the monthly laboratory samples are not collected at the site, the safety monitoring (assessments of AEs, SAEs, concomitant medications and methods of contraception) should 
be done via a telephone call that must be documented in the subject’s file.
k.
For participants who transition to a continued access program (post-trial access program or other open-label extension study), the EOT visit is defined as the EOS.


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CORE PROTOCOL
1
BACKGROUND 
1.1
Indication
Chronic thromboembolic pulmonary hypertension (CTEPH), one of the leading causes of 
severe pulmonary hypertension (PH), develops from the obstruction of pulmonary artery 
branches following episodes of pulmonary embolism (PE) with incomplete thrombus 
resolution, formation of fibrosis and remodeling of pulmonary blood vessels. 
Consequently, pulmonary vascular resistance (PVR) is increased, leading to PH and 
progressive right heart failure [Jenkins 2012]. CTEPH belongs to the World Health 
Organization (WHO) Group 4 [Simonneau 2009].
There are no specific signs or symptoms for CTEPH. Patients generally present with 
progressive dyspnea on exertion, edema and/or signs of right heart dysfunction including 
fatigue, chest pain and syncope [Pepke-Zaba 2011]. 
The incidence of CTEPH is not precisely known although estimates have ranged from 0.5% 
to 3.8% of patients after an acute PE, and in up to 10% of those with a history of recurrent 
PE [Haythe 2012]. 
CTEPH should be considered in all patients with unexplained PH. When left untreated, 
CTEPH is responsible for significant morbidity and mortality. Historically, 3-year 
mortality has been reported to be as high as 90% in patients with a mean pulmonary artery 
pressure of > 50 mmHg [Jenkins 2012]. 
All patients with suspected CTEPH should be referred to an expert center for a proper 
diagnostic evaluation to exclude or confirm the diagnosis. There are a number of modalities 
available to diagnose CTEPH. Ventilation–perfusion lung scanning is one of the most 
important diagnostic tests to help distinguish CTEPH from other forms of pulmonary 
arterial hypertension (PAH). Pulmonary arteriography is essential to determine whether or 
not a patient is a candidate for surgical intervention. Furthermore, hemodynamic evaluation 
by right heart catheterization provides vital prognostic information [Haythe 2012].
Pulmonary endarterectomy (PEA) is the gold standard treatment for CTEPH and represents 
a potentially curative option in eligible patients [Jamieson 2003]. However, many patients 
with CTEPH are considered non-operable due to predominantly distal thromboembolic 
pathology, or concomitant small-vessel arteriopathy. Therefore, there is a high need for 
medical treatments for CTEPH patients who are inoperable.
To date, none of the pharmacologic therapies approved for PAH (WHO Group 1) have 
demonstrated a clear benefit in randomized controlled trials in CTEPH. However, in a 
recently completed Phase 3 clinical trial in CTEPH patients who were deemed to be 
inoperable or who had persistent or recurrent PH after undergoing PEA, riociguat (a 
guanylate cyclase stimulator) demonstrated a significant improvement in exercise capacity 
and PVR [Ghofrani 2013a]. This new drug also significantly improved the exercise 


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capacity in a recently completed Phase 3 clinical trial in PAH patients [Ghofrani 2013b].
Riociguat has gained regulatory approval for the treatment of CTEPH in several countries, 
including the United States (US), Canada, Japan and European Union (EU). To date, 
riociguat is not approved world-wide. 
1.2
Macitentan
Macitentan (ACT-064992) is an orally active, non-peptide, potent dual endothelin (ET) 
ETA and ETB receptor antagonist (ERA) in clinical development. ERAs are being 
developed for a variety of diseases associated with the deleterious effects of ET, 
particularly in the pulmonary and cardiovascular fields. 
A summary of available macitentan preclinical and clinical data relevant to this study can 
be found in the AC-055E201 / MERIT-1 protocol. For more detailed information, please 
see the most recent version of the Investigator’s Brochure (IB) [Macitentan IB].
1.2.1
Macitentan – Summary of risks and safety measures
Nonclinical studies with macitentan did not identify important risks of likely relevance to 
humans except for teratogenicity, a class effect of ERAs. The protocol includes stringent 
requirements for pregnancy testing and reliable methods of contraception for female 
subjects of childbearing potential.
Macitentan was well tolerated in the completed Phase 1, 2, and 3 studies. A total of 
863 patients received macitentan treatment and 370 patients received placebo in 
randomized, double-blind (DB), placebo-controlled, Phase 2 and 3 studies for a period of 
up to 188 weeks. This represents a total of 1120 patient-years exposure to macitentan 
treatment, and 484 patient-years exposure to placebo treatment.
In 3 placebo-controlled studies with macitentan, no significant imbalance in liver test (LT) 
elevations was observed across macitentan treatment groups (< 3 mg, 3 mg, 10 mg) and 
placebo. The proportions of patients with alanine aminotransferase (ALT) and/or aspartate 
amino transferase (AST) elevations > 3 × the upper limit of normal range (ULN) were 
similar across the treatment groups, but a higher percentage of patients treated with 
macitentan 10 mg had ALT > 3 × ULN compared to placebo. However, there were no 
patients in the studies who met the Hy’s Law criteria (i.e., ALT/AST > 3 × ULN and total 
bilirubin > 2 × ULN), and who had no associated increase in alkaline phosphatase (AP) in 
the absence of alternative explanations which were possibly or likely the cause of the 
elevations. Subjects with serum AST and/or ALT > 3 × ULN will be excluded from the 
proposed clinical trial, and LTs will be assessed every month during the treatment period 
and 30 days after study drug discontinuation. The protocol also includes clear instructions 
regarding re-tests and criteria for treatment discontinuation in the case of clinically relevant 
elevations of aminotransferases.
Treatment with ERAs has been associated with increased incidence of edema, anemia 
and/or decreased hemoglobin [Abman 2009; O’Callaghan 2011]. Treatment with 


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macitentan was associated with a dose-related reduction in hemoglobin levels, which was 
established within the first 3 months of treatment. Decreased hemoglobin levels tended to
show recovery towards baseline after discontinuation of treatment. Higher incidences of 
anemia adverse events (AEs) were reported in a dose-related fashion in the patients treated 
with macitentan in comparison to those treated with placebo. Anemia required transfusion 
in some patients treated with macitentan. Patients with hemoglobin < 100 g/L will be 
excluded from the proposed clinical trial. During the treatment period, hemoglobin levels
will be assessed every month during the first 6 months, and every 3 months thereafter; it 
will be assessed again 30 days after study drug discontinuation. The protocol also includes 
clear instructions regarding re-tests and criteria for treatment discontinuation in the case of 
clinically relevant anemia.
The incidences of edema AEs were similar in the macitentan and placebo groups, although 
subgroup analyses indicated fluctuations in the incidence of edema, with no clear pattern 
according to treatment (macitentan vs placebo) or macitentan dose. Edema serious adverse 
events (SAEs) were uncommon with macitentan treatment and only 3 patients (2 on 
placebo and 1 on macitentan 10 mg) discontinued treatment due to an edema AE. Overall, 
there is no indication that edema represents a significant safety concern with macitentan 
therapy.
Due to the vasodilatory effects of macitentan, effects on blood pressure (BP) might occur. 
In the DB PAH population, there was a slightly higher incidence of AEs denoting 
hypotension, relative to placebo on macitentan. However, hypotension SAEs were reported 
less frequently on macitentan than on placebo, and only one macitentan-treated patient 
discontinued due to this AE. Hypotension AEs were predominantly reported for female 
patients and there was no indication of an increased incidence in other potentially 
vulnerable subgroups, such as the elderly, or patients with renal function impairment at 
baseline. Patients with systolic blood pressure (SBP) < 90 mmHg will be excluded from 
the proposed study.
Reductions from baseline in leukocyte and platelet counts may be observed with 
macitentan. In the AC-055-302 / SERAPHIN study, macitentan was associated with 
modest and non-dose-dependent decreases in mean leukocyte count from baseline to 
End-of-Treatment (EOT). A small proportion of PAH patients, in both placebo and 
macitentan groups, showed markedly reduced platelet counts, with or without bleeding 
complications, at some time during the study. Resolution during continued treatment with 
macitentan was observed, as well as absence of recurrence after treatment re-initiation, 
findings that make a specific, causal relationship to macitentan unlikely.
In the AC-055-302 / SERAPHIN study (macitentan in PAH), menstrual disorder AEs 
(mainly menorrhagia, metrorrhagia, dysfunctional bleed) and ovarian cysts were reported 
at a low incidence overall, but more frequently on macitentan than placebo, in females of 
childbearing potential. None of the events led to discontinuation of study drug, there was 
no consistent drug-dose or drug-exposure pattern, and resolution of menstrual disorder 


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during ongoing treatment was reported in the majority of cases. Confounding factors were 
present in the majority of these cases. A causal relationship to macitentan remains 
uncertain.
In clinical trials, a higher reporting rate of upper respiratory tract infections but also 
bronchitis was seen with macitentan vs placebo. It is likely that many such events may 
represent symptoms of congestion due to local vasodilatation (e.g. rhinitis), rather than 
actual infection. For the clinically more relevant lower respiratory tract infections, 
especially pneumonia, there was no relevant difference between macitentan and placebo. 
In addition, there was a higher incidence of urinary tract infections and gastroenteritis in 
the patients who received macitentan treatment compared to those who received placebo. 
However, given that there was no imbalance in the incidence of these events that were 
reported as SAEs or that led to discontinuation of treatment, coupled with the fact that there 
was no increase in the reporting rate over time, these AEs were considered to be of limited 
clinical relevance. 
Given the extensive and long-term controlled data available with macitentan in PAH and 
the careful follow-up of subjects mandated by the protocol, the benefit/risk assessment 
supports the conduct of the study in subjects with CTEPH.
1.3
Purpose and rationale of the study
The purpose of this study is to gather additional experience with macitentan 10 mg in 
subjects with inoperable CTEPH beyond the 24 weeks of treatment in the DB AC-055E201 
/ MERIT-1 study. 
The rationale of this study relies on the fact that the long term safety of macitentan in this 
population is not known. It is also unknown whether the efficacy of macitentan (if any) 
reaches a plateau at 24 weeks (end of the DB study) or would still increase over a longer 
treatment period. 
In addition, the opportunity will be given to subjects who were on placebo in the DB 
AC-055E201 / MERIT-1 study to receive macitentan 10 mg and benefit from a potentially
active treatment.


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2
STUDY OBJECTIVES
Safety objective:
To evaluate the long-term safety and tolerability of macitentan 10 mg in subjects with 
inoperable CTEPH.
Efficacy objective:
To evaluate the long term effects of macitentan 10 mg on exercise capacity and 
functional class (FC).
3
OVERALL STUDY DESIGN AND PLAN
3.1
Study design 
This study is a multi-center, single-arm, open-label (OL), Phase 2 extension study to assess 
the long-term safety, tolerability and efficacy of macitentan in subjects with inoperable 
CTEPH.
The study will be conducted in approximately 60 centers in approximately 15 countries. 
Up to 78 subjects (males or females) from the DB AC 055E201 / MERIT-1 study will be 
enrolled in this OL study. Subjects will be rolled over from the AC-055E201 / MERIT-1 
study to this OL study without knowledge of their previous study drug (macitentan 10 mg 
or placebo).
Subjects who complete the 24 weeks of the DB MERIT-1 study as scheduled can be 
enrolled in the MERIT-2 OL extension study.
After the Enrollment visit, subjects will come to the site at Month 1 (Visit 2), 
Month 6 (Visit 3), and every 6 months thereafter (Visits 4, 5, 6…), up to the EOT visit [see
Figure 1]. In addition, subjects will perform monthly laboratory and safety monitoring. 
For each subject, the OL treatment duration will last from his/her Enrollment (Visit 1) until 
the EOT, i.e., until the earliest of (i) the commercial availability of macitentan in this 
indication in the subject’s country, or (ii) Actelion decides to stop this AC-055E202 / 
MERIT-2 OL extension study (e.g., if results of the AC-055E201 / MERIT-1 study do not 
show a statistically favorable effect of macitentan in this subject population), or (iii) the 
subject or the investigator decides to discontinue the study drug.
Unscheduled visits may also take place anytime during the study. 
A post-treatment Safety follow-up period (30 days) will follow the permanent study drug 
discontinuation. At the end of this Safety follow-up period, the Safety follow-up / End-of-
Study (EOS) visit will be performed [see Figure 1]; this corresponds to the end of the OL 
study for an individual subject. For patients who are entering a continued access program, 
the enrollment into the continued access program (post-trial access program or other open-
label study) must occur on the day of the last visit of the MERIT-2 study (EOS, which 
corresponds to EOT in this case).




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specific medications such as PDE-5 inhibitors and hence can potentially benefit from 
further treatment. It should be noted that subjects who experience a disease progression 
during the DB study (see AC-055E201 / MERIT-1 study protocol section 6.1.3) can be 
treated with the available standard of care. If they continue into the study up to the 24-week 
visit they are allowed to enter this OL extension, if they still fulfill the selection criteria.
4.2
Inclusion criteria
For inclusion in the study, all of the following inclusion criteria must be fulfilled:
1.
Written informed consent to participate in the study obtained from the subject, 
according to local regulations, prior to initiation of any study mandated procedure.
2.
Subject with CTEPH having completed the DB AC-055E201 / MERIT-1 study as 
scheduled (i.e., who remained in the DB study up to Week 24).
3.
Females of childbearing potential must have a negative pre-treatment serum 
pregnancy test, be advised on appropriate methods of contraception, and agree to use 
2 reliable methods of contraception concurrently during study treatment and for at 
least 30 days after study treatment discontinuation.
Of the 2 contraceptive methods that must be used, one must be from Group 1, and 
one must be from Group 2, defined as follows:
-
Group 1: Oral, implantable, transdermal or injectable hormonal contraceptives, 
intrauterine devices, female sterilization (tubal ligation or non-surgical 
sterilization [e.g., permanent contraception with Essure procedure]), or 
partner’s sterilization (vasectomy). 
o If a hormonal contraceptive is chosen from this group, it must have been
taken for at least 1 month prior to randomization.
o If the Essure procedure is chosen as a contraceptive method, a 
hysteron-salpingogram must have been performed to confirm correct 
location of the microinserts and tubal occlusion (as per manufacturer’s 
recommendations).
-
Group 2: Female or male condoms, diaphragm or cervical cap; any of these 
contraceptive methods must be used in combination with a spermicide.
True abstinence from intercourse with a male partner is considered an acceptable 
method of contraception for this study (not requiring a second reliable of method 
of contraception) only when this is in line with the preferred lifestyle of the subject 
(e.g., homosexual females and females in religious order, nuns for example). 
Note 1: Sexual abstinence not meeting the above-definition, rhythm methods, or 
contraception by the partner alone are not considered as acceptable methods of 
contraception for this study.
Note 2: A female is considered to be of childbearing potential unless she meets at 
least one of the following criteria:
-
Previous bilateral salpingo- and/or oophorectomy, or hysterectomy.


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-
Premature ovarian failure confirmed by a specialist.
-
Pre-pubescence, XY genotype, Turner syndrome, uterine agenesis.
-
Postmenopausal, defined as 12 consecutive months with no menses, without 
an alternative medical cause.
4.3
Exclusion criteria
Eligible subjects must meet none of the following exclusion criteria:
1. Permanent discontinuation of DB study treatment due to an hepatic adverse event or 
liver aminotransferase abnormalities.
2. Hemoglobin < 100g/L.
3. Serum AST and/or ALT > 3 × ULN.
4. SBP < 90 mmHg.
5. Treatment with strong cytochrome P-450 3A4 (CYP3A4) inducers such as rifabutin, 
rifampin, rifampicin, rifapentin, carbamazepine, phenobarbital, phenytoin, St. John’s 
wort.
6. Treatment with another ERA (e.g., bosentan, ambrisentan).
7. Any known factor (e.g., drug or substance abuse) or disease (e.g., unstable psychiatric 
illness) that, in the opinion of the investigator, may interfere with treatment compliance 
or interpretation of the results, or that may influence the ability to comply with any of 
the study requirements.
8. Known hypersensitivity to drugs of the same class as macitentan, or any of the study 
drug excipients. 
9. Females who are pregnant or plan to become pregnant during the study, or are lactating.
5
TREATMENTS
5.1
Study treatments
5.1.1
Study drugs
All subjects will receive macitentan 10 mg during the course of the study.
5.1.2
Dose rationale
In the completed AC-055-302 / SERAPHIN study, two doses of macitentan, 3 mg and 
10 mg, demonstrated efficacy in PAH patients by improving clinical outcomes, functional 
status and exercise capacity. A dose-response was identified with the greatest efficacy 
demonstrated in the 10 mg dose group. Macitentan 10 mg in this patient population was 
well tolerated. For detailed information see the MERIT-1 protocol (section 1.2.2.4 and 
section 1.3) and macitentan IB [Macitentan IB].
Therefore, macitentan 10 mg was selected as the target dose for the MERIT-1 study. The 
same dose will be used in the MERIT-2 OL extension study to assess its longer term safety 


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Protocol AC-055E202, MERIT-2
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in this population and to assess whether the effect observed with this dose in the MERIT-1 
study, if any, reached the plateau or would still increase over time, and whether the 
achieved effect would be maintained over a long treatment period.
5.1.3
Investigational drug
Macitentan 10 mg will be provided as film-coated tablets debossed with ‘10’ on either one 
or both sides.
If the subject is eligible, the first intake of study drug will take place at site, during the 
Enrollment visit, after successful completion of all assessments.
Thereafter, one tablet should be administered orally every morning irrespective of food 
intake. On the day of study visits, the morning dose of the study medication should be 
withheld until all visit assessments have been performed. The tablet should be taken from 
the bottle(s) that is(are) being dispensed during the visit.
5.1.4
Treatment assignment
All eligible subjects will receive macitentan 10 mg. 
At Visit 1 (Enrollment visit), after completion of all assessments, and if the subject is 
eligible, the investigator/delegate will contact the Interactive Voice / Web Recognition 
System (IXRS), which will allocate medication bottles to the subject. 
All study drug bottle numbers must be assigned through the IXRS.
5.1.5
Blinding
Not applicable.
5.1.6
Study drug supply
Actelion will supply all study drug to the site according to local regulations. 
All drug supplies are to be used only in accordance with this protocol, and not for any other 
purpose. 
5.1.6.1
Study drug packaging and labeling
The labeling and packaging of macitentan is conducted according to Good Manufacturing 
Practice, Good Clinical Practice (GCP), and any applicable laws and regulations of each 
country.
5.1.6.1.1 Study drug packaging 
Study drug is provided as tablets and supplied in childproof bottles containing 36 tablets 
each.


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5.1.6.1.2 Study drug labeling
Each medication bottle has a label with a tear-off part specifying the study protocol 
number, the batch number and the bottle number. When the medication is issued to the 
subject, the investigator, pharmacist (if applicable), or designee must remove the tear-off 
part and attach it to the Investigational Medicinal Product (IMP) Label Dispensing Log.
5.1.6.2
Study drug distribution and storage 
The investigator is responsible for safe and proper handling and storage of the study drug 
at the investigational site and for ensuring that the study drug is administered only to 
subjects enrolled in the study and in accordance with the protocol.
5.1.6.2.1
Study drug distribution
The study centers will be supplied with study drug according to the center’s needs, 
depending on the number of subjects enrolled in the AC-055E201 / MERIT-1 study. Each 
center will have an individual stock of study drug, which will be timely re-supplied as soon 
as a predefined minimum level of study drug has been reached.
At each visit the medication bottle numbers will be allocated to the subjects through IXRS. 
Subjects will receive 1 medication bottle (childproof bottles containing 36 tablets each) at 
Enrollment (Visit 1), 5 medication bottles at Month 1 (Visit 2), and 6 medication bottles 
every 6 months thereafter (Visits 3, 4, 5…) up to the EOT visit.
Note: Alternatively, if the subject comes to the investigational site every month for the 
monthly laboratory and safety monitoring, it is possible to dispense and return one 
medication bottle on a monthly basis.
Once a subject has been enrolled and the IMP assigned, the corresponding bottles must not
be used for another subject. If a subject has been allocated a bottle in error (one that has 
not been allocated yet to another subject), the IXRS helpdesk must immediately be 
contacted to advise of the misallocation of bottle numbers in all cases.
At the time study drug is distributed, the subject must be educated on the proper storage 
conditions at home. Study drug dispensing must be performed only upon written 
confirmation by an authorized study physician listed on the delegation of authority (DoA) 
form.
5.1.6.2.2
Study drug storage
Study drug must be kept in a locked room or a locked cupboard in a restricted access room, 
which can be accessed only by the pharmacist, the investigator, or another duly designated 
person as specified on the DoA. Study drug must be kept in an appropriate secure area and 
stored according to the conditions specified on the label.
A temperature log must be maintained and temperature control must occur at least on a 
weekly basis at the site. Actelion will provide a temperature log; however, the use of the 


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Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 31/90
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log is not mandatory if the site has an acceptable means of recording the temperature. Any 
temperature recording system routinely used at site is acceptable as long as all required 
information is included and certification of calibration is provided. If the temperature is 
captured electronically, a print-out should be made available to the monitor during each 
on-site visit. 
In case a deviation from the defined temperature range is identified by the site, the deviation 
is to be reported to the monitor, preferably in writing and with supportive documentation 
(e.g. copy of the temperature log showing data for all excursion days), within 24 h of the 
excursion. The monitor must immediately notify Actelion for further advice. The study 
drug affected by a deviation will not be used (e.g., segregated physically at the 
investigational site) until confirmation by Actelion that it is safe to be used. In case the 
temperature deviation is defined as acceptable, a corresponding message is returned to the 
site via the monitor.
In case the temperature deviation is defined as not acceptable and the quality of the study 
drug might be affected, the IMP is kept segregated at the investigational site and returned 
to Actelion following internal drug return processes. New study drug supplies will be 
provided to the clinical investigator site.
Site temperature deviations correspondence must be kept in the Investigator Site File (ISF).
5.1.6.3
Study drug return and destruction 
The site must record the number of study drug received, dispensed, used, lost, returned 
during the study.
On an ongoing basis and/or on termination of the study, the monitor will collect used and 
unused subject bottles, and document the collection in the appropriate form before sending 
the bottles to the warehouse, where Actelion or its deputy will check drug reconciliation. 
In certain circumstances, used and unused drug containers may be destroyed at the site 
once drug accountability is finalized and has been checked by Actelion or its deputy, and 
written permission for destruction has been obtained from Actelion. 
5.1.7
Compliance with study treatment
An accurate record of the date and amount of study drug dispensed to each subject must be 
available for inspection at any time. An IMP dispensing and accountability log is to be 
completed on an ongoing basis, preferably on the visit day, for each subject. Subjects are 
instructed to return used and unused study drug (including empty bottles) at each visit. 
Study drug accountability must be performed on an ongoing basis by the study staff on the 
day of the visit and before providing further study treatment, in order to ensure that the 
subject is compliant with study requirements. Study drug accountability is also to be 
recorded in the electronic case report form (eCRF) and checked by the monitor during site 
visits.


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Prior to each new dispensation, the visit compliance must be evaluated by the site staff, 
based on drug accountability, as per formula below: 
Compliance = [(number of tablets provided to subject −number of tablets returned) / Total 
number of tablets that should have been taken during the period] × 100
The site staff must discuss any compliance issue with the subject and re-educate them on 
correct administration of study drug. Details of such discussion must be documented in the 
subject’s file. 
If the compliance with study drug intake is < 80% or > 120%, permanent discontinuation 
of study drug may be considered after consultation with Actelion.
5.1.8
Study drug interruption and premature discontinuation of study drug
The investigator should temporarily interrupt or permanently discontinue treatment with 
the study drug for a given subject if, on balance, he/she believes that continued 
administration would be contrary to the best interests of the subject, or if the subject is not 
compliant with study requirements (e.g., low compliance with study drug intake or visit 
attendance).
5.1.8.1
Study drug interruption
Study drug interruption should be avoided as much as possible. 
If study drug intake is interrupted by the subject for any reason, she/he must immediately 
inform the investigator.
Interruptions of study drug must not last longer than 2 consecutive weeks. Longer 
interruptions must lead to permanent discontinuation of study drug. 
All study drug interruptions as well as the reasons for interruptions must be recorded in the 
eCRF.
5.1.8.2
Premature discontinuation of study drug
Premature discontinuation of study drug may occur independently from study withdrawal. 
The subject may discontinue not only from study treatment but also from the study
[withdrawal from study see Section 9.1]. 
The reason for premature discontinuation from study drug, the decision owner (as 
applicable), and whether subject decision to discontinue study treatment does or does not 
include study withdrawal must be documented in the eCRF. Reasons for premature 
discontinuation are mutually exclusive and only the primary reason for premature 
discontinuation must be recorded in the eCRF.
Study drug must be discontinued if any of the specific discontinuation criteria 
described in Section 5.1.8.3 is met.


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 33/90
EDMS-RIM-263288, 3.0  
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Permanent discontinuation of study drug leads to the EOT visit and subsequently to the 30-
day Safety follow-up period.
The premature EOT must be registered in the IXRS in a timely manner to avoid any 
automatic study drug re-supply. The date entered into the system must be the date of the 
last study drug intake. 
5.1.8.3
Study-specific criteria for study drug interruption / permanent discontinuation 
of study drug
A) Pregnancy
If a female subject becomes pregnant while on study drug, study drug must be discontinued 
immediately, and a Pregnancy Form must be completed [see Section 10.3].
B) Liver aminotransferases abnormalities
Interruption of study drug
Study drug must be interrupted in the following cases:

Aminotransferases (i.e., ALT and/or AST) > 3 and ≤8 × ULN 
In such a case, a re-test of aminotransferases (ALT and AST), total and direct bilirubin, 
and AP must be performed within one week. If AST and/or ALT elevation is confirmed, 
aminotransferases, total and direct bilirubin, and AP levels must be monitored 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, reintroduction of study 
treatment can be considered. Interruptions must be for less than 2 consecutive weeks; 
longer interruptions must lead to permanent discontinuation of study drug. 
Reintroduction of study treatment after treatment interruption should only be considered if 
the potential benefits of treatment with macitentan outweigh the potential risks and when 
liver aminotransferase values are within pre-treatment levels or within normal ranges. The 
advice of a hepatologist is recommended.
Liver aminotransferase levels must then be checked within 3 days after reintroduction, then 
again after a further 2 weeks and thereafter according to the recommendations above (i.e., 
at monthly intervals).
Permanent discontinuation of study drug
Study drug must be stopped and its reintroduction is not to be considered in the following 
cases:

Aminotransferases > 8 × ULN

Aminotransferases > 3 × ULN and associated clinical symptoms of liver injury, 
e.g., nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy or fatigue, 
flu-like syndrome (arthralgia, myalgia, fever)


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Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 34/90
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
Aminotransferases ≥3 × ULN and associated increase in total bilirubin 
≥2 × ULN
In such cases, aminotransferases, total and direct bilirubin, and AP levels must be 
monitored weekly after study drug discontinuation until values return to pre-treatment 
levels or within normal ranges.
Other diagnoses (e.g., viral hepatitis, mononucleosis, toxoplasmosis, cytomegalovirus) 
and/or etiologies (e.g., acetaminophen-related liver toxicity) should be considered and 
ruled out by performing the appropriate tests.
All liver aminotransferases abnormalities leading to study drug interruption or 
discontinuation must be recorded as AEs [see Section 10].
An independent ILSB (an external expert committee of hepatologists) provides ongoing 
assessment and advice regarding any serious hepatic events that may require further 
evaluation during the study. 
C) Hemoglobin abnormalities
In case of hemoglobin decrease from baseline* of > 20 g/L, a re-test must be performed 
within 10 days, with additional laboratory evaluations that may include, but are not limited 
to, any of the following: 

Red blood cell cellular indices (mean corpuscular volume, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration), peripheral blood smear, 
reticulocyte count, iron status (iron level, serum ferritin, total iron binding capacity, 
transferrin saturation), lactate dehydrogenase, indirect bilirubin.
If hemoglobin decrease remains >20 g/L below baseline value at subsequent visits, 
further retests are to be performed as per investigator’s judgement.
Study drug should be temporarily interrupted if clinically mandated based on the 
investigator’s judgment, or in any of the following situations:
- A decrease in hemoglobin to < 80 g/L (< 4.9 mmol/L)
- A decrease in hemoglobin from baseline* of > 50 g/L
- The need for transfusion. 
Reintroduction of study medication may be considered if hemoglobin recovery, defined as 
a return of hemoglobin above the lower limit of the normal range or to baseline is achieved.
Interruption of study medication must not last longer than 2 consecutive weeks; longer 
interruption must lead to permanent discontinuation of study drug.
*Baseline hemoglobin: last value obtained prior to first intake of DB study treatment.


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 35/90
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D) Start of an ERA / strong CYP3A4 inducer / strong CYP3A4 inhibitors / moderate 
dual CYP3A4/CYP2C9 inhibitors / combination of moderate CYP3A4 and 
moderate CYP2C9 inhibitors / investigational drug
Study drug must be permanently discontinued if an ERA and/or a strong CYP3A4 inducer 
and/or strong CYP3A4 inhibitors and/or moderate dual CYP3A4/CYP2C9 inhibitors 
and/or coadministration of a combination of moderate CYP3A4 and moderate CYP2C9 
inhibitors and/or another investigational drug is started during treatment period.
5.2
Concomitant medications
5.2.1
Definition
A concomitant medication is any medication that started, stopped, or was ongoing between 
Enrollment (first dose of OL study drug) and last subject’s visit.
5.2.2
Reporting of concomitant medications in the eCRF
Concomitant medications will be reviewed at each visit.
All concomitant medications taken from Enrollment (Visit 1) up to EOS visit are to be 
recorded in eCRF (and subject’s file). This includes prescription, over the counter, herbal, 
recreational drugs and dietary supplements. Generic name, start/end dates of administration 
(as well as whether it was ongoing at start of treatment and/or EOS), route, dosage, and 
indication will be collected.
5.2.3
Forbidden concomitant medications
Strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, phenobarbital, rifampin /
rifampicin, rifabutin, rifapentin, St. John’s wort)
Strong 
CYP3A4 
inhibitors 
(e.g., 
ketoconazole, 
itraconazole, 
voriconazole, 
clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) or moderate dual 
CYP3A4/CYP2C9 inhibitors (e.g., fluconazole, amiodarone) or co-administration of a 
combination of moderate CYP3A4 (e.g., ciprofloxacin, cyclosporine, diltiazem, 
erythromycin, verapamil) and moderate CYP2C9 inhibitors (e.g., miconazole, piperine) 
until study intervention discontinuation. For other examples of CYP inhibitors, refer to 
the FDA website [Food and Drug Administration 2020].
* If patients are currently stable on a strong CYP3A4 inhibitors (e.g., ketoconazole, 
itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and 
saquinavir), moderate dual CYP3A4/CYP2C9 inhibitors (e.g., fluconazole, amiodarone) 
or co-administration of a combination of moderate CYP3A4 (e.g., ciprofloxacin, 
cyclosporine, diltiazem, erythromycin, verapamil) and moderate CYP2C9 inhibitors 
(e.g., miconazole, piperine), the patient may remain on current treatment per the 
investigator’s discretion based on his/her clinical judgement and risk-benefit assessment.
Another ERA
Another investigational drug (other than macitentan 10 mg)


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Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 36/90
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6
STUDY ENDPOINTS
6.1
Exploratory efficacy endpoints
Exploratory endpoints:
Change from baseline to each scheduled time point in exercise capacity, as measured by 
the 6-minute walk distance (6MWD)
Change from baseline to each scheduled time point in Borg dyspnea index collected at 
the end of the 6-minute walk test (6MWT)
Proportion of subjects with worsening of WHO FC from baseline to each scheduled time 
point.
6.2
Safety and tolerability endpoints
Treatment-emergent AEs up to 30 days after study drug discontinuation.
AEs leading to premature discontinuation of study drug.
Treatment-emergent SAEs up to 30 days after study drug discontinuation.
Treatment-emergent marked laboratory abnormalities [as detailed in Appendix 4] up to 
30 days after study drug discontinuation.
Change in vital signs (BP [i.e., DBP and SBP], HR) and body weight from baseline to 
all assessed time points during the study.
7
STUDY ASSESSMENTS
All study assessments are to be performed by a qualified study staff member: medical, 
nursing, or specialist technical staff. 
The following order of assessments is recommended:

Vital signs and physical exam

WHO FC

6MWT

Borg dyspnea index
7.1
Baseline parameters 
7.1.1
Baseline demographics and disease characteristics
Baseline demographic, height, and disease characteristics of interest for this OL study will 
be taken from the AC-055E201 / MERIT-1 database.


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7.2
Efficacy assessments
7.2.1
Six-minute walk test and Borg dyspnea index 
7.2.1.1
6MWT
The 6MWT is performed at Enrollment (Visit 1), each 6-monthly visit (Visits 3, 4, 5…), 
and EOT visit. 6MWT must be performed before the Borg dyspnea index evaluation. 
It is a non-encouraged test that measures the distance walked in 6 min. 
Detailed guidelines on correct execution of these tests, the ‘Actelion guidelines for 
6MWT’, are provided in Appendix 1.
Site team members conducting the 6MWT must be trained on these 6MWT guidelines. A 
training log must be collected upon completion of the training. Note: for site team members 
conducting 6MWTs in both the MERIT-1 and MERIT-2 studies, training performed for 
MERIT-1 does not need to repeated for MERIT-2.
Minor deviations from these guidelines (such as corridor length 25–30 m [instead of 30 m], 
corridor marked every 5 m [instead of every 3 m]) will be first discussed with Actelion, 
and formal approval must be obtained from Actelion before performing any study-specific 
6MWT.
It is important that, for each individual subject, the 6MWT is conducted under the same 
conditions throughout the study (e.g., same corridor). In addition, if possible, for each
individual subject, the 6MWT should be conducted by the same tester and preferably at the 
same time at each visit in this OL study. Moreover, as much as possible, the same 
conditions as in the AC-055E201 / MERIT-1 study should be used.
Note: If oxygen supplementation is needed during the 6MWT at Enrollment, then oxygen 
should be delivered using the same method and the same flow during all study 6MWTs by 
that subject. If the flow must be increased during subsequent visits (e.g., due to worsening), 
this should be indicated in the source notes (as well as in the Concomitant Medication 
forms of the eCRF).
The data related to 6MWT will be recorded in the eCRF.
7.2.1.2
Borg dyspnea index
The Borg dyspnea index is evaluated after each 6MWT. It rates dyspnea on a scale from 
‘0’ to ‘10’ [Appendix 2]. Borg dyspnea index will be collected in the eCRF.
7.2.2
WHO functional class
The WHO FC [Appendix 3] is assessed at Enrollment (Visit 1), each 6-monthly visit (Visits 
3, 4, 5…), and EOT visit. When applicable, WHO FC should be performed before the 
6MWT. The WHO FC will be collected in the eCRF.


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
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7.3
Safety and tolerability assessments
The definitions, reporting and follow-up of AEs, SAEs and potential pregnancies are 
described in Section 10.
7.3.1
Vital signs
Vital signs (SBP, diastolic BP [DBP], HR) will be measured at Enrollment (Visit 1), Month 
1 (Visit 2), each 6-monthly visit (Visits 3, 4, 5…), EOT visit, and Safety follow-up / EOS 
visit. Data will be recorded in the eCRF.
When applicable, vital signs should be performed before the 6MWT. SBP, DBP and pulse 
rate will be measured with the subject either in a supine or sitting position after having 
rested for at least 5 min. The right or left arm may be used. However, the same position 
and arm should be used throughout the trial for an individual subject. 
7.3.2
Weight 
Body weight will be measured at Enrollment (Visit 1), Month 1 (Visit 2), each 6-monthly 
visit (Visits 3, 4, 5…), EOT visit, and Safety follow-up / EOS visit. Data will be recorded 
in the eCRF.
Weight should be measured without shoes. The same scale should be used for each weight 
measurement.
7.3.3
Physical examination
Physical examination is to be performed at Enrollment (Visit 1), Month 1 (Visit 2), each 
6-monthly visit (Visits 3, 4, 5…), EOT visit, and Safety follow-up / EOS visit. Data will 
be recorded in the eCRF.
Physical examination will be recorded by body system in the eCRF as normal or abnormal. 
If an abnormality is detected, it must be specified in the eCRF, describing the signs related 
to the abnormality (e.g., systolic murmur) not the diagnosis (e.g., mitral valve 
insufficiency).
Clinically relevant findings meeting the definition of an AE (new AE or worsening of 
previously existing condition) must be recorded as an AE in the eCRF.
7.3.4
Laboratory assessments
7.3.4.1
Type of laboratory
A central laboratory (see separate Laboratory Manual for contact details) will be used for 
the analysis of all laboratory tests described in the protocol. 
Central laboratory data will be automatically transferred from the central laboratory 
database to the Actelion clinical database. 
Blood samples will be collected at site and sent for analysis to the central laboratory, 
except at Visit 1 / Enrollment where an additional blood sample will be analysed by the 


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
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Amendment 3, Version 4, 22 June 2021, page 39/90
EDMS-RIM-263288, 3.0  
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local laboratory (on top of the sample sent to the central laboratory) to check the eligibility 
of the subject on the day of Enrollment. 
Under specific circumstances (e.g., subject lives far away from the site and cannot return 
every month), laboratory samples could be drawn in a local laboratory close to where the 
subject lives, and analyzed at central laboratory (Note: a local phlebotomy service set-up 
may be used). In that event, the local laboratory must be provided with the central 
laboratory kits, which must be used for blood collection. The blood samples collected 
locally will be shipped by the local laboratory to the central laboratory for analysis. Such 
a local laboratory shall be identified as soon as possible, but no later than upon enrollment 
of the subject in the study. 
In case a central laboratory sample is lost, deteriorates, or is not analyzable for whatever 
reason, the investigator will collect an additional sample as soon as possible for repeat 
analysis, unless a local laboratory sample was drawn within the same time-window and the 
local laboratory results are available.
In the exceptional event (e.g., subject is hospitalized in a different hospital from the site or 
in case of an emergency) where a local laboratory is utilized for the collection and analysis 
of blood samples, the local laboratory results of parameters required by the protocol (with 
the corresponding normal ranges) will be entered into the clinical database via dedicated 
eCRF pages [see Section 7.3.4.2].
For these local laboratories, the investigator/delegate will provide Actelion with the name, 
professional degree and curriculum vitae (CV) of the laboratory director, a copy of the 
laboratory’s certification, and the normal ranges for each laboratory test that is evaluated 
in the study. These laboratory references must be updated whenever necessary.
Further details regarding blood sampling procedures, collection and shipment of samples 
and reporting of results are described in the Central Laboratory Manual. 
Central laboratory reports will be communicated to the investigator [see separate 
Laboratory Manual]. All laboratory reports (from central and local laboratories, if 
applicable) must be reviewed, signed and dated by the principal investigator or other 
qualified study personnel at the study site as soon as possible (but no later than 5 days) 
after receipt/acknowledgement, and filed with the source documentation. 
Note: Alert reports from the central laboratory must be reviewed, signed and dated by the 
investigator or designated physician within 24 h of receipt. The person reviewing the 
laboratory report must indicate whether the abnormal values are considered clinically 
significant (CS) or not clinically significant (NCS); if CS an AE must be reported in the 
eCRF.


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In case of specific (pre-defined) laboratory abnormalities, the central laboratory will alert 
Actelion and the concerned site. Alert flags that will trigger such notifications are displayed 
in Appendix 5.
Central laboratory normal ranges are provided in Appendix 6.
Any clinically relevant laboratory abnormalities (including ALT/AST abnormalities 
> 3 ULN) occurring after study drug initiation, which meet the definition of an AE must 
be reported by the investigator as an AE and/or SAE, as appropriate [see Section 10]. In 
such a case, repeated assessments are mandatory until they return to normal range or 
baseline value, stabilize, or until the change is no longer clinically relevant.
7.3.4.2
Data to be collected in eCRF if a local laboratory is used to analyze a blood 
sample
As a minimum, the following local laboratory parameters/results (i.e., results from samples 
drawn and analyzed locally) will be collected in the eCRF (together with the normal 
ranges):
-
Any ALT, AST, AP, and total and direct bilirubin result related to the detection, 
confirmation and/or monitoring of ALT and/or AST elevations of > 3 × ULN. 
-
Any hematology work-up related to the detection, confirmation and/or monitoring of 
hemoglobin decrease from baseline of > 20 g/L, a value of hemoglobin < 100 g/L, or a 
hemoglobin decrease requiring transfusion. 
-
Any local laboratory test documenting the result of a parameter requested per protocol 
(e.g., in case no sample was sent to central laboratory at a planned visit because the 
patient was hospitalized at another hospital, or in case sample sent to central laboratory 
was hemolyzed). 
-
Any local laboratory result related to the documentation or follow-up of an AE or an 
SAE, including clinically relevant abnormal laboratory results and their follow-up. 
In the event that several local laboratory samples have been drawn on the same day or if 
the sample was tested several times, the ‘worst’ value (e.g., highest value for ALT/AST) 
should be reported in the eCRF (together with the local laboratory reference ranges).  
7.3.4.3
Laboratory parameters
At Enrollment/Visit 1, about 25–30 mL will be collected (half of this will be sent to the 
central laboratory for analysis, the rest will be analyzed locally to check the eligibility). At 
each of the following visit, about 15 mL will be collected. The total amount of blood 
collected per year is approximately 200 mL.
Hematology
Hematology tests will be performed at Enrollment (Visit 1), Month 1 (Visit 2), each 
6-monthly visit (Visits 3, 4, 5…), EOT visit, and Safety follow-up visit.


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
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EDMS-RIM-263288, 3.0  
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These tests include:
–
Hemoglobin*
–
Hematocrit
–
Erythrocyte count
–
Leucocyte count with differential
–
Platelet count
–
Coagulation tests (partial thromboplastin time, International Normalized Ratio [INR]).
* In addition, hemoglobin will be measured every month during the first 6 months, and 
every 3 months thereafter up to EOT visit.
Rules for study drug interruption and laboratory re-tests in case of hemoglobin abnormality 
are provided in Section 5.1.8.3.
Blood chemistry
Blood chemistry tests will be performed at Enrollment (Visit 1), Month 1 (Visit 2), each 6-
monthly visit (Visits 3, 4, 5…), EOT visit, and Safety follow-up visit. 
These tests include measurement of:
–
LTs*: liver aminotransferases (ALT and AST), AP, total and direct bilirubin
–
Creatinine
–
Blood urea nitrogen (BUN)
–
Uric acid
–
Glucose
–
Sodium
–
Potassium
–
Magnesium
–
Calcium
–
Albumin
–
C-reactive protein (CRP).
* In addition, LTs will be measured every month up to EOT visit.
Rules for study drug interruption / permanent discontinuation and laboratory re-tests in 
case of ALT and/or AST elevation are provided in Section 5.1.8.3.
On a case-by-case basis, if an abnormal ALT/AST value was observed, Actelion could 
request the analysis of additional parameters (e.g., acetaminophen concentration to rule out 
an acetaminophen-related liver toxicity). This additional analysis would be done on already 
collected samples. 
Pregnancy test
For females of childbearing potential [Section 4.2], a serum pregnancy test must be 
performed at Enrollment (Visit 1) and every month (+/- 1 week) thereafter up to at least 30 


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 42/90
EDMS-RIM-263288, 3.0  
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days after study drug discontinuation. In addition, a serum pregnancy test must be 
performed at anytime if pregnancy is suspected during the study.
In the event of pregnancy, a Pregnancy Form must be completed [see Section 10.3].
For females of childbearing potential, each month, the study personnel must verify whether 
the methods of contraception are in accordance with the protocol [Section 4.2] and 
correctly used by the subject. Documentation that the discussion with the subject took place 
must be available in the subject’s source notes. Methods of contraception will be collected 
in the eCRF.
8
SCHEDULE OF VISITS
Table 1 provides a summary of all visits and assessments described in the following 
sections.
8.1
Treatment period
8.1.1
Enrollment visit (Visit 1)
It is the responsibility of the investigator to obtain written informed consent from each 
subject (during the Enrollment visit at the latest) after adequate face-to-face explanation of 
the methods, objectives and potential hazards of the study, and prior to any study-specific 
assessment. After discussing the study with the investigator and after agreeing to study 
participation by signing the Informed Consent Form (ICF), subjects will be assigned 
medication bottles by the IXRS provider. The same subject number as the one assigned in 
the MERIT-1 study will identify the subject throughout the OL study.
This Enrollment visit will be combined with the Week 24 visit (i.e., Visit 5/Week 24) of 
the DB AC-055E201 / MERIT-1 study [see Figure 1].
This visit includes:
Recording of concomitant medications 
Recording of methods of contraception (for females of childbearing potential only)
Physical examination
Measurement of vital signs and weight 
Assessment of WHO FC
6MWT
Completion of Borg dyspnea index, after the 6MWT
Complete laboratory tests including: hematology, blood chemistry, and serum 
pregnancy test (for females of childbearing potential only) 
After completion of all Enrollment assessments/procedures and verification of all entry 
criteria: dispensing of 1 medication bottle for the next month. 
Recording of AEs and SAEs: 


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–
All SAEs (except for those already reported in the AC-055E201 / MERIT-1 study) 
occurring from signature of the consent form to first OL drug administration must 
be recorded in the OL eCRF and on an SAE form.
–
All AEs occurring from the initiation of the OL study drug must be recorded in the 
OL eCRF.
Note 1: Tests are not to be repeated if performed for the AC-055E201 / MERIT-1 study on 
the day of this Enrollment visit.
Note 2: In order to check the eligibility of the subject on the day of Enrollment, local 
laboratory results are required in addition to the sample sent to the central laboratory.
The investigator will check all the inclusion/exclusion criteria and decide on the subject’s 
eligibility for the study. It must be verifiable in the source documents that the subject meets 
each of the inclusion criteria and none of the exclusion criteria.
The first tablet of study drug must be taken at site once all study assessments are performed. 
The site staff must inform the subject to then take one tablet every morning, irrespective of 
food intake. Subjects must be instructed not to take the study drug in the morning of the 
next visit day and to return the study drug bottle (even empty) and unused medication at 
the next visit.  
8.1.2
Month 1 visit (Visit 2)
This visit is scheduled one month (± 1 week) from the day of Enrollment, and includes:
Recording of concomitant medications 
Recording of methods of contraception (for females of childbearing potential only)
Physical examination
Measurement of vital signs and weight
Complete laboratory tests including: hematology, blood chemistry, and serum 
pregnancy test (for females of childbearing potential only)
Recording of AEs and SAEs
Return of study drug bottle and unused medication 
Dispensing of 5 medication bottles (macitentan) for 5 months. Alternatively, if the 
subject comes to the investigational site every month for the monthly laboratory and 
safety monitoring, it is possible to dispense (and return) one medication bottle on a 
monthly basis.
Subjects must be instructed not to take the study drug in the morning of the next visit day 
and to return the study drug bottles (even empty) and unused medication at the next visit. 
Study drug must be taken from the bottle(s) that is(are) being dispensed.


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8.1.3
Monthly laboratory and safety monitoring (Months 2, 3, 4, 5, 7, 8, 9….)
These monthly visits will occur between regular visits, every month (± 1 week) from the 
day of Enrollment, and include:
Recording of concomitant medications 
Recording of methods of contraception (for females of childbearing potential only)
Laboratory tests including: 
- LTs
- Serum pregnancy test (for females of childbearing potential only)
- Hemoglobin, if applicable (i.e., each month during the first 6 months, and every 
3 months thereafter)
Recording of AEs and SAEs
If the subject comes to the investigational site every month for the monthly laboratory 
tests, it is possible to dispense (and return) one medication bottle on a monthly basis.
Note: Since one bottle contains 36 tablets, in case of monthly dispensing of study drug, the 
interval between 2 consecutive visits should not exceed 36 days in total.
In the specific cases where the monthly laboratory samples are not collected at the site [see 
Section 7.3.4.1], the safety monitoring (assessments of AEs, SAEs, concomitant 
medications and methods of contraception) should be done via a telephone call that must 
be documented in the subject’s file.
8.1.4
Visits at 6-monthly intervals (Visits 3, 4 etc.)
These 6-monthly visits are scheduled every 6 months ± 2 weeks, from the day of 
Enrollment, and include:
Recording of concomitant medications 
Recording of methods of contraception (for females of childbearing potential only)
Physical examination
Measurement of vital signs and weight
Assessment of WHO FC
6MWT 
Completion of Borg dyspnea index, after the 6MWT
Complete laboratory tests including: hematology, blood chemistry, and serum 
pregnancy test (for females of childbearing potential only)
Recording of AEs and SAEs
Return of study drug bottles and unused medication 


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Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 45/90
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Dispensing of 6 medication bottles (macitentan) for 6 months. Alternatively, if the 
subject comes to the investigational site every month for the monthly laboratory tests, 
it is possible to dispense (and return) one medication bottle on a monthly basis.
Subjects must be instructed not to take the study drug in the morning of the next visit day
and to return the study drug bottles (even empty) and unused medication at the next visit. 
Study drug must be taken from the bottle(s) that is(are) being dispensed.
8.1.5
EOT visit
Actelion will notify all concerned sites when an EOT visit should be planned (upon 
commercial availability of macitentan in this indication in the respective country, or in case 
Actelion decides to stop the study; see Section 3.1). 
End of treatment (EOT): The end of all study treatment for an individual participant.
At the end of the OL study, the EOT visit is scheduled for all subjects still participating in 
this OL study. For subjects entering a continued access program, the EOT visit is defined 
as the EOS visit.
Subjects prematurely discontinuing macitentan treatment must also undergo the EOT visit. 
Permanent study drug discontinuation must be reported in the IXRS in a timely manner to 
avoid any automatic study drug re-supply. Date entered into the system must be the date 
of the last study drug intake.
The EOT visit should be performed as soon as possible after permanent discontinuation of 
study drug and, whenever possible, no later than 7 days after the last dose of study drug.
This visit includes:
Recording of concomitant medications
Recording of methods of contraception (for females of childbearing potential only)
Physical examination
Measurement of vital signs and weight
Assessment of WHO FC
6MWT 
Completion of Borg dyspnea index, after the 6MWT
Complete laboratory tests including: hematology, blood chemistry and serum pregnancy 
test (for females of childbearing potential only)
Recording of AEs and SAEs 
Return of study drug bottles and unused medication 


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Chronic thromboembolic pulmonary hypertension 
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Amendment 3, Version 4, 22 June 2021, page 46/90
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Schedule an appointment for the safety follow-up visit 30 days after last intake of study 
drug.  
8.2
Safety follow-up period
For each subject, a post-treatment Safety follow-up period (30 days) will follow the 
permanent study drug discontinuation. For patients who are entering a continued access 
program, the enrollment into the continued access program (post-trial access program or 
other open-label study) must occur on the day of the last visit of the MERIT-2 study (EOS, 
which corresponds to EOT visit in this case).
8.2.1
EOS visit
For an individual participant, EOS visit is defined as follows:

For participants that complete treatment, EOS visit is defined as the safety follow-up 
visit 30–35 days after last study treatment intake. 

For participants that prematurely discontinue study treatment, EOS visit is defined as 
the safety follow-up visit 30–35 days after last study treatment intake.

For participants who complete treatment and who are entering a continued access 
program (post-trial access or other open-label extension study) the EOS visit is defined 
as the EOT visit.
All attempts should be made to perform the Safety follow-up / EOS Visit 30 days after the 
permanent discontinuation of study drug; a window of + 3 days is acceptable. 
This visit includes:
Recording of concomitant medications
Recording of methods of contraception (for females of childbearing potential only)
Physical examination
Measurement of vital signs and weight
Complete laboratory tests including: hematology, blood chemistry, and serum 
pregnancy test (for females of childbearing potential only)
Reporting of any AEs and SAEs occurring up to 30 days after study drug discontinuation 
in the eCRF and on an SAE form (if applicable)
8.3
Unscheduled visits
An unscheduled site visit may be performed at any time during the study (between 
scheduled visits), as necessary, based on investigator discretion. These visits include (but 
are not limited to) those performed due to safety (e.g., occurrence of an adverse event, 
laboratory abnormalities) and/or CTEPH related (e.g., disease progression) issues.  
The date of the visit and the reason for such visits as well as any data related to study 
assessments performed at unscheduled visits will be recorded in the eCRF. If any of the 


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 47/90
EDMS-RIM-263288, 3.0  
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laboratory parameters listed in Section 7.3.4.3 need to be analyzed, this must be done at 
the central laboratory (except in case of emergency). If it has been done at a local 
laboratory, results must be recorded in the eCRF [see Section 7.3.4.2].
During such visits, any of the following assessments may be performed:
Assessment of concomitant medications 
Assessment of methods of contraception (for females of childbearing potential only)
Physical examination 
Measurement of vital signs and/or body weight
WHO FC
6MWT
Borg dyspnea index, after the 6MWT
Complete laboratory tests including: hematology, blood chemistry, and serum 
pregnancy test (for females of childbearing potential only)
Assessment of AEs and SAEs
Return of study drug bottles and unused medication and dispensing of new bottle(s), if 
appropriate.
9
STUDY COMPLETION
All enrolled subjects who received study drug must be followed up to the EOS, whether or 
not they are prematurely discontinued from study treatment. 
For an individual subject, the end of this OL study corresponds to EOS visit.
For all subjects, the reason for premature discontinuation from study and the decision 
owner (as applicable) must be documented in the eCRF.
9.1
Withdrawal from study
Subjects may voluntarily withdraw from the study for any reason at any time. Subjects are
considered withdrawn from the study if they state an intention to withdraw further 
participation in all components of the study, die, or are lost to follow-up for any other 
reason. The investigator may withdraw a subject from the study (without regard to the 
subject’s consent) if, on balance, he/she believe that continued participation in the study 
would be contrary to the best interests of the subject. Withdrawal from the study may also 
result from a decision by Actelion for any reason, including premature termination or 
suspension of the study [see Section 9.3].
A subject who prematurely discontinues study drug is not considered as withdrawn from 
the study and will be followed-up for Safety [as outlined in Section 8.2].


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The site must take preventive measures to avoid a subject being lost to follow-up 
(e.g., document different ways of contact such as telephone number, home address, e-mail 
address, person to be contacted in case the subject cannot be reached). If the subject cannot 
be reached, the site must make a reasonable effort to contact the subject and document all 
attempts. The following methods must be used: at least three telephone calls must be placed 
to the last available telephone number, and one registered letter must be sent by post to the 
last available home address; this information will be collected in the eCRF. Additional 
methods may be acceptable if they are compliant with local rules/regulations, respecting 
the subject’s right to privacy. 
If the subject is still unreachable after all contact attempts listed above, he/she will be 
considered to be lost to follow-up.
9.2
End of the trial
The end of the trial is reached when all the subjects have either completed their EOS visit, 
died or are lost to follow-up.
9.3
Premature termination or suspension of the study
Actelion reserves the right to terminate the study at any time globally or locally. In 
particular, if the results of the DB MERIT-1 study do not support further use of macitentan 
in CTEPH subjects, the MERIT-2 OL extension study will be discontinued.
Investigators can terminate the participation of their site in the study at any time.
If the study is prematurely suspended or terminated, Actelion will promptly inform the 
investigators, the Institutional Review Board (IRB) / Independent Ethics Committee (IEC)
and Health Authorities, as appropriate, and provide the reasons for the suspension or 
termination. 
If the study is suspended or prematurely terminated for any reason, the investigator in 
agreement with Actelion must promptly inform all enrolled subjects, and ensure their 
appropriate treatment and follow-up.
In addition, if the investigator suspends or terminates the study without prior agreement 
from Actelion, the investigator must promptly inform Actelion and the IRB/IEC, and must 
provide Actelion and the IRB/IEC with a detailed written explanation of the termination or 
suspension.
If the IRB/IEC suspends or terminates its approval/favorable opinion of the study, the 
investigator must promptly notify Actelion and provide Actelion with a detailed written 
explanation of the termination or suspension.
Any suspension or premature termination of the study must be discussed with the SC.


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Chronic thromboembolic pulmonary hypertension 
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9.4
Medical care of subjects after End-of-Study
After the last subject’s visit, the investigator/delegate will explain to subjects which
treatment(s)/medical care(s) would be necessary and available according to local 
regulations, whether the subject completed study treatment or not. Local regulations on 
continued access will always take precedence.
10 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS
10.1 Adverse events
10.1.1 Definitions of adverse events
An AE is any adverse change from the subject’s baseline condition*, i.e., any unfavorable 
and unintended sign, including an abnormal laboratory finding, symptom or disease, that 
occurs during the course of the study, whether or not considered related to the study drug. 
* Subject’s condition prior to initiating the OL study drug.
A treatment-emergent AE is any AE temporally associated with the use of a study drug 
(from study drug initiation until 30 days after study drug discontinuation) whether or not 
considered related to the study drug. 
AEs include:
−
Exacerbation of a pre-existing disease.
−
Increase in frequency or intensity of a pre-existing episodic disease or medical 
condition.
−
Disease or medical condition detected or diagnosed after study drug administration 
even though it may have been present prior to the start of the study.
−
Continuous persistent disease or symptoms present at baseline that worsen following 
the start of the study. 
−
Abnormal assessments, e.g., change on physical examination, ECG findings, if they 
represent a clinically significant finding that was not present at baseline or worsened 
during the course of the study.
−
Laboratory test abnormalities if they represent a clinically significant finding, 
symptomatic or not, which was not present at baseline or worsened during the course 
of the study or led to dose reduction, interruption or permanent discontinuation of 
study drug.
Overdose, misuse and abuse of the study drug should be reported as AE. These events with 
the study medication should also be documented in the study drug log/accountability log 
of the eCRF (if possible).
For this study, any dose of study medication higher than the planned total daily dose in a 
single day will be considered an overdose.   In the event of an overdose, standard supportive 
measures must be taken, as required.


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10.1.2 Intensity of adverse events
The intensity of clinical AEs is graded on a three-point scale – mild, moderate, severe –
and is reported on specific AE forms of the eCRF. 
If the intensity of an AE worsens during study drug administration, only the worst intensity
should be reported on the AE page. If the AE lessens in intensity, no change in the severity 
is required.
The three categories of intensity are defined as follows:

Mild
The event may be noticeable to the subject. It does not influence daily activities, and 
usually does not require intervention.

Moderate
The event may make the subject uncomfortable. Performance of daily activities may be 
influenced, and intervention may be needed.

Severe
The event may cause noticeable discomfort, and usually interferes with daily activities. 
The subject may not be able to continue in the study, and treatment or intervention is 
usually needed.
A mild, moderate, or severe AE may or may not be serious [see Section 10.2.1]. These 
terms are used to describe the intensity of a specific event. Medical judgment should be 
made on a case per case basis. 
Seriousness, rather than severity assessment, determines the regulatory reporting 
obligations.
10.1.3 Relationship to study drug 
Each adverse event must be assessed by the investigator as to whether or not there is a 
reasonable possibility of causal relationship to the study drug, and reported as either 
‘suspect’ (i.e., related) or ‘not suspect’ (i.e., not related).
10.1.4 Reporting of adverse events
All AEs occurring from initiation of the OL study drug and up to 30 days after study drug 
discontinuation (up to EOS for participants who enter a continued access program on the 
same day as the EOS visit, see Section 8.2.1) are defined as treatment-emergent AEs and 
must be recorded on specific AE forms of the OL eCRF.These AEs must be documented 
in the corresponding subject medical records. Data such as evaluation of maximum 
intensity and evaluation of possible relationship to study drug are also to be documented 
in the source documents. The investigator who performed the AE assessment should be 
identifiable in the source documents.


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Chronic thromboembolic pulmonary hypertension 
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Amendment 3, Version 4, 22 June 2021, page 51/90
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10.1.5 Follow-up of adverse events
AEs still ongoing 30 days after study drug discontinuation must be followed up until they 
are no longer clinically significant.The investigator is obligated to perform or arrange for 
the conduct of supplemental measurements and evaluations as medically indicated to 
elucidate the nature and causality of the AE, SAE, or product quality compliant (PQC) as 
fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals.
10.2 Definitions of serious adverse events
10.2.1 Serious adverse events
An SAE is defined by the International Council on Harmonisation (ICH) guidelines as any 
AE fulfilling at least one of the following criteria:
−Fatal
−Life-threatening: refers to an event in which the subject was at risk of death at the time 
of the event. It does not refer to an event that hypothetically might have caused death 
had it been more severe.
−Requiring inpatient hospitalization, or prolongation of existing hospitalization.
−Resulting in persistent or significant disability or incapacity.
−Congenital anomaly or birth defect.
−Medically significant: refers to important medical events that may not immediately 
result in death, be life-threatening, or require hospitalization but may be considered to 
be SAEs when, based upon appropriate medical judgment, they may jeopardize the 
subject, and may require medical or surgical intervention to prevent one of the outcomes 
listed in the definitions above. 
The following reasons for hospitalization are exempted from being reported:
−Hospitalizations for cosmetic elective surgery, or social and/or convenience reasons.
−Hospitalizations for pre-planned (i.e., planned prior to signing informed consent)
standard monitoring of a pre-existing disease or medical condition that did not worsen, 
e.g., hospitalization for coronary angiography in a subject with stable angina pectoris.
However, complications that occur during hospitalization are AEs or SAEs (for 
example, if a complication prolongs hospitalization).
10.2.1.1 Serious adverse events associated with study design or protocol mandated 
procedures 
An SAE is defined as related to study design or protocol mandated procedures if it appears 
to have a reasonable possibility of a causal relationship to either the study design or to 
protocol-mandated invasive procedures. Examples include discontinuation of a subject’s 


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previous treatment during a washout period leading to exacerbation of underlying disease 
or a complication of an invasive procedure specifically required by the protocol.
10.2.2 Reporting of serious adverse events
10.2.2.1 Prior to start of OL treatment period
All SAEs (except for those already reported in the AC-055E201 / MERIT-1 study), as well 
as PQCs, occurring from signature of the ICF to first drug administration in the OL must 
be reported in the eCRF and on an SAE form of the MERIT-2 OL extension study (i.e., 
AC-055E202). 
Note: All SAEs occurring between DB study drug initiation and up to 30 days after study 
drug (DB) discontinuation, or until initiation of study drug in the OL study (whichever 
occurs first) are to be reported on SAE forms and also on AE forms in the 
AC-055E201 / MERIT-1 eCRF.
10.2.2.2 During treatment and follow-up periods
All SAEs, regardless of causal relationship, as well as PQCs, occurring from the initiation 
of the OL study drug and up to 30 days after study drug discontinuation (up to EOS for 
participants who enter a continued access program on the same day as the EOS visit, see 
Section 8.2.1) must be reported on an SAE form and also on AE forms in the eCRF.Follow-
up of serious adverse events 
Serious adverse events still ongoing at the EOS visit must be followed up until resolution 
or stabilization, or until the event outcome is provided e.g., fatal outcome. 
10.2.3 After the 30-day follow-up period 
New SAEs occurring after the 30-day follow-up period must be reported to the Sponsor
within 24 h of the investigator’s knowledge of the event, only if considered causally related 
to previous exposure to the study medication by the investigator.
10.2.4 Reporting procedures
All SAEs must be recorded on an SAE form, whether or not this event is considered by the 
investigator to be related to study drug.
All SAEs must be reported by the investigator to the Sponsor within 24 h of the 
investigator’s first knowledge of the event. The reporting of the initial SAE should not be 
delayed if some information is unavailable at time of reporting.
The principal investigator or designee must complete the SAE form in English, and must 
assess the causal relationship of the event to study drug. Only a site team member 
authorized for this task as per the DoA should sign off the SAE form, thus confirming that 
the assessment of the event, especially causality, has been made by a physician. The 
completed SAE form must be sent to the Sponsor (see contact details provided on the SAE 
form).


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Upon request, the detailed description of the event provided in the SAE form can be 
supplemented by copies of additional source documents that may include (but are not 
limited to): copies of autopsy reports, and hospital discharge summaries, as applicable.
If the subject is hospitalized in a hospital other than the study site, it is the investigator’s 
responsibility to contact this hospital to obtain all SAE relevant information and 
documentation.
Once an SAE form is sent, no additional information must be added to the existing form. 
In case of new information, a new SAE form must be completed and ‘follow-up’ ticked 
and sent again to the Sponsor. Follow-up information about a previously reported SAE 
must also be reported within 24 h of the investigator’s first knowledge of the new 
information. 
Sponsor will confirm receipt of the initial SAE report, or any update provided thereafter, 
by sending an acknowledgement of receipt. If an acknowledgment of receipt is not received 
within 2–3 working days, the site should contact the monitor to clarify if the SAE form 
was received by Sponsor.
The Sponsor may contact the investigator to obtain further information. The principal 
investigator or designee should respond as soon as possible. The response should be filed 
at site with the appropriate SAE form. 
The eCRF entries must be consistent with the event term, relationship to study drug, 
seriousness, onset/resolution date and outcome recorded on the SAE form(s), follow-up 
information and in the corresponding subject’s source documents.
SAEs must be reported to the ECs/IRBs according to the site- and country-specific 
reporting requirements. Copies of all communication regarding the SAE to the ECs/IRBs 
and to the Sponsor must be appropriately filed in the ISF. Investigational New Drug Safety 
Updates or CIOMS reports must be submitted to ECs/IRBs as per local requirements.
Suspected (considered related to the study drug) and unexpected (not previously described 
in the reference safety document) serious adverse reactions (SUSARs) will be expedited 
by the Sponsor to Health Authorities, ECs/IRBs and investigators, as appropriate. Either
the Sponsor or the investigators will submit the reports to the ECs/IRBs, as required by 
local regulations.
The reference safety document to assess whether or not a SUSAR should be reported by 
the Sponsor to Health Authorities, ECs/IRBs and investigators is section 6 of the 
Investigator’s Brochure [Macitentan IB].
10.3 Pregnancy
Due to the potential teratogenicity of macitentan, appropriate precautions must be taken by 
females of childbearing potential. Females must not become pregnant during the study and 
up to 30 days after study drug discontinuation.


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If a woman becomes pregnant while on study drug, study drug must be discontinued 
immediately. The investigator must counsel the subject and discuss the risks of continuing 
with the pregnancy and the possible effects on the fetus.
10.3.1 Reporting of pregnancy
Any pregnancy occurring in female participants or partners of male participants during 
study drug administration and up to 30 days following study drug discontinuation (up to 
EOS for participants who enter a continued access program on the same day as the EOS 
visit, see Section 8.2.1) must be reported within 24 h of the investigator’s knowledge of 
the event. 
Pregnancies must be reported on the Pregnancy Notification form, which is sent to the 
Sponsor (see contact details provided on the respective Pregnancy form), and entered in
the eCRF. All reporting requirements and timelines specified in Section 10.2.4 also apply 
to the reporting of a pregnancy.
10.3.2 Follow-up of pregnancy 
Any pregnancies in female paticipants or partners of male participants must be followed to 
its conclusion and its outcome must be reported to the Sponsor on the End of Pregnancy -
Collection Form B and on the Product Exposure During Pregnancy - Collection Form A.
Any AE and SAE associated with the pregnancy (including outcome e.g., 
spontaneous/therapeutic abortion) occurring up to 30 days after study drug discontinuation 
must be reported on separate AE pages in the eCRF. Abnormal pregnancy outcomes (e.g., 
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are 
considered SAEs and any SAE occurring during the pregnancy must be reported on an
SAE form as described in Section 10.2.4.
10.4 Study safety monitoring
Clinical study safety information (AEs, SAEs, laboratory values, vital signs, and 
project-specific labs/examinations as required) is monitored and reviewed on a continuous 
basis by the Actelion Clinical team (in charge of ensuring subjects’ safety as well as data 
quality) by periodically monitoring clinical studies activities from protocol conception to 
database closure. 
10.5 Product quality complaint handling
A PQC is defined as any suspicion of a product defect related to manufacturing, labeling, 
or packaging, i.e., any dissatisfaction relative to the identity, quality, durability, or 
reliability of a product, including its labeling or package integrity. A PQC may have an 
impact on the safety and efficacy of the product. Timely, accurate, and complete reporting 
and analysis of PQC information from studies are crucial for the protection of participants, 
investigators, and the Sponsor, and are mandated by regulatory agencies worldwide. The 
Sponsor has established procedures in conformity with regulatory requirements worldwide 


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to ensure appropriate reporting of PQC information; all studies conducted by the Sponsor 
or its affiliates will be conducted in accordance with those procedures.
10.5.1 Procedures
All initial PQCs must be reported to the Sponsor by the study site personnel within 24 hours 
after being made aware of the event.
A sample of the suspected product should be maintained under the correct storage 
conditions until a shipment request is received from the Sponsor.
10.5.2 Contacting sponsor regarding product quality
The names (and corresponding telephone numbers) of the individuals who should be 
contacted regarding product quality issues are listed in the Contact Information page(s), 
which will be provided as a separate document.
10.6 Special reporting situations
Safety events of interest on a sponsor study intervention in an interventional study that may 
require expedited reporting or safety evaluation include, but are not limited to:

Overdose of a sponsor study intervention

Suspected abuse/misuse of a sponsor study intervention

Accidental or occupational exposure to a sponsor study intervention

Medication error, intercepted medication error, or potential medication error involving 
a Johnson & Johnson medicinal product (with or without patient exposure to the 
Johnson & Johnson medicinal product, eg, product name confusion, product label 
confusion, intercepted prescribing or dispensing errors)

Exposure to a sponsor study intervention from breastfeeding.
Special reporting situations should be recorded in the eCRF. Any special reporting situation 
that meets the criteria of an SAE should be recorded on the SAE page of the eCRF.
11 STATISTICAL METHODS
All statistical analyses will be conducted by Actelion or by designated CROs supervised 
by Actelion.
A Statistical Analysis Plan (SAP) will be written and finalized before database closure and
will provide full details of the analyses, data displays, and algorithms to be used for data 
derivations.
Individual subject listings will be provided for efficacy, and safety endpoints, as well as 
for baseline and other subject characteristics. Each listing will be broken down by treatment 
group, site, subject number, and assessment date, where appropriate.


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11.1 Variables
This OL extension study will only contain analyses related to exploratory efficacy and 
safety endpoints.
For the analysis of exploratory endpoints, baseline will be defined in one of two ways, 
depending on the analysis:
1) As the last value obtained up to and including the day of first administration of 
randomized study drug in the DB AC-055E201 / MERIT-1 study or, 
2) As the last value obtained up to and including the day of first administration of 
macitentan 10 mg study drug during this study, the AC-055E202 / MERIT-2 OL extension 
study.
Exploratory endpoint variables will be calculated in reference to their baseline values at 
each scheduled time point in either AC-055E201 / MERIT-1 or AC-055E202 / 
MERIT-2 OL extension depending on the analysis.
11.1.1 Time windows
In order to minimize missing data and to analyze the data at the relevant planned 
(scheduled) visits, all recorded assessments up to EOS are re-assigned to the most 
appropriate time point according to the best fitting time-window for that assessment. Any 
unscheduled assessment (including endpoint variable, EOT and EOS assessments) will 
also be mapped to a time-window. The windows are based on the number of days since 
baseline corresponding to the date of assessment recording.
Should more than one assessment fall within the same time window, then the closest value 
to the planned time point will be assigned to the said time point for use in data summaries 
and analyses. In case of values that are equidistant to the planned time point, the last 
assessment will be considered for the analyses. If more than one value falls on the same 
day then the worst value will be used (e.g. for 6MWD the smallest value will be used).
For 6MWD and Borg dyspnea index, the date of 6MWT will be used to perform the 
mapping.


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11.1.2 Exploratory variables
11.1.2.1 Six-minute walk distance (6MWD)
Absolute change in meters from baseline to time point in the 6MWD defined as:
(6()   −6()  )
is the variable for the analysis of the exploratory endpoint, change from baseline to each 
scheduled time point in exercise capacity, as measured by the 6MWT.
11.1.2.2 Borg dyspnea index
Absolute change from baseline to time point in Borg dyspnea index defined as:
(      −    )
is the variable for the analysis of the exploratory endpoint, change from baseline to each 
scheduled time point in Borg dyspnea index collected at the end of the 6MWT.
For Borg dyspnea index, the baseline value is the value reported at the same assessment as 
baseline 6MWD.
11.1.2.3 WHO Functional Class (WHO FC)
Occurrence of worsening in WHO FC level at time point as compared to baseline is 
considered and the following dichotomous variable is defined:
Xi =    !
1 # (##$ %      &' ()) > 0
0 # (##$ %     &' () ) ≤0
The proportion of subjects experiencing any increase in WHO FC level at time point as 
compared to baseline, defined as the proportion of subjects who have occurrence of 
worsening (Xi = 1) is the variable for the analysis of the exploratory endpoint, proportion 
of subjects with worsening of WHO FC from baseline to each scheduled time point.
11.1.3 Safety variables(s)
A treatment-emergent AE is any AE temporally associated with the use of a study drug 
(from study drug initiation until 30 days after study drug discontinuation).
Baseline will be defined as the last value obtained up to and including the day of first 
administration of macitentan 10 mg during the DB or OL period.
Safety and tolerability endpoints will be analyzed for the combination of DB and OL 
periods from first administration of macitentan 10 mg in the DB or OL period for subjects 
who received at least one dose of macitentan 10 mg during the OL extension study.

Treatment-emergent AEs up to 30 days after study drug discontinuation.


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
AEs leading to premature discontinuation of study drug.

Treatment-emergent SAEs up to 30 days after study drug discontinuation.

Treatment-emergent marked laboratory abnormalities [as detailed in Appendix 4] up 
to 30 days after study drug discontinuation.

Change in vital signs (BP [i.e., DBP and SBP], HR) and body weight from baseline to 
all assessed time points during the study.
11.2
Analysis Sets
11.2.1 Full Analysis Set (FAS)
The Full Analysis Set (FAS), used for analysis in the DB study only, and reported here for 
completeness, comprises subjects from the DB AC-055E201 / MERIT-1 study who were 
randomized to either placebo or macitentan 10 mg.
11.2.2 Open-Label Analysis Set (OLAS)
The OL analysis set (OLAS), comprises all data from subjects who enrolled into the OL 
extension study, from the time they enter the OL extension study (Table 2).  
11.2.3 Restricted Analysis Set (RAS)
The restricted analysis set (RAS), comprises all data from subjects enrolled in the OL 
extension study who received macitentan 10 mg during the AC-055E201 / MERIT-1, from 
the time they enter the DB study (Table 2).
11.2.4 Open-Label Safety Set (OLSS)
OL Safety Set (OLSS), comprises all DB and OL study subject data from subjects enrolled 
in OL extension study and who received macitentan 10 mg at least once, during either the 
DB or OL extension study for the period they are exposed to macitentan 10 mg (Table 2).
11.2.5 Role of the different analysis sets
The analyses of the exploratory efficacy endpoints will be performed on the OLAS and 
RAS:
1. On the OLAS, as change from baseline of the OL extension study, by randomized 
treatment group in AC-055E201 / MERIT-1, 
2. On the RAS, as change from baseline of the DB core study in macitentan 10 mg 
only.  
The OLSS will be used for the analyses of the safety variables. Listings will be prepared 
on the RAS, OLAS, and OLSS as appropriate. Subject disposition will be summarized for 
the OLAS. No per protocol analyses will be conducted.


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Table 2
Use of analysis sets for analysis of efficacy and safety variables
Analysis Sets
Variable
OLAS
RAS
OLSS
Efficacy
6MWD
X
X
Borg dyspnea index
X
X
WHO FC
X
X
Safety
AEs
X
SAEs
X
Marked laboratory abnormalities 
X
Vital signs
X
Subject Disposition
X
Demographics
X
Exposure
X
6MWD = 6-minute walk distance; AEs = adverse events; FC = functional class; OLAS = Open-Label Analysis Set; OLSS = Open-Label 
Safety Set; RAS = Restricted Analysis Set; WHO = World Health Organization.
11.2.6 Randomization and stratification
The sample size for the OL extension study will be up to 78 randomized 
(1:1 to placebo:macitentan 10 mg) subjects from the AC-055E201 / MERIT-1 DB study, 
who are eligible for and consent to enter the OL extension.
Randomization in the AC-055E201 / MERIT-1 DB study was not stratified.
11.3 Description of statistical analyses
11.3.1 General considerations

Unblinding of study drug code will occur only after AC-055E201 / MERIT-1 study
database closure in accordance with Actelion standard operating procedures (SOPs). 

Analyses will be conducted only on subject data from subjects who enroll in the OL 
study and are exposed to macitentan 10 mg at least once, during either the DB or OL
extension studies.

For the analysis of the exploratory endpoints on the OLAS where comparisons 
between original randomized groups are made, the experiment-wise significance level 
will be controlled at the two-sided α = 0.05 level and two-sided 95% confidence 
intervals will be provided. Any two-sided p-value ≤ 0.05 will be identified as 


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statistically significant but will be considered as exploratory result. No multiplicity 
adjustment will be made.

Given the small sample size in this study only the following model covariates may be 
considered for inclusion in the analysis of the exploratory endpoints: randomized 
treatment, time or visit, and baseline value related to the outcome variable of interest.

AEs will be coded using the same version of the MedDRA dictionary used in the 
AC-055E201 / MERIT-1 study. Concomitant Medications will be coded using the 
same versions of the WHO drug code and the Anatomic Therapeutic Chemical class 
code dictionaries as used in the AC-055E201 / MERIT-1 study.

All important protocol deviations related to study inclusion or exclusion criteria, 
conduct of the study, patient management, or patient assessment will be described in 
the final report. Subject listings for protocol deviations will be presented broken down 
by center.

SAS version 9.2 or higher will be used for all statistical analysis. 

All analysis variables will be listed and presented in tables; variables to be presented 
in figures will be specified in the SAP.  

Data will be listed and summarized by appropriate descriptive statistics (tables or 
figures), typically including:
−
Number of non-missing observations, number of missing observations, mean, 
standard deviation, minimum, Q1, median, Q3 and maximum for continuous 
variables
−
Number of events, number of censored observations , number of subjects at risk, 
and Kaplan-Meier estimates of the survival function for time-to-event variables
−
Number of non-missing observations, number of missing observations and 
frequency with percentage per category (percentages based on the sum of number 
of non-missing observations and total number of observations) for categorical 
variables. 
Absolute changes from baseline are defined as: post-baseline value minus baseline value, 
such that a positive sign indicates an increase as compared to baseline.
11.3.2 Analysis of subject disposition and study completion/withdrawal
A study flowchart will be used to show the disposition of study subjects throughout the 
progression of the study. It will display the numbers of patients randomized into the 
AC-055E201 / MERIT-1 study divided into the placebo and macitentan 10 mg treatment 
groups to which they were randomized. The number of subjects by treatment group 
entering into the AC-055E202 / MERIT-2 OL extension study along with the number of 
subjects continuing and discontinuing treatment and follow-up during the OL extension 


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study, along with reasons for discontinuations will be displayed. The final row of the 
flowchart will result in the number of subjects completing the OL extension study in each 
treatment group.
The items in the flowchart will be supported by tables and listings related to each level and 
will be presented by randomized treatment group:

Summary of patient recruitment by country and center in the OLAS

Summary of reasons for premature study discontinuation in the OLAS

Summary of reasons for treatment discontinuation in the OLAS.
The number and percent of patients included in and excluded from each analysis set, based 
on the set definitions in Section 11.2 will be summarized in tables and listings, and will be 
supported by a summary table of major protocol deviations. Major protocol deviations will 
be displayed by region.
11.3.3 Analysis of the exploratory variables
Analysis of the exploratory efficacy variables will be conducted on both the OLAS and 
RAS analysis sets.
11.3.3.1 6MWD and Borg dyspnea index
The change from baseline to window-based time points for 6MWD and Borg dyspnea 
index will be displayed using descriptive statistics for continuous variables as described in 
Section 11.3.1 along with 95% two-sided confidence limits (CL) of means and medians.
For the analyses based on the OLAS, comparing by randomized groups, a repeated 
measures analysis will be performed using mixed model techniques, allowing for 
estimation of the adjusted overall treatment effect and treatment effect at each visit. The 
dependent variable of the model will be the change from baseline. Study visit, treatment, 
treatment by visit interaction and baseline value will be included as fixed effects in the 
model, while patient will be included as random effect.
The results will be displayed in a summary table showing: the p-value for the treatment by 
visit interaction, the adjusted means and 95% CL for each treatment and visit, as well as 
the adjusted differences to placebo with 95% CL at each visit. If the treatment by visit 
interaction is not significant at the 0.05 level then the model will be re-run without 
including the interaction term and the overall treatment effects will be displayed in the 
summary table.
11.3.3.2 WHO FC
The change from baseline to window-based time points for proportion of patients 
worsening will be displayed using descriptive statistics for categorical variables as 
described in Section 11.3.1.


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For the analyses based on the OLAS, comparing by randomized groups, changes from 
baseline to all window-based time points in WHO FC will be analyzed comparing the 
proportion of patients worsening in the two treatment groups by means of the Fisher’s exact 
test. A shift table will display the change in WHO FC from baseline to each window-based 
time point. In addition, the relative risk will be displayed with its 95% CL.
11.3.4 Exposure to study drug
Analysis of exposure to study drug will be conducted on the OLAS during the OL period.
Exposure will be described in terms of duration and dose. The duration of exposure is 
defined as the time elapsing between study drug initiation and discontinuation, inclusive. 
The duration of exposure, mean daily dose and compliance will be tabulated using the usual 
location and scale summary statistics by randomized treatment group.
The mean daily dose per subject is defined as the ratio between the total study drug dose 
taken during the treatment period and the total exposure time. Compliance, in percent, is 
defined as percent of doses taken divided by expected number of doses during follow-up.
11.3.5 Demographic and baseline characteristics
Summaries for demographic and baseline characteristics will be performed on the OLAS. 
The variables age, sex, race, height, weight, BMI, geographical location, and baseline 
disease characteristics corresponding to the endpoint variables will be summarized per 
treatment group and overall. 
11.3.6 Analysis of the safety variables
The OLSS will be used to perform all safety analyses. 
All safety data will be included in listings, with flags for quantitative abnormalities.
11.3.6.1 Adverse Events
The number and percentage of subjects experiencing treatment-emergent AEs and SAEs 
at least once from baseline up to 30 days following study drug discontinuation will be 
tabulated by randomized treatment group and by:

System organ class (SOC) and individual preferred term within each SOC, in 
descending order of incidence within the macitentan 10 mg treatment group

Proportion of subjects with events coded with the same preferred term, in descending 
order of incidence in the macitentan 10 mg treatment group
Furthermore, treatment-emergent AEs and SAEs occurring up to 30 days after study drug 
discontinuation will be tabulated as described above by severity and relationship to study 
drug.
AEs leading to premature discontinuation of study drug and death will also be summarized 
as described above.


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Listings will be provided for all reported AEs, including SAEs. In addition, separate 
listings will be provided for SAEs, for AEs leading to premature discontinuation of study 
drug, and for AEs leading to death. 
11.3.6.2 Laboratory Parameters
Descriptive summary statistics by visit and study treatment will be provided for observed 
values and absolute changes, from baseline up to EOT plus 30 days, in both hematology 
and blood chemistry laboratory tests. In order to minimize missing data and to allow for 
unscheduled visits, all recorded assessments up to EOT plus 30 days will be assigned to 
the most appropriate visit time point according to the best fitting time-window for that 
assessment.
Actelion internal guidelines will be used for the definitions of marked abnormalities and 
for the standardization of numeric values obtained from different laboratories and/or using 
different normal ranges. Standard numeric laboratory variables are transformed to standard 
units. All laboratory data transferred are taken into account regardless of whether they 
correspond to scheduled (per protocol) or unscheduled assessments. 
Marked laboratory abnormalities will be summarized for each laboratory parameter 
providing their incidence and frequency. The summary will be conducted by treatment 
group for the OL period only. Absolute values and changes of laboratory parameter values 
during the course of the study from baseline up to EOT plus 30 days will be summarized 
using the usual location and scale summary statistics by treatment group.
11.3.6.3 Vital signs and body weight 
Similarly to laboratory parameters, descriptive summary statistics by visit and study 
treatment will be provided for observed values and absolute changes, from baseline up to 
EOT plus 30 days, both for vital signs and body weight. In order to minimize missing data 
and to allow for unscheduled visits, all recorded assessments up to EOT plus 30 days will 
be assigned to the most appropriate visit time point according to the best fitting time-
window for that assessment.
11.4 Sample size
The sample size for the OL extension study will be up to 78 randomized subjects from the 
DB study (AC-055E201 / MERIT-1), who are eligible for and consent to enter the OL 
extension. 
12 DATA HANDLING
12.1 Data collection
The investigator/delegate is responsible for ensuring the accuracy, completeness, legibility 
and timeliness of the data reported. All source documents should be completed in a neat, 
legible manner to ensure accurate interpretation of the data. Data reported in the eCRF 
derived from source documents must be consistent with the source documents.


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CRF data will be captured via electronic data capture (EDC) using the Rave system 
provided by Medidata Solutions, Inc., a web-based tool. 
Site team members who obtained access to the eCRF in the AC-055E201/ MERIT-1 study 
will use the same account to access to the eCRF of the OL study. 
The investigator and site staff will be trained to enter and edit the data via a secure network, 
with secure access features (username, password and identification – an electronic 
password system). A complete electronic audit trail will be maintained. The 
investigator/delegate will approve the data (i.e., confirm the accuracy of the data recorded) 
using an electronic signature (ref. to 21 CFR Part 11).
Subject Enrollment data will be completed for all subjects (i.e., eligible and non-eligible) 
through IXRS and eCRF.
For each subject enrolled, regardless of study drug initiation, an eCRF must be completed 
and signed by the investigator/delegate. This also applies to those subjects who fail to 
complete the study. If a subject withdraws from the study or in case of premature treatment 
discontinuation, then the reason must be noted on the eCRF.
12.2 Maintenance of data confidentiality
The investigator/delegate must ensure that data confidentiality is maintained. On eCRFs or 
other documents submitted to Actelion, subjects must be identified only by study-specific 
subject number, and never by name, initials, or hospital subject number. The 
investigator/delegate must keep a subject identification code list, at the site, showing the 
study-specific subject number, the subject’s name, date of birth and address or any other 
locally accepted identifiers. Documents identifying the subjects (e.g., signed ICFs) must 
not be sent to Actelion, and must be kept in strict confidence by the investigator/delegate.
12.3 Database management and quality control
Electronic CRFs will be used for all subjects. The investigator will have access to the site 
eCRF data throughout the study. The eCRF must be kept current to reflect subject status at 
any time point during the course of the study.
While entering the data, the investigator/delegate will be prompted by logical checks/error 
messages built into the web-based data entry screening performed on the data. Other 
protocol-specific validation programs will run routinely to perform more extensive data 
checks for accuracy and completeness. Additional data review will be processed in parallel 
by Actelion to look for unexpected patterns in data and study monitoring. In the case that
problematic data are detected, a query specifying the problem and requesting clarification 
will be issued and visible to the investigator/delegate via the eCRF, so that the 
investigator/delegate can respond and clarify directly onto the eCRF. 
The investigator/delegate must, on request, supply Actelion with any required background 
data from the study documentation or clinical records. This is particularly important when 


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errors in data transcription are suspected. In the case of Health Authority queries, it is also 
necessary to have access to the complete study records, provided that subject
confidentiality is protected.
Laboratory samples will be processed through a central laboratory and the results will be 
sent electronically to Actelion. If local laboratory data is obtained, it must be entered in the 
eCRF by the site, as defined in Section 7.3.4.2.
After the database has been declared complete and accurate, the database will be closed. 
Any changes to the database after that time may only be made as described in the 
appropriate SOP. At the end of the trial, the investigator will receive the eCRF of the 
subjects of her/his site (including all data changes made) on a CD-ROM or as a paper copy.
13 PROCEDURES AND GOOD CLINICAL PRACTICE
13.1 Ethics and Good Clinical Practice
Actelion and the investigators will ensure that the study is conducted in full compliance 
with ICH-GCP Guidelines, the principles of the “Declaration of Helsinki” and with the 
laws and regulations of the country in which the research is conducted.  
For any site staff member responsible for performing a critical task as confirmed on the 
DoA and/or listed on the FDA1572 form (IND sites only), ICH GCP experience and 
training must be documented on the CV. Actelion will train any site staff member not 
familiar with ICH GCP or having conducted an ICH GCP training more than one year prior 
to initiation or start of involvement in the study.
13.2 Independent Ethics Committee / Institutional Review Board
The investigator will submit this protocol and any related document provided to the subject
(such as Subject Information Leaflet used to obtain informed consent) to an IRB/IEC. 
Approval from the committee must be obtained before starting the study, and must be 
documented in a dated letter to the investigator, clearly identifying the study, the 
documents reviewed, and the date of approval. 
A list of members participating in the meeting must be provided, including the names, 
qualifications and functions of these members. If that is not possible, the attempts made to 
obtain this information along with an explanation as to why it cannot be obtained or 
disclosed must be documented in the study documentation. If a study staff member was 
present during a meeting, it must be clear that this person did not vote.
Modifications made to the protocol after receipt of the approval must also be submitted as 
amendments by the investigator to the IRB/IEC in accordance with local procedures and 
regulations [see Section 13.6].
In cases where an investigator is moving to a new site location, or a new principal 
investigator is taking over a study site, regulatory documents will need to be updated to 


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reflect the correct and current situation. In accordance with laws and regulations of the
country and as per IRB/IEC requirements, the updated information will be submitted for 
approval/notification, as appropriate.
13.3 Informed consent
It is the responsibility of the investigator/delegate to obtain informed consent from each 
individual participating in this study and/or legal representative, according to ICH-GCP 
guidelines and local regulations. The investigator/delegate must explain to subjects that 
they are completely free to refuse to enter the study, or to withdraw from it at any time for 
any reason. The subject should be given ample time review the information provided by 
the investigator/delegate.
When the results of the DB AC-055E201 / MERIT-1 study become available, the 
investigator/delegate should inform the subjects about these results. Details of such 
discussion must be documented in the subject’s file
The ICF will be provided in the local language(s) of the country.
Site staff authorized to participate in the consent process and/or to obtain consent from the 
subject and/or legal representative will be listed on the Actelion DoA form. A study 
physician must always be involved in the consent process. 
The subject and/or legal representative must personally sign and date (including the time, 
if appropriate) the ICF before any study-related procedures (i.e., any procedures required 
by the protocol) begin. The ICF must also be personally signed and dated (including the 
time, if appropriate by the authorized site staff listed on Actelion DoA form.
A copy of the signed and dated ICF is given to the subject and/or legal representative; the 
original is filed in the site documentation (alternatively, 2 originals may be signed [one 
original given to the subject, one filed at site]; it must be clearly documented at site which 
procedure is being followed). 
The informed consent process must be fully documented in the subject’s medical records, 
including study reference, subject number, date/time (if applicable) of when the subject 
was first introduced to the Actelion clinical study, date/time (if applicable) of consent, who 
participated in the consent discussion, who consented on behalf of the subject and any 
additional person present during the consent process (e.g., subject family member), and a 
copy of the signed ICF given to the subject / legal representative.
If the signing of informed consent and performance of the first study-specific procedures 
or assessments take place on the same day, it must be clearly stated in the source documents 
that the subject has given fully informed consent prior to the first study-specific procedures 
or assessments.
If the site would like to recruit a subject who would be considered as vulnerable (e.g.,
subject cannot read, does not speak or understand the ICF language), additional measures 


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Amendment 3, Version 4, 22 June 2021, page 67/90
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must be implemented in order to ensure subject rights are respected and the consent 
obtained is legally valid. Actelion, the regulatory authorities (if applicable) and the 
IRB/IEC must be informed prior to the recruitment. The consent process (e.g., involvement 
of an impartial witness) must be fully described, submitted to, and approved by the 
IRB/IEC, according to procedures. 
13.4 Compensation to subjects and investigators
Actelion provides insurance in order to indemnify (with both legal and financial coverage) 
the investigator/site against claims arising from the study, except for claims that arise from 
malpractice and/or negligence.
The compensation of the subject in the event of study-related injuries will comply with 
applicable regulations.
13.5 Protocol adherence/compliance
The investigator must conduct the study in compliance with the approved version of the 
protocol and must not implement any violation/deviation/change from the protocol, except 
when the change involves only logistical or administrative aspects (e.g., change in 
telephone number), or in case it would be necessary to eliminate an immediate hazard to 
the subject. 
If a protocol deviation occurs, the investigator/delegate will inform Actelion or its 
representative, in a timely manner. The investigator/delegate must document and explain 
any 
violation/deviation/change 
from 
the 
approved 
protocol. 
Protocol 
violation/deviation/change must also be submitted to IRB/IEC and to the regulatory 
authority(ies), according to their requirements.  
13.6 Protocol amendment
Any change to the protocol can only be made through a written protocol amendment 
approved by Actelion. A protocol amendment must be submitted to IRB/IEC, and 
regulatory authority(ies), according to their requirements.  
Approval must be obtained before any change can be implemented, except when the 
change involves only logistical or administrative aspects (e.g., change in telephone 
number), or in case it would be necessary to eliminate an immediate hazard to the subject;
in this case. IRB/IEC and regulatory authority(ies) must be notified as soon as possible, 
according to their requirements, but not later than 15 calendar days.
13.7 Essential documents and retention of documents
The investigator/delegate must maintain adequate records necessary for the reconstruction 
and evaluation of the study. A number of attributes are considered of universal importance 
to source data and the records that hold those data. These include that the data and records 


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 68/90
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are accurate, legible, contemporaneous, original (or certified copy), attributable, complete, 
consistent, enduring and available when needed.  
These records are to be classified into two different categories of documents: investigator’s 
file, and subject clinical source documents. 
These records must be kept by the investigator for as long as is necessary to comply with 
Actelion’s requirements (e.g., as specified in the clinical study agreement), and national 
and/or international regulations, whichever would be the longest period. If the investigator 
cannot guarantee this archiving requirement at the investigational site for any or all of the 
documents, special arrangements, respecting the data confidentiality, must be made 
between the investigator and Actelion to store these documents outside the site, so that they 
can be retrieved in case of a regulatory inspection. No study document should be destroyed 
without prior written approval from Actelion. Should the investigator wish to assign the 
study records to another party, or move them to another location, Actelion must be notified 
in advance. 
Documentation of study assessment, even data that are not reported in the eCRF, must be 
available 
in 
the 
subject’s
medical 
records, 
including 
the 
study-specific 
procedures/assessments prior to enrollment.
If the site is using an electronic/computerized system to store subject medical records, it 
can be used for the purpose of the clinical study if it is validated (as per 21 CFR Part 11 or 
equivalent standard) and if the monitor has been provided personal access to verify 
consistency between electronic source data and the eCRF during monitoring visits.
If the site is using an electronic/computerized system to store subject medical records but 
the validation of the system cannot be confirmed, or if the monitor could not be provided 
with access to the system, the site is requested to print the complete set of source data 
needed for verification by the monitor. The print-outs must be numbered, stapled together 
with a coversheet, signed and dated by the investigator/delegate to confirm that these 
certified copies are exact copies containing the same information as the original subject’s 
data. The printouts will be considered as the official clinical study records. 
In order to verify that the process the site uses to prepare certified copies is reliable, the 
monitor must be able to observe this process and confirm that the comparison of the source 
documents and the certified copy did not reveal inconsistencies. The monitor does not need 
to verify this process for all data of all subjects but at least for some of them (e.g., first 
subject; regular check during the study of critical data like inclusion/exclusion criteria, 
endpoints for some subjects) as per Actelion’s instructions. If the monitor is not able to 
observe this process, then the site’s certified copies cannot be relied upon, and therefore 
the site cannot be used for the clinical study. The printouts should be filed either with the 
subject medical records or with the subject’s CRF.


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Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
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13.8 Monitoring
The monitor will contact and visit the investigational site regularly, and on request must be 
permitted access to trial facilities and all source documents needed to verify adherence to 
the protocol and the completeness, consistency and accuracy of the data being entered on 
the eCRFs and other protocol-related documents. Actelion monitoring standards require 
full verification that informed consent has been provided, and verification of adherence to 
the inclusion/exclusion criteria, documentation of SAEs, and the recording of the main 
efficacy, safety and tolerability endpoints. Additional checks of the consistency of the 
source data with the eCRFs will be performed according to the study-specific monitoring 
plan.
The required site personnel must be available during monitoring visits and must allow 
adequate time to meet with the monitor to discuss study related issues. An initiation visit 
will be performed after the required essential documents are received at Actelion and 
before the first subject is included in the study. Monitoring visits will be conducted 
regularly; frequency will be based on subject recruitment rate and critical data collection 
times. A close-out visit will be performed for any initiated site.
The investigator agrees to cooperate with the monitor(s) to ensure that any issues detected 
in the course of these monitoring visits are resolved. If the subject is hospitalized or dies in 
a hospital other than the study site, the investigator is responsible for contacting that 
hospital in order to document the SAE.
13.9 Audit 
Actelion’s Global Quality Management representative may audit the investigator site 
(during the study or after its completion). The purpose of this visit will be to determine the 
investigator’s adherence to ICH-GCP, the protocol, applicable regulations, and Actelion’s 
requirements (e.g., SOPs). Prior to initiating this audit, the investigator will be contacted 
by Actelion to arrange a convenient time for the audit. 
The investigator and staff must cooperate with the auditor(s) and allow access to all study 
documentation (e.g., subject records) and facilities.
13.10 Inspections
Health Authorities and/or IRB/IEC may also wish to conduct an inspection of Actelion’s 
clinical study (during the study or after its completion). 
Should an inspection be requested by a Health Authority and/or IRB/IEC, the investigator 
must inform Actelion immediately, (usually via the monitor), that such a request has been 
made. 
The investigator and staff must cooperate with inspector(s) and allow access to all study 
documentation (e.g. subject records) and study facilities.


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Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 70/90
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13.11 Reporting of study results and publication 
Study results will be documented in a clinical study report that will be signed by Actelion 
representatives and the Coordinating Investigator.
The Coordinating Investigator and the SC will have the opportunity to review the analysis 
of the data and to discuss the interpretation of the study results with Actelion prior to 
publication.
Janssen Pharmaceutical Companies (Actelion) will post results from Phase 1–4 clinical 
studies on external registries as required by law, and from interventional studies in patients 
for marketed products. In accordance with Good Publication Practices and ethical practice, 
the results of the study will be submitted for publication in a peer-reviewed journal. For 
observational studies, the first publication will include data in their entirety and not as 
individual site data. Study results can be submitted for presentation at a congress before 
publication in a peer-reviewed journal.
Authorship will be determined in accordance with the International Committee of Journal 
Editors criteria, and be based on:

Substantial contributions to the conception and design, or acquisition of data, or 
analysis and interpretation of data; and

Drafting of the publication or critical review for important intellectual content; and 

Providing final approval of the version to be published.
The list of authors of any publication of study results may include representatives of 
Actelion, and will be determined by mutual agreement.
Any study-related publication written independently by investigators must be submitted to 
Actelion for review at least 30 days prior to submission for publication or presentation. 
Upon review, Actelion may provide comments, and may also request alterations and/or 
deletions for the sole purpose of protecting its confidential information and/or patent rights. 
Neither the institution nor the investigator should permit publication during such a review 
period.


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 71/90
EDMS-RIM-263288, 3.0  
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14 REFERENCES
[Abman 2009] Abman SH. Role of endothelin receptor antagonists in the treatment of 
pulmonary arterial hypertension. Annu Rev Med. 2009;60:13-23
[ATS Guidelines 2002] American Thoracic Society (2002) ATS statement: guidelines for 
the six-minute walk test. Am J Respir Crit Care Med 2002;166:111–117.
[Food and Drug Administration 2020]. Food and Drug Administration. Drug Development 
and Drug Interactions: Table of Substrates, Inhibitors and Inducers (Table 2-2). 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers. Accessed 09 July 2020.
[Ghofrani 2013a] Ghofrani HA, D’Armini AM, Grimminger F, et al. Riociguat for the 
treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 
2013;369(4):319-329.
[Ghofrani 2013b] Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment 
of pulmonary arterial hypertension. N Engl J Med 2013;369(4):330-340. 
[Haythe 2012] Haythe J. Chronic thromboembolic pulmonary hypertension: A review of 
current practice Progress in Cardiovascular Diseases 55 (2012) 134–143.
[Jamieson 2003] Jamieson SW, Kapelanski DP, Sakakibara N, et al. Pulmonary 
endarterectomy: experience and lessons learned in 1,500 cases. Ann Thorac Surg 
2003;76:1457– 1462.
[Jenkins 2012] Jenkins D, Mayer E, Screaton N, Madani M. State-of-the-art chronic 
thromboembolic pulmonary hypertension diagnosis and management. Eur Respir 
Rev 2012; 21: 123, 32–39.
[Macitentan IB] Investigator’s Brochure: JNJ-67896062 Opsumit® (Macitentan), Edition 
18. Actelion Pharmaceuticals Ltd, December 2020. 
[O’Callaghan 2011] O’Callaghan DS, Savale L, Montani D, et al. Treatment of pulmonary 
arterial hypertension with targeted therapies. Nat Rev Cardiol. 2011;8(9):526-38.
[Pepke-Zaba 2011] Pepke-Zaba J, Delcroix M, Lang I, et al. Chronic thromboembolic 
pulmonary hypertension (CTEPH): results from an international prospective registry. 
Circulation 2011; 124: 1973–1981.
[Simonneau 2009] Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical 
classification of pulmonary hypertension. J Am Coll Cardiol 2009;54:Suppl:S43-
S54.


Macitentan / ACT-064992
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Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 72/90
EDMS-RIM-263288, 3.0  
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15 APPENDICES
Appendix 1
Sponsor Guidelines for 6MWT 
6-Minute Walk Test (6MWT) 
General instructions 
The American Thoracic Society published an official statement on the 6MWT in 
2002 [ATS Guidelines 2002]. Only a brief summary of these guidelines is included here.
The 6MWT should be performed indoors, along a long, flat, straight, enclosed 
corridor with a hard surface that is seldom traveled. The use of a treadmill is forbidden.
The walking distance used for the test should be 30 meters (100 feet) in length. This 
distance should be marked every 3 meters (10 feet). The turnaround point should be 
marked with a cone. A starting line, which marks the beginning and the end of each 60-
m lap, should be marked on the floor using brightly colored tape. 
The study staff member administering the 6MWT should stand near the starting line 
during the test and must not walk with the subject!
Intermittent rest periods are allowed if the subject can no longer continue. If the subject 
needs to rest, he/she may pause, lean against the wall or sit and should continue walking
whenever he/she feels able. The timer must continue to run. The test can be stopped at 
any moment in case the subject complains of having chest pain, intolerable dyspnea, leg 
cramps, or has a pale or ashen appearance.
The 6MWT is a non-encouraged test. No instructions or encouragement will be given 
during the test. Eye contact and body language signaling the subject to speed up should 
be avoided during the test. 
For an individual subject, repeat testing should always be conducted under the same 
conditions throughout the study (e.g., same corridor). Whenever possible, repeat testing 
for an individual subject should be conducted by the same tester, and preferably at about 
the same time of the day to minimize variability.
If oxygen supplementation is needed during the 6MWT at Enrollment, then during all 
study 6MWTs by that subject oxygen should be delivered in the same way with the 
same flow (if possible). If the flow must be increased during subsequent visits (e.g., due 
to worsening), this should be indicated in the source notes.


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Required equipment:

Countdown timer (or stop watch)

Mechanical lap counter

Two small cones for the turnaround points

A chair that can be easily moved along the walking course

Worksheets on a clipboard

Sphygmomanometer

Automated electronic defibrillator

Source of oxygen
Subject preparation

The subject should wear comfortable clothing and appropriate walking shoes.

The meals preceding the test should be light, and the subject should not have exercised 
vigorously within 2 h of beginning the test.

The subject should sit at rest for at least 10 min before the test starts. 

Subjects should receive their usual medication on the day of the test. If the subject is 
used to taking bronchodilators before a walk, he/she should take them 5–30 min before 
the test.
Measurement of the 6-minute walk distance / 6-minute walk test – Instructions to the 
subject
The person administering the test will use the following exact dialogue with the subject:
“The object of this test is to walk as far as possible for 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 to.
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 for 6 minutes, but don’t run 
or jog. I will tell you when 2 minutes, 4 minutes have elapsed. Keep walking when I 
talk.”
After these instructions are given to the subject, the person administering the test will then 


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 74/90
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ask: 
“Do you have any questions about the test?”
“Please explain what you are going to do.”
“Are you ready?”
“Start now, or whenever you are ready”
As soon as the subject starts to walk, the tester will start the timer and write down 
start time.
The tester will tell the subject the time elapsed by saying:
“You have 4 minutes to go.”
“You have 2 minutes to go.”
When the timer is 15 seconds from completion, the tester says: 
“In a moment I’m going to tell you to stop. When I do, just stop right where you are 
and I will come to you”.
When the timer alarm rings the tester says:
“Stop!”
The tester walks over to the subject, marks the spot where the subject stopped, records the 
total distance walked in the worksheet and congratulates the subject on a good effort.
Borg dyspnea index
As soon as possible following the walk test, the subject is asked to rate his/her dyspnea 
using the Borg Scale [Appendix 2]. The tester will use the following dialog:
“I would like to use the following scale to indicate the maximal shortness of breath you 
had during the walk test (indicate the Borg scale). 
If there was no shortness of breath at all you would point to 0; 
if the shortness of breath was not very great you would choose from 0.5 to 2; 
if you were somewhat more short of breath you would select 3; 
and if the breathing was getting very difficult, you would choose 4 to 9, depending on just 
how hard it was; 
10 represents the greatest shortness of breath you have ever experienced in your life.”


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 75/90
EDMS-RIM-263288, 3.0  
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Appendix 2
Borg Dyspnea Index (Perceived Breathlessness / Borg Scale)
0
NOTHING AT ALL
0.5
VERY, VERY SLIGHT (just noticeable)
1
VERY SLIGHT
2
SLIGHT (light)
3
MODERATE
4
SOMEWHAT SEVERE
5
SEVERE (heavy)
6
7
VERY SEVERE
8
9
10
VERY, VERY SEVERE (maximal)


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Appendix 3
WHO Functional 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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Appendix 4
Laboratory Abnormalities 
Laboratory abnormalities according to the most updated version of CTCAE.
A marked abnormality is defined based on the following list (SI units).
Parameter
LL
LLL
HH
HHH
HHHH
Hemoglobin 
(g/L)
< 100
< 80
Increase in (> 20
g/L above
ULN) or above
baseline if
baseline is above 
ULN
Increase in (> 40
g/L above ULN)
or above 
baseline
if baseline is
above ULN
Hematocrit
< 28% 
for
females 
< 32% 
for 
males
< 20%
> 60% in men
> 55% in women
> 65%
Platelet count 
(109 /L)
< 75
< 25
> 600
> 999
Leucocytes 
(× 10e9 /L)
< 3.0
<2.0
> 20.0
> 100.0
Neutrophils 
(109 /L)
< 1.5
<1.0
NA
NA
Eosinophils 
> 5.0 × 10e9      
or > 5%
NA
Lymphocyte 
(109 /L)
< 0.8
< 0.5
> 4.0
> 20.0
AST (U/L)
NA
NA
> 3 ULN
> 5 ULN
> 8 ULN
ALT (U/L)
NA
NA
> 3 ULN
> 5 ULN
> 8 ULN
AP
NA
NA
> 2.5 ULN
> 5 ULN
Total bilirubin 
(umol/L)
NA
NA
> 2 ULN
> 5 ULN


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Parameter
LL
LLL
HH
HHH
HHHH
INR
> 1.5 × ULN or
>1.5 times above 
baseline if on 
anticoagulation
> 2.5 × ULN or
> 2.5 times 
above baseline if 
on 
anticoagulation
Creatinine 
(umol/L)
NA
NA
> 1.5 ULN or     
1.5 × baseline
> 3 ULN or    
> 3× 
baseline
Glucose (mmol 
/ L)
< 3.0
< 2.2
> 8.9
> 13.9
Calcium 
(mmol/L)
< 2.0
< 1.75
> 2.9
> 3.1
Sodium 
(mmol/L)
< 130
> 150
> 155
Potassium 
(mmol/L)
< 3.2
< 3.0
> 5.5
> 6.0
Magnesium 
(mmol/L)
< 0.5
< 0.4
-
> 1.23
Uric acid 
(mmol/L)
-
-
> 0.59
> 0.72
Albumin (g/L)
< 30
< 20
-
-
BUN
-
-
> 2.5 ULN
> 5 ULN
ALT alanine aminotransferase; AP alkaline phosphatase; AST aspartate aminotransferase; BUN blood urea 
nitrogen; CTCAE common terminology criteria for adverse events; LL / HH = marked abnormalities; LLL / HHH / 
HHHH = alert values; INR international normalized ratio; NA not applicable; SI international system of unit; ULN 
upper limit of the normal range.


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Appendix 5
Central Laboratory Alert Flags 

On top of the flags described below, at a minimum, results above the upper limit or below the 
lower limit of the reference range for normal subjects will be flagged. 

Exclusionary Alert Value – At Enrollment (V1): The result is outside the study-specific 
defined limit for inclusion in the study.
Hemoglobin < 100 g/L
AST > 3 × ULN
ALT > 3 × ULN
Serum pregnancy test positive

Total Bilirubin flag Alert Value – All visits except Enrollment (V1): In combination with ALT 
and/or AST > 3 x ULN, study medication should be stopped.
Total bilirubin ≥2 x ULN

Interruption or permanent discontinuation of study medication – All visits except 
Enrollment (V1): Please refer to the study protocol; study medication must be interrupted or 
stopped (see protocol Section 5.1.8.3).
AST > 8 × ULN
ALT > 8 × ULN
Serum pregnancy test positive
Hemoglobin < 80 g/L
Hemoglobin > 50 g/L decrease from baseline in MERIT-1

Repeat Alert value – All visits except Enrollment (V1): Repeat testing is needed (+ interrupt 
study medication in case of ALT and/or AST > 3 × ULN) (see protocol Section 5.1.8.3).
AST > 3 × ULN
ALT > 3 × ULN
Hemoglobin > 20 g/L decrease from baseline in MERIT-1










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Protocol AC-055E202, MERIT-2
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Appendix 7
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
Amendment 2 (28-Sep-2020)
Overall Rationale for the Amendment: The main reason for the amendment is to update 
the description of the investigational medicinal product used in this study from debossed 
on one side to debossed on either one or both sides. The regulatory status of riociguat for 
treatment of chronic thromboembolic pulmonary hypertension (CTEPH) and the 
investigational drug storage conditions have been updated. Procedural changes for safety 
reporting process have been included following integration of safety reporting/procedures 
between Actelion and Janssen.
The updates are indicated in bold text and strike-through for the deleted text in the 
following table.
Section Number
and Name
Description of Change
Brief Rationale
Contract Research 
Organizations Information
Additional details of Central Study Drug 
Re-supply was included.
To 
update 
the 
information of Central 
Study 
Drug 
Re-
Supply.
SYNOPSIS, Study 
Committees, 3.2 Study 
Committees
Modified the statement: A Publication 
Committee is involved in the preparation of 
potential manuscript(s) and will be consulted 
for authorship criteria (if applicable).
To 
allow 
the 
Publication 
Committee to prepare 
a 
manuscript 
or 
publication if required.
1.1 Indication
Information regarding recent updates about 
riociguat’s approval for CTEPH treatment in 
various countries is included as follows:
“Riociguat has gained regulatory approval 
for the treatment of CTEPH in several 
countries, including the United States (US), 
Canada, Japan and European Union (EU). 
To date, riociguat is not approved 
world-wide.
To 
include 
the 
approval and clinical 
use of riociguat for 
CTEPH treatment.
5.1.3 Investigational drug
The original statement from Version 1 is 
revised to: “Macitentan 10 mg will be 
provided as film-coated tablets debossed with 
‘10’ on either one or both sides.”  
To 
update 
the 
description related to 
appearance
of 
investigational product 
from new batches.
5.1.6.2.2
Study drug storage
A revised statement regarding study drug 
storage is included:

Opened bottles of study drug must be 
The text is changed to 
make the label as a 
primary 
reference 


Macitentan / ACT-064992
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Section Number
and Name
Description of Change
Brief Rationale
stored at room temperature, below 30 °C 
(86 °F), and must be protected from 
moisture.
Unopened, 
sealed 
study 
medication bottles can be stored either at 
room temperature, below 30 °C [86 °F],
or in refrigerators at a temperature of at 
least 2 °C (36 °F).

Study drug must be kept in an 
appropriate secure area and stored 
according to the conditions specified on 
the label.

If the temperature at a subject’s home 
exceeds 30 °C (86 ºF) the subject must be 
instructed to store the unopened bottles of 
study drug in his/her refrigerator. Frozen 
storage (below + 2 °C / 36 °F) is not 
permitted. Opened or unsealed bottles 
must not be stored in the refrigerator.
source 
for 
storage 
conditions 
requirement 
and 
remove 
the 
details 
from the protocol.
5.1.8.3 Study-specific criteria 
for study drug interruption / 
permanent discontinuation of 
study drug
B) Liver aminotransferases abnormalities
Following statement is deleted:
In 
order 
to
ensure 
the 
proper 
and 
comprehensive evaluation of cases of ALT 
and/or AST increase > 3 X ULN, additional 
subject data will be collected in the hepatic 
event questionnaire of the eCRF.
To delete information 
as the data collection 
form is not available or 
required.   
C) Hemoglobin abnormalities
Added the statement:
If hemoglobin decrease remains >20 g/L 
below baseline value at subsequent visits, 
further retests are to be performed as per 
investigator’s judgement.
Added the text to 
clarify 
retests 
if 
hemoglobin decrease 
remains >20g/L below 
baseline
SYNOPSIS, Study 
Committees, 3.2 Study 
Committees, 5.1.8.3 Study-
specific criteria for study drug 
interruption / permanent 
discontinuation of study drug
Added the text:
An independent ILSB (an external expert 
committee of hepatologists) provides ongoing 
assessment and advice regarding any serious
hepatic events that may require further 
evaluation during the study.
The ILSB provides 
ongoing assessments 
and advice regarding
only serious hepatic 
events.
10.1.1 Definition of adverse 
events
Additional information on reporting of AEs 
associated with overdose, misuse and abuse 
of study drug was added. 
To 
provide 
clarity 
about reporting of such 
AEs. 
10.1.5 Follow-up of adverse
events
New paragraph added:
The investigator is obligated to perform or 
arrange for the conduct of supplemental 
measurements 
and 
evaluations 
as 
medically indicated to elucidate the nature 
Additional 
information regarding 
conduct 
of 
supplemental 
measurements 
and 


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 86/90
EDMS-RIM-263288, 3.0
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Section Number
and Name
Description of Change
Brief Rationale
and causality of the AE, SAE, or product 
quality compliant (PQC) as
fully as 
possible. This may include additional 
laboratory 
tests 
or 
investigations, 
histopathological 
examinations, 
or 
consultation 
with 
other 
health 
care 
professionals.
evaluations was added.
10.2.2.1 Prior to start of OL 
treatment period;
10.2.2.2 During treatment and 
follow-up periods
Inclusion of PQCs as reportable events in 
addition to SAEs
PQCs 
included 
to 
comply with internal 
procedures.
10.2.4 After the 30-day 
follow-up period; 
10.2.5 Reporting procedures
The 
‘Actelion 
Global 
Drug 
Safety 
department’ is updated to ‘Sponsor’. Updated 
the Reporting procedure for serious adverse 
events (SAEs).
Text updated due to 
Actelion and Janssen 
safety 
process 
integration.
10.2.5 Reporting procedures
Waiving of SAEs related to the underlying 
disease was removed.
Disease-relatedness 
removed 
due 
to 
Actelion and Janssen 
safety 
process 
integration.
10.3.1 Reporting of pregnancy
Reporting of pregnancy in partners of male 
participants included.
Removal of the use of Actelion and change in 
the name of the Pregnancy form.
To 
provide 
more 
clarification 
on 
the 
reporting 
procedure 
and 
to 
capture 
reproduction-related 
information in case 
pregnancy of all study 
participants to comply 
with 
internal 
procedures 
due 
to 
Actelion and Janssen 
safety 
process 
integration. 
Change in pregnancy 
forms  due to Actelion 
and 
Janssen 
safety 
process integration.
10.3.2 Follow-up of pregnancy
Name of pregnancy forms were added and 
text modified.
10.5 Product quality complaint 
handling
A new section on PQC handling and reporting 
was added.
PQC handling section 
added to comply with 
internal 
procedures 
due to Actelion and 
Janssen safety process 


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 87/90
EDMS-RIM-263288, 3.0
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Section Number
and Name
Description of Change
Brief Rationale
integration.
10.6 Special reporting 
situations
A new section on special reporting situations 
was added. 
To 
define 
special 
reporting situations to 
comply with internal 
procedures 
due 
to 
Actelion and Janssen 
safety 
process 
integration. 
12.3 Database management 
and quality control
The eCRF must be kept current to reflect 
subject status at any time point during the 
course of the study (i.e., the data should be 
entered in the system within 10 days of the 
subject’s visit/assessment completion).
To 
follow 
Janssen 
Guidelines.
13.11 Reporting of study 
results and publication
Statement regarding Actelion’s policy for  
study data disclosure was revised as: ‘Janssen 
Pharmaceutical Companies (Actelion) will 
post results from Phase 1-4 clinical studies 
on external registries as required by law 
and from interventional studies in patients 
for marketed products.’  
To follow Janssen’s 
policy on scientific 
publications.
Deleted reference to Actelion’s Policy on 
Scientific Publications
Throughout the protocol
Minor grammatical, formatting, or spelling 
changes were made.
Minor 
errors 
were 
noted 
and 
updates 
were made.
Amendment 1 (15 July 2020)
Overall Rationale for the Amendment: The purpose of this amendment is to update the 
study specific criteria for drug interruption / permanent discontinuation and forbidden 
concomitant medication sections to prohibit strong CYP3A4 inhibitors, moderate dual 
CYP3A4 / CYP2C9 inhibitors, and concomitant administration of moderate CYP3A4 and 
CYP2C9 inhibitors.
Inclusions are presented below in bold.
Section number
and Name
Description of Change
Brief Rationale
Sponsor Contact Details, 
Actelion Contributors to 
the Protocol, Signature 
Details of Clinical Trial Physician, Trial 
Statistician, and Drug Safety Physician are 
updated.
To 
update 
the 
information of study 
responsible physician 


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 88/90
EDMS-RIM-263288, 3.0
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Page for Actelion 
Pharmaceuticals Ltd
and 
protocol 
contributors.
Signatories are updated.
To 
update 
the 
information of new 
signatories.
Synopsis (concomitant 
medications); and Section 
5.2.3 Forbidden 
concomitant medication.
Additional restriction included for CYP3A4 and 
CYP2C9 inhibitors.

Strong CYP3A4 inhibitors (eg, 
ketoconazole, itraconazole, voriconazole, 
clarithromycin, telithromycin, nefazodone, 
ritonavir, and saquinavir) or moderate 
dual CYP3A4/CYP2C9 inhibitors (e.g. 
fluconazole, amiodarone) or co-
administration of a combination of 
moderate CYP3A4 (e.g. ciprofloxacin, 
cyclosporine, diltiazem, erythromycin, 
verapamil) and moderate CYP2C9 
inhibitors (e.g. miconazole, piperine) until 
study intervention discontinuation. 
* If patients are currently stable on a strong 
CYP3A4 inhibitors (eg, ketoconazole, 
itraconazole, voriconazole, clarithromycin, 
telithromycin, nefazodone, ritonavir, and 
saquinavir), moderate dual CYP3A4/CYP2C9 
inhibitors (e.g. fluconazole, amiodarone) or co-
administration of a combination of moderate 
CYP3A4 (e.g. ciprofloxacin, cyclosporine, 
diltiazem, erythromycin, verapamil) and 
moderate CYP2C9 inhibitors (e.g. miconazole, 
piperine), the patient may remain on current 
treatment per the investigator’s discretion 
based on his/her clinical judgement and risk-
benefit assessment
To 
add 
strong 
CYP3A4 inhibitors or 
moderate 
dual 
CYP3A4/CYP2C9 
inhibitors 
or 
co-
administration of a 
combination 
of 
moderate 
CYP3A4 
and 
moderate 
CYP2C9 inhibitors to 
the list of forbidden 
concomintant 
medications.
Section 5.1.8.3 Study 
specific criteria for study 
drug interruption / 
permanent 
discontinuation of study 
drug;
Start of an ERA / strong CYP3A4 inducer / strong 
CYP3A4 inhibitors / moderate dual 
CYP3A4/CYP2C9 
inhibitors 
/ 
combination of moderate CYP3A4 and 
moderate 
CYP2C9 
inhibitors
/ 
investigational drug
–
Study drug must be permanently discontinued 
if an ERA and/or a strong CYP3A4 inducer 
and/or strong CYP3A4 inhibitors and/or 
moderate dual CYP3A4/CYP2C9 inhibitors 
and/or coadministration of a combination 
To 
add 
strong 
CYP3A4 inhibitors or 
moderate 
dual 
CYP3A4/CYP2C9 
inhibitors 
or 
co-
administration of a 
combination 
of 
moderate 
CYP3A4 
and 
moderate 
CYP2C9 inhibitors to 
the list of forbidden 


Macitentan / ACT-064992
Chronic thromboembolic pulmonary hypertension 
Protocol AC-055E202, MERIT-2
Amendment 3, Version 4, 22 June 2021, page 89/90
EDMS-RIM-263288, 3.0
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
of 
moderate 
CYP3A4 and 
moderate 
CYP2C9 
inhibitors 
and/or
another 
investigational drug is started during treatment 
period.
concomintant 
medications.
Section 5.2.3 Forbidden 
concomintant medication; 
and 14 References
A new reference was added to Section 5.2.3 and to 
the reference list.
To 
provide 
investigators 
with 
some 
examples 
of 
CYP3A4 
and 
CYP2C9 inhibitors




CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 21 June 2021
Actelion Pharmaceuticals Ltd
Janssen Research & Development*
Clinical Protocol
COVID-19 Appendix
Protocol Title
Long-term, multicenter, single-arm, open-label extension study of the MERIT-1 study, to 
assess the safety, tolerability and efficacy of macitentan in subjects with inoperable chronic 
thromboembolic pulmonary hypertension (CTEPH)
MERIT-2
Macitentan in thE tReatment of Inoperable chronic Thromboemolic pulmonary 
hypertension (Open-Label)
Protocol AC-055E202; Phase 2
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.; Janssen Research & Development, LLC; or
Actelion Pharmaceuticals Ltd. The term “sponsor” is used throughout the protocol to represent these various
legal entities; the sponsor is identified on the Contact Information page that accompanies the protocol.
EudraCT Number: 2013-003457-25
Status:
Approved  
Date:
21 June 2021
Prepared by:
Actelion Pharmaceuticals Ltd and Janssen Research & Development, a division of 
Janssen Pharmaceutica NV
EDMS number:
EDMS-RIM-265560, 3.0
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL
AC-055E202
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.
NCT02060721


COVID-19 Appendix
ACT-064992 (macitentan)
Clinical Protocol AC-055E202
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 21 June 2021
COVID-19 APPENDIX
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by 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 guidelines or 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 unacceptable 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 between the participant and investigator, 
and with the agreement of the sponsor (see below). 
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
ACT-064992 (macitentan)
Clinical Protocol AC-055E202
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved, Date: 21 June 2021
GUIDANCE SPECIFIC TO THIS PROTOCOL

Certain protocol-mandated visits to the study site may not be possible during the COVID-19 
outbreak. Therefore, temporary measures may be implemented if considered appropriate by 
the sponsor and investigator to maintain continuity of participant care and study integrity. 
Certain measures, such as those listed below, may be necessary and should be instituted in 
accordance with applicable (including local) laws, regulations, guidelines, and procedures:
o
Remote (eg, by phone / telemedicine) or in-person, off-site (eg, in-home) interactions 
between site staff (or designees) and participants for study procedures eg, those related 
to safety monitoring / efficacy evaluation / study intervention storage and 
administration (including training where pertinent). The following assessments should 
be made and documented in the eCRF and source documents: 

Follow-up on ongoing AEs, recording of new AEs

Changes in concomitant mediations

Study intervention compliance 

Contraceptive method and results from urine pregnancy test, as applicable
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 subject and/or results of physical evaluation [as applicable]
performed by the trained site staff or treating physician).
o
Procurement of study intervention by participants (or designee) or shipment of study 
intervention from the study site directly to participants for at home administration 
(including the potential for self-administration of study intervention). The subject will 
be asked to return empty study medication bottles/unused tablets at their next on-site 
visit. Intervention compliance will meanwhile be assessed via visit phone calls.
o
Laboratory assessments using a suitably accredited local laboratory; for selected 
measures (eg, urine pregnancy tests), home testing may be employed. Safety laboratory 
testing should include LTs (LTs: liver aminotransferases [ALT and AST], AP, total 
and direct bilirubin) and hemoglobin (per protocol Table 1 [Visit and assessment 
schedule]) at a minimum. 
o
The investigator must review all safety assessments to confirm the participant can 
pursue his/her study intervention. If the safety assessments cannot be performed and 
reviewed by the investigator in a timely manner, the investigator may decide to 
interrupt or discontinue permanently study intervention, if it is in the best interest of 
the participant.


COVID-19 Appendix
ACT-064992 (macitentan)
Clinical Protocol AC-055E202
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved, Date: 21 June 2021
Once restrictions are lifted, the subject should return to the site as soon as possible to perform all 
safety and efficacy assessments that have been missed. If assessments are done at a time other than 
a scheduled visit, an unscheduled visit should be created in the eCRF to record the results:

Missed or out of window assessments/visits will be captured in the case report form (CRF)
for protocol deviations. Discontinuations of study interventions and withdrawal from the 
study should be documented with the prefix “COVID-19-related” in the CRF. Other 
relevant study data elements impacted by the pandemic should also be documented / 
labeled as “COVID-19-related” in CRFs and / or other study systems, if applicable. These 
may include missed / delayed / modified study visits / assessments / dosing, and instances 
where temporary measures such as those above are implemented.  

The sponsor will evaluate the totality of impact of COVID-19 on collection of key study 
data and additional data analyses will be outlined in study SAP(s). 
Guidance on consenting and monitoring:

Before implementing any of the above mitigations for an individual subject, the subject 
must provide consent for the mitigation action. If allowed by local HA/IRB/EC, verbal 
consent, based on the local regulations, is acceptable and must be documented in the 
subject source notes. Documentation of verbal consent must include: who consented, when 
they were consented, what they were told at the time, how they consented (eg, telephone, 
etc.), who captured the oral/verbal consent (including signature of the investigator or staff 
member who captured the consent), and an identification of impartial witness who was 
present at the time of consent as well as how the impartial witness was selected.

Site monitoring will, in general, be limited to remote monitoring until further notice; 
however, certain regions and countries may continue to have on-site monitoring at this 
time, as allowed per country COVID-19 guidance/travel restrictions. The Site Manager 
will be in contact with the study site to schedule the next remote or on-site monitoring 
visit. 
STUDY CONDUCT RELATED TO COVID-19 VACCINE DEPLOYMENT FOR 
NONCOVID-19 CLINICAL TRIALS

Study participants can undergo a COVID-19 vaccination procedure in compliance with 
applicable local governmental regulations. 

No pharmacokinetic interaction between the study intervention and currently available 
COVID-19 vaccines are expected. In addition, based on the mechanism of action of the 
study intervention and COVID-19 vaccines, no relevant interaction is expected. 

Any COVID-19 vaccine administered to a study participant is considered a concomitant 
medication and should be reported on the electronic case report form (eCRF).

For serious adverse events (SAEs) reported after COVID-19 vaccination, the investigator 
should provide narrative details on the SAE form to allow adequate assessment of causal 
relationship between the reported SAE and vaccination. This is particularly relevant in 
cases where the reported SAE is an expected event with the study intervention and the 
COVID-19 vaccine. If the event is serious and considered to be related to both the 
COVID-19 vaccine and the study intervention, it is a serious adverse reaction and 
expectedness must be assessed. Suspected unexpected serious adverse reaction (SUSAR) 
reporting will be performed if the serious adverse reaction is unexpected per applicable 
reference safety document.



SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 25 March 2022
Actelion Pharmaceuticals Ltd
(a Janssen Pharmaceutical Company of
Johnson & Johnson)*
Statistical Analysis Plan (SAP) for Clinical Study Report (CSR)
Long term, multicenter, single-arm, open-label extension study of the MERIT-1 study, to 
assess the safety, tolerability and efficacy of macitentan in subjects within operable chronic 
thromboembolic pulmonary hypertension (CTEPH)
MERIT-2: Macitentan in thE tReatment of Inoperable chronic Thromboembolic 
pulmonary hypertension (Open-Label)
Protocol AC-055E202; Phase 2
JNJ-67896062 (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.
Status:
Approved
Date:
25 March 2022
Prepared by:
Actelion Pharmaceuticals Ltd (a Janssen Pharmaceutical Company of Johnson & 
Johnson)
Document No.: EDMS-589863, 2.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or otherwise.
NCT02060721


JNJ-67896062  (Macitentan)
Statistical Analysis Plan AC-055E202
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 25 March 2022
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
VERSION HISTORY..................................................................................................................................... 4
1.
INTRODUCTION.................................................................................................................................. 5
2.
OBJECTIVES ...................................................................................................................................... 6
2.1.
Safety Objective............................................................................................................................... 6
2.2.
Efficacy Objectives........................................................................................................................... 6
3.
STUDY DESIGN .................................................................................................................................. 6
3.1.
AC-055E201(MERIT-1).................................................................................................................... 6
3.2.
AC-055E202 (MERIT-2)................................................................................................................... 6
3.3.
Study periods ................................................................................................................................... 7
3.3.1.
Treatment Period.......................................................................................................................... 7
3.3.2.
Safety Follow-up Period................................................................................................................ 7
3.3.3.
Unscheduled Visits ....................................................................................................................... 8
3.4.
Data Displays and Cohorts .............................................................................................................. 8
4.
STATISTICAL HYPOTHESES.......................................................................................................... 10
4.1.
Sample Size Determination ........................................................................................................... 10
5.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS..................................................................... 10
5.1.
Use of Analyses Sets..................................................................................................................... 10
6.
DEFINITION OF VARIABLES........................................................................................................... 11
7.
DISPOSITION.................................................................................................................................... 13
7.1.
Disposition of Subjects................................................................................................................... 13
8.
STATISTICAL ANALYSES............................................................................................................... 13
8.1.
General Considerations ................................................................................................................. 13
8.2.
Rules for Reporting Descriptive Statistics...................................................................................... 14
8.3.
Definition of Baseline ..................................................................................................................... 15
8.4.
Visit Windows................................................................................................................................. 15
8.5.
Efficacy........................................................................................................................................... 16
8.5.1.
Definition of Exploratory Efficacy Variables................................................................................ 17
8.5.1.1.
Six-minute Walk Distance........................................................................................................ 17
8.5.1.2.
Borg Dyspnea Index ................................................................................................................ 17
8.5.1.3.
WHO Functional Class ............................................................................................................ 17
8.5.2.
Analysis of the Exploratory Efficacy Variables ........................................................................... 18
8.5.2.1.
6-minute Walk Distance (m) .................................................................................................... 18
8.5.2.2.
Borg Dyspnea Index ................................................................................................................ 19
8.5.2.3.
WHO Functional Class ............................................................................................................ 19
8.6.
Safety ............................................................................................................................................. 19
8.6.1.
Definition of Safety and Tolerability Variables............................................................................ 20
8.6.1.1.
Treatment-emergent AE.......................................................................................................... 20
8.6.1.1.1.
Intensity of Adverse Events.................................................................................................. 21
8.6.1.1.2.
Relationship to Study Drug .................................................................................................. 21
8.6.1.2.
Adverse Events Leading to Premature Discontinuation of Study Drug................................... 21
8.6.1.3.
Treatment-emergent Serious Adverse Events ........................................................................ 22
8.6.1.4.
Laboratory Parameters............................................................................................................ 22
8.6.1.4.1.
Central Laboratory Alert Flags ............................................................................................. 22
8.6.1.5.
Treatment-emergent Marked Laboratory Abnormalities ......................................................... 22
8.6.1.6.
Vital Signs and Body Weight ................................................................................................... 24
8.6.1.7.
Physical Examination .............................................................................................................. 24


JNJ-67896062  (Macitentan)
Statistical Analysis Plan AC-055E202
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved, Date: 25 March 2022
8.6.1.8.
Deaths ..................................................................................................................................... 24
8.6.2.
Analysis of the Safety Variables ................................................................................................. 25
8.6.2.1.
Treatment-emergent Adverse Events ..................................................................................... 25
8.6.2.2.
Adverse Events Leading to Premature Discontinuation of Study Drug................................... 25
8.6.2.3.
Treatment-emergent Serious Adverse Events ........................................................................ 25
8.6.2.4.
Treatment-emergent Adverse Events of Special Interest ....................................................... 26
8.6.2.5.
Laboratory Parameters............................................................................................................ 26
8.6.2.6.
Treatment-emergent Marked Laboratory (Liver Test and Hemoglobin, Only) 
Abnormalities........................................................................................................................... 26
8.6.2.6.1.
Liver Test Abnormalities (Including Unscheduled Visits)..................................................... 26
8.6.2.6.2.
Incidence of Abnormal Hemoglobin Tests ........................................................................... 27
8.6.2.6.3.
Liver Tests and Hemoglobin Abnormalities Adjusted for Subject-Years Exposure............. 28
8.6.2.7.
Vital Signs and Body Weight ................................................................................................... 28
8.6.2.8.
Physical Examination .............................................................................................................. 28
8.6.2.9.
Deaths ..................................................................................................................................... 28
8.6.2.9.1.
Estimation of Overall Survival .............................................................................................. 28
8.6.2.9.2.
Follow-up.............................................................................................................................. 29
9.
HANDLING OF MISSING, INCOMPLETE OR INCONSISTENT DATE AND TIME VALUES......... 29
9.1.
Handling Incomplete/Missing Dates............................................................................................... 29
10.
OTHER SAFETY ANALYSES........................................................................................................... 31
10.1.
Extent of Exposure......................................................................................................................... 31
10.2.
Treatment Compliance................................................................................................................... 32
11.
DATA MONITORING COMMITTEE (DMC) OR OTHER REVIEW BOARD..................................... 32
12.
SUPPORTING DOCUMENTATION .................................................................................................. 33
12.1.
Appendix 1 List of Abbreviations.................................................................................................... 33
12.2.
Appendix 2 Changes to Protocol-Planned Analyses ..................................................................... 34
12.3.
Appendix 3 Demographics and Baseline Characteristics.............................................................. 35
12.4.
Appendix 4 Protocol Deviations ..................................................................................................... 36
12.5.
Appendix 5 Concomitant Medications............................................................................................ 37
12.6.
Appendix 7 Adverse Events of Special Interest............................................................................. 39
12.8.
Appendix 8 Central Laboratory Normal Ranges ............................................................................ 43
12.9.
Appendix 9 Example SAS Code for Adjusted Incidence Rates and 95% CL................................ 46
REFERENCES............................................................................................................................................ 47


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VERSION HISTORY
Table 1 – SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1
19 November 2021
Not Applicable
Initial release




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2.
OBJECTIVES
2.1.
Safety Objective
To evaluate the long-term safety and tolerability of macitentan 10 mg in subjects with inoperable
CTEPH.
2.2.
Efficacy Objectives
To evaluate the long-term effects of macitentan 10 mg on exercise capacity and functional class 
(FC).
3.
STUDY DESIGN
3.1.
AC-055E201(MERIT-1)
A total of 80 subjects with inoperable CTEPH in World Health Organization Functional Class 
(WHO FC) II–IV with a pulmonary vascular resistance (PVR) ≥ 400 dyn∙sec/cm−5 and 6-minute 
walk distance (6MWD) ≥ 150 m and ≤ 450 m were randomized 1:1 to macitentan or placebo and 
received double blind treatment for 24 weeks. Treatment with phosphodiesterase type-5 inhibitors 
(PDE-5i) or oral/inhaled prostanoids was allowed for subjects in WHO FC III-IV, but not for 
subjects in WHO FC II.
In MERIT-1 (Figure 1), the safety follow-up period was up to EOT + 30 days, or up to the start of 
MERIT-2 OL treatment (whichever occurred first). 
Figure 1 – AC-055E201 (MERIT-1) DB study design  
Source: AC-055E201 (MERIT-1) Clinical Study Report, Figure 9-1.
EOT = End-of-Treatment; F-U = follow-up; OL = open-label; PTOP = post-treatment observational period.
3.2.
AC-055E202 (MERIT-2).
In total, 76 subjects (males or females) who remained in the DB AC-055E201 / MERIT-1 study 
up to Week 24 (see Table 5), irrespective of premature discontinuation of study treatment (except 
if discontinuation was due to a hepatic AE or liver aminotransferase abnormalities) were eligible 
to enter this OL extension study and were treated with macitentan 10 mg. The investigators and 


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subjects did not know the treatment assignment in MERIT-1 (macitentan 10 mg or placebo) at the 
time of inclusion into MERIT-2. The study is conducted in 4 geographical regions (15 countries 
and 35 activated sites)). Site in Switzerland was initiated and then closed as the subjects did not 
roll over.
A post-treatment safety follow-up period (30 days) follows the permanent study drug 
discontinuation.
Figure 2 – AC-055E202 (MERIT-2) OL study design
EOS = End-of-Study; EOT = End-of-Treatment; OL = open-label.
*For subjects who are entering a continued access program, the enrollment into the continued access program (post-
trial access program or other open-label study) must occur on the day of the last visit of the MERIT-2 study (EOS, 
which corresponds to EOT visit in this case).
3.3.
Study periods
The MERIT-2 OL study comprises the following consecutive periods:
3.3.1.
Treatment Period
For each subject, the OL treatment duration will last from his/her enrollment (Visit 1) up to the 
End-of-Treatment, i.e., until whichever of the following occurs first:  

Commercial availability of macitentan in this indication in the subject’s country

Sponsor decides to stop this study (AC-055E202 / MERIT-2 OL extension)

The subject or the investigator decides to discontinue the study drug.
After the Enrollment visit, subjects were to come to the site at Month 1 (Visit 2), Month 6 (Visit 
3), and every 6 months thereafter (Visits 4, 5, 6…), up to the EOT visit (see Figure 2). In addition, 
subjects will perform monthly laboratory and safety monitoring (see Table 3).
3.3.2.
Safety Follow-up Period
For each subject, a post-treatment Safety follow-up period (30 days) will follow the permanent 
study drug discontinuation. For subjects who are entering a continued access program, the 
enrollment into the continued access program (post-trial access program or other open-label study) 
must occur on the day of the last visit of the MERIT-2 study (EOS, which corresponds to EOT 
visit in this case), see Figure 2.


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3.3.3.
Unscheduled Visits 
Unscheduled visits may also take place anytime during the study.  These visits include (but are not 
limited to) those performed due to safety (e.g., occurrence of an adverse event, laboratory 
abnormalities) and/or CTEPH related (e.g., disease progression) issues. 
The date of the visit and the reason for such visits as well as any data related to study assessments 
performed at unscheduled visits are recorded in the 'Unscheduled visit - Reason' CRF form. Any 
of the analyzed laboratory parameters listed in Section 7.3.4.3 of the Protocol, should be analyzed 
at the central laboratory (except in case of emergency). The results done at a local laboratory, are
checked as 'Yes' in the 'Local lab summary' CRF form (see Section 7.3.4.2 of the Protocol).
Table 3 – Visit and Assessment Schedule
3.4.
Data Displays and Cohorts
For the statistical analyses, following cohorts were defined in this SAP (see Table 5) in accordance 
with the analysis sets defined in the Protocol (see Section 5 of this SAP and Section 11.2 of the 
Protocol).


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Table 4 – Cohorts vs Analysis sets
Cohorts defined in this document
Analysis sets defined in MERIT-2 protocol 
Macitentan 10 mg MERIT (DB/OL)
Restricted Analysis set (RAS)
Macitentan 10 mg MERIT-2 (OL)
Open-Label Analysis Set (OLAS)
Macitentan 10 mg Pool
Open-Label Safety Set (OLSS)
DB = double-blind, OL = open-label
Analyses will be provided for the following cohorts:

Macitentan 10 mg MERIT (DB/OL) (N = 40): All subjects randomized to macitentan 10 
mg in MERIT-1 DB and who received at least one dose of macitentan in MERIT-2. This 
cohort is not subject to any cross-over effect of treatment and includes subjects who received 
macitentan in MERIT-1 and MERIT-2 (see Table 5).

Macitentan 10 mg MERIT-2 (OL) (N = 76): All subjects enrolled in MERIT-2 and treated 
with macitentan 10 mg in MERIT-2 OL (regardless of randomized treatment in MERIT-1 
DB). This is MERIT-2 OL analyses population (see Table 5).

Macitentan 10 mg Pool (N = 76): All subjects treated with macitentan in MERIT-1 DB 
and/or the MERIT-2 OL extension study and subjects who received “any time macitentan”. 
Table 5 – Definition of Cohorts
Cohort
Population
Database
Reasons and additional 
comments
From
Until
Macitentan 10 mg 
MERIT (DB/OL) 
(N =40)
All subjects
randomized to 
macitentan 10 
mg in MERIT-1 
DB and 
received at least 
one dose of 
macitentan 10 
mg in MERIT-2
OL
Date of 
randomization 
(efficacy) / 
start of 
macitentan 
treatment 
(safety) in 
MERIT-1 DB
study.
EOS for all 
subjects 
(except for 
Chinese 
subjects 
until 17 
OCT 2019)
Long-term efficacy, safety and 
survival will be summarized for 
subjects who received macitentan
10mg
in MERIT-1 DB and 
MERIT-2 OL (including data 
from MERIT-2 OL extension 
study). 
The 
time 
period 
is 
MERIT-1 and MERIT-2.
For baseline definitions, see 
Section 8.3.
Macitentan 10 mg 
MERIT-2 (OL) 
(N =76 )
Previously on DB 
Macitentan 10 mg 
(n = 40)
Previously on DB 
Placebo (n =36 )
All subjects (N = 76)
All subjects
enrolled and 
treated with 
macitentan 10 
mg in MERIT-2 
OL
Start of 
macitentan 
treatment in 
MERIT-2 OL 
study
EOS for all 
subjects 
(except for 
Chinese 
subjects 
until 17 
OCT 2019)
MERIT-2 safety and efficacy will 
be summarized. The time period 
is MERIT-2 only. 
The results in this cohort will be 
presented overall and by prior 
double-blind 
treatment 
in 
MERIT-1, 
i.e., 
placebo 
or 
macitentan 10 mg).
For 
baseline 
definition, 
see 
Section 8.3.
Macitentan 10 mg Pool
(N = 76)
All subjects
treated with 
macitentan 10 
mg in MERIT-1 
Start of 
macitentan 
treatment in 
MERIT-1 DB 
EOS all 
subjects 
(except for 
Chinese 
Safety
and survival
will be 
summarized for subjects who 
received 
macitentan 
10 
mg 
anytime.


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DB and/or 
MERIT-2 OL 
or MERIT-2 
OL study
subjects 
until 17 
OCT 2019)
For baseline definitions, see 
Section 8.3.
Largest body of macitentan safety 
data
based 
on 
cumulative
exposure to macitentan
from 
MERIT-1 and MERIT-2
4.
STATISTICAL HYPOTHESES
As the primary objective of the study is long-term safety and all the efficacy analyses are 
considered exploratory, no formal hypothesis testing will be performed. 
4.1.
Sample Size Determination
No sample size calculation was done in the OL study, as subjects were not randomized. The 
number of subjects in the OL study was based on the number of subjects in the DB study that were 
eligible to transition to the OL study.
5.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
Analysis Sets
Description
Open-Label Analysis Set (OLAS)
The OL analysis set (OLAS), comprises all data from 
subjects who enrolled into the OL extension study, from 
the time they enter the OL extension study.
Restricted Analysis Set (RAS)
The restricted analysis set (RAS), comprises all data 
from subjects enrolled in the OL extension study who 
received macitentan 10 mg during the AC-055E201 / 
MERIT-1, from the time they enter the DB study.
Open-Label Safety Set (OLSS)
OL Safety Set (OLSS), comprises all DB and OL study 
subject data from subjects enrolled in OL extension 
study and who received macitentan 10 mg at least once, 
during either the DB or OL extension study for the period 
they are exposed to macitentan 10 mg.
5.1.
Use of Analyses Sets
1.
The analyses of the exploratory efficacy endpoints will be performed on the OLAS and RAS:

On the OLAS, as change from baseline of the OL extension study, by randomized treatment 
group (see Section 3.4 and Table 8).

On the RAS, as change from baseline of the DB core study in macitentan 10 mg only (see 
Section 3.4 and Table 8).
2.
The analyses of the safety endpoints will be performed on the OLSS, OLAS and RAS:

The OLSS, OLAS and RAS will be used for the analyses of the safety variables (see 
Section 3.4 and Table 9). 

The RAS and OLSS will be also used in estimation of overall survival.
Duration of treatment exposure will be evaluated on all analysis sets, OLAS, RAS and OLSS.


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Listings will be prepared on the RAS, OLAS, and OLSS as appropriate. 
Subject disposition will be summarized for the OLAS. 
No per protocol analyses will be conducted.
Table 6 – Use of Analysis Sets for Analysis of Efficacy and Safety Variables
Analysis Sets
Variable
OLAS
RAS
OLSS
Efficacy
6MWD
x
x
Borg dyspnea index
x
x
WHO FC
x
x
Safety
AEs*
x
x
x
SAEs
x
x
x
Deaths
x
x
x
Overall survival 
x
x
Laboratory parameters and 
marked laboratory abnormalities
x
x
x
Vital Signs and body weight
x
x
x
Physical examination
x
x
x
Subject Disposition
x
Demographics
x
Exposure
x
x
x
Compliance
x
Protocol Deviations
x
Concomitant medications
x
6MWD = 6-minute walk distance; *AEs = adverse events, including AESI, AEs leading to treatment 
discontinuation; SAE = serious adverse event, including SAEs with fatal outcome; FC = functional class; 
OLAS = Open-Label Analysis Set; OLSS = Open-Label Safety Set; RAS = Restricted Analysis Set; WHO 
= World Health Organization.
6.
DEFINITION OF VARIABLES
The following dates will be used to define the treatment durations and safety reporting periods. 
For imputation of partial/ missing date, refer to Section 9.


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The study end date (EOSDT2) for Chinese data will be associated with the cut-off date 
(CUTOFDT).

Start date of treatment in MERIT-1 DB (TRTSDT1): Date of the start of treatment in MERIT-
1 DB.

End date of Treatment in MERIT-1 DB (TRTEDT1): Date of end of treatment in MERIT-1 
DB.

Start date of macitentan in MERIT-2 OL (TRTSDT2): Date of treatment start in MERIT-2 
OL. This is the first treatment start date (in chronological order) recorded in the 'Study Drug 
Log' case report form (CRF).

End date of macitentan in MERIT-2 OL (TRTEDT2): Date of end of treatment in MERIT-2 
OL. This is the last treatment end date (in chronological order) recorded in the 'Study Drug 
Log' CRF. For subjects who are still ongoing (as long as there is no corresponding record in 
the Disposition [DS] domain), it will be assumed that they are still on-treatment at their last 
contact date (LCTDT202), and the end date of macitentan is the earliest of (last contact date, 
death date). For subjects entering a continued access program, the EOT visit is defined as the 
EOS visit.

EOT: For subjects in all cohorts (see definitions in Table 5) this is TRTEDT2.

Cut-off date (CUTOFDT): 17 October 2019 is the cut-off date to apply for the China’s data 
collected in MERIT-2 OL. Except as otherwise specified, all data collected will be included 
in the analyses.

Date of death (DTHDT): Actual date of death of a subject as reported in the ‘Death Form’ of 
the CRF, prior to the EOT+30 days, except where otherwise specified.

MERIT-1 DB EOS date (EOSDT1): EOS visit date from the MERIT-1 DB study.

MERIT-2 OL EOS date (EOSDT2): all enrolled subjects who received study drug must be 
followed up to the EOS, whether or not they are prematurely discontinued from study 
treatment. 

For an individual participant, EOS visit is defined as follows:

For participants that complete treatment, EOS visit is defined as the safety follow-up visit 
30–35 days after last study treatment intake.

For participants that prematurely discontinue study treatment, EOS visit is defined as the 
safety follow-up visit 30–35 days after last study treatment intake.

For participants who complete treatment and who are entering a continued access
program (post-trial access or other open-label extension study) the EOS visit is defined
as the EOT visit. For all subjects, the reason for premature discontinuation from study 
and the decision owner (as applicable) are documented in the 'Premature study 
discontinuation' eCRF form. 

MERIT-2 OL last contact date (LCTDT202): Last contact date is the date of the last visit, or, 
in case of lost to follow-up, the date of the last successful contact attempt (as reported in ‘Lost 
to follow-up’ form of the CRF) prior to the EOS. If any of the components (visit date or last 
successful contact attempt) is partial, the lower limit will be applied.


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
OL study day: ‘OL study day’ refers to the number of days elapsed since OL study treatment 
start date (TRTSDT2) +1. For dates prior to study treatment start date, study day is the 
negative number of days elapsed between the date under consideration and the study treatment 
start date. Therefore, the study day is always different from 0.

DB study day: ‘DB study day’ refers to the number of days elapsed since the day of 
randomization plus 1 (as randomization is considered Day 1). For dates prior to 
randomization, study day is the negative number of days between the date under consideration 
and randomization date. Therefore, the study day is always different from 0.
7.
DISPOSITION
7.1.
Disposition of Subjects
A study flowchart will be used to show the disposition of study subjects throughout the progression 
of the study. It will display the numbers of subjects randomized into the AC-055E201 / MERIT-1 
study divided into the placebo and macitentan 10 mg treatment groups to which they were 
randomized. The number of subjects by treatment group entering into the AC-055E202 / MERIT-
2 OL extension study along with the number of subjects continuing and discontinuing treatment 
and follow-up during the OL extension study, along with reasons for discontinuations will be 
displayed. The final row of the flowchart will result in the number of subjects completing the OL 
extension study in each DB treatment group of the Macitentan 10 mg OL cohort (see Section 3.4). 
The items in the flowchart will be supported by tables and listings related to each level and will be 
presented on the OLAS (Macitentan 10 mg OL cohort, see Section 3.4): 

The number and percentage of subjects who completed the study treatment.

The number and percentage of subjects who discontinued the study treatment early.

The number and percentage of subjects who completed the study.

The number and percentage of subjects who discontinued the study.

Reasons for premature study treatment discontinuation.

Reasons for premature study discontinuation.
Reasons for study drug discontinuation and reasons for study discontinuation will be retrieved 
from the ‘Premature Permanent Discontinuation of Study Treatment’ and 'Premature study 
discontinuation' CRF forms respectively.
The number and percent of subjects included and excluded from OLAS, based on the analysis set 
definitions in Section 5 will be summarized in tables and listings. Major protocol deviations will 
also be summarized in a table. (see Appendix 4 ). Major protocol deviations will be displayed by 
region, country, and site.
8.
STATISTICAL ANALYSES
8.1.
General Considerations

Unblinding of study drug code occurred after AC-055E201 / MERIT-1 study database closure 
in accordance with sponsor standard operating procedures (SOPs).   


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
Analyses will be conducted only on data from subjects who enrolled in the OL study and were
exposed to macitentan 10 mg at least once, during either the DB or OL extension studies. 

AEs will be coded using the latest version 24.1 of the MedDRA dictionary. Concomitant 
Medications (Appendix 5) will be coded using the same versions of the WHO drug code and 
the Anatomic Therapeutic Chemical class code dictionaries as used in the AC-055E201 / 
MERIT-1 study.

All major protocol deviations (Appendix 4 ) related to study inclusion or exclusion criteria, 
conduct of the study, subject management, or subject assessment will be described in the final 
report. Subject listings for protocol deviations will be presented broken down by region, 
country and site.

All analysis variables will be summarized and listed; variables to be presented in figures are
specified in the corresponding Sections 8.5.2 and 8.6.2 of the SAP.   

Data will be listed and summarized by appropriate descriptive statistics (tables or figures), 
typically including: 

Number of non-missing observations, number of missing observations, mean, standard 
deviation, minimum, Q1, median, Q3 and maximum for continuous variables.

For time points where only one observation is available, the descriptive summary 
statistics will be provided with the NE (Not Evaluable) standard deviation (SD).

Number of events, number of censored observations, number of subjects at risk, and 
Kaplan-Meier estimates of the survival function for time-to-event variables.

Number of non-missing observations, number of missing observations and frequency 
with percentage per category (percentages based on the sum of number of non-missing 
observations and total number of observations) for categorical variables.  
Absolute changes from baseline are defined as: post-baseline value minus baseline value.
Study data tabulation model (SDTM) datasets of AC-055E202 / MERIT-2 study provided by 
Sponsor Clinical Development Data Management (CDDM) via the Life Science Analytics 
Framework (LSAF) system and Analysis Data Model (ADaM) datasets from AC-055E201 / 
MERIT-1, hereafter referred to as the double-blind (DB) study, are used as source data for the 
statistical analyses.
In the listings based on OLAS, only data split by groups 'Previously on DB Macitentan 10 mg' and 
'Previously on DB Placebo' will be provided (not for All subjects).
All descriptive or formal statistical analyses will be performed using SAS statistical software 
(Version 9.4), unless otherwise specified.
Major protocol deviations are defined as 'Important' in the eCRF.
8.2.
Rules for Reporting Descriptive Statistics
There are three J&J standard alternatives, please refer to the table below, where X is the number 
of decimals in the SDTM:


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Default Conventions
Alternative 1
Alternative 2
Individual values
X
X
X
Mean
X+1
X+1
X
SD
X+2
X+1
X
Range (Min; Max)
X; X
X; X
X; X
Median
X+1
X+1
X
Q1; Q3
X+1; X+1
X+1; X+1
X; X
The following rules will be applied in reporting descriptive statistics:

Always use the ‘Default Conventions’. 

Use ‘Alternative 2’ only when is an issue for displaying statistics according to the layout (for 
example for laboratory when there are 3 decimals from SDTM).

p values: please use 4 decimal places; if the p-value is less than 0.0001, the p-value has to be 
presented as <0.0001.
8.3.
Definition of Baseline
The baseline for MERIT-1 safety and efficacy analysis is defined as:

for the efficacy endpoints, the baseline value is the value from the last non-missing assessment 
obtained prior to, i.e., before or on the day of, randomization.

For the safety and tolerability endpoints, the baseline value is the value from the last non-
missing assessment obtained prior to, i.e., before or on the day of the start of study drug (CSR 
AC-055E201).
The MERIT-1 baseline will be used for summaries in ‘Macitentan 10 mg MERIT (DB/OL)’ cohort
(see Section 3.4).
For the MERIT-2 summaries in cohort ‘Macitentan 10 mg MERIT-2 (OL)’ baseline value is the 
last non-missing assessment obtained prior to the start of macitentan in MERIT-2 OL.
For the ‘Macitentan 10 mg Pool’ cohort, baseline value is the last non-missing assessment obtained 
prior to the start of macitentan in MERIT-1 DB or MERIT-2 OL.
8.4.
Visit Windows
To minimize missing data and to analyze the data at the relevant planned (scheduled) visits, all 
recorded assessments up to EOS are re-assigned to the most appropriate time point according to 
the best fitting time-window for that visit (see Table 7). Any unscheduled assessment (including 
endpoint variable, EOT and EOS assessments) will also be mapped to a time-window. 
Should more than one assessment fall within the same time window, then the closest value to the 
planned time point will be assigned to the said time point for use in data summaries and analyses. 
In case of values that are equidistant to the planned time point, the last assessment will be 
considered for the analyses. If more than one value falls on the same day, then the worst value will 
be used (e.g. for 6MWD the smallest value will be used). 


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For 6MWD and Borg dyspnea index, the date of 6MWD will be used to perform the mapping. For 
WHO visits the 6MWD dates will be assigned as described in Section 8.5.2.
Table 7 – Visit Windows
Mapping Visits to:
Study Day*
(nominal
value)
Lower limit 
study day*
Upper limit 
study day
Period
MERIT-1
Baseline
NA
1
Efficacy and Safety
Week 8
57
2
85
Efficacy and Safety
Week 16
113
86
141
Efficacy and Safety
Week 24 
169
142
NA**
Efficacy and Safety
MERIT-2
Baseline 
(Week 24 of MERIT-1)
-
NA
1
Efficacy and Safety
Month 6
180
2
270
Every 6 months Efficacy 
Month 12
360
271
450
Every 6 months Efficacy
Month Y
Y*30
Y*30 -90+1
Y*30 +90
Every 6 months Efficacy
Month 1
30
2
45
Monthly Safety
Month 2
60
46
75
Monthly Safety
Month 3
90
76
105
Monthly Safety
Month 4
120
106
135
Monthly Safety
Month X
X*30
X*30 -15+1
X*30 +15
Monthly Safety
etc.
…
…
…
…
Month 1
30
2
105
Every 6 months Safety
Month 6
180
106
270
Every 6 months Safety
Month 12
360
271
450
Every 6 months Safety
Month Y
Y*30
Y*30 -90+1
Y*30 +90
Every 6 months Safety
*Study day in MERIT-1 or MERIT-2 are derived based on DB or OL treatment start date.**NA = not applicable 
as Week 24 was the end of MERIT-1
8.5.
Efficacy
There are no primary or secondary efficacy variables defined for MERIT-2 OL; exploratory 
efficacy variables are described in protocol Section 11.1.2 and are presented below.


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8.5.1.
Definition of Exploratory Efficacy Variables

Change from baseline to each scheduled time point in exercise capacity, as measured by the 
6-minute walk distance (6MWD)

Change from baseline to each scheduled time point in Borg dyspnea index collected at the end 
of the 6-minute walk test (6MWT)

Proportion of subjects with worsening of WHO FC from baseline to each scheduled time 
point.
Table 8 – Efficacy Endpoints/Cohorts
Macitentan
10 mg
MERIT
(DB/OL)
MERIT-2
Macitentan 10 mg MERIT-2 (OL)
Efficacy Endpoint
(N=40)
Previously on 
DB Macitentan 
10 mg
(N = 40)
Previously on DB 
Placebo 
(N = 36) 
All subjects
(N=76)
6MWD
Yes*
Yes*
Yes*
Yes*
Borg dyspnea index
Yes*
Yes*
Yes*
Yes*
WHO FC
Yes*
Yes*
Yes*
Yes*
6MWD = 6 minute walk distance; DB = double-blind; NA = not applicable; OL = open-label; WHO FC = WHO 
functional class.
* Baseline as defined in MERIT-1 will be used for Macitentan 10 mg Merit (DB/OL) cohort. For the MERIT-2 
summaries (‘Previously on DB Placebo’, ‘Previously on DB Macitentan 10 mg’ and ‘All subjects’), baseline 
value is the last non-missing assessment obtained prior to the start of study drug intake in MERIT-2 OL.
8.5.1.1.
Six-minute Walk Distance
Absolute change in meters from baseline to time point in the 6MWD defined as:
(6MWD(m) at time point − 6MWD(m) at baseline)
is the variable for the analysis of the exploratory endpoint, change from baseline to each scheduled 
time point in exercise capacity, as measured by the 6MWT.
8.5.1.2.
Borg Dyspnea Index
Absolute change from baseline to time point in Borg dyspnea index defined as:
(Borg dyspnea index at time point - Borg dyspnea index at baseline)
is the variable for the analysis of the exploratory endpoint, change from baseline to each scheduled 
time point in Borg dyspnea index collected at the end of the 6MWT.
For Borg dyspnea index, the baseline value is the value reported at the same assessment as baseline 
6MWD.
8.5.1.3.
WHO Functional Class
Occurrence of worsening in WHO FC level at time point as compared to baseline (see definition 
in 8.3) is considered and the following dichotomous variable is defined:


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 = 1 	
 (	

  	 	  	 	  ) > 0
0 	
 (	

  	 	  	 	  ) ≤0
The proportion of subjects experiencing any increase in WHO FC level at time point as compared 
to baseline, defined as the proportion of subjects who have occurrence of worsening (Xi = 1) is the 
variable for the analysis of the exploratory endpoint, proportion of subjects with worsening of 
WHO FC from baseline to each scheduled time point.
8.5.2.
Analysis of the Exploratory Efficacy Variables
Analysis of the exploratory efficacy endpoint variables will be conducted on the OLAS 
(Macitentan 10 mg MERIT-2 (OL) cohort) and RAS (Macitentan 10 mg MERIT (DB/OL) cohort), 
see Section 3.4 and Table 8:

On the OLAS, as change from baseline of the OL extension study, by randomized treatment 
group in the DB core study.

On the RAS, as change from baseline of the DB core study (single arm).
No imputation of data will be performed in the analysis of the exploratory endpoints. 
In order to maximize the use of collected data and to analyze the data at relevant time points, a 
time-windowing approach (see Section 8.4) will be employed to include data from all study 
assessments up to EOS.
There is an assumption that the measurement of 6MWD and WHO were taken on the same dates 
based on visits planned in the Protocol. MERIT-2 OL dates of visits of the WHO endpoint are 
missing (sdtm: XP.XPDTC) but with reported values (sdtm: XP.XPSTRESC). In accordance with 
the Visit Windows rules (Section 8.4) these dates should be re-assigned to the most appropriate 
time point. In absence of these time points for WHO, the 6MWD dates (sdtm: XP.XPDTC) of 
coincident visits (sdtm: XP.VISIT) will be used for re-assignment.
8.5.2.1.
6-minute Walk Distance (m)
The summary tables based on observed values will be presented for 6MWD at baseline (MERIT-
2, see Section 8.3), Month 6 (MERIT-2), Month 12 (MERIT-2), Month 18 (MERIT-2) and every 
6 Months up to EOT visit on OLAS (Macitentan 10 mg MERIT-2 (OL) cohort) as defined in 
Table 8. The summary tables based on observed values will be presented for 6MWD at baseline 
(MERIT-1, see Section 8.3), Week 8 (MERIT-1), Week 16 (MERIT-1), Week 24 (MERIT-1; 
Baseline of MERIT-2), Month 6 (MERIT-2), Month 12 (MERIT-2), Month 18 (MERIT-2)  and 
every 6 Months up to EOT visit on RAS (Macitentan 10 mg MERIT (DB/OL) cohort) as defined 
in Table 8.  
The change in 6MWD from baseline to each timepoint defined above (both on the OLAS and 
RAS) will be displayed using descriptive statistics for continuous variables as described in 
Section 12.3 along with 95% two-sided confidence limits (CL) of means and medians. 
In addition to summaries, the following graphical presentations of data will be provided for 
6MWD:


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
Box plots on change of 6MWD values from baseline over time (Month 6 (MERIT-2), Month 
12 (MERIT-2), Month 18 (MERIT-2) and  every 6 Months up to the EOT by DB randomized 
groups of the Macitentan 10 mg MERIT-2 (OL) cohort and at Week 8 (MERIT-1), Week 16
(MERIT-1), Week 24 (MERIT-1; Baseline of MERIT -2), Month 6 (MERIT-2), Month 12 
(MERIT-2), Month 18 (MERIT-2)  and every 6 Months up to EOT visit on Macitentan 10 mg 
MERIT (DB/OL) cohort), see Table 8. 
8.5.2.1.1.
Sensitivity analysis
To investigate the impact of 6MWT not performed according to Actelion guidelines, a sensitivity 
analysis will be performed. This analysis will be done as defined in section 8.5.2.1, excluding 
subjects for whom at least 1 protocol deviation “PD_MM.206: 6MWD at a 6-monthly visit not 
performed as per the Actelion Guidelines (except for deviations approved by Actelion)” reported 
in Merit-2 eCRF.
8.5.2.2.
Borg Dyspnea Index
The summary tables based on observed OLAS and RAS values will be presented for the Borg
dyspnea index at Baseline and each timepoint as described for 6MWD in Section 8.5.2.1.
In addition to summaries, the graphical presentations of data will be provided for Borg dyspnea 
index as it is described for 6MWD in Section 8.5.2.1.
8.5.2.3.
WHO Functional Class
The proportion (with 95% CLs) of subjects worsening (subjects who have an occurrence of 
worsening (Xi = 1), see Section 8.5.1.3) by each post-baseline visit as defined for 6MWD in 
Section 8.5.2.1 will be summarized on Macitentan 10 mg MERIT-2 (OL) and Macitentan 10 mg 
MERIT (DB/OL) cohorts (see Table 8) and visualized by means of bar charts over time (see 
Section 8.5.2.1). 
Observed WHO FC scores on the OLAS (Macitentan 10 mg MERIT-2 (OL) cohort, see Table 8) 
and on the RAS (Macitentan 10 mg MERIT (DB/OL) cohort, see Table 8) will be tabulated at 
baseline and each post-baseline visit as defined for 6MWD in Section 8.5.2.1. The separate 
summary table will be created for worsening in WHO FC at each post-baseline visit as defined for 
6MWD in Section 8.5.2.1 in respect to baseline as defined in Section 8.5.1.3.
For the analyses based on the RAS (Macitentan 10 mg MERIT (DB/OL) cohort, see Table 8), a
shift table will display the change in WHO FC from baseline (MERIT-1, see Section 8.3) to Week 
8 (MERIT-1), Week 16 (MERIT-1), Week 24 (MERIT-1; Baseline of MERIT -2), Month 6 
(MERIT-2), Month 12 (MERIT-2), Month 18 (MERIT-2)  and every 6 Months up to EOT visit 
and based on the OLAS (Macitentan 10 mg MERIT-2 (OL) cohort, see Table 8), a shift table will 
display the change in WHO FC from baseline (MERIT-2, see Section 8.3) to Month 6, Month 12, 
Month 18 and  every 6 Months up to EOT.
8.6.
Safety
The following Safety and Tolerability variables will be considered in this study:

Treatment-emergent AEs up to 30 days after study drug discontinuation.


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
AEs leading to premature discontinuation of study drug.

Treatment-emergent SAEs up to 30 days after study drug discontinuation.

Treatment-emergent marked laboratory abnormalities up to 30 days after study drug 
discontinuation.

Adverse events of special interest up to 30 days after study drug discontinuation

Deaths.

Change in vital signs (BP (DBP and SBP) and HR) and body weight from baseline to all 
assessed time points during the study.

Laboratory parameters.

Vital signs and body weight.

Physical examination.
Table 9 – Safety Endpoints/Cohorts
Macitentan 
10 mg 
MERIT 
(DB/OL)
MERIT-2
Macitentan 10 mg MERIT-2 OL
Macitentan 
10 mg Pool
(N=40)
Previously 
on DB 
Macitentan 
10 mg
(N=40)
Previously 
on DB 
Placebo
(N=36)
All 
subjects
(N=76)
(N=76)
Exposure
Yes
Yes
Yes
Yes
Yes
AEs/SAEs/AESIs/AEs leading to 
permanent discontinuation*
Yes
Yes
Yes
Yes
Yes
Deaths
Yes
Yes
Yes
Yes
Yes
Vital Signs and body weight
Yes
Yes
Yes
Yes
Yes
Physical examination
Yes
Yes
Yes
Yes
Yes
Laboratory parameters
Yes
Yes
Yes
Yes
Yes
AE = adverse events; DB = double-blind, OL = open-label, SAEs = serious adverse events.
*AEs causing treatment premature discontinuations and AEs of special interest (hepatic events of special interest,
edema and fluid retention, anemia and decrease of hemoglobin, hypotension) will also be summarized
# Selected laboratory parameters will be also analyzed [Section 8.6.1.4].
For baseline definitions, see Section 8.3.
Note: all safety endpoints will be evaluated up to EOS for subjects who enter a continued access 
program (UMBRELLA or PTA, see 'Study Drug Log' eCRF page) on the same day as the EOS 
visit, which corresponds to EOT visit in this case.
8.6.1.
Definition of Safety and Tolerability Variables
8.6.1.1.
Treatment-emergent AE
A treatment-emergent AE is any AE temporally associated with the use of a study drug (from study 
drug initiation until 30 days after EOT) with an onset date on the same date or after the date of 
first dose, or with a previous onset date but worsening severity (see definition in Section 8.6.1.1.1).
Safety and tolerability endpoints will be analyzed for the combination of DB and OL periods:


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
for the Macitentan 10 mg Pool cohort (see Section 3.4 and Table 9), with onset date ≥ start 
date ( TRTSDT1 or TRTSDT2) and up to 30 days (inclusive) after EOT, or with an onset date 
before these dates but worsening severity after TRTSDT1 or TRTSDT2.

for the Macitentan 10 mg MERIT (DB/OL) (see Section 3.4 and Table 9), with onset date ≥ 
start date (TRTSDT1) and up to 30 days (inclusive) after EOT, or with an onset date before 
these dates but worsening severity after TRTSDT1.
as well as for the OL period only:

for the Macitentan 10 mg MERIT-2 (OL) (see Section 3.4 and Table 9), with onset date ≥ start 
date (TRTSDT2) and up to 30 days (inclusive) after EOT, or with an onset date before these 
dates but worsening severity after TRTSDT2. 
AEs are reported by the investigator in the “Adverse Event” CRF form (see definition details in 
the Section 10.1.1 of the Protocol).
The original terms used by the investigators to describe AEs are assigned preferred terms (PT) for 
classification and tabulation using the latest implemented version of MedDRA.
Imputation of AE onset/resolution date is described in the Section 9.
AEs reported more than once (as qualified by the same PT) for a subject are counted only once in 
the frequency table.
8.6.1.1.1.
Intensity of Adverse Events
The intensity of clinical AEs is graded on a three-point scale:

Mild

Moderate

Severe
and is reported on “Adverse Event” eCRF form.
If the intensity of an AE worsens during study drug administration, only the worst intensity should
have been reported on the AE page. If the AE lessens in intensity, no change in the severity was 
required.
8.6.1.1.2.
Relationship to Study Drug
Relationship to study treatment is defined as ‘related’ or ‘not related’. An AE is considered related 
if the answer to the 'Is there a reasonable possibility that the Adverse Event was related to the use 
of study drug?' is checked as 'Yes' on the 'Adverse Event' CRF form. For treatment emergent AEs 
reported more than once (as qualified by the same PT) for a subject, the worst relationship (i.e., 
'related') is considered. Adverse events with missing relationship are considered in any analysis as 
'related'.
8.6.1.2.
Adverse Events Leading to Premature Discontinuation of Study Drug
An AE is considered as leading to discontinuation of study treatment if the tick box ‘Permanently 
discontinued’ of ‘Action taken with study drug’ is checked in the Adverse Event CRF form.


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8.6.1.3.
Treatment-emergent Serious Adverse Events
An AE is considered serious if the tick box ‘Yes’ for ‘Serious?’ is checked on the 'Adverse Event' 
CRF form (see the details in Section 10.2.1 of the Protocol). If the information on seriousness is 
missing, the AE is assumed to be a SAE for the purpose of the summaries.
Treatment-emergent SAEs are determined as for TEAEs in Section 8.6.1.1.
8.6.1.4.
Laboratory Parameters
A central laboratory data will be used for the analysis of all laboratory tests. The local laboratory 
data will be also used in the analyses of laboratory abnormalities.
Hematology and blood laboratory chemistry tests include all the parameters listed in Appendix 8. 
8.6.1.4.1.
Central Laboratory Alert Flags
On top of the flags described below, at a minimum, results above the upper limit or below the 
lower limit of the reference range for normal subjects will be flagged. 

Exclusionary Alert Value – At Enrollment (V1): The result is outside the study-specific 
defined limit for inclusion in the study.

Hemoglobin < 100 g/L

AST ≥ 3 × ULN

ALT ≥ 3 × ULN

Total Bilirubin flag Alert Value – All visits except Enrollment (V1): In combination with ALT 
and/or AST ≥ 3 x ULN, study medication should be stopped.

Total bilirubin ≥ 2 x ULN

Interruption or permanent discontinuation of study medication – All visits except Enrollment 
(V1): 

AST ≥ 8 × ULN

ALT ≥ 8 × ULN

Hemoglobin < 80 g/L

Hemoglobin > 50 g/L decrease from baseline in MERIT-1 or in MERIT-2

Repeat Alert value – All visits except Enrollment (V1): 

AST ≥ 3 × ULN

ALT ≥ 3 × ULN

Hemoglobin > 20 g/L decrease from baseline in MERIT-1 or in MERIT-2
8.6.1.5.
Treatment-emergent Marked Laboratory Abnormalities
TE MLAs are all marked laboratory abnormalities which occur during the DB/OL (OLSS and RAS 
Set, Table 6) or OL treatment-emergent period (OLAS Set, Table 6), that were not present at 
baseline (see Section 8.3).




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Glucose (mmol / 
L)
< 3.0
< 2.2
> 8.9
> 13.9
NA
Calcium 
(mmol/L)
< 2.0
< 1.75
> 2.9
> 3.1
NA
Sodium (mmol/L)
< 130
> 150
> 155
NA
Potassium 
(mmol/L)
< 3.2
< 3.0
> 5.5
> 6.0
NA
Magnesium 
(mmol/L)
< 0.5
< 0.4
NA
> 1.23
NA
Uric acid 
(mmol/L)
NA
NA
> 0.59
> 0.72
NA
Albumin (g/L)
< 30
< 20
NA
NA
NA
BUN
NA
NA
> 2.5 ULN
> 5 ULN
NA
ALT alanine aminotransferase; AP alkaline phosphatase; AST aspartate aminotransferase; BUN blood urea 
nitrogen; CTCAE common terminology criteria for adverse events; LL / HH = marked abnormalities; LLL / HHH 
/ HHHH = alert values; NA not applicable; SI international system of unit; ULN upper limit of the normal range; 
INR international normalized ratio. *For INR, a subject is considered to be on anticoagulation if the subject took 
antithrombotic agent (ATC codes B01A) and date of INR assessments is on or after start of anticoagulation therapy.
Note: changes implemented to this table are specified in Sections 8.6.1.4.1 and 8.6.2.6.1 and  listed in Appendix 2 
8.6.1.6.
Vital Signs and Body Weight
Vital signs (systolic and diastolic blood pressures (SBP and DBP), pulse rate) and body weight are 
measured at Enrollment, Month 1, Month 6, and every 6 Months thereafter up to EOT + 30 days 
and reported in the "Vital Signs" CRF form. 
Absolute change from baseline (Section 8.3) to each visit in SBP, DBP, pulse rate and body weight 
defined as (Value at visit X assessment available) - (value at baseline) will be calculated.
8.6.1.7.
Physical Examination
Physical examination is performed at Enrollment (Visit 1), Month 1 (Visit 2), each 6-monthly visit 
(Visits 3, 4, 5…), EOT visit, and Safety follow-up / EOS visit. 
Physical examination is recorded by body system in the eCRF as normal or abnormal. If an 
abnormality is detected, it must be specified in the eCRF, describing the signs related to the 
abnormality (e.g., systolic murmur) not the diagnosis (e.g., mitral valve insufficiency).
Data are retrieved from the SDTM PE domain.
8.6.1.8.
Deaths
The date/time of death and associated primary cause are recorded in the CRF "Death form" form. 
The original terms used by the investigator to describe death (i.e., primary cause of death) are 
assigned PTs for classification and tabulation using latest implemented version of MedDRA. 


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Treatment-emergent deaths are determined in the same way as for TEAEs according to the date of 
death.
8.6.2.
Analysis of the Safety Variables
The OLSS, OLAS and RAS will be used to perform safety analyses. The RAS and OLSS analysis 
sets will be used for selected safety analyses as specified in Section 5.1.
All safety data will be included in listings, with flags for quantitative abnormalities.
Safety and tolerability endpoints will be analyzed for the combination of DB and OL periods (see 
Section 1.2.1).
8.6.2.1.
Treatment-emergent Adverse Events
A table presenting an overall summary of the proportion of subjects with at least one AE as defined 
in Section 8.6.1.1, SAEs, AEs leading to treatment discontinuation and AESI (hepatic events of 
special interest (liver abnormalities), edema and fluid retention, anemia and decrease of 
hemoglobin, hypotension, see Appendix 7 ) and the proportion of deaths will be provided. Events 
occurring during the reporting DB and OL periods will be considered.

The number and percentage of subjects experiencing treatment-emergent AEs at least once 
from baseline (see Section 8.3) up to 30 days following study drug discontinuation will be 
tabulated as defined in Table 9 and by:

System organ class (SOC) and individual preferred term within each SOC, in descending order 
of incidence within the Macitentan 10 mg Pool cohort (see Table 9).

Proportion of subjects with events coded with the same preferred term, in descending order of 
incidence within the Macitentan 10 mg Pool cohort (see Table 9).
Furthermore, all treatment-emergent AEs listed above occurring up to 30 days after study drug 
discontinuation will be tabulated as described above by severity and relationship to study drug.
A listing of all AEs with date of onset (as defined in Section 8.6.1.1) and up to 30 days (inclusive) 
after EOT will be provided with flags for quantitative abnormalities and SAEs.
To account for differences in exposure, incidence rates adjusted for subject-years for all AEs will 
be calculated in a similar manner as described for AESIs (Appendix 7 ).
8.6.2.2.
Adverse Events Leading to Premature Discontinuation of Study Drug
The number and percentage of subjects experiencing at least one AE leading to discontinuation of 
study treatment up to EOT (see Section 8.3) will be tabulated and listed as described in Section
8.6.2.1.
8.6.2.3.
Treatment-emergent Serious Adverse Events
The number and percentage of subjects experiencing at least one SAE will be presented by 
descending SOC/PT and descending PT frequency as described in Section 8.6.2.1.
A listing of all SAEs with date of onset over treatment period (see Section 3.3.1) and up to 30 days 
(inclusive) after EOT will be provided with flags for quantitative abnormalities.


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8.6.2.4.
Treatment-emergent Adverse Events of Special Interest
Treatment-emergent AESI (see Appendix 7) occurring up to 30 days after study drug 
discontinuation will be summarized as described in Section 8.6.2.1 (by SOC and PT). 
In addition, serious treatment-emergent AESI occurring up to EOT + 30 days and treatment-
emergent AESI leading to premature study drug discontinuation occurring up to EOT will be 
summarized as described above.
Listings for all AESI with date of onset (as defined in Section 8.6.1.1) and up to EOT + 30 days 
(inclusive) will be provided with flags for serious AESI. This listing will be supported by separate 
listing of treatment-emergent AESI up to EOT (inclusive) leading to premature drug 
discontinuation.
8.6.2.5.
Laboratory Parameters
Descriptive summary statistics by visit and study treatment will be provided for observed values 
and absolute changes, from baseline up to EOT plus 30 days, in both hematology and blood 
chemistry laboratory tests. In order to minimize missing data and to allow for unscheduled visits, 
all recorded assessments up to EOT plus 30 days will be assigned to the most appropriate visit 
time point (see Table 7) according to the best fitting time-window for that assessment.
The listings of all hematology and separately of blood chemistry parameters will be provided with 
corresponding flags as described in Section 8.6.1.4.1.
8.6.2.6.
Treatment-emergent Marked Laboratory (Liver Test and Hemoglobin, 
Only) Abnormalities
Marked laboratory abnormalities will be summarized for each laboratory parameter providing their 
frequency and incidence (n (%) with the two-sided 95% CLs) for subjects with abnormalities.
Baseline laboratory values are defined as the latest values recorded before or on the date of the 
first dose of study medication (TRTSDT1 / TRTSDT2 (see baseline definition in the 8.3) for 
cohorts defined in Table 9). Baseline values are identified among test results from central 
laboratory. Post baseline values occurring within EOT + 30 days will be considered in the tables.
8.6.2.6.1.
Liver Test Abnormalities (Including Unscheduled Visits)
Liver tests (LTs) for alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total 
bilirubin will be presented by incidence (n%) with two-sided 95% CLs using a binomial 
proportion, tabulated for subjects with abnormalities during the reporting period.
Hepatic abnormality criteria are specified below:

(ALT ≥3 × upper limit of normal range [ULN]) OR (AST ≥3 × ULN)

(ALT ≥5 × ULN) AND/OR (AST ≥5 × ULN)

(ALT ≥8 × ULN) OR (AST ≥8 × ULN)

Total Bilirubin ≥2 × ULN

{(ALT ≥3 × ULN) AND/OR (AST≥3 × ULN)} AND (Total Bilirubin ≥2 × ULN)


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
ALT AND/OR AST ≥3 AND <5 × ULN

ALT AND/OR AST ≥5 AND <8 × ULN
For each subject, the worst abnormal value (i.e., the highest ALT, AST or total bilirubin values) 
will be considered and assigned to the appropriate category (may be more than one per subject).

Using “evaluation of drug-induced serious hepatotoxicity” (eDISH) plots, graphical 
representations of total bilirubin versus ALT and of total bilirubin versus AST will be 
produced for cohorts defined in Table 9, to identify possible Hy’s Law cases. The graph will 
present, for each subject, the peak total bilirubin × ULN against the peak ALT and AST × 
ULN in the same reporting period, on a log10 scale. Two reference lines will be plotted 
identifying the 2 × ULN for total bilirubin and 3 × ULN for ALT and AST. The peak is the 
maximum value from treatment start to last available assessment within the treatment period 
and up to EOT plus 30 days.
A listing will present all liver test data collected up to 30 days (inclusive) after EOT. 
A supportive listing will be provided for subjects with liver abnormalities collected up to 30 days 
(inclusive) after EOT.
8.6.2.6.2.
Incidence of Abnormal Hemoglobin Tests

Subject counts (up to EOT + 30), percent (and corresponding two-sided 95% CLs), for the 
following categories of hemoglobin abnormality will be presented for cohorts defined in
Table 9:

Hemoglobin < 80 g/L

Hemoglobin < 100 g/L

Hemoglobin ≥ 80 g/L and < 100 g/L

Hemoglobin < 100 g/L and a decrease from baseline  >20 g/L 

A decrease in hemoglobin from baseline of >20 g/L

A decrease in hemoglobin from baseline of >20 g/L and ≤ 50 g/L

A decrease in hemoglobin from baseline of >50 g/L.
For each subject, the worst abnormal value (i.e., the lowest hemoglobin value) will be considered 
and assigned to the appropriate category.
A listing will be provided and will present all hemoglobin collected up to 30 days (inclusive) after 
EOT. Clinically significant flags will be presented in accordance with the following changes from 
baseline:

A decrease in hemoglobin to < 80 g/L (< 4.9 mmol/L)

A decrease in hemoglobin from baseline of > 50 g/L
A supportive listing will be provided for subjects with hemoglobin abnormalities collected up to 
30 days (inclusive) after EOT. Clinically significant flags will be presented as described above.


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8.6.2.6.3.
Liver Tests and Hemoglobin Abnormalities Adjusted for Subject-Years 
Exposure
To account for differences in exposure, incidence rates adjusted for subject-years for LTs and 
hemoglobin abnormalities will be calculated in a similar manner as described for AESIs
(Appendix 7 ).
8.6.2.7.
Vital Signs and Body Weight
Similarly to laboratory parameters, descriptive summary statistics by visit will be provided for 
observed values and absolute changes, from baseline up to EOT plus 30 days, both for vital signs 
and body weight. In order to minimize missing data and to allow for unscheduled visits, all 
recorded assessments up to EOT plus 30 days will be assigned to the most appropriate visit time 
point (see Table 7) according to the best fitting time window for that assessment.
A supportive listing will be provided for vital signs and body weight.
8.6.2.8.
Physical Examination
Physical examinations performed during the study (see definition in Section 8.6.1.7) are reported 
in a subject listing.
8.6.2.9.
Deaths
The number (and percentage) of subjects who died will be presented by SOC (with subjects 
counted once within each SOC), and cause of death (PT, with subjects counted once for each PT). 
SOC and PT will be presented by descending frequency based on the Macitentan 10 mg Pool 
cohort (see Table 9) and will include deaths occurring during the reporting period as defined in 
Section 8.6.1.1. 
The tables above will also be repeated including all deaths that occurred from treatment start up to 
and beyond EOT + 30, i.e., all deaths reported in the database will be summarized by SOC and 
PT.
A listing of all deaths will be provided.
8.6.2.9.1.
Estimation of Overall Survival

Time to death (TTD; in months) will be estimated by the Kaplan-Meier (KM) product-limit 
method and summarized on RAS (Macitentan 10 mg DB/OL cohort) and OLSS (Macitentan 
10 mg Pool cohort). The same approach as described for time to first occurrence of AESI (see  
Appendix 7 ) will be followed.
TTD (in days) and censoring flag (CENS) will be derived using the dates defined in Section 6 as:
Macitentan 10 mg DB/OL cohort

TTD=DTHDT - TRTSDT1 and CENS=0 for subjects who died prior to EOT+30 days
and

TTD=min (LCTDT202, EOT+30 days) - TRTSDT1 and CENS=1 for subjects who did not 
die prior to EOT+30 days


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Macitentan 10 mg Pool cohort

TTD=DTHDT - TRTSDT1/TRTSDT2 (the start of the 10 mg therapy) and CENS=0 for 
subjects who died prior to EOT+30 days
and

TTD=min (LCTDT202, EOT+30 days) - TRTSDT1/TRTSDT2 (the start of the 10 mg 
therapy) and CENS=1 for subjects who did not die prior to EOT+30 days
TTD (in months) = TTD (in days) / 30.4375.
8.6.2.9.2.
Follow-up
The median study follow-up will be estimated using the reverse Kaplan-Meier of long-term 
survival (Schemper 1996). It will be calculated in the same way as the KM estimate of the long-
term survival (Section 8.6.2.9.1) but reversing censored subjects and deaths. Thus, in this analysis, 
death (CENS = 0) censors the true but unknown observation time of a subject and censoring in the 
survival analysis (CENS = 1) is an endpoint. The unobservable follow-up time of a deceased 
subject is interpreted as the follow-up time that potentially would have been obtained had that 
subject not died.
Median study follow-up will be presented with corresponding 25% and 75% percentiles and 95% 
confidence intervals using the method of Brookmeyer (Brookmeyer 1982).
9.
HANDLING OF MISSING, INCOMPLETE OR INCONSISTENT DATE AND 
TIME VALUES
9.1.
Handling Incomplete/Missing Dates
3.
Dates are split into 3 parts: year, month and day. Year is the top level, month is medium level, 
and day is low level. If a part expected to contain a number is numeric but the value is outside 
a valid range, the complete date is handled as missing. For example, if date = 44Nov2000, the 
whole date is considered to be missing.
4.
If a part expected to contain a number is not numeric, i.e., contains values such as for example 
ND, NA, --, ??, 2?, it is considered as missing.
5.
If a part is missing, all other parts of a lower level are considered to be missing. This means 
that a ddmmyy date ‘21ND99’ is considered as ‘----99’.
6.
Missing parts are changed into acceptable non-missing values in a way depending on the type 
of date to be replaced.
In Table 11, ‘lower limit’ and ‘upper limit’ refer to the minimum or maximum, respectively, of a 
possible date. For example, if the day is missing, the lowest limit is the first day of the given month 
and the upper limit is the last day of the given month. If the day and month are missing, the lower 
limit refers to the first day of the given year and the upper limit to the last day of the given year. 
The earliest and the latest dates refer to the first or last date, respectively, when ordered in 
sequence. All other missing or incomplete data not mentioned below are treated as missing.


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Table 11 – Handling of Missing, Incomplete, or Inconsistent Date and Time Values
Type of date 
Date is incomplete
Date is missing
Date of birth 
Day missing: 15th of the month
Day and month missing: 
30th of June
No replacement
Date of death 
(DTHDT)
Use the lower limit
No replacement
AE resolution
date
The upper limit 
No approximation, the AE is 
considered as ongoing.
AE onset date
If the end date of the AE is not before the start of study 
treatment, and if the study treatment start falls in the 
range of possible dates, it is the study treatment start 
date. In all other cases, it is the lower limit.
Of note, treatment start date is TRTSDT1 for macitentan
10 mg MERIT (DB/OL), TRTSDT2 for macitentan 10 
mg MERIT-2 (OL), TRTSDT1 or TRTSDT2 for 
Macitentan 10 mg pool.
The earlier of the date of 
resolution of the AE and the 
study treatment start date 
(TRTSDT1 for macitentan 10 mg 
MERIT [DB/OL], TRTSDT2 for 
macitentan 10 mg MERIT-2 [OL] 
and TRTSDT1/TRTSDT2 for 
macitentan 10 mg pool).
Concomitant
medication
start date
Lower limit except when:
Not tagged as ongoing at start of treatment in Macitentan 
10 mg OL
AND
Medication stop date not collected or with the upper 
limit after study drug start
AND
the treatment start day falls in the range of possible 
dates.
In which case it is the study drug start day
No replacement, the therapy is 
considered to have started before 
the study
Concomitant
therapy end
date
Upper limit except when:
Therapy start is before study treatment start or missing
AND
Upper limit is after the study treatment start
AND
Not tagged as ongoing at start of treatment
In which case it is 1 day before study treatment start.
No replacement (considered 
ongoing)
End-of-
Treatment°
Use the earliest date between the: 
• upper limit 
• last contact date* 
• date of death 
Use the earliest date between the: 
• last contact date* 
• date of death 
For Chinese subjects only:
• CUTOFDT


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Type of date 
Date is incomplete
Date is missing
End-of-Study°
Use the earliest date between the: 
• upper limit 
• last contact date* 
• date of death 
Use the earliest date between the: 
• last contact date* 
• date of death 
For Chinese subjects only:
• CUTOFDT
Death date 
Use the lower limit 
No replacement 
* Last contact date is the date of the last visit, or, in case of loss to follow-up, the date of the last successful contact 
attempt (as reported in SDTM DS domain under DSTERM = “LAST CONTACT”
° please note that for subjects who enter a continued access program (UMBRELLA or PTA, see 'Study Drug Log' 
eCRF page) on the same day as the EOS visit, EOS corresponds to EOT visit in this case.
10.
OTHER SAFETY ANALYSES
10.1.
Extent of Exposure
Analysis of exposure to study drug will be conducted on the OLAS, RAS and OLSS analysis sets
(see Section 3.4 and Table 6). 
Treatment duration of study drug will be described in terms of duration in months and years and 
produced for each cohort (see Section 5.1). The duration of treatment is defined as the timeelapsing 
between study drug initiation and discontinuation, inclusive, regardless of treatment interruptions.
The treatment duration (expressed in months and years) will be tabulated using the usual location 
and scale summary statistics for continuous variable (see Section 8.1).
The cumulative treatment duration will be displayed per 6-month interval over time. Subject-year 
exposure will also be displayed and will be derived as the duration of exposure for which each 
subject received treatment, as defined above, divided by 365.25. The total subject-years of a 
treatment group is the sum over individual subjects in each cohort defined below.
Treatment duration is the number of days a subject was on treatment, regardless of interruptions.

For subjects in the ‘Macitentan 10 mg MERIT (DB/OL)’ cohort:
Duration (days) = TRTEDT2 – TRTSDT1 +1

For subjects in the ‘Macitentan 10 mg MERIT-2 (OL)’ cohort:
Duration (days) = TRTEDT2 – TRTSDT2 +1

For subjects in the ‘Macitentan 10 mg Pool’ cohort:
Duration (days) = TRTEDT2 – TRTSDT1 +1 - if subject starts macitentan treatment in 
MERIT-1.
Duration (days) = TRTEDT2 – TRTSDT2 +1 - if subject starts macitentan treatment in 
MERIT-2.
Duration (months) = Duration (days)/30.4375


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Duration (years) = Duration (days)/ 365.25
10.2.
Treatment Compliance
The mean daily dose per subject is defined as the ratio between the total study drug dose (number 
of tablets provided to subject − number of tablets returned) taken during the treatment period and 
the total exposure time. 
Compliance, in percent, is defined as percent of doses taken divided by expected number of doses 
during follow-up:
Compliance = [(number of tablets provided to subject − number of tablets returned) /
Total number of tablets that should have been taken during the period] ×100
where the total number of tablets that should have been taken during the period is defined as: 
(  −  +1)
The compliance with study drug intake < 80% or > 120% will be also reported in summary tables 
per each cohort defined above
Mean daily dose and study treatment compliance will be tabulated using the usual location and 
scale summary statistics (see Section 8.1).
All information will be also presented in subject listings with corresponding flags for the 
compliance with study drug intake < 80% or > 120%. Reasons for not dispensing the assigned 
treatment to a participant will be also reported in listing at each accountability visit (Month 1, 
Month 2, Month 6 and every 6 months thereafter).
11.
DATA MONITORING COMMITTEE (DMC) OR OTHER REVIEW BOARD

The same Steering Committee (SC) as the one involved in the AC-055E201 / MERIT-1 study 
was involved in the MERIT-2 study design and will provide guidance on the conduct of the 
study. 
An independent International Liver Safety Data Review Board (ILSDRB): an external expert 
committee of hepatologists provided ongoing assessment and advice regarding serious hepatic 
events that required further evaluation during the study. 


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12.
SUPPORTING DOCUMENTATION
12.1.
Appendix 1 List of Abbreviations
AE 
Adverse event
ALT 
Alanine aminotransferase
AP 
Alkaline phosphatase
AST 
Aspartate aminotransferase
BMI 
Body mass index
BP 
Blood pressure
BUN 
Blood urea nitrogen
CL
Confidence limits
CRF
Case report form 
CRO 
Clinical Research Organization
CSR
Clinical Study Report 
CTEPH 
Chronic thromboembolic pulmonary hypertension
DB 
Double-blind
DBP 
Diastolic blood pressure
DTHDT
Date of death 
eCRF 
Electronic case report form
EOS 
End-of-Study
EOT 
End-of-Treatment
ERA 
Endothelin receptor antagonist
FC 
Functional class
FDA 
Food and Drug Administration
INR
International normalized ratio
IXRS
Interactive voice/web recognition system
LCTDT202
MERIT-2 OL last contact date 
LT 
Liver test
LSAF
Life Science Analytics Framework
MedDRA 
Medical Dictionary for Regulatory Activities
MERIT 
Macitentan in thE tReatment of Inoperable chronic Thromboembolic pulmonary hypertension
6MWD 
Six-minute walk distance
6MWT 
Six-minute walk test
OL 
Open-label
OLAS 
Open-Label Analysis Set
OLSS 
Open-Label Safety Set
PEA 
Pulmonary endarterectomy
PAH 
Pulmonary arterial hypertension
PH 
Pulmonary hypertension
PVR 
Pulmonary vascular resistance
RAS 
Restricted Analysis Set
SAE 
Serious adverse event
SAP 
Statistical Analysis Plan
SBP 
Systolic blood pressure
SC 
Steering committee
SOC 
System organ class
SOP 
Standard operating procedure
TIBC
Total iron binding capacity
TRTEDT1
End date of treatment in MERIT-1 DB 
TRTEDT2
End date of treatment in MERIT-2 OL
TRTSDT1
Start date of macitentan in MERIT-1 DB
TRTSDT2
Start date of macitentan in MERIT-2 OL
TTD
Time to death
ULN 
Upper limit of the normal range
WHO 
World Health Organization


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12.2.
Appendix 2 Changes to Protocol-Planned Analyses
1.
The definition of adverse events of special interest (AESI) and their evaluations were 
embedded in this SAP (see  Appendix 7 ) to be consistent with other macitentan studies.
2.
The statistical analyses to evaluate the differences in efficacy of treatment in randomized 
treatment arms as specified in the Protocol (11.3.3.1 and 11.3.3.2) were excluded from current 
analyses (see Section 8.5.2) due to the single-arm study design. 
3.
The RAS analysis set will be used to assess the long-term survival on subjects who was on 10 
mg study treatment from the start of treatment in the DB and up to EOS in the OL as well as 
in the assessment of AEs and Deaths.
4.
The OLSS analysis set will be used to assess the long-term survival on subjects who had any 
time 10 mg macitentan from the start of treatment in the DB or OL and up to EOS in the DB 
or OL whichever comes later.
5.
The duration of treatment exposure will be assessed on all analysis sets, OLAS, RAS and 
OLSS. 
6.
For consistency with the Macitentan/UNISUS study, in the hepatic abnormality criteria were 
included subjects who had values higher OR EQUAL to ULN for ALT, AST and bilirubin
parameters.
7.
The local laboratory data will be also used in the analyses of laboratory abnormalities.
8.
Serum pregnancy test positive flags were excluded from alert flags (see Section 8.6.1.4.1 of 
the SAP and Appendix 5 of the Protocol) as were not reported in the eCRF.
9.
The baseline in MERIT-2 was added to central laboratory alert flags for change from baseline 
in hemoglobin as far as flags are considered in listings and laboratory tests will be listed  based 
on OLSS analysis set, where for subjects who started macitentan 10 mg in OL trial, the 
MERIT-2 baseline only is considered (see changes in Section 8.6.1.4.1).
10. Sensitivity analysis for 6MWD endpoint was implemented as defined in section 8.5.2.1 
excluding those subjects for whom there is at least one protocol deviation “PD_MM.206: 
6MWD at a 6-monthly visit not performed as per the Actelion Guidelines (except for 
deviations approved by Actelion)” reported in Merit-2 eCRF.
11. Additional rules were added in section 8.6.2.6.1 to align them with Macitentan/UNISUS 
study, i.e. ALT AND/OR AST ≥3 AND <5 × ULN and ALT AND/OR AST ≥5 AND <8 × 
ULN


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12.3.
Appendix 3 Demographics and Baseline Characteristics
Demographics, and baseline characteristics will be summarized by each cohort as appropriate (see 
Table 6 and Section 3.4).

Continuous variables (e.g., 6MWD, Borg dyspnea score or cardiac output, etc.) will be 
summarized by the number of non-missing observations, mean, standard deviation, minimum, 
Q1, median, Q3 and maximum will be presented.

For dichotomous or categorical variables (e.g., age, sex, geographical region, etc.), the number 
of non-missing observations, and frequency with percentage per category will be presented. 
Denominators for percentages are the number of subjects in corresponding cohort (see Table 
6 and Section 3.4), unless otherwise specified.
Baseline demographic, height, and disease characteristics of interest for this OL study will be taken 
from the AC-055E201 / MERIT-1 database.
12.3.1 Demographics
The MERIT-2 OL baseline demographics will be summarized using descriptive statistics for 
continuous or categorical variables as defined in Section 12.3.
The number of subjects in each analysis set will be summarized and listed. In addition, the 
distribution of subjects by region, country and site ID will be presented unless otherwise noted.
Summaries for demographic characteristics will be performed on the OLAS (see Table 6 and 
Section 3.4). The variables in Table 12 will be summarized per originally randomized treatment 
group and overall.
Table 12 – Demographic Variables
Continuous Variables:
Summary Type
Age (years)
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum], and IQ range).
Weight (kg)
Height (cm)
Body Mass Index (BMI) (kg/m2)
Categorical Variables
Age (< 18; ≥18 and <65; ≥65 and <85; ≥ 85 years)
Frequency distribution with the 
number and percentage of subjects
in each category.
Age (< 65, ≥ 65 years)
Sex (male, female)
Race (White, Asian)
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
Childbearing potential status (Yes/No), and reason (why a female is 
considered not to be of childbearing potential)
Geographical region (Asia, Eastern Europe, Western Europe, Latin 
America)
Age (years) at the start of treatment in the OL is referred to date at screening in the DB (MERIT-
1) and will be reported as number of completed years.


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12.4.
Appendix 4 Protocol Deviations
The description of each protocol deviation (PD) is agreed in the sponsor Protocol Deviation Code 
List (TPL-100062) specific for this study. According to this document, each PD is classified as 
major or not and categorized into periods as follows:

Protocol Deviation before enrollment.

Protocol Deviation at Study Entry (enrolled in IXRS).

Protocol Deviation during treatment period and follow-up (see Table 6).
Protocol deviations will be summarized by category, displaying counts and percentages of subjects 
with at least one PD for the OLAS Set (Macitentan 10 mg OL cohort, see Section 3.4). A similar 
table is presented for major protocol deviations (related to study inclusion or exclusion criteria, 
conduct of the study, subject management, or subject assessment).
This summary table is sorted, within each category, by frequency, in descending order according 
to the incidence in the 'All subjects' column of the ‘Macitentan 10 mg MERIT-2 (OL)’ cohort (with 
the highest number of occurrences appear first); if a tie occurs, the tied characteristics will be 
sorted alphabetically. This will be supported by a summary table of major protocol deviations. 
Major protocol deviations will be displayed by region, country, and site.
All reported PDs will be reported in a subject listing broken down by region, country, and site. 
Major PDs will  be flagged accordingly.


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12.5.
Appendix 5 Concomitant Medications
A concomitant medication is any medication that started, stopped, or was ongoing between 
Enrollment (first dose of OL study drug, TRTSDT2) and last subject’s visit (LCTDT202 ):
Concomitant medication is defined as any medication that is taken at the start of study drug 
(TRTSDT2). This includes any medication with the tick box “ongoing” checked, or with a start 
date before or on the day of study drug start (TRTSDT2) and the end date not before study drug 
start (TRTSDT2). Start and end dates that are incomplete will be handled according to the rules 
for partial and missing concomitant medication dates in Section 9.
Concomitant medications will be reviewed at each visit. 
Study-treatment concomitant therapies are summarized by Anatomical Therapeutic Chemical 
(ATC) class and PT Enrollment (Visit 1) up to 30 days after study drug discontinuation (EOS 
visit).
A listing of all study-treatment concomitant medications with onset date up to 30 days after EOT  
(after study drug discontinuation (EOS visit) ) will be provided.
Methods of contraception are collected in the Contraceptive Methods Log page of the eCRF. 
Change in childbearing potential status is collected in the Childbearing Potential Status Change 
page of the eCRF. A supportive listing will be provided for childbearing potential and 
contraception on female population. 
The summary tables are presented in descending order according to the incidence in the 'All 
subjects' column of the ‘Macitentan 10 mg MERIT-2 (OL)’ cohort (i.e., ATC and individual PT 
within each ATC with the highest number of occurrences appear first). Equal frequency of 
different ATC / individual PTs is sorted in alphabetical order of the ATC / individual PT.
Start and end dates that are incomplete are handled according to the rules for partial and missing 
concomitant medication dates; refer to Section 9.
12.5.1
Special Interest Category: PAH therapies
Concomitant medications of special interest, ie, PAH therapies, are defined as follows:
Endothelin Receptor Antagonists (ERAs): 
Ambrisentan, 
Bosentan, 
Macitentan
Phosphodiesterase Inhibitors (PDE 5 Inhibitors): 
Sildenafil, 
Tadalafil, 
Vardenafil
Prostacyclin Analogue: 
Oral Treprostinil, 


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Beraprost
Inhalated prostacyclins:
Iloprost, 
Inhaled Treprostinil
Selective IP Receptor Agonist:
Selexipag
Soluble Guanylate Cyclase (sGC) Stimulators:
Riociguat
Intravenous and subcutaneous Treprostinil
Epoprostenol
Note: subjects may receive more than one treatment and may be included in more than one treatment class.
Concomitant medications of special interest, ie, PAH therapies, will be summarized in the same 
way as concomitant medications, see Section 12.5. A participant listing of concomitant 
medications of special interest will also be provided.


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12.6.
Appendix 7 Adverse Events of Special Interest
The number and percentage of subjects experiencing at least one AESI will be presented similarly 
to other treatment-emergent adverse events, as described in Section 8.6.2.1, by descending SOC 
and PT frequencies based on the “Macitentan 10 mg Pool” cohort (see Table 9). 
Separate listing will be provided for each AESI.
The following groups of AESIs are considered:

Hepatic events of special interest
Any treatment-emergent AE (see definition in Section 8.6.1.1) included in the following grouping. 
SMQ Drug related hepatic disorders – comprehensive search (includes all sub-SMQs within),
excluding sub-SMQ:
Liver-related coagulation and bleeding disturbances, 
and excluding PTs:
Ascites
Bacterascites
Biliary ascites
Haemorrhagic ascites

Edema and fluid retention
Any treatment-emergent AE (see definition in Section 8.6.1.1) with PT listed in the Standardized 
MedDRA Query (SMQ) ‘Haemodynamic oedema, effusions and fluid overload (SMQ)’ or with 
PT equal to ‘Pulmonary congestion’ defined in the latest available MedDRA version with the 
exception of PTs containing ‘site’.

Anemia
Any treatment-emergent AE (see definition in Section 8.6.1.1) with a PT within the SMQs 
‘Haematopoietic erythropenia’ OR ‘Haematopoietic cytopenias affecting more than one type of 
blood cell (SMQ)’ (with the exception of two unspecific PTs: ‘blood disorder’, ‘blood count 
abnormal’) OR an event with any MedDRA PT containing the text ‘anaemia’.

Hypotension
Any treatment-emergent AE in accordance with the Standardized MedDRA query (SMQ):
1)Actelion AMQ hypotension:

Blood pressure ambulatory decreased

Blood pressure decreased

Blood pressure diastolic decreased

Blood pressure immeasurable

Blood pressure orthostatic decreased


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
Blood pressure systolic decreased

Blood pressure systolic inspiratory decreased

CT hypotension complex

Diastolic hypotension

Hypotension

Mean arterial pressure decreased

Neonatal hypotension

Orthostatic hypotension

Post procedural Hypotension

Procedural hypotension
excluding PTs: Neonatal hypotension, Postoperative hypotension, Post procedural Hypotension, 
Procedural hypotension.
2) Actelion AMQ symptomatic hypotension (selected PTs only):

Acute hypotension

Blood pressure ambulatory decreased

Blood pressure decreased

Blood pressure diastolic decreased

Blood pressure immeasurable

Blood pressure orthostatic decreased

Blood pressure systolic decreased

Blood pressure systolic inspiratory decreased

Circulatory collapse

CT hypotension complex

Diastolic hypotension

Dizziness

Dizziness postural

Fall

Hypotension

Hypotension paroxysm

Hypotension symptomatic

Loss of consciousness

Mean arterial pressure decreased

Neonatal hypotension


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
Orthostatic hypotension

Persistent postural-perceptual dizziness

Postoperative hypotensionPost procedural Hypotension

Preshock

Presyncope

Procedural hypotension

Shock

Shock symptom

Syncope

Vertigo
Note: Any modifications of terms may occur based on later dictionary updates and/or external guidance.
Only the following PTs within this AMQ are included:

Acute hypotension

Circulatory collapse

Loss of consciousness

Presyncope

Shock

Shock symptom

Syncope
12.6.1
AESI adjusted for subject-years exposure
Incidence rates of treatment-emergent AESIs will be presented as adjusted for number of subject-
years (SY) exposure.
The following method will be applied for adjusted incidence rates:
Person-time will be calculated by summing the days of treatment duration for each subject.
Subject-year exposure (SYE) will be calculated by dividing the total subject time by 365.25 days.
The incidence rate for an AE per 100 person-years will be calculated by dividing the number of 
subjects with AEs by the SYE and multiplying by 100.
Adjusted Incidence Rate = 100 × (Number of subjects with at least one treatment-emergent
AE/SYE).
Subjects without event are censored at EOT+30.
The adjusted incidence rate is interpreted as the number of events occurring in 100 subject-years. 
It is based on the assumption that the occurrences of a specific event are following an independent 


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Poisson process, so the events occur with a constant rate over time. Hence, the 95% CLs of the 
adjusted incidence rate will be computed using a Poisson regression model with log of time at risk 
as an offset (SAS PROC GENMOD; see Appendix 9 for code example).
The following information will be displayed:
n = The number of subjects with at least one event. Subjects with multiple events will be counted 
only once (only the initial event will be counted).
T = The total of the subject’s time on treatment in years.
Adj Rate = The adjusted event incidence rate per 100-SY. It is interpreted as the number of events 
occurring in 100-SY.
Note: these rates will only be presented overall and not at a PT level.
12.6.2
Time to first occurrence of AESI
Time to first occurrence of treatment-emergent AESI will be estimated by the Kaplan-Meier (KM) 
product-limit method and summarized for Macitentan 10 mg MERIT (DB/OL), Macitentan 10 mg 
MERIT Pool and Macitentan 10 mg MERIT (OL) cohorts at pre-specified time points (e.g., 6 
months, 12 months, etc.), number of subjects at risk, number of subjects with event (%), number 
of subjects censored (%), KM estimates, and 95% CLs. The standard error of the KM estimate will 
be calculated using Greenwood’s formula (Collett 1994).
Time to occurrence will be limited to time to first occurrence of event of interest. Subjects with no 
events will be censored as presented in Table 13.
KM plots for time to AESI will be truncated at the timepoint after which less than 10% of the 
subjects remain at risk (Pocock 2002).
The following table describes various situations for events and the rules for handling them. If more 
than one situation applies, the rule for the first applicable date is to be followed.
Censoring rules for time to first occurrence of AESI are presented in Table 13.
Table 13 – Censoring rules for time to first occurrence of the treatment-emergent AESI
Situation
Time to Event
Status of time-to-event 
variable
Start-date
End-date
A
Subject with an event*
Date start of study 
treatment
Date of first onset of 
AE
Event
B
Subject died
Date start of study 
treatment
Date of death if 
occurring on or before 
30 days after end of 
treatment.
Censor
C
Subject with no event 
(subject discontinued from 
the study treatment)
Date start of study 
treatment
EOT + 30 days
Censor
D
Subject with no event 
(subject still on treatment)
Date start of study 
treatment
EOT + 30 days
Censor
* Event is the first occurrence of AESI. AE = adverse event; AESI = AE of special interest; EOT = End-of-Treatment.






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ALT = alanine aminotransferase; AP = alkaline phosphatase; AST = aspartate aminotransferase; BUN = blood urea 
nitrogen; LDH = lactate dehydrogenase; MCH = mean cell hemoglobin; MCHC = mean corpuscular hemoglobin 
concentration; MCV = mean cell volume; SI = international system of unit; TIBC = total iron binding capacity; *
Pregnancy (serum) is reported in the eCRF as Choriogonadotropin Beta


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Status: Approved, Date: 25 March 2022
12.9.
Appendix 9 Example SAS Code for Adjusted Incidence Rates and 95% CL
Note: time should be in years for GENMOD


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Status: Approved, Date: 25 March 2022
REFERENCES
Brookmeyer R, Crowley J (1982). A CI for the median survival time. Biometrics 1982;38:29–41.
Clinical Study Report AC-055E201. MERIT-1: Macitentan in the treatment of inoperable chronic thromboembolic 
pulmonary hypertension. Actelion Pharmaceuticals Ltd; D-17.097 (4 Jul 2017).
Collett D (1994). Modelling survival data in medical research. 1st edition. London: Chapman & Hall/CRC; 1994.
Pocock SJ, Clayton TC, Altman DG (2002). Survival plots of time-to-event outcomes in clinical trials: good practice 
and pitfalls. The Lancet 2002;359:1686-89
Schemper M, Smith TL (1996). A note on quantifying follow-up in studies of failure time. Control Clin Trials 1996 
Aug;17(4):343-6.


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Status: Approved, Date: 19 November 2021
Actelion Pharmaceuticals Ltd.
Statistical Analysis Plan for COVID-19 Impact Assessment
Long term, multicenter, single-arm, open-label extension study of the MERIT-1study, to 
assess the safety, tolerability and efficacy of macitentan in subjects within operable chronic 
thromboembolic pulmonary hypertension (CTEPH)
MERIT-2: Macitentan in thE tReatment of Inoperable chronic Thromboembolic 
pulmonary hypertension (Open-Label)
Protocol AC-055E202; Phase 2
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.
Status:
Approved
Date:
19 November 2021
Prepared by:
Actelion Pharmaceuticals Ltd., a Janssen Pharmaceutical Company of Johnson &
Johnson
Document No.: EDMS-589874, 1.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or otherwise.
NCT02060721


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                                                                    Statistical Analysis Plan for COVID-19 Impact Assessment AC-055E202
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Status: Approved, Date: 19 November 2021
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
VERSION HISTORY..................................................................................................................................... 3
1.
INTRODUCTION.................................................................................................................................. 4
1.1.
Objectives ........................................................................................................................................ 4
1.2.
Study Design.................................................................................................................................... 4
2.
STATISTICAL HYPOTHESES............................................................................................................ 4
3.
SAMPLE SIZE DETERMINATION...................................................................................................... 4
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS....................................................................... 5
5.
STATISTICAL ANALYSES................................................................................................................. 5
5.1.
General Definitions........................................................................................................................... 5
5.1.1.
COVID-19 periods of the pandemic.............................................................................................. 5
5.2.
Subject information .......................................................................................................................... 6
5.2.1.
Disposition .................................................................................................................................... 6
5.2.2.
Extent of Exposure ....................................................................................................................... 6
5.2.3.
Protocol Deviations....................................................................................................................... 7
5.2.4.
Concomitant Medications ............................................................................................................. 7
5.3.
Safety Analyses ............................................................................................................................... 7
5.3.1.
Adverse Events............................................................................................................................. 7
5.3.2.
Deaths........................................................................................................................................... 8
5.3.3.
Clinical laboratory test .................................................................................................................. 8
6.
SUPPORTING DOCUMENTATION .................................................................................................... 9
6.1.
Appendix 1 List of Abbreviations...................................................................................................... 9
6.2.
Appendix 2 List of COVID-19 related AEs ..................................................................................... 10


JNJ - 67896062 / ACT-064992  (Macitentan)
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Status: Approved, Date: 19 November 2021
VERSION HISTORY
Table 1 – SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1.0
19 November 2021
Not Applicable
Initial release




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Status: Approved, Date: 19 November 2021
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
The OLAS, RAS and OLSS analysis sets described in section 3.0 of the CSR SAP will be used in 
current analyses as appropriate.
5.
STATISTICAL ANALYSES
5.1.
General Definitions
5.1.1.
COVID-19 Periods of the Pandemic
Based on the declaration by the World Health Organization Director-General at the media briefing 
on COVID-19 on March 11th, 2020, COVID-19 can be characterized as a pandemic and its periods 
could be identified as follows:
Table 3 – COVID-19 periods of the pandemic
Period
Definition
Pre COVID-19
Defined as the period before March 11th, 2020 unless there is prior evidence of 
COVID-19 by the data collection. In that case, March, 11th 2020 is replaced by 
the date of the first evidence of COVID-19 (see definition below).
During COVID-19*
Defined as the period between March 11th 2020 (or earlier in case of prior 
evidence of COVID-19) and the end date of the pandemic (limits included) or 
the date of the study closure, whichever comes first.
Post COVID-19*
Defined as the period starting immediately after the end date of pandemic
onwards.
* Given that the pandemic still ongoing at the time of this document, no end date of the pandemic is available.
Therefore, an open end is set for the 'During COVID-19' period and the 'Post COVID-19' period cannot be 
considered for the analyses.
Prior evidence of COVID-19 (i.e., before March, 11th 2020) can be identified as follows:

Date of premature study treatment discontinuation / study withdrawal: reasons for 
premature study treatment discontinuation / study withdrawal are identified in the 
corresponding eCRF modules prefixed with the text “COVID-19 related”, as appropriate (i.e., 
either for AE, or medical or non-medical reason, whether subject or physician decision). 

Onset date of adverse events (AEs): COVID-19 related AEs are identified if the 
corresponding preferred terms (PTs) are included in the list as provided in Appendix 2.

Date of death: if the death is COVID-19 related, the primary cause of death should contain 
the text "COVID-19" in the "Death" eCRF module. (Note: "COVID-19" should then also be 
reported in the corresponding (S)AE).

Protocol deviations (PDs): if a PD is linked to COVID-19, the PD term should be prefixed 
with the text “COVID-19 related”.
Each assessment/visit will be associated to the COVID-19 periods of the pandemic as defined 
above considering their date respect to the cut-off date of March,11th 2020 (or earlier, as 
applicable). For example, if the Vital signs assessment was performed before the cut-off date of 
March,11th 2020, and there is no prior evidence of COVID-19, that assessment is associated to the 
'Pre COVID-19' period, otherwise it is associated to the 'During COVID-19' period. 


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Note that it is possible that 'COVID-19 related' data occurred in the 'Pre COVID-19' period, due 
to the fact that the study is running since 2014 and the pandemic start date selected for the analyses
(11 March 2020) does not necessarily coincide with the COVID-19 virus circulation start date in 
all centers/countries.
Listing of pandemic start and end dates (based on the definitions above) will be provided per
region, country and site for those sites where at least 1 subject was affected. Visit mapping
To minimize the amount of missing data and the possibility to delay the assessments until the on-
site visits can be resumed, scheduled visits can be done in remote mode (eg, by phone / 
telemedicine) or in-person, off-site (eg, in-home) interactions between site staff (or designees) and 
subjects for study procedures e.g. those related to safety monitoring / efficacy evaluation / study 
intervention storage and administration (including training where pertinent) according to the 
COVID-19 protocol appendix.
5.2.
Subject information
A total of 76 subjects entered MERIT-2, with enrollment activities completed28 Sep 2016. Study 
Treatment 
5.2.1.
Disposition
Reasons for premature discontinuation of the study due to COVID-19 are captured in the 
"Premature study discontinuation" eCRF form.
Reasons for premature study treatment discontinuation due to COVID-19 are captured in the "
Premature Permanent Discontinuation of Study Treatment" eCRF form.
The corresponding summaries for study and study treatment disposition as planned in the CSR 
SAP section 7.1 will show details for subjects who reported reasons for discontinuation due to 
COVID-19. Therefore, no specific summary will be provided.
Listings of subjects will be provided for the following categories:

Subjects who discontinued study prematurely due to COVID-19 

Subjects who discontinued study treatment prematurely due to COVID-19.
5.2.2.
Extent of Exposure
A subject is considered to have a dose not administered if he/she has a study treatment interruption
(i.e., if a reason associated with a study treatment end is ‘Temporarily interrupted due to an AE’
in the "Study Drug Log" eCRF form).
Treatment modifications due to COVID-19 (identifiable from the linked AE) will be listed on the 
OLAS: temporary study treatment interruptions reported in the "Study Drug Log" eCRF as
'COVID-19 related' AEs with action taken with study drug="Temporarily interrupted" in the 
'Adverse Event' eCRF form. A supportive listing will be provided for COVID-19 related AEs 


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Status: Approved, Date: 19 November 2021
leading to temporarily interruption with action taken with study drug="Temporarily interrupted" 
in the 'Adverse Event' eCRF form. Additional listing will be provided for these subjects with the 
study drug dispensed.
5.2.3.
Protocol Deviations 
COVID-19 related protocol deviations are identified with the text ‘COVID-19 related’ as a prefix
of the PD description.
Subjects with major (see the definition in the CSR SAP, section 8.1) 'COVID-19 related' PDs will 
be summarized by displaying counts and percentages of subjects with at least one major 'COVID-
19 related' PD within each category (as defined in Appendix 4 of the CSR SAP) on OLAS (see 
table 6 of the CSR SAP) . 
All reported 'COVID-19 related' PDs will be described in a subject listing. Major (important)
'COVID-19 related' PDs will be flagged accordingly.
5.2.4.
Concomitant Medications 
Study treatment concomitant therapies are defined in the CSR SAP (see Appendix 5).
A summary of 'COVID-19 related' medications will be provided on OLAS for subjects who 
experienced at least one COVID-19 related AE, as specified in Appendix 5 of the CSR SAP.
Those medications reported with an indication for COVID-19 are defined as "COVID-19 related"
and contain the words "COVID-19" (including any COVID-19 vaccine that should be reported on 
the eCRF).
Individual subject's listing of concomitant medications for COVID-19 infection for subjects who 
experienced at least one COVID-19 related AE will be provided.
5.3.
Safety Analyses
All safety analyses and listings will be based on the OLAS, OLSS and RAS analyses sets.
All definitions and conventions used in the CSR SAP Section 8.5 of this study (AC-055E202
/MERIT-2) will be applied, unless otherwise specified.
5.3.1.
Adverse Events
COVID-19 related AEs are identified if the corresponding PTs are included in the list as provided 
in Appendix 2.
Overall summary table of COVID-19 related treatment-emergent AEs will be provided, containing 
number and percentages of subjects having experienced at least one occurrence and number of 
AEs for the following categories of TEAEs due to Covid-19:

Treatment-emergent COVID-19 related AEs

Severe treatment-emergent COVID-19 related AEs 


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
COVID-19 related AEs with fatal outcome 

Treatment-emergent serious COVID-19 related AEs (SAEs)

COVID-19 related AEs leading to premature discontinuation of study treatment
Summary tables by PT will provided for each category defined above.
Summary of overall safety profile will be provided for all AEs by SOC and PT, distinguishing 
between subjects with and without COVID-19.
In addition, a listing with all COVID-19 related AEs will be provided for subjects who had 
experienced at least one COVID-19 related AE.
5.3.2.
Deaths
A summary table will be provided, containing number and percentages of subjects on the OLAS,
OLSS and RAS who died due to COVID-19 during the treatment-emergent period. Frequencies 
for the following parameters will be included in the summary table:

Number of subjects who died.

Cause term.

COVID-19 related cause term.
The summary will be based on the "Death form" eCRF form. The summary will be provided if at 
least 3 deaths have occurred overall. The summary table is presented by descending order of PT
according to the incidence of deaths in the 'Macitentan 10 mg Pool' cohort.
A listing will be provided for subjects who had experienced COVID-19 related death.
5.3.3.
Clinical Laboratory Test
The positive results from COVID-19 testing will be captured as COVID-19 related AEs and 
reported as described in Section 5.3.1 of this document.
Options for the conduct of safety laboratory assessments during the COVID-19 periods of the 
pandemic (i.e., during COVID-19) are described in the COVID-19 Appendix to Protocol. A 
summary display will show the percentage of laboratory data (considering all parameters) that 
were conducted at central and local laboratory during different COVID-19 periods as defined in 
section 5.3.1 by cohorts defined in section 8.5 of the CSR SAP. This summary output will be 
presented for all assessments conducted during the course of the study as defined in Table 3 of the 
SCR SAP.


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                                                                    Statistical Analysis Plan for COVID-19 Impact Assessment AC-055E202
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Status: Approved, Date: 19 November 2021
6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
ADaM
AE
Analysis Data Model
Adverse Event
COVID
Corona Virus Disease
CSR
Clinical Study Report
eCRF
electronic Case Report Form
PD
Protocol Deviation
PT
RAS
Preferred Term
Restricted Analysis Set
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
OL
OLAS
OLSS
Open-Label
Open-Label Analysis Set
Open-Label Safety Set


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Status: Approved, Date: 19 November 2021
6.2.
Appendix 2 List of COVID-19 related AEs
AEs are considered as “COVID-19 related” if their coded PTs are: 
Asymptomatic COVID-19, 
Congenital COVID-19, 
Coronavirus infection, 
Coronavirus test positive, 
COVID-19, 
COVID-19 immunization, 
COVID-19 pneumonia, 
COVID-19 prophylaxis, 
COVID-19 treatment, 
Exposure to SARS-CoV-2, 
Multisystem inflammatory syndrome in children, 
Occupational exposure to SARS-CoV-2, 
Post-acute COVID-19 syndrome, 
SARS-CoV-2 antibody test positive,
SARS-CoV-2 carrier, 
SARS-CoV-2 RNA decreased, 
SARS-CoV-2 RNA fluctuation, 
SARS-CoV-2 RNA increased, 
SARS-CoV-2 sepsis, 
SARS-CoV-2 test false negative, 
SARS-CoV-2 test positive, 
SARS-CoV-2 viraemia, 
Suspected COVID-19, 
Vaccine derived SARS-CoV-2 infection, 
Antiviral prophylaxis, 
Antiviral treatment, 
Coronavirus test, 
Coronavirus test negative, 
COVID-19 screening, 
Exposure to communicable disease, 
Pneumonia viral, 
SARS-CoV-2 antibody test, 
SARS-CoV-2 antibody test negative, 
SARS-CoV-2 RNA, 
SARS-CoV-2 RNA undetectable, 
SARS-CoV-2 test, 
SARS-CoV-2 test false positive, 
SARS-CoV-2 test negative.