A Prospective, Multicenter, Single-arm, Open-label, Phase 4 Study to Evaluate the Effects of Macitentan on Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension Assessed by Cardiac Magnetic Resonance Imaging
Phase: PHASE4
Conditions: Pulmonary Arterial Hypertension
Sponsor: Actelion

 
 
TPL-000052_v10 
Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403 
REPAIR: Right vEntricular remodeling 
in Pulmonary ArterIal hypeRtension 
A prospective, multicenter, single-arm, open-label, Phase 4 study to evaluate the 
effects of macitentan on Right vEntricular remodeling in Pulmonary ArterIal 
hypeRtension assessed by cardiac magnetic resonance imaging 
 
Study Phase: 
4 
EudraCT Number: 
2014-004066-20 
Status and version: 
Final Version 6 
Date: 
8 November 2016 
Actelion document number 
(Doc No.): 
D-16.554 
 
Confidentiality statement 
The information contained in this document, especially unpublished data, is the property of the sponsor of 
this study, Actelion Pharmaceuticals Ltd. It is therefore provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an Ethics Committee or Institutional 
Review Board. It is understood that this information will not be disclosed to others without written 
authorization from Actelion Pharmaceuticals Ltd, except to the extent necessary to obtain informed consent 
from those persons to whom the study treatment may be administered. 
 
 
NCT02310672

Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 2/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
SPONSOR CONTACT DETAILS 
SPONSOR  
 
ACTELION Pharmaceuticals Ltd 
Gewerbestrasse 16 
CH-4123 Allschwil 
Switzerland 
Clinical Trial Physician  
 
Maziar Assadi-Gehr / Global Medical Affairs 
Physician 
 
Fax 
E-mail 
MEDICAL HOTLINE 
Toll phone number: 
 
 
 
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 Scientist 
 
Clinical Trial Statistician 
Nicolas Martin, Expert Statistician 
 
Drug Safety Physician 
 Senior Clinical Drug Safety 
Physician 
 
COORDINATING INVESTIGATOR 
Name / Title 
Address 
Nazzareno Galiè, MD 
Istituto di Cardiologia, Universita` di Bologna  
via Massarenti,  
, Italy 
 
 
NCT02310672

Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 3/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
CONTRACT RESEARCH ORGANIZATIONS INFORMATION 
CENTRAL LABORATORY 
 
Covance Central Laboratory Services SA 
 
Switzerland 
CENTRAL IMAGE REPOSITORY 
(Cardiac MRI, RHC curves, 
PET-MR, Echo) 
World Care Clinical (WCC) 
 
USA 
IMAGE ANALYSIS CENTER-
cardiac MRI 
 
VUMC 
The Netherlands 
CENTRAL ASSESSMENT-PET-
MR 
 
MGH Massachusetts General Hospital 
Massachusetts 
CENTRAL ASSESSMENT-Echo 
 
World Care Clinical (WCC) 
 
USA 
CRO (MONITORING) 
 
TFS 
Sweden 
Chiltern International 
 UK 
HOME PHLEBOTOMY SERVICE 
Global Care Clinical Trials Ltd 
USA 
BIOSTATISTICS 
Datametrix 
 
 Switzerland 
A list of site-specific contact details for CROs can be found in the Investigator Site File. 
 
 
 
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Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 4/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
SIGNATURE PAGE FOR ACTELION PHARMACEUTICALS LTD 
Hereinafter called Actelion 
 
Treatment name / number 
Macitentan / ACT-064992 
Indication 
Pulmonary arterial hypertension 
Protocol number, study acronym, study title 
AC-055-403, REPAIR, A prospective, multicenter, single-arm, open-label, Phase 4 study 
to evaluate the effects of macitentan on Right vEntricular remodeling in Pulmonary 
ArterIal hypeRtension assessed by cardiac magnetic resonance imaging 
I approve the design of this study. 
 
 
 
 
 
 
 
 
NCT02310672

Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 5/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
INVESTIGATOR SIGNATURE PAGE 
Treatment name / number 
Macitentan / ACT-064992 
Indication 
Pulmonary arterial hypertension 
Protocol number, study acronym, study title 
AC-055-403, REPAIR, A prospective, multicenter, single-arm, open-label, Phase 4 study 
to evaluate the effects of macitentan on Right vEntricular remodeling in Pulmonary 
ArterIal hypeRtension assessed by cardiac magnetic resonance imaging 
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 patients (other than those procedures necessary for the 
wellbeing of the patients). 
I agree to conduct this study in accordance with the Declaration of Helsinki principles, 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, 
and applicable regulations and laws. I will obtain approval by an Institutional Review 
Board or Independent Ethics Committee (IRB/IEC) prior to study start and signed 
informed consent from all patients 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 participates in: 
 Metabolism sub-study 
 Biopsy sub-study 
 Echo sub-study 
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Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
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Confidential  
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Doc No. D-16.554  
 
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 ..........................................................14 
PROTOCOL SYNOPSIS AC-055-403 .............................................................................17 
1 
BACKGROUND .........................................................................................................34 
1.1 
Indication ......................................................................................................34 
1.1.1 
Pulmonary arterial hypertension .......................................................34 
1.1.2 
Treatments ........................................................................................34 
1.2 
Study treatment .............................................................................................35 
1.2.1 
Endothelin pathway ..........................................................................35 
1.2.2 
Macitentan ........................................................................................35 
1.2.2.1 
Nonclinical results ...................................................................36 
1.2.2.2 
Phase 1 results .........................................................................36 
1.2.2.3 
Phase 2 results .........................................................................36 
1.2.2.4 
Phase 3 efficacy results ...........................................................37 
1.2.2.5 
Summary of potential risks and risk management ..................37 
1.3 
Purpose and rationale of the study ................................................................39 
1.3.1 
Purpose of the study ..........................................................................39 
1.3.2 
Rationale ...........................................................................................39 
1.3.2.1 
Importance of the right ventricle in PAH ................................39 
1.3.2.2 
Pulmonary vascular resistance ................................................40 
1.3.2.3 
Cardiac magnetic resonance imaging ......................................40 
1.3.2.4 
Ventriculo-arterial coupling ....................................................40 
1.3.2.5 
Up-front combination therapy .................................................41 
1.3.2.6 
Overall benefit-risk ratio .........................................................41 
2 
STUDY OBJECTIVES ...............................................................................................41 
2.1 
Primary objective ..........................................................................................41 
2.2 
Secondary objective ......................................................................................41 
2.3 
Exploratory objectives ..................................................................................41 
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Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
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2.4 
Sub-studies rationale and objectives .............................................................42 
2.4.1 
Metabolism sub-study (in selected US sites only) ............................42 
2.4.1.1 
Rationale ..................................................................................42 
2.4.1.2 
Objectives ................................................................................42 
2.4.2 
Biopsy sub-study ...............................................................................42 
2.4.2.1 
Rationale for taking biopsies ...................................................42 
2.4.2.2 
Rationale for mRNA transcript analysis .................................42 
2.4.2.3 
Objectives ................................................................................43 
2.4.3 
Echo sub-study ..................................................................................43 
2.4.3.1 
Rationale ..................................................................................43 
2.4.3.2 
Objective .................................................................................43 
3 
OVERALL STUDY DESIGN AND PLAN ...............................................................43 
3.1 
Study design .................................................................................................43 
3.2 
Study design rationale ..................................................................................45 
3.3 
Site personnel and their roles ........................................................................46 
3.4 
Study committees .........................................................................................46 
3.4.1 
Steering Committee ..........................................................................46 
3.4.2 
Central imaging .................................................................................46 
3.4.3 
Independent Liver Safety Data Review Board .................................46 
4 
PATIENT POPULATION ..........................................................................................47 
4.1 
Patient population description ......................................................................47 
4.2 
Rationale for the selection of the study population ......................................47 
4.3 
Inclusion criteria ...........................................................................................47 
4.4 
Exclusion criteria ..........................................................................................48 
4.5 
Reliable contraception for women of childbearing potential .......................50 
4.5.1 
Definition of woman of childbearing potential .................................50 
4.5.2 
Europe and Asia ................................................................................50 
4.5.3 
North America and Australia ............................................................51 
4.6 
Patient population in sub-studies ..................................................................51 
4.6.1 
Metabolism sub-study .......................................................................51 
4.6.2 
Biopsy sub-study ...............................................................................52 
4.6.3 
Echo sub-study ..................................................................................52 
5 
TREATMENTS ..........................................................................................................52 
5.1 
Study treatment .............................................................................................52 
5.1.1 
Investigational treatment: description and rationale .........................52 
5.1.2 
Study treatment administration .........................................................52 
5.1.3 
Treatment assignment .......................................................................52 
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Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
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5.1.4 
Patient identification .........................................................................52 
5.1.5 
Blinding ............................................................................................53 
5.1.6 
Study treatment supply .....................................................................53 
5.1.6.1 
Study treatment packaging and labeling .................................53 
5.1.6.2 
Study treatment storage and distribution .................................53 
5.1.6.3 
Study treatment dispensing .....................................................53 
5.1.6.4 
Study treatment return and destruction ...................................54 
5.1.7 
Compliance with study treatment .....................................................54 
5.1.8 
Study treatment interruptions ............................................................54 
5.1.9 
Premature discontinuation of study treatment ..................................54 
5.1.10 
Study-specific 
criteria 
for 
interruption 
/ 
premature 
discontinuation of study treatment ....................................................55 
5.1.10.1 
Pregnancy ................................................................................55 
5.1.10.2 
Liver aminotransferases abnormalities ....................................56 
5.1.10.3 
Hemoglobin abnormalities ......................................................57 
5.1.10.4 
Start of an ERA / strong CYP3A4 inducer or inhibitor / 
investigational drug .................................................................58 
5.2 
Previous and concomitant therapy ................................................................58 
5.2.1 
Definitions ........................................................................................58 
5.2.2 
Reporting of previous/concomitant therapy in the CRF ...................58 
5.2.3 
Allowed concomitant therapy ...........................................................59 
5.2.3.1 
Until Week 26 RHC ................................................................59 
5.2.3.2 
After Week 26 RHC ................................................................59 
5.2.4 
Forbidden concomitant therapy ........................................................59 
5.2.5 
Rescue therapy before Week 26 RHC ..............................................60 
6 
STUDY ENDPOINTS ................................................................................................60 
6.1 
Efficacy endpoints ........................................................................................60 
6.1.1 
Primary efficacy endpoints ...............................................................60 
6.1.2 
Secondary efficacy endpoints ...........................................................61 
6.1.3 
Exploratory efficacy endpoints .........................................................61 
6.2 
Safety endpoints ...........................................................................................63 
6.3 
Exploratory endpoints in sub-studies ...........................................................63 
6.3.1 
Metabolism sub-study .......................................................................63 
6.3.2 
Biopsy sub-study ...............................................................................64 
6.3.3 
Echo sub-study ..................................................................................64 
7 
STUDY ASSESSMENTS ...........................................................................................65 
7.1 
Screening/baseline assessments ....................................................................66 
7.1.1 
Eligibility criteria ..............................................................................66 
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Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
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Confidential  
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Doc No. D-16.554  
 
7.1.2 
Demographic and baseline characteristics ........................................66 
7.1.3 
Medical history .................................................................................66 
7.1.4 
Medications .......................................................................................66 
7.1.5 
Birth control methods .......................................................................66 
7.1.6 
6-minute walk test .............................................................................66 
7.1.7 
WHO Functional Class .....................................................................67 
7.1.8 
Cardiac MRI .....................................................................................67 
7.1.9 
Right heart catheterization ................................................................68 
7.1.10 
Pressure-volume relationship ............................................................68 
7.1.11 
Blood tests .........................................................................................69 
7.1.12 
Sub-studies ........................................................................................69 
7.1.12.1 
Metabolism sub-study .............................................................69 
7.1.12.2 
Biopsy sub-study .....................................................................69 
7.1.12.3 
Echo sub-study ........................................................................70 
7.2 
Efficacy assessments ....................................................................................72 
7.2.1 
6-minute walk test .............................................................................72 
7.2.2 
WHO Functional Class .....................................................................72 
7.2.3 
Cardiac MRI .....................................................................................72 
7.2.4 
Hemodynamics .................................................................................72 
7.2.5 
Pressure-volume relationship ............................................................72 
7.2.6 
Laboratory tests .................................................................................72 
7.3 
Safety assessments ........................................................................................73 
7.3.1 
Adverse events ..................................................................................73 
7.3.2 
Vital signs .........................................................................................73 
7.3.3 
Weight ...............................................................................................73 
7.3.4 
Physical examination ........................................................................73 
7.3.5 
Laboratory assessments ....................................................................73 
7.3.5.1 
Type of laboratory ...................................................................73 
7.3.5.2 
Laboratory tests .......................................................................75 
7.3.5.3 
Potential additional laboratory tests ........................................76 
7.4 
Exploratory assessments in sub-studies ........................................................76 
7.4.1 
Metabolism sub-study .......................................................................77 
7.4.2 
Biopsy sub-study ...............................................................................77 
7.4.3 
Echo sub-study ..................................................................................77 
8 
SCHEDULE OF VISITS ............................................................................................77 
8.1 
Screening period ...........................................................................................77 
8.2 
Treatment period ...........................................................................................78 
8.2.1 
Treatment Initiation Visit ..................................................................78 
8.2.2 
Rescue Therapy Initiation Visit ........................................................79 
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Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
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8.2.3 
Week 26 visit ....................................................................................79 
8.2.4 
Unscheduled visits ............................................................................80 
8.2.5 
Premature End of Treatment visit .....................................................81 
8.2.5.1 
Patients discontinuing the study ..............................................81 
8.2.5.2 
Patients agreeing to limited participation ................................81 
8.2.6 
End of Treatment visit ......................................................................82 
8.3 
Safety follow-up ...........................................................................................82 
9 
STUDY COMPLETION AND POST-STUDY TREATMENT/MEDICAL 
CARE ..........................................................................................................................83 
9.1 
Study completion ..........................................................................................83 
9.2 
Premature withdrawal from study ................................................................83 
9.3 
Premature termination or suspension of the study ........................................84 
9.4 
Medical care of patients after study completion/withdrawal from study .....85 
10 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ...........................85 
10.1 
Adverse events ..............................................................................................85 
10.1.1 
Definitions of adverse events ............................................................85 
10.1.2 
Intensity of adverse events ................................................................86 
10.1.3 
Relationship to study treatment ........................................................86 
10.1.4 
Adverse events associated with study design or protocol 
mandated procedures ........................................................................86 
10.1.5 
Reporting of adverse events ..............................................................87 
10.1.6 
Follow-up of adverse events .............................................................87 
10.2 
Serious adverse events ..................................................................................87 
10.2.1 
Definitions of serious adverse events ...............................................87 
10.2.1.1 
Serious adverse events .............................................................87 
10.2.1.2 
Serious adverse events associated with the study design 
or protocol mandated procedures ............................................88 
10.2.2 
Reporting of serious adverse events .................................................88 
10.2.2.1 
During screening period ..........................................................88 
10.2.2.2 
During treatment period ..........................................................88 
10.2.2.3 
During follow-up period ..........................................................88 
10.2.3 
Follow-up of serious adverse events .................................................88 
10.2.4 
After the 30-day follow-up period ....................................................88 
10.2.5 
Reporting procedures ........................................................................88 
10.3 
Pregnancy .....................................................................................................89 
10.3.1 
Reporting of pregnancy ....................................................................89 
10.3.2 
Follow-up of pregnancy ....................................................................90 
10.4 
Study safety monitoring ................................................................................90 
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Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
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11 STATISTICAL METHODS .......................................................................................90 
11.1 
Analysis Sets .................................................................................................90 
11.1.1 
Screened Patients Set ........................................................................90 
11.1.2 
Safety Set ..........................................................................................90 
11.1.3 
Full Analysis Set ...............................................................................90 
11.1.4 
Per Protocol Set ................................................................................91 
11.1.5 
Other analysis sets ............................................................................91 
11.1.6 
Usage of the analysis sets .................................................................91 
11.2 
Variables .......................................................................................................91 
11.2.1 
Primary efficacy variables ................................................................91 
11.2.2 
Secondary efficacy variables ............................................................92 
11.2.3 
Exploratory efficacy variables ..........................................................92 
11.2.3.1 
Hemodynamic variables and pressure-volume variables ........92 
11.2.3.2 
Variables related to maintenance of treatment effect ..............92 
11.2.3.3 
Variables related to the left ventricle ......................................92 
11.2.3.4 
Potential variables for disease monitoring ..............................93 
11.2.3.5 
Clinical endpoint .....................................................................93 
11.2.4 
Safety variables .................................................................................93 
11.2.5 
Other variables ..................................................................................94 
11.3 
Description of statistical analyses .................................................................94 
11.3.1 
Overall testing strategy .....................................................................94 
11.3.2 
Analysis of the primary efficacy variables .......................................94 
11.3.2.1 
Hypotheses and statistical model ............................................94 
11.3.2.2 
Handling of missing data .........................................................94 
11.3.2.3 
Main analysis ...........................................................................95 
11.3.2.4 
Supportive/sensitivity analyses ...............................................96 
11.3.2.5 
Subgroup analyses ...................................................................96 
11.3.3 
Analysis of the secondary efficacy variables ....................................97 
11.3.4 
Analysis of the exploratory efficacy variables .................................97 
11.3.5 
Analysis of safety variables ..............................................................98 
11.3.5.1 
Adverse events ........................................................................98 
11.3.5.2 
Laboratory parameters .............................................................98 
11.3.5.3 
Vital signs and body weight ....................................................99 
11.3.6 
Analysis of other variables ...............................................................99 
11.4 
Interim analyses ............................................................................................99 
11.4.1 
Rationale ...........................................................................................99 
11.4.2 
Conduct ...........................................................................................100 
11.4.3 
Statistical analysis ...........................................................................101 
11.5 
Sample size .................................................................................................101 
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Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
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Confidential  
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Doc No. D-16.554  
 
12 DATA HANDLING ..................................................................................................102 
12.1 
Data collection ............................................................................................102 
12.2 
Maintenance of data confidentiality ...........................................................103 
12.3 
Database management and quality control .................................................103 
13 PROCEDURES AND GOOD CLINICAL PRACTICE ...........................................104 
13.1 
Ethics and Good Clinical Practice ..............................................................104 
13.2 
Independent Ethics Committee / Institutional Review Board ....................104 
13.3 
Informed consent ........................................................................................104 
13.4 
Compensation to patients and investigators ...............................................105 
13.5 
Protocol adherence/compliance ..................................................................105 
13.6 
Protocol amendments .................................................................................106 
13.7 
Essential documents and retention of documents .......................................106 
13.8 
Monitoring ..................................................................................................107 
13.9 
Investigator site file ....................................................................................108 
13.10 
Audit ...........................................................................................................108 
13.11 
Inspections ..................................................................................................109 
13.12 
Reporting of study results and publication .................................................109 
14 REFERENCES ..........................................................................................................111 
 
 
 
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Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
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LIST OF TABLES 
 
Table 1 
Visit and assessment schedule ......................................................................32 
Table 2 
New data published in 2015/2016 ...............................................................100 
Table 3 
Efficacy boundaries for RVSV endpoint at interim/final analyses .............102 
Table 4 
Efficacy boundaries for PVR endpoint at interim/final analyses ................102 
 
 
LIST OF FIGURES 
 
Figure 1 
Study design ..................................................................................................45 
 
 
LIST OF APPENDICES 
 
Appendix 1 Actelion guidelines for RHC .......................................................................117 
Appendix 2 Actelion guidelines for 6MWT ...................................................................119 
Appendix 3 Borg dyspnea index .....................................................................................122 
Appendix 4 WHO Functional Classification of pulmonary hypertension ......................123 
Appendix 5 Study drug storage ......................................................................................124 
Appendix 6 Central laboratory........................................................................................125 
Appendix 7 Eligibility questionnaire ..............................................................................126 
 
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Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
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Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
LIST OF ABBREVIATIONS AND ACRONYMS 
2D  
2-dimensional 
3D  
3-dimensional 
6MWD  
6-minute walk distance 
6MWT  
6-minute walk test 
AE  
Adverse event 
ALT  
Alanine aminotransferase 
ANCOVA  
Analysis of Covariance  
aPTT  
Activated partial thromboplastin time  
AST  
Aspartate aminotransferase 
BMI  
Body mass index 
BSA  
Body surface area 
CD  
Compact Disc 
CFR  
Code of Federal Regulations (US) 
CI  
Confidence interval 
CIR  
Central Image Repository 
CL  
Confidence limit 
CO  
Cardiac output 
CRF  
Case Report Form 
CRO  
Contract Research Organization 
CV  
Coefficients of Variation 
CYP  
Cytochrome P450 
CYP3A4  
Cytochrome P450 isozyme 3A4 
DLCO  
Diffusing capacity of the lung for carbon monoxide  
dPAP  
Diastolic pulmonary arterial pressure 
dSAP  
Diastolic systemic arterial pressure 
ECG  
Electrocardiogram 
eCRF  
electronic Case Report Form 
EOS  
End of Study 
EOT  
End of Treatment 
ERA  
Endothelin receptor antagonist 
ET-1  
Endothelin-1 
ETA  
Endothelin A receptor 
ETB  
Endothelin B receptor 
FAS  
Full Analysis Set 
FC  
Functional Class 
FDG  
Fluorodeoxyglucose 
FEV1  
Forced expiratory volume in 1 second 
FVC  
Forced vital capacity 
GCP  
Good Clinical Practice 
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Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
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Confidential  
EudraCT 2014-004066-20 
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GDF-15  
Growth differentiation factor-15 
GMP  
Good Manufacturing Practice 
HAESI  
Hepatic adverse events of special interest 
HIV  
Human immunodeficiency virus 
HR  
Heart rate 
i.v.  
Intravenous 
IAC  
Image Analysis Center 
IB  
Investigator’s Brochure 
ICF  
Informed Consent Form 
ICH  
International Council for Harmonisation 
ICMJE  
International Committee of Journal Editors 
IEC  
Independent Ethics Committee 
ILSDRB  
Independent Liver Safety Data Review Board 
INR  
International Normalized Ratio 
IPF  
Idiopathic pulmonary fibrosis 
IRB  
Institutional Review Board 
IRT  
Interactive Response Technology 
ISF  
Investigative Site File 
IUD  
Intrauterine device 
IUS  
Intrauterine system 
LDH  
Lactate dehydrogenase 
LFT  
Liver function test 
LLN  
Lower limit of the normal range 
LV  
Left Ventricular 
LVEDP  
Left Ventricular End Diastolic Pressure 
LVEDV  
Left Ventricular End Diastolic Volume 
LVEF  
Left Ventricular Ejection Fraction 
LVESV  
Left Ventricular End Systolic Volume 
LVSV  
Left Ventricular Stroke Volume 
MedDRA  
Medical Dictionary for Regulatory Activities 
mPAP  
Mean pulmonary arterial pressure 
MR  
Magnetic resonance 
mRAP  
Mean right atrial pressure 
MRI  
Magnetic resonance imaging 
mRNA  
Messenger RNA 
NT-proBNP  
N-terminal pro-brain natriuretic peptide 
PAH  
Pulmonary arterial hypertension 
PAP  
Pulmonary arterial pressure 
PBMC  
Peripheral blood mononuclear cell 
PCWP  
Pulmonary capillary wedge pressure 
NCT02310672

Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 16/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
PDE-5  
Phosphodiesterase type-5 
PET  
Positron Emission Tomography 
PH  
Pulmonary hypertension 
PPS  
Per Protocol Set 
PT  
Preferred term 
PVR  
Pulmonary vascular resistance 
RHC  
Right heart catheterization 
RTI  
Rescue Therapy Initiation 
RV  
Right ventricle, right ventricular 
RVEDV  
Right Ventricular End Diastolic Volume 
RVEF  
Right Ventricular Ejection Fraction 
RVESV  
Right Ventricular End Systolic Volume 
RVSV  
Right Ventricular Stroke Volume 
s.c.  
Subcutaneous 
SAE  
Serious adverse event 
SAP  
Statistical Analysis Plan 
SIV  
Site Initiation Visit 
SOC  
System organ class 
SOP  
Standard operating procedure 
sPAP  
Systolic pulmonary arterial pressure 
SS  
Safety Set 
sSAP  
Systolic systemic arterial pressure 
TAPSE  
Tricuspid annular plane systolic excursion 
TNF  
Tumor Necrosis Factor 
ULN  
Upper limit of the normal range 
VEGF  
Vascular Endothelial Growth Factor 
WHO  
World Health Organization 
WU  
Woods Units 
 
 
 
 
NCT02310672

Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 17/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
PROTOCOL SYNOPSIS AC-055-403 
TITLE 
A prospective, multicenter, single-arm, open-label, Phase 4 
study to evaluate the effects of macitentan on Right vEntricular 
remodeling in Pulmonary ArterIal hypeRtension assessed by 
cardiac magnetic resonance imaging. 
ACRONYM 
REPAIR: Right vEntricular remodeling in Pulmonary ArterIal 
hypeRtension 
OBJECTIVES 
Primary objective 
To evaluate the effect of macitentan on right ventricular and 
hemodynamic 
properties 
in 
patients 
with 
symptomatic 
pulmonary arterial hypertension (PAH). 
Secondary objective 
To evaluate the safety and tolerability of macitentan in patients 
with symptomatic PAH. 
Exploratory objectives 
To investigate the effect of macitentan on disease-related 
circulating biomarkers in patients with symptomatic PAH. 
To explore a potential association between change in right 
ventricular properties and clinical outcome in patients with 
symptomatic PAH. 
To investigate the effect of macitentan on ventriculo-arterial 
coupling in patients with symptomatic PAH. 
To evaluate the effect of macitentan on left ventricular (LV) 
properties in patients with symptomatic PAH. 
DESIGN 
Prospective, multicenter, single-arm, open-label, Phase 4 study. 
PERIODS 
Screening: from informed consent signature to initiation of 
study treatment, may last up to 28 days. 
Treatment period: from first dose intake (Day 1) to End of 
Treatment (EOT) at Week 52 ± 7 days or at premature 
discontinuation of study treatment. 
The Safety follow-up period lasts at least 30 days and ends 
with the End of Study (EOS) Visit 30 to 37 days after EOT. 
NCT02310672

Macitentan / ACT-064992 
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PLANNED DURATION 
Approximately 3 years from first patient, first visit to last 
patient, last visit. 
SITE(S) 
/ COUNTRY(IES)  
Approximately 50 sites in approximately 12 countries in Asia, 
Australia, Europe, and North America. 
SUBJECTS / GROUPS 
100 patients enrolled in one group. 
MAIN INCLUSION 
CRITERIA 
1. Signed informed consent prior to any study-mandated 
procedure. 
2. Symptomatic PAH. 
3. World Health Organization (WHO) Functional Class (FC) 
I to III. 
4. PAH etiology belonging to one of the following groups 
according to Nice classification: 
1.1 Idiopathic PAH 
1.2 Heritable PAH 
1.3 Drug- and toxin-induced PAH 
1.4.1 PAH associated with connective tissue disease 
1.4.4 PAH associated with congenital heart diseases: 
only simple (atrial septal defect, ventricular septal 
defect, patent ductus arteriosus) congenital systemic to 
pulmonary shunts at least 2 year post surgical repair. 
5. Hemodynamic diagnosis of PAH confirmed by right heart 
catheterization (RHC) performed between Day −28 and Day 
1 (inclusion RHC; RHC data obtained at study site within 
this time frame, prior to obtaining signed informed consent, 
are acceptable) showing: 
• Mean 
pulmonary 
arterial 
pressure 
(mPAP) 
≥ 25 mmHg and 
− Pulmonary capillary wedge pressure (PCWP) 
or left ventricular end diastolic pressure 
(LVEDP) ≤ 12 mmHg and pulmonary 
vascular resistance (PVR) ≥ 4 Woods Units 
(WU) (320 dyn.sec.cm-5) or 
− 12 mmHg ≤ PCWP or LVEDP ≤ 15 mmHg 
and PVR ≥ 6 WU (480 dyn.sec.cm-5). 
6. 6-minute walk distance (6MWD) ≥ 150 m during screening. 
7. For patients treated with oral loop diuretics, treatment dose 
must have been stable at least 1 month prior to the inclusion 
RHC. 
NCT02310672

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8. For patients treated with phosphodiesterase type-5 (PDE-5) 
inhibitors, treatment dose must have been stable at least 
3 months prior to the inclusion RHC (initiation of PDE-5 
inhibitors during screening is allowed after all screening 
assessments have been performed). 
9. For patients treated with beta blockers, treatment dose must 
have been stable at least 1 month prior to the inclusion 
RHC. 
10. Men or women ≥ 18 and < 75 years. For patients aged ≥ 65 
and < 75 years, an eligibility form will be submitted to a 
Steering Committee member who will reserve the right to 
exclude the patient. 
11. Women of childbearing potential [see Section 4.5.1] 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 [see 
Section 4.5] 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. 
MAIN EXCLUSION 
CRITERIA 
1. Body weight < 40 kg. 
2. Body mass index (BMI) > 35kg/m2. For patients with 
30kg/m2 < BMI < 35kg/m2, an eligibility form will be 
submitted to a Steering Committee member who will 
reserve the right to exclude the patient. 
3. Pregnancy, breastfeeding, or intention to become pregnant 
during the study. 
4. Recently started (< 8 weeks prior to informed consent 
signature) or planned cardio-pulmonary rehabilitation 
program. 
5. Known concomitant life-threatening disease with a life 
expectancy < 12 months. 
6. Any condition likely to affect protocol or treatment 
compliance. 
7. Hospitalization for PAH (except for diagnosis of PAH) 
within 3 months prior to informed consent signature. 
8. Left atrial volume indexed for body surface area (BSA) 
≥ 43mL/m2 by echocardiography or cardiac MRI. 
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9. Moderate to severe left-heart valvular disease. 
10. History of pulmonary embolism or deep vein thrombosis. 
11. Presence of one or more of the following signs of relevant 
lung disease at any time up to screening: 
− Diffusing capacity of the lung for carbon monoxide 
(DLCO) < 40% of predicted (eligible only if no or 
mild 
interstitial 
lung 
disease 
on 
computed 
tomography). 
− Forced vital capacity (FVC) < 60% of predicted. 
− Forced expiratory volume in one second (FEV1) 
< 60% of predicted. 
12. Moderate to severe restrictive lung disease (i.e., total lung 
capacity < 60% of predicted value) at any time prior to 
enrollment. 
13. Historical evidence of significant coronary artery disease 
established by: 
− History of myocardial infarction or 
− More than 50% stenosis in a coronary artery (by 
percutaneous coronary intervention or angiography) 
or 
− Elevation of the ST segment on electrocardiogram 
or 
− History of coronary artery bypass grafting or 
− Stable angina. 
14. Known uncontrolled diabetes mellitus (in the opinion of the 
investigator). 
15. Severe renal insufficiency (calculated creatinine clearance 
< 30 mL/min). 
16. Cancer. 
17. Systolic blood pressure < 90 mmHg. 
18. Severe hepatic impairment (with or without cirrhosis) 
according to National Cancer Institute organ dysfunction 
working group criteria, defined as total bilirubin > 3 × upper 
limit of the normal range (ULN) accompanied by an 
aspartate aminotransferase (AST) elevation > ULN at 
screening. 
19. Hemoglobin < 100g/L. 
20. Serum AST and/or alanine aminotransferase (ALT)  
> 3 × ULN. 
NCT02310672

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Version 6 
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Confidential  
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21. Need for dialysis. 
22. Responders to acute vasoreactivity test based on medical 
history. 
23. Prior use of endothelin receptor antagonists (ERAs), 
stimulators of soluble guanylate cyclase or prostacyclin or 
prostacyclin analogs. 
24. Treatment with strong inducers of cytochrome P450 
isozyme 3A4 (CYP3A4) within 4 weeks prior to study 
treatment 
initiation 
(e.g., 
carbamazepine, 
rifampicin, 
rifabutin, phenytoin and St. John’s Wort). 
25. Treatment with strong inhibitors of CYP3A4 within 4 weeks 
prior to study treatment initiation (e.g., ketoconazole, 
itraconazole, voriconazole, clarithromycin, telithromycin, 
nefazodone, ritonavir, and saquinavir). 
26. Treatment with another investigational drug (planned, or 
taken within the 3 months prior to study treatment 
initiation). 
27. Hypersensitivity to any ERA or any excipients of the 
formulation of macitentan (lactose, magnesium stearate, 
microcrystalline 
cellulose, 
povidone, 
sodium 
starch 
glycolate, polyvinyl alcohol, polysorbate, titanium dioxide, 
talc, xanthan gum, and lecithin soya). 
28. Claustrophobia. 
29. MRI-incompatible permanent cardiac pacemaker, automatic 
internal cardioverter. 
30. Metallic implant (e.g., defibrillator, neurostimulator, hearing 
aid, permanent use of infusion device). 
31. Atrial fibrillation, multiple premature ventricular or atrial 
contractions, or any other condition that would interfere 
with proper cardiac gating during MRI. 
32. For patients enrolling in the metabolism sub-study only: 
glucose intolerance. 
33. For patients enrolling in the biopsy sub-study only: PAH 
etiology belonging to Nice classification 1.4.4: PAH 
associated with congenital heart diseases or 1.4.1: PAH 
associated with connective tissue disease. 
NCT02310672

Macitentan / ACT-064992 
Pulmonary arterial hypertension 
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Version 6 
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STUDY TREATMENTS 
Investigational treatment 
Open-label macitentan 10 mg once daily, oral. 
Comparator and/or placebo 
Not applicable. 
CONCOMITANT 
THERAPY 
Allowed concomitant therapy until Week 26 RHC 
• Therapies allowed at baseline based on eligibility criteria. 
• Oral loop diuretics if used at a stable dose for 1 week prior 
to Week 26 RHC. 
• Use of rescue therapy (see below) only in case of disease 
progression. 
• A PDE-5 inhibitor may be initiated from the time when all 
screening assessments have been performed until Day 14, 
provided that dose optimization is complete at the latest 
14 days after study treatment initiation. 
Allowed concomitant therapy after Week 26 RHC 
Treatment initiation and dose changes for: 
• Loop diuretics. 
• PDE-5 inhibitors. 
• Prostanoid analogs by any route of administration. 
• Stimulators of soluble guanylate cyclase. 
• Any other PAH-specific therapy that may obtain marketing 
authorization during study conduct. 
Forbidden concomitant therapy 
ERAs other than study drug, investigational drug other than 
study drug, strong CYP3A4 inhibitors (e.g., ketoconazole, 
itraconazole, 
voriconazole, 
clarithromycin, 
telithromycin, 
nefazodone, ritonavir, and saquinavir) and strong inducers of 
CYP3A4 (e.g., carbamazepine, rifampicin, rifabutin, phenytoin 
and St. John’s Wort). 
Initiation of one of these forbidden medications will lead to 
premature discontinuation of study treatment. 
Rescue therapy before Week 26 RHC 
The following treatment changes are allowed before Week 26 
RHC only in case of disease progression: 
 
 
NCT02310672

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• Initiation of: 
− Intravenous (i.v.) loop diuretics 
− PDE-5 inhibitors 
− Prostanoid analogs by any route of administration 
− Stimulators of soluble guanylate cyclase 
− Any other PAH-specific therapy that may obtain 
marketing authorization during study conduct. 
• Up-titration of PDE-5 inhibitors. 
Disease progression is defined as: 
• Decrease in 6MWD by more than 15% associated with 
worsening in WHO FC, or 
• Need for subcutaneous (s.c.) or i.v. prostanoid therapy, or 
• Hospitalization for PAH (investigator’s assessment). 
After Week 26 RHC, treatment changes are allowed. 
ENDPOINTS 
Primary efficacy endpoints 
The study has two primary efficacy endpoints: 
- 
Change from baseline to Week 26 in Right Ventricular 
(RV) Stroke Volume (RVSV) assessed by cardiac MRI 
from pulmonary artery flow. 
- 
Ratio of Week 26 to baseline PVR assessed by RHC. 
Secondary efficacy endpoints 
Change from baseline to Week 26 in: 
- 
RV End Diastolic Volume (RVEDV) 
- 
RV End Systolic Volume (RVESV)  
- 
RV Ejection Fraction (RVEF) 
- 
RV mass 
- 
6MWD 
- 
WHO FC 
Exploratory endpoints 
Change from baseline to Week 26 in: 
- 
mPAP 
- 
Mean right atrial pressure 
- 
Cardiac index 
- 
Arterial elastance 
- 
RV end-systolic elastance 
- 
RV maximum isovolumic pressure 
NCT02310672

Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 24/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
Change from baseline to Week 52 in: 
- 
RVSV determined by cardiac MRI from pulmonary 
artery flow 
- 
RVEDV 
- 
RVESV 
- 
RVEF 
- 
RV mass 
- 
6MWD 
- 
WHO FC 
Change from baseline to Week 26 and Week 52 in: 
- 
Left Ventricular Stroke Volume (LVSV) determined by 
cardiac MRI from the aortic flow 
- 
LV End Diastolic Volume (LVEDV) 
- 
LV End Systolic Volume (LVESV) 
- 
LV Ejection Fraction (LVEF) 
- 
LV mass 
- 
RVEDV/LVEDV 
- 
RVESV/LVESV 
- 
N-terminal pro-brain natriuretic peptide (NT-proBNP) 
- 
Uric acid 
- 
Red cell distribution width 
- 
Activin A 
- 
Cystatin C 
- 
Follistatin 
- 
Galectin-3 
- 
Growth Differentiation Factor (GDF)-15 
- 
Cardiac troponin T 
- 
Lactate dehydrogenase (LDH) 
- 
Osteoprotegerin 
- 
Tumor Necrosis Factor (TNF) alpha 
Time to first clinical worsening event defined as: 
- 
Decrease in 6MWD by > 15% from baseline associated 
with worsening in WHO FC, or 
- 
Initiation of s.c. or i.v. prostanoid therapy, or 
- 
Hospitalization for PAH (investigator’s assessment), or 
- 
Death 
 
 
NCT02310672

Macitentan / ACT-064992 
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Safety endpoints 
- 
Treatment-emergent adverse events (AEs) up to 30 days 
after EOT. 
- 
Treatment-emergent serious adverse events (SAEs) up 
to 30 days after EOT. 
- 
AEs leading to premature discontinuation of study drug 
- 
Treatment-emergent marked laboratory abnormalities up 
to 30 days after EOT. 
- 
Occurrence of liver function test (ALT and/or AST) 
abnormality (≥ 3; ≥ 3 and < 5 × ULN; ≥ 5 and 
< 8 × ULN; ≥ 8 × ULN) up to EOT. 
- 
Occurrence of hemoglobin abnormality (≤ 80 g/L; 
> 80 and ≤ 100 g/L) up to EOT. 
- 
Occurrence of ALT and/or AST abnormality ≥ 3 × ULN 
associated with bilirubin ≥ 2 × ULN. 
ASSESSMENTS 
Refer to the schedule of assessments in Table 1. 
STATISTICAL 
METHODOLOGY  
• Analysis sets 
The Full Analysis Set (FAS) includes all patients who received 
at least one dose of study drug and who had a baseline as well 
as a post-baseline measurement for both primary endpoints 
(RVSV and PVR). 
The Modified FAS comprises all patients from the FAS who 
had a post-baseline measurement taken between 16 and 
30 weeks of treatment. 
The Safety Set (SS) includes all patients who received at least 
one dose of study drug. 
• Primary efficacy endpoints 
The study has two primary efficacy endpoints: 
• Change from baseline to Week 26 in RVSV assessed by 
cardiac MRI from pulmonary artery flow. 
• Ratio of Week 26 to baseline PVR assessed by RHC. 
• Null and alternative hypotheses 
The null hypothesis is: 
The mean change from baseline in RVSV is less than or equal 
to zero AND the geometric mean ratio of Week 26 to baseline 
PVR is greater than or equal to one. 
 
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The alternative hypothesis is: 
The mean change from baseline in RVSV is greater than zero 
OR the geometric mean ratio of Week 26 to baseline PVR is 
less than one. 
• Type-I and -II errors and power 
The overall type I error (α) of 0.025 (one-sided) will be split 
between the endpoints: change from baseline in RVSV will be 
tested at α = 0.02 and ratio to baseline PVR will be tested at 
α = 0.005.  
Per endpoint the type II error is set to 0.10 and the power to 
90%. 
• Primary efficacy analysis 
The primary efficacy analyses (interim and final) will be 
performed on the Modified FAS. Change from baseline in 
RVSV will be analyzed using an Analysis of Covariance 
(ANCOVA) with a factor for other PAH-specific therapy (none, 
background or initiated at baseline) and a covariate for baseline 
RVSV. The mean change from baseline and its 96% confidence 
interval (CI) will be estimated based on the model. 
The ratio of Week 26 to baseline PVR will be log transformed 
(base e) and analyzed using an ANCOVA with a factor for 
other PAH-specific therapy (none, background or initiated at 
baseline) and a covariate for baseline log PVR. The mean 
change from baseline (on log scale) and its 99% CI will be 
estimated based on the model. The Geometric Mean Ratio 
(versus baseline) and its 99% CI will be obtained by 
exponentiation. 
If a patient discontinues treatment prematurely before Week 26 
or initiates rescue therapy before Week 26, RVSV and PVR 
obtained at study treatment discontinuation will be carried 
forward, provided that these measurements were taken after at 
least 16 weeks of study treatment. 
The null hypothesis will be tested at interim and final analysis, 
if study continues, and may be rejected based on pre-defined 
boundaries. 
 
NCT02310672

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• Secondary analyses 
Secondary efficacy variables will be analyzed for the Modified 
FAS only at final analysis at α = 0.025 (one-sided) using 95% 
CIs. No correction for multiple testing will be applied for these 
analyses. 
Association between (change from baseline to Week 26 in) 
cardiac MRI variables and time to first clinical worsening event 
will be explored using Cox models. 
• Safety endpoints 
Safety data will be summarized using descriptive statistics. 
Safety analyses will be performed on the SS. 
• Interim analysis 
An interim analysis will be conducted when 42 patients have 
available assessments data for both primary endpoints. To 
declare the study positive at the interim analysis, both endpoints 
must be met. 
• Sample size calculation 
For MRI-based RVSV, no individual patient data are available 
at Actelion. Individual RVSV was approximated in the 
hemodynamic 
sub-study 
of 
SERAPHIN 
(AC-055-302) 
combining the cardiac index obtained from the RHC with BSA 
and heart rate from vital signs measurements. The change from 
baseline in approximate RVSV was around 9 mL, in line with 
literature suggesting that a difference of 8–12 mL is clinically 
relevant [Van Wolferen 2011]. Assuming a standard deviation 
of 18–22 mL, also based on the hemodynamic sub-study of 
SERAPHIN, the sample size for 90% power is 30–93 evaluable 
patients for final analysis (α = 0.02, one-sided). The number of 
patients and efficacy boundaries for the interim analysis are 
described in Table 3. 
For PVR, an integrated analysis of two bosentan studies, 
BENEFIT (AC-052-366) and EARLY (AC-052-364), and the 
hemodynamic sub-study of SERAPHIN suggested that the 
mean change from baseline is expected to be around −0.24 on 
log scale (95% CI: −0.29, −0.19) and that the within group 
standard deviation is around 0.41 on log scale (90% CI: 0.39, 
0.43). Under these assumptions, 30–84 evaluable patients are 
needed for final analysis for 90% power (α = 0.005, one-sided). 
NCT02310672

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The number of patients and efficacy boundaries for the interim 
analysis are described in Table 4. 
To account for patient dropout and non-evaluable images, the 
sample size was set at 100 patients for the final analysis. 
STUDY COMMITTEES 
A Steering Committee is involved in the design of the study, 
will provide guidance on study conduct and interpretation of 
results, and will support study publications. The committee is 
governed by a Steering Committee charter. 
An Image Analysis Center will centrally assess all cardiac MRI 
results and all pressure-volume results. Assessments will be 
performed according to a dedicated charter. 
All variables that are specific to the metabolism sub-study will 
be centrally assessed. Assessments will be performed according 
to a dedicated charter. 
All Echo results will be centrally assessed. Assessments will be 
performed according to a dedicated 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 (HAESI) that require further evaluation 
during the study as per ILSDRB charter. 
SUB-STUDIES 
Three sub-studies are planned and described under the same 
protocol. 
The sub-studies will be conducted in selected centers. In these 
centers, all patients eligible for the main study will be offered to 
participate in the sub-study(ies). 
Metabolism sub-study, in the US only 
Patients: From 10 to 30 patients eligible for the main study and 
not matching the additional exclusion criterion number 32: 
glucose intolerance. 
Objectives: To assess the effect of macitentan on cardiac and 
arterial metabolism in patients with symptomatic PAH by 
Positron Emission Tomography (PET)-Magnetic Resonance 
(MR) imaging. 
 
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Exploratory endpoints:  
Change from baseline to Week 26 and to Week 52 in: 
- RV 18F-fluorodeoxyglucose (FDG) uptake 
- Aortic 18F-FDG uptake 
- Right common carotid 18F-FDG uptake 
- Left common carotid 18F-FDG uptake 
Biopsy sub-study 
Patients: From 10 to 20 patients eligible for the main study and 
not matching the additional exclusion criterion number 33: PAH 
etiology belonging to Nice classification 1.4.4: PAH associated 
with congenital heart diseases or 1.4.1: PAH associated with 
connective tissue disease. 
Objectives: To assess the histological and biochemical effects 
of macitentan on the endomyocardium of the interventricular 
septum in patients with symptomatic PAH. 
To assess the biochemical effects of macitentan on peripheral 
blood mononuclear cells (PBMC) in patients with symptomatic 
PAH. 
Exploratory endpoints:  
Change from baseline to Week 26 in: 
- Qualitative assessment of endomyocardium function 
markers in biopsies 
- Relative quantitative assessment of endomyocardium 
function markers in biopsies 
- Number of capillaries per cardiomyocyte 
- Mean cardiomyocyte volume 
- Qualitative assessment of cardiomyocytes 
- mRNA transcript analysis 
- PBMC mRNA transcript analysis 
Echo sub-study 
Patients: From 40 to 50 patients eligible for the main study. 
Objective: To assess the effect of macitentan on right and left 
ventricular function by echocardiography in patients with 
symptomatic PAH. 
Exploratory endpoints:  
Change from baseline to Week 26 and Week 52 in: 
- LV eccentricity index at end-diastole 
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- LV eccentricity index at end-systole 
- Minimum diameter of the inferior vena cava (at 
inspiration) 
- Maximum diameter of the inferior vena cava (at 
end-expiration) 
- Tricuspid annular plane systolic excursion (TAPSE) 
- Pericardial effusion size scored from 0 to 4 
- RV acceleration time, by tissue Doppler and pulsed wave 
Doppler 
- RV ejection time, by tissue Doppler and pulsed wave 
Doppler 
- Total RV Systolic Time (duration of tricuspid insufficiency 
jet) 
- Doppler RV index (RV myocardial performance index), by 
tissue Doppler and pulsed wave Doppler 
- Tricuspid peak jet velocity 
- RV systolic pressure (estimated by tricuspid valve 
Doppler) 
- Early diastolic velocity of the jet of pulmonary valve 
regurgitation 
- End-diastolic velocity of the jet of pulmonary valve 
regurgitation 
- Cardiac output determined from LV outflow tract 
- Mitral E-wave velocity 
- Mitral A-wave velocity 
- Mitral annulus peak early diastolic velocity E’ 
- E/A ratio 
- E/E’ ratio 
- 2-dimensional (2D) RV dimension end-diastole 
- Tricuspid peak annular velocity s’ 
- RV end diastolic area 
- RV end systolic area 
- RV fractional area change 
- RVSV determined from pulmonary valve Doppler and 
pulmonary annulus dimension 
- Tricuspid peak E, peak A, deceleration time 
- Tricuspid peak diastolic annular velocities e’, a’ 
- LVEDV determined from 2D measurements 
- LVESV determined from 2D measurements 
- Mitral deceleration time 
NCT02310672

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- Mitral annular plane tissue Doppler velocity a’ 
- 2D Global Longitudinal RV strain 
- 2D circumferential RV strain 
- Time to peak RV strain 
- RVSV 
- RVEDV 
- RVESV 
- RVEF 
- RV mass 
- LVSV 
- LVEDV 
- LVESV 
- LVEF 
- LV mass 
- RVEDV/LVEDV 
- RVESV/LVESV 
NCT02310672

Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
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Confidential  
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Table 1 
Visit and assessment schedule 
PERIODS 
SCREENING 
TREATMENT 
 
FOLLOW-UP 
Duration 
Up to 28 days 
52 weeks 
 
Up to 37 days 
VISITS name 
Screening 
Treatment 
initiation  
RTI visit 
Premature EOT visit (if 
before Week 26 RHC) 
Week 26 visit 
Premature EOT visit 
(if after Week 26 
RHC) 
EOT visit1 
Unscheduled 
visit 
EOS visit 
(phone) 
Time 
Day −28 to 
Day 1 
Day 1 
 
Prior to initiation of 
rescue therapy 
Prem. EOT: latest 7 days 
after decision to end 
study treatment 
Week 26 
(± 14 days) 
Latest 7 days after 
decision to end study 
treatment 
Week 52 
(± 7 days) 
 
30 to 37 days 
after EOT 
Informed consent 
X 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
Demographic & baseline 
characteristics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
X 
X 
X 
X 
X 10 
 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Birth control methods7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam and vital signs 
X 
X 
X 
X 
X 
X 
X 
X 10 
 
6MWT and Borg 
X 
 
X 
X 
X 
X 
X 
X 10 
 
WHO FC 
X 
 
X 
X 
X 
X 
X 
X 10 
 
Cardiac MRI 
X 2 
 
X 2,3,4 
X 2,3,4 
X 2 
X 6 
X 
 
 
RHC 
X 2, 11 
 
X 2,3,4 
X 2,3,4 
X 2 
 
 
 
 
Laboratory tests incl. storage 5 
X 
 
X 
X 
X 
X 
X 
 
 
Liver and hemoglobin tests 
X 
Monthly during the first 6 months 
Recommended monthly 
 
 
Pregnancy test7,8  
 
X 
Monthly 
X 
 
X 
PET-MR scan 
X 9 
 
X 4,9 
X 4,9 
X 9 
X 9 
X 9 
 
 
Biopsy 
X 9 
 
X 3,4,9 
X 3,4,9 
X 9 
 
 
 
 
Echo 
X 9 
 
X 4,9 
X 4,9 
X 9 
X 9 
X 9 
 
 
Study drug dispensing/return 
 
X 
 
X 
X 
X 
X 
 
 
AEs and SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NCT02310672

Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 33/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
6MWT, six-minute walk test; AE, adverse event; EOS, end of study; EOT, end of treatment; MRI, magnetic resonance imaging; PET-MR, positron emission tomography- magnetic resonance; Prem., 
premature; RHC, right heart catheterization; RTI, rescue therapy initiation; SAE, serious AE; WHO FC, World Health Organization functional class. 1. Not performed for patients who had a premature 
EOT previously; 2. Cardiac MRI and RHC must be performed within 21 days of each other; 3. If visit is before Week 16, decision to conduct the exam based on clinical judgment; 4. Done once only 
and replaces Week 26 exam; 5.Stored samples will be destroyed 1 year after the last patient’s last visit; 6.If visit is before Week 48, decision to conduct the exam based on clinical judgment; 7. For 
women of childbearing potential only; 8. Pregnancy tests will be done using the monthly blood draws where applicable, and with urine pregnancy tests otherwise; 9. For patients in the respective sub-
study only; 10. Assessed if clinically indicated; 11. RHC data obtained at study site between Day −28 and Day 1, prior to obtaining signed informed consent, are acceptable. 
NCT02310672

Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 34/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
PROTOCOL 
1 
BACKGROUND 
1.1 Indication 
1.1.1 Pulmonary arterial hypertension 
The most serious chronic disorder of the pulmonary circulation is pulmonary arterial 
hypertension (PAH), a syndrome of diverse etiology and pathogenesis characterized by a 
progressive increase in pulmonary arterial pressure (PAP) and in pulmonary vascular 
resistance (PVR) potentially leading to right heart failure and death [Benza 2010, 
Kylhammar 2014, Oudiz 2013]. 
PAH is associated with structural changes in both pulmonary vasculature and right 
ventricle. The changes in vascular structure involve three combined elements: 
vasoconstriction, vascular-wall remodeling, and thrombosis in situ [Humbert 2004]. The 
changes in the right ventricle mainly consist of hypertrophy, dilation, altered contractility 
and septal bowing [Rich 2012, Franco 2012, Vonk-Noordegraaf 2011]. Collectively these 
changes of the right ventricle are termed remodeling. 
PAH is hemodynamically defined as a resting mean pulmonary arterial pressure (mPAP) 
greater than 25 mmHg with normal pulmonary capillary or left atrial pressure 
(< 15 mmHg) and a PVR greater than 3 Woods Units (WU) [Hoeper 2013]. 
The updated clinical classification of pulmonary hypertension (PH; Nice 2013) 
[Simonneau 2013] classifies the numerous conditions that are known to lead or be 
associated with the development of PAH into 4 groups, based on their similar clinical 
presentation, pathology, pathophysiology, prognosis and, most of all, similar therapeutic 
approach. PAH may occur in the absence of a demonstrable cause (idiopathic), in a 
familial setting (heritable), as the result of the use of drugs and toxins, or it can be 
associated with a connective tissue disease, HIV infection, portal hypertension, 
congenital heart disease, or schistosomiasis. 
1.1.2 Treatments 
Currently, there is no cure for PAH. However, recent advances in the understanding of 
the pathogenic factors leading to the pulmonary vascular disease have led to the 
development of new therapies targeting specific pathways (prostacyclin pathway, 
endothelin pathway, and nitric oxide pathway) [Galiè 2013] that are believed to play 
important pathogenic roles. 
Several agents are currently approved for the treatment of PAH in the United States, 
Europe, and Australia. Intravenous (i.v.) prostacyclin (epoprostenol), prostanoid analogs, 
i.e., treprostinil (i.v., subcutaneous [s.c.], inhaled and oral), and iloprost (i.v. and inhaled), 
NCT02310672

Macitentan / ACT-064992 
Pulmonary arterial hypertension 
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dual endothelin receptor antagonists (ERAs; bosentan and macitentan), a selective ERA 
(ambrisentan), phosphodiesterase type 5 (PDE-5) inhibitors (sildenafil and tadalafil), and 
more recently, a stimulator of soluble guanylate cyclase (riociguat). 
Vasodilators, such as calcium channel blockers, are effective only in a minority of 
patients who have an acute response to vasodilator testing [Rich 1992, Sitbon 2005]. 
Despite these achievements, PAH remains a serious life-threatening condition 
[Galiè 2013, Benza 2010], and new compounds continue to be explored. 
1.2 Study treatment 
1.2.1 Endothelin pathway 
Endothelin-1 (ET-1), a 21 amino acid-peptide, is one of the most potent vasoconstrictors 
and mitogens for smooth muscle, and contributes to increased vascular tone and 
proliferation in pulmonary vasculopathy [Galiè 2004]. 
There are two distinct receptors for ET-1, endothelin receptor A (ETA) and endothelin 
receptor B (ETB). Each receptor has unique binding location and affinity for the 
endothelin peptide [Benigni 1995, Massaki 1998]. 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, 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 mediate the mitogenic action of ET-1 [Clarke 1989, Chua 1992, 
Davie 2002, Sugawara 1996]. 
Laboratory and clinical investigations have 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]. 
1.2.2 Macitentan 
Macitentan is approved for the treatment of PAH in the US, EU, Australia, Canada, 
Japan, Switzerland, New Zealand, Mexico, Israel, Kuwait, South Korea, Argentina, 
Chile, Singapore, Taiwan, Turkey, Russia, Columbia, Morocco, and Hong Kong. 
NCT02310672

Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
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Confidential  
EudraCT 2014-004066-20 
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1.2.2.1 Nonclinical results 
Macitentan is an orally active, non-peptide, potent dual ETA and ETB receptor 
antagonist. Macitentan showed dose dependent efficacy in nonclinical models of 
hypertension and PH. In nonclinical safety studies, no effects on normal physiological 
functions or ECG variables, including cardiac repolarization, were observed, with the 
exception of a decrease in arterial blood pressure observed in a cardiovascular study in 
dogs. Macitentan has no genotoxic and no carcinogenic 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. 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]. 
1.2.2.2 Phase 1 results 
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. 
More detailed information on macitentan can be found in the IB [Macitentan IB]. 
1.2.2.3 Phase 2 results 
Phase 2 studies were conducted in patients with mild-to-moderate essential hypertension, 
and in patients with idiopathic pulmonary fibrosis (IPF). In both indications, macitentan 
was well tolerated across all dose levels, ranging from 0.3 mg to 10 mg. 
A Phase 2 dose-finding study [Macitentan IB] was conducted in patients with 
mild-to-moderate essential hypertension. In this study, treatment with the 10 mg dose of 
macitentan was associated with a statistically significant reduction (versus placebo) from 
baseline to Week 8 in mean sitting diastolic blood pressure at trough, which was the 
primary endpoint of the study. Macitentan was well tolerated with an overall frequency of 
AEs similar to that observed in the placebo group. The numbers of patients with at least 
one serious adverse event (SAE) were evenly distributed across active treatment groups. 
There were no deaths. 
In a Phase 2 study in patients with IPF [Raghu 2013], the primary endpoint (change in 
forced vital capacity [FVC]) was not met, but it was shown that macitentan treatment 
with 10 mg dose was well tolerated. Overall, the safety profile was similar in the 
macitentan 10 mg and placebo groups. The incidence of treatment-emergent AEs was 
similar in both groups. 
More detailed information on macitentan can be found in the IB [Macitentan IB]. 
NCT02310672

Macitentan / ACT-064992 
Pulmonary arterial hypertension 
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1.2.2.4 Phase 3 efficacy results 
Effectiveness was established in a long-term study in PAH patients with predominantly 
WHO Functional Class (FC) II-III symptoms treated for an average of 2 years 
[Pulido 2013]. Patients had idiopathic or heritable PAH (57%), PAH caused by 
connective tissue disorders (31%), and PAH caused by congenital heart disease with 
repaired shunts (8%) and were treated with macitentan monotherapy or in combination 
with PDE-5 inhibitors or inhaled prostanoids. 
The trial demonstrated that macitentan 10 mg reduces the risk of morbidity/ mortality in 
patients with symptomatic PAH, with a hazard ratio versus placebo of 0.547, 97.5% 
confidence limits (CLs) 0.392–0.762, p < 0.0001. This represents a risk reduction of 
45%. 
The placebo-corrected mean change in 6-minute walk distance (6MWD) from baseline to 
Month 6 showed an increase of 22.0 m (97.5% CLs 3.2, 40.8) with macitentan 10 mg 
versus placebo. 
A hemodynamic sub-study showed a reduction of PVR from baseline to Month 6 of 
36.5%, CLs 21.7–49.2) with macitentan 10 mg. 
More detailed information on macitentan can be found in the IB [Macitentan IB]. 
1.2.2.5 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 the 3 placebo-controlled studies with macitentan, no significant imbalance in liver test 
elevations was observed across macitentan treatment groups and placebo. The 
proportions of patients with alanine aminotransferase (ALT) and/or aspartate 
aminotransferase (AST) elevations > 3 × upper limit of the normal range (ULN) were 
similar across the treatment groups, but a higher percentage of patients treated with 
macitentan 10 mg had ALT > 3 × ULN compared to placebo. However, there were no 
patients in the studies who met the Hy’s Law criteria (i.e., ALT/AST > 3 × ULN and total 
bilirubin > 2 × ULN), and who had no associated increase in alkaline phosphatase in the 
absence of alternative explanations which were possibly or likely the cause of the 
elevations. Patients with serum AST and/or ALT > 3 × ULN are excluded from the study, 
and monthly liver tests are mandatory during the first 6 months and recommended 
thereafter. The protocol also includes clear instructions regarding re-tests and criteria for 
treatment 
discontinuation 
in 
the 
case 
of 
clinically 
relevant 
elevations 
of 
aminotransferases. 
NCT02310672

Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
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Treatment with ERAs has been associated with increased incidence of edema, anemia 
and/or decreased hemoglobin [Abman 2009, O’Callaghan 2011]. Treatment with 
macitentan was associated with a dose-related reduction in hemoglobin levels, which was 
established within the first 3 months of treatment. Decreased hemoglobin levels tended to 
show recovery towards baseline after discontinuation of treatment. Higher incidences of 
anemia AEs were reported in a dose-related fashion in the patients treated with 
macitentan in comparison to those treated with placebo. Anemia required transfusion in 
some patients treated with macitentan. Patients with hemoglobin < 100 g/L are excluded 
from the study. Monthly hemoglobin tests are mandatory during the first 6 months and 
recommended thereafter. The protocol also includes clear instructions regarding re-tests 
and criteria for treatment discontinuation in the case of clinically relevant anemia. 
The incidences of edema AEs were similar in the macitentan and placebo groups, 
although subgroup analyses indicated fluctuations in the incidence of edema, with no 
clear pattern according to treatment (macitentan versus placebo) or macitentan dose. 
Edema SAEs were uncommon with macitentan treatment and only 3 patients (2 on 
placebo and 1 on macitentan 10 mg) discontinued treatment due to an edema AE. 
Overall, there is no indication that edema represents a significant safety concern with 
macitentan therapy in PAH. 
Due to the vasodilatory effects of macitentan, effects on blood pressure might occur. In 
patients with normal blood pressure prior to initiation of macitentan treatment, there was 
a slightly higher incidence of AEs denoting hypotension, relative to placebo on 
macitentan. However, hypotension SAEs were reported less frequently on macitentan 
than on placebo, and only one macitentan-treated patient discontinued due to this AE. 
Hypotension AEs were predominantly reported for female patients and there was no 
indication of an increased incidence in other potentially vulnerable subgroups, such as the 
elderly, or patients with renal function impairment at baseline. Patients with systolic 
blood pressure < 90 mmHg are excluded from the study. 
Reductions from baseline in leukocyte and platelet counts may be observed with 
macitentan. In the AC-055-302 / SERAPHIN study, macitentan was associated with 
modest and non-dose-dependent decreases in mean leukocyte count from baseline to End 
of Treatment (EOT). A small proportion of PAH patients, in both placebo and macitentan 
groups, showed markedly reduced platelet counts, with or without bleeding 
complications, at some time during the study. Resolution during continued treatment with 
macitentan was observed, as well as absence of recurrence after treatment re-initiation, 
findings that make a specific, causal relationship to macitentan unlikely. 
In the AC-055-302 / SERAPHIN study, menstrual disorder AEs (mainly menorrhagia, 
metrorrhagia, and dysfunctional bleed) and ovarian cysts were reported at a low 
incidence overall, but more frequently on macitentan than placebo, in females of 
NCT02310672

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Pulmonary arterial hypertension 
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childbearing potential. None of the events led to discontinuation of study drug, there was 
no consistent drug-dose or drug-exposure pattern, and resolution of menstrual disorder 
during ongoing treatment was reported in the majority of cases. Confounding factors 
were present in the majority of these cases. A causal relationship to macitentan remains 
uncertain. 
In clinical trials, a higher reporting rate of upper respiratory tract infections but also 
bronchitis was seen with macitentan versus placebo. It is likely that many such events 
may represent symptoms of congestion due to local vasodilatation (e.g., rhinitis), rather 
than actual infection. For the clinically more relevant lower respiratory tract infections, 
specially pneumonia, there was no relevant difference between macitentan and placebo. 
In addition, there was a higher incidence of urinary tract infections and gastroenteritis in 
the patients who received macitentan treatment compared to those who received placebo. 
However, given that there was no imbalance in the incidence of these events that were 
reported as SAEs or that led to discontinuation of treatment, coupled with the fact that 
there was no increase in the reporting rate over time, these AEs were considered to be of 
limited clinical relevance. 
Given the extensive and long-term controlled data available with macitentan in PAH and 
the careful follow-up of patients mandated by the protocol, the benefit/risk assessment 
supports the use of macitentan in the current study. 
1.3 Purpose and rationale of the study 
1.3.1 Purpose of the study 
The purpose of the study is to further extend the knowledge of macitentan by assessing 
the effects of macitentan on the cardiac muscle, and specifically on the right ventricle. 
1.3.2 Rationale 
1.3.2.1 Importance of the right ventricle in PAH 
The pathophysiologic mechanisms of PAH are initiated by progressive obstructive 
changes of the pulmonary vasculature which result in increased afterload of the right 
ventricle. The right ventricle responds by remodeling with increased contractility. 
Progressively, this increased contractility is no longer sufficient to maintain an 
appropriate blood supply, the right ventricle hypertrophies, which translates into a thicker 
myocardium. Dilation is then achieved to increase the blood volume in the right ventricle. 
Gradually, the right ventricle becomes more spherical so that the septum between right 
and left ventricles flattens. Right ventricular remodeling compensates for a variable 
period of time but ultimately may no longer suffice, leading to right heart failure and 
death. 
NCT02310672

Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
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Although PAH is a disease of the pulmonary vasculature, the geometry and function of 
the right ventricle are tightly linked with survival [Van Wolferen 2007, Yamada 2012, 
Swift 2014, Raymond 2002, Van de Veerdonk 2011]. In fact, the primary cause of death 
in PAH is right ventricular failure. The function of the right ventricle is, therefore, of 
critical importance in this condition. 
While the safety and efficacy of macitentan have been studied in PAH clinical trials, its 
effects on the right ventricle are yet to be determined. 
The capacity of the right ventricle to undergo reverse remodeling has been described in 
PAH patients who underwent lung transplant [Kasimir 2004], and in patients with PAH 
treated with single [Wilkins 2005, Galiè 2003, Van Wolferen 2006, Hinderliter 1997, 
Roeleveld 2004, Blalock 2010] or combined PAH-targeted therapies [Peacock 2014]. 
It therefore seems reasonable to hypothesize that macitentan reverses right ventricular 
remodeling. 
1.3.2.2 Pulmonary vascular resistance 
PAH is characterized by an increased resistance to blood flow in the pulmonary 
vasculature, quantified by PVR. PVR represents the resistance against which the right 
ventricle needs to pump. In PAH, a decrease in PVR is therefore beneficial for the right 
ventricle. 
PVR is determined by right heart catheterization (RHC). Since this procedure is 
indispensable for the diagnosis of PAH and to evaluate treatment response [Galiè 2013], 
sites treating PAH patients are well experienced with RHC. The study will be run in sites 
specialized in PAH. RHC procedures in patients with PH in experienced centers are 
reported to be associated with low morbidity and mortality rates [Hoeper 2006] and 
deemed acceptable in this study. 
1.3.2.3 Cardiac magnetic resonance imaging 
Cardiac magnetic resonance imaging (cardiac MRI) is a safe imaging technique as it is 
non-invasive and does not use ionizing radiations. Images of slices in any plane can be 
obtained with very good spatial and temporal resolution. This translates into a low 
variability of inter-study and inter-rater cardiac MRI assessments which allows a reduced 
sample size for clinical trials compared to other imaging tools [Addetia 2014]. 
Cardiac MRI is, therefore, the method of choice to study the evolution of the right 
ventricle under treatment. 
1.3.2.4 Ventriculo-arterial coupling 
Beyond the measurement of volumes, a more comprehensive understanding of the 
balance between right ventricle and the arterial system can be achieved by considering 
NCT02310672

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ventriculo-arterial coupling, which is quantified by the ratio of ventricular end-systolic 
elastance to arterial elastance [Foëx 1994]. Ventricular end-systolic elastance represents 
the intrinsic, load-independent contractility of the ventricle. Likewise, arterial elastance 
represents the load from the pulmonary vasculature that the right ventricle faces. 
Elastances are determined from the relationship between volume and pressure in the 
ventricle. While volume can be measured by cardiac MRI [Trip 2013], the determination 
of pressure requires RHC [Sunagawa 1980, Takeuchi 1991, Kuehne 2004, 
Brimioulle 2003]. Determination of ventriculo-arterial coupling does not require any 
additional procedure for the patient beside cardiac MRI and RHC, which are part of the 
study. 
1.3.2.5 Up-front combination therapy 
Based on recent data [Galiè 2014], targeting more than one disease pathway from initial 
diagnosis may be beneficial. 
Thus, combination of a PDE-5 inhibitor and an ERA in a treatment-naïve patient is 
allowed. 
1.3.2.6 Overall benefit-risk ratio 
Given the data available with macitentan in PAH, the careful follow-up of patients 
mandated by the protocol and the acceptable risks of the study procedures, the 
benefit/risk assessment supports the conduct of the current study. 
2 
STUDY OBJECTIVES 
2.1 Primary objective 
The primary objective of the study is to evaluate the effect of macitentan on right 
ventricular and hemodynamic properties in patients with symptomatic PAH. 
2.2 Secondary objective 
To evaluate the safety and tolerability of macitentan in patients with symptomatic PAH. 
2.3 Exploratory objectives 
To investigate the effect of macitentan on disease-related circulating biomarkers in 
patients with symptomatic PAH. 
To explore a potential association between change in right ventricular properties and 
clinical outcome in patients with symptomatic PAH. 
To investigate the effect of macitentan on ventriculo-arterial coupling in patients with 
symptomatic PAH. 
To evaluate the effect of macitentan on LV properties in patients with symptomatic PAH. 
NCT02310672

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2.4 Sub-studies rationale and objectives 
2.4.1 Metabolism sub-study (in selected US sites only) 
2.4.1.1 Rationale 
In PAH, right ventricle hypertrophy causes a greater oxygen requirement. This induces an 
adaptation of the metabolic pathways by a shift from fatty acid to glucose consumption 
[Archer 2013]. Glucose consumption can be assessed by Positron Emission Tomography 
(PET) [Bokhari 2011]. 
2.4.1.2 Objectives 
To assess the effect of macitentan on cardiac and arterial metabolism in patients with 
symptomatic PAH by PET-MR imaging. 
2.4.2 Biopsy sub-study 
2.4.2.1 Rationale for taking biopsies 
Right ventricular remodeling is associated with tissue changes such as fibrosis, capillary 
rarefaction and with changes at the cellular and sub-cellular level, for example changes in 
cardiomyocyte size and mitochondrial morphology. In addition, there are expression 
changes in the messenger RNA (mRNA) encoding receptor and enzyme proteins and 
expression changes in functionally important proteins. 
Biopsies may bring complementary information that could not be obtained by other 
means. There are inherent risks to biopsies of the endomyocardium of the interventricular 
septum, such as perforation of the septum. Risks are further mitigated here by involving 
only sites with solid experience in this sub-study. Therefore, the risks are deemed 
acceptable. 
2.4.2.2 Rationale for mRNA transcript analysis 
The functioning of cells is governed by proteins such as enzymes, receptors or hormones. 
mRNA transcript analysis allows the identification of proteins synthetized in cells. 
In this study, mRNA transcript analysis is performed both in endomyocardial cells and in 
peripheral blood mononuclear cells (PBMC) in order to compare proteins and expressed 
mRNA in PBMC with those expressed in the endomyocardial cells and to test the 
hypothesis that the expression pattern of the peripheral circulating PBMC may reflect 
changes observed in the endomyocardium and thus serve as a surrogate for the heart 
tissue sample in the assessment of targets influenced by macitentan treatment. 
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2.4.2.3 Objectives 
To assess the histological and biochemical effects of macitentan on the endomyocardium 
of the interventricular septum in patients with symptomatic PAH. 
To assess the biochemical effects of macitentan on PBMC in patients with symptomatic 
PAH. 
2.4.3 Echo sub-study 
2.4.3.1 Rationale 
Three-dimensional (3D), 2-dimensional (2D), M-mode and Doppler echocardiography 
allow to assess the geometry and function of the right and left ventricles, thereby offering 
the potential to further extend the knowledge of the effects of macitentan on the heart in 
PAH. 
2.4.3.2 Objective 
To assess the effect of macitentan on right and left ventricular function by 
echocardiography in patients with symptomatic PAH. 
3 
OVERALL STUDY DESIGN AND PLAN 
3.1 Study design  
This is a prospective, multi-center, single-arm, open-label, Phase 4 study to evaluate the 
effects of macitentan on right ventricular remodeling in PAH assessed by cardiac 
magnetic resonance imaging. 
One hundred patients will be enrolled in approximately 50 sites in approximately 
12 countries in Asia, Australia, Europe, and North America. Enrollment will be 
competitive across participating sites. 
The study consists of the following time points and periods: 
Screening commences from signature of the Informed Consent Form (ICF) and ends 
with study treatment initiation (up to 28 days after informed consent signature). 
Baseline: baseline values are those from the inclusion RHC and those collected during 
screening or at Treatment Initiation Visit (Day 1) before initiation of study treatment. 
Treatment Period starts with the 1st dose of study drug (Day 1 of study) and ends with 
EOT on the day of the last dose of study drug which is at premature discontinuation of 
study drug or Week 52 ± 7 days. For patients prematurely discontinuing study drug, an 
EOT visit must be organized as soon as possible and no later than 7 days after the 
decision to end study treatment. 
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The Safety follow-up period starts immediately after the last dose of study drug and 
ends 30 to 37 days after EOT, with End of Study (EOS) Visit. For patients who withdraw 
their consent, the investigator will seek agreement to conduct the safety follow-up. 
EOS for a patient is the end of safety follow-up, or date of death, or date of consent 
withdrawal, or date of last contact for patients lost to follow-up. 
Sub-studies 
As part of this protocol, three sub-studies will be conducted in selected centers. In these 
centers, all patients eligible for the main study will be offered to participate in the 
sub-study(ies). 
1. Metabolism sub-study (selected US sites only). 
2. Biopsy sub-study. 
3. Echo sub-study. 
Study Duration 
For an individual patient, treatment duration will be up to 371 days. Patient participation 
in the study will be approximately 14 months. Once the study treatment is finished, 
patients will receive local standard medical care. 
The overall study ends with the last patient’s last visit.  
An interim analysis will be conducted when 42 patients have available assessment data 
for both primary endpoints. If the interim analysis concludes that the study is positive on 
both primary endpoints, enrollment may stop. Otherwise, the study will continue until 
100 patients are enrolled. The decision to stop or continue the study will be taken jointly 
by the Steering Committee and the sponsor, considering statistical analysis results as well 
as clinical expertise. 
The overall study design is depicted in Figure 1. 
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Figure 1 
Study design 
 
 
 
 
 
 
ICF, informed consent form (signature); EOT, end of treatment; EOS, end of study. 
3.2 Study design rationale 
Cardiac MRI allows the assessment of right ventricular geometry and function, with a 
low 
between-study 
[Grothues 
2003, 
Bradlow 2010] 
and 
between-observer 
[Bradlow 2010] variability. It is, therefore, the method of choice for assessing right 
ventricular remodeling. 
Non-controlled, open-label trials are classically used in imaging studies that assess 
cardiac changes in PAH [Wilkins 2005, Van Wolferen 2006, Hinderliter 1997, 
Roeleveld 2004, Blalock 2010, Peacock 2014]. 
Open-label trials have a potential for bias. Bias in the assessment of the primary endpoint 
is reduced by the use of objective measurements. 
Objectivity of cardiac MRI images assessment is ensured by central assessment of images 
by assessors who are blinded to the patient and time point of the cardiac MRI, i.e., before 
or during treatment. Since PAH is a progressive disease, a reverse remodeling is not 
expected to be observed unless it is induced by a treatment. Therefore, patients may be 
used as their own control, i.e., a patient’s post-baseline values may be compared to the 
corresponding baseline values. 
To ensure that the effects observed on the right ventricle are due to the newly introduced 
treatment, eligibility criteria are designed to select for: 
• Treatment-naïve patients, who may initiate macitentan alone or combined with a 
PDE-5 inhibitor;  
• And patients on a stable dose of PDE-5 inhibitors, who will initiate macitentan only. 
The primary endpoint is defined at 26 weeks because it is deemed late enough to observe 
a relevant change and early enough to have a relatively low proportion of patients 
ICF 
EOS
EOT Visit 
52 weeks ± 7 days 
Treatment Initiation
Visit - Day 1 
Screening
Up to 28 days 
Treatment 
52 weeks ± 7 days
Follow-up 
30 days 
Week 26 Visit 
26 weeks ± 14 days  
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dropping out for the primary endpoint, either by discontinuing study treatment or by 
initiating additional PAH therapy. 
The endpoints defined at 52 weeks aim to determine whether the treatment effect at 
26 weeks is maintained at 52 weeks. 
3.3 Site personnel and their roles 
• The site physician will conduct physical examinations. 
• The site physician or nurse will administer the 6-minute walk test (6MWT). 
• Study-mandated RHCs will be performed by an experienced cardiologist or surgeon 
designated by the site. 
• Cardiac MRI will be performed by an experienced imaging specialist designated by 
the site. 
In the corresponding sub-studies: 
• PET-MR scan will be done by an experienced imaging specialist designated by the 
site. 
• The biopsy will be done by the person conducting the RHC. 
• Echo will be done by a specialist designated by the site. 
3.4 Study committees  
3.4.1 Steering Committee 
A Steering Committee is involved in the design of the study, will provide guidance on 
study conduct and interpretation of results, and will support study publications. The 
committee is governed by a steering committee charter. 
3.4.2 Central imaging 
Central imaging committees composed of trained imaging specialists have been 
appointed by Actelion to assess the following variables according to a dedicated charter: 
• Cardiac MRI results: (analyzed by the Image Analysis Center [IAC]). 
• Pressure-volume relationships (analyzed by the IAC). 
• Variables that are specific to the metabolism sub-study. 
• Echo results. 
3.4.3 Independent Liver Safety Data Review Board 
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 (HAESI) that require further evaluation during 
the study (as per ILSDRB charter). 
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4 
PATIENT POPULATION 
4.1 Patient population description 
Adult and elderly patients will be enrolled with idiopathic PAH, heritable PAH, 
drug- and toxin-induced PAH, PAH associated with connective tissue disease or PAH 
associated with congenital heart diseases under certain conditions [see Section 4.3]. 
It is planned to enroll 100 patients. In case of insufficient recruitment, additional sites 
may be invited to participate in the study. 
4.2 Rationale for the selection of the study population 
Patients included must have WHO group I PAH, in accordance with the approved 
indication for macitentan. The PAH etiologies selected have very similar characteristics, 
although patients with PAH associated with connective tissue disease suffer from diverse 
comorbidities and their prognosis is worse [Benza 2010, Fisher 2006]. In systemic 
sclerosis, right ventricular function is more depressed [Hassoun 2009, Tedford 2013, 
Fisher 2006] with a lower contractility [Overbeek 2008]. The prevalence of pericardial 
effusion is also higher [Fisher 2006]. Despite the specificities of PAH associated with 
connective tissue disease, recent data using cardiac MRI have shown a significant 
treatment effect of combination therapy in a sub-population of patients with PAH 
associated with connective tissue disease without significant restrictive or obstructive 
lung disease [Hassoun 2015].  
Furthermore, previous PAH treatments are limited to PDE-5 inhibitors only, in order to 
capture the full effect of the newly added treatment. The absence of clinically relevant 
interaction between macitentan and the PDE-5 inhibitor sildenafil and its metabolite 
(N-desmethyl-sildenafil) has been shown [Macitentan IB]. 
The study population is, therefore, expected to be relatively homogeneous and suitable to 
achieve the study objectives. 
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 patient: 
1. Signed informed consent prior to any study-mandated procedure. 
2. Symptomatic PAH. 
3. WHO FC I to III. 
4. PAH etiology belonging to one of the following groups according to Nice 
classification: 
1.1 Idiopathic PAH 
1.2 Heritable PAH 
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1.3 Drug- and toxin-induced PAH 
1.4.1 PAH associated with connective tissue disease 
1.4.4 PAH associated with congenital heart diseases: only simple (atrial septal 
defect, ventricular septal defect, patent ductus arteriosus) congenital systemic to 
pulmonary shunts at least 2 year post surgical repair. 
5. Hemodynamic diagnosis of PAH confirmed by RHC performed between Day −28 
and Day 1 (inclusion RHC; RHC data obtained at study site within this time frame, 
prior to obtaining signed informed consent, are acceptable) showing: 
• mPAP ≥ 25 mmHg and 
o Pulmonary capillary wedge pressure (PCWP) or left ventricular end 
diastolic 
pressure 
(LVEDP) 
≤ 12 mmHg 
and 
PVR 
≥ 4WU 
(320 dyn.sec.cm-5) or 
o 12 mmHg ≤ PCWP or LVEDP ≤ 15 mmHg and PVR ≥6 WU 
(480 dyn.sec.cm-5). 
6. 6MWD ≥ 150 m during screening. 
7. For patients treated with oral loop diuretics, treatment dose must have been stable at 
least 1 month prior to the inclusion RHC. 
8. For patients treated with PDE-5 inhibitors, treatment dose must have been stable at 
least 3 months prior to the inclusion RHC (initiation of PDE-5 inhibitors during 
screening is allowed after all screening assessments have been performed). 
9. For patients treated with beta blockers, treatment dose must have been stable at least 
1 month prior to the inclusion RHC. 
10. Men or women ≥ 18 and < 75 years. For patients aged ≥ 65 and < 75 years, an 
eligibility form [Appendix 7] will be submitted to a Steering Committee member who 
will reserve the right to exclude the patient. 
11. Women of childbearing potential [see Section 4.5.1] must: 
a. Have a negative serum pregnancy test at screening and a negative urine 
pregnancy test on Day 1, and 
b. Agree to use reliable methods of contraception [see Section 4.5] 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. 
4.4 Exclusion criteria 
Patients must not fulfill any of the following exclusion criteria. It is not permitted to 
waive any of the criteria for any patient: 
1. Body weight < 40 kg. 
2. Body mass index (BMI) > 35kg/m2. For patients with 30kg/m2 < BMI < 35kg/m2, an 
eligibility form will be submitted to a Steering Committee member who will reserve 
the right to exclude the patient [Appendix 7]. 
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3. Pregnancy, breastfeeding, or intention to become pregnant during the study. 
4. Recently started (< 8 weeks prior to informed consent signature) or planned 
cardio-pulmonary rehabilitation program. 
5. Known concomitant life-threatening disease with a life expectancy < 12 months. 
6. Any condition likely to affect protocol or treatment compliance. 
7. Hospitalization for PAH (except for diagnosis of PAH) within 3 months prior to 
informed consent signature. 
8. Left atrial volume indexed for body surface area (BSA) ≥ 43mL/m2 by 
echocardiography or cardiac MRI. 
9. Moderate to severe left-heart valvular disease. 
10. History of pulmonary embolism or deep vein thrombosis. 
11. Presence of one or more of the following signs of relevant lung disease at any time up 
to screening: 
− Diffusing capacity of the lung for carbon monoxide (DLCO) < 40% of predicted 
(eligible only if no or mild interstitial lung disease on computed tomography). 
− FVC < 60% of predicted. 
− Forced expiratory volume in one second (FEV1) < 60% of predicted. 
12. Moderate to severe restrictive lung disease (i.e., total lung capacity < 60% of 
predicted value) at any time prior to enrollment. 
13. Historical evidence of significant coronary artery disease established by: 
− History of myocardial infarction or 
− More than 50% stenosis in a coronary artery (by percutaneous coronary 
intervention or angiography) or 
− Elevation of the ST segment on electrocardiogram or 
− History of coronary artery bypass grafting or 
− Stable angina. 
14. Known uncontrolled diabetes mellitus (in the opinion of the investigator). 
15. Severe renal insufficiency (calculated creatinine clearance < 30 mL/min). 
16. Cancer. 
17. Systolic blood pressure < 90 mmHg. 
18. Severe hepatic impairment (with or without cirrhosis) according to National Cancer 
Institute organ dysfunction working group criteria, defined as total bilirubin 
> 3 × ULN accompanied by an AST elevation > ULN at screening 
19. Hemoglobin < 100 g/L. 
20. Serum AST and/or ALT > 3 × ULN. 
21. Need for dialysis. 
22. Responders to acute vasoreactivity test based on medical history. 
23. Prior use of ERAs, stimulators of soluble guanylate cyclase or prostacyclin or 
prostacyclin analogs. 
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24. Treatment with strong inducers of cytochrome P450 isozyme 3A4 (CYP3A4) within 
4 weeks prior to study treatment initiation (e.g., carbamazepine, rifampicin, rifabutin, 
phenytoin and St. John’s Wort). 
25. Treatment with strong inhibitors of CYP3A4 within 4 weeks prior to study treatment 
initiation 
(e.g., 
ketoconazole, 
itraconazole, 
voriconazole, 
clarithromycin, 
telithromycin, nefazodone, ritonavir, and saquinavir). 
26. Treatment with another investigational drug (planned, or taken within the 3 months 
prior to study treatment initiation). 
27. Hypersensitivity to any ERA or any excipients of the formulation of macitentan 
(lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch 
glycolate, polyvinyl alcohol, polysorbate, titanium dioxide, talc, xanthan gum, and 
lecithin soya). 
28. Claustrophobia. 
29. MRI-incompatible permanent cardiac pacemaker, automatic internal cardioverter. 
30. Metallic implant (e.g., defibrillator, neurostimulator, hearing aid, permanent use of 
infusion device). 
31. Atrial fibrillation, multiple premature ventricular or atrial contractions, or any other 
condition that would interfere with proper cardiac gating during MRI. 
32. For patients enrolling in the metabolism sub-study only: glucose intolerance. 
33. For patients enrolling in the biopsy sub-study only: PAH etiology belonging to 
Nice classification 1.4.4: PAH associated with congenital heart diseases or 1.4.1: 
PAH associated with connective tissue disease. 
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 Asia 
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 
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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. 
4.5.3 North America and Australia 
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 IUD 
 
Estrogen and 
 
Diaphragm with 
 
Partner’s vasectomy 
(Copper T380A IUD) 
Intrauterine system 
 
progesterone oral 
contraceptives (“the  
 
spermicide 
Cervical cap with  
 
PLUS one method 
from this list: 
(LNg 20IUS: 
 
pill”) 
 
spermicide 
 
Male condom 
progesterone IUS) 
Progesterone implant 
 
Estrogen and 
progesterone  
 
PLUS one method 
from this list: 
 
Diaphragm with 
spermicide 
Tubal sterilization 
 
transdermal patch 
 
Male condom 
 
Cervical cap with 
 
 
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  
 
 
 
Estrogen and 
progesterone 
transdermal patch  
spermicide 
Vaginal ring  
 
 
 
 
 
 
Progesterone injection 
IUD, intrauterine device; IUS, intrauterine system. 
4.6 Patient population in sub-studies 
4.6.1 Metabolism sub-study 
Between 10 and 30 patients enrolled in the main study will also be enrolled in the 
metabolism sub-study. For this sub-study, patients with glucose intolerance are excluded 
because the tracer used for PET-MR imaging is a glucose analog, contra-indicated in 
these patients. 
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4.6.2 Biopsy sub-study 
Between 10 and 20 patients enrolled in the main study will also be enrolled in the biopsy 
sub-study. For this sub-study, patients with PAH etiology belonging to Nice classification 
1.4.4 (PAH associated with congenital heart diseases) or 1.4.1 (PAH associated with 
connective tissue disease) are excluded because their endomyocardium presents 
differences from the endomyocardium in the other etiologies enrolled in the study. 
4.6.3 Echo sub-study 
Between 40 and 50 patients enrolled in the main study will also be enrolled in the Echo 
sub-study. 
5 
TREATMENTS 
5.1 Study treatment 
5.1.1 Investigational treatment: description and rationale 
The study treatment is macitentan 10 mg, for once daily oral administration. 
The dose and regimen are in accordance with product labeling. The efficacy and safety of 
macitentan 10 mg in patients with PAH were demonstrated in the AC-055-302 / 
SERAPHIN study [Pulido 2013]. The risk of a morbidity/mortality event was reduced by 
45% with macitentan 10 mg compared to placebo (p < 0.0001), and the treatment was 
well tolerated. Further details can be found in Section 1.2.2.4 and in the IB 
[Macitentan IB]. 
5.1.2 Study treatment administration 
One tablet of macitentan 10 mg must be taken once daily orally, preferably at the same 
time of the day. Macitentan can be taken with or without food. 
Up- or down-titration does not apply. If a dose is missed, the patient must take it as soon 
as possible that day and take the next dose at the next scheduled time. The patient should 
not take two doses at the same time if a dose has been missed. 
Study assessments will be performed at trough [see Section 7]. 
5.1.3 Treatment assignment 
All patients will receive open-label macitentan 10 mg once daily. 
5.1.4 Patient identification 
When screening a patient, the investigator/delegate contacts the Interactive Response 
Technology (IRT) system which assigns a patient number to the patient. The patient 
number consists of 4 digits identifying the site and 3 digits identifying the patient, 
e.g., 1234567. 
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After having confirmed a patient’s eligibility, and prior to study treatment initiation, the 
investigator/delegate contacts the IRT system which assigns a treatment kit number to the 
patient.  
5.1.5 Blinding 
Not applicable. 
5.1.6 Study treatment supply 
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. 
5.1.6.1 Study treatment packaging and labeling 
5.1.6.1.1 Study treatment packaging 
Study treatment is provided as tablets and supplied in childproof bottles containing 
36 tablets each (1 month supply). At Treatment Initiation Visit and Week 26 visit, 
six bottles will be provided to the patients. 
5.1.6.1.2 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 will have a label with a tear-off part specifying study protocol 
number, batch number, and bottle number. When study medication is issued to the 
patient, the investigator, pharmacist (if applicable), or designee must remove the tear-off 
part and attach it to the Investigational Medicinal Product Label Dispensing Log. 
5.1.6.2 Study treatment storage and distribution 
Treatment supplies must be kept in an appropriate, secure area and stored according to 
the conditions specified on the medication labels. Detailed instructions regarding the 
handling and storage of study treatment are provided in Appendix 5. 
5.1.6.3 Study treatment dispensing 
Patients will receive sufficient study treatment to cover the period up to the next 
scheduled visit. Patients are asked to return all used, partially used and unused study 
bottles at each visit. The protocol-mandated study drug 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 patient must be available for 
inspection at any time. 
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5.1.6.4 Study treatment return and destruction  
On an ongoing basis and/or on termination of the study, the monitor will collect used and 
unused patient 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 Actelion or the deputy, and written permission for destruction has been 
obtained from Actelion. 
5.1.7 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 patient is 
compliant with study requirements. Study treatment accountability is recorded in the 
Case Report Form (CRF) and checked by the monitor during site visits and at the end of 
the study.  
Compliance is based on study treatment accountability. 
Compliance =
(number of tablets provided to patient − number of tablets returned)
Total number of Tablets that should have been taken during the period) × 100  
Compliance with study treatment intake < 80% or > 120% will be considered a deviation 
from the protocol. 
5.1.8 Study treatment 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 5.1.10. 
If study treatment intake is interrupted by the patient for any reason, he/she must 
immediately inform the investigator. 
Interruptions of study treatment must be kept as short as possible, and must be recorded 
in the CRF. An interruption for more than 4 consecutive weeks will lead to permanent 
treatment discontinuation. 
5.1.9 Premature discontinuation of study treatment 
The decision to prematurely discontinue study treatment may be made by the patient, the 
investigator, or Actelion. 
A patient 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. 
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A patient enrolled in a sub-study may discontinue either the sub-study only, or both the 
study and the sub-study. 
The investigator must discontinue study treatment for a given patient if, on balance, 
he/she believes that continued administration would be contrary to the best interests of 
the patient. 
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]. 
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 (e.g., non-compliance with study requirements, such as non-compliance with 
study treatment intake or visit attendance), or if the patient is lost to follow-up. 
study-specific criteria for discontinuation of study treatment are described in 
Section 5.1.10. 
The main reason and whether discontinuation of study treatment is the decision of the 
patient, the investigator, or Actelion must be documented in the CRF. 
A patient who prematurely discontinues study treatment is NOT considered as withdrawn 
from the study and will be followed up until 30 to 37 days after EOT, provided that the 
patient’s consent for this limited participation in the study has not been withdrawn. 
Patients prematurely discontinuing study treatment will be asked to return for a 
Premature EOT Visit within 7 days of decision to end study treatment. The EOS visit will 
take place 30 to 37 days after EOT. 
A patient who prematurely discontinues study treatment and withdraws consent to 
participate in any further study assessments is considered as withdrawn from the study. 
Patients 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 patients withdrawn from the 
study is described in Sections 9.2 and 9.4, respectively. 
5.1.10 Study-specific criteria for interruption / premature discontinuation of study 
treatment 
5.1.10.1 Pregnancy 
If a female patient becomes pregnant while on study drug, study drug must be 
discontinued immediately, and a Pregnancy Form must be completed [see Section 10.3]. 
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5.1.10.2 Liver aminotransferases abnormalities 
Interruption of study drug 
Study drug must be interrupted in the following cases: 
• Aminotransferases (i.e., ALT and/or AST) ≥ 3 and ≤ 8 × ULN without associated 
clinical symptoms of liver injury and without associated increase in total bilirubin 
≥ 2 ×ULN. 
In such a case, a re-test of aminotransferases (ALT and AST), total and direct bilirubin, 
and alkaline phosphatase must be performed within one week. If AST and/or ALT 
elevation is confirmed, monitoring of aminotransferases, total and direct bilirubin, and 
alkaline phosphatase levels must be continued 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 4 consecutive weeks; longer interruptions must lead to 
permanent discontinuation of study drug.  
Reintroduction of study treatment after treatment interruption should only be considered 
if the potential benefits of treatment with macitentan outweigh the potential risks and 
when liver aminotransferase values are within pre-treatment levels or within normal 
ranges. The advice of a hepatologist is recommended. 
Liver aminotransferase levels must then be checked within 3 days after reintroduction, 
then again after a further 2 weeks and thereafter according to the protocol 
[Section 7.3.5.2]. 
Permanent discontinuation of study drug 
Study drug must be stopped and its reintroduction is not to be considered in the following 
cases: 
• Aminotransferases > 8 × ULN. 
• Aminotransferases ≥ 3 × ULN and associated clinical symptoms of liver injury, 
e.g., nausea, vomiting, fever, abdominal pain, jaundice, anorexia, dark urine, itching, 
unusual lethargy or fatigue, flu like syndrome (arthralgia, myalgia, fever). 
• Aminotransferases ≥ 3 × ULN and associated increase in total bilirubin ≥ 2 ×ULN. 
In such cases, aminotransferases, total and direct bilirubin, and alkaline phosphatase 
levels must be monitored weekly after study drug discontinuation until values return to 
pre-treatment levels or within normal ranges. 
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Other diagnoses (e.g., viral hepatitis, mononucleosis, toxoplasmosis, cytomegalovirus) 
and/or etiologies (e.g., acetaminophen-related liver toxicity) must be considered and 
ruled out by performing the appropriate tests. 
All liver aminotransferases abnormalities leading to study drug interruption or 
discontinuation must be recorded as AEs [see Section 10]. 
An ILSDRB (an external expert committee of hepatologists) provides ongoing 
assessment and advice regarding serious HAESI that require further evaluation during the 
study (as per ILSDRB charter).  
5.1.10.3 Hemoglobin abnormalities 
In case of hemoglobin decrease from baseline1 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 drug should be temporarily interrupted if clinically mandated based on the 
investigator’s judgment, or in any of the following situations: 
• A decrease in hemoglobin to < 80 g/L (< 4.9 mmol/L).  
• A decrease in hemoglobin from baseline1 of > 50 g/L.  
• The need for transfusion.  
Reintroduction of study medication may be considered if hemoglobin recovery, defined 
as a return of hemoglobin above the lower limit of the normal range (LLN) or if it returns 
to a value close to that at baseline.  
Interruption of study medication must not last longer than 4 consecutive weeks; longer 
interruptions must lead to permanent discontinuation of study drug. 
                                                 
1 Baseline hemoglobin: last value obtained prior to first intake of study treatment. 
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5.1.10.4 Start of an ERA / strong CYP3A4 inducer or inhibitor / investigational drug 
Study drug must be permanently discontinued if another ERA and/or a strong CYP3A4 
inducer and/or a strong CYP3A4 inhibitor and/or another investigational drug is started 
during treatment period. 
5.2 Previous and concomitant therapy 
5.2.1 Definitions 
A previous therapy is any treatment for which the end date is prior to informed consent 
signature.  
A therapy that is study-concomitant is any treatment that is either ongoing at informed 
consent signature or initiated thereafter, up to 30 days after the end of study treatment.  
A therapy that is study treatment-concomitant is any treatment that is either ongoing 
at the initiation of study treatment or is initiated thereafter, up to 30 days after the end of 
study treatment. 
Concomitant treatments of special interest are those susceptible to influence PAH 
disease, namely PAH-specific therapies and loop diuretics. These therapies are allowed at 
baseline under certain conditions [see Section 4.3]. Initiation of these therapies or 
up-titration of PDE-5 inhibitors before Week 26 is allowed only in case of disease 
progression [see Section 5.2.5], except for patients naïve to PAH treatment who are 
allowed to initiate and titrate a PDE-5 inhibitor within 2 weeks of study drug initiation 
[see Section 5.2.3.1]. 
5.2.2 Reporting of previous/concomitant therapy in the CRF 
The use of all study-concomitant therapy (including contraceptives and traditional and 
alternative medicines, i.e., plant-, animal-, or mineral-based medicines) will be recorded 
in the CRF. 
Previous therapy must be recorded in the CRF if discontinued less than 3 months prior to 
study treatment initiation. 
For all therapy, the generic name, start/end dates of administration (as well as whether it 
was ongoing at study treatment initiation and/or EOS), route, dose, and indication will be 
recorded in the CRF. 
For the following therapies, treatment dose and every dose change must be recorded in 
the CRF: 
• Loop diuretics. 
• PDE-5 inhibitors. 
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• Prostanoid analogs by any route of administration. 
• Stimulators of soluble guanylate cyclase. 
• Beta-blockers. 
• Any other PAH-specific therapy that may obtain marketing authorization during 
study conduct. 
5.2.3 Allowed concomitant therapy 
5.2.3.1 Until Week 26 RHC 
The following therapies are allowed until Week 26 RHC: 
• Therapies allowed at baseline based on eligibility criteria [see Sections 4.3 and 4.4]. 
• Oral loop diuretics if used at a stable dose for 1 week prior to Week 26 RHC. 
• Use of rescue therapy [see Section 5.2.5] only in case of disease progression. 
• A PDE-5 inhibitor may be initiated from the time when all screening assessments 
have been performed until Day 14, provided that dose optimization is complete at the 
latest 14 days after study treatment initiation. 
5.2.3.2 After Week 26 RHC 
After Week 26 RHC, treatment initiation and dose changes are allowed for: 
• Loop diuretics. 
• PDE-5 inhibitors. 
• Prostanoid analogs by any route of administration. 
• Stimulators of soluble guanylate cyclase. 
• Any other PAH-specific therapy that may obtain marketing authorization during 
study conduct. 
5.2.4 Forbidden concomitant therapy 
Therapies acting though the same therapeutic pathway as study drug are forbidden: 
• ERAs other than study drug. 
Therapies that are not well characterized are forbidden: 
• Investigational drug other than study drug. 
Therapies altering the exposure to study drug are forbidden to avoid under- and over-dose 
[Macitentan IB, section 1.7.2]: 
• Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, voriconazole, 
clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir). 
• Strong inducers of CYP3A4 (e.g., carbamazepine, rifampicin, rifabutin, phenytoin 
and St. John’s Wort). 
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Initiation of one of these prohibited medications will lead to premature discontinuation of 
study treatment. 
Disease-specific treatments are forbidden, except in specific situations, since they would 
interfere with efficacy evaluation [Section 5.2.5]. 
5.2.5 Rescue therapy before Week 26 RHC 
The following treatment changes are allowed before Week 26 RHC only in case of 
disease progression: 
• Initiation of: 
− i.v. loop diuretics. 
− PDE-5 inhibitors. 
− Prostanoid analogs by any route of administration. 
− Stimulators of soluble guanylate cyclase. 
− Any other PAH-specific therapy that may obtain marketing authorization during 
study conduct. 
• Up-titration of PDE-5 inhibitors. 
Use of these treatments does not require study treatment discontinuation. 
Disease progression is defined as: 
• Decrease in 6MWD by more than 15% associated with worsening in WHO FC, or 
• Need for s.c. or i.v. prostanoid therapy, or 
• Hospitalization for PAH (investigator’s assessment). 
Disease progression must be recorded as an AE in the CRF. Decreases in 6MWD > 15% 
from baseline in conjunction with worsening WHO FC that occur between scheduled 
visits and do not result in a rescue therapy initiation (RTI) visit must be recorded in the 
electronic CRF (eCRF) using an unscheduled visit form. 
After Week 26 RHC, treatment changes are allowed. 
6 
STUDY ENDPOINTS 
6.1 Efficacy endpoints 
6.1.1 Primary efficacy endpoints 
The study has two primary efficacy endpoints: 
• Change from baseline to Week 26 in Right Ventricular (RV) Stroke Volume (RVSV) 
assessed by cardiac MRI from pulmonary artery flow. 
• Ratio of Week 26 to baseline PVR assessed by RHC. 
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RVSV is determined by the IAC. Assessors are blinded to the patient identity and to the 
date of image acquisition. 
RVSV indexed for BSA was shown to predict outcome [Van Wolferen 2007]. RVSV 
quantifies blood flow independently of heart rate (HR). An increase in RVSV would 
reflect a favorable, reverse remodeling of the right ventricle and is expected to reduce 
PAH symptoms through a better oxygenation. 
A decrease in PVR appears as the primary direct effect expected from a PAH therapy. 
Furthermore it is an objective measurement of disease progression. 
The primary endpoint is defined at 26 weeks because it is deemed late enough to observe 
a relevant change and early enough to have a relatively low proportion of patients 
dropping out for the primary endpoint, either by discontinuing study treatment or by 
initiating additional PAH therapy. 
6.1.2 Secondary efficacy endpoints 
In the same way as the primary endpoints, secondary endpoints are assessed at 26 weeks. 
They consist of characteristics of the right ventricle, and of widely accepted tools to 
assess PAH progression: 
Change from baseline to Week 26 in: 
• RV End Diastolic Volume (RVEDV) 
• RV End Systolic Volume (RVESV)  
• RV Ejection Fraction (RVEF) 
• RV mass 
• 6MWD 
• WHO FC 
MRI variables will be assessed by the IAC. 
6.1.3 Exploratory efficacy endpoints 
The following endpoints are usual tools to monitor disease progression or treatment 
response and will be assessed: 
Change from baseline to Week 26 in: 
• mPAP 
• Mean right atrial pressure (mRAP) 
• Cardiac index 
• Arterial elastance 
• RV end-systolic elastance 
• RV maximum isovolumic pressure 
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The following exploratory endpoints aim to determine whether the treatment effect at 
26 weeks is maintained at 52 weeks. Primary and secondary endpoints are repeated at 
52 weeks except for variables assessed by RHC since this procedure is not performed at 
52 weeks. 
Change from baseline to Week 52 in: 
• RVSV determined by cardiac MRI from pulmonary artery flow 
• RVEDV 
• RVESV 
• RVEF 
• RV mass 
• 6MWD 
• WHO FC 
Variables pertaining to the left ventricle will also be assessed, at 26 weeks and 52 weeks. 
Change from baseline to Week 26 and Week 52 in: 
• Stroke Volume determined by cardiac MRI from the aortic flow 
• LV End Diastolic Volume (LVEDV) 
• LV End Systolic Volume (LVESV) 
• LV Ejection Fraction (LVEF) 
• LV mass 
• RVEDV/LVEDV 
• RVESV/LVESV 
MRI variables and variables determined from pressure-volume relationship will be 
assessed by the IAC. 
The following exploratory endpoints aim to investigate potential simple methods for 
disease monitoring, as opposed to RHC, MRI or echocardiography: 
Change from baseline to Week 26 and Week 52 in: 
• N-terminal pro-brain natriuretic peptide (NT-proBNP) 
• Uric acid 
• Red cell distribution width 
• Activin A 
• Cystatin C 
• Follistatin 
• Galectin-3 
• Growth Differentiation Factor (GDF)-15 
• Cardiac troponin T 
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• Lactate dehydrogenase (LDH) 
• Osteoprotegerin 
• Tumor Necrosis Factor (TNF) alpha 
These variables will be assessed by the central laboratory. 
The following endpoint is designed to investigate patient outcome. 
• Time to first clinical worsening event defined as: 
− Decrease in 6MWD by > 15% from baseline associated with worsening in WHO 
FC, or 
− Initiation of s.c. or i.v. prostanoid therapy, or 
− Hospitalization for PAH (investigator’s assessment), or 
− Death. 
6.2 Safety endpoints 
• Treatment-emergent AEs up to 30 days after EOT. 
• Treatment-emergent SAEs up to 30 days after EOT. 
• AEs leading to premature discontinuation of study drug. 
• Treatment-emergent marked laboratory abnormalities up to 30 days after EOT. 
• Occurrence of liver function test ([LFT] ALT and/or AST) abnormality (≥ 3; ≥ 3 and 
< 5 × ULN; ≥ 5 and < 8 × ULN; ≥ 8 × ULN) up to EOT. 
• Occurrence of hemoglobin abnormality (≤ 80 g/L; > 80 and ≤ 100 g/L) up to EOT. 
• Occurrence of ALT and/or AST abnormality ≥ 3 × ULN associated with bilirubin 
≥ 2 × ULN. 
6.3 Exploratory endpoints in sub-studies 
6.3.1 Metabolism sub-study 
Exploratory endpoints: 
• Change from baseline to Week 26 and to Week 52 in: 
- 
RV 18F-fluorodeoxyglucose (FDG) uptake 
- 
Aortic 18F-FDG uptake 
- 
Right common carotid 18F-FDG uptake 
- 
Left common carotid 18F-FDG uptake 
All variables that are specific to the metabolism sub-study will be centrally assessed 
according to a charter. 
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6.3.2 Biopsy sub-study 
Exploratory endpoints:  
• Change from baseline to Week 26 in: 
- 
Qualitative assessment of endomyocardium function markers in biopsies 
- 
Relative quantitative assessment of endomyocardium function markers in biopsies 
- 
Number of capillaries per cardiomyocyte 
- 
Mean cardiomyocyte volume 
- 
Qualitative assessment of cardiomyocytes 
- 
Endomyocardium cells mRNA transcript analysis 
- 
PBMC mRNA transcript analysis 
Biopsy and blood samples will be analyzed by the central laboratory. 
6.3.3 Echo sub-study 
Exploratory endpoints:  
• Change from baseline to Week 26 and Week 52 in: 
- 
LV eccentricity index at end-diastole 
- 
LV eccentricity index at end-systole 
- 
Minimum diameter of the inferior vena cava (at inspiration) 
- 
Maximum diameter of the inferior vena cava (at end-expiration) 
- 
Tricuspid annular plane systolic excursion (TAPSE) 
- 
Pericardial effusion size scored from 0 to 4 
- 
RV acceleration time, by tissue Doppler and pulsed wave Doppler 
- 
RV ejection time, by tissue Doppler and pulsed wave Doppler 
- 
Total RV Systolic Time (duration of tricuspid insufficiency jet) 
- 
Doppler RV index (RV myocardial performance index), by tissue Doppler and 
pulsed wave Doppler 
- 
Tricuspid peak jet velocity 
- 
RV systolic pressure (estimated by tricuspid valve Doppler) 
- 
Early diastolic velocity of the jet of pulmonary valve regurgitation 
- 
End-diastolic velocity of the jet of pulmonary valve regurgitation 
- 
Cardiac output determined from LV outflow tract 
- 
Mitral E-wave velocity 
- 
Mitral A-wave velocity 
- 
Mitral annulus peak early diastolic velocity E’ 
- 
E/A ratio 
- 
E/E’ ratio 
- 
2D RV dimension end-diastole 
- 
Tricuspid peak annular velocity s’ 
- 
RV end diastolic area 
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- 
RV end systolic area 
- 
RV fractional area change 
- 
RVSV determined from pulmonary valve Doppler and pulmonary annulus 
dimension 
- 
Tricuspid peak E, peak A, deceleration time 
- 
Tricuspid peak diastolic annular velocities e’, a’ 
- 
LVEDV determined from 2D measurements 
- 
LVESV determined from 2D measurements 
- 
Mitral deceleration time 
- 
Mitral annular plane tissue Doppler velocity a’ 
- 
2D Global Longitudinal RV strain 
- 
2D circumferential RV strain 
- 
Time to peak RV strain 
- 
RVSV 
- 
RVEDV 
- 
RVESV 
- 
RVEF 
- 
RV mass 
- 
Left Ventricular Stroke Volume (LVSV) 
- 
LVEDV 
- 
LVESV 
- 
LVEF 
- 
LV mass 
- 
RVEDV/LVEDV 
- 
RVESV/LVESV 
In this study protocol, Echo refers to 3D, 2D, M-mode and Doppler echocardiography. 
All Echo results will be centrally assessed according to a charter. 
7 
STUDY ASSESSMENTS 
All study assessments will be performed at trough. During site visits, patients will be 
instructed to take their daily study medication after all study assessments have been 
made. 
All study assessments are performed by a qualified study staff member: medical, nursing, 
or specialist technical staff, and are recorded in the CRF, unless otherwise specified. 
Study assessments performed during unscheduled visits (RTI, premature EOT, other 
unscheduled visit) will also be recorded in the CRF. 
If the principal investigator delegates any study procedure/assessment for a patient, 
e.g., RHC, MRI, blood sampling, etc., to an external facility, he/she must inform Actelion 
to whom these tasks are delegated. The set-up and oversight will be agreed upon with 
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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 enrollment of the first patient: 
• Temperature measurement devices for study medication storage area and freezer. 
7.1 Screening/baseline assessments 
7.1.1 Eligibility criteria 
Eligibility criteria will be collected in the CRF. 
7.1.2 Demographic and baseline characteristics 
The following baseline variables will be collected in the CRF during the screening period 
for all screened patients: 
• Age, gender, height, weight. 
• Race if allowed by local regulations. 
• PAH etiology, age at PAH diagnosis. 
7.1.3 Medical history 
The patient’s relevant medical history up to start of study (i.e., informed consent 
signature) must be recorded in the CRF and should include, but is not limited to: 
− Complications or symptoms associated with PAH (e.g., peripheral edema or right 
heart failure) 
− Any chronic conditions (e.g., diabetes, hypertension, angina pectoris) 
− Acute conditions present at screening or which occurred in the past with sequelae 
− Any serious condition in the past resolved without sequelae (e.g., acute peritonitis) 
7.1.4 Medications 
Previous [see Section 5.2.2] and concomitant medications must be recorded in the CRF. 
Each treatment taken by the patient must be matched by a corresponding symptom or 
condition in medical history (except prophylactic treatments). 
7.1.5 Birth control methods 
For women of childbearing potential [see Section 4.3], birth control methods must be 
recorded in the CRF. 
7.1.6 6-minute walk test 
The 6MWT is a non-encouraged test which measures the distance covered over a 
6-minute walk [ATS Statement 2002]. The Borg dyspnea index is evaluated after each 
6MWT. It rates dyspnea on a scale from ‘0’ to ‘10’ [Appendix 3]. 
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Detailed guidelines on correct execution of these tests ‘Actelion guidelines for 6MWT’ 
[Appendix 2] must be followed. For patients who have never performed a 6MWT 
previously, a training test will be requested before the qualifying test for inclusion. 
7.1.7 WHO Functional Class 
WHO FC [Appendix 4] is a classification which reflects disease severity based on 
symptoms. 
7.1.8 Cardiac MRI 
Images will be taken in accordance with the Cardiac MRI image acquisition protocol 
and uploaded to the Central Image Repository (CIR) through a dedicated web application 
or sent to the CIR by courier (on a CD). A quality check will be performed as soon as the 
data sets are received. 
The actual assessments will be done on data sets blinded to the patient identity and to the 
date of image acquisition, and only after a patient’s study completion or withdrawal. An 
exception to this rule will be made for patients analyzed for the interim analysis and who 
have not yet completed the study or withdrawn. For these patients, available images will 
be analyzed at the time of interim analysis. 
All sets of images for each patient will be assessed at the same time by the same assessor, 
in order to ensure rigorously consistent assessment. Thus, patients analyzed for the 
interim analysis and who have not yet completed the study or withdrawn will be analyzed 
twice if new images become available: 
• Available images will be analyzed at interim analysis, and the results used for the 
interim analysis. 
• All images will be analyzed at final analysis, and the results used for the final 
analysis. 
The IAC will assess the following variables according to a dedicated charter and the 
results will be sent to Actelion: 
• RVSV determined from pulmonary artery flow 
• RVEDV 
• RVESV 
• RVEF 
• RV mass 
• LVSV determined from aortic flow 
• LVEDV 
• LVESV 
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• LVEF 
• LV mass 
• RVEDV/LVEDV 
• RVESV/LVESV 
7.1.9 Right heart catheterization 
The Actelion guidelines for RHC [Appendix 1], including formulas, will be followed. 
Digitally sampled right ventricle pressure curve and pulmonary artery pressure curve, 
simultaneous with ECG sampling, must be recorded. The record must cover at least 
10 cardiac cycles. Sample frequency must be at least 200Hz. Calibration must be 
provided. The curves will be uploaded to the CIR through a dedicated web application, 
and blinded to the patient identity as well as to the date of acquisition. 
Where electronic recording of pressure curves is not possible at a site, alternative 
solutions will be determined on a case by case basis before any patient can be enrolled. 
The following variables will be determined locally and entered in the CRF: 
• PVR 
• mPAP 
• Systolic pulmonary artery pressure (sPAP) 
• Diastolic pulmonary artery pressure (dPAP) 
• PCWP or LVEDP 
• mRAP 
• Cardiac output (CO) 
• HR during RHC 
• Systolic systemic artery pressure (sSAP) 
• Diastolic systemic artery pressure (dSAP) 
• The date of RHC will be entered in the CRF 
7.1.10 Pressure-volume relationship 
The IAC will assess pressure-volume relationship based on cardiac MRI results and RHC 
pressure curves. 
The IAC will assess the following variables according to a dedicated charter and the 
results will be sent to Actelion: 
• Arterial elastance 
• RV end-systolic elastance 
• RV maximum isovolumic pressure 
The methods used to determine these variables will be described in a charter. 
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7.1.11 Blood tests 
Blood samples will be taken and analyzed by a central lab. These analyses are listed in 
Section 7.3.5.2. The results will be transferred to Actelion. 
7.1.12 Sub-studies 
7.1.12.1 Metabolism sub-study 
18F-FDG PET-MR scan will be performed according to the guidelines detailed in the 
PET-MR image acquisition protocol. The 18F-FDG PET-MR scan of the sub-study will 
be combined with the cardiac MRI of the main study. 
Complete results will be blinded to the patient identity and to the date of image 
acquisition prior to the assessment. The following variables will be centrally assessed 
according to a dedicated charter and the results will be sent to Actelion: 
• RV 18F-FDG uptake 
• Aortic 18F-FDG uptake 
• Right common carotid 18F-FDG uptake 
• Left common carotid 18F-FDG uptake 
During the course of the PET-MR procedure, a blood sample will be taken (see PET-MR 
image acquisition protocol) and sent to the central laboratory which will assess the 
following variables and transfer the results to Actelion: 
• Glucose 
• Insulin 
• Free fatty acid 
7.1.12.2 Biopsy sub-study 
During each RHC, a maximum of 4 biopsy samples will be withdrawn. Patients 
participating in the biopsy sub-study will also have additional blood samples taken at the 
same time points. Samples will be sent to the central laboratory which will coordinate the 
assessment of the following variables and transfer the results to Actelion: 
Biopsies 
• Immunochemistry: qualitative description of the samples after staining for: 
− Fibrosis 
− VEGF B 
− PCNA 
− Cleaved caspase 3 
− LC3B2 
− Caveolin 
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− E NOS 
− NOX-2  
• Relative quantitative assessment of selected proteins in biopsies, determined by 
Reverse Phase Protein Array2 
• Determination by electron/light microscopy of: 
− Number of capillaries per cardiomyocyte 
− Mean cardiomyocyte volume 
− Description of cardiomyocytes and mitochondria 
• Endomyocardium cells mRNA transcript analysis 
Blood 
• PBMC mRNA transcript analysis 
7.1.12.3 Echo sub-study 
Echo (i.e., 3D, 2D, M-mode and Doppler echocardiography) will be performed according 
to the guidelines detailed in the Echo image acquisition protocol. Complete results will 
be blinded to the patient identity and to the date of image acquisition. The following 
variables will be centrally assessed according to a dedicated charter and the results will 
be sent to Actelion: 
• LV eccentricity index at end-diastole 
• LV eccentricity index at end-systole 
• Minimum diameter of the inferior vena cava (at inspiration) 
• Maximum diameter of the inferior vena cava (at end-expiration) 
• Tricuspid annular plane systolic excursion (TAPSE) 
• Pericardial effusion size scored from 0 to 4 
• Right ventricle acceleration time, by tissue Doppler and pulsed wave Doppler 
• Right ventricle ejection time, by tissue Doppler and pulsed wave Doppler 
• Total RV Systolic Time (duration of tricuspid insufficiency jet) 
• Doppler RV index (RV myocardial performance index), by tissue Doppler and pulsed 
wave Doppler 
• Tricuspid peak jet velocity 
• RV systolic pressure (estimated by tricuspid valve Doppler) 
• Early diastolic velocity of the jet of pulmonary valve regurgitation 
• End-diastolic velocity of the jet of pulmonary valve regurgitation 
                                                 
2 Akt - phosphor, AMPK alpha - phospho, Caspase-1, Caspase 3 - cleaved, Caveolin-1, c-Kit, CREB, CREB - phospho, 
Dihydropyrimidine dehydrogenase, DPYD, Erk1/2 - phospho, FAK1 - phospho, FAK1 - phospho, GDF-15, IGF1R, 
KLF-5, mTOR, mTOR - phospho, NF-kappaB p65, Nrf2, p53, PARP, PARP - cleaved, PCNA, PTEN, Raptor, 
STAT 3, STAT 3 - phospho, Superoxide dismutase (Cu/Zn). 
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• Cardiac output determined from LV outflow tract 
• Mitral E-wave velocity 
• Mitral A-wave velocity 
• Mitral annulus peak early diastolic velocity E’ 
• E/A ratio 
• E/E’ ratio 
• 2D RV dimension end-diastole 
• Tricuspid peak annular velocity s’ 
• RV end diastolic area 
• RV end systolic area 
• RV fractional area change 
• RVSV determined from pulmonary valve Doppler and pulmonary annulus dimension 
• Tricuspid peak E, peak A, deceleration time 
• Tricuspid peak diastolic annular velocities e’, a’ 
• LVEDV determined from 2D measurements 
• LVESV determined from 2D measurements 
• Mitral deceleration time 
• Mitral annular plane tissue Doppler velocity a’ 
• 2D Global Longitudinal RV strain 
• 2D circumferential RV strain 
• Time to peak RV strain 
• RVSV 
• RVEDV 
• RVESV 
• RVEF 
• RV mass 
• LVSV 
• LVEDV 
• LVESV 
• LVEF 
• LV mass 
• RVEDV/LVEDV 
• RVESV/LVESV 
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7.2 Efficacy assessments 
7.2.1 6-minute walk test 
The 6MWT will be evaluated as described in Section 7.1.6 during screening, at Week 26 
and at Week 52. 6MWT will also be performed at RTI visit or premature EOT visit 
where applicable. 6MWT may be performed at other unscheduled visits if clinically 
indicated. 
7.2.2 WHO Functional Class 
WHO FC will be assessed as described in Section 7.1.7 during screening, at Week 26 and 
at Week 52. WHO FC will also be assessed at RTI visit or premature EOT visit where 
applicable. WHO FC may be assessed at other unscheduled visits if clinically indicated. 
7.2.3 Cardiac MRI 
Cardiac MRI will be performed as described in Section 7.1.8 during screening, at 
Week 26, and at Week 52. 
In case of rescue therapy initiation or premature end of treatment (where applicable), 
cardiac MRI will be conducted depending on the visit date [Table 1] and will replace the 
Week 26 or Week 52 cardiac MRI. 
7.2.4 Hemodynamics 
RHC will be performed as described in Section 7.1.9 during screening and at Week 26. 
In case of rescue therapy initiation or premature end of treatment before Week 26 (where 
applicable), RHC will be conducted depending on the visit date [Table 1] and will replace 
the Week 26 RHC. 
7.2.5 Pressure-volume relationship 
Pressure-volume relationship will be assessed as described in Section 7.1.10 based on 
cardiac MRI and RHC assessments performed during screening and at Week 26. 
In case of rescue therapy initiation or premature end of treatment before Week 26 (where 
applicable), pressure-volume relationship will be assessed at the corresponding time 
point, provided RHC and cardiac MRI results are available for this time point. 
7.2.6 Laboratory tests 
Exploratory efficacy laboratory assessments [Section 7.3.5.2] will be done on blood 
samples collected during screening, at Week 26 and at Week 52. They will also be 
assessed at RTI visit or premature EOT visit where applicable. 
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7.3 Safety assessments 
7.3.1 Adverse events 
The definitions, reporting and follow-up of AEs, SAEs, and pregnancies are described in 
Section 10. 
7.3.2 Vital signs 
Vital signs will be assessed during screening, at Treatment Initiation Visit, at Week 26, 
and at EOT. They will also be assessed at RTI visit or premature EOT visit where 
applicable. Vital signs may be assessed at other unscheduled visits if clinically indicated. 
Systolic and diastolic blood pressure and HR will be measured non-invasively in the 
supine position throughout the study. 
7.3.3 Weight  
Body weight (in underwear) will be measured during screening, at Week 26 and at 
Week 52. Weight will also be measured at RTI visit or premature EOT visit where 
applicable. Weight may be assessed at other unscheduled visits if clinically indicated. 
Weight will be used in the calculation of BMI and of hemodynamic indices. 
7.3.4 Physical examination 
Physical examination (i.e., inspection, percussion, palpation and auscultation) will be 
performed during screening, at Treatment Initiation Visit, at Week 26 and at EOT. It will 
also be performed at RTI visit or premature EOT visit where applicable. Physical exam 
may be performed at other unscheduled visits if clinically indicated. 
The observations must be reported according to body system in the CRF as either normal 
or abnormal. If an abnormality is found it must be specified on the corresponding CRF 
page, 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 PAH that were present at the time of informed consent signature) must be 
recorded on the Medical History CRF page. Physical examination findings made after 
study start, that meet the definition of an AE [Section 10.1.1] must be recorded by the 
investigator on the AE page of the CRF. 
7.3.5 Laboratory assessments 
7.3.5.1 Type of laboratory 
A central laboratory (Covance; see central laboratory manual for contact details) will be 
used for all protocol-mandated laboratory tests, including re-tests due to laboratory 
abnormalities and laboratory tests performed at unscheduled visits. Central laboratory 
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data will be automatically transferred from the central laboratory database to Actelion’s 
clinical database. 
During screening, patient eligibility may be determined using local laboratory tests as 
long as the central laboratory kit is used in parallel. 
Under specific circumstances (e.g., if the patient lives distant 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. If applicable, the investigator/delegate will provide Actelion with 
the name, professional degree, and curriculum vitae of the director of the satellite 
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. 
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 6. 
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 
Complete laboratory tests (hematology, clinical chemistry, coagulation tests, pregnancy 
test, and exploratory efficacy) will be performed during screening, at Week 26 and at 
Week 52. These tests will also be performed at RTI visit or premature EOT visit where 
applicable. 
Monthly LFT and hemoglobin monitoring are mandatory during the first 6 months of 
study drug treatment. Patients must be monitored for signs of hepatic injury, and monthly 
LFT monitoring is recommended beyond the first 6 months of study treatment. 
All laboratory tests results will be transferred from the central laboratory to the clinical 
database. 
Pregnancy tests will be performed for women of childbearing potential at Treatment 
Initiation Visit, monthly until end of study treatment, at EOS, and if pregnancy is 
suspected during the study. 
Negative urine pregnancy test results will not be entered in the CRF. 
Hematology 
• Hemoglobin, hematocrit 
• Erythrocyte count (reticulocyte count) 
• Leukocyte count with differential counts 
• Platelet count 
Clinical chemistry 
• LFT: Aminotransferases (AST/ALT), alkaline phosphatase, total and direct bilirubin, 
LDH 
• Creatinine, urea 
• Uric acid 
• Glucose 
• Cholesterol, triglycerides 
• Sodium, potassium, chloride, calcium 
• Protein, albumin 
Coagulation tests 
• Prothrombin time and/or International Normalized Ratio (INR) 
• Activated partial thromboplastin time (aPTT) 
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Pregnancy test for women of childbearing potential 
Serum pregnancy tests will be performed at each blood draw (during screening, at 
Week 26 Visit, at EOT, at RTI visit or premature EOT visit where applicable) and if 
pregnancy is suspected during the study. 
Urine pregnancy tests will be performed at Treatment Initiation Visit and at EOS.  
Monthly pregnancy tests will be performed using the monthly blood draws where 
applicable, and with urine pregnancy tests otherwise. 
Urine pregnancy test kits will be provided by the central laboratory or the contract 
research organization (CRO). 
Pregnancy reporting requirements are described in Section 10.3. 
Efficacy / Exploratory 
• NT-proBNP 
• Uric acid 
• Red cell distribution width 
• Activin A 
• Cystatin C 
• Follistatin 
• Galectin-3 
• GDF-15 
• Cardiac troponin T 
• LDH 
• Osteoprotegerin 
• TNF alpha 
• Potential additional laboratory tests [see Section 7.3.5.3]. 
7.3.5.3 Potential additional laboratory tests 
The list of biomarkers in this protocol may be expanded with additional circulating 
biomarkers reflecting cardiac remodeling or function based on available scientific 
evidence. No genetic testing will be performed. The samples will be stored at the central 
laboratory until one year after the last patient’s last visit and destroyed after that date. 
7.4 Exploratory assessments in sub-studies 
These assessments are carried out only in patients enrolling in the respective sub-study. 
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7.4.1 Metabolism sub-study 
18F-FDG PET-MR scan will be performed as described in Section 7.1.12.1 during 
screening, at Week 26 and at Week 52. 
In case of rescue therapy initiation or premature end of treatment (where applicable), 
18F-FDG PET-MR scan will be conducted depending on the visit date [Table 1] and will 
replace the Week 26 or Week 52 18F-FDG PET-MR scan. 
7.4.2 Biopsy sub-study 
Biopsies will be taken during the RHC procedure as described in Section 7.1.12.2 and an 
additional blood sample will be taken. Biopsy and blood draw will be conducted during 
screening and at Week 26. If a RHC is performed at RTI or premature EOT, biopsies and 
an additional blood sample will be taken at that time and will replace the Week 26 
biopsy. 
7.4.3 Echo sub-study 
Echo will be performed as described in Section 7.1.12.3 during screening, at Week 26 
and at Week 52. 
In case of rescue therapy initiation or premature end of treatment (where applicable), 
Echo will be conducted and will replace the Week 26 or Week 52 Echo. 
8 
SCHEDULE OF VISITS 
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 patients 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. All 
screening assessments must then be repeated at the time of re-screening. 
For a tabulated summary of all visits and assessments described in the following sections 
see Table 1. 
8.1 Screening period 
Assessments of the screening period must be performed within 28 days prior to 
Treatment Initiation Visit (Day 1). It is the responsibility of the investigator to obtain 
written informed consent from each patient participating in the study after adequate 
explanation of the objectives, methods and potential hazards of the study. 
The ICF must be signed and dated by both parties prior to any study assessment or 
procedure at the latest. 
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The screening period includes [see Table 1]: 
• Eligibility criteria check 
• Recording of demographic and baseline characteristics 
• Recording of medical history 
• Weight 
• Recording of previous and concomitant medications 
• Recording of birth control methods for women of childbearing potential 
• Physical examination and vital signs 
• 6MWT 
• WHO FC 
• Cardiac MRI 
• RHC (provided that the above mentioned criteria are compatible with study eligibility 
criteria) 
• Blood tests 
• Recording of AEs and SAEs 
Cardiac MRI and RHC must be conducted within 21 days of each other. 
For patients enrolling in the corresponding sub-study only, the following 
assessments/procedures must also be conducted during the screening period: 
• PET-MR scan with injection of 18F-FDG (combined with cardiac MRI) 
• Endomyocardium biopsy and additional blood sample 
• Echo 
8.2 Treatment period 
8.2.1 Treatment Initiation Visit 
Treatment Initiation Visit may occur on the day of the last screening assessment, 
provided that all assessments are done before study drug intake. 
Treatment Initiation Visit includes: 
• Recording of concomitant medications 
• Recording of birth control methods for women of childbearing potential 
• Physical examination and vital signs 
• Urine pregnancy test for women of childbearing potential 
• First intake of study drug 
• Recording of AEs and SAEs 
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8.2.2 Rescue Therapy Initiation Visit 
In case of disease progression that requires initiation of rescue therapy before Week 26 
RHC, a site visit is organized and the following assessments are to be performed before 
the actual rescue therapy initiation: 
• Weight 
• Recording of concomitant medications 
• Recording of birth control methods for women of childbearing potential 
• Physical examination and vital signs 
• 6MWT 
• WHO FC 
• Cardiac MRI 
− Before Week 16: decision to conduct the exam based on clinical judgment 
− Between Week 16 and Week 26 RHC: must be performed and replaces Week 26 
cardiac MRI 
• RHC 
− Before Week 16: decision to conduct the exam based on clinical judgment 
− Between Week 16 and Week 26 RHC: must be performed and replaces Week 26 
RHC 
• Blood tests 
• Recording of AEs and SAEs 
Cardiac MRI and RHC must be conducted within 21 days of each other. 
For patients in the corresponding sub-study only, the following assessments/procedures 
are also conducted: 
• PET-MR scan with injection of 18F-FDG (combined with cardiac MRI), replaces 
Week 26 18F-FDG PET-MR scan 
• Endomyocardium biopsy and additional blood sample if a RHC is performed. This 
replaces Week 26 biopsy and blood sample 
• Echo, replaces Week 26 Echo 
For patients with multiple opportunities to undergo cardiac MRI, RHC, PET-MR scan, 
biopsy and Echo in replacement of Week 26 (e.g., several RTI before Week 26 RHC or 
RTI and EOT before Week 26 RHC), these exams are done once only. 
8.2.3 Week 26 visit 
At Week 26 (± 14 days), the following assessments will be performed: 
• Weight 
• Recording of concomitant medications 
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• Recording of birth control methods for women of childbearing potential  
• Physical examination and vital signs 
• 6MWT 
• WHO FC 
• Cardiac MRI 
• RHC 
• Blood tests 
• Recording of AEs and SAEs 
Cardiac MRI and RHC must be conducted within 21 days of each other. 
For patients in the corresponding sub-study only: 
• PET-MR scan with injection of 18F-FDG (combined with cardiac MRI) 
• Endomyocardium biopsy and additional blood sample 
• Echo 
8.2.4 Unscheduled visits 
Unscheduled visits may be performed at any time during the study. Depending on the 
reason for the unscheduled visit (e.g., loss of efficacy, AE, etc.), appropriate assessments 
may be performed based on the judgment of the investigator and must be recorded in the 
CRF. After an unscheduled visit, the regular scheduled study visits must continue 
according to the planned visit and assessment schedule. 
Assessments performed may include: 
• Weight if clinically indicated 
• Recording of concomitant medications 
• Recording of birth control methods for women of childbearing potential  
• Physical examination and vital signs if clinically indicated 
• 6MWT if clinically indicated 
• WHO FC if clinically indicated 
• Recording of AEs and SAEs 
Decreases in 6MWD > 15% from baseline in conjunction with worsening WHO FC that 
occur between scheduled visits and do not result in an RTI visit must be recorded in the 
eCRF using an unscheduled visit form. 
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8.2.5 Premature End of Treatment visit 
8.2.5.1 Patients discontinuing the study 
The reason for premature discontinuation from the study and the person making the 
decision will be collected [see Section 9.2]. The investigator must seek and document 
agreement to conduct the safety follow-up. 
For patients enrolled in a sub-study, the investigator must clarify whether the patient 
wants to discontinue the sub-study only, or both the main study and the sub-study. 
8.2.5.2 Patients agreeing to limited participation 
For patients permanently discontinuing study treatment who accept to continue study 
assessments [see Section 9.2], the premature EOT visit takes place at the latest 7 days 
after the decision to end study treatment and includes: 
• Reason for premature discontinuation and person taking the decision 
• Weight 
• Recording of concomitant medications 
• Recording of birth control methods for women of childbearing potential 
• Physical examination and vital signs 
• 6MWT 
• WHO FC 
• Cardiac MRI 
− Before Week 16: decision to conduct the exam based on clinical judgment 
− Between Week 16 and Week 26 RHC: must be performed and replaces Week 26 
cardiac MRI  
− Between Week 26 RHC and Week 48: decision to conduct the exam based on 
clinical judgment 
− After Week 48: must be performed and replaces Week 52 cardiac MRI 
• RHC 
− Before Week 16: decision to conduct the exam based on clinical judgment 
− Between Week 16 and Week 26 RHC: must be performed and replaces Week 26 
RHC 
• Blood tests 
• Recording of AEs and SAEs 
Cardiac MRI and RHC must be conducted within 21 days of each other. 
For patients in the corresponding sub-study only, the following assessments/procedures 
are also conducted: 
• PET-MR scan with injection of 18F-FDG (combined with cardiac MRI) 
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− Before Week 26 RHC: must be performed and replaces Week 26 18F-FDG 
PET-MR scan  
− Between Week 26 RHC and Week 48: must be performed and replaces Week 52 
18F-FDG PET-MR scan 
• Endomyocardium biopsy and additional blood sample if a RHC is performed. This 
replaces Week 26 biopsy and blood sample 
• Echo 
− Before Week 26 RHC: must be performed and replaces Week 26 Echo 
− Between Week 26 RHC and Week 48: must be performed and replaces Week 52 
Echo 
For patients with multiple opportunities to undergo cardiac MRI, RHC, PET-MR scan, 
biopsy and Echo in replacement of Week 26 (e.g., several RTI before Week 26 RHC or 
RTI and EOT before Week 26 RHC), these exams are done once only. 
Premature EOT visit is followed by the safety follow-up, 30 to 37 days after study 
treatment discontinuation. 
8.2.6 End of Treatment visit 
At Week 52 (± 7 days), the following assessments will be repeated: 
• Weight 
• Recording of concomitant medications 
• Recording of birth control methods for women of childbearing potential 
• Physical examination and vital signs 
• 6MWT 
• WHO FC 
• Cardiac MRI 
• Blood tests 
• Recording of AEs and SAEs 
For patients in the corresponding sub-study only: 
• PET-MR scan with 18F-FDG (combined with cardiac MRI) 
• Echo 
8.3 Safety follow-up 
EOS visit 
The EOS visit occurs 30 to 37 days after study drug discontinuation. Agreement to 
conduct the safety follow-up must have been sought for patients who withdrew their 
consent. The visit can be done via telephone, and includes: 
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• Recording of concomitant medications. 
• Urine pregnancy test for women of childbearing potential. 
• Recording of birth control methods for women of childbearing potential. 
• Recording of AEs and SAEs. 
9 
STUDY COMPLETION AND POST-STUDY TREATMENT/MEDICAL 
CARE 
9.1 Study completion 
Sites will be informed once planned enrollment is met for the study and the sub-studies, 
or if enrollment is stopped early following interim analysis results. Patients in screening 
will be allowed to continue in the study. No additional patient can be screened after 
enrollment closure. 
For an individual patient, study is completed at the EOS Visit. 
The end of the study as a whole is the date of the last patient’s last visit. 
9.2 Premature withdrawal from study 
Patients may voluntarily withdraw from the study for any reason at any time. Patients are 
considered withdrawn if: 
• They state an intention to withdraw further participation in all components of the 
study. 
• They die. 
• They are lost to follow-up for any other reason (see below). 
• The investigator believes that continued participation in the study would be contrary 
to the best interests of the patient. 
• Actelion makes this decision for any reason, including premature termination or 
suspension of the study [see Section 9.3]. 
Patients are considered as lost to follow-up if all reasonable attempts by the investigator 
to communicate with the patient fail. The site must take preventive measures to avoid a 
patient being lost to follow-up (e.g., document different ways of contact such as 
telephone number, home address, e-mail address, person to be contacted in case the 
patient cannot be reached). If the patient cannot be reached, the site must make a 
reasonable effort to contact the patient, document all attempts and enter the loss of 
follow-up information into the CRF. The following methods must be used: at least three 
telephone calls must be placed to the last available telephone number and one registered 
letter must be sent by post to the last available home address. Additional methods may be 
acceptable if they are compliant with local rules/regulations (e.g., site staff visit to the 
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patient’s home), respecting the patient’s right to privacy. If the patient 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 (patient, investigator, or Actelion) must be 
recorded in the CRF. 
If for any reason (except death or loss-to-follow-up) a patient is withdrawn from the 
study, the investigator must make efforts to conduct a last visit to assess the safety and 
well-being of the patient, collect unused study drug and discuss follow-up medical care. 
The investigator must provide follow-up medical care for all patients 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 prematurely suspended or terminated, Actelion will promptly inform the 
investigators, the Institutional Review Boards or Independent Ethics Committees 
(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 patients, and ensure their 
appropriate treatment and follow-up, as described in Section 9.2 for patients prematurely 
withdrawn from the study. 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 
patients’ 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 patients after study completion/withdrawal from study 
After the patient’s study completion or premature withdrawal from the study, whichever 
applies, the investigator/delegate will explain to patients what treatment(s)/medical care 
is necessary and available according to local regulations. 
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 patient 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 EOS, which is 30 to 37 days after study 
treatment discontinuation) whether or not considered by the investigator as related to 
study treatment. 
AEs: 
• 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 
course of the study or led to dose reduction, interruption or permanent discontinuation 
of study treatment.  
Overdose, misuse and abuse of the study treatment must be reported as an AE and, in 
addition, study treatment errors must be documented in the study drug log of the CRF. 
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10.1.2 Intensity of adverse events 
The intensity of clinical AEs is graded on a three-point scale – mild, moderate, severe – 
and is reported on specific AE pages of the CRF.  
If the intensity of an AE worsens during study treatment administration, only the worst 
intensity must 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 patient. It does not influence daily activities, and 
usually does not require intervention. 
 Moderate 
The event may make the patient 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 patient 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 must 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 drug caused the AE will be 
provided by an investigator who is a qualified physician. 
10.1.4 Adverse events associated with 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 patient’s previous 
treatment during a washout period leading to exacerbation of underlying disease. 
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10.1.5 Reporting of adverse events 
All AEs occurring after informed consent signature and up to EOS, which is 30 to 
37 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 International Council for Harmonisation (ICH) guidelines as 
any AE fulfilling at least one of the following criteria: 
• Fatal. 
• Life-threatening: refers to an event in which the patient 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 
patient, 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 informed consent signature) 
surgery or standard monitoring of a pre-existing disease or medical condition that did 
not worsen, e.g., hospitalization for coronary angiography in a patient with stable 
angina pectoris. 
• However, complications that occur during hospitalization are AEs or SAEs (for 
example, if a complication prolongs hospitalization). 
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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 patient’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 informed consent signature must be reported.  
These SAEs must be reported on an SAE form and on the AE pages 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 and on the AE pages in the CRF. 
10.2.2.3 During follow-up period 
All SAEs which occur up to 30 days after study treatment discontinuation must be 
reported. 
These SAEs must be reported on an SAE form and on the AE pages in the CRF. 
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 h of the investigator’s knowledge of the event, only if 
considered causally related to previous exposure to the study treatment or study design or 
protocol-mandated procedures by the investigator.  
10.2.5 Reporting procedures 
All SAEs must be reported by the investigator to the Actelion drug safety department 
within 24 h of the investigator’s first knowledge of the event. 
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All SAEs must be recorded on an SAE form, irrespective of the study treatment received 
by the patient, and whether or not this event is considered by the investigator to be related 
to study treatment or study design or protocol-mandated procedures.  
The SAE forms must be faxed or emailed 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 h of receiving it. The Actelion drug safety department may contact the investigator to 
obtain further information.  
If the patient 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 reported by the sponsor to Health Authorities, ECs/IRBs and investigators is 
the reference safety information section of the IB.  
The SAEs listed below are commonly seen with the underlying disease and are therefore 
expected to occur in this patient population. These SAEs must be reported on an SAE 
form and on the CRF. These SAEs do not require systematic expedited reporting to 
Health Authorities, IRBs/IECs, and investigators. 
The following events that are expected to occur in patients with PH or PAH will be 
considered as ‘disease-related’ and ‘expected’ for regulatory reporting purposes in this 
population: signs and symptoms of PAH/PH, worsening/exacerbation/progression 
including fatal outcome, and, in particular, abdominal pain, anorexia, chest pain, 
cyanosis, diaphoresis, dizziness, pre-syncope, dyspnea, orthopnea, fatigue, hemoptysis, 
heart failure, hypoxia, palpitations, syncope, collapse, systemic arterial hypotension, and 
tachycardia. 
10.3 Pregnancy 
If a woman becomes pregnant while on study treatment, study treatment must be 
discontinued. The investigator must counsel the patient and discuss the risks of 
continuing with the pregnancy and the possible effects on the fetus.  
10.3.1 Reporting of pregnancy 
Any pregnancy occurring from treatment initiation until the end of the 30 days safety 
follow-up must be reported within 24 h of the investigator’s knowledge of the event.  
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Pregnancies must be reported on the Actelion Pregnancy form, which is faxed or emailed 
to the Actelion drug safety department (see contact details provided on the Actelion 
Pregnancy form), and on an AE page or a pregnancy page in the CRF. 
10.3.2 Follow-up of pregnancy  
Any pregnancy must be followed to its conclusion and its outcome must be reported to 
Actelion drug safety department. 
Any AE associated with the pregnancy occurring during the follow-up period after study 
drug 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) is monitored 
and reviewed on a continuous basis by the Actelion clinical team (in charge of ensuring 
patients’ 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 CROs 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 Patients Set 
This analysis set includes all patients who were screened and received a patient number. 
11.1.2 Safety Set 
The Safety Set (SS) includes all patients from the Screened Patients Set who received at 
least one dose of study drug. 
11.1.3 Full Analysis Set 
The Full Analysis Set (FAS) includes all patients from the SS who had a baseline as well 
as a post-baseline measurement for both primary endpoints (RVSV and PVR).  
The Modified FAS comprises all patients included in the FAS who had a post-baseline 
measurement taken between 16 weeks and 30 weeks of treatment for both primary 
endpoints. 
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11.1.4 Per Protocol Set 
The Per Protocol Set (PPS) comprises all patients included in the Modified FAS without 
major protocol deviations that affect the main analysis of the primary efficacy variables. 
The reasons for excluding patients from the PPS will be fully defined and documented in 
the SAP. 
11.1.5 Other analysis sets 
The specific RVSV Analysis Set includes all patients from the SS who had a baseline as 
well as a post-baseline measurement taken between 16 weeks and 30 weeks of treatment 
for RVSV. 
The specific PVR Analysis Set includes all patients from the SS who had a baseline as 
well as a post-baseline measurement taken between 16 weeks and 30 weeks of treatment 
for PVR. 
Specific analysis sets for the sub-studies will be defined in the SAP. 
11.1.6 Usage of the analysis sets 
The primary efficacy analysis will be performed on the Modified FAS. Secondary and 
exploratory efficacy analyses will be performed on the FAS. 
The PPS will be used for performing a sensitivity analysis on the primary endpoints. 
The specific RVSV and PVR Analysis Sets will only be used if the intersection of the 
two sets (i.e., the Modified FAS) is markedly smaller than the union. Criteria will be 
specified in the SAP. 
Safety analyses will be performed on the SS. Patient listings will be based on the 
Screened Patients Set, unless otherwise specified. 
Patient disposition will be described for the Screened Patients Set. 
11.2 Variables 
11.2.1 Primary efficacy variables 
The two primary efficacy variables are: 
• Change from baseline to Week 26 in RVSV assessed by cardiac MRI from 
pulmonary artery flow. 
• Ratio of Week 26 to baseline PVR assessed by RHC. 
Change from baseline in RVSV (mL) is calculated as RVSV at Week 26 minus RVSV at 
baseline. A positive change from baseline corresponds to an improvement.  
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PVR [dyn·s·cm-5] is calculated as (mPAP − PCWP) / CO × 80 [refer to Appendix 1]. 
A ratio versus baseline < 1 corresponds to an improvement. 
11.2.2 Secondary efficacy variables 
Secondary efficacy variables are absolute changes from baseline to Week 26 in: 
• RVEDV (mL) 
• RVESV (mL) 
• RVEF (%) 
• RV mass (g) 
• 6MWD (m) 
• WHO FC (I–IV) 
11.2.3 Exploratory efficacy variables 
11.2.3.1 Hemodynamic variables and pressure-volume variables 
These variables include changes from baseline to Week 26 in: 
• mPAP (mmHg) 
• mRAP (mmHg) 
• Cardiac index (L/min/m2) 
• Arterial elastance (mmHg/mL) 
• RV end-systolic elastance (mmHg/mL) 
• RV maximum isovolumic pressure (mmHg) 
11.2.3.2 Variables related to maintenance of treatment effect 
These variables include changes from baseline to Week 52 for the primary and secondary 
efficacy variables (except those determined by RHC which is not performed at Week 52): 
• RVSV determined by cardiac MRI from pulmonary artery flow 
• RVEDV 
• RVESV 
• RVEF 
• RV mass 
• 6MWD 
• WHO FC 
11.2.3.3 Variables related to the left ventricle  
These variables include changes from baseline to Week 26 and Week 52 in: 
• LVSV determined by cardiac MRI from the aortic flow (mL) 
• LVEDV (mL) 
• LVESV (mL) 
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• LVEF (%) 
• LV mass (g) 
• RVEDV/LVEDV (1) 
• RVESV/LVESV (1) 
11.2.3.4 Potential variables for disease monitoring 
These endpoints include changes from baseline to Week 26 and Week 52 in: 
• NT-proBNP 
• Uric acid 
• Red cell distribution width 
• Activin A 
• Cystatin C 
• Follistatin 
• Galectin-3 
• GDF-15 
• Cardiac troponin T 
• LDH 
• Osteoprotegerin 
• TNF alpha 
11.2.3.5 Clinical endpoint 
The clinical endpoint is the time from the initiation of treatment to first clinical 
worsening defined as the first occurrence of: 
• Decrease in 6MWD by > 15% from baseline associated with worsening in WHO FC, 
or 
• Initiation of s.c. or i.v. prostanoid therapy, or 
• Hospitalization for PAH (investigator’s assessment), or 
• Death 
11.2.4 Safety variables 
Safety variables include: 
• Treatment-emergent AEs up to 30 days after EOT 
• Treatment-emergent SAEs up to 30 days after EOT 
• AEs leading to premature discontinuation of study drug 
• Treatment-emergent marked laboratory abnormalities up to 30 days after EOT 
• Occurrence of LFT (ALT or AST) abnormalities up to EOT, classified as: 
− ≥ 3 × ULN 
− ≥ 3 × ULN and < 5 × ULN 
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− ≥ 5 × ULN and < 8 × ULN 
− ≥ 8 × ULN 
• Occurrence of hemoglobin abnormalities up to EOT, classified as: 
− ≤ 80 g/L 
− > 80 g/L and ≤ 100 g/L 
• Occurrence of ALT and/or AST abnormality ≥ 3 × ULN associated with bilirubin 
≥ 2 × ULN 
11.2.5 Other variables 
Variables associated with the sub-studies will be described in the SAP. 
11.3 Description of statistical analyses 
11.3.1 Overall testing strategy 
The overall type I error is α = 0.025 (one-sided) and will be split between the two 
primary endpoints RVSV (α = 0.02) and PVR (α = 0.005). The justification for the 
unequal split is that PVR is a well-known endpoint (hence, the smaller part of the α), 
whereas RVSV is less well-known, i.e., more uncertainty of the estimate/variability 
(hence, the larger part of the α).  
Per endpoint the type II error is set to 0.10 and the power to 90%.  
An efficacy interim analysis is introduced in protocol Version 6 and corresponding 
statistical considerations are provided in Section 11.4.3. 
11.3.2 Analysis of the primary efficacy variables 
11.3.2.1 Hypotheses and statistical model 
The null hypothesis is: 
The mean change from baseline to Week 26 in RVSV is less than or equal to zero AND 
the geometric mean ratio of Week 26 to baseline PVR is greater than or equal to one. 
The alternative hypothesis is: 
The mean change from baseline in RVSV is greater than zero OR the geometric mean 
ratio of Week 26 to baseline PVR is less than one. 
11.3.2.2 Handling of missing data 
General. RVSV will be based on pulmonary artery flow. If, however, RVSV determined 
from pulmonary artery flow differs from RVSV determined from aortic flow by more 
than 20% (in either direction), then RVSV should be determined by volumetric 
assessment. 
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If PVR cannot be calculated due to missing PCWP but mPAP and CO are available for 
the same visit, one of the following methods will be applied: 
1. If PCWP is missing both at baseline and post-baseline, the study population median 
PCWP (baseline and post-baseline, respectively) will be imputed (based on the 
Modified FAS). 
2. If PCWP is missing either at baseline or post-baseline, the patient’s available PCWP 
will be imputed. 
This imputation is based on the clinical assumption that macitentan does not affect 
PCWP. 
Baseline. Patients without a baseline RVSV or PVR measurement will be excluded from 
the analyses.  
Post-baseline. In patients without a Week 26 RVSV or PVR the last post-baseline 
measurement (presumably taken at treatment discontinuation or initiation of rescue 
therapy) will be carried forward, provided that this measurement was taken after at least 
16 weeks of treatment. Week 26 measurements taken after 30 weeks of treatment will be 
excluded from the analyses. 
11.3.2.3 Main analysis 
The primary efficacy analysis will be performed on the Modified FAS for the interim and 
the final analysis.  
RVSV will be summarized by time point (baseline, Week 26) using descriptive statistics 
(n, mean, SD, median, Q1 and Q3). The change from baseline to Week 26 in RVSV will 
be summarized similarly.  
Change from baseline in RVSV will be analyzed using an Analysis of Covariance 
(ANCOVA) with a factor for other PAH-specific therapy (none, background or initiated 
at baseline) and a covariate for baseline RVSV. The mean change from baseline and its 
96% confidence interval (CI) will be estimated based on the model. 
PVR will be summarized by time point using descriptive statistics as well as geometric 
means and Coefficients of Variation (CVs). The Week 26 versus baseline ratio in PVR 
will be summarized similarly. 
The ratio of Week 26 versus baseline PVR will be log-transformed (base e) and analyzed 
using an ANCOVA with a factor for other PAH-specific therapy (none, background or 
initiated at baseline) and a covariate for baseline log PVR. The mean change from 
baseline (on log scale) and its 99% CI will be estimated based on the model. The 
geometric mean ratio (versus baseline) and its 99% CI will be obtained by 
exponentiation. 
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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 null hypothesis will be tested at interim and final analysis, if study continues, and 
may be rejected based on pre-defined boundaries defined in Section 11.4.3. 
11.3.2.4 Supportive/sensitivity analyses 
A sensitivity analysis will be performed on the FAS. In patients without a Week 26 
RVSV or PVR the last post-baseline measurement will be carried forward, regardless of 
the time it was taken. Week 26 measurements performed after 30 weeks of treatment will 
be excluded from the analysis. 
Another sensitivity analysis will be performed on the PPS that will (at least) be restricted 
to completers, i.e., patients with Week 26 RVSV and PVR measurements taken between 
22 and 30 weeks of treatment. 
A sensitivity analysis will also be performed on the SS that may include patients without 
post-baseline RVSV or PVR. For those patients, the Week 26 RVSV or PVR 
measurement needs to be imputed. Imputation rules will be specified in the SAP. 
Sensitivity analyses for RVSV and PVR may also be performed for the specific RVSV 
and PVR Analysis Sets, respectively, but only if deemed necessary as specified in the 
SAP. 
11.3.2.5 Subgroup analyses 
Subgroup analyses for the primary endpoints will be performed only at final analysis for 
patients with versus without PAH-specific therapy at baseline using the ANCOVA 
models specified in Section 11.3.2.3, but without the factor for PAH-specific therapy. In 
this analysis 95% CIs will be used. 
Subgroup analyses for RVSV and log PVR will also be performed for patients on 
WHO FC I–II versus III using the ANCOVA models specified in Section 11.3.2.3, In this 
analysis 95% CIs will be used. 
Additional subgroup analyses will be specified in the SAP. 
Exploratory analyses will be performed aimed at identifying prognostic factors for 
changes from baseline in RVSV and log PVR. This will be done using linear regression 
models. Candidate prognostic factors will be specified in the SAP. 
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11.3.3 Analysis of the secondary efficacy variables 
Secondary efficacy analyses will be performed only at final analysis on the Modified 
FAS at α = 0.025 (one-sided) using 95% CIs. Supportive secondary efficacy analyses will 
also be performed on the FAS. No correction for multiple testing will be applied for these 
analyses. 
MRI-based secondary efficacy variables (changes from baseline to Week 26 in RVEDV, 
RVESV, RVEF, RV mass) will be summarized and analyzed as described for RVSV in 
Section 11.3.2.3. 
The 6MWD will be summarized by time point using descriptive statistics. Change from 
baseline to Week 26 will be summarized similarly. Change from baseline in 6MWD will 
be analyzed using an ANCOVA with a factor for other PAH-specific therapy (none, 
background or initiated at baseline) and a covariate for baseline 6MWD and WHO FC.  
WHO FC will be summarized by time point using frequency tables. Changes from 
baseline in WHO FC 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 a factor for background PAH-specific therapy at baseline. 
NT-proBNP will be summarized by time point using descriptive statistics as well as 
geometric means and CVs. The Week 26 versus baseline ratio will be summarized 
similarly. The ratio versus baseline in NT-proBNP will be log-transformed and analyzed 
using an ANCOVA with a factor for other PAH-specific therapy (none, background or 
initiated at baseline) and a covariate for baseline log NT-proBNP.  
11.3.4 Analysis of the exploratory efficacy variables 
Other efficacy variables will be summarized for the Modified FAS using descriptive 
statistics only. No statistical analyses will be performed. 
Hemodynamic variables [Section 11.2.3.1] will be summarized by time point using 
descriptive statistics. Week 52 variables [Section 11.2.3.2] will be summarized similarly 
to the corresponding Week 26 measurements.  
Pressure-volume variables (changes from baseline to Week 26 in arterial elastance, RV 
end-systolic elastance, RV maximum isovolumic pressure) will be summarized and 
analyzed as described for PVR in Section 11.3.2.3, but without the log-transformation. 
Variables related to the left ventricle [Section 11.2.3.3] will be summarized similarly as 
the corresponding right ventricular variables. The ratios RVEDV/LVEDV and 
RVESV/LVESV will be summarized using descriptive statistics as well as geometric 
means and CVs. Potential variables for disease monitoring [Section 11.2.3.4] will be 
summarized similarly as NT-proBNP. 
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The clinical endpoint, time to first clinical worsening [Section 11.2.3.5] will be 
summarized using a Kaplan-Meier plot. 
Association between (change from baseline to Week 26 in) cardiac MRI variables and 
time to first clinical worsening event will be explored using Cox models. 
11.3.5 Analysis of safety variables 
All safety analyses will be performed on the SS. 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 drug 
from study drug initiation until 30 days after study drug discontinuation. 
The number and percentage of patients experiencing treatment emergent AEs and SAEs 
at least once from baseline up to 30 days following study drug discontinuation will be 
tabulated by: 
• 
MedDRA system organ class (SOC) and individual preferred term (PT) within each 
SOC, in descending order of incidence. 
• 
Frequency of patients with events coded with the same PT, in descending order of 
incidence.  
Furthermore, treatment-emergent AEs and SAEs occurring up to 30 days after study drug 
discontinuation will be tabulated as described above by severity and relationship to study 
drug.  
AEs leading to premature discontinuation of study drug and death will also be 
summarized as described above.  
Listings will be provided for all reported AEs, including SAEs. In addition, separate 
listings will be provided for SAEs, for AEs leading to premature discontinuation of study 
drug, and for AEs leading to death. 
11.3.5.2 Laboratory parameters 
Descriptive summary statistics by visit and study treatment will be provided for observed 
values and absolute changes, from baseline up to EOT plus 30 days, in both hematology, 
clinical chemistry and coagulation laboratory tests. In order to minimize missing data and 
to allow for unscheduled visits, all recorded assessments up to EOT plus 30 days will be 
assigned to the most appropriate visit time point according to the best fitting 
time-window for that assessment. 
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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 
incidence and frequency. Absolute values and changes of laboratory parameter values 
during the course of the study from baseline up to EOT plus 30 days will be summarized 
using the usual location and scale summary statistics. 
Laboratory parameters include: 
• Hematology: hemoglobin, hematocrit, erythrocyte count (reticulocyte count), 
leukocyte count with differential counts, platelet count. 
• Blood chemistry: AST, ALT, alkaline phosphatase, total and direct bilirubin, LDH, 
creatinine, urea, uric acid, glucose, cholesterol, triglycerides, sodium, potassium, 
chloride, calcium, protein, albumin. 
• Coagulation tests: prothrombin time, INR, aPTT. 
The number and percentage of patients with LFT abnormalities [classified as in 
Section 11.2.4] up to 30 days after study drug discontinuation will be tabulated. 
The number and percentage of patients with hemoglobin abnormalities [classified as in 
Section 11.2.4] up to 30 days after study drug discontinuation will be tabulated. 
11.3.5.3 Vital signs and body weight  
Vital signs parameters blood pressure (i.e., diastolic blood pressure and systolic blood 
pressure), HR, and body weight will be summarized at each study visit up to EOT using 
the usual location and scale summary statistics for both absolute values and changes from 
baseline. Patients for whom no post-baseline value is available are excluded from the 
analysis of the changes from baseline in the SS. 
11.3.6 Analysis of other variables 
Analyses associated with the sub-studies will be described in the SAP. 
11.4 Interim analyses 
11.4.1 Rationale 
The determination of the sample size necessary to conclude on RVSV at final analysis 
relied on assumptions derived from a single source [Section 11.5]. Therefore, a 
conservative approach was taken and led to a large sample size, i.e., 100 patients, to 
increase the probability of this study being conclusive. 
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Literature recently published [Hassoun 2015, Trip 2015, Brewis 2016] [Table 2] is in line 
with the initial assumptions, and suggests that the treatment effect on RVSV might be 
demonstrated before reaching 100 patients. Therefore, an interim analysis will be 
performed to allow for an early completion of the study for efficacy. 
Table 2 
New data published in 2015/2016 
Reference 
Patients with 
follow-up data 
Reported data 
[Hassoun 2015] 
24 incident 
CTD-PAH patients 
treated with PDE-5 
inhibitor–ERA 
combination for 
36 weeks 
Median (Q1-Q3) Baseline RVEDV (mL): 151.2 (138.4–177.4) 
Median (Q1-Q3) Post-treatment RVEDV (mL): 146.4 (120.5–165.4) 
 
Median (Q1-Q3)  Baseline RVESV (mL): 82.1 (65.6–97.7) 
Median (Q1-Q3) Post-treatment RVESV (mL):  
55.8 (49.4–79.2) 
 
[Brewis 2016] 
42 incident PAH 
patients mainly 
treated with PDE-5 
inhibitor and/or 
ERA for  
3–8 months 
Mean (SD) Baseline Stroke volume index (mL/min2): 27 (8) 
Mean (SD) Post-treatment Stroke volume index (mL/m2): 32 (9) 
 
[Trip 2015] 
 
30 incident IPAH 
or HPAH patients 
treated with PAH 
therapies for  
0.5–2.5 years 
Median (Q1-Q3) Baseline RVEDV (mL): 140 (124–161) 
Median (Q1-Q3) Post-treatment RVEDV (mL): 137 (117–163) 
 
Median (Q1-Q3) Baseline RVESV (mL): 93 (72–109) 
Median (Q1-Q3) Post-treatment RVESV (mL): 73 (54–91) 
 
CTD-PAH = Connective Tissue Disease - Pulmonary Arterial Hypertension; HPAH = Heritable Pulmonary Arterial 
Hypertension; IPAH = Idiopathic Pulmonary Arterial Hypertension; PAH = Pulmonary Arterial Hypertension; 
PDE-5 = Phosphodiesterase type 5; ERA = Endothelin Receptor Antagonist; RVEDV = Right Ventricular End 
Diastolic Volume; RVESV = Right Ventricular End Systolic Volume. 
11.4.2 Conduct 
An interim analysis will be conducted when the first 42 evaluable patients (i.e., included 
in the Modified FAS) are available for primary efficacy analysis.  
The interim analysis will use a hierarchical testing approach to maintain the overall type I 
error. As a first step, change from baseline to Week 26 in RVSV will be tested. If the test 
is negative, i.e., the pre-defined efficacy boundary (p-value) is not crossed, recruitment 
will continue until 100 patients are enrolled. If it is positive (pre-defined efficacy 
boundary crossed), then PVR (ratio of Week 26 to baseline) will be tested. 
RVSV is to be tested first, as the potential effects of PAH-specific therapy on this 
variable are not so well known. The effect of such therapies on PVR is better known with 
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robust treatment effect estimates, i.e., there is less uncertainty on the treatment effect 
estimate. 
If the test on PVR is also positive, then the study will be declared positive for its primary 
endpoint. If the test on PVR is negative, no conclusion can be made with regards to the 
primary endpoint, and patient accrual will continue until 100 patients are enrolled. 
To declare the study positive at the interim analysis, both endpoints must be met. This 
contrasts with the final analysis, where it is sufficient to meet one endpoint. The reason 
for this choice is to mitigate the risk of closing the study too early to observe the full 
potential of macitentan. 
11.4.3 Statistical analysis 
The interim analysis will be performed on the Modified FAS. Efficacy boundaries are 
defined in Table 3 and Table 4, and are calculated with 90% power, 1-sided 0.02 alpha 
for RVSV test, 1-sided 0.005 alpha for PVR test and are based on assumptions described 
in Section 11.5 (sample size). To accommodate the need for the same number of patients 
included in the interim analysis of each primary endpoint, the selected information 
fraction (around 50%) is slightly different for RVSV and PVR. 
11.5 Sample size 
For MRI-based RVSV, no individual patient data are available at Actelion. Individual 
RVSV was approximated in the hemodynamic sub-study of SERAPHIN (AC-055-302) 
combining the cardiac index obtained from the RHC with BSA and HR from vital signs 
measurements. The change from baseline in approximate RVSV was around 9 mL, in 
line with literature suggesting that a difference of 8–12 mL is clinically relevant 
[Van Wolferen 2011]. Assuming a standard deviation of 18–22 mL, also based on the 
hemodynamic sub-study of SERAPHIN, the sample size for 90% power is 30–93 
evaluable patients for final analysis (α = 0.02, one-sided). The number of patients and 
efficacy boundaries for the interim analysis are described in Table 3. 
For PVR, an integrated analysis of two bosentan studies, BENEFIT (AC-052-366) and 
EARLY (AC-052-364), and the hemodynamic sub-study of SERAPHIN suggested that 
the mean change from baseline is expected to be around −0.24 on log scale (95% CI:  
−0.29, −0.19) and that the within group standard deviation is around 0.41 on log scale 
(90% CI: 0.39, 0.43). Under these assumptions, 30–84 evaluable patients are needed for 
final analysis for 90% power (α = 0.005, one-sided). The number of patients and efficacy 
boundaries for the interim analysis are described in Table 4. 
The scenario retained to compute number of patients and p-value boundaries for 
interim/final analyses is based on conservative assumptions (lowest change and highest 
variability), and is described in Table 3 (RVSV) and Table 4 (PVR) below. 
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Table 3 
Efficacy boundaries for RVSV endpoint at interim/final analyses 
Change from 
baseline 
SD 
Information 
fraction for 
interim 
analysis 
Number of 
patients needed 
at interim 
analysis 
Number of 
patients 
needed at 
final analysis 
Efficacy 
Boundary on 
p-value scale (Lan 
DeMets Pocock) 
– Interim analysis 
Efficacy 
Boundary on 
p-value scale 
(Lan DeMets 
Pocock) – 
Final analysis 
8 
22 
0.45 
42 
93 
0.01149 
0.01138 
RVSV = Right Ventricular Stroke Volume; SD = Standard Deviation.  
 
Table 4 
Efficacy boundaries for PVR endpoint at interim/final analyses 
Change from 
baseline on 
log scale 
SD 
Information 
fraction for 
interim analysis 
Number of 
patients 
needed at 
interim 
analysis 
Number of 
patients 
needed at 
final analysis 
Efficacy 
Boundaries on 
p-value scale 
(LanDeMets 
Pocock) – Interim 
analysis* 
Efficacy 
Boundaries on 
p-value scale 
(LanDeMets 
Pocock) – 
Final 
analysis** 
−0.19 
0.43 
0.5 
42 
84 
0.0031 
0.00247 
* Test at interim only if RVSV crossed pre-defined efficacy boundary. The information fraction for PVR is higher than 
for RVSV to fit same number of patients at interim analysis for both endpoints. 
** Boundary is 0.005 if not tested at interim 
PVR = Pulmonary Vascular Resistance; RVSV = Right Ventricular Stroke Volume; SD = Standard Deviation. 
To account for patient dropout and non-evaluable images, the sample size was set at 
100 patients for the final analysis. 
12 DATA HANDLING 
12.1 Data collection 
The investigator/delegate is responsible for ensuring the accuracy, completeness, and 
timeliness of the data reported. All source documents must be completed in a neat, legible 
manner to ensure accurate interpretation of the data. Data reported in the electronic CRF 
derived from source documents must be consistent with the source documents. 
CRF data will be captured via electronic data capture (using the Rave system provided by 
Medidata Solutions, Inc., a web-based tool). The investigator and site 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 
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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). 
Patient screening data will be completed for all patients (i.e., eligible and non-eligible) 
through the IRT system and CRF. 
For each patient screened, regardless of study treatment initiation, a CRF must be 
completed and signed by the investigator/delegate. This also applies to those patients who 
fail to complete the study. If a patient withdraws from the study, the reason must be noted 
on the CRF.  
12.2 Maintenance of data confidentiality 
The investigator/delegate must ensure that data confidentiality is maintained. On CRFs or 
other documents submitted to Actelion, patients must be identified only by number, and 
never by name or initials, hospital numbers or any other identifier. The 
investigator/delegate must keep a patient identification code list, at the site, showing the 
screening number, the patient’s name, date of birth and address or any other locally 
accepted identifiers. Documents identifying the patients (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 patients. Investigators will have full 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 patient 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 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 patient confidentiality is protected. This process will continue until 
database closure. 
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Laboratory samples will be processed through a central laboratory and the results will be 
sent electronically to Actelion.  
Cardiac MRI, PET-MR, Echo and biopsies will be centrally assessed and the results will 
be sent electronically to Actelion. 
After the database has been declared complete and accurate, it will be closed. Any 
changes to the database after that time may only be made as described in the appropriate 
standard operating procedure (SOP). After database closure, the investigator will receive 
the CRF of the patients of her/his site (including all data changes made) on electronic 
media or as a paper copy. 
13 PROCEDURES AND GOOD CLINICAL PRACTICE 
13.1 Ethics and Good Clinical Practice 
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 
patient (such as Patient Information Leaflet used to obtain informed consent) to an 
IRB/IEC. Approval from the committee must be obtained before starting the study, and 
must be documented in a dated letter to the investigator, clearly identifying the study, the 
documents reviewed, and the date of approval.  
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 patients that 
they are completely free to refuse to enter the study, or to withdraw from it at any time 
for any reason. 
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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 patient and/or legal representative will be listed on the Delegation of Authority form. 
A study physician must always be involved in the consent process.  
The patient and/or legal representative must sign and personally date and time (if 
appropriate) the ICF before any study-related procedures begin (i.e., any procedures 
required by the protocol). The ICF must also be signed and personally dated and timed (if 
appropriate) by the authorized site staff listed on the Delegation of Authority form. 
A copy of the signed and dated ICF is given to the patient and/or legal representative; the 
original is filed in the site documentation.  
The informed consent process must be fully documented in the patient’s medical records, 
including study reference, patient number, date/time (if applicable) when the patient was 
first introduced to Actelion clinical study, date/time (if applicable) of consent, who 
participated in the consent discussion, who consented the patient and any additional 
person present during the consent process (e.g., patient family member). A copy of the 
signed ICF must be given to the patient and/or legal representative. 
In the case that the site would like to recruit a patient who would be considered as 
vulnerable (e.g., patient cannot read or write, does not speak or understand the ICF 
language), additional measures must be implemented in order to ensure patient 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 such patients are 
recruited.  
13.4 Compensation to patients 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 patient 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 patient.  
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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. 
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 patient 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 patient 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 patients 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 patient 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 
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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 
patient’s data. The printouts will be considered as the official clinical study records.  
In order to verify that the process the site uses to prepare certified copies is reliable, the 
monitor must be able to observe this process and confirm that the comparison of the 
source documents and the certified copy did not reveal inconsistencies. The monitor does 
not need to verify this process for all data of all patients but at least for some of them 
(e.g., first patient; regular check during the study of critical data like inclusion/exclusion 
criteria, endpoints for some patients) 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 must be filed either with the patient medical records or with the patient’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 patients. 
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 Investigative Site File (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 patient recruitment rate and critical data collection times. 
The principal investigator must ensure that the CRF is completed after a patient’s visit to 
the site, and that all requested patient 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 
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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 patient is hospitalized or dies in a 
hospital other than the study site, the investigator is responsible for contacting that 
hospital in order to document the SAE, in accordance with local regulations. 
A close-out visit will be performed for any initiated site and when there are no more 
active patients 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 patients, 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 must 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 will change, or if the site will relocate, 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., patient records) and facilities. 
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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.  
Should an inspection be requested by a Health Authority and/or IRB/IEC, the investigator 
must inform Actelion immediately, (usually via the monitor), that such a request has been 
made.  
The investigator and staff must cooperate with inspector(s) and allow access to all study 
documentation (e.g. patient 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. 
The coordinating investigator and the Steering Committee 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 
(SMADAR), 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_clinical-research-
information.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.  
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The list of authors of any publication of study results may include representatives of 
Actelion, and will be determined by mutual agreement. 
Any study-related publication written independently by investigators must be submitted 
to Actelion for review at least 30 days prior to submission for publication or presentation. 
Upon review, Actelion may provide comments, and may also request alterations and/or 
deletions for the sole purpose of protecting its confidential information and/or patent 
rights. Neither the institution nor the investigator should permit publication during such a 
review period. 
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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[Grothues 2003] Grothues F, Moon JC, Bellenger NG, Smith GS, Klein HU, Pennell DJ. 
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[Hassoun 2009] Hassoun PM. Therapies for scleroderma-related pulmonary arterial 
hypertension. Expert Rev Respir Med. 2009;3(2):187-196. 
[Hassoun 2015] Hassoun PM, Zamanian, RT, Damico R, et al. Ambrisentan and tadalafil 
upfront combination therapy in scleroderma-associated PAH. AJRCCM. 
2015;192(9):1102-1110. 
[Hinderliter 1997] Hinderliter AL, Willis PW, Barst RJ, Rich S, Rubin LJ, Badesch DB, 
Groves BM. Effects of long-term infusion of prostacyclin (epoprostenol) on 
echocardiographic measures of right ventricular structure and function in primary 
pulmonary hypertension. Primary Pulmonary Hypertension Study Group. 
Circulation. 1997 Mar 18;95(6):1479-86. 
[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 2006] Hoeper MM, Lee SH, Voswinckel R, Palazzini M, Jais X, Marinelli A, et 
al. Complications of right heart catheterization procedures in patients with 
pulmonary hypertension in experienced centers. J Am Coll Cardiol. 2006 Dec 
19;48(12):2546-52. 
[Hoeper 2013] Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, Khanna D, Kurzyna M. 
Definitions and Diagnosis of Pulmonary Hypertension. J Am Coll Cardiol 
2013;62:D42-50. 
[Humbert 2004] Humbert M, Morell NW, Archer SL, et al. Cellular and Molecular 
Pathobiology of pulmonary Arterial Hypertension. J Am Coll Cardiol 2004;43: 
13S-24S. 
[Kasimir 2004] Kasimir MT, Seebacher G, Jaksch P, Winkler G, Schmid K, Marta GM. 
Reverse cardiac remodelling in patients with primary pulmonary hypertension after 
isolated lung transplantation. Eur J Cardiothorac Surg. 2004 Oct;26(4):776-81. 
[Kuehne 2004] Kuehne T, Yilmaz S, Steendijk P, Moore P, Groenink M, Saaed M. 
Magnetic resonance imaging analysis of right ventricular pressure-volume loops: in 
vivo validation and clinical application in patients with pulmonary hypertension. 
Circulation. 2004 Oct 5;110(14):2010-6. 
[Kylhammar 2014] Kylhammar D, Persson L, Hesselstrand R, Rådegran G. Prognosis 
and response to first-line single- and combination therapy in pulmonary arterial 
hypertension. Scand Cardiovasc J. 2014 Jun 10:1-23. 
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Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 114/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
[Macitentan IB] Investigator’s Brochure. Macitentan ACT-064992. Endothelin receptor 
antagonist, Version 11. Actelion Pharmaceuticals Ltd, November 2013. 
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530-3. 
[O’Callaghan 2011] O’Callaghan DS, Savale L, Montani D, et al. Treatment of 
pulmonary arterial hypertension with targeted therapies. Nat Rev Cardiol. 
2011;8(9):526-38. 
[Oudiz 2013] Oudiz RJ. Death in Pulmonary Arterial Hypertension. Am J Respir Crit 
Care Med. 2013 Aug 1;188(3):269-70.  
[Overbeek 2008] Overbeek MJ, Lankhaar JW, Westerhof N, Voskuyl AE, Boonstra A, 
Bronzwaer JGF. Right ventricular contractility in systemic sclerosis-associated and 
idiopathic pulmonary arterial hypertension. Eur Respir J 2008;31:1161-1166. 
[Peacock 2014] Peacock A, Crawley S, McLure L, Blyth K, Vizza CD, Poscia R. 
Changes in right ventricular function measured by cardiac magnetic resonance 
imaging in patients receiving pulmonary arterial hypertension-targeted therapy The 
EURO-MR study. Circ Cardiovasc. Imaging. 2014;7:107-114. 
[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. 
[Raghu 2013] Raghu G, Million-Rousseau R, Morganti A, Perchenet L, Behr J. 
Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised 
controlled MUSIC Trial. Eur Respir J. 2013 Dec;42(6):1622-32. 
[Raymond 2002] Raymond RJ, Hinderliter AL, Willis PW, Ralph D, Caldwell EJ, 
Williams W. Echocardiographic predictors of adverse outcomes in primary 
pulmonary hypertension. J Am Coll Cardiol. 2002 Apr 3;39(7):1214-9. 
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blockers on survival in primary pulmonary hypertension. N Engl J Med 
1992;327(2):76-81. 
[Rich 2012] Rich S. Right Ventricular Adaptation and Maladaptation in Chronic 
Pulmonary Arterial Hypertension. Cardiol Clin. 2012 May;30(2):257-69. 
[Roeleveld 2004] Roeleveld RJ, Vonk-Noordegraaf A, Marcus JT, Bronzwaer JG, 
Marques KM, Postmus PE. Effects of epoprostenol on right ventricular hypertrophy 
and dilatation in pulmonary hypertension. Chest. 2004 Feb;125(2):572-9. 
NCT02310672

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Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 115/130 
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EudraCT 2014-004066-20 
Doc No. D-16.554  
 
[Simonneau 2013] Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, 
Ghofrani A. Updated Clinical Classification of Pulmonary Hypertension. J Am Coll 
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[Sugawara 1996] Sugawara F, Ninomiya H, Okamoto Y, et al. Endothelin-1-
inducedmitogenic responses of Chinese hamster ovary expressing human 
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Pharmacol 1996;49:447-57. 
[Sunagawa 1980] Sunagawa K, Yamada A, Senda Y, Kikuchi Y, Nakamura M, 
Shibahara T. Estimation of the hydromotive source pressure from ejecting beats of 
the left ventricle. IEEE Trans Biomed Eng. 1980 Jun;27(6):299-305. 
[Swift 2014] Swift AJ, Rajaram S, Campbell MJ, Hurdman J, Thomas S, Capener D. 
Prognostic value of cardiovascular magnetic resonance imaging measurements 
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Cardiovasc Imaging. 2014 Jan;7(1):100-6. 
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[Tedford 2013] Tedford RJ, Mudd JO, Girgis RE, Mathai SC, Zaiman AL, Housten-
Harris T. Right ventricular dysfunction in systemic sclerosis-associated pulmonary 
arterial hypertension. Circ Heart Fail. 2013 Sep 1;6(5):953-63. 
[Trip 2013] Trip P, Kind T, van de Veerdonk MC, Marcus JT, de Man FS, Westerhof N. 
Accurate assessment of load-independent right ventricular systolic function in 
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50-5. 
[Trip 2015] Trip P, Rain S, Handoko ML, van der Bruggen C, Bogaard HJ, Marcus JT, 
Boonstra A. Clinical relevance of right ventricular diastolic stiffness in pulmonary 
hypertension. Eur Respir J. 2015 Jun; 45(6):1603-12 
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Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
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Confidential  
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Doc No. D-16.554  
 
[Van de Veerdonk 2011] van de Veerdonk MC, Kind T, Marcus JT, Mauritz GJ, 
Heymans MW, Bogaard HJ, Boonstra A. Progressive right ventricular dysfunction 
in patients with pulmonary arterial hypertension responding to therapy. J Am Coll 
Cardiol. 2011 Dec 6;58(24):2511-9. 
[Van Wolferen 2006] van Wolferen SA, Boonstra A, Marcus JT, Marques KM, 
Bronzwaer JG, Postmus PE. Right ventricular reverse remodelling after sildenafil 
in pulmonary arterial hypertension. Heart. 2006 Dec;92(12):1860-1. 
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Marcus JT, Marques KM. Clinically significant change in stroke volume in 
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[Van Wolferen 2007] van Wolferen SA, Marcus JT, Boonstra A, Marques KM, 
Bronzwaer JG, Spreeuwenberg MD. Prognostic value of right ventricular mass, 
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[Vonk-Noordegraaf 2011] Vonk-Noordegraaf A, Galiè N. The role of the right ventricle 
in pulmonary arterial hypertension. Eur Respir Rev. 2011;20(122):243-253. 
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Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension 
(SERAPH) study. Am J Respir Crit Care Med. 2005 Jun 1;171(11):1292-7. 
[Yamada 2012] Yamada Y, Okuda S, Kataoka M, Tanimoto A, Tamura Y, Abe T. 
Prognostic value of cardiac magnetic resonance imaging for idiopathic pulmonary 
arterial hypertension before initiating intravenous prostacyclin therapy. Circ J. 
2012;76(7):1737-43. 
 
 
NCT02310672

Macitentan / ACT-064992 
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Confidential  
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Appendix 1 
Actelion guidelines for RHC 
RIGHT HEART CATHETERIZATION 
These guidelines should be followed where possible. If historical RHC data have been 
used at baseline according to inclusion criterion 5 and do not fully comply with these 
guidelines, any post-baseline RHC must be performed in the same way as the baseline 
RHC to ensure data consistency.  
1 
Material and methods 
• Patients will undergo right heart catheterization (RHC) at the study site or other 
institution in case no suitable laboratory is available at the study site in an appropriate 
care setting (e.g., cardiac catheterization laboratory, medical procedures unit, 
intensive care unit). Left heart catheterization, if needed, must be carried out in the 
cardiac catheterization laboratory. 
• Hemodynamic evaluations will be carried out with the patient in the supine position. 
Patients will breathe room air. If the patient requires supplemental oxygen during 
catheterization, oxygen must be given during both baseline and the follow-up 
assessments (if applicable). Electrocardiogram for the assessment of the heart rate 
(HR) will be monitored continuously. Systolic and diastolic systemic arterial 
pressures (sSAP, dSAP) will be measured by the cuff method at the brachial artery 
level. 
• RHC will be performed according to laboratory’s standard procedures through the 
internal jugular, subclavian, or femoral vein by a balloon catheter placed into either 
the right or left pulmonary artery. A triple-lumen, balloon-tipped thermodilution 
catheter will be used for measurement of selected intracardiac pressures (at end-
expiration) and cardiac output (CO). A four-lumen, balloon-tipped thermodilution 
catheter can be used, if obtaining accurate pulmonary capillary wedge pressure 
(PCWP) or pulmonary arterial pressure (PAP) is problematic.  
• CO will be measured by thermodilution. 
• For those patients on background medication that includes anticoagulants 
(e.g., warfarin), the usual safety measures, as routinely used by the study site for 
cessation of these drugs prior to and after the procedure, must be taken. 
2 
Assessments 
2.1 
Hemodynamic parameters measured during RHC: 
• HR 
• CO 
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• Pulmonary artery pressure (systolic, diastolic, electronic mean: sPAP, dPAP, mPAP) 
• Mean right atrial pressure (mRAP) 
• PCWP or left atrial end diastolic pressure (LVEDP). See Section 2.3. 
• Noninvasive sSAP and dSAP) 
2.2 
Measurement and selection of hemodynamic parameters: 
• Hemodynamic pressures (mPAP, mRAP, and PCWP, or LVEDP) will be measured in 
duplicate (10 minutes apart), or until 2 consecutive values do not differ > 10%: the 
last value will be recorded in the RHC page of the Case Report Form (CRF). 
• For the measure of PCWP, the same method must be used consistently throughout the 
study. 
• HR and systemic arterial pressure: will be measured in duplicate (10 minutes apart), 
or until 2 consecutive values do not differ > 10%: the last value will be recorded in 
the RHC page of the CRF. 
• CO will be measured in triplicate, or until 3 consecutive values do not differ > 10%: 
the mean value will be recorded in the RHC page of the CRF. 
• All measured hemodynamic values, including those not reported in the RHC page of 
the CRF, and the time when the measurements were taken must be included in the 
catheterization report or recorded in a source document. 
2.3 
Calculated hemodynamic parameters: 
• Pulmonary vascular resistance (dyn.sec.cm-5): 𝑃𝑉𝑅= ቀ
𝑚𝑃𝐴𝑃−𝑃𝐶𝑊𝑃
𝐶𝑂
ቁ∗80 
• Total pulmonary vascular resistance (dyn.sec.cm-5): 𝑇𝑃𝑅=
𝑚𝑃𝐴𝑃
𝐶𝑂*80 
• Cardiac index (l.min-1.m-2): 𝐶𝐼=
𝐶𝑂
𝐵𝑆𝐴 
• Body surface area (m2): 𝐵𝑆𝐴= 0.007184 ∗(𝑤𝑒𝑖𝑔ℎ𝑡0.425) ∗(ℎ𝑒𝑖𝑔ℎ𝑡0.725) 
with weight expressed in kg and height in cm. 
2.4 
Data transmission for central assessment: 
Right ventricle and pulmonary artery pressure signals over at least 10 heartbeats, 
simultaneous with ECG sampling, is requested. Sample frequency must be at least 
200Hz. Pressure calibration must be provided. Pressure curves will be uploaded in a 
specially designed web site and will be centrally assessed. 
NCT02310672

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Appendix 2 
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 must 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 must 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 must be approved in written form by Actelion before 
implementation. 
• The study staff member administering the 6MWT will 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 must 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 must 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. 
 
NCT02310672

Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 122/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
Appendix 3 
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) 
 
NCT02310672

Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
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EudraCT 2014-004066-20 
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Appendix 4 
WHO Functional Classification of pulmonary hypertension 
Class I 
Patients with pulmonary hypertension but without resulting limitation of 
physical activity. Ordinary physical activity does not cause undue dyspnea 
of fatigue, chest pain or near syncope. 
Class II 
Patients with pulmonary hypertension resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary physical activity 
causes undue dyspnea or fatigue, chest pain or near syncope. 
Class III 
Patients with pulmonary hypertension resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary activity 
causes undue dyspnea or fatigue, chest pain or near syncope. 
Class IV 
Patients with pulmonary hypertension with inability to carry out any 
physical activity without symptoms. These patients manifest signs of right 
heart failure. Dyspnea and/or fatigue may even be present at rest. 
Discomfort is increased by any physical activity. 
 
NCT02310672

Macitentan / ACT-064992 
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Version 6 
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Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
Appendix 5 
Study drug storage 
The investigator is responsible for safe and proper handling and storage of the study drug 
at the investigational site, and for ensuring that the study drug is administered only to 
patients enrolled in the study, in accordance with the protocol. 
Study drug must be kept in a locked room, or a locked cupboard in a restricted access 
room, which can be accessed only by the pharmacist, the investigator, or another duly 
designated person as specified on the Delegation of Authority form. 
The study drug must be stored below 30 °C and must be protected from moisture. 
Unopened, sealed study medication bottles may be stored in refrigerators (between the 
temperature range of +2 °C to 30 °C). If the temperature at a patient’s home exceeds 
30 °C, the patient must be instructed to store the unopened bottles of the study drug in 
his/her refrigerator. Frozen storage (below +2 °C) is not permitted. Unsealed bottles must 
not be stored in the refrigerator. 
At the site, a temperature log must be maintained, and temperature control should occur 
at least on a weekly basis. 
Actelion will provide a temperature log if not available on site, 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 the site is acceptable, as long as all 
required information is included and certification of calibration is provided. If the 
temperature is captured electronically, a printout must be made available to the monitor 
during each on-site visit. 
In case a deviation from the defined temperature range is identified by the site, the 
deviation is to be reported to the monitor, preferably in writing and with supportive 
documentation (e.g., a copy of the temperature log showing data for all excursion days). 
The monitor must immediately notify Actelion for further advice. The study drug 
affected by a deviation will not be used (e.g., segregated physically at the investigational 
site) until confirmation by Actelion that it is safe to be used. In case the temperature 
deviation is defined as acceptable, a corresponding message is returned to the site via the 
monitor. 
In case the temperature deviation is defined as not acceptable and the quality of the study 
drug might be affected, the study drug is kept segregated at the investigational site and 
returned to Actelion following internal drug return processes. New study drug supplies 
will be provided to the site. 
Site temperature deviations correspondence must be kept in the Investigator Site File. 
The study centers will be supplied with the study drug according to the centers’ needs, 
depending on the rate of patient enrollment. 
NCT02310672

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Version 6 
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EudraCT 2014-004066-20 
Doc No. D-16.554  
 
Appendix 6 
Central laboratory 
In case of laboratory abnormalities at any visit corresponding to the thresholds below, the 
central laboratory will alert Actelion and the concerned site. Alert flags will trigger these 
notifications. 
Analyte 
Threshold 
ALT 
≥ 3 × ULN 
AST 
≥ 3 × ULN 
Hemoglobin 
< 80 g/L, or 
Decrease by > 20g/L from last value before 
study drug initiation 
Beta-human chorionic gonadotropin 
> 5 mIU/ml 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit 
of the normal range. 
NCT02310672

Macitentan / ACT-064992 
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Version 6 
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EudraCT 2014-004066-20 
Doc No. D-16.554  
 
Appendix 7 
Eligibility questionnaire 
Site Identification 
Principal Investigator 
_____________________________ 
 Patient Identification 
Patient number 
└─┴─┴─┴─┴─┴─┴─┘ 
Age  └─┴─┘ 
Please complete the questionnaire below to document which tests/procedures have been performed in 
order to exclude other causes of pulmonary hypertension for the patient indicated above. 
This questionnaire must be completed prior to treatment initiation for all patients: 
a) with 30 < BMI < 35 kg/m2, and/or  
b) with 65 ≤ Age < 75 years 
1. Patient characteristics 
Body mass index └─┴─┘.└─┘ kg/m
2 
Gender 
 
 
□Male  
□Female 
PAH etiology 
 
□ Idiopathic PAH 
 
 
 
 
□ Heritable PAH 
 
 
 
 
□ Drug- and toxin-induced PAH 
 
 
 
 
□ PAH associated with connective tissue disease 
 
 
 
 
□ PAH associated with congenital heart diseases, only simple  
 
 
 
 
congenital systemic to pulmonary shunts at least 2 year post surgical 
 
 
 
 
repair 
Most recent Right Heart Catheterization date:  └─┴─┘└─┴─┴─┘└─┴─┘  
 
  dd 
        mmm 
yy 
mPAP: 
PVR: 
PCWP: 
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LVEDP: 
If RHC curves are available, please provide them. 
 
Ongoing 
Not 
ongoing 
Relevant medical history: ---------------------------------------------------------------
---------------------------------------------------------------------------------------------------
---------------------------------------------------------------------------------------------------
---------------------------------------------------------------------------------------------------
---------------------------------------------------------------------------------------------------
---------------------------------------------------------------------------------------------------
---------------------------------------------------------------------------------------------------
--------------------------------------------------------------------------------------------------- 
---------------------------------------------------------------------------------------------------
---------------------------------------------------------------------------------------------------
--------------------------------------------------------------------------------------------------- 
 
 
 
Yes 
No 
2. Was an echocardiography performed? ----------------------------------------------------------------------------------------- 
a. If yes, date of the most recent echocardiography: 
 
└─┴─┘└─┴─┴─┘└─┴─┘  
 
  dd 
        mmm 
yy 
b. If yes, did it show  
i. left ventricular systolic dysfunction? ----------------------------------------------------------- 
ii. left ventricular diastolic dysfunction?---------------------------------------------------------- 
iii. enlarged left ventricle ? --------------------------------------------------------------------------------------- 
iv. enlarged left atrium? ---------------------------------------------------------------------------------------------- 
v. left-sided valvular heart disease? ------------------------------------------------------------------- 
If you have answered “Yes” to one or more of the questions above, how did you 
exclude this/these finding(s) as the main reason for pulmonary hypertension? 
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Version 6 
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Yes 
No 
2. Was a ventilation/perfusion lung scan performed? ------------------------------------------------ 
a. If yes, date of the most recent scan:  
Ventilation Scan └─┴─┘└─┴─┴─┘└─┴─┘ 
 
  dd 
        mmm 
yy 
        Perfusion Scan └─┴─┘└─┴─┴─┘└─┴─┘ 
 
  dd 
        mmm 
yy 
 
b. If yes, did it show significant perfusion defects? -------------------------------------------------- 
If you have answered “Yes” to the question above, how did you exclude 
pulmonary thromboembolism as the main reason for pulmonary hypertension? 
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3. Were lung function tests performed? -------------------------------------------------------------------------------------------- 
a. If yes, date of the most recent lung function tests: 
 
Spirometry └─┴─┘└─┴─┴─┘└─┴─┘ 
   
                                                                              dd 
        mmm 
yy 
Body Plethysmography └─┴─┘└─┴─┴─┘└─┴─┘ 
 
    dd 
        mmm 
yy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NCT02310672

Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 129/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
b. If yes, did it show 
i. FEV1/FVC < 70%? ------------------------------------------------------------------------------------------------ 
ii. FEV1 < 65% of predicted value?-------------------------------------------------------------------- 
iii. Total Lung Capacity < 60% of predicted value? ------------------- 
If you have answered “Yes” to one or more of the questions above, how did you 
exclude moderate to severe obstructive lung disease or moderate to severe 
restrictive lung disease as the main reason for pulmonary hypertension? 
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Yes 
No 
1. Were any other relevant tests (e.g., contrast-enhanced computed tomography, 
spiral computed tomography, high resolution computed tomography, magnetic 
resonance imaging) performed to exclude other etiology than PAH? ----------------- 
2. If yes, which type of test(s) and when (indicate most recent)? 
i. 
---------------------------------------- 
└─┴─┘└─┴─┴─┘└─┴─┘ 
 
   
  dd 
        mmm 
yy 
ii. 
---------------------------------------- 
└─┴─┘└─┴─┴─┘└─┴─┘ 
 
   
  dd 
        mmm 
yy 
iii. 
---------------------------------------- 
└─┴─┘└─┴─┴─┘└─┴─┘ 
 
  dd 
        mmm 
yy 
Please briefly describe the results of this/these procedures(s) 
3. ------------------------------------------------------------------------------------------------------------
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NCT02310672

Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 130/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
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Investigator name: 
 
 
 
 
Date (DDMMMYYYY): 
Investigator signature: 
Please email form to 
 
CRA name, signature and date AFTER SDV performed: 
 
NCT02310672