Conditions: Pulmonary Arterial Hypertension
Keywords: Eisenmenger Syndrome exercise capacity
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 217
Healthy volunteers: no

Brief summary:
Long-term study to evaluate if macitentan is safe, tolerable and efficient enough to be used for treatment of Eisenmenger syndrome.

Detailed description:

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

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

Protocol document:
Prot_000.pdf: 
 
 
TPL-052-CLI-GL-V6_040809 
 
 
 
Macitentan / ACT-064992 
Eisenmenger Syndrome 
Protocol AC-055-308 
MAESTRO-OL: MAcitentan in Eisenmenger Syndrome To RestOre exercise 
capacity (Open-Label) 
Long term, single-arm, open-label extension study of protocol AC-055-305 to assess 
the safety, tolerability and efficacy of macitentan in subjects with Eisenmenger 
Syndrome 
 
Study Phase: 
3 
Identifier: 
NCT02382016 
Date: 
16 May 2014 
Version and History: 
Final Version 4 (following Global Amendment 3) 
Global Amendment 2, Final Version 3, 19 September 2013 
Global Amendment 1, Final Version 2, 03 April 2013 
Final Version 1, 12 October 2012 
 
 
 
 
 
Confidentiality statement 
Property of Actelion Pharmaceuticals Ltd. May not be used, divulged, published or otherwise disclosed 
without consent of Actelion Pharmaceuticals Ltd. 


Macitentan / ACT-064992 
Eisenmenger Syndrome 
Protocol AC-055-308, MAESTRO-OL 
Final Version 4 
16 May 2014, page 2/102 
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Doc No D-14.170 
 
 
SPONSOR AND CRO CONTACT DETAILS 
SPONSOR  
 
ACTELION Pharmaceuticals Ltd 
Gewerbestrasse 16 
CH-4123 Allschwil 
Switzerland 
Clinical Project Team Leader 
 
 
 
Fax 
 
e-mail 
 
Clinical Project Physician 
 
 
 
Fax 
 
e-mail 
 
Clinical Area Head 
 
 
 
 
Fax 
 
e-mail 
 
Drug Safety Physician 
 
 
 
 
Fax 
 
 
e-mail 
 
CENTRAL 
LABORATORY 
 
 
 
 
 
 
Contact person 
Please refer to the Investigator Lab Manual. 
CENTRAL STUDY DRUG 
RE-SUPPLY 
 
 
 
 
 
Contact person 
Please refer to the Investigator Site File binder. 
MEDICAL HOTLINE 
Toll-free Hotline telephone numbers for participating 
countries can be found in the Investigator Site File binder. 
For countries where no toll-free number is available, a 
toll telephone number will be used. 
The medical hotline is intended for the use by health care 
professionals. Subjects should be asked to contact the 
investigator in case of any medical emergency or any 
other health problem. 


Macitentan / ACT-064992 
Eisenmenger Syndrome 
Protocol AC-055-308, MAESTRO-OL 
Final Version 4 
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Doc No D-14.170 
 
 
SIGNATURE PAGE FOR ACTELION PHARMACEUTICALS LTD 
Hereinafter called Actelion 
 
Drug name / number 
Macitentan / ACT-064992 
Indication 
Eisenmenger Syndrome 
Protocol number, acronym, title  
AC-055-308, MAESTRO-OL, Long term, single-arm, open-label extension study of 
protocol AC-055-305 to assess the safety, tolerability and efficacy of macitentan in 
subjects with Eisenmenger Syndrome 
 
 
 
NAME (TITLE) 
DATE 
 SIGNATURE 
Clinical Project Team 
Leader 
 
 
 
Clinical Project 
Physician 
 
 
 
Trial Statistician 
 
 
 
 


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Final Version 4 
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INVESTIGATOR SIGNATURE PAGE 
Drug name / number 
Macitentan / ACT-064992 
Indication 
Eisenmenger Syndrome 
Protocol number, acronym, title  
AC-055-308, MAESTRO-OL, Long term, single-arm, open-label extension study of 
protocol AC-055-305 to assess the safety, tolerability and efficacy of macitentan in 
subjects with Eisenmenger Syndrome 
I agree to the terms and conditions relating to this study as defined in this protocol, the 
Case Report Form (CRF), and any other protocol-related documents. I fully understand 
that any changes instituted by the investigator(s) without previous agreement with the 
sponsor would constitute a violation of the protocol, including any ancillary studies or 
procedures performed on study subjects (other than those procedures necessary for the 
wellbeing of the subjects). 
I agree to conduct this study in accordance with the Declaration of Helsinki and its 
amendments, International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines, and applicable regulations and laws. In particular, I will obtain 
approval by an Ethics Committee or Institutional Review Board (EC/IRB) prior to study 
start and signed informed consent from all subjects included in this study. In addition, I 
will allow direct access to source documents and agree to inspection by auditors from the 
sponsor and Health Authorities. I will ensure that the study drug(s) supplied by the 
sponsor are being used only as described in this protocol. Furthermore, I confirm 
herewith that the sponsor is allowed to enter and utilize my professional contact details 
and function in an electronic database for internal purposes and for submission to Health 
Authorities worldwide. 
 
Country 
Center 
number 
Town 
Date 
 
Signature 
Country 
Coordinating 
Investigator 
 
 
 
 
 
 
Center Principal 
Investigator 
 
 
 
 
 
 


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Eisenmenger Syndrome 
Protocol AC-055-308, MAESTRO-OL 
Final Version 4 
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TABLE OF CONTENTS 
SPONSOR AND CRO CONTACT DETAILS ...................................................................2 
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................10 
PROTOCOL SYNOPSIS AC-055-308 .............................................................................13 
1 
BACKGROUND AND RATIONALE .......................................................................20 
1.1 
Eisenmenger Syndrome ................................................................................20 
1.2 
Endothelin-1 and pulmonary hypertension ...................................................21 
1.3 
Macitentan ....................................................................................................22 
1.3.1 
Macitentan – Preclinical information ...............................................22 
1.3.2 
Macitentan – Clinical information ....................................................23 
1.3.2.1 
Phase 1 studies .........................................................................23 
1.3.2.2 
Phase 2 study in patients with essential hypertension .............25 
1.3.2.3 
Phase 2 study in patients with idiopathic pulmonary 
fibrosis .....................................................................................25 
1.3.2.4 
Phase 3 study in patients with pulmonary arterial 
hypertension ............................................................................26 
1.3.3 
Macitentan – Summary of potential risks and risk management ......27 
1.4 
Study rationale ..............................................................................................28 
1.4.1 
Medical and regulatory background .................................................28 
1.4.2 
Subject population ............................................................................29 
1.4.3 
Study design ......................................................................................29 
1.4.4 
Dose selection ...................................................................................29 
1.4.5 
Treatment duration ............................................................................29 
1.4.6 
Primary endpoint ...............................................................................29 
1.4.7 
Statistical hypotheses and sample size ..............................................29 
2 
STUDY OBJECTIVES ...............................................................................................29 
3 
INVESTIGATIONAL PLAN .....................................................................................30 
3.1 
Overall study design and plan ......................................................................30 
3.2 
Study population ...........................................................................................31 
3.2.1 
Subject population ............................................................................31 
3.2.2 
Inclusion criteria ...............................................................................31 
3.2.3 
Exclusion criteria ..............................................................................32 
3.2.4 
Concomitant medications .................................................................33 
3.3 
Study drug .....................................................................................................33 


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3.3.1 
Administration of the study drug ......................................................33 
3.3.2 
Study drug storage and dispensing ...................................................34 
3.3.3 
Study drug up- and down-titration ....................................................35 
3.4 
Study drug discontinuation and study withdrawal .......................................35 
3.4.1 
Study drug interruption or discontinuation .......................................35 
3.4.2 
Subject’s follow-up after study drug discontinuation .......................36 
3.4.3 
Withdrawal of consent and lost to follow-up ....................................36 
3.4.4 
Replacement policy ...........................................................................36 
3.4.4.1 
Subjects ...................................................................................36 
3.4.4.2 
Centers .....................................................................................36 
3.5 
Treatment exposure, compliance and drug accountability ...........................36 
3.6 
Treatment assignment ...................................................................................37 
3.6.1 
Blinding ............................................................................................37 
3.6.2 
Emergency procedure for unblinding ...............................................37 
3.7 
Study drug packaging and labeling ..............................................................37 
3.7.1 
Study drug packaging .......................................................................37 
3.7.2 
Study drug labeling ...........................................................................38 
3.8 
Study endpoints ............................................................................................38 
3.8.1 
Efficacy exploratory endpoints .........................................................38 
3.8.2 
Safety and tolerability endpoints ......................................................38 
3.9 
Study assessments .........................................................................................38 
3.9.1 
Safety and tolerability assessments ...................................................39 
3.9.1.1 
Vital signs ................................................................................39 
3.9.1.2 
Body Weight ............................................................................39 
3.9.1.3 
Physical examination ...............................................................39 
3.9.1.4 
Laboratory assessments ...........................................................40 
3.9.1.5 
General management of Eisenmenger Syndrome ...................45 
3.9.2 
Efficacy exploratory assessments .....................................................45 
3.9.2.1 
WHO functional class .............................................................45 
3.9.2.2 
Six-minute walk test and Borg dyspnea index ........................45 
3.9.2.3 
Oxygen saturation (SpO2) .......................................................46 
3.9.3 
Baseline parameters and concomitant medications ..........................46 
3.9.3.1 
Baseline demographics and disease characteristics .................46 
3.9.3.2 
Concomitant medications ........................................................46 
3.10 
Visit and assessment schedule ......................................................................47 
3.10.1 
Enrollment visit (Visit 1) ..................................................................47 
3.10.2 
Treatment period ...............................................................................48 
3.10.2.1 
Month 1 visit (Visit 2) .............................................................48 
3.10.2.2 
Monthly Lab and Safety Monitoring .......................................48 


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3.10.2.3 
Month 6 and Month 12 visits (Visits 3 and 4, 
respectively) ............................................................................49 
3.10.2.4 
Visits at 6-monthly intervals (Visits 5, 6 etc.) .........................50 
3.10.2.5 
EOT visit .................................................................................50 
3.10.3 
Unscheduled visit(s) .........................................................................51 
3.10.4 
30-day safety follow-up / EOS visit .................................................51 
4 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ...........................52 
4.1 
Summary table ..............................................................................................52 
4.2 
Adverse events ..............................................................................................53 
4.2.1 
Definitions of adverse events ............................................................53 
4.2.2 
Intensity of adverse events ................................................................54 
4.2.3 
Relationship to study drug ................................................................54 
4.2.4 
Reporting of new adverse events ......................................................55 
4.2.5 
Follow-up of ongoing adverse events ...............................................55 
4.3 
Serious adverse events ..................................................................................55 
4.3.1 
Definitions ........................................................................................55 
4.3.1.1 
Serious adverse events .............................................................55 
4.3.1.2 
Hospitalization – prolongation of existing hospitalization ......56 
4.3.1.3 
Serious adverse events related to study-mandated 
procedures ...............................................................................56 
4.3.2 
Reporting of new serious adverse events ..........................................56 
4.3.2.1 
Prior to start of OL treatment period .......................................56 
4.3.2.2 
Treatment and follow-up periods ............................................57 
4.3.2.3 
After Follow-up period ............................................................57 
4.3.2.4 
Reporting procedures ..............................................................57 
4.3.3 
Follow-up of ongoing serious adverse events ...................................59 
4.4 
Pregnancy .....................................................................................................59 
4.4.1 
Teratogenicity ...................................................................................59 
4.4.2 
Reporting of pregnancy ....................................................................59 
4.4.3 
Follow-up of pregnancy ....................................................................59 
5 
STATISTICAL METHODOLOGY AND ANALYSES ............................................59 
5.1 
Statistical Analysis Plan ...............................................................................59 
5.2 
Analysis sets .................................................................................................60 
5.3 
Exploratory efficacy endpoints .....................................................................60 
5.4 
Safety and tolerability endpoints ..................................................................61 
5.4.1 
Adverse events, serious adverse events, reasons for death, and 
premature discontinuation .................................................................62 
5.4.2 
Laboratory parameters ......................................................................62 


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5.5 
Exposure to study drug .................................................................................62 
5.6 
Baseline parameters and concomitant medications ......................................63 
5.7 
Exploratory analyses .....................................................................................63 
5.8 
Interim analyses ............................................................................................63 
6 
PROCEDURES AND GOOD CLINICAL PRACTICE .............................................64 
6.1 
Procedures ....................................................................................................64 
6.1.1 
Protocol amendments ........................................................................64 
6.1.1.1 
Non-substantial amendment ....................................................64 
6.1.1.2 
Substantial amendment ............................................................64 
6.1.1.3 
Urgent amendment ..................................................................64 
6.1.2 
Monitoring ........................................................................................65 
6.1.3 
Data management .............................................................................66 
6.1.3.1 
Data collection .........................................................................66 
6.1.3.2 
Database management and quality control ..............................67 
6.1.4 
Recording of data and retention of documents .................................67 
6.1.5 
Audit .................................................................................................68 
6.1.6 
Handling of study drug .....................................................................69 
6.1.7 
Publication and reporting of study results ........................................69 
6.1.8 
Disclosure and confidentiality ..........................................................69 
6.1.9 
Premature termination or suspension of the study ............................70 
6.2 
Good Clinical Practice ..................................................................................70 
6.2.1 
Ethics and Good Clinical Practice ....................................................70 
6.2.2 
Ethics Committee / Institutional Review Board ...............................71 
6.2.3 
Informed consent ..............................................................................71 
6.2.4 
Compensation to subjects and investigators .....................................72 
6.2.5 
DoA, FDA1572, CV, GCP Declaration Form and Financial 
Disclosure Form ................................................................................72 
7 
REFERENCES ............................................................................................................74 
 
LIST OF TABLES 
Table 1 
Visit and assessment schedule ...................................................................18 
 
LIST OF FIGURES 
Figure 1 
Study design ..............................................................................................31 
 
 


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Final Version 4 
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LIST OF APPENDICES 
Appendix 1 
Clinical Classification of Pulmonary Hypertension ..................................78 
Appendix 2 
Actelion Guidelines for 6MWT.................................................................80 
Appendix 3 
Borg dyspnea index (Borg Scale) / Perceived Breathlessness ..................85 
Appendix 4 
WHO functional classification of Pulmonary Hypertension .....................86 
Appendix 5 
Central laboratory ranges ..........................................................................87 
Appendix 6 
Alert flags ..................................................................................................93 
Appendix 7 
List of protocol amendments .....................................................................99 


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Final Version 4 
16 May 2014, page 10/102 
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Doc No D-14.170 
 
LIST OF ABBREVIATIONS AND ACRONYMS 
 
6MWD  
6-minute walk distance 
6MWT  
6-minute walk test 
AE  
Adverse event 
ALT  
Alanine aminotransferase/serum glutamic pyruvic transaminase 
(SGPT) 
ASD  
Atrial septal defect 
AST  
Aspartate aminotransferase/serum glutamic oxaloacetic 
transaminase (SGOT) 
BP  
Blood pressure 
BUN  
Blood urea nitrogen 
CHD  
Congenital heart disease 
CL  
Confidence limit(s) 
CV  
Curriculum Vitae 
CYP  
Cytochrome P-450 
DB  
Double-blind 
DBP  
Diastolic blood pressure 
DCF  
Data Clarification Form 
DMC  
Data Monitoring Committee 
DoA  
Delegation of Authority 
DS  
Down Syndrome 
EC  
Ethics Committee 
ECG  
Electrocardiogram 
eCRF  
Electronic Case Report Form 
EOS  
End-of-Study 
EOT  
End-of-Treatment 
ERA  
Endothelin receptor antagonist 


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Final Version 4 
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ES  
Eisenmenger Syndrome 
ET-1  
Endothelin 1 
ETA  
Endothelin receptor A 
ETB  
Endothelin receptor B 
FDA  
Food and Drug Administration 
GCP  
Good Clinical Practice 
IB  
Investigator’s Brochure 
ICF  
Informed Consent Form 
ICH  
International Conference on Harmonisation 
IMP  
Investigational Medicinal Product 
IND  
Investigational New Drug 
IPF  
Idiopathic pulmonary fibrosis 
IRB  
Institutional Review Board 
ISF  
Investigator Site File 
IXRS  
Interactive Voice or Web Response System 
LDH  
Lactate dehydrogenase 
LT  
Liver test 
MCH  
Mean corpuscular hemoglobin 
MCHC  
Mean corpuscular hemoglobin concentration 
MCV  
Mean corpuscular volume 
MedDRA  
Medical Dictionary for Regulatory Activities 
MLA  
Marked laboratory abnormality(ies) 
OL  
Open-label 
PAH  
Pulmonary arterial hypertension 
PD  
Pharmacodynamics 
PK  
Pharmacokinetics 
SAE  
Serious adverse event 


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Final Version 4 
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SAP  
Statistical Analysis Plan 
SBP  
Systolic blood pressure 
SDV  
Source Data Verification 
SiDBP  
Sitting diastolic blood pressure  
SiSBP  
Sitting systolic blood pressure 
SOC  
System organ class 
SpO2  
Saturation of peripheral oxygen 
SUSAR  
Suspected unexpected serious adverse reaction 
TIBC  
Total iron binding capacity 
ULN  
Upper limit of normal 
VSD  
Ventricular septal defect 
WHO  
World Health Organization 


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PROTOCOL SYNOPSIS AC-055-308 
TITLE 
Long term, single-arm, open-label extension study of protocol 
AC-055-305 to assess the safety, tolerability and efficacy of 
macitentan in subjects with Eisenmenger Syndrome 
ACRONYM 
MAESTRO-OL: MAcitentan in Eisenmenger Syndrome To 
RestOre exercise capacity (Open-Label) 
OBJECTIVES 
To assess the long-term safety, tolerability and efficacy of 
macitentan in subjects with Eisenmenger Syndrome (ES). 
DESIGN / PHASE 
Multi-center, open-label (OL) extension, single-arm, Phase 3 
study. 
STUDY PLANNED 
DURATION 
First subject 
First visit 
Q2 
2013 
Last 
subject 
First visit 
Q1 
2016 
Last subject 
Last visit 
Open 
CENTERS/COUNTRIES 
Approximately 90 centers in approximately 30 countries. 
SUBJECTS / GROUPS 
Up to 220 subjects in one group*. 
* Sample size may be increased up to 330 subjects based on the interim blind 
sample size review during the double-blind AC-055-305 / MAESTRO study.  
INCLUSION CRITERIA 
1. Written informed consent/assent to participate in the study 
must be obtained from the subject or a parent / legal 
representative, and from the caregiver, where applicable, 
according to local regulations, prior to initiation of any 
study-mandated procedure. 
2. Subjects with ES (including those with DS) having 
completed the double-blind AC-055-305 / MAESTRO study 
as scheduled, i.e., who remained in the double-blind study 
up to Week 16 (whether or not they were still taking study 
drug at the end of this period). 
3. Females of childbearing potential must have a negative 
serum pregnancy test prior to first intake of OL study drug, 
and must use 2 reliable methods of contraception at the 
same time from enrollment up to at least 30 days after study 
treatment discontinuation. True abstinence is permissible 
under specific circumstances [see Section 3.2.2 of the 
protocol for more details]. 
EXCLUSION CRITERIA 
1. Subjects who prematurely discontinue double-blind study 
drug during the AC-055-305 / MAESTRO study due to: 
• an adverse event (AE) assessed as related to the use of study 


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drug, or 
• elevated liver tests (LTs; related or unrelated to study drug). 
2. Subjects with Down Syndrome (DS) who are not fully 
independent and need help to perform daily activities, and 
who do not have a caregiver or family member who agrees 
to accompany them to all visits, provide information about 
the participant as required by the protocol, and ensure 
compliance with study medication schedule. 
3. Systolic blood pressure (SBP) < 85 mmHg. 
4. Hemoglobin or hematocrit < 75% of the lower limit of 
normal. 
5. Serum aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) > 3  the upper limit of normal 
(ULN). 
6. Severe hepatic impairment according to National Cancer 
Institute organ dysfunction working group criteria defined as 
total bilirubin > 3  ULN accompanied by any AST 
elevation above the ULN. 
7. Any known factor or disease that 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 excipients.  
9. Females who are pregnant or plan to become pregnant 
during the study or are lactating. 
CONCOMITANT 
MEDICATIONS 
Prohibited 
• Any 
endothelin 
receptor 
antagonist 
(ERA) 
or 
any 
investigational drug other than macitentan. 
• Cytochrome P-450 (CYP) 3A inducers (e.g., carbamazepine, 
phenytoin, phenobarbital, rifampin/rifampicin, rifapentin, 
rifabutin, St. John’s wort). 
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 (EOT), i.e., until whichever of the following 
occurs first:  
• Commercial availability of macitentan in this indication in 
the subject’s country, 
• The sponsor decides to stop this AC-055-308 OL study, 


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• The subject or the investigator decides to discontinue the 
study drug. 
Post-treatment safety follow-up / End-of-Study (EOS): for 
an individual subject, the end of this OL study corresponds to 
the 30-day safety follow-up / EOS visit, which should be 
performed 30 days after the permanent discontinuation of study 
drug. 
TRIAL DRUG 
Macitentan 10 mg tablet, once daily. 
REFERENCE DRUG  
Not applicable. 
EFFICACY ENDPOINTS Exploratory endpoints: 
Change from baseline of the OL* to Month 6 and Month 12 in: 
• Exercise capacity, as measured by the 6-minute walk 
distance (6MWD), 
• World Health Organization (WHO) functional class,  
• Dyspnea (assessed by the Borg dyspnea index), 
• Oxygen saturation, assessed by pulse oximetry: saturation of 
peripheral oxygen (SpO2) at rest before the 6-minute walk 
test (6MWT). 
* Baseline is defined as the last value obtained prior to or on the day of first 
administration of macitentan during this AC-055-308 OL study. 
For subjects who received macitentan during the double-blind 
AC-055-305 / MAESTRO study: 
Change from baseline** of AC-055-305 / MAESTRO to 
Month 6 and Month 12 in: 
• Exercise capacity, as measured by the 6MWD, 
• WHO functional class,  
• Dyspnea (assessed by the Borg dyspnea index), 
• Oxygen saturation, assessed by pulse oximetry: SpO2 at rest 
before the 6MWT. 
** Baseline is defined as the last value obtained prior to or on the day of first 
administration 
of 
macitentan 
during 
the 
double-blind 
AC-055-305 / MAESTRO study. 
TOLERABILITY / 
SAFETY ENDPOINTS 
• Treatment-emergent AEs up to 30 days after study drug 
discontinuation. 
• AEs leading to premature discontinuation of study drug. 


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• Treatment-emergent serious adverse events (SAEs) up to 
30 days after study drug discontinuation. 
• Treatment-emergent marked laboratory abnormalities (MLA) 
up to EOT. 
• Proportion of subjects with treatment-emergent ALT and/or 
AST abnormality (> 3 and ≤ 5  ULN; > 5 and ≤ 8  ULN; 
> 8  ULN) associated or not with total bilirubin > 2  ULN, 
up to EOT. 
STATISTICAL 
METHODOLOGY  
The statistical evaluation of the safety, tolerability, and 
exploratory efficacy endpoints will be carried out descriptively. 
Safety and tolerability analysis will be based in combination 
with data from the AC-055-305 / MAESTRO study. More 
precisely, the analysis will be based on the All-treated DB + OL 
set, which includes the union of (i) all subjects who received at 
least one dose of macitentan in this AC-055-308 / MAESTRO-
OL study, AND (ii) all subjects who received macitentan during 
the double-blind AC-055-305 / MAESTRO study and did not 
enter the OL study. The observation period for the individual 
subject starts at the time of the first administration of 
macitentan and ends with the permanent discontinuation of 
macitentan, regardless of administration type (i.e., double-blind 
or open-label). 
Efficacy exploratory analyses will be conducted both: 
• Taking as baseline the last value obtained prior to or on the 
day of first administration of macitentan during this 
AC-055-308 OL study (All-enrolled set), 
and 
• Taking as baseline the baseline of the AC-055-305 / 
MAESTRO study and including data from the start of 
AC-055-305 / MAESTRO up to Month 12 in this 
AC-055-308 OL study, only for subjects who received 
macitentan 
during 
the 
double-blind 
AC-055-305 
/ 
MAESTRO study (restricted All-enrolled set). 
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. 
• In order to ensure subjects’ safety, an independent Data 


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Monitoring Committee (DMC) will review the data from the 
AC-055-308 / MAESTRO-OL study on a regular basis until 
the end of the double-blind AC-055-305 / MAESTRO study 
(i.e., OL data will be reviewed only in combination with the 
data of the double-blind study). 
 


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Table 1 
Visit and assessment schedule 
PERIODS 
TREATMENT 
FOLLOW-
UP 
 
VISITS 
Number 
1 
2 
Monthly Lab 
& Safety 
Monitoring5 
3, 4 
5, 6, etc. 
EOT 
Safety 
follow-up / 
EOS 
U1, 2,… 
Name 
Enrollment2 Month 1 
Month 6, 
Month 12 
Month 18, 
Month 24, etc.  
Unscheduled 
visits6 
Time 
Day 1 
Month 1 
± 1 week 
Month 2 & 
every month 
thereafter up 
to EOT ± 1 
week 
Month 6 
& 
Month 12  
± 2 weeks 
Month 18 & 
every 6 months 
thereafter  
± 2 weeks 
Within 7 
days after 
study 
drug disc. 
30–33 days 
after study 
drug disc. 
Anytime 
during the 
study 
Informed consent / assent 
X 
 
 
 
 
 
 
 
Vital signs, Body Weight, 
Physical examination 
X  
X  
 
X 
X 
X 
 
X6 
Concomitant medications 
X  
X  
X 
X 
X 
X 
X 
X6 
SpO2 
X 
 
 
X 
 
X 
 
X6 
WHO functional class / 
6MWT/Borg dyspnea index 
X 
 
 
X 
 
X 
 
X6 
Complete laboratory tests1 
X3 
 
 
X 
X 
X 
 
X6 
Serum pregnancy test / 
methods of contraception (if 
applicable)4 
X3, 8 
X 
X 
X8 
X8 
X8 
X 
X6 
Hemoglobin7 
X3, 8 
X 
X7  
X8 
X8 
X8 
X 
X6 
LT 
X3, 8 
X 
X  
X8 
X8 
X8 
X 
X6 
Study drug dispensing 
X 
 
X11 
X 
X 
 
 
 
Study drug return 
 
 
 
X 
X 
X 
 
 
AEs9 
X 
X 
X 
X 
X 
X 
X 
X6 
SAEs9 
X 
X 
X 
X 
X 
X 
X10 
X6 


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1. Complete laboratory tests: hematology (including hemoglobin), blood chemistry (including LTs), and serum pregnancy test. Laboratory samples at all visits will be 
sent to and analyzed by the central laboratory.  
2. The enrollment visit is combined with the Week 16 (i.e., Visit 6 for subjects who complete the 16 weeks of double-blind treatment, or Visit 6a for subjects who 
prematurely discontinue double-blind treatment) in the AC-055-305 study. Tests are not to be repeated if performed for the Visit 6 or Visit 6a of the AC-055-305 
study but are to be reported in the eCRF of both studies (if applicable). 
3. 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 
for analysis.  
4. Only concerns females of childbearing potential.  
5. Whenever possible, the monthly laboratory samples will be collected at site and analyzed centrally. Site staff should take this opportunity to meet the subject to 
discuss any (S)AEs that could have occurred since previous visit, and assess the concomitant medications and methods of contraception (if applicable). However, 
under specific circumstances (e.g., subject lives far away from the site and cannot return every month), monthly laboratory samples could be collected in a local 
laboratory close to where the subject lives and analyzed centrally; in these cases, the assessment of (S)AEs should be done via a telephone call.  
6. At any time during the study (between Enrollment and End-of-Study visit) unscheduled site visits may be performed (based on investigator discretion). These 
include (but are not limited to) visits performed in case of safety concerns (e.g., new (S)AE, worsening of symptoms/assessment of 6MWD, adequate follow-up of any 
safety issues). Any study-specific procedures/assessments may be performed at an unscheduled visit, in which case the data will be collected in the eCRF. 
7. Hemoglobin concentration will be measured every month during the first 6 months, every 3 months thereafter up to the EOT visit, and 30 days after study drug 
discontinuation (EOS visit).  
8. Measured as part of the complete laboratory tests panel.  
9. All new SAEs and AEs occurring from first dose of OL study drug up to 30 day after study drug discontinuation must be reported in this OL study.  
10. New SAEs occurring after the 30-day follow-up period must be reported to the Actelion drug safety department, within 24 hours of the investigator’s knowledge of 
the event, if considered causally related to previous exposure to the study medication by the investigator. They are reported on an SAE form but not on the eCRF. 
11. Study drug may be dispensed on a monthly basis during monthly lab and safety monitoring.  
 
6MWT = 6-minute walk test; AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; eCRF = electronic Case Report Form; 
EOS = end-of-study; EOT = end-of-treatment; LT = liver test (liver aminotransferases [AST/ALT], alkaline phosphatase, total and direct bilirubin); MLA = marked 
laboratory abnormality(ies); OL = open-label; SAE = serious adverse event; SpO2 = saturation of peripheral oxygen.  


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1 
BACKGROUND AND RATIONALE 
1.1 Eisenmenger Syndrome 
Eisenmenger Syndrome (ES) belongs to group 1.4.4 of the Dana Point clinical 
classification of pulmonary hypertension [Simonneau 2009; see Appendix 1]. ES 
represents the most advanced form of congenital heart disease (CHD)-induced pulmonary 
arterial hypertension (PAH) [Beghetti 2009]. It is characterized by elevated pulmonary 
vascular resistance and right-to-left shunting through a systemic-to-pulmonary circulation 
connection. The disease is a progressive, multi-organ disorder, the symptoms and 
complications of which include dyspnea, cyanosis, syncope, fatigue, hemoptysis, 
erythrocytosis, cerebrovascular accidents, brain abscesses, arrhythmias and eventually 
right heart failure [Baumgartner 2010, Diller 2007]. Due to advances in surgery and 
pediatric cardiology, the prevalence of ES in the Western world has been reduced by an 
estimated 50% in the past 50 years. It is now estimated that more than 50% of patients 
with ES reach their fifth decade [Moons 2009]. Nevertheless, it remains a devastating 
condition with high mortality and considerable impact on patients’ lives [Diller 2005, 
Diller 2006].  
The most common cardiac defects leading to pulmonary vascular disease include 
ventricular septal defects (VSDs), atrial septal defects (ASDs), atrioventricular septal 
defects, and patent ductus arteriosus [Diller 2007]. Approximately 50% of all patients 
with unrepaired VSDs, approximately 10% of patients with large unrepaired ASDs, and 
almost all patients with unrepaired truncus arteriosus are at risk of developing ES 
[Vongpatanasin 1998]. 
The starting point in the development of ES is a left-to-right shunt, which generates an 
increased pulmonary blood flow and in turn induces severe pulmonary vascular disease 
and PAH. Eventually, this results in reversal of the shunt direction and central cyanosis 
[Baumgartner 2010]. The underlying mechanisms leading to PAH are not fully 
understood but involve blood flow-induced shear stress and circumferential stress, 
vasoconstriction, 
inflammation, 
thrombosis, 
cell 
proliferation 
and 
fibrosis 
[Humbert 2004a]. Molecular mediators of these phenomena include endothelin-1 (ET-1), 
prostacyclin, nitric oxide, angiopoietin-1 and thromboxane A2 [Beghetti 2009, 
Morrell 2009].  
Available treatment options for patients with ES have been limited to empirical palliative 
measures including oxygen, warfarin, diuretics, high-dose calcium channel blockers, and 
long-term 
continuous 
intravenous 
epoprostenol 
[Galiè 
2008], 
until 
the 
BREATHE-5 placebo-controlled trial and the following open-label (OL) study revealed 
beneficial effects of bosentan-mediated dual endothelin receptor blockade in this patient 
population [Galiè 2006, Gatzoulis 2008]. Currently, patients with ES are usually treated 
with the endothelin receptor antagonist (ERA) bosentan or other PAH-specific therapies 


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(e.g., phosphodiesterase-5 inhibitors, prostanoids), but only bosentan has demonstrated 
efficacy in a controlled, multi-center trial. Lung transplant with repair of the cardiac 
defect or heart-lung transplantation is the final treatment option for patients with markers 
of poor prognosis, but has offered limited survival benefit [Baumgartner 2010, 
Moons 2009, Trulock 2001]. 
1.2 Endothelin-1 and pulmonary hypertension 
ET-1, a 21 amino acid peptide, is one of the most potent vasoconstrictors and mitogens 
for smooth muscle, and contributes to increased vascular tone and proliferation in 
pulmonary vasculopathy [Galiè 2004]. 
There are 2 distinct receptors for ET-1: endothelin receptor A (ETA) and endothelin 
receptor B (ETB). The 2 receptors have unique binding locations and affinities for the 
endothelin peptide [Benigni 1995, Masaki 2004].The ETA receptors are expressed on 
pulmonary vascular smooth muscle cells, whereas ETB receptors are present both on 
pulmonary vascular endothelial smooth muscle cells and adventitial fibroblasts.  
When activated, the ETA receptor located in pulmonary vascular smooth muscle cells 
mediates a potent vasoconstrictive response, and ETB receptors on endothelial cells 
mediate vasodilatation via increased production of nitric oxide and prostacyclin 
[Hirata 1993, de Nucci 1988]. ET-1 is also known to be a potent mitogen, with the ability 
to induce cell proliferation in vascular smooth muscle cells. Both the ETA and ETB 
receptors mediate the mitogenic action of ET-1 [Clarke 1989, Chua 1992, Davie 2002, 
Sugawara 1996]. 
Laboratory and clinical investigations have clearly shown that ET-1 is over-expressed in 
several forms of pulmonary vascular disease. ET-1 is likely a major player in the 
vasodilator and vasoconstrictor imbalance, as well as in the abnormal pulmonary vascular 
remodeling present in the development and progression of pulmonary hypertension of 
various etiologies [Stewart 1991, Giaid 1993]. Plasma levels of ET-1 correlate with 
pulmonary hemodynamics [Giaid 1993], PAH severity and prognosis [Rubens 2001]. The 
introduction of the ERA bosentan has represented a major advance in the treatment of 
PAH [Rubin 2002, Channick 2004, Humbert 2004b]. 
As in other forms of PAH, ET-1 is overexpressed in patients with CHD and 
shunt-associated PAH [Beghetti 2009, Tutar 1999, Yoshibayashi 1991, Cacoub 1993, 
Giaid 1993]. In the first double-blind study performed in patients with ES 
(BREATHE-5), blockade of the endothelin signaling system by bosentan was shown to 
improve exercise capacity and hemodynamic parameters without compromising 
peripheral 
oxygen 
saturation 
[Galiè 
2006]. 
Further 
studies, 
including 
the 
BREATHE-5 OL extension and a long-term survival study (median follow up of 


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4.0 years), have supported the beneficial effects of ERA administration in this patient 
population [Gatzoulis 2008, Dimopoulos 2010]. 
1.3 Macitentan 
1.3.1 Macitentan – Preclinical information 
Macitentan / ACT-064992 is an orally active, non-peptide, potent dual ETA and ETB 
receptor antagonist selected for clinical development in PAH and other indications 
associated with an activated endothelin (ET) system. Macitentan shows dose-dependent 
efficacy similar to that observed with bosentan (Tracleer®, the first ERA registered for 
the treatment of patients with PAH) in preclinical models of hypertension and PAH, but 
macitentan is approximately 10 times more potent than bosentan. In preclinical safety 
studies, no effects on normal physiological functions or electrocardiogram (ECG) 
variables, including cardiac repolarization, were observed, with the exception of a 
decrease in arterial blood pressure (BP) observed in a cardiovascular study in dogs. 
Macitentan has no genotoxic potential. In the pivotal 26-week and 39-week toxicity 
studies, the exposures in animals found at the no-observed-adverse-effect levels 
(NOAEL) are above the anticipated clinical exposures and provide a margin of safety for 
studies in man. A study conducted in hairless rats showed that macitentan is not 
phototoxic in vivo. Macitentan does not bind relevantly to melanin. Reproductive toxicity 
studies showed that macitentan is teratogenic without affecting male or female fertility. 
Teratogenicity is considered to be an ERA class effect. 
Macitentan has been selected for further clinical development due to the following 
characteristics: 
• Its potency and selectivity for endothelin receptors 
• Its efficacy in preclinical models of hypertension and PAH 
• The absence of significant inhibitory effects on bile salt transport, suggesting an 
improved liver safety profile compared to bosentan 
• A pharmacokinetic (PK) profile consistent with once-daily dosing 
• Lipophilic physicochemical properties facilitating the crossing of cell membranes 
• A good safety and tolerability profile 
• Low potential for drug-drug interactions 
 
 
 


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1.3.2 Macitentan – Clinical information 
1.3.2.1 Phase 1 studies 
During the Phase 1 program, more than 200 healthy subjects and about 30 patients (with 
renal and hepatic impairment) were treated with macitentan. Macitentan was well 
tolerated in all studies. The most frequently reported adverse event (AE) was headache. 
No clear dose relationship could be discerned for any AE. However, in the 
single-ascending dose study, subjects receiving a dose of 600 mg reported markedly more 
AEs (headache, nausea, vomiting, rhinitis, and others) than subjects receiving placebo. A 
dose of 300 mg was identified as the maximum tolerated dose. 
Treatment with macitentan up to 600 mg as a single dose and 30 mg as multiple doses for 
10 days (highest doses tested) was not associated with clinically relevant changes in 
systolic and diastolic blood pressures (SBP and DBP, respectively), heart rate, or ECG 
intervals or morphology.  
Eight cases of asymptomatic increases in aminotransferases were observed in the 
Phase 1 program (6 received macitentan, 2 received placebo). Of these increases, only 
3 (all 3 subjects received macitentan) were > 3 × upper limit of normal (ULN), and none 
exceeded 4 × ULN. The increase in aminotransferases was not reported as an AE in any 
of the cases, and all cases resolved within 14 days of observation. 
In healthy male subjects, the plasma concentration-time profile of macitentan (capsule 
formulation) can be described as slow absorption with maximum plasma concentrations 
achieved approximately 8 h after dosing. The apparent elimination half-life was 
approximately 16 h. After multiple dosing, the PK of macitentan were dose-proportional 
over the dose range tested. Steady-state conditions were reached by Day 3, and 
macitentan accumulated approximately 1.5-fold in plasma. Two metabolites were 
identified in plasma: one pharmacologically active metabolite (ACT-132577) and one 
metabolite (ACT-373898) that showed no effect on ET receptors. ACT-132577 reached 
steady state by Day 7 and had an apparent elimination half-life of about 2 days. The 
accumulation factor was approximately 8.5. The PK of ACT-132577 were 
dose-proportional after multiple dose administrations. Based on the PK of macitentan and 
its metabolite ACT-132577, as well as the observation that macitentan had no effect on 
the urinary 6-hydroxycortisol / cortisol ratio, no signs of auto-induction were detected in 
this study. 
Macitentan increased plasma ET-1 concentrations for all single doses from 5 mg 
upwards. When given as multiple doses, a dose-dependent increase in plasma 
ET-1 concentrations was observed with doses from 1 to 10 mg, with no further increases 
noted for the 30 mg dose. Therefore it was concluded that 10 mg once daily would be the 
dose that would produce the maximum effect on the ET system for this indication. 


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Results from the food interaction study showed that macitentan can be taken irrespective 
of food intake. 
Macitentan did not influence the PK and pharmacodynamics (PD) of warfarin. Similarly, 
co-administration of warfarin with macitentan appeared not to have an impact on the 
exposure of macitentan.  
There were no clinically relevant effects of sildenafil 20 mg 3 times daily on the PK of 
macitentan and its metabolite ACT-132577. Also, no effect of macitentan was observed 
on the PK of sildenafil and its metabolite (N-desmethyl sildenafil). 
Exposure to macitentan increased by approximately a factor of 2 after concomitant 
treatment with ketoconazole, a potent cytochrome P-450 (CYP) 3A4 inhibitor. 
Ketoconazole treatment reduced ACT-132577 exposure by 26%. The magnitude of the 
interaction is not considered to be clinically relevant and, therefore, macitentan may be 
concomitantly administered with CYP3A4 inhibitors.  
Concomitant treatment with cyclosporine was well tolerated and did not have any 
clinically relevant effect on the exposure to macitentan or its metabolites ACT-132577 
and ACT-373898 at steady-state. Concomitant treatment with rifampicin was well 
tolerated, but significantly reduced the exposure to macitentan and its metabolite 
ACT-373898 at steady-state. Exposure to the metabolite ACT-132577 was not affected to 
a clinically relevant extent by rifampicin. Reduced efficacy of macitentan in the presence 
of rifampicin should be considered. 
The plasma concentrations of macitentan and ACT-132577 were generally lower in 
subjects with hepatic impairment than in healthy subjects. No correlation between the 
severity of hepatic impairment and the mean plasma concentrations of macitentan and 
ACT-132577 were apparent. Minor clinically non-relevant differences between PK 
parameters of macitentan, ACT-132577, and ACT-373898 were observed between 
healthy subjects and subjects with mild, moderate, and severe liver impairment.  
Minor differences in the PK parameters of macitentan and ACT-132577 were noted 
between healthy subjects and subjects with severe renal impairment. However, marked 
differences in the PK parameters of the pharmacologically inactive metabolite, 
ACT-373898, were noted between healthy subjects and subjects with severe renal 
impairment. The safety profile of macitentan was similar in healthy subjects and subjects 
with severe renal impairment.  
 
 


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1.3.2.2 Phase 2 study in patients with essential hypertension 
A Phase 2 dose-finding study was conducted over 8 weeks in 379 patients with mild to 
moderate essential hypertension. Four doses of macitentan (0.3 mg, 1 mg, 3 mg, and 
10 mg) and enalapril (20 mg) once daily were evaluated versus placebo. The primary 
efficacy endpoint was the change from baseline to Week 8 in mean sitting diastolic blood 
pressure (SiDBP) at trough (i.e., 24 h post dose). 
This study demonstrated that macitentan is efficacious in reducing BP in patients with 
mild to moderate essential hypertension. Treatment with the 10 mg dose showed a 
statistically significant reduction versus placebo in SiDBP and sitting SBP (SiSBP) at 
trough, and a dose-related effect was indicated. The 2 highest doses of macitentan tested 
in the study were estimated to have a greater treatment effect than enalapril 20 mg once a 
day (study was not powered to compare to enalapril). Most of the BP reduction with 
macitentan was reached within 4 weeks of treatment. The PK/PD analysis supported the 
clinical findings, and indicated that the 10 mg dose is close to the plateau of the 
pharmacological effect.  
Macitentan was well tolerated across all 4 dose levels. The overall frequency of AEs was 
similar to that observed in the placebo group. The numbers of patients with at least one 
serious adverse event (SAE) were equally distributed across groups. There were no 
deaths.  
The study was terminated prematurely following the sponsor’s decision to break the blind 
for a safety evaluation of 5 cases of increased liver enzymes  3  ULN. These 5 cases 
occurred in the macitentan groups, without obvious dose relationship (one, 2, one, and 
one in the 0.3 mg, 1 mg, 3 mg, and 10 mg dose groups, respectively). In 3 cases, there 
were other plausible reasons for increased liver enzymes (pancreatic cancer, surgery with 
general anesthesia, and concomitant antibiotic therapy, respectively). Most of the 
episodes of liver enzyme elevations resolved without sequelae within 2–3 weeks of 
observation. An episode of liver enzyme increase in a patient with pancreatic cancer 
resolved 48 days after surgery for pancreatic cancer.  
 
 
1.3.2.3 Phase 2 study in patients with idiopathic pulmonary fibrosis 
A 
double-blind, 
randomized, 
placebo-controlled, 
multi-center, 
parallel 
group 
Phase 2 study to evaluate the efficacy and safety of a 10 mg dose of macitentan in 
178 patients with idiopathic pulmonary fibrosis (IPF) has recently been completed. The 
primary endpoint (change in forced vital capacity) was not met, but it was shown that 
macitentan treatment with 10 mg dose was well tolerated. Overall, the safety profile was 
similar in the macitentan 10 mg and placebo groups. The overall incidence of 


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treatment-emergent AEs was similar in both groups. Dyspnea, peripheral edema, anemia, 
pneumonia and nausea occurred at a higher incidence in patients on macitentan than on 
placebo. The incidences of cough and pulmonary hypertension were lower on macitentan 
than on placebo. 
An equal proportion of patients in the 2 treatment groups experienced SAEs and died 
during the study. The most frequently reported SAEs and causes of death were associated 
with lung disorders (worsening of IPF, hypoxia, respiratory failure, acute respiratory 
failure and pulmonary embolism), all known consequences of the underlying disease. 
Mean changes in laboratory variables were generally small and unremarkable in both 
groups. Seven patients treated with macitentan had a decrease in hemoglobin levels to 
≤ 10 g/dL at some point during the study. Of these patients, 5 experienced transient 
decreases, one showed improvement by the time of treatment discontinuation, and one 
died due to pulmonary embolism prior to resolution of the hemoglobin decrease. 
The overall incidence of elevations in liver aminotransferases was similar to placebo 
(3.4% and 5.1% incidence of alanine aminotransferase [ALT] or aspartate 
aminotransferase [AST] > 3  ULN in the macitentan and placebo groups, respectively). 
 
 
1.3.2.4 Phase 3 study in patients with pulmonary arterial hypertension 
A randomized, placebo-controlled, event-driven Phase 3 study (AC-055-302 / 
SERAPHIN) has recently been completed to assess the effects of 3 mg and 10 mg of 
macitentan on morbidity and mortality in patients with symptomatic PAH. Global 
enrollment was completed in December 2009 with a total of 742 patients randomized. 
Mean exposure to study treatment was 85.3 weeks for placebo patients (n = 249), 
99.5 weeks for patients on 3 mg (n = 250) and 103.9 weeks for patients on 10 mg 
(n = 242). Macitentan, at both the 3 mg and 10 mg dose, decreased the risk of a 
morbidity/mortality event over the treatment period versus placebo. This risk was 
reduced by 45% in the 10 mg dose group (p < 0.0001). At 3 mg, the observed risk 
reduction was 30% (p = 0.0108).  
Treatment with macitentan was well tolerated. The number of AEs reported and patients 
discontinuing treatment due to AEs was similar across all groups. The overall incidence 
of elevations in liver aminotransferases was similar to placebo (4.5%, 3.6% and 3.4% 
incidence of ALT or AST > 3  ULN in the placebo, macitentan 3 mg and macitentan 
10 mg groups, respectively). In addition, no differences were observed between 
macitentan and placebo on fluid retention (edema). A decrease in hemoglobin – reported 
as an AE – was observed more frequently on macitentan than placebo, with no difference 
in treatment discontinuation between groups. 


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1.3.3 Macitentan – Summary of potential risks and risk management 
Preclinical 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 contraception for female subjects of 
child-bearing potential. 
In the SERAPHIN study, macitentan 10 mg once daily was well-tolerated and associated 
with a lower incidence of SAEs and AEs leading to study drug discontinuation than 
placebo. Of note, macitentan was not associated with a definite signal of adverse hepatic 
effects, and edema / fluid retention, an adverse effect reported with other endothelin 
antagonists, was reported with similar incidence across macitentan and placebo treatment 
groups. 
Elevations of liver aminotransferases (AST, ALT) have been associated with PAH and 
with other ERAs. The liver safety data observed in clinical trials with macitentan are 
described in previous sections of this protocol
 
. Subjects with serum AST and/or ALT > 3  ULN and those with 
severe hepatic impairment will be excluded from the proposed clinical trial, and liver 
tests (LTs) will be assessed every month during the treatment period and 30 days after 
study drug discontinuation. 
Treatment with ERAs has been associated with increased incidences of anemia / 
hemoglobin decrease. This is ascribed to plasma volume expansion and is reversible upon 
treatment discontinuation. Overall, the findings with macitentan in this respect are very 
similar to those for the approved ERAs. Importantly, the incidence of SAEs of anemia in 
macitentan-treated patients in SERAPHIN was low, and anemia did not lead to an excess 
of study treatment discontinuation with macitentan. Patients with hemoglobin or 
hematocrit < 75% of the lower limit of normal will be excluded from the proposed 
clinical trial. The protocol also includes clear instructions regarding work-up and criteria 
for treatment discontinuation in the case of clinically relevant anemia. 
Due to the vasodilatory effects of macitentan, effects on BP might occur. Hypotension is 
therefore considered to be a potential risk associated to treatment with macitentan, and 
patients with SBP < 85 mmHg will be excluded from the proposed study. 
Reductions from baseline in leukocyte and platelet counts may be observed with 
macitentan. In the 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 


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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 SERAPHIN study, menstrual disorder AEs (mainly menorrhagia, metrorrhagia, 
dysfunctional bleed) were reported at a low incidence overall, but more frequently on 
macitentan than placebo. 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 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 and further information will be collected during the study [see 
Section 4.2.4].  
In clinical trials, a higher reporting rate of upper respiratory tract infections was seen with 
macitentan versus placebo. It is likely that many such events may represent symptoms of 
congestion due to local vasodilatation, rather than actual infection. For the clinically more 
relevant lower respiratory tract infections, especially pneumonia, there was no relevant 
difference between macitentan and placebo.  
To further ensure trial participant safety, an independent Data Monitoring Committee 
(DMC) will review safety and tolerability data from the AC-055-308 / MAESTRO-OL 
study on a regular basis until the end of the double-blind AC-055-305 / MAESTRO 
study. 
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 patients with ES. 
1.4 Study rationale 
1.4.1 Medical and regulatory background 
The ERA bosentan was the first drug showing efficacy in patients with ES in a controlled 
clinical trial, demonstrating improvement in cardiac hemodynamics and exercise 
capacity. Endothelin receptor antagonism has thus emerged as an important therapeutic 
strategy in pulmonary vasculopathy associated with ES. In the recently completed 
AC-055-302 / SERAPHIN study, macitentan demonstrated efficacy in PAH patients by 
improving clinical outcomes, functional status and exercise capacity.  
The present OL study aims to assess the long-term safety and tolerability of macitentan in 
subjects with ES beyond the treatment of the double-blind AC-055-305 study, and to 
assess the long-term effect of macitentan on exercise capacity in this patient population. 


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1.4.2 Subject population 
The subject population will consist of subjects with ES who have completed the 
double-blind AC-055-305 / MAESTRO study as scheduled, i.e., subjects who remained 
in the double-blind study up to Week 16 (whether or not they were still taking study drug 
at the end of this period), unless the double-blind treatment was discontinued for a safety 
issue. 
1.4.3 Study design 
This trial is an OL, non-comparative, multi-center, Phase 3 extension study of protocol 
AC-055-305, which aims to assess the long-term safety, tolerability and efficacy of 
macitentan in subjects with ES. 
The OL study design has been discussed and approved by the Steering Committee 
members. 
1.4.4 Dose selection  
The proposed dose of macitentan (10-mg tablet once daily) for this OL study is the same 
dose as that used in the double-blind AC-055-305 / MAESTRO study. 
1.4.5 Treatment duration 
Study treatment duration for each subject 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) the sponsor decides to stop this OL study (e.g., 
request from the DMC [see Section 3.1] for safety reasons, or if results of AC-055-305 / 
MAESTRO 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. 
1.4.6 Primary endpoint 
No primary endpoint is considered for this OL extension study. 
1.4.7 Statistical hypotheses and sample size 
No statistical hypothesis is considered for this OL extension study. 
2 
STUDY OBJECTIVES 
The present OL study aims to assess the long-term safety and tolerability of macitentan in 
subjects with ES beyond the treatment of the double-blind AC-055-305 study, and to 
assess the long-term effect of macitentan on exercise capacity in this patient population. 


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3 
INVESTIGATIONAL PLAN 
3.1 Overall study design and plan 
This trial is a multi-center, OL, non-comparative, Phase 3 extension study to assess the 
long-term safety, tolerability and efficacy of macitentan in subjects with ES. 
The study will be conducted in approximately 90 centers in approximately 30 countries. 
Up to 220 subjects (males or females) from the double-blind AC-055-305 study will be 
enrolled in this OL study [see Section 1.4.2]. Subjects will be rolled over from the 
AC-055-305 study to this OL study without knowledge of their previous study drug 
(macitentan or placebo). 
The sample size may be increased up to 330 subjects based on the interim blind sample 
size review during the double-blind AC-055-305 / MAESTRO study 
. 
Enrollment in the AC-055-308 OL study (OL Visit 1) will be combined with the 
Week 16 visit (i.e., Visit 6 [Week 16 / EOT], or Visit 6a [Week 16 / premature EOT], if 
applicable) of the double-blind AC-055-305 / MAESTRO study [see Figure 1]. 
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. In 
addition, subjects will undergo monthly lab and safety monitoring site visits. 
A post-treatment safety follow-up period (30 days) will follow the permanent study drug 
discontinuation [see Figure 1]. At the end of this safety follow-up period, the safety 
follow-up / End-of-Study (EOS) visit will be performed. 
The study drug, 10-mg tablet of macitentan, will be taken orally, once daily in the 
morning, irrespective of food intake. Subjects will receive 6 medication bottles at 
enrollment (Visit 1), and thereafter every 6 months up to the EOT visit. 
Note: Alternatively, if the subject comes to the investigational site every month for the 
monthly lab and safety monitoring, then it is possible to dispense one medication bottle 
on a monthly basis. 
A Steering Committee was involved in the study design and will provide guidance on the 
conduct of the study. 
In order to ensure subjects’ safety, an independent DMC will review the data from the 
AC-055-308 / MAESTRO-OL study on a regular basis until the end of the double-blind 
AC-055-305 / MAESTRO study (i.e., OL data will be reviewed only in combination with 
the data of the double-blind study).  


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Figure 1 
Study design 
 
 
 
 
 
 
 
 
 
 
3.2 Study population 
3.2.1 Subject population 
The subject population will consist of subjects with ES who have completed the 
double-blind AC-055-305 / MAESTRO study as scheduled, i.e., who have remained in 
the double-blind study up to Week 16 (whether or not they were still taking study drug at 
the end of this period), unless the double-blind treatment was discontinued for a safety 
issue. 
3.2.2 Inclusion criteria 
Eligible subjects must meet all of the following inclusion criteria: 
1. Written informed consent/assent to participate in the study must be obtained from the 
subject or a parent / legal representative, and from the caregiver, where applicable, 
according to local regulations, prior to initiation of any study-mandated procedure. 
2. Subjects with ES (including those with DS) who completed the double-blind 
AC-055-305 / MAESTRO study as scheduled, i.e., who remained in the double-blind 
study up to Week 16 (whether or not they were still taking study drug at the end of this 
period). 
3. Females of childbearing potential must have a negative serum pregnancy test prior to 
first intake of OL study drug, and must use 2 reliable methods of contraception at the 
same time from enrollment and up to at least 30 days after study treatment 
discontinuation. 
Enrollment 
OL (Visit 1) 
16 weeks                
in the AC-055-305 study 
Macitentan 10 mg 
Open-label treatment 
Safety  
Follow-up 
EOT        
Visit 
Safety 
follow-up / 
EOS visit 
Double-blind               
Week 16 
V6 or  
V6a (if applicable) 
X 
Time 
(months) 
1 
6 
12 
18 


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• A female is considered to have childbearing potential unless she meets at least one 
of the following criteria: 
– Previous bilateral salpingo and/or oophorectomy, or hysterectomy. 
– 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. 
• 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). If a hormonal contraceptive is chosen from this 
group, it must be taken for at least one month prior to enrollment. Alternatively, 
if the Essure procedure is chosen as a contraceptive method, a 
hysterosalpingogram 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 them in 
combination with a spermicide. 
• True abstinence from intercourse with a male partner is considered as an acceptable 
method of contraception for this study (not requiring a second reliable method of 
contraception) only when this is in line with the preferred and established lifestyle 
of the subject (e.g., homosexual females, females in religious order [e.g., nuns]), or 
when hormonal contraception is contraindicated. 
• 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.  
• The methods of contraception will be collected in the electronic Case Report Form 
(eCRF). 
3.2.3 Exclusion criteria 
Eligible subjects must meet none of the following exclusion criteria: 
1. Subjects who prematurely discontinue double-blind study drug during the 
AC-055-305 (MAESTRO) study due to: 
• an AE assessed as related to the use of study drug, or 
• LTs (related or unrelated to study drug). 


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2. Subjects with Down Syndrome (DS) who are not fully independent and need help to 
perform daily activities, and who do not have a caregiver or family member who 
agrees to accompany them to all visits, provide information about the participant as 
required by the protocol, and ensure compliance with study medication schedule. 
3. SBP < 85 mmHg. 
4. Hemoglobin or hematocrit < 75% of the lower limit of normal. 
5. Serum AST and/or ALT > 3  ULN. 
6. Severe hepatic impairment according to National Cancer Institute organ dysfunction 
working group criteria, defined as total bilirubin > 3  ULN accompanied by any AST 
elevation above the ULN. 
7. Any known factor or disease that 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 
excipients. 
9. Females who are pregnant or plan to become pregnant during the study or are 
lactating. 
3.2.4 Concomitant medications 
Prohibited concomitant medications: 
• Any ERA or any investigational drug other than macitentan. 
• CYP3A 
inducers 
(e.g., 
carbamazepine, 
phenytoin, 
phenobarbital, 
rifampin/rifampicin, rifapentin, rifabutin, St. John’s wort). 
Note: Study drug must be permanently discontinued if an ERA and/or another 
investigational drug is started during the treatment period. 
3.3 Study drug 
All subjects will receive macitentan 10-mg film-coated tablets once daily. 
3.3.1 Administration of the study drug 
If the subject is eligible, the first administration of OL study drug will take place during 
the enrollment visit after successful completion of all assessments. 
Thereafter, one tablet should be administered orally, once daily, every morning, 
irrespective of food intake. On the day of study visits, the tablet should be taken from the 
bottle that is being returned to the site. 


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3.3.2 Study drug storage and dispensing 
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 the 
subjects enrolled in the study and in accordance with the protocol. 
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 Delegation of Authority (DoA). The study drug 
must be stored below 25°C (77°F) and must be protected from moisture. Unopened, 
sealed study medication bottles may be stored in refrigerators (between the temperature 
range of +2°C [36°F] to 25°C [77°F]). If the temperature at a patient’s home exceeds 
25°C (77ºF), the patient should 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 
bottles must not be stored in the refrigerator. 
A temperature log must be maintained and temperature control should occur at least on a 
weekly basis.  
Actelion will provide a temperature log. However, the use of the log is not mandatory if 
the site has an acceptable means of recording the temperature. Any temperature recording 
system used at site can be used 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). 
The monitor should 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 study drug is to be kept segregated at the investigational site 
and returned to Actelion following internal drug return processes. New study drug 
supplies will be provided to the site. 
Site temperature deviations correspondence must be kept in the Investigator Site File 
(ISF). 


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The study centers will be supplied with study drug according to the centers’ needs, 
depending on the number of subjects enrolled.  
Medication bottles will be allocated through the Interactive Voice or Web Response 
System (IXRS). Subjects will receive 6 medication bottles at the enrollment visit (Visit 1) 
and at each 6-monthly visit thereafter (Visits 3, 4, 5…) up to the EOT visit. Each 
childproof bottle contains study drug for one month (each bottle contains 36 tablets). 
Alternatively, if the subject comes to the investigational site every month for the monthly 
lab and safety monitoring, then it is possible to dispense one medication bottle on a 
monthly basis. 
Once a subject has been enrolled and Investigational Medicinal Product (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 dispensed, the subject should be educated on the proper storage 
conditions at their home. 
Study drug dispensing must be performed only upon written confirmation by an 
authorized study physician listed on the DoA form.  
3.3.3 Study drug up- and down-titration 
Not applicable. 
3.4 Study drug discontinuation and study withdrawal 
3.4.1 Study drug interruption or discontinuation 
The investigator must temporarily interrupt or permanently discontinue the study drug if 
continued administration of the study drug is believed to be contrary to the best interests 
of the subject.  
The interruption or premature discontinuation of study drug might be triggered by an AE, 
a diagnostic or therapeutic procedure, an abnormal assessment (e.g., ECG or laboratory 
abnormalities), withdrawal of the subject’s consent, or might be due to administrative 
reasons.  
Interruptions should be no longer than 2 consecutive weeks. Longer interruptions should 
lead to permanent discontinuation of study drug. All interruptions of study drug 
(including reason for interruption) should be recorded on the study drug log in the eCRF. 


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In case a subject discontinues study drug permanently, the EOT has to be registered in the 
IXRS in a timely manner to avoid any automatic study drug re-supply. Date entered into 
the system should be the date of the last study drug intake.  
The reason for premature discontinuation from study drug (e.g., death, lost to follow-up, 
physician’s decision / adverse event, subject’s (or legal representative’s) withdrawal of 
consent or withdrawal from treatment only, sponsor’s decision to discontinue study) must 
be documented in the eCRF. 
3.4.2 Subject’s follow-up after study drug discontinuation 
All enrolled subjects who received study drug must be followed up for at least 30 days 
after permanent discontinuation of study drug (safety follow-up period). 
3.4.3 Withdrawal of consent and lost to follow-up 
A subject will be considered as withdrawn from the study if, and only if, he/she has 
withdrawn his/her consent to participate in the study, or is lost to follow-up after 
unsuccessful and exhaustive attempts by the investigator to contact him/her. 
If a subject is lost to follow-up, all reasonable means of contact must be used and all the 
attempts (at least 3 by telephone) must be recorded in the subject’s chart. This 
information will be collected in the eCRF. In addition, a certified letter must be sent to 
the subject and a copy filed in the subject’s medical record.  
The potential follow-up of subjects after their withdrawal of consent will depend upon 
local regulations or specific agreement with the subjects.  
The reason(s) for discontinuing the study and the decision owner (if applicable), must be 
documented in the eCRF. 
3.4.4 Replacement policy 
3.4.4.1 Subjects 
Subjects prematurely discontinued from study drug for any reason will not be replaced. 
3.4.4.2 Centers 
Not applicable. 
3.5 Treatment exposure, compliance and drug accountability 
Adequate records of study drug received, dispensed, used, lost, returned and intervals 
between visits are to be kept during the study. Study drug accountability is to be 
performed on an ongoing basis by the study staff and an IMP Dispensing and 
Accountability Log is to be completed on an ongoing basis for each subject who has 
received study drug. The IMP Dispensing and Accountability Log will be checked by the 


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monitor during site visits and at completion of the study. Information from this log will 
be entered by the site into the Drug Accountability eCRF page. Treatment exposure will 
be calculated (by the sponsor) from this data. 
Subjects should be instructed to return used and unused study drug (including empty 
bottles) at each visit. Study drug accountability must be performed each time the subject 
returns study drug to the study site by counting the number of remaining tablets in the 
returned bottles in order to evaluate the compliance. Prior to each new dispensation, the 
visit compliance must be evaluated by the site staff (as per formula below), who should 
then discuss any compliance issue with the subject and re-educate them on correct 
administration of study drug. 
Compliance = (N° of Tablets taken / Total N° of Tablets that should have been taken 
during the period)  100 
If the compliance is < 80% or > 120%, a comment must be documented on the IMP 
Dispensing and Accountability log. 
At the conclusion of the study, all remaining drug supplies, used and unused, shall be 
collected and returned to the sponsor for destruction by the sponsor’s representative. 
Destruction must be documented. 
3.6 Treatment assignment 
All subjects will receive macitentan 10 mg tablets. All drug bottle numbers must be 
assigned through the IXRS. 
3.6.1 Blinding 
Not applicable. 
3.6.2 Emergency procedure for unblinding 
Not applicable. 
3.7 Study drug packaging and labeling 
The labeling and packaging of macitentan will be conducted according to Good 
Manufacturing Practice, Good Clinical Practice (GCP), and any local or national 
regulatory requirements.  
3.7.1 Study drug packaging  
Actelion will provide macitentan as tablets in childproof bottles containing 36 tablets 
each.  


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3.7.2 Study drug labeling 
Each medication bottle will have 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 IMP Label Dispensing Log. 
3.8 Study endpoints 
3.8.1 Efficacy exploratory endpoints 
Change from baseline of the OL* to Month 6 and Month 12 in: 
• Exercise capacity, as measured by the 6-minute walk distance (6MWD), 
• World Health Organization (WHO) functional class,  
• Dyspnea (assessed by the Borg dyspnea index),  
• Oxygen saturation, assessed by pulse oximetry: saturation of peripheral oxygen (SpO2) 
at rest before the 6-minute walk test (6MWT). 
* Baseline is defined as the last value obtained prior to or on the day of first administration of macitentan 
during this AC-055-308 OL study. 
For subjects who received macitentan during the double-blind AC-055-305 / MAESTRO 
study: 
Change from baseline** of AC-055-305 / MAESTRO to Month 6 and Month 12 in: 
• Exercise capacity, as measured by the 6MWD, 
• WHO functional class,  
• Dyspnea (assessed by the Borg dyspnea index), 
• Oxygen saturation, assessed by pulse oximetry: SpO2 at rest before the 6MWT. 
** Baseline is defined as the last value obtained prior to or on to the day of first administration of 
macitentan in the double-blind AC-055-305 / MAESTRO study. 
3.8.2 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 (MLAs) up to EOT. 
• Proportion of subjects with treatment-emergent ALT and/or AST abnormality (> 3 and 
≤ 5  ULN; > 5 and ≤ 8  ULN; > 8  ULN) associated or not with total bilirubin 
> 2  ULN, up to EOT. 
3.9 Study assessments 
All on-site study assessments are performed by a qualified study staff member: medical, 
nursing, or specialist technical staff.  


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Site team members conducting the 6MWT must be instructed on the Actelion 6MWT 
guideline [Appendix 2] and a training log must be collected upon completion. 
Site team members must be specially trained on the management of subjects with DS and 
on the study-specific considerations in this patient population, and a training log must be 
collected upon completion of the training. The training material will be provided 
separately by the sponsor. 
The investigator or designated physician will review laboratory reports, AEs or other 
safety information as soon as possible (but no later than 3 calendar days for laboratory 
reports, and 5 days for AEs / safety information) after receipt/acknowledgment, and have 
the corresponding documents signed and dated (if applicable). 
The following order of assessments is recommended: 
• Vital signs  
• WHO functional class  
• SpO2 (at rest prior to 6MWT) 
• 6MWT  
• Borg dyspnea index 
3.9.1 Safety and tolerability assessments 
The definitions, reporting and follow-up of AEs, SAEs and potential pregnancies are 
described in Section 4. 
3.9.1.1 Vital signs 
Vital signs (SBP and DBP, pulse rate) will be measured at enrollment, Month 1, each 
6-monthly visit, and EOT. The data will be recorded in the eCRF.  
3.9.1.2 Body Weight  
Body weight will be measured at enrollment, Month 1, each 6-monthly visit, and EOT. 
The data will be recorded in the eCRF. 
3.9.1.3 Physical examination 
Physical examination will be performed at enrollment, Month 1, each 6-monthly visit, 
and EOT. The data will be recorded in the eCRF. Clinically relevant findings found after 
study drug initiation and meeting the definition of an AE must be recorded on an AE 
page of the eCRF. 
The following could be examined during such an assessment:  
general appearance; head, ears, eyes, nose, throat; neck; heart; lungs; abdomen; lymph 
nodes; genitourinary system; extremities; neurological system; skin; musculoskeletal 
system. 


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3.9.1.4 Laboratory assessments 
3.9.1.4.1 Type of laboratory 
A central laboratory (see Investigator Laboratory Manual for contact details) will be 
used for the analysis of blood samples described in the protocol.  
Whenever possible, all blood samples will be collected at site and sent for analysis to the 
central laboratory.  
However, under specific circumstances (e.g., the subject lives far away from the site and 
cannot return every month), laboratory samples could be collected at a local laboratory 
close to where the subject lives, and analyzed by the central laboratory. In that event, the 
site should provide the local laboratory with the central laboratory kits that will be used 
for blood collection. The blood samples collected locally will be shipped by the local 
laboratory to the central laboratory for analysis. Such local laboratory shall be identified 
as soon as possible, and whenever possible, no later than upon enrollment of the subject 
in MAESTRO-OL.  
Details about the collection and shipment of samples, the reporting of results and 
abnormalities can be found in the laboratory manual provided to the investigator. 
In the exceptional event that a local laboratory is utilized for the collection and analysis 
of blood samples (e.g., the subject is hospitalized in a hospital other than the site), 
laboratory certification / reference ranges / laboratory director’s CV will be collected 
retrospectively by Actelion. Local laboratory results* and reference ranges will be 
collected in the eCRF.  
*As a minimum, the following local laboratory results (i.e., results from samples 
collected and analyzed locally) will be collected in the eCRF: 
• Any local laboratory result related to the diagnostic work-up (i.e., detection, 
confirmation and/or monitoring) of ALT and/or AST elevations of > 3 × ULN. In 
such cases, the minimum data to be analyzed and entered in the eCRF are ALT, AST, 
alkaline phosphatase, and total and direct bilirubin.  
• Any local laboratory result related to the diagnostic work-up (i.e., detection, 
confirmation and/or monitoring) of hemoglobin decrease from baseline (i.e., last 
value obtained prior to first intake of OL study treatment) of > 2.0 g/dL, a value of 
hemoglobin < 8.0 g/dL, or a hemoglobin decrease requiring transfusion.  
• Any local laboratory test documenting the result of an assessment requested per 
protocol and for which no central laboratory result is available (e.g., in the case that 
no sample was sent to the central laboratory at a planned visit because the subject was 
hospitalized at another hospital, or in the case that the sample sent to the central 
laboratory is uninterpretable [because, for example, the sample was hemolyzed]).  


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• Any local laboratory result related to the documentation or follow-up of an AE or an 
SAE, including clinically significant abnormal laboratory results and their follow-up.  
In the event that several local laboratory samples have been collected 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). 
Central laboratory reports will be transmitted to the investigator by fax.  
In the case of specific (pre-defined) laboratory abnormalities, the central laboratory will 
alert the sponsor and the site concerned. Alert flags that will trigger such notifications are 
displayed in Appendix 6. 
All laboratory reports (from central and local laboratories) 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 3 calendar days) after receipt, and filed with the source 
documentation.  
Any clinically significant laboratory abnormalities (including ALT/AST abnormalities 
> 3  ULN) occurring after study drug initiation must be reported by the investigator as 
an AE and/or SAE, as appropriate [see Section 4], and must be followed by additional 
laboratory evaluations until they return to normal range, stabilize, or until the change is 
no longer clinically relevant except when otherwise specified (e.g., in the case of 
ALT/AST abnormalities, see Section 3.9.1.4.3). Further laboratory analysis should be 
performed as indicated and according to the judgment of the investigator. 
Any pregnancy occurring during the treatment period and up to 30 days after study drug 
discontinuation must be reported immediately to the Actelion Global Drug Safety 
department using the Actelion Pregnancy Form [see Section 4.4]. 
3.9.1.4.2 Laboratory parameters 
Complete laboratory parameters (i.e., standard hematology tests [including hemoglobin], 
blood chemistry tests [including LTs], and serum pregnancy tests [if applicable]) will be 
measured at enrollment (Visit 1), each 6-monthly visit, and EOT. 
In addition,  
• LTs will be monitored monthly up to 30 days after study drug discontinuation;  
• Serum pregnancy tests (if applicable) will be performed monthly up to 30 days after 
study drug discontinuation;  
• Hemoglobin will be monitored every month up to Month 6, every 3 months thereafter 
up to the EOT visit, and 30 days after study drug discontinuation (EOS visit). 
 


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Hematology 
• Hemoglobin 
• Hematocrit 
• Erythrocyte count 
• Leukocyte count with differential 
• Platelet count 
 
Blood chemistry 
• LTs: liver aminotransferases (AST/ALT), alkaline phosphatase, total and direct 
bilirubin 
• Creatinine  
• Urea or blood urea nitrogen (BUN) 
• Uric acid 
• Glucose 
• Sodium 
• Potassium 
• Magnesium 
• Calcium 
• Albumin 
Serum pregnancy test 
For females of childbearing potential, a serum pregnancy test must be performed at 
enrollment (Visit 1), and monthly thereafter up to at least 30 days after study drug 
discontinuation.  
Each month, it must be verified whether the methods of contraception previously used are 
still valid, in accordance with the protocol [see Section 3.2.2], and correctly used by the 
subject. Documentation on the discussion with the subject must be available in the 
subject’s source documents. 
For pre-pubescent females, childbearing potential must be assessed each month, and the 
subject must be requested to use 2 reliable methods of contraception as soon as 
childbearing potential has been established. 
In the event of pregnancy, a Pregnancy Form must be completed [see Section 4.4.2]. 
3.9.1.4.3 Liver function monitoring and study treatment adjustments 
Liver function monitoring: LTs (liver aminotransferases [AST/ALT], alkaline 
phosphatase, and total and direct bilirubin) must be measured at enrollment (Visit 1), at 


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Month 1, each monthly lab monitoring, each 6-monthly visit (Visits 3, 4, 5…), EOT visit, 
and at the 30-day safety follow-up / EOS visit. 
Study treatment adjustment in case of ALT and/or AST elevations 
ALT and/or AST 
Treatment and monitoring recommendations 
 3 and  8 × ULN 
Interrupt 
study 
medication. 
Perform 
a 
re-test 
of 
aminotransferases, total and direct bilirubin and alkaline 
phosphatase within one week of the previous blood collection. If 
AST and/or ALT elevation is confirmed, continue to monitor 
aminotransferases, total and direct bilirubin and alkaline 
phosphatase levels weekly until values return to pre-treatment* 
levels or to normal ranges. If the aminotransferase values return 
to pre-treatment levels or to normal ranges, reintroduction of 
study treatment can be considered. Interruptions should be for 
less than 2 consecutive weeks; longer interruptions should 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). 
* Pre-treatment level: level prior to first intake of open-label study treatment. 
ALT =alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal. 
In case of 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), in case of aminotransferases > 3 × ULN 
and associated increase in total bilirubin > 2  ULN, or in case of aminotransferases 
> 8  ULN, study drug must be stopped and its reintroduction is not to be considered. 
Aminotransferase, total and direct bilirubin, and alkaline phosphatase levels must be 
monitored weekly after study drug discontinuation until values return to pre-treatment 
levels or to normal ranges. 


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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. 
Whenever possible, all laboratory testing performed to confirm and/or monitor ALT 
and/or AST elevations of > 3 × ULN, will be collected at site and sent to the central 
laboratory. For other cases see Section 3.9.1.4.1.  
Note: If an abnormal ALT/AST value is observed, the sponsor may request additional 
assessments to be performed on a case by case basis (e.g., acetaminophen concentration 
to rule out an acetaminophen-related liver toxicity). This additional analysis would be 
performed using samples that have already been collected.  
All LT abnormalities leading to study drug interruption or discontinuation must be 
recorded as AEs [see Section 4.2]. 
An independent Liver Safety Data Review Board (an external expert committee of 
hepatologists) provides ongoing assessment and advice regarding any hepatic events that 
may require further evaluation.  
In order to ensure the proper and comprehensive evaluation of cases of ALT and/or AST 
increase > 3  ULN, additional subject data will be collected in the LT questionnaire of 
the eCRF. 
3.9.1.4.4 Hemoglobin concentration monitoring 
Hemoglobin will be measured at Visit 1 (enrollment) as part of the blood hematology 
tests, Visit 2 (Month 1), then monthly thereafter during the first 6 months, followed by 
every 3 months until the EOT visit, and 30 days after study drug discontinuation (EOS 
visit). 
In case of a decrease from baseline* of > 2.0 g/dL, a retest should be performed with 
additional laboratory evaluations that may include, but are not limited to, any of the 
following: red blood cell cellular indices (mean corpuscular volume [MCV], mean 
corpuscular hemoglobin [MCH], mean corpuscular hemoglobin concentration [MCHC]), 
peripheral blood smear, reticulocyte count, iron status (iron level, serum ferritin, total 
iron binding capacity [TIBC], transferrin saturation), lactate dehydrogenase [LDH], 
indirect bilirubin. 
This work-up should be performed within 10 days of the previous blood collection 
(additional re-tests may be performed at the discretion of the investigator), but should not 
result in study drug interruption or discontinuation, unless clinically mandated based on 
the investigator’s judgment or in the following situation: 


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A decrease in hemoglobin to < 8.0 g/dL (< 4.9 mmol/L), a decrease in hemoglobin from 
baseline* of > 5.0 g/dL, or the need for transfusion should result in temporary 
interruption of study medication. Reintroduction of study medication can be considered if 
hemoglobin recovery, defined as a return of hemoglobin to within 1.0 g/dL of the 
baseline* value, is achieved. Interruption of study medication should last no longer than 
2 consecutive weeks; longer interruption should lead to permanent discontinuation of 
study drug. 
All of the above re-test/work-up/follow-up laboratory samples for hemoglobin 
monitoring should be collected at the site and sent to the central laboratory.  
* Baseline hemoglobin: last value obtained prior to first intake of OL study treatment. 
3.9.1.5 General management of Eisenmenger Syndrome  
In addition to the study-specific safety assessments listed above, it is recommended that 
standard of care for the management of ES and clinical practice guidelines 
[ACC/AHA 2008] are considered in the light of each subject’s individual circumstances. 
3.9.2 Efficacy exploratory assessments 
3.9.2.1 WHO functional class 
The WHO functional class [see Appendix 4] is assessed at enrollment (Visit 1), 
Month 6 (Visit 3), Month 12 (Visit 4), and EOT visit.  
3.9.2.2 Six-minute walk test and Borg dyspnea index  
The 6MWT is performed at enrollment (Visit 1), Month 6 (Visit 3), Month 12 (Visit 4) 
and EOT visit.  
It is a non-encouraged test, which measures the distance walked in 6 minutes. However, 
for subjects with DS, standardized encouragement and positive reinforcement should be 
given according to the “Actelion guidelines for 6MWT”, provided in Appendix 2. 
Details on the correct execution of these tests are provided in Appendix 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 the 
sponsor, and formal approval should be obtained from the sponsor before performing any 
study-specific 6MWT in the corresponding corridor. 
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-055-305 / MAESTRO study should be used. A trained tester 
must assess the reliability of each visit. 


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The 6MWT may be invalidated due to environmental factors, or other factors unrelated to 
the cardiopulmonary status resulting from the physical exertion required by the test. If the 
test is determined to be invalid by the trained tester, it may be repeated only once, either 
on the same day, at least 2 h later, or on another day provided it is still within the time 
window for the particular study visit. 
If the 6MWT is repeated, then all the 6MWT-related assessments (i.e., Borg dyspnea 
index, and SpO2) must be repeated as well. Any 6MWT-related assessments already 
performed for the first (invalid) 6MWT will be recorded in the source notes, but not 
entered in the eCRF, except for the date of the invalidated test and reason for considering 
the test to be invalid, which will be captured in the eCRF. 
The Borg dyspnea index is evaluated after each 6MWT. It rates dyspnea on a scale from 
‘0’ to ‘10’ [see Appendix 3]. 
3.9.2.3 Oxygen saturation (SpO2) 
SpO2 is measured at rest prior to each 6MWT, i.e., at enrollment (Visit 1), 
Month 6 (Visit 3), Month 12 (Visit 4) and EOT visit.  
Oxygen saturation will be assessed by pulse oximetry (SpO2). As much as possible, for 
each individual subject, oxygen saturation measurements will be performed based on 
which location has the best pulsatile vascular bed (finger, earlobe). The same part of the 
body (e.g., finger) and the same pulse oximeter as in the AC-055-305 / MAESTRO study 
should be used throughout this OL study. 
For subjects with patent ductus arteriosus, oxygen saturation during Visit 1 (Enrollment) 
will be measured on a toe. All subsequent oxygen saturation measurements will be 
performed based on which location has the best pulsatile vascular bed (right hand or 
earlobe).  
3.9.3 Baseline parameters and concomitant medications 
3.9.3.1 Baseline demographics and disease characteristics 
Baseline demographic and disease characteristics of interest for this OL study will be 
taken from the AC-055-305 database. 
3.9.3.2 Concomitant medications 
Concomitant medications will be reviewed at all visits.  
All concomitant medications taken from enrollment (Visit 1) up to 30 days after study 
drug discontinuation (EOS visit) will be recorded on the Concomitant Medication page of 
the eCRF. Generic name, start/end date of administration, route, dosage, frequency, and 
indication will be collected.  


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3.10 Visit and assessment schedule 
Table 1 provides a summary of all visits and assessments described in the following 
sections. 
3.10.1 Enrollment visit (Visit 1) 
This visit is to be combined with Visit 6 of the AC-055-305 study for subjects who 
completed the 16-week double-blind treatment, or with Visit 6a of the AC-055-305 study 
for subjects who prematurely discontinued double-blind study treatment but came back at 
Week 16 [see Figure 1]. 
It is the responsibility of the investigator to obtain written informed consent/assent [as per 
Section 6.2.3] from each subject and/or from parent(s) / legal representative(s) (if 
applicable), and from caregivers (if applicable) after adequate face-to-face explanation of 
the methods and objectives of the study.  
The informed consent/assent form must be signed and dated at the clinic/hospital, during 
the enrollment visit at the latest, and prior to any study-related assessment or procedure. 
This visit includes: 
• Subject / parent(s) / legal representative(s) / caregiver information and consent/assent 
form signature  
• Physical examination 
• Measurement of vital signs and body weight 
• Recording of concomitant medications  
• Recording of methods of contraception 
• WHO functional class 
• Measurement of oxygen saturation (SpO2) at rest, prior to the 6MWT 
• 6MWT 
• Borg dyspnea index, after the 6MWT 
• Complete laboratory tests including: 
– Hematology (including hemoglobin), 
– Blood chemistry (including LT), 
– Serum pregnancy test (for females of childbearing potential) 
• After completion of all enrollment assessments and procedures and verification of all 
entry criteria: dispensing of study drug (enough for a 1 or 6-month treatment period). 
• Recording of AEs and SAEs:  
– All AEs occurring from the initiation of the OL study drug must be recorded in 
the OL eCRF. 


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– All SAEs (except for those already reported in the AC-055-305 / MAESTRO 
study) occurring from signature of the consent/assent form to first OL drug 
administration must be recorded in the OL eCRF and on an SAE form. 
Note 1: Tests are not to be repeated if performed for the Visit 6 or Visit 6a of the 
AC-055-305 study, but are to be reported in the eCRF of both studies. 
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. 
Note 3: The first administration of OL study drug should take place during this visit after 
the successful completion of all assessments. Subsequently, the site staff should instruct 
the subject to take one tablet irrespective of food intake every morning. 
3.10.2 Treatment period 
3.10.2.1 Month 1 visit (Visit 2) 
This visit is scheduled one month (± 1 week) from the day of enrollment. 
This visit includes: 
• Physical examination 
• Measurement of vital signs and body weight 
• Recording of changes in concomitant medications 
• Recording of methods of contraception (for females of childbearing potential) 
•  Laboratory tests consist of: 
– Hemoglobin, 
– LT, 
– Serum pregnancy test (for females of childbearing potential) 
• Recording of AEs and SAEs 
3.10.2.2 Monthly Lab and Safety Monitoring 
All blood samples will be collected at site and sent for analysis to the central laboratory, 
whenever possible. 
LTs and serum pregnancy test (for females of childbearing potential) must be assessed 
monthly ± 1 week after initiation of the OL study drug and up to at least 30 days after 
study drug discontinuation.  
Hemoglobin must be assessed monthly ± 1 week during the first 6 months, every 
3 months thereafter up to the EOT visit, and 30 days after study drug discontinuation 
(EOS visit). 
If the monthly laboratory samples are collected at the study site, site staff should take this 
opportunity to meet the subject to monitor their safety (i.e., assessment of AEs and 
SAEs), and assess the concomitant medications and methods of contraception (if 


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applicable). Study drug may be dispensed at this time as an alternative to 6-monthly 
dispensing. In the specific cases where the monthly laboratory samples are not collected 
at the site, the safety monitoring (AEs, SAEs, concomitant medications, methods of 
contraception if applicable) should be done via a telephone call that should be 
documented in the subject’s file. 
All AEs and SAEs occurring from the initiation of the OL study drug up to 30 days after 
permanent study drug discontinuation must be recorded.  
Note: At any time during the study, unscheduled site visits may be performed, as 
necessary, at the discretion of the investigator [see Section 3.10.3]. These include (but are 
not limited to) visits performed in the case of safety concerns (e.g., new (S)AE, 
worsening of symptoms / assessment of 6MWD, adequate follow-up of any safety 
issues). 
3.10.2.3 Month 6 and Month 12 visits (Visits 3 and 4, respectively) 
These visits are scheduled 6 months (± 2 weeks) and 12 months (± 2 weeks) from the day 
of enrollment.  
These visits include: 
• Physical examination 
• Measurement of vital signs and body weight 
• Recording of changes in concomitant medications  
• Recording of methods of contraception (for females of childbearing potential) 
• WHO functional class 
• Measurement of oxygen saturation (SpO2) at rest, prior to the 6MWT 
• 6MWT 
• Borg dyspnea index, after the 6MWT 
• Complete laboratory tests including: 
– Hematology (including hemoglobin), 
– Blood chemistry (including LT), 
– Serum pregnancy test (for females of childbearing potential) 
• Recording of AEs and SAEs 
• Return of unused medication including all empty bottles  
• Dispensing of study drug (enough for a 1 or 6-month treatment period) 
Note: On the day of these visits, the morning dose of study drug should be taken as usual; 
this tablet should be taken from the bottle that is being returned to the site. 


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3.10.2.4 Visits at 6-monthly intervals (Visits 5, 6 etc.) 
These 6-monthly visits are scheduled every 6 months ± 2 weeks, from the day of 
enrollment.  
These visits include: 
• Physical examination 
• Measurement of vital signs and body weight 
• Recording of changes in concomitant medications 
• Recording of methods of contraception (for females of childbearing potential) 
• Complete laboratory tests including: 
– Hematology (including hemoglobin), 
– Blood chemistry (including LT), 
– Serum pregnancy test (for females of childbearing potential) 
• Recording of AEs and SAEs 
• Return of unused medication including all empty bottles  
• Dispensing of study drug (enough for a 1 or 6-month treatment period) 
Note: On the day of these visits, the morning dose of study drug should be taken as usual; 
this tablet should be taken from the bottle that is being returned to the site. 
3.10.2.5 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 the sponsor decides to stop the study; see Section 1.4.5).  
At the end of the OL study, the EOT visit is scheduled for all subjects still participating in 
this OL study. Any visit formerly scheduled within 2 weeks of the EOT will not be 
performed. 
Subjects prematurely discontinuing macitentan treatment must also undergo the EOT 
visit. Permanent study drug discontinuation has to be reported in the IXRS in a timely 
manner to avoid any automatic study drug re-supply. Date entered into the system should 
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. 
The EOT visit includes: 
• Physical examination 
• Measurement of vital signs and body weight 
• Recording of changes in concomitant medications 


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• Recording of methods of contraception (for females of childbearing potential)  
• WHO functional class 
• Measurement of oxygen saturation (SpO2) at rest, prior to the 6MWT 
• 6MWT 
• Borg dyspnea index, after the 6MWT 
• Complete laboratory tests including: 
– Hematology (including hemoglobin), 
– Blood chemistry (including LT), 
– Serum pregnancy test (for females of childbearing potential) 
• Recording of AEs and SAEs 
• Return of unused medication including all empty bottles 
3.10.3 Unscheduled visit(s) 
At any time during the study, unscheduled site visits may be performed, as necessary, at 
the discretion of the investigator. 
These include (but are not limited to) visits performed in the case of safety concerns (e.g., 
new (S)AE, worsening of symptoms / assessment of 6MWD, adequate follow-up of any 
safety issues). The reason why such visits are performed will be recorded in the eCRF. 
If any of the following assessments are performed, the corresponding data will be 
collected in the eCRF: 
• Physical examination 
• Measurement of vital signs and body weight 
• Recording of changes in concomitant medications 
• Recording of methods of contraception (for females of childbearing potential)  
• WHO functional class 
• Measurement of oxygen saturation (SpO2) at rest, prior to the 6MWT 
• 6MWT 
• Borg dyspnea index, after the 6MWT 
• Assessment of AEs and SAEs 
If a laboratory sample is collected, it should be sent to the central laboratory for analysis 
(using the laboratory kits for “unscheduled” visits).  
3.10.4 30-day safety follow-up / EOS visit 
For an individual subject, the end of this OL study corresponds to the 30-day safety 
follow-up / EOS visit. 
All attempts should be made to have this visit performed 30 to 33 days after the 
permanent discontinuation of study drug. 


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This visit includes: 
• 
Recording of changes in concomitant medications 
• 
Recording of methods of contraception (for females of childbearing potential) 
• 
LTs, hemoglobin, and serum pregnancy tests (for females of childbearing potential) 
• 
Reporting of any AE and/or SAEs occurring up to 30 days after permanent 
discontinuation of study drug in the eCRF and on an SAE form.  
For all subjects, the reason for discontinuing the study and (if applicable) the decision 
owner (physician, subject, or sponsor) must be documented in the eCRF. 
 
4 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
4.1 Summary table 
Periods 
Prior to start of 
treatment 
Treatment 
Follow-up 
After follow-up 
Time frame 
From signing the ICF 
to first OL drug 
administration 
During study drug 
administration  
30 days after study drug 
discontinuation 
After 30 days 
AE/SAE 
reporting  
on eCRF AE 
page 
All SAEs (except for 
those already reported 
in the AC-055-305 / 
MAESTRO study) 
All AEs / SAEs 
All AEs / SAEs 
None 
SAE reporting 
on SAE form 
All SAEs (except for 
those already reported 
in the AC-055-305 / 
MAESTRO study) 
All SAEs  
All SAEs 
All SAEs related 
to previous study 
drug exposure 
Reconciliation 1 
Yes 
Yes 
Yes 
Not applicable 
Clinical study 
report 
Analyzed 
Analyzed 
Analyzed 
Might be 
described 
1 Reconciliation between clinical and drug safety databases.  
AE = adverse event; eCRF = electronic Case Report Form; ICF = Informed Consent Form; OL = open-label; SAE = 
serious adverse event 


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4.2 Adverse events 
4.2.1 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, 
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. 
• Lack of efficacy in the acute treatment of a life-threatening disease. 
• Events considered by the investigator to be related to study-mandated procedures.  
• 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, medication errors and uses outside what is foreseen in the protocol, 
including misuse and abuse of the product. 
AEs do not include: 
• Medical or surgical procedure, e.g., surgery, endoscopy, tooth extraction, transfusion. 
However, the event leading to the procedure is an AE. If this event is serious, the 
procedure must be described in the SAE narrative. 
• Pre-existing disease or medical condition present at baseline that does not worsen. 
• Situations in which an adverse change did not occur, e.g., hospitalizations for cosmetic 
elective surgery or for social and/or convenience reasons. 


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4.2.2 Intensity of adverse events 
The intensity of clinical AEs is graded on a 3-point scale – mild, moderate, severe – and 
is reported on specific AE pages 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 3 categories of intensity are defined as follows: 
 Mild 
The event may be noticeable to the subject. It does not influence daily activities, and does 
not usually 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 4.3.1]. These 
terms are used to describe the intensity of a specific event (as in mild, moderate, or severe 
myocardial infarction). However, a severe event (such as severe headache) may be of 
relatively minor medical significance and is not necessarily serious. For example, nausea 
lasting several hours may be rated as severe, but may not be clinically serious. Fever of 
39°C that is not considered severe may become serious if it prolongs hospital discharge 
by a day [see Section 4.3.1.2]. Seriousness rather than severity serves as a guide for 
defining regulatory reporting obligations. 
4.2.3 Relationship to study drug  
Each AE 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 related or 
unrelated. 
 Related to study drug 
This category applies to any AE (whether serious or not) that appears to have a 
reasonable possibility of causal relationship to the use of the study drug (i.e., a 
relationship cannot be ruled out). Guidelines to determine whether an event might be 
considered related include (but are not limited to) the following:  


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• The event occurred in close temporal relationship to study drug administration. 
• The event abated (diminished) or disappeared when treatment with the study drug was 
down-titrated, interrupted, or discontinued.  
• The event reoccurred when treatment was reintroduced. 
• Environmental factors such as clinical state and other treatments could equally have 
caused the event. 
 Unrelated to study drug 
This category applies to any AE (whether serious or not) that does not appear to have a 
reasonable relationship to the use of study drug (see above guidelines). 
4.2.4 Reporting of new adverse events 
All AEs occurring from initiation of the OL study drug and up to 30 days after study drug 
discontinuation are defined as treatment-emergent AEs and must be recorded on specific 
AE pages 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. 
Additional safety information will be collected for AEs related to menstrual disorders 
(e.g., menorrhagia, increased menstrual bleeding) and ovarian cysts, in order to better 
characterize these events, in compliance with the EU Risk Management Plan for 
Opsumit®. This additional information will be entered in the drug safety database only. 
4.2.5 Follow-up of ongoing adverse events 
AEs still ongoing 30 days after study drug discontinuation must be followed up until they 
are no longer clinically significant. 
4.3 Serious adverse events 
4.3.1 Definitions  
4.3.1.1 Serious adverse events 
An SAE is defined by the International Conference on Harmonisation (ICH) guidelines as 
any AE fulfilling at least one of the following criteria: 
• Fatal 
• Life-threatening 
• Requiring inpatient hospitalization, or prolongation of existing hospitalization 
• Resulting in persistent or significant disability or incapacity 
• Congenital anomaly or birth defect 


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• Medically significant, or requires intervention to prevent at least one of the outcomes 
listed above 
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. 
Important medical events that may not immediately result in death, be life-threatening, or 
require hospitalization 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 reference safety document to assess whether or not an SAE should be reported by the 
sponsor to Health Authorities, Ethics Committees / Institutional Review Boards 
(ECs/IRBs) and investigators in an expedited fashion is the IB 
. 
4.3.1.2 Hospitalization – prolongation of existing hospitalization 
The following reasons for hospitalizations are not considered AEs, and are therefore also 
not SAEs:  
• Hospitalizations for cosmetic elective surgery, or social and/or convenience reasons. 
• Standard monitoring of a pre-existing disease or medical condition (present at 
baseline) that did not worsen, e.g., hospitalization for coronary angiography in a 
subject with stable angina pectoris. 
• Elective treatment of a pre-existing disease or medical condition (present at baseline) 
that did not worsen, e.g., elective hip replacement for arthritis. Complications that 
occur during hospitalization are AEs or SAEs (for example, if a complication prolongs 
hospitalization). 
4.3.1.3 Serious adverse events related to study-mandated procedures  
An SAE is defined as related to study-mandated procedures if it appears to have a 
reasonable possibility of a causal relationship (i.e., a relationship cannot be ruled out) to 
such a procedures (other than administration of study drug). Examples of study-mandated 
procedures include discontinuation of a subject’s previous treatment during a washout 
period, complication of a mandated invasive procedure such as blood sampling or heart 
catheterization, car accident on the way to the hospital for a study visit, etc. 
4.3.2 Reporting of new serious adverse events  
4.3.2.1 Prior to start of OL treatment period 
All SAEs occurring from signing the Informed Consent Form to first drug administration 
in the OL are to be reported in the eCRF and on an SAE form, except for those already 
reported in the AC-055-305 / MAESTRO study.  


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4.3.2.2 Treatment and follow-up periods 
All SAEs, including those related to study-mandated procedures and regardless of causal 
relationship, must be reported. Those SAEs occurring from the initiation of the OL study 
drug and up to 30 days after study drug discontinuation are defined as 
treatment-emergent SAEs. 
These treatment-emergent SAEs are reported on SAE forms and also on AE pages in the 
eCRF. They are therefore entered into both the drug safety and clinical databases, and 
must be reconciled before study closure.  
4.3.2.3 After Follow-up period 
New SAEs occurring at any time after the 30-day follow-up period after study drug 
discontinuation must be reported to the Actelion Global Drug Safety department within 
24 hours of the investigator’s knowledge of the event, if considered causally related to 
previous exposure to the study medication by the investigator. These SAEs are only 
entered in the drug safety database, and hence will not affect study closure.  
4.3.2.4 Reporting procedures 
All SAEs (whether or not considered by the investigator to be related to study drug) must 
be reported by the investigator or designee to the Actelion Global Drug Safety 
department within 24 hours of the investigator’s first knowledge of the event. The initial 
reporting of the SAE should not be delayed if some information is unavailable at time of 
first knowledge of the event.  
The Principal Investigator or designee must complete the SAE form in English (unless 
otherwise specified), and must assess the 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 events, especially causality, has been made by 
a physician. The completed SAE form must be faxed to the Actelion Global Drug Safety 
department (see contact details on page 2). 
Actelion Global Drug Safety will confirm receipt of the initial SAE report, or any update 
provided thereafter, by sending an acknowledgement of receipt (via email). If an email 
acknowledging the receipt is not received within 2–3 working days, the site should 
contact the monitor to clarify if the fax SAE form was received by Actelion Global Drug 
Safety. 
Such preliminary reports will be followed by detailed descriptions that may include 
copies of hospital case reports, autopsy reports, hospital discharge summaries and other 
documents when requested and applicable.  
The Actelion Global Drug Safety department may contact the investigator to obtain 
further information and may email/fax a Data Clarification Form (DCF) to the site. The 


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Principal Investigator or designee should complete the DCF as soon as possible and fax it 
to the fax number specified on the form. The original DCF should be filed at site with the 
appropriate SAE form.  
Once an SAE form is faxed, 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 faxed again to Actelion Global Drug Safety. Follow-up information about a 
previously reported SAE must also be reported within 24 hours of the investigator’s first 
knowledge of the new information. 
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), DCF 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 Actelion to Health Authorities, ECs/IRBs and investigators, as appropriate. 
Either Actelion or the investigators will submit the reports to the ECs/IRBs, as required 
by local regulations. 
SAEs that are expected due to underlying disease: 
The following events that are expected to occur in subjects with pulmonary hypertension 
or PAH will be considered as ‘disease-related’ and ‘expected’ for regulatory reporting 
purposes 
in 
this 
population: 
signs 
and 
symptoms 
of 
PAH 
worsening/exacerbation/progression, heart failure, worsening right heart failure, collapse, 
syncope, hemoptysis, anorexia, abdominal pain, chest pain, cyanosis, diaphoresis, 
dizziness, pre-syncope, hypoxia, fatigue, dyspnea, orthopnea, palpitations, systemic 
arterial hypotension, and tachycardia. 
For expedited reporting purposes, these SAEs will be treated as ‘disease-related’ and 
expected, and will therefore not require systematic unblinding and will not require 
expedited reporting to Health Authorities, ECs/IRBs, and investigators.  
However, all safety data (including these events) obtained in this AC-055-308 / 
MAESTRO-OL study until the end of the double-blind AC-055-305 / MAESTRO study 
will be monitored during the study by the DMC. 


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4.3.3 Follow-up of ongoing serious adverse events  
SAEs 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).  
4.4 Pregnancy 
4.4.1 Teratogenicity 
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. 
If pregnancy is suspected, the subject must immediately stop taking the study drug. If the 
pregnancy is confirmed, the subject must be discontinued from the study, and Actelion 
Global Drug Safety must be notified within 24 hours. The investigator must counsel the 
subject and discuss the risks of continuing with the pregnancy and the possible effects on 
the fetus. 
4.4.2 Reporting of pregnancy 
Any pregnancy occurring during study drug administration or during the 30 days 
following study drug discontinuation must be reported to Actelion Global Drug Safety 
within 24 hours of the investigator’s knowledge of the event. 
Pregnancies must be reported on the Actelion Pregnancy form, which is faxed to the 
Actelion Global Drug Safety department (see contact details provided on the pregnancy 
form), and on an AE page of the eCRF. All reporting requirements and timelines 
specified in Section 4.3.2.4 (Reporting Procedures for SAEs) also apply to the reporting 
of a pregnancy. 
4.4.3 Follow-up of pregnancy  
Any pregnancy must be followed to its conclusion and its outcome must be reported to 
the Actelion Global Drug Safety department. 
Such follow-up information will only be entered in the drug safety database, and hence 
will not affect study closure. 
5 
STATISTICAL METHODOLOGY AND ANALYSES 
5.1 Statistical Analysis Plan 
A Statistical Analysis Plan (SAP) will be written and finalized before study closure, 
i.e., database closure. The SAP will provide full details of the analyses, data displays, and 
algorithms to be used for data derivations.  


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The SAP will include the definition of the protocol deviations and the link between 
protocol deviations and the analysis sets. The protocol deviations will be identified by 
trained staff before study closure.  
All the listings will be presented by previous treatment group during AC-055-305 (i.e., 
former placebo and former macitentan), site, subject number, and assessment date, where 
appropriate. Where appropriate, all the summaries and graphics will be presented by 
previous treatment group during AC-055-305 (i.e., former placebo and former 
macitentan) and all subjects pooled together. 
5.2 Analysis sets 
Three different analysis sets are defined.  
 All-enrolled set 
This analysis set comprises all subjects enrolled in this AC-055-308 OL study, whether or 
not they took at least one dose of macitentan during the OL study.  
 Restricted all-enrolled set  
This analysis set comprises all subjects in the All-enrolled set who received macitentan 
during the AC-055-305 / MAESTRO study. 
 All-treated DB + OL set 
This analysis set comprises the union of (i) all subjects who received at least one dose of 
macitentan in this AC-055-308 OL study AND (ii) all subjects who received macitentan 
during the AC-055-305 / MAESTRO study and did not participate in the OL study.  
5.3 Exploratory efficacy endpoints  
For a detailed description of the exploratory efficacy endpoints, see Section 3.8.1. 
The All-enrolled set is used to perform the efficacy analyses, except otherwise specified.  
Each endpoint is analyzed descriptively and displayed depending on its nature as follows: 
For numerical variables: 
• Mean and 95% confidence limits (CLs) for the absolute values at selected time-points 
will be plotted over time including data from the start of AC-055-305/MAESTRO up 
to Month 12 in this AC-055-308 OL study. These graphs will serve to draw the pattern 
of the raw data for subjects included in this OL study.  
• Mean and 95% CLs for the changes from baseline to selected time-points will be 
plotted over time: 


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– Taking as baseline the last value obtained prior to or on the day of first 
administration of macitentan during this AC-055-308 OL study. These graphs 
will serve to draw the pattern of the data during the OL phase alone. 
– Taking as baseline the baseline of the AC-055-305 / MAESTRO study and 
including data from the start of AC-055-305 / MAESTRO up to Month 12 in this 
AC-055-308 OL study, only for subjects who received macitentan during the 
double-blind AC-055-305 / MAESTRO study. These graphs will serve to draw 
the pattern of the data for subjects who received macitentan during the entire 
study (double-blind and OL phase). The restricted All-enrolled set is used to 
perform this analysis. 
All the graphics will be accompanied by summary tables displaying descriptive summary 
statistics (i.e., number of observations [n], mean, median, standard deviation, standard 
error, quartiles, minimum, maximum and 95% 2-sided CLs of mean and median). 
For categorical variables: 
A shift table will be computed and displayed. The proportions of subjects in each 
category at the different time points will be displayed, as well as the proportion of 
subjects having an improvement/worsening together with the 95% CLs.  
5.4 Safety and tolerability endpoints  
For a detailed description of the safety endpoints, see Section 3.8.2. 
The All-treated DB + OL set is used to perform safety analyses, unless otherwise 
specified. 
The observation period for each individual subject starts at the time of the first 
administration of macitentan and ends with the permanent discontinuation of macitentan, 
regardless of administration type (i.e., double-blind or open-label). 
Unless otherwise specified, the baseline is defined as the baseline of the AC-055-305 
study for the subjects who received macitentan during the double-blind AC-055-305 / 
MAESTRO study, or as the last value obtained prior to first administration of macitentan 
during this AC-055-308 OL study, for the subjects who received placebo during the 
double-blind AC-055-305 / MAESTRO study. 
Numerical safety and tolerability endpoints will be displayed using descriptive statistics 
(i.e., number of observations [n], mean, median, standard deviation, quartiles, minimum, 
maximum) at the different time points of assessment (if available).  


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5.4.1 Adverse events, serious adverse events, reasons for death, and premature 
discontinuation  
All AEs and SAEs as well as reasons for death are coded using the latest available 
version of the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. 
The number and percentage of subjects who experienced treatment-emergent SAEs up to 
30 days after study drug discontinuation will be tabulated: 
• by system organ class (SOC), and individual preferred terms within each SOC (in 
descending order according to the overall incidence) 
• by frequency of terms coded with the same preferred term (in descending order 
according to the overall incidence).  
Additionally, the following will be summarized in a similar manner to that used for 
treatment-emergent SAEs: 
• AEs and AEs leading to premature discontinuation of study drug 
• Reasons for death 
• Reasons for premature discontinuation from study drug 
• Reasons for premature discontinuation from the study  
5.4.2 Laboratory parameters 
The sponsor’s internal guidelines will be used for the definition of MLAs. In rare cases 
when a local laboratory performs the analysis, normalization of local laboratory data will 
be done by the sponsor based on the central laboratory ranges [see Appendix 5]. 
The number and percentage of subjects with treatment-emergent MLAs up to EOT will 
be tabulated for each laboratory assessment by treatment group. 
The number and percentage of subjects with treatment-emergent ALT and/or AST 
abnormalities (> 3 and ≤ 5  ULN; > 5 and ≤ 8  ULN; > 8  ULN), associated or not 
with total bilirubin > 2  ULN, up to EOT will be tabulated providing their incidence and 
frequency. 
5.5 Exposure to study drug 
Exposure to macitentan will be described in terms of duration and compliance. The 
duration of exposure is defined as the time elapsing between the first administration of 
macitentan (included) and permanent discontinuation of macitentan (included) regardless 
of administration type (i.e., double-blind or open-label). Duration of exposure to 
macitentan during this AC-055-308 OL study only will be also evaluated. The exposure 
time will be summarized as a numerical variable using descriptive statistics. It will be 
also summarized as categorical variable: the cumulative distribution of exposure time by 


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different class intervals (e.g., at least 4 weeks, at least 8 weeks, and at every interval of 
4 weeks thereafter) will be tabulated to show counts and percentages of subjects in each 
class interval.  
Compliance is defined as the total number of tablets taken divided by the total number of 
tablets that should have been taken, in percentage, for the time period under 
consideration. Overall compliance and compliance at each visit will be summarized using 
descriptive statistics. 
5.6 Baseline parameters and concomitant medications 
Baseline demographic (except for age) and disease characteristics are those collected in 
the double-blind AC-055-305 / MAESTRO study. 
Continuous/numerical demographic characteristics (e.g., age, height, weight, body mass 
index, etc.) and baseline disease characteristics (e.g., time from ES, 6MWD and Borg 
dyspnea index, SpO2, etc.) will be summarized displaying descriptive statistics. 
Qualitative demographic characteristics (e.g., sex, race, etc.) and baseline disease 
characteristics (e.g., WHO functional class etc.) will be summarized displaying counts 
and percentages.  
Inclusion/exclusion checklist will only be listed for subjects in the All-enrolled set. 
Concomitant medications will be coded according to the latest available version of the 
WHO drug code and the Anatomic Therapeutic Chemical class code. They will be 
summarized by type in a similar manner to that used for treatment-emergent AEs (i.e., by 
treatment class and individual preferred terms within each class, and by frequency of 
preferred term). 
Distributions of these parameters will only be compared descriptively between the 
treatment groups. No statistical inference will be performed. 
5.7 Exploratory analyses 
Not applicable. 
5.8 Interim analyses 
No interim efficacy analysis is planned. 


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6 
PROCEDURES AND GOOD CLINICAL PRACTICE  
6.1 Procedures 
6.1.1 Protocol amendments 
Any change to a protocol must be considered to be an amendment if the documents have 
already been submitted to ECs/IRBs or Health Authorities. An amendment could 
therefore occur before or after the approval of these documents by ECs/IRBs or Health 
Authorities. Each amendment must be documented in writing and approved by Actelion, 
and must be reviewed by the Coordinating/Principal Investigator or Steering Committee, 
as appropriate. 
Changes to the Core Information Leaflet and Informed Consent/Assent Form requested 
by ECs/IRBs are not considered to be formal amendments, as long as they do not 
significantly change the core document or affect the protocol. 
6.1.1.1 Non-substantial amendment 
Purely administrative or minor logistical changes require only a non-substantial 
amendment. Such changes include but are not limited to changes in Actelion study staff 
or contact details (e.g., Actelion instead of Contract Research Organization monitors), or 
minor changes in the packaging or labeling of study drug.  
The implementation of a non-substantial amendment may be undertaken with or without 
notification to the appropriate ECs/IRBs and Health Authorities (subject to national 
regulations).  
6.1.1.2 Substantial amendment 
A substantial amendment is required for significant changes. These include, but are not 
limited to, new data affecting the safety of subjects, and changes to the objectives or 
endpoints of the study, eligibility criteria, dose regimen, study assessments/procedures, or 
treatment or study duration, with or without the need to modify the Core Information 
Leaflet and Informed Consent/Assent Form. 
Substantial amendments must be approved by the appropriate ECs/IRBs, and in some 
jurisdictions by the Health Authorities. The implementation of a substantial amendment 
may only occur after formal approval by the appropriate ECs/IRBs and/or Health 
Authorities, and must be signed by the investigators. 
6.1.1.3 Urgent amendment 
An urgent amendment might become necessary to preserve the safety of the subjects 
included in the study. The requirements for approval must not prevent any immediate 
action being taken by the investigators or Actelion in the best interests of the subjects. If 


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deemed necessary, an investigator may therefore implement an immediate change to the 
protocol for safety reasons, and in such exceptional cases the implementation of urgent 
amendments will occur before submission to, and approval by, ECs/IRBs and Health 
Authorities.  
In such cases, the investigator must notify Actelion within 24 hours. A related substantial 
amendment will be prepared and submitted by Actelion to the appropriate ECs/IRBs and 
Health Authorities within 10 working days of receiving the notification.  
6.1.2 Monitoring 
The monitor will contact and visit the investigator regularly and, on request, must be 
permitted to have access to all source documents needed to verify the entries on the eCRF 
and other protocol-related documents, provided that subject confidentiality is maintained 
in accordance with local regulations.  
Prior to or at the latest at initiation, the monitor must have verified which type of source 
documents are used at the site and confirm adequate access to these documents to allow 
Source Data Verification (SDV) as required per monitoring guidelines upon the first 
monitoring visit. In case electronic source documents are used, the requirements 
described in Section 6.1.4 must be adhered to.  
It will be the monitor’s responsibility to inspect the eCRFs at regular intervals throughout 
the study, to verify adherence to the protocol and the completeness, consistency and 
accuracy of the data being entered on the CRFs. 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 CRFs will be performed according to the study-specific monitoring 
plan. Any protocol violation identified will be discussed with the site and notified to the 
ECs/IRBs, as required per local regulation. No protocol waivers are allowed in this study. 
The investigator must ensure that subject anonymity is maintained on all documents 
submitted to Actelion. On these documents, subjects must be identified only by 
study-specific subject number, and never by name, initials, or hospital subject number. 
The investigator must keep a subject identification code list showing the subject number, 
the subject’s name, date of birth and address or any other locally accepted identifiers. 
Documents identifying the subjects (e.g., signed informed consent forms) should not be 
sent to Actelion, and must be kept in strict confidence by the investigator. 
Adequate workspace, including Internet access for verification of eCRF, should be 
provided to the monitor and to any Actelion representative during an on-site visit. The 
monitor(s) and any Actelion representative must have access to the study drug storage 


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and the laboratory sample collection facility, as appropriate. The required site personnel 
must be available during the on-site visit and allow adequate time to meet with the 
monitor(s) and any Actelion representative to discuss study-related issues. The 
investigator and co-investigators agree 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 center, the investigator is 
responsible for contacting that hospital in order to document the SAE. 
The investigator must on request supply Actelion with any required background data 
from the study documentation or clinical records. This is particularly important when 
errors in data transcription are suspected. In the case of special problems and/or 
governmental queries, it is also necessary to have access to the complete study records, 
provided that subject confidentiality is protected. 
An initiation visit will be performed before the first subject is included in this OL study. 
Monitoring visits and contacts will occur at regular intervals thereafter, according to a 
frequency defined in the study-specific monitoring plan. A close-out visit will be 
performed after study closure. 
6.1.3 Data management 
6.1.3.1 Data collection 
CRF data will be captured via electronic data capture using the Rave system provided by 
Medidata Solutions, Inc., a web-based tool. The investigator site staff will enter and edit 
the data via a secure network, with secure access features (username, password and 
secure identification – an electronic password system). A complete electronic audit trail 
will be maintained. The investigator will approve the data using an electronic signature 
(ref. to 21 CFR Part 11), and this approval is used to confirm accuracy of the data 
recorded. 
Site team members who obtained access to the eCRF in the AC-055-305 study will use 
the same account to access to the eCRF of the OL study. 
For a new user to obtain access to the eCRF the following information should be verified 
and confirmed: 
• Personal email account for collection of log-in details for every user 
• Completion of eLearning for every user requiring access 
At least one site team member must have access to the system prior to or at the latest at 
site initiation visit. 
The eCRF information need to be completed as soon as possible after each subject’s visit 
(but no later than 5 days after the subject’s visit), and all eCRF entries must be supported 
by the site source documents. An eCRF will be completed for each enrolled subject. 


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6.1.3.2 Database management and quality control 
eCRFs will be used for all subjects. The investigator will have access to the data 
throughout the trial life cycle. The eCRF must be kept current to reflect subject status at 
any time point during the course of the trial.  
While entering the data, the investigator will be prompted by logical checks (error 
messages) built into the web-based data entry screens 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 the Clinical Trial Team, to look for unexpected patterns in data, and other 
summaries needed for study monitoring. In case problematic data are detected, a query 
specifying the problem and requesting clarification will be issued and visible via the 
eCRF by the investigator, who will then respond and clarify directly onto the eCRF. 
This process will continue until database closure. 
After the database has been declared complete and accurate, the database will be locked. 
6.1.4 Recording of data and retention of documents 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, and the study data to be subsequently verified. These 
documents are to be classified into 2 different categories: ISF, and subject clinical source 
documents. 
• The ISF will be provided prior to or at the latest during the initiation visit and will 
contain all the essential documents that are required onsite.  
The ISF will contain the protocol and all protocol amendments, the FDA1572 form for 
studies conducted under an Investigational New Drug (IND; applicable for IND sites 
only), a financial disclosure form, the eCRFs together with all data changes made 
(CD_ROM provided after database closure), EC/IRB and Health Authority approval 
with correspondence, informed consent, drug records, staff CVs and authorization 
forms, 
screening 
and 
enrollment 
logs, 
and 
other 
appropriate 
documents/correspondence in accordance with ICH GCP and local regulations. The 
ISF must be stored in a secure area during and after the study.  
• Subject clinical source documents include, but are not limited to, hospital/clinic 
records, physicians’ and nurses’ notes, appointment book, original laboratory reports, 
ECG, X-ray, pathology and special assessment reports, consultant letters, etc.  
If the site source documents are available on an electronic hospital/office database, it 
is requested to print out the complete set of source data needed for the SDV prior to 
the monitoring visit, unless the site confirmed that they are 21 CFR part 11 compliant 


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and provide access (personal user ID and password) to the monitor and/or any other 
Actelion representative during an on-site visit to verify electronic source documents 
with eCRF. The print-outs should be numbered, stapled, if possible, but at least kept 
together with a coversheet, signed and dated by the investigator or designee to confirm 
the accuracy and completeness of the subject’s data. After monitoring the source 
documents, the monitor will sign and date the coversheet stating that attached source 
documents have been used for SDV. The coversheet should contain the following 
information: total number of pages, signature and date of Principal Investigator or 
designee, signature and date of monitor. Any new source data information added after 
sign off of the initial cover sheet should be initialed and dated by the responsible site 
team member and information updated on the cover sheet by all parties involved. Any 
new print-outs will be added, following the same process and information will be 
added on the same cover page. 
Any changes of critical data in the source documents should be attributable to the site 
personnel doing the changes and if several source documents are available for the 
same assessment, the site must clearly state which source document is used for the 
data reported in the eCRF. 
Source documents and investigator’s file must be kept on file by the investigator for as 
long as is necessary to comply with national and international regulations (generally 
2 years after either discontinuation of clinical development, or the last marketing 
approval, of the investigational drug). 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 in writing. 
When source documents are required for the continued care of the subject, appropriate 
copies should be made for storing off site. 
Copies of the eCRFs together with all data changes made will be supplied to the 
investigator at the end of the trial (CD-ROM provided after database closure). The 
investigator will be responsible for retaining all records pertaining to the trial as specified 
in the appropriate contract. 
6.1.5 Audit 
The Actelion Global Quality Management department may conduct audits of clinical 
research activities in accordance with internal standard operating procedures to evaluate 
compliance with the principles of GCP- and ICH-related guidelines.  
Health Authorities may also wish to conduct an inspection (during the study or after its 
completion). Should an inspection be requested by a Health Authority, the investigator 
must inform Actelion immediately that such a request has been made. 


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The investigator must permit such audits by Actelion or Health Authorities, and must 
facilitate them by providing access to the relevant source documents. 
6.1.6 Handling of study drug 
Actelion will supply study drug to the site according to local regulations. Drug supplies 
must be kept in an appropriate, secure area and stored according to the conditions 
specified on the drug labels. The site must maintain an accurate record of the shipment 
and dispensing of study drug on an accountability form, which must be given to the 
monitor at the end of the study. An accurate record of the date and amount of study drug 
dispensed to each subject must be available for inspection at any time. 
All drug supplies are to be used only in accordance with this protocol, and not for any 
other purpose. The responsible person must not destroy any drug labels or unused drug 
supply. On termination of the study, the monitor will collect used and unused subject 
bottles, which will be sent to the warehouse, where the sponsor or its deputy will check 
drug accountability. In certain circumstances, used and unused drug containers may be 
destroyed at the site once drug accountability is final and has been checked by the 
sponsor or its deputy, and written permission for destruction has been obtained from 
Actelion. 
6.1.7 Publication and reporting of study results 
Study results will be documented in a clinical study report that will be signed by Actelion 
representatives and the Coordinating Investigator. 
In accordance with standard editorial and ethical practice, the results of 
Actelion-sponsored studies will be published. Results from multi-center studies must be 
published or presented at congresses only in their entirety and not as individual center 
data, except for ancillary studies. 
The Coordinating Investigator and the Steering Committee will have the opportunity to 
review the analysis of the data and to discuss with the sponsor the interpretation of the 
study results prior to publication. 
Any study-related article or abstract written independently by investigators must be 
submitted to Actelion for review at least 60 days prior to submission for publication or 
presentation. 
The list of authors of any formal publication or presentation of study results may include, 
as appropriate, representatives of Actelion, and will be determined by mutual agreement. 
6.1.8 Disclosure and confidentiality 
By signing this protocol, the investigator agrees to keep all information provided by 
Actelion in strict confidence, and to request similar confidentiality from his or her staff 


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and the EC/IRB. Study documents provided by Actelion (including IBs, protocols, eCRFs 
and other protocol-related documents) will be stored appropriately to ensure their 
confidentiality. The information provided by Actelion to the investigator may not be 
disclosed to others without direct written authorization from Actelion, except to the 
extent necessary to obtain informed consent from subjects who wish to participate in the 
trial.  
6.1.9 Premature termination or suspension of the study 
Both Actelion and the investigator reserve the right to terminate the study at any time.  
If a study is prematurely terminated or suspended, Actelion will promptly inform the 
investigators, the ECs/IRBs and Health Authorities, as appropriate, and provide the 
reasons for the termination or suspension.  
If the study is prematurely terminated or suspended 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 terminates or suspends a study without prior agreement 
from Actelion, the investigator must promptly inform Actelion and the EC/IRB, and must 
provide Actelion and the EC/IRB with a detailed written explanation of the termination 
or suspension. 
If the EC/IRB terminates or suspends its approval/favorable opinion of a study, the 
investigator must promptly notify Actelion and provide Actelion with a detailed written 
explanation of the termination or suspension. 
Any premature termination or suspension of the study must be discussed with Steering 
Committee, as appropriate. 
6.2 Good Clinical Practice 
6.2.1 Ethics and Good Clinical Practice 
The investigator will ensure that this study is conducted in full compliance with the 
principles of the ‘Declaration of Helsinki’ (as amended in Tokyo, Venice, Hong Kong, 
Somerset West, Edinburgh and Seoul), and with the laws and regulations of the country 
in which the clinical research is conducted. A copy of the Declaration of Helsinki will be 
provided to each investigational site.  
All studies must follow ICH GCP Guidelines and, if applicable, the US Code of Federal 
Regulations. In other jurisdictions in which GCP Guidelines exist, the investigators will 
strictly ensure adherence to the stated provisions. 


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For any site staff member responsible for performing a critical task as confirmed on the 
DoA and/or listed on the FDA1572 form, ICH GCP experience and training must be 
documented on the CV. Actelion will train any site staff member not familiar with or 
having conducted an ICH GCP training more than one year prior to initiation or start of 
involvement in the study. 
If an investigator is moving to a new site location, an on-site visit by the monitor is 
required, to assess if the new facility(ies) are compliant with study-specific requirements. 
If a new Principal Investigator takes over a site, an assessment of the new Principal 
Investigator’s credentials needs to be performed. In both cases, regulatory documents will 
need to be updated to reflect the correct and current situation.  
In accordance with laws and regulations of the country and as per EC/IRB requirements, 
the updated information will be submitted for approval/notification, as appropriate. 
6.2.2 Ethics Committee / Institutional Review Board 
The investigator will submit this protocol and any related document provided to the 
subject (such as subject information used to obtain informed consent) to an EC or IRB. 
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 trial, the 
documents reviewed, and the date of approval. A list of members participating in the 
meeting must be provided, including the functions of these members. If study staff were 
present, it must be clear that none of these persons voted. 
Modifications made to the protocol after receipt of the EC/IRB approval must also be 
submitted as amendments by the investigator to the EC/IRB in accordance with local 
procedures and regulations [see Section 6.1.1]. 
6.2.3 Informed consent 
It is the responsibility of the investigator to obtain informed consent according to GCP 
and local regulations from each individual participating in this study as well as from the 
parent(s) / legal representative(s) (if applicable), and from caregivers (if applicable), after 
adequate explanation of the methods, objectives and potential hazards of the study. The 
investigator must also explain to the 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 / parent(s) / 
legal representative(s) / caregiver should have ample time to review the information 
obtained and sign an informed consent. 
The ICF/Assent must be obtained in person at the site and the subject and/or 
parent(s) / legal representative(s) / caregiver must sign, personally date and time the 
ICF/Assent before any study-related procedure begins. The ICF/Assent must also be 
signed, personally dated and timed by the person who conducted the informed consent 


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discussion. The whole consenting process must be clearly documented in the subject’s 
medical record.  
If the person conducting the informed consent discussion is a non-physician, all medical 
questions must be addressed and answered by a physician. The investigator performing 
the informed consent discussion must be listed on the FDA1572 and DoA forms. 
The Information Leaflet and ICF will be provided in the local language. A special ICF 
(assent) will be provided for subjects who are minors and for subjects with DS who are 
not able to personally read and sign the informed consent (if needed according to the 
local regulations). 
Appropriate forms for documenting informed consent will be provided to the sites prior 
to the study. The original Information Leaflet-ICF/Assent is to be filed on-site, and a 
copy must be given to the subject and/or legal representative / caregiver. 
The Subject Identification Log must be maintained for all patients who consented to 
participate in the study, whether or not they were enrolled. 
6.2.4 Compensation to subjects and investigators 
The sponsor provides insurance in order to indemnify (with both legal and financial 
coverage) the investigator/center 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. 
6.2.5 DoA, FDA1572, CV, GCP Declaration Form and Financial Disclosure Form  
The DoA must be available at the site initiation visit with all sections completed by the 
site according to instructions on the form. 
The Principal Investigator may delegate some of his/her responsibilities to the 
appropriate site personnel. The DoA must be completed by all site personnel delegated by 
the Principal Investigator to perform any procedures before performing any study-related 
tasks, and filed in the ISF.  
The DoA will list the critical tasks, which may only be delegated to a physician. 
However, the 6MWT may be delegated to a qualified non-physician.  
For the delegated tasks, there must be evidence that the person has been sufficiently 
trained to carry out the task (CV / training records must be available at site). Training 
must be given and documented before the task is performed.  
The Principal Investigator must authorize the assignment of the task and confirm 
appropriate training is received by the site team member by signing and dating the 


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approval column for each individual site member. The Principal Investigator’s approval 
date must be prior to or on the study involvement start date of the corresponding site 
personnel. If there is any discrepancy between the Principal Investigator approval date 
and the site personnel start date, a comment must be provided by the Principal 
Investigator. 
The DoA must be updated on an ongoing basis and any change must be dated and signed 
by the Principal Investigator.  
It is recommended that each task be assigned to at least 2 persons. Several tasks may be 
assigned to one person. 
The Principal Investigator must sign and date the DoA at the end of the study. 
If site personnel listed on the DoA are responsible for a critical task, s/he must be listed 
on the form FDA1572 (IND sites only) and must provide a signed and dated CV, 
professional license (if applicable), authorization for data use and data transfer form, 
GCP training declaration form and Financial Disclosure Form before performing any task 
associated with the protocol. In case of changes in site personnel performing critical 
tasks, the FDA1572 (IND sites only) must be updated, and if necessary other required 
documents must be collected and appropriate training given and documented. 


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7 
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[Diller 2005] Diller GP, Dimopoulos K, Okonko D, et al. Exercise intolerance in adult 
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[Diller 2007] Diller GP, Gatzoulis MA. Pulmonary vascular disease in adults with 
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Wort SJ, Gatzoulis MA. Improved survival among patients with Eisenmenger 
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Circulation. 2010 Jan 5;121(1):20–5. 
[Galiè 2004] Galiè N, Manes A, Branzi A. The endothelin system in pulmonary arterial 
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[Galiè 2008] Galiè N, Manes A, Palazzini M et al. Management of pulmonary arterial 
hypertension associated with congenital systemic-to-pulmonary shunts and 
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[Gatzoulis 2008] Gatzoulis MA, Beghetti M, Galiè N et al. Longer-term bosentan therapy 
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[Giaid 1993] Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in 
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[Hirata 1993] Hirata Y, Emori T, Eguchi S. Endothelin receptor subtype B mediates 
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[Humbert 2004b] Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial 
hypertension. N Engl J Med 2004; 351: 1425–36. 
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[Morrell 2009] Morrell NW, Adnot S, Archer SL et al. Cellular and molecular basis of 
pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S20–31 
[Rubens 2001] Rubens C, Ewert R, Halank M et al. Big endothelin-1 and endothelin-1 
plasma levels are correlated with the severity of primary pulmonary hypertension. 
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[Rubin 2002] Rubin LJ, Badesch DB, Barst RJ et al. Bosentan therapy for pulmonary 
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classification of pulmonary hypertension. J Am Coll Cardiol. 2009 Jun 
30;54(1 Suppl):S43–54. 
[Stewart 1991] Stewart DJ, Levy RD, Cernacek P, et al. Increased plasma endothelin-1 in 
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Pharmacol 1996;49:447–57. 
[Trulock 2001] Trulock EP. Lung transplantation for primary pulmonary hypertension. 
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[Tutar 1999] Tutar HE, Imamoglu A, Atalay S et al. Plasma endothelin-1 levels in 
patients with left-to-right shunt with or without pulmonary hypertension. Int J 
Cardiol. 1999 Jul 1;70(1):57–62. 
[Vongpatanasin 1998] Vongpatanasin W, Brickner ME, Hillis LD, Lange RA. The 
Eisenmenger syndrome in adults. Ann Intern Med 1998;128(9):745-5. 
[Yoshibayashi 1991] Yoshibayashi M, Nishioka K, Nakao K et al. Plasma endothelin 
concentrations in patients with pulmonary hypertension associated with congenital 
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Appendix 1 
Clinical Classification of Pulmonary Hypertension 
Updated Clinical Classification of Pulmonary Hypertension (Dana Point, 2008) 
[Simonneau 2009] 
 
1 Pulmonary arterial hypertension (PAH) 
1.1 Idiopathic PAH 
1.2 Heritable 
1.2.1 BMPR2 
1.2.2 ALK1, endoglin (with or without hereditary hemorrhagic telangiectasia) 
1.2.3 Unknown 
1.3 Drug- and toxin-induced 
1.4 Associated with 
1.4.1 Connective tissue diseases 
1.4.2 HIV infection 
1.4.3 Portal hypertension 
1.4.4 Congenital heart diseases 
1.4.5 Schistosomiasis 
1.4.6 Chronic hemolytic anemia 
1.5 Persistent pulmonary hypertension of the newborn 
1’ Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary 
hemangiomatosis (PCH) 
2 Pulmonary hypertension owing to left heart disease 
2.1 Systolic dysfunction 
2.2 Diastolic dysfunction 
2.3 Valvular disease 
3 Pulmonary hypertension owing to lung diseases and/or hypoxia 
3.1 Chronic obstructive pulmonary disease 
3.2 Interstitial lung disease 
3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 
3.4 Sleep-disordered breathing 
3.5 Alveolar hypoventilation disorders 
3.6 Chronic exposure to high altitude 
3.7 Developmental abnormalities 
4 Chronic thromboembolic pulmonary hypertension (CTEPH) 
5 Pulmonary hypertension with unclear multifactorial mechanisms 
5.1 Hematologic disorders: myeloproliferative disorders, splenectomy 


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5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis:
lymphangioleiomyomatosis, neurofibromatosis, vasculitis 
5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid 
disorders 
5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure 
on dialysis 


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Appendix 2 
Actelion Guidelines for 6MWT 
6-Minute Walk Test (6MWT)  
➢ General instructions  
The American Thoracic Society (ATS) published an official statement on the 6MWT in 
2002 [ATS Guidelines 2002]. Only a brief summary of these guidelines is included here. 
Where applicable, adaptations (indicated by an asterisk and footnote) have been made for 
subjects with Down Syndrome. 
• The 6MWT should be performed indoors, along a long, flat, straight, enclosed 
corridor with a hard surface that is seldom traveled. The use of 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. 
*For subjects with Down Syndrome the tester may walk behind the subject, but 
must avoid body contact (e.g., holding hands). 
• 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 subjects with Down Syndrome standard encouragement should be given at 
each 1 minute interval, as per the dialogue provided below. 
• 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. 
Required equipment: 
- Countdown timer (or stop watch) 


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- 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.  
- Oximeter 
 
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 hours of beginning the test. 
• The subject should sit at rest for at least 10 minutes 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 ask:  


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EudraCT 2012-004411-31 
Doc No D-14.170 
 
“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 good effort. 
*For Down Syndrome subjects the dialogue is modified to include standardized 
familiarization components in order to meet the needs of diverse learners and 
maintain focus for the entirety of the 6 minutes. This is meant to replace the above: 
“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 talk to you during the test. Keep walking when I talk.” 
After these instructions are given to the subject, the person administering the test will 
then ask:  


Macitentan / ACT-064992 
Eisenmenger Syndrome 
Protocol AC-055-308, MAESTRO-OL 
Final Version 4 
16 May 2014, page 83/102 
Confidential  
EudraCT 2012-004411-31 
Doc No D-14.170 
 
“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 uses an even tone of voice when using the standard phrases of 
encouragement: 
After the first minute, tell the patient the following: 
“You are doing well INSERT FIRST NAME HERE. You have 5 minutes to go.” 
 
When the timer shows 4 minutes remaining, tell the patient the following: 
“Keep up the good work INSERT FIRST NAME HERE. You have 4 minutes to go.” 
 
When the timer shows 3 minutes remaining, tell the patient the following: 
“Great effort. Keep it up INSERT FIRST NAME HERE. You are halfway done.” 
 
When the timer shows 2 minutes remaining, tell the patient the following: 
“Keep up the good work INSERT FIRST NAME HERE. You have 2 minutes to go.” 
 
When the timer shows 1 minute remaining, tell the patient the following: 
“You are doing well. You have only 1 minute 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 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 3]. 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).  


Macitentan / ACT-064992 
Eisenmenger Syndrome 
Protocol AC-055-308, MAESTRO-OL 
Final Version 4 
16 May 2014, page 84/102 
Confidential  
EudraCT 2012-004411-31 
Doc No D-14.170 
 
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 
Eisenmenger Syndrome 
Protocol AC-055-308, MAESTRO-OL 
Final Version 4 
16 May 2014, page 85/102 
Confidential  
EudraCT 2012-004411-31 
Doc No D-14.170 
 
Appendix 3 
Borg dyspnea index (Borg Scale) / Perceived Breathlessness 
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) 


Macitentan / ACT-064992 
Eisenmenger Syndrome 
Protocol AC-055-308, MAESTRO-OL 
Final Version 4 
16 May 2014, page 86/102 
Confidential  
EudraCT 2012-004411-31 
Doc No D-14.170 
 
Appendix 4 
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 
of 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Macitentan / ACT-064992 
Eisenmenger Syndrome 
Protocol AC-055-308, MAESTRO-OL 
Final Version 4 
16 May 2014, page 87/102 
Confidential  
EudraCT 2012-004411-31 
Doc No D-14.170 
 
Appendix 5 
Central laboratory ranges  
The ranges below are valid at the time of protocol finalization. Any changes to these ranges during the course of the study will 
be reflected in the ranges displayed in the laboratory reports sent from the central laboratory to the investigational sites. 
 
Test Name 
Full 
Department 
Age 
Low 
Age 
Low 
Unit 
Age 
High 
Age 
High 
Unit 
Sex 
Conv. 
Ref. 
Interval 
Low 
Conv. 
Ref. 
Interval 
High 
Conv. 
Unit 
Conv. 
Factor 
SI to 
Conv 
SI 
Ref. 
Interval 
Low 
SI 
Ref. 
Interval 
High 
SI 
Unit 
Conv. 
Report 
limit 
Low 
SI 
Report 
limit 
Low 
Hemoglobin 
Hematology 
5 
y 
14 
y 
M/F 
11.4 
15.1 
g/dL 
0.1 
114 
151 
g/L 
 
 
Hemoglobin 
Hematology 
15 
y 
999 
y 
M 
13.5 
17.5 
g/dL 
0.1 
135 
175 
g/L 
 
 
Hemoglobin 
Hematology 
15 
y 
999 
y 
F 
12.0 
16.0 
g/dL 
0.1 
120 
160 
g/L 
 
 
Hematocrit 
Hematology 
5 
y 
14 
y 
M/F 
36 
47 
% 
100 
0.36 
0.47 
L/L 
 
 
Hematocrit 
Hematology 
15 
y 
999 
y 
M 
40 
52 
% 
100 
0.40 
0.52 
L/L 
 
 
Hematocrit 
Hematology 
15 
y 
999 
y 
F 
36 
46 
% 
100 
0.36 
0.46 
L/L 
 
 
Erythrocyte 
Count 
Hematology 
5 
y 
14 
y 
M/F 
4.0 
5.6 
x10E6/uL 
1 
4.0 
5.6 
x10E12/L 
 
 
Erythrocyte 
Count 
Hematology 
15 
y 
999 
y 
M 
4.6 
5.8 
x10E6/uL 
1 
4.6 
5.8 
x10E12/L 
 
 
Erythrocyte 
Count 
Hematology 
15 
y 
999 
y 
F 
4.1 
5.2 
x10E6/uL 
1 
4.1 
5.2 
x10E12/L 
 
 
MCV 
Hematology 
5 
y 
14 
y 
M/F 
78 
95 
fL 
1 
78 
95 
fL 
 
 
MCV 
Hematology 
15 
y 
999 
y 
M/F 
81 
98 
fL 
1 
81 
98 
fL 
 
 
MCH 
Hematology 
5 
y 
999 
y 
M/F 
27 
34 
pg 
1 
27 
34 
pg 
 
 


Macitentan / ACT-064992 
Eisenmenger Syndrome 
Protocol AC-055-308, MAESTRO-OL 
Final Version 4 
16 May 2014, page 88/102 
Confidential  
EudraCT 2012-004411-31 
Doc No D-14.170 
 
Test Name 
Full 
Department 
Age 
Low 
Age 
Low 
Unit 
Age 
High 
Age 
High 
Unit 
Sex 
Conv. 
Ref. 
Interval 
Low 
Conv. 
Ref. 
Interval 
High 
Conv. 
Unit 
Conv. 
Factor 
SI to 
Conv 
SI 
Ref. 
Interval 
Low 
SI 
Ref. 
Interval 
High 
SI 
Unit 
Conv. 
Report 
limit 
Low 
SI 
Report 
limit 
Low 
MCHC 
Hematology 
5 
y 
999 
y 
M/F 
32.0 
37.0 
g/dL 
0.1 
320 
370 
g/L 
 
 
Leukocyte 
Count 
Hematology 
5 
y 
999 
y 
M/F 
4.0 
10.7 
x10E3/uL 
1 
4.0 
10.7 
x10E9/L 
 
 
Neutrophils (%) Hematology 
7 
y 
999 
y 
M/F 
43 
74 
% 
1 
43 
74 
% 
 
 
Total Lymphs 
(%) 
Hematology 
7 
y 
12 
y 
M/F 
12 
49 
% 
1 
12 
49 
% 
 
 
Total Lymphs 
(%) 
Hematology 
13 
y 
999 
y 
M/F 
20 
44 
% 
1 
20 
44 
% 
 
 
Monocytes (%) Hematology 
7 
y 
999 
y 
M/F 
3 
10 
% 
1 
3 
10 
% 
 
 
Eosinophils (%) Hematology 
7 
y 
12 
y 
M/F 
0 
6 
% 
1 
0 
6 
% 
 
 
Eosinophils (%) Hematology 
13 
y 
999 
y 
M/F 
0 
7 
% 
1 
0 
7 
% 
 
 
Basophils (%) Hematology 
31 
d 
999 
y 
M/F 
0 
2 
% 
1 
0 
2 
% 
 
 
Neutrophils 
(Abs) 
Hematology 
7 
y 
999 
y 
M/F 
1.6 
7.4 
x10E3/uL 
1 
1.6 
7.4 
x10E9/L 
 
 
Total Lymphs 
(Abs) 
Hematology 
7 
y 
12 
y 
M/F 
1.0 
3.9 
x10E3/uL 
1 
1.0 
3.9 
x10E9/L 
 
 
Total Lymphs 
(Abs) 
Hematology 
13 
y 
999 
y 
M/F 
1.0 
4.0 
x10E3/uL 
1 
1.0 
4.0 
x10E9/L 
 
 
Monocytes 
(Abs) 
Hematology 
7 
y 
999 
y 
M/F 
0.1 
0.9 
x10E3/uL 
1 
0.1 
0.9 
x10E9/L 
 
 
Eosinophils 
(Abs) 
Hematology 
7 
y 
12 
y 
M/F 
0.0 
0.5 
x10E3/uL 
1 
0.0 
0.5 
x10E9/L 
 
 
Eosinophils 
(Abs) 
Hematology 
13 
y 
999 
y 
M/F 
0.0 
0.7 
x10E3/uL 
1 
0.0 
0.7 
x10E9/L 
 
 


Macitentan / ACT-064992 
Eisenmenger Syndrome 
Protocol AC-055-308, MAESTRO-OL 
Final Version 4 
16 May 2014, page 89/102 
Confidential  
EudraCT 2012-004411-31 
Doc No D-14.170 
 
Test Name 
Full 
Department 
Age 
Low 
Age 
Low 
Unit 
Age 
High 
Age 
High 
Unit 
Sex 
Conv. 
Ref. 
Interval 
Low 
Conv. 
Ref. 
Interval 
High 
Conv. 
Unit 
Conv. 
Factor 
SI to 
Conv 
SI 
Ref. 
Interval 
Low 
SI 
Ref. 
Interval 
High 
SI 
Unit 
Conv. 
Report 
limit 
Low 
SI 
Report 
limit 
Low 
Basophils (Abs) Hematology 
31 
d 
999 
y 
M/F 
0.0 
0.2 
x10E3/uL 
1 
0.0 
0.2 
x10E9/L 
 
 
Platelets count Hematology 
5 
y 
14 
y 
M/F 
175 
420 
x10E3/uL 
1 
175 
420 
x10E9/L 
 
 
Platelets count Hematology 
15 
y 
999 
y 
M/F 
150 
350 
x10E3/uL 
1 
150 
350 
x10E9/L 
 
 
Reticulocytes 
(%) 
Hematology 
12 
y 
17 
y 
M/F 
0.7 
2.5 
% 
1 
0.7 
2.5 
% 
 
 
Reticulocytes 
(%) 
Hematology 
18 
y 
999 
y 
M/F 
0.7 
2.5 
% 
1 
0.7 
2.5 
% 
 
 
Reticulocytes 
(Abs) 
Hematology 
12 
y 
17 
y 
M/F 
25 
115 
x10E3/uL 
1 
25 
115 
x10E9/L 
 
 
Reticulocytes 
(Abs) 
Hematology 
18 
y 
999 
y 
M/F 
30 
110 
x10E3/uL 
1 
30 
110 
x10E9/L 
 
 
Iron 
Hematology 
0 
y 
999 
y 
M 
59 
178 
ug/dL 
5.58 
11 
32 
umol/L 
5 
1 
Iron 
Hematology 
0 
y 
999 
y 
F 
37 
173 
ug/dL 
5.58 
7 
31 
umol/L 
5 
1 
Ferritin 
Hematology 
0 
y 
999 
y 
M 
22 
322 
ug/L 
1 
22 
322 
ug/L 
 
 
Ferritin 
Hematology 
0 
y 
999 
y 
F 
10 
291 
ug/L 
1 
10 
291 
ug/L 
 
 
Transferrin 
Saturation 
Hematology 
0 
y 
999 
y 
M/F 
20 
55 
% 
1 
20 
55 
% 
 
 
TIBC 
Hematology 
0 
y 
999 
y 
M/F 
250 
452 
ug/dL 
5.58 
45 
81 
umol/L 
 
 


Macitentan / ACT-064992 
Eisenmenger Syndrome 
Protocol AC-055-308, MAESTRO-OL 
Final Version 4 
16 May 2014, page 90/102 
Confidential  
EudraCT 2012-004411-31 
Doc No D-14.170 
 
Test Name 
Full 
Department 
Age 
Low 
Age 
Low 
Unit 
Age 
High 
Age 
High 
Unit 
Sex 
Conv. 
Ref. 
Interval 
Low 
Conv. 
Ref. 
Interval 
High 
Conv. 
Unit 
Conv. 
Factor 
SI to 
Conv 
SI 
Ref. 
Interval 
Low 
SI 
Ref. 
Interval 
High 
SI 
Unit 
Conv. 
Report 
limit 
Low 
SI 
Report 
limit 
Low 
Sodium 
Chemistry 
0 
y 
999 
y 
M/F 
135 
148 
mmol/L 
1 
135 
148 
mmol/L 
 
 
Potassium 
Chemistry 
0 
y 
999 
y 
M/F 
3.5 
5.3 
mmol/L 
1 
3.5 
5.3 
mmol/L 
 
 
BUN (Urea) 
Chemistry 
10 
y 
15 
y 
M/F 
5 
18 
mg/dL 
2.801 
1.8 
6.4 
mmol/L 
2.0 
0.9 
BUN (Urea) 
Chemistry 
16 
y 
18 
y 
M/F 
5 
20 
mg/dL 
2.801 
1.8 
7.1 
mmol/L 
2.0 
0.9 
BUN (Urea) 
Chemistry 
19 
y 
999 
y 
M/F 
6 
25 
mg/dL 
2.801 
2.1 
8.9 
mmol/L 
2.0 
0.9 
Creatinine 
Chemistry 
4 
y 
12 
y 
M/F 
0.24 
0.77 
mg/dL 
0.0113 
21 
68 
umol/L 
0.20 
18 
Creatinine 
Chemistry 
13 
y 
18 
y 
M 
0.35 
1.20 
mg/dL 
0.0113 
31 
106 
umol/L 
0.20 
18 
Creatinine 
Chemistry 
13 
y 
18 
y 
F 
0.46 
1.00 
mg/dL 
0.0113 
41 
88 
umol/L 
0.20 
18 
Creatinine 
Chemistry 
19 
y 
999 
y 
M 
0.70 
1.20 
mg/dL 
0.0113 
62 
106 
umol/L 
0.20 
18 
Creatinine 
Chemistry 
19 
y 
999 
y 
F 
0.50 
0.91 
mg/dL 
0.0113 
44 
80 
umol/L 
0.20 
18 
Uric Acid 
Chemistry 
10 
y 
12 
y 
M/F 
2.2 
5.8 
mg/dL 
16.8 
0.13 
0.34 
mmol/L 
0.2 
0.01 
Uric Acid 
Chemistry 
13 
y 
15 
y 
M 
3.1 
7.0 
mg/dL 
16.8 
0.18 
0.42 
mmol/L 
0.2 
0.01 
Uric Acid 
Chemistry 
13 
y 
15 
y 
F 
2.2 
6.4 
mg/dL 
16.8 
0.13 
0.38 
mmol/L 
0.2 
0.01 
Uric Acid 
Chemistry 
16 
y 
59 
y 
M 
4.0 
8.5 
mg/dL 
16.8 
0.24 
0.51 
mmol/L 
0.2 
0.01 
Uric Acid 
Chemistry 
16 
y 
999 
y 
F 
2.5 
7.5 
mg/dL 
16.8 
0.15 
0.45 
mmol/L 
0.2 
0.01 


Macitentan / ACT-064992 
Eisenmenger Syndrome 
Protocol AC-055-308, MAESTRO-OL 
Final Version 4 
16 May 2014, page 91/102 
Confidential  
EudraCT 2012-004411-31 
Doc No D-14.170 
 
Test Name 
Full 
Department 
Age 
Low 
Age 
Low 
Unit 
Age 
High 
Age 
High 
Unit 
Sex 
Conv. 
Ref. 
Interval 
Low 
Conv. 
Ref. 
Interval 
High 
Conv. 
Unit 
Conv. 
Factor 
SI to 
Conv 
SI 
Ref. 
Interval 
Low 
SI 
Ref. 
Interval 
High 
SI 
Unit 
Conv. 
Report 
limit 
Low 
SI 
Report 
limit 
Low 
Uric Acid 
Chemistry 
60 
y 
999 
y 
M 
3.4 
8.7 
mg/dL 
16.8 
0.20 
0.52 
mmol/L 
0.2 
0.01 
Albumin 
Chemistry 
0 
y 
999 
y 
M/F 
3.2 
5.5 
g/dL 
0.1 
32 
55 
g/L 
 
 
Total Bilirubin 
Chemistry 
8 
d 
999 
y 
M/F 
0.1 
1.2 
mg/dL 
0.0585 
2 
21 
umol/L 
0.1 
2 
Direct Bilirubin 
Chemistry 
0 
y 
999 
y 
M/F 
0.0 
0.4 
mg/dL 
0.0585 
0 
7 
umol/L 
0 
0 
indirect Bilirubin
Chemistry 
0 
y 
999 
y 
M/F 
0.0 
0.7 
mg/dL 
0.0585 
0 
12 
umol/L 
 
 
AST 
Chemistry 
7 
y 
999 
y 
M/F 
0 
41 
U/L 
1 
0 
41 
U/L 
4 
4 
ALT 
Chemistry 
10 
y 
18 
y 
M 
5 
30 
U/L 
1 
5 
30 
U/L 
4 
4 
ALT 
Chemistry 
10 
y 
18 
y 
F 
5 
20 
U/L 
1 
5 
20 
U/L 
4 
4 
ALT 
Chemistry 
19 
y 
999 
y 
M/F 
0 
45 
U/L 
1 
0 
45 
U/L 
4 
4 
AP (Alk Phos) 
Chemistry 
1 
y 
12 
y 
M/F 
0 
299 
U/L 
1 
0 
299 
U/L 
1 
1 
AP (Alk Phos) 
Chemistry 
13 
y 
17 
y 
M 
0 
389 
U/L 
1 
0 
389 
U/L 
1 
1 
AP (Alk Phos) 
Chemistry 
13 
y 
17 
y 
F 
0 
186 
U/L 
1 
0 
186 
U/L 
1 
1 
AP (Alk Phos) 
Chemistry 
18 
y 
999 
y 
M 
40 
129 
U/L 
1 
40 
129 
U/L 
1 
1 
AP (Alk Phos) 
Chemistry 
18 
y 
999 
y 
F 
35 
104 
U/L 
1 
35 
104 
U/L 
1 
1 
LDH 
Chemistry 
7 
y 
12 
y 
M 
145 
325 
U/L 
1 
145 
325 
U/L 
5 
5 


Macitentan / ACT-064992 
Eisenmenger Syndrome 
Protocol AC-055-308, MAESTRO-OL 
Final Version 4 
16 May 2014, page 92/102 
Confidential  
EudraCT 2012-004411-31 
Doc No D-14.170 
 
Test Name 
Full 
Department 
Age 
Low 
Age 
Low 
Unit 
Age 
High 
Age 
High 
Unit 
Sex 
Conv. 
Ref. 
Interval 
Low 
Conv. 
Ref. 
Interval 
High 
Conv. 
Unit 
Conv. 
Factor 
SI to 
Conv 
SI 
Ref. 
Interval 
Low 
SI 
Ref. 
Interval 
High 
SI 
Unit 
Conv. 
Report 
limit 
Low 
SI 
Report 
limit 
Low 
LDH 
Chemistry 
7 
y 
12 
y 
F 
140 
280 
U/L 
1 
140 
280 
U/L 
5 
5 
LDH 
Chemistry 
13 
y 
15 
y 
M 
120 
290 
U/L 
1 
120 
290 
U/L 
5 
5 
LDH 
Chemistry 
13 
y 
15 
y 
F 
100 
275 
U/L 
1 
100 
275 
U/L 
5 
5 
LDH 
Chemistry 
16 
y 
999 
y 
M 
100 
242 
U/L 
1 
100 
242 
U/L 
5 
5 
LDH 
Chemistry 
16 
y 
999 
y 
F 
100 
220 
U/L 
1 
100 
220 
U/L 
5 
5 
Glucose 
Chemistry 
0 
y 
999 
y 
M/F 
70 
140 
mg/dL 
18.0147
7 
3.9 
7.8 
mmol/L 
 
 
Calcium 
Chemistry 
0 
y 
999 
y 
M/F 
8.6 
10.5 
mg/dL 
4.0 
2.14 
2.62 
mmol/L 
 
 
Magnesium 
Chemistry 
0 
y 
999 
y 
M/F 
1.8 
2.4 
mg/dL 
2.43 
0.74 
0.99 
mmol/L 
0.1 
0.03 
Pregnancy 
(serum) 
Immunochem
istry 
0 
y 
999 
y 
F 
0 
9 
mIU/mL 
1 
0 
9 
IU/L 
2 
2 
 
 
 
 
 
 
 


Macitentan / ACT-064992 
Eisenmenger Syndrome 
Protocol AC-055-308, MAESTRO-OL 
Final Version 4 
16 May 2014, page 93/102 
Confidential  
EudraCT 2012-004411-31 
Doc No D-14.170 
 
Appendix 6 
Alert flags 
Exclusionary (TE) Alert Value - At Enrollment (V1) 
 
 
 
 
 
Test Name Full 
Age Low 
Age Low Unit 
Age High 
Age High Unit 
Sex 
xULN 
Alert Range 
Conventional 
Conventional 
Unit 
Alert Range SI 
SI Unit 
Hemoglobin 
5 
y 
14 
y 
M/F 
< 75 % LLN 
< 8.6 
g/dL 
< 86 
g/L 
Hemoglobin 
15 
y 
999 
y 
M 
< 75 % LLN 
< 10.2 
g/dL 
< 102 
g/L 
Hemoglobin 
15 
y 
999 
y 
F 
< 75 % LLN 
< 9.0 
g/dL 
< 90 
g/L 
Hematocrit 
5 
y 
14 
y 
M/F 
< 75% LLN 
< 27 
% 
< 0.27 
L/L 
Hematocrit 
15 
y 
999 
y 
M 
< 75% LLN 
< 30 
% 
< 0.30 
L/L 
Hematocrit 
15 
y 
999 
y 
F 
< 75% LLN 
< 27 
% 
< 0.27 
L/L 
AST 
7 
y 
999 
y 
M/F 
>3 ULN 
> 123 
U/L 
> 123 
U/L 
ALT 
10 
y 
18 
y 
M 
>3 ULN 
> 90 
U/L 
> 90 
U/L 
ALT 
10 
y 
18 
y 
F 
>3 ULN 
> 60 
U/L 
> 60 
U/L 
ALT 
19 
y 
999 
y 
M/F 
>3 ULN 
> 135 
U/L 
> 135 
U/L 
Pregnancy (serum) 
0 
y 
999 
y 
F 
 
>9 
mIU/mL 
>9 
IU/L 
 
 
 
 
 
 
 


Macitentan / ACT-064992 
Eisenmenger Syndrome 
Protocol AC-055-308, MAESTRO-OL 
Final Version 4 
16 May 2014, page 94/102 
Confidential  
EudraCT 2012-004411-31 
Doc No D-14.170 
 
Exclusionary (TY) Alert Value - At Enrollment (V1) 
 
 
 
 
 
 
Test Name Full 
Age Low 
Age Low Unit 
Age High 
Age High Unit 
Sex 
xULN 
Alert Range 
Conventional 
Conventional 
Unit 
Alert Range SI 
SI Unit 
total bilirubin 
0 
y 
999 
y 
M/F 
> 3 ULN 
> 3.6 
mg/dL 
> 63 
umol/L 
 
AST 
7 
y 
18 
y 
M/F 
> ULN 
> 41 
U/L 
> 41 
U/L 
 
 
 
 
 
 
Total Bilirubin flag (TB) Alert Value - All visits  
 
 
 
 
Test Name Full 
Age Low 
Age Low Unit 
Age High 
Age High Unit 
Sex 
xULN 
Alert Range 
Conventional 
Conventional 
Unit 
Alert Range SI 
SI Unit 
total bilirubin 
0 
y 
999 
y 
M/F 
> 2 x ULN 
> 2.4 
mg/dL 
> 42 
umol/L 
 
 
 
 
 
 
 
 


Macitentan / ACT-064992 
Eisenmenger Syndrome 
Protocol AC-055-308, MAESTRO-OL 
Final Version 4 
16 May 2014, page 95/102 
Confidential  
EudraCT 2012-004411-31 
Doc No D-14.170 
 
 
Study medication stop (TM) Alert Value - All visits except enrollment visit (V1) 
 
Test Name Full 
Age Low 
Age Low Unit 
Age High 
Age High Unit 
Sex 
xULN 
Alert Range 
Conventional 
Conventional 
Unit 
Alert Range SI 
SI Unit 
AST 
7 
y 
999 
y 
M/F 
> 8 x ULN 
> 328 
U/L 
> 328 
U/L 
ALT 
10 
y 
18 
y 
M 
> 8 x ULN 
> 240 
U/L 
> 240 
U/L 
ALT 
10 
y 
18 
y 
F 
> 8 x ULN 
> 160 
U/L 
> 160 
U/L 
ALT 
19 
y 
999 
y 
M/F 
> 8 x ULN 
> 360 
U/L 
> 360 
U/L 
Pregnancy (serum) 
0 
y 
999 
y 
F 
 
>9 
mIU/mL 
>9 
IU/L 
 
 
 
Repeat (TR) Alert value - All visits except enrollment visit (V1)  
 
Test Name Full 
Age Low 
Age Low Unit 
Age High 
Age High Unit 
Sex 
xULN 
Alert Range 
Conventional 
Conventional 
Unit 
Alert Range SI 
SI Unit 
AST 
7 
y 
999 
y 
M/F 
> 3 x ULN 
> 123 
U/L 
> 123 
U/L 
ALT 
10 
y 
18 
y 
M 
> 3 x ULN 
> 90 
U/L 
> 90 
U/L 
ALT 
10 
y 
18 
y 
F 
> 3 x ULN 
> 60 
U/L 
> 60 
U/L 
ALT 
19 
y 
999 
y 
M/F 
> 3 x ULN 
> 135 
U/L 
> 135 
U/L 


Macitentan / ACT-064992 
Eisenmenger Syndrome 
Protocol AC-055-308, MAESTRO-OL 
Final Version 4 
16 May 2014, page 96/102 
Confidential  
EudraCT 2012-004411-31 
Doc No D-14.170 
 
 
Notable (T) Alert Values – All Visits 
 
Test Name Full 
Age Low 
Age Low Unit 
Age High 
Age High Unit 
Sex 
xULN 
Alert Range 
Conventional 
Conventional 
Unit 
Alert Range SI 
SI Unit 
Hemoglobin 
0 
y 
999 
y 
M/F 
 
< 7.0 and > 
20.0 
g/dL 
< 70 and > 200 
g/L 
Leucocyte Count 
0 
y 
999 
y 
M/F 
 
< 2.0 and > 
35.0 
x10E3/uL 
< 2.0 and > 35.0 
x10E9/L 
Platelets count 
0 
y 
999 
y 
M/F 
 
< 50 and > 
1000 
x10E3/uL 
< 50 and > 1000 
x10E9/L 
ALT 
0 
y 
999 
y 
M/F 
>2000 
U/L 
>2000 
U/L 
Calcium 
0 
y 
999 
y 
M/F 
 
<6.0 and 
>12.0 
mg/dL 
<1.50 and >3.00 
mmol/L 
Sodium 
0 
y 
999 
y 
M/F 
 
< 125 and > 
155 
mmol/L 
< 125 and > 155 
mmol/L 
Potassium 
0 
y 
999 
y 
M/F 
 
< 2.5 and > 
6.5 
mmol/L 
< 2.5 and > 6.5 
mmol/L 
Creatinine 
0 
y 
999 
y 
M/F 
> 3.39 
mg/dL 
> 300 
umol/L 
Glucose 
0 
y 
999 
y 
M/F 
 
< 40 and > 
500 
mg/dL 
< 2.2 and > 27.8 
mmol/L 
 
 
 
 
 
 
 
 
 
 


Macitentan / ACT-064992 
Eisenmenger Syndrome 
Protocol AC-055-308, MAESTRO-OL 
Final Version 4 
16 May 2014, page 97/102 
Confidential  
EudraCT 2012-004411-31 
Doc No D-14.170 
 
Notable (TF) alert Values - All visits except enrollment visit (V1) 
 
Test Name Full 
Age Low 
Age Low Unit 
Age High 
Age High Unit 
Sex 
xULN 
Alert Range 
Conventional 
Conventional 
Unit 
Alert Range SI 
SI Unit 
Hemoglobin 
0 
y 
999 
y 
M/F 
 
> 2.0 decrease 
from baseline 
g/dL 
> 20 decrease from 
baseline 
g/L 
 
 
 
 
Notable (TG) alert Values - All visits except enrollment visit (V1) 
 
Test Name Full 
Age Low 
Age Low Unit 
Age High 
Age High Unit 
Sex 
xULN 
Alert Range 
Conventional 
Conventional 
Unit 
Alert Range SI 
SI Unit 
Hemoglobin 
0 
y 
999 
y 
M/F 
 
< 8.0 
g/dL 
< 80 
g/L 
Hemoglobin 
0 
y 
999 
y 
M/F 
 
> 5.0 decrease 
from baseline 
g/dL 
> 50 decrease from 
baseline 
g/L 
 
 
 
 
 
 
 


Macitentan / ACT-064992 
Eisenmenger Syndrome 
Protocol AC-055-308, MAESTRO-OL 
Final Version 4 
16 May 2014, page 98/102 
Confidential  
EudraCT 2012-004411-31 
Doc No D-14.170 
 
Flag 
Legend 
H 
The result is above the upper limit of the reference range for normal subjects. 
L 
The result is below the lower limit of the reference range for normal subjects. 
TE 
The result is outside the study specific defined limit for inclusion in the study. 
TY 
Subject should be excluded only if the TY flag is appearing for both AST and bilirubin. 
TB  
In combination with TR (ALT and/or AST) on the report, study medication should be stopped. 
TM 
Please refer to the study protocol; study medication must be stopped. 
TR 
In case there is no TM flag a repeat testing is needed. 
TF 
Repeat testing is needed. 
TG 
Please refer to the study protocol; study medication should be interrupted. 
T 
Notable value.  
 


Macitentan / ACT-064992 
Eisenmenger Syndrome 
Protocol AC-055-308, MAESTRO-OL 
Final Version 4 
16 May 2014, page 99/102 
Confidential  
EudraCT 2012-004411-31 
Doc No D-14.170 
 
Appendix 7 
List of protocol amendments  
Document Date 
Global Amendment 
Changes 
3 Apr 2013 
Amendment 1, and resulting 
Global Protocol Version 2  
 
A summary of the potential risks associated with macitentan and the methodology for 
risk management were added. 
 
Group 1 contraceptive methods were revised to add non-surgical sterilization methods 
(e.g., the Essure procedure) 
 
Measures to be taken with the study medication in the event of significantly decreased 
hemoglobin (to < 8.0 g/dL, of more than 0.5 g/dL from baseline, or requiring 
transfusion) were added, including a temporary interruption-re-introduction schedule or 
permanent discontinuation.  
 
Sections related to liver function monitoring and study treatment adjustments were 
slightly modified to: 
(a) consider other etiologies (e.g., acetaminophen -related liver toxicity) by performing 
appropriate tests. 
(b) ensure that all local laboratory data used to monitor ALT and/or AST > 3 ULN 
were collected in the eCRF along with the normal ranges. In addition, the corresponding 
total and direct bilirubin values were required to be entered into the eCRF. 
 
Sections related to study assessments (for e.g., review of the documents, order of 
assessments, 6MWT and Borg dyspnea index, etc.) were slightly modified in order to 
clarify the instructions relevant to the investigators. 
 
References to “major and minor” protocol deviations were removed. 
 
The “risks” section of the ICF was revised to account for the possibility of interruption 
or permanent discontinuation of study medication based on specific decreases in 
hemoglobin levels. 
 
The ICF was revised to include additional information about the potential risk of 
macitentan to align with updates to the Macitentan IB for non-oncology indications. 
The ICF was also updated to clarify the duties of the trial subjects following a change in 
the sponsor’s insurance company. 


Macitentan / ACT-064992 
Eisenmenger Syndrome 
Protocol AC-055-308, MAESTRO-OL 
Final Version 4 
16 May 2014, page 100/102 
Confidential  
EudraCT 2012-004411-31 
Doc No D-14.170 
 
 
19 Sep 2013 
Amendment 2, and resulting 
Global Protocol Version 3  
 
The number of study sites was increased to improve the rate of recruitment. 
 
Results of all protocol-mandated laboratory assessments to be collected in the database. 
A Central Laboratory was to be used for the analysis of all laboratory variables 
requested in the protocol. 
 
Results of all assessments requested for the purpose of the study were to be collected in 
the clinical database. 
 
Monthly laboratory and safety monitoring at a site visit was added in order to improve 
sponsor oversight. 
 
Analysis of all laboratory samples in a central laboratory within confirmation of 
eligibility via local laboratory were added. 
 
The reason for permanent discontinuation was now documented in the eCRF. 
 
Throughout the protocol, upper limits for liver abnormality were updated to reflect the 
FDA guidance on DILI (i.e., > 3 × ULN, rather than ≥ 3 × ULN for ALT/AST and 
> 2 × ULN rather than ≥ 2 × ULN for total bilirubin). 
 
For hemoglobin monitoring, clarification on re-tests for assessing hemoglobin change 
was provided. 
 
Assessment and recording of methods of contraception was changed to occur at each 
visit. 
 
Collection of information on concomitant medication was extended to all visits. 
 
Instructions for collection and handling of local laboratory samples and, where 
applicable, reporting of results within the eCRF of local analyses of local laboratory 
samples were added. 
 
Instructions on performing and recording unscheduled visits were added.] 
 
Updated definitions of alert flags for abnormal laboratory values were included in the 
appropriate appendix. 
 
The ICF was updated to reflect the increased number of planned study sites. 
 
The ICF was updated to reflect the assessment and recording of methods of 
contraception was changed to occur at each visit. 
 
The ICF was updated to reflect the expanded instructions for unscheduled visits. 
 
The risk section of the ICF was updated to account for the latest results of controlled 
studies. 


Macitentan / ACT-064992 
Eisenmenger Syndrome 
Protocol AC-055-308, MAESTRO-OL 
Final Version 4 
16 May 2014, page 101/102 
Confidential  
EudraCT 2012-004411-31 
Doc No D-14.170 
 
 
16 May 2014 
Amendment 3, and resulting 
Global Protocol Version 4  
 
 
The recruitment period was made consistent with the updated study planned duration of 
the AC-055-305 / MAESTRO-DB study. 
 
The SBP exclusion criterion was lowered to SBP < 85 mmHg. 
 
The hepatic exclusion criterion was updated to exclude “severe hepatic failure” 
 
Eligibility criteria was opened up to females of childbearing potential truly abstinent 
and to subjects with DS (if they had support from a caregiver or family member). 
 
To address anticipated difficulties in DS subjects, adaptations were made to the 6MWT 
to accommodate these subjects and to safeguard study outcome. 
 
The schedule of visits and assessments was updated to mention the monthly assessment 
of methods of contraception. Unscheduled visits were re-labeled from A to U. 
 
The number of study centers selected for the AC-055-305 / MAESTRO-DB study was 
increased to improve recruitment speed. The same change was implemented in the 
MAESTRO-OL protocol. 
 
Clarification regarding which prohibited concomitant treatments must lead to study 
treatment discontinuation was added. 
 
To be consistent with section 3.9.1.4.4, “Hemoglobin concentration monitoring”, a 
correction was made to the examples of local laboratory results that were collected in 
the eCRF. 
 
Clarifications were added on when to perform the requested laboratory re-tests for 
hemoglobin monitoring. 
 
The timeline to review the laboratory report was shortened in order to identify any 
potential clinically significant abnormality as early as possible. The measurement of 
peripheral oxygen saturation in subjects with patent ductus arteriosus is unstable on 
upper extremities. For baseline, the lower extremities are used. For assessment in the 
context of 6MWTs, the best pulsatile vascular bed is chosen. 
 
Information collected in the eCRF for each concomitant medication includes the 
frequency. Methods of contraception and changes in concomitant medications are 
assessed and reported in the eCRF at each visit. 
 
Clarifications on medication errors and pre-existing medical conditions were added. 
 
The sponsor Global Drug Safety department collected AEs related to menstrual 
disorders to comply with the EU RMP for the marketed compound. 
 
The ICF was updated to reflect the protocol changes. 


Macitentan / ACT-064992 
Eisenmenger Syndrome 
Protocol AC-055-308, MAESTRO-OL 
Final Version 4 
16 May 2014, page 102/102 
Confidential  
EudraCT 2012-004411-31 
Doc No D-14.170 
 
6MWT = 6-minute walk test; ALT = alanine aminotransferase; AST = aspartate aminotransferase;  DILI = drug-induced liver injury; DS = Down Syndrome; 
eCRF = electronic Case Report Form;  FDA = (US) Food and Drug Administration; IB = Investigator’s Brochure; ICF = Informed Consent Form; LFT = liver 
function test; LT = liver test; RMP = risk management plan; SBP = systolic blood pressure; ULN = upper limit of normal; VHP = Voluntary Harmonisation 
Procedure. 
 

SAP_001.pdf: 
 
 
TPL-000241 v02 
 
 
 
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY 
REPORT 
AC-055-308 / MAESTRO-OL 
Long-term, single-arm, open-label extension study of protocol AC-055-305 
to assess the safety, tolerability and efficacy of macitentan in subjects with 
Eisenmenger Syndrome 
 
Purpose of Analysis 
Clinical Study Report 
Investigational Drug 
Macitentan / ACT-064992 
Protocol Number 
AC-055-308 / MAESTRO-OL 
Actelion Document Number 
D-17.554 
Document Status/Version Number 
Final 1.0 
Date 
6 December 2017 
 
Author 
 
Reviewer 
 
Reviewer 
  
Reviewer 
 
Reviewer 
 
Reviewer 
 
Reviewer 
 
Reviewer 
 
 
Reviewer 
 
Reviewer 
 
 
Reviewer 
 
Confidentiality statement 
Property of Actelion Pharmaceuticals Ltd. May not be used, divulged, published or 
otherwise disclosed without the consent of Actelion Pharmaceuticals Ltd. 


Macitentan / ACT-064992 
Study AC-055-308, MAESTRO-OL 
Version 1.0 
6 December 2017, page 2/58 
Confidential  
Statistical Analysis Plan 
Doc No D-17.554 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND ACRONYMS ............................................................7 
1 
INTRODUCTION .........................................................................................................9 
2 
STUDY DESIGN AND FLOW ....................................................................................9 
2.1 
Study design ...................................................................................................9 
2.2 
Study visit and assessment schedule ..............................................................9 
3 
OBJECTIVES .............................................................................................................13 
3.1 
Primary objective(s) .....................................................................................13 
4 
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE 
STUDY PROTOCOL .................................................................................................13 
4.1 
Changes to the analyses planned in the study protocol ................................13 
5 
DEFINITIONS OF VARIABLES ..............................................................................14 
5.1 
Screening failures .........................................................................................14 
5.2 
Subject characteristics ..................................................................................14 
5.2.1 
Demographics ...................................................................................14 
5.2.2 
Baseline disease characteristics ........................................................15 
5.2.2.1 
General characteristics ............................................................15 
5.2.3 
Medical history .................................................................................15 
5.2.4 
Previous and concomitant therapies .................................................15 
5.2.4.1 
Previous therapies ....................................................................15 
5.2.4.2 
Study-concomitant therapies ...................................................16 
5.2.5 
Other subject characteristics .............................................................16 
5.2.5.1 
Contraceptive methods ............................................................16 
5.3 
Study treatment exposure and compliance ...................................................16 
5.3.1 
Exposure ...........................................................................................16 
5.3.2 
Compliance with study treatment .....................................................17 
5.3.3 
Study treatment discontinuation .......................................................17 
5.3.4 
Study treatment adjustments or interruptions ...................................18 
5.4 
Study discontinuation ...................................................................................18 
5.5 
Efficacy variables .........................................................................................19 
5.5.1 
Efficacy variable: 6MWD .................................................................19 
5.5.2 
Efficacy variable: WHO functional class .........................................19 
5.5.3 
Efficacy variable: Borg dyspnea index .............................................20 
5.5.4 
Efficacy variable: SpO2 ....................................................................20 
5.6 
Safety variables .............................................................................................20 


Macitentan / ACT-064992 
Study AC-055-308, MAESTRO-OL 
Version 1.0 
6 December 2017, page 3/58 
Confidential  
Statistical Analysis Plan 
Doc No D-17.554 
 
5.6.1 
Adverse events ..................................................................................21 
5.6.1.1 
Treatment-emergent AEs ........................................................21 
5.6.1.2 
Frequency of treatment-emergent AEs ....................................21 
5.6.1.3 
Intensity of treatment-emergent AEs ......................................21 
5.6.1.4 
Relationship of treatment-emergent AEs ................................21 
5.6.2 
Deaths ...............................................................................................22 
5.6.3 
Serious adverse events ......................................................................22 
5.6.4 
Adverse events leading to premature discontinuation of study 
treatment ...........................................................................................22 
5.6.5 
Other significant adverse events .......................................................22 
5.6.5.1 
AEs with fatal outcome ...........................................................22 
5.6.5.2 
AEs of special interest (AESI) ................................................22 
5.6.5.3 
Non-serious AEs ......................................................................23 
5.6.6 
Vital signs and body weight ..............................................................23 
5.6.7 
Electrocardiogram .............................................................................24 
5.6.8 
Laboratory .........................................................................................24 
5.6.8.1 
MLAs .......................................................................................25 
5.6.8.2 
Additional liver and hemoglobin laboratory 
abnormalities ...........................................................................27 
5.6.9 
Other safety variables .......................................................................28 
5.6.9.1 
Physical examination ...............................................................28 
6 
DEFINITION OF PROTOCOL DEVIATIONS .........................................................28 
7 
ANALYSIS SETS .......................................................................................................28 
7.1 
Definitions of analysis sets ...........................................................................28 
7.1.1 
All-enrolled set .................................................................................28 
7.1.2 
All-treated DB + OL set....................................................................29 
7.2 
Usage of the analysis sets .............................................................................29 
8 
DEFINITION OF SUBGROUPS ................................................................................29 
9 
GENERAL STATISTICAL METHODOLOGY ........................................................29 
9.1 
Statistical methods for efficacy data .............................................................30 
9.2 
Statistical methods for safety data ................................................................30 
10 STATISTICAL ANALYSES ......................................................................................30 
10.1 
Overall testing strategy .................................................................................30 
10.2 
General rules for data presentations .............................................................30 
10.3 
Display of subject disposition, protocol deviations and analysis sets ..........31 
10.3.1 
Subject disposition ............................................................................31 


Macitentan / ACT-064992 
Study AC-055-308, MAESTRO-OL 
Version 1.0 
6 December 2017, page 4/58 
Confidential  
Statistical Analysis Plan 
Doc No D-17.554 
 
10.3.2 
Protocol deviations ...........................................................................32 
10.3.3 
Analysis sets .....................................................................................32 
10.4 
Analyses of subject characteristics ...............................................................32 
10.4.1 
Demographics ...................................................................................32 
10.4.2 
Baseline disease characteristics ........................................................32 
10.4.3 
Medical history .................................................................................32 
10.4.4 
Previous and concomitant therapies .................................................33 
10.4.5 
Other subject characteristics .............................................................33 
10.4.5.1 
Contraceptive methods ............................................................33 
10.5 
Analysis of study treatment exposure and compliance.................................33 
10.5.1 
Exposure ...........................................................................................33 
10.5.2 
Compliance with study treatment .....................................................34 
10.5.3 
Study treatment discontinuation .......................................................34 
10.5.4 
Study treatment adjustments and interruptions .................................34 
10.6 
Analysis of efficacy variables .......................................................................34 
10.6.1 
Efficacy variable: 6MWD .................................................................35 
10.6.1.1 
Handling of missing data .........................................................35 
10.6.2 
Efficacy variable: WHO functional class .........................................35 
10.6.2.1 
Handling of missing data .........................................................36 
10.6.3 
Efficacy variable: Borg dyspnea index .............................................36 
10.6.3.1 
Handling of missing data .........................................................36 
10.6.4 
Efficacy variable: SpO2 ....................................................................37 
10.6.4.1 
Handling of missing data .........................................................37 
10.6.5 
Supportive/sensitivity analyses .........................................................37 
10.6.6 
Subgroup analyses ............................................................................37 
10.7 
Analysis of safety variables ..........................................................................37 
10.7.1 
Adverse events ..................................................................................37 
10.7.2 
Deaths, other serious adverse events ................................................38 
10.7.2.1 
Death .......................................................................................38 
10.7.2.2 
SAEs ........................................................................................38 
10.7.2.3 
AEs leading to premature discontinuation of study 
treatment ..................................................................................39 
10.7.2.4 
Other significant AEs ..............................................................39 
10.7.3 
Electrocardiography ..........................................................................39 
10.7.4 
Laboratory tests .................................................................................39 
10.7.4.1 
MLAs .......................................................................................40 
10.7.5 
Vital signs and body weight ..............................................................40 
10.7.6 
Other safety variables .......................................................................41 
10.7.6.1 
Physical examination ...............................................................41 
11 GENERAL DEFINITIONS AND DERIVATIONS ...................................................41 


Macitentan / ACT-064992 
Study AC-055-308, MAESTRO-OL 
Version 1.0 
6 December 2017, page 5/58 
Confidential  
Statistical Analysis Plan 
Doc No D-17.554 
 
11.1 
OL enrollment date .......................................................................................41 
11.2 
End-of-Study date .........................................................................................41 
11.3 
Study treatment start date .............................................................................41 
11.3.1 
DB treatment start date .....................................................................41 
11.3.2 
OL treatment start date .....................................................................41 
11.3.3 
Macitentan treatment start date .........................................................41 
11.4 
Study treatment end date/study treatment discontinuation (EOT) ...............42 
11.4.1 
DB treatment end date ......................................................................42 
11.4.2 
OL treatment end date .......................................................................42 
11.4.3 
Macitentan treatment end date ..........................................................42 
11.5 
Period ............................................................................................................42 
11.5.1 
DB period ..........................................................................................42 
11.5.2 
OL period ..........................................................................................42 
11.5.3 
DB + OL period ................................................................................42 
11.6 
Study Day (Day) ...........................................................................................42 
11.6.1 
OL study day .....................................................................................42 
11.6.2 
DB study day ....................................................................................43 
11.7 
Baseline ........................................................................................................43 
12 HANDLING OF MISSING/INCOMPLETE DATE AND TIME FIELDS ...............43 
13 LIST OF SUMMARY TABLES, LISTINGS AND FIGURES .................................44 
13.1 
Subject disposition ........................................................................................45 
13.2 
Protocol deviations .......................................................................................45 
13.3 
Subject characteristics ..................................................................................45 
13.3.1 
Demographics ...................................................................................45 
13.3.2 
Baseline disease characteristics ........................................................46 
13.3.3 
Medical history .................................................................................46 
13.3.4 
Previous and concomitant therapies .................................................46 
13.3.5 
Specific previous and concomitant therapies ....................................47 
13.3.6 
Other subject characteristics .............................................................47 
13.3.6.1 
Contraceptive methods ............................................................47 
13.4 
Study treatment exposure and compliance ...................................................47 
13.4.1 
Exposure ...........................................................................................47 
13.4.2 
Compliance with study treatment .....................................................48 
13.4.3 
Study treatment discontinuation .......................................................48 
13.4.4 
Study treatment adjustment/interruptions .........................................48 
13.5 
Study discontinuation ...................................................................................48 
13.6 
Efficacy analyses ..........................................................................................49 
13.7 
Safety analyses .............................................................................................50 
13.7.1 
Adverse events ..................................................................................50 


Macitentan / ACT-064992 
Study AC-055-308, MAESTRO-OL 
Version 1.0 
6 December 2017, page 6/58 
Confidential  
Statistical Analysis Plan 
Doc No D-17.554 
 
13.7.2 
Deaths ...............................................................................................50 
13.7.3 
Serious adverse events ......................................................................51 
13.7.4 
Adverse events leading to premature discontinuation of study 
treatment ...........................................................................................52 
13.7.5 
Other significant adverse events .......................................................53 
13.7.5.1 
AEs with fatal outcome ...........................................................53 
13.7.5.2 
AEs of special interest .............................................................53 
13.7.5.3 
Non-serious AEs ......................................................................54 
13.8 
Electrocardiogram ........................................................................................54 
13.9 
Laboratory tests ............................................................................................54 
13.10 
Vital signs and body weight .........................................................................56 
13.11 
Other safety variables ...................................................................................56 
13.11.1 
Physical Examination .......................................................................56 
14 REFERENCES ............................................................................................................57 
15 APPENDICES .............................................................................................................58 
 
LIST OF TABLES 
 
Table 1 
Visit and assessment schedule ........................................................................10 
Table 2 
Definition of marked laboratory abnormalities ...............................................26 
Table 3 
Overview of the different analysis sets and their usage ..................................29 
 
LIST OF APPENDICES 
 
Appendix A 
Document history ..............................................................................58 
 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
6MWD  
6-minute walk distance 
6MWT  
6-minute walk test 
AE  
Adverse event 
AESI  
Adverse events of special interest 
ALT  
Alanine aminotransferase 
AST  
Aspartate aminotransferase 
ATC  
Anatomic Therapeutic Chemical 
BMI  
Body Mass Index 
BP  
Blood pressure 
CDDM  
Clinical Development Data Management 
CL  
Confidence limit(s) 
CSR  
Clinical study report 
DB  
Double-blind 
DBP  
Diastolic blood pressure 
eCRF  
Electronic case report form 
ENR  
All-enrolled analysis set 
EOS  
End-of-Study 
EOT  
End-of-Treatment 
ES  
Eisenmenger Syndrome 
ICE  
Integrated computer environment 
IXRS  
Interactive Voice or Web Response System 
LOCF  
Last observation carried forward 
MedDRA  
Medical Dictionary for Regulatory Activities 
MLA  
Marked laboratory abnormalities 
NT-pro-BNP  
N-terminal pro-B type natriuretic peptide 
NYHA  
New York Heart Association 
OL  
Open-label 


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PD  
Protocol deviation 
PDE-5  
Phosphodiesterase-5 
PR  
Pulse rate 
PT  
Preferred Term 
SAE  
Serious adverse event 
SAP  
Statistical Analysis Plan 
SAS  
Statistical Analysis System 
SBP  
Systolic blood pressure 
SD  
Standard deviation 
SDTM  
Study Data Tabulation Model 
SI  
Standard International 
SMQ  
Standardised MedDRA Query 
SOC  
System organ class 
SpO2  
Saturation of peripheral oxygen 
TLF  
Tables Listings Figures 
TTS  
All-treated DB + OL set 
ULN  
Upper limit of the normal range 
WHO  
World Health Organization 
WHODRUG  
WHO drug dictionary 


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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes in detail the conduct and content of the 
statistical analyses of safety and efficacy data, for the purpose of the Clinical Study 
Report (CSR) of the open-label (OL) study AC-055-308 (MAESTRO-OL), hereafter 
referred to as the OL study.  
Study data tabulation model (SDTM) datasets of the OL study provided by Actelion 
Clinical Development Data Management (CDDM) via the Integrated Computer 
Environment (ICE) system and Analysis Data Model datasets from the AC-055-305 
(MAESTRO) CSR, hereafter referred to as the double-blind (DB) study, are used as 
source data for the statistical analyses.  
A separate programming specification and conventions document has been prepared in 
line with this document to provide programming details necessary for implementing the 
statistical analysis. 
2 
STUDY DESIGN AND FLOW 
AC-055-308 protocol version 4 [16 May 2014, D-14.170] is used as reference.  
2.1 Study design 
This trial is an OL, non-comparative, multi-center, Phase 3 extension study of protocol 
AC-055-305, which aims to assess the long-term safety, tolerability and efficacy of 
macitentan in subjects with Eisenmenger Syndrome (ES). 
A total of 226 subjects were randomized in a 1:1 ratio to macitentan 10 mg (n = 114) and 
placebo (n = 112) in the MAESTRO DB study. Subjects who completed the DB 
AC-055-305/MAESTRO study as scheduled (i.e., remained in the DB study up to 
Week 16, whether or not they were still taking study drug at the end of this period) were 
eligible to enter into the OL study, unless the DB treatment was discontinued for a safety 
issue. Subjects were rolled over from the AC-055-305 study to this OL study without 
knowledge of their previous study drug (macitentan or placebo). 
The OL study is being conducted in 51 centers in 19 countries. 
Protocol-mandated procedures and assessments are performed according to the visit 
and assessment schedule in Table 1. 
2.2 Study visit and assessment schedule 
See Table 1 for a detailed plan of the visit and assessment schedule [AC-055-308 
protocol version 4, 16 May 2014, D-14.170]. 
 


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Table 1 
Visit and assessment schedule 
PERIODS 
TREATMENT 
FOLLOW-UP 
 
VISITS 
Number 
1 
2 
Monthly Lab & 
Safety 
Monitoring5 
3, 4 
5, 6, etc. 
EOT 
Safety follow-
up / EOS 
U1, 2,… 
Name 
Enrollment2 
Month 1 
Month 
6,
Month 12 
Month 
18, 
Month 24, etc.  
Unscheduled 
visits6 
Time 
Day 1 
Month 1 
± 1 week 
Month 2 & 
every month 
thereafter up to 
EOT ± 1 week 
Month 6 
& Month 12 
± 2 weeks 
Month 18 & every 
6 months 
thereafter  
± 2 weeks 
Within 7 
days after 
study drug 
disc. 
30–33 days 
after study 
drug disc. 
Anytime 
during the 
study 
Informed consent / assent 
X 
 
 
 
 
 
 
 
Vital signs, body weight, 
physical examination 
X  
X  
 
X 
X 
X 
 
X6 
Concomitant medications 
X  
X  
X 
X 
X 
X 
X 
X6 
SpO2 
X 
 
 
X 
 
X 
 
X6 
WHO functional class / 
6MWT/Borg dyspnea index 
X 
 
 
X 
 
X 
 
X6 
Complete laboratory tests1 
X3 
 
 
X 
X 
X 
 
X6 
Serum pregnancy test / 
methods of contraception  
(if applicable)4 
X3, 8 
X 
X 
X8 
X8 
X8 
X 
X6 
Hemoglobin7 
X3, 8 
X 
X7  
X8 
X8 
X8 
X 
X6 
LT 
X3, 8 
X 
X  
X8 
X8 
X8 
X 
X6 
Study drug dispensing 
X 
 
X11 
X 
X 
 
 
 
Study drug return 
 
 
 
X 
X 
X 
 
 
AEs9 
X 
X 
X 
X 
X 
X 
X 
X6 


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PERIODS 
TREATMENT 
FOLLOW-UP 
 
VISITS 
Number 
1 
2 
Monthly Lab & 
Safety 
Monitoring5 
3, 4 
5, 6, etc. 
EOT 
Safety follow-
up / EOS 
U1, 2,… 
Name 
Enrollment2 
Month 1 
Month 
6,
Month 12 
Month 
18, 
Month 24, etc.  
Unscheduled 
visits6 
Time 
Day 1 
Month 1 
± 1 week 
Month 2 & 
every month 
thereafter up to 
EOT ± 1 week 
Month 6 
& Month 12 
± 2 weeks 
Month 18 & every 
6 months 
thereafter  
± 2 weeks 
Within 7 
days after 
study drug 
disc. 
30–33 days 
after study 
drug disc. 
Anytime 
during the 
study 
SAEs9 
X 
X 
X 
X 
X 
X 
X10 
X6 
1. 
Complete laboratory tests: hematology (including hemoglobin), blood chemistry (including LTs), and serum pregnancy test. Laboratory samples at all visits will be sent to and 
analyzed by the central laboratory.  
2. 
The enrollment visit is combined with the Week 16 (i.e., Visit 6 for subjects who complete the 16 weeks of DB treatment, or Visit 6a for subjects who prematurely discontinue 
DB treatment) in the AC-055-305 study. Tests are not to be repeated if performed for the Visit 6 or Visit 6a of the AC-055-305 study but are to be reported in the eCRF of both 
studies (if applicable). 
3. 
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 for analysis.  
4. 
Only concerns females of childbearing potential.  
5. 
Whenever possible, the monthly laboratory samples will be collected at site and analyzed centrally. Site staff should take this opportunity to meet the subject to discuss any 
(S)AEs that could have occurred since previous visit, and assess the concomitant medications and methods of contraception (if applicable). However, under specific 
circumstances (e.g., subject lives far away from the site and cannot return every month), monthly laboratory samples could be collected in a local laboratory close to where the 
subject lives and analyzed centrally; in these cases, the assessment of (S)AEs should be done via a telephone call.  
6. 
At any time during the study (between Enrollment and EOS visit) unscheduled site visits may be performed (based on investigator discretion). These include (but are not limited 
to) visits performed in case of safety concerns (e.g., new (S)AE, worsening of symptoms/assessment of 6MWD, adequate follow-up of any safety issues). Any study-specific 
procedures/assessments may be performed at an unscheduled visit, in which case the data will be collected in the eCRF. 
7. 
Hemoglobin concentration will be measured every month during the first 6 months, every 3 months thereafter up to the EOT visit, and 30 days after study drug discontinuation 
(EOS visit).  
8. 
Measured as part of the complete laboratory tests panel.  
9. 
All new SAEs and AEs occurring from first dose of OL study drug up to 30 days after study drug discontinuation must be reported in this OL study.  
10. New SAEs occurring after the 30-day follow-up period must be reported to the Actelion drug safety department, within 24 hours of the investigator’s knowledge of the event, if 
considered causally related to previous exposure to the study medication by the investigator. They are reported on an SAE form but not on the eCRF. 
11. Study drug may be dispensed on a monthly basis during monthly lab and safety monitoring.  


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6MWD = 6-minute walk distance; 6MWT = 6-minute walk test; AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; eCRF = electronic Case 
Report Form; EOS = end-of-study; EOT = end-of-treatment; LT = liver test (liver aminotransferases [AST/ALT], alkaline phosphatase, total and direct bilirubin); OL = open-label; 
SAE = serious adverse event; SpO2 = saturation of peripheral oxygen.  


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3 
OBJECTIVES 
This OL study aims to assess the long-term safety and tolerability of macitentan in 
subjects with ES beyond the treatment of the DB study, and to assess the long-term effect 
of macitentan on exercise capacity in this subject population. 
3.1 Primary objective(s) 
No primary endpoint is defined in this OL extension study.  
4 
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN 
THE STUDY PROTOCOL 
4.1 Changes to the analyses planned in the study protocol 
As the MAESTRO DB study did not demonstrate a statistically significant effect of 
macitentan on the primary efficacy endpoint of exercise capacity in subjects with ES 
assessed at Week 16, for this OL study it was decided to minimize the number of 
analyses related to the exploratory efficacy endpoints. Therefore, the analyses of the 
“Change from baseline of the OL to Month 6 and Month 12” for the exploratory efficacy 
endpoints (i.e., 6-minute walk distance [6MWD], Borg dyspnea index, WHO Functional 
Class and saturation of peripheral oxygen [SpO2]) as described in section 3.8.1 of the 
protocol have been removed [D-14.170].  
The analyses of the efficacy endpoints will focus on the absolute values and on the 
change from DB baseline to Week 16 in the DB study and to Month 6 and Month 12 in 
the OL study. Summary tables will be created for absolute values, and change from DB 
baseline values. The change from DB baseline values will be plotted only for 6MWD. 
In protocol section 5.2 the “Restricted all-enrolled set” is defined as all subjects enrolled 
in the OL study who received macitentan during the DB study; this set is used for 
efficacy analysis. Given that the efficacy analyses in this OL CSR will present the results 
as per treatment received during the DB period, and the analyses on the restricted all-
enrolled set would therefore be redundant, it has then been decided not to present 
analyses based on this analysis set. 
Per protocol, treatment-emergent marked laboratory abnormalities (MLAs) are analyzed 
up to EOT. For consistency across all safety endpoints in this study (i.e., with the 
treatment-emergent period reported for adverse events [AEs]), and with the MLA 
reporting in the DB study, MLAs will be analyzed up to End-of-Treatment (EOT) + 30 
days. This revision ensures that any event/assessment performed after EOT, as well as 
any safety assessment performed beyond EOT, will be captured.  
The analyses of liver enzymes have been revised to align with project-specific definitions 
for abnormal values. 


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Section 5.4.1 of the protocol states that deaths and the reason for death will be 
summarized in a similar manner to serious adverse events (SAEs), although deaths are 
not explicitly listed as an endpoint in section 3.8.2 of the protocol. This SAP clarifies that 
deaths are considered to be a safety endpoint to better characterize the safety profile. 
AEs of special interest (AESI) are not described in the OL protocol; however, the 
analysis on AESIs are included in this SAP. 
5 
DEFINITIONS OF VARIABLES 
The variable derivations and conventions are consistent (unless explicitly specified) with 
the AC-055-305/MAESTRO CSR SAP 
. 
5.1 Screening failures 
Subjects are not screened prior to entry in this OL extension study and no screening 
information is collected.  
5.2 Subject characteristics 
5.2.1 Demographics 
With the exception of age at start of OL, all subject demographic characteristics will be 
taken from the DB study database. The following subject demographic characteristics 
will be reported: sex, age at start of OL (years), weight (kg), height (cm), body mass 
index (BMI [kg/m2]), race, ethnicity, and geographical region.  
The following age categories will be derived: 
• CSR categorization: 12–17, 18–55, ≥ 56 years; 
• EudraCT categorization: 12–17, 18–64, 65–84, ≥ 85 years. 
Regions are defined as follows and subjects will be categorized depending on the 
countries involved in this OL study, as applicable: 
• Asia-Pacific: China, Malaysia, Philippines, Vietnam; 
• Eastern Europe: Bulgaria, Czech Republic, Hungary, Poland, Romania, Russia, 
Serbia; 
• Latin America: Chile, Mexico; 
• North America: Canada, USA; 
• Western Europe-Israel: Austria, France, Germany, Greece, Israel, Portugal, South 
Africa, Spain, Turkey, United Kingdom.  


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5.2.2 Baseline disease characteristics 
5.2.2.1 General characteristics 
All subject baseline disease characteristics will be taken from the DB study database. The 
following baseline disease characteristics will be reported: 
• Down Syndrome status (yes/no); 
• Time from ES diagnosis (years) to the screening date of DB study; 
• 6MWD (m); 
• WHO functional class (I, II, III, IV);  
• Borg dyspnea score (0–10); 
• SpO2 at rest (%); 
• Phosphodiesterase-5 (PDE-5) inhibitors (yes/no); 
• Smoking behavior (never, former, current). 
5.2.3 Medical history 
No medical history information is collected as part of this OL protocol. Medical history 
information collected prior to entry into the DB study is reported in the DB clinical study 
report 
 and will not be replicated in this OL study report. 
5.2.4 Previous and concomitant therapies  
All therapies as collected in the “Concomitant medication” module of the OL electronic 
case report form (eCRF) including hormonal contraceptives (for females of childbearing 
potential only) collected in the dedicated module “Contraception methods”. The original 
terms used by the investigators to describe therapies are assigned Preferred Terms (PTs) 
for classification and tabulation using the latest implemented WHODRUG version 
dictionary. 
Rules for handling missing/incomplete start/end dates of medications are detailed in 
Section 11.7. 
5.2.4.1 Previous therapies  
A previous therapy is any therapy recorded on the “Concomitant medication” module of 
the OL eCRF for which the end date is prior to the date of enrollment visit in the OL 
study. 


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5.2.4.2 Study-concomitant therapies 
Study-concomitant therapies are all therapies recorded on the “Concomitant medication” 
module of the OL eCRF: 
• With “Ongoing at start of treatment?” answered “Yes” or with “Ongoing at last 
visit?” answered “Yes”; OR  
• With the start date prior to the start of OL study (i.e., date of enrollment, see 
definition in Section 11.1) AND the end date on or after the start of study; OR 
• With the start date on or after the start of study AND on or before the date of End-of-
Study (EOS) visit [see definition in Section 11.2]. 
5.2.5 Other subject characteristics 
5.2.5.1 Contraceptive methods 
The use of contraceptive methods (for females of childbearing potential only) are 
collected in the dedicated OL eCRF module. For each contraceptive method used, the 
start date, end date, combination with spermicide (Y/N), ongoing at start of treatment 
(Y/N), and ongoing at last visit (Y/N) are collected. For hormonal contraceptives, the 
generic name, dose, units, and frequency are also collected. 
In addition, for females of childbearing potential only, serum pregnancy tests 
(i.e., choriogonadotropin beta) are performed at the same visits as the other laboratory 
tests. The results are provided by the central laboratory. 
5.3 Study treatment exposure and compliance 
5.3.1 Exposure 
The exposure is evaluated first in terms of study treatment duration including study 
treatment interruptions. The study treatment duration of macitentan, irrespective of study 
treatment interruptions, is derived in weeks as: 
 
(study treatment end date − study treatment start date + 1) / 7. 
Study treatment duration of macitentan will be derived over the following periods: 
• Combined DB + OL period  
where 
study 
treatment 
start 
date 
= 
macitentan 
treatment 
start 
date 
[see  Section 11.3.3], and study treatment end date = macitentan treatment end date 
[see Section 11.4.3]; 
• OL only period  
where study treatment start date = OL treatment start date [see Section 11.3.2], and 
study treatment end date = OL treatment end date [see Section 11.4.2]. 


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In addition, the study treatment exposure is evaluated in terms of actual weeks exposed to 
study treatment, excluding any temporary interruptions [see details below in 
Section 5.3.4].  
5.3.2 Compliance with study treatment 
The compliance during the OL study is calculated by CDDM according to the formula in 
section 3.5 of the protocol (see below) and recorded in the “Drug accountability” module 
of the eCRF: 
Compliance during OL = (number of tablets taken / total number of tablets that 
should have been taken during the treatment period) * 100. 
Compliance (in %) with study treatment is calculated at each dispensing/return visit as 
well as for the whole OL treatment period. Reasons for non-compliance since last visit 
are also collected. 
The number of tablets dispensed/returned during the DB study is recorded in the drug 
accountability dataset for the DB study. 
The compliance to macitentan treatment during the combined DB + OL period will be 
derived in the analysis datasets using the same formula as specified above. 
5.3.3 Study treatment discontinuation 
Study treatment discontinuations include all subjects, i.e., those who prematurely 
discontinued and those who completed treatment as per protocol. 
Study treatment discontinuations are collected in the “Exposure” eCRF module per the 
reason associated with the study treatment end date [see definition in Section 11.4.2].  
Subjects who completed the study treatment as per protocol are those with the question 
“What was the reason for treatment end?” answered “COMPLETED AS PER 
PROTOCOL”. 
Subjects who prematurely discontinued study treatment are those with the question 
“What was the reason for treatment end?” answered “PREMATURE PERMANENT 
DISCONTINUATION”.  
Detailed reasons for study treatment discontinuations are collected in the “Premature 
Permanent Study Drug Discontinuation” eCRF module (i.e., Death, Lost to follow-up, 
Physician’s decision/AE, Physician’s decision/Other, Subject’s or legal representative’s 
decision to withdraw consent from treatment only, Subject’s or legal representative’s 
decision to withdraw consent from study, Subject’s or legal representative’s 
decision/Other, Sponsor’s decision/Study discontinuation, Sponsor’s decision/Other, 
Other specify). 


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5.3.4 Study treatment adjustments or interruptions 
Study treatment dose adjustments are not permitted per protocol. 
Per protocol section 3.4.1, study treatment interruptions should be avoided where 
possible, and interruptions exceeding two consecutive weeks must lead to permanent 
discontinuation of study treatment. 
Any temporary interruptions in macitentan intake are collected in the ‘Exposure’ eCRF 
module for the OL study and in the ‘Study drug log’ eCRF module for the DB study. 
The exposure to macitentan is calculated for both the combined DB + OL period and the 
OL-only period as: 
Study treatment duration of macitentan during the treatment period − total duration 
of interruptions during the period treatment. 
Where total duration of interruptions is the sum of all treatment interruptions, and the 
duration of each treatment interruption is calculated as: 
Treatment start date following interruption − treatment end date preceding 
interruption −1. 
5.4 Study discontinuation 
Study discontinuation includes all subjects, i.e., those who prematurely discontinued and 
those who completed the study as per protocol. 
Subjects who completed the study as per protocol are those with the question “Did the 
subject complete the study?” answered “Yes” in the “End of Study” eCRF module. 
Subjects who discontinued prematurely are those with the question “Did the subject 
complete the study?” answered “No”.  
For subjects who discontinued study prematurely, the detailed reason for study 
discontinuation is collected, i.e., Death, Lost to follow-up, Physician’s decision (Specify), 
Sponsor’s decision/Study discontinuation, Sponsor’s decision/Other, Subject’s or legal 
representative’s decision to withdraw consent from study, Subject’s or legal 
representative’s decision/Other. 
EOS date is collected in the “End of Study” eCRF module. 


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5.5 Efficacy variables 
Efficacy endpoints of the study are defined as: 
• Change from DB baseline [see Section 11.7] to Week 16 in the DB study, Month 6 
and Month 12 in the OL study, in: 
– Exercise capacity, as measured by the 6MWD; 
– WHO functional class; 
– Dyspnea (assessed by the Borg dyspnea index); 
– Oxygen saturation, assessed by pulse oximetry: SpO2 at rest before the 6-minute 
walk test (6MWT). 
No re-mapping is performed for this analysis: unscheduled visits, if any, are presented 
only in the individual subject listings. 
Absolute change from baseline for all continuous efficacy endpoints is calculated as: 
Post-baseline value − baseline value,  
The following will be derived for all efficacy endpoints: 
• Change from DB baseline to each post-baseline scheduled visit (i.e., Week 16 of DB 
study, Month 6 and Month 12 of the OL study); 
5.5.1 Efficacy variable: 6MWD 
The 6MWT is performed at Enrollment visit (Visit 1), Visit 3/Month 6, Visit 4/Month 12, 
and EOT. Unscheduled visits may be performed at any time during the study if necessary.  
Absolute change from baseline for the 6MWD is calculated as described in Section 5.5 
above.  
5.5.2 Efficacy variable: WHO functional class 
The WHO functional class is assessed at Enrollment visit (Visit 1), Visit 3/Month 6, 
Visit 4/Month 12, and EOT. Unscheduled visits may be performed at any time during the 
study if necessary. 
Change from baseline to Week 16 in the DB study, and to Month 6 and Month 12 in the 
OL study, in WHO functional class is categorized as follows: 
• Improvement (i.e., shift to lower class [e.g., from III to II]) or  
• Worsening (i.e., shift to higher class [e.g., from III to IV]) or 
• Unchanged (i.e., no shift). 


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5.5.3 Efficacy variable: Borg dyspnea index 
The Borg dyspnea index is evaluated after each 6MWT at Enrollment visit (Visit 1), 
Visit 3/Month 6, Visit 4/Month 12, and EOT. Unscheduled visits may be performed at 
any time during the study if necessary. Dyspnea is rated on a scale from ‘0’ to ‘10’. 
Absolute change from baseline for the Borg dyspnea index is calculated as described in 
Section 5.5 above.  
5.5.4 Efficacy variable: SpO2 
Oxygen saturation is assessed by pulse oximetry (SpO2). SpO2 is measured at rest before 
the 6MWT at Enrollment visit (Visit 1), Visit 3/Month 6, Visit 4/Month 12, and EOT.  
Absolute change from baseline for the SpO2 is calculated as described in Section 5.5 
above.  
5.6 Safety variables 
The following safety variables will be evaluated: 
• Treatment-emergent AEs up to 30 days after study treatment discontinuation; 
• AEs leading to premature discontinuation of study treatment; 
• Deaths up to 30 days after study treatment discontinuation; 
• Treatment-emergent SAEs up to 30 days after study treatment discontinuation; 
• Treatment-emergent AESIs up to 30 days after study treatment discontinuation 
• Treatment-emergent MLAs up to 30 days after study treatment discontinuation; 
• Change from baseline up to 30 days after study treatment discontinuation in 
laboratory parameters; 
• Treatment-emergent 
alanine 
aminotransferase 
(ALT) 
and/or 
aspartate 
aminotransferase (AST) abnormality (> 3 × upper limit of normal [ULN]; > 5 × ULN; 
> 8 × ULN) associated or not with total bilirubin > 2 × ULN up to 30 days after study 
treatment discontinuation; 
• Change from baseline up to 30 days after study treatment discontinuation in vital 
signs (arterial blood pressure [BP], pulse rate) and body weight. 
Unless otherwise specified, the following apply throughout this section: 
• All safety variables are summarized over the combined DB + OL period 
[see Section 11.5.3], using the all-treated DB + OL set.  


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• The study treatment start date as defined in Section 11.3.3 (i.e., date of first intake of 
macitentan) and the study treatment end date / study treatment discontinuation (EOT) 
defined in Section 11.4.3 are used. 
• The observation period for each individual subject starts at the time of the first 
administration of macitentan [see Section 11.3.3] and ends with the permanent 
discontinuation of macitentan [see Section 11.4.3] + 30 days, regardless of study 
(i.e., DB or OL). 
• The baseline for a given measurement is the macitentan baseline as defined in 
Section 11.3.3.  
• The last post-baseline value up to 30 days after study treatment discontinuation 
[see Section 11.4.3], including values from unscheduled visits, is evaluated in the 
relevant analysis. 
5.6.1 Adverse events 
An AE is defined as any term reported by the investigator in the “Adverse Event” eCRF 
module. The original terms used by the investigators to describe AEs are assigned PTs 
for classification and tabulation using the latest implemented MedDRA version 
dictionary. If events are coded with an older MedDRA version, these events will be re-
coded using the latest implemented MedDRA version dictionary. 
5.6.1.1 Treatment-emergent AEs 
Treatment-emergent AEs are all AEs with onset on or after the study treatment start date 
and up to the study treatment discontinuation plus 30 days. 
5.6.1.2 Frequency of treatment-emergent AEs 
Except where otherwise specified, the counting of treatment-emergent AEs in the 
summary table is handled as follows: 
• Subjects who experienced the same AE (as qualified by the same PT[s]) more than 
once are counted only once. 
5.6.1.3 Intensity of treatment-emergent AEs 
Subjects who experienced the same AE (as qualified by the same PT[s]) more than once, 
but with different intensities, are counted only once, with the maximum intensity in the 
corresponding analysis. In case of missing intensity, “severe” is imputed. 
5.6.1.4 Relationship of treatment-emergent AEs 
Relationship to study treatment is defined as ‘related’ or ‘not related’. An AE is 
considered related if the question ‘Is there a reasonable possibility that the Adverse Event 
was related to the use of study drug?’ is answered ‘Yes’. For AEs reported more than 


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once (as qualified by the same PT[s]) within a subject, the worst relationship (i.e., 
related) is considered. AEs with a missing relationship are considered as related in any 
analysis. 
5.6.2 Deaths 
The date of death and associated primary cause are recorded in the “Death Form” of the 
eCRF. The original terms used by the investigators to describe deaths (i.e., primary 
cause) are assigned PTs for classification and tabulation using the latest implemented 
MedDRA version dictionary.  
Treatment-emergent deaths are all deaths with the date on or after the study treatment 
start date and up to the date of study treatment discontinuation plus 30 days. 
5.6.3 Serious adverse events 
An SAE is any AE with the question “Serious?” answered “Yes” by the investigator. 
SAEs leading to hospitalization are any SAEs with the question “Did the adverse event 
require subject hospitalization” answered “Yes” by the investigator. 
Treatment-emergent SAEs are all SAEs with onset on or after the study treatment start 
date and up to the date of study treatment discontinuation plus 30 days. 
For the disclosure of the results to EudraCT and ClinicalTrials.gov, SAEs during the OL 
study will be summarized. 
Treatment-emergent SAEs during the OL study are all SAEs with onset on or after the 
OL treatment start date [see Section 11.3.2] and up to the OL treatment end date 
[see Section 11.4.2] plus 30 days. 
5.6.4 Adverse events leading to premature discontinuation of study treatment 
An AE leading to premature discontinuation of study treatment is defined as any AE with 
“Action taken with study drug” reported as “Permanently discontinued” by the 
investigator. 
5.6.5 Other significant adverse events 
5.6.5.1 AEs with fatal outcome 
An AE/SAE with fatal outcome is any AE/SAE with “Outcome” reported as “Death” by 
the investigator. 
Treatment-emergent AEs with fatal outcome are those with onset on or after the study 
treatment start date and up to the study treatment discontinuation plus 30 days. 
5.6.5.2 AEs of special interest (AESI) 
Standardized MedDRA Queries (SMQs) are available in SDTM. 


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• “Anaemia” 
Treatment-emergent AEs with PTs within the SMQs “Haematopoietic erythropenia 
(SMQ)” 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” 
Treatment-emergent AEs with one of the following PTs: 
- 
Blood pressure ambulatory decreased 
- 
Blood pressure decreased 
- 
Blood pressure diastolic decreased 
- 
Blood pressure immeasurable 
- 
Blood pressure orthostatic decreased 
- 
Blood pressure systolic decreased 
- 
Diastolic hypotension 
- 
Hypotension 
- 
Orthostatic hypotension 
- 
Procedural hypotension 
- 
Mean arterial pressure decreased 
• “Oedema and fluid overload” 
Treatment-emergent AEs with PTs listed in the SMQ “Haemodynamic oedema, effusions 
and fluid overload (SMQ)” or with PT equal to “Pulmonary congestion”, excluding any 
PT containing the text “site”  
5.6.5.3 Non-serious AEs 
For the disclosure of the results to EudraCT and ClinicalTrials.gov, non-serious AEs will 
be summarized. 
A non-serious AE is any AE with the question “Serious?” answered “No” by the 
investigator.  
Treatment-emergent non-serious AEs are all non-serious AEs with onset on or after the 
OL treatment start date [see Section 11.3.2] and up to the OL treatment end date 
[see Section 11.4.2] plus 30 days. 
5.6.6 Vital signs and body weight 
Vital signs are measured at all scheduled visits (i.e., Visit 1/Enrollment, Visit 2/Month 1, 
each 6-monthly visit, and EOT) in a supine or sitting position. Unscheduled visits may be 
performed at any time during the study if necessary. BP measurements are collected in 
the “Vital Signs” eCRF modules and include: 


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• Systolic blood pressure (SBP) in mmHg 
• Diastolic blood pressure (DBP) in mmHg 
• Pulse rate (PR) in beats per minute. 
Body weight (kg) is collected at the same visits in the “Vital Signs” eCRF module. 
The absolute change from macitentan baseline at each post-baseline scheduled visit 
(i.e., Visit 3/Week 4, Visit 4/Week 8, Visit 5/Week 12, and Visit 6/Week 16/EOT in the 
DB study, and Visit 2/Month 1, each 6-monthly visit, and EOT in the OL study) and last 
value up to 30 days after study treatment discontinuation for vital signs and body weight 
is calculated as: 
(post-baseline value) − (value at macitentan baseline). 
5.6.7 Electrocardiogram 
Not applicable. 
5.6.8 Laboratory 
Complete laboratory parameters will be measured at enrollment (Visit 1), each 6-monthly 
visit, and EOT. Unscheduled visits may be performed at any time during the study if 
necessary.  
Data are evaluated in Standard International (SI) units as provided by the central 
laboratory. In case of a local laboratory, values are converted in SI according to the 
Actelion OTH-000005 QS document. The tests converted in SI are available in SDTM 
for the analysis. All values reported as below or above the limit of detection (e.g., ‘< 3’, 
‘> 100’) are substituted with the limit of detection (e.g., ‘< 3’, is substituted by ‘3’) for 
the purpose of the analysis. The values are listed including the < or > sign. 
Data (i.e., hemoglobin values collected for the calculation of hemodynamic parameters) 
from cardiac catheterization are not included in any analysis. 
In the event that more than one value for a laboratory parameter is assessed on the same 
day, both from central and local laboratory, the value from the central laboratory is 
considered for the analysis. 
The absolute change from baseline at each post-baseline scheduled visit (i.e., Visit 
3/Week 4, Visit 4/Week 8, Visit 5/Week 12, and Visit 6/Week 16/EOT in the DB study, 
and Visit 2/Month 1, each 6-monthly visit, and EOT in the OL study) and last value up to 
30 days after study treatment discontinuation for laboratory parameters is calculated as: 
(post-baseline value) − (value at macitentan baseline). 


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Laboratory parameters include: 
• Hematology: 
– Hemoglobin (g/L) 
– Hematocrit (L/L) 
– Erythrocytes (1012/L) 
– Leukocytes (109/L) 
– Platelets (109/L) 
• Clinical Chemistry: 
– ALT (U/L) 
– AST (U/L) 
– Alkaline phosphatase (U/L) 
– Bilirubin (umol/L) 
– Direct bilirubin (umol/L) 
– Creatinine (umol/L) 
– Blood urea nitrogen (mmol/L) 
– Uric acid 
– Glucose (mmol/L) 
– Sodium (mmol/L) 
– Potassium (mmol/L) 
– Magnesium (mmol/L) 
– Calcium (mmol/L) 
– Albumin (g/L). 
Liver tests (ALT, AST, alkaline phosphatase, total and direct bilirubin) are also assessed 
at Safety follow-up. 
5.6.8.1 MLAs 
The following MLAs are derived according to the sponsor’s internal guidelines 
(OTH-000005). 
Treatment-emergent MLAs are all MLAs with onset after the study treatment start and up 
to 30 days after study treatment discontinuation, that were not present at baseline.  
For hemoglobin and creatinine (HH/HHH categories, only), treatment-emergent MLAs 
are those occurring after study treatment start and up to 30 days after study treatment 
discontinuation, as it is not possible to have HH or HHH flags at baseline per definition 
of the abnormality. 


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Table 2 
Definition of marked laboratory abnormalities 
Parameter  
LL marked 
LLL marked 
HH marked 
HHH marked 
Hematology 
 
 
 
 
Hemoglobin 
(baseline value within 
normal range or 
below LLN) 
< 100 g/L 
< 80 g/L 
> 20 g/L above ULN  
> 40 g/L above ULN 
Hemoglobin 
(baseline value > 
ULN) 
< 100 g/L 
< 80 g/L 
> 20 g/L above 
baseline 
> 40 g/L above 
baseline 
Hematocrit 
< 0.28 L/L for 
females  
< 0.32 L/L for 
males 
< 0.20 L/L 
 
> 0.55 L/L for 
females 
> 0.60 L/L for males 
> 0.65 L/L  
 
Leukocytes 
< 3.0 × 109/L 
< 2.0 × 109/L 
> 20.0 × 109/L 
> 100.0 × 109/L 
Neutrophils 
< 1.5 × 109/L 
< 1.0 × 109/L 
NA 
NA 
Lymphocytes 
< 0.8 × 109/L  
< 0.5 × 109/L  
> 4.0 × 109/L  
> 20.0 × 109/L  
Eosinophils 
NA 
NA 
> 5 × 109/L 
NA 
Platelets  
< 75 × 109/L 
< 50 × 109/L 
> 600 × 109/L  
> 999 × 109/L  
Clinical chemistry 
 
 
 
 
ALT*  
NA 
NA 
> 3 × ULN 
> 5 × ULN 
AST*  
NA 
NA 
> 3 × ULN 
> 5 × ULN 
Alkaline phosphatase 
NA 
NA 
> 2.5 × ULN 
> 5 × ULN 
Total bilirubin 
NA 
NA 
> 2 × ULN 
> 5 × ULN 
Creatinine  
(baseline value within 
normal range or 
below LLN) 
NA 
NA 
> 1.5 × ULN 
> 3 × ULN 
Creatinine (baseline 
value > ULN) 
NA 
NA 
> 1.5 × above baseline 
> 3 × above baseline 
BUN 
NA 
NA 
> 2.5 × ULN 
> 5 × ULN 


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Glucose 
< 3.0 mmol/L 
< 2.2 mmol/L 
> 8.9 mmol/L 
> 13.9 mmol/L 
Sodium 
NA 
< 130 mmol/L 
> 150 mmol/L 
> 155 mmol/L 
Potassium 
< 3.2 mmol/L 
< 3.0 mmol/L 
> 5.5 mmol/L 
> 6.0 mmol/L 
Magnesium 
< 0.5 mmol/L 
< 0.4 mmol/L 
NA 
> 1.23 mmol/L 
Calcium 
< 2.0 mmol/L 
< 1.75 
mmol/L 
> 2.9 mmol/L 
> 3.1 mmol/L 
Urate 
NA 
NA 
> 590 µmol/L 
> 720 µmol/L 
Albumin 
< 30 g/L 
< 20 g/L 
NA 
NA 
 
 
 
 
 
* For ALT and AST, additional threshold (HHHH) are to be reported namely > 8 × ULN 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; LLN = lower limit of 
the normal range; NA = not applicable; ULN = upper limit of the normal range. 
5.6.8.2 Additional liver and hemoglobin laboratory abnormalities 
The following elevated liver test abnormalities are defined: 
• (ALT > 3 × ULN) OR (AST > 3 × ULN)  
• (ALT > 5 × ULN) OR (AST > 5 × ULN)  
• (ALT > 8 × ULN) OR (AST > 8 × ULN)  
• Total bilirubin > 2 × ULN 
• {(ALT > 3 × ULN) OR (AST > 3 × ULN)} AND (Total Bilirubin > 2 × ULN at any 
time) 
If a subject has observations in different categories, he/she will be counted once in the 
worst category (i.e., the highest ALT, AST or total bilirubin values). If a subject has more 
than 1 observation within the same category, the subject will be counted once in that 
category. A supportive listing will be provided and will present all abnormal liver test 
data. Treatment emergent results will be flagged. 
Treatment-emergent liver test laboratory abnormalities are those which occur after the 
study treatment start and up to 30 days after study treatment discontinuation, that were 
not present at baseline.  
The following hemoglobin abnormalities are defined: 
• Hemoglobin ≤ 80 g/L 
• Hemoglobin > 80 and ≤ 100 g/L 
• Hemoglobin decrease from baseline ≥ 20 g/L and < 50 g/L 


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• Hemoglobin decrease from baseline ≥ 50 g/L 
• Hemoglobin < 100 g/L and concurrent (i.e., at the same time) decrease from baseline 
≥ 20 g/L. 
Treatment-emergent hemoglobin laboratory abnormalities are those which occur after the 
study treatment start and up to 30 days after study treatment discontinuation, that were 
not present at baseline (except for the decreases from baseline, which cannot be present at 
baseline per definition). 
The lowest hemoglobin value / maximum decrease from baseline at any post-baseline 
time point of assessment up to 30 days after study treatment discontinuation is 
considered, as defined above.  
5.6.9 Other safety variables 
5.6.9.1 Physical examination 
Physical examination is performed at all scheduled visits, collected in the dedicated 
module of the eCRF “Physical Examination” with general assessment performed. If an 
abnormality is found (i.e., Result = “Abnormal”), further details describing the signs and 
symptoms related to the abnormality are specified. The abnormality is clinically 
significant if the question “Clinically significant” is answered “Yes”.  
6 
DEFINITION OF PROTOCOL DEVIATIONS 
The description of each protocol deviation (PD) is agreed in the sponsor protocol 
deviation code list. According to this document, each PD is classified as important or not 
and categorized as follows: 
• PDs before OL enrollment 
• PDs at OL study entry (enrolled in IXRS) 
• PDs during OL treatment period and follow-up  
The data are available in SDTM. 
7 
ANALYSIS SETS 
7.1 Definitions of analysis sets 
7.1.1 All-enrolled set 
The All-enrolled analysis set (ENR) includes all subjects enrolled in this AC-055-308 OL 
study (i.e., with a date of enrollment), whether or not they took at least one dose of 
macitentan during the OL study. 


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7.1.2 All-treated DB + OL set  
The All-treated DB + OL set (TTS) comprises the union of:  
(i) All subjects who received at least one dose of macitentan in this AC-055-308 OL 
study AND 
(ii) All subjects who received macitentan during the AC-055-305 / MAESTRO study and 
were not enrolled in the OL study. 
7.2 Usage of the analysis sets 
Table 3 
Overview of the different analysis sets and their usage 
Analyses 
All-enrolled set  
All-treated DB + OL set 
Subject disposition 
 
 
Protocol deviations  
 
 
Demographic characteristics 
 
 
Baseline disease characteristics 
 
 
Previous and concomitant therapies 
 
 
Other subject characteristics 
 
 
Study treatment exposure / discontinuations 
 
 
Study discontinuation 
 
 
Efficacy endpoints 
 
 
Safety endpoints 
 
 
Demographic and  
baseline disease  
characteristics, other baseline characteristics, 
protocol deviation and efficacy  
listings 
 
 
Disposition, safety listing 
 
 
DB = double-blind; OL = open-label. 
8 
DEFINITION OF SUBGROUPS 
Not applicable. 
9 
GENERAL STATISTICAL METHODOLOGY 
SAS (Statistical Analysis System®) version 9.3 is used for all the statistical analyses. 
This section describes in general terms the statistical analysis methods which are applied 
in the subsequent sections.  


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9.1 Statistical methods for efficacy data 
For each DB treatment group and overall (as applicable), efficacy data are summarized 
(tables or figures) at specified time points of assessments by appropriate descriptive 
statistics displaying: 
• For continuous variables: number of non-missing observations, mean, standard 
deviation (SD), median, first and third quartile, minimum and maximum. 
• For dichotomous variables: proportion of subjects in each category together with the 
2-sided 95% confidence limits (CLs) (i.e., according to Clopper-Pearson formula).  
• For categorical variables: a shift table from baseline to Month 6 and Month 12. The 
proportion of subjects having improvement/worsening are presented, together with 
the 2-sided 95% CLs (i.e., Clopper-Pearson formula).  
9.2 Statistical methods for safety data 
For each DB treatment group and overall, subject characteristics and safety data are 
summarized (tables or figures) by appropriate descriptive statistics displaying: 
• For continuous variables: number of non-missing observations, mean, SD, median, 
first and third quartile (Q3), minimum and maximum.  
• For dichotomous/categorical variables; number of non-missing observations, 
frequency and percentages for the two categories. Denominators for percentages are 
the number of non-missing observations in the analysis set and treatment group under 
evaluation, unless otherwise specified.  
• Number of missing values are displayed only if > 0 and as follows: 
– For continuous variables after the n (number of non-missing observations) 
– For dichotomous/categorical variables after the last category. 
10 STATISTICAL ANALYSES 
10.1 Overall testing strategy 
No hypothesis testing will be performed; hence no p-values will be presented. All 
efficacy analyses are considered exploratory. 
10.2 General rules for data presentations 
This section describes the general rules applied for all data displays. 
Unless otherwise specified in this document: 
• All listings are sorted by country, site, treatment group received during DB study, 
subject number and when appropriate by visit / date of assessment. All data collected 
are displayed, including unscheduled visits (if any). 


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• All summaries on the All-enrolled set and the All-treated DB + OL set will be 
presented overall and by DB treatment group (treatment received during DB study), 
i.e., Previously on DB macitentan and Previously on DB placebo.  
• In summary tables, columns will be presented in the following order from left to 
right: “DB-Macitentan”, “DB-Placebo” and “Total”.  
10.3 Display of subject disposition, protocol deviations and analysis sets 
10.3.1 Subject disposition 
Subject disposition is summarized on the All-enrolled set. 
Counts and percentages of subjects enrolled in the OL study by country and site within 
each country are presented by DB treatment group and overall. The summary table is 
sorted by geographical region (i.e., Asia-Pacific, Eastern Europe, Latin America, North 
America, Western Europe-Israel-South Africa). 
A summary table is provided for the OL study to display the following information by 
DB treatment group and overall: 
• Counts of subjects enrolled; 
• Counts of subjects treated (who received at least one dose of study treatment); 
• Counts of subjects who completed study treatment [see definition in Section 5.3.3]; 
• Counts of subjects who prematurely discontinued study treatment [see definition in 
Section 5.3.3]; 
• Counts of subjects who completed study [see definition in Section 5.4]; 
• Counts of subjects who prematurely discontinued study [see definition in Section 
5.4]. 
A separate summary table is provided for the OL study to display, by DB treatment group 
and overall:  
• Counts and percentages of subjects who prematurely discontinued from the study 
[see definition in Section 5.4]  
• Reason associated with premature discontinuation from the study [see definition in 
Section 5.4]. 
For subjects who prematurely discontinued study treatment and/or prematurely 
discontinued from the OL study, the EOT status and the EOS status with associated EOT 
and EOS dates, together with reasons for discontinuation, are reported in a subject listing.  


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10.3.2 Protocol deviations 
Protocol deviations are summarized by category [see Section 6], displaying counts and 
percentages of subjects with at least one PD by DB treatment group and overall. A 
similar table is presented for important protocol deviations. 
Protocol deviations are summarized on the All-enrolled set.  
All reported PDs [as defined in Section 6] are reported in a subject listing. Important PDs 
are flagged accordingly. 
10.3.3 Analysis sets 
A table displaying counts and percentages of subjects included in each analysis is 
provided. 
A listing displaying in which analysis sets each subject participates is provided. 
Refer to Section 7 for the definition of analysis sets. 
10.4 Analyses of subject characteristics 
10.4.1 Demographics 
Demographic characteristics are summarized on the All-enrolled set.  
Continuous and categorical demographic characteristics [see definition in Section 5.2.1] 
are summarized by DB treatment group and overall, using descriptive statistics.  
Age categories (12–17, 18–64, 65–84, ≥ 85 years) are also provided in a separate 
summary table by DB treatment group and overall for the disclosure of the results to 
EudraCT and ClinicalTrials.gov. 
All demographic data as defined in Section 5.2.1 are reported in a subject listing. 
10.4.2 Baseline disease characteristics 
Baseline disease characteristics are summarized on the All-enrolled set.  
Continuous and categorical baseline disease characteristics [see definition in 
Section 5.2.2.1] are summarized, by DB treatment group and overall, using descriptive 
statistics.  
In addition to tabulations, all data are reported in a subject listing. 
10.4.3 Medical history 
Not applicable. 


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10.4.4 Previous and concomitant therapies 
Study-concomitant therapies and previous therapies are summarized on the All-enrolled 
set.  
Counts and percentages of subjects having taken at least one concomitant therapy 
[see definition in Section 5.2.4.1] are presented, separately, by Anatomic Therapeutic 
Chemical (ATC) class and PT within each ATC class, as well as by PT. The summary 
tables are presented in descending order according to the incidence in the macitentan DB 
treatment group (e.g., ATC and PT within each ATC with the highest number of 
occurrences appear first). Equal frequency of different ATC/PTs is sorted in alphabetical 
order of the ATC/PT. 
Subjects who took the same therapy more than once (as qualified by the same PT) are 
counted only once.  
Previous therapies are similarly summarized.  
In addition to tabulations, study-concomitant therapies and previous therapies (including 
hormonal contraceptives, for females of childbearing potential only) are reported in a 
subject listing. Previous and study concomitant therapies are flagged accordingly. 
10.4.5 Other subject characteristics 
Other subject characteristics are summarized on the All-enrolled set.  
10.4.5.1 Contraceptive methods 
For females of childbearing potential only, contraceptive methods [as defined in 
Section 5.2.5.1] together with serum pregnancy tests data (i.e., choriogonadotropin beta) 
are presented in separate subject listings. 
10.5 Analysis of study treatment exposure and compliance 
Exposure data as well as drug accountability are provided in subject listings. 
10.5.1 Exposure 
Duration of exposure over the combined DB + OL period will be summarized using the 
All-treated DB + OL set.  
Duration of exposure over the OL only period will be summarized using the All-enrolled 
set.  
The duration of study treatment (irrespective of any treatment interruptions, see definition 
in Section 5.3.1) as well as the study treatment exposure (excluding interruptions see 
definition in Section 5.3.4) is summarized using descriptive statistics by DB treatment 
group. The study treatment duration is also summarized as a categorical variable, 
presenting the cumulative distribution of treatment duration by class interval (i.e., at least 


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4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, and every 4 weeks 
thereafter) and displaying counts and percentages of subjects in each class interval.  
10.5.2 Compliance with study treatment 
Compliance in combined DB + OL period will be summarized on the All-treated 
DB + OL set.  
Compliance in OL period will be summarized on the All-enrolled set.  
Compliance [see definition in Section 5.3.2] with study treatment for the Combined 
DB + OL period and for OL only period is summarized overall and by DB treatment 
group.  
The counts and percentages of subjects with compliance < 80% and > 120% will be 
displayed. 
10.5.3 Study treatment discontinuation  
A summary table is provided for display, for each DB treatment group, and overall: 
• Counts and percentages of subjects who prematurely discontinued study treatment 
[see definition in Section 5.3.3].  
• Reason associated with study treatment discontinuation [see definition in 
Section 5.3.3]. 
Only the study treatment discontinuations during OL are included. 
10.5.4 Study treatment adjustments and interruptions 
The analysis of study treatment exposure, excluding interruptions is covered in 
Section 10.5.1 above. 
10.6 Analysis of efficacy variables 
No primary efficacy variables are described in this study. All efficacy analyses are 
considered exploratory. No hypothesis test comparisons will be made between the 
treatment groups. All efficacy endpoints are evaluated on the all-enrolled set.  
• All efficacy endpoints are evaluated over the combined DB + OL period, using the 
DB baseline.  
All results collected for 6MWD, WHO functional class, Borg dyspnea index and SpO2, 
including those from unscheduled visits, are reported in a subject listing. Imputed values 
are flagged with their corresponding reason for imputation.  


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10.6.1 Efficacy variable: 6MWD 
Descriptive statistics are presented for 6MWD by DB treatment group and overall 
(as applicable), for the following values: 
• Observed value at baseline 
• Observed value at each scheduled post-baseline Visit X  
• Absolute change from baseline to Visit X.  
A summary will be created for the combined DB + OL period. The summary will be 
repeated for the imputed values.  
The following graphical displays for observed values will be created: 
• Mean and 95% CLs for the change from DB baseline values for 6MWD over the 
combined DB + OL period (observed values); 
• Mean and 95% CLs for the change from DB baseline values for 6MWD over the 
combined DB + OL period (imputed values). 
10.6.1.1 Handling of missing data 
Missing 6MWD values for assessments in the DB study are imputed as per the 
imputation mechanism described in the MAESTRO DB SAP 
. 
In the DB study only three subjects had missing 6MWD values at Week 16, all in the 
macitentan treatment group. The reasons and with the imputed values were:  
• 1 death (at 14.3 weeks), imputed with zero meters; 
• 2 subjects with no assessment (1 subject discontinued study treatment on Day 12; 
1 subject hospitalized after 10.6 weeks), imputed with ~0 meters.  
Consequently, a simplified imputation mechanism is applied for missing values in the OL 
study. For missing 6MWD values in the OL study, the following imputation rules are 
applied:  
• If the reason for missing data is death, a distance of zero (0) meters is imputed for all 
6MWD visits from the date of death; 
• For any other reasons, the last available value is carried forward. 
10.6.2 Efficacy variable: WHO functional class 
WHO functional class is summarized in shift tables by DB treatment group displaying: 
• Counts of subjects in each category at baseline; 


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• Counts and percentages of subjects in each category at each scheduled post-baseline 
Visit X by category at baseline; 
• Counts and percentages of subjects with improvement (i.e., shifted to a lower class), 
worsening (i.e., shifted to a higher class), and no change at Visit X together with the 
95% confidence limits.  
Summary will be created for the combined DB + OL period. 
10.6.2.1 Handling of missing data 
Missing WHO functional class values for assessments in the DB study are imputed as per 
the imputation mechanism described in the MAESTRO DB SAP 
 
For missing WHO functional class values in the OL study, the following imputation rules 
are applied: 
• If the reason for missing data is death, class IV is imputed for all WHO visits from 
the date of death;  
• For any other reasons, the last available value is carried forward. 
10.6.3 Efficacy variable: Borg dyspnea index 
Descriptive statistics are presented for Borg dyspnea index by DB treatment group, for 
the following values: 
• Observed value at baseline 
• Observed value at each scheduled post-baseline Visit X 
• Absolute change from baseline to Visit X.  
Summary will be created for the combined DB + OL period. 
10.6.3.1 Handling of missing data 
Missing Borg dyspnea index values for assessments in the DB study are imputed as per 
the imputation mechanism described in the MAESTRO DB SAP 
 
For missing Borg dyspnea index values in the OL study, the following imputation rules 
are applied: 
• If the reason for missing data is death, a value of 10 is imputed for all Borg visits 
from the date of death;  
• For any other reasons, the last available value is carried forward. 


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10.6.4 Efficacy variable: SpO2 
Descriptive statistics are presented for SpO2 index by DB treatment group, for the 
following values: 
• Observed value at baseline 
• Observed value at each scheduled post-baseline Visit X 
• Absolute change from baseline to Visit X.  
At each post-baseline timepoint, only subjects who had both the assessment at baseline 
and the post-baseline visit are included. Separate summaries will be created for the 
combined DB + OL period. 
10.6.4.1 Handling of missing data 
No imputation of missing data for SpO2 will be applied. 
10.6.5 Supportive/sensitivity analyses 
Not applicable. 
10.6.6 Subgroup analyses 
Not applicable. 
10.7 Analysis of safety variables 
All safety analyses will be performed on the Combined DB + OL period, using the all-
DB + OL treated set. 
10.7.1 Adverse events 
All AEs captured are reported in the subject listing together with the assigned PT / 
system organ class (SOC). Treatment-emergent AEs [see definition in Section 5.6.1.1] 
are flagged accordingly. 
A summary table with an overview of treatment-emergent AEs is provided by DB 
treatment group, displaying counts and percentages of subjects having experienced at 
least one treatment-emergent AE, severe AE, study-treatment related AE, AE leading to 
study treatment discontinuation, SAE, study-treatment related SAE, and fatal SAE. 
Treatment-emergent AEs are summarized by DB treatment group displaying counts and 
percentages of subjects having experienced at least one treatment-emergent AE, together 
with counts and percentages one together with corresponding counts by SOC and by PT 
within each SOC. The summary tables are presented in descending order according to the 
DB-Macitentan incidence (e.g., SOC and PT within each SOC with the highest number of 
occurrences appears first). Equal frequency of different SOC/PTs is sorted in alphabetical 
order of the SOC/PT.  


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Treatment-emergent AEs related to study treatment are summarized similarly. 
Treatment-emergent AEs by maximum intensity are summarized similarly by PT, only. 
10.7.2 Deaths, other serious adverse events 
10.7.2.1 Death 
All death cases are reported in the subject listing. Treatment-emergent deaths 
[see definition in Section 5.6.2] are flagged accordingly. 
Counts and percentages of subjects who died (i.e., all deaths) are presented by PT 
(associated with the cause of death). The summary table is presented in descending order 
according to the DB-Macitentan incidence (e.g., PTs with the highest number of 
occurrences appears first). Equal frequency of different PTs is sorted in alphabetical 
order. 
10.7.2.2 SAEs 
All SAEs are reported in the subject listing. Treatment-emergent SAEs are flagged 
accordingly. All SAEs leading to hospitalization are reported in a separate subject listing 
with start date of admission and end date of discharge. 
Treatment-emergent SAEs are summarized similarly to treatment-emergent AEs 
[see Section 10.7.1, by SOC and PT within each SOC as well as by PT].  
For the disclosure of the results to EudraCT and ClinicalTrials.gov (and not for the 
purpose of the clinical study report), separate similar summary tables are provided by 
SOC and PT within each SOC for: 
• Treatment-emergent SAEs related to study treatment  
• Treatment-emergent SAEs with fatal outcome 
• Treatment-emergent SAEs related to study treatment with fatal outcome. 
In addition, for the disclosure of the results to EudraCT and ClinicalTrials.gov, 
treatment-emergent SAEs are summarized displaying counts and percentages of subjects 
with at least one treatment-emergent SAE in the OL study plus the number of events 
(counted exactly the number of times they occurred also within a subject) by SOC and 
PT. The summary table is presented in descending order (i.e., SOC and PT within each 
SOC with the highest number of occurrences appears first). Equal frequency of different 
PTs is sorted in alphabetical order of the PT.  


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10.7.2.3 AEs leading to premature discontinuation of study treatment  
A separate subject listing is provided with all AEs leading to premature discontinuation 
of study treatment.  
AEs leading to premature discontinuation of study treatment are summarized similarly to 
treatment-emergent AEs [see Section 10.7.1, by SOC and PT within each SOC as well as 
by PT].  
10.7.2.4 Other significant AEs 
Treatment-emergent AEs with fatal outcome [see definition in Section 5.6.5.1] are 
summarized similarly to treatment-emergent AEs [see Section 10.7.1, by SOC and PT 
within each SOC as well as by PT].  
For each area of clinical interest, treatment-emergent AESIs [see definition in 
Section 5.6.5.2] are summarized displaying counts and percentages of subjects having 
experienced at least one treatment-emergent AESI. Counts and percentages of subjects 
having experienced at least one treatment-emergent AESI are presented by frequency of 
PT within each SOC. Separate subject listings are provided with all AEs for the area of 
clinical interest. 
For the disclosure of the results to EudraCT and ClinicalTrials.gov (and not for the 
purpose of the clinical study report), treatment-emergent non-serious AEs [see definition 
in Section 5.6.5.3] with frequencies ≥ 5% are summarized displaying counts and 
percentages of subjects with at least a treatment-emergent non-serious frequent AE plus 
the number of events (counted exactly the number of times they occurred also within a 
subject) by SOC and PT. The summary table is presented in descending order according 
to the number of events (i.e., SOC and PT within each SOC with the highest number of 
occurrences appears first). Equal frequency of individual PTs is sorted in alphabetical 
order of the individual PT.  
10.7.3 Electrocardiography 
Not applicable. 
10.7.4 Laboratory tests 
All hematology and chemistry parameters [see Section 5.6.8] provided by the central and 
local laboratory are displayed in subject listings, including those from unscheduled visits. 
MLAs are flagged accordingly. 
For each post-baseline visit (i.e., Visit 3/Week 4, Visit 4/Week 8, Visit 5/Week 12, 
Visit 6/Week 16/EOT in the DB study, and Visit 2/Month 1, each 6-monthly visit, and 
EOT in the OL study) laboratory test parameters (excluding serum pregnancy tests) are 
summarized, by DB treatment group, displaying descriptive statistics for: 


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• Observed value at baseline, at Visit X 
• Absolute change from baseline to Visit X  
Each evaluation includes only subjects who had both the assessments at baseline and the 
considered post-baseline visit. Similarly, laboratory test parameters (excluding serum 
pregnancy tests) are summarized, by DB treatment group, displaying descriptive statistics 
for: 
• Observed value at baseline, up to 30 days after study treatment discontinuation 
• Absolute change from baseline up to 30 days after study treatment discontinuation 
In this evaluation, values from unscheduled visits are included. 
Separate summaries are presented for hematology and clinical chemistry laboratory tests. 
10.7.4.1 MLAs 
For the evaluation of MLAs, values from unscheduled visits are included. Separate 
summaries are presented for hematology and clinical chemistry laboratory tests. 
A dictionary listing of definitions of MLA (LL, LLL, HH, HHH) is provided for each 
parameter. 
For each category (i.e., LL, LLL, HH, HHH, HHHH), treatment-emergent MLAs [see 
definition in Section 5.6.8.1] are summarized by DB treatment group, displaying counts 
and percentages of subjects with at least one treatment-emergent MLA for each 
parameter for which the marked abnormality is defined. Percentages are calculated as 
number of subjects with experiencing the abnormality for the parameter under 
consideration at least once, divided by the number of subjects with any post-baseline 
laboratory measurement (and for hemoglobin and creatinine, also with a valid baseline 
value based on the definition of the abnormality).  
10.7.5 Vital signs and body weight 
Body weight values [see definition in Section 5.6.6] including those from unscheduled 
visits are reported in a subject listing. BP measurements are reported in a separate subject 
listing. 
For each post-baseline visit (i.e., Visit 3/Week 4, Visit 4/Week 8, Visit 5/Week 12, 
Visit 6/Week 16/EOT in the DB study, and Visit 2/Month 1, each 6-monthly visit, and 
EOT in the OL study) SBP, DBP, PR are summarized, by DB treatment group, displaying 
descriptive statistics for: 
• Observed value at baseline, at Visit X 
• Absolute change from baseline to Visit X.  


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In each evaluation, are included only subjects who had both the assessments at baseline 
and the considered post-baseline visit. 
Similarly, SBP, DBP, PR, and body weight are summarized, by DB treatment group, 
displaying descriptive statistics for: 
• Observed value at baseline, up to 30 days after study treatment discontinuation 
• Absolute change from baseline up to 30 days after study treatment discontinuation. 
In this evaluation, values from unscheduled visits are considered. 
10.7.6 Other safety variables 
10.7.6.1 Physical examination 
Physical examinations [as defined in Section 5.6.9.1] performed during the course of the 
study are reported in a subject listing. 
11 GENERAL DEFINITIONS AND DERIVATIONS 
11.1 OL enrollment date 
Date of OL enrollment collected in the “Enrollment” eCRF module. 
11.2 End-of-Study date 
Date of EOS visit collected in the “End of Study” eCRF module. 
11.3 Study treatment start date  
11.3.1 DB treatment start date  
The study treatment start date in the DB study. 
11.3.2 OL treatment start date  
It is the first day of intake of study treatment during OL study. It is derived as the first 
treatment start date (in chronological order) in the “Exposure” eCRF module.  
For analyses on the OL-only period the OL treatment start date is used as the “Study 
treatment start date” 
11.3.3 Macitentan treatment start date  
The date of first drug intake of macitentan. For subjects who received macitentan during 
the DB study, it is the study treatment start date of DB study as defined in Section 11.3.1, 
otherwise it is the study treatment start date of this OL study as defined in Section 11.3.2. 
For analyses on the combined DB + OL period, the Macitentan treatment start date is 
used as the “Study treatment start date”. 


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11.4 Study treatment end date/study treatment discontinuation (EOT) 
11.4.1 DB treatment end date  
It is the study treatment end date in the DB study. 
11.4.2 OL treatment end date  
It is the last day of intake of study treatment during OL study. It is derived as the last 
treatment end date (in chronological order) in the “Exposure” eCRF module.  
For analyses on the OL only period the OL treatment end date is used as the “Study 
treatment end date/study treatment discontinuation (EOT)”. 
11.4.3 Macitentan treatment end date  
It is the last drug intake of macitentan. For subjects who did not enter the OL study this is 
the study treatment end date of DB study as defined in Section 11.4.1, otherwise it is the 
study treatment end date (EOT) as defined in Section 11.4.2. 
For analyses on the combined DB + OL period, the Macitentan treatment end date is used 
as the “Study treatment end date/study treatment discontinuation (EOT)”. 
11.5 Period 
11.5.1 DB period 
The DB period is the period from DB treatment start date [see Section11.3.1] to DB 
treatment end date [see Section 11.4.1]. 
11.5.2 OL period 
The OL period is the period from OL treatment start date [see Section11.3.1] to OL 
treatment end date [see Section 11.4.1]. 
11.5.3 DB + OL period 
The DB + OL period is the period from macitentan start date (see Section11.3.1) to 
macitentan treatment end date [see Section 11.4.1]. 
11.6 Study Day (Day) 
11.6.1 OL study day 
‘OL study day’ refers to the number of days elapsed since OL study treatment start date 
[Section 11.3.2] plus 1 (e.g., Day 1 is the day of study treatment start date). For dates 
prior to study treatment start date, study day is the negative number of days elapsed 
between the date under consideration and the day of study treatment start date. Therefore, 
the study day is always different from 0. 


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11.6.2 DB study day 
‘DB study day’ refers to the number of days elapsed since DB study treatment start date 
[Section 11.3.2] plus 1 (e.g., Day 1 is the day of study treatment start date). For dates 
prior to study treatment start date, study day is the negative number of days elapsed 
between the date under consideration and the day of study treatment start date. Therefore, 
the study day is always different from 0. 
11.7 Baseline 
Except where otherwise specified, the baseline for a given measurement is the last value 
assessed ≤ the start date of study treatment defined in Section 11.3. If unscheduled/re-test 
visits are performed on the same day as treatment start, the available value from this test 
is considered for baseline. 
The DB baseline is defined as the last value assessed ≤ the DB treatment start date 
defined in Section 11.3.1. 
The OL baseline is defined as the last value assessed ≤ the OL treatment start date 
defined in Section 11.3.3.  
The macitentan baseline is defined as the last value assessed ≤ the macitentan treatment 
start date defined in Section 11.3.3.  
12 HANDLING OF MISSING/INCOMPLETE DATE AND TIME FIELDS 
Incomplete or missing dates/times are handled as follows for the purpose of the analysis. 
If the month is missing, then the day is also considered missing (if present). 
In the following, ‘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 of different dates 
refer to the first or last date, respectively, when ordered in sequence.  
Data from the AC-055-305/MAESTRO study are taken from the analysis database using 
the imputation rules applied in AC-055-305/MAESTRO study; thus this section refers 
only to SDTM collected for the AC-055-308/MAESTRO-OL study. 


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Type 
of 
date/time  
Date/time is incomplete 
Date/time is missing 
AE resolution 
date 
The upper limit 
No approximation, the AE is 
considered as ongoing in the 
analysis 
AE onset date 
If the end date of the AE is not before 
the start of study treatment OL, and if 
the study treatment start OL falls in 
the range of possible dates, it is the 
study treatment start date OL. In all 
the other cases, it is the lower limit 
The earlier of the resolution 
of the AE and the study 
treatment start date 
Concomitant 
therapy 
start 
date 
If the end date of the therapy is not 
before the start of study treatment OL 
and the start of study treatment date 
OL falls in the range of possible dates, 
the start of study treatment date OL is 
used. In all other cases, it is the lower 
limit 
No replacement, the therapy 
is considered as study /study 
treatment-concomitant if the 
end date is on or after the 
study treatment start date OL. 
Concomitant 
therapy 
end 
date 
 
The upper limit 
No replacement (considered 
as ongoing)  
13 LIST OF SUMMARY TABLES, LISTINGS AND FIGURES 
This section lists all outputs (i.e., tables, listings, and figures) produced to report the 
results of the analyses defined in the sections above.  
The table, listing and figures naming conventions have three components: Type (T, L, F), 
Name (free text, not longer than eight characters), Suffix (for example, for analysis sets, 
or subgroups, not longer than four characters). Multiple suffixes can be added; 
components/suffixes are separated by ‘_’. 
Whenever possible, naming conventions and mock layouts are according to the BST 
Standard Outputs, version 3.0 as of 31 March 2016. Mock layouts are displayed in a 
separate document (Layouts for Tables 
Listings 
Figures [TLFs] of study  
AC-055-308/MAESTRO-OL).  
Key deliverables are marked as a priority. 


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13.1 Subject disposition 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
ENRCS 
T 
Enrolled subjects by country 
and by site 
ENR 
 
TS1 
 
DISP 
T 
Disposition of subjects  
ENR 
 
TS2 
 
ANSET
OV 
T 
Overview of analysis sets  
TTS 
 
TS3 
ANSET 
L 
Listing of subject participation 
in the different analysis sets 
TTS  
 
LS1 
* T = Summary table, L = Listing, **ENR = All-enrolled set, TTS =All-treated DB + OL set. 
13.2 Protocol deviations 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
PRDEV
A 
T 
All protocol deviations 
ENR 
 
TS4 
PRDEVI T 
Important protocol deviations  
ENR 
 
TS4 
PRDEV 
L 
Listing of protocol deviations 
ENR 
 
LS2 
* T = Summary table, L = Listing, **ENR = All-enrolled set. 
13.3 Subject characteristics 
13.3.1 Demographics 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
DEMO
G 
T 
Demographic characteristics 
ENR  
  
TS5 
AGECA
TEU 
T 
EudraCT age categories 
ENR 
 
TS6 


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Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
DEMO
G 
L 
Listing 
of 
demographic 
characteristics 
ENR 
 
LS3 
* T = Summary table, L = Listing, **ENR = All-enrolled set. 
13.3.2 Baseline disease characteristics 
 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
BLDIS
CHR 
T 
Baseline disease characteristics 
of subjects who entered the 
open-label study 
ENR 
  
 
TS7 
BASDC 
L 
Listing of baseline disease 
characteristics 
ENR 
 
LS4 
* T = Summary table, L= Listing, **ENR = All-enrolled set. 
 
13.3.3 Medical history 
Not applicable. 
13.3.4 Previous and concomitant therapies 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
CTSAT
CPR 
T 
Study-concomitant 
therapies 
by 
anatomical 
therapeutic 
chemical (ATC) class and 
preferred term 
ENR 
 
TS8 
CTSPR 
T 
Study-Concomitant 
therapies 
by preferred term 
ENR 
 
TS9 


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Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
PCTHE
R 
L 
Listing 
of 
subjects 
with 
previous 
and 
study-concomitant 
therapies 
including 
hormonal 
contraceptives (for females of 
childbearing potential only) 
ENR 
 
LS5 
* T = Summary table, L = Listing, ** ENR = All-enrolled set.. 
13.3.5 Specific previous and concomitant therapies 
Not applicable. 
13.3.6 Other subject characteristics 
13.3.6.1 Contraceptive methods 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
PREGN 
L 
Listing 
of 
childbearing 
potential and contraception 
ENR 
 
LS6 
PREGN_
SERUM 
L 
Listing of serum pregnancy 
data 
ENR 
 
LS7 
* L = Listing, **ENR = All-enrolled set. 
13.4 Study treatment exposure and compliance 
13.4.1 Exposure 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
TREXP 
T 
Study 
treatment 
exposure 
combined DB+OL 
TTS 
 
 
TS10 
TREXP_
OL 
T 
Study treatment exposure OL 
ENR 
 
 
TS10 
TREXP 
L 
Listing of exposure 
TTS 
 
LS8 
* T = Summary table, L = Listing, **ENR = All-enrolled set, TTS =All-treated DB + OL set. 


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13.4.2 Compliance with study treatment 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
COMPA 
T 
Compliance combined 
DB+OL 
TTS 
 
TS11 
COMPA
_OL 
T 
Compliance OL 
ENR 
 
TS11 
COMPA 
L 
Listing of compliance  
TTS 
 
LS9 
* T = Summary table, L = Listing, **ENR = All-enrolled set, TTS =All-treated DB + OL set. 
13.4.3 Study treatment discontinuation 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
PDISCT
R 
T 
Reasons 
for 
premature 
discontinuation 
of 
study 
treatment 
ENR 
  
 
TS12 
* T = Summary table, **ENR = All-enrolled set. 
13.4.4 Study treatment adjustment/interruptions 
Not applicable. 
13.5 Study discontinuation 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
PDISCS
T 
T 
Reasons for premature study 
discontinuation 
ENR 
  
 
TS13 
PDISC 
L 
Listing 
of 
discontinued 
subjects 
ENR 
 
LS10 
* T = Summary table, L = Listing, ** ENR = All-enrolled set, 
 


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13.6 Efficacy analyses 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
6MWDD
BOL 
T 
Absolute values and change 
from DB baseline for 6MWD - 
combined DB + OL period 
ENR  
 
TS14 
6MWDD
BOL 
F 
Mean (95% CL) for change 
from DB baseline in 6MWD - 
combined DB + OL period 
(observed values) 
ENR 
 
FS1 
6MWDI
DBOL 
F 
Mean (95% CL) for change 
from DB baseline in 6MWD - 
combined DB + OL period 
(imputed values) 
ENR 
 
FS1 
WHODB
OL 
T 
Shift table from baseline to 
post-baseline visits in WHO 
functional class - combined 
DB + OL period 
ENR 
  
TS15 
BORGD
BOL 
T 
Absolute values and change 
from DB baseline for Borg 
dyspnea index - combined DB 
+ OL period 
ENR  
 
TS14 
SPO2DB
OL 
T 
Absolute values and change 
from DB baseline for SpO2 - 
combined DB + OL period 
ENR  
 
TS14 
EFF 
L 
Listing of all efficacy data 
ENR 
 
LS11 
* T = Summary table, L = Listing, F = Figure, **ENR = All-enrolled set, TTS =All-treated DB + OL set. 
 


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Doc No D-17.554 
 
 
13.7 Safety analyses 
13.7.1 Adverse events 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
AEOV 
T 
Overview 
of 
treatment-
emergent adverse events (AE) 
TTS 
 
TS16 
AESCP
R 
T 
Treatment-Emergent 
adverse 
events (AE) by system organ 
class and preferred term 
TTS 
 
 
TS17 
AEPR 
T 
Treatment-Emergent 
adverse 
events (AE) by preferred term 
TTS 
 
TS18 
AEPRI
N 
T 
Treatment-Emergent 
adverse 
events (AE) by maximum 
intensity 
TTS 
 
TS19 
AERES
CPR 
T 
Treatment-Emergent 
adverse 
events (AE) related to study 
treatment by system organ 
class (SOC) and preferred term 
TTS 
 
TS17 
AEREP
R 
T 
Treatment-Emergent 
adverse 
events (AE) related to study 
treatment by preferred term 
TTS 
 
TS18 
AE 
L 
Listing of adverse events (AE) 
TTS 
 
LS12 
* T = Summary table, L = Listing, F = Figure, , **ENR = All-enrolled set, TTS =All-treated DB + OL set. 
13.7.2 Deaths 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
DEAPR 
T 
Cause of death  
TTS 
 
TS20 
DEATH 
L 
Listing of deaths 
TTS 
 
LS14 
* T = Summary table, L = Listing, **ENR = All-enrolled set, TTS =All-treated DB + OL set. 
 


Macitentan / ACT-064992 
Study AC-055-308, MAESTRO-OL 
Version 1.0 
6 December 2017, page 51/58 
Confidential  
Statistical Analysis Plan 
Doc No D-17.554 
 
 
13.7.3 Serious adverse events 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
SAESC
PR 
T 
Treatment-Emergent 
serious 
adverse 
events 
(SAE) 
by 
system organ class (SOC) and 
preferred term 
TTS 
 
TS17 
SAEPR 
T 
Treatment-Emergent 
serious 
adverse 
events 
(SAE) 
by 
preferred term 
TTS 
 
TS18 
SAERE
SCPR 
T 
Treatment-Emergent 
serious 
adverse events (SAE) related 
to study treatment by system 
organ 
class 
(SOC) 
and 
preferred term 
TTS 
 
TS17 
SAEFA
SCPR 
T 
Treatment-Emergent 
serious 
adverse events (SAE) with 
fatal outcome by system organ 
class (SOC) and preferred 
term 
TTS 
 
TS17 
SAERF
SCPR 
T 
Treatment-Emergent 
serious 
adverse events (SAE) related 
to study treatment with fatal 
outcome by system organ 
class (SOC) and preferred 
term 
TTS 
 
TS17 
SAESC
PRE 
T 
Occurrence 
of 
treatment-
emergent 
serious 
adverse 
events (SAE) 
ENR 
 
TS21 


Macitentan / ACT-064992 
Study AC-055-308, MAESTRO-OL 
Version 1.0 
6 December 2017, page 52/58 
Confidential  
Statistical Analysis Plan 
Doc No D-17.554 
 
 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
SAE 
L 
Listing of serious adverse 
events (SAE) 
TTS 
 
LS12 
SAEHO
SP 
L 
Listing of serious adverse 
events 
(SAE) 
leading 
to 
hospitalization 
TTS 
 
LS13 
* T = Summary table, L = Listing, **ENR = All-enrolled set, TTS =All-treated DB + OL set. 
13.7.4 Adverse events leading to premature discontinuation of study treatment  
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
AEPDS
CPR 
T 
Adverse events (AE) leading 
to premature discontinuation 
of study treatment by system 
organ 
class 
(SOC) 
and 
preferred term 
TTS 
 
TS17 
AEPDP
R 
T 
Adverse events (AE) leading 
to premature discontinuation 
of study treatment by preferred 
term 
TTS 
 
TS18 
AEPD 
L 
Listing of adverse events (AE) 
leading 
to 
premature 
discontinuation 
of 
study 
treatment  
TTS 
 
LS12 
* T = Summary table, L = Listing, **ENR = All-enrolled set, TTS =All-treated DB + OL set. 


Macitentan / ACT-064992 
Study AC-055-308, MAESTRO-OL 
Version 1.0 
6 December 2017, page 53/58 
Confidential  
Statistical Analysis Plan 
Doc No D-17.554 
 
 
13.7.5 Other significant adverse events 
13.7.5.1 AEs with fatal outcome 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
AEFA
SCPR 
T 
Treatment-Emergent 
adverse 
events (AE) with fatal outcome 
by system organ class (SOC) 
and preferred term 
TTS 
 
TS17 
AEFA
PR 
T 
Treatment-Emergent 
adverse 
events (AE) with fatal outcome 
by preferred term 
TTS 
 
TS18 
* T = Summary table, **ENR = All-enrolled set, TTS =All-treated DB + OL set. 
13.7.5.2 AEs of special interest 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
AESIP
R_ANA
E 
T 
Treatment-Emergent 
adverse 
events (AE) of special interest 
related to anaemia by preferred 
term 
TTS 
 
TS18 
AESIP
R_HYP
O 
T 
Treatment-Emergent 
adverse 
events (AE) of special interest 
related 
to 
hypotension 
by 
preferred term 
TTS 
 
TS18 
AESIP
R_OED
E 
T 
Treatment-Emergent 
adverse 
events (AE) of special interest 
related to oedema and fluid 
overload 
TTS 
 
TS18 
AESI_
ANAE 
L 
Listing of adverse events (AE) 
of special interest related to 
anaemia  
TTS 
 
LS12 


Macitentan / ACT-064992 
Study AC-055-308, MAESTRO-OL 
Version 1.0 
6 December 2017, page 54/58 
Confidential  
Statistical Analysis Plan 
Doc No D-17.554 
 
 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
AESI_
HYPO 
L 
Listing of adverse events (AE) 
of special interest related to 
hypotension  
TTS 
 
LS12 
AESI_
OEDE 
L 
Listing of adverse events (AE) 
of special interest related to 
oedema and fluid overload 
TTS 
 
LS12 
* T = Summary table, **ENR = All-enrolled set, TTS =All-treated DB + OL set. 
13.7.5.3 Non-serious AEs  
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
NSAEF
SCPRE 
T 
Occurrence 
of 
non-serious 
frequent 
treatment-emergent 
adverse events (AE) 
ENR 
 
TS21 
* T = Summary table, **ENR = All-enrolled set, TTS =All-treated DB + OL set. 
 
13.8 Electrocardiogram 
Not Applicable. 
13.9 Laboratory tests 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
LABCG
TPA_H
EM 
T 
Hematology: 
change 
in 
laboratory tests from baseline 
up to 30 days after study 
treatment discontinuation 
TTS 
 
TS22 
 
LABCG
TPB_H
EM 
T 
Hematology: 
change 
in 
laboratory tests from baseline 
to 
each 
scheduled 
post-
baseline visit 
TTS 
 
TS22 
 


Macitentan / ACT-064992 
Study AC-055-308, MAESTRO-OL 
Version 1.0 
6 December 2017, page 55/58 
Confidential  
Statistical Analysis Plan 
Doc No D-17.554 
 
 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
LABCG
TPA_C
HE 
T 
Clinical chemistry: change in 
laboratory tests from baseline 
up to 30 days after study 
treatment discontinuation 
TTS 
 
TS22 
LABCG
TPB_C
HE 
T 
Clinical chemistry: change in 
laboratory tests from baseline 
to 
each 
scheduled 
post-
baseline visit 
TTS 
 
TS22 
LABML
A_HEM 
T 
Hematology: 
treatment-
emergent marked laboratory 
abnormalities up to 30 days 
after 
study 
treatment 
discontinuation 
TTS 
 
TS23 
LABML
A_CHE 
T 
Clinical chemistry: treatment-
emergent marked laboratory 
abnormalities up to 30 days 
after 
study 
treatment 
discontinuation 
TTS 
 
TS23 
LABAB
LIV 
T 
Treatment-emergent 
elevated 
liver 
tests 
and 
additional 
hemoglobin 
laboratory 
abnormalities up to 30 days 
after 
study 
treatment 
discontinuation 
TTS 
 
TS24 
LAB 
L 
Listing 
of 
individual 
laboratory measurements (SI 
units) 
TTS 
 
LS15 
LABOR
I 
L 
Listing 
of 
individual 
laboratory 
measurements 
(original units) 
TTS 
 
LS16 


Macitentan / ACT-064992 
Study AC-055-308, MAESTRO-OL 
Version 1.0 
6 December 2017, page 56/58 
Confidential  
Statistical Analysis Plan 
Doc No D-17.554 
 
 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
LABLM
A_DEF 
L 
Listing 
of 
definitions 
of 
marked laboratory abnormality 
Not 
applic-
able 
 
LS17 
LABLM
A 
L 
Listing 
of 
individual 
laboratory 
measurements, 
subjects with at least an 
additional liver or hemoglobin 
laboratory abnormality  
TTS 
 
LS15 
* T = Summary table, L = Listing, **ENR = All-enrolled set, TTS =All-treated DB + OL set. 
13.10 Vital signs and body weight 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
VITCG
TPA 
 
T 
Vital signs and body weight: 
change from baseline up to 30 
days after study treatment 
discontinuation 
TTS 
 
TS22 
VITCG
TPB 
 
T 
Vital signs and body weight: 
change from baseline to each 
scheduled post-baseline visit 
TTS 
 
TS22 
VIT_BP
M 
L 
Listing of vital signs: blood 
pressure measurements and 
body weight 
TTS 
 
LS18 
* T = Summary table, L = Listing, **ENR = All-enrolled set, TTS =All-treated DB + OL set. 
13.11 Other safety variables 
13.11.1 Physical Examination 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
deliverable 
Mock 
layout 
PHYS
F 
L 
Listing of physical findings 
TTS 
 
LS19 
* L = Listing, ** TTS =All-treated DB + OL set. 


Macitentan / ACT-064992 
Study AC-055-308, MAESTRO-OL 
Version 1.0 
6 December 2017, page 57/58 
Confidential  
Statistical Analysis Plan 
Doc No D-17.554 
 
 
14 REFERENCES 
[D-14.170] AC-055-308 MAESTRO-OL: Long term, single-arm, open-label extension 
study of protocol AC-055-305 to assess the safety, tolerability and efficacy of 
macitentan in subjects with Eisenmenger Syndrome. Actelion Pharmaceuticals Ltd; 
Global Protocol Version 4, 16 May 2014. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Macitentan / ACT-064992 
Study AC-055-308, MAESTRO-OL 
Version 1.0 
6 December 2017, page 58/58 
Confidential  
Statistical Analysis Plan 
Doc No D-17.554 
 
 
15 APPENDICES 
Appendix A 
Document history 
Version 
Effective Date 
Reason 
1.0 
6-DEC-17 
New