Clinical trial NCT02310672
Conditions: Pulmonary Arterial Hypertension
Keywords: Pulmonary Arterial Hypertension
Sponsor: Actelion
Start date: 2015-06-01; Completion date: 2019-09-10
Enrollment: 89 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study evaluates the effect of macitentan on right ventricular and hemodynamic properties in patients with symptomatic pulmonary arterial hypertension. Patients are treated with macitentan for 1 year. Patients undergo right heart catheterization (RHC) at baseline and Week 26. They also undergo cardiac magnetic resonance imaging (MRI) at baseline, Week 26 and Week 52. Safety is monitored throughout the study. The study has three stub-studies. Each patient can participate in no sub-study or in one sub-study. The sub-studies are: (1) metabolism sub-study (with PET-MR scans); (2) biopsy sub-study (biopsies taken during the RHC); (3) Echo sub-study.

Detailed description:

Arms: arm 1: All patients take open-label macitentan 10mg o.d.
Interventions: intervention 1: Macitentan
Intervention descriptions: intervention 1: All patients take open-label macitentan 10mg o.d.

Protocol documents:
Prot_000.pdf: 
 
 
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The information contained in this document, especially unpublished data, is the property of the sponsor of 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  
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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 
 
 
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Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
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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 
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Confidential  
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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 
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Confidential  
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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 
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TABLE OF CONTENTS 
SPONSOR CONTACT DETAILS ......................................................................................2 
ACTELION CONTRIBUTORS TO THE PROTOCOL .....................................................2 
COORDINATING INVESTIGATOR.................................................................................2 
CONTRACT RESEARCH ORGANIZATIONS INFORMATION ...................................3 
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................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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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 
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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 
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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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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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Protocol AC-055-403, REPAIR 
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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 
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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 
 
NCT02310672


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  
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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 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 18/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
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


Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 19/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
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. 
NCT02310672


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


Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 21/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
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 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 22/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
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


Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 23/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
• 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 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 25/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
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. 
 
NCT02310672


Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 26/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
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


Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 27/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
• 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


Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 28/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
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. 
 
NCT02310672


Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 29/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
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 
NCT02310672


Macitentan / ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 30/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
- 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


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  
 
- 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


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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 
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Confidential  
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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


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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]. 
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Macitentan / ACT-064992 
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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 
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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 
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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 
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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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14 REFERENCES 
[Abman 2009] Abman SH. Role of endothelin receptor antagonists in the treatment of 
pulmonary arterial hypertension. Annu Rev Med. 2009;60:13-23. 
[Addetia 2014] Addetia K, Bhave MN, Tabit CE, Gomberg-Maitland M, Freed BH, Dill 
KE. Sample size and cost analysis for pulmonary arterial hypertension drug trials 
using various imaging modalities to assess right ventricular size and function end 
points. Circ Cardiovasc Imaging. 2014;7:115-124. 
[Archer 2013] Archer SL, Fang YH, Ryan JJ, Piao L. Metabolism and bioenergetics in 
the right ventricle and pulmonary vasculature in pulmonary hypertension. Pulm 
Circ. 2013 Jan;3(1):144-52. 
[ATS Statement 2002] Guidelines for the Six-Minute Walk Test. Am J Respir Crit Care 
Med 2002;166:111-7. 
[Benigni 1995] Benigni A. Defining the role of endothelins in renal pathophysiology on 
the basis of selective and unselective endothelin receptor antagonist studies. Curr 
Opin Nephrol Hypertens 1995;4:349-53. 
[Benza 2010] Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, 
Coffey CS. Predicting survival in pulmonary arterial hypertension insights from the 
registry to evaluate early and long-term pulmonary arterial hypertension disease 
management (REVEAL). Circulation. 2010;122:164-172. 
[Blalock 2010] Blalock SE, Matulevicius S, Mitchell LC, Reimold D, Warner J, Peshock 
R. Long-term outcomes with ambrisentan monotherapy in pulmonary arterial 
hypertension. J Cardiac Fail 2010;16:121-127. 
[Bokhari 2011] Bokhari S, Raina A, Rosenweig EB, Schulze PC, Bokhari J, Einstein AJ. 
PET imaging may provide a novel biomarker and understanding of right ventricular 
dysfunction in patients with idiopathic pulmonary arterial hypertension. Circ 
Cardiovasc Imaging. 2011 Nov;4(6):641-7. 
[Bradlow 2010] Bradlow WM, Hughes ML, Keenan NG, Bucciarelli-Ducci C, Assomull 
R, Gibbs JS. Measuring the heart in pulmonary arterial hypertension (PAH): 
implications for trial study size. J Magn Reson Imaging. 2010 Jan;31(1):117-24. 
[Brewis 2016] Brewis MJ, Bellofiore A, Vanderpool RR, Chesler NC, Johnson MK, 
Naeije R. Imaging right ventricular function to predict outcome in pulmonary 
arterial hypertension. Int J Cardiol. 2016 Sep 1; 218:206-11 
[Brimioulle 2003] Brimioulle S, Wauthy P, Ewalenko P, Rondelet B, Vermeulen F, 
Kerbaul F. Single-beat estimation of right ventricular end-systolic pressure-volume 
relationship. 
Am 
J 
Physiol 
Heart 
Circ 
Physiol. 
2003 
May;284(5): 
H1625-30. 
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[Chua 1992] Chua B, Krebs CT, Chua CC, et al. Endothelin stimulates protein synthesis 
in smooth muscle cells. Am J Physiol 1992;262:E412-6. 
[Clarke 1989] Clarke J, Benjamin N, Larkin W, et al. Endothelin is a potent long lasting 
vasoconstrictor in men. Am J Physiol 1989;257:H2033-5. 
[Davie 2002] Davie N, Haleen SJ, Upton PD, et al. ETA and ETB receptors modulate the 
proliferation of human pulmonary artery smooth muscle cells. Am J Respir Crit 
Care Med 2002;165:398-405. 
[de Nucci 1988] de Nucci G, Thomas R, D Orleans-Juste P, et al. Pressor effects of 
circulating endothelin are limited by its removal in the pulmonary circulating 
endothelin are limited by its removal in the pulmonary circulation and by the 
release of prostacyclin-derived relaxing factor. Proc Natl Acad Sci USA 
1988;85:9797-800. 
[Fisher 2006] Fisher MR, Mathai SC, Champion HC, Girgis RE, Housten-Harris T, 
Hummers L. Clinical differences between idiopathic and scleroderma-related 
pulmonary hypertension. Arthritis Rheum. 2006 Sep;54(9):3043-50. 
[Foëx 1994] Foëx P, Leone BJ. Pressure-volume loops: a dynamic approach to the 
assessment of ventricular function. J Cardiothorac Vasc Anesth. 1994 Feb;8(1): 
84-96. 
[Franco 2012] Franco V. Right Ventricular Remodeling in Pulmonary Hypertension. 
Heart Failure Clin 8 (2012):403-412. 
[Galiè 2003] Galiè N, Hinderliter AL, Torbicki A, Fourme T, Simonneau G, Pulido T. 
Effects of the oral endothelin-receptor antagonist bosentan on echocardiographic 
and doppler measures in patients with pulmonary arterial hypertension. J Am Coll 
Cardiol. 2003 Apr 16;41(8):1380-6. 
[Galiè 2004] Galiè N, Manes A, Branzi A. The endothelin system in pulmonary arterial 
hypertension. Cardiovasc Res 2004;61:227-37. 
[Galiè 2013] Galiè N, Corris PA, Frost A, Girgis RE, Granton J, Jing ZC. Updated 
Treatment Algorithm of Pulmonary Arterial Hypertension. J Am Coll Cardiol 
2013;62:D60-72. 
[Galiè 2014] Galie N, Albert Barbera J, Frost A, Ardeschir Ghofrani H, Hoeper M, 
Mclaughlin V et al. AMBITION: A randomised, multicenter study of first-line 
ambrisentan and tadalafil combination therapy in subjects with pulmonary arterial 
hypertension (PAH). Eur Respir J. 2014;Suppl 58:44. 
[Giaid 1993]. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in 
the lungs of patients with pulmonary hypertension. N Engl J Med. 1993;328: 
1732–9. 
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[Grothues 2003] Grothues F, Moon JC, Bellenger NG, Smith GS, Klein HU, Pennell DJ. 
Interstudy reproducibility of right ventricular volumes, function, and mass with 
cardiovascular magnetic resonance. Am Heart J. 2004 Feb;147(2):218-23. 
[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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[Macitentan IB] Investigator’s Brochure. Macitentan ACT-064992. Endothelin receptor 
antagonist, Version 11. Actelion Pharmaceuticals Ltd, November 2013. 
[Massaki 1998] Massaki T. The discovery of endothelins. Cardiovasc Res 1998;39: 
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. 
[Rich 1992] Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel 
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. 
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[Simonneau 2013] Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, 
Ghofrani A. Updated Clinical Classification of Pulmonary Hypertension. J Am Coll 
Cardiol 2013;62:D34-41. 
[Sitbon 2005] Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium 
channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005; 
111:3105-11. 
[Stewart 1991] Stewart DJ, Levy RD, Cernacek P, et al. Increased plasma endothelin-1 in 
pulmonary hypertension: marker or mediator of disease? Ann Intern Med 
1991;114:464-9. 
[Sugawara 1996] Sugawara F, Ninomiya H, Okamoto Y, et al. Endothelin-1-
inducedmitogenic responses of Chinese hamster ovary expressing human 
endothelin A: the role of a wortmannin-sensitive signalling pathway. Molec 
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 
corrected for age and sex in idiopathic pulmonary arterial hypertension. Circ 
Cardiovasc Imaging. 2014 Jan;7(1):100-6. 
[Takeuchi 1991] Takeuchi M, Igarashi Y, Tomimoto S, Odake M, Hayashi T, Tsukamoto 
T. Single-beat estimation of the slope of the end-systolic pressure-volume relation 
in the human left ventricle. Circulation. 1991 Jan;83(1):202-12. 
[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 
patients with pulmonary hypertension. J Heart Lung Transplant. 2013 Jan;32(1): 
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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[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. 
[Van Wolferen 2011] van Wolferen SA, van de Veerdonk MC, Mauritz GJ, Jacobs W, 
Marcus JT, Marques KM. Clinically significant change in stroke volume in 
pulmonary hypertension. Chest. 2011 May;139(5):1003-9. 
[Van Wolferen 2007] van Wolferen SA, Marcus JT, Boonstra A, Marques KM, 
Bronzwaer JG, Spreeuwenberg MD. Prognostic value of right ventricular mass, 
volume, and function in idiopathic pulmonary arterial hypertension. Eur Heart J. 
2007 May;28(10):1250-7. 
[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. 
[Wilkins 2005] Wilkins MR, Paul GA, Strange JW, Tunariu N, Gin-Sing W, Banya WA. 
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. 
 
 
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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. 
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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. 
 
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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) 
 
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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. 
 
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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. 
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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. 
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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: ---------------------------------------------------------------
---------------------------------------------------------------------------------------------------
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---------------------------------------------------------------------------------------------------
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--------------------------------------------------------------------------------------------------- 
---------------------------------------------------------------------------------------------------
---------------------------------------------------------------------------------------------------
--------------------------------------------------------------------------------------------------- 
 
 
 
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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Pulmonary arterial hypertension 
Protocol AC-055-403, REPAIR 
Version 6 
8 November 2016, page 128/130 
Confidential  
EudraCT 2014-004066-20 
Doc No. D-16.554  
 
-----------------------------------------------------------------------------------------------------------------
-----------------------------------------------------------------------------------------------------------------
----------------------------------------------------------------------------------------------------------------- 
-----------------------------------------------------------------------------------------------------------------
-----------------------------------------------------------------------------------------------------------------
----------------------------------------------------------------------------------------------------------------- 
 
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? 
-----------------------------------------------------------------------------------------------------------------
-----------------------------------------------------------------------------------------------------------------
-----------------------------------------------------------------------------------------------------------------
-----------------------------------------------------------------------------------------------------------------
----------------------------------------------------------------------------------------------------------------- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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? 
-----------------------------------------------------------------------------------------------------------------
-----------------------------------------------------------------------------------------------------------------
-----------------------------------------------------------------------------------------------------------------
-----------------------------------------------------------------------------------------------------------------
--------------------------------------------------------------------------------------------------------------- 
 
 
 
 
 
 
 
 
 
 
 
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. ------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------
 
 
 
 
 
 
 
 
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  
 
------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------
----------------------------------------------------------------------------------------------------------- 
Investigator name: 
 
 
 
 
Date (DDMMMYYYY): 
Investigator signature: 
Please email form to 
 
CRA name, signature and date AFTER SDV performed: 
 
NCT02310672

SAP_001.pdf: 
TPL-000241 v02
STATISTICAL ANALYSIS PLAN
FOR CSR (AMENDMENT 1)
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
The REPAIR study
Purpose of Analysis
Clinical Study Report
Investigational Drug
Macitentan / ACT-064992
Protocol Number
AC-055-403 (REPAIR)
Actelion Document Number
D-16.633
Document Status/Version Number
Final 1.0
Date
20 March 2018
Authors
Graham Wetherill, Nicolas Martin, Trial Statisticians
Reviewer
Maziar Assadi-Gehr, Physician
Reviewer
Emmanuelle Cottreel, Clinical Scientist
Reviewer
Loïc Perchenet, Global Post Approval Studies Director
Reviewer
Reviewer
Reviewer
Lada Mitchell, Senior Expert Statistician
Dmitri Petratchenko, Trial Statistical Programmer
Marianne Soergel, Drug Safety Physician
Confidential
Property of Actelion Pharmaceuticals Ltd. May not be used, divulged, published or otherwise 
disclosed without the consent of Actelion Pharmaceuticals Ltd.
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TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND ACRONYMS ............................................................8
1
INTRODUCTION.......................................................................................................11
1.1
Study documents...........................................................................................11
2
STUDY DESIGN AND FLOW..................................................................................11
2.1
Study design .................................................................................................11
2.2
Study visit and assessment schedule ............................................................11
3
OBJECTIVES .............................................................................................................12
3.1
Primary objectives ........................................................................................12
3.2
Secondary objectives ....................................................................................12
3.3
Exploratory objectives..................................................................................12
4
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE 
STUDY PROTOCOL .................................................................................................13
4.1
Changes to the analyses planned in the study protocol ................................13
4.2
Changes in the conduct of the study / data collection ..................................14
4.3
Clarifications concerning endpoint definitions and related variables or 
statistical methods.........................................................................................14
5
DEFINITIONS OF VARIABLES ..............................................................................14
5.1
Screening failures .........................................................................................15
5.2
Subject characteristics ..................................................................................15
5.2.1
Demographics ...................................................................................15
5.2.2
Baseline disease characteristics ........................................................15
5.2.3
Other baseline characteristics ...........................................................16
5.2.4
Medical history .................................................................................16
5.2.5
Previous and concomitant therapies .................................................16
5.2.5.1
Previous therapies....................................................................16
5.2.5.2
Study-concomitant therapies...................................................16
5.2.5.3
Study-treatment concomitant therapies...................................16
5.2.5.4
PAH-specific and PAH-related therapies................................17
5.2.6
Other subject characteristics.............................................................17
5.3
Study treatment exposure and compliance ...................................................17
5.3.1
Exposure ...........................................................................................17
5.3.2
Compliance with study treatment .....................................................18
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5.3.3
Study treatment interruptions............................................................19
5.3.4
Premature discontinuation of study treatment ..................................19
5.4
Study discontinuation ...................................................................................19
5.5
Efficacy variables .........................................................................................19
5.5.1
Primary efficacy variable(s)..............................................................19
5.5.2
Secondary efficacy variables ............................................................20
5.5.3
Other efficacy variables....................................................................20
5.5.3.1
Hemodynamic variables and pressure-volume variables ........20
5.5.3.2
Variables related to maintenance of treatment effect..............21
5.5.3.3
RVSV with imputation from RV volumes..............................21
5.5.3.4
Variables related to the left ventricle ......................................21
5.5.3.5
Potential variables for disease monitoring ..............................22
5.5.3.6
Clinical endpoint .....................................................................22
5.6
Safety variables.............................................................................................23
5.6.1
Adverse events..................................................................................23
5.6.1.1
Treatment-emergent adverse events........................................24
5.6.1.2
Frequency of treatment-emergent adverse events...................24
5.6.1.3
Intensity of treatment-emergent adverse events......................24
5.6.1.4
Relationship of treatment-emergent adverse events................24
5.6.2
Deaths ...............................................................................................24
5.6.3
Serious adverse events......................................................................25
5.6.4
Adverse events leading to discontinuation of study treatment .........25
5.6.5
Other significant adverse events.......................................................25
5.6.6
Physical examinations, Vital signs and body weight........................25
5.6.7
Electrocardiogram.............................................................................25
5.6.8
Laboratory.........................................................................................25
5.6.9
Other safety variables .......................................................................28
5.7
Pregnancy test...............................................................................................28
5.8
Quality of life variables ................................................................................28
5.9
Pharmacoeconomic variables .......................................................................28
5.10
Pharmacodynamic variables.........................................................................28
5.11
Pharmacokinetic variables............................................................................28
5.12
Sub-studies....................................................................................................29
6
DEFINITION OF PROTOCOL DEVIATIONS.........................................................31
7
ANALYSIS SETS.......................................................................................................31
7.1
Definitions of analysis sets...........................................................................31
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7.1.1
Screened Analysis Set.......................................................................31
7.1.2
Safety Set ..........................................................................................31
7.1.3
Full analysis Set................................................................................31
7.1.4
Modified full analysis Set.................................................................31
7.1.5
Per-protocol analysis Set ..................................................................31
7.1.6
Other analysis sets ............................................................................32
7.2
Usage of the analysis sets .............................................................................32
8
DEFINITION OF SUBGROUPS................................................................................32
9
GENERAL STATISTICAL METHODOLOGY........................................................33
10 STATISTICAL ANALYSES......................................................................................33
10.1
Overall testing strategy.................................................................................33
10.2
General rules for data presentations .............................................................34
10.3
Display of subject disposition, protocol deviations and analysis sets ..........34
10.3.1
Subject disposition............................................................................34
10.3.2
Protocol deviations ...........................................................................34
10.3.3
Analysis sets .....................................................................................34
10.4
Analyses of subject characteristics...............................................................34
10.4.1
Disposition of patients ......................................................................34
10.4.2
Demographics ...................................................................................34
10.4.3
Baseline disease characteristics ........................................................35
10.4.4
Other baseline characteristics ...........................................................35
10.4.5
Medical history .................................................................................35
10.4.6
Previous and concomitant therapies .................................................35
10.4.7
Other subject characteristics.............................................................36
10.5
Analysis of study treatment exposure and compliance.................................36
10.5.1
Exposure ...........................................................................................36
10.5.2
Compliance with study treatment .....................................................36
10.5.3
Study treatment interruptions............................................................36
10.5.4
Study treatment discontinuation .......................................................36
10.6
Study discontinuation ...................................................................................37
10.7
Analysis of the primary efficacy variable(s) ................................................37
10.7.1
Hypothesis and statistical model.......................................................37
10.7.2
Handling of missing data ..................................................................37
10.7.3
Main analysis ....................................................................................37
10.7.4
Supportive/sensitivity analyses.........................................................38
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10.7.5
Subgroup analyses ............................................................................38
10.7.6
Exploratory analyses of the primary endpoints ................................39
10.8
Analysis of the secondary efficacy variables ...............................................39
10.8.1
Hypothesis and statistical model.......................................................39
10.8.2
Handling of missing data ..................................................................39
10.8.3
Statistical analysis.............................................................................39
10.8.4
Supportive/sensitivity analyses.........................................................39
10.8.5
Subgroup analyses ............................................................................39
10.9
Analysis of other efficacy variables .............................................................40
10.10
Analysis of safety variables..........................................................................40
10.10.1
Adverse events..................................................................................41
10.10.2
Deaths, other serious adverse events ................................................41
10.10.2.1
Death .......................................................................................41
10.10.2.2
Serious adverse events.............................................................41
10.10.2.3
Adverse events leading to study treatment discontinuations 
or death....................................................................................41
10.10.2.4
Other significant adverse events..............................................41
10.10.3
Electrocardiography (ECG) ..............................................................42
10.10.4
Laboratory tests.................................................................................42
10.10.5
Physical examinations, vital signs and body weight.........................43
10.10.6
Other safety variables .......................................................................43
10.11
Interim analysis.............................................................................................43
10.12
Analysis of pharmacoeconomic variables ....................................................44
10.13
Analysis of epidemiological measures and risk-benefit evaluations............44
10.14
Analysis of pharmacodynamic variables......................................................45
10.15
Analysis of pharmacokinetic variables.........................................................45
10.16
Sub-studies analysis......................................................................................45
11 GENERAL DEFINITIONS AND DERIVATIONS...................................................45
11.1
Baseline ........................................................................................................45
11.2
Post-baseline assessment ..............................................................................45
11.3
Treatment period start date...........................................................................45
11.4
Treatment period end date (EOT).................................................................45
11.5
Extension treatment period start date ...........................................................45
11.6
Extension period end date (EOTOLE) .........................................................46
11.7
End of Study (EOS) date ..............................................................................46
11.8
Study day......................................................................................................46
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11.9
Time windows ..............................................................................................46
12 HANDLING OF MISSING/INCOMPLETE DATE AND TIME FIELDS ...............47
13 LIST OF SUMMARY TABLES, LISTINGS AND FIGURES .................................49
13.1
Subject disposition........................................................................................49
13.2
Protocol deviations .......................................................................................50
13.3
Subject characteristics ..................................................................................50
13.3.1
Demographics ...................................................................................50
13.3.2
Baseline disease characteristics ........................................................50
13.3.3
Medical history .................................................................................50
13.3.4
Previous and concomitant therapies .................................................51
13.3.5
Other subject characteristics .............................................................51
13.4
Study treatment exposure and compliance ...................................................51
13.4.1
Exposure ...........................................................................................51
13.4.2
Compliance with study treatment .....................................................52
13.4.3
Study treatment interruption.............................................................52
13.4.4
Study treatment discontinuation .......................................................52
13.5
Study discontinuation ...................................................................................52
13.6
Primary efficacy analyses.............................................................................53
13.6.1
Main analysis ....................................................................................53
13.6.2
Supportive/sensitivity analyses.........................................................53
13.6.3
Subgroup analyses ............................................................................54
13.7
Secondary/exploratory efficacy analyses .....................................................55
13.7.1
Main analyses ...................................................................................55
13.8
Other efficacy analyses.................................................................................55
13.9
Sub-studies....................................................................................................56
13.10
Safety analyses .............................................................................................56
13.10.1
Adverse events..................................................................................56
13.10.2
Deaths ...............................................................................................56
13.10.3
Serious adverse events......................................................................57
13.10.4
Adverse events leading to study treatment discontinuation..............57
13.10.5
Other significant adverse events.......................................................57
13.11
Laboratory tests ............................................................................................58
13.12
Physical examination, vital signs and body weight......................................59
13.13
Pregnancy test...............................................................................................59
13.14
Other evaluations..........................................................................................59
13.14.1
Quality of life analyses .....................................................................59
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13.14.2
Pharmacoeconomic analyses ............................................................59
13.14.3
Benefit-risk evaluations ....................................................................59
13.14.4
Pharmacodynamic analyses ..............................................................59
13.14.5
Pharmacokinetic analyses.................................................................59
14 REFERENCES............................................................................................................60
15 APPENDICES.............................................................................................................60
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LIST OF ABBREVIATIONS AND ACRONYMS
6MWD
Six-minute walk-distance
AE
Adverse event
BP
Blood pressure
bpm
Beats per minute
CFR
(US) Code of Federal Regulations
CRF
Case report form
CI
Confidence interval
CRO
Contract research organization
CL
Confidence limit(s)
CSR
Clinical study report
ECG
Electrocardiograph
eCRF
Electronic case report form
EMA
European Medicines Agency
EOS
End-of-study
EOT
End-of-treatment
FAS
Full analysis set
FC
(WHO) Functional Class
FDA
(US) Food and Drug Administration
FSFV
First subject first visit
GCP
Good Clinical Practice
GDF
Growth Differentiation Factor
IAC
Imaging Acquisition Center
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IVRS
Interactive voice recognition system
IWRS
Interactive web recognition system
KM
Kaplan-Meier
MedDRA
Medical Dictionary for Regulatory Activities
mFAS
Modified Full Analysis Set
LDH
Lactate dehydrogenase
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LSLV
Last subject last visit
LV
Left Ventricle
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
mPAP
Mean pulmonary arterial pressure
mRAP
Mean right atrial pressure
NCI
(US) National Cancer Institute
NT-proBNP
N-terminal pro-brain natriuretic peptide
OLE
Open Label Extension
PCWP
Pulmonary capillary wedge pressure
PD
Pharmacodynamic
PK
Pharmacokinetic
PPS
Per-protocol analysis set
PVR
Pulmonary Vascular Resistance
QTCF
QT interval corrected for heart rate using Fridericia’s formula
RHC
Right heart catheterization
RV
Right Ventricle
RVEDV
Right Ventricular End Diastolic Volume
RVEF
Right Ventricular Ejection Fraction
RVESV
Right Ventricular End Systolic Volume 
RVSV
Right Ventricular Stroke Volume
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical analysis plan
SAS
Statistical analysis system
SOC
System organ class
SOP
Standard operating procedure
SDTM
Study Data Tabulation Model 
SI
Standard International
TNF
Tumor Necrosis Factor
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ULN
Upper limit of the normal range
WHO
World Health Organization
WHO FC
WHO Functional Class
WHODRUG
WHO drug dictionary
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1
INTRODUCTION
This Statistical Analysis Plan (SAP) describes the statistical data analyses conducted for the 
purpose of the CSR of the study AC-055-403 (REPAIR). 
The CSR analyses will be performed on the locked database following completion of study  
core phase only (approximately 52 weeks). Data from the Open Label extension (OLE, 
France) will be presented at time of core phase completion in listings and included in some 
additional tables.
An interim analysis will be performed when 42 patients have available data for both primary 
endpoints. The study is single-arm, open-label with data available on ongoing basis, therefore 
all analyses (interim and final) will be performed without any restriction to data access or 
separated team.
1.1
Study documents 
The following study documents are used for the preparation of the SAP:

Protocol AC-055-403, version 06, dated 08 Nov. 2016,

Case Report Form (CRF): version 08, dated 05 Dec 2016,

PD Code list, version 4, dated 10 Jun. 2016.
Any change to any of those documents affecting the biostatistics deliverables will require this 
SAP and related documents to be updated accordingly. 
2
STUDY DESIGN AND FLOW
The section below describes the protocol key features only, for additional details please refer 
to the protocol.
2.1
Study design
The study is a prospective, multicenter, single-arm, open-label, Phase 4 study. It is planned to 
be conducted in 100 adult patients with idiopathic PAH, heritable PAH, drug- and 
toxin-induced PAH, PAH associated with connective tissue diseases or PAH associated with 
congenital heart diseases under certain conditions as defined in the protocol. An interim 
analysis will be performed when 42 patients have available data for both primary endpoints.
The study planned to include three sub-studies that are conducted in selected centers, where 
eligible patients for the main study are offered to participate in the sub-study(ies).

Metabolism sub-study (selected US sites only).

Biopsy sub-study (cancelled on 18-Aug-2017).

Echo sub-study.
2.2
Study visit and assessment schedule
The study includes 3 main periods:
1. Screening period: from the date of informed consent signature to initiation of study 
treatment (excluded), may last up to 28 days. 
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2. Treatment period: from the first dose intake (Day 1) to the date of End of Treatment 
(EOT) which may occur as per protocol at Week 52 7 days, or earlier in case of
premature discontinuation of study treatment.  For patients in France entering the 
OLE, EOT is the last date of treatment in the core phase of the study.
3. Safety follow-up period: from the date of EOT (excluded) until the date of the End of 
Study (EOS) visit, and lasts at least 30 days.  Patients that enter the OLE are not 
included in this safety follow-up period, as they continue to take study treatment.
EOTOLE is the date of the last study treatment in the open label extension.
When this SAP refers to EOT or EOS, unless otherwise indicated, this means EOT and EOS 
relating to the core part of the study (excluding the open label extension).
The overall study design is depicted in Figure 1.
Figure 1
Study design (without extension)
3
OBJECTIVES
3.1
Primary objectives

To evaluate the effect of macitentan on right ventricular and on hemodynamic 
properties in patients with symptomatic PAH.
3.2
Secondary objectives

To evaluate the safety and tolerability of macitentan in patients with symptomatic 
PAH.
3.3
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.
ICF
EOS
EOT +30-37 days
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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
To evaluate the effect of macitentan on left ventricular properties in patients with 
symptomatic PAH.
4
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE 
STUDY PROTOCOL
4.1
Changes to the analyses planned in the study protocol
Following changes are considered in SAP: 

The RVSV primary variable will be “Change from baseline to Week 26 in Right 
Ventricular (RV) Stroke Volume (RVSV) assessed by cardiac MRI from pulmonary 
artery flow” as stated in protocol section 6.1.1, but without the adjustment specified in 
protocol section 11.3.2.2.  That is, the primary variable will always be RVSV from 
pulmonary artery flow, and not RVSV determined by RV volumes.
o
Note that the adjustment only comes into effect when LVSV determined from 
aortic flow” differs from “RVSV from pulmonary artery flow” by more than 
20% (in either direction).
o
The RVSV including the adjustment specified in protocol section 11.3.2.2 will 
be an exploratory analysis, with the analysis of RVSV by volumes and LVSV.  
Reason: The adjustment (implicitly) assumes that when “LVSV determined 
from aortic flow” differs from “RVSV from pulmonary artery flow”, that 
“RVSV determined by RV volumes” would be close to “LVSV determined 
from aortic flow”. Early data (from the first 12 subjects) shows that this is not 
necessarily the case.  Therefore, “RVSV from pulmonary artery flow” is used 
as a simpler and more precise primary variable.

It is clarified in this SAP that all analyses for secondary/exploratory endpoints are 
performed on mFAS and SS.  Similarly, analyses for the sub-studies will use all 
patients from the SS that are in the sub-study, and repeated for sub-study patients in 
the mFAS.  The main reporting will use the SS, results for the mFAS for secondary / 
exploratory / sub-study endpoints are for reference,
Reason: to use all available data for the (secondary/exploratory) endpoints; subjects 
who do not have data for both primary endpoints are excluded from the FAS and 
mFAS, but may have data on secondary endpoints.

Subgroup analyses have been added (see Section 8 for the definition of subgroups).  
Reason: to further investigate the data.

Safety analysis: specific areas of clinical interest for macitentan have been defined 
(see Section 5.6.5) to further characterize AEs. Therefore, the unplanned safety 
analysis on “Treatment-emergent AEs of special interest” has been added.    
Reason: to further characterize AEs.

For PCWP/LVEDP imputations mentioned in Section 10.7.2, the largest analysis set 
(SS) is used instead of mFAS.
Reason: To include all data for these endpoints.
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
Borg Dyspnea Index is not listed as efficacy endpoint in protocol. However this 
parameter is recorded in the CRF and will be summarized descriptively and listed.  
Reason: for complete reporting of the study.

The following data will be listed only: Arterial elastance (mmHg/mL); RV end-
systolic elastance (mmHg/mL) and RV maximum isovolumic pressure (mmHg).  
These were listed as exploratory endpoints in the protocol, with an associated 
exploratory objective. 
Reason: The analysis of right ventricular pressure-volume loops requires both cardiac 
MRI and RHC in suitable digital data.  There were difficulties in obtaining suitable
RHC files from the sites.  Consequently very little data was available.

Ventriculo-arterial coupling will be listed

Data for the metabolism sub-study will be listed only, due to the lack of patients.
4.2
Changes in the conduct of the study / data collection
The biopsy sub-study was cancelled on 18-Aug-2017 (without any patient having an ICF date 
in the CRF for the biopsy sub-study) and therefore no data will be reported.  Reason: futility 
due to no recruitment.
4.3
Clarifications concerning endpoint definitions and related variables or 
statistical methods
Following clarifications are considered in SAP:

For PPS, the analysis will be restricted to patients who had a post-baseline 
measurement taken between 22 weeks and 30 weeks of treatment for both primary 
endpoints (as mentioned in protocol Section 11.3.2.4).  
Reason: The PPS is used for reporting of the primary endpoints at Week 26.

P-values boundaries have been also specified in case of a 2-sided test (Section 10.11).

The required monthly laboratory liver and hemoglobin tests will be summarized.
5
DEFINITIONS OF VARIABLES
Note that applies to all variables: for patients entering OLE, EOT will consider last dose in 
core phase. All data with start date during the OLE will be reported in listings, and included 
in certain additional tables.  Unless otherwise specified, variables and tables will only include 
data up to EOT or EOS in the core phase.  Exposure data, AE data, liver and hemoglobin 
laboratory abnormalities for the OLE will be included in additional tables.
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5.1
Screening failures
A patient who did not have a Day 1 visit (i.e. no data in CRF available at Day 1 visit), is 
considered a screening failure.
If a subject is screened twice, only the data assessed during the second screening attempt if 
before the study treatment initiation are displayed and included in any analysis. The data 
coming from the first screening are included in the corresponding analysis if not available at 
re-screening or they are assessed after or on treatment initiation.
5.2
Subject characteristics
5.2.1
Demographics
The following baseline variables were collected in the CRF during the screening period for 
all screened patients:

Age, sex, height, weight,

Country

Race as allowed by local regulations, ethnicity

Childbearing potential.
Demographics include the BMI (kg/m2) calculated as:
 = 	
 ℎ 
ℎ
5.2.2
Baseline disease characteristics
Baseline disease characteristics include:

PAH etiology, 

Age at PAH diagnosis (years)

6-minute walk-distance (6MWD, meter),

Borg dyspnea index (rated dyspnea on scale from 0 to 10),

WHO Functional Class (severity score based on symptoms: I, II, III and IV),

Heart Rate (HR, bpm) assessed by RHC, 

Calculated Pulmonary Vascular Resistance (PVR, dyn.sec.cm-5) assessed by RHC, 

Mean Pulmonary Arterial Pressure (mPAP, mmHg) assessed by RHC, 

Systolic Pulmonary Arterial Pressure (sPAP, mmHg) assessed by RHC, 

Diastolic Pulmonary Arterial Pressure (dPAP, mmHg) assessed by RHC, 

Pulmonary Capillary Wedge Pressure (PCWP, mmHg) assessed by RHC,

Left Ventricular End Diastolic Pressure (LVEDP, mmHg) assessed by RHC,

Mean Right Atrial Pressure (mRAP, mmHg) assessed by RHC, 

Cardiac Output (CO, L/min) assessed by RHC.
PVR (dyn.sec.cm-5) as calculated by the investigator and recorded in eCRF will be listed 
only. All PVR analyses will be based on calculated PVR (see formula in Section 5.5.1).
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5.2.3
Other baseline characteristics
Other baseline characteristics include:

Treatment strategy (Patient previously treated with a PDE-5 inhibitor, 
PAH-specific treatment-naive patient with intention to start study drug only, 
PAH-specific treatment-naive patient with intention to start upfront PDE-5 inhibitor 
and study drug combination therapy), as ticked on CRF.
5.2.4
Medical history
Collected information on medical history includes:

Clinically significant past or concomitant disease or diagnosis (yes/no)

Main Disease or Diagnosis (prior and/or ongoing)
Any disease or diagnosis is defined as concomitant if ‘Ongoing at Screening’ is answered 
with ‘Yes’; all other diseases/diagnoses are considered as previous.
5.2.5
Previous and concomitant therapies
5.2.5.1
Previous therapies
A previous therapy is any treatment for which the end date of treatment is prior to the start of 
study treatment.
If the end date is missing and the start date is prior to the date of study treatment start, then 
the therapy is considered as previous if “Ongoing at start of treatment?” is not ticked with 
“Yes”.
5.2.5.2
Study-concomitant therapies
Study-concomitant therapies are all treatments that are ongoing or initiated after start of study 
(i.e., signed informed consent), or initiated up to EOS. Study-concomitant therapies at 
Baseline are treatments taken on the day of first dose (see Section 11.3). All data with start 
date in the OLE will be reported in listing only.
5.2.5.3
Study-treatment concomitant therapies
Study-treatment concomitant therapies are any treatment that is either ongoing at the start of 
study treatment or is initiated during the treatment period. All data with start date in the OLE 
will be reported in listing only.
Previous, study-concomitant therapies (including therapies concomitant at baseline) and 
study treatment concomitant therapies are retrieved from the Concomitant Medication and 
Contraceptive Methods forms of the eCRF.
Concomitant medications and contraceptive methods collected on the eCRF forms
Concomitant Medication - Open Label Extension and Contraceptive Methods - Open Label 
Extension respectively will be only listed.
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5.2.5.4
PAH-specific and PAH-related therapies 
PAH-specific therapies are any of the following medications: 
Table 1 - PAH-specific treatment
Class
Active compound
Oral PDE5i
sildenafil
tadalafil
vardenafil
Prostanoid
beraprost
treprostinil
iloprost
epoprostenol
selexipag
ERA
bosentan
ambrisentan
Macitentan
sGC stimulator
riociguat
Note: selection of terms should be done by searching terms provided in active compound 
only in the preferred term. For example any occurrence of "sildenafil citrate" will be reported 
under 'Oral PDE5i'.
5.2.6
Other subject characteristics
The following historical pulmonary function tests (Pulmonary Function Test form) are 
reported at Screening only:

FEV1/FVC [%] irrespective of bronchodilator administration,

FEV1 as a percent of predicted value irrespective of bronchodilator administration
[%],

Total Lung Capacity (TLC) as a percent of predicted value [%],

DLco (Diffusing capacity of the lung for carbon monoxide) as a percent of predicted 
value [%], 

FVC as a percent of predicted value [%], 
Under protocol version 3, the pulmonary function test was to be done after administration of 
a bronchodilator.  This was not required in subsequent versions of the protocol.

FEV1 and TLC are collected in the eCRF from protocol version 3 onwards.

DLco and FVC are collected in the eCRF with protocol versions 5 and 6.

FEV1/FVC is collected in the eCRF with protocol versions 3 and 4, but not collected 
with protocol versions 5 and 6.
Data will be summarized as collected in the eCRF; data will not be derived.
5.3
Study treatment exposure and compliance
5.3.1
Exposure
Study treatment exposure is recorded via the study drug log in the eCRF ('Study Drug Log' 
and 'Study Drug Log - OLE' forms) and retrieved from the SDTM EX domain. The number 
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of subjects exposed will be displayed per 4-week interval over time. Exposure to study drug 
will be described in terms of duration in weeks.
The study treatment duration for the core phase is defined as the number of weeks elapsing 
between study drug initiation and discontinuation, inclusive, regardless of treatment 
interruptions, calculated as:
 	 	 () −  	 + 1
7
Study treatment exposure including the OLE will be summarized separately, from the 
treatment start date to the last dose in the OLE (EOTOLE):
 	 	 (!(, #)) −  	 + 1
7
5.3.2
Compliance with study treatment
Compliance (in %) with study treatment is calculated based on recorded drug accountability 
data retrieved from the eCRF forms: 'Study Drug Dispensing & Accountability' and 'Study 
Drug Dispensing & Accountability OLE'. Dispensing and returns for the OLE will be listed 
only and will not be included in the calculation of study drug compliance [for the core phase].
Compliance with study treatment is assessed through drug accountability. Compliance, in 
percent, is calculated as:
100 ×
(&' ( ') *+		  &',- − &' ( ') &	)
!*-	 &' ( ') . 	& ℎ  *	
Where the number of tablets provided and number of tablets returned relates to study treatment 
for the core phase only, and the expected number of tablets taken during the core treatment 
period is defined as:
( 	 	 () −   	 + 1)
as macitentan 10 mg is taken once daily.  If the no bottles are returned, (no returns at any 
timepoint), then compliance is also missing. If there are some returns, the compliance will be 
calculated using the all dispensing and available returns data (assume zero if the bottle is not 
returned).
Compliance will not be calculated for the OLE.  Dispensing and returns for the OLE will be 
listed only.
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5.3.3
Study treatment interruptions
Study treatment interruptions are recorded in the Study drug Log. A subject is considered to have 
had a study treatment interruption if the reason for treatment end is either ‘Temporarily 
interrupted due to an AE’ or ‘Temporarily interrupted not due to an AE’.
For each period of temporary interruption, the duration of study treatment interruption is 
determined as 
  	 − 	 	 −1
and summed up per subject.
Treatment exposure in days is determined as the study treatment duration subtracted by the 
sum of days of treatment interruption.
5.3.4
Premature discontinuation of study treatment 
A subject is considered to have prematurely discontinued study treatment if the "reason for 
treatment end" in the Study Drug Log eCRF is ‘Premature Discontinuation’. The reason for 
premature discontinuation will be taken from the Premature Discontinuation of Study 
Treatment form of the eCRF.
5.4
Study discontinuation
Subjects who completed the study as per protocol are those with the question “Did the subject 
complete the Follow up?” answered “Yes” in the End of Follow Up form of the eCRF. 
On the other hand, a subject is considered to have prematurely discontinued the study if the 
answer to the question ‘Did the subject complete the Follow up?’ in the End of Follow Up
eCRF form is ‘No’. 
The date and the reason for end of study are collected in the same form. 
The date of withdrawal of consent from sub-study is collected in the Withdrawal of Consent 
from Sub-study form.
5.5
Efficacy variables
5.5.1
Primary efficacy variable(s)
The study has two primary efficacy endpoints:

Change from Baseline at Week 26 in RVSV assessed by cardiac MRI from 
pulmonary artery flow.

Ratio of Week 26 to Baseline PVR (assessed by RHC).
While PVR value was computed by the investigators and entered into the CRF, the PVR 
value used for the statistical analyses will be re-computed in the analysis datasets using 
PCWP (or LVEDP if missing PCWP) according to the formula:
/01 = 80 ∗/4/ −(/56/  #07/ ( /56/  +)'))
5
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The PVR computed by the investigators (and entered into the CRF) will be listed only.
Programming note: RVSV in the SDTM morphology data (SDTM.MO) has 2 subcategories 
(variable MOSCAT, which is in capitals): “Determined from pulmonary artery flow” and 
“Determined from RV volumes”.  These sub-categories also apply to RVEF, LVSV and LVEF.  
There are also 2 sub-categories (variable MOSCAT) for HR by Cardiac MRI: “During cine 
imaging” or “During flow imaging”
5.5.2
Secondary efficacy variables
As for the primary endpoints, secondary endpoints consist of change from Baseline at Week 
26 of the following right ventricular and functional characteristics:

RVEDV (mL) assessed by cardiac MRI

RVESV (mL) assessed by cardiac MRI

RVEF (%) based on pulmonary artery flow assessed by cardiac MRI

RV mass (g) assessed by cardiac MRI

6MWD (m)

WHO FC
5.5.3
Other efficacy variables
Other efficacy variables are used to assess the effect of macitentan on different aspects of the 
disease.
5.5.3.1
Hemodynamic variables and pressure-volume variables
First set of variables include endpoints that are usual tools to monitor disease progression, 
and are expressed as change from Baseline at Week 26 of:

mPAP (mmHg) assessed by RHC,

mRAP (mmHg) assessed by RHC,

Cardiac index (L/min/m2) calculated according to the formula:
o
5 =
89
:;<, where BSA is body surface area (m2) where
CO = Cardiac Output assessed by RHC
BSA [m2]= 0.007184 × weight0.425 [kg] × height0.725 [cm].
For the calculation of CI, considering that multiple weight measures are recorded during the 
study, all the weight assessments will be first re-assigned to the most appropriate visit 
according to the time windows described in Section 11.9 and then used for deriving the 
parameter. Height at Baseline is used for the calculation of CI.
Pressure-volume variables (assessed by combining cardiac MRI and RHC):

Arterial elastance (mmHg/mL),

RV end-systolic elastance (mmHg/mL),

RV maximum isovolumic pressure (mmHg)

Ventriculo-arterial coupling.
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5.5.3.2
Variables related to maintenance of treatment effect
The additional variables include endpoints aiming at assessing maintenance of treatment 
effect by change from Baseline at Week 52 of:

RVSV (mL) by pulmonary artery flow or by RV volumes as described in Section 
5.5.1 assessed by MRI,

RVEDV (mL) assessed by MRI,

RVESV (mL) assessed by MRI,

RVEF (%) by RV volumes assessed by MRI,

RV mass (g) assessed by MRI,

6MWD (m),

WHO FC.
RVSV and RVEF by RV volumes are included as these are traditional ways of measuring.  
Where corresponding endpoints to Week 26 are not primary or secondary, the endpoints to 
Week 26 are included as exploratory.
5.5.3.3
RVSV with imputation from RV volumes
RVSV assessed by cardiac MRI including imputation according to the formula in the 
protocol:  RVSV will be based on pulmonary artery flow. If, however, RVSV determined 
from pulmonary artery flow differs from volume determined from aortic flow (which refers 
to the variable "LVSV determined from aortic flow") by more than 20% (in either direction), 
then RVSV determined by RV volumes is used (equal to RVEDV minus RVESV).  This will 
be calculated for weeks 26 and 52.
The following calculation will be used (all these assessments are by Cardiac MRI):
1. Percentage difference = 100 * abs(RVSVp - LVSVa) / min(RVSVp,LVSVa)
2. If this percentage <= 20%, then use RVSVp
3. If this percentage > 20%, then use RVSVv = RVEDV - RVESV
Where:
RVSVp = RVSV based on pulmonary artery flow
LVSVa = LVSV determined from aortic flow
RVSVv = RVSV determined by RV volumes (equal to RVEDV minus RVESV);
Programming note: The percentage difference (1) will need to be calculated and RVSV 
derived from RVSVp and RVSVv according to the above rules.
5.5.3.4
Variables related to the left ventricle 
The following variables aim at analyzing change from Baseline at Week 26 and at Week 52 
of left ventricle characteristics:

LVSV (mL) determined from aortic flow as assessed by MRI,

LVSV (mL) determined from LV volumes

LVEDV (mL) assessed by MRI,

LVESV (mL) assessed by MRI,

LVEF (%) determined from aortic flow as assessed by MRI,

LVEF (%) determined from LV volumes
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
LV mass (g) assessed by MRI,

RVEDV/LVEDV ratio assessed by MRI,

RVESV/LVESV ratio assessed by MRI.
LVSV and LVEF by LV volumes are included as these are traditional ways of measuring.
5.5.3.5
Potential variables for disease monitoring
The following exploratory endpoints aim to investigate potential simple laboratory methods 
for disease monitoring, as opposed to RHC, MRI or echocardiography:
Change from Baseline at Week 26 and at Week 52 of:

N-terminal pro-brain natriuretic peptide NT-proBNP (ng/L)

Uric acid (umol/L)

Red cell distribution width (%)

Activin A (ng/L)

Cystatin C (mg/L)

Follistatin (ng/L)

Galectin-3 (ug/L)

GDF-15 (ng/L)

Cardiac troponin T (ng/L)

LDH (IU/L)

Osteoprotegerin (pmol/L)

TNF alpha (ng/L).
5.5.3.6
Clinical endpoint
The time to first clinical worsening event is used to investigate patient outcome, and is
defined as the time from start of study treatment to first occurrence of any of the following:

More than 15% decrease from Baseline of 6MWD  associated with worsening in 
WHO FC, if either 6MWD or WHO FC are missing, then clinical worsening will 
(only) be identified by initiation of sc/iv prostanoid therapy, hospitalization for PAH
or death,

Initiation of s.c. or i.v. prostanoid therapy,

Hospitalization for PAH (investigator’s assessment),

Death.
The date of the clinical worsening event 'Decrease from Baseline of 6MWD > 15% associated 
with worsening in WHO FC' is the first between the dates of the 6MWD and WHO FC 
assessment falling in the same time window, according to Table 5 of Section 11.9.
The date of initiation of s.c. or i.v. prostanoid therapy is the first date after the study treatment 
start date (see definition in Section 11.3) corresponding to treatment with s.c. or i.v. treprostinil or 
iloprost or epoprostenol (see Section 5.2.5.4). 
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The tick boxes "Did the Adverse Event require subject hospitalization?" and " If yes, due to 
PAH?" in the Adverse Event form of the CRF are used for the definition of the hospitalizations
due to PAH; the date of admission is used in the time to event derivation of PAH worsening.
For time of event endpoint, patients without a PAH-worsening event are right censored at the 
End of Study (EOS) date (see Section 11.7 for definition), or the date of the first dose from 
the OLE, whichever is earlier.  Data from the OLE are not included as neither 6MWD nor 
WHO FC are recorded in the OLE.
5.6
Safety variables
The following safety variables are considered for the core phase:

Treatment-emergent AEs and SAEs up to 30 days after study drug discontinuation in the 
core phase (EOT+30), except patients in the OLE who will be evaluated up to EOT.  

AEs leading to premature discontinuation of study treatment.

Treatment-emergent AEs of special interest up to 30 days after study drug discontinuation
in the Core phase (EOT+30), except patients in France entering open label extension who 
will be evaluated up to EOT. 

Treatment-emergent marked laboratory abnormalities up to 30 days after study drug 
discontinuation (EOT+30), except patients in France entering open label extension who 
will be evaluated up to EOT. .

Changes in vital signs body weight, and BMI from baseline to all assessed time points 
during the study up to EOT,

Changes in laboratory variables from baseline to all assessed time points during the study
up to EOT.
For tables including the core phase and the OLE, the following safety variables are considered:

Treatment-emergent AEs and SAEs up to 30 days after study drug discontinuation 
(EOT+30) or (EOTOLE+30), whichever is later.

AEs leading to premature discontinuation of study treatment,

Treatment-emergent AEs of special interest up to 30 days after study drug discontinuation 
(EOT+30) or (EOTOLE+30), whichever is later.

Treatment-emergent liver and hemoglobin laboratory abnormalities up to 30 days after 
study drug discontinuation (EOT+30) or (EOTOLE+30), whichever is later.
5.6.1
Adverse events
All below statements also apply to all types of AEs. All adverse events with start date in OLE
(patients in France) will only be included in the additional tables that specifically include the 
OLE, and will be reported in the listings with a specific flag.
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5.6.1.1
Treatment-emergent adverse events
Treatment-emergent AEs are defined as those AEs occurring from treatment start up 
(included) to 30 days after end of study treatment (except patients in France entering open 
label extension who will be evaluated up to EOT).
Treatment-emergent AEs including OLE are defined up to 30 days after study drug 
discontinuation (EOT+30) or (EOTOLE+30), whichever is later.
5.6.1.2
Frequency of treatment-emergent adverse events
Treatment-emergent AEs reported more than once within a subject (as qualified by the same 
preferred term(s)) are counted once in the frequency table.
In the event that the reported AE is assigned to several preferred terms, subjects are counted 
for each individual preferred term.
5.6.1.3
Intensity of treatment-emergent adverse events
For treatment-emergent AEs reported more than once within a subject (as qualified by the 
same preferred term(s)) with different intensities, the worst intensity is considered. The 
categories of intensity are defined as follows:

Mild 

Moderate

Severe
If intensity is missing, the event is considered severe.
5.6.1.4
Relationship of treatment-emergent adverse events
Relationship to study treatment is defined as ‘related’ (yes) or ‘not related’ (no). For 
treatment-emergent AEs reported more than once within a subject (as qualified by the same 
preferred term(s)), the strongest relationship reported (i.e. 'related') is considered. Adverse 
events with missing relationship are considered in any analysis as related.
5.6.2
Deaths
Death is considered to have occurred if it is recorded in the eCRF death form. 
The original terms used by the investigators to describe deaths (i.e., death cause) are assigned 
PTs for classification and tabulation using the latest implemented MedDRA version 
dictionary.
Treatment-emergent AEs with fatal outcome occurring from treatment start, up to 30 days 
after EOT will be summarised (except patients in France entering open label extension who
will be evaluated up to EOT). Other deaths occurring outside this time frame, if reported, will 
be listed only.
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5.6.3
Serious adverse events
A SAE is an AE for which the corresponding [Serious] field in the CRF AE form is ticked 
"Yes". Treatment-emergent SAEs occurring from treatment start, up to 30 days after EOT 
will be summarised, (except patients in France entering open label extension who will be 
evaluated up to EOT).  
Treatment-emergent SAEs including OLE is defined up to 30 days after study drug 
discontinuation (EOT+30) or (EOTOLE+30), whichever is later.
5.6.4
Adverse events leading to discontinuation of study treatment
An AE is defined as leading to discontinuation of study treatment if the corresponding 
[Action taken with study treatment] field in the eCRF AE form is ticked "PERMANENTLY 
DISCONTINUED".  Discontinuations on or after the date of first dose in the OLE will only 
be counted in the additional table including the OLE.
5.6.5
Other significant adverse events
The following treatment-emergent adverse events of special interest will be analyzed:

"Edema and fluid retention”
Any treatment-emergent AE with PT listed in the Standardised MedDRA Query (SMQ) 
“Haemodynamic oedema, effusions and fluid overload (SMQ)” or with PT equal to 
“Pulmonary congestion” defined in the latest available MedDRA version with the exception 
of PTs containing “site”. 

“Anemia” 
Any treatment-emergent AE with a PT within the SMQs “Haematopoietic erythropenia” OR 
“Haematopoietic cytopenias affecting more than one type of blood cell (SMQ)” (with the 
exception of two unspecific PTs: “blood disorder”, “blood count abnormal”) OR an event 
with any MedDRA PT containing the text “anaemia".
5.6.6
Physical examinations, Vital signs and body weight
Vital signs data and physical examinations are collected at Screening, at treatment initiation 
(Day 1), prior to initiation of rescue therapy, at Week 26 and Week 52/EOT (unscheduled 
assessment could be performed if clinically indicated). 
Vital sign data includes: weight, BMI, heart rate, systolic blood pressure and diastolic blood 
pressure. Note that heart rate is also collected as part of the RHC and will be listed.
5.6.7
Electrocardiogram
Not applicable.
5.6.8
Laboratory
Safety laboratory parameters include:
Hematology: hemoglobin, hematocrit, erythrocyte count (reticulocyte count), leukocyte 
count with differential counts, platelet count.
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Blood chemistry: AST, ALT, alkaline phosphatase, total and direct bilirubin, LDH, 
creatinine, urea, blood urea nitrogen, uric acid, glucose, cholesterol, triglycerides, sodium,
potassium, chloride, calcium, protein, albumin.
Coagulation tests: prothrombin time, INR, aPTT.
Pregnancy test: serum and urine pregnancy tests for women of childbearing potential.
Laboratory tests will be summarized for baseline, Week 26 and Week 52, The required 
monthly liver and hemoglobin laboratory tests (hemoglobin, hematocrit, AST, ALT, alkaline 
phosphatase, total and direct bilirubin and LDH) will be summarized by month for the first 6 
months, in addition to baseline and Week 52.
Treatment-emergent marked laboratory abnormalities are defined as those lab marked 
abnormalities occurring from treatment start up to 30 days after end of study treatment
(except patients in France entering open label extension who will be evaluated up to EOT), 
that were not present at baseline (see section 11.1 for definition).  If central and local 
laboratory results are available for the same day, the central results are to be used.
Liver and hemoglobin test abnormalities will also be evaluated for the entire study (including 
data for OLE).
For the occurrence of post-baseline liver test abnormalities the following events are 
considered:

ALT and /or AST ≥3ULN,

ALT and/or AST ≥5 ULN,

ALT and /or AST ≥8 ULN,

ALT and /or AST ≥3 ULN and < 5 ULN,

ALT and /or AST ≥ 5 ULN and < 8 ULN,

ALT and/or AST ≥3 ULN and at the same time total bilirubin ≥2 ULN.

ALT and/or AST ≥3 ULN and at any time total bilirubin ≥2 ULN.
The highest ALT or AST value at any post-baseline time point of assessment is considered in 
the evaluation of incidences.
Treatment-emergent liver test abnormalities are those which were not present at baseline.
For the occurrence of post-baseline hemoglobin abnormalities the following events are 
considered in the evaluation of incidences:

Hemoglobin 80 g/L,

Hemoglobin > 80 and 100 g/L,

Hemoglobin decrease from baseline ≥20 g/L and < 50 g/L,

Hemoglobin decrease from baseline ≥50 g/L,

Hemoglobin < 100 g/L and concurrent (i.e. at the same time) decrease from baseline 
≥20 g/L. 
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The lowest hemoglobin value at any post-baseline time point of assessment is considered in 
the evaluation of incidences.
Treatment-emergent hemoglobin abnormalities are those that were not present at baseline.
Marked lab abnormalities are defined according to Actelion internal guidelines for individual 
parameters (see Table 2).
When determining treatment-emergent marked laboratory 
abnormalities, all assessments (including the unscheduled ones) are considered.
For women of childbearing potential, urine as well as serum pregnancy tests are performed, 
but these results will not be summarized as part of the laboratory data. Positive pregnancy 
tests (if any) will be reported.
Data from the OLE will be listed.
Table 2
Laboratory Abnormalities
Parameter 
LL marked
LLL marked
HH marked
HHH marked
Hemoglobin
< 100 g/L
< 80 g/L
[post-baseline > 
(baseline + 20 g/L) 
AND (baseline > ULN)] 
OR
[post-baseline > 
(ULN + 20 g/L) 
AND baseline ≤ ULN]
[post-baseline > 
(baseline + 40 g/L) 
AND (baseline > ULN)] 
OR
[post-baseline > 
(ULN + 40 g/L) 
AND baseline ≤ ULN]
Hematocrit
< 0.28 L/L for 
females
< 0.32 L/L for 
males
< 0.20 L/L
> 0.55 L/L for females
> 0.60 L/L for males
> 0.65 L/L
Platelets 
< 75 × 109/L
< 50 × 109/L
> 600 × 109/L  
> 999 × 109/L  
Leukocytes
< 3.0 × 109/L
< 2.0 × 109/L
> 20.0 × 109/L
> 100.0 × 109/L
Neutrophils
< 1.5 × 109/L
< 1.0 × 109/L
NA
NA
Eosinophils
NA
NA
> 5% OR
> 5 × 109/L
NA
Lymphocytes
< 0.8 × 109/L  
< 0.5 × 109/L
> 4.0 × 109/L  
> 20 × 109/L  
ALT 
NA
NA
> 3 × ULN
> 5 × ULN*
AST 
NA
NA
> 3 × ULN
> 5 × ULN*
Alkaline 
phosphatase
NA
NA
> 2.5 × ULN
> 5 × ULN
Bilirubin
NA
NA
> 2 × ULN
> 5 × ULN
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Parameter 
LL marked
LLL marked
HH marked
HHH marked
INR
NA
NA
> 1.5 × ULN OR
> 1.5 times above 
baseline 
> 2.5 × ULN OR
> 2.5 times above 
baseline 
Creatinine
NA
NA
> 1.5 × baseline OR
> 1.5 × ULN
> 3 × baseline OR
> 3 × ULN
Glucose
< 3.0 mmol/L
< 2.2 mmol/L
> 8.9 mmol/L
> 13.9 mmol/L
Calcium
< 2.0 mmol/L
< 1.75 mmol/L > 2.9 mmol/L
> 3.1 mmol/L
Sodium
NA
< 130 mmol/L > 150 mmol/L
> 155 mmol/L
Potassium
< 3.2 mmol/L
< 3.0 mmol/L
> 5.5 mmol/L
> 6.0 mmol/L
Magnesium
< 0.5 mmol/L
< 0.4 mmol/L
NA
> 1.23 mmol/L
Uric acid, Urate
NA
NA
> 590 umol/L
> 720 umol/L
Albumin
< 30 g/L
< 20 g/L
NA
NA
Blood Urea 
Nitrogen
NA
NA
> 2.5 × ULN
> 5 × ULN
* Also HHHH as > 8 × ULN
ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = international 
normalized ratio; NA = not applicable/available; ULN = upper limit of normal.
5.6.9
Other safety variables
No additional safety data will be summarized.
5.7
Pregnancy test
Contraceptive Methods (type, start/end date, etc...) for women of childbearing potential are 
collected in the Contraceptive Methods form of the CRF.
5.8
Quality of life variables
Not applicable.
5.9
Pharmacoeconomic variables 
Not applicable.
5.10 Pharmacodynamic variables
Not applicable.
5.11 Pharmacokinetic variables
Not applicable.
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5.12 Sub-studies
Biopsy sub-study was cancelled (without any patient) and therefore no data will be reported.
For metabolism sub-study, variables are changes 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.
For echo sub-study, variables are changes from baseline to Week 26 and to Week 52 in: 
- Pericardial effusion size scored from 0 to 4 
- 2D RV dimension (mm) end-diastole 
- RV end diastolic area (cm2)
- RV end systolic area (cm2)
- RV fractional area change (%)
- Tricuspid annular plane systolic excursion (TAPSE, cm) 
- Tricuspid peak annular velocity s’ (cm/s)
- Tricuspid peak E-wave velocity (cm/s)
- Tricuspid peak A-wave velocity (cm/s)
- Tricuspid deceleration time (ms)
- Tricuspid peak early diastolic annular velocities (cm/s) e’ and a’ 
- RV acceleration time (ms), by tissue Doppler and by pulsed wave Doppler
- RV ejection time (ms), by tissue Doppler and by pulsed wave Doppler 
- RV Early diastolic velocity (m/s) of the jet of pulmonary valve regurgitation 
- RV End-diastolic velocity (m/s) of the jet of pulmonary valve regurgitation 
- RVSV (mL) determined by combining pulmonary valve Doppler and pulmonary annulus 
dimension 
- Tricuspid regurgitation peak jet velocity (m/s)
- RV systolic pressure (estimated by tricuspid valve Doppler, mmHg) 
- Total RV Systolic Time (duration of tricuspid insufficiency jet, ms) by tissue Doppler and 
by pulsed wave Doppler
- Doppler RV index (RV myocardial performance index) by tissue Doppler and by pulsed 
wave Doppler 
- 2D Global Longitudinal RV strain (%)
- 2D circumferential RV strain (%)
- Time to peak RV strain (ms)
- Minimum diameter (cm) of the inferior vena cava (at inspiration) 
- Maximum diameter (cm) of the inferior vena cava (at end-expiration) 
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- RVEDV (assessed in 3D, mL)
- RVESV (assessed in 3D, mL)
- RVSV (assessed in 3D, mL)
- RVEF (%)
- RV mass (g)
- LV eccentricity index at end-diastole 
- LV eccentricity index at end-systole 
- LVEDV determined from 2D measurements (assessed in BIPLANE MOD) (mL)
- LVESV determined from 2D measurements (assessed in BIPLANE MOD) (mL)
- Mitral peak E-wave velocity (cm/s)
- Mitral peak A-wave velocity (cm/s)
- Mitral E wave deceleration time (ms)
- Mitral annulus peak early diastolic velocity E’ (cm/s) 
- Mitral annulus peak late diastolic velocity a’ (cm/s)
- Mitral E/A wave velocity ratio 
- Mitral E/E’ velocity ratio 
- Left Ventricular Stroke Volume (LVSV, mL) by aortic flow (Doppler method)
- Cardiac output (mL/min) determined from LV outflow tract 
- LVEDV assessed in 3D (mL)
- LVESV assessed in 3D (mL)
- Left Ventricular Stroke Volume (LVSV, mL) assessed in 3D
- LVEF (%)
- LV mass (g) 
- RVEDV/LVEDV assessed in 3D
- RVESV/LVESV assessed in 3D
These variables will be listed only:
- Heart Rate (bpm)
- Pulmonary artery annulus dimension (mm)
- Pulmonic valve Doppler TVI (measured at annulus, cm)
- LV Short Axis (SAX) end diastole (parallel to septum and perpendicular to septum, cm) 
- LV Short Axis (SAX) end-systole (parallel to septum and perpendicular to septum, cm) 
- LV Outflow Tract dimension (mm)
- LV Outflow Tract pulsed wave Doppler TVI (cm)
Where the tests are done by “pulsed wave Doppler” and by “Tissue Doppler”, these will be 
presented separately. The tests are distinguished in SDTM in the variable MOSCAT.  There are 
also different sub-categories for:

LVEDV (3D or biplane mod)

LV SAX dimensions (parallel to septum or perpendicular to septum).
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6
DEFINITION OF PROTOCOL DEVIATIONS
Protocol deviations include deviations from inclusion and/or exclusion criteria and deviations 
from the protocol during the conduct of the study. Moreover the PD will be classified, as per 
latest version of protocol deviation code list, as related to:

Protocol Deviations at Screening or re-screening

Protocol Deviations at study drug assignment in IVRS

Protocol Deviations at Treatment initiation Visit and thereafter.
7
ANALYSIS SETS
7.1
Definitions of analysis sets
7.1.1
Screened Analysis Set 
This analysis set (SCR) includes all patients who were screened and received a patient 
number.
7.1.2
Safety Set 
The Safety Set (SS) includes all patients from the Screened Patients set who received at least 
one dose of study drug.
7.1.3
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 assessed by cardiac MRI from 
pulmonary artery flow and PVR by RHC).
7.1.4
Modified full analysis Set 
The Modified FAS (mFAS) 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.
Note: day window used to apply this definition will be [112; 210] with nominal value Day 
182 (26 weeks), i.e. the planned time point.
7.1.5
Per-protocol analysis Set 
The Per-protocol analysis Set (PPS) comprises all patients included in the mFAS without 
major protocol deviations that affect the main analysis of the primary efficacy variables. 
The major protocol deviations leading to exclude the patients from the PPS are defined as:
PD100, PD105, PD207, PD251, PD304. It also restrict to patients who had a post-baseline 
measurement taken between 22 weeks and 30 weeks of treatment for both primary endpoints.
The day window used to apply this definition will be [154; 210] with nominal value Day 182 
(26 weeks).
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7.1.6
Other analysis sets 
The specific RVSV Modified FAS (RVSVmFAS) 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 assessed by cardiac MRI from pulmonary artery flow.
The specific PVR Modified FAS (PVRmFAS) 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.
The specific RVSV and PVR Modified FAS will only be used if the patients that are in both
sets (i.e., the patients in the mFAS) corresponds to less than 70% of the patients that are in at 
least one of RVSVmFAS and PVRmFAS. These analysis sets will be created but will only be 
used if applicable (if criterion mentioned above is met).
7.2
Usage of the analysis sets
Primary efficacy analysis will be performed on the mFAS. Sensitivity analyses for primary 
endpoints will be performed on PPS, FAS, SS, RVSVmFAS and PVRmFAS (if condition 
from 7.16 is met).
Secondary and exploratory efficacy analyses will be performed on the mFAS and SS.
Safety analyses will be performed on the SS.
Patient disposition will be described for the SCR.
Patient listings will be based on the SCR.
Sub-studies analyses will be based on the mFAS and SS, restricted to subjects participating 
in each sub-study.
8
DEFINITION OF SUBGROUPS
The following subgroups will be considered as part of this analysis plan:
1. PAH background therapy (as ticked on CRF, variable 'Treatment Strategy' in the 
Treatment Strategy form): 
(1) "Patient previously treated with a PDE-5 inhibitor"
(2) "Naïve patient with intention to start study drug only", 
(3) "Naïve patient with intention to start upfront PDE-5 inhibitor and study drug 
combination therapy", 
and pool of (1)+(2) – i.e. all patients that fall into either (1) or (2).
2. WHO FC groups at baseline: FC I-II, FC III-IV.
3. Sex: male, female.
4. Age at Screening: < 65, >= 65.
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9
GENERAL STATISTICAL METHODOLOGY
SAS (Statistical Analysis System®) version 9.3 or higher will be used for all the statistical 
analysis.
Data are listed and summarized by appropriate descriptive statistics (tables or figures), 
typically including:

Number of non-missing observations, mean, standard deviation, minimum, Q1, median, 
Q3 and maximum for continuous variables,

Number of events, number of censored observations, number of subjects at risk, and 
Kaplan-Meier estimates of the survival function for time-to-event variables,

Number of non-missing observations, frequency with percentage per category 
(percentages based on the number of non-missing observations) for categorical safety 
variables,

Number of missing observations and frequency with percentage per category (percentages 
based on the total number of observations) for categorical variables other than safety 
variables.
The number of missing values is displayed only if > 0. For continuous variables it is 
displayed after the number of non-missing observations, for categorical variables after the 
last category.
Absolute changes from baseline are defined as: post-baseline value minus baseline value, 
such that a positive sign indicates an increase compared to baseline. Ratio of post-baseline
versus baseline is defined as post-baseline value divided by baseline value.
10 STATISTICAL ANALYSES
10.1 Overall testing strategy
The overall type I error is α = 0.025 (one-sided) and is split unequally between the two 
primary endpoints RVSV assessed by cardiac MRI from pulmonary artery flow (α = 0.02) 
and PVR by RHC (α = 0.005), which is equivalent to 2-sided overall type I error with α = 
0.05 (split into RVSV with α = 0.04 and PVR with α = 0.01). All analyses will be performed 
using 2-sided statistical tests. 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 (hence, 
the larger part of the α).
If the analysis of at least one of those primary endpoints is statistically significant, i.e. p value 
below nominal alpha, the study is declared positive.
An interim analysis will be performed once 42 patients have available data for primary 
endpoint (see Section 10.11).
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10.2 General rules for data presentations
General rules for data presentations as described here below are followed unless otherwise 
specified.
In general, data are listed and summarized by appropriate descriptive statistics (tables or 
figures) as described in Section 9. 
Listings are grouped by country, site (if applicable, screen failures are listed last), subject 
number and assessment date as applicable. 
Raw data listings if required are based on datasets as received. All data collected are 
displayed, including unscheduled visits (if any).
10.3 Display of subject disposition, protocol deviations and analysis sets
10.3.1 Subject disposition
The disposition of patients includes the following categories of patients:

Screened patients, 

Treated patients,

Patients who prematurely discontinued study treatment (core phase)

Patients who completed study treatment (core phase)

Patients who completed study (core phase)

Patients who entered in the OLE
Number and percentage of patients within each category will be tabulated. Number and 
percentage of patients included in each sub-study will be summarized. 
10.3.2 Protocol deviations
Number and percentage of patients within each protocol deviation (PD) category will be 
tabulated (important and all). Individual data listing will be provided for all screened patients.
10.3.3 Analysis sets
Number and percentage of patients within each analysis set will be tabulated. This table will 
consider all screened patients. All criteria/events which lead to exclusion of subjects from the 
analysis sets will be reported in a subject listing.
10.4 Analyses of subject characteristics
10.4.1 Disposition of patients
See Section10.3.1.
10.4.2 Demographics
The variables age, sex, race, ethnicity, height, country, as well as body weight, BMI, and 
childbearing potential status at baseline will be summarized using descriptive statistics for 
continuous and categorical data. Summaries are given for SS and mFAS.
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10.4.3 Baseline disease characteristics
Baseline disease characteristics [as defined in Section 5.2.2] are summarized using 
descriptive statistics for continuous and categorical data. Summaries are given for SS and 
mFAS.
10.4.4 Other baseline characteristics
Treatment strategy will be summarized among baseline disease characteristics, by 
frequencies and proportions, on SS and mFAS.
10.4.5 Medical history
All previous and/or ongoing diseases/diagnoses are reported in a subject listing. Ongoing as 
well as previous diseases/diagnoses are flagged accordingly.
Previous and/or ongoing diseases/diagnoses including specific previous and/or concomitant 
diseases/diagnoses are summarized on SS, displaying counts and percentages of subjects 
having at least a disease/diagnosis. Counts and percentages of subjects having at least a 
disease/diagnosis are presented by system organ class (SOC) and individual PT within each 
SOC. The summary table is presented in descending order (e.g., SOC and individual PT
within each SOC with the highest number of occurrences appears first). Equal frequency of 
different SOC/individual PTs is sorted in alphabetical order of the SOC/individual PT.
Subjects with two or more occurrences of the same disease (as qualified by the same PT[s]) 
are counted only once. In case the reported disease is assigned to several PTs, subjects are 
counted for each individual PT.
10.4.6 Previous and concomitant therapies
Previous and concomitant therapies are classified according to the Anatomic Therapeutic 
Chemical (ATC) class code and summarized by tabulating the number and percentages of
subjects using the SS.
Study-treatment concomitant therapies are summarized by ATC class and PT. 
For study reporting purposes, all previous and study-concomitant therapies are reported in the 
subject listings. It is indicated if the therapy is previous or concomitant.
Therapies present at baseline are those taken on the day of first dose.
Counts and percentages of subjects having taken at least a previous/concomitant therapy at 
baseline/concomitant medication are presented, separately, by ATC class and individual PT
within each ATC class as well as by individual PT. The summary tables are presented in 
descending order (i.e., ATC and individual PT within each ATC with the highest number of 
occurrences appear first). Equal frequency of different ATC/individual PTs is sorted in 
alphabetical order of the ATC/individual PT. All percentages are based on the SS.
Subjects who took the same medication more than once (as qualified by the same PT(s)) are 
counted only once. In case the reported medication is assigned to several PTs, subjects are 
counted for each individual PT.
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Separately, specific previous/concomitant therapy at baseline/concomitant medication are 
similarly presented with counts and percentages in summary tables.
10.4.7 Other subject characteristics
Historical pulmonary function test variables will be described using either descriptive 
statistics or frequencies and proportions as relevant.
10.5 Analysis of study treatment exposure and compliance
10.5.1 Exposure
Exposure to study drug will be described in terms of duration on SS.  
The exposure time (weeks) will be summarized using descriptive statistics for continuous 
data. It will also be summarized as categorical variable: the cumulative distribution of 
exposure time by different class intervals (e.g., less than 12 weeks, at least 12 weeks, at least 
24 weeks, and at every interval of 12 weeks thereafter) will be tabulated to show counts and 
percentages of patients in each class interval.
10.5.2 Compliance with study treatment
The study treatment compliance will be summarized on SS and tabulated by compliance 
category < 80%, 80 % - 120 % and >120%.
10.5.3 Study treatment interruptions
Study treatment interruptions defined in Section 5.3.3 are listed and summarized on SS using 
descriptive statistics for categorical data.
Frequency tables will be presented displaying the number of subjects with at least one 
interruption and the reasons from the study drug log CRF page “Temporarily interrupted due 
to an AE” and/or “Temporarily interrupted not due to an AE”. The numbers in the categories 
may sum to a number greater than the number of subjects with an interruption as a single 
subject could have multiple interruptions for multiple reasons.
Percentages of subjects with the sum of all interruptions of study drug intake of more than 7, 
14, 21 and 28 days will be displayed. These counts will be “cumulative”, i.e., if a subject 
interrupts treatment for more than 21 days (but less than 28 days), they are counted in three
categories: “more than 7 days”, “more than 14 days”, “more than 21 days”.
The total duration of study treatment interruptions will be summarized using descriptive 
statistics for continuous data.
10.5.4 Study treatment discontinuation
Proportion and number of patients having permanently discontinued study treatment will be 
provided on SS. The cause for permanent discontinuation will be tabulated as frequency and 
percentage. 
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10.6 Study discontinuation
Study discontinuation (see Section 5.4) reporting is conducted as part of subjects disposition 
described in section 10.3.1. Reasons for study discontinuation will be reported in a subject 
listing on SCR.
10.7 Analysis of the primary efficacy variable(s)
10.7.1 Hypothesis and statistical model
The null hypothesis is:

The mean change from baseline to Week 26 in RVSV assessed by cardiac MRI from 
pulmonary artery flow 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.
10.7.2 Handling of missing data
RVSV assessed by cardiac MRI from pulmonary artery flow is taken from the raw data.
PVR is calculated as described in section 5.5.1. If PVR cannot be calculated due to missing 
PCWP and LVEDP but mPAP and CO are available for the same visit, one of the following 
methods is applied:
1. If PCWP and LVEDP are missing both at baseline and post-baseline, the study 
population median PCWP (baseline and post-baseline, respectively) is imputed (based 
on the SS).
2. If PCWP and LVEDP are missing either at baseline or post-baseline, the patient’s 
available PCWP (or LVEDP if PCWP missing) is imputed.
This imputation is based on the clinical assumption that macitentan does not affect PCWP.

Baseline: Patients with no RVSV assessed by cardiac MRI from pulmonary artery 
flow or PVR by RHC measurement at baseline will have missing values for the 
change and so are excluded from the analyses. 

Post-baseline: For patients with no RVSV assessed by cardiac MRI from pulmonary 
artery flow or PVR by RHC values at Week 26, the last post-baseline measurement 
(presumably taken at treatment discontinuation or initiation of rescue therapy) is 
carried forward, provided that this measurement was taken after at least 16 weeks of 
treatment. Week 26 measurements taken after 30 weeks of treatment are excluded 
from the analyses.
10.7.3 Main analysis
The primary analysis is performed on the mFAS. 
RVSV assessed by cardiac MRI from pulmonary artery flow 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 PAH background therapy as ticked on CRF and a covariate for 
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baseline RVSV. The mean change from baseline and its 96% confidence interval (CI) will be 
estimated based on the model and p-values will be interpreted based on boundaries set in 
Section 10.11.
PVR by RHC 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 PAH background therapy 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, and p-values will be interpreted based on boundaries set in 
Section 10.11. The geometric mean ratio (versus baseline) and its CI will be obtained by 
exponentiation. 
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.
Listings of cardiac MRI variables and of Right Heart Catheterization (RHC) will be provided.
10.7.4 Supportive/sensitivity analyses
A sensitivity analysis will be performed on the FAS. Week 26 measurements performed after 
30 weeks of treatment will be excluded from the Week 26 analysis.
Another sensitivity analysis will be performed on the PPS that will be restricted to 
completers, i.e., patients with RVSV assessed by cardiac MRI from pulmonary artery flow
and PVR by RHC measurements at Week 26 taken between 22 and 30 weeks of treatment.
A sensitivity analysis will be performed on the SS for patients without post-baseline RVSV
assessed by cardiac MRI from pulmonary artery flow or PVR by RHC. For those patients, the 
last available post-baseline measurement will be carried forward (see section 10.7.2 for 
details).
10.7.5 Subgroup analyses
The primary endpoints, i.e. RVSV assessed by cardiac MRI from pulmonary artery flow and 
PVR by RHC, will be analyzed on mFAS by status of PAH background therapy (as ticked on 
CRF) using the ANCOVA models as specified for the main analysis but excluding PAH
background therapy factor from the model. In this analysis, 95% CIs will be used.
Similarly, those endpoints will be analyzed on mFAS by WHO FC category at baseline (FC I
or II versus FC III or FC IV), sex (male versus female) and age group (< 65 versus >= 65). 
This will be done using same ANCOVA model as specified in section 10.7.3. In this analysis 
95% CIs will be used.
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10.7.6 Exploratory analyses of the primary endpoints
Exploratory analyses will be performed aimed at identifying prognostic factors for changes 
from baseline in RVSV assessed by cardiac MRI from pulmonary artery flow and change in 
log(PVR). This will be done on mFAS using ANCOVA analyses including all following 
candidate prognostic factors together in model:

PAH etiology;

Baseline 6MWD (m);

Baseline WHO FC ("I-II", "III-IV");

Sex (male, female);

Age group (< 65, >= 65).
10.8 Analysis of the secondary efficacy variables
10.8.1 Hypothesis and statistical model 
Secondary efficacy analyses will be performed on the mFAS and SS at α = 0.05 (two-sided) 
using 95% CIs. 
10.8.2 Handling of missing data 
No specific imputation will be performed for secondary endpoints.
10.8.3 Statistical analysis
MRI-based secondary efficacy variables (changes from baseline to Week 26 in RVEDV, 
RVESV, RVEF by pulmonary artery flow and RV mass) will be summarized and analyzed as 
described for RVSV assessed by cardiac MRI from pulmonary artery flow in Section 10.7.3
(using 95% CI). 
The 6MWD and the Borg dyspnea index will be summarized by time point using descriptive 
statistics. Change from baseline to Week 26 in 6MWD will be analyzed using an ANCOVA 
with a factor for PAH background therapy and a covariates for baseline 6MWD and WHO 
FC.
WHO FC will be summarized by time point using frequency tables. Changes from baseline to 
Week 26 in WHO FC will be dichotomized as worsening (i.e., change > 0) versus no change 
or improvement (i.e., change ≤ 0). Worsening at Week 26 will be analyzed using an exact
logistic regression model with a factor for PAH background therapy as ticked on CRF. 
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 PAH background therapy and a covariate for baseline log NT-
proBNP.
10.8.4 Supportive/sensitivity analyses
Not applicable for secondary efficacy variables.
10.8.5 Subgroup analyses
Not applicable for secondary efficacy variables.
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10.9 Analysis of other efficacy variables
Week 52 endpoints will be summarized and analyzed similarly to the Week 26 endpoints.
Hemodynamic variables will be summarized and analyzed by time point using descriptive 
statistics.  Week 52 variables will be summarized and analyzed similarly to the corresponding 
Week 26 measurements.
Pressure-volume variables (arterial elastance, RV end-systolic elastance, RV maximum 
isovolumic pressure, ventriculo-arterial coupling) will be listed only.
Potential variables for disease monitoring, ratios RVEDV/LVEDV and RVESV/LVESV will 
be summarized and analyzed as PVR. The 95% CI and the associated p-value will be 
presented.
RVSV by RV volumes will be analyzed as an exploratory endpoint.
Variables related to the left ventricle will be summarized and analyzed similarly as the 
corresponding right ventricular variables. 
An exploratory analysis will be performed using RVSV with imputation from RV volumes 
(see section 5.5.3.3), which are analyzed like the primary RVSV parameter (see section 
10.7.3)5.5.3.3.
RVSV and RVEF by pulmonary artery flow and by RV volumes will be listed together with 
LVSV by aortic flow and LVSV by volumes. The percentage difference between RVSV from 
pulmonary artery flow and LVSV from aorta flow will be presented (see section 5.5.3.3).  
Differences of more than 20% will be flagged.
Potential laboratory variables for disease monitoring (see section 5.5.3.5 for definition) will 
be analyzed descriptively displaying observed values and absolute changes from baseline to 
Week 26 and Week 52. In this evaluation, only subjects who had both the assessments at 
baseline and the Week 26/Week 52 assessment (respectively) will be included.
In order to minimize missing data and to allow for unscheduled visits, all recorded 
assessments are assigned to the most appropriate visit time point according to the best fitting 
time window for the assessment. If laboratory test results are given by threshold values (‘<x’ 
or ‘>x’), the threshold values are considered for quantitative analysis.
Data will be presented in SI units. All the variables will also be displayed in a subject listing.
The clinical endpoint, time to first clinical worsening (as defined in section 5.5.3.6) will be 
summarized using a Kaplan-Meier (KM) plot. KM estimates and its associated 95% CI will 
also be provided. 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 
(analysis to be done only if at least 10% of patients have an event).
10.10 Analysis of safety variables
All safety analyses will be performed on the SS. All safety data will be listed. In the main 
summary tables, for patients entering the OLE, EOT will consider last dose in core phase.   
Where specified below, additional tables will be produced for all data in the study, including 
data for OLE.
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10.10.1  Adverse events
All AEs captured from signature of informed consent up to EOS, including the open label 
extension, are reported in the subject listings.
The number and percentage of patients experiencing treatment-emergent AEs and SAEs at 
least once (see section 5.6.1.1 for definition) 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. 
The above tables will be repeated for all data including the OLE.
Furthermore, treatment-emergent AEs will be tabulated as described above by severity and 
relationship to study drug. 
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 deaths.
10.10.2  Deaths, other serious adverse events
10.10.2.1 Death
Treatment-emergent deaths will be tabulated (frequency and percentage), overall and by 
reason. Death along the causing reason will also be listed from screening to EOS, including 
the open label extension.
10.10.2.2 Serious adverse events
Treatment emergent SAEs will be tabulated as described in Section 10.10.1.
Treatment 
emergent SAEs will also be tabulated by SOC and PT for all data including the OLE.
SAEs from screening to EOS will also be listed, including the open label extension.
10.10.2.3 Adverse events leading to study treatment discontinuations or death
AEs leading to premature discontinuation of study treatment will also be summarized as 
described above.
10.10.2.4 Other significant adverse events
For the disclosure of the results to EudraCT and ClinicalTrials.gov (and not for the purpose 
of the clinical study report), treatment-emergent non-serious AEs with frequencies 5% are 
summarized displaying counts and percentages of subjects with at least a treatment-emergent 
non-serious frequent AE plus the number of events (counted exactly the number of times they 
occurred also within a subject) by SOC and individual PT. The summary table is presented in 
descending order (i.e., SOC and individual PT within each SOC with the highest number of 
occurrences appears first). PTs that are reported at equal frequencies are sorted in 
alphabetical order. 
For the disclosure of the results to EudraCT and ClinicalTrials.gov, a summary table with an 
overview of treatment-emergent AEs is provided displaying counts and percentages of 
subjects having experienced at least a treatment-emergent AE, a severe AE, a study-treatment 
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related AE, an AE leading to study treatment discontinuation, a non-serious frequent AE, a 
serious AE, a study-treatment related serious AE, a fatal SAE.
The above tables for disclosure will be repeated for all data including the OLE.
In addition, the adverse events of special interest (see Section 5.6.5 for definition) will be 
summarized on SS. For each area of clinical interest, treatment-emergent AEs of special 
interest will be summarized displaying counts and percentages of subjects having 
experienced at least a treatment-emergent AE of special interest. Counts and percentages of 
subjects having experienced at least a treatment-emergent AE will be presented by frequency 
of individual PT within each SOC.
10.10.3 Electrocardiography (ECG)
Not applicable.
10.10.4 Laboratory tests
All hematology and chemistry variables provided by the central and local laboratory are 
provided in a subject listing. Marked laboratory abnormalities are flagged accordingly. All 
laboratory data transferred are taken into account regardless of whether they correspond to 
scheduled (per protocol) or unscheduled assessments.
If laboratory test results are given by threshold values (‘<x’ or ‘>x’), the threshold values are 
considered for quantitative analysis.
Laboratory data will be presented in SI units.
Laboratory tests will be summarized for baseline, Week 26 and Week 52, The required 
monthly liver and hemoglobin laboratory tests (hemoglobin, hematocrit, AST, ALT, alkaline 
phosphatase, total and direct bilirubin and LDH) will be summarized by month for the first 6 
months, in addition to baseline and Week 52.
Descriptive summary statistics by visit are displayed for observed values and absolute 
changes from baseline. In order to minimize missing data and to allow for unscheduled visits, 
all recorded assessments up to EOS are assigned to the most appropriate visit time point 
according to the best fitting time window for the assessment. 
In each evaluation, only subjects are included who had both the assessments at baseline and 
the considered post-baseline assessment.
Treatment emergent marked laboratory abnormalities (i.e., fulfilling the applicable condition 
for LL / HH as listed in Table 2) are summarized for each laboratory parameter providing 
their incidence, frequency, and number of subjects with available assessments.
Percentages are calculated as number of subjects who had at least one occurrence of the 
abnormality, for the variable under consideration divided by the number of subjects with any
post-baseline laboratory measurement.
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Shift tables are used to summarize the worst treatment-emergent laboratory abnormalities, 
based on the definition of marked laboratory test abnormalities listed in Table 2. The worst 
category is taken for the analysis for each direction.
If HH, HHH, LL or LLL is not defined for a variable, “NA” will appear in the table for the
corresponding variable. Percentages are calculated based on the number of subjects in the 
analysis set. 
Separate tables with the incidence of liver test abnormalities and hemoglobin abnormalities 
are produced including summaries on criteria as defined in Section 5.6.8. An eDISH plot will 
also be produced for the core part of the study (excluding the OLE as liver values are not 
recorded in the eCRF for the OLE).
For these plots the maximum post-baseline value of 
ALT / AST and total Bilirubin will be used, excluding samples taken after the start of the 
OLE.
The tables for liver and hemoglobin test abnormalities will be repeated for the entire study 
(including data for OLE).
10.10.5 Physical examinations, vital signs and body weight
Physical examinations data are listed only. 
Vitals signs, body weight and BMI, including changes from baseline, are summarized over 
time for each parameter using descriptive statistics for continuous data. 
In each evaluation, only subjects are included who had both the assessments at baseline and the 
considered post-baseline assessment.
All recorded assessments up to EOS are assigned to the most appropriate visit time point 
according to the best fitting time window for the assessment. 
10.10.6 Other safety variables
Not applicable.
10.11 Interim analysis
An interim analysis will be conducted when the first 42 evaluable patients (i.e., included in 
the mFAS) 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 assessed by cardiac MRI 
from pulmonary artery flow 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 assessed by cardiac MRI from pulmonary artery flow 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 robust treatment effect estimates, i.e., there is 
less uncertainty on the treatment effect estimate. 
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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.
The interim analysis will be performed on the mFAS. 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 protocol 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.
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.
As stated in the protocol (section 11.3.2.3 final sentence) the primary analysis / hypothesis 
will only be tested at the final analysis (after study closure and database lock), if the interim 
analysis is not positive.  If the interim analysis is positive, then analyses after final database 
closure are supportive, as the primary analysis is completed with the interim analysis.
Table 3 Efficacy boundaries for RVSV assessed by cardiac MRI from pulmonary artery flow 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 (one-sided) or 
0.02298 (two-sided)
0.01138 (one-sided) or 
0.02276 (two-sided)
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 (one-sided) or 
0.0062 (two-sided)
0.00247 (one-sided) or 
0.00494 (two-sided)
* 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 (one-sided) if not tested at interim 
10.12 Analysis of pharmacoeconomic variables
Not applicable.
10.13 Analysis of epidemiological measures and risk-benefit evaluations
Not applicable.
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10.14 Analysis of pharmacodynamic variables
Not applicable.
10.15 Analysis of pharmacokinetic variables
Not applicable.
10.16 Sub-studies analysis
Changes from baseline to Week 26 and Week 52 in echo variables (see Section 5.12) will be 
summarized using descriptive statistics on the FAS (restricted to subjects participating to 
each sub-study respectively).  Echo variables will also be analyzed as for RVSV assessed by 
cardiac MRI from pulmonary artery flow.
Individual subject listings will be provided on the SCR (restricted to subjects participating to 
each sub-study respectively).
11 GENERAL DEFINITIONS AND DERIVATIONS
11.1 Baseline
The baseline value is the value from the last non-missing assessment obtained prior to, 
i.e., before or on the day of the start of study drug.
11.2 Post-baseline assessment 
Post-baseline assessment is any assessment performed after baseline and up to EOS. 
11.3 Treatment period start date
It is the first day of intake of study treatment. It is derived from the first treatment start date (in 
chronological order) in the Study Drug Log CRF (retrieved from the STDM EX domain where 
EXCAT='STUDY DRUG').
11.4 Treatment period end date (EOT)
It is derived from the treatment end date, from the last interval in chronological order, 
recorded in the Study Drug Log CRF and the reason for treatment end is not “
TEMPORARILY
INTERRUPTED 
DUE 
TO 
AN 
AE” 
or 
“TEMPORARILY 
INTERRUPTED NOT DUE TO AN AE”. If missing or incomplete, rules in Section 12 are 
followed according to Table 6
The treatment period is the period from the start up to the end of treatment (limits included).
11.5 Extension treatment period start date
It starts immediately after EOT for those subjects treated at French sites who completed the 
core phase of the study as scheduled and opt to continue receiving study treatment. It is derived 
from the first treatment start date (in chronological order) in the Study Drug Log eCRF where 
the ‘Study Period’ is ‘OPEN LABEL EXTENSION STUDY DRUG'.
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11.6 Extension period end date (EOTOLE)
This is the “Treatment end date” from the last interval, in chronological order, recorded in the 
study drug log eCRF where the ‘Study Period’ is ‘OPEN LABEL EXTENSION STUDY 
DRUG'. If missing or incomplete, rules in Section 12Error! Reference source not found.
are followed according to Table 6Error! Reference source not found.
The extension treatment period is the period from the start up to the end of extension
treatment (limits included).
Note: for reporting purpose, in the exceptional situation that the end date of a period is equal 
to the start date of the next period (for example the end date of treatment period is equal to 
the start date of the extension treatment period), the 'event' is associated with the first of the 
two periods (in the example, it is associated with the treatment period).
11.7 End of Study (EOS) date
This is the date of the "End of Follow Up" form of the eCRF.
11.8 Study day
Is the number of days elapsed since the study treatment start date plus 1 (study treatment start 
date is considered Day 1). For dates prior to study treatment start date, study day is the 
negative number of days between the date under consideration and the study treatment 
initiation. Therefore, the study day is always different from 0.
11.9 Time windows
To allow analysis of data at the relevant planned (scheduled) visits, recorded assessments, 
including unscheduled ones, are re-assigned to the most appropriate visit according to the 
best fitting time-window for that visit (see Table 5). The visit windows are based on the 
number of days from study treatment start (study treatment days).  The window for Week 26 
is based on the protocol specification for the primary endpoint.  The window for Week 52 is 
calculated similarly to Week 26 (resulting in a wider Week 52 window than the protocol 
window). As EOS is a telephone visit, EOS is not included in the list of visits, so summary 
statistics are not applicable for EOS.
Should more than one assessment fall within the same time window, then the closest value to 
the planned time point (nominal value) will be assigned for presentation in data summaries 
and analyses. In case of values that are equidistant to the planned time point, the later 
assessment will be considered for the analyses. If more than one value falls on the same time 
point then the one with the last sequential number in SDTM will be used.  (For lab 
assessments, if more than one lab assessment falls on the same time point, the central 
assessment is to be used.  If this is still more than one value, the last sequential number in 
SDTM will be used.)
Programming note: values that are not retained for presentation in summaries per visit should 
be kept in the datasets and used as appropriate when applying substitution rules for missing 
data.
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Individual data listings consider all data by nominal visit identifier with data flagged if 
considered for time windows.
Table 5 - Visits time windows
Mapping of all visits to:
Study day
(nominal value)
Lower limit
study day
Upper limit
study day
Baseline
1
No limit
1
Week 26 visit
182
112
210
Week 52 visit
364
294
434
For monthly lab tests (hemoglobin, hematocrit, AST, ALT, alkaline phosphatase, total and 
direct bilirubin and LDH):
Baseline
1
No limit
1
Month 1
30
15
44
Month 2
60
45
74
Month 3
90
75
104
Month 4
120
105
134
Month 5
150
135
164
Month 6
180
165
210
Week 52 visit
364
294
434
Using an ITT approach, assessments are not required to be during treatment.
12 HANDLING OF MISSING/INCOMPLETE DATE AND TIME FIELDS
All dates and times used in the analyses are supposed to be complete, apart from the types 
included in the table below.
Missing or incomplete dates are handled as follows:

Dates are split into 3 parts: year, month and day. Year is the top -level, month is medium 
level and day is low level. If a part that is expected to contain a number is numeric but the 
value is outside a valid range, the complete date is handled as missing. For example, if 
date = 44Nov2000 the whole date is considered to be missing.

If a part that is expected to contain a number is not numeric, i.e., contains values like such 
as ND, NA, --, ??, 2?, it is considered to be missing.

If a part is missing, all lower level parts are considered to be missing. This means that a 
ddmmyy date ‘21ND99’ is considered as ‘----99’.
Missing parts for specific dates/times are changed into acceptable non-missing values 
depending on the type of date to be replaced.
In Table 6, ‘lower limit’ and ‘upper limit’ refer to the minimum or maximum of a possible 
date. As an example, if only the day is missing, the lowest limit is the first day of the given 
month and the upper limit is the last day of the given month. If the day and month are 
missing, the lower limit refers to the first day of the given year and the upper limit to the last 
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day of the given year. The earliest and the latest dates refer to the first or last date, 
respectively, when ordered in sequence.
Table 6
Types of missing or incomplete date/time fields
Type of date/time Date/time is incomplete
Date/time is missing
AE 
resolution 
date
The upper limit
No replacement, the 
AE is considered as 
ongoing in the analysis
AE onset date
If the end date of the AE is not before the study 
treatment start date, and if the study treatment 
start falls in the range of possible dates, the study 
treatment start date is used. In all the other cases, 
the lower limit is used.
The earlier of the date 
of resolution of the AE 
and the study treatment
start date 
Previous/ 
concomitant 
therapy start 
date
Lower limit except when:
Not tagged as ongoing at start of treatment
AND
Therapy end date not collected or with the upper 
limit after the study treatment start date
AND
the study treatment start day falls in the range of 
possible dates.
In which case it is the study treatment start day
No replacement, the 
therapy is considered 
to have started before 
the study
Previous/
concomitant
therapy end date
Upper limit except when:
Therapy start is before study treatment start or 
missing
AND
Upper limit is after the study treatment start
AND
Not tagged as ongoing at start of treatment.
In which case it is 1 day before study treatment 
start
No replacement 
(considered ongoing)
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Type of date/time Date/time is incomplete
Date/time is missing
Hospitalization
admission date
If the onset date of the AE leading to 
hospitalization falls in the range of possible 
dates, it is the onset date of the AE. In all the 
other cases, it is the lower limit.
The onset date of the 
AE 
leading 
to 
hospitalization
EOS
Upper limit
Core phase database 
lock date
EOT
Use the earliest date between the:
upper limit
EOS
date of death
Use the earliest date 
between the:
EOS
date of death
EOTOLE
Use the earliest date between the:
upper limit
EOS
date of death
Use the earliest date 
between the:
EOS
date of death
Death date
Use the lower limit
No replacement
13 LIST OF SUMMARY TABLES, LISTINGS AND FIGURES
This section lists all outputs (i.e., listings, tables and figures) produced to display the results 
of the analyses defined in the sections above. In addition, original SAS output will be 
provided in CSR section 16.1.9.
The table, listing and figures naming conventions have three components: Type (T, L, F), 
Name (free text, not longer than ten characters), Suffix (for example, for analysis sets, or 
subgroups, not longer than four characters). Multiple suffixes can be added;
components/suffixes are separated by ‘_’.
Key deliverables are marked as being of priority.
All outputs flagged as key table will be produced at interim analysis. 
13.1 Subject disposition
Output
name
Display
*
Title (Description)
Analysis 
set(s)**
Key 
deliverable
Mock 
layout
DISP
T
Disposition of subjects
SCR

T1
ANSETOV
T
Overview of analysis sets 
SCR

T2
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Output
name
Display
*
Title (Description)
Analysis 
set(s)**
Key 
deliverable
Mock 
layout
ANSETEXR
T
Reasons for exclusion from analysis sets
SS
T2a
ANSET
L
Listing of subject participation in the different 
analysis sets
SCR

L35
ANSETEXR
L
Listing of reasons for exclusion from analysis 
sets
SCR

L1
SUBST
T
Overview of each sub-study
SS
T6
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set, 
PPS=Per-protocol analysis set, SS=Safety analysis set, mFAS: Modified full analysis set 
13.2 Protocol deviations
Output 
name
Display*
Title (Description)
Analysis 
set(s)**
Key 
deliverable
Mock 
layout
PRDEVI
T
Important protocol deviations
SS

T8
PRDEVA
T
All protocol deviations
SS
T8
PRDEV
L
Listing of protocol deviations
SCR

L4
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set, 
PPS=Per-protocol analysis set, SS=Safety analysis set, mFAS: Modified full analysis set 
13.3 Subject characteristics
13.3.1 Demographics
Output 
name
Disp
lay*
Title (Description)
Analysis 
set(s)**
Key 
deliverable
Mock 
layout
DEMOG
T
Demographic characteristics
SS, mFAS

T10
DEMOG
L
Listing of demographic characteristics
SCR

L5
AGECATEU
T
EudraCT age categories
SS
T10a
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set, 
PPS=Per-protocol analysis set, SS=Safety analysis set, mFAS: Modified full analysis set 
13.3.2 Baseline disease characteristics
Output 
name
Display*
Title (Description)
Analysis 
set(s)**
Key 
deliverable
Mock 
layout
BASDC
T
Baseline disease characteristics
SS, mFAS

T11
BASDC
L
Listing of baseline disease characteristics
SCR

L6
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set, 
PPS=Per-protocol analysis set, SS=Safety analysis set, mFAS: Modified full analysis set 
13.3.3 Medical history
Output 
name
Display
*
Title (Description)
Analysis 
set(s)**
Key 
deliverable
Mock 
layout
MHSCPR
T
Medical history by primary system organ class 
(SOC) and preferred term
SS

T12
CDSCPR
T
Concomitant diseases by primary system organ 
class (SOC) and preferred term
SS

T12
NCT02310672


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Study AC-055-403
20-March-2018, page 51/60
Confidential 
Statistical Analysis Plan
Doc No D-16.633
TPL-000241 v02
Output 
name
Display
*
Title (Description)
Analysis 
set(s)**
Key 
deliverable
Mock 
layout
PCMHIST
L
Listing 
of 
subjects 
with 
previous 
and 
concomitant medical history
SCR

L7
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set, PPS=Per-protocol analysis 
set, SS=Safety analysis set, mFAS: Modified full analysis set 
13.3.4 Previous and concomitant therapies
Output name
Display
*
Title (Description)
Analysis 
set(s)**
Key 
deliverable
Mock 
layout
CTTATCPR
T
Study-treatment concomitant therapies by 
anatomic therapeutic chemical class (ATC) 
and preferred term
SS

T14
CTSATCPR
T
Study concomitant therapies by anatomic 
therapeutic chemical
class (ATC) and 
preferred term
SS
T14
CTSBLATCPR
T
Study concomitant therapies at baseline by 
anatomic therapeutic chemical class (ATC) 
and preferred term
SS
T14
PTATCPR
T
Previous therapies by anatomic therapeutic 
chemical class (ATC) and preferred term
SS
T14
CTTSP
T
Study treatment concomitant PAH specific 
therapies by preferred term
SS

T15
CTSSP
T
Study concomitant PAH specific therapies 
by preferred term
SS
T15
CTSBLSP
T
Study concomitant PAH specific therapies at 
baseline by preferred term 
SS
T15
PTSP
T
Previous PAH specific previous therapies by 
preferred term 
SS 
T15
PCTHER
L
Listing of subjects with previous and 
concomitant therapies 
SCR

L9
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set, |
PPS=Per-protocol analysis set, SS=Safety analysis set, mFAS: Modified full analysis set 
13.3.5 Other subject characteristics
Output 
name
Display*
Title (Description)
Analysis 
set(s)**
Key 
deliverable
Mock 
layout
HPFT
T
Historical Pulmonary function tests
SS, mFAS
T16
HPFT
L
Listing of historical Pulmonary function tests
SCR
L6a
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set, 
PPS=Per-protocol analysis set, SS=Safety analysis set, mFAS: Modified full analysis set 
13.4 Study treatment exposure and compliance
13.4.1 Exposure
Output name
Display
*
Title (Description)
Analysis 
set(s)**
Key 
deliverable
Mock 
layout
TREXP
T
Study treatment exposure
SS

T17
NCT02310672


Macitentan / ACT-064992
Study AC-055-403
20-March-2018, page 52/60
Confidential 
Statistical Analysis Plan
Doc No D-16.633
TPL-000241 v02
Output name
Display
*
Title (Description)
Analysis 
set(s)**
Key 
deliverable
Mock 
layout
TREXP_OLE
T
Study treatment exposure including the Open 
Label Extension (OLE)
SS
T17
TREXP
L
Listing of exposure 
SCR

L16
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set, 
PPS=Per-protocol analysis set, SS=Safety analysis set, mFAS: Modified full analysis set; OLE=Open Label Extension
13.4.2 Compliance with study treatment
Output 
name
Display
*
Title (Description)
Analysis 
set(s)**
Key 
deliverable
Mock 
layout
COMPA
T
Compliance (based on drug accountability)
SS
T18
COMPA
L
Listing 
of 
compliance 
(based 
on 
drug 
accountability)
SCR
L17
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set, 
PPS=Per-protocol analysis set, SS=Safety analysis set, mFAS: Modified full analysis set 
13.4.3 Study treatment interruption
Output 
name
Display*
Title (Description)
Analysis 
set(s)**
Key 
deliverable
Mock 
layout
TREINT
T
Reasons for study treatment interruptions
SS

T19
TREINT
L
Listing of study treatment interruptions
SCR
L18
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set, 
PPS=Per-protocol analysis set, SS=Safety analysis set, mFAS: Modified full analysis set 
13.4.4 Study treatment discontinuation
Output 
name
Display*
Title (Description)
Analysis 
set(s)**
Key 
deliverable
Mock 
layout
PDISCTR
T
Reasons for premature discontinuation 
of study treatment
SS

T4
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set, PPS=Per-protocol analysis 
set, SS=Safety analysis set, mFAS: Modified full analysis set 
13.5 Study discontinuation
Output 
name
Display*
Title (Description)
Analysis 
set(s)**
Key 
deliverable
Mock 
layout
PDISCST
T
Reasons for premature study discontinuation
SS

T5
PDISC
L
Listing of discontinued subjects
SCR

L3
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set, PPS=Per-protocol analysis 
set, SS=Safety analysis set, mFAS: Modified full analysis set 
NCT02310672


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Study AC-055-403
20-March-2018, page 53/60
Confidential 
Statistical Analysis Plan
Doc No D-16.633
TPL-000241 v02
13.6 Primary efficacy analyses
13.6.1 Main analysis
Output 
name
Disp
lay*
Title (Description)
Analysis set(s)**
Key 
deliverable
Mock 
layout
PVR
T
Change from baseline to Week 26 in PVR
mFAS, PVRmFAS 
(if applicable)

T20
PVRSP
F
Scatterplot of PVR at Week 26 versus 
baseline
mFAS

F2
PVRCI
F
Confidence interval of PVR at Week 26
expressed as percent of PVR at baseline 
mFAS
F4
RVSV
T
Change from baseline to Week 26/52 in 
RVSV
assessed
by cardiac MRI
from 
pulmonary artery flow
mFAS,
RVSVmFAS 
(if applicable)

T21
RVSVSP
F
Scatterplot of RVSV assessed by cardiac 
MRI from pulmonary artery flow at Week 
26/52 versus baseline
mFAS

F2
RVSVCI
F
Confidence interval of RVSV assessed by 
cardiac MRI from pulmonary artery flow at 
Week 26/ 52
mFAS
F4
MRI
L
Listing of cardiac MRI variables values
SCR

L10
MRIC
L
Listing of cardiac MRI ventricular volumes, 
comparing RVSV and LVSV
SCR

L12
RHC
L
Listing of Right Heart Catheterization (RHC) 
variables values
SCR

L10
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set, 
PPS=Per-protocol analysis et, SS=Safety analysis set, mFAS: Modified full analysis set;
PVRmFAS: PVR Modified full analysis set; RVSVmFAS: RVSV Modified full analysis set
The primary analysis is to Week 26 for mFAS.  Analyses with PVRmFAS and RVSVmFAS are sensitivity analyses.
Analyses to Week 52 are exploratory.  A footnote will be added for the Week 52 analyses.
13.6.2 Supportive/sensitivity analyses
Output
name
Disp
lay*
Title (Description)
Analysis 
set(s)**
Key 
delive
rable
Mock 
layout
PVRO
T
Change from baseline to Week 26 in PVR by RHC
(Observed data)
PPS
T20
RVSVO
T
Change from baseline to Week 26 and Week 52 in RVSV
assessed by cardiac MRI from pulmonary artery flow
(Observed data)
PPS
T21
PVR
T
Change from baseline to Week 26 in PVR by RHC (with 
LOCF imputation)
Programming note: please show the bracket (with LOCF 
imputation) only for SS
FAS, SS
T20
RVSV
T
Change from baseline to Week 26 and Week 52 in RVSV 
assessed by cardiac MRI from pulmonary artery flow (with 
LOCF imputation)
Programming note: please show the bracket (with LOCF 
imputation) only for SS
FAS, SS
T21
NCT02310672


Macitentan / ACT-064992
Study AC-055-403
20-March-2018, page 54/60
Confidential 
Statistical Analysis Plan
Doc No D-16.633
TPL-000241 v02
Output
name
Disp
lay*
Title (Description)
Analysis 
set(s)**
Key 
delive
rable
Mock 
layout
PRIM1
F
Scatterplot of PVR absolute change from baseline to Week 
26 versus RVSV assessed by Cardiac MRI from pulmonary 
artery flow absolute change from baseline to Week 26
Note to programmer: figure is based on observed data
mFAS
F3
PRIM2
F
Scatterplot of PVR Ratio of Week 26 to baseline versus 
RVSV assessed by Cardiac MRI from pulmonary artery flow
Ratio of Week 26 to baseline
Note to programmer: figure is based on observed data
mFAS
F3
PRIM3
F
Scatterplot of PVR absolute change from baseline to Week 
26 versus six-minute walk-distance (6MWD)
absolute 
change from baseline to Week 26
Note to programmer: figure is based on observed data
mFAS
F3
PRIM4
F
Scatterplot of RVSV assessed by Cardiac MRI from 
pulmonary artery flow absolute change from baseline to 
Week 26 versus six-minute walk-distance  (6MWD) absolute 
change from baseline to Week 26
Note to programmer: figure is based on observed data
mFAS
F3
EXPL1
T
Analysis of change from baseline to week 26 in RVSV
assessed by cardiac MRI from pulmonary artery flow using 
PAH etiology, baseline 6MWD, baseline WHO FC, sex and 
age group (< 65, >= 65) as prognostic factors 
mFAS

T45
EXPL2
T
Analysis of change from baseline to week 26 in log(PVR)  
PAH etiology, baseline 6MWD, baseline WHO FC, sex and 
age group (< 65, >= 65) as prognostic factors
mFAS

T45
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set, 
PPS=Per-protocol analysis set, SS=Safety analysis set, mFAS: Modified full analysis set 
13.6.3 Subgroup analyses
Output
name
Display*
Title (Description)
Analysis 
set(s)**
Key 
deliverable
Mock 
layout
PVRS
T
Change from baseline to Week 26 in PVR by 
subgroup
mFAS

T20b
PVRS
F
Forest plot of  PVR Ratio of Week 26 versus 
baseline by subgroup and overall
mFAS
F6
RVSVS
T
Change from baseline to Week 26 and Week 52
in RVSV assessed by cardiac MRI from 
pulmonary artery flow by subgroup
mFAS

T21b
RVSVS
F
Forest plot of change from baseline to Week 26
and Week 52 in RVSV assessed by cardiac MRI 
from pulmonary artery flow by subgroup and 
overall
mFAS
F6
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set, 
PPS=Per-protocol analysis set, SS=Safety analysis set, mFAS: Modified full analysis set;
PVR=pulmonary vascular resistance; RVSV=right ventricular stroke volume
NCT02310672


Macitentan / ACT-064992
Study AC-055-403
20-March-2018, page 55/60
Confidential 
Statistical Analysis Plan
Doc No D-16.633
TPL-000241 v02
13.7 Secondary/exploratory efficacy analyses
13.7.1 Main analyses
Output 
name
Disp
lay*
Title (Description)
Analysis 
set(s)**
Key 
deliverable
Mock 
layout
MRI1
T
Change from baseline to Week 26 and Week 52 in the 
Right Ventricle (RV) assessments by cardiac MRI
SS, mFAS
T21
6MWD
T
Change from baseline to Week 26 and Week 52 in
six-minute walk-distance (6MWD)
SS, mFAS
(only on 
SS)
T21
BORG
T
Change from baseline to Week 26 and Week 52 in
Borg index
SS, mFAS
T21
WHO
T
Shift table of change in WHO functional class from 
baseline to Week 26 and 52
SS, mFAS
(only on 
SS)
T27
WHOLR
T
WHO functional class: Number (%) of subjects who 
worsened at Week 26 and Week 52
SS, mFAS
(only on 
SS)
T27b
BNP
T
Change from baseline to Week 26 and Week 52 in NT 
pro-BNP
SS, mFAS
T20d
EFF
L
Listing of six-minute walk-distance (6MWD), WHO 
functional class and Borg index
SCR
(only on 
SS)
L10
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set, 
PPS=Per-protocol analysis set, SS=Safety analysis set, mFAS: Modified full analysis set 
13.8 Other efficacy analyses
Output 
name
Disp
lay*
Title (Description)
Analysis
set(s)**
Key 
deliverable
Mock 
layout
MRI2
T
Change from baseline to Week 26 and Week 52 in
the Left Ventricle (LV) assessments by cardiac MRI
SS, mFAS
T21
MRI3
T
Change from baseline to Week 26 and Week 52 in
ratio RVEDV/LVEDV and ratio RVESV/LVESV
assessed by cardiac MRI
SS, mFAS
T20c
RHC
T
Change from baseline to Week 26 in mPAP, mRAP 
and Cardiac Index (CI) assessed by Right Heart 
Catheterization (RHC)
SS, mFAS
T21
DISMON
T
Change from baseline to Week 26 and Week 52 in 
potential variables for disease monitoring
SS, mFAS
T20c
CLINW
T
Time to first clinical worsening event
SS, mFAS
T28
CLINW
F
Kaplan-Meier plot of time to first clinical worsening 
event
SS, mFAS
F5
PRESS
L
Listing of pressure-volume
variables: Arterial 
elastance, RV end-systolic elastance and
RV 
maximum isovolumic pressure values assessed by 
Cardiac 
MRI 
combined 
with 
Right 
Heart 
Catheterization (RHC)
SCR
L10
DISMON
L
Listing of potential laboratory variables for disease 
monitoring values
SCR
L10
CLINW
L
Listing of clinical worsening events
SCR
L11
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set, 
PPS=Per-protocol analysis set, SS=Safety analysis set, mFAS: Modified full analysis set 
NCT02310672


Macitentan / ACT-064992
Study AC-055-403
20-March-2018, page 56/60
Confidential 
Statistical Analysis Plan
Doc No D-16.633
TPL-000241 v02
13.9 Sub-studies
Output 
name
Disp
lay*
Title (Description)
Analysis set(s)**
Key 
deliverable
Mock 
layout
ECHO
T
Change from baseline to 
Week 26 and Week 52 in
echo variables 
SS, mFAS
(restricted to subjects 
participating in the echo sub-study)
T21
ECHO
L
Listing of echo variables 
values
SCR (restricted to subjects participating 
in the echo sub-study)
L10
MTB
L
Listing 
of 
metabolism 
variables values
SCR (restricted to subjects participating 
in the metabolism sub-study)
L10
13.10 Safety analyses
13.10.1 Adverse events
Output 
name
Display
*
Title (Description)
Analysis 
set(s)**
Key 
delive
rable
Mock 
layout
AEOV
T
Overview of treatment-emergent adverse events (AE)
SS

T33 
AEOV_O
LE
T
Overview of treatment-emergent adverse events (AE),
including  the Open Label Extension (OLE)
SS
T33 
AESCPR
T
Treatment-emergent adverse events (AE) by system 
organ class (SOC) and preferred term
SS
T34 
AESCPR_
OLE
T
Treatment-emergent adverse events (AE) by system 
organ class (SOC) and preferred term, including the 
Open Label Extension (OLE)
SS
T34 
AEPR
T
Treatment-emergent adverse events (AE) by preferred 
term
SS
T35 
AEPRIN
T
Treatment-emergent adverse events (AE) by maximum 
intensity and preferred term
SS
T36 
AERESC
PR
T
Treatment-emergent adverse events (AE) related to 
study treatment by system organ class (SOC) and 
preferred term
SS
T34 
AE
L
Listing of adverse events (AE)
SCR

L23 
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set, 
PPS=Per-protocol analysis set, SS=Safety analysis set, mFAS: Modified full analysis set; OLE=Open Label Extension
13.10.2 Deaths
Output 
name
Display
*
Title (Description)
Analysis 
set(s)**
Key 
deliverable
Mock 
layout
AEFASCPR
T
Treatment-emergent adverse events (AE) with 
fatal outcome by system organ class (SOC) and 
preferred term
SS

T34 
AEFAPR
T
Treatment-emergent adverse events (AE) with 
fatal outcome by preferred term
SS
T35 
DEAPR
T
Cause of death
SS

T37 
DEATH
L
Listing of deaths
SCR

L24 
NCT02310672


Macitentan / ACT-064992
Study AC-055-403
20-March-2018, page 57/60
Confidential 
Statistical Analysis Plan
Doc No D-16.633
TPL-000241 v02
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set,
PPS=Per-protocol analysis set, SS=Safety analysis set, mFAS: Modified full analysis set 
13.10.3 Serious adverse events
Output name
Display
*
Title (Description)
Analysis 
set(s)**
Key 
deliverable
Mock 
layout
SAESCPR
T
Treatment-emergent serious adverse events 
(SAE) by system organ class (SOC) and 
preferred term
SS

T34 
SAESCPR_O
LE
T
Treatment-emergent serious adverse events 
(SAE) by system organ class (SOC) and 
preferred term, including the Open Label 
Extension (OLE)
SS
T34 
SAEPR
T
Treatment-emergent serious adverse events 
(SAE) by preferred term
SS
T35 
SAERESCPR
T
Treatment-emergent serious adverse events 
(SAE) related to study treatment by system 
organ class (SOC) and preferred term
SS
T34
SAE
L
Listing of serious adverse events (SAE)
SCR

L23 
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set, 
PPS=Per-protocol analysis set, SS=Safety analysis set, mFAS: Modified full analysis set; OLE=Open Label Extension
13.10.4 Adverse events leading to study treatment discontinuation
Output name
Display
*
Title (Description)
Analysis 
set(s)**
Key 
deliverable
Mock 
layout
AEPDSCPR
T
Adverse events (AE) leading to premature 
discontinuation of study treatment by system 
organ class (SOC) and preferred term
SS

T34 
AEPDSCPR_
OLE
T
Adverse events (AE) leading to premature 
discontinuation of study treatment by system 
organ class (SOC) and preferred term, 
including the Open Label Extension (OLE)
SS

T34 
AEPDPR
T
Adverse events (AE) leading to premature 
discontinuation 
of 
study 
treatment 
by 
preferred term
SS
T35 
AEPD
L
Listing of adverse events (AE) leading to 
premature discontinuation of study treatment
SCR

L23 
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set, 
PPS=Per-protocol analysis set, SS=Safety analysis set, mFAS: Modified full analysis set; OLE=Open Label Extension
13.10.5 Other significant adverse events
Output 
name
Disp
lay*
Title (Description)
Analysis 
set(s)**
Key 
delive
rable
Mock 
layout
NSAEFSCP
RE
T
Occurrence of non-serious frequent (>=5%) treatment-
emergent adverse events (AE) 
SS
T38 
NSAEFSCP
RE_OLE
T
Occurrence of non-serious frequent (>=5%) treatment-
emergent adverse events (AE), including the Open 
Label Extension (OLE)
SS
T38 
NCT02310672


Macitentan / ACT-064992
Study AC-055-403
20-March-2018, page 58/60
Confidential 
Statistical Analysis Plan
Doc No D-16.633
TPL-000241 v02
Output 
name
Disp
lay*
Title (Description)
Analysis 
set(s)**
Key 
delive
rable
Mock 
layout
AESISCPR
T
Treatment-emergent adverse events of special interest
(AESI) by system organ class (SOC) and preferred term
SS
T34 
AESISCPR
_OLE
T
Treatment-emergent adverse events of special interest
(AESI) by system organ class (SOC) and preferred 
term, including the Open Label Extension (OLE)
SS
T34 
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set, 
PPS=Per-protocol analysis set, SS=Safety analysis set, mFAS: Modified full analysis set; OLE=Open Label Extension
13.11 Laboratory tests
Output name
Disp
lay*
Title (Description)
Analysis 
set(s)**
Key 
delive
rable
Mock 
layout
LABCGTPHEM
T
Hematology: Change in laboratory tests from 
baseline to each time point
SS
T40 
LABCGTPBCH
T
Chemistry: Change in laboratory tests from 
baseline to each time point
SS
T40 
LABMLAHEM
T
Hematology: Marked laboratory abnormalities 
SS

T41 
LABMLAHEM_OLE
T
Hematology: Marked laboratory abnormalities
including the Open Label Extension OLE)
SS

T41 
LABMLABCH
T
Chemistry: Marked laboratory abnormalities 
SS

T41 
LABMLABCH_OLE
T
Chemistry: Marked laboratory abnormalities 
including the Open Label Extension OLE)
SS

T41 
LABMLA
L
Listing of definitions of marked laboratory 
abnormality
NA
L24a
LABLHLA
T
Liver and hemoglobin laboratory abnormalities 
SS

T42 
LABLHLA_OLE
T
Liver and hemoglobin laboratory abnormalities, 
including the Open Label Extension (OLE)
SS
T42 
LABEDISH
F
eDISH plot showing maximum post-baseline 
ALT/AST against bilirubin
SS
F7
LABEDISH_OLE
F
eDISH plot showing maximum post-baseline 
ALT/AST against bilirubin, including the Open 
Label Extension (OLE)n
SS
F7
LABSHHEMLOW
T
Hematology: Shift in laboratory tests from 
baseline to the worst low value 
SS
T43 
LABSHHEMHIGH
T
Hematology: Shift in laboratory tests from 
baseline to the worst high value 
SS
T43 
LABSHBCHLOW
T
Chemistry: Shift in laboratory tests from 
baseline to the worst low value 
SS
T43 
LABSHBCHHIGH
T
Chemistry: Shift in laboratory tests from 
baseline to the worst high value 
SS
T43 
LABSI
L
Listing of individual laboratory measurements 
(SI units)
SCR
L25 
LABORIG
L
Listing of individual laboratory measurements 
(original units)
SCR
L25 
NCT02310672


Macitentan / ACT-064992
Study AC-055-403
20-March-2018, page 59/60
Confidential 
Statistical Analysis Plan
Doc No D-16.633
TPL-000241 v02
Output name
Disp
lay*
Title (Description)
Analysis 
set(s)**
Key 
delive
rable
Mock 
layout
LABLMA
L
Listing of individual laboratory measurements 
(subjects with at least one marked abnormality)
SCR
L25
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set, 
PPS=Per-protocol analysis set, SS=Safety analysis set, mFAS: Modified full analysis set; OLE=Open Label Extension
13.12 Physical examination, vital signs and body weight
Output 
name
Display*
Title (Description)
Analysis 
set(s)**
Key 
deliverable
Mock 
layout
VS
T
Change from baseline to each post-baseline 
assessment in vital signs, body weight and 
BMI
SS
T44 
VS
L
Listing of vital signs, body weight, BMI and 
height
SCR
L30 
PHYSF
L
Listing of physical findings
SCR
L34
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set,
PPS=Per-protocol analysis set, SS=Safety analysis set, mFAS: Modified full analysis set 
13.13 Pregnancy test
Output 
name
Display
*
Title (Description)
Analysis 
set(s)**
Key 
deliverable
Mock 
layout
CHILD
L
Listing of childbearing potential and contraception
SCR
L33a
PREGN
L
Listing of pregnancy test data
SCR
L33b
* T=Summary table, L= Listing, F=Figure, **SCR=Screened analysis set, FAS=Full analysis set,
PPS=Per-protocol analysis set, SS=Safety analysis set, mFAS: Modified full analysis set 
13.14 Other evaluations
13.14.1
Quality of life analyses
Not applicable
13.14.2
Pharmacoeconomic analyses
Not applicable
13.14.3
Benefit-risk evaluations
Not applicable
13.14.4
Pharmacodynamic analyses
Not applicable
13.14.5
Pharmacokinetic analyses
Not applicable
NCT02310672


Macitentan / ACT-064992
Study AC-055-403
20-March-2018, page 60/60
Confidential 
Statistical Analysis Plan
Doc No D-16.633
TPL-000241 v02
14 REFERENCES
[Not applicable]
15 APPENDICES
A. Document history
Summarize the main changes and rationale for changes from one approved version to the 
next.
Version
Effective Date
Reason
1.0
20.Oct.2015
New
1.1
28.Oct.2015
Update according to comments from Clinical Science
1.2
29.Feb.2016
Adding the Shell outputs
1.0
31.May.2016
Final Version
Amendment 
1 version 1.0
20.March.2018
Major updates following protocol amendment and 
change in vendor for statistics/programming.
NCT02310672


 
 
 
 
 
 
 
 
Document ID: 
 
Note: Signature page is not included in the page count of this document 
 
ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(yyyy-MM-dd HH:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AC-055-403_CSR_SAP_Amendment1 2018-03-20
Macitentan_PRCL_AC-055-403_18.004728
Emmanuelle Cottreel
Clinical Approval
2018-03-21 11:12 GMT+010
Graham Wetherill
Clinical Approval
2018-03-21 11:12 GMT+010
Maziar Assadi Gehr
Clinical Approval
2018-03-21 11:14 GMT+010
Lada Mitchell
Clinical Approval
2018-03-21 11:40 GMT+010
Loic Perchenet
Clinical Approval
2018-03-21 15:01 GMT+010
Marianne Soergel
Clinical Approval
2018-03-26 09:22 GMT+020
Nicolas Martin
Clinical Approval
2018-03-26 10:27 GMT+020
Dmitri Petratchenko
Clinical Approval
2018-03-28 08:24 GMT+020
NCT02310672