A Randomized, Double-blind, Placebo-controlled, Prospective, Multicenter, Parallel Group Study to Assess the Safety and Efficacy of Macitentan in Patients With Portopulmonary Hypertension
Phase: PHASE4
Conditions: Portopulmonary Hypertension
Sponsor: Actelion

 
 
TPL-000052_v09 
 
Macitentan / ACT-064992 
Portopulmonary hypertension 
AC-055-404 
PORTICO 
A randomized, double-blind, placebo-controlled, prospective, multicenter, parallel 
group study to assess the safety and efficacy of macitentan in patients with 
portopulmonary hypertension 
 
 
Study Phase: 
4 
ClinicalTrials.gov Identifier 
NCT02382016 
Date: 
21 April 2016 
Document Version 
Final Version 3 
Document History: 
21 April 2016: Global Amendment 2, resulting in Final 
Version 3 
15 January 2015: Global Amendment 1, resulting in 
Final Version 2 
05 December 2014: Final Version 1 
 
 
 
 
 
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 
Portopulmonary hypertension 
Protocol AC-055-404 
Version 3 
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Confidential 
EudraCT 2014-004624-21 
Doc No D-16.102 
 
 
SPONSOR CONTACT DETAILS 
SPONSOR  
 
ACTELION Pharmaceuticals Ltd 
Gewerbestrasse 16 
CH-4123 Allschwil 
Switzerland 
Clinical Trial Physician  
 
 
 
 
Fax 
 
email 
 
MEDICAL HOTLINE 
 
Toll phone number:  
 
 
+ 41 61 227 05 63 
 
 
Site-specific toll telephone numbers and toll-free numbers for the Medical Hotline can 
be found in the Investigator Site File. 
 
 
ACTELION CONTRIBUTORS TO THE PROTOCOL 
Clinical Trial Scientist 
 
 
Clinical Trial Statistician 
 
 
Drug Safety Physician 
 
 
Clinical Pharmacologist 
 
 
COORDINATING INVESTIGATOR 
Name / Title 
Address 
 
 
 
 
 
 
 

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CONTRACT RESEARCH ORGANIZATIONS INFORMATION 
 
CENTRAL LABORATORY 
 
 
 
 
CENTRAL 
RANDOMIZATION 
 
 
 
 
 
CRO 
 
 
  
 
 
 
 
 
A list of site-specific contact details for CROs can be found in the Investigator Site File. 
 

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SIGNATURE PAGE FOR ACTELION PHARMACEUTICALS LTD 
Hereinafter called Actelion 
 
Treatment name / number 
Macitentan / ACT-064992 
Indication 
Portopulmonary hypertension 
Protocol number, study acronym, study title 
AC-055-404, PORTICO: A randomized, double-blind, placebo-controlled, prospective, 
multicenter, parallel group study to assess the safety and efficacy of macitentan in 
patients with portopulmonary hypertension 
I approve the design of this study. 
 
 
 

Macitentan / ACT-064992 
Portopulmonary hypertension 
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Version 3 
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Confidential 
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INVESTIGATOR SIGNATURE PAGE 
Treatment name / number 
Macitentan / ACT-064992 
Indication 
Portopulmonary hypertension 
Protocol number, study acronym, study title  
AC-055-404, PORTICO, A randomized, double-blind, placebo-controlled, prospective, 
multicenter, parallel group study to assess the safety and efficacy of macitentan in 
patients with portopulmonary hypertension 
I agree to the terms and conditions relating to this study as defined in this protocol, the 
electronic 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 protocol deviation, including any ancillary studies or 
procedures performed on study subjects (other than those procedures necessary for the 
wellbeing of the subjects). 
I agree to conduct this study in accordance with the Declaration of Helsinki principles, 
International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) 
guidelines, and applicable regulations and laws. I will obtain approval by an Institutional 
Review Board or Independent Ethics Committee (IRB/IEC) prior to study start and 
signed informed consent from all subjects included in this study. If an amendment to the 
protocol is necessary, I will obtain approval by an IRB/IEC and ensure approval by 
regulatory authorities (if applicable) have been obtained before the implementation of 
changes described in the amendment. I will allow direct access to source documents and 
study facilities to sponsor representative(s), particularly monitor(s) and auditor(s), and 
agree to inspection by regulatory authorities or IRB/IEC representative. I will ensure that 
the study treatment(s) supplied by the sponsor are being used only as described in this 
protocol. 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 
Site 
number 
Town 
Date 
 
Signature 
Site Principal 
Investigator 
 
 
 
 
 
 
 
This center is performing the: 
 Pharmacokinetic substudy     
 Hepatic vein catheterization 

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TABLE OF CONTENTS 
SPONSOR CONTACT DETAILS ......................................................................................2 
ACTELION CONTRIBUTORS TO THE PROTOCOL .....................................................2 
COORDINATING INVESTIGATOR.................................................................................2 
CONTRACT RESEARCH ORGANIZATIONS INFORMATION ...................................3 
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................13 
PROTOCOL SYNOPSIS AC-055-404 .............................................................................17 
1 
BACKGROUND .........................................................................................................29 
1.1 
Indication ......................................................................................................29 
1.2 
Epidemiology and natural history .................................................................29 
1.3 
Current management .....................................................................................30 
1.4 
Endothelin-1 and pulmonary hypertension ...................................................31 
1.5 
Macitentan ....................................................................................................31 
1.5.1 
Nonclinical results ............................................................................31 
1.5.2 
Clinical information ..........................................................................32 
1.5.2.1 
Phase 1 studies .........................................................................32 
1.5.2.2 
Phase 2 studies .........................................................................33 
1.5.2.3 
Phase 3 study in patients with pulmonary arterial 
hypertension ............................................................................34 
1.5.2.4 
Summary of potential risks and risk management ..................35 
1.6 
Purpose and rationale of the study ................................................................36 
2 
STUDY OBJECTIVES ...............................................................................................36 
2.1 
Primary objective ..........................................................................................36 
2.2 
Secondary objectives ....................................................................................36 
3 
OVERALL STUDY DESIGN AND PLAN ...............................................................37 
3.1 
Study design .................................................................................................37 
3.2 
Study design rationale ..................................................................................38 
3.3 
Study Committees .........................................................................................39 
4 
SUBJECT POPULATION ..........................................................................................39 
4.1 
Subject population description .....................................................................39 

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4.2 
Rationale for the selection of the study population ......................................40 
4.3 
Inclusion criteria ...........................................................................................40 
4.4 
Exclusion criteria ..........................................................................................41 
4.5 
Reliable contraception for women of childbearing potential .......................43 
4.5.1 
Definition of woman of childbearing potential .................................43 
4.5.2 
Europe and Latin America ................................................................43 
4.5.3 
North America ..................................................................................44 
4.6 
Medical history .............................................................................................44 
5 
TREATMENTS ..........................................................................................................45 
5.1 
Study treatment .............................................................................................45 
5.1.1 
Investigational treatment: description and rationale .........................45 
5.1.2 
Matching placebo: description and rationale ....................................45 
5.1.3 
Study treatment administration .........................................................45 
5.1.4 
Treatment assignment .......................................................................45 
5.1.5 
Blinding ............................................................................................46 
5.1.6 
Unblinding ........................................................................................46 
5.1.6.1 
Unblinding for final analyses ..................................................46 
5.1.6.2 
Unblinding for SUSARs ..........................................................46 
5.1.6.3 
Emergency procedure for unblinding ......................................47 
5.1.7 
Study treatment supply .....................................................................47 
5.1.7.1 
Study treatment packaging and labeling .................................47 
5.1.7.2 
Study treatment distribution and storage .................................48 
5.1.7.3 
Study treatment dispensing .....................................................49 
5.1.7.4 
Study treatment return and destruction ...................................49 
5.1.8 
Compliance with study treatment .....................................................49 
5.1.9 
Study treatment dose adjustments and interruptions ........................50 
5.1.10 
Premature discontinuation of study treatment ..................................50 
5.1.11 
Study-specific criteria for interruption / premature 
discontinuation of study treatment ....................................................51 
5.2 
Previous and concomitant therapy ................................................................54 
5.2.1 
Definitions ........................................................................................54 
5.2.2 
Reporting of previous/concomitant therapy in the CRF ...................54 
5.2.3 
Allowed concomitant therapy ...........................................................54 
5.2.4 
Forbidden concomitant therapy ........................................................55 
6 
STUDY ENDPOINTS ................................................................................................55 
6.1 
Efficacy endpoints ........................................................................................55 
6.1.1 
Double-blind treatment period ..........................................................55 
6.1.1.1 
Primary efficacy endpoint .......................................................55 
6.1.1.2 
Secondary efficacy endpoints ..................................................56 

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6.1.1.3 
Other efficacy endpoints .........................................................56 
6.1.2 
Macitentan-treatment period .............................................................56 
6.2 
Safety endpoints ...........................................................................................56 
6.2.1 
Double-blind treatment period ..........................................................56 
6.2.2 
Macitentan-treatment period safety endpoints ..................................57 
6.3 
Pharmacokinetic endpoints ...........................................................................57 
7 
STUDY ASSESSMENTS ...........................................................................................58 
7.1 
Screening/baseline assessments ....................................................................58 
7.2 
Efficacy assessments ....................................................................................59 
7.2.1 
Hemodynamic measurements − Right heart catheterization ............59 
7.2.2 
Hemodynamic measurements − Hepatic vein catheterization ..........60 
7.2.3 
WHO functional class .......................................................................60 
7.2.4 
6-minute walk test .............................................................................61 
7.2.5 
Borg dyspnea index ..........................................................................61 
7.2.6 
Serum NT-proBNP ...........................................................................61 
7.3 
Safety assessments ........................................................................................61 
7.3.1 
Vital signs .........................................................................................61 
7.3.2 
Weight and height .............................................................................62 
7.3.3 
Physical examination ........................................................................62 
7.3.4 
Child-Pugh classification and/or MELD Score assessment .............62 
7.3.5 
Laboratory assessments ....................................................................62 
7.3.5.1 
Type of laboratory ...................................................................62 
7.3.5.2 
Laboratory tests .......................................................................64 
8 
SCHEDULE OF VISITS ............................................................................................65 
8.1 
Screening Period ...........................................................................................65 
8.1.1 
Screening (Visit 1) ............................................................................65 
8.2 
Double-blind treatment period ......................................................................66 
8.2.1 
Randomization (Visit 2) ....................................................................66 
8.2.2 
Week 4 (Visit 3) ................................................................................67 
8.2.3 
Week 8 (Visit 4) ................................................................................67 
8.2.4 
EOT-DB (scheduled Visit 5) ............................................................68 
8.3 
Open-label treatment period .........................................................................68 
8.3.1 
Week 16 (Visit 6) ..............................................................................68 
8.3.2 
Week 20 (Visit 7) ..............................................................................69 
8.3.3 
EOT-OL (scheduled Visit 8) .............................................................69 
8.4 
EOS ...............................................................................................................70 
9 
STUDY COMPLETION AND POST-STUDY TREATMENT/MEDICAL 
CARE ..........................................................................................................................70 

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9.1 
Study completion ..........................................................................................70 
9.2 
Premature withdrawal from study ................................................................70 
9.3 
Premature termination or suspension of the study ........................................71 
9.4 
Medical care of subjects after study completion/ withdrawal from 
study ..............................................................................................................72 
10 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ...........................72 
10.1 
Adverse events ..............................................................................................72 
10.1.1 
Definitions of adverse events ............................................................72 
10.1.2 
Intensity of adverse events ................................................................73 
10.1.3 
Relationship to study treatment ........................................................73 
10.1.4 
Adverse events associated to study design or protocol 
mandated procedures ........................................................................74 
10.1.5 
Reporting of adverse events ..............................................................74 
10.1.6 
Follow-up of adverse events .............................................................74 
10.2 
Serious adverse events ..................................................................................74 
10.2.1 
Definitions of serious adverse events ...............................................74 
10.2.1.1 
Serious adverse events .............................................................74 
10.2.1.2 
Serious adverse events associated with the study design 
or protocol mandated procedures ............................................75 
10.2.2 
Reporting of serious adverse events .................................................75 
10.2.2.1 
During screening period ..........................................................75 
10.2.2.2 
During treatment period ..........................................................75 
10.2.2.3 
During 30-day follow-up period ..............................................75 
10.2.3 
Follow-up of serious adverse events .................................................75 
10.2.4 
After the 30-day follow-up period ....................................................75 
10.2.5 
Reporting procedures ........................................................................76 
10.3 
Pregnancy .....................................................................................................76 
10.3.1 
Reporting of pregnancy ....................................................................76 
10.3.2 
Follow-up of pregnancy ....................................................................76 
10.4 
Study safety monitoring ................................................................................77 
11 STATISTICAL METHODS .......................................................................................77 
11.1 
Analysis Sets .................................................................................................77 
11.1.1 
Screened Analysis Set .......................................................................77 
11.1.2 
Full Analysis Set ...............................................................................77 
11.1.3 
Per-Protocol Set ................................................................................77 
11.1.4 
Safety Set ..........................................................................................77 
11.1.5 
Other analysis sets ............................................................................77 
11.1.6 
Usage of the analysis sets .................................................................78 
11.2 
Variables .......................................................................................................78 

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11.2.1 
Primary efficacy variable ..................................................................78 
11.2.2 
Secondary efficacy variables ............................................................78 
11.2.3 
Other efficacy variables ....................................................................79 
11.2.3.1 
Double-blind treatment period ................................................79 
11.2.3.2 
Macitentan treatment period ....................................................79 
11.2.4 
Safety variables .................................................................................79 
11.2.4.1 
Double-blind treatment period ................................................79 
11.2.4.2 
Macitentan treatment period ....................................................80 
11.2.5 
Other variables ..................................................................................80 
11.3 
Description of statistical analyses .................................................................80 
11.3.1 
Overall testing strategy .....................................................................80 
11.3.2 
Analysis of the primary efficacy variable(s) .....................................80 
11.3.2.1 
Hypotheses and statistical model ............................................80 
11.3.2.2 
Handling of missing data .........................................................80 
11.3.2.3 
Main analysis ...........................................................................81 
11.3.2.4 
Supportive/sensitivity analyses ...............................................81 
11.3.2.5 
Subgroup analyses ...................................................................82 
11.3.3 
Analysis of the secondary efficacy variable(s) .................................82 
11.3.4 
Analysis of the other efficacy variables ............................................83 
11.3.5 
Analysis of the safety variables ........................................................83 
11.3.5.1 
Adverse events ........................................................................83 
11.3.5.2 
Laboratory variables ................................................................84 
11.3.5.3 
Vital signs and body weight ....................................................84 
11.3.6 
Analysis of other variables ...............................................................85 
11.4 
Interim analyses ............................................................................................85 
11.5 
Sample size ...................................................................................................85 
11.5.1 
Sample size justification ...................................................................85 
11.5.2 
Sample size sensitivity ......................................................................85 
12 DATA HANDLING ....................................................................................................86 
12.1 
Data collection ..............................................................................................86 
12.2 
Maintenance of data confidentiality .............................................................87 
12.3 
Database management and quality control ...................................................87 
13 PROCEDURES AND GOOD CLINICAL PRACTICE .............................................88 
13.1 
Ethics and Good Clinical Practice ................................................................88 
13.2 
Independent Ethics Committee / Institutional Review Board ......................88 
13.3 
Informed consent ..........................................................................................88 
13.4 
Compensation to subjects and investigators .................................................89 
13.5 
Protocol adherence/compliance ....................................................................89 
13.6 
Protocol amendments ...................................................................................90 

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13.7 
Essential documents and retention of documents .........................................90 
13.8 
Monitoring ....................................................................................................91 
13.9 
Investigator site file ......................................................................................92 
13.10 
Audit .............................................................................................................92 
13.11 
Inspections ....................................................................................................92 
13.12 
Reporting of study results and publication ...................................................93 
14 REFERENCES ............................................................................................................95 
15 APPENDICES .............................................................................................................99 

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LIST OF TABLES 
Table 1 
Visit and assessment schedule ......................................................................27 
Table 2 
Treatment effects (differences on log-scale as well as % reduction 
versus placebo), variability in integrated analysis of three studies 
(AC-052-366, AC-052-364 and AC-055-302) and associated sample 
size for 90% power in the PORTICO study. ................................................86 
 
 
LIST OF FIGURES 
Figure 1 
Study design .................................................................................................38 
Figure 2 
PK substudy design ....................................................................................100 
 
LIST OF APPENDICES 
Appendix 1  PORTICO PK substudy ................................................................................99 
Appendix 2 Child-Pugh, MELD, and hepatic encephalopathy scales in 
classification of liver disease ......................................................................105 
Appendix 3 Actelion guidelines for 6MWT ...................................................................106 
Appendix 4 Borg dyspnea index ....................................................................................109 
Appendix 5 WHO functional classification of pulmonary hypertension .......................110 
Appendix 6 Laboratory abnormalities ............................................................................111 
Appendix 7 Central laboratory alert flags ......................................................................113 
Appendix 8 List of protocol amendments ......................................................................114 

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LIST OF ABBREVIATIONS AND ACRONYMS 
6MWD  
6-minute walk distance 
6MWT  
6-minute walk test 
AE  
Adverse event 
ALT  
Alanine aminotransferase 
ANCOVA  
Analysis of Covariance 
AST  
Aspartate aminotransferase 
ATS  
American Thoracic Society 
AUC  
Area under plasma concentration-time curves 
AUC0-∞  
Area under the plasma concentration-time curve from zero to 
infinity 
AUC0-t  
Area under the plasma concentration-time curve from time zero to 
time t 
AUCτ  
Area under the plasma concentration-time curve during one dosing 
interval 
BDI  
Borg Dyspnea index 
BLQ  
Below limit of qualification 
BP  
Blood pressure 
BSA  
Body surface area 
BUN  
Blood urea nitrogen 
CI  
Cardiac index 
Cmax  
Maximum plasma concentration 
CO  
Cardiac output 
CRA  
Clinical Research Associate 
eCRF  
electronic Case Report Form 
CRO  
Contract Research Organization 
CV  
Coefficient of Variation 
CYP  
Cytochrome P450 
DBP  
Diastolic blood pressure 
DoA  
Delegation of Authority 
ECG  
Electrocardiogram 
EDTA  
Ethylenediaminetetraacetic acid 

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EMA  
European Medicines Agency 
EOMT  
End of macitentan treatment 
EOS  
End of Study 
EOT-DB  
End of Treatment (double-blind) 
EOT-OL  
End of Treatment (open-label) 
ERA  
Endothelin receptor antagonist 
ERS  
European Respiratory Society 
ET-1  
Endothelin-1 
ETA  
Endothelin receptor A 
ETB  
Endothelin receptor B 
FAS  
Full Analysis Set 
FDA  
Food and Drug Administration 
GCP  
Good Clinical Practice 
GGT  
Gamma-glutamyl transferase 
GMP  
Good Manufacturing Practice 
GMR  
Geometric Mean Ratio 
HIV  
Human immunodeficiency virus 
HR  
Heart rate 
HVC  
Hepatic vein catheterization 
HVPG  
Hepatic venous pressure gradient 
IB  
Investigator’s Brochure 
ICF  
Informed Consent Form 
ICH  
International Conference on Harmonisation 
IEC  
Independent Ethics Committee 
ILSDRB  
Independent Liver Safety Data Review Board 
INR  
International Normalized Ratio 
IRB  
Institutional Review Board 
ISF  
Investigator Site File 
IUD  
Intrauterine device 
i.v.  
Intravenous 
IxRS  
Interactive Voice/Web Response System 
LDH  
Lactate dehydrogenase 

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LFT   
Liver function test 
LOQ  
Limit of quantification 
LVEDP  
Left ventricular end diastolic pressure 
MedDRA  
Medical Dictionary for Regulatory Activities 
MELD  
Model for End-stage Liver Disease 
mPAP  
Mean pulmonary arterial pressure 
mRAP  
Mean right atrial pressure 
MTS  
Macitentan Treatment Set 
NT-proBNP  
N-terminal pro-hormone brain natriuretic peptide 
OLT  
Orthotopic liver transplantation 
PAH  
Pulmonary arterial hypertension 
PAWP  
Pulmonary artery wedge pressure 
PDE5i  
Phosphodiesterase type 5 inhibitor 
PH  
Pulmonary hypertension 
PK  
Pharmacokinetic 
PoPH  
Portopulmonary hypertension 
PPS  
Per-protocol Set 
PT-INR  
Prothrombin time and International Normalized Ratio 
PVR  
Pulmonary vascular resistance 
RHC  
Right heart catheterization 
SAE  
Serious adverse event 
SAP  
Statistical Analysis Plan 
SBP  
Systolic blood pressure 
s.c.  
Subcutaneous 
SD  
Standard deviation 
sGC  
Soluble guanylate cyclase (stimulator, riociguat) 
SIV  
Site initiation visit 
SOC  
System organ class 
SOP  
Standard Operating Procedure 
SUSAR  
Suspected unexpected serious adverse reaction 
SVO2  
Venous oxygen saturation 
TIPS  
Transjugular intrahepatic portosystemic shunt 

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tmax  
Time to reach maximum plasma concentration 
TPR  
Total pulmonary resistance 
ULN  
Upper limit of the normal range 
WHO  
World Health Organization 
WU  
Wood Units 

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PROTOCOL SYNOPSIS AC-055-404 
TITLE 
A randomized, double-blind, placebo-controlled, prospective, 
multicenter, parallel group study to assess the safety and 
efficacy of macitentan in patients with portopulmonary 
hypertension 
ACRONYM 
PORTICO 
PORtopulmonary hypertension Treatment wIth maCitentan  
─ a randOmized clinical trial 
OBJECTIVES 
Primary objective 
• To evaluate the effect of macitentan on pulmonary vascular 
resistance (PVR) as compared to placebo in patients with 
portopulmonary hypertension (PoPH). 
Secondary objectives 
• To evaluate the effect of macitentan as compared to placebo 
on cardio-pulmonary hemodynamics, hepatic portal vein 
pressure, disease severity, and exercise capacity in patients 
with PoPH. 
• To evaluate the safety and tolerability of macitentan as 
compared to placebo in patients with PoPH. 
• To evaluate the pharmacokinetics (PK) of macitentan and its 
active metabolite ACT-132577 in patients with PoPH (PK 
substudy). 
DESIGN 
Randomized, double-blind, placebo-controlled, prospective, 
multicenter, parallel group study. 
PERIODS 
The study comprises a 28-day Screening period, followed by a 
12-week double-blind treatment period. All subjects completing 
the double-blind treatment period as scheduled will have the 
opportunity to enter a 12-week open-label treatment period with 
macitentan. A 30-day Safety follow up period follows 
discontinuation of study treatment (double-blind or open-label) 
before the End of Study (EOS) for a subject can occur. 
PLANNED DURATION 
Approximately 18 months from first subject, first visit to last 
subject, last visit. 
SITE(S) 
/ COUNTRY(IES) 
45 sites in 7 countries (planned):  
BRA, CZE, DEU, ESP, FRA, GBR, USA. 

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SUBJECTS / GROUPS 
84 subjects in 2 groups; 42 subjects per group (randomized 1:1). 
Randomization will be stratified by region (Europe/North 
America/Latin America) and by use of background pulmonary 
arterial hypertension (PAH)-specific therapy (yes/no). 
INCLUSION CRITERIA 
1) Signed informed consent prior to any study-mandated 
procedure  
2) Male or female ≥ 18 years of age with symptomatic PoPH: 
• Documented diagnosis of portal hypertension 
• PAH by right heart catheterization at screening: 
− Mean 
pulmonary 
arterial 
pressure 
(mPAP)  
≥ 25 mmHg 
− Pulmonary artery wedge pressure (PAWP) or left 
ventricular 
end 
diastolic 
pressure 
(LVEDP)  
≤ 15 mmHg 
3) PVR ≥ 4 Wood Units (WU) or ≥ 320 dyn.s.cm-5 at 
screening1 
4) 6-minute walk distance (6MWD) ≥ 50 m at screening 
5) Women of childbearing potential must: 
a) Have a negative serum pregnancy test during screening 
and a negative urine pregnancy test on Day 1, and 
b) Agree to use reliable methods of contraception from 
screening up to 30 days after study treatment 
discontinuation, and 
c) Agree to perform monthly pregnancy tests up to 30 days 
after study treatment discontinuation. 
EXCLUSION CRITERIA 
1. PAH due to any other condition than portal hypertension 
2. Severe hepatic impairment, as defined by Child-Pugh Class 
C liver disease or Model for End-stage Liver Disease 
(MELD) score ≥ 19  
3. Unstable liver disease (in the opinion of the investigator) 
4. History of transjugular intrahepatic portosystemic shunt 
(TIPS) within 6 months prior to randomization 
5. Documented severe obstructive or restrictive lung disease 
(in the opinion of the investigator) 
                                                 
 
 
1 Cardiac output measured by thermodilution technique only. 

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6. Documented pulmonary veno-occlusive disease 
7. Systolic blood pressure (SBP) < 90 mmHg at Screening 
8. Body weight < 40 kg at Screening 
9. Patients undergoing dialysis 
10. Initiation of diuretics or beta blockers within 1 week prior to 
baseline right heart catheterization (RHC) or patients on 
oral diuretics or beta blockers in whom the dose has not 
been stable for at least 1 week prior to baseline RHC 
11. Hemoglobin < 100 g/L at Screening 
12. Serum aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) ≥ 3 × the upper limit of the normal 
range (ULN) at Screening 
13. Bilirubin ≥ 3 mg/dL at Screening 
14. Grades 2, 3, or 4 hepatic encephalopathy 
15. History of liver transplantation  
16. Documented hepatocellular carcinoma  
17. Documented schistosomiasis infection 
18. Gastrointestinal bleeding or esophageal variceal bleeding  
< 3 months prior to randomization 
19. Recently started (< 3 months prior to randomization) or 
planned cardio-pulmonary rehabilitation program based on 
exercise 
20. Treatment with calcium channel blockers, endothelin 
receptor antagonists (ERA), intravenous/subcutaneous 
(i.v./s.c.) or oral prostanoids within 3 months prior to 
randomization 
21. Initiation, 
change 
in 
dose 
or 
discontinuation 
of 
phosphodiesterase type 5 inhibitors (PDE5i), or soluble 
guanylate cyclase stimulator within 3 months prior to 
randomization 
22. Treatment with interferon within 3 months prior to 
randomization 
23. Treatment with any investigational drug within 3 months 
prior to randomization 
24. Treatment with strong cytochrome P450 (CYP) 3A4 
inducers 
(e.g., 
carbamazepine, 
rifampin, 
rifampicin, 
rifabutin, 
rifapentin, 
phenobarbital, 
phenytoin, 
and 

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St. John’s wort) within 4 weeks prior to randomization 
25. Treatment 
with 
strong 
CYP3A4 
inhibitors 
(e.g., ketoconazole, 
itraconazole, 
voriconazole, 
clarithromycin, 
telithromycin, 
nefazodone, 
ritonavir, 
boceprevir, telaprevir, saquinavir, lopinavir, fosamprenavir, 
darunavir, tipranavir, atazanavir, nelfinavir, amprenavir, 
indinavir, and paritaprevir) within 4 weeks prior to 
randomization 
26. Known hypersensitivity to macitentan or its excipients or 
drugs of the same class 
27. Pregnancy, breastfeeding, or intention to become pregnant 
during the study 
28. Known concomitant life-threatening disease with a life 
expectancy of < 6 months 
29. Any known factor or disease that might interfere with 
treatment compliance, study conduct, or interpretation of 
results 
30. Suspected or known current drug or alcohol abuse. 
STUDY TREATMENTS 
Investigational treatment 
Macitentan film-coated tablet 10 mg once daily.  
Comparator and/or placebo 
During the double-blind treatment period: Matching placebo 
tablet once daily. 
CONCOMITANT 
THERAPY 
Allowed concomitant therapy 
Oral PDE5i, inhaled prostacyclin analogues, soluble guanylate 
cyclase (sGC) stimulator are allowed if present for at least 
3 months prior to randomization at a stable dose (which must 
remain unchanged during the double-blind treatment period 
unless the patient experiences worsening of PAH).  
Treatment with oral diuretics is allowed if ongoing at a stable 
dose for at least 1 week prior to baseline right heart 
catheterization; the dose may be optimized during the treatment 
period. 
Beta blockers are allowed if present for at least 1 week prior to 
baseline right heart catheterization at a stable dose (which 
should remain unchanged during the study). If discontinuation 
of beta blockers occurs during the study the patient should 

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complete the study as scheduled.  
During the open-label period, i.v. and s.c. prostanoid therapy 
(e.g., epoprostenol, treprostinil) is permitted at any time. 
The following antiviral hepatitis C medications are permitted: 
simeprevir, sofosbuvir, daclatasvir, ombitasvir, dasabuvir, 
ledipasvir, etravirine, raltegravir, maraviroc, and ribavirin. 
Forbidden concomitant medication 
• ERAs (e.g., bosentan, ambrisentan) 
• During the double-blind period, i.v./s.c. and oral prostanoid 
therapy (e.g., epoprostenol, treprostinil) is forbidden  
• Calcium channel blockers 
• Strong CYP3A4 inducers (e.g., carbamazepine, rifampin, 
rifampicin, rifabutin, rifapentin, phenobarbital, phenytoin, 
and St. John’s wort) 
• Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, 
voriconazole, clarithromycin, telithromycin, nefazodone, 
ritonavir, lopinavir, fosamprenavir, darunavir, tipranavir, 
atazanavir, nelfinavir, amprenavir, indinavir, boceprevir, 
telaprevir, paritaprevir and saquinavir) 
• Treatment with interferon 
• Any other investigational drug. 
ENDPOINTS 
Double-blind treatment period 
(Baseline is the last assessment prior to initiation of 
double-blind treatment). 
Primary efficacy endpoint 
Relative change from Baseline to Week 12 in PVR.  
Secondary efficacy endpoints 
• Change from Baseline to Week 12 in mean right atrial 
pressure (mRAP), mPAP, cardiac index (CI), total 
pulmonary resistance (TPR), and mixed venous oxygen 
saturation (SVO2), all measured at rest 
• Change from Baseline to Week 12 in 6MWD 
• Change from Baseline to Week 12 in WHO functional class 
• Change from Baseline to Week 12 in NT-proBNP. 
Other efficacy endpoints 
• Change from Baseline to Week 12 in hepatic venous 
pressure gradient (HVPG) 

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• Change from Baseline to Week 12 in Borg dyspnea index. 
Macitentan treatment period (all patients receiving macitentan 
in either double-blind or open-label treatment periods). 
(Macitentan Baseline is the last assessment prior to initiation of 
macitentan treatment). 
• Change from macitentan Baseline to each time point in  
WHO functional class 
• Change from macitentan Baseline to each time point in 
NT-proBNP 
• Change from macitentan Baseline to each time point in 
6MWD 
• Change from macitentan Baseline to each time point in 
Borg dyspnea index. 
Safety endpoints 
Double-blind treatment period 
(Treatment-emergent is defined as from first intake of study 
treatment until to end of double-blind treatment + 30 days or 
start of open-label treatment, whichever occurs first). 
• Treatment-emergent deaths 
• Treatment-emergent adverse events (AEs) 
• Treatment-emergent 
AEs 
leading 
to 
premature 
discontinuation of double-blind study treatment 
• Treatment-emergent serious adverse events (SAEs) 
• Proportion of patients with treatment-emergent ALT and/or 
AST abnormality (≥ 3, ≥ 5, and ≥ 8 × ULN)  
• Proportion of patients with treatment-emergent ALT and/or 
AST abnormality (≥ 3 × ULN) associated with total 
bilirubin ≥ 2 × ULN (and increased as compared to 
baseline)  
• Proportion of patients with treatment-emergent hemoglobin 
abnormality (< 100 g/L, and < 80 g/L) 
• Treatment-emergent marked lab abnormalities  
• Change from Baseline to End of Treatment (double-blind) 
(EOT-DB) in vital signs 
• Change from Baseline to EOT-DB in laboratory variables 
• Change from Baseline to EOT-DB in Child-Pugh 

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classification 
• Change from Baseline to EOT-DB in MELD Score. 
Macitentan treatment period (all patients receiving macitentan 
in either double-blind or open-label treatment periods) 
Macitentan treatment-emergent is defined as from first intake of 
macitentan up to EOS (i.e., 30 days after discontinuation of 
macitentan treatment). End of macitentan treatment (EOMT) is 
defined as EOT-DB or End of Treatment (open-label) 
(EOT-OL), whichever comes last. Macitentan Baseline is 
defined as last assessment prior to first intake of macitentan. 
• Macitentan treatment-emergent deaths 
• Macitentan treatment-emergent AEs 
• Macitentan treatment-emergent AEs leading to premature 
discontinuation of macitentan treatment 
• Macitentan treatment-emergent SAEs 
• Proportion of patients with macitentan treatment-emergent 
ALT and/or AST abnormality (≥ 3, ≥ 5, and ≥ 8 × ULN) up 
to EOMT 
• Proportion of patients with macitentan treatment-emergent 
ALT and/or AST abnormality (≥ 3 ULN) associated with 
total bilirubin ≥ 2 × ULN (and increased as compared to 
baseline) up to EOMT 
• Proportion of patients with macitentan treatment-emergent 
hemoglobin abnormality (< 100 g/L, and < 80 g/L) up to 
EOMT 
• Macitentan treatment-emergent marked lab abnormalities up 
to EOMT 
• Change from macitentan Baseline to EOMT in vital signs 
• Change from macitentan Baseline to EOMT in laboratory 
variables 
• Change from macitentan Baseline to EOMT in Child-Pugh 
classification 
• Change from macitentan Baseline to EOMT in MELD 
Score. 
ASSESSMENTS 
Refer to the schedule of assessments in Table 1. 
STATISTICAL 
METHODOLOGY 
Double-blind treatment period 
• Analysis sets 
The Full Analysis Set (FAS) includes all randomized patients 

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who received at least one dose of study treatment and who have 
a baseline value for the primary endpoint (PVR).  
The Per-Protocol Set (PPS) comprises all patients included in 
the FAS without major protocol deviations that affect the main 
analysis of the primary efficacy variable. 
The Safety Set includes all patients who received at least one 
dose of study treatment. 
The PK set comprises all patients from the FAS who did not 
deviate from the protocol in a way that might affect the 
evaluation of the PK endpoints. 
• Primary endpoint 
The primary endpoint is the relative change from baseline to 
Week 12 in PVR. 
• Statistical hypotheses 
The null hypothesis is that the treatment difference (macitentan 
minus placebo) in mean relative change from baseline to 
Week 12 in PVR is greater than or equal to zero. 
The alternative hypothesis is that the treatment difference in 
mean relative change from baseline in PVR is less than zero. 
• Type-I and -II errors and power 
The type I error (α) is set to 0.025 (one-sided), the type II error 
is set to 0.10 and the power to 90%. 
• Sample size calculation 
An integrated analysis of two bosentan studies, BENEFIT 
(AC-052-366) 
and 
EARLY 
(AC-052-364), 
and 
the 
hemodynamic 
substudy 
of 
SERAPHIN 
(AC-055-302) 
suggested that the treatment group difference is expected to be 
around −0.31 on log scale (95% confidence interval: −0.38, 
−0.23) and that the within group standard deviation is around 
0.41 on log scale. Under these assumptions, 76 evaluable 
patients will be needed for 90% power (38 patients per group). 
Accounting for 10% non-evaluable patients, approximately 
84 patients will need to be randomized. 
• Primary analysis 
The primary analysis will be performed on the FAS. 
The Week 12 versus baseline ratio in PVR will be 
log transformed (base e) and analyzed using an Analysis of 

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Covariance (ANCOVA) with factors for treatment group, 
region and background PAH-specific therapy and a covariate 
for baseline log PVR. The treatment group difference in mean 
change from baseline (on log scale) and its 95% confidence 
interval will be estimated based on the model. The Geometric 
Mean Ratio (GMR, macitentan versus placebo) and its 95% 
confidence interval will be obtained by exponentiation. The null 
hypothesis will be rejected if the entire 95% confidence interval 
is below one. 
The treatment effect will be expressed as (GMR-1) × 100%, 
where a negative value indicates a reduction of PVR in the 
macitentan group as compared to the placebo group.  
If PVR cannot be calculated due to missing PAWP but mPAP 
and cardiac output (CO) are available for the same visit, PAWP 
will be imputed. Post-baseline PVR values obtained earlier than 
Week 12 will be carried forward. For patients where no 
post-baseline PVR measurement is available, data will be 
imputed. 
Secondary analyses 
Secondary efficacy variables will be analyzed for the FAS at 
α=0.025 (one-sided) using 95% confidence intervals. No 
correction for multiple testing will be applied for these analyses. 
• Safety endpoints 
Safety data will be summarized using descriptive statistics. 
Safety analyses will be performed on the Safety Set. 
• Interim analysis 
No interim analysis is planned. 
Macitentan treatment period 
• Analysis sets 
The Macitentan Treated Set (MTS) consists of all patients who 
received at least one dose of macitentan in the double-blind 
period or open-label period. 
• Statistical hypotheses 
No formal hypothesis testing will be performed. Efficacy and 
safety data will be summarized using descriptive statistics. 
STUDY COMMITTEES 
A Steering Committee will help design the study, provide 
guidance on the study conduct evaluation of the results, and 

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support study publications. 
An Independent Liver Safety Data Review Board (ILSDRB, an 
external expert committee of hepatologists) will provide 
ongoing assessment and advice regarding serious hepatic 
adverse events of special interest that require further evaluation 
during the study as per ILSDRB charter. 
SUB-STUDIES 
PK substudy 
This substudy is planned during the open-label treatment period 
and described under the same protocol. It will be conducted in 
participating centers. In these centers, all patients continuing in 
the open-label treatment period will be offered to participate in 
the substudy. 
At least 20 patients eligible for the open-label treatment period 
will be enrolled. The plasma PK variables will be derived by 
non-compartmental analysis of the plasma concentration-time 
profiles. Peak maximum plasma concentration (Cmax) and area 
under the plasma concentration-time curve during one dosing 
interval (AUCt) values are assumed to be log-normally 
distributed. 
PK endpoints are for both macitentan and ACT-132577: 
• The area under the plasma concentration-time curve during 
one dosing interval (AUCt).  
• Maximum plasma concentration (Cmax) during a dosing 
interval.  
• The time to reach maximum plasma concentration (tmax) 
during a dosing interval. 
 

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Table 1 
Visit and assessment schedule 
PERIODS 
Name 
SCREENING 
DOUBLE-BLIND TREATMENT 
OPEN-LABEL TREATMENT 
 
FOLLOW-UP 
 
Duration 
28 days 
12 weeks 
12 weeks 
 
30 days 
VISITS  
Number 
1 
2 
3/4 
5 
6/7 
8 
U1, U2… 
 
 
Name 
Screening 
Random-
ization 
Visits 3/4 
EOT-DB1 
Visits 6/7 
EOT-OL1 
Unscheduled visit 2 
EOS3 
 
Time 
Day −28 
Day 1 
Weeks 4/8 
(± 4 days)  
Week 12 
(± 4 days) 
Weeks 16/20 
(± 4 days)  
Week 24 
(± 4 days) 
Any day between Day 
1 and Week 24 
EOT-DB/OL  
+ 30–33 days 
Informed consent 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
 
Physical examination4 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
 
 
X 
 
X 
X 
 
Height5 and weight 
X 
 
 
X 
 
X 
 
 
Laboratory tests6 
X7 
X 
X 
X 
X 
X 
X 
 
Serum pregnancy test 
X 
X8 
X 
X 
X 
X 
X 
X15 
Child-Pugh assessment and/or 
MELD Score 
X 
 
 
X 
 
X 
 
 
Right heart catheterization9 
X 
 
 
X 
 
 
 
 
Hepatic vein catheterization10 
X 
 
 
X11 
 
 
 
 
6MWT & BDI 
X 
X 
X 
X 
X 
X 
X 
 
WHO functional class 
X 
X 
X 
X 
X 
X 
X 
 
NT-proBNP 
 
X 
 
X 
 
X 
X 
 
PK substudy 
 
 
 
 
X12 
 
 
 
Study drug dispensing/ return13 
 
X 
X 
X 
X 
X 
 
 
Adverse Events14 
X 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse Events14 
X 
X 
X 
X 
X 
X 
X 
X 

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6MWT = 6-minute walk test; AE = adverse event; BDI = borg dyspnea index; CRF = case report form; EOT-DB = end of treatment (double-
blind); EOT-OL = end of treatment (open-label); EOS = end of study; HVC = hepatic vein catheterization; MELD = Model for End-stage Liver 
disease; PK = pharmacokinetics; PT-INR = prothrombin time and international normalized ratio; RHC = right heart catheterization; SAE = 
serious adverse event; WHO = World Health Organization. 
 
1 If subject does not reach Week 12 (Visit 5) or does not enter into open-label phase, EOT-DB visit must be performed including RHC, followed 
by EOS after 30 days. If a subject enters open-label phase, but does not reach Week 24 (Visit 8), EOT-OL visit must be performed but without 
RHC, followed by EOS after 30 days. 
2 Unscheduled visits may be performed at any time during the study and may include all or some of the indicated assessments, based on the 
judgment of the investigator. 
3 Visit may be performed by phone. 
4 Data not collected in the CRF; abnormal findings to be recorded as Adverse Events. 
5 Height recorded at Screening only. 
6 Includes hematology, general blood chemistry, liver functions tests, serum bile acids, PT-INR. To be performed monthly during study conduct. 
7 Eligibility to be assessed using Screening laboratory data only 
8 Urine dipstick pregnancy test to be performed in addition to serum.  
9 Cardiac output to be measured using thermodilution technique only. 
10 HVC is not required at sites that do not perform the procedure routinely. 
11 To be performed on or within 7 days prior to EOT-DB (if previously performed at Baseline). 
12 Separate PK substudy Informed Consent Form to be completed prior to any substudy procedure. Can be performed at any time point on or 
between Visits 6 and 7. 
13 Scheduled study treatment dispensing/return procedures may be adapted according to the site practice. 
14 All AEs and SAEs that occur after signing the Informed Consent Form and up to 30 days after study treatment discontinuation must be 
reported. 
15 Urine dipstick test. 

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PROTOCOL 
1 
BACKGROUND 
1.1 Indication 
Portopulmonary hypertension (PoPH) is defined as pulmonary arterial hypertension 
(PAH) associated with portal hypertension with or without underlying hepatic disease. 
PoPH belongs to Group I (PAH) of the WHO classification of pulmonary hypertension 
(PH) [Simmoneau 2013]. Diagnosis of PoPH is based on pulmonary hemodynamic 
criteria for PAH obtained via right heart catheterization (RHC), including mean 
pulmonary arterial pressure (mPAP) ≥ 25 mmHg at rest, mean pulmonary artery wedge 
pressure (PAWP) ≤ 15 mmHg, within the context of portal hypertension: portal vein 
pressure > 10 mmHg or hepatic venous pressure gradient (HVPG) > 5 mmHg. 
The pathogenesis of PoPH is not fully understood. The development of PoPH appears to 
be independent of the cause and severity of portal hypertension, but rather as a 
consequence of the portal hypertension itself in genetically predisposed patients  
[Cartin-Ceba 2014]. Although the pulmonary vascular changes in PoPH are 
indistinguishable from those of other forms of PAH, the pathological processes that lead 
to such changes are not completely understood. It is likely that a combination of aberrant 
vasoactive and angiogenic signaling due to portal hypertension coupled with a 
hyperdynamic circulatory state resulting in disruption of the normal hepatopulmonary 
circulation, increased vascular shear/mechanical stress in the lung vasculature, and thus 
the pathogenic changes observed in PoPH [Al-Naamani 2013]. 
On average, PAH is diagnosed 4 to 7 years after the diagnosis of portal hypertension 
[Halank 2006]. The most common presenting symptom of PoPH is dyspnea on exertion. 
Other nonspecific symptoms include syncope, chest pain, fatigue, light-headedness, 
orthopnea, and edema. However, patients often present no specific symptoms indicative 
of PAH, and PoPH is most commonly diagnosed during evaluation for liver 
transplantation. 
1.2 Epidemiology and natural history 
Although PoPH is an uncommon complication of portal hypertension, it accounts for a 
sizeable percentage of patients with PAH. Recent registries estimate the prevalence of 
PoPH to be approximately 5–10% of all PAH patients [Humbert 2006, Krowka 2012]. 
Similarly, the prevalence of PoPH is described to be 5–8.5% amongst all portal 
hypertension patients undergoing evaluation for liver transplantation in the three largest 
registries reported to date [Ramsay 1997, Colle 2003, Krowka 2006]. The mean age at 
presentation of PoPH is during the fifth decade of life (49 ± 13 years). No differences in 
prevalence between men and woman are observed [Golbin 2007]. 

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The prognosis for patients with PoPH is poor. Historically, 5-year survival outcome was 
less than 10% [Robalino 1991] but in the modern era with PAH-specific pharmacological 
intervention available, survival outcomes had improved in the US to 40% at 5 years but 
still with a 4-fold risk of death versus idiopathic PAH [Benza 2010]. In France, survival 
outcomes at 5 years were reported to be comparable to that of idiopathic PAH at 68%  
[Le Pavec 2008]. Causes of death reflect the existence of two serious illnesses: advanced 
liver disease and PAH with right heart failure [Safdar 2012]. 
1.3 Current management 
The European Respiratory Society (ERS) Task Force on Pulmonary-Hepatic Vascular 
Disorders [Rodriguez-Roisin 2004] outlines PoPH treatment options as including: 
intravenous (i.v.) prostacyclin (epoprostenol), prostacyclin analogs (inhaled iloprost), and 
endothelin receptor antagonists ([ERA]s bosentan). In the intervening time, clinical 
experience with other newly approved PAH medications, including the phosphodiesterase 
type 5 inhibitor (PDE5i) sildenafil [Reichenberger 2006, Gough 2009, Hemnes 2009,  
Hollatz 2012], inhaled and i.v. treprostinil (prostacyclin analog) [Reichenberger 2006, 
Hollatz 2012, Sakai 2009], and the ERA ambrisentan [Cartin-Ceba 2011, Halank 2011, 
Condliffe 2014], has been reported suggesting beneficial effects of vasodilator therapy in 
PoPH. This clinical experience is limited mainly to single-center, open-label studies.  
As a whole, clinical experience with ERAs has been favorable in terms of efficacy and 
safety, as reported in the literature. Studies with bosentan both as a monotherapy  
[Hoeper 2005, Hoeper 2007] and in combination with sildenafil [Savale 2013] reported 
improvements in hemodynamic and exercise capacity. As with clinical studies of 
bosentan in PAH, treatment was discontinued in a proportion of patients after transient 
elevation in liver transaminases was detected. In constrast, in the three studies reported to 
date on ambrisentan use in PoPH, no drug-related liver safety events were reported. No 
randomized clinical trial has been undertaken specifically in PoPH, leaving a paucity of 
data to demonstrate efficacy or safety of any PAH medication in PoPH. The PATENT-1 
study of riociguat in PAH (a soluble guanylate cyclase [sGC] stimulator) showed 
improvement in the primary endpoint of change in 6-minute walk test (6MWT); however, 
no data on the subgroup of 13 PoPH patients were reported [Ghofrani 2013].   
Orthotopic liver transplantation (OLT) is indicated in advanced liver disease, including 
portal hypertension, but is contra-indicated in patients who are compromised in terms of 
their cardiopulmonary hemodynamics, including PoPH. The ERS Task Force 
[Rodriguez-Roisin 2004] provides an algorithm for PoPH indicating patients with mild 
(mPAP < 35mmHg) disease as eligible for OLT; patients with moderate (mPAP  
≥ 35–45 mmHg) disease should receive pulmonary vasodilator therapy prior to OLT to 
try to stabilize cardiopulmonary hemodynamics (i.e., lower both mPAP and pulmonary 
vascular resistance [PVR]); and for patients with severe (mPAP > 45 mmHg) disease, 

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OLT is contraindicated but chronic vasodilator therapy to manage PAH should be 
considered. 
1.4 Endothelin-1 and pulmonary hypertension  
Endothelin-1 (ET-1), a 21 amino acid peptide, is one of the most potent vasoconstrictors 
and mitogens for smooth muscle cells, 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, Massaki 1998]. The ETA receptors are expressed on 
pulmonary vascular smooth muscle cells, whereas ETB receptors are present both on 
pulmonary vascular cells and on smooth muscle cells.  
When activated, the ETA receptors located in pulmonary vascular smooth muscle cells 
mediate 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. It has been shown that 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 overexpressed 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 PH of various etiologies 
[Stewart 1991, Giaid 1993]. 
1.5 Macitentan 
Macitentan 10 mg (Opsumit®) is approved in the US, Europe, Australia, Canada, Israel, 
Mexico, and Switzerland for the treatment of PAH. 
1.5.1 Nonclinical results 
Macitentan is an orally active, non-peptide, potent dual ETA and ETB. Macitentan shows 
dose-dependent efficacy in nonclinical models of hypertension and PH, and is 
approximately 10 times more potent than bosentan (Tracleer®). In nonclinical safety 
studies, no effects on normal physiological functions or electrocardiogram 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 were above the 
anticipated clinical exposures and provided a margin of safety for studies in humans. A 

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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. 
More detailed information on macitentan can be found in the Investigator’s Brochure (IB) 
[Macitentan IB]. 
1.5.2 Clinical information 
1.5.2.1 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. Eight cases of asymptomatic 
increases in aminotransferases were observed in the Phase 1 program (6 received 
macitentan, 2 received placebo). Of these increases, 3 (all 3 subjects received macitentan) 
were > 3 × the upper limit of the normal range (ULN), and none exceeded 4 × ULN. All 
cases resolved within 14 days of observation. 
The potential for a mutual drug-drug interaction between macitentan and sildenafil was 
studied in a randomized, crossover study. The pharmacokinetic (PK) profile of 
macitentan and its metabolite ACT-132577 (the only pharmacologically active metabolite 
circulating in plasma) was not affected by sildenafil treatment. In addition, although 
treatment with macitentan resulted in increased maximum plasma concentration (Cmax) 
and area under the plasma concentration-time curve during one dosing interval (AUCτ) 
values, the PK profile of N-desmethyl sildenafil was not affected. No dose adjustment of 
either compound is required when given concomitantly.    
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.  
Minor differences in the PK parameters of macitentan and ACT-132577 were noted 
between healthy subjects and those with severe renal impairment. However, marked 
differences in the PK parameters of the pharmacologically inactive metabolite, 
ACT-373898, were noted between healthy subjects and those with severe renal 
impairment. The safety profile of macitentan was similar in healthy subjects and those 
with severe renal impairment. 
More detailed information on macitentan can be found in the IB [Macitentan IB]. 

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1.5.2.1.1 Hepatic impairment 
The effects of mild, moderate or severe hepatic impairment due to liver cirrhosis on the 
PK of a single oral dose of 10 mg macitentan were studied in a dedicated Phase 1 study. 
No correlation between the severity of hepatic impairment and the mean plasma 
concentrations of macitentan, ACT-132577, and ACT-373898 were apparent. Minor 
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. These differences were not considered to be clinically relevant, therefore no 
dose adjustments are required. There was no correlation between laboratory components 
of Child-Pugh score and area under the plasma concentration-time curve from zero to 
infinity (AUC0-∞), area under the plasma concentration-time curve from time zero to time 
t (AUC0-t), Cmax, and t½. No relevant differences in macitentan and ACT-132577 protein 
binding were observed between subjects with mild, moderate, or severe hepatic 
impairment and healthy subjects. A reduction in the extent of plasma protein binding of 
the inactive minor metabolite, ACT-373898, was observed, and the extent of the decrease 
correlated with the severity of hepatic impairment. This is not expected to be clinically 
relevant and is not expected to influence clinical outcome. 
Only one subject with hepatic impairment experienced elevations in liver function tests 
(LFTs) that were considered by the investigator as clinically significant. The increases in 
alanine aminotransferase [ALT], aspartate aminotransferase [AST], and gamma-glutamyl 
transferase (GGT) observed in this subject were also reported as AEs. Total bilirubin 
remained within the normal range. Other clinical chemistry findings were unremarkable. 
More detailed information on macitentan Phase 1 studies can be found in the IB 
[Macitentan IB]. 
1.5.2.2 Phase 2 studies 
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 of change from baseline to Week 8 in mean sitting diastolic blood 
pressure at trough (i.e., 24 h post-dose) was met. 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. 
Five cases of increased liver enzymes > 3 × ULN occurred in the macitentan groups, 
without obvious dose relationship (one, two, 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 

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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.  
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 did not meet the primary endpoint (change in forced 
vital capacity). Overall, 10 mg macitentan was well tolerated with a similar safety profile 
in both treatment groups. The incidence of 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.  
An equal proportion of patients in the 2 treatment groups experienced SAEs or died 
during the study. The most frequently reported SAEs and causes of death were all 
consequences of the underlying disease. Seven patients treated with macitentan had a 
decrease in hemoglobin levels to ≤ 10 g/dL at some point during the study and the overall 
incidence of elevations in liver aminotransferases > 3 × ULN was similar to placebo 
(3.4% in the macitentan group versus 5.1% in the placebo group).  
More detailed information on this macitentan Phase 2 study can be found in the IB 
[Macitentan IB]. 
1.5.2.3 Phase 3 study in patients with pulmonary arterial hypertension 
Efficacy in patients with WHO functional class II-IV PAH was demonstrated with the 
long-term outcomes SERAPHIN study. The trial demonstrated that macitentan 10 mg 
reduces the risk of morbidity or mortality in patients with symptomatic PAH, with a 
hazard ratio versus placebo of 0.547, 97.5% confidence interval 0.392–0.762, p < 0.0001. 
This represents a risk reduction of 45% [Pulido 2013]. 
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. 
More detailed information on the Phase 3 study in PAH can be found in the IB 
[Macitentan IB]. 

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1.5.2.4 Summary of potential risks and risk management 
Nonclinical studies with macitentan did not identify important risks of likely relevance to 
humans except for teratogenicity, a class effect of ERAs. The protocol, therefore, 
includes stringent requirements for pregnancy testing and reliable methods of 
contraception for female patients of childbearing potential. 
In a Phase 1 study of macitentan in patients with chronic hepatic impairment, one patient 
being treated with macitentan experienced clinically relevant ALT/AST elevations 
although bilirubin remained in the normal range. In three placebo-controlled studies, a 
higher percentage of patients treated with macitentan 10 mg had ALT > 3 × ULN 
compared to placebo. Although an independent review of all data by the Independent 
Liver Safety Data Review Board (ILSDRB) concluded that there is no definite 
hepatotoxicity signal, precaution has been taken in this study to exclude subjects with 
severe hepatic impairment, as described in the Opsumit® prescribing information, or 
unstable liver disease due to the poor prognosis. Therefore, subjects with a Child-Pugh 
class C grading or Model for End-stage Liver Disease (MELD) score of ≥ 19 are 
excluded, as well as those with gastrointestinal or esophageal variceal bleeding within 
3 months or transjugular intrahepatic portosystemic shunt (TIPS) within 6 months of 
randomization, or in the opinion of the investigator the subject is too unstable to enter the 
study. In addition, subjects must not meet the exclusion criteria of ALT/AST ≥ 3 × ULN 
and total bilirubin ≥ 3 mg/dL. The inclusion of patients with moderate hepatic 
impairment is considered justified in this study due to the unaltered PK profile of 
macitentan between mild, moderate or severe hepatic impairment in the Phase 1 study 
described above, as well as a fixed rule for discontinuation of study drug in the event of 
liver aminotransferase elevations. Monthly LFTs are mandatory throughout the study and 
recommended up to 30 days after study treatment discontinuation. Hepatic 
encephalopathy is frequent in patients with severe hepatic impairment and can lead to 
varying degrees of reversible dementia. In order to ensure subjects are fully able to give 
informed consent, hepatic encephalopathy of Grade 2 and higher has been excluded.  
Macitentan treatment was associated with a dose-related reduction in hemoglobin levels. 
Therefore, patients with hemoglobin < 100 g/L are excluded from the study. Furthermore, 
hemoglobin levels are monitored monthly throughout the study. 
Due to the vasodilator effect of macitentan, effects on BP might occur. In patients with 
normal BP at baseline, there was a slightly higher incidence of AEs denoting hypotension 
with macitentan than with placebo. Thus, patients with systolic blood pressure (SBP)  
< 90 mmHg are excluded from this study. 

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1.6 Purpose and rationale of the study 
Although PoPH is included in the WHO Group I Pulmonary Hypertension spectrum of 
diseases (PAH) according to the updated guidelines for clinical classification of PH 
[Simmoneau 2013], no targeted PAH therapy has to date demonstrated efficacy in this 
patient population in a randomized, controlled clinical trial. PoPH patients have been 
excluded from protocols in PAH due to the potential for altered drug metabolism as a 
consequence of the underlying hepatic disease. However, as PoPH is essentially 
pre-capillary PH, these patients are managed on a day-to-day basis with commercially 
available PAH medications including ERAs. Use of these pulmonary vasodilators has 
been mostly based on evidence from single-center, open-label experience.  
In the Phase 3 AC-055-302/SERAPHIN study, macitentan demonstrated efficacy in PAH 
by improving long-term clinical outcomes, functional status and exercise capacity. In 
addition, incidences of ALT/AST elevations > 3 × ULN were similar to placebo. Phase 1 
data in chronic hepatic impairment showed no clinically relevant change in the PK of 
macitentan and its metabolites in varying grades of liver disease severity [Macitentan IB].  
Therefore, it is believed that macitentan could be an efficacious treatment for PoPH with 
a safety and tolerability profile unaffected by the underlying hepatic disease.   
The aim of this study is to investigate the efficacy of macitentan on cardiopulmonary 
hemodynamics as well as the safety and tolerability in patients with PoPH in a 
randomized, placebo- controlled study setting. 
2 
STUDY OBJECTIVES 
2.1 Primary objective  
• To evaluate the effect of macitentan on PVR as compared to placebo in patients with 
PoPH. 
2.2 Secondary objectives  
• To evaluate the effect of macitentan as compared to placebo on cardio-pulmonary 
hemodynamics, hepatic portal vein pressure, disease severity, and exercise capacity in 
patients with PoPH. 
• To evaluate the safety and tolerability of macitentan in patients with PoPH 
• To evaluate the PK of macitentan and its active metabolite ACT-132577 in patients 
with PoPH (PK substudy).  
 

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3 
OVERALL STUDY DESIGN AND PLAN 
3.1 Study design  
This study is designed as a randomized, double-blind, placebo-controlled, prospective, 
multicenter, parallel group Phase 4 study assessing the efficacy and safety of macitentan 
in PoPH. 
Approximately 84 adult subjects with PoPH will be randomized (1:1) to receive either 
macitentan 10 mg, or matching placebo, once daily orally. Subject allocation to treatment 
groups will be stratified by background PAH therapy receipt (yes/no) to ensure balance 
within this subgroup. Stratification by region of enrollment will also be performed as the 
number of enrolled subjects per center is expected to be low and variation in total subject 
numbers will exist on a country-to-country level. Attrition rate is expected to be 10%, 
leaving 76 evaluable patients at Week 12. 
Subjects must have confirmed diagnosis of PoPH with a PVR of ≥ 4 Wood Units (WU) 
(≥ 320 dyn.s.cm-5) at enrollment but not have severe hepatic impairment (defined as 
Child-Pugh Class C or MELD score ≥ 19). Subjects must have 6-minute walk distance 
(6MWD) ≥ 50 m at enrollment but may be in any WHO functional class. 
The study will be conducted in approximately 45 sites in 7 countries. Randomization will 
proceed until the required number of subjects has been reached. It will be competitive 
across participating sites. Actelion may wish to replace sites with no subject enrollment. 
The study consists of the following study periods: 
Screening Period commences from signature of the Informed Consent Form (ICF) and 
ends with subject randomization (up to 28 days after signed informed consent). 
Double-Blind Treatment Period starts immediately after randomization with the first 
dose of double-blind study treatment at the end of Visit 2 (Day 1 of study) and ends with 
End of Treatment (double-blind) (EOT-DB) on the day of the last dose of double-blind 
study treatment (scheduled Day 84, Week 12, or earlier in case of premature 
discontinuation of double-blind study treatment).  
Open-Label Treatment Period starts immediately after EOT-DB (for patients who 
reach Week 12 of double-blind study treatment) with the first dose of open-label study 
treatment at the end of Visit 5 and ends with End of Treatment (open-label) (EOT-OL) on 
the day of the last dose of open-label study treatment (scheduled Day 168, Week 24, or 
earlier in case of premature discontinuation of open-label study treatment).  
Safety Follow-up Period starts immediately after the last dose of study treatment 
(double-blind study treatment or open-label study treatment) and ends with the End of 
Study (EOS) 30 to 33 days after the last dose of study treatment. 

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EOS must occur in any patient discontinuing either double-blind or open-label study 
treatment prematurely and having completed the Safety follow-up period. 
Study Duration 
Subject participation in the study will be maximum 33 weeks (up to 28 days Screening 
+ 24 weeks’ treatment + 30 days safety follow up). The overall study design is depicted 
in Figure 1. 
Figure 1 
Study design 
 
EOT-DB = end of treatment (double-blind); EOT-OL = end of treatment (open-label); EOS = end of study. 
3.2 Study design rationale 
A placebo-controlled trial conducted in a randomized, double-blind fashion provides the 
most definite and rigorous method of evaluating the efficacy and safety of a medical 
treatment. 
The present study aims at assessing whether macitentan improves hemodynamic 
variables and whether this improvement translates into symptomatic and clinical 
improvement in PoPH subjects. Subjects will receive macitentan or placebo for 12 weeks 
followed by 12 weeks of open-label macitentan treatment and then a 30-day safety 
follow-up.  
The 12-week double-blind treatment period is selected because it is considered to be 
adequate to observe the anticipated treatment effect on the primary endpoint of change in 
PVR, but short enough to minimize risk of randomization to placebo. The risk of bias 

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introduction from patients initiating add-on therapy is deemed relatively low in this 
timeframe and the number of missing assessments due to premature study discontinuation 
is also expected to be minimized. Additionally, in studies involving hemodynamics and 
exercise capacity, variability and placebo effect are of sufficient magnitude to justify the 
inclusion of a placebo control group [Wright 2009]. Risk of exposure to placebo is also 
minimized by permitting into the study subjects already receiving stable background oral 
PDE5i, sGC stimulator, or inhaled prostanoid PAH therapy. Once in the open-label 
period patients may also receive i.v. or subcutaneous (s.c.) prostanoid PAH-therapy at the 
investigator’s discretion. 
Treatment with ERAs has been associated with increased incidence of edema, anemia 
and/or decreased hemoglobin as well as LFT abnormalities. From 3 placebo-controlled 
studies with macitentan, no significant imbalance in LFT elevations was observed across 
macitentan treatment groups (any dose) and placebo. However, due to underlying liver 
disease in PoPH, liver safety events are likely to occur in this population and a placebo 
arm is the only way to show quantitatively whether there is a likely association of liver 
abnormalities with the use of the study treatment. 
The 12-week open-label treatment period is intended to offer all patients the opportunity 
to receive active study treatment and allows time for organizing appropriate treatment 
after the study. In addition, the open-label phase is being used to perform a substudy in a 
minimum of 20 participating subjects in order to obtain information on the PK of 
macitentan in PoPH. 
3.3 Study Committees  
A Steering Committee has been appointed by Actelion to design the protocol, oversee the 
conduct of the study, evaluate the results and support publications. The committee is 
governed by a steering committee charter.  
An Independent Liver Safety Data Review Board (ILSDRB, an external expert 
committee of hepatologists) provides ongoing assessment and advice regarding serious 
hepatic adverse events of special interest that require further evaluation during the study 
(as per ILSDRB charter). 
4 
SUBJECT POPULATION 
4.1 Subject population description 
Subjects enrolled will be male or female aged 18 years and over with a confirmed 
diagnosis of symptomatic PoPH and a baseline PVR of ≥ 4 WU (≥ 320 dyn.s.cm-5), in 
any WHO functional class and capable of performing a 6MWT. Subjects may be 
PAH-treatment naïve or receiving background PDE5i, sGC stimulators, or inhaled 

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prostanoid therapy. Subjects must not have severe hepatic impairment, as defined by 
Child-Pugh class C liver disease or a MELD score ≥ 19.  
A minimum of 84 subjects will be enrolled. An assumed attrition rate of 10% will leave 
76 evaluable patients at Week 12 for the primary analysis.   
4.2 Rationale for the selection of the study population 
The primary objective of the study is to demonstrate a reduction in PVR versus baseline 
with macitentan treatment as compared to placebo. A subset of PoPH patients with 
elevated PVR (≥ 4 WU or 320 dyn.s.cm-5) has been selected to improve the chance of 
observing the planned placebo-corrected reduction of 27% from baseline. No restriction 
on WHO functional class and a minimum 6MWD of ≥ 50 m will permit patients with 
severely symptomatic PH to be enrolled, as macitentan is expected to show a treatment 
effect on PVR in these patients as well. 
As PoPH is managed clinically with PAH-targeted therapy, subjects receiving 
concomitant background PDE5i, sGC stimulators, or inhaled prostacyclin therapy at a 
stable dose may be enrolled. This is also to mitigate the risk of exposure to placebo 
during the study. Subjects receiving strong vasodilator therapy at baseline (i.v. or s.c. 
prostanoids) are excluded.  
Subjects with severe hepatic impairment (defined here as Child-Pugh C or MELD score 
≥ 19) are not permitted to be enrolled due to their poor prognosis, as are those whose 
liver disease is unstable in the opinion of the investigator. Such patients have an 
increased risk of premature discontinuation, transplantation or death during the 
double-blind phase of the study which would impact the study’s ability to achieve its 
primary objective. Other indicators of severe liver disease and/or poor prognosis include 
gastrointestinal and esophageal variceal bleeding, as well as total serum bilirubin  
≥ 3 mg/dL. 
As there is limited data on macitentan in pediatric PAH, subjects under the age of 
18 years are excluded. 
4.3 Inclusion criteria 
For inclusion in the study, all of the following inclusion criteria must be fulfilled. It is not 
permitted to waive any of the criteria for any subject: 
1. Signed informed consent prior to any study-mandated procedure  
2. Male or female ≥ 18 years of age with symptomatic PoPH: 
• Documented diagnosis of portal hypertension  

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• PAH by right heart catheterization at screening: 
− mPAP ≥ 25 mmHg 
− PAWP or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg 
3. PVR ≥ 4 WU or ≥ 320 dyn.s.cm-5 at screening2 
4. 6MWD ≥ 50 m at screening 
5. Women of childbearing potential must: 
• Have a negative serum pregnancy test during screening and a negative urine 
pregnancy test on prior to randomization on Day 1, and 
• Agree to use reliable methods of contraception [see Section 4.5] from 
screening up to 30 days after study treatment discontinuation, and 
• Agree to perform monthly pregnancy tests up to 30 days after study treatment 
discontinuation. 
4.4 Exclusion criteria 
Subjects must not meet any of the following exclusion criteria. It is not permitted to 
waive any of the criteria for any subject: 
1. PAH due to any other condition than portal hypertension 
2. Severe hepatic impairment, as defined by Child-Pugh Class C liver disease or MELD 
score ≥ 19  
3. Unstable liver disease (in the opinion of the investigator) 
4. History of TIPS within 6 months prior to randomization 
5. Documented severe obstructive or restrictive lung disease (in the opinion of the 
investigator) 
6. Documented pulmonary veno-occlusive disease  
7. Systolic blood pressure (SBP) < 90 mmHg at Screening 
8. Body weight < 40 kg at Screening 
9. Patients undergoing dialysis 
                                                 
 
 
2 Cardiac output measured by thermodilution technique only. 

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10. Initiation of diuretics or beta blockers within 1 week prior to baseline RHC or 
patients on oral diuretics or beta blockers in whom the dose has not been stable for at 
least 1 week prior to baseline RHC 
11. Hemoglobin < 100 g/L at Screening 
12. Serum AST and/or ALT ≥ 3 × ULN at Screening 
13. Bilirubin ≥ 3 mg/dL at Screening 
14. Grades 2, 3, or 4 hepatic encephalopathy 
15. History of liver transplantation  
16. Documented hepatocellular carcinoma  
17. Documented schistosomiasis infection 
18. Gastrointestinal bleeding or esophageal variceal bleeding < 3 months prior to 
randomization 
19. Recently started (< 3 months prior to randomization) or planned cardio-pulmonary 
rehabilitation program based on exercise 
20. Treatment with calcium channel blockers, an endothelin receptor antagonist (ERA), 
i.v./s.c. or oral prostanoids within 3 months prior to randomization 
21. Initiation, change in dose or discontinuation of PDE5i or soluble guanylate cyclase 
stimulator within 3 months prior to randomization 
22. Treatment with interferon within 3 months prior to randomization 
23. Treatment with any investigational drug within 3 months prior to randomization 
24. Treatment with strong cytochrome P450 (CYP) 3A4 inducers (e.g., carbamazepine, 
rifampin, rifampicin, rifabutin, rifapentin, phenobarbital, phenytoin, and St. John’s 
wort) within 4 weeks prior to randomization 
25. Treatment with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, 
voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, boceprevir, 
telaprevir, saquinavir, lopinavir, fosamprenavir, darunavir, tipranavir, atazanavir, 
nelfinavir, amprenavir, indinavir, and paritaprevir) within 4 weeks prior to 
randomization 
26. Known hypersensitivity to macitentan or its excipients or drugs of the same class 
27. Pregnancy, breastfeeding, or intention to become pregnant during the study 
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29. Any known factor or disease that might interfere with treatment compliance, study 
conduct, or interpretation of results 
30. Suspected or known current drug or alcohol abuse. 
4.5 Reliable contraception for women of childbearing potential 
4.5.1 Definition of woman of childbearing potential 
A woman is considered to be of childbearing potential unless she meets at least one of the 
following criteria: 
• Previous bilateral salpingo-oophorectomy or hysterectomy. 
• Premature ovarian failure confirmed by a specialist. 
• Pre-pubescence, XY genotype, Turner syndrome, uterine agenesis. 
• Post-menopausal, defined as 12 consecutive months with no menses without an 
alternative medical cause (ICH M3 definition). 
4.5.2 Europe and Latin America 
The use of at least one of the following methods is regarded as reliable contraception: 
1. Oral, implantable, transdermal, or injectable hormonal contraceptives or intrauterine 
devices (IUD), or 
2. True abstinence from intercourse with a male partner only when this is in line with 
the preferred lifestyle of the patient, or 
3. Permanent female sterilization (tubal occlusion/ligation at least 6 weeks prior to 
screening), or 
4. Sterilization of the male partner, with documented post-vasectomy confirmation of 
the absence of sperm in the ejaculate.  
Rhythm methods, use of a condom by the male partner alone, use of a female condom or 
diaphragm alone are not considered acceptable methods of contraception for this study. 

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4.5.3 North America  
The use of one of the following options is regarded as reliable contraception: 
Option 1 
 
Option 2 
 
Option 3 
 
Option 4 
One method from 
this list: 
 
One method from 
this list: 
 
One method from 
this list: 
 
One method from 
this list: 
Standard intrauterine  
Estrogen and 
 
Diaphragm with 
 
Partner’s vasectomy 
device (IUD) 
(Copper T380A IUD) 
 
progesterone oral 
contraceptives (“the  
 
spermicide 
Cervical cap with  
 
PLUS one method 
from this list: 
Intrauterine system  
 
Pill”) 
 
spermicide 
 
Male condom 
(LNg 20IUS: 
progesterone IUS) 
 
Estrogen and 
progesterone  
 
PLUS one method 
from this list: 
 
Diaphragm with 
spermicide 
Progesterone implant  
transdermal patch 
 
Male condom 
 
Cervical cap with 
Tubal sterilization 
 
Vaginal ring  
 
 
 
spermicide 
 
 
Progesterone 
injection 
 
 
 
Estrogen and 
progesterone oral 
 
 
PLUS one method 
from this list: 
 
 
 
contraceptives (“the 
pill”) 
 
 
Male condom 
Diaphragm with 
spermicide 
Cervical cap with 
spermicide 
 
 
 
Estrogen and 
progesterone 
transdermal patch 
Vaginal ring 
Progesterone  
 
 
 
 
 
 
 
injection 
IUD, intrauterine device; IUS, intrauterine system. 
4.6 Medical history 
Relevant medical history, as defined below, must be recorded in the electronic Case 
Report Form (eCRF):  
• Chronic medical conditions and new acute medical conditions within the past 
6 months (e.g., anemia, hepatitis C infection, HIV infection, obstructive or restrictive 
lung disease, hypertension, renal disease) 
• Complications or symptoms associated with the PAH (e.g., right heart failure, 
peripheral edema) or portal hypertension (e.g., liver decompensation) 
• Cause of portal hypertension (e.g., cirrhosis, hepatitis infection, thrombosis) 
• History of TIPS and date of procedure 

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• History of spontaneous or congenital porto-systemic shunts 
• History of esophageal varices or gastrointestinal bleeding, ascites, hepatic 
encephalopathy (including Grade) 
• History of alcoholism and/or drug abuse 
• Any previous life-threatening conditions, including date (e.g., myocardial infarction). 
5 
TREATMENTS 
5.1 Study treatment 
Study treatment in this study includes double-blind as well as open-label study treatment. 
Double-blind treatment comprises investigational treatment (i.e., macitentan 10 mg) or 
matching placebo administered orally once daily. Open-label study treatment consists of 
open-label macitentan 10 mg and is also administered orally once daily. 
5.1.1 Investigational treatment: description and rationale 
The investigational treatment is macitentan 10 mg and is administered orally once daily, 
in accordance with the Opsumit® prescribing information. 
5.1.2 Matching placebo: description and rationale 
Matching placebo is administered orally and also once daily. Rationale for the use of a 
placebo arm is provided in Section 3.1. 
5.1.3 Study treatment administration 
The first administration of study treatment will take place at site during the 
randomization visit (Visit 2), and only after successful completion of the ICF procedure 
and all screening/randomization assessments. At all subsequent visits (apart from PK 
substudy), study treatment must only be taken after all study procedures have been 
performed. 
At home, one tablet (macitentan 10 mg or matching placebo) must be taken orally every 
morning irrespective of food intake. If a dose is missed, take the next dose at the next 
scheduled time point (i.e., do not take one tablet in the evening and then one table the 
next morning). Two tablets must never be taken on the same day. 
5.1.4 Treatment assignment 
Eligible subjects will be randomized in a 1:1 ratio to either macitentan 10 mg or matching 
placebo. Treatment allocation will be stratified based on receipt of background PAH 
therapy (Yes/No) and by region (Europe/North America/Latin America). 

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At Visit 1 (Screening), all screened subjects will be assigned a study-specific subject 
number by the Interactive Voice/Web Response System (IxRS) provider. Note: In case of 
re-screening, the original number will also be used the second time. 
At Visit 2 (Randomization), after having confirmed the eligibility of the subject and prior 
to the start of study treatment, the investigator/delegate will contact the IxRS to 
randomize the subject. The IxRS will assign a randomization number to the subject, and 
assign the treatment bottle number which matches the treatment arm assigned by the 
randomization list to the randomization number. The bottle with this unique number will 
then be dispensed to the subject and the first dose administered. 
The randomization list is generated by an independent Contract Research Organization 
(CRO)
 using SAS version 9.3, and kept strictly confidential. 
5.1.5 Blinding 
The first part of this study will be performed in a double-blind fashion. The investigator 
and study staff, the subjects, the monitors, Actelion and CRO staff involved in the 
conduct of the study will remain blinded to the treatment until study closure.  
Although the second part of the study will be performed in an open-label manner, all 
subjects and study-related staff will remain blinded as to the patient’s original 
randomization group. 
Until the time of unblinding for final data analysis, the randomization list is kept strictly 
confidential, and accessible only to authorized persons who are not involved in the 
conduct of the study.  
The investigational treatment and its matching placebo are indistinguishable and all 
subject kits will be packaged in the same way. 
5.1.6 Unblinding 
5.1.6.1 Unblinding for final analyses 
Full randomization information will be made available for data analysis only after 
database closure in accordance with Actelion Standard Operating Procedures (SOPs). 
5.1.6.2 Unblinding for SUSARs 
When a suspected unexpected serious adverse reaction (SUSAR) occurs for a subject 
participating in the study, Actelion Global Drug Safety will request the unblinding of the 
treatment assignment. The randomization code will not be communicated to the site staff 
or to the Actelion study team; unblinded SUSAR information will be anonymized and 
provided to Actelion Global Drug Safety, respective health authorities and IRBs/IECs 
only. SUSARs will be reported to investigators in a blinded fashion. 

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5.1.6.3 Emergency procedure for unblinding 
The investigator, study staff and sponsor staff must remain blinded to the subject’s 
treatment assignment. The identity of the study treatment may be revealed only if the 
subject experiences a medical event, the management of which would require knowledge 
of the blinded treatment assignment. The occurrence of OLT during the double-blind 
treatment period could constitute such an event. In this case, the investigator can receive 
the unblinded randomization code for study treatment allocation through the IxRS. In 
these situations, the decision to unblind resides solely with the investigator. Whenever it 
is possible and if it does not interfere with (or does not delay) any decision in the best 
interest of the subject, the investigator is invited to discuss the intended code break with 
Actelion. 
The occurrence of any code break during the study must be clearly justified and 
explained by the investigator. In all cases, Actelion must be informed as soon as possible 
before or after the code break. 
The circumstances leading to the code break must be documented in the subject’s site file 
and eCRF. 
Refer to the IxRS manual for complete information regarding the IxRS procedures for 
randomization, study treatment assignment, and unblinding.  
5.1.7 Study treatment supply 
Actelion will supply all study treatments to the site according to the local regulations. 
Manufacture, labeling, packaging and supply of study treatments will be conducted 
according to Good Manufacturing Practice (GMP), Good Clinical Practice (GCP) and 
any local or national regulatory requirements. 
All treatment supplies are to be used only in accordance with this protocol, and not for 
any other purpose. 
5.1.7.1 Study treatment packaging and labeling 
5.1.7.1.1 Study treatment packaging 
Study treatment is provided as tablets and supplied in childproof bottles containing 
36 tablets. 
5.1.7.1.2 Study treatment labeling 
Study treatment is labeled to comply with the applicable laws and regulations of the 
countries in which the study sites are located. Each medication bottle has a label with a 
tear-off part specifying the study protocol number, the packaging batch number, and the 
bottle number. When the study treatment is given to the subject, this tear-off part must be 
removed and attached to the Study Treatment Dispensing Log.  

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5.1.7.2 Study treatment distribution and storage  
Treatment supplies must be kept in an appropriate, secure area and stored according to 
the conditions specified on the medication labels. The investigator is responsible for the 
safe and proper handling and storage at the investigational site. 
5.1.7.2.1  Study treatment distribution  
The study centers will be supplied with study treatment according to the centers’ needs, 
depending on the rate of subject enrollment. Each center will have an individual stock of 
study treatment, which will be re-supplied continuously as soon as a predefined minimum 
level of study treatment has been reached.  
5.1.7.2.2 Study treatment storage  
Study treatment 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) form.  
The subject must be educated on the proper study treatment storage conditions at home.  
The study treatment must be stored below 30 °C (86 °F) and must be protected from 
moisture. Unopened, sealed study medication bottles may be stored in refrigerators 
(above +2 °C [36 °F]). Storage below +2 °C / 36 °F (e.g., in the freezer) 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 at the site. 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 routinely used at site is acceptable as long as all 
required information is included and certification of calibration is provided. If the 
temperature is captured electronically, a print-out should be made available to the CRA 
during each on-site visit for filing in the Investigator Site File (ISF).  
In case a deviation from the defined temperature range is identified by the study center, 
the deviation must be reported to the CRA, preferably in writing and with supporting 
documentation (e.g., copy of the temperature log showing data for all excursion days). 
The CRA should immediately contact Actelion for further advice. The affected study 
treatment will not be used (e.g., it will be segregated physically at the study center) until 
confirmation from Actelion is obtained that its use is safe. In case the temperature 
deviation is outside of the acceptable limit, the study treatment is kept segregated at the 
study center and returned to Actelion following internal study treatment return processes. 
New study treatment supplies will be provided to the study center.  
Temperature deviations correspondence must be kept in the ISF.  

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5.1.7.3 Study treatment dispensing 
Study treatment can only be dispensed upon written prescription by an authorized study 
physician listed on the DoA form.  
The subjects will receive sufficient study treatment to cover the period up to the next 
scheduled visit. Subjects are asked to return all used, partially used and unused study 
treatment bottles at each visit. The protocol-mandated study treatment dispensing/return 
procedures may not be altered without prior written approval from Actelion. An accurate 
record of the date and amount of study treatment dispensed to each subject must be 
available for inspection at any time.  
Once a subject has been randomized and study treatment assigned, the corresponding 
bottle must not be used for another subject. If a subject has been dispensed a bottle in 
error (one that has not been allocated yet to another subject), the IxRS helpdesk must 
immediately be contacted.  
At the time study treatment is distributed, the subject should be educated on the proper 
storage conditions at home [see Section 5.1.7.2.2].  
5.1.7.4 Study treatment return and destruction  
The site must record the amount of study treatment received, dispensed, used, lost and 
returned during the study. 
On an ongoing basis and/or on termination of the study, the monitor will collect used and 
unused subject kits, which will be sent to the warehouse, where Actelion or a deputy will 
check treatment reconciliation. In certain circumstances, used and unused treatment 
containers may be destroyed at the site once treatment accountability is finalized and has 
been checked by the CRA, and written permission for destruction has been obtained from 
Actelion. 
5.1.8 Compliance with study treatment 
Study treatment accountability must be performed by the study staff on the day of the 
visit and before providing further study treatment, in order to ensure that the subject is 
compliant with study requirements. Study treatment accountability is recorded in the 
eCRF and checked by the monitor during site visits and at the end of the study. An 
accurate record of the date and amount of study treatment dispensed to each subject must 
be available for inspection at any time. 

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Prior to each new dispensation, the visit compliance must be evaluated by the site staff, 
based on study treatment accountability, as per formula below: 
Compliance = [(number of tablets provided to subject - number of tablets returned) / 
Total number of Tablets that should have been taken during the period]  
× 100 
The site staff should discuss any compliance issue with the subject and re-educate 
him/her on correct administration of study treatment. Details of such discussion must be 
documented in the subject’s file.  
If the compliance with study treatment intake is < 80% or > 120%, permanent 
discontinuation of study treatment may be considered after consultation with Actelion.  
5.1.9 Study treatment dose adjustments and interruptions 
Study treatment may be temporarily interrupted in response to an AE, a diagnostic or 
therapeutic procedure, a laboratory abnormality, or for administrative reasons. 
Study-specific criteria for interruption of study treatment are described in Section 5.1.11. 
If study treatment intake is interrupted by the subject for any reason, she/he must 
immediately inform the investigator. 
Interruptions of study treatment should be kept as short as possible. If treatment is 
stopped for more than 14 days, reintroduction is not permitted and treatment must be 
permanently discontinued [see Section 5.1.11]. 
Study treatment dose errors/interruptions must be recorded in the eCRF. 
5.1.10 Premature discontinuation of study treatment 
The decision to prematurely discontinue study treatment may be made by the subject, the 
investigator or Actelion. 
A subject has the right to prematurely discontinue study treatment at any time by 
withdrawal from treatment only or by withdrawal from treatment and any further 
participation in the study. 
The investigator should discontinue study treatment for a given subject if, on balance, 
he/she believes that continued administration would be contrary to the best interests of 
the subject. 
Premature discontinuation of study treatment may also result from a decision by 
Actelion, e.g., in case of premature termination or suspension of the study [see 
Section 9.3]. 

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Study treatment may be discontinued in response to an AE, lack of efficacy (including 
disease progression, treatment failure, worsening of patient condition), a protocol 
deviation (including eligibility failure, non-compliance with study requirements, such as 
non-compliance with study treatment intake or visit attendance), or if the subject is lost to 
follow-up. Study-specific criteria for discontinuation of study treatment are described in 
Section 5.1.11. 
The main reason and whether discontinuation of study treatment is the decision of the 
subject, the investigator or Actelion must be documented in the eCRF. 
A subject who prematurely discontinues study treatment is NOT considered as withdrawn 
from the study and will be followed up until EOS or 30 days after study treatment 
discontinuation, provided that the subject’s consent for this limited participation in the 
study has not been withdrawn. 
A subject who prematurely discontinues study treatment and withdraws consent to 
participate in any further study assessments is considered as withdrawn from the study. 
Subjects who die or are lost to follow-up are also considered as withdrawn from the 
study. Withdrawal from the study and follow-up medical care of subjects withdrawn from 
the study is described in Sections 9.2 and 9.4, respectively. 
5.1.11 Study-specific criteria for interruption / premature discontinuation of study 
treatment 
A) Pregnancy 
If a female subject becomes pregnant while on study treatment, study treatment must be 
discontinued immediately, and a Pregnancy Form must be completed [see Section 10.3]. 
B) Liver aminotransferases abnormalities 
Interruption of study treatment 
Study treatment must be interrupted in the following cases: 
• Asymptomatic increase in aminotransferases (i.e., ALT and/or AST) ≥ 3 and  
< 8 × ULN. 
In such a case, perform a re-test of aminotransferases (ALT and AST), total and direct 
bilirubin, and alkaline phosphatase within one week. If AST and/or ALT elevation is 
confirmed, continue to monitor aminotransferases, total and direct bilirubin, and alkaline 
phosphatase levels weekly until values return to pre-treatment levels or within normal 
ranges. If the aminotransferase values return to pre-treatment levels or within normal 
ranges, reintroduction of study treatment can be considered. Interruptions must be for less 
than 2 consecutive weeks; longer interruptions must lead to permanent discontinuation of 
study treatment.  

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Reintroduction of study treatment after treatment interruption should only be considered 
if the potential benefits of treatment with macitentan outweigh the potential risks and 
when liver aminotransferase values are within pre-treatment levels or within normal 
ranges. The advice of a hepatologist is recommended. 
Liver aminotransferase levels must then be checked within 3 days after reintroduction, 
then again after a further 2 weeks and thereafter according to the recommendations above 
(i.e., at monthly intervals). 
Permanent discontinuation of study treatment 
Study treatment must be stopped and its reintroduction is not to be considered in the 
following cases: 
• Aminotransferases ≥ 8 × ULN 
• Aminotransferases ≥ 3 × ULN and associated with new or worsening clinical 
symptoms of liver injury, e.g., nausea, vomiting, fever, abdominal pain, jaundice, 
unusual lethargy or fatigue, flu like syndrome (arthralgia, myalgia, fever) 
• Aminotransferases ≥ 3 × ULN associated with total bilirubin ≥ 2 × ULN and 
increased as compared to baseline 
In such cases, aminotransferases, total and direct bilirubin, and alkaline phosphatase 
levels must be monitored weekly after study treatment discontinuation until values return 
to pre-treatment levels or within normal ranges. 
Other diagnoses (e.g., viral hepatitis, mononucleosis, toxoplasmosis, cytomegalovirus,) 
and/or etiologies (e.g., acetaminophen-related liver toxicity) should be considered and 
ruled out by performing the appropriate tests. 
All liver aminotransferases abnormalities leading to study treatment interruption or 
discontinuation must be recorded as AEs [see Section 10]. 
An ILSDRB (an external expert committee of hepatologists) provides ongoing 
assessment and advice regarding any hepatic events that require further evaluation during 
the study.  

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C) Hemoglobin abnormalities 
In case of hemoglobin decrease from baseline* of > 20 g/L, a retest must be performed 
within 10 days, with additional laboratory evaluations that may include, but are not 
limited to, any of the following:  
• Red blood cell cellular indices (mean corpuscular volume, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration), peripheral blood smear, 
reticulocyte count, iron status (iron level, serum ferritin, total iron binding capacity, 
transferrin saturation), lactate dehydrogenase, indirect bilirubin. 
Study treatment should be temporarily interrupted if clinically mandated based on the 
investigator’s judgment, or in any of the following situations: 
− A decrease in hemoglobin to < 80 g/L (< 4.9 mmol/L),  
− A decrease in hemoglobin from baseline* of > 50 g/L,  
− The need for transfusion.  
Reintroduction of study treatment may be considered if hemoglobin recovery, defined as 
a return of hemoglobin above the lower limit of the normal range or if it returns to a value 
close to that at baseline.  
Interruption of study treatment must not last longer than 2 consecutive weeks; longer 
interruption must lead to permanent discontinuation of study treatment. 
*Baseline hemoglobin: last value obtained prior to first intake of double-blind study 
treatment. 
D) Child-Pugh classification or MELD Score worsening 
If a subject is assessed as being Child-Pugh class C of liver disease or MELD Score  
≥ 19 at EOT-DB then study treatment must be permanently discontinued and the 30-day 
Safety follow-up is to be performed. The subject must not initiate open-label treatment. 
E) Start of a PAH specific therapy / strong CYP3A inducer / investigational drug 
Double-blind study treatment must be permanently discontinued if escalation of 
PAH-specific therapy is required (e.g., other ERAs, i.v./s.c. prostanoids), strong CYP3A4 
inducers and/or any other investigational treatments are started during the double-blind 
treatment period.  
Open-label study treatment must only be discontinued in the open-label period if an ERA, 
strong CYP3A4 inducer, and/or any other investigational treatments is started. I.v./s.c. 
prostanoids are permitted in the open-label period at the investigator’s discretion. 

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F) Orthotopic Liver transplantation  
If a subject undergoes OLT during the double-blind treatment phase, they must stop all 
study treatment at the earliest convenience and undergo EOS after 30 days’ safety follow 
up.  
If a subject undergoes OLT during the open-label treatment phase, continued treatment 
with OL study medication is permitted until Week 24 (EOT-OL), after which the 
30 days’ safety follow up should be performed. 
5.2 Previous and concomitant therapy 
5.2.1 Definitions 
A previous therapy is any treatment for which the end date is prior to the start of study 
(i.e., date of informed consent). 
A concomitant therapy is any treatment that is either initiated or ongoing during 
Screening, after Randomization, or up to 30 days after the end of study treatment.  
5.2.2 Reporting of previous/concomitant therapy in the CRF 
Any previous treatment for PAH / right heart failure (including diuretics) and/or portal 
hypertension (including beta blockers, hepatitis C medications) that has been 
discontinued within 3 months prior to randomization must be recorded in the eCRF. 
Generic name, route, start/end date of administration (as well as whether it was ongoing 
at start of study treatment and/or EOS) and dose will be collected. Any change in dose or 
route of administration will be captured on the log by completing a new line.  
All medications (including dietary supplements, traditional and alternative medicines, 
i.e., plant-, animal-, or mineral-based medicines) taken between Screening visit and EOS 
are to be recorded on the concomitant medications page of the eCRF. Generic name, 
start/end dates of administration (as well as whether it was ongoing at start of treatment 
and/or EOS), route, dose, and indication will be recorded in the eCRF.  
Hormonal contraceptives will be recorded on the contraception page of the eCRF.  
5.2.3 Allowed concomitant therapy 
Oral PDE5i, inhaled prostacyclin analogues, soluble guanylate cyclase (sGC) stimulator 
are allowed if present for at least 3 months prior to randomization at a stable dose (which 
must remain unchanged during the double-blind treatment period unless the patient 
experiences worsening of PAH).  
Treatment with oral diuretics is allowed if ongoing at a stable dose for at least 1 week 
prior to baseline right heart catheterization; the dose may be optimized during the 
treatment period. 

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Beta blockers are allowed if present for at least 1 week prior to baseline right heart 
catheterization at a stable dose (which should remain unchanged during the study). If 
discontinuation of beta blockers occurs during the study the patient should complete the 
study as scheduled.  
During the open-label period, i.v. and s.c. prostanoid therapy (e.g., epoprostenol, 
treprostinil) is permitted at any time. 
The following antiviral hepatitis C medications are permitted: simeprevir, sofosbuvir, 
daclatasvir, ombitasvir, dasabuvir, ledipasvir, etravirine, raltegravir, maraviroc, and 
ribavirin. 
5.2.4 Forbidden concomitant therapy 
• ERAs (e.g., bosentan, ambrisentan) 
• During 
the 
double-blind 
period, 
i.v./s.c. 
and 
oral 
prostanoid 
therapy 
(e.g., epoprostenol, treprostinil) is forbidden  
• Calcium channel blockers 
• Strong CYP3A4 inducers (e.g., carbamazepine, rifampin, rifampicin, rifabutin, 
rifapentin, phenobarbital, phenytoin, and St. John’s wort) 
• Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, voriconazole, 
clarithromycin, telithromycin, nefazodone, ritonavir, lopinavir, fosamprenavir, 
darunavir, tipranavir, atazanavir, nelfinavir, amprenavir, indinavir, boceprevir, 
telaprevir, paritaprevir, and saquinavir) 
• Treatment with interferon 
• Any other investigational drug. 
6 
STUDY ENDPOINTS 
6.1 Efficacy endpoints 
6.1.1 Double-blind treatment period 
Baseline is the last assessment prior to initiation of double-blind treatment. 
6.1.1.1 Primary efficacy endpoint 
The primary efficacy endpoint is relative change from baseline to Week 12 in PVR.  
A geometric mean in the active group showing a reduction of at least 20% in PVR when 
compared to the placebo geometric mean is considered clinically relevant in this patient 
population. 

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6.1.1.2 Secondary efficacy endpoints 
• Change from Baseline to Week 12 in mean right atrial pressure (mRAP), mPAP, 
cardiac index (CI), total pulmonary resistance (TPR), and mixed venous oxygen 
saturation (SVO2), all measured at rest 
• Change from Baseline to Week 12 in 6MWD 
• Change from Baseline to Week 12 in WHO functional class  
• Change from Baseline to Week 12 in NT-proBNP. 
6.1.1.3 Other efficacy endpoints 
• Change from Baseline to Week 12 in hepatic venous pressure gradient (HVPG) 
• Change from Baseline to Week 12 in Borg dyspnea index. 
6.1.2 Macitentan-treatment period  
Macitentan Baseline is the last assessment prior to initiation of macitentan treatment 
(i.e., double-blind baseline for subjects randomized to receive blinded macitentan 10 mg, 
or Week 12/EOT-DB for subjects assigned to placebo during the double-blind treatment 
period). 
• Change from macitentan Baseline to each time point in WHO functional class  
• Change from macitentan Baseline to each time point in NT-proBNP 
• Change from macitentan Baseline to each time point in 6-minute walk distance 
(6MWD) 
• Change from macitentan Baseline to each time point in Borg dyspnea index.  
6.2 Safety endpoints 
6.2.1 Double-blind treatment period 
For the double-blind treatment period, treatment-emergent is defined as from first intake 
of study treatment until end of double-blind treatment + 30 days, or initiation of 
open-label treatment, whichever occurs first). 
• Treatment-emergent deaths 
• Treatment-emergent AEs 
• Treatment-emergent AEs leading to premature discontinuation of double-blind study 
treatment 
• Treatment-emergent SAEs 
• Proportion of patients with treatment-emergent ALT and/or AST abnormality (≥ 3, 
≥ 5, and ≥ 8 × ULN)  
• Proportion of patients with treatment-emergent ALT and/or AST abnormality  
(≥ 3 × ULN) associated with total bilirubin ≥ 2 × ULN (and increased as compared to 
baseline) up to EOT-DB 

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• Proportion of patients with treatment-emergent hemoglobin abnormality (< 100 g/L, 
and < 80 g/L)  
• Treatment-emergent marked lab abnormalities 
• Change from Baseline to EOT-DB in vital signs 
• Change from Baseline to EOT-DB in laboratory variables 
• Change from Baseline to EOT-DB in MELD score  
• Change from Baseline to EOT-DB in Child-Pugh classification. 
Marked laboratory abnormalities are defined in Actelion internal guidelines as detailed in  
Appendix 6. 
6.2.2 Macitentan-treatment period safety endpoints 
Macitentan treatment-emergent is defined as from first intake of macitentan up to EOS 
(i.e., 30 days after discontinuation of macitentan treatment). End of macitentan treatment 
(EOMT) is defined as EOT-DB or EOT-OL, whichever comes last. Macitentan baseline 
is defined as last assessment prior to first intake of macitentan. 
• Macitentan treatment-emergent deaths 
• Macitentan treatment-emergent AEs 
• Macitentan treatment-emergent AEs leading to premature discontinuation of 
macitentan treatment 
• Macitentan treatment-emergent SAEs 
• Proportion of patients with macitentan treatment-emergent ALT and/or AST 
abnormality (≥ 3, ≥ 5, and ≥ 8 × ULN) up to EOMT 
• Proportion of patients with macitentan treatment-emergent ALT and/or AST 
abnormality (≥ 3 ULN) associated with total bilirubin ≥ 2 × ULN (and increased as 
compared to baseline) up to EOMT 
• Proportion of patients with macitentan treatment-emergent hemoglobin abnormality 
(< 100 g/L, and < 80 g/L) up to EOMT 
• Macitentan treatment-emergent marked lab abnormalities up to EOMT 
• Change from macitentan Baseline to EOMT in vital signs 
• Change from macitentan Baseline to EOMT in laboratory variables 
• Change from macitentan Baseline to EOMT in Child-Pugh classification 
• Change from macitentan Baseline to EOMT in MELD Score. 
6.3 Pharmacokinetic endpoints 
A PK substudy will be performed in consenting patients at any time on or between Visit 6 
/ Week 16 and Visit 7 / Week 20 (open-label period). Recruitment into the substudy will 
be stopped only after a minimum of 20 subjects have provided sufficient plasma samples 
of good quality to allow evaluation of the PK profile of macitentan in PoPH. Please see 
Appendix 1 for a detailed description of procedures. 

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7 
STUDY ASSESSMENTS 
All study assessments are performed by a qualified study staff member: medical, nursing, 
or specialist technical staff, and are recorded in the eCRF, unless otherwise specified. 
Study assessments performed during unscheduled visits will also be recorded in the 
eCRF. When applicable, the assessments should be performed in the following order:  
• Blood sampling 
• Physical examination  
• WHO functional class  
• 6-minute walk test 
• Borg dyspnea index 
• Right heart/hepatic vein catheterization at rest 
If the principal investigator delegates any study procedure/assessment for a subject, 
e.g., RHC, blood sampling etc., to an external facility, he/she should inform Actelion to 
whom these tasks are delegated. The set-up and oversight will be agreed upon with 
Actelion. The supervision of any external facilities remains under the responsibility of the 
principal investigator. 
Calibration certificates for the following devices used to perform study assessments must 
be available prior to the randomization of the first subject:  
• Temperature measurement devices for study medication storage area and freezer, 
• Right heart/hepatic catheterization equipment, 
• Scale for measuring body weight. 
7.1 Screening/baseline assessments 
Date of informed consent, baseline demographics (sex, age, race, ethnicity, body weight, 
height) as well as a reason for why a woman is not considered to be of childbearing 
potential (if applicable) are to be recorded in the eCRF at Visit 1/Screening only after 
informed consent has been signed. 
Complete, clinically relevant medical history (previous and ongoing at randomization) as 
described in Section 4.6 and liver disease characteristics: 
• Date and mode of portal hypertension diagnosis (liver biopsy, hepatic vein 
catheterization, ultrasound, presence of esophageal varices, ascites, history of TIPS, 
other 
• Cause of portal hypertension: Intrahepatic (autoimmune hepatitis, alcohol cirrhosis, 
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biliary cirrhosis); pre-hepatic (portal vein thrombosis/clots, congenital); post-hepatic 
(hepatic vein thrombosis, inferior vena cava thrombosis); other 
• Child-Pugh class and/or MELD Score are also to be assessed and documented in the 
eCRF at Visit 1/Screening. 
PAH disease characteristics such as 6MWT, Borg dyspnea index, WHO functional class, 
as well as vital signs, body mass index, and ongoing medications are to be documented in 
the eCRF at Visit 1/Screening. 
Right heart and hepatic vein catheterization data are to be collected in the eCRF at 
Visit 1/Screening. Hepatic vein catheterization is not a required procedure for study entry 
but should be collected where possible. Reason for Screen failure, if applicable, must also 
be given in the eCRF at Visit 1/Screening.   
At Visit 2/Randomization, WHO functional class, 6MWT, Borg dyspnea index, and 
ongoing medications are to be collected in the eCRF. Any SAEs occurring during 
Screening relating to study-mandated procedures are to be documented in the eCRF. 
A physical examination of the subject should be performed at both Visit 1/Screening and 
Visit 2/Randomization. Data are not collected in the eCRF though abnormal findings are 
to be recorded as AEs. Serum laboratory and pregnancy testing should be performed at 
Visit 1/Screening and repeated at Visit 2/Randomization (urine pregnancy test required in 
addition at Visit 2 prior to randomization [see Section 4.3]), whereas blood sampling for 
baseline NT-proBNP should only be performed at Visit 2/Randomization. Laboratory 
data are only collected in the eCRF for local lab assessments [see Section 7.3.5]. Only 
laboratory data from Visit 1/Screening are to be considered for subject eligibility. Vital 
signs are to be assessed and documented in the eCRF at Visit 1/Screening. 
AEs and SAEs occurring during the Screening and Randomization Visit phase are to be 
documented in the eCRF.  
7.2 Efficacy assessments 
7.2.1 Hemodynamic measurements − Right heart catheterization  
Invasive cardiac hemodynamic variables are measured according to the Actelion RHC 
guidelines (see the PORTICO catheterization handbook) at Baseline and Week 12, or at 
permanent discontinuation of double-blind study treatment if prior to Week 12 (at the 
investigator’s discretion).  
A maximum of 2 RHC are performed during the study duration. Catheterizations should 
be performed according to the Actelion guidelines and the thermodilution technique 
should be used to measure cardiac output (CO).  

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The following variables are to be measured and collected in the eCRF: Heart rate (HR), 
PAWP or LVEDP (if PAWP is not available), mRAP, systolic/diastolic/mean PAP, CO, 
SVO2. Non-invasive SBP and diastolic blood pressure (DBP) are collected and entered 
into the eCRF. PVR will be calculated locally and entered into the eCRF at 
Visit 1/Screening. 
The following hemodynamic variables will be calculated by Actelion for analysis 
purposes [see Section 11.2 and the PORTICO catheterization handbook for formulae]: 
PVR, TPR, CI. 
RHC reports, including traces, must be signed by the person performing the procedure, or 
by the principal investigator and filed at site in the subject’s file. 
7.2.2 Hemodynamic measurements − Hepatic vein catheterization 
HVPG, an estimate of portal pressure, is measured by hepatic vein catheterization (HVC) 
at Baseline and Week 12, or at permanent discontinuation of double-blind study 
treatment if prior to Week 12 (at the investigator’s discretion). 
HVPG should be measured at the same time as RHC variables where possible, but within 
1 week prior to EOT-DB if the procedure cannot be performed on the same day. HVC is 
not required at sites that do not perform the procedure routinely. 
HVPG measurements will be done after at least 4 hours of fasting, at rest, in the supine 
position, under local anesthesia and mild sedation. A catheter introducer will be placed 
into the right jugular vein (or femoral) by the Seldinger technique. It will be used to 
advance a balloon-tipped catheter into the main right hepatic vein for repeated 
measurements of wedged (occluded) and free hepatic venous pressures. Intravascular 
pressures will be measured using highly sensitive pressure transducers, calibrated before 
each measurement. HVPG will be calculated as the difference between wedged and free 
hepatic venous pressures. Measurements will be performed at least as duplicates and 
repeated until, ideally, the 2 consecutive reliable measurements do not differ by more 
than 1 mmHg. The mean of these two measurements will be considered final. It is up to 
the investigator, according to his best clinical judgment, to identify the reliable value in 
case that this requirement is not fulfilled. Only the final value will be recorded in the 
CRF. 
HVC reports must be signed by the person performing the procedure, or by the principal 
investigator. Corresponding HVC documents must be filed at site in the subject’s file. 
7.2.3 WHO functional class 
WHO functional class is evaluated at Screening, Baseline/Randomization, and then every 
Visit until EOT-DB or EOT-OL, whichever comes last [see Appendix 5 for more details 
on performing the assessment]. 

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7.2.4 6-minute walk test 
The 6MWT [ATS Statement 2002] is evaluated at Screening, Baseline/Randomization, 
and then every Visit until EOT-DB or EOT-OL, whichever comes last. It is a test which 
measures the distance walked by the subject in six minutes. 
Detailed guidelines on the correct execution of this test, the “Actelion guidelines for 
6MWT”, can be found in the Appendix 3. It is important that for each individual subject 
the 6MWT is conducted under the same conditions throughout the study (e.g., same 
location, same tester, same time of day, with or without nasal oxygen therapy [and with 
same flow rate as Baseline]). 
7.2.5 Borg dyspnea index 
The Borg dyspnea index is evaluated after each 6MWT. It rates dyspnea on a scale from 
0 to 10 [see Appendix 4 for more details on performing the assessment]. 
7.2.6 Serum NT-proBNP 
A blood sample will be drawn at Baseline/Randomization (Visit 2), EOT-DB, and  
EOT-OL for the analysis of serum NT-proBNP.  
Serum NT-proBNP samples will be shipped to the central laboratory on dry ice as soon 
as possible after blood sample has been drawn or stored frozen at −20 °[−4 °F] ± 2 °C 
[± 3.6 °F] until the shipment can occur. A temperature log must be maintained and 
temperature control should occur at least on a weekly basis. NT-proBNP samples will be 
processed through the central laboratory and the results will be sent electronically to 
Actelion on an ongoing basis. Further details regarding blood sampling procedures, 
collection and shipment of biomarker samples are described in the central laboratory 
manual.   
7.3 Safety assessments 
The definitions, reporting and follow-up of AEs, SAEs [and pregnancies] are described in 
Section 10. 
7.3.1 Vital signs 
Vital signs (BP, pulse rate) will be measured at Screening (Visit 1), EOT-DB, and 
EOT-OL, and entered in the eCRF. BP (systolic and diastolic) and pulse rate will be 
measured in a supine or sitting position after the subject has rested for at least 5 minutes. 
The right or left arm may be used. The same position and arm should be used throughout 
the trial for an individual subject. When applicable, vital signs should be measured before 
the 6MWT.  

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7.3.2 Weight and height 
Height and weight are measured at Visit 1/Screening and entered into the eCRF. Weight 
is measured again at EOT-DB. 
7.3.3 Physical examination 
Physical examination (i.e., inspection, percussion, palpation and auscultation) is to be 
performed during the course of the study. If an abnormality is found it should be 
specified in the eCRF, describing the signs related to the abnormality (e.g., systolic 
murmur) and not the diagnosis (e.g., mitral valve insufficiency). Clinically relevant 
findings (other than those related to PoPH) that are present at study start (i.e., signing of 
informed consent) must be recorded on the Medical History CRF page. Physical 
examination findings made after study start, which meet the definition of an AE 
[Section 10.1.1] must be recorded by the investigator on the AE page of the CRF. 
7.3.4 Child-Pugh classification and/or MELD Score assessment 
Assessment of liver disease severity using the Child-Pugh classification and/or MELD 
Score [see Appendix 2 for definitions] is to be performed at Screening/Visit 1, EOT-DB, 
and EOT-OL and entered into the eCRF. Serum laboratory analyses used for calculating 
either assessment must be performed using study lab kits but local labs may also be used 
in parallel and data entered into the eCRF. An ultrasound scan of the abdomen should be 
performed for assessing the Child-Pugh class. Data must be complete for Screening 
purposes. 
In case a patient has progressed to Child-Pugh C or MELD Score ≥ 19 at Week 12, 
open-label medication must not be started. Serum laboratory analyses used for calculating 
either assessment must be performed using study lab kits but local labs may also be used 
in parallel and data entered into the eCRF. EOS must be completed after a 30-day Safety 
follow-up period.  
7.3.5 Laboratory assessments 
7.3.5.1 Type of laboratory 
A central laboratory (
) will be 
used for all protocol-mandated laboratory tests, including re-tests due to laboratory 
abnormalities and laboratory tests performed at unscheduled visits. Central laboratory 
data will be automatically transferred from the central laboratory database to Actelion’s 
clinical database.  
Eligibility of subjects in Screening may be determined using local laboratory tests as long 
as the central laboratory kit is used in parallel. Similarly, at Week 12 (EOT-DB), 
laboratory assessments for calculating the MELD Score and/or Child-Pugh classification 

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may be performed using local laboratory testing if a central laboratory kit is used in 
parallel.  
All local laboratory data must be entered into the clinical database via dedicated eCRF 
pages. The investigator/delegate will provide Actelion with the name, professional 
degree, and curriculum vitae of the director of the local laboratory, a copy of the 
laboratory’s certification, and the normal ranges for each laboratory test that is evaluated 
in the study. These laboratory references must be updated whenever necessary. 
Under specific circumstances (e.g., if the patient lives far from the site and cannot return 
every month), laboratory samples may be collected at a laboratory close to where the 
patient lives (satellite laboratory), and sent to the central laboratory for analysis. In such a 
case, the satellite laboratory must be provided with the central laboratory sampling kits. 
Shipment of the samples will be organized by the satellite laboratory. If this process is 
implemented, the satellite laboratory must be identified prior to enrollment of the patient 
in the study. The supervision of the satellite laboratory remains under the responsibility 
of the principal investigator. 
In exceptional cases (e.g., patient is hospitalized in a different hospital from the study 
center due to a medical emergency, missing laboratory values) the local laboratory results 
(with the corresponding normal ranges) will be entered into the clinical database via 
dedicated CRF pages.  
In case a central laboratory sample is lost or cannot be analyzed for any reason, the 
investigator will collect an additional sample as soon as possible for repeat analysis, 
unless a local laboratory sample was collected within the same time-window and these 
test results are available. 
Central laboratory reports will be sent to the investigator. In case of specific (pre-defined) 
laboratory abnormalities, the central laboratory will alert Actelion and the concerned site. 
Alert flags that will trigger such notifications are displayed in Appendix 7. 
All laboratory reports must be signed and dated by the principal investigator or delegate 
within 3 working days of receipt and filed with the source documentation. The 
investigator/delegate must indicate on the laboratory report whether abnormal values are 
considered clinically relevant or not. Clinically relevant laboratory findings that are 
known at the time of informed consent signature must be recorded on the medical history 
page of the CRF. Any clinically relevant laboratory abnormalities detected after informed 
consent signature must be reported as an AE or SAE as appropriate [see Section 10], and 
must be followed until the value returns to within the normal range or is stable, or until 
the change is no longer clinically relevant. Further laboratory analyses must be performed 
as indicated and according to the judgment of the investigator. 

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Details about the collection, sampling, storage, shipment procedures, and reporting of 
results and abnormal findings can be found in the laboratory manual. 
7.3.5.2 Laboratory tests 
The total amount of blood collected during the study will not exceed 200 mL: 
1. At Visit 1/Screening approximately 15 mL of blood will be collected 
2. At Visit 2/Randomization, EOT-DB and EOT-OL approximately 25 mL of blood will 
be collected 
3. At Visits 3 and 4 approximately 15 mL of blood will be collected 
4. At Visits 6 and 7 approximately 15 mL of blood will be collected 
5. At the PK substudy (optional), approximately 24 mL will be collected. 
Hematology 
Hematology tests will be performed at every Visit (1–8) and include: 
• Hemoglobin, hematocrit 
• Erythrocyte count (reticulocyte count) 
• Leukocyte count with differential counts 
• Platelet count. 
Rules for study treatment interruption in case of hemoglobin abnormalities are provided 
in Section 5.1.11. 
Clinical chemistry 
• Aminotransferases (AST/ALT), alkaline phosphatase, total and direct bilirubin 
• GGT 
• Bile acids 
• Creatinine, blood urea nitrogen (BUN) 
• Uric acid 
• Lactate dehydrogenase (LDH), cholesterol, triglycerides 
• Glucose 
• Sodium, potassium, calcium, chloride 
• Albumin, protein. 

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Rules for study treatment interruption in case of liver enzymes abnormalities are provided 
in Section 5.1.11. 
Coagulation tests 
• Prothrombin time and International Normalized Ratio (PT-INR). 
Pregnancy test 
A serum pregnancy test for women of childbearing potential will be performed monthly 
from Visits 1 to 8 and if pregnancy is suspected during the study. At Visit 2 and at the 
end of the 30-day Safety follow up, a urine dipstick pregnancy test is to be performed. 
8 
SCHEDULE OF VISITS 
Table 1 provides a summary of all visits and assessments described in the following 
sections.  
To ensure compliance, at each visit the study personnel must remind women of 
childbearing potential to use the methods of contraception defined for this study. The 
reminders must be documented in the hospital chart. 
It is permitted to re-screen subjects once, if the reason for non-eligibility was transient 
(e.g., abnormal laboratory test, insufficient wash-out period of a forbidden medication, 
etc.), provided that documented authorization has been received from Actelion. Only 
screening assessments that will be older than 28 days at the time of randomization need 
to be repeated at the time of re-screening. 
8.1 Screening Period 
8.1.1 Screening (Visit 1) 
All Screening assessments must be performed within 28 days prior to Randomization. 
Historical data for Baseline RHC and HVC may be entered into the eCRF if the 
procedure was performed within 28 days of Randomization and per the requirements 
described in Sections 7.2.1 and 7.2.2. Screening commences with signature of the ICF 
and ends with subject randomization (up to 28 days after signed informed consent).  
It is the responsibility of the investigator to obtain written informed consent from each 
subject participating in this study after adequate face to face explanation of the 
objectives, methods, and potential hazards of the study. The subjects who agree to 
participate in the study must sign the ICF prior to any study-related assessment or 
procedure. Screening and Randomization cannot occur on the same day. 
Visit 1 includes:  
• Subject information leaflet and consent form signature 

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• Obtain subject number from IxRS 
• Recording of demographics, medical history, cause of portal hypertension, date and 
method of portal hypertension diagnosis, date of PoPH diagnosis 
• Physical examination 
• Complete laboratory tests, including serum pregnancy test for women of childbearing 
potential 
• Child-Pugh and/or MELD score assessment 
• Recording of previous and concomitant medications 
• Recording of methods of contraception (for females of childbearing potential only) 
and initiation of protocol-compliant contraception if applicable. The reason why a 
female is not considered to be of childbearing potential will also be collected in the 
eCRF 
• Measurement of vital signs, height and body weight 
• WHO functional class 
• 6MWT and Borg dyspnea index 
• RHC and HVC 
• Recording of AEs and SAEs.  
The investigator will check all the inclusion/exclusion criteria and decide on the subject’s 
eligibility for the study. HVC is not required at sites that do not perform the procedure 
routinely. Only laboratory data from Visit 1/Screening are to be considered for subject 
eligibility. Eligibility of subjects may be determined using local laboratory tests as long 
as the central laboratory kit is used in parallel and the results entered into the eCRF. It 
must be verifiable in the source documents that the subject met each of the inclusion 
criteria and none of the exclusion criteria. If the subject is not randomized, the reason for 
screening failure is to be documented in the eCRF.  
8.2 Double-blind treatment period 
8.2.1 Randomization (Visit 2) 
Visit 2 corresponds to the start of the treatment period (Day 1 of the study) for subjects 
that are eligible after all Screening assessments have been performed. It must take place 
within 28 days after start of Screening. However, Screening and Randomization cannot 
take place on the same day. 
Visit 2 includes: 
• Recording of changes in concomitant medications  
• Assessment of methods of contraception (for females of childbearing potential only)  
• Physical examination  
• WHO functional class  

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• 6MWT and Borg dyspnea index  
• Complete laboratory tests, including serum & urine pregnancy test for women of 
childbearing potential [see Section 4.3]  
• Blood sample for serum NT-proBNP  
• Recording of AEs/SAEs:  
− All AEs occurring after study treatment initiation are to be reported in the eCRF  
− All SAEs occurring after signing of the ICF are to be reported in the eCRF and on 
an SAE form. 
Laboratory values from Visit 2/Randomization are not to be considered for subject 
eligibility. After completion of all Screening and Randomization assessments and 
confirmation of eligibility (i.e., verification of all entry criteria) by the investigator: 
o Randomization via IxRS to obtain Randomization and study treatment bottle 
number 
o Dispensing of 1 bottle of study treatment [see Section 5.1.7.3] 
8.2.2 Week 4 (Visit 3)  
Visit 3 is scheduled 4 weeks (± 4 days) after Randomization.  
Visit 3 includes: 
• Recording of changes in concomitant medications  
• Assessment of methods of contraception (for females of childbearing potential only)  
• Physical examination  
• WHO functional class  
• 6MWT and Borg dyspnea index  
• Complete laboratory tests, including serum pregnancy test for women of childbearing 
potential [see Section 4.3]  
• Recording of AEs and SAEs  
• Study medication return and dispensing of a new bottle. 
8.2.3 Week 8 (Visit 4)  
Visit 4 is scheduled 8 weeks (± 4 days) after Randomization.  
Visit 4 includes: 
• Recording of changes in concomitant medications  
• Assessment of methods of contraception (for females of childbearing potential only)  
• Physical examination  
• WHO functional class  
• 6MWT and Borg dyspnea index  

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• Complete laboratory tests, including serum pregnancy test for women of childbearing 
potential [see Section 4.3]  
• Recording of AEs and SAEs  
• Study medication return and dispensing of a new bottle. 
8.2.4 EOT-DB (scheduled Visit 5)  
EOT-DB is scheduled 12 weeks (± 4 days) after Randomization, or earlier in case of 
premature discontinuation of double-blind study treatment.  
EOT-DB includes: 
• Recording of changes in concomitant medications  
• Assessment of methods of contraception (for females of childbearing potential only)  
• Physical examination  
• Measurement of vital signs and body weight  
• WHO functional class  
• 6MWT and Borg dyspnea index  
• RHC and HVC  
• Complete laboratory tests, including serum pregnancy test for women of childbearing 
potential [see Section 4.3]  
• Child-Pugh and/or MELD score assessment 
• Blood sample for serum NT-proBNP 
• Recording of AEs and SAEs 
• Study medication return and dispensing of open-label medication. 
Once EOT-DB has been performed, subjects should continue the study in the open-label 
treatment period. 
8.3 Open-label treatment period 
8.3.1 Week 16 (Visit 6)  
Visit 6 is scheduled 16 weeks (± 4 days) after Randomization.  
Visit 6 includes: 
• PK substudy, if applicable [see Appendix 1] 
• Recording of changes in concomitant medications  
• Assessment of methods of contraception (for females of childbearing potential only)  
• Physical examination  
• WHO functional class  
• 6MWT and Borg dyspnea index  

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• Complete laboratory tests, including serum pregnancy test for women of childbearing 
potential [see Section 4.3]  
• Recording of AEs and SAEs  
• Study medication return and dispensing of a new bottle. 
8.3.2 Week 20 (Visit 7)  
Visit 7 is scheduled 20 weeks (± 4 days) after Randomization.  
Visit 7 includes: 
• PK substudy, if applicable [see Appendix 1] 
• Recording of changes in concomitant medications  
• Assessment of methods of contraception (for females of childbearing potential only)  
• Physical examination  
• WHO functional class  
• 6MWT and Borg dyspnea index  
• Complete laboratory tests, including serum pregnancy test for women of childbearing 
potential [see Section 4.3]  
• Recording of AEs and SAEs  
• Study medication return and dispensing of a new bottle. 
8.3.3 EOT-OL (scheduled Visit 8)  
EOT-OL is scheduled 24 weeks (± 4 days) after Randomization, or earlier in case of 
premature discontinuation of open-label study treatment.  
EOT-OL includes: 
• Recording of changes in concomitant medications  
• Assessment of methods of contraception (for females of childbearing potential only)  
• Physical examination  
• Measurement of vital signs  
• WHO functional class  
• 6MWT and Borg dyspnea index  
• Complete laboratory tests, including serum pregnancy test for women of childbearing 
potential [see Section 4.3]  
• Child-Pugh and/or MELD score assessment 
• Blood sample for serum NT-proBNP 
• Recording of AEs and SAEs 
• Study medication return. 

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8.4 EOS 
After permanent study treatment discontinuation (double-blind OR open-label), all 
subjects will enter a 30-day Safety follow-up period.  
EOS is scheduled 24 weeks + 30 to 33 days after randomization. It must be performed at 
least 30 days after study treatment discontinuation (double-blind OR open-label) and may 
be performed by telephone. 
EOS includes: 
• Urine pregnancy test 
• Recording of AEs with onset up to 24 hours after study treatment discontinuation 
• SAEs with onset up to 30 days after study treatment discontinuation. 
9 
STUDY COMPLETION AND POST-STUDY TREATMENT/MEDICAL 
CARE 
9.1 Study completion 
For an individual subject the study is only considered completed once EOT-DB or  
EOT-OL has been performed and the 30-day Safety follow up is complete (EOS).  
The study is considered complete when all subjects have performed the 30-day Safety 
follow up (EOS).  
9.2 Premature withdrawal from study 
Subjects may voluntarily withdraw from the study for any reason at any time. Subjects 
are considered withdrawn if they state an intention to withdraw further participation in all 
components of the study, die or are lost to follow-up for any other reason. The 
investigator may withdraw a subject from the study (without regard to the subject’s 
consent) if, on balance, they believe that continued participation in the study would be 
contrary to the best interests of the subject. Withdrawal from the study may also result 
from a decision by Actelion for any reason, including premature termination or 
suspension of the study [see Section 9.3]. 
Subjects are considered as lost to follow-up if all reasonable attempts by the investigator 
to communicate with the individual fail. The site must take preventive measures to avoid 
a subject being lost to follow-up (e.g., document different ways of contact such as 
telephone number, home address, email address, person to be contacted in case the 
subject cannot be reached). If the subject cannot be reached, the site must make a 
reasonable effort to contact the subject, document all attempts and enter the loss of 
follow-up information into the eCRF. The following methods must be used: at least three 
documented telephone calls on different days must be placed to the last available 
telephone number and one registered letter must be sent by post to the last available home 

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address. Additional methods may be acceptable if they are compliant with local 
rules/regulations (e.g., site staff visit to the subject’s home), respecting the subject’s right 
to privacy. If the subject is still unreachable after all contact attempts listed above, he/she 
will be considered to be lost to follow-up.  
If premature withdrawal occurs for any reason, the reason for premature withdrawal from 
the study, along with who made the decision (subject, investigator or Actelion) must be 
recorded in the eCRF. 
If for whatever reason (except death or loss-to-follow-up) a subject was withdrawn from 
the study, the investigator should make efforts to conduct a last visit/contact to assess the 
safety and well-being of the subject, collect unused study treatment and discuss follow-up 
medical care. The investigator must provide follow-up medical care for all subjects who 
are prematurely withdrawn from the study, or must refer them for appropriate ongoing 
care, as described in Section 9.4. 
9.3 Premature termination or suspension of the study 
Actelion reserves the right to terminate the study at any time globally or locally. 
Investigators can terminate the participation of their site in the study at any time. 
If a study is suspended or prematurely terminated, Actelion will promptly inform the 
investigators, the IRBs/IECs and Health Authorities, as appropriate, and provide the 
reasons for the suspension or termination.  
If the study is suspended or prematurely terminated for any reason, the investigator in 
agreement with Actelion must promptly inform all enrolled subjects, and ensure their 
appropriate treatment and follow-up, as described in Section 9.4. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the subjects’ interests. 
In addition, if the investigator suspends or terminates a study without prior agreement 
from Actelion, the investigator must promptly inform Actelion and the IRB/IEC, and 
provide both with a detailed written explanation of the termination or suspension. 
If the IRB/IEC suspends or terminates its approval/favorable opinion of a study, the 
investigator must promptly notify Actelion and provide a detailed written explanation of 
the termination or suspension. 
Any suspension or premature termination of the study must be discussed with the 
Steering Committee. 

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9.4 Medical care of subjects after study completion/ withdrawal from study 
After the subject’s study completion or premature withdrawal from the study, whichever 
applies, the investigator/delegate will explain to subjects what treatment(s)/medical care 
is necessary and available according to local regulations.  
After premature study withdrawal, the investigator must remind the subject that he/she 
must not use any other investigational treatment in the 30 days following study treatment  
discontinuation. Female subjects of childbearing potential need to be reminded of the 
requirement to continue using a reliable method of contraception until 30 days after 
intake of the last dose of study treatment.  
10 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
10.1 Adverse events 
10.1.1 Definitions of adverse events 
An AE is any adverse change, i.e., any unfavorable and unintended sign, including an 
abnormal laboratory finding, symptom or disease that occurs in a subject during the 
course of the study, whether or not considered by the investigator as related to study 
treatment.  
A treatment-emergent AE is any AE temporally associated with the use of study 
treatment (from study treatment initiation until 30 days after study treatment 
discontinuation) whether or not considered by the investigator as related to study 
treatment. 
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 during the course of the study 
even though it may have been present prior to the start of the study. 
• Continuous persistent disease or symptoms present at study start that worsen 
following the start of the study.  
• Abnormal assessments, e.g., change on physical examination, ECG findings, if they 
represent a clinically significant finding that was not present at study start or 
worsened during the course of the study. 
• Laboratory test abnormalities if they represent a clinically significant finding, 
symptomatic or not, which was not present at study start or worsened during the 

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course of the study or led to dose reduction, interruption or permanent discontinuation 
of study treatment.  
Overdose, misuse and abuse of the study treatment should be reported as an AE and, in 
addition, study treatment errors must be documented in the study treatment log of the 
CRF. 
10.1.2 Intensity of adverse events 
The intensity of clinical AEs is graded on a three-point scale – mild, moderate, severe – 
and is reported on specific AE pages of the CRF.  
If the intensity of an AE worsens during study treatment administration, only the worst 
intensity should be reported on the AE page. If the AE lessens in intensity, no change in 
the severity is required. 
The three categories of intensity are defined as follows: 
 Mild 
The event may be noticeable to the subject. It does not influence daily activities, and 
usually does not require intervention. 
 Moderate 
The event may make the subject uncomfortable. Performance of daily activities may be 
influenced, and intervention may be needed. 
 Severe 
The event may cause noticeable discomfort, and usually interferes with daily activities. 
The subject may not be able to continue in the study, and treatment or intervention is 
usually needed. 
A mild, moderate, or severe AE may or may not be serious [see Section 10.3.1]. These 
terms are used to describe the intensity of a specific event. Medical judgment should be 
used on a case-by-case basis.  
Seriousness, rather than severity assessment, determines the regulatory reporting 
obligations. 
10.1.3 Relationship to study treatment  
Each AE must be assessed by the investigator as to whether or not there is a reasonable 
possibility of causal relationship to the study treatment, and reported as either related or 
unrelated. The determination of the likelihood that the study treatment caused the AE will 
be provided by an investigator who is a qualified physician. 

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10.1.4 Adverse events associated to study design or protocol mandated procedures 
An AE is defined as related to study design or protocol mandated procedures if it appears 
to have a reasonable possibility of a causal relationship to either the study design or to 
protocol-mandated procedures. Examples include discontinuation of a subject’s previous 
treatment during a washout period leading to exacerbation of underlying disease. 
10.1.5 Reporting of adverse events 
All AEs occurring after study start (i.e., signing of informed consent) and up to 30 days 
after study treatment discontinuation must be recorded on specific AE pages of the CRF.  
10.1.6 Follow-up of adverse events 
AEs still ongoing more than 30 days after study treatment discontinuation must be 
followed up until they are no longer considered clinically relevant. 
10.2 Serious adverse events 
10.2.1 Definitions of serious adverse events 
10.2.1.1 Serious adverse events 
An SAE is defined by the ICH guidelines as any AE fulfilling at least one of the 
following criteria: 
• Fatal. 
• Life-threatening: refers to an event in which the subject was at risk of death at the 
time of the event. It does not refer to an event that hypothetically might have caused 
death had it been more severe. 
• Requiring inpatient hospitalization, or prolongation of existing hospitalization. 
• Resulting in persistent or significant disability or incapacity. 
• Congenital anomaly or birth defect. 
• Medically significant: refers to important medical events that may not immediately 
result in death, be life-threatening, or require hospitalization but may be considered to 
be SAEs when, based upon appropriate medical judgment, they may jeopardize the 
subject, and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definitions above.  
The following reasons for hospitalization are exempted from being reported:  
• Hospitalization for cosmetic elective surgery, or social and/or convenience reasons. 
• Hospitalization for pre-planned (i.e., planned prior to signing informed consent) 
surgery or standard monitoring of a pre-existing disease or medical condition that did 

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not worsen, e.g., hospitalization for coronary angiography in a subject with stable 
angina pectoris. 
However, complications that occur during hospitalization are AEs or SAEs (for example 
if a complication prolongs hospitalization). 
10.2.1.2 Serious adverse events associated with the study design or protocol mandated 
procedures  
An SAE is defined as related to study design or protocol mandated procedures if it 
appears to have a reasonable possibility of a causal relationship to either the study design 
or to protocol-mandated procedures. Examples include discontinuation of a subject’s 
previous treatment during a washout period leading to exacerbation of underlying disease 
or a complication of an invasive procedure that is specifically required by the protocol. 
10.2.2 Reporting of serious adverse events  
10.2.2.1 During screening period  
All SAEs that occur after study start (i.e., signing of informed consent) must be reported 
(whether considered associated or not associated to study design or study-mandated 
procedures).  
These SAEs must be reported on an SAE form and also in the CRF.  
10.2.2.2 During treatment period 
All SAEs, regardless of investigator-attributed causal relationship, must be reported. 
These SAEs must be reported on an SAE form (except if waived [see Section 10.2.5]) 
and also on the AE pages in the eCRF. 
10.2.2.3 During 30-day follow-up period 
All SAEs, regardless of investigator-attributed causal relationship, which occur up to 
30 days after study treatment discontinuation must be reported on AE pages in the eCRF 
and on an SAE form (except if waived [see Section 10.2.5]).  
10.2.3 Follow-up of 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., death.  
10.2.4 After the 30-day follow-up period  
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, only 
if considered causally related to previous exposure to the study treatment by the 
investigator.  

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10.2.5 Reporting procedures 
All SAEs must be reported by the investigator to the Actelion drug safety department 
within 24 hours of the investigator’s first knowledge of the event. 
All SAEs must be recorded on an SAE form, irrespective of the study treatment received 
by the subject, and whether or not this event is considered by the investigator to be 
related to study treatment.  
The SAE forms must be faxed to the Actelion drug safety department (contact details are 
provided on the SAE form). The investigator must complete the SAE form in English, 
and must assess the causal relationship of the event to study treatment. 
Follow-up information about a previously reported SAE must also be reported within 
24 hours of receiving it. The Actelion drug safety department may contact the 
investigator to obtain further information.  
If the subject is hospitalized in a hospital other than the study site, it is the investigator’s 
responsibility to contact this hospital to obtain all SAE relevant information and 
documentation. 
The reference safety document to assess expectedness of a suspect serious adverse 
reaction and the need for expedited reporting by the sponsor to Health Authorities, 
ECs/IRBs and investigators is the reference safety information section of the IB 
[Macitentan IB].  
10.3 Pregnancy 
If a woman becomes pregnant while on study treatment, study treatment must be 
discontinued. The investigator must counsel the subject and discuss the risks of 
continuing with the pregnancy and the possible effects on the fetus.  
10.3.1 Reporting of pregnancy 
Irrespective of the treatment received by the subject, any pregnancy occurring during the 
study including during the 1 month following study treatment discontinuation must be 
reported 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 drug safety department (see contact details provided on the Actelion Pregnancy 
form), and on an AE page in the eCRF. 
10.3.2 Follow-up of pregnancy  
Any pregnancy must be followed to its conclusion and its outcome must be reported to 
the Actelion drug safety department. 

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Any AE associated with the pregnancy occurring during the follow-up period after study 
treatment discontinuation must be reported on separate AE pages in the CRF. Any SAE 
occurring during the pregnancy must be reported on an SAE form as described in 
Section 10.3.1. 
10.4 Study safety monitoring 
Clinical study safety information (AEs, SAEs, laboratory values, vital signs, and project-
specific labs/examinations as required) is monitored and reviewed on a continuous basis 
by the Actelion Clinical team (in charge of ensuring subjects’ safety as well as data 
quality) by periodically monitoring clinical studies activities from protocol conception to 
database closure.  
11 STATISTICAL METHODS 
All statistical analyses will be conducted by Actelion or by designated Contract Research 
Organizations supervised by Actelion. 
A Statistical Analysis Plan (SAP) will provide full details of the analyses, data displays, 
and algorithms to be used for data derivations.  
11.1 Analysis Sets 
11.1.1 Screened Analysis Set 
This analysis set includes all patients who were screened and received a screening 
number. 
11.1.2 Full Analysis Set 
The Full Analysis Set (FAS) includes all randomized patients who received at least one 
dose of study treatment in the double-blind treatment period and have a baseline value for 
the primary endpoint (PVR). 
11.1.3 Per-Protocol Set 
The Per-Protocol Set (PPS) comprises all patients included in the FAS without major 
protocol deviations that might affect the main analysis of the primary efficacy variable. 
The reasons for excluding patients for the PPS will be fully defined and documented in 
the SAP. 
11.1.4 Safety Set 
The Safety Set includes all patients who received at least one dose of study treatment in 
the double-blind treatment period. 
11.1.5 Other analysis sets 
The Macitentan Treated Set (MTS) consists of all patients who received at least one dose 
of macitentan in the double-blind or open-label treatment period. 

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The PK set comprises all patients from the FAS who did not deviate from the protocol in 
a way that might affect the evaluation of the PK endpoints. 
11.1.6 Usage of the analysis sets 
The primary efficacy analysis will be performed on the FAS based on treatment as 
randomized. Secondary and exploratory efficacy analyses will also be performed on the 
FAS. 
Safety analyses related to the double-blind treatment period will be performed on the 
Safety Set based on treatment as received. 
Summaries of efficacy and safety data obtained in all subjects who received macitentan 
(regardless of the treatment period) will be performed on the MTS. 
Subject listings will be based on the Safety Set, unless otherwise specified. Subject 
disposition will be described for the Screened Analysis Set. 
Analysis of PK in the PK substudy will be performed on the PK Set.  
11.2 Variables 
11.2.1 Primary efficacy variable 
The primary efficacy variable is the relative change from baseline to Week 12 in PVR. 
PVR [dyn·s·cm-5] is calculated as (mPAP − PAWP) / CO × 80 (also refer to the 
PORTICO catheterization handbook). The relative change from baseline is equal to the 
ratio of Week 12 to baseline PVR, minus one. The ratio of Week 12 to baseline PVR will 
be the variable used in the analyses. 
11.2.2 Secondary efficacy variables 
Secondary efficacy variables are changes from baseline to Week 12 in: 
• mRAP [mmHg] 
• mPAP [mmHg] 
• CI [L/min/m2], calculated as CO / body surface area (BSA) where  
BSA [m2]= 0.007184 × weight0.425 [kg] × height0.725 [cm] 
• TPR [dyn·s·cm-5], calculated as mPAP / CO. 
• SVO2 [%]  
• WHO functional class [I–IV] 
• 6MWD [m] 
• NT-proBNP [pmol/L] 

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11.2.3 Other efficacy variables 
11.2.3.1 Double-blind treatment period 
For all patients, changes from baseline to Week 12 in: 
• HVPG [mmHg] 
• Borg dyspnea index (range 6–20) 
11.2.3.2 Macitentan treatment period 
For patients who received macitentan in the double-blind or open-label treatment period, 
changes from macitentan Baseline to each time point for the following variables: 
• WHO functional class 
• 6MWD 
• NT-proBNP 
• Borg dyspnea index 
Macitentan baseline is defined as last assessment prior to macitentan initiation, i.e., for 
patients who received macitentan already in the double-blind period baseline is the start 
of double-blind macitentan and for patients who received macitentan only in the 
open-label period baseline is Week 12. 
11.2.4 Safety variables 
11.2.4.1 Double-blind treatment period 
Treatment-emergent is defined as from first intake of study treatment until to end of 
double-blind treatment + 30 days or start of open-label treatment, whichever occurs first. 
For all patients, safety variables include: 
• Treatment-emergent AEs up to EOT-DB 
• Treatment-emergent deaths up to EOT-DB 
• Treatment-emergent SAEs up to EOT-DB 
• AEs leading to premature discontinuation of study treatment up to EOT-DB 
• Occurrence of LFT (ALT or AST) abnormalities up to EOT-DB, classified as: 
o ≥ 3 × ULN; 
o ≥ 3 × ULN and < 5 × ULN; 
o ≥ 5 × ULN and < 8 × ULN; 
o ≥ 8 × ULN. 
• Occurrence of hemoglobin abnormalities up to EOT-DB, classified as: 
o < 80 g/L; 
o ≥ 80 g/L and < 100 g/L. 
• Occurrence of ALT and/or AST abnormality ≥ 3 × ULN associated with total 
bilirubin ≥ 2 × ULN (and increased as compared to baseline) up to EOT-DB 
• Treatment-emergent marked laboratory abnormalities up to EOT-DB 

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• Change from baseline to EOT-DB in vital signs 
• Change from baseline to EOT-DB in laboratory variables 
• Change from baseline to EOT-DB in Child-Pugh classification  
• Change from baseline to EOT-DB in MELD score 
11.2.4.2 Macitentan treatment period 
For patients who received macitentan in the double-blind or open-label treatment period 
the same safety variables as in the Section 11.2.4.1 will be considered with macitentan 
treatment emergent instead of treatment emergent, and EOMT instead of EOT-DB. 
11.2.5 Other variables 
Variables associated with the PK substudy are described in Appendix 1. 
11.3 Description of statistical analyses 
11.3.1 Overall testing strategy 
The overall type I error is α = 0.025 (one-sided). The type II error is set to 0.10 and the 
power to 90%.  
11.3.2 Analysis of the primary efficacy variable(s) 
11.3.2.1 Hypotheses and statistical model 
The null hypothesis is: 
The treatment difference (macitentan minus placebo) in mean relative change from 
baseline to Week 12 in PVR is greater than or equal to zero or, equivalently, the 
geometric mean ratio (macitentan versus placebo) of the ratios of Week 12 to baseline 
PVR is greater than or equal to one. 
The alternative hypothesis is: 
The treatment difference in mean relative change from baseline in PVR is less than zero 
or, equivalently, the geometric mean ratio is less than one. 
11.3.2.2 Handling of missing data 
If PVR cannot be calculated due to missing PAWP but mPAP and CO are available for 
the same visit, one the following will be applied: 
1. If PAWP is missing both at baseline and post-baseline, the treatment group medians 
will be imputed (based on the FAS). 
2. If PAWP is missing either at baseline or post-baseline, the patient’s available PAWP 
will be imputed. 

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This imputation is based on the clinical assumption that macitentan does not affect 
PAWP. 
Baseline: Patients without a baseline PVR measurement will be excluded from the 
analyses.  
Post-baseline: In patients with a post-baseline PVR measurement obtained before 
Week 12, the post-baseline PVR measurement will be carried forward. For patients where 
no post-baseline PVR measurement is available, data will be imputed. Imputation rules 
will be specified in the SAP. 
11.3.2.3 Main analysis 
The primary analysis will be performed on the FAS.  
PVR will be summarized by time point and treatment group using descriptive statistics as 
well as geometric means and Coefficients of Variation (CVs). The ratio of Week 12 to 
baseline PVR will be summarized similarly. 
The ratio of Week 12 to baseline PVR will be log-transformed (base e) and analyzed 
using an Analysis of Covariance (ANCOVA) with factors for treatment group 
(macitentan versus placebo), background PAH-specific therapy at baseline, region and a 
covariate for baseline log PVR. The treatment group difference (on log scale) and its 
95% confidence interval will be estimated based on the model. The geometric mean ratio 
(macitentan versus placebo) and its 95% confidence interval will be obtained by 
exponentiation. The null hypothesis will be rejected if the entire 95% confidence interval 
is below one. 
The log transformation for PVR is justified by the fact that ratios versus baseline follow a 
normal distribution more closely after a log transformation. In addition, mean absolute 
changes from baseline on log scale can be translated into (geometric) mean ratios by 
exponentiation.  
The treatment effect will be expressed as (Geometric Mean Ratio [GMR]-1) × 100%, 
where a negative value indicates a reduction of PVR in the macitentan group as compared 
to the placebo group.  
11.3.2.4 Supportive/sensitivity analyses 
A sensitivity analysis will be performed on the FAS where, for patients with a 
post-baseline PVR measurement obtained before Week 12, a model-based imputation 
will be used for the log-transformed PVR: 
• log PVR [at Week 12] = log PVR [at week t<12] + (12-t) × slope where  

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• slope is the expected change from baseline in log PVR based on the main analysis 
model, restricted to patients who had their post-baseline PVR measurement at 
Week 12. 
Another sensitivity analysis will be performed on the PP set that will (at least) be 
restricted to completers, i.e., patients with a Week 12 PVR measurement taken at 
Week 12. 
Additional sensitivity analyses may be specified in the SAP.  
11.3.2.5 Subgroup analyses 
A subgroup analysis for the primary endpoint will be performed for patients with versus 
without PAH-specific therapy at baseline using the ANCOVA model specified in  
Section 11.3.2.3, but without the factor for PAH-specific therapy. 
Another subgroup analysis will be performed by region using the ANCOVA model 
without the factor for region.  
Additional subgroup analyses will be specified in the SAP. Interactions between 
treatment and subgroups will be explored. 
11.3.3 Analysis of the secondary efficacy variable(s) 
Secondary efficacy analyses will be performed on the FAS at α = 0.025 (one-sided) using 
95% confidence intervals. No correction for multiple testing will be applied for these 
analyses. 
Changes from baseline to Week 12 in pressure-volume variables (mRAP, mPAP, CI, 
TPR) and SVO2 will be summarized and analyzed as described in Section 11.3.2.3, but 
without the log-transformation. 
WHO functional class will be summarized by time point and treatment group using 
frequency tables. Changes from baseline in WHO functional class will be dichotomized 
as worsening (i.e., change > 0) versus no change or improvement (i.e., change ≤ 0). 
Worsening will be analyzed using a logistic regression model with covariates for 
treatment group, background PAH-specific therapy at baseline and region. 
6MWD will be summarized by time point and treatment group using descriptive 
statistics. Change from baseline to each time point will be summarized similarly. Change 
from baseline in 6MWD will be analyzed using a repeated measurements model with 
factors for treatment group, time point, treatment by time interaction, background PAH-
specific therapy at baseline and region, and covariates for baseline 6MWD and WHO 
functional class. An unstructured covariance matrix will be used to account for the 
correlation between repeated measurements from the same subject. NT-proBNP will be 
summarized by time point and treatment group using descriptive statistics as well as 

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geometric means and CVs. The ratio of Week 12 to baseline NT-proBNP will be 
summarized similarly. The ratio versus baseline in NT-proBNP will be log-transformed 
and analyzed using an ANCOVA with covariates for treatment group, background PAH-
specific therapy at baseline, region and baseline log NT-proBNP.  
11.3.4 Analysis of the other efficacy variables 
Changes from baseline to Week 12 in HPVG and Borg dyspnea index (related to the 
double-blind treatment period) will be summarized by treatment group in the FAS using 
descriptive statistics. 
Changes from macitentan baseline to each time point in WHO functional class, 6MWD, 
NT-proBNP and Borg dyspnea index (related to the macitentan treatment period) will be 
summarized for the MTS using descriptive statistics. 
11.3.5 Analysis of the safety variables 
The safety analyses described below will be performed on the Safety Set for data from 
the 
double-blind 
treatment 
period. 
For 
these 
analyses 
the 
(double-blind) 
treatment-emergent period is defined from start of double-blind treatment up to the start 
of open-label treatment or 30 days after double-blind treatment discontinuation, 
whichever occurs first. 
The safety analyses will also be performed on the MTS for data from the macitentan 
treatment period. For these analyses, macitentan treatment-emergent is defined as from 
first intake of macitentan up to EOS (i.e., 30 days after discontinuation of macitentan 
treatment). EOMT is defined as EOT-DB or EOT-OL, whichever comes last. Macitentan 
baseline is defined as last assessment prior to intake macitentan. 
All safety data will be listed, with flags for quantitative abnormalities. 
11.3.5.1 Adverse events 
A treatment-emergent AE is any AE temporally associated with the use of a study 
treatment. The number and percentage of patients experiencing treatment emergent AEs 
and SAEs at least once will be tabulated by treatment group and by: 
• 
MedDRA System organ class (SOC) and individual preferred term within each SOC, 
in descending order of incidence. 
• 
Frequency of patients with events coded with the same preferred term, in descending 
order of incidence.  
Furthermore, treatment-emergent AEs and SAEs will be tabulated as described above by 
severity and relationship to study treatment.  

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AEs leading to premature discontinuation of study treatment and death will also be 
summarized as described above.  
Listings will be provided for all reported AEs, including SAEs. In addition, separate 
listings will be provided for SAEs, for AEs leading to premature discontinuation of study 
treatment, and for AEs leading to death. 
11.3.5.2 Laboratory variables 
Descriptive summary statistics by visit and treatment group will be provided for observed 
values and absolute changes from baseline, in both hematology and blood chemistry 
laboratory tests. In order to minimize missing data and to allow for unscheduled visits, all 
recorded assessments up to EOT-DB plus 30 days will be assigned to the most 
appropriate visit time point according to the best fitting time-window for that assessment. 
Actelion internal guidelines will be used for the definitions of marked abnormalities and 
for the standardization of numeric values obtained from different laboratories and/or 
using different normal ranges. Standard numeric laboratory variables are transformed to 
standard units. All laboratory data transferred are taken into account regardless of 
whether they correspond to scheduled (per protocol) or unscheduled assessments.  
Marked laboratory abnormalities will be summarized for each laboratory parameter by 
treatment group providing their incidence and frequency. Absolute values and changes 
from baseline of laboratory parameter values during the course of the study will be 
summarized using the usual location and scale summary statistics by treatment group. 
Laboratory variables are the following: 
• Hematology: hemoglobin, hematocrit, erythrocyte count, leukocyte count with 
differential counts, platelet count, prothrombin time and coagulation tests (PT-INR). 
• Blood chemistry: AST, ALT, alkaline phosphatase, total and direct bilirubin, LDH, 
creatinine, uric acid, glucose, cholesterol, triglycerides, Sodium, potassium, chloride, 
calcium, protein, albumin, GGT, bile acids, and BUN. 
The number and percentage of patients with LFT abnormalities (classified as in  
Section 11.2.4) will be tabulated by treatment group. 
The number and percentage of patients with hemoglobin abnormalities (classified as in 
Section 11.2.4) will be tabulated by treatment group. 
11.3.5.3 Vital signs and body weight  
Blood pressure (i.e., DBP and SBP), HR, and body weight will be summarized for each 
study visit where recorded using the usual location and scale summary statistics by 
treatment group for both absolute values and changes from baseline. Patients for whom 

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no post-baseline value is available are excluded from the analysis of the changes from 
baseline in the Safety Set. 
Changes from baseline in Child-Pugh score and MELD score will be summarized 
similarly as vital signs. 
11.3.6 Analysis of other variables 
See Section 4.3.1 of Appendix 1 for analysis of PK variables. 
11.4 Interim analyses 
No interim analysis is planned for this trial. 
11.5 Sample size 
11.5.1 Sample size justification 
An integrated analysis of two bosentan studies, BENEFIT (AC-052-366) and EARLY 
(AC-052-364), and the hemodynamic substudy of SERAPHIN (AC-055-302) with 
macitentan suggested that the treatment group difference on PVR is expected to be 
around −0.31 on log scale (95% confidence intervals: −0.38, −0.23) and that the within 
group standard deviation (SD) is around 0.41 on log scale (90% confidence 
intervals: 0.39, 0.43). Under these assumptions, 76 evaluable patients will be needed for 
90% power (38 patients per group). Accounting for 10% non-evaluable patients, 
approximately 84 patients will need to be randomized. 
11.5.2 Sample size sensitivity 
Table 2 gives more details about the integrated analysis of PVR. It also shows the ‘best’ 
and ‘worst’ case sample sizes based on the 95% confidence interval around the treatment 
effect for each study as well as for the integrated analysis. It appears that the proposed 
sample size of 84 patients is robust to some deviations from the assumptions given above.  

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Table 2 Treatment effects (differences on log-scale as well as % reduction versus 
placebo), variability in integrated analysis of three studies (AC-052-366, 
AC-052-364 and AC-055-302) and associated sample size for 90% power in 
the PORTICO study. 
Study 
Protocol 
Treatment 
Effect 
95% CI 
of Effect 
SD 
90% CI 
of SD 
Sample 
Size* 
Best 
Case 
Worst 
Case 
EARLY 
AC-052-364 
−0.26 
−23% 
−0.41 
−0.11 
0.50 
0.45 
0.54 
158 
64 
924 
BENEFIT 
AC-052-366 
−0.25 
−22% 
−0.35 
−0.15 
0.32 
0.29 
0.35 
70 
36 
204 
SERAPHIN 
AC-055-302 
−0.45 
−36% 
−0.58 
−0.32 
0.38 
0.35 
0.43 
32 
20 
64 
Overall 
 
−0.31 
−27% 
−0.39 
−0.23 
0.41 
0.39 
0.44 
76 
48 
132 
Corrected for 
Baseline PVR 
 
−0.31 
−26% 
−0.38 
−0.23 
0.41 
0.39 
0.43 
76 
48 
132 
*For 90% power and a two-sided alpha of 5% 
Best case: based on lower limit of 95% CI for effect 
Worst case: based on upper limit of 95% CI for effect 
CI = confidence interval; PVR = pulmonary vascular resistance; SD = standard deviation. 
12 DATA HANDLING 
12.1 Data collection 
The investigator/delegate is responsible to ensure the accuracy, completeness, and 
timeliness of the data reported. All source documents should be completed in a neat, 
legible manner to ensure accurate interpretation of the data. Data reported in the eCRF 
derived from source documents must be consistent with the source documents. 
CRF data will be captured via electronic data capture (EDC using the Rave system 
provided by Medidata Solutions, Inc., a web-based tool). The investigator and site staff 
will be trained to enter and edit the data via a secure network, with secure access features 
(username, password and identification – an electronic password system). A complete 
electronic audit trail will be maintained. The investigator/delegate will approve the data 
(i.e., confirm the accuracy of the data recorded) using an electronic signature (ref. to 
21 CFR Part 11). 
Subject Screening and Enrollment data will be completed for all subjects (i.e., eligible 
and non-eligible) through the IxRS system and eCRF. 
For each subject enrolled, regardless of study treatment initiation, a CRF must be 
completed and signed by the investigator/delegate. This also applies to those subjects 
who fail to complete the study. If a subject withdraws from the study, the reason must be 
noted on the CRF.  

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12.2 Maintenance of data confidentiality 
The investigator/delegate must ensure that data confidentiality is maintained. On CRFs or 
other documents submitted to Actelion, subjects must be identified only by number, and 
never by name or initials, hospital numbers or any other identifier. The 
investigator/delegate must keep a subject identification code list, at the site, showing the 
randomization number, the subject’s name, date of birth and address or any other locally 
accepted identifiers. Documents identifying the subjects (e.g., signed ICFs) must not be 
sent to Actelion, and must be kept in strict confidence by the investigator/delegate. 
12.3 Database management and quality control 
Electronic CRFs will be used for all subjects. The investigator will have access to the site 
CRF data until the database is locked. Thereafter, they will have read-only access. The 
CRF must be kept current to reflect subject status at any time point during the course of 
the study.  
While entering the data, the investigator/delegate will be instantly alerted to data queries 
by validated programmed checks. Additional data review will be performed by Actelion 
on an ongoing basis to look for unexpected patterns in data and study monitoring. If 
discrepant data are detected, a query specifying the problem and requesting clarification 
will be issued and visible to the investigator/delegate via the CRF. All electronic queries 
visible in the system either require a data correction (when applicable) and/or a response 
from the investigator/delegate to clarify the queried data directly in the CRF, or simply a 
data correction in the CRF. The investigator/delegate must, on request, supply Actelion 
with any required background data from the study documentation or clinical records. This 
is particularly important when errors in data transcription are suspected. In the case of 
Health Authority queries, it is also necessary to have access to the complete study 
records, provided that subject confidentiality is protected. 
This process will continue until database closure. 
Laboratory samples will be processed through a central laboratory and the results will be 
sent electronically to Actelion. PK samples will be processed through a bioanalytical 
laboratory and the results will be sent electronically to Actelion.  
After the database has been declared complete and accurate, the database will be closed. 
Any changes to the database after that time may only be made as described in the 
appropriate SOP. After database closure, the investigator will receive the CRF of the 
subjects of her/his site (including all data changes made) on electronic media or as a 
paper copy. 

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13 PROCEDURES AND GOOD CLINICAL PRACTICE 
13.1 Ethics and Good Clinical Practice 
Actelion and the investigators will ensure that the study is conducted in full compliance 
with ICH-GCP Guidelines, the principles of the “Declaration of Helsinki” and with the 
laws and regulations of the country in which the research is conducted.  
13.2 Independent Ethics Committee / Institutional Review Board 
The investigator will submit this protocol and any related document provided to the 
subject (such as Subject Information Leaflet used to obtain informed consent) to an IRB 
or IEC. Approval from the committee must be obtained before starting the study, and 
must be documented in a dated letter to the investigator, clearly identifying the study, the 
documents reviewed, and the date of approval.  
Modifications made to the protocol after receipt of the approval must also be submitted as 
amendments by the investigator to the IRB/IEC in accordance with local procedures and 
regulations [see Section 13.6]. 
A list of members participating in the IRB/IEC meetings must be provided, including the 
names, qualifications and functions of these members. If that is not possible, the attempts 
made to obtain this information along with an explanation as to why it cannot be obtained 
or disclosed must be documented in the study documentation. If a study staff member 
was present during a meeting, it must be clear that this person did not vote. 
13.3 Informed consent 
It is the responsibility of the investigator/delegate to obtain informed consent according 
to ICH-GCP guidelines and local regulations from each individual participating in this 
study and/or legal representative. The investigator/delegate must explain to subjects that 
they are completely free to refuse to enter the study, or to withdraw from it at any time 
for any reason. 
The ICF will be provided in the country local language(s). 
Site staff authorized to participate to the consent process and/or to obtain consent from 
the subject and/or legal representative will be listed on Actelion Delegation of Authority 
form. A study physician must always be involved in the consent process.  
The subject and/or legal representative must sign, personally date and time (if 
appropriate) the ICF before any study-related procedures (i.e., any procedures required by 
the protocol) begin. The ICF must also be signed, personally dated and timed (if 
appropriate) by the authorized site staff listed on Actelion Delegation of Authority form. 

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A copy of the signed and dated ICF is given to the subject and/or legal representative; the 
original is filed in the site documentation.  
The informed consent process must be fully documented in the subject’s medical records, 
including study reference, subject number, date/time (if applicable) when the subject was 
first introduced to Actelion clinical study, date/time (if applicable) of consent, who 
participated in the consent discussion, who consented the subject and any additional 
person present during the consent process (e.g., subject family member), copy of the 
signed ICF given to the subject / legal representative. 
In the case that the site would like to recruit a subject who would be considered as 
vulnerable (e.g., subject cannot read or write, does not speak or understand the ICF 
language), additional measures must be implemented in order to ensure subject rights are 
respected and the consent obtained is legally valid. Actelion, the regulatory authorities (if 
applicable) and the IRB/IEC must be informed prior to the recruitment. The consent 
process (e.g., involvement of an impartial witness) must be fully described, submitted to, 
and approved by the IRB/IEC, according to procedures and before subjects are recruited.  
13.4 Compensation to subjects and investigators 
Actelion provides insurance in order to indemnify (with both legal and financial 
coverage) the investigator/site against claims arising from the study, except for claims 
that arise from malpractice and/or negligence. 
The compensation of the subject in the event of study-related injuries will comply with 
applicable regulations. 
13.5 Protocol adherence/compliance 
The investigator must conduct the study in compliance with the approved version of the 
protocol and must not implement any deviation/change from the protocol, except when 
the change involves only logistical or administrative aspects (e.g., change in telephone 
number), or in case it would be necessary to eliminate an immediate hazard to the 
subject.  
If a protocol deviation occurs, the investigator/delegate will inform Actelion or its 
representative, in a timely manner. The investigator/delegate must document and explain 
any deviation from the approved protocol. IRB/IEC and regulatory authorities must be 
informed, according to their requirements, but no later than 15 calendar days after the 
event. 

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13.6 Protocol amendments 
Any change to the protocol can only be made through a written protocol amendment. A 
protocol amendment must be submitted to IRB/IEC, and regulatory authorities, according 
to their requirements. 
13.7 Essential documents and retention of documents 
The investigator/delegate must maintain adequate records necessary for the 
reconstruction and evaluation of the study. A number of attributes are considered of 
universal importance to source data and the records that hold those data. These include 
that the data and records are accurate, legible, contemporaneous, original (or certified 
copy), attributable, complete, consistent, enduring and available when needed. 
These records are to be classified into two different categories of documents: 
investigator’s file, and subject clinical source documents.  
These records must be kept by the investigator for as long as is necessary to comply with 
Actelion’s requirements (e.g., as specified in the clinical study agreement), and national 
and/or international regulations, whichever would be the longest period. If the 
investigator cannot guarantee this archiving requirement at the investigational site for any 
or all of the documents, special arrangements, respecting the data confidentiality, must be 
made between the investigator and Actelion to store these documents outside the site, so 
that they can be retrieved in case of a regulatory inspection. No study document should 
be destroyed without prior written approval from Actelion. Should the investigator wish 
to assign the study records to another party, or move them to another location, Actelion 
must be notified in advance.  
If the site is using an electronic/computerized system to store subject medical records, it 
can be used for the purpose of the clinical study if it is validated (as per 21 CFR Part 11 
or equivalent standard) and if the monitor has been provided personal and restricted 
access to study subjects only, to verify consistency between electronic source data and 
the CRF during monitoring visits. 
If the site is using an electronic/computerized system to store subject medical records but 
it could not be confirmed that the system is validated or if the monitor could not be 
provided access to the system, the site is requested to print the complete set of source 
data needed for verification by the monitor. The print-outs must be numbered, stapled 
together with a coversheet, signed and dated by the investigator/delegate to confirm that 
these certified copies are exact copies having the same information as the original 
subject’s data. The printouts will be considered as the official clinical study records.  
In order to verify that the process the site uses to prepare certified copies is reliable, the 
monitor must be able to observe this process and confirm that the comparison of the 

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source documents and the certified copy did not reveal inconsistencies. The monitor does 
not need to verify this process for all data of all subjects but at least for some of them 
(e.g., first subject; regular check during the study of critical data like inclusion/exclusion 
criteria, endpoints for some subjects) as per Actelion’s instructions. If it were not possible 
for the monitor to observe this process, it would not be possible to rely on the site’s 
certified copies and therefore the site cannot be selected for the clinical study. The 
printouts should be filed either with the subject medical records or with the subject’s 
CRF. 
13.8 Monitoring 
Prior to study start, a site initiation visit (SIV) will be performed after the required 
essential study documents are approved by Actelion. The study treatment will be shipped 
to the site upon approval of the required essential documents.  
The principal investigator must ensure that all site personnel involved in the study will be 
present during the SIV and will dedicate enough time to it. Site Information Technology 
support should also be available during the initiation visit.  
The SIV must be completed before the site can start the screening of study subjects. 
Following the SIV, a copy of the completed initiation visit report and follow-up letter 
will be provided to the principal investigator and filed in the ISF. 
During the study, the monitor will contact and visit the investigational site regularly, and 
on request must be permitted to have access to trial facilities and all source documents 
needed to verify adherence to the protocol and the completeness, consistency and 
accuracy of the data being entered in the CRFs and other protocol-related documents. 
Actelion monitoring standards require full verification that informed consent has been 
provided, and verification of adherence to the inclusion/exclusion criteria, documentation 
of SAEs, and the recording of the main efficacy, safety and tolerability endpoints. 
Additional checks of the consistency of the source data with the CRFs will be performed 
according to the study-specific monitoring plan. The frequency of the monitoring visits 
will be based on subject recruitment rate and critical data collection times. 
The principal investigator must ensure that the CRF is completed after a subject’s visit to 
the site, and that all requested subject files (e.g., ICFs, medical notes/charts, other 
documentation verifying the activities conducted for the study) are available for review 
by the monitor. The required site personnel must be available during monitoring visits 
and allow adequate time to meet with the monitor to discuss study related issues.  
The investigator agrees to cooperate with the monitor(s) to ensure that any issues 
detected in the course of these monitoring visits are resolved. If the subject is hospitalized 

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or dies in a hospital other than the study site, the investigator is responsible for contacting 
that hospital in order to document the SAE, in accordance with local regulations. 
A close-out visit will be performed for any initiated site and when there are no more 
active subjects and after all study data have been accepted by medical review and all 
follow-up issues have been resolved. In case a site does not enroll any subjects, the 
close-out visit may be performed prior to study database closure at the discretion of 
Actelion. 
13.9 Investigator site file 
Each site will be provided with an ISF prior to the initiation visit. It will contain all the 
essential documents that are required to always be up-to-date and filed at site as per ICH 
GCP section 8. 
The ISF will include a table of content listing the essential documents. All study related 
documentation must be maintained in the ISF. 
In some cases, exceptions can be discussed with the monitor regarding the filing of the 
study documents outside the ISF. It should be clearly documented where each document 
is filed. This note to file should be present in the specific tab of the document in the ISF. 
The ISF must be stored in a secure and access-restricted area during and after the study. It 
must be kept by the site for as long as needed to comply with any applicable rules and 
regulations, ICH GCP as well as instructions from Actelion. If the site needs to transfer 
the ISF to another location and/or if site facility can no longer store the ISF, the principal 
investigator must inform Actelion immediately.  
If the principal investigator changes, or if the site relocates, the monitor must be notified 
as soon as possible.  
13.10 Audit 
Actelion’s Global Quality Management representatives may audit the investigator site 
(during the study or after its completion). The purpose of this visit will be to determine 
the investigator’s adherence to ICH-GCP, the protocol, and applicable regulations; 
adherence to Actelion’s requirements (e.g., SOPs) will also be verified. Prior to initiating 
this audit, the investigator will be contacted by Actelion to arrange a time for the audit.  
The investigator and staff must cooperate with the auditor(s) and allow access to all study 
documentation (e.g., subject records) and facilities. 
13.11 Inspections 
Health Authorities and/or IRB/IEC may also wish to conduct an inspection of Actelion’s 
clinical study (during the study or after its completion).  

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Should an inspection be requested by a Health Authority and/or IRB/IEC, the investigator 
must inform Actelion immediately, (usually via the CRA), that such a request has been 
made.  
The investigator and staff must cooperate with inspector(s) and allow access to all study 
documentation (e.g., subject records) and study facilities. 
13.12 Reporting of study results and publication  
Study results will be documented in a clinical study report that will be signed by Actelion 
representatives and the coordinating investigator (or principal investigator for 
single-center studies). 
The coordinating investigator and the Steering Committee, if any, will have the 
opportunity to review the analysis of the data and to discuss the interpretation of the 
study results with Actelion prior to publication. 
Actelion will post results from its clinical studies on Actelion’s Clinical Trial Register, 
and on external/national registries, as required by law. 
Actelion’s Policy on Disclosure of Clinical Research Information can be found at:  
http://www.actelion.com/documents/corporate/policies-charters/policy-scientific-
publications.pdf 
In accordance with the Good Publication Practices and ethical practice, the results of the 
study will be submitted for publication in a peer-reviewed journal. Study results can be 
submitted for presentation at a congress before publication in a peer-reviewed journal. 
Authorship will be determined in accordance with the International Committee of Journal 
Editors (ICMJE) criteria, and be based on: 
• substantial contributions to: the conception or design of the study, or the acquisition, 
analysis or interpretation of data; and 
• drafting of the publication or critical review for important intellectual content; and  
• providing final approval of the version to be published; and 
• agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.  
The list of authors of any publication of study results may include representatives of 
Actelion, and will be determined by mutual agreement. 
Any study-related publication written independently by investigators must be submitted 
to Actelion for review at least 30 days prior to submission for publication or presentation. 
Upon review, Actelion may provide comments, and may also request alterations and/or 

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deletions for the sole purpose of protecting its confidential information and/or patent 
rights. Neither the institution nor the investigator should permit publication during such a 
review period. 
Actelion’s Policy on Scientific Publications can be found at: 
http://www.actelion.com/documents/corporate/policies-charters/policy-scientific-
publications.pdf 

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14 REFERENCES 
[Al-Naamani 2013] Al-Naamani N, Roberts K. Portopulmonary hypertension. Clin Chest 
Med 2013;34:719-737. 
[ATS Statement 2002] Guidelines for the Six-Minute Walk Test. Am J Respir Crit Care 
Med 2002;166:111-7. 
[Benigni 1995] Benigni A. Defining the role of endothelins in renal pathophysiology on 
the basis of selective and unselective endothelin receptor antagonist studies. Curr 
Opin Nephrol Hypertens 1995;4:349-53.  
[Benza 2010] Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, 
Coffey CS, et al. Predicting survival in pulmonary arterial hypertension: insights 
from the Registry to Evaluate Early and Long-Term Pulmonary Arterial 
Hypertension Disease Management (REVEAL). Circulation 2010;122:164-72.  
[Cartin-Ceba 2011] Cartin-Ceba R, Swanson K, Iyer V, Wiesner RH, Krowka MJ. Safety 
and efficacy of ambrisentan for the treatment of portopulmonary hypertension. 
Chest 2011 Jan;139:109-14.  
[Cartin-Ceba 2014] Cartin-Ceba R, Krowka M.J. Portopulmonary hypertension. Clin 
Liver Dis 2014;18:421-438. 
[Chua 1992] Chua B, Krebs CT, Chua CC, et al. Endothelin stimulates protein synthesis 
in smooth muscle cells. Am J Physiol 1992;262:E412-6. 
[Clarke 1989] Clarke J, Benjamin N, Larkin W, et al. Endothelin is a potent long lasting 
vasoconstrictor in men. Am J Physiol 1989;257:H2033-5. 
[Colle 2003] Colle IO, Moreau R, Godinho E, Belghiti J, Ettori F, Cohen-Solal A, et al. 
Diagnosis of portopulmonary hypertension in candidates for liver transplantation: 
a prospective study. Hepatology 2003;37:401-9. 
[Condliffe 2014] Condliffe R, Elliot CA, Hurdman J, Sabroe I, Billings C, Kiely DG, 
Hamilton N. Ambrisentan therapy in pulmonary hypertension: clinical use and 
tolerability in a referral centre. Ther Adv Respir Dis 2014;8:71-77.  
[Davie 2002] Davie N, Haleen SJ, Upton PD, et al. ETA and ETB receptors modulate the 
proliferation of human pulmonary artery smooth muscle cells. Am J Respir Crit 
Care Med 2002;165:398-405. 
[de Nucci 1988] de Nucci G, Thomas R, D’Orleans-Juste P, et al. Pressor effects of 
circulating endothelin are limited by its removal in the pulmonary circulating 
endothelin are limited by its removal in the pulmonary circulation and by the 
release of prostacyclin-derived relaxing factor. Proc Natl Acad Sci U S A 1988; 
85:9797-800.  

Macitentan / ACT-064992 
Portopulmonary hypertension 
Protocol AC-055-404 
Version 3 
21 April 2016, page 96/115 
Confidential 
EudraCT 2014-004624-21 
Doc No D-16.102 
 
[Galiè 2004] Galiè N, Manes A, Branzi A. The endothelin system in pulmonary arterial 
hypertension. Cardiovasc Res 2004;61:227-37.  
[Ghofrani 2013] Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, 
et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J 
Med 2013;369:330-40.  
[Giaid 1993]. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in 
the lungs of patients with pulmonary hypertension. N Engl J Med. 1993;328: 
1732–9.  
[Golbin 2007] Golbin JM, Krowka MJ. Portopulmonary hypertension. Clin Chest 
Med 2007;28:203-218. 
[Gough 2009] Gough MS, White RJ. Sildenafil therapy is associated with improved 
hemodynamics in liver transplantation candidates with pulmonary arterial 
hypertension. Liver Transpl 2009 Jan;15:30-6.  
[Halank 2006] Halank M, Ewert R, Seyfarth H-J, Höffken G. Portopulmonary 
hypertension. J Gastroenterol 2006;41:1133. 
[Halank 2011] Halank M, Knudsen L, Seyfarth H-J, Ewert R, Wiedemann B, Kolditz M, 
et al. Ambrisentan improves exercise capacity and symptoms in patients with 
portopulmonary hypertension. Z Gastroenterol 2011;49:1258-1262. 
[Hemnes 2009] Hemnes AR, Robbins IM. Sildenafil monotherapy in portopulmonary 
hypertension can facilitate liver transplantation. Liver Transpl 2009 Jan;15:15-9. 
[Hirata 1993] Hirata Y, Emori T, Eguchi S. Endothelin receptor subtype B mediates 
synthesis of nitric oxide by cultured bovine endothelial cells. J Clin Invest 1993; 
91:1367-73.  
[Hoeper 2005] Hoeper MM, Halank M, Marx C, Hoeffken G, Seyfarth HJ, Schauer J, et 
al. Bosentan therapy for portopulmonary hypertension. Eur Respir J 2005;25: 
502-508.  
[Hoeper 2007] Hoeper MM, Seyfarth HJ, Hoeffken G, Wirtz H, Spiekerkoetter E, Pletz 
MW, et al. Experience with inhaled iloprost and bosentan in portopulmonary 
hypertension. Eur Respir J. 2007;30:1096-102. 
[Hollatz 2012] Hollatz TJ, Musat A, Westphal S, Decker C, D’Alessandro AM, Keevil J, 
et al. Treatment with sildenafil and treprostinil allows successful liver 
transplantation of patients with moderate to severe portopulmonary hypertension. 
Liver Transpl 2012 Jun;18:686-95.  

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[Humbert 2006] Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, et 
al. Pulmonary arterial hypertension in France: results from a national registry. Am 
J Respir Crit Care Med 2006;173:1023-30. 
[Krowka 2006] Krowka MJ, Swanson KL, Frantz RP, McGoon MD, Wiesner RH. 
Portopulmonary hypertension: Results from a 10-year screening algorithm. 
Hepatology 2006. 44:1502-10. 
[Krowka 2012] Krowka MJ, Miller DP, Barst RJ, Taichman D, Dweik RA, Badesch 
DB, McGoon MD. Portopulmonary hypertension: A report from the US-based 
REVEAL Registry. CHEST 2012;141:906-915. 
[Le Pavec 2008] Le Pavec J, Souza R, Herve P, Lebrec D, Savale L, Tcherakian C, et al. 
Portopulmonary hypertension: survival and prognostic factors. Am J Respir Crit 
Care Med 2008;178:637-643. 
[Macitentan IB] Investigator’s Brochure. Macitentan ACT-064992. Endothelin receptor 
antagonist, Version 12. Actelion Pharmaceuticals Ltd, November 2014. 
[Massaki 1998] Massaki T. The discovery of endothelins. Cardiovasc Res 1998;39: 
530-533.  
[Pulido 2013] Pulido T, Adzerikho I, Channick RN, Delcroix M, Galiè N, Ghofrani A. 
Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension. N 
Engl J Med 2013;369:809-18.  
[Ramsay 1997] Ramsay MA, Simpson BR, Nguyen AT, Ramsay KJ, East C, Klintmalm 
GB. Severe pulmonary hypertension in liver transplant candidates. Liver Transpl 
Surg 1997;3:494-500. 
[Reichenberger 2006] Reichenberger F, Voswinckel R, Steveling E, Enke B, Kreckel A, 
Olschewski H, et al. Sildenafil treatment for portopulmonary hypertension. Eur 
Respir J 2006;28:563-567.  
[Robalino 1991] Robalino BD, Moodie DS. Association between primary pulmonary 
hypertension and portal hypertension: analysis of its pathophysiology and clinical, 
laboratory and hemodynamic manifestations. J Am Coll Cardiol 1991;17:492-8. 
[Rodriguez-Roisin 2004] Rodríguez-Roisin R1, Krowka MJ, Hervé P, Fallon MB; ERS 
Task Force Pulmonary-Hepatic Vascular Disorders (PHD) Scientific Committee. 
Pulmonary-Hepatic vascular Disorders (PHD). Eur Respir J 2004;24:861-880. 
[Safdar 2012] Safdar Z, Bartolome S, Sussman N. Portopulmonary hypertension: An 
update. Liver Transpl 2012;18:881-891. 

Macitentan / ACT-064992 
Portopulmonary hypertension 
Protocol AC-055-404 
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Doc No D-16.102 
 
[Sakai 2009] Sakai T, Planinsic RM, Mathier MA, de Vera ME, Venkataramanan R. 
Initial experience using continuous intravenous treprostinil to manage pulmonary 
arterial hypertension in patients with end-stage liver disease. Transpl Int 2009;22: 
554-561.  
[Savale 2013] Savale L, Magnier R, Le Pavec J, Jaïs X, Montani D, O’Callaghan DS, et 
al. Efficacy, safety and pharmacokinetics of bosentan in portopulmonary 
hypertension. Eur Respir J 2013;41:96-103. 
[Simmoneau 2013] Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, 
Ghofrani A. Updated Clinical Classification of Pulmonary Hypertension. J Am 
Coll Cardiol 2013;62:D34-41. 
[Stewart 1991] Stewart DJ, Levy RD, Cernacek P, et al. Increased plasma endothelin-1 in 
pulmonary hypertension: marker or mediator of disease? Ann Intern Med 1991; 
114:464-9. 
[Sugawara 1996] Sugawara F, Ninomiya H, Okamoto Y, et al. Endothelin-1-
inducedmitogenic responses of Chinese hamster ovary expressing human 
endothelin A: the role of a wortmanninsensitive signalling pathway. Molec 
Pharmacol 1996; 49:447-57.  
[Wright 2009] Wright G, Porcari JP, Foster CC, et al. Placebo effects on exercise 
performance. Gundersen Lutheren Medical Journal 2009; Volume 6, Number 1. 
 
 

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15 APPENDICES 
Appendix 1  
PORTICO PK substudy 
1 
STUDY OBJECTIVES 
This substudy aims to assess the pharmacokinetics (PK) of macitentan and its metabolite 
ACT-132577 in patients with portopulmonary hypertension from the PORTICO study.  
2 
INVESTIGATIONAL PLAN 
2.1 
Overall study design and plan 
This PORTICO PK substudy is a prospective, multicenter, open-label, single-arm study 
including at least 20 patients that are on steady-state treatment with macitentan in the 
open-label period of the AC-055-404/PORTICO study. The substudy will be conducted 
in consenting patients from all centers who agree to participate and in all regions.  
The study will consist of the following periods: 
• Screening period: 
A Screening visit will be scheduled within 28 days before enrollment into the PK 
substudy. At this visit the study will be discussed with the patient and the Informed 
Consent Form will be signed. 
• PK assessments period: 
PK assessments will be performed after open-label study treatment for the  
AC-055-404/PORTICO study has been taken for at least 4 weeks. The substudy may be 
performed on or at any time between the scheduled Visit 6 and Visit 7 of the 
OL treatment period. The PORTICO PK substudy will consist of two visits (Day 1 and 
Day 2). On the first study day of the PORTICO PK substudy (Day 1), eligibility will be 
checked before start of assessments. Following the check, a pre-dose blood sample will 
be drawn (preferably before 10.00 am). 
On Day 1, the study treatment, one 10 mg tablet of macitentan, will be taken directly 
after the morning pre-dose blood sample. Following this, the patient will be considered 
enrolled into the PORTICO PK substudy. Blood samples for PK will then be drawn at 
specified time points after study treatment administration over a 24-hour time period as 
presented in Figure 2. In order to ensure timely blood sampling, patients may be offered 
an overnight stay at the clinic or sampling may be performed local to the patient’s home. 
The last PK blood sample will be drawn 24 hours after study treatment intake on Day 1. 
Study treatment intake on Day 2 must only occur after this last blood draw, which 
concludes the PORTICO PK substudy.  

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Version 3 
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Figure 2 
PK substudy design 
 
2.2 
Study population 
2.2.1 Patient population 
The patient population will consist of patients who are participating in the open-label 
period of the AC-055-404/PORTICO study and have received the open-label study 
treatment (10 mg of macitentan, once daily oral dose) for at least 4 weeks. 
2.2.2 Inclusion criteria 
• Signed Informed Consent Form prior to initiation of any study-mandated procedure. 
• Patients participating in the open-label period of the AC-055-404/PORTICO study 
and having received the open-label study treatment for at least 4 weeks. 
• Pre-dose PK blood sampling done prior to study medication on Day 1. 
2.2.3 Exclusion criteria 
• Clinical instability during the week prior to enrollment into the substudy. 
• Ongoing renal failure or dialysis. 
• Arm veins unsuitable for i.v. puncture. 
2.2.4 Concomitant medications 
All other concomitant medications are allowed, but must be kept stable for at least one 
week prior to enrollment on Day 1 and during the 24 hours of PK sampling. 
2.2.4.1 Prohibited concomitant medications 
All prohibited concomitant medications are listed in Section 5.2.4 of the 
AC-055-404/PORTICO study protocol. 

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2.3 
Study treatment 
The study treatment is macitentan, 10 mg provided for the AC-055-404/PORTICO study.  
2.3.1 Treatment dose and administration 
Patients can only be enrolled if the study treatment for the AC-055-404/PORTICO study 
was continuously taken for at least 4 weeks during the open-label period. On Day 1 of the 
PORTICO PK substudy, the study treatment will be taken directly after the pre-dose 
blood sample. On Day 2 study treatment will be taken after the last (24 h) PK blood 
sample was drawn. If the study treatment intake during the PK sampling days is 
performed at the clinic, patients must bring at least two tablets when visiting the site on 
Day 1. The study treatment intake on Day 1 and Day 2 must be observed by the 
investigator / study coordinator / phlebotomist and the date and exact times will be 
recorded in the electronic Case Report Form (eCRF). 
2.3.2 Pharmacokinetic and pharmacodynamic endpoints 
Plasma PK variables of ACT-132577 and metabolites will be derived by 
noncompartmental analysis of the plasma concentration-time profiles. 
PK endpoints for both macitentan and ACT-132577:  
• The area under the plasma concentration-time curve during one dosing interval 
(AUCτ). 
• Maximum plasma concentration (Cmax) during a dosing interval. 
• The time to reach maximum plasma concentration (tmax) during a dosing interval. 
2.3.2.1 Calculation of PK endpoints and assumptions 
The PK endpoints will be derived as follows: 
• The measured individual plasma concentrations of macitentan and its metabolite, 
ACT-132577 will be used to directly obtain Cmax and tmax. 
• AUCτ will be calculated according to the linear trapezoidal rule using the measured 
concentration-time values above the limit of quantification (LOQ) during one dosing 
interval. 
• The PK variables will be calculated on the basis of the real (actual) blood sampling 
time points.  
All areas under plasma concentration-time curves (AUC) and Cmax values are assumed to 
be log-normally distributed. Depending on the data obtained compartmental models may 
be used. 

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2.4 
Study assessments 
2.4.1 Pharmacokinetic and pharmacodynamic assessments 
2.4.1.1 Timing for sampling 
If applicable, patients should arrive at the clinic on Day 1 so that the pre-dose sample can 
be drawn before 10.00 a.m. 
For the PK assessment the blood samples must be drawn at the following time points: 
Day 1: Immediately before administration of the dose of study treatment in the morning 
(pre-dose) and 1 h, 3 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 12 h, and 14 h post-dose. 
Day 2: 24 h post-dose. 
2.4.1.2 Procedures for sampling 
Approximately 2 mL of blood will be collected in tubes containing ethylene diamine K3 
tetra-acetic acid via an i.v. catheter placed in an antecubital vein in the arm. The 
indwelling catheter will be kept patent (e.g. by insertion of a mandrin), which will be 
changed after each blood sampling. Immediately following collection of the required 
blood volume, the tubes will be slowly tilted backwards and forwards (no shaking) to 
bring the anti-coagulant into solution, and immediately cooled on ice.  
Within 30 minutes of collection, the tubes will be centrifuged at approximately 1500 × g 
for 10 minutes at 2–8 °C. When a centrifuge that can be cooled is not available, the blood 
samples and the bucket of the centrifuge must be cooled on ice prior to centrifugation. 
Following centrifugation, the plasma will be transferred into one labeled polypropylene 
tube. All samples will be stored in an upright position at −20 °C. The date and exact 
actual clock time of each blood sample draw will be entered into the eCRF. 
2.4.1.3 Labeling 
The tubes and labels for the samples will be provided to the investigator and/or site staff. 
The labeling will comply with the applicable laws and regulations of the countries in 
which this substudy is conducted. 
2.4.1.4 Bioanalysis 
The concentrations of macitentan and its metabolite ACT-132577 in plasma will be 
determined using a validated liquid chromatography coupled to mass spectrometry 
method. The foreseen LOQ in plasma for macitentan and ACT-132577 is 1 ng/mL. The 
concentrations will be calculated by interpolation from the calibration curve. Quality 
control samples will be analyzed throughout the study. Their measured concentrations 
will be used to determine between-run and overall precision and accuracy of the analysis. 

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2.4.1.5 Shipping procedures 
The investigator and/or site staff are responsible for shipment of the samples. Samples 
must be sent from the site to the central laboratory 
 using an appropriate courier 
service at time intervals specified in laboratory guidelines. The central laboratory will 
organize the shipment of PK plasma samples to 
 at Actelion 
Pharmaceuticals Ltd 
 at time intervals agreed with the 
sponsor. The plasma samples must be temperature controlled, tracked and packed 
securely with the completed shipment forms in polystyrene-insulated shipping containers 
together with enough dry ice to last for 48 hours. 
2.4.1.6 Total blood volume 
The total blood volume to be taken for the PK assessments will be approximately 
12 × 2 mL = 24 mL 
2.5 
Assessment schedule 
Figure 2 provides an overview of the chronological sequence of the assessments. 
3 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
For a detailed description of the safety definitions and reporting requirements, refer to 
Section 10 of the AC-055-404/PORTICO protocol. 
All AEs occurring from screening period to the 24-hour time point (Day 2) will be 
reported as AEs in the AC-055-404/PORTICO CRF and will be analyzed and reported in 
the context of the AC-055-404/PORTICO study. 
4 
STATISTICAL METHODOLOGY AND ANALYSES 
4.1 
Statistical Analysis Plan 
A SAP will be written and finalized before database closure. The SAP will provide full 
details of the analyses (including PK), data displays, and algorithms to be used for data 
derivations.  
The SAP will include the definition of major and minor protocol deviations and the link 
between major protocol deviations and the analysis sets.  
Major and minor protocol deviations will be identified by medically trained staff before 
study closure.  

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4.2 
Analysis sets 
The PK analysis will be performed on the PK set.  
This analysis set comprises all patients who did not deviate from the protocol in a way 
that might affect the evaluation of the PK endpoints. 
4.3 
Pharmacokinetic analysis 
4.3.1 Pharmacokinetic statistical analysis and endpoint display 
Individual plasma concentration-time data will be listed by patient. The individual and 
mean plasma concentration-time profiles will be plotted on a linear scale. 
The derived PK variables for macitentan and ACT-132577 (AUCτ, Cmax, and tmax) will be 
listed by patient.  
For mean value calculations, all values below the LOQ (below the limit of quantification 
[BLQ] values) will be set to zero if ≤ 50% of the values at a given time point are BLQ. If 
> 50% of the values at a given time point are BLQ, no mean value will be calculated. 
Mean concentration-time profiles will be generated using these criteria. 
Plasma concentrations per time point will be summarized using arithmetic mean, 
minimum, median, maximum, standard deviation (SD), standard error (SE), and 
two-sided 95% confidence interval of the mean. 
AUCτ, Cmax, tmax * will be summarized with arithmetic mean, geometric mean, minimum, 
median, maximum, SD, SE, CVb in %, and 95% confidence interval of the arithmetic and 
geometric means. 
(* For tmax the geometric mean and its 95% confidence interval will not be calculated). 

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Version 3 
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Appendix 2 
Child-Pugh, MELD, and hepatic encephalopathy scales in 
classification of liver disease 
1) Child-Pugh Classification 
The Child-Pugh classification will be used for assessing the severity of the liver 
disease according to the following criteria: 
Score 
Bilirubin 
 
(mg/dL) 
Albumin 
 
(g/dL) 
Prothrombin 
time 
 
(sec prolonged) 
Ascites 
 
(grade) 
Encephalopathy 
 
(grade) 
1 
< 2 
> 3.5 
< 4 
Absent 
None 
2 
2–3 
2.8–3.5 
4–6 
Slight 
1–2 
3 
> 3 
< 2.8 
> 6 
Moderate 
3–4 
Child-Pugh class: 
A (mild): 5–6; 
B (moderate): 7–9; 
C (severe): ≥ 10 
2) MELD Score 
The MELD score is calculated using the following formula:  
MELD Score = 0.957 × Loge(creatinine mg/dL) + 0.378 × Loge(bilirubin mg/dL) + 
1.120 × Loge(INR) + 0.6431  
Multiply the score by 10 and round to the nearest whole number.  
• 
Laboratory values less than 1.0 are set to 1.0 for the purposes of the MELD score 
calculation. The maximum serum creatinine considered within the MELD score 
equation is 4.0 mg/dL.  
• 
If subject had dialysis twice within a week prior to the serum creatinine test then the 
MELD score will be calculated with a serum creatinine value of 4.0 mg/dL.  
3) Hepatic encephalopathy grades are defined in the table below. 
 
Grade 0 
Normal consciousness, personality, neurological examination, electroencephalogram 
Grade 1 
Restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps 
waves 
Grade 2 
Lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves 
Grade 3 
Somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves 
Grade 4 
Unrousable coma, no personality/behavior, decerebrated, slow 2–3 cps delta activity 
 

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Appendix 3 
Actelion guidelines for 6MWT 
The American Thoracic Society (ATS) published an official statement on the 6-minute 
walk test (6MWT) in 2002 [ATS Statement 2002]. Only a brief summary of these 
guidelines is included here. 
• The 6MWT should be performed indoors, along a long, flat, straight, enclosed 
corridor with a hard surface that is seldom traveled. The use of 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-meter lap, should be marked on the floor using brightly colored tape. Any 
deviation from this should be approved in written form by Actelion before 
implementation. 
• The study staff member administering the 6MWT should stand near the starting line 
during the test and must not walk with the patient! Intermittent rest periods are 
allowed if the patient can no longer continue. If the patient 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 patient complains of having chest pain, intolerable dyspnea, leg cramps, or has a 
pale or ashen appearance. 
• The 6MWT is a non-encouraged test. No instructions or encouragement will be given 
during the test. Eye contact and body language signaling the patient to speed up 
should be avoided during the test. 
• For an individual patient, repeat testing should always be conducted, if possible, by 
the same tester, at the same location, and preferably at about the same time of the day 
to minimize variability. 
Required equipment: 
• 
Countdown timer (or stop watch) 
• 
Mechanical lap counter 
• 
Two small cones for the turnaround points 
• 
A chair that can be easily moved along the walking course 
• 
Worksheets on a clipboard 
• 
Sphygmomanometer 
• 
Automated electronic defibrillator 
• 
Source of oxygen 

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Patient preparation 
• The patient should wear comfortable clothing and appropriate walking shoes. 
• The meals preceding the test should be light, and the patient should not have 
exercised vigorously within 2 hours of beginning the test. 
• The patient should sit at rest for at least 10 minutes before the test starts. 
• Patients should receive their usual medication on the day of the test. If the patient is 
used to taking bronchodilators before a walk, he/she should take them 5–30 minutes 
before the test. 
• For patients receiving continuous 24-hour oxygen therapy, it is recommended that the 
flow rate remains constant for the duration of the study. However, from one hour 
prior to and until the completion of the 6MWT, the flow rate must remain constant. 
Measurement of the 6MWD/6MWT – Instructions to the patient 
The person administering the test will use the following exact dialogue with the patient: 
“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 patient, the person administering the test will 
then ask: 
“Do you have any questions about the test?” 
“Please explain what you are going to do.” 
“Are you ready?” 
“Start now, or whenever you are ready.” 

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As soon as the patient starts to walk, the tester will start the timer and write down start 
time. 
The tester will tell the patient 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 patient, marks the spot where the patient stopped, records the 
total distance walked in the worksheet and congratulates the patient on good effort. 
 

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Version 3 
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Appendix 4 
Borg dyspnea index 
Borg rating 
Perceived exertion 
0 
0.5 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Nothing at all 
Very, very slight (just noticeable) 
Very slight 
Slight (light) 
Moderate 
Somewhat severe 
Severe (heavy) 
 
Very severe 
 
 
Very, very severe (maximal) 
 

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Version 3 
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Appendix 5 
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. 
 

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Version 3 
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Appendix 6 
Laboratory abnormalities 
 
Laboratory abnormalities according to the most updated version of CTCAE. A marked 
abnormality is defined based on the following list (SI units). 
 
 
 
Parameter 
LL 
LLL 
HH 
HHH 
HHHH 
Hemoglobin (g/L) 
< 100 
< 80 
Increase in 
(> 20 g/L above 
ULN) or above 
baseline if baseline 
is above ULN 
Increase in 
(> 40 g/L 
above ULN) or 
above baseline 
if baseline is 
above ULN 
Hematocrit 
< 28% 
for 
females 
< 32% 
for 
males 
< 20% 
> 60% in men 
> 55% in women 
> 65% 
Platelet count 
(109 /L) 
< 75 
< 25 
> 600 
> 999 
Leucocytes 
(× 109 /L) 
< 3.0 
< 2.0 
> 20.0 
> 100.0 
Neutrophils 
(109 /L) 
< 1.5 
< 1.0 
NA 
NA 
Eosinophils 
> 5.0 × 10e9 
or > 5% 
NA 
Lymphocyte 
(109 /L) 
< 0.8 
< 0.5 
> 4.0 
> 20.0 
AST (U/L) 
NA 
NA 
≥ 3 × ULN 
≥ 5 × ULN 
≥ 8 × ULN 
ALT (U/L) 
NA 
NA 
≥ 3 × ULN 
≥ 5 × ULN 
≥ 8 × ULN 
AP 
NA 
NA 
≥ 2.5 × ULN 
≥ 5 × ULN 
Total bilirubin 
(umol/L) 
NA 
NA 
≥ 2.5 × ULN 
≥ 5 × ULN 

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

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Appendix 7 
Central laboratory alert flags 
On top of the flags described below, at a minimum, results above the upper limit or 
below the lower limit of the reference range for normal subjects will be flagged. 
•  Exclusionary Alert Value - At Screening (V1): The result is outside the study 
specific defined limit for inclusion in the study. 
− Hemoglobin < 100 g/L  
− AST ≥ 3 × ULN 
− ALT ≥ 3 × ULN 
− Bilirubin ≥ 3 mg/dL 
− Serum pregnancy test positive 
•  Total Bilirubin flag Alert Value - All visits except screening (V1):  
In combination with ALT and/or AST ≥ 3 × ULN 
− Total bilirubin ≥ 2 × ULN 
Dependent on previous total bilirubin assessment, stopping study treatment should be 
considered (i.e., worsening). 
• Interruption or permanent discontinuation of study treatment - All visits except 
screening (V1): 
Please refer to the study protocol; study treatment must be interrupted [see protocol  
Section 5.1.11]: 
− Asymptomatic increase ALT and/or AST ≥ 3 and < 8 × ULN  
Study treatment must be permanently stopped in case of: 
− Aminotransferases ≥ 8 × ULN 
− Aminotransferases ≥ 3 × ULN and associated with new or worsening 
clinical symptoms of liver injury, e.g., nausea, vomiting, fever, abdominal 
pain, jaundice, unusual lethargy or fatigue, flu like syndrome (arthralgia, 
myalgia, fever) 
− Aminotransferases ≥ 3 × ULN and associated with total bilirubin 
≥ 2 × ULN and increased as compared to baseline 
− Serum pregnancy test positive 
− Hemoglobin < 80 g/L 
− Hemoglobin > 50 g/L decrease from baseline 
•  Repeat Alert value - All visits after randomization (V2): 
Repeat testing is needed:  
− AST ≥ 3 × ULN  
− ALT ≥ 3 × ULN 
− Hemoglobin > 20 g/L decrease from baseline 

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Appendix 8 
List of protocol amendments 
Document 
Date 
Amendment 
Changes 
15 JAN 2015 Amendment 1, 
resulting in Global 
Protocol Version 2 
• 
Visit window was changed to ± 4 days from ± 7 days to 
ensure patients had enough study treatment until the next 
visit. 
• 
Reference to hepatic event questionnaire was removed 
as this form was removed from the eCRF 
• 
Daclatasvir was added as permitted Hepatitis C 
medication following its approval 
• 
Analysis of urea was removed as it was not needed in 
addition to blood urea nitrogen. 
• 
NT-proBNP storage/shipping text was further clarified 
• 
It was clarified that laboratory assessments to be used 
for eligibility assessment were those performed at 
Visit 1 / Screening (not Visit 2 / Randomization). 
• 
A urine dipstick pregnancy test was added to the 
assessments at Visit 2 / Randomization in order to have 
the result prior to treatment assignment. 
• 
It was clarified that HVC was not mandatory 
• 
It was clarified that PAH or PoPH medications stopped 
within 3 months prior to randomization were required to 
be documented in the eCRF. 
9 JUN 2015 
Local Amendment, 
resulting in Local 
protocol version 
2.FRA.A 
• 
An OLE period was added to the study in order to ensure 
that patients continued receiving study treatment after 
study completion (i.e., including the OL period)  
5 AUG 2015 
Local Amendment 
resulting in Local 
protocol version 
2.GBR.A 
• 
Inclusion was restricted to WHO FC III–IV, in order to 
enroll only patients for whom the local commissioning 
guidelines would permit continued macitentan treatment 
after study completion. 
21 APR 2016 Amendment 2, 
resulting in Global 
Protocol Version 3 
and Local protocol 
version 3.GBR.A 
• 
It was clarified that  local laboratory assessments were 
allowed in order to simplify eligibility assessment and 
implementation of the stopping rule (i.e., for calculating 
MELD score and/or Child-Pugh classification) at Week 
12. It was further clarified that the central laboratory kit 
was required to be used in parallel to the use of local 
laboratory assessments.  
• 
It was clarified that study treatment was allowed to be 
continued in case of OLT during the OL period of the 

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Document 
Date 
Amendment 
Changes 
study, based on medical consideration. 
• 
It was allowed to perform the PK substudy closer to the 
patient’s home to ease participation 
• 
Certain eligibility criteria were modified based on 
medical considerations, e.g., exclusion criterion 15: 
transplant expected within 3 months removed; exclusion 
21: CCBs moved to exclusion 20; beta blockers moved 
to exclusion 10) 
• 
The list of allowed and forbidden medications was 
updated with newly approved antiviral medications 
• 
It was clarified that screening started on the day of ICF 
signature  
• 
The definition of the Full Analysis Set was modified to 
include patients for whom post-baseline PVR was 
imputed. 
21 APR 2016 Local Amendment, 
resulting in Local 
protocol version 
3.FRA.B 
• 
It was also allowed to perform the PK substudy during 
the OLE as the requirement to have been on OL 
treatment for 4 weeks is met during the OLE.  
 
CCB = calcium channel blocker; eCRF  = electronic Case Report Form; FC = functional class; HVC = hepatic vein 
catheterization; ICF = informed consent form; MELD = Model for End-Stage Liver Disease; NT-proBNP = N-
terminal pro-brain natriuretic peptide; OL = open-label; OLE = open-label extension; OLT = orthotopic liver 
transplantation; PAH = pulmonary arterial hypertension; PoPH = portopulmonary hypertension; PK = 
pharmacokinetic; PVR = pulmonary vascular resistance; WHO = World Health Organization.