Clinical trial NCT02554903
Conditions: Pulmonary Hypertension
Keywords: LVAD
Sponsor: Actelion
Start date: 2016-03-28; Completion date: 2020-03-13
Enrollment: 57 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
STUDY OBJECTIVES Primary objective To evaluate the effect of macitentan 10 mg on pulmonary vascular resistance (PVR) as compared to placebo in subjects with pulmonary hypertension (PH) after left ventricular assist device (LVAD) implantation.

Secondary objectives To evaluate the effect of macitentan 10 mg as compared to placebo on cardio-pulmonary hemodynamics and disease severity in subjects with PH after LVAD implantation.

To evaluate the safety and tolerability of macitentan 10 mg in subjects with PH after LVAD implantation.

Exploratory objectives To explore the potential effect of macitentan 10 mg as compared to placebo on right ventricular function in subjects with PH after LVAD implantation.

To explore the potential effect of macitentan 10 mg as compared to placebo on selected clinical events in subjects with PH after LVAD implantation.

To explore the potential effect of macitentan 10 mg as compared to placebo on renal function as measured by glomerular filtration rate (GFR) in subjects with PH after LVAD implantation.

Detailed description:

Arms: arm 1: Approximately 78 adult subjects with PH post-LVAD implantation will be randomized (1:1) to receive either macitentan 10 mg, or matching placebo, once daily orally. arm 2: Approximately 78 adult subjects with PH post-LVAD implantation will be randomized (1:1) to receive either macitentan 10 mg, or matching placebo, once daily orally.
Interventions: intervention 1: Macitentan 10mg intervention 2: Placebo sugar pill
Intervention descriptions: intervention 1: 2 groups, randomized in a 1:1 ratio by an Interactive Voice/Web Randomization System to macitentan 10 mg or placebo intervention 2: 2 groups, randomized in a 1:1 ratio by an Interactive Voice/Web Randomization System to macitentan 10 mg or placebo

Protocol documents:
Prot_000.pdf: 
 
 
TPL-000052_v11 
Macitentan / ACT-064992 
 
Pulmonary hypertension post-left ventricular assist device 
implantation 
Protocol AC-055-205 
SOPRANO: Macitentan in pulmonary hypertenSiOn Post-left ventRiculAr assist device 
implaNtatiOn 
A prospective, multicenter, double-blind, randomized, placebo-controlled, 
parallel-group study to assess the efficacy and safety of macitentan in patients  
with pulmonary hypertension after left ventricular assist device implantation 
 
Study Phase: 
2 
Status and version: 
Version 3 
Date: 
10 March 2017 
Document type 
Amended global protocol 
Actelion document number 
(Doc No.): 
D-17.154 
 
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. 
 
 
 
NCT02554903


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SPONSOR CONTACT DETAILS 
SPONSOR 
 
Actelion Pharmaceuticals US, Inc. 
5000 Shoreline Court 
South San Francisco, CA 94080 
USA 
Clinical Trial Physician  
Mona Selej, M.D., M.S. / Associate Director, Medical 
Affairs 
 
 
 
Fax 
 
 
e-mail 
 
 
MEDICAL HOTLINE 
 
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 
Mona Selej, M.D., M.S. / Associate Director, Medical 
Affairs  
 
 
Fax 
  
Clinical Trial Statistician 
Carol Zhao, M.S. / Associate Director, Biostatistics 
 
 
 
Fax 
 
e-mail 
.
 
Clinical Project Manager 
, B.S.N, R.N. / Associate Director, 
Clinical Operations 
 
 
 
Fax 
+
 
e-mail  
 
Lead Medical Science 
Liaison 
, Ph.D. / Senior MSL 
 
 
 
Fax 
 
 
e-mail  
 
Drug Safety Physician 
/ Senior Drug Safety Physician 
 
 
 
Fax 
 
 
e-mail  
 
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CONTRACT VENDOR INFORMATION 
 
CENTRAL ECHO 
LABORATORY  
Cardiocore Lab, LLC d/b/a BioTelemetry 
Research 
One Preserve Parkway, Suite 600 
Rockville, MD 20852, U.S.A 
 
CENTRAL INDEPENDENT 
REVIEW BOARD 
Quorum Review IRB 
1501 Fourth Avenue, Suite 800 
Seattle, WA 98101 
 
CENTRAL LABORATORY 
LabConnect, LLC 
605 1st Avenue, Suite 300 
Seattle, WA 98104, U.S.A  
 
CONTRACT RESEARCH 
ORGANIZATION 
Pharmaceutical Research Associates, Inc. 
4130 Parklake Avenue, Suite 400 
Raleigh, NC 27612, U.S.A 
 
DRUG DEPOT 
Almac Group Ltd. 
Almac House, 20 Seagoe Industrial Estate 
Craigavon, BT63 5QD, U.K. 
 
ELECTRONIC DATA CAPTURE/ 
DATA MANAGEMENT 
Pharmaceutical Research Associates, Inc. 
4130 Parklake Avenue, Suite 400 
Raleigh, NC 27612, U.S.A 
 
RANDOMIZATION 
PAREXEL International. PAREXEL 
Informatics, 4 Canal Street, Castle Wharf, 
Nottingham. NG1 7EH. UK. 
 
 


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SIGNATURE PAGE FOR ACTELION PHARMACEUTICALS LTD 
Hereinafter called Actelion 
 
Treatment name / number 
Macitentan / ACT-064992 
Indication 
Pulmonary hypertension post-left ventricular assist device implantation 
Protocol number, study acronym, study title 
AC-055-205, SOPRANO: A prospective, multicenter, double-blind, randomized, 
placebo-controlled, parallel-group study to assess the efficacy and safety of macitentan in 
patients with pulmonary hypertension after left ventricular assist device implantation 
 
I approve the design of this study. 
 
 
 
 
PPD


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INVESTIGATOR SIGNATURE PAGE 
Treatment name / number 
Macitentan / ACT-064992 
Indication 
Pulmonary hypertension post-left ventricular assist device implantation 
Protocol number, study acronym, study title 
AC-055-205, SOPRANO: A prospective, multicenter, double-blind, randomized, 
placebo-controlled, parallel-group study to assess the efficacy and safety of macitentan in 
patients with pulmonary hypertension after left ventricular assist device implantation. 
I agree to the terms and conditions relating to this study as defined in this protocol, the 
electronic Case Report Form (eCRF), and any other protocol-related documents. I fully 
understand that any changes instituted by the investigator(s) without previous agreement 
with the sponsor would constitute a protocol deviation, including any ancillary studies or 
procedures performed on study subjects (other than those procedures necessary for the 
wellbeing of the subjects). 
I agree to conduct this study in accordance with the Declaration of Helsinki principles, 
International 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 subjects included in this study. If an amendment to the 
protocol is necessary, I will obtain approval by an IRB/IEC and ensure approval by 
regulatory authorities (if applicable) have been obtained before the implementation of 
changes described in the amendment. I will allow direct access to source documents and 
study facilities to sponsor representative(s), particularly monitor(s) and auditor(s), and 
agree to inspection by regulatory authorities or IRB/IEC representative. I will ensure that 
the study treatment(s) supplied by the sponsor are being used only as described in this 
protocol. I confirm herewith that the sponsor is allowed to enter and utilize my 
professional contact details and function in an electronic database for internal purposes 
and for submission to Health Authorities worldwide. 
 
Country 
Site 
number 
Town 
Date 
 
Signature 
Principal 
Investigator 
 
 
 
 
 
 


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TABLE OF CONTENTS 
SPONSOR CONTACT DETAILS ......................................................................................2 
ACTELION CONTRIBUTORS TO THE PROTOCOL .....................................................2 
CONTRACT VENDOR INFORMATION .........................................................................3 
SUBSTANTIAL GLOBAL AMENDMENT 2 .................................................................16 
PROTOCOL SYNOPSIS AC-055-205 .............................................................................19 
PROTOCOL ......................................................................................................................30 
1 
BACKGROUND .........................................................................................................30 
1.1 
Indication ......................................................................................................30 
1.2 
Epidemiology ................................................................................................30 
1.3 
Current management .....................................................................................31 
1.4 
Endothelin-1 and pulmonary hypertension ...................................................32 
1.5 
Macitentan ....................................................................................................33 
1.5.1 
Nonclinical results ............................................................................33 
1.5.2 
Phase 1 results ...................................................................................33 
1.5.3 
Phase 2 results ...................................................................................33 
1.5.4 
Phase 3 efficacy results in PAH ........................................................34 
1.5.5 
Summary of potential risks and risk management ............................34 
1.6 
Purpose and rationale of the study ................................................................37 
2 
STUDY OBJECTIVES ...............................................................................................37 
2.1 
Primary objective(s) .....................................................................................37 
2.2 
Secondary objectives ....................................................................................37 
2.3 
Exploratory objectives ..................................................................................38 
3 
OVERALL STUDY DESIGN AND PLAN ...............................................................38 
3.1 
Study design .................................................................................................38 
3.2 
Study design rationale ..................................................................................40 
3.3 
Study committees .........................................................................................41 
4 
SUBJECT POPULATION ..........................................................................................42 


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4.1 
Subject population description .....................................................................42 
4.2 
Rationale for the selection of the study population ......................................42 
4.3 
Inclusion criteria ...........................................................................................42 
4.4 
Exclusion criteria ..........................................................................................43 
4.5 
Criteria for women of childbearing potential ...............................................44 
4.5.1 
Definition of childbearing potential ..................................................44 
4.5.2 
Acceptable methods of contraception ...............................................45 
4.6 
Medical history .............................................................................................46 
5 
TREATMENTS ..........................................................................................................46 
5.1 
Study treatment .............................................................................................46 
5.1.1 
Investigational treatment: description and rationale .........................46 
5.1.2 
Comparator(s) and/or matching placebo: description and 
rationale ............................................................................................46 
5.1.3 
Study treatment administration .........................................................46 
5.1.4 
Treatment assignment .......................................................................47 
5.1.5 
Blinding ............................................................................................47 
5.1.6 
Unblinding ........................................................................................47 
5.1.6.1 
Unblinding for final analyses .................................................. 47 
5.1.6.2 
Unblinding ............................................................................... 47 
5.1.6.3 
Unblinding for SUSARs .......................................................... 48 
5.1.6.4 
Emergency procedure for unblinding ...................................... 48 
5.1.7 
Study treatment supply .....................................................................48 
5.1.7.1 
Study treatment packaging and labeling ................................. 48 
5.1.7.2 
Study treatment distribution and storage ................................. 49 
5.1.7.3 
Study treatment dispensing ..................................................... 50 
5.1.7.4 
Study treatment return and destruction ................................... 50 
5.1.8 
Study treatment accountability and compliance with study 
treatment ...........................................................................................51 
5.1.8.1 
Study treatment accountability ................................................ 51 
5.1.8.2 
Study treatment compliance .................................................... 51 
5.1.9 
Study treatment dose adjustments and interruptions ........................51 
5.1.10 
Premature discontinuation of study treatment ..................................52 
5.1.11 
Study-specific criteria for interruption / premature 
discontinuation of study treatment ....................................................53 
5.2 
Previous and concomitant therapy ................................................................56 
5.2.1 
Definitions ........................................................................................56 
5.2.2 
Reporting of previous/concomitant therapy in the eCRF .................56 
5.2.3 
Allowed concomitant therapy ...........................................................56 
5.2.4 
Prohibited concomitant therapy ........................................................56 


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5.3 
Allowed LVAD flow rate .............................................................................57 
6 
STUDY ENDPOINTS ................................................................................................57 
6.1 
Efficacy endpoints ........................................................................................57 
6.1.1 
Primary efficacy endpoint(s) ............................................................57 
6.1.2 
Secondary efficacy endpoints ...........................................................57 
6.1.3 
Exploratory efficacy endpoints .........................................................57 
6.2 
Safety endpoints ...........................................................................................58 
6.3 
Biomarker endpoints .....................................................................................58 
7 
STUDY ASSESSMENTS ...........................................................................................58 
7.1 
Screening/Baseline assessments ...................................................................59 
7.2 
Efficacy assessments ....................................................................................60 
7.2.1 
Hemodynamic measurements - right heart catheterization ...............60 
7.2.2 
WHO functional class .......................................................................61 
7.2.3 
Serum NT-proBNP ...........................................................................61 
7.2.4 
Echocardiography .............................................................................61 
7.2.5 
Clinical events ...................................................................................62 
7.2.6 
Duration of heart failure hospitalization ...........................................62 
7.2.7 
Glomerular filtration rate ..................................................................62 
7.3 
Safety assessments ........................................................................................62 
7.3.1 
Vital signs .........................................................................................62 
7.3.2 
Weight and height .............................................................................63 
7.3.3 
Physical examination ........................................................................63 
7.3.4 
Laboratory assessments ....................................................................63 
7.3.4.1 
Type of laboratory ................................................................... 63 
7.3.4.2 
Laboratory tests ....................................................................... 65 
7.4 
Biomarker and genetic assessments .............................................................66 
8 
SCHEDULE OF VISITS ............................................................................................66 
8.1 
Screening period ...........................................................................................66 
8.1.1 
Screening (Visit 1) ............................................................................66 
8.2 
Double-blind study treatment period ............................................................67 
8.2.1 
Randomization (Visit 2) ....................................................................67 
8.2.2 
Week 4 (Visit 3) ................................................................................68 
8.2.3 
Week 8 (Visit 4) ................................................................................69 
8.2.4 
End-of-Treatment (Visit 5) ...............................................................69 
8.2.5 
End-of-Study (Visit 6) ......................................................................70 
8.2.6 
Unscheduled Visits (U1, U2, etc) .....................................................70 


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9 
STUDY COMPLETION AND POST-STUDY TREATMENT/MEDICAL 
CARE ..........................................................................................................................70 
9.1 
Study completion ..........................................................................................70 
9.2 
Premature withdrawal from study ................................................................71 
9.3 
Premature termination or suspension of the study ........................................71 
9.4 
Medical care of subjects after study completion/withdrawal from 
study ..............................................................................................................72 
10 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ...........................72 
10.1 
Adverse events ..............................................................................................72 
10.1.1 
Definitions of adverse events ............................................................72 
10.1.2 
Intensity of adverse events ................................................................73 
10.1.3 
Relationship to study treatment ........................................................74 
10.1.4 
Adverse events associated to study design or 
protocol-mandated procedures ..........................................................74 
10.1.5 
Reporting of adverse events ..............................................................74 
10.1.6 
Follow-up of adverse events .............................................................74 
10.2 
Serious adverse events ..................................................................................75 
10.2.1 
Definitions of serious adverse events ...............................................75 
10.2.1.1 
Serious adverse events ............................................................. 75 
10.2.2 
Reporting of serious adverse events .................................................75 
10.2.3 
Follow-up of serious adverse events .................................................76 
10.2.4 
After the 30-day follow-up period ....................................................76 
10.2.5 
Reporting procedures ........................................................................76 
10.3 
Pregnancy .....................................................................................................77 
10.3.1 
Reporting of pregnancy ....................................................................77 
10.3.2 
Follow-up of pregnancy ....................................................................77 
10.4 
Study safety monitoring ................................................................................77 
11 STATISTICAL METHODS .......................................................................................77 
11.1 
Analysis sets .................................................................................................78 
11.1.1 
Screened Analysis Set .......................................................................78 
11.1.2 
Safety Set ..........................................................................................78 
11.1.3 
Full Analysis Set ...............................................................................78 
11.1.4 
Modified Full Analysis Set ...............................................................78 
11.1.5 
Per-Protocol Set ................................................................................78 
11.1.6 
Usage of the analysis sets .................................................................78 
11.2 
Variables .......................................................................................................79 
11.2.1 
Primary efficacy variable(s) ..............................................................79 


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11.2.2 
Secondary efficacy variables ............................................................79 
11.2.3 
Exploratory efficacy variables ..........................................................79 
11.2.4 
Safety variables .................................................................................80 
11.3 
Description of statistical analyses .................................................................80 
11.3.1 
Overall testing strategy .....................................................................80 
11.3.2 
Analysis of the primary efficacy variable(s) .....................................80 
11.3.2.1 
Hypotheses and statistical model ............................................ 80 
11.3.2.2 
Handling of missing data ......................................................... 81 
11.3.2.3 
Main analysis ........................................................................... 81 
11.3.2.4 
Supportive/sensitivity analyses ............................................... 82 
11.3.2.5 
Subgroup analyses ................................................................... 82 
11.3.3 
Analysis of the secondary efficacy variable(s) .................................82 
11.3.4 
Analysis of the exploratory efficacy variable(s) ...............................82 
11.3.5 
Analysis of the safety variable(s) ......................................................83 
11.3.5.1 
Adverse events ........................................................................ 83 
11.3.5.2 
Laboratory variables ................................................................ 84 
11.3.5.3 
Vital signs and body weight .................................................... 84 
11.4 
Interim analyses ............................................................................................85 
11.5 
Sample size ...................................................................................................85 
11.5.1 
Sample size justification ...................................................................85 
11.5.2 
Sample size sensitivity ......................................................................85 
12 DATA HANDLING ....................................................................................................86 
12.1 
Data collection ..............................................................................................86 
12.2 
Maintenance of data confidentiality .............................................................86 
12.3 
Database management and quality control ...................................................87 
13 PROCEDURES AND GOOD CLINICAL PRACTICE .............................................88 
13.1 
Ethics and Good Clinical Practice ................................................................88 
13.2 
Independent Ethics Committee / Institutional Review Board ......................88 
13.3 
Informed Consent .........................................................................................88 
13.4 
Compensation to subjects and investigators .................................................89 
13.5 
Protocol adherence/compliance ....................................................................89 
13.6 
Protocol amendments ...................................................................................90 
13.7 
Essential documents and retention of documents .........................................90 
13.8 
Monitoring ....................................................................................................91 
13.9 
Investigator site file ......................................................................................92 
13.10 
Audit .............................................................................................................92 
13.11 
Inspections ....................................................................................................92 
13.12 
Reporting of study results and publication ...................................................93 


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14 REFERENCES ............................................................................................................95 
15 APPENDICES .............................................................................................................99 
 
LIST OF TABLES 
 
Table 1 
Visit and assessment schedule ..................................................................... 28 
Table 2 
Treatment effects (differences on log-scale as well as % reduction 
versus placebo), variability in integrated analysis of four studies 
(AC-052-366, AC-052-364, AC-055-302 and AC-055E201), and 
associated sample size for 80% power. ........................................................ 86 
 
LIST OF FIGURES 
 
Figure 1 
Study design ................................................................................................. 40 
 
 
LIST OF APPENDICES 
 
Appendix 1 WHO functional classification of pulmonary hypertension ......................... 99 
Appendix 2 Glossary ...................................................................................................... 100 
 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
2D  
Two-dimensional  
3D  
Three-dimensional  
6MWD  
6-minute walk distance  
A’  
Tricuspid peak diastolic annular velocity a’ 
AE  
Adverse event 
ALT  
Alanine aminotransferase 
ANCOVA  
Analysis of covariance  
AST  
Aspartate aminotransferase 
BMI  
Body mass index 
BP  
Blood pressure 
BSA  
Body surface area 
BUN  
Blood urea nitrogen 
CI  
Cardiac index  
CL  
Confidence limit 
CO  
Cardiac output  
CRA  
Clinical research associate 
CRO  
Contract Research Organization 
CV  
Curriculum vitae  
CVs  
Coefficients of variation 
CYP3A4  
Cytochrome P450 isozyme 3A4 
DBP  
Diastolic blood pressure  
DoA  
Delegation of Authority 
DT  
Destination therapy  
E’  
Tricuspid peak diastolic annular velocity e’ 
ECG  
Electrocardiogram 
eCRF  
Electronic case report form  
EOS  
End-of-Study  
EOT  
End-of-Treatment  
ERA  
Endothelin receptor antagonist  
ET-1  
Endothelin-1 


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ETA  
Endothelin receptor A 
ETB  
Endothelin receptor B 
FAS  
Full Analysis Set 
FC  
Functional class  
FDA  
Food and Drug Administration 
FEV1  
Forced expiratory volume in 1 second 
FVC  
Forced vital capacity 
GCP  
Good Clinical Practice 
GDF-15  
Growth differentiation factor-15 
GFR  
Glomerular filtration rate 
GMP  
Good Manufacturing Practice 
GMR  
Geometric mean ratio 
HF  
Heart failure  
hsCRP  
High sensitivity C-reactive protein  
hs-cTnT  
High sensitivity cardiac troponin T 
i.v.  
Intravenous 
IB  
Investigator’s brochure 
ICF  
Informed consent form 
ICH  
International Conference On Harmonisation 
IDMC  
Independent Data Monitoring Committee 
IEC  
Independent Ethics Committee 
IL-6  
Interleukin-6 
iNO  
Inhaled nitric oxide  
INTERMACS  
Interagency Registry for Mechanically Assisted Circulatory 
Support 
IPF  
Idiopathic pulmonary fibrosis 
IRB  
Institutional Review Board 
ISF  
Investigator site file 
IxRS  
Interactive Voice/Web Response System 
LDH  
Lactate dehydrogenase 
LFT  
Liver function test  


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LVAD  
Left ventricular assist device  
MedDRA  
Medical Dictionary For Regulatory Activities 
mPAP  
Mean pulmonary arterial pressure  
mRAP  
Mean right atrial pressure 
NGAL  
Neutrophil gelantinase-associated lipocalin 
NT-proBNP  
N-terminal prohormone of brain natriuretic peptide 
PAC  
Pulmonary artery catheter 
PAH   
Pulmonary arterial hypertension  
PAWP  
Pulmonary artery wedge pressure  
PDE5   
Phosphodiesterase-5  
PH  
Pulmonary hypertension  
PI  
Principal investigator 
PPS  
Per-Protocol Set 
PVR  
Pulmonary vascular resistance  
RHC  
Right heart catheterization 
RRT  
Renal replacement therapy  
RV  
Right ventricle  
RVAD  
Right ventricular assist device  
RVF  
Right ventricular failure 
RVFAC  
Right ventricular fractional area change  
RVLS  
Global RV longitudinal strain 
RVSI  
Right ventricular sphericity index  
s.c.  
Subcutaneous 
S’  
Tricuspid peak annular velocity s’ 
SAE  
Serious adverse event 
SAP  
Statistical analysis plan 
SBP  
Systolic blood pressure  
SD  
Standard deviation  
SIV  
Site initiation visit 
SOC  
System organ class 
SOP  
Standard operating procedure 


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SOPRANO  
Macitentan in pulmonary hypertension post-left ventricular assist 
device implantation 
SS  
Safety Set  
ST2  
Member of the interleukin 1 receptor family  
SUSAR  
Suspected unexpected serious adverse reaction 
SVO2  
Mixed venous oxygen saturation 
TAH  
Total artificial heart 
TAPSE  
Tricuspid annular plane systolic excursion 
TNF-α  
Tumor necrosis factor- α 
TPR  
Total pulmonary resistance 
ULN  
Upper limit of the normal range 
WHO  
World Health Organization 
WU  
Wood unit 
 


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SUBSTANTIAL GLOBAL AMENDMENT 2 
Amendment rationale  
This amendment1 applies to protocol AC-055-205 Version 2, dated 25 August 2015. The 
resulting amended global protocol is Version 3, dated 10 March 2017.  
The main reason for this amendment is to extend the 45-day post-left ventricular assist 
device Screening window to 90 days.  
Other changes include:  
• Addition of a Glossary to clarify protocol terms. 
• Sample size re-estimation updates based on recently released study results 
(e.g., MERIT). 
• Re-definition of Baseline right heart catheterization (RHC) with emphasis on the 
required thermodilution method for Baseline and Week 12 (End-of-Treatment) RHC.  
• Removal of any language pertaining to pulmonary artery catheter (PAC) assessments 
(as PAC serving as the source of Baseline RHC hemodynamics is expected to be 
rare). 
• Addition of the requirement that Randomization must take place within 14 days of 
Baseline RHC (new inclusion criterion).  
• General text edits for greater clarity in study execution and training.  
• Description of the core responsibilities of the Clinical Event Committee and Core 
Hemodynamics Laboratory. 
• Primary, secondary and exploratory efficacy analyses to be performed on the Full 
Analysis Set (FAS), no longer the modified FAS. 
Changes to the protocol  
Two versions of the amended protocol will be prepared: 1) a clean version and 2) a Word 
comparison document, showing deletions and insertions in comparison to the previous 
protocol version. 
                                                 
1 This amendment is global amendment 2, applicable to all sites in the study. The previous amendment was local 
amendment 1 (US). However, as this study only has sites in the US, the amendment type has been revised to 
‘global’ to clarify that it is applicable to all sites in the study. 


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Amended protocol sections 
The main sections of the protocol affected by this amendment are listed below. Where 
applicable, the same changes have also been made to the corresponding sections of the 
protocol synopsis and to the Table of Assessments: 
1.5.5  
Summary of potential risks and risk management 
3.1 
 
Study design 
3.3 
 
Study committees  
4.2 
 
Rationale for the selection of the study population 
4.3 
 
Inclusion criteria 
4.4 
 
Exclusion criteria  
5.1.3  
Study treatment administration 
5.1.6.2  
Unblinding 
5.1.7.2.2 
Study treatment storage  
5.1.7.3  
Study treatment dispensing  
5.1.8.2  
Study treatment compliance  
5.1.11 
Study-specific criteria for interruption / premature discontinuation of study 
treatment 
5.2.1  
Definitions 
5.2.3  
Allowed concomitant therapy 
5.3 
 
Allowed LVAD flow rate 
6.1.1  
Primary efficacy endpoint(s) 
6.3 
 
Biomarker endpoints 
7.2.1  
Hemodynamic measurements – right heart catheterization 
7.2.4  
Echocardiography 
7.3.4.1  
Type of laboratory 
7.4 
 
Biomarker and genetic assessments 
8.1.1  
Screening (Visit 1)  
8.2.1  
Randomization (Visit 2)  
10.1.5  
Reporting of adverse events 
10.2.2  
Reporting of serious adverse events 
10.3.1  
Reporting of pregnancy 
11.1.6  
Usage of the analysis sets 
11.3.2.2 
Handling of missing data 
11.3.2.3 
Main analysis 
11.3.2.4 
Supportive/sensitivity analyses 
11.3.3  
Analysis of the secondary efficacy variable(s) 
11.3.4  
Analysis of the exploratory efficacy variable(s) 
11.5.1  
Sample size justification  
11.5.2  
Sample size sensitivity 
13.8 
 
Monitoring 


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Summary of previous amendments 
Amendment 
Date 
Main reason(s) 
1 
25 August 2015 
The hemodynamic variables decided on by the 
AC-055-205 study team and approved by Protocol 
Approval Committee were listed correctly in the 
protocol synopsis and Section 4.2 of the final protocol. 
However, the updated hemodynamic variables were 
not incorporated in Section 4.3 of the final protocol. 
The amendment was to reflect the accurate inclusion 
criteria and to have consistency across the sections of 
the protocol.  
 


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PROTOCOL SYNOPSIS AC-055-205 
TITLE 
A 
prospective, 
multicenter, 
double-blind, 
randomized, 
placebo-controlled, parallel-group study to assess the efficacy 
and safety of macitentan in patients with pulmonary 
hypertension after left ventricular assist device implantation. 
ACRONYM 
SOPRANO: Macitentan in pulmonary hypertenSiOn Post-left 
ventRiculAr assist device implaNtatiOn 
OBJECTIVES 
Primary objective 
To evaluate the effect of macitentan 10 mg on pulmonary 
vascular resistance (PVR) as compared to placebo in subjects 
with pulmonary hypertension (PH) after left ventricular assist 
device (LVAD) implantation. 
Secondary objectives 
• To evaluate the effect of macitentan 10 mg as compared to 
placebo on cardio-pulmonary hemodynamics and disease 
severity in subjects with PH after LVAD implantation. 
• To evaluate the safety and tolerability of macitentan 10 mg 
in subjects with PH after LVAD implantation. 
Exploratory objectives 
• To explore the potential effect of macitentan 10 mg as 
compared to placebo on right ventricular function in 
subjects with PH after LVAD implantation.  
• To explore the potential effect of macitentan 10 mg as 
compared to placebo on selected clinical events in subjects 
with PH after LVAD implantation. 
• To explore the potential effect of macitentan 10 mg as 
compared to placebo on renal function as measured by the 
glomerular filtration rate (GFR) in subjects with PH after 
LVAD implantation.  
DESIGN 
Prospective, 
multicenter, 
double-blind, 
randomized, 
placebo-controlled, parallel-group Phase 2 study. 


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PERIODS 
Screening period: Up to 90 days from LVAD implantation 
until Randomization. 
Treatment period: From Randomization up to Week 12 or 
earlier in case of premature discontinuation of study treatment. 
Subjects who prematurely discontinue study treatment must 
have an End-of-Treatment (EOT) visit within 7 days of study 
treatment discontinuation.  
Study treatment is defined as the dosing (intake) by the subject 
of double-blind study drug (macitentan or placebo). 
Post-treatment safety follow-up period: Subjects who 
complete the treatment period as planned, i.e., full 12-week 
study period, and those who prematurely discontinue study 
treatment, will enter a 30-day safety follow-up period which 
ends with the End-of-Study (EOS) visit at least 30 days after the 
permanent discontinuation of study treatment. 
PLANNED DURATION 
Approximately 36 months from first subject, first visit to last 
subject, last visit. 
SITE(S) 
/ COUNTRY(IES) 
Approximately 50 clinical sites in the United States. 
SUBJECTS / GROUPS 
78 subjects in 2 groups, randomized in a 1:1 ratio by an 
Interactive Voice/Web Randomization System to macitentan 
10 mg or placebo. 
INCLUSION CRITERIA 
 
 
 
 
 
 
 
 
 
 
1 Written Informed Consent prior to initiation of any 
study-mandated procedure. 
2 Males or females ≥ 18 years of age. 
3 Surgical implantation of LVAD within 90 days prior to 
Randomization. 
4 Hemodynamic evidence of PH on Baseline right heart 
catheterization (RHC) by the thermodilution method. 
Baseline RHC is defined as the last hemodynamic 
measurements after LVAD implantation and prior to the 
first dose of study treatment. PH is defined as: 
a) Mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg 
and 
b) Pulmonary artery wedge pressure (PAWP) ≤ 18 mmHg 
and 
c) PVR > 3 Wood units. 


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INCLUSION CRITERIA 
(cont’d) 
5 Stabilization of the patient for 48 h prior to the Baseline 
RHC, defined as: 
a) No LVAD pump speed/flow rate changes and 
b) Stable dose of oral diuretics and 
c) No intravenous (i.v.) inotropes or vasopressors and 
d) Patient able to ambulate. 
6 A woman of childbearing potential is eligible only if she 
has: 
a) A negative serum pregnancy test result during the 
Screening period (Visit 1) and Randomization (Visit 2) 
and  
b) Agreement to undertake monthly serum pregnancy tests 
during the study and up to 30 days after study treatment 
discontinuation and 
c) Agreement to use one of the methods of contraception / 
follow 
the 
contraception 
scheme 
described 
in 
Section 4.5 from Screening and up to at least 30 days 
after study treatment discontinuation. 
7 Patient must be randomized within 14 days of Baseline 
RHC. 
EXCLUSION CRITERIA 
 
 
 
 
 
 
 
 
 
 
 
1 Documented severe obstructive lung disease defined as: 
forced expiratory volume in 1 second / forced vital capacity 
(FEV1/FVC) < 0.7 associated with FEV1 < 50% of predicted 
value after bronchodilator administration. 
2 Documented moderate to severe restrictive lung disease 
defined as: total lung capacity < 60% of predicted value. 
3 Documented pulmonary veno-occlusive disease. 
4 Patients undergoing dialysis. 
5 Hemoglobin < 8.5 g/dL at Randomization. 
6 Aspartate 
aminotransferase 
(AST) 
or 
alanine 
aminotransferase (ALT) > 3 × the upper limit of normal 
(ULN) at Randomization. 
7 Severe hepatic impairment, e.g., Child-Pugh Class C liver 
disease. 
8 Body weight < 40 kg at Randomization. 
9 Doppler 
mean 
blood 
pressure 
< 
65 
mmHg 
at 
Randomization. 
10 GFR < 30 mL/min at Randomization. 
11 Pregnant, planning to become pregnant during the study 
period, or breastfeeding. 


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EXCLUSION CRITERIA 
(cont’d) 
 
12 Treatment with endothelin receptor antagonists (ERAs), 
phosphodiesterase-5 (PDE5) inhibitors, i.v., subcutaneous 
(s.c.), or oral prostanoids, or guanylate cyclase stimulators 
within 7 days prior to Baseline RHC or study treatment 
initiation. 
13 Treatment 
with 
inhaled 
prostanoids 
(e.g., 
iloprost, 
epoprostenol) or nitric oxide within 24 h prior to Baseline 
RHC or study treatment initiation. 
14 Treatment with strong inducers of cytochrome P450 
isozyme 3A4 (CYP3A4) within 28 days prior to study 
treatment 
initiation 
(e.g., 
carbamazepine, 
rifampicin, 
rifabutin, phenytoin and St. John’s Wort).  
15 Treatment with strong inhibitors of CYP3A4 within 28 days 
prior to study treatment initiation (e.g., ketoconazole, 
itraconazole, voriconazole, clarithromycin, telithromycin, 
nefazodone, ritonavir, saquinavir, boceprevir, telaprevir, 
iopinavir, fosamprenavir, darunavir, tipranavir, atazanavir, 
nelfinavir, amprenavir, and idinavir). 
16 Treatment with another investigational drug (planned, or 
taken) within 28 days prior to study treatment initiation. 
17 Known hypersensitivity to ERAs, or to any of the study 
treatment excipients. 
18 Any condition that prevents compliance with the protocol or 
adherence to therapy.  
19 Known concomitant life-threatening disease with a life 
expectancy < 12 months. 
STUDY TREATMENTS 
Investigational treatment 
Macitentan oral tablet, 10 mg once daily. 
Comparator and/or placebo 
Matching placebo, once daily. 
CONCOMITANT 
THERAPY 
 
 
 
 
Allowed concomitant medication  
Oral and i.v. diuretics are allowed and may be adjusted during 
the treatment period.  
(Treatment with oral diuretics is allowed if ongoing at a stable 
dose for at least 48 h prior to the Baseline RHC.) 
 


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CONCOMITANT 
THERAPY 
(cont’d) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LVAD Flow Rate 
Prohibited concomitant medications 
• Pulmonary arterial hypertension-specific therapy (ERAs, 
i.v., s.c., inhaled or oral prostanoids, PDE5 inhibitors, 
guanylate cyclase stimulators). 
• Inhaled nitric oxide. 
• Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, 
voriconazole, clarithromycin, telithromycin, nefazodone, 
ritonavir,saquinavir, 
boceprevir, 
telaprevir, 
iopinavir, 
fosamprenavir, darunavir, tipranavir, atazanavir, nelfinavir, 
amprenavir, and idinavir) and strong inducers of CYP3A4 
(e.g., carbamazepine, rifampicin, rifabutin, phenytoin and 
St. John’s Wort). 
• Any investigational drug. 
Initiation of one of these prohibited medications will lead to 
premature discontinuation of study treatment. 
Allowed LVAD Flow Rate  
The LVAD pump speed/flow rate may be adjusted during the 
treatment period and during the Baseline RHC.  
(LVAD pump speed/flow rate must be stable for at least 48 h 
prior to the Baseline RHC). 
ENDPOINTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Definitions 
Baseline is defined as the last value obtained prior to first dose 
of study treatment. 
Primary efficacy endpoint 
PVR ratio of Week 12 to Baseline. PVR is obtained by the 
thermodilution method. 
Secondary efficacy endpoints 
Change from Baseline to Week 12 in mean right atrial pressure, 
mPAP, PAWP, cardiac index (CI), total pulmonary resistance, 
and mixed venous oxygen saturation, all measured at rest. 
Change in NT-proBNP from Baseline to Week 12.  
Change in WHO functional class from Baseline to Week 12. 


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ENDPOINTS 
(cont’d) 
Exploratory efficacy endpoints 
Change in echocardiographic variables from Baseline to 
Week 12. These variables include: 
• 2D global RV longitudinal strain  
• RV sphericity index  
• RV end systolic area 
• RV end diastolic area  
• Tricuspid annular plane systolic excursion  
• Tricuspid peak annular velocity s’ 
• RV fractional area change  
• Tricuspid peak diastolic annular velocities e’, a’ 
Time to first encounter of clinical events, from enrollment to 
Week 12. These clinical events include:  
• Hospital admission for heart failure (HF)  
• Re-initiation of i.v. diuretics ≥ 48 h duration  
• Re-initiation of i.v. inotropes ≥ 48 h duration  
• Initiation of PDE5 inhibitors 
• Need for right ventricular assist device / total artificial heart 
• Need for renal replacement therapy 
• Death.  
Days in the hospital after hospitalization for HF. 
Change in GFR from Baseline to Week 12. 
Safety endpoints 
1 Treatment-emergent adverse events (AEs) up to 30 days 
after study treatment discontinuation. 
2 AEs leading to premature discontinuation of study 
treatment. 
3 Death up to 30 days after study treatment discontinuation. 
4 Treatment-emergent serious adverse events (SAEs) up to 
30 days after study treatment discontinuation. 
5 Change from Baseline to EOT in vital signs. 
6 Occurrence of liver function test (ALT and/or AST) 
abnormality (≥ 3 × ULN; ≥ 3 and < 5 × ULN; ≥ 5 and 
< 8 × ULN; ≥ 8 × ULN) up to EOT. 
7 Occurrence of ALT and/or AST abnormality ≥ 3 × ULN 
associated with bilirubin ≥ 2 × ULN up to EOT. 


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8 Proportion of patients with treatment-emergent hemoglobin 
abnormality (< 10.0 g/dL, and < 8.0 g/dL) as compared to 
Baseline up to EOT. 
9 Treatment-emergent marked laboratory abnormalities up to 
EOT. 
ASSESSMENTS 
Refer to the schedule of assessments in Table 1. 
STATISTICAL 
METHODOLOGY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Analysis sets 
The Screened Analysis Set includes all patients who were 
screened and received a Screening number. 
The Safety Set (SS) includes all patients who received at least 
one dose of study drug in the double-blind treatment period. 
The Full Analysis Set (FAS) includes all patients randomized. 
The modified FAS includes all patients in the FAS that have 
received at least one dose of study drug in the treatment period 
and have a Baseline, and at least one post-Baseline, PVR 
measurement. 
The Per-Protocol Set (PPS) comprises all patients included in 
the modified FAS without major protocol deviations.  
Primary efficacy variable 
The primary efficacy variable is the PVR ratio of Week 12 to 
Baseline. 
Statistical hypotheses 
The null hypothesis is that the mean PVR ratio is the same in 
the macitentan and placebo groups. 
The alternative hypothesis is that the mean PVR ratio is lower 
in the macitentan group as compared to the placebo group. 
Type-I and -II errors and power 
The type I error (α) is set to 0.025 (one-sided), the type II error 
is set to 0.20 and the power to 80%. 
Sample size calculation 
There are no randomized trial data in this patient population. 
However, an integrated analysis of two bosentan studies, 
BENEFIT (AC-052-366) and EARLY (AC-052-364), the 
hemodynamic sub-study of SERAPHIN (AC-055-302), and the 
recently completed MERIT study (AC-055E201) of macitentan 


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STATISTICAL 
METHODOLOGY 
(cont’d) 
in patients with inoperable chronic thromboembolic pulmonary 
hypertension, suggest that the treatment group difference on 
PVR is around −0.28 on log scale (ranged from −0.45 to −0.17 
with 95% confidence interval: −0.35, −0.21) and that the within 
group standard deviation is around 0.40 (90% confidence 
interval: 0.38, 0.42) on log scale.  
Under assumptions of the treatment group difference −0.28 and 
the within group standard deviation 0.41 on log scale, 
70 evaluable patients will be needed for 80% power (35 patients 
per group). Accounting for 10% non-evaluable patients, 
78 patients will need to be randomized. 
Primary analysis 
The primary analysis will be performed on the FAS. 
The Week 12 versus Baseline ratio in PVR will be 
log-transformed (base e) and analyzed using an analysis of 
covariance with a factor for treatment group and a covariate for 
Baseline log PVR. The treatment group difference in mean 
change from Baseline (on log scale) and its 95% CI will be 
estimated based on the model. The geometric mean ratio (GMR; 
macitentan vs. placebo) and its 95% CI will be obtained by 
exponentiation. The null hypothesis will be rejected if the entire 
95% CI is below one. 
The treatment effect will be expressed as (GMR−1) × 100%, 
where a negative value indicates a reduction of PVR in the 
macitentan group as compared to the placebo group.  
If PVR cannot be calculated due to missing PAWP but mPAP 
and cardiac output are available for the same visit, PAWP will 
be imputed. In patients with a post-Baseline PVR measurement 
obtained before Week 12, the last post-Baseline PVR 
measurement will be carried forward. If a patient has no 
post-Baseline PVR measurement, the ratio of Week 12 to 
Baseline PVR will be imputed using the treatment group 
median based on the FAS. Patients who do not have Baseline 
PVR will be not evaluable and excluded from the analysis. 
 
 


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Secondary and exploratory analyses 
Secondary and exploratory efficacy variables will be analyzed 
on the FAS at α = 0.025 (one-sided) using 95% confidence 
limits. No correction for multiple testing will be applied for 
these analyses. 
Safety endpoints 
Safety data including AEs and SAEs will be summarized using 
the SS. 
STUDY COMMITTEES 
A Steering Committee is involved in the study design and will 
be consulted prior to and during the study for relevant medical 
issues and study publications. 
An Independent Data Monitoring Committee (IDMC), with 
members representing the specialties of cardiology and 
biostatistics, has overall responsibility for safeguarding the 
interests of subjects by monitoring data from the study and may 
recommend modification, discontinuation, or completion of the 
study. The composition and operation of the IDMC is described 
in the IDMC charter. 
A Clinical Event Committee (CEC) is an independent 
committee appointed by Actelion to review blinded data on 
hospital admission events for HF and death due to any cause. 
This standardized assessment of HF admission events is 
expected to limit variability and potential for bias associated 
with site-based event(s). The composition and operation of the 
CEC is described in the CEC charter. 
A Core Hemodynamics Laboratory (CHL) has been appointed 
to review RHC tracings to allow for a standardized assessment 
of data quality. The RHC tracings data will be recorded by the 
CHL in a CHL Case Report Form, entered into the study 
database, and analyzed for variability. Services of the CHL are 
governed by a CHL charter.  


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Table 1 
Visit and assessment schedule 
 
PERIODS 
Name 
SCREENING 
DOUBLE-BLIND TREATMENT 
FOLLOW-UP 
 
Duration 
Up to 90 days 
12 Weeks 
 
30 days 
VISITS  
Number 
1 
2 
3 
4 
5 
U1, U2, etc. 
6 
 
Name 
Screening1a 
Randomization1b 
Week 4 
Week 8 
Week 12 or EOT2 
Unscheduled Visit3 
EOS4 
 
Time 
Day −90 to Day −1 
Day 1 
Day 28 
(± 7 days)  
Day 56 
(± 7 days) 
Day 84 
(± 7 days) 
Any day between Days 
1 and 84 
30 days (+ 7 days) 
after last dose 
Informed Consent 
X 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Demographics & baseline 
characteristics 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Medications 
X 
X 
X 
X 
X 
X 
X 
Physical examination5 
X 
 
 
 
X 
X 
 
Vital signs, body weight, height 
and BMI6 
X 
X 
 
 
X 
X 
 
Screening laboratory tests 
X7a 
X7a 
 
 
 
 
 
Central laboratory tests 
 
X7b 
X 
X 
X 
X 
X 
Contraception check & Pregnancy 
test8 
X 
X 
X 
X 
X 
X 
X 
RHC by the thermodilution 
method 
X9a 
 
 
 
X9b 
X9c 
 
Echocardiography  
 
X10 
 
 
X 
X11 
 
NT-proBNP 
 
X 
 
 
X 
X 
 
WHO functional class 
 
X 
 
 
X 
X 
 
Study treatment dispensing/return 
 
X 
X 
X 
X12 
X 
 
AEs and SAEs13 
X 
X 
X 
X 
X 
X 
X 
 
 


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1a Written Informed Consent must be obtained prior to initiation of any study-mandated procedures. Screening and Randomization visits may be conducted on the same 
day, provided eligibility is confirmed and all study-mandated procedures are completed prior to Randomization. 
1b Randomization must be within 14 days of Baseline RHC. Study treatment starts immediately after Randomization.  
2 EOT must occur on the day of the last dose of study treatment or within 7 days of study treatment discontinuation if prior to Week12 (Day 84). 
3 Unscheduled Visits can be performed at any time during the study, as necessary, at the investigator’s discretion. Study specific procedure/assessments that are marked 
(X) may be performed during an Unscheduled Visit, and corresponding data will be collected in the eCRF. 
4 Subjects who complete the study as planned, i.e., full 12-week study period and those who prematurely discontinue study treatment will enter a 30-day safety follow-up 
period, which ends with the EOS visit at least 30 days after the permanent discontinuation of study treatment.  
5 Clinically relevant findings at the time of signing of Informed Consent must be recorded on the Medical History eCRF page. Findings made after signing of informed 
consent, and which meet the definition of an AE [Section 10.1.1], must be recorded on the AE page of the eCRF. 
6 Height is only measured at Screening (in cm). 
7a At the time of Screening, local laboratory results may be used for determination of subject status (e.g., guiding RHC decision-making). At the time of Randomization, 
local laboratory results will be used to determine subject eligibility.  
7b Central lab results must be collected and submitted once eligibility is confirmed and prior to Randomization. Laboratory testing includes hematology and blood 
chemistry. Additionally, NT proBNP, biomarkers and calculated GFR will be performed on Visits 2 and 5. 
8 For women of childbearing potential only. Randomization (Visit 2) pregnancy test result must be negative prior to Randomization. 
9a  The last hemodynamic measurements after LVAD implantation and prior to the first dose of study treatment. Randomization must be within 14 days of Baseline RHC.  
9b Repeated at Week 12 or within 7 days of permanent discontinuation of study treatment if prior to Week 12. All RHC hemodynamics must be obtained by the 
thermodilution method.  
9c  RHC may be performed at an Unscheduled Visit, and must be recorded in the eCRF. If the Unscheduled RHC is the last RHC, the data should be entered as Week 12 or 
EOT RHC (see 9b). If the Unscheduled RHC is before the last (Week 12 or EOT) RHC, the data should be entered as Unscheduled Visit.  
10 Baseline ECHO must occur on the day of Randomization. 
11 ECHO may be performed at an Unscheduled Visit, and must be recorded in the eCRF. 
12 If study treatment discontinuation occurs prior to Week 12 (Day 84), record drug return as per standard procedure (e.g., on the eCRF Study Drug Dispensing and 
Accountability form). 
13All AEs and SAEs that occur after signing the Informed Consent Form and up to 30 days after study treatment discontinuation must be reported in the eCRF.  
 
AE = adverse event; BMI = body mass index; eCRF = electronic case report form; EOS = End-of-Study; EOT = End-of-Treatment; GFR = glomerular filtration rate; 
LVAD = left ventricular assist device; NT-proBNP = N-terminal prohormone of brain natriuretic peptide; SAE = serious adverse event; WHO = World Health 
Organization. 
 
 


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PROTOCOL 
1 
BACKGROUND 
1.1 Indication 
End-stage heart failure (HF) is a debilitating condition for which heart transplant offers 
the best treatment option, but the need for donor hearts greatly exceeds supply. This 
shortage of donor hearts underscores the need for alternative treatment options. Since the 
first approval by the Food and Drug Administration (FDA) of a left ventricular assist 
device (LVAD) as bridge to transplant in 1994 and as destination therapy (DT) in 2002, 
LVADs have become an increasingly frequent treatment option for patients with 
end-stage HF [Rommel 2014]. In patients with advanced HF, the use of continuous flow 
LVADs results in clinically meaningful survival benefits and improved quality of life 
[Rose 2002, Slaughter 2009]. 
While LVADs improve left-sided hemodynamic variables, right ventricular failure (RVF) 
occurring after the implantation of LVADs is a major cause of morbidity and mortality 
[Patlolla 2013, Grant 2012]. Pre-operative right ventricular dysfunction often does not 
improve after left ventricular mechanical unloading and may even worsen. Persistently 
elevated pulmonary vascular resistance (PVR) is associated with RVF after LVAD 
implantation [Rommel 2014]. Patlolla et al suggest that LVADs cause geometrical and 
functional changes in the right ventricle (RV) [Patlolla 2013]. The dynamic change in 
ventricular interdependence, ventriculo-arterial coupling, afterload and preload following 
LVAD insertion may determine RV compensation following LVAD. Patients with 
baseline dilated RV, decreased RV contractility, or severely increased stiffness may be 
particularly susceptible to ventriculo-arterial uncoupling and RVF after LVAD insertion. 
The indication of this study is pulmonary hypertension (PH) appearing, maintaining, or 
worsening after LVAD implantation. The diagnosis of PH is based on pulmonary 
hemodynamic criteria obtained via right heart catheterization (RHC), i.e., mean 
pulmonary arterial pressure (mPAP) ≥ 25 mmHg at rest.  
1.2 Epidemiology 
Over the last several years, LVADs have become a more frequent treatment choice for 
patients with end-stage HF. This is due to the improvement in the engineering design and 
reduction in size of these devices. For example, the US-based Interagency Registry for 
Mechanically Assisted Circulatory Support (INTERMACS) has over 12,000 LVADs in 
their database, of which 6000 were implanted since 2012 [Kirklin 2014]. 
While LVADs improve left-sided hemodynamic variables (e.g., increase cardiac output 
[CO], reduce pulmonary artery wedge pressure [PAWP]), RVF occurring after the 


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implantation of LVADs is a major cause of morbidity and mortality [Patlolla 2013, 
Grant 2012, Kukucka 2011b, Kormos 2010]. The incidence of RVF ranges from 9–44%, 
depending on the definition of RVF used, the type of device used (pulsatile or continuous 
flow), the indication for LVAD support (bridge to transplantation, bridge to recovery, or 
DT) and finally, the baseline characteristics or comorbidities of the studied population 
[Patlolla 2013]. 
1.3 Current management 
The management of PH post-LVAD implantation starts with measures to prevent RVF in 
the preoperative period. Preoperatively, identifying high-risk patients, choosing the 
optimal timing of implanting an LVAD and consideration of total artificial heart or initial 
biventricular assist device are imperative. Intraoperatively, interventions for RVF 
management include short-term right heart bypass, implantation of a temporary right 
ventricular assist device (RVAD) and inhaled pulmonary vasodilators. Post-operatively, 
the management of PH complicated with RVF in these patients includes the use of 
pulmonary vasodilators, changing the pump speed under echocardiography guidance and 
if refractory RVF, consideration of an RVAD implantation [Patlolla 2013]. 
To date, the role of pulmonary vasodilators in LVAD patients with PH has only been 
investigated in small pilot studies. Inhaled nitric oxide (iNO) decreased pulmonary 
arterial pressures and improved LVAD flow in a study in which 11 LVAD patients 
received inhaled iNO at 20 ppm post-operatively [Argenziano 1998]. These results, 
however, were not reproduced in two small studies in which LVAD patients were given 
iNO at 40 ppm intra- and post-operatively [Kukucka 2011a, Potapov 2011]. Antoniou et 
al examined the use of iloprost in 7 patients with right ventricular dysfunction 
post-LVAD insertion treated simultaneously with inotropes and iNO [Antoniou 2012]. 
The authors reported a significant reduction in PVR, mPAP, PAWP, and an increase in 
LVAD flow post-combined inhaled therapy. 
In an open-label study of 26 LVAD recipients, sildenafil therapy plus LVAD support was 
more effective than LVAD alone in lowering PVR [Tedford 2008]. Specifically, the 
average PVR in the sildenafil-treated group fell from 5.9 to 3 Wood units (WU) while the 
PVR in the LVAD recipients not receiving sildenafil was reduced by less than 1 WU. 
Klodell et al also investigated the role of sildenafil in LVAD patients with persistent PH 
[Klodell 2007]. In 10 patients on inotropic therapy with dobutamine and milrinone, 
sildenafil administration produced a significant reduction in systolic PAP within 90 min 
of oral administration. 
A case report published by Imamura et al reported on the effects of bosentan in a case of 
persistent PH post-implantation of a continuous-flow LVAD resulting in significantly 
decreased PVR [Imamura 2013]. LaRue et al investigated 50 patients on bosentan in a 


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single center series; treated for a mean duration of 16.3 (± 12.1) months, including 
30 patients for greater than 1 year [LaRue 2013]. The study results showed the drug to be 
well tolerated in this patient cohort. In addition, at 6-month follow-up there was 
right-sided decongestion with improvement in both the bilirubin and alkaline phosphatase 
levels. These studies were replicated in a follow-up single center retrospective study by 
LaRue [LaRue 2013]. In this cohort, consecutive patients with mean PA > 25 mmHg 
were treated with bosentan after LVAD implantation for a mean duration of 15.7 (± 12.4) 
months. Comparison of the baseline to 6-month follow-up data revealed laboratory 
evidence of decreased BNP, hepatic decongestion as well as improvement in 
echo-derived pulmonary hemodynamics including PVR decrease of 1.4 WU. Ten patients 
discontinued the drug for possible side effects, including 3 for liver function test (LFT) 
abnormalities [LaRue 2013].  
The current International Society for Heart and Lung Transplantation guidelines on 
mechanical circulatory support [Feldman 2013] suggest PH-specific therapies for patients 
with persistent PH who exhibit signs of right ventricular dysfunction in the non-intensive 
care unit post-operative period (Class IIb, Level of Evidence C). 
1.4 Endothelin-1 and pulmonary hypertension 
Endothelin-1 (ET-1), a 21 amino acid peptide, is one of the most potent vasoconstrictors 
and mitogens for smooth muscle, and contributes to increased vascular tone and 
proliferation in pulmonary vasculopathy [Galiè 2004].  
There are 2 distinct receptors for ET-1: endothelin receptor A (ETA) and endothelin 
receptor B (ETB). The 2 receptors have unique binding locations and affinities for the 
endothelin peptide [Benigni 1995, Massaki 1998]. The ETA receptors are expressed on 
pulmonary vascular smooth muscle cells, whereas ETB receptors are present both on 
pulmonary vascular endothelial cells and on smooth muscle cells.  
When activated, the ETA receptors located in pulmonary vascular smooth muscle cells 
mediate a potent vasoconstrictive response, and ETB receptors on endothelial cells 
mediate vasodilatation via increased production of nitric oxide and prostacyclin 
[Hirata 1993, de Nucci 1988]. ET-1 is also known to be a potent mitogen, with the ability 
to induce cell proliferation in vascular smooth muscle cells. It has been shown that both 
the ETA and ETB receptors mediate the mitogenic action of ET-1 [Clarke 1989, 
Chua 1992, Davie 2002, Sugawara 1996].  
Laboratory and clinical investigations have clearly shown that ET-1 is overexpressed in 
several forms of pulmonary vascular disease. ET-1 is likely a major factor 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]. 


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1.5 Macitentan 
Macitentan is approved in the US, EEA, Canada, Australia, Switzerland, Japan, and 
additional countries in the Middle East, Asia and Latin America for the treatment of 
pulmonary arterial hypertension (PAH). 
1.5.1 Nonclinical results 
Macitentan is an orally active, non-peptide, potent dual ETA and ETB antagonist. 
Macitentan showed dose-dependent efficacy in nonclinical models of hypertension and 
PH, and is approximately 10 times more potent than bosentan (Tracleer®). In nonclinical 
safety studies, no effects on normal physiological functions or electrocardiogram 
variables, including cardiac repolarization, were observed – with the exception of a 
decrease in arterial blood pressure (BP) observed in a cardiovascular study in dogs. 
Macitentan has no genotoxic potential. In the pivotal 26-week and 39-week toxicity 
studies, the exposures in animals at the no-observed-adverse-effect levels were above the 
anticipated clinical exposures and provided a margin of safety for studies in humans. 
A study conducted in hairless rats showed that macitentan is not phototoxic in vivo. 
Macitentan does not bind relevantly to melanin. Reproductive toxicity studies showed 
that macitentan is teratogenic without affecting male or female fertility. Teratogenicity is 
considered to be an endothelin receptor antagonist (ERA) class effect. 
More detailed information on macitentan can be found in the Investigator’s Brochure (IB) 
[Macitentan IB]. 
1.5.2 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]. 
1.5.3 Phase 2 results 
Phase 2 studies were conducted in patients with mild-to-moderate essential hypertension, 
and in patients with idiopathic pulmonary fibrosis (IPF).  
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 (vs. placebo) from 
baseline to Week 8 in mean sitting diastolic blood pressure (DBP) at trough, which was 
the primary endpoint of the study. 


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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.  
More detailed information on macitentan can be found in the IB [Macitentan IB]. 
1.5.4 Phase 3 efficacy results in PAH 
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] [Appendix 1]. 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 (36%) or in 
combination with phosphodiesterase-5 (PDE5) inhibitors (61%) or inhaled/oral 
prostanoids (5%). 
The trial demonstrated that macitentan 10 mg reduces the risk of morbidity/ mortality in 
patients with symptomatic PAH by 45% as compared to placebo of (hazard ratio 0.547, 
97.5% confidence limits (CLs) 0.392–0.762, p < 0.0001).  
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. Additionally, improvements in WHO FC from baseline to Month 6 were 
reported for 22.3% of patients in the macitentan 10 mg group, compared to 12.9% of 
patients in the placebo group. This translates into a 74% higher chance relative to placebo 
of WHO FC improvement in patients on the 10 mg dose (relative risk 1.74, 97.5% CLs 
1.10, 2.74, p = 0.0063). The treatment effect of macitentan on WHO FC was maintained 
over time. 
The median change versus placebo in NT-proBNP from baseline to Month 6 was  
–160 fmol/mL (97.5% CLs –235, –95) with macitentan 10 mg. In a hemodynamic 
substudy, the observed placebo-corrected treatment effect of reduction in PVR after 
6 months of treatment with macitentan 10 mg was 36.5% (97.5% CLs 21.7, 49.2), The 
placebo-corrected median change in cardiac index (CI) (L/min/m2) from baseline to 
Month 6 was 0.58 (97.5% CLs 0.28, 0.93) in the macitentan 10 mg group.  
More detailed information on macitentan can be found in the IB [Macitentan IB]. 
1.5.5 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. 


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In three placebo-controlled studies with macitentan (two Phase 2 studies in essential 
hypertension and IPF and one Phase 3 study in PAH), 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. Additionally, cases with ALT/AST > 3 × ULN and 
total bilirubin > 2 × ULN, suggesting Hy’s Law, were reported with very similar 
incidences across macitentan and placebo treatment groups. All of these events were 
characterized by confounding factors; linked to the underlying disease or to concomitant 
disease or medications. Overall, these findings do not indicate that macitentan is 
associated with a definite hepatotoxicity signal. Patients with serum AST and/or ALT 
> 3 × ULN are excluded from the study, and monthly liver tests are mandatory during the 
study. 
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 < 8.5 g/dL and who do 
not recover during the Screening period are excluded from the study. Monthly 
hemoglobin tests are mandatory during the study. 
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 serious adverse events (SAEs) were uncommon with macitentan treatment and 
only 3 patients (2 on placebo and 1 on macitentan 10 mg) discontinued treatment due to 
an edema AE. Overall, there is no indication that edema represents a significant safety 
concern with macitentan therapy 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. 


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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 
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 disorders 
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, 
especially pneumonia, there was no relevant difference between macitentan and placebo. 
In addition, there was a higher incidence of urinary tract infections and gastroenteritis in 
the patients who received macitentan treatment compared to those who received placebo. 
However, given that there was no imbalance in the incidence of these events that were 
reported as SAEs or that led to discontinuation of treatment, coupled with the fact that 
there was no increase in the reporting rate over time, these AEs were considered to be of 
limited clinical relevance. 
Macitentan has not been studied in PH post-LVAD implantation. Thus, a number of 
safeguards have been implemented in the current protocol, i.e., monthly follow-up of 
patients and ongoing safety and efficacy data review by an Independent Data Monitoring 
Committee (IDMC). 
For detailed information on the efficacy and safety profile of macitentan in PAH and 
other indications, please refer to the most recent version of the macitentan IB 
[Macitentan IB]. 
It is the investigator’s responsibility to monitor the benefit-risk ratio of study treatment 
administration, as well as the degree of distress caused by study procedures on an 


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individual subject level, and to discontinue study treatment or the study if, on balance, 
he/she believes that continuation would be detrimental to the subjects’ well-being. 
1.6 Purpose and rationale of the study 
PH after LVAD implantation is associated with a worse prognosis. To date, no targeted 
PAH therapy has demonstrated efficacy and safety in this patient population in a 
randomized, placebo-controlled clinical trial. The patients are managed on a day-to-day 
basis with commercially available PAH medications including PDE5 inhibitors, ERAs, 
iNO and prostanoids. Use of these pulmonary vasodilators has been mostly based on 
evidence from single-center, open-label experiences. Specifically, iNO and iloprost have 
been shown to reduce PVR and right ventricular dysfunction in the perioperative setting, 
while data from small, uncontrolled studies suggest utility of bosentan and sildenafil as 
long-term therapy in reducing PVR, thus reducing risk of RVF [Argenziano 1998, 
Antoniou 2012].  
Macitentan is an ERA, currently approved for the treatment of PAH in the US. In the 
Phase 3 AC-055-302/SERAPHIN study, macitentan demonstrated efficacy in PAH by 
improving long-term clinical outcomes, functional status and exercise capacity. Based on 
the aforementioned results with sildenafil and bosentan in PH after LVAD implantation, 
it is believed that macitentan could be an efficacious treatment for this patient population. 
The purpose of this study is to investigate the effect of macitentan on cardiopulmonary 
hemodynamics as well as the safety and tolerability in patients with PH post-LVAD 
implantation in a randomized, placebo-controlled study setting. 
2 
STUDY OBJECTIVES 
2.1 Primary objective(s) 
To evaluate the effect of macitentan 10 mg on PVR as compared to placebo in subjects 
with PH after LVAD implantation. 
2.2 Secondary objectives 
To evaluate the effect of macitentan 10 mg as compared to placebo on cardio-pulmonary 
hemodynamics and disease severity in subjects with PH after LVAD implantation. 
To evaluate the safety and tolerability of macitentan 10 mg in subjects with PH after 
LVAD implantation. 


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2.3 Exploratory objectives 
To explore the potential effect of macitentan 10 mg as compared to placebo on right 
ventricular function in subjects with PH after LVAD implantation. 
To explore the potential effect of macitentan 10 mg as compared to placebo on selected 
clinical events in subjects with PH after LVAD implantation. 
To explore the potential effect of macitentan 10 mg as compared to placebo on renal 
function as measured by glomerular filtration rate (GFR) in subjects with PH after LVAD 
implantation.  
3 
OVERALL STUDY DESIGN AND PLAN 
3.1 Study design 
This study is designed as a prospective, double-blind, placebo-controlled, multicenter, 
parallel-group Phase 2 study assessing the efficacy and safety of macitentan in PH 
post-LVAD implantation. 
Approximately 78 adult subjects with PH post-LVAD implantation will be randomized 
(1:1) to receive either macitentan 10 mg, or matching placebo, once daily orally. The 
attrition rate is expected to be 10%, leaving 70 evaluable patients at Week 12.  
After implantation of the LVAD, subjects must meet Baseline hemodynamic criteria of 
PH via RHC during the last measurement prior to the first dose of study treatment, 
defined as mPAP ≥ 25 mmHg at rest and PAWP ≤ 18 mmHg and PVR > 3 WU. Patients 
must be randomized within 90 days of surgical implantation of LVAD and within 14 days 
of Baseline RHC. 
Patients must be considered stable for 48 h prior to the Baseline RHC. Stability is defined 
as having no LVAD pump speed/flow rate changes, being on a stable dose of oral 
diuretics, receiving no intravenous (i.v.) inotropes or vasopressors, and being able to 
ambulate, for 48 h prior to the Baseline RHC. 
The study will be conducted in approximately 50 clinical sites in the US. Randomization 
will proceed until the required number of subjects has been reached. Enrollment will be 
competitive across participating sites. Actelion may replace sites with no study subject 
enrollment. The planned study duration is approximately 36 months from first subject, 
first visit to last subject, last visit. 
The study consists of the following study periods: 
Screening period: Commences immediately following LVAD implantation and ends 
with subject Randomization (up to a maximum of 90 days after surgical implantation of 


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LVAD). The Screening visit is the date at which signature on the Informed Consent Form 
(ICF) is obtained prior to initiation of any study-mandated procedures. Screening and 
Randomization visits may be conducted on the same day provided that eligibility is 
confirmed and all study-mandated procedures are completed prior to Randomization. 
Treatment period: Study treatment is defined as the dosing (intake) by the subject of 
double-blind study drug (macitentan or placebo). The treatment period starts immediately 
after Randomization with the first dose of study drug at the end of Visit 2 (Day 1 of 
study) and ends with EOT on the day of the last dose of study drug (scheduled Day 84, 
Week 12), or earlier in case of premature discontinuation of study treatment.  
Subjects who prematurely discontinue study treatment must have an EOT visit within 
7 days of study treatment discontinuation. 
Post-treatment safety follow-up period: Subjects who complete the study treatment as 
planned, i.e., a full 12-week study period, and those who prematurely discontinue study 
treatment, will enter a 30-day safety follow-up period, which ends with the End-of-Study 
(EOS) visit at least 30 days after the permanent discontinuation of study treatment. 
In addition, Unscheduled Visits may also take place during the treatment and follow-up 
periods [see Table 1]. 
For an individual subject, the study has ended once the EOT has been performed and the 
30-day safety follow-up is complete (EOS). 
The study is considered complete when all subjects have ended as detailed above. 
Study Duration: Subject participation in the study will be up to 90 days (Screening 
period) + 12 weeks (double-blinded treatment period) + 30 days (safety follow-up 
period). The overall study design is depicted in Figure 1. 


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Figure 1 
Study design 
 
* Subjects who complete the study as planned, i.e., full 12-week study period and those who prematurely discontinue 
study treatment will enter a 30-day safety follow-up period, which ends with the EOS visit at least 30 days after the 
permanent discontinuation of study treatment. 
EOT = End-of-Treatment; EOS = End-of-Study, LVAD = left ventricular assist device; RHC = right heart 
catheterization. 
3.2 Study design rationale 
A placebo-controlled trial conducted in a randomized, double-blind fashion provides the 
most definite and rigorous method of evaluating the efficacy and safety of a medical 
treatment. 
The present study aims at assessing whether macitentan improves hemodynamic 
variables, and whether this improvement would translate into functional improvement in 
subjects with PH post-LVAD implantation. The study also assesses the safety of 
macitentan in this patient population. Subjects will receive macitentan or placebo for 
12 weeks followed by a 30-day safety follow-up. The 12-week double-blind treatment 
period is selected because it is considered to be adequate to observe the anticipated 
treatment effect on the primary endpoint of change in PVR, but short enough to minimize 
risk of Randomization to placebo. The number of missing assessments due to premature 
study discontinuation is also expected to be minimized. The lack of an appropriate 
control arm in the previous small trials that tested pulmonary vasodilators in the 
post-LVAD implantation population is a limitation. Such limitation stems from the 
inability to differentiate between the mechanical unloading effects of the LVAD, and at 
Placebo
Macitentan 10 mg 
 
 
 
 
 
        84 days 
30 days 
 
 
 
  EOT  
  RHC  
 
EOS 
SCREENING 
PERIOD 
LVAD to Randomization  
≤90 days 
LVAD 
Implantation 
Randomization 
Visit 
DOUBLE‐BLIND 
TREATMENT PERIOD 
FOLLOW‐UP PERIOD* 
        ≤14 days 
Baseline  
    RHC 


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times of concomitant therapies such as inotropes and iNO, from the pharmacologic 
pulmonary vasodilatory properties of the individual agent being examined. Additionally, 
in studies involving hemodynamics, variability and placebo effect are of sufficient 
magnitude to justify the inclusion of a placebo control group [Wright 2009]. Most 
importantly, HF patients with “fixed” PH have been reported to demonstrate a marked 
reduction in pulmonary pressures at 6 months with LVAD therapy alone [Mikus 2011], 
which strongly suggests that a placebo arm is greatly needed to capture the true effects of 
the study drug rather than those of the LVAD itself. As most of the benefit from 
pulmonary vasodilators is likely to exist in patients with persistently elevated PVR and/or 
RV dysfunction after LVAD implantation, the need exists to evaluate post-LVAD 
hemodynamics for appropriate patient selection [LaRue 2015]. Hence, the present study 
aims to utilize post-LVAD hemodynamics as Baseline variables for a planned 
comparison with 12-week hemodynamics.  
Treatment with ERAs has been associated with increased incidence of edema, anemia 
and/or 
decreased 
hemoglobin 
as 
well 
as 
LFT 
abnormalities. 
From 
three 
placebo-controlled studies with macitentan, involving 863 patients on macitentan and 
370 patients on placebo, no significant imbalance in LFT elevations was observed across 
macitentan treatment groups (any dose) and placebo. However, due to the underlying 
disease in this patient population that increases the likelihood of safety events, a placebo 
arm is the only definitive way to draw (or rule out) an association between the use of the 
study treatment and those potential safety events. 
3.3 Study committees   
A Steering Committee has been appointed by Actelion to contribute to the design of the 
protocol, oversee the conduct of the study, evaluate the results, and support publications. 
The committee is governed by a Steering Committee charter. 
An IDMC with members representing the specialties of cardiology and biostatistics, has 
overall responsibility for safeguarding the interests of subjects by monitoring safety and 
efficacy data from the study and may recommend modification, discontinuation or 
completion of the study, thus ensuring that the study is being conducted with the highest 
scientific and ethical standards. The IDMC will be fully operational prior to enrollment of 
the first subject into the study. The composition and operation of the IDMC is described 
in the IDMC charter.  
A Clinical Event Committee (CEC) has been appointed by Actelion to review data on 
hospital admission for HF and death due to any cause (in a blinded fashion), so as to 
allow for a standardized assessment of HF admission events, limiting variability and 
potential biases associated with site-based event(s). The Committee is governed by a 
Clinical Endpoints Committee charter. 


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A Core Hemodynamics Laboratory (CHL) has been appointed by Actelion to review 
RHC tracings, so as to allow for a standardized assessment of data quality. The RHC 
tracings data will be recorded by the CHL in a CHL eCRF, entered into the study 
database, and analyzed for variability. Services of the CHL will be governed by a charter. 
4 
SUBJECT POPULATION 
4.1 Subject population description 
Subjects enrolled will be male or female aged 18 years and over, and meeting the 
hemodynamic criteria of PH post-LVAD implantation. Patients must be considered 
clinically stable. 
4.2 Rationale for the selection of the study population 
The primary objective of the study is to demonstrate a reduction in PVR versus Baseline 
with macitentan treatment as compared to placebo. Thus, patients need to present with 
elevated PVR (> 3 WU). Patients need to present with PAWP ≤ 18 mmHg to rule out that 
their elevated PVR and mPAP is due to left-sided dysfunction. 
The absence of restriction on WHO FC and 6MWD will permit patients with severely 
symptomatic PH to be enrolled. 
Patients with hemoglobin < 8.5 g/dL, or AST and/or ALT > 3 × ULN, and who do not 
recover during the Screening period are excluded. Such patients are at increased risk of 
premature discontinuation and would impact on the study’s ability to achieve its primary 
objective [see Section 1.5.5].  
As there is limited data on macitentan in pediatric PAH, subjects under the age of 
18 years are excluded. 
4.3 Inclusion criteria 
For inclusion in the study, all of the following inclusion criteria must be fulfilled. It is not 
permitted to waive any of the criteria for any subject: 
1. 
Written Informed Consent prior to initiation of any study-mandated procedure(s). 
2. 
Males or females ≥ 18 years of age. 
3. 
Surgical implantation of LVAD within 90 days prior to Randomization. 
4. 
Hemodynamic evidence of PH on Baseline RHC by the thermodilution method. 
Baseline RHC is defined as the last hemodynamic measurements after LVAD 
implantation and prior the first dose of study treatment. PH is defined as: 
a.  mPAP ≥ 25 mmHg and 
b.  PAWP ≤ 18 mmHg and 
c. PVR > 3 WU. 


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5. 
Stabilization of the patient for 48 h prior to the Baseline RHC, defined as: 
a. No LVAD pump speed/flow rate changes and 
b. Stable dose of oral diuretics and 
c. No i.v. inotropes or vasopressors and 
d. Patient able to ambulate. 
6. 
A woman of childbearing potential [see definition in Section 4.5.1] is eligible only 
if the following applies: 
a. A negative serum pregnancy test result during the Screening period 
(Visit 1) and Randomization (Visit 2) and 
b. Agreement to undertake monthly serum pregnancy tests during the study 
and up to 30 days after study treatment discontinuation and 
c. Agreement to use one of the methods of contraception / follow the 
contraception scheme described in Section 4.5 from Screening and up to at 
least 30 days after study treatment discontinuation. 
7. 
Patient must be randomized within 14 days of Baseline RHC. 
4.4 Exclusion criteria 
Subjects must not fulfill any of the following exclusion criteria. It is not permitted to 
waive any of the criteria for any subject: 
1. 
Documented severe obstructive lung disease defined as: forced expiratory volume 
in 1 second / forced vital capacity (FEV1/FVC) < 0.7 associated with FEV1 < 50% 
of predicted value after bronchodilator administration. 
2. 
Documented moderate to severe restrictive lung disease defined as: total lung 
capacity < 60% of predicted value. 
3. 
Documented pulmonary veno-occlusive disease. 
4. 
Patients undergoing dialysis. 
5. 
Hemoglobin < 8.5 g/dL at Randomization. 
6. 
AST or ALT > 3 × ULN at Randomization. 
7. 
Severe hepatic impairment, e.g., Child-Pugh Class C liver disease. 
8. 
Body weight < 40 kg at Randomization. 
9. 
Doppler mean blood pressure < 65 mmHg at Randomization. 
10. 
GFR < 30 mL/min at Randomization. 
11. 
Pregnant, planning to become pregnant during the study period, or breastfeeding. 
12. 
Treatment with ERAs, PDE5 inhibitors, i.v., subcutaneous (s.c.) or oral 
prostanoids, or guanylate cyclase stimulators within 7 days prior to Baseline RHC 
or study treatment initiation. 
13. 
Treatment with inhaled prostanoids (e.g., iloprost, epoprostenol) or nitric oxide 
within 24 h prior to Baseline RHC or study treatment initiation. 


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14. 
Treatment with strong inducers of cytochrome P450 isozyme 3A4 (CYP3A4) 
within 28 days prior to study treatment initiation (e.g., carbamazepine, rifampicin, 
rifabutin, phenytoin and St. John’s Wort).  
15. 
Treatment with strong inhibitors of CYP3A4 within 28 days prior to study 
initiation (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, 
telithromycin, nefazodone, ritonavir, saquinavir, boceprevir, telaprevir, iopinavir, 
fosamprenavir, darunavir, tipranavir, atazanavir, nelfinavir, amprenavir, and 
idinavir). 
16. 
Treatment with another investigational drug (planned, or taken) within 28 days 
prior to study treatment initiation. 
17. 
Known hypersensitivity to ERAs, or to any of the study treatment excipients. 
18. 
Any condition that prevents compliance with the protocol or adherence to therapy.  
19. 
Known concomitant life-threatening disease with a life expectancy < 12 months. 
4.5 Criteria for women of childbearing potential 
4.5.1 Definition of childbearing potential 
A woman is considered to be of childbearing potential unless she meets at least one of the 
following criteria: 
• Previous bilateral salpingectomy, bilateral salpingo-oophorectomy or hysterectomy. 
• Premature ovarian failure confirmed by a specialist. 
• Pre-pubescence2, XY genotype, Turner syndrome, uterine agenesis. 
• Post-menopausal, defined as 12 consecutive months with no menses without an 
alternative medical cause (International Council for Harmonisation [ICH] M3 
definition). 
                                                 
2 Childbearing potential status and pregnancy status will be assessed at each visit and recorded in the electronic case 
report form (eCRF). 


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4.5.2 Acceptable methods of contraception 
Women of childbearing potential must use a reliable method of contraception. The use of one of the following options is 
regarded as reliable contraception: 
Option 1 
 
Option 2 
 
Option 3 
 
Option 4 
One method from this 
list: 
 
One method from this 
list: 
 
One method from this list: 
 
One method from this list: 
Standard intrauterine 
 
Estrogen and 
 
Diaphragm with 
 
Partner’s vasectomy 
device (IUD) (Copper 
T380A IUD) 
 
progesterone oral 
contraceptives (“the  
 
spermicide 
Cervical cap with  
 
PLUS one method from this 
list: 
Intrauterine system  
 
Pill”) 
 
spermicide 
 
Male condom 
(LNg 20IUS: progesterone 
IUS) 
 
Estrogen and progesterone  
 
PLUS one method from this 
list: 
 
Diaphragm with spermicide 
Progesterone implant 
 
transdermal patch 
 
Male condom 
 
Cervical cap with 
Tubal sterilization 
 
Vaginal ring  
 
 
 
spermicide 
 
 
Progesterone injection 
 
 
 
Estrogen and progesterone 
oral contraceptives 
 
 
PLUS one method from 
this list: 
 
 
 
(“the pill”) 
 
 
Male condom 
Diaphragm with spermicide 
Cervical cap with 
spermicide 
 
 
 
Estrogen and progesterone 
transdermal patch 
Vaginal ring  
Progesterone injection 
 


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4.6 Medical history 
Relevant medical history either previous to or ongoing at time of Randomization 
(Visit 2), as defined below, must be recorded in the eCRF: 
• Chronic medical conditions and acute medical conditions within the past 6 months 
(e.g., anemia, hepatitis C infection, HIV infection, obstructive or restrictive lung 
disease, hypertension, renal disease) 
• Any previous life-threatening conditions, including date (e.g., myocardial infarction). 
5 
TREATMENTS 
5.1 Study treatment 
Treatment in this study is double-blind, and comprises investigational treatment 
(i.e., active drug macitentan) or matching placebo administered orally once daily. Up- or 
down-titration does not apply. 
5.1.1 Investigational treatment: description and rationale 
The investigational treatment is macitentan at the approved dose for PAH of 10 mg and is 
administered orally and at a frequency of once daily. 
5.1.2 Comparator(s) and/or matching placebo: description and rationale 
Matching placebo is administered orally and also once daily. Rationale for the use of a 
placebo arm is provided in Section 3.2. 
5.1.3 Study treatment administration 
The first administration of study treatment will take place at the clinical site during 
Randomization (Visit 2), and only after: successful completion of the ICF procedure, 
completion of all Screening/Randomization assessments, and confirmation that the 
patient meets all study eligibility criteria. 
Thereafter, one tablet (macitentan 10 mg or matching placebo) must be taken orally every 
morning irrespective of food intake. If a morning dose is missed, the next dose must be 
taken at the next scheduled morning time point (i.e., do not take one tablet in the evening 
and then one tablet the next morning). Two tablets must never be taken on the same day. 
At all subsequent visits, study treatment must be taken before any study procedures are 
performed. If a dose is not taken in the morning prior to arrival for the clinic visit, the 
next dose can be administered at the time of the clinic visit and prior to any study-related 
assessments. 


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5.1.4 Treatment assignment 
Eligible subjects will be randomized in a 1:1 ratio to either macitentan 10 mg or matching 
placebo. At Visit 1 (Screening), all screened subjects will be assigned a study-specific 
subject number by the Interactive Voice/Web Response System (IxRS) provider. Details 
are provided in the IxRS manual. At Visit 2 (Randomization), and after having confirmed 
the eligibility of the subject and prior to the start of study treatment, the 
investigator/delegate contacts the IxRS to randomize the subject. The IxRS assigns a 
Randomization number to the subject, and assigns the treatment bottle number which 
matches the treatment arm assigned by the Randomization list to the Randomization 
number. The bottle with this unique number is then dispensed to the subject and the first 
dose is administered. 
The Randomization list is generated by an independent Contract Research Organization 
(CRO) and kept strictly confidential. 
5.1.5 Blinding 
This study will be performed in a double-blind fashion. The investigator and study staff, 
the subjects, the monitors, Actelion and CRO staff involved in the conduct of the study 
will remain blinded to the treatment until study closure.  
Until the time of unblinding for final data analysis, the Randomization list is kept strictly 
confidential, and accessible only to authorized persons who are not involved in the 
conduct of the study. The Randomization code will be provided to the independent 
statistical analysis center of the IDMC. 
The investigational treatment and its matching placebo are indistinguishable and all 
subject kits will be packaged in the same way. 
5.1.6 Unblinding 
5.1.6.1 Unblinding for final analyses 
Full Randomization information will be made available for internal Actelion data 
analysis only after database closure, and in accordance with Actelion standard operating 
procedures (SOPs). 
5.1.6.2 Unblinding  
The IDMC has overall responsibility for safeguarding the interests of subjects by 
monitoring data from the study and may recommend modification, discontinuation or 
completion of the study. The process for IDMC review of unblinded data is defined in the 
IDMC charter.  


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5.1.6.3 Unblinding for SUSARs 
When a suspected unexpected serious adverse reaction (SUSAR) occurs for a subject 
participating in the study, Actelion Global Drug Safety will request the unblinding of the 
treatment assignment. The Randomization code will not be communicated to the site staff 
or to the Actelion study team; unblinded SUSAR information will be anonymized and 
provided to Actelion Global Drug Safety, respective health authorities and Institutional 
Review Boards / Independent Ethics Committees (IRBs/IECs) only. SUSARs will be 
reported to investigators in a blinded fashion. 
5.1.6.4 Emergency procedure for unblinding 
The investigator, study staff and sponsor staff must remain blinded to the subject’s 
treatment assignment. The identity of the study treatment may be revealed only if the 
subject experiences a medical event, the management of which would require knowledge 
of the blinded treatment assignment. In this case, the investigator can receive the 
unblinded Randomization code for study treatment allocation through the IxRS. In these 
situations, the decision to unblind resides solely with the investigator. Whenever it is 
possible and if it does not interfere with (or does not delay) any decision in the best 
interest of the subject, the investigator is invited to discuss the intended code break with 
Actelion. 
The occurrence of any code break during the study must be clearly justified and 
explained by the investigator. In all cases, Actelion must be informed as soon as possible 
before or after the code break. 
The circumstances leading to the code break must be documented in the site study file 
and eCRF. 
5.1.7 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. 
5.1.7.1 Study treatment packaging and labeling 
5.1.7.1.1 
Study treatment packaging 
Study treatment is provided as tablets and supplied in childproof bottles. 


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5.1.7.1.2 
Study treatment labeling 
Study treatment is labeled to comply with the applicable US laws and regulations. Each 
medication bottle has a label with a tear-off part specifying the study protocol number, 
the packaging batch number, and the bottle number. When the study treatment is given to 
the subject, this tear-off part must be removed and attached to the Study Treatment 
Dispensing Log. 
5.1.7.2 Study treatment distribution and storage 
Treatment supplies must be kept in an appropriate, secure area and stored according to 
the conditions specified on the medication labels. The investigator is responsible for the 
safe and proper handling and storage at the investigational site and that the study 
treatment is administered only to patients enrolled in the study and in accordance with the 
protocol. 
5.1.7.2.1 
Study treatment distribution 
The study centers will be supplied with study treatment according to the centers’ needs, 
depending on the rate of subject enrollment. Each center will have an individual stock of 
study treatment, which will be re-supplied continuously as soon as a predefined minimum 
level of study treatment has been reached.  
5.1.7.2.2 
Study treatment storage  
Study treatment must be kept in a locked room or a locked cupboard in a restricted access 
room, which can be accessed only by the pharmacist, the investigator, or another duly 
designated person as specified on the Delegation of Authority (DoA) form. 
The subject must be educated on the proper study treatment storage conditions at home.  
The study treatment must be stored below 30 °C (86 °F). Keep the bottle tightly closed to 
protect from moisture. Unopened, sealed medication bottles may be stored in the 
refrigerator (above +2 ºC [36 ºF]). Storage below +2 ºC [36 ºF] (e.g., in the freezer) is not 
permitted. Opened bottles of study drug must not be stored in the refrigerator or freezer. 
A temperature log must be maintained and temperature control should occur at least on a 
weekly basis at the site. Actelion will provide a temperature log; however, the use of the 
log is not mandatory if the site has an acceptable means of recording the temperature. 
Any temperature recording system routinely used at site is acceptable as long as all 
required information is included and certification of calibration is provided. If the 
temperature is captured electronically, a print-out should be made available to the clinical 
research associate (CRA) during each on-site visit for filing in the investigator site file 
(ISF).  


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If a deviation from the defined temperature range is identified by the study center, the 
deviation must be reported to the CRA, preferably in writing and with supporting 
documentation (e.g., copy of the temperature log showing data for all excursion days). 
The CRA should immediately contact Actelion for further advice. The affected study 
treatment will not be used (e.g., it will be segregated physically at the study center) until 
confirmation from Actelion is obtained that its use is safe. If the temperature deviation is 
outside of the acceptable limit, the study treatment is kept segregated at the study center, 
and returned to Actelion following internal study treatment return processes. New study 
treatment supplies will be provided to the study center.  
Site temperature deviations correspondence must be kept in the ISF.  
5.1.7.3 Study treatment dispensing 
Study treatment can only be dispensed by an authorized study investigator or delegate 
listed on the DoA form. 
The subjects will receive the study treatment (one childproof bottle containing 36 tablets 
each) at Visit 2 (Randomization), Visit 3 (Week 4), and Visit 4 (Week 8) to cover the 
treatment period up to the EOT (Week 12) visit. Subjects are asked to return all used, 
partially used, and unused study treatment bottles at the Week 4, 8, and 12 visits. 
The protocol-mandated study treatment dispensing/return procedures may not be altered 
without prior written approval from Actelion. An accurate record of the date and amount 
of study treatment dispensed to each subject must be available for inspection at any time.  
Once a subject has been randomized and study treatment assigned, the corresponding 
bottle must not be used for another subject. If a subject has been dispensed a bottle in 
error (one that has not been allocated yet to another subject), the IxRS helpdesk and study 
monitor / CRA must immediately be contacted.  
At the time study treatment is distributed, the subject should be educated on the proper 
timing of dosing and the proper storage conditions of study treatment at home 
[see Section 5.1.7.2.2]. 
5.1.7.4 Study treatment return and destruction 
The site must record the amount of study treatment received, dispensed, used, lost and 
returned during the study. 
On an ongoing basis and/or on termination of the study, the monitor will collect used and 
unused study treatment bottles, which will be sent to the warehouse, where Actelion or a 
sponsor delegate will check treatment reconciliation. In certain circumstances, used and 
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finalized and has been checked by Actelion or their delegate, and written permission for 
destruction has been obtained from Actelion. 
5.1.8 Study treatment accountability and compliance with study treatment 
5.1.8.1 Study treatment accountability 
The inventory of study treatment dispensed and returned (i.e., study treatment 
accountability) must be performed by the study staff on the day of the subject visit and 
before providing further study treatment. It is recorded on the IMP dispensing and 
accountability log and in the eCRF and checked by the CRA during site visits and at the 
end of the study. The study treatment accountability log in the eCRF will include at least 
the following information for each study treatment unit dispensed to the subject: 
• Dispensed bottle number 
• Date dispensed / number of tablets dispensed 
• Date returned / number of tablets returned. 
All study treatment supplies, including partially used or empty bottles must be retained at 
the site for review by the CRA. 
If the subject forgets to bring the remaining study treatment to a study visit, he/she must 
be instructed to not take any tablet/capsules from the remaining study treatment, and to 
bring it at the next visit. 
5.1.8.2 Study treatment compliance 
Study treatment compliance is based on study treatment accountability, as per formula 
below: 
Compliance = [(number of tablets provided to subject - number of tablets returned) / 
total number of tablets that should have been taken during the period] 
× 100 
During the study, and at each visit, compliance is expected to be between 80% and 120%. 
The investigator must check the reasons for any non-compliance with the subject and 
discuss actions to be taken to avoid re-occurrence at the next visit. 
5.1.9 Study treatment dose adjustments and interruptions 
Study treatment may be temporarily interrupted only in response to an AE, a diagnostic 
or therapeutic procedure, a laboratory abnormality, or for administrative reasons. 
Study-specific criteria for interruption of study treatment are described in Section 5.1.11. 


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If study treatment intake is interrupted by the subject for any reason, she/he must 
immediately inform the investigator. 
Interruptions of study treatment should be kept as short as possible. If treatment is 
stopped for more than 14 consecutive days, reintroduction is not permitted and treatment 
must be permanently discontinued [see Section 5.1.11]. 
Study treatment dose errors/interruptions must be recorded in the eCRF. 
5.1.10 Premature discontinuation of study treatment 
The decision to prematurely discontinue study treatment may be made by the subject, the 
investigator, or Actelion. The main reason, and whether discontinuation of study 
treatment is the decision of the subject, the investigator, or Actelion, must be documented 
in the eCRF. 
A subject has the right to prematurely discontinue study treatment at any time by 
withdrawal from study treatment only, or by withdrawal from any further participation in 
the study [i.e., premature withdrawal from the study, see Section 9.2]. 
The investigator should discontinue study treatment for a given subject if, on balance, 
he/she believes that continued administration would be contrary to the best interests of 
the subject. 
Study treatment may be discontinued in response to an AE, lack of efficacy (including 
disease progression, treatment failure, worsening of subject’s condition), a protocol 
deviation (including eligibility failure, non-compliance with study requirements), a 
diagnostic or therapeutic procedure, a laboratory abnormality, or for administrative 
reasons.  
A subject’s prior enrollment in an LVAD device study does not constitute eligibility 
failure. Additionally, simultaneous observational or non-interventional clinical trials 
(limited to blood sample collection) do not constitute basis for premature discontinuation 
of study treatment.  
Study-specific criteria for discontinuation of study treatment are described in 
Section 5.1.11. 
A subject who prematurely discontinues study treatment is NOT considered as withdrawn 
from the study, and will be followed up until EOS or 30 days after study treatment 
discontinuation, provided that the subject’s consent for this limited participation in the 
study has not been withdrawn. 
A subject who prematurely discontinues study treatment and withdraws consent to 
participate in any further study assessments is considered as withdrawn from the study. 


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Subjects who die or are lost to follow-up are also considered as withdrawn from the 
study. Withdrawal from the study and follow-up medical care of subjects withdrawn from 
the study are described in Section 9.2 and Section 9.4, respectively. 
5.1.11 Study-specific criteria for interruption / premature discontinuation of study 
treatment 
A) Pregnancy 
If a female subject becomes pregnant while on study treatment, study treatment must be 
discontinued immediately, and a Pregnancy Form must be completed [see Section 10.3]. 
B) Liver aminotransferases abnormalities 
For abnormal laboratory results early in the study’s Screening period (e.g., high ALT or 
AST), the patient should be monitored, provided with appropriate treatment, and 
reassessed throughout the Screening period (90 days from LVAD implantation) for 
eligibility. 
Interruption of study treatment 
Study treatment must be interrupted in the following cases: 
• Aminotransferases (i.e., ALT and/or AST) ≥ 3 and ≤ 8 × ULN  
In such a case, a re-test of aminotransferases (ALT and AST), total and direct bilirubin, 
and alkaline phosphatase must be performed within one week. If AST and/or ALT 
elevation is confirmed, aminotransferases, total and direct bilirubin, and alkaline 
phosphatase levels must continue to be monitored weekly until values return to 
pre-treatment levels, or within normal ranges. If the aminotransferase values return to 
pre-treatment levels or within normal ranges, reintroduction of study treatment can be 
considered. Interruptions must be for less than 2 consecutive weeks; longer interruptions 
must lead to permanent discontinuation of study treatment.  
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. Local laboratories can be used for 
determination of subject status. However, a central laboratory specimen must also be 
collected and submitted prior to reintroduction of study treatment. 
Liver aminotransferase levels must then be checked within 3 days after reintroduction, 
again after a further 2 weeks, and thereafter according to the recommendations above 
(i.e., at monthly intervals). Specimens should be collected and submitted to the central 
laboratory as Unscheduled Visits. 


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Permanent discontinuation of study treatment 
Study treatment must be stopped and its reintroduction is not to be considered in the 
following cases: 
• Aminotransferases > 8 × ULN 
• Aminotransferases ≥ 3 × ULN and associated clinical symptoms of liver injury, e.g., 
nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy or fatigue, flu 
like syndrome (arthralgia, myalgia, fever) 
• Aminotransferases ≥ 3 × ULN and associated increase in total bilirubin ≥ 2 ×ULN. 
In such cases, aminotransferases, total and direct bilirubin, and alkaline phosphatase 
levels must be monitored weekly after study treatment discontinuation until values return 
to pre-treatment levels, or within normal ranges. 
Other diagnoses (e.g., viral hepatitis, mononucleosis, toxoplasmosis, cytomegalovirus) 
and/or etiologies (e.g., acetaminophen-related liver toxicity) should be considered and 
ruled out by performing the appropriate tests. 
All liver aminotransferases abnormalities leading to study treatment interruption or 
discontinuation must be recorded as AEs [see Section 10]. 
C) Hemoglobin abnormalities 
For abnormal laboratory results early in the study’s Screening period (e.g. low 
hemoglobin), the patient should be monitored, appropriate treatment provided, and 
reassessed throughout the Screening period (90 days from LVAD implantation) for 
eligibility. 
In case of hemoglobin decrease from Baseline* of > 2.0 g/dL, a re-test must be 
performed within 10 days, with additional laboratory evaluations that may include, but 
are not limited to, any of the following:  
• Red blood cell cellular indices (mean corpuscular volume, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration), peripheral blood smear, 
reticulocyte count, iron status (iron level, serum ferritin, total iron binding capacity, 
transferrin saturation), lactate dehydrogenase, indirect bilirubin. 
Study treatment should be temporarily interrupted if clinically mandated based on the 
investigator’s judgment, or in any of the following situations: 
• A decrease in hemoglobin to < 6.5 g/dL,  
• A decrease in hemoglobin from Baseline* of > 5.0 g/dL,  


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• The need for transfusion.  
Reintroduction of study medication may be considered if hemoglobin recovery, defined 
as a return of hemoglobin above the lower limit of the normal range or if it returns to a 
value close to that at Baseline.  
Interruption of study medication must not last longer than 2 consecutive weeks; longer 
interruption must lead to permanent discontinuation of study treatment.  
Local laboratories can be used for determination of subject status. However, a central 
laboratory specimen must also be collected and submitted prior to reintroduction of study 
treatment. 
*Baseline hemoglobin: last value obtained prior to first dose of study treatment. 
D) Initiation of a prohibited concomitant medication  
Study treatment must be permanently discontinued if a prohibited concomitant 
medication is initiated. Prohibited concomitant medications are listed in Section 5.2.4.  
E) Clinical evidence of worsening PH or HF  
Study treatment may be discontinued if the study subject demonstrates signs and 
symptoms of progressive HF reflecting worsening PH and RVF. Examples include, but 
are not limited to, the need for RV support pharmacologically with inotropes or 
mechanically with the implantation of RVAD, the development of diuretics resistance, 
objective evidence of declining RV function on echocardiography, evidence of increased 
PVR and/or decreased CO on RHC, and the need for escalation of PH therapies (as 
covered in D). The decision to discontinue the study treatment is based upon the clinical 
judgment and discretion of the principal investigator (PI) and is not limited to the 
examples listed above but will be documented in the eCRF.  
F) Cardiac transplantation  
Study treatment must be permanently discontinued if a subject becomes a recipient of a 
cardiac transplant. RHC obtained prior to cardiac transplantation, to define the subject 
candidacy, must be captured as EOT RHC.  
In case of premature study treatment discontinuation, all EOT assessments, especially 
RHC, should be performed as detailed per EOT visit.  


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5.2 Previous and concomitant therapy 
5.2.1 Definitions 
A previous therapy is any treatment for which the end date is prior to the signing of 
informed consent.  
A therapy that is study-concomitant is any treatment for which the start date is on or after 
the signing of informed consent or up to 30 days after study treatment discontinuation. 
A therapy that is study treatment-concomitant is any treatment for which the start date is 
on or after the first administration of study treatment up to Week 12 or earlier in case of 
premature discontinuation of study treatment. 
5.2.2 Reporting of previous/concomitant therapy in the eCRF 
The use of all concomitant therapy (including contraceptives and traditional and 
alternative medicines, i.e., plant-, animal-, or mineral-based medicines) will be recorded 
in the eCRF. Previous therapy must be recorded in the eCRF if discontinued less than 
28 days prior to Randomization. The generic name, start/end dates of administration (as 
well as whether it was ongoing at start of treatment and/or EOS), route, dose, and 
indication will be recorded in the eCRF. 
Hormonal contraceptives will be recorded on the contraception page of the eCRF.  
5.2.3 Allowed concomitant therapy 
Oral or i.v. diuretics are allowed and may be adjusted during the treatment period.  
(Treatment with oral diuretics is allowed if ongoing at a stable dose for at least 48 h prior 
to the Baseline RHC.) 
5.2.4 Prohibited concomitant therapy 
• PAH-specific therapy (ERAs, i.v., s.c., inhaled or oral prostanoids, PDE5 inhibitors, 
guanylate cyclase stimulators). 
• iNO. 
• Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, voriconazole, 
clarithromycin, 
telithromycin, 
nefazodone, 
ritonavir,saquinavir, 
boceprevir, 
telaprevir, iopinavir, fosamprenavir, darunavir, tipranavir, atazanavir, nelfinavir, 
amprenavir, and idinavir) and strong inducers of CYP3A4 (e.g., carbamazepine, 
rifampicin, rifabutin, phenytoin and St. John’s Wort). 
• Any investigational drug. 
Initiation of one of these prohibited medications will lead to premature discontinuation of 
study treatment. 


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5.3 Allowed LVAD flow rate 
The LVAD pump speed/flow rate may be adjusted during the treatment period, and 
during the Baseline RHC.  
(The LVAD pump speed/flow rate must be stable for at least 48 h prior to Baseline 
RHC.) 
6 
STUDY ENDPOINTS  
Baseline is defined as the last value obtained prior to first dose of study treatment. 
6.1 Efficacy endpoints 
6.1.1 Primary efficacy endpoint(s) 
The primary efficacy endpoint is PVR ratio of Week 12 to Baseline. PVR is obtained by 
the thermodilution method. 
6.1.2 Secondary efficacy endpoints 
• Change from Baseline to Week 12 in mean right atrial pressure (mRAP), mPAP, 
PAWP, CI, total pulmonary resistance (TPR), and mixed venous oxygen saturation 
(SVO2), all measured at rest. 
• Change from Baseline to Week 12 in NT-proBNP. 
• Change from Baseline to Week 12 in WHO FC. 
6.1.3 Exploratory efficacy endpoints 
• Change from Baseline to Week 12 in echocardiographic variables that include: 
− 2D global RV longitudinal strain (global RVLS) 
− RV sphericity index (RVSI) 
− RV end systolic area 
− RV end diastolic area  
− Tricuspid annular plane systolic excursion (TAPSE)  
− Tricuspid peak annular velocity s’ (S’) 
− RV fractional area change (RVFAC) 
− Tricuspid peak diastolic annular velocities e’, a’ (E’, A’) 
• Time to first occurrence of clinical events, from enrollment to Week 12. These 
clinical events include:  
− Hospital admission for HF  
− Re-initiation of i.v. diuretics ≥ 48 h duration 
− Re-initiation of i.v. inotropes ≥ 48 h duration  


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− Initiation of PDE5 inhibitors 
− Need for RVAD / total artificial heart (TAH) 
− Need for renal replacement therapy (RRT) 
− Death 
• Days in the hospital after hospitalization for HF. 
• Change in GFR from Baseline to Week 12. 
6.2 Safety endpoints 
• Treatment-emergent AEs up to 30 days after study treatment discontinuation. 
• AEs leading to premature discontinuation of study treatment. 
• Death up to 30 days after study treatment discontinuation. 
• Treatment-emergent SAEs up to 30 days after study treatment discontinuation. 
• Change from Baseline to EOT in vital signs. 
• Occurrence of liver function test (ALT and/or AST) abnormality (≥ 3 × ULN; ≥ 3 and  
< 5 × ULN; ≥ 5 and < 8 × ULN; ≥ 8 × ULN) up to EOT. 
• Occurrence of ALT and/or AST abnormality ≥ 3 × ULN associated with bilirubin 
≥ 2 × ULN up to EOT. 
• Proportion of patients with treatment-emergent hemoglobin abnormality (< 10.0 g/dL, 
and < 8.0 g/dL) as compared to Baseline up to EOT. 
• Treatment-emergent marked laboratory abnormalities up to EOT. 
Marked laboratory abnormalities are defined in the central laboratory manual. 
6.3 Biomarker endpoints 
Change in NT-proBNP will be assessed from Baseline to Week 12 (EOT) as part of the 
secondary efficacy endpoints analysis [see Section 6.1.2]. Additional circulating 
biomarkers may be analyzed in an exploratory format (post-hoc) based on available 
scientific evidence. No genetic testing will be performed.  
7 
STUDY ASSESSMENTS 
All study assessments are performed by a qualified study staff member: medical, nursing, 
or specialist technical staff, and are recorded in the eCRF, unless otherwise specified. 
Study assessments performed during Unscheduled Visits will also be recorded in the 
eCRF. When applicable, the assessments should be performed in the following order: 
• 
Blood sampling 
• 
Physical examination  


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• 
WHO FC  
• 
RHC at rest 
• 
Echo (i.e., 3D, 2D, M-mode and Doppler echocardiography)  
If the PI delegates any study procedure/assessment for a subject, e.g., RHC, blood 
sampling etc., to an external facility, he/she should inform Actelion of to whom these 
tasks are delegated. The set-up and oversight will be agreed upon with Actelion. The 
supervision of any external facilities remains under the responsibility of the PI. 
Calibration certificates for the following devices used to perform study assessments must 
be available prior to the Randomization of the first subject:  
• Temperature measurement devices for study medication storage area and freezer 
• RHC equipment 
• Scale for measuring body weight 
7.1 Screening/Baseline assessments 
Date of informed consent, Baseline demographics (sex, age, race, ethnicity, body weight, 
height) as well as a reason for why a woman is not considered to be of child-bearing 
potential (if applicable) are to be recorded in the eCRF at Visit 1 / Screening only after 
Informed Consent has been signed. 
Complete, clinically relevant medical history (previous and ongoing at Randomization) 
as described in Section 4.6 and disease characteristics, vital signs, body mass index 
(BMI), and previous/ongoing medications [see Section 5.2.2] are to be documented in the 
eCRF at Visit 1 / Screening. Historical data of pre-LVAD RHC and non-Baseline 
post-LVAD RHC may be entered into the eCRF.  
A physical examination of the subject should be performed at Visit 1 / Screening and 
Visit 2 / Randomization. Data are not collected in the eCRF though abnormal findings are 
to be recorded as AEs. 
Reason for Screening failure, if applicable, must be recorded in the eCRF.  
Serum laboratory and pregnancy testing should be performed at Visit 1 / Screening and 
repeated at Visit 2 / Randomization, whereas blood sampling for Baseline NT-proBNP 
should only be performed at Visit 2 / Randomization. 
At Visit 2 / Randomization, WHO FC, vital signs, and body weight is to be assessed and 
ongoing medications are to be collected in the eCRF. Study medication is dispensed at 
this visit.  


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AEs and SAEs occurring during the course of the study are to be documented in the 
eCRF.  
7.2 Efficacy assessments 
7.2.1 Hemodynamic measurements - right heart catheterization  
Eligibility for the SOPRANO study should be considered for all post-LVAD patients 
provided they have clinical or hemodynamic evidence of PH (e.g., PVR > 3 WU) on 
pre-LVAD RHC or immediate post-LVAD hemodynamics. Subjects without clinical or 
hemodynamic evidence of PH should not be screened for the study.  
The patient must be stable for 48 h prior to the Baseline RHC. Stabilization is defined as:  
• No LVAD pump speed/flow rate changes, and  
• Stable dose of oral diuretics, and  
• No i.v. inotropes or vasopressors, and  
• Patient able to ambulate.  
 
Baseline RHC is defined as the last hemodynamic measurements after LVAD 
implantation and prior to first dose of study treatment. Hemodynamic evidence of PH on 
Baseline RHC is one of the inclusion criteria of SOPRANO. PH is defined as: mPAP 
≥ 25 mmHg, PAWP ≤ 18 mmHg and PVR > 3 WU.  
An RHC conducted prior to signing the Informed Consent may be accepted as the 
Baseline RHC. Baseline RHC must be performed by the thermodilution method, after 
LVAD implantation and prior to first dose of study treatment (which must occur within 
90 days post-surgical implantation of LVAD, see Section 3). Randomization (Visit 2) 
must be within 14 days of Baseline RHC. Patients are excluded if they were treated with 
ERAs, PDE5 inhibitors, i.v., s.c., or oral prostanoids, or guanylate cyclase stimulators 
within 7 days prior to Baseline RHC or study treatment initiation. Patients are excluded if 
they were treated with inhaled prostanoids (e.g., iloprost, epoprostenol), nitric oxide or 
i.v. inotropes or vasopressors within 24 h prior to Baseline RHC or study treatment 
initiation. LVAD pump speed/flow rate may be adjusted during the treatment period and 
during the Baseline RHC. 
An RHC is repeated at Week 12, or within 7 days of permanent discontinuation of study 
treatment if prior to Week 12. The Week 12 RHC must be performed by the 
thermodilution method, and not within 24 h of treatment with i.v. inotropes or 
vasopressors. 
All RHC procedures must be performed according to the Actelion RHC Instructions. 
Hemodynamic tracings, and the Hemodynamic Checklist and Data Worksheet (as 


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provided by Actelion) must be completed and signed by the PI, and filed at site in the 
subject’s file. 
The following variables are to be measured and collected in the eCRF: pulse rate, PAWP, 
mRAP, systolic/diastolic/mean PAP, CO, and SVO2. Non-invasive mean, SBP and DBP 
if available, are collected and entered into the eCRF. PVR will be calculated locally and 
entered into the eCRF. CO measurements, and PVR calculations, during both Baseline 
and Week 12 RHC must be obtained via the thermodilution method. All primary end 
point calculations must be based on thermodilution method-calculated PVR.  
The following hemodynamic variables will be calculated by Actelion for analysis 
purposes [see Section 11.2 and the SOPRANO Right Heart Catheterization Instructions 
for formulae]: PVR, TPR, and CI. 
7.2.2 WHO functional class 
WHO FC is evaluated at Baseline/Randomization and EOT. 
7.2.3 Serum NT-proBNP 
A blood sample will be drawn at Randomization (Visit 2) and EOT (Visit 5) for the 
analysis of serum NT-proBNP. 
Serum NT-proBNP samples will be stored frozen at −20 °C (−4 °F) ± 2 °C (± 3.6 °F). A 
temperature log must be maintained and temperature control should occur at least on a 
weekly basis. NT-proBNP samples will be processed through the central laboratory and 
the results will be sent electronically to Actelion on an ongoing basis. Further details 
regarding blood sampling procedures, collection and shipment of biomarker samples are 
described in the central laboratory manual. 
7.2.4 Echocardiography 
Echo (i.e., 3D, 2D, M-mode and Doppler echocardiography) will be performed according 
to the guidelines detailed in the Actelion Echo image acquisition protocol on 
Visit 2 / Randomization, which will represent the Baseline measurements and be repeated 
at the Week 12 visit. Baseline ECHO must occur on the day of Randomization. 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 sent to Actelion: 
• 2D RVLS 
• RVSI 
• RV end systolic area 
• RV end diastolic area  


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• TAPSE  
• S’ 
• RVFAC 
• E’, A’ 
7.2.5 Clinical events 
Time to first occurrence of clinical events, from enrollment to Week 12 will be recorded. 
These clinical events include:  
• Hospital admission for HF  
• Re-initiation of i.v. diuretics ≥ 48 h duration.  
• Re-initiation of i.v. inotropes ≥ 48 h duration.  
• Initiation of PDE5 inhibitors 
• Need for RVAD/TAH 
• Need for RRT 
• Death 
Hospital admissions for HF, as an exploratory endpoint, will be adjudicated by the 
SOPRANO Steering Committee.  
7.2.6 Duration of heart failure hospitalization  
Duration of HF hospitalization will be captured as the number of days in the hospital 
after hospitalization for HF, excluding rehabilitation stay. A hospitalization for HF is 
defined as a hospitalization in which the principal diagnosis is HF. Hospital admissions 
for HF, as an exploratory endpoint, will be adjudicated by the SOPRANO Steering 
Committee.  
7.2.7 Glomerular filtration rate 
Change in GFR from Baseline to Week 12 will be recorded. GFR will be estimated on 
the basis of serum creatinine levels. The formula can be found in the central laboratory 
manual. 
7.3 Safety assessments 
The definitions, reporting and follow-up of AEs, SAEs, and pregnancies are described in 
Section 10. 
7.3.1 Vital signs 
Vital signs (BP, pulse rate) will be measured via Doppler at Screening (Visit 1), 
Randomization (Visit 2), and EOT (Visit 5), and collected in the eCRF. BP (mean, 
systolic and diastolic, if available) and pulse rate will be measured in a supine or sitting 


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position after the subject has rested for at least 5 min. The right or left arm may be used. 
The same position and arm should be used throughout the trial for an individual subject. 
7.3.2 Weight and height 
Height will be measured at Visit 1 / Screening. Body weight will be measured at 
Visit 1 / Screening, Randomization, and EOT. 
7.3.3 Physical examination 
Physical examination (i.e., inspection, percussion, palpation and auscultation) is to be 
performed during the Screening period (Visit 1) and EOT. The data are not collected in 
the eCRF, but clinically relevant findings that are present at the signing of Informed 
Consent must be recorded on the Medical History eCRF page, while physical 
examination findings made after the signing of Informed Consent and which meet the 
definition of an AE [Section 10.1.1] must be recorded by the investigator on the AE page 
of the eCRF. 
7.3.4 Laboratory assessments 
7.3.4.1 Type of laboratory 
A central laboratory (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 data will be 
automatically transferred from the central laboratory database to Actelion’s clinical 
database.  
• For the follow-up of abnormal values such as ALT/AST and/or hemoglobin 
[see Section 5.1.11] central laboratory specimens must be obtained in parallel with 
local laboratories for re-test and prior to reintroduction of study treatment.  
Local laboratory results will be collected in the following situations: 
• In case of missing central laboratory values, any local laboratory values noted as 
significant are to be recorded in the eCRF, especially local laboratory results related 
to the diagnostic work-up (i.e., detection, confirmation and/or monitoring) of 
ALT/AST elevations and hemoglobin decreases. In the event that several local 
laboratory samples are taken on the same day or if the sample was tested several 
times, the significance of the ‘worst’ value (e.g., highest value for ALT/AST, lowest 
value for hemoglobin) should be reported in the eCRF. 
• In exceptional cases (e.g., subject is hospitalized in a different hospital from the study 
center due to a medical emergency) where a local laboratory is used for the collection 


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and analysis of blood samples, the results noted as significant will be entered into the 
clinical database via dedicated eCRF pages. For local laboratories, the 
investigator/delegate will provide Actelion with the name, professional degree and 
curriculum vitae (CV) of the laboratory director, a copy of the laboratory’s 
certification, and the normal ranges for each laboratory test that is evaluated in the 
study. These laboratory references must be updated whenever necessary. 
• At the time of Screening, local laboratory results may be used for checking subject 
eligibility (since central laboratory results would not be available immediately). 
Central laboratory results should be collected once eligibility is confirmed. 
Laboratory variables required at Visit 2 are repeated at the central laboratory to be 
used as the Baseline values for safety laboratory endpoints specified in the protocol. 
Laboratory certification / reference ranges / laboratory director’s CV will be collected 
by the sponsor for all local laboratories providing data that are entered into the 
clinical and/or safety databases. 
If a central laboratory sample is lost, has deteriorated or cannot be analyzed for whatever 
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 the central laboratory 
manual. 
All laboratory reports must be signed and dated by the 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 signature of Informed Consent must be recorded on the medical 
history page of the eCRF. Any clinically relevant laboratory abnormalities detected after 
signature of Informed Consent 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 should be performed as indicated and according to the judgment of the 
investigator. 
Details about the collection, sampling, storage, shipment procedures, and reporting of 
results and abnormal findings can be found in the laboratory manual. 
The last laboratory sample collected for the study will be analyzed prior to database lock. 
Laboratory samples will be destroyed within one year of database lock. 


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7.3.4.2 Laboratory tests 
Hematology 
Hematology tests will be performed at every visit (Visits 1 to 6) and include: 
• Hemoglobin, hematocrit 
• Erythrocyte count 
• Leukocyte count with differential counts 
• Platelet count 
 
Rules for study treatment interruption in case of hemoglobin abnormalities are provided 
in Section 5.1.11. 
Clinical chemistry 
Clinical chemistry tests will be performed at every visit (Visits 1 to 6) and include: 
• Aminotransferases (AST/ALT), alkaline phosphatase, total and direct bilirubin, 
lactate dehydrogenase (LDH) 
• Creatinine, blood urea nitrogen (BUN) 
• Uric acid 
• Glucose 
• Cholesterol, triglycerides 
• Sodium, potassium, chloride, calcium 
• Protein, albumin 
Rules for study treatment interruption in case of liver function abnormalities are provided 
in Section 5.1.11. 
GFR 
GFR will be estimated on the basis of serum creatinine levels. The formula can be found 
in the central laboratory manual. 
Pregnancy test 
A serum pregnancy test for women of childbearing potential will be provided by the 
central laboratory and will be performed at Visits 1 to 6 and if pregnancy is suspected 
during the study. A locally approved test can be used; however, the subject must come to 
the site for a confirmatory serum pregnancy test to be performed by the central 
laboratory.  


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7.4 Biomarker and genetic assessments 
Besides NT-proBNP, additional circulating biomarkers such as: interleukin-6 (IL-6), 
tumor necrosis factor-α (TNF-α), high sensitivity C-reactive protein (hsCRP), ET-1, 
galectin-3, growth differentiation factor-15 (GDF-15), interleukin 1 receptor ST2, 
neutrophil gelatinase-associated lipocalin (NGAL), copeptin, high sensitivity cardiac 
troponin T (hs-cTnT), Cystatin-C and osteopontin, may be analyzed in an exploratory 
format (post-hoc) based on available scientific evidence.  
The last laboratory sample collected for the study will be analyzed prior to database lock. 
Laboratory samples will be destroyed within one year of database lock. 
8 
SCHEDULE OF VISITS 
Table 1 provides a summary of all visits and assessments described in the following 
sections.  
To ensure compliance, at each visit, the study personnel must remind women of 
childbearing potential to use the methods of contraception defined for this study. The 
reminders must be documented in the hospital chart. 
If the reason for non-eligibility was transient (e.g., abnormal laboratory test, insufficient 
wash-out period of a prohibited medication, etc.), patients can be re-screened provided 
that documented authorization has been received from Actelion. All Screening 
assessments should then be repeated at the time of re-screening.  
8.1 Screening period 
8.1.1 Screening (Visit 1) 
All Screening assessments must be performed within the 90-day Screening period, 
beginning with LVAD implantation and prior to Randomization. Historical data of 
pre-LVAD RHC and non-Baseline post-LVAD RHC may be entered into the eCRF.  
It is the responsibility of the investigator to obtain written Informed Consent from each 
subject participating in this study after adequate face-to-face explanation of the 
objectives, methods, and potential hazards of the study. The subjects who agree to 
participate in the study must sign the ICF prior to any study-related assessment or 
procedure.  
The date of Informed Consent should be recorded as the date of the Screening visit in 
IxRS. 
Screening and Randomization can occur on the same day, provided that all procedures of 
Visit 1 are completed before the procedures of Visit 2 are initiated. 


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Visit 1 includes:  
• ICF signature. 
• Obtain subject number from IxRS. 
• Recording of demographics, Baseline characteristics, and medical history. 
• Recording of previous and concomitant medications. 
• Physical examination. 
• Measurement of vital signs, height and body weight. 
• Complete laboratory tests, including pregnancy test for women of childbearing 
potential. 
• Recording of methods of contraception (for females of childbearing potential only) 
and initiation of protocol-compliant contraception if applicable. The reason why a 
female is not considered to be of childbearing potential will also be collected in the 
eCRF. 
• RHC (unless the procedure was already performed and would be within 90 days of 
Randomization, and per the requirements described in Section 7.2.1). 
• Recording of AEs and SAEs.  
The investigator will check all the inclusion/exclusion criteria and decide on the subject’s 
eligibility for the study. It must be verifiable in the source documents that the subject met 
each of the inclusion criteria and none of the exclusion criteria. If the subject is a Screen 
failure and not randomized, the reason for Screen failure is to be documented in the IxRS 
system and in the eCRF. 
8.2 Double-blind study treatment period 
8.2.1 Randomization (Visit 2) 
Visit 2 corresponds to the start of the treatment period (Day 1 of the study) for subjects 
that are eligible after all Screening assessments have been performed. It must be within 
90 days after LVAD implantation and within 14 days of Baseline RHC. 
Visit 2 includes: 
• Recording of changes in concomitant medications. 
• Measurement of vital signs and body weight. 


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• Complete laboratory tests, including serum pregnancy test for women of childbearing 
potential. 
• Assessment of methods of contraception (for females of childbearing potential only). 
• Blood sample for serum NT-proBNP.  
• Blood sample for additional circulating biomarkers such as: IL-6, TNF-α, hsCRP, 
ET-1, galectin-3, GDF-15, interleukin 1 receptor ST2, NGAL, copeptin, hs-cTnT, 
Cystatin-C and osteopontin, will be collected and may be analyzed in an exploratory 
format (post-hoc) based on available scientific evidence.  
• WHO FC.  
• Echo (i.e., 3D, 2D, M-mode and Doppler echocardiography) will be performed. 
Those include: TAPSE, S’, RVFAC, E’, A’, global RVLS, RV area and RVSI. 
Additionally, right and left ventricular echo variables may be analyzed in an 
exploratory format (post-hoc) based on available scientific evidence. Baseline ECHO 
must occur on the day of Randomization. 
• Recording of AEs/SAEs. 
After completion of all Screening and Randomization assessments and confirmation of 
eligibility (i.e., verification of all entry criteria) by the investigator: 
• Randomization via IxRS to obtain Randomization and study treatment bottle number. 
• Dispensing of 1 bottle of study treatment [see Section 5.1.7.3]. 
8.2.2 Week 4 (Visit 3) 
Visit 3 is scheduled 4 weeks (± 7 days) after Randomization. Visit 3 includes: 
• Recording of changes in concomitant medications.  
• Complete laboratory tests, including serum pregnancy test for women of childbearing 
potential. 
• Assessment of methods of contraception (for females of childbearing potential only). 
• Recording of AEs and SAEs. 
• Dispensing of 1 bottle of study treatment [see Section 5.1.7.3]. 
• Study medication return; subjects are asked to return all used, partially used, and 
unused study treatment bottles [see Section 5.1.7.3]. 


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8.2.3 Week 8 (Visit 4) 
Visit 4 is scheduled 8 weeks (± 7 days) after Randomization. Visit 4 includes: 
• Recording of changes in concomitant medications. 
• Complete laboratory tests, including serum pregnancy test for women of childbearing 
potential. 
• Assessment of methods of contraception (for females of childbearing potential only). 
• Recording of AEs and SAEs. 
• Dispensing of 1 bottle of study treatment [see Section 5.1.7.3]. 
• Study medication return; subjects are asked to return all used, partially used, and 
unused study treatment bottles [see Section 5.1.7.3]. 
8.2.4 End-of-Treatment (Visit 5) 
EOT is scheduled 12 weeks (± 7 days) after Randomization, or earlier in case of 
premature discontinuation of study treatment.  
EOT includes: 
• Recording of changes in concomitant medications. 
• Physical examination. 
• Measurement of vital signs and body weight. 
• Complete laboratory tests, including serum pregnancy test for women of childbearing 
potential. 
• Assessment of methods of contraception (for females of childbearing potential only). 
• RHC. 
• Blood sample for serum NT-proBNP.  
• Blood sample for additional circulating biomarkers such as: IL-6, TNF-α, hsCRP, 
ET-1, galectin-3, GDF-15, interleukin 1 receptor ST2, NGAL, copeptin, hs-cTnT, 
Cystatin-C and osteopontin, will be collected and may be analyzed in an exploratory 
format (post-hoc) based on available scientific evidence. 
• WHO FC.  


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• Echo (i.e., 3D, 2D, M-mode and Doppler echocardiography) will be performed. 
Those include: TAPSE, S’, RVFAC, E’, A’, global RVLS, RV area and RVSI. 
Additionally right and left ventricular echo variables may be analyzed in an 
exploratory format (post-hoc) based on available scientific evidence. 
• Study medication return; subjects are asked to return all used, partially used, and 
unused study treatment bottles [see Section 5.1.7.3]. 
• Recording of AEs and SAEs. 
8.2.5 End-of-Study (Visit 6) 
Subjects who complete the study as planned, i.e., full 12-week study period and those 
who prematurely discontinue study treatment will enter a 30-day safety follow-up period, 
which ends with the EOS visit at least 30 days (+ 7 days) after the permanent 
discontinuation of study treatment (last dose of study drug). EOS includes: 
• Recording of changes in concomitant medications. 
• Complete laboratory tests, including serum pregnancy test for women of childbearing 
potential. 
• Assessment of methods of contraception (for females of childbearing potential only). 
• Recording of AEs and SAEs. 
8.2.6 Unscheduled Visits (U1, U2, etc) 
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), appropriate assessments 
[as specified in Table 1] may be performed based on the judgment of the investigator and 
must be recorded in the eCRF. After an Unscheduled Visit, the regular scheduled study 
visits must continue according to the planned visit and assessment schedule. 
9 
STUDY COMPLETION AND POST-STUDY TREATMENT/MEDICAL 
CARE 
9.1 Study completion 
For an individual subject, the study is considered completed once EOT has been 
performed and the 30-day safety follow-up is complete (EOS). 
The study is considered complete when all subjects have completed as detailed above. 
The planned study duration is approximately 24 months from first subject, first visit to 
last subject, last visit. 


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9.2 Premature withdrawal from study 
Subjects may voluntarily withdraw from the study for any reason at any time. Subjects 
are considered withdrawn if they state an intention to withdraw further participation in all 
components of the study, die or are lost to follow-up. The investigator may withdraw a 
subject from the study (without regard to the subject’s consent) if, on balance, they 
believe that continued participation in the study would be contrary to the best interests of 
the subject. Withdrawal from the study may also result from a decision by Actelion for 
any reason, including premature termination or suspension of the study [see Section 9.3]. 
Subjects are considered as lost to follow-up if all reasonable attempts by the investigator 
to communicate with the individual fail. The site must take preventive measures to avoid 
a subject being lost to follow-up (e.g., document different ways of contact such as 
telephone number, home address, e-mail address, person to be contacted in case the 
subject cannot be reached). If the subject cannot be reached, the site must make a 
reasonable effort to contact the subject, document all attempts and enter the loss of 
follow-up information into the eCRF. 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 
subject’s home), respecting the subject’s right to privacy. If the subject is still 
unreachable after all contact attempts listed above, he/she will be considered to be lost to 
follow-up.  
If premature withdrawal occurs for any reason, the reason for premature withdrawal from 
the study, along with who made the decision (subject, investigator or Actelion) must be 
recorded in the eCRF. 
If, for whatever reason (except death or loss-to-follow-up), a subject was withdrawn from 
the study, the investigator should make efforts to conduct a last visit/contact to assess the 
safety and well-being of the subject, collect unused study drug and discuss follow-up 
medical care. The investigator must provide follow-up medical care for all subjects who 
are prematurely withdrawn from the study, or must refer them for appropriate ongoing 
care, as described in Section 9.4. 
9.3 Premature termination or suspension of the study 
Actelion reserves the right to terminate the study at any time globally or locally. 
Investigators can terminate the participation of their site in the study at any time. 
If a study is prematurely suspended or terminated, Actelion will promptly inform the 
investigators, the IRBs/IECs, and Health Authorities, as appropriate, and provide the 
reasons for the suspension or termination. 


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If the study is suspended or prematurely terminated for any reason, the investigator in 
agreement with Actelion must promptly inform all enrolled subjects, and ensure their 
appropriate treatment and follow-up, as described in Section 9.2. Actelion may inform 
the investigator of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the subjects’ interests. 
In addition, if the investigator suspends or terminates a study without prior agreement 
from Actelion, the investigator must promptly inform Actelion and the IRB/IEC, and 
provide both with a detailed written explanation of the termination or suspension. 
If the IRB/IEC suspends or terminates its approval/favorable opinion of a study, the 
investigator must promptly notify Actelion and provide a detailed written explanation of 
the termination or suspension. 
Any suspension or premature termination of the study must be discussed with the IDMC 
and Steering Committee. 
9.4 Medical care of subjects after study completion/withdrawal from study 
After the subject’s study completion or premature withdrawal from the study, whichever 
applies, the investigator/delegate will explain to subjects what treatment(s)/medical care 
is necessary and available according to local regulations. 
After premature study withdrawal, the investigator must remind the subject that he/she 
must not use any other investigational treatment in the 30 days following study treatment 
discontinuation. Female subjects of childbearing potential need to be reminded of the 
requirement to continue using a reliable method of contraception until 30 days after 
intake of the last dose of study treatment. 
10 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
10.1 Adverse events 
10.1.1 Definitions of adverse events 
An AE is any adverse change, i.e., any unfavorable and unintended sign, including an 
abnormal laboratory finding, symptom, or disease that occurs in a subject during the 
course of the study, whether or not considered by the investigator as related to study 
treatment. 
AEs include: 
• Exacerbation of a pre-existing disease. 


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• 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 (i.e., signing of informed consent). 
• 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. 
A treatment-emergent AE is any AE temporally associated with the use of study 
treatment (from study treatment initiation until 30 days after study treatment 
discontinuation), whether or not considered by the investigator as related to study 
treatment. 
Overdose, misuse, and abuse of the study treatment should be reported as an AE and, in 
addition, study treatment errors must be documented in the study drug log of the eCRF. 
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 eCRF. 
If the intensity of an AE worsens during study treatment administration, only the worst 
intensity should be reported on the AE page. If the AE lessens in intensity, no change in 
the severity is required. 
If the intensity of an AE with an onset date between Informed Consent signature and start 
of study treatment and which is ongoing at the start of treatment worsens after the start of 
study treatment, a new AE page must be completed. The onset date of this new AE 
corresponds to the date of worsening in intensity. 
The three categories of intensity are defined as follows: 
 Mild 
The event may be noticeable to the subject. It does not influence daily activities, and 
usually does not require intervention. 


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 Moderate 
The event may make the subject uncomfortable. Performance of daily activities may be 
influenced, and intervention may be needed. 
 Severe 
The event may cause noticeable discomfort, and usually interferes with daily activities. 
The subject may not be able to continue in the study, and treatment or intervention is 
usually needed. 
A mild, moderate, or severe AE may or may not be serious [see Section 10.3.1]. These 
terms are used to describe the intensity of a specific event. Medical judgment should be 
used on a case-by-case basis. 
Seriousness, rather than severity assessment, determines the regulatory reporting 
obligations. 
10.1.3 Relationship to study treatment 
Each AE must be assessed by the investigator as to whether or not there is a reasonable 
possibility of causal relationship to the study treatment, and reported as either related or 
unrelated. The determination of the likelihood that the study treatment caused the AE will 
be provided by an investigator who is a qualified physician. 
10.1.4 Adverse events associated to study design or protocol-mandated procedures 
An AE is defined as related to study design or protocol-mandated procedures if it appears 
to have a reasonable possibility of a causal relationship to either the study design or to 
protocol-mandated procedures. Examples include discontinuation of a subject’s previous 
treatment during a washout period leading to exacerbation of underlying disease. 
10.1.5 Reporting of adverse events 
All AEs occurring after the signing of Informed Consent and up to 30 days after study 
treatment discontinuation must be recorded on specific AE pages of the eCRF of study 
AC-055-205.  
10.1.6 Follow-up of adverse events 
Adverse events still ongoing more than 30 days after study treatment discontinuation 
must be followed up until they are no longer considered clinically relevant. 


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10.2 Serious adverse events 
10.2.1 Definitions of serious adverse events 
10.2.1.1 Serious adverse events 
An SAE is defined by the ICH guidelines as any AE fulfilling at least one of the 
following criteria: 
• Fatal. 
• Life-threatening: refers to an event in which the subject was at risk of death at the 
time of the event. It does not refer to an event that hypothetically might have caused 
death had it been more severe. 
• Requiring inpatient hospitalization, or prolongation of existing hospitalization. 
• Resulting in persistent or significant disability or incapacity. 
• Congenital anomaly or birth defect. 
• Medically significant: refers to important medical events that may not immediately 
result in death, be life-threatening, or require hospitalization but may be considered to 
be SAEs when, based upon appropriate medical judgment, they may jeopardize the 
subject, and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definitions above. 
The following reasons for hospitalization are exempted from being reported: 
• Hospitalization for cosmetic elective surgery, or social and/or convenience reasons. 
• Hospitalization for pre-planned (i.e., planned prior to signing informed consent) 
surgery or standard monitoring of a pre-existing disease or medical condition that did 
not worsen, e.g., hospitalization for coronary angiography in a subject with stable 
angina pectoris. 
However, complications that occur during hospitalization are AEs or SAEs (for example, 
if a complication prolongs hospitalization). 
10.2.2 Reporting of serious adverse events 
All SAEs occurring after the signing of Informed Consent and up to 30 days after study 
treatment discontinuation must be reported on AE pages in the eCRF of study 
AC-055-205, and on an SAE form, regardless of the investigator-attributed causal 
relationship with study treatment or study-mandated procedures.  


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10.2.3 Follow-up of serious adverse events 
SAEs still ongoing at the EOS visit for study AC-055-205 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 by the investigator to be causally related to previous exposure to the study 
treatment. 
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. 
All SAEs must be recorded on an SAE form, irrespective of the study treatment received 
by the subject, and whether or not this event is considered by the investigator to be 
related to study treatment. 
The SAE forms must be faxed to the Actelion Drug Safety department (contact details are 
provided on the SAE form). The investigator must complete the SAE form in English, 
and must assess the causal relationship of the event to study treatment. 
Follow-up information about a previously reported SAE must also be reported within 
24 h of receiving it. The Actelion Drug Safety department may contact the investigator to 
obtain further information. 
If the subject is hospitalized in a hospital other than the study site, it is the investigator’s 
responsibility to contact this hospital to obtain all SAE relevant information and 
documentation. The reference safety document to assess expectedness of a suspect 
serious adverse reaction and reported by the sponsor to Health Authorities, IRBs/IECs, 
and investigators is the reference safety information section of the Investigator’s 
Brochure [Macitentan IB]. 
The following events that are expected to occur in patients with PAH/PH 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, 
HF, hypoxia, palpitations, syncope, collapse, systemic arterial hypotension, and 
tachycardia. These SAEs must also be reported on AE pages in the eCRF and on an SAE 
form 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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10.3 Pregnancy 
If a woman becomes pregnant while on study treatment, study treatment must be 
discontinued. The investigator must counsel the subject and discuss the risks of 
continuing with the pregnancy and the possible effects on the fetus. 
10.3.1 Reporting of pregnancy 
Irrespective of the treatment received by the subject, any pregnancy occurring after the 
signing of Informed Consent and up to 1 month following study treatment 
discontinuation must be reported within 24 h of the investigator’s knowledge of the 
event. 
Pregnancies must be reported on the Actelion Pregnancy form, which is faxed to the 
Actelion drug safety department (see contact details provided on the Actelion Pregnancy 
form), and on an AE page in the eCRF. 
10.3.2 Follow-up of pregnancy 
Any pregnancy must be followed to its conclusion and its outcome must be reported to 
the Actelion drug safety department. 
Any AE associated with the pregnancy occurring during the follow-up period after study 
treatment discontinuation must be reported on separate AE pages in the eCRF. 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, ECGs, vital signs, and 
project-specific labs/examinations as required) is monitored and reviewed on a 
continuous basis by the Actelion Clinical Team (in charge of ensuring subjects’ safety as 
well as data quality) by periodically monitoring clinical studies activities from protocol 
conception to database closure. 
In addition, an IDMC is monitoring data from the study and may recommend 
modification, discontinuation or completion of the study [see Section 3.3]. 
11 STATISTICAL METHODS 
All statistical analyses will be conducted by Actelion or by designated CRO 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.  


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11.1 Analysis sets 
11.1.1 Screened Analysis Set 
This analysis set includes all patients who were screened and received a Screening 
number. 
11.1.2 Safety Set 
The Safety Set (SS) includes all patients who received at least one dose of study drug in 
the treatment period. 
11.1.3 Full Analysis Set 
The Full Analysis Set (FAS) includes all patients randomized. 
11.1.4 Modified Full Analysis Set 
The modified FAS includes all patients in the FAS that have received at least one dose of 
study treatment in the treatment period and have a Baseline and at least one post-Baseline 
PVR measurement. 
11.1.5 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 variable. 
The reasons for excluding patients from the PPS will be fully defined and documented in 
the SAP. 
11.1.6 Usage of the analysis sets 
The primary efficacy analysis will be performed on the FAS based on treatment as 
randomized. Secondary and exploratory efficacy analyses will also be performed on the 
FAS. Sensitivity analyses will be conducted based on the modified FAS for the primary 
and selected secondary efficacy endpoints. 
Safety analyses related to the double-blind treatment period will be performed on the SS 
based on treatment as received. 
Subject listings will be based on the SS, unless otherwise specified. Subject disposition 
will be described for the Screened Analysis Set. 


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11.2 Variables 
11.2.1 Primary efficacy variable(s)  
The primary efficacy variable is PVR ratio of Week 12 to Baseline. PVR [WU] is 
calculated as (mPAP − PAWP) / CO.  
11.2.2 Secondary efficacy variables 
Secondary efficacy variables are changes from Baseline to Week 12, for: 
• mRAP (mmHg) 
• mPAP (mmHg) 
• PAWP (mmHg) 
• CI (L/min/m2), calculated as CO / body surface area (BSA) where BSA 
(m2) = 0.007184 × weight0.425 (kg) × height0.725 (cm) 
• TPR (WU), calculated as mPAP / CO  
• SVO2 (%)  
• NT-proBNP (pmol/L) 
• WHO FC (I–IV). 
11.2.3 Exploratory efficacy variables 
• Echocardiographic variables including: 
− 2D global RVLS 
− RVSI 
− RV end systolic area 
− RV end diastolic area  
− TAPSE  
− S’ 
− RVFAC 
−  E’, A.’ 
• Clinical events including: 
− Hospital admission for HF  
− Re-initiation of i.v. diuretics ≥ 48 h duration 
− Re-initiation of i.v. inotropes ≥ 48 h duration  
− Initiation of PDE5 inhibitors 
− Need for RVAD/TAH 
− Need for RRT 
− Death.  
• Days in the hospital after index hospitalization for HF. 


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• Change in GFR from Baseline to Week 12. 
11.2.4 Safety variables 
• Treatment-emergent AEs up to 30 days after study treatment discontinuation.  
• AEs leading to premature discontinuation of study treatment. 
• Death up to 30 days after study treatment discontinuation. 
• Treatment-emergent SAEs up to 30 days after study treatment discontinuation. 
• Change from Baseline to EOT in vital signs. 
• Proportion of patients with treatment-emergent ALT and/or AST abnormalities from 
Baseline up to EOT, classified as: 
− ≥ 3 × ULN; 
− ≥ 3 × ULN and < 5 × ULN; 
− ≥ 5 × ULN and < 8 × ULN; 
− ≥ 8 × ULN. 
• Proportion of patients with ALT and/or AST abnormality ≥ 3 × ULN in combination 
with total bilirubin ≥ 2 × ULN from Baseline up to EOT. 
• Proportion of patients with treatment-emergent hemoglobin abnormalities as 
compared to Baseline up to EOT, classified as: 
− < 8.0 g/dL 
− < 10.0 g/dL. 
• Treatment-emergent marked laboratory abnormalities up to EOT. 
11.3 Description of statistical analyses 
11.3.1 Overall testing strategy 
The overall type I error is α = 0.025 (one-sided). The type II error is set to 0.20 and the 
power to 80%. 
11.3.2 Analysis of the primary efficacy variable(s) 
11.3.2.1 Hypotheses and statistical model 
The null hypothesis is that the mean PVR ratio is the same in the macitentan and placebo 
groups. 
The alternative hypothesis is that the mean PVR ratio is lower in the macitentan group as 
compared to the placebo group.  


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11.3.2.2 Handling of missing data 
If PVR cannot be calculated due to missing PAWP, but mPAP and CO are available for 
the same visit, one of the following will be applied: 
1. If PAWP is missing both at Baseline and post-Baseline, the treatment group medians 
will be imputed (based on the FAS). 
2. If PAWP is missing either at Baseline or post-Baseline, the patient’s available PAWP 
will be imputed. 
This imputation is based on the clinical assumption that macitentan does not affect 
PAWP. 
Baseline: Patients without a Baseline PVR measurement will be excluded from the 
analyses.  
Post-Baseline: In patients with a post-Baseline PVR measurement obtained before 
Week 12, the last post-Baseline PVR measurement will be carried forward. 
If a patient has no post-Baseline PVR measurement, the ratio of Week 12 to Baseline 
PVR will be imputed using the treatment group median based on the FAS.  
Other imputation methods for PVR values will be considered (e.g., multiple imputations) 
as sensitivity analysis. Details will be specified in the SAP. 
11.3.2.3 Main analysis 
The primary analysis will be performed on the FAS.  
PVR will be summarized by time point and treatment group using descriptive statistics as 
well as geometric means and coefficients of variation (CVs). The ratio of Week 12 to 
Baseline PVR will be summarized similarly. 
The ratio of Week 12 to Baseline PVR will be log-transformed (base e) and analyzed 
using an analysis of covariance (ANCOVA) with a factor for treatment group and a 
covariate for Baseline log PVR (macitentan vs. placebo). The treatment group difference 
(on log scale) and its 95% CLs will be estimated based on the model. The geometric 
mean ratio (GMR; macitentan vs. placebo) and its 95% confidence interval will be 
obtained by exponentiation. The null hypothesis will be rejected if the entire 95% 
confidence interval is below one. 
The treatment effect will be expressed as (GMR−1) × 100%, where a negative value 
indicates a reduction of PVR in the macitentan group as compared to the placebo group. 


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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. 
11.3.2.4 Supportive/sensitivity analyses 
The primary and selected secondary efficacy endpoints will be analyzed on the modified 
FAS as sensitivity analyses. Details of supportive/sensitivity analyses will be specified in 
the SAP. 
11.3.2.5 Subgroup analyses 
Additional subgroup analyses will be specified in the SAP. 
11.3.3 Analysis of the secondary efficacy variable(s) 
Secondary efficacy analyses will be performed on the FAS at α =0.025 (one-sided) using 
95% CLs. No correction for multiple testing will be applied for these analyses. 
Changes from Baseline to Week 12 in pressure-volume variables (e.g., mRAP, mPAP, 
PAWP, CI TPR) and SVO2 will be summarized and analyzed as described in 
Section 11.3.2.3, but without the log-transformation. 
NT-proBNP will be summarized by time point and treatment group using descriptive 
statistics as well as geometric means and CVs. The ratio of Week 12 to Baseline 
NT-proBNP will be summarized similarly. The ratio versus Baseline in NT-proBNP will 
be log-transformed and analyzed using an ANCOVA with covariates for treatment group 
and Baseline log NT-proBNP. 
WHO FC will be summarized by time point and treatment group 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 covariates for treatment group and WHO FC.  
11.3.4 Analysis of the exploratory efficacy variable(s) 
Exploratory efficacy analyses will be performed on the FAS at α = 0.025 (one-sided) 
using 95% CLs. No correction for multiple testing will be applied for these analyses. 
Echocardiographic variables including TAPSE, S’, RVFAC, E’, A’, RVLS, RV area and 
RVSI will be summarized by treatment and time point (Baseline, Week 12/EOT) using 
descriptive statistics (n, mean, SD, median, Q1, Q3, and range). The change from 
Baseline to Week 12/EOT in these variables will be summarized similarly and analyzed 
using an ANCOVA with a factor for treatment and covariates Baseline log PVR and 


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Baseline TAPSE, S’, RVFAC, E’, A’, RVLS, RV area and RVSI, respectively. The 
adjusted treatment effect and its 95% CI will be presented. 
Clinical events including: hospital admission for HF, re-initiation of i.v. diuretics ≥ 48 h, 
re-initiation of i.v. inotropes ≥ 48 h, need for RVAD/TAH, need for RRT and death will 
be summarized by treatment group and time-to-event treatment differences will be 
analyzed using the log-rank test. 
Duration of hospital stay excluding rehabilitation stay will be summarized by treatment 
group and analyzed using analysis of covariance with treatment and Baseline PVR in the 
model.  
GFR will be summarized by treatment and time point (Baseline, Week 12/EOT) using 
descriptive statistics (n, mean, SD, median, Q1, Q3, and range). The change from 
Baseline to Week 12/EOT in GFR will be summarized similarly. Change from Baseline 
in GFR will be analyzed using an ANCOVA with a factor for treatment and covariates 
Baseline log PVR and Baseline GFR. The adjusted treatment effect and its 
95% confidence interval will be presented. 
11.3.5 Analysis of the safety variable(s) 
The safety analyses described below 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 
treatment. The number and percentage of patients experiencing treatment-emergent AEs 
and SAEs at least once will be tabulated by treatment group and by: 
• MedDRA system organ class (SOC) and individual preferred term within each SOC, 
in descending order of incidence. 
• Frequency of patients with events coded with the same preferred term, in descending 
order of incidence.  
Furthermore, treatment-emergent AEs and SAEs will be tabulated as described above by 
severity and relationship to study treatment.  
AEs leading to premature discontinuation of study treatment and death will also be 
summarized as described above.  
Listings will be provided for all reported AEs, including SAEs. In addition, separate 
listings will be provided for SAEs, for AEs leading to premature discontinuation of study 
treatment, and for AEs leading to death. 


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11.3.5.2 Laboratory variables 
Descriptive summary statistics by visit and treatment group will be provided for observed 
values and absolute changes from Baseline, in both hematology and blood chemistry 
laboratory tests. In order to minimize missing data and to allow for Unscheduled Visits, 
all recorded assessments up to EOT plus 30 days will be assigned to the most appropriate 
visit time point according to the best fitting time-window for that assessment. 
The central laboratory manual outlines the definitions of marked abnormalities and 
provides guidance 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 variable by 
treatment group providing their incidence and frequency. Absolute values and changes 
from Baseline of laboratory values during the course of the study will be summarized 
using the usual location and scale summary statistics by treatment group. 
Laboratory variables are the following: 
• Hematology: hemoglobin, hematocrit, erythrocyte count, leukocyte count with 
differential counts, platelet count 
• Blood chemistry: AST, ALT, alkaline phosphatase, total and direct bilirubin, LDH, 
creatinine, BUN, uric acid, glucose, cholesterol, triglycerides, sodium, potassium, 
chloride, calcium, protein, albumin. 
The number and percentage of patients with liver function test abnormalities [classified 
as in Section 11.2.4] will be tabulated by treatment group. 
The number and percentage of patients with hemoglobin abnormalities [classified as in 
Section 11.2.4] will be tabulated by treatment group. 
11.3.5.3 Vital signs and body weight 
Blood pressure (i.e., DBP and SBP), pulse rate, and body weight (in kg) will be 
summarized at each study visit using the usual location and scale summary statistics by 
treatment group 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. 


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11.4 Interim analyses 
No interim analysis will be conducted. 
An Independent Statistical Center will have access to the study data exclusively for 
review by the IDMC. The IDMC will be fully operational prior to enrollment of the first 
subject into the study. The composition and operation of the IDMC is described in the 
IDMC charter. 
11.5 Sample size 
11.5.1 Sample size justification 
There are no randomized clinical trial data in this patient population. However, an 
integrated analysis of two bosentan studies, BENEFIT (AC-052-366) and EARLY 
(AC-052-364), the hemodynamic substudy of SERAPHIN (AC-055-302), and the 
recently completed MERIT study (AC-055E201) of macitentan in patients with 
inoperable chronic thromboembolic pulmonary hypertension, suggest that the treatment 
group difference on PVR is around −0.28 on log scale (ranged from −0.45 to −0.17 with 
95% confidence interval: −0.35, −0.21) with the within group standard deviation (SD) 
around 0.40 on log scale (90% confidence interval:0.38, 0.42).  
Based on the following assumptions: 
• Type I error of 2.5% (1-sided); 
• 80% power; 
• Treatment assignment ratio 1:1 between placebo and macitentan 10 mg; 
• Treatment group difference on PVR ratio of Week 12 to Baseline −0.28 (a GMR of 
0.76 macitentan/placebo); 
• Within group SD of 0.41; 
• A normal distribution for the log-transformed percent of Baseline PVR; 
70 evaluable patients will be needed for 80% power (35 patients per group) to test the 
primary hypothesis of interest. Accounting for 10% non-evaluable patients, 
approximately78 patients will need to be randomized.  
11.5.2 Sample size sensitivity 
Table 2 gives more details about the integrated analysis of PVR. It also shows the ‘best’ 
and ‘worst’ case sample sizes based on the 95% CLs around the treatment effect for each 
study as well as for the integrated analysis. It appears that the proposed sample size of 
70 patients is robust to some deviations from the assumptions given above. 


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Table 2 
Treatment effects (differences on log-scale as well as % reduction 
versus placebo), variability in integrated analysis of four studies 
(AC-052-366, AC-052-364, AC-055-302 and AC-055E201), and 
associated sample size for 80% power. 
 
Study 
Protocol 
Treatment 
Effect 
95% CI 
of Effect 
SD 
90% CI 
of SD 
Sample 
Size1 
Best 
Case 
Worst 
Case 
EARLY 
AC-052-364 
−0.26 −23% 
−0.41 
−0.11 0.50 
0.45 
0.54 
120 
50 
652 
BENEFIT 
AC-052-366 
−0.25 −22% 
−0.35 
−0.15 0.32 
0.29 
0.35 
54 
30 
146 
SERAPHIN 
AC-055-302 
−0.45 −36% 
−0.58 
−0.32 0.38 
0.35 
0.43 
26 
16 
48 
MERIT 
AC-055E201 
-0.17 
−16% 
−0.29 
−0.01 0.39 
0.35 
0.45 
166 
58 
> 1000 
Overall 
−0.28 −24% 
−0.35 
−0.21 0.40 
0.38 
0.42 
66 
44 
114 
1For 80% power and a two-sided alpha of 5% 
Best case: based on lower limit of 95% CI for effect 
Worst case: based on upper limit of 95% CI for effect 
CI = confidence interval; PVR = pulmonary vascular resistance; SD = standard deviation. 
12 DATA HANDLING 
12.1 Data collection 
The investigator/delegate is responsible for ensuring the accuracy, completeness, and 
timeliness of the data reported. All source documents should be completed in a neat, 
legible manner to ensure accurate interpretation of the data. Data reported in the eCRF 
derived from source documents must be consistent with the source documents. 
eCRF data will be captured via electronic data capture. The investigator and site staff will 
be trained to enter and edit the data via a secure network, with secure access features 
(username, password, and identification – an electronic password system). A complete 
electronic audit trail will be maintained. The investigator/delegate will approve the data 
(i.e., confirm the accuracy of the data recorded) using an electronic signature. 
For each subject enrolled, regardless of study treatment initiation, an eCRF must be 
completed and signed by the investigator/delegate. This also applies to those subjects 
who fail to complete the study. If a subject withdraws from the study, the reason must be 
noted on the eCRF. 
12.2 Maintenance of data confidentiality 
The investigator/delegate must ensure that data confidentiality is maintained. On eCRFs 
or other documents (e.g., documents attached to SAE reports) submitted to Actelion and 
any external service providers, subjects must be identified only by number, and never by 


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name or initials, hospital numbers, or any other identifier. The investigator/delegate must 
keep a subject identification code list, at the site, showing the Screening/Randomization 
number, the subject’s name, date of birth, and address or any other locally accepted 
identifiers. Documents identifying the subjects (e.g., signed ICFs) must not be sent to 
Actelion, and must be kept in strict confidence by the investigator/delegate. 
12.3 Database management and quality control 
Electronic CRFs will be used for all subjects. The investigator will have access to the site 
eCRF data until the database is locked. Thereafter, they will have read-only access. The 
eCRF must be kept current to reflect subject status at any time point during the course of 
the study.  
While entering the data, the investigator/delegate will be 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 eCRF. 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 eCRF, or simply a 
data correction in the eCRF. The investigator/delegate must, on request, supply Actelion 
with any required background data from the study documentation or clinical records. This 
is particularly important when errors in data transcription are suspected. In the case of 
Health Authority queries, it is also necessary to have access to the complete study 
records, provided that subject confidentiality is protected. 
This process will continue until database closure. 
Laboratory samples will be processed through a central laboratory and the results will be 
sent electronically to Actelion. 
After the database has been declared complete and accurate, the database will be closed. 
Any changes to the database after that time may only be made as described in the 
appropriate SOP. After database closure, the investigator will receive the eCRFs of the 
subjects of her/his site (including all data changes made) on electronic media or as a 
paper copy. 


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13 PROCEDURES AND GOOD CLINICAL PRACTICE 
13.1 Ethics and Good Clinical Practice 
Actelion and the investigators will ensure that the study is conducted in full compliance 
with ICH-GCP Guidelines, the principles of the “Declaration of Helsinki”, and with the 
laws and regulations of the country in which the research is conducted. 
13.2 Independent Ethics Committee / Institutional Review Board 
The investigator will submit this protocol and any related document provided to the 
subject (such as the Subject Information Leaflet used to obtain informed consent) to an 
IRB/IEC. Approval from the committee must be obtained before starting the study, and 
must be documented in a dated letter to the investigator, clearly identifying the study, the 
documents reviewed, and the date of approval. 
Modifications made to the protocol or subject information leaflet after receipt of the 
approval must also be submitted as amendments by the investigator to the IRB/IEC in 
accordance with local procedures and regulations [see Section 13.6]. 
A list of members participating in the IRB/IEC meetings must be provided, including the 
names, qualifications, and functions of these members. If that is not possible, the attempts 
made to obtain this information along with an explanation as to why it cannot be obtained 
or disclosed must be documented in the study documentation. If a study staff member 
was present during a meeting, it must be clear that this person did not vote. 
13.3 Informed Consent 
It is the responsibility of the investigator/delegate to obtain Informed Consent according 
to ICH-GCP guidelines and local regulations from each individual participating in this 
study and/or legal representative. The investigator/delegate must explain to subjects that 
they are completely free to refuse to enter the study, or to withdraw from it at any time 
for any reason and without having to provide any justification. 
The ICF will be provided in English. 
Site staff authorized to participate to the consent process and/or to obtain consent from 
the subject and/or legal representative will be listed on an Actelion DoA form. A study 
physician must always be involved in the consent process. 
The subject and/or legal representative must sign, personally date, and time (if 
appropriate) the ICF before any study-related procedures (i.e., any procedures required by 
the protocol) begin. The ICF must also be signed, personally dated, and timed (if the first 


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study-mandated procedure was performed on the same day Informed Consent was 
obtained) by the authorized site staff listed on the Actelion DoA form. 
A copy of the signed and dated ICF is given to the subject and/or legal representative; the 
original is filed in the site documentation. The Informed Consent process must be fully 
documented in the subject’s medical records. This must include the study reference, the 
subject number, the date and, if applicable, time when the subject was first introduced to 
the Actelion clinical study, ; the date and, if applicable, time of consent, who participated 
in the consent discussion, who consented the subject, and any additional person present 
during the consent process (e.g., subject family member), and a copy of the signed ICF 
given to the subject / legal representative. 
In the case that the site would like to recruit subjects who are considered as vulnerable 
(e.g., subject cannot read or write, does not speak or understand the ICF language), 
additional measures must be implemented in order to ensure subject’s rights are respected 
and the consent obtained is legally valid. Actelion, the regulatory authorities (if 
applicable), and the IRB/IEC must be informed prior to the recruitment. The consent 
process (e.g., involvement of an impartial witness) must be fully described, submitted to, 
and approved by the IRB/IEC, according to procedures and before subjects are recruited. 
13.4 Compensation to subjects and investigators 
Actelion provides insurance in order to indemnify (with both legal and financial 
coverage) the investigator/site against claims arising from the study, except for claims 
that arise from malpractice and/or negligence. 
The compensation of the subject in the event of study-related injuries will comply with 
applicable regulations. 
13.5 Protocol adherence/compliance 
The investigator must conduct the study in compliance with the approved version of the 
protocol and must not implement any deviation/change from the protocol, except when 
deviation is necessary to eliminate an immediate hazard to the subject. 
If a protocol deviation occurs, the investigator/delegate will inform Actelion or its 
representative, in a timely manner. The investigator/delegate must document and explain 
any deviation from the approved protocol. Deviations considered to be a violation of 
GCP must be reported to the IRB/IEC and regulatory authorities according to Actelion or 
(overruling) local requirements. 


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13.6 Protocol amendments 
Any change to the protocol can only be made through a written protocol amendment. A 
protocol amendment must be submitted to the 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: ISF and 
subject clinical source documents. 
These records must be kept by the investigator for as long as is necessary to comply with 
Actelion’s requirements (i.e., 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 site for any or all of the 
documents, special arrangements, respecting the data confidentiality, must be made 
between the investigator and Actelion to store these documents outside the site, so that 
they can be retrieved in case of a regulatory inspection. No study document should be 
destroyed without prior written approval from Actelion. Should the investigator wish to 
assign the study records to another party, or move them to another location, Actelion 
must be notified in advance. 
If the site is using an electronic/computerized system to store subject medical records, it 
can be used for the purpose of the clinical study if it is validated (as per 21 CFR Part 11 
or equivalent standard) and if the monitor has been provided personal and restricted 
access to study subjects only, to verify consistency between electronic source data and 
the eCRF during monitoring visits. 
If the site is using an electronic/computerized system to store subject medical records but 
it could not be confirmed that the system is validated or if the monitor could not be 
provided access to the system, the site is requested to print the complete set of source 
data needed for verification by the monitor. The print-outs must be numbered, stapled 
together with a cover sheet, signed and dated by the investigator/delegate to confirm that 
these certified copies are exact copies having the same information as the original 
subject’s data. The printouts will be considered as the official clinical study records and 
must be filed either with the subject medical records or with the subject’s eCRF. 


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In order to verify that the process the site uses to prepare certified copies is reliable, the 
monitor must be able to observe this process and confirm that the comparison of the 
source documents and the certified copy did not reveal inconsistencies. The monitor does 
not need to verify this process for all data of all subjects but at least for some of them 
(e.g., first subject; regular check during the study of critical data like inclusion/exclusion 
criteria, endpoints for some subjects) as per Actelion’s instructions. If 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. 
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 PI must ensure that all site personnel involved in the study are present during the SIV 
and will dedicate enough time to it. Site Information Technology support should also be 
available during the initiation visit. 
The SIV must be completed before the site can start the Screening of study subjects. 
Following the SIV, a copy of the completed initiation visit report and follow-up letter 
will be provided to the PI and filed in the ISF. 
During the study, the monitor will contact and visit the site regularly and must be 
permitted, on request, to have access to study 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 eCRFs and other protocol-related documents. Actelion 
monitoring standards require full verification that Informed Consent has been provided, 
verification of adherence to the inclusion/exclusion criteria, documentation of SAEs, and 
the recording of the main efficacy, safety, and tolerability endpoints. Additional checks 
of the consistency of the source data with the eCRFs will be performed according to the 
study-specific monitoring plan. The frequency of the monitoring visits will be based on 
subject recruitment rate and critical data collection times. 
The PI must ensure that the eCRF is completed within 5 days after a subject’s visit (site 
visit or phone call), and that all requested subject files (e.g., ICFs, medical notes/charts, 
and other documentation verifying the activities conducted for the study) are available for 
review by the monitor. The required site personnel must be available during monitoring 
visits and allow adequate time to meet with the monitor to discuss study related issues. 
The investigator agrees to cooperate with the monitor(s) to ensure that any issues 
detected in the course of these monitoring visits are resolved. If the subject is hospitalized 


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or dies in a hospital other than the study site, the investigator is responsible for contacting 
that hospital in order to document the SAE, in accordance with local regulations. 
A close-out visit will be performed for any initiated site when there are no more active 
subjects and all follow-up issues have been resolved. In case a site does not enroll any 
subjects, the close-out visit may be performed prior to study database closure at the 
discretion of Actelion. 
13.9 Investigator site file 
Each site will be provided with an ISF prior to the initiation visit. It will contain all the 
essential documents that are required to always be up-to-date and filed at site as per ICH 
E6 GCP section 8. 
The ISF will include a Table of Contents listing the essential documents. All 
study-related documentation must be maintained in the ISF. 
In some cases, exceptions can be discussed with the monitor regarding the filing of the 
study documents outside the ISF. It should be clearly documented where each document 
is filed. This note to file should be present in the specific tab of the document in the ISF. 
The ISF must be stored in a secure and access-restricted area during and after the study. It 
must be kept by the site for as long as needed to comply with any applicable rules and 
regulations, ICH-GCP, as well as instructions from Actelion. If the site needs to transfer 
the ISF to another location and/or if site facility can no longer store the ISF, the PI must 
inform Actelion immediately. 
If the PI changes, or if the site relocates, the monitor must be notified as soon as possible. 
13.10 Audit 
Actelion’s Global Quality Management representatives may audit the investigator site 
(during the study or after its completion). The purpose of this visit will be to determine 
the investigator’s adherence to ICH-GCP, the protocol, and applicable regulations; 
adherence to Actelion’s requirements (e.g., SOPs) will also be verified. Prior to initiating 
this audit, the investigator will be contacted by Actelion to arrange a time for the audit. 
The investigator and staff must cooperate with the auditor(s) and allow access to all study 
documentation (e.g., subject records) and facilities. 
13.11 Inspections 
Health Authorities and/or IRB/IEC may also conduct an inspection of Actelion’s clinical 
study (during the study or after its completion). 


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Should an inspection be announced by a Health Authority and/or an IRB/IEC, the 
investigator must inform Actelion immediately, (usually via the monitor), that such a 
request has been made. 
The investigator and staff must cooperate with inspector(s) and allow access to all study 
documentation (e.g., subject records) and study facilities. 
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. 
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 the clinical study on Actelion’s Clinical Trial Register and 
on external/national registries, as required by local 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 criteria, and be based on: 
• Substantial contributions to the conception or design of the study, or the acquisition, 
analysis, or interpretation of data; and 
• Drafting of the publication or critical review for important intellectual content; and 
• Providing final approval of the version to be published; and 
• Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 
The list of authors of any publication of study results may include representatives of 
Actelion and will be determined by mutual agreement. 
Any study-related publication written independently by investigators must be submitted 
to Actelion for review at least 30 days prior to submission for publication or presentation. 
Upon review, Actelion may provide comments, and may also request alterations and/or 
deletions for the sole purpose of protecting its confidential information and/or patent 


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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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[Patlolla 2013] Patlolla B, Beygui R, Haddad F. Right-ventricular failure following left 
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ventricular assist device implantation: a prospective, randomized, doubleblind, 
multicenter, placebo-controlled trial. J Heart Lung Transplant 2011; 30(8): 870-8. 
[Pulido 2013] Pulido T, Adzerikho I, Channick RN, Delcroix M, Galiè N, Ghofrani A. 
Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension. N 
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controlled MUSIC Trial. Eur Respir J. 2013 Dec;42(6):1622-32. 
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Ventricular Assist Device For End-stage Heart Failure. N Engl J Med 2001; 
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[Slaughter 2009] Slaughter M, Rogers J, Milano C, et al. Advanced heart failure treated 
with continuous-flow left ventricular assist device. N Engl J Med. 2009; 361(23): 
2241-51. 
[Stewart 1991] Stewart DJ, Levy RD, Cernacek P, et al. Increased plasma endothelin-1 in 
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inducedmitogenic responses of Chinese hamster ovary expressing human 
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[Tedford 2008] Tedford RJ, Hemnes AR, Russell SD, et al. PDE5A inhibitor treatment of 
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15 APPENDICES 
Appendix 1 
WHO functional classification of pulmonary hypertension 
 
Class I 
Patients with pulmonary hypertension but without resulting limitation of 
physical activity. Ordinary physical activity does not cause undue dyspnea 
of fatigue, chest pain or near syncope. 
Class II 
Patients with pulmonary hypertension resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary physical activity 
causes undue dyspnea or fatigue, chest pain or near syncope. 
Class III 
Patients with pulmonary hypertension resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary activity 
causes undue dyspnea or fatigue, chest pain or near syncope. 
Class IV 
Patients with pulmonary hypertension with inability to carry out any 
physical activity without symptoms. These patients manifest signs of right 
heart failure. Dyspnea and/or fatigue may even be present at rest. 
Discomfort is increased by any physical activity. 
 


Macitentan / ACT-064992 
PH post-LVAD implantation 
Protocol AC-055-205, SOPRANO 
Version 3 
10 March 2017, page 100/103 
Confidential 
Doc No D-17.154 
 
 
Appendix 2 
Glossary 
 
Term 
Definition 
Adverse Event (AE) 
Any adverse change, i.e., any unfavorable and unintended sign, 
including an abnormal laboratory finding, symptom, or disease 
that occurs in a subject during the course of the study, whether 
or not considered by the investigator as related to study 
treatment. 
AEs include: 
• 
Exacerbation of a pre-existing disease. 
• 
Increase in frequency or intensity of a pre-existing 
episodic disease or medical condition. 
• 
Disease or medical condition detected or diagnosed 
during the course of the study, even though it may have 
been present prior to the start of the study. 
• 
Continuous persistent disease or symptoms present at 
study start that worsen following the start of the study 
(i.e., signing of informed consent). 
• 
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. 
A treatment-emergent AE is any AE temporally associated with 
the use of study treatment (from study treatment initiation until 
30 days after study treatment discontinuation) whether or not 
considered by the investigator as related to study treatment. 
Baseline 
The last value obtained prior to first dose of study treatment. 
Baseline Right Heart 
Catheterization (RHC) 
The last hemodynamic measurements after LVAD implantation 
and prior to the first dose of study treatment. 


Macitentan / ACT-064992 
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Protocol AC-055-205, SOPRANO 
Version 3 
10 March 2017, page 101/103 
Confidential 
Doc No D-17.154 
 
 
Childbearing potential 
A woman is considered to be of childbearing potential unless 
she meets at least one of the following criteria: 
• 
Previous bilateral salpingectomy, 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 
(International Council for Harmonisation [ICH] M3 
definition). 
Hemoglobin recovery 
Return of hemoglobin above the lower limit of the normal range 
or return to a value close to that at Baseline. 
Hospitalization for 
heart failure (HF) 
A hospitalization in which the principal diagnosis is HF. 
Intensity of adverse 
events 
Mild 
• 
The event may be noticeable to the subject. It does not 
influence daily activities, and usually does not require 
intervention. 
Moderate 
• 
The event may make the subject uncomfortable. 
Performance of daily activities may be influenced, and 
intervention may be needed. 
Severe 
• 
The event may cause noticeable discomfort, and usually 
interferes with daily activities. The subject may not be 
able to continue in the study, and treatment or 
intervention is usually needed. 
Medical history 
• 
Chronic medical conditions and new acute medical 
conditions within the past 6 months (e.g., anemia, 
hepatitis C infection, HIV infection, obstructive or 
restrictive lung disease, hypertension, renal disease) 
• 
Any previous life-threatening conditions, including date 
(e.g., myocardial infarction). 
Moderate to severe 
restrictive lung disease 
(an exclusion 
criterion) 
Total lung capacity < 60% of predicted value. 


Macitentan / ACT-064992 
PH post-LVAD implantation 
Protocol AC-055-205, SOPRANO 
Version 3 
10 March 2017, page 102/103 
Confidential 
Doc No D-17.154 
 
 
Post-menopausal 
Twelve consecutive months with no menses without an 
alternative medical cause (ICH M3 definition). 
Previous therapy 
Any treatment for which the end date is prior to the signing of 
informed consent 
Pulmonary 
Hypertension (PH) 
• 
Mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg 
and 
• 
Pulmonary artery wedge pressure (PAWP) ≤ 18 mmHg 
and 
• 
PVR > 3 Wood units. 
Serious Adverse Event 
(SAE), as per ICH 
guidelines 
Any AE fulfilling at least one of the following criteria 
• 
Fatal. 
• 
Life-threatening: refers to an event in which the subject 
was at risk of death at the time of the event. It does not 
refer to an event that hypothetically might have caused 
death had it been more severe. 
• 
Requiring inpatient hospitalization, or prolongation of 
existing hospitalization. 
• 
Resulting in persistent or significant disability or 
incapacity. 
• 
Congenital anomaly or birth defect. 
• 
Medically significant: refers to important medical events 
that may not immediately result in death, be 
life-threatening, or require hospitalization but may be 
considered to be SAEs when, based upon appropriate 
medical judgment, they may jeopardize the subject, and 
may require medical or surgical intervention to prevent 
one of the outcomes listed in the definitions above. 
Severe obstructive 
lung disease (an 
exclusion criterion) 
Forced expiratory volume in 1 second / forced vital capacity 
(FEV1/FVC) < 0.7 associated with FEV1 < 50% of predicted 
value after bronchodilator administration. 


Macitentan / ACT-064992 
PH post-LVAD implantation 
Protocol AC-055-205, SOPRANO 
Version 3 
10 March 2017, page 103/103 
Confidential 
Doc No D-17.154 
 
 
Stabilization of the 
patient for 48 h prior 
to the Baseline RHC 
• 
No LVAD pump speed/flow rate changes 
and 
• 
Stable dose of oral diuretics  
and 
• 
No intravenous (i.v.) inotropes or vasopressors 
and 
• 
Patient able to ambulate 
Study-concomitant 
therapy 
Any treatment for which the start date is on or after the signing 
of Informed Consent up to 30 days after study treatment 
discontinuation. 
Study treatment 
Administration of double-blind study drug (macitentan or 
placebo). 
Study treatment-
concomitant 
Any treatment for which the start date is on or after the first 
administration of study treatment up to Week 12 or earlier in 
case of premature discontinuation of study treatment. 
 

SAP_001.pdf: 
Statistical Analysis Plan
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Protocol no: AC-055-205
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Statistical Analysis Plan
Sponsor:
Actelion Pharmaceuticals US, Inc.
Protocol No:
AC-055-205
Version No./Date
3.0/10-Mar-2017
Title
A prospective, multicenter, double-blind, randomized, placebo-controlled, parallel-
group study to assess the efficacy and safety of macitentan in patients with pulmonary 
hypertension after left ventricular assist device implantation
CRF Version 
No./Date
11.0/24-Oct-2018
PRA Project Id:
ATE55205-055205
SAP Version
No./Date:
2.0/13-July -2020 (SAP Amendment)
Approvals
Sponsor
Sponsor Name:
Actelion Pharmaceuticals US, Inc.
Representative/Title:
Mu,Yi (Lisa) / Senior Biostatistician, Biostatistics
Signature/Date:
PRA
Project Manager/Title
Matt Shirley / Senior Project Manager
Signature/Date:
Biostatistician/Title 
(Owner):
Sheila Quinn / Lead Biostatistician
Signature/Date:
PPD
PPD
PPD
NCT02554903


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Table of Contents
Approvals.....................................................................................................................................................................................1
1.0 Introduction ........................................................................................................................................................................ 5 
1.1 Changes from Protocol ............................................................................................................................................... 5 
2.0 Study Objectives ................................................................................................................................................................ 5 
2.1 Primary objective ......................................................................................................................................................... 5 
2.2 Secondary objectives .................................................................................................................................................. 5 
2.3 Exploratory objectives ............................................................................................................................................... 5 
3.0 Study Design ........................................................................................................................................................................ 5 
3.1 Sample Size Considerations ..................................................................................................................................... 7 
3.2 Randomization .............................................................................................................................................................. 7 
3.3 Study Endpoints ............................................................................................................................................................ 7 
3.3.1 Efficacy endpoints ......................................................................................................................................... 7 
3.3.2 Safety endpoints ............................................................................................................................................. 9 
3.3.3 Biomarker endpoints ................................................................................................................................... 9 
4.0 Predetermined Covariates and Prognostic Factors ............................................................................................ 9 
5.0 Definitions ......................................................................................................................................................................... 10 
5.1 Adverse Events ........................................................................................................................................................... 10 
5.1.1 Treatment-emergent AEs and treatment-emergent laboratory values ............................... 10 
5.1.2 Death / AEs leading to death ................................................................................................................. 10 
5.2 Exposure and Compliance ....................................................................................................................................... 10 
5.2.1 Total number of tablets taken ............................................................................................................... 10 
5.2.2 Compliance .................................................................................................................................................... 10 
5.2.3 Total exposure ............................................................................................................................................. 11 
5.2.4 Average daily dose (mg/day) ................................................................................................................ 11 
5.2.5 Patient-year of exposure ......................................................................................................................... 11 
5.2.6 Duration of therapy ................................................................................................................................... 11 
5.3 Medications ................................................................................................................................................................... 11 
5.3.1 Imputation of prior and concomitant medication dates ............................................................ 11 
5.3.2 Prior and study-treatment concomitant medications ................................................................. 12 
5.3.3 Study-concomitant medications ........................................................................................................... 13 
5.3.4 Prohibited Medications ............................................................................................................................ 14 
5.3.5 Pulmonary artery hypertension medications ................................................................................. 14 
5.4 Miscellaneous ............................................................................................................................................................... 14 
5.4.1 Body mass index ......................................................................................................................................... 14 
5.4.2 Hospital admission for HF ...................................................................................................................... 14 
5.4.3 Need for RVAD/TAH.................................................................................................................................. 15 
5.4.4 Need for RRT ................................................................................................................................................ 15 
5.4.5 eGFR-prog ...................................................................................................................................................... 15 
5.5 Populations ................................................................................................................................................................... 16 
5.5.1 Patients randomized ................................................................................................................................. 16 
5.5.2 Derivation of patients with at least one dose of study drug ..................................................... 16 
5.6 Right Heart Catheterization Parameters (RHCA) .......................................................................................... 16 
5.6.1 BSA-prog ........................................................................................................................................................ 16 
5.6.2 mPAP-prog .................................................................................................................................................... 16 
5.6.3 PVR-prog ........................................................................................................................................................ 17 
5.6.4 PVR ratio of Week 12 or EOT to Baseline ......................................................................................... 17 


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5.6.5 PVR ratio of Week 12 or EOT to Baseline, Investigator .............................................................. 17 
5.6.6 CI-prog ............................................................................................................................................................ 17 
5.6.7 TPR-prog ........................................................................................................................................................ 17 
5.6.8 TPG-prog........................................................................................................................................................ 17
5.6.9 DPG-prog ........................................................................................................................................................ 18 
5.6.10 PAPi-prog .................................................................................................................................................... 18 
5.6.11 PAC-prog ...................................................................................................................................................... 18 
5.6.12 RVSWI-prog ................................................................................................................................................ 18 
5.6.13 Ea-prog ......................................................................................................................................................... 18 
5.6.14 VO2-prog ..................................................................................................................................................... 19 
5.6.15 Indirect Fico CO-prog ............................................................................................................................. 19 
5.6.16 Indirect Fick PVR-prog .......................................................................................................................... 19 
5.6.17 Direct Fick PVR-prog .............................................................................................................................. 19 
5.7 Study Times, Dates, Visits, and Windows ........................................................................................................... 19 
5.7.1 Baseline ........................................................................................................................................................... 19 
5.7.2 Change from Baseline ............................................................................................................................... 20 
5.7.3 Study Day 1 ................................................................................................................................................... 20 
5.7.4 Study day ........................................................................................................................................................ 20 
5.7.5 Laboratory visits and laboratory visit windowing ....................................................................... 20 
5.7.6 Last follow-up date .................................................................................................................................... 21 
5.7.7 Missing and partial dates ........................................................................................................................ 21 
5.7.8 Days in the hospital after hospitalization for heart failure ....................................................... 21 
5.7.9 Date of heart transplant ........................................................................................................................... 22 
5.7.10 Date last patient completed the study ............................................................................................. 22 
5.7.11 Time from Left Ventricular Assist Device (LVAD) implantation to treatment ............... 22 
5.7.12 Time to first occurrence of clinical events, from Day 1 to week 12 .................................... 22 
6.0 Analysis Sets ..................................................................................................................................................................... 23 
6.1 Screened Analysis Set .............................................................................................................................................. 23 
6.2 Screen Failure Set ...................................................................................................................................................... 23
6.3 Safety Set ....................................................................................................................................................................... 23 
6.4 Full Analysis Set ......................................................................................................................................................... 24 
6.5 Modified Full Analysis Set ...................................................................................................................................... 24 
6.6 Per-Protocol Set ......................................................................................................................................................... 24 
6.7 Evaluable Set ............................................................................................................................................................... 24 
6.8 Usage of the Analysis Sets ...................................................................................................................................... 24 
7.0 Data Review ...................................................................................................................................................................... 24 
7.1 Data Handling and Transfer .................................................................................................................................. 24 
7.2 Data Screening ............................................................................................................................................................ 25 
8.0 Statistical Methods ........................................................................................................................................................ 25 
8.1 Patient Disposition ................................................................................................................................................... 25 
8.2 Protocol Deviations .................................................................................................................................................. 26 
8.3 Treatments ................................................................................................................................................................... 26 
8.3.1 Extent of Study Drug Exposure and Compliance ........................................................................... 26 
8.3.2 Concomitant Medications........................................................................................................................ 26 
8.4 Demographic and Baseline Characteristics .................................................................................................... 27 
8.5 Efficacy Analyses ....................................................................................................................................................... 28 
8.5.1 Primary Endpoint ....................................................................................................................................... 28 
8.5.2 Multiplicity .................................................................................................................................................... 31 


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8.5.3 Pooling of Sites ............................................................................................................................................ 31 
8.5.4 Secondary Endpoints ................................................................................................................................ 31 
8.5.5 Exploratory Endpoints ............................................................................................................................. 33 
8.6 Safety Analyses........................................................................................................................................................... 35
8.6.1 Adverse Events ............................................................................................................................................ 35 
8.6.2 Deaths and Serious Adverse Events.................................................................................................... 36 
8.6.3 Laboratory Data .......................................................................................................................................... 36 
8.6.4 Vital Signs ...................................................................................................................................................... 39 
8.6.5 Other Data ...................................................................................................................................................... 40 
9.0 Validation .......................................................................................................................................................................... 40 
10.0 References ...................................................................................................................................................................... 40 
Appendix 1 Glossary of Abbreviations ......................................................................................................................... 41 
Appendix 2 Tables, Figures, Listings, and Supportive SAS Output Appendices .......................................... 44 
Appendix 3 List of Additional Protocol Violation/ Protocol Deviation Identification Listings ............. 44 
Appendix 4 Shells for In-Text Tables, Figures, and Listings ................................................................................ 44 
Appendix 5 Shells for Additional Protocol Violation/Deviation Identification Listings .......................... 44 
Appendix 6 Criteria for Adverse Events of Special Interest................................................................................. 45 
Appendix 7 Prohibited Medication List ........................................................................................................................ 50 
  


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1.0 Introduction
This statistical analysis plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under Actelion Pharmaceuticals US, Inc. Protocol AC-055-205.
This SAP should be read in conjunction with the study protocol and case report forms (CRF). This version 
of the plan has been developed using the protocol version 3 dated 10MAR2017 and CRF version 11.0
dated 24OCT2018. Any further changes to the protocol or CRF may necessitate updates to the SAP.
Once the SAP is finalized programming can begin. Changes following approval of SAP will be tracked in 
the SAP Change Log (spreadsheet PRS 005 T 19) and a SAP amendment.
1.1 Changes from Protocol
The protocol defines prior medications relative to the date of signing informed consent. However prior 
medications are defined in the analysis plan as any treatment for which the end date is prior to Study Day 
1 (which is based on the first dose of study medication or randomization). In addition the protocol does not 
classify medications which are ongoing at the start of the study into either a prior or concomitant category. 
The analysis plan assigns these medications as both prior and concomitant to study treatment.
According to the protocol, the Screened Analysis Set (SAS) should be used for patient disposition. However 
it is the patient population table that will be presented for the SAS instead since information on completion 
of the study is not collected for screen failures. 
2.0 Study Objectives
2.1 Primary objective
The primary objective is to evaluate the effect of macitentan 10 mg on pulmonary vascular resistance (PVR)
as compared to placebo in patients with pulmonary hypertension (PH) after left ventricular assist device 
(LVAD) implantation.
2.2 Secondary objectives
The secondary objectives are:
•
To evaluate the effect of macitentan 10 mg as compared to placebo on cardio-pulmonary 
hemodynamics and disease severity in patients with PH after LVAD implantation.
•
To evaluate the safety and tolerability of macitentan 10 mg in patients with PH after LVAD 
implantation.
2.3 Exploratory objectives
•
To explore the potential effect of macitentan 10 mg as compared to placebo on right ventricular 
function in patients with PH after LVAD implantation.
•
To explore the potential effect of macitentan 10 mg as compared to placebo on selected clinical 
events in patients with PH after LVAD implantation.
•
To explore the potential effect of macitentan 10 mg as compared to placebo on renal function as 
measured by the glomerular filtration rate (GFR) in patients with PH after LVAD implantation.
3.0 Study Design
This is a prospective, multicenter, double-blind, randomized, placebo-controlled, parallel-group Phase 2
study. It is planned to randomize 78 patients into 2 groups (macitentan 10 mg or placebo) in a 1:1 ratio by 
an Interactive Web Randomization System (IXRS). Approximately 50 sites in the United States are planned.
The study duration is planned to be approximately 36 months from first patient, first visit to last patient, last 


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visit. Patient participation in the study is up to 90 days from LVAD (screening period) + 12 weeks 
(double-blinded treatment period) + 30 days (safety follow-up period). The key inclusion criteria are:
•
Surgical implantation of LVAD within 90 days prior to Randomization.
•
Hemodynamic evidence of PH on Baseline right heart catheterization (RHC) by the thermodilution
method. Baseline RHC is defined as the last hemodynamic measurements after LVAD implantation 
and prior to the first dose of study drug treatment. PH is defined as:
o
mmillimeter of mercury (mmHg) and
o
and
o
PVR > 3 WU (Wood units).
•
Stabilization of the patient for 48 hours prior to the Baseline RHC, defined as:
o
No LVAD pump speed/flow rate changes and
o
Stable dose of oral diuretics and 
o
No intravenous (i.v.) inotropes or vasopressors and 
o
Patient able to ambulate. 
•
Patient must be randomized within 14 days of Baseline RHC.
The study consists of the following study periods:
Screening period: Commences immediately following LVAD implantation and ends with patient
randomization (up to a maximum of 90 days after surgical implantation of LVAD). The Screening visit is the 
date at which signature on the Informed Consent Form (ICF) is obtained prior to initiation of any 
study-mandated procedures. Screening and Randomization visits may be conducted on the same day, 
provided that eligibility is confirmed and all study-mandated procedures are completed prior to 
Randomization.
Treatment period: Study treatment is defined as the dosing (intake) by the patient of double-blind study 
drug (macitentan or placebo). The treatment period starts immediately after Randomization with the first 
dose of study drug at the end of Visit 2 (Day 1 of study) and ends with end of treatment (EOT) on the day 
of the last dose of study drug (scheduled Day 84, Week 12), or earlier in case of premature discontinuation 
of study treatment.
Patients who prematurely discontinue study treatment must have an EOT visit within 7 days of study 
treatment discontinuation.
Post-treatment safety follow-up period: Patients who complete the study treatment as planned, i.e., a 
full 12-week study period, and those who prematurely discontinue study treatment will enter a 30-day safety 
follow-up period, which ends with the End-of-Study (EOS) visit at least 30 days after the permanent 
discontinuation of study treatment.
In addition, Unscheduled Visits may also take place during treatment and follow-up periods. 
For an individual patient, the study ends once the EOT has been performed and the 30-day safety follow-up
is complete (EOS).
The study is considered complete when all patients have ended as detailed above.
An Independent Statistical Center (managed by PRA and excluding Actelion) has access to the study data 
and patients’ treatment assignment for review by the Independent Data Monitoring Committee (IDMC). The 
IDMC will be fully operational prior to enrollment of the first patient into the study. The composition and 
operation of the IDMC is described in the IDMC charter.
Hospital admissions for heart failure (HF), as an exploratory endpoint, will be adjudicated by the clinical 
events committee (CEC) for this study.


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3.1 Sample Size Considerations
An integrated analysis of two bosentan studies, BENEFIT (AC-052-366) and EARLY (AC-052-364), the 
hemodynamic sub-study of SERAPHIN (AC-055-302), and the recently completed MERIT study 
(AC-055E201) of macitentan in patients with inoperable chronic thromboembolic pulmonary hypertension, 
suggest that the treatment group difference on PVR is expected to be around -0.28 on log scale (ranged 
from -0.45 to -
is around 0.40 (90% confidence interval: 0.38, 0.42) on log scale. 
Based on the following assumptions: 
•
Type I error of 2.5% (1-sided) 
•
80% power 
•
Treatment assignment ratio 1:1 between placebo and macitentan 10 mg 
•
geometric mean ratio 
(GMR) of 0.76 macitentan/placebo) 
•
Within group SD of 0.41 
•
A normal distribution for the log-transformed percent of Baseline PVR 
Seventy evaluable patients will be needed for 80% power (35 patients per group) to test the primary 
hypothesis of interest. Accounting for 10% non-evaluable patients, approximately 78 patients need to be 
randomized. 
3.2 Randomization
Eligible patients will be randomized into two groups (macitentan 10 mg or placebo) in a 1:1 ratio by an 
IXRS, with no stratification. Block randomization is performed within each investigator site. The pre-defined 
block size is masked from the investigators and all study personnel except for the statistician who is
preparing the randomization schedule at the IXRS vendor and the independent IDMC statistician. At Visit 
1 (Screening), all screened patients will be assigned a study-specific patient number by the IXRS provider.
At Visit 2 (Randomization), and after having confirmed the eligibility of the patient and prior to the start of 
study treatment, the investigator/delegate will contact the IXRS to randomize the patient. The IXRS will 
assign a randomization number to the patient, and will assign the treatment bottle number which matches 
the treatment arm assigned by the randomization list to the randomization number. The bottle with this 
unique number will be dispensed to the patient and the first dose is administered.
Assignment to the treatment arms is based on a computer-generated randomization schedule created 
before the start of the study. The randomization schedule has been prepared by a statistician not otherwise 
involved in the conduct of the study.   
The randomization list is generated by another independent Contract Research Organization (CRO),
Parexel, and kept strictly confidential.
3.3 Study Endpoints
3.3.1 Efficacy endpoints 
3.3.1.1 Primary efficacy endpoint(s) 
The primary efficacy endpoint is PVR ratio of Week 12 to Baseline. PVR is obtained by the thermodilution 
method. 
The primary efficacy endpoint PVR will be
and will be presented in 
WU, where the thermodilution method has been used.
If the thermodilution method was not used for CO then PVR by thermodilution will not be calculated.


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3.3.1.2 Secondary efficacy endpoints 
•
Change from Baseline to Week 12 in the following hemodynamic measurements all measured at 
rest:
o
mean right atrial pressure (mRAP) 
o
mPAP 
o
PAWP 
o
cardiac index (CI), CI will be calculated as CO/body surface area (BSA); where CO is 
captured on CRF and BSA will be calculated as specified in section 5.6.1.
o
total pulmonary resistance (TPR), calculated as mPAP / CO and 
o
mixed venous oxygen saturation (SvO2). (This is recorded on CRF as Pulmonary arterial 
oxygen saturation.
•
Change from Baseline to Week 12 in N-terminal prohormone of brain natriuretic peptide 
(NT-proBNP).
•
Change from Baseline to Week 12 in World Health Organization functional class (WHO FC).
3.3.1.3 Exploratory efficacy endpoints 
•
Change from Baseline to Week 12 in echocardiographic variables that include: 
o
2D global right ventricle (RV) longitudinal strain (global right ventricular longitudinal strain 
[RVLS])
o
RV sphericity index (RVSI) 
o
RV end systolic area (RVSA)
o
RV end diastolic area (RVDA)
o
Tricuspid annular plane systolic excursion (TAPSE) 
o
S', Tricuspid peak annular velocity s’ (TPAVS)
o
RV fractional area change (RVFAC) 
o
E', Tricuspid peak diastolic annular velocity (TPDAV)
o
A', Tricuspid Inflow Peak E-Velocity (TIFE)
•
Time to first occurrence of clinical events, from enrollment (using the Study Day 1 definition in 
section 5.7.3) to Week 12. These clinical events include: 
o
Hospital admission for HF 
o
Re-
o
Re-
o
Initiation of phosphodiesterase type 5 inhibitors (PDE5I) inhibitors 
o
Need for RVAD / total artificial heart (TAH) 
o
Need for renal replacement therapy (RRT) 
o
Death 
•
Days in the hospital after hospitalization for HF. 
•
Change in GFR from Baseline to Week 12


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3.3.2 Safety endpoints 
•
Treatment-emergent adverse events (AEs) up to 30 days after study treatment discontinuation. 
•
AEs leading to premature discontinuation of study treatment. 
•
Death up to 30 days after study treatment discontinuation. 
•
Treatment-emergent serious AEs (SAEs) up to 30 days after study treatment discontinuation. 
•
Change from Baseline to EOT in vital signs. 
•
Occurrence 
of 
liver 
function 
test 
alanine 
aminotransferase 
(ALT)
and/or 
aspartate 
aminotransferase (AST) abnormality [
upper limit of normal (ULN)
LN] up to EOT. 
•
EOT. 
•
Proportion of patients with treatment-emergent hemoglobin abnormality (< 10.0 g/dL, and < 8.0 
g/dL) as compared to Baseline up to EOT. 
•
Treatment-emergent marked laboratory abnormalities up to EOT. Marked laboratory abnormalities 
are defined in Section 8.6.3.
3.3.3 Biomarker endpoints 
Change in NT-proBNP will be assessed from Baseline to Week 12 (EOT) as part of the secondary efficacy 
endpoints analysis.
Additional circulating biomarkers may be analyzed in an exploratory format (post-hoc) based on available 
scientific evidence. No genetic testing will be performed.
•
Interleukin-6 (IL-6)
•
Tumor necrosis factor-
(TNF-
•
High sensitivity C-reactive protein (hsCRP)
•
ET-1
•
Galectin-3
•
Growth differentiation factor-15 (GDF-15)
•
Interleukin 1 receptor ST2
•
Neutrophil gelatinase-associated lipocalin (NGAL)
•
Copeptin
•
High sensitivity cardiac troponin T (hs-cTnT)
•
Cystatin-C
•
Osteopontin
4.0 Predetermined Covariates and Prognostic Factors
In addition to treatment as a prognostic factor there are several predetermined covariates. 
•
Baseline log PVR is the predetermined covariate for the primary analysis of the log ratio of Week 12
to Baseline PVR. See Section 8.5.1 and 8.5.1.2.


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•
The secondary analysis of change from baseline to Week 12 (without log transformation) in
pressure-volume variables (e.g., mRAP, mPAP, PAWP, CI, TPR) and SVO2 will be adjusted for
Baseline log PVR which did not use planned treatment group median for imputation in Section 
8.5.1.2, and the Baseline of the variable to be analyzed.
•
Baseline log NT-proBNP is the predetermined covariate for the secondary analysis of NT-proBNP.
•
Baseline WHO FC group (I/II vs. III/IV), is the predetermined covariate for the secondary analysis 
of WHO FC.
•
For the exploratory analyses of echocardiographic variables, Baseline log PVR which did not use 
planned treatment group median for imputation in Section 8.5.1.2 and Baseline TAPSE, S’, RVFAC, 
E’, A’, RVLS, RV area, and RVSI are predetermined covariates for the separate analyses of 
TAPSE, S’, RVFAC, E’, A’, RVLS, RV area, and RVSI, respectively.
•
Baseline GFR and Baseline log PVR which did not use planned treatment group median for 
imputation in Section 8.5.1.2 are the predetermined covariates for the exploratory analysis of GFR.
5.0 Definitions
In the following sections the item numbers on the blank CRF specification have been referred to.
5.1 Adverse Events
5.1.1 Treatment-emergent AEs and treatment-emergent laboratory values
Treatment-emergent AEs are those that occur on the date of or after the first dose of study medication and 
within 30 days of the date of last dose of study medication. There should be no missing or partial event 
dates. In the event that there is a missing date start date for the AE, the AE will be considered to be 
treatment emergent. 
Treatment-emergent laboratory values are those that occur on a date after the first dose of study medication 
and within 37 days of the date of last dose of study medication. If a patient had abnormalities outside the 
limits defined in the laboratory table for liver function abnormalities at both Baseline and post-Baseline (or 
just during the post-Baseline period), the patient still qualifies as having treatment-emergent abnormalities.
5.1.2 Death / AEs leading to death
Even though deaths are being adjudicated, the number of deaths and time to death will be based on the 
CRF data, and not the adjudication database. AEs leading to death will only be based on the number of 
treatment-emergent AEs where at least one of the following is true:
•
the outcome is equal to Fatal or 
•
the answer to the question “Did the adverse event result in death?” is Y or
•
there is a non-missing date of death on the SAE CRF page. 
5.2 Exposure and Compliance
5.2.1 Total number of tablets taken
The total number of tablets taken will be calculated as follows:
Total number of tablets taken = total number of tablets dispensed – total number of tablets returned
5.2.2 Compliance
Study treatment compliance is based on study treatment accountability on the Study Drug Dispensing and 
Accountability CRF page, as per formula below:


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Compliance = [(total number of tablets dispensed – total number of tablets returned) / duration of 
therapy (days)] x 100
If the number of tablets returned and/or the number of tablets dispensed is missing the CRF question 
“number of doses missed” will be used in the calculation as follows:
Compliance = (duration of therapy in days – total number of doses missed)/duration of therapy x
100
5.2.3 Total exposure
Total exposure (mg) will be calculated by statistical programming as:
(total number of tablets dispensed across all visits – total number of tablets returned across all visits) x 10
If there is a missing number of dispensed and/or returned tablets then the total exposure will be calculated 
as:
(duration of therapy in days – total number of doses missed) x 10 
5.2.4 Average daily dose (mg/day)
Average daily dose will be calculated by statistical programming as total exposure / duration of therapy 
(days).
5.2.5 Patient-year of exposure
Patient-year of exposure will be calculated as follows:
Patient-year of exposure = Number of patients x mean exposure (years)
5.2.6 Duration of therapy
Duration of therapy will be calculated by statistical programming using the date of first dose of study 
medication on the Study Drug Dispensing and Accountability CRF page and the date of last dose of study 
medication on the End of Treatment CRF page. The date of last treatment visit will not be used if the date 
of last dose of study medication is missing (i.e. the duration of therapy will be set to missing if the date of 
last dose of study medication is missing). It will be calculated as follows:
Date of last dose of study medication on the End of Treatment CRF page - date of first dose of study 
medication on the Study Drug Dispensing and Accountability CRF page + 1
For deliveries prior to database freeze (e.g. IDMC deliveries, three-monthly reports, Development Safety 
Update Reports but not the pre-freeze dry run, post-freeze dry run or the post-lock delivery) if the data of 
last dose of study medication on the end of treatment CRF page is missing it will be imputed with the data 
cut date.
5.3 Medications
5.3.1 Imputation of prior and concomitant medication dates
Partial dates can be entered into the CRF (missing date parts are presented as “UNK”). 
If the day of the start date is missing:
•
If the month and the year is the same as the month and the year of Study Day 1 then the day of 
Study Day 1 will be imputed
•
Otherwise the 1st of the month will be imputed.
If the month of the start date is missing:
•
If the year is the same as the year of Study Day 1 then the month of Study Day 1 will be imputed


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•
Otherwise January will be imputed.
If the day of the end date is missing then the last day of the month will be imputed.
If the month of the end date is missing then December will be imputed.
If the complete date is missing then it will not be imputed. 
The imputed dates will only be used for derivations. The raw (partial) dates will be presented in the listings. 
5.3.2 Prior and study-treatment concomitant medications
Study-treatment concomitant medications are defined as medications that were recorded on the Prior and 
Concomitant Medications CRF page and taken from the day after the date of first dose of study drug but 
no later than the earliest of Week 12 (Day 84) or premature discontinuation of study treatment. This means 
the following medications are to be classified as study-treatment concomitant:
•
Start date is before Study Day 1, and end date is on or after Study Day 1 or missing
•
Start date is between Study Day 1 and the last dose day (inclusive), and end date is on or after 
Study Day 1 or missing
•
Start date is missing, and end date 
•
If both start and end date are missing
Prior (to study treatment) medications are defined as medications that were recorded on the Prior and 
Concomitant Medications CRF page and taken on the day of Study Day 1 or earlier. This means the 
medications are to be classified as prior if:
•
Start date is before Study Day 1, and end date is any date or missing 
•
Start date is missing, and end date is before Study Day 1
•
If both start and end date are missing, then “Ongoing at start of treatment” can be answered as No
or Yes
It is possible for medications to be classified as both prior and concomitant, provided they meet the criteria 
of both concomitant and prior medication definitions.  
The following table summarizes the above text and gives the corresponding assigned values for PREFL 
(prior flag Y/N/blank) and ONTRTFL (concomitant flag Y/N/blank).
Med Start Date
Med End Date
Prior/Concomitant
PREFL
ONTRTFL
< Day 1
< Day1
Prior
Y
N
< Day 1
Last 
Dose Day
Prior and 
Concomitant
Y
Y
< Day 1
> Last Dose
Prior and 
Concomitant
Y
Y
< Day 1
Missing
Prior and 
Concomitant
Y
Y
Dose Day
< Day1
not possible, query
<blank>
<blank>
Dose Day
Dose Day
Concomitant 
N
Y
Dose Day
> Last Dose
Concomitant 
N
Y
Dose Day
Missing
Concomitant
N
Y
> Last Dose
< Day1
not possible, query
<blank>
<blank>


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Med Start Date
Med End Date
Prior/Concomitant
PREFL
ONTRTFL
> Last Dose
Dose Day
not possible, query
<blank>
<blank>
> Last Dose
> Last Dose
Neither
(Post treatment)
N
N
> Last Dose
Missing
Neither
(Post treatment)
N
N
Missing
< Day1
Prior
Y
N
Missing
Dose Day
query 
Y
Y
Missing
> Last Dose
query
Y
Y
Missing
Missing
query
Y if “Ongoing at 
start of treatment” = 
No or Yes
Y
5.3.3 Study-concomitant medications
Study concomitant medication consist of medication recorded on the Prior and Concomitant Medications 
CRF page that is ongoing or initiated after signing of informed consent, or initiated up to 30 days after the 
study treatment discontinuation i.e. where the start date is up to and including 30 days after the date of last 
dose of study medication (Week 12/Day84 or premature discontinuation of study treatment).  This means 
the medications with the following start and end dates are to be classified as study concomitant:
•
Start date is before the informed consent date, and end date is on or after the informed consent 
date or missing
•
Start date is between the informed consent date and the last dose day + 30 (inclusive), and end 
date is on or after the informed consent date or missing
•
Start date is missing, and end date is between the informed consent date and last dose day + 30 
(inclusive)
•
If both start and end date are missing
The following table summarizes the above text and gives the corresponding assigned values for 
ONSTUDFL (on study Y/N/blank).
Med Start Date
Med End Date
Concomitant Study
ONSTUDFL
< IC date
< IC Date
No
N
< IC date
Study Concomitant
Y
< IC date
> Last Dose + 30
Study Concomitant
Y
< IC date
Missing
Study Concomitant
Y
< IC Date
not possible, query
<blank>
Study Concomitant 
Y
> Last Dose + 30
Study Concomitant 
Y
Last Dose Day + 30
Missing
Study Concomitant
Y
> Last Dose + 30
< IC Date
not possible, query
<blank>
> Last Dose + 30
not possible, query
<blank>
> Last Dose + 30
> Last Dose + 30
No
N
> Last Dose + 30
Missing
No
N
Missing
< IC Date
No
N
Missing
Study Concomitant
Y
Missing
> Last Dose + 30
query
<blank>
Missing
Missing
query
Y


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5.3.4 Prohibited Medications
Prohibited medications will fall in the general categories below:  but not limited to the following:
•
PAH-specific therapy (as defined in section 8.3.2)
•
Inhaled nitric oxide 
•
Strong CYP3A4 inhibitors and inducers
•
Inotropes
•
Vasopressors
•
Diuretics
•
Any investigational drug
The specific prohibited medication list is a working list and will be updated by the sponsor as needed.
5.3.5 Pulmonary artery hypertension medications
Pulmonary artery hypertension medications will be identified by programming by name and route:
•
Epoprostenol IV
•
Treprostinil ORAL, RESPIR, IV, SC
•
Iloprost RESPIR
•
Bosentan
•
Ambrisentan
•
Sildenafil
•
Tadalafil
•
Riociguat
•
Selexipag ORAL
•
Avanafil
•
Vardenafil
•
Nitric Oxide RESPIR
This medication list is a living definition and will be updated when there are new medications added to the 
list.
5.4 Miscellaneous
5.4.1 Body mass index
Body mass index (BMI) is entered by the investigators directly on the CRF. However BMI will be calculated 
as follows by the statistical programmers using the height and weight:
Weight in [kilograms (kg)] /(Height at Baseline in m)2
5.4.2 Hospital admission for HF
Data on hospital admission for HF and death is collected on the CRF and adjudicated by the CEC. The 
sites would be queried in cases of discordance between the CEC and the site. However, if agreement 


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cannot be reached, since the CEC is adjudicating HF admissions, their data will be used in the analysis of 
hospital admission for HF as explained below.
The number of patients admitted to hospital for HF will be equal to the number of patients who have “Y” 
answered at least once to the question:
•
“Does the submitted case constitute a hospital admission for heart failure as the primary reason for 
admission?” for any adjudicated event according to the CEC/Adjudication Evaluation data
I.e. if no records have “Y” answered for the above question then the patient will be counted as having no 
hospital admission for HF. A missing answer to the CRF question will not be considered to be a “Yes”. 
Other questions such as the answer to the CRF questions:
•
“Was hospitalization for heart failure rehabilitation only?” on the AE CRF page and 
•
“Indication/Reason for prescribing” equal to “Hospital admission for HF” on the Prior and 
Concomitant CRF page
will not be taken into consideration in the definition of hospitalization for HF. 
If the investigator updates the clinical database data used for adjudication and the adjudication committee 
re-reviews then an additional visit will be added to the adjudication data. The adjudication data will have 
multiple rows per SAE row number and the latest adjudication record based on the adjudication date for
each SAE row number will be used in the analysis.
5.4.3 Need for RVAD/TAH
The number of patients needing RVAD will be defined as the number of patients who have at least one
treatment-emergent AE (see section 5.1.1) where:
•
“Yes” is answered on the AE CRF page to the question “Did the adverse event require Right 
Ventricular Assist Device implantation?”
The number of patients needing TAH will be defined as the number of patients who have at least one 
treatment-emergent AE where:
•
“Yes” is answered on the AE CRF page to the question “Did the Adverse Event require a Total 
Artificial Heart?”
Having a medication on the Prior and Concomitant Medication CRF page where “Indication/Reason for 
prescribing” is equal to either “Needed for RVAD” and / or “Needed for TAH” will not qualify the patient as 
needing RVAD/TAH.
5.4.4 Need for RRT
The number of patients needing RRT will be defined as the number of patients who have at least one 
treatment-emergent AE where the question “Did the adverse event require Renal Replacement Therapy?” 
was answered “Yes”.
5.4.5 eGFR-prog
Estimated Glomerular Filtration Rate(eGFR) ) will be calculated as CKD-EPI Creatinine Equation (2009) by 
the statistical programmer (GFR-calc), unit as mL/min/1.73 m2
_
= 141 × min
, 1
× max
, 1
.
× 0.993
× 1.018[
 
] × 1.159[
 
]
Where  
= Standardized serum creatine, mg/dL in CRF
= 0.7 ( 
) 
 0.9 (
)
= -0.329 (female) or -0.411 (male)


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min = minimum of 
1
max = maximum of 
 
  1
Age = Age at visit, years
If the subject is a non-‘black or African American’ male:
141 × min(standardized serum creatinine/0.9, 1)-0.411 ×
          max(standardized serum creatinine/0.9, 1)-1.209× 0.993Age
If the subject is a black or African American male:
141 × min(standardized serum creatinine/0.9, 1)-0.411 ×
          max(standardized serum creatinine/0.9, 1) -1.209 × 0.993Age × 1.159
If the subject is a non-‘black or African American’ female:
141 × min(standardized serum creatinine/0.7, 1)-0.329 ×
           max(standardized serum creatinine/0.7, 1) -1.209 × 0.993Age × 1.018
If the subject is a black or African American female:
141 × min(standardized serum creatinine/0.7, 1)-0.329 ×
          max(standardized serum creatinine/0.7, 1) -1.209× 0.993Age × 1.018 × 1.159
The programmatically derived values will be used in efficacy analyses.
5.5 Populations
5.5.1 Patients randomized
The definition of patients randomized is patients who have a date of randomization on the Enrolled CRF 
page. This set of patients will define the Full Analysis Set (FAS).
5.5.2 Derivation of patients with at least one dose of study drug
Those patients who have the date of first dose of study medication on the Study Drug Dispensing and 
Accountability form and for whom the total number of tablets dispensed is greater than zero and the total 
number of tablets returned will be considered to have taken at least one dose of study drug. This set of 
patients will define the Safety Set (SS) and the modified FAS (MFAS).
5.6 Right Heart Catheterization Parameters (RHCA)
The following definitions only cover parameters that are programmed/derived outside of the CRF. 
5.6.1 BSA-prog
Body surface area (BSA) will be derived as follows by statistical programming:
BSA-prog = 0.007184 × weight (kg)0.425 × Baseline height ((centimeters (cm))0.725 
5.6.2 mPAP-prog
Although mean pulmonary artery pressure (mPAP) is calculated by the CRF, it is also derived by statistical 
programming as: 
mPAP-prog = 0.61 x sPAP + 2
where sPAP = systolic pulmonary artery pressure entered in the CRF.


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5.6.3 PVR-prog
 PVR_prog =
mPAP –  PAWP 
Thermodilution CO
where the following CRF parameters are used: mPAP = Mean pulmonary artery pressure (mmHg) (end-
expiratory mean line), PAWP = Pulmonary artery wedge pressure (mmHg) (end-expiratory mean line), and 
Thermodilution CO= Cardiac Output (L/min), thermodilution.
In addition, the thermodilution PVR-prog will be imputed to using the methods in section 8.5.1.2 (Handling
of Missing Data for the Primary Analysis).
5.6.4 PVR ratio of Week 12 or EOT to Baseline
The PVR ratio of Week 12 or EOT to Baseline will be derived by statistical programming as follows:
PVR ratio =  Week 12 or EOT PVR_prog
Baseline PVR_prog
Section 8.5.1.2 (Handling of Missing Data for the Primary Analysis) provides details about how to impute 
PVR ratio for primary analysis.
5.6.5 PVR ratio of Week 12 or EOT to Baseline, Investigator
PVR ratio_inv = Week 12 or EOT PVR-Inv / Baseline PVR using PVR-inv
where PVR-inv = thermodilution PVR entered in the CRF by the investigator
5.6.6 CI-prog
Although cardiac index (CI) is calculated in the CRF, it is also derived by statistical programming as:   
CI-prog = CO / BSA-prog
where CO = Thermodilution Cardiac Output (L/min) from the CSR.
5.6.7 TPR-prog
Although Total Pulmonary Resistance (TPR) is calculated in the CRF, it is also derived by statistical 
programming as: 
TPR-prog = mPAP / CO
where the following CRF parameters are used: mPAP = Mean pulmonary artery pressure (mmHg) (end-
expiratory mean line), and CO = Thermodilution Cardiac Output (L/min).
5.6.8 TPG-prog
Although Transpulmonary gradient (TPG) is calculated in the CRF, it is also derived by statistical 
programming as: 
TPG-prog = mPAP – PAWP
where the following CRF parameters are used: mPAP = Mean pulmonary artery pressure (mmHg) (end-
expiratory mean line), and PAWP = Pulmonary artery wedge pressure (mmHg) (end-expiratory mean line).


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5.6.9 DPG-prog
Although Diastolic pressure gradient (DPG) is calculated in the CRF, it is also derived by statistical 
programming as: 
DPG-prog = dPAP - PAWP
where the following CRF parameters are used: dPAP = Diastolic pulmonary artery pressure (mmHg), and 
PAWP = Pulmonary artery wedge pressure (mmHg) (end-expiratory mean line).
5.6.10 PAPi-prog
Although Pulmonary Artery Pulsatility index (PAPi) is calculated in the CRF, it is also derived by statistical 
programming as: 
PAPi
prog =  sPAP – dPAP
mRAP
where the following CRF parameters are used: sPAP = systolic pulmonary artery pressure dPAP = Diastolic 
pulmonary artery pressure (mmHg), and mRAP = mean right atrial pressure (mmHg) – mean of the a wave.
5.6.11 PAC-prog
Although Pulmonary arterial compliance (PAC) is calculated in the CRF, it is also derived by statistical 
programming as: 
PAC_prog =
CO
HR × 1000
sPAP
dPAP
where the following CRF parameters are used: 
CO = Thermodilution Cardiac Output (L/min), 
HR = Heart rate (HR) (bpm) (per ECG during PAP measurement)
sPAP= Systolic pulmonary artery pressure (sPAP) (mmHg),
dPAP = Diastolic pulmonary artery pressure (mmHg)
5.6.12 RVSWI-prog
Although Right ventricle stroke work index (RVSWI) is calculated in the CRF, it is also derived by statistical 
programming as: 
RVSWI
= (mPAP
mRAP) ×
CI
HR
× 1000 × 0.0136
where CI-prog(5.6.5) and the following CRF parameters are used: mPAP = Mean pulmonary artery 
pressure (mmHg) (end-expiratory mean line), mRAP = mean right atrial pressure (mmHg) – mean of the a 
wave, and HR = hearth rate (bpm) (per ECG during PAP measurement).
5.6.13 Ea-prog
Although Effective arterial elastance (Ea) is calculated in the CRF, it is also derived by statistical 
programming as: 
EA_prog = 
sPAP
CO
HR × 1000


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where the following CRF parameters are used: sPAP = systolic pulmonary artery pressure. CO = 
Thermodilution Cardiac Output (L/min), and HR = hearth rate (bpm) (per ECG during PAP measurement).
5.6.14 VO2-prog
Resting oxygen consumption is recorded on CRF as Resting maximum consumption. Although Resting 
maximum oxygen consumption (VO2) is calculated in the CRF, it is also derived by statistical programming 
as:
VO2-prog = BSA-prog × 125
5.6.15 Indirect Fico CO-prog
 
Indirect Fick CO_prog =   
VO2_prog
Hgb × 13.6 × (SpO2
SvO2) × 100 
where VO2-prog ( 5.6.14) and the following CRF parameters are used: Hgb= Hemoglobin (Hgb) 
(g/dL), SpO2= Pulse oximetry (SpO2) (%) (during PAP measurement) on: room air (RA) or O2 at 
(L/min), SvO2= Pulmonary arterial oxygen saturation (SvO2) (%) 
 
5.6.16 Indirect Fick PVR-prog
Indirect Fick PVR =
mPAP
PAWP 
 Indirect Fick CO_prog
where Indirect Fick CO_prog (5.6.14) the following CRF parameters are used: mPAP = Mean 
pulmonary artery pressure (mmHg) (end-expiratory mean line), PAWP = Pulmonary artery wedge 
pressure (mmHg) (end-expiratory mean line) 
5.6.17 Direct Fick PVR-prog
Direct Fick  PVR_prog = mPAP –  PAWP 
Direct Fick CO  
Where the following CRF parameters are used: mPAP = Mean pulmonary artery pressure (mmHg) 
(end-expiratory mean line), PAWP = Pulmonary artery wedge pressure (mmHg) (end-expiratory 
mean line), Direct Fick CO= Cardiac Output (L/min) Direct Fico. 
 
5.7 Study Times, Dates, Visits, and Windows
5.7.1 Baseline
Baseline is defined as the last non-missing measurement post LVAD implantation (on or after LVAD 
implantation) and before or on the date of the first dose of double-blind study drug (i.e. it is assumed that 
measurements taken on the date of the first dose occur before the first dose). It is thus possible for the 
Baseline date to differ between parameters. Baseline RHC is defined as the last RHC visit where the 
question ‘Was a right heart catheterization performed?’ was answered with ‘Y’. Any pre-study RHC data is 


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collected on the Pulmonary Hypertension Relevant Disease History form and is thus automatically not 
considered as Baseline by programming.
5.7.2 Change from Baseline
Change from Baseline will be calculated by statistical programming as follows:
Post Baseline measurement – Baseline measurement
5.7.3 Study Day 1
Study Day 1 is the date of first study drug administration (Date of first dose of study medication on the Study 
Drug and Accountability page). For patients who are randomized but not dosed after the initial 
randomization, Study Day 1 is defined as the date of randomization. 
5.7.4 Study day
A study day will be calculated by statistical programming as follows:
•
Before date of Study Day 1:
Study Day = (Date of the assessment – date of Study Day 1)
•
On or after date of Study Day 1:
Date of the assessment – date of Study Day 1 + 1
Adding 1 day enables randomization to be calculated as Day 1 and, Day 84 for example to be at 12 weeks. 
This variable will be used in the windowing of laboratory variables and in the AE listings. 
5.7.5 Laboratory visits and laboratory visit windowing
For laboratory variables, in order to minimize missing data and to allow for unscheduled visits, all recorded 
assessments up to EOT plus 37 days will be assigned to the most appropriate visit time point according to 
the most appropriate time-window for that assessment.
Lab Visit Window
Value to be presented in the table per parameter
Screening
Visit label is ‘Visit 1 Screening’ and no other windows apply
Day 1
Baseline as defined in section 5.7.1
Day 28  
Non-missing post-Baseline value closest to Day 28 in the window of 
Day 1 – Day 42, on or before the last dose
Day 56 
Non-missing post-Baseline value closest to Day 56 in the window of 
Day 43 – Day 70, on or before the last dose
Day 84 
Non-missing post-Baseline value closest to Day 84 in the window of 
Day 71 – Day 98, on or before the last dose
End of Study
Visit label is ‘Visit 6 End of Study’ regardless of whether the date falls 
within any other window except Day 1.
Derived Record
Last visit post-Baseline
Last non-missing value post-Baseline
Overall post-Baseline
Worst post baseline value. The highest value post baseline is 
selected for the serum chemistry and hepatic parameters. The 
lowest value post baseline is selected for hematology parameters.


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For descriptive summaries (e.g. result and change from Baseline), if more than one actual visit (including 
the unscheduled visits) falls within the same defined window, the visit closest to the target day with non-
missing data will be considered for analysis. If two actual visit dates are at the same distance from the 
target day, the first visit with non-missing data will be considered for analysis. If two non-missing laboratory 
assessments are on the same day, then the later of the two will be used for descriptive summaries.
For abnormality tables by timepoint or shift summaries by timepoint (e.g. of post-Baseline hemoglobin 
abnormalities by timepoint), the worst value within the window will be used. For the marked abnormality 
tables the worst of both directions will be presented. Thus a patient could be counted in both LLL and HH 
for a visit. However for the shift summary from low, normal to high laboratory values the worst value is 
defined as follows i.e. only one direction will be considered:
•
For serum chemistry and hepatic parameters such as ALT and AST the highest value within the 
window will be the worst. 
•
For hematology parameters such as hemoglobin the lowest value within the window will be the 
worst. 
The Baseline definition will be the same for all analyses as defined in section 5.7.1 i.e. there is not a 
separate definition to take the worst value within the window.
5.7.6 Last follow-up date
The last follow-up date is used in the censoring of the Kaplan-Meier analyses for events from Day 1 to 
Week 12. Thus the last follow-up will be defined as the last/latest of the following, provided the date is on 
or before Day 84:
•
date of last dose of study medication on the EOT CRF page
•
date of last treatment visit on the EOT CRF page
Otherwise, if the dates above occur beyond Day 84 then the last follow-up date will be set to the last date 
out of the following visits (scheduled and unscheduled):
•
study drug dispensing and accountability visits up to Day 98
•
last laboratory sample up to Day 98
•
RHC up to Day 98
•
echocardiogram up to Day 98. 
Otherwise, if no last follow-up date has been assigned it will be set to the date of Day 98. 
The statistical programmers will incorporate warnings into the derived data set program and inform the lead 
statistician if a patient has a missing last follow-up date. 
5.7.7 Missing and partial dates
It is not expected that any dates apart from medications or medical history will be partially completed. No 
imputation of medical history dates will be performed. AE data is recorded with a complete date and time. 
The date is the only information used for determining treatment emergence. Imputations will be defined 
prior to final database lock.
5.7.8 Days in the hospital after hospitalization for heart failure
For hospital admission for HF adjudicated by the adjudication committee (see definition in section 5.4.2), 
the SAE number will be used to link SAE eCRF where information will be obtained to calculate the duration 
as follows:


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Days in the hospital after hospitalization for heart failure will be calculated by statistical programming based 
on the “Hospitalization Admission Date” and “Hospitalization Discharge Date” on the SAE CRF page as 
follows: 
Hospitalization Discharge Date – Hospitalization Admission Date + 1 - Duration of HF rehab (days).
The duration will be set to missing if a patient was hospitalized due to HF but has a missing or partial 
Hospitalization Discharge or Admission Date. Should a patient have more than one hospital admission for 
HF stay, the durations will be summed to a total within a patient for the analysis.  
5.7.9 Date of heart transplant
It will be derived as the date of heart transplant as procedure.
5.7.10 Date last patient completed the study
The date the last patient completed the study will be defined as the last of the following dates across all 
patients: 
•
date of last treatment visit (on the EOT CRF page)
•
date of last dose of study medication (on the EOT CRF page)
•
date of contact (on the follow-up CRF page)
5.7.11 Time from Left Ventricular Assist Device (LVAD) implantation to treatment
Time from LVAD implantation to treatment will be calculated by statistical programming as follows:
Study Day 1 - Date of Left Ventricular Assist Device (LVAD) implantation.
5.7.12 Time to first occurrence of clinical events, from Day 1 to week 12
The earliest of the following dates on or after Study Day 1 but before study day 98 will be used to calculate 
the time to occurrence of the first clinical event. The dates will be obtained as follows:
•
Hospital admission for HF 
The Hospitalization Admission Date on the SAE eCRF for the SAE where the question 
“Does the submitted case constitute a hospital admission for heart failure as the primary 
reason for admission?” has been answered as Y based on latest adjudication performed
(see section 5.4.2).
•
Re-
The number of patients needing re-
ours will be based on the 
number of patients for whom at least one of the answers to the question “Indication/Reason 
for prescribing” is “Re-initiation of i.v. diuretics >/=48 h duration” on the Prior and 
Concomitant Medication CRF page, provided the medication was classified as a study-
treatment concomitant medication. The start date of the medication will be used as the 
event date in the calculation of time to event. The question “Did the adverse event require 
re-initiation of i.v. diuretics >/= 48 h duration?” on the AE CRF page will not be considered 
when defining re-
to re-initiation calculations and the number of patients re-initiating. 
•
Re-
The number of patients needing re-
the number of patients for whom at least one of the answers to the question 
“Indication/Reason for prescribing” is “Re-initiation of i.v. inotropes >/=48 h duration” on the
Prior and Concomitant Medication CRF page, provided the medication was classified as a 
study-treatment concomitant medication. The start date of the medication will be used as 


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the event date in the calculation of time to event. The question “Did the adverse event 
require re-initiation of i.v. inotropes >/= 48 h duration?” on the AE CRF page will not be 
considered when defining re-
•
Initiation of PDE5 inhibitors, start date of PDE5 inhibitors from the concomitant medication CRF 
page will be used.
•
Need for RVAD / total artificial heart (TAH), the Right Ventricular Assist Device implantation 
date/Total Artificial Heart Date from the AE CRF page will be used. 
•
Need for RRT, the “Renal Replacement Therapy Date” from the AE CRF page will be used as the 
event date. 
•
Death (all cause)
Date of Death on the SAE CRF page for the treatment-emergent AE where death was 
indicated according to the definition in section 5.1.2Error! Reference source not found..
If the date of death is missing but the patient died according to this definition, then the date 
of last follow-up will be used as the event date in the calculation below instead. 
Time to the event will be calculated as:
The earliest of the above dates – the date of Study Day 1 +1.
Patients who have none of the above clinical events will be censored at the last follow-up date and the time 
will be calculated by statistical programming as follows:
Last follow-up date – the date of Study Day 1 +1. 
No patients should have a missing value for time to first clinical event or censoring. 
A censoring variable will be derived as indicator for censoring at the end of the time interval (0 = if the 
subject had a clinical event, 1 = if the subject had a heart transplant, and 2 = otherwise) for the survival 
analyses. In the Kaplan-Meier analysis values of 1 and 2 will be considered censored. 
6.0 Analysis Sets
6.1 Screened Analysis Set
This analysis set includes all patients who were screened and received a patient ID on the screening CRF 
page (i.e. all patients who signed the informed consent form). The usage of this analysis set is described 
in section 6.7.
6.2 Screen Failure Set
This analysis set includes all patients who were screened but for whom the question “Did the subject fail 
screening” was answered Y. No summaries will be generated based on this analysis set. Only a data listing 
of screen failure will be created.
6.3 Safety Set
The SS includes all patients who received at least one dose of study drug. Patients who receive the wrong 
treatment in error are analyzed as treated and not as randomized. If a patient has been randomized to 
placebo but receives active treatment at any time, they will be analyzed as an active patient. However if a
patient who has been randomized to active treatment receives at least one dose of active treatment, they 
will be analyzed under the active treatment, even if they received placebo as well at any time.
I.e. a placebo-randomized patient will be counted in the macitentan arm if, at least at one visit, according 
to the bottle number on the drug accountability CRF page, the patient erroneously received a bottle/kit 
number that corresponds to macitentan treatment in the IXRS master kit data set. However if a patient who 


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has been randomized to macitentan receives a macitentan kit/bottle at least at one visit according to the 
bottle number on the drug accountability CRF page, she or he will still be analyzed under the macitentan 
arm, even if they erroneously received a bottle/kit corresponding to placebo at one of the other visits.
6.4 Full Analysis Set
The FAS includes all patients randomized. Patients who receive the wrong treatment in error are still 
analyzed as randomized and not as treated.
6.5 Modified Full Analysis Set
The modified FAS includes all patients in the FAS that have received at least one dose of study drug in the 
treatment period and have a Baseline, and at least one post-Baseline PVR measurement for the primary 
endpoint (after the imputations in section 8.5.1.2 have been performed). Patients who receive the wrong 
treatment in error are still analyzed as randomized and not as treated.
6.6 Per-Protocol Set
The Per-Protocol Set (PPS) comprises all patients included in the FAS without important protocol deviations 
that affect the main analysis of the primary efficacy variable. See section 8.2 for the explanation of how 
important protocol deviations are being defined on an ongoing basis. For the reasons for excluding patients
from the PPS see section 8.2. A separate document file will be finalized to list reasons of exclusion from 
PP for each subject in FAS.
6.7 Evaluable Set
The Evaluable Set comprises all patients in the FAS that have received at least one dose of study drug in 
the treatment period and have baseline and at least one post-baseline thermodilution PVR after imputation,
but no treatment group specific median was used for imputation in section 8.5.1.2.1 (PAWP imputation) or 
8.5.1.2.3 (PVR ratio imputation). Patients who receive the wrong treatment in error are still analyzed as 
randomized and not as treated.
6.8 Usage of the Analysis Sets
The primary efficacy analyses will be performed on the FAS based on treatment as randomized. Secondary 
and exploratory efficacy analyses will be performed on the FAS. Sensitivity analyses of the ANCOVA for 
the primary efficacy variable will be performed as described in subsequent sections based on the PPS,
Modified FAS, and Evaluable set.
Safety analyses related to the double blind treatment period will be performed on the SS based on treatment 
as received. Patient listings will be based on the SS, unless otherwise specified. 
Patient populations will be described for the SAS and listed for the FAS. The Screen Failure Set will be 
used in the Screen Failure listing.
The FAS will be used in the randomization assignments listing, enrollment by center, disposition, prior and 
concomitant medication tables and in the listing of discontinued patients, and protocol deviations.
7.0 Data Review
The data provided to statistical programming for the pre-freeze deliverable will be a clean data snapshot. 
7.1 Data Handling and Transfer
Please see the Data Management Plan.


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7.2 Data Screening
Beyond the data screening built into the PRA Data Management Plan, the PRA programming of analysis 
datasets, tables, figures, and listings (TFL) provides additional data screening. Presumed data issues will 
be output into SAS logs identified by the word “Problem” and extracted from the logs by a SAS macro and 
sent to Data Management.
Review of a pre-freeze TFL run on clean patients and a post-freeze TFL run on the frozen database allow 
for further data screening prior to lock. The pre-freeze TFLs will be run on clean patients (definition of clean 
will be outlined in Data Transfer Plan) and a post-freeze TFL will be run on the frozen database. The post-
freeze TFL will be discussed with Actelion in a data review meeting to identify any final data issues and 
seek corrections prior to database lock. The PRA statistician and Actelion must approve database lock.
8.0 Statistical Methods
All analyses will use SAS Version 9.4 or higher. Unless otherwise noted, categorical variables will be 
summarized using counts and percentages. Percentages will be rounded to one decimal place; except 
100% will be displayed without any decimal places and percentages will not be displayed for zero counts. 
A row for missing values will only be presented if there are any missing values for the specific variable and 
the missing value observations will be included in the denominator used to calculate percentages. 
Continuous variables will be summarized using the number of observations (n), mean, standard deviation 
(SD), median, lower and upper quartiles (Q1, Q3), minimum and maximum. The median, Q1, Q3, minimum 
and maximum values will be displayed to the same level of precision as the raw data, the mean to a further 
decimal place and the SD to two additional decimal places.
0.05 (two-sided).
The p-values presented for the ANCOVAs will be from two-sided tests unless otherwise specified. P-values 
presented for survival analyses and the logistic regression will be two-sided. There will be no adjustments 
for multiplicity. 95% confidence intervals will be displayed for summary statistics.
The only stratification in the analysis will be treatment group. All summary tables will be presented for 
Macitentan and Placebo only, i.e. no total column, with the exception of the IDMC tables, demographics,
patient populations’ tables, and one time to first clinical event Kaplan-Meier analysis for clinical events 
(FAS) table, which will include a total column. No pooling of centers or other variables is planned, nor is a 
treatment-by-center interaction since center is not included in the models. No other interaction terms will 
be explored.
8.1 Patient Disposition
The number and percentage of patients in each analysis set will be presented. The number and percentage 
of patients who stopped study treatment prematurely according to the question “Did the patient complete 
all 12 weeks of study treatment?” on the EOT CRF page and a breakdown of the corresponding reasons 
for stopping study treatment will be presented in a separate table.
A tabulation of the number and percentage of patients randomized at each center will be presented. A
separate table will present the following dates for the SAS: 
•
first patient screened
•
first patient randomized
•
last assessment date of primary endpoint 
•
last patient completed study
A listing of details of whether the patients completed or discontinued study treatment prematurely will be 
presented as will a listing of Patient Populations. The screen failure data will be listed for the Screen Failure 
Set. Details on informed consent will be listed for the FAS.


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8.2 Protocol Deviations 
Per PRA processes, protocol deviation data will be entered into our Clinical Trials Management System 
(CTMS). The study team and the sponsor would conduct on-going reviews of the protocol deviation data 
from CTMS and the resulting set of evaluable patients throughout the study, adjusting the protocol deviation 
criteria as seems appropriate. Important protocol deviations will exclude patients from the PPS. The set of 
evaluable patients must be finalized at the post-freeze data review meeting (or earlier), prior to database 
lock. No statistical programmatic checks of protocol deviations will be done in addition to edit check and 
monitoring. The important protocol deviations excluding patients from PPS will all have been confirmed
prior to database lock and unblinding for final analysis by reviewing the listing of protocol deviations.
Please see the SOPRANO Protocol Deviation Guidelines for a list of criteria for protocol deviations. 
Unimportant protocol deviations correspond to the protocol deviations listed in the protocol deviation plan 
as having N against the “Important protocol deviation (Y/N)” column. The number of patients who had at 
least one important protocol deviation, along with a break down as follows.
The protocol deviations will be sorted by important/unimportant classification and then according to the 
descending order of frequency of the following protocol deviation category order:
•
Inclusion criteria
•
Exclusion criteria
•
Study drug
•
Assessment - safety                                                   
•
Efficacy Endpoints
•
Visit window
•
Informed consent  
•
Contraception
•
Met Discontinuation Criteria
•
Drug Not Interrupted
•
ICH/GCP
•
Other
A listing of protocol deviations will be presented based on the protocol deviation data entered into CTMS.
8.3 Treatments
8.3.1 Extent of Study Drug Exposure and Compliance
The duration of therapy, average dose per day and total dose will be presented using summary statistics
along with the number and percentage of patients in each of the compliance categories (< 80%, 
80% and 
120%, and > 120%) for the SS. Information on study drug exposure, dispensing and accountability and 
compliance will be listed in separate listings for the SS. 
8.3.2 Concomitant Medications
Anatomic Therapeutic Classification (ATC) coding will be performed for this study according to WHODRUG 
(version 01Mar2016 Drug Dictionary Enhanced (DDE) with yearly upgrades).
The number and percentage of patients using study-treatment concomitant medications will be displayed 
together with the number and percentage of patients using at least one medication within each second level 
ATC category (e.g., “A01”), and WHO preferred name (i.e., generic level, code ending in 01001). Records 


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are assigned as study-treatment concomitant based on the rules described in section 5.3.2. Study-
concomitant medications will also be presented by second level ATC category and WHO preferred name. 
Prior medications will also be displayed together with the number and percentage of patients using at least 
one medication within each second level ATC category (e.g., “A01”), and WHO preferred name (i.e., generic 
level, code ending in 01001) for the FAS.
A listing of prior and concomitant medications will be presented for the SS. The prohibited and PAH 
medications will be flagged in a listing. A second listing of the prior and concomitant medications will detail 
the medical history and AEs associated with the medications for the SS. A listing of medications that are 
started after 30 days of the last dose will be presented.
8.4 Demographic and Baseline Characteristics
Demographic characteristics will be presented for the FAS. The distribution of race, ethnicity, sex, age and 
sex distribution within each age group will be presented. Age groups will be categorized as < 65 years, 
65 years – < 75 years, and 75 years. Baseline characteristics will be presented for the FAS. BMI, height,
weight, Baseline functional class, time from LVAD implantation to treatment, and the following RHC 
parameters will be presented in a table:
•
Heart rate
•
Systemic blood pressure: mean (non-invasive or invasive) 
•
Systemic blood pressure: systolic (non-invasive or invasive) 
•
Systemic blood pressure: diastolic (non-invasive or invasive)
•
Hemoglobin
•
Peripheral arterial oxygen saturation (SpO2) by pulse oximetry
•
mRAP
•
Kussmaul Sign
•
Right atrial oxygen saturation
•
Right ventricle systolic pressure (RVSP)
•
Right ventricle end-diastolic pressure (RVEDP)
•
sPAP
•
Diastolic pulmonary artery pressure
•
mPAP (end-expiratory mean line)
•
SvO2
•
PAWP (mean of the wave)
•
PAWP (end-expiratory mean line)
•
LVEDP
•
Pulmonary artery wedge oxygen saturation
•
LVAD Speed
•
LVAD flow rate
•
LVAD power
•
Thermodilution CO 
•
Direct Fick CO 


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•
Thermodilution PVR-inv 
•
Thermodilution PVR-prog
•
Direct Fick PVR - calculated
•
Indirect Fick PVR - calculated
•
Indirect Fick CO
•
mPAP (calculated directly on the CRF as 0.61 x sPAP + 2)
•
BSA
•
CI
•
TPR
•
Transpulmonary gradient (TPG)
•
Diastolic pressure gradient (DPG)
•
Pulmonary Artery Pulsatility index (PAPi)
•
Pulmonary arterial compliance (PAC)
•
Right ventricle stroke work index (RVSWI)
•
Effective arterial elastance (Ea)
•
Resting maximum oxygen consumption (VO2).
No imputations using planned group median will be performed on PAWP and thus the results may be 
slightly inconsistent with the primary analysis. 
Demographic and Baseline characteristics will be listed for the FAS.
Medical history and pulmonary hypertension relevant disease history will be listed in separate listings. 
Medical history will be coded using the MedDRA version 19.0 with yearly updates. The Baseline 
thermodilution PVR-inv presented in the demographics table will also be based on the following raw CRF 
variable (thermodilution method):
Pulmonary vascular resistance (PVR) [mPAP-PAWP]/CO (WU)
Baseline thermodilution PVR-prog will also be presented in the demographics table for the thermodilution 
method.
The demographics and Baseline characteristics table will present both thermodilution PRV-inv and the 
thermodilution PVR-prog.
8.5 Efficacy Analyses
Fixed effects will be used in all models. Hemodynamic measurements from RHC CRF page which are 
conducted post a heart transplant at any time during or prior to the study will be excluded from statistical 
analysis but included in the listings.
8.5.1 Primary Endpoint
The primary analysis will be performed on the FAS. Thermodilution PVR-prog will be summarized by time 
point and treatment group using descriptive statistics as well as geometric means and coefficients of 
variation (CVs). The ratio of Week 12 to Baseline thermodilution PVR-prog will be summarized similarly.
The ratio of Week 12 to Baseline thermodilution PVR-prog will be log-transformed (base e) and analyzed 
using an ANCOVA with a factor for treatment group (macitentan vs. placebo) and a covariate for Baseline


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log thermodilution PVR-prog. The treatment group difference (on log scale) and its 95% CI will be estimated 
based on the model. The GMR (macitentan vs. placebo) and its 95% CI will be obtained by exponentiation. 
The null hypothesis is that the mean PVR ratio is the same in the macitentan and placebo groups.
The alternative hypothesis is that the mean PVR ratio is lower in the macitentan group as compared to the 
placebo group.
The null hypothesis will be rejected if the entire 95% CI is below one.
The treatment effect will be ex
of PVR in the macitentan group as compared to the placebo group.
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. Code similar to the below will be used:
proc mixed data=pvr;
class trt;
model logratio_Week_12_to_Baseline_PVR
= baseline_log_PVR trt;
/* active treatment / Placebo at 12 weeks */
estimate ‘Macitentan vs Placebo’       trt  1 -1 /cl;
lsmeans trt / diff cl;
ods output Estimates=Est LSMeans=lsmeans Diffs=Diffs;
run;
where logratio_Week_12_to_Baseline_PVR = is the variable for the logarithm of the ratio of Week 12 to 
Baseline.
The p-value obtained from the above code is two-sided, and if this p-value is less than 0.05 then the ratio 
will be considered to be statistically significant (provided that the estimated mean PVR ratio is less than 
one).
The derived thermodilution PVR-prog variable without imputation will be listed for the FAS. The PVR data 
measured post-heart transplant will be included in the listing of PVR, but will not be used in the primary and 
secondary efficacy analysis.
8.5.1.1 Assumption Checking
8.5.1.1.1 Homogeneity of Covariate Regression Coefficients
ANCOVA assumes homogeneity of covariate regression coefficients. This is ANCOVA's "equality of 
regressions" or "homogeneity of regressions" assumption. Because a single slope is used to adjust all 
observations in the experiment, the covariate coefficients (i.e. the slopes of the regression lines) must be 
the same for each level of the categorical variable being analyzed (i.e. all slopes must estimate the same 
common slope ). In other words, the adjustment of the Y values using a single for all treatments is based 
on the assumption that there is a constant regression relationship among groups. The test for heterogeneity 
of slopes tests the validity of this assumption; that is, it tests whether or not the regression coefficients are 
constant over groups. 
A regression relationship that differs among treatment groups reflects an interaction between the treatment 
groups and the independent variable or covariate. To test the assumption of homogeneity of slopes, this 
assumption will be checked using a scatter plot of the log of the ratio of Week 12 thermodilution PVR-prog 
(including imputed values) vs. Baseline logged thermodilution PVR-prog by treatment group for the FAS.


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8.5.1.1.2 Normality of Residuals
To test for normality of residuals, the residuals from the ANCOVA model will be plotted. If the assumptions 
for the ratio are violated, non-parametric tests may be investigated in an exploratory analysis.
8.5.1.2 Handling of Missing Data for the Primary Analysis
The following imputation methods will be performed on the following primary endpoints.
thermodilution PVR-prog = [mPAP-PAWP]/thermodilution CO (WU) (derived by programming) at 
baseline and the Day 84 or EOT visit
PVR ratio = Week 12 PVR / Baseline PVR
8.5.1.2.1 PAWP imputation
When missing, PAWP (mmHg) (end-expiratory mean line) will be imputed as follows:
1.1 If PAWP is missing but the left ventricular end-diastolic pressure (LVEDP) from the RHCA CRF 
page is not-missing at the same visit, then PAWP will be imputed with LVEDP.
1.2 Else if PAWP and LVEDP are missing, then PAWP will be imputed with the closest non-missing 
PAWP value in days, choosing the later day if 2 visits are equally close.
1.3 Else if no other PAWP or LVEDP values are available for that subject, then PAWP will be 
imputed with the median imputed PAWP values over all other subjects in the Full Analysis Set from 
the same planned treatment group and same visit.
8.5.1.2.2 PVR-prog imputation
When missing, PVR-prog will be imputed as follows:
2.1  For the baseline visit, if mPAP and CO are not missing, then PVR-prog will be imputed using 
the imputed PAWP value at baseline.
For the Day 84 or EOT visit:
2.2.1  If mPAP, CO and an imputed PAWP are not missing, then PVR-prog will be imputed 
using the imputed PAWP value at Day 84 or EOT.
2.2.2  Else PVR-prog will be imputed using the last post-baseline unscheduled PVR-prog 
before Week 84 or EOT.
8.5.1.2.3 PVR ratio
When PVR is non-missing at Baseline, but still missing Day 84 or EOT after imputation at 8.5.1.2.2,
then PVR ratio will be imputed with the median imputed PVR ratio values over all other subjects 
with non-missing PVR ratio in the Full Analysis Set from the same planned treatment group and 
same visit. 
The above imputations will be performed on all PVR analyses, including the sensitivity analyses.
Specifically, they will be applied in both the primary summary statistic table and the ANCOVA as well as 
the analysis of the primary variable in the FAS and modified FAS. The imputations for Baseline 
thermodilution PVR-prog will be used in both the calculation of the primary endpoint (ratio of Week 12 to 
Baseline of thermodilution PVR) and for the covariate adjustment of the primary endpoint (Baseline log 
thermodilution PVR-prog).
The imputation rules will not be applied to the results presenting change from Baseline in PVR.
Multiple imputation is not planned.


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8.5.1.3 Sensitivity Analysis
8.5.1.3.1 Ratio of Week 12 to Baseline PVR for the Modified FAS
To investigate the robustness of the results, the same analysis and descriptive statistics of primary endpoint 
will be performed in the Modified FAS in section 6.5.
8.5.1.3.2 PVR based on investigator-reported/calculated results
The analysis of primary endpoint will be repeated for the FAS based on the thermodilution PVR-inv recorded 
on the eCRF.
8.5.1.3.3 Ratio of Week 12 to Baseline PVR based on the Evaluable Set
The analysis of primary endpoint will be repeated for the evaluable set in section 6.7, where no planned
treatment group specific median used for imputation in section 8.5.1.2.1 (PAWP imputation) or 8.5.1.2.3 
(PVR ratio imputation)
8.5.1.3.4 Ratio of Week 12 to Baseline PVR for the PPS
The analysis of primary endpoint will be repeated for the Per Protocol set in section 6.6.
8.5.2 Multiplicity
No adjustments for multiplicity will be made. 
8.5.3 Pooling of Sites
Pooling of sites is not planned since site is not included in any of the models.
8.5.4 Secondary Endpoints
Secondary efficacy analyses will be performed on the FAS using 95% CIs. No correction for multiple testing 
will be applied for these analyses and no imputation of missing values will be performed, except for BSA. 
For BSA the last observed value, including baseline and screening values, will be carried forward. 
Secondary analyses will be conducted based on the FAS for selected secondary endpoints as described 
below.
Changes from Baseline to Week 12 in pressure-volume variables (i.e., mRAP, mPAP, PAWP, CI, TPR and 
SVO2) will be analyzed, but without the log-transformation or imputation. The ANCOVAs for mRAP, mPAP 
(end-expiratory mean line), PAWP, CI, TPR and SVO2 will be adjusted for Baseline log PVR and the 
Baseline of the variable to be analyzed as in section 4.0, e.g. for mRAP the ANCOVA will be adjusted for 
Baseline log thermodilution PVR which did not use planned treatment group median for imputation in 
section 8.5.1.2,) and Baseline mRAP. A summary table for change from Baseline will be presented for the 
following parameters on the RHCA CRF page:
•
Heart rate
•
Systemic blood pressure: mean (non-invasive or invasive) 
•
Systemic blood pressure: systolic (non-invasive or invasive) 
•
Systemic blood pressure: diastolic (non-invasive or invasive)
•
Hemoglobin
•
SpO2 by pulse oximetry
•
mRAP
•
Right atrial oxygen saturation
•
RVSP


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•
RVEDP
•
sPAP
•
Diastolic pulmonary artery pressure
•
mPAP (end-expiratory mean line)
•
SvO2
•
PAWP (mean of the wave)
•
PAWP (end-expiratory mean line)
•
LVEDP
•
Pulmonary artery wedge oxygen saturation
•
LVAD Speed
•
LVAD flow rate
•
LVAD power
•
Thermodilution CO 
•
Direct Fick CO 
•
Thermodilution PVR-inv 
•
Thermodilution PVR-prog
•
Direct Fick PVR - calculated
•
Indirect Fick PVR - calculated
•
Indirect Fick CO
•
mPAP (calculated directly on the CRF as 0.61 x sPAP + 2)
•
BSA
•
CI
•
TPR
•
TPG
•
DPG
•
PAPi
•
PAC
•
RVSWI
•
Ea
•
VO2
The summary table will be repeated in the modified FAS for the calculated parameters (not those reported 
by the site). A table for Kussmaul Sign will be presented for the FAS and a separate table will also be 
presented in the modified FAS.
All data collected on the RHC CRF data will be listed (with the exception of the raw variables derived on 
the CRF for thermodilution PRV-prog and BSA since these will be derived by statistical programming). 
PVR-inv and thermodilution PRV-prog will be presented in a separate listing with CO.


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For patients who receive a heart transplant at any time during or prior to the study, RHC conducted after 
heart transplant will be excluded from the above secondary efficacy analyses which are based on RHC
variables. The PVR data for patients with post- heart transplant will be included only in the listing of right 
heart catherization parameters and will not be used for PVR calculation.
NT-proBNP will be summarized by time point and treatment group using descriptive statistics as well as 
geometric means and CVs. The ratio of Week 12 to Baseline NT-proBNP will be summarized similarly. The 
ratio versus Baseline in NT-proBNP will be log-transformed and analyzed using an ANCOVA with 
covariates for treatment group and Baseline log NT-proBNP. NT-proBNP and the ratio versus Baseline will 
be listed for the FAS. The summary table will be repeated in the modified FAS.
WHO FC will be summarized by time point and treatment group using frequency tables in the FAS and
repeated in the modified FAS. A shift table will also be presented in the FAS.
Changes from Baseline in WHO FC will be categorized as worsening (change > 0 e.g. Class I at Baseline
and class II to IV at the Week 12 / end of treatment visit) ; improvement (change < 0 : e.g. Class IV at 
Baseline and class I /II/III at the Week 12 / end of treatment visit); or no change (change =0 : remains in 
same class from baseline to Week 12/end of treatment visit) . The change of WHO FC will be compared 
using proportional odds model (ordered logistic regression, reference level= worsening) with covariates for 
treatment group and baseline WHO FC (I/II vs. III/IV) in the FAS. Improving will also be analyzed using the 
logistic regression model (reference level = no change or worsening) with covariates for treatment group 
and baseline WHO FC (I/II vs. III/IV) in the FAS. 
Worsening will be analyzed using a logistic regression model (reference level =no change or improvement)
with covariates for treatment group and Baseline WHO FC in the FAS. Baseline WHO FC will be entered 
in the model as a categorical covariate as (FC I/II vs. III/IV). The outcome to be modelled will be set to 1 if 
the patient has any worsening (i.e., change > 0) during the study (including any post-Baseline unscheduled 
visits) and 0 if the patient does not have any worsening (i.e., change <= 0) during the study. The treatment 
effect will be expressed in terms of an odds ratio. If a patient has no post-Baseline FC data they will be 
excluded from logistic regression. The dummy variable for treatment will be coded as macitentan=1 and 
placebo=0. WHO FC results will be listed for the FAS.
Analysis results for WHO FC will be reported if the models converge.
8.5.5 Exploratory Endpoints
Exploratory efficacy analyses will be performed on the FAS using 95% CIs.
Echocardiographic variables including TAPSE, S’, RVFAC, E’, A’, RVLS, RV end systolic area, RV end 
diastolic area, and RVSI will be summarized by treatment and scheduled time point (Baseline, Week 
12/EOT) using descriptive statistics (n, mean, SD, median, Q1, Q3, and range). Unscheduled visits will not 
be included in the table but will be listed in listings. Based on data availability, the change from Baseline to 
Week 12/EOT in these variables will be summarized similarly and analyzed using an ANCOVA with a factor 
for treatment and covariates including Baseline log PVR and Baseline TAPSE, S’, RVFAC, E’, A’, RVLS, 
RV end systolic area, RV end diastolic area and RVSI, respectively. The adjusted treatment effect and its 
95% CI will be presented. Echocardiography will be listed for the FAS. The assessment of clinically 
significance for echocardiography variables will also be listed for the FAS.
Time to first occurrence of clinical events, from enrollment to last follow-up date (section 5.7.6) will be 
summarized. These clinical events include: 
•
Hospital admission for HF 
•
Re-initiation of i
ours duration 
•
Re-
ours duration 
•
Initiation of PDE5 inhibitors 
•
Need for RVAD / TAH 


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Need for RRT 
•
Death
The number of patients with at least one post-Baseline clinical event and the number of patients with each 
type of clinical event will be presented in a summary table. 
Survival analyses will also be performed on for the time to the first post-Baseline clinical event. The survival 
analysis will be presented overall for all the above clinical events, and not separately for each type of event.
Cox proportional hazards model will be used to estimate the hazard ratio for the time to the first clinical 
event and the 95% confidence interval of the hazard ratio. Treatment group will be the only covariate in the 
model. 
A p-value will be calculated for the time-to-event treatment differences using the unstratified log-rank test 
and a Kaplan-Meier analysis will be performed to estimate the median, 25%, 75% time with 95% confidence 
intervals.
A summary table will present the number of patients by first clinical event. A separate table will present the 
cumulative number of patients with events, the number of patients at risk and the event-free survival 
estimate for the following time intervals:
•
Day 0
•
Day 7
•
Day 14
•
Day 28
•
Day 56
•
Day 84
•
Day 98
A listing of first clinical event after Study Day 1 will be presented. If a patient has more than one type of 
event on the same day, the first alphabetically will be presented in the listing.
A Kaplan-Meier figure for the time to the first clinical event will be presented for this analysis in addition to 
the Cox proportional hazards model.
Duration of Hospitalization for HF will be summarized by treatment group. The descriptive summary 
statistics table will only be presented for patients who had hospitalization due to HF according to the 
adjudication committee. Hospitalization for HF will be listed for the FAS. The CEC data will also be listed 
for the FAS.
All AEs where an RVAD or a TAH was required will be listed for the FAS, including non-treatment emergent 
adverse events. 
GFR derived from statistical programming in section 5.4.5 will be summarized by treatment and scheduled 
time point (Baseline, Week 12/EOT) using descriptive statistics (n, mean, SD, median, Q1, Q3, and range). 
Unscheduled visits will not be presented in the tables but will still be listed in the listing. The change from 
Baseline to Week 12/EOT in GFR will be summarized similarly. Change from Baseline in GFR will be 
analyzed using an ANCOVA with a factor for treatment and covariates Baseline log PVR and Baseline GFR
as in section 4. The adjusted treatment effect and its 95% CI will be presented. GFR will be listed for the 
SS. 
The additional “Systemic blood pressure: Mean, systolic and diastolic (mmHg) (Noninvasive or invasive)”
variable will not be reported in any tables or listings or used in any derivations for the results created based 
on this SAP since the other systemic blood pressure variables are to be completed by the centers.


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8.6 Safety Analyses
All safety data will be listed, with flags for quantitative abnormalities.
8.6.1 Adverse Events
A treatment-emergent AE is any AE temporally associated with the use of a study treatment and the full 
definition is provided in section 5.1.1. In practice all AEs which change in severity or relationship to study 
drug are assigned a new start date and captured as a new record. These events do not need combining 
since patients with AEs (rather than events) are the unit of analysis. A summary of treatment-emergent 
adverse events, including the number and percentage of patients reporting at least one adverse event, the 
number and percentage of patients discontinuing due to an adverse event, the number and percentage of 
patients with at least one SAE, severe AEs, related AEs, the number of patients with at least one AE of 
interest, the number of patients with any severe treatment-related AEs, the number of patients with any 
treatment-related serious AEs, the number of patients with any treatment-related AEs leading to treatment 
discontinuation and the number and percentage of deaths will be presented.
The number and percentage of patients experiencing treatment emergent AEs and SAEs at least once will 
be tabulated by treatment group and by:
•
MedDRA System organ class (SOC) and individual preferred term within each SOC, in descending 
order of incidence for both the SOC and preferred term. Note that counting will be by patient not 
event and patients are only counted once within each SOC or preferred term. I.e. if a patient had 
Nausea and Vomiting, which are both coded under the SOC “Gastrointestinal disorders” this patient
would be counted once under Nausea and again separately under the Vomiting preferred term, but
only once under the SOC.
•
Preferred term, in descending order of incidence.
Furthermore, treatment-emergent AEs will be tabulated as described above by maximum severity. Missing 
severities will be counted as severe in the table but listed as missing in the listings. A table of patients with 
related AEs by SOC and preferred term and a table of the number of patients with treatment-related AEs 
by preferred term will be presented for the SS. Missing relationship will be counted as related in the tables 
but listed as missing in the listings. For the related AE tables, patients with multiple events within a particular 
body system or preferred term will be counted under the category of their most drug-related event within 
that SOC or preferred term. For tables by severity, patients with multiple events within a particular SOC or 
preferred term will be counted under the category of their most severe event within that SOC or preferred 
term.
AEs leading to premature discontinuation of study treatment will also be summarized as described above.
The table by SOC and preferred term will include both non-treatment-emergent and treatment-emergent 
AEs with an action taken of “Drug withdrawn”. The table by preferred term will only include treatment-
emergent AEs with an action taken of “Drug withdrawn”.
Listings will be provided for all reported AEs, including AEs and SAEs. In addition, separate listings will be 
provided for AEs leading to premature discontinuation of study treatment. The discontinuation date will be 
the date of last dose of study medication on the End-of-Treatment CRF page. Two listings will present the 
results from the adjudication. 
Version 19.0 of the MedDRA dictionary will be used and updated on a yearly basis. 
Any heart transplant that is recorded on the AE or SAE page will be included in the AE outputs. 
8.6.1.1 Events of Interest
An Event of Interest (EOI) is defined as a noteworthy event for a particular product or class of products that 
a sponsor may wish to monitor carefully. It could be serious or non-serious, and could include events that 
might be potential precursors or prodromes for more serious medical conditions in susceptible individuals 
(Council for International Organizations of Medical Sciences VI, 2005). The EOIs for this study will include: 


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•
Anaemia
•
Hypotension 
•
Oedema/fluid retention
AE preferred terms that are potentially representative of EOIs will be retrieved for review and analysis using 
the criteria in Appendix 6 Criteria for Adverse Events of Special Interest. The "narrow" or "wide" is irrelevant 
because (1) we work with preferred term lists, and because (2) we usually have Actelion Medical Queries
(not SMQs) for which no scope is defined.
Patient incidence of treatment-emergent EOIs will be tabulated by treatment group, the type of event, and 
the maximum severity.
8.6.2 Deaths and Serious Adverse Events
Investigators complete the AE page (which is the input for the raw AE data set) and if the AE is serious a 
second page is opened (which is the input for the raw SAE data set). Thus there is information on SAEs in 
both the AE page and the SAE page. These two data sources can be linked through the investigator 
entering the SAE row number in the AE page should data recorded on the AE page about SAEs be required 
from the AE page. 
The number and percentage of patients experiencing treatment-emergent SAEs at least once will be 
tabulated by treatment group and by:
•
MedDRA SOC and individual preferred term within each SOC, in descending order of incidence. 
Note that counting will be by patient not event and patients are only counted once within each SOC 
or preferred term.
•
Preferred term, in descending order of incidence.
AEs leading to death will also be summarized as described above. Please see section 5.1.2 for the definition 
of AE leading to death. In addition, separate listings will be provided for treatment emergent SAEs (SAE 
detail listing, the SAE relationship to study drug listing and the significant laboratory test results relevant to 
the SAE) and for AEs leading to death.
8.6.3 Laboratory Data
Descriptive summary statistics by visit and treatment group will be provided for observed values and 
absolute changes from Baseline, in both hematology and blood chemistry laboratory tests. In order to 
minimize missing data and to allow for unscheduled visits, all recorded assessments up to EOT plus 37 
days will be assigned to the most appropriate visit time point according to the best fitting time window for 
that assessment. Once the windowing has been performed summary statistics for Baseline, Day 28, Day 
56, Day 84, EOS will be presented in the table but any laboratory listings would still present all visits a
patient attended.
The central laboratory manual outlines the definitions of marked abnormalities and provides guidance 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 will be taken into account regardless of whether they correspond to scheduled (per-protocol) or 
unscheduled assessments.
A listing of marked laboratory parameters will be provided i.e. values of HHHH, HHH, HH, LL, LLL as per 
the table below.
Absolute values and changes from Baseline of laboratory values during the course of the study will be 
summarized using the usual location and scale summary statistics by treatment group.
The following laboratory variables will be presented in the units provided by the central laboratory:


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•
Hematology: hemoglobin, hematocrit, erythrocyte count, leukocyte count with differential counts, 
platelet count. For differentials only the K (1000 cells)/µL results will be presented in the table. Both 
percentage and K/µL results will be presented in the listings.
•
Blood chemistry: AST, ALT, alkaline phosphatase, total and direct bilirubin, lactate dehydrogenase 
(LDH), creatinine, blood urea nitrogen (BUN), uric acid (urate), glucose, cholesterol, triglycerides, 
sodium, potassium, chloride, calcium, protein, albumin.
The number and percentage of patients with hemoglobin abnormalities will be tabulated by treatment group
by presenting a shift table showing the number of patients whose hemoglobin was less than 8.0 g/dL at 
time points up to end of study (including overall post-Baseline), the number of patients whose hemoglobin 
was greater than or equal to 8.0 g/dL but less than 10.0 g/dL at time points up to end of study and for 
completeness the number of patients whose hemoglobin was 
10 g/dL at the windowed time points up to 
the EOS and last visit post-Baseline. For this table, the lowest value within the visit window will be used in 
the table.
For the overall study period (Baseline to EOS), the following categories will be presented for hemoglobin 
abnormalities:
•
Hemoglobin < 8.0 g/L
•
Hemoglobin 
8.0 and < 10.0 g/dL
•
Hemoglobin decrease from Baseline
2.0 g/dL and < 5.0 g/dL
•
Hemoglobin decrease from Baseline
5.0 g/dL
•
Hemoglobin < 10.0 g/dL and concurrent (i.e., at the same time point) decrease from Baseline
2.0 g/dL
The lowest non-missing hemoglobin value at any post-Baseline time point of assessment up to the EOS 
will be considered in the evaluation of incidences. Thus a patient can only be counted once in either the
“< 8.0 g/L“ or “
8.0 and < 10.0 g/dL” category, and once in the “decrease from Baseline
< 5.0 g/dL” or “decrease from Baseline
” category.
The cumulative number and percentage of patients with liver function test abnormalities will be tabulated 
by treatment group. For the overall study period (Baseline to EOS), the proportion of patients falling in the 
following categories for liver test abnormalities will be presented:
•
ALT and /or AST > 1 x ULN and < 3 x ULN
•
•
•
•
x ULN
•
x ULN
•
The 
proportion of patients with 
in combination with concurrent 
× ULN from Baseline (exclusive) up to EOS will be presented i.e. treatment-
emergent laboratory values are those that occur on a date after the first dose of study medication.
The qualifying ALT or AST test result must be from the same blood sample as the total bilirubin 
result. 
Patients will be counted once at the worst level within a category. Patients may be counted once in each of 
the 
3 x ULN, 
5 x ULN and 
8 x ULN categories and a maximum of once in the worst of the remaining 


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The highest ALT or AST value at any post-Baseline time point of assessment up to the EOS is considered 
in the evaluation of incidences.
Separate listings of hematology, biochemistry, and l circulating biomarker results and their change from 
Baseline will be presented for the SS. 
For both the tables and the listings there will be no exclusion of laboratory data, even if the reference range 
indicator is equal to E for exclusion and regardless of the data entered in the completion status variable.
Low, normal and high categories will be included in the table as per the central laboratory reference ranges.
Thus a laboratory test abnormality is defined as any value outside the normal range as provided by the 
central laboratory. The direction of the abnormality (below or above the normal range) is indicated using ‘H’ 
and ‘L’. A marked laboratory test abnormality is defined as any value up to EOS that fulfills the applicable 
condition for LL / HH. Marked abnormality variables of interest are defined in standard international units 
for the laboratory variables of interest and are listed in Table 1 below. The most severe marked 
abnormalities are indicated by LLL / HHH, where applicable. 
Table 1
Laboratory Abnormalities
Parameter 
LL marked
LLL marked
HH marked
HHH marked
Hemoglobin
< 10 g/dL
< 8 g/dL
[post-Baseline >
(Baseline + 2 g/dL) 
AND (Baseline >
ULN)] 
OR
[post-Baseline >
(ULN + 2 g/dL) AND
Baseline
[post-Baseline >
(Baseline + 4 g/dL) 
AND (Baseline >
ULN)] 
OR
[post-Baseline >
(ULN + 4 g/dL) 
AND Baseline
ULN]
Hematocrit
< 28 % for 
females
< 32 % for males
< 20 %
> 55 % for females
> 60 % for males
> 65 %
Platelets 
< 75 × K/uL
< 50 × K/uL
> 600 × K/uL
> 999 × K/uL
Leukocytes (white 
blood cells)
< 3.0 × K/uL
< 2.0 × K/uL
> 20.0 × K/uL
> 100.0 × K/uL
Neutrophils
< 1.5 × K/uL
< 1.0 × K/uL
NA
NA
Eosinophils
NA
NA
> 5% OR
> 5 × K/uL
NA
Lymphocytes
< 0.8 × K/uL
< 0.5 × K/uL
> 4.0 × K/uL K/uL
> 20 × K/uL


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Parameter 
LL marked
LLL marked
HH marked
HHH marked
ALT 
NA
NA
> 3 × ULN
> 5 × ULN*
AST 
NA
NA
> 3 × ULN
> 5 × ULN*
Alkaline 
phosphatase
NA
NA
> 2.5 × ULN
> 5 × ULN
Total Bilirubin
NA
NA
> 2 × ULN
> 5 × ULN
Direct Bilirubin
NA
NA
> 2 × ULN
> 5 × ULN
Creatinine
NA
NA
> 1.5 × Baseline
OR
> 1.5 × ULN
> 3 × Baseline OR
> 3 × ULN
Glucose Random
< 54 mg/dL
< 40 mg/dL
> 160 mg/dL
> 250 mg/dL
Calcium
< 8.0 mg/dL
< 7.0 mg/dL
> 11.6 mg/dL
> 12.4 mg/dL
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
Uric acid (Urate)
NA
NA
> 9.9 mg/dL
> 12.1 mg/dL
Albumin
< 3 g/dL
< 2 g/dL
NA
NA
Blood Urea Nitrogen NA
NA
> 2.5 × ULN
> 5 × ULN
* Also HHHH as > 8 × ULN
ALT = alanine aminotransferase; AST = aspartate aminotransferase; NA = not applicable/available; ULN = 
upper limit of normal.
Treatment-emergent marked laboratory abnormalities are all marked laboratory abnormalities with onset 
after the study treatment start and before or on ET plus 37 days [see definitions in section 5.1.1], that were 
not present at Baseline. An additional “last visit post-Baseline” will also be presented. Shift tables will be 
included that summarize the number and percent of patients with LLL, LL, L, Normal, H, HH, HHH at each 
windowed visit and the last visit post-Baseline compared to the Baseline visit. L and H will be values outside 
the normal range but not reaching the marked abnormality criteria. If HH, HHH, LL or LLL is not defined for 
a variable, ‘NA’ will be displayed for LL, LLL, HH, and HHH categories. Percentages will be calculated 
based on the number of patients in the analysis set. Shift tables will be used to summarize the worst 
treatment-emergent laboratory abnormalities, based on the on the definition of the marked laboratory test 
abnormalities listed in Table 1, above. The worst category is taken for the analysis for each direction so a 
patient can be counted under LLL and HH within the same windowed timepoint. Note that worse categories 
in each direction can result from multiple records for a subject within a visit window, or one record satisfying 
2 abnormalities in different directions.
8.6.4 Vital Signs
Blood pressure (i.e., diastolic blood pressure (DBP) and systolic blood pressure (SBP)), pulse rate, BMI as 
programmed by statistical programming and weight will be summarized at each scheduled study visit using 
the usual location and scale summary statistics by treatment group for both absolute values and changes 
from Baseline, i.e. no windowing will be necessary to include data from unscheduled visits; unscheduled 
visits would only be presented in any listings. Patients for whom no post-Baseline value is available are 


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excluded from the analysis of the changes from Baseline in the SS. Height, BMI calculated by the 
investigator, and mean blood pressure will not be included in the table.  
Vital signs including the parameters listed above as well as height, BMI as programmed by statistical 
programming, BMI calculated by the investigator, and mean blood pressure will be listed. 
8.6.5 Other Data
Pregnancy test results will be listed for the SS.
9.0 Validation
PRA Health Sciences' goal is to ensure that each TFL delivery is submitted to the highest level of quality. 
Our quality control procedures will be documented separately in the study specific quality control plan. 
10.0 References
National Research Council 2010. The Prevention and Treatment of Missing Data in Clinical Trials. Panel 
on Handling Missing Data in Clinical Trials
http://www.nap.edu/catalog/12955/the-prevention-and-
treatment-of-missing-data-in-clinical-trials
Little RJA, Rubin DB. Statistical Analysis with Missing Data. 2nd ed. New York: John Wiley, 2002


Statistical Analysis Plan
Effective Date: 13-Jul-2020/Version 2.0
Sponsor: Actelion Pharmaceuticals US, Inc.
Protocol no: AC-055-205
PRS 005 T 17 E
Page 41 of 50
Strictly Confidential.  © 2004-2014, PRA Health Sciences.  All rights reserved.
Appendix 1 Glossary of Abbreviations
Glossary of Abbreviations:
A’
Tricuspid Inflow Peak E-Velocity  
AE
Adverse event
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
AST
Aspartate aminotransferase
ATC
Anatomic Therapeutic Classification
BMI
Body mass index
BSA
Body surface area
BUN
Blood urea nitrogen
CCMP
Central clinical monitoring plan
CEC
Clinical Events Committee
CI
Confidence interval / Cardiac index
cm
Centimeters
CO
Cardiac output
CRF
Case Report Form
CRO
Clinical Research Organization
CTMS
Clinical Trials Management System
CV
Coefficient of variation
DBP
Diastolic blood pressure
DDE
Drug Dictionary Enhanced
DPG
Diastolic pressure gradient
E’
Tricuspid peak diastolic annular velocity 
Ea
Effective arterial elastance
EOI
Event of interest
EOS
End of study
EOT
End of treatment
FAS
Full Analysis Set
GFR
Glomerular filtration rate
GLM
Generalized Linear Models
GMR
Geometrics Mean Ratio
h
Hours
HF
Heart failure


Statistical Analysis Plan
Effective Date: 13-Jul-2020/Version 2.0
Sponsor: Actelion Pharmaceuticals US, Inc.
Protocol no: AC-055-205
PRS 005 T 17 E
Page 42 of 50
Strictly Confidential.  © 2004-2014, PRA Health Sciences.  All rights reserved.
ICF
Informed consent form
IDMC
Independent Data Monitoring Committee
inv
Investigator-reported
ISAC
Independent statistical analysis center
i.v.
Intravenous
IxRS
Interactive Web Response System
K/µL
Thousand cells per micro liter
kg
Kilograms
LDH
Lactate dehydrogenase
L/min/m2
Liter/minute/meter squared
LVAD
Left ventricular assist device
LVEDP
Left ventricle/ventricular end-diastolic pressure
MedDRA
Medical Dictionary for Regulatory Activities
mmHg
Milligrams of mercury
mPAP
Mean pulmonary artery pressure
mRAP
Mean right atrial pressure
NT-proBNP
N-terminal prohormone of brain natriuretic peptide
ODS
Output Delivery System
PAC
Pulmonary arterial compliance
PAH
Pulmonary artery hypertension 
PAPi
Pulmonary Artery Pulsatility index
PAWP
Pulmonary artery wedge pressure
PDE5I
Phosphodiesterase type 5 inhibitors
PH
Pulmonary hypertension
pmol/L
Pikomol per liter
PP
Per Protocol
PPS
Per Protocol Set
PRA
Pharmaceutical Research Associates
prog
As programmed by statistical programming
PVR
Pulmonary vascular resistance
Q1
Lower quartile
Q3
Upper quartile
RA
Room Air
RBC
Red Blood Cell


Statistical Analysis Plan
Effective Date: 13-Jul-2020/Version 2.0
Sponsor: Actelion Pharmaceuticals US, Inc.
Protocol no: AC-055-205
PRS 005 T 17 E
Page 43 of 50
Strictly Confidential.  © 2004-2014, PRA Health Sciences.  All rights reserved.
RHC
Right heart catheterization
RPM
Revolutions per minute
RRT
Renal replacement therapy
RV
Right ventricle
RVAD
Right ventricular assist device
RVEDP
Right ventricle end-diastolic pressure
RVFAC
Right ventricular fractional area change
RVLS
Global RV longitudinal strain
RVSI
Right ventricular sphericity index
RVSP
Right ventricle systolic pressure
RVSWI
Right ventricle stroke work index
S’
Tricuspid peak annular velocity S
SAP
Statistical Analysis Plan
SAS
Screened Analysis Set / Statistical Analysis System
SAE
Serious Adverse Event
SBP
Systolic Blood Pressure
Scr
Serum creatinine
SD
Standard deviation
SOC
System organ class
SOPRANO
Macitentan in pulmonary hypertenSiOn Post-left ventRiculAr assist device implantation
sPAP
Systolic pulmonary artery pressure
SpO2
Peripheral arterial oxygen saturation
SS
Safety Set
SVO2
Mixed venous oxygen saturation (Pulmonary arterial oxygen saturation)
TAH
Total artificial heart 
TAPSE
Tricuspid annular plane systolic excursion
TFL
Tables, figures and listings
TPG
Transpulmonary Gradient
TPR
Total pulmonary resistance
ULN
Upper limit of normal
VO2
Resting maximum oxygen consumption Resting oxygen consumption
WBC
White Blood Cell
WHO FC
World Health Organization functional class
WU
Wood unit


Statistical Analysis Plan
Effective Date: 13-Jul-2020/Version 2.0
Sponsor: Actelion Pharmaceuticals US, Inc.
Protocol no: AC-055-205
PRS 005 T 17 E
Page 44 of 50
Strictly Confidential.  © 2004-2014, PRA Health Sciences.  All rights reserved.
Appendix 2 Tables, Figures, Listings, and Supportive SAS Output 
Appendices
See separate document containing tables, figures and listings specifications. 
Appendix 3 List of Additional Protocol Violation/ Protocol Deviation 
Identification Listings
There are no additional listings defined but the following tables summarizes the post-text listings that will 
be looked at to identify protocol deviations/violations. A medical director at Actelion will look through the 
medications to determine any prohibited medications that may have been missed during the clinical 
research associates review.
List of Additional Protocol Violation/ Protocol Deviation Identification Listings:
Output 
Title 1
Title 2
Post-Text Listing 16.2.1.1.1
Inclusion and Exclusion Criteria (SAS)
Post-Text Listing 16.2.2.1
Protocol Deviations (FAS)
Post-Text Listing 16.2.3
Patient Populations (FAS)
Post-Text Listing 16.2.4.4
Prior and Concomitant Medications (SS)
Post-Text Listing 16.2.4.5.1
Prior and Concomitant Medications: Additional Information:
Medical History and Adverse Events (SS)
Post-Text Listing 16.2.5.1
Compliance (SS)
Post-Text Listing 16.2.5.2
Study Drug Dispensing and Accountability (SS)
Post-Text Listing 16.2.6.1
Right Heart Catheterization Parameters (FAS)
Post-Text Listing 16.2.6.2.1
PVR (FAS)
Appendix 4 Shells for In-Text Tables, Figures, and Listings
None are currently specified.
Appendix 5 Shells for Additional Protocol Violation/Deviation 
Identification Listings
No additional PDV listings are required to aid the identification of protocol deviations to ensure that the 
team has all the information required to identify the protocol violations/deviators, so no listing shells have 
been designed in the SAP.


Statistical Analysis Plan
Effective Date: 13-Jul-2020/Version 2.0
Sponsor: Actelion Pharmaceuticals US, Inc.
Protocol no: AC-055-205
PRS 005 T 17 E
Page 45 of 50
Strictly Confidential.  © 2004-2014, PRA Health Sciences.  All rights reserved.
Appendix 6 Criteria for Adverse Events of Special Interest
The MedDRA dictionary version is updated yearly. Actelion will provide any updates to the list of preferred 
terms to be included in the definition of the adverse events of special interest 90 days in advance of the 
delivery for  which updates are needed. 
Anaemia: The case will be included in this subgroup if it contains an event within the “Haematopoietic 
erythropenia” SMQ or the “Haematopoietic cytopenias affecting more than one type of blood cell” SMQ 
(with the exception of 2 unspecific PTs: “Blood disorder”, “Blood count abnormal”), or it contains an event 
with any MedDRA Preferred Term containing the text “anaemia”. This includes the following preferred terms
in MedDRA:
Anaemia
Anaemia folate deficiency
Anaemia Heinz body
Anaemia macrocytic
Anaemia megaloblastic
Anaemia neonatal
Anaemia of chronic disease
Anaemia of malignant disease
Anaemia of pregnancy
Anaemia postoperative
Anaemia prophylaxis
Anaemia splenic
Anaemia vitamin B12 deficiency
Anaemia vitamin B6 deficiency
Aplasia pure red cell
Aplastic anaemia
Aspiration bone marrow abnormal
Autoimmune aplastic anaemia
Autoimmune haemolytic anaemia
Bicytopenia
Biopsy bone marrow abnormal
Blood incompatibility haemolytic anaemia of newborn
Blood loss anaemia neonatal
Bone marrow disorder
Bone marrow failure
Bone marrow infiltration
Bone marrow myelogram abnormal


Statistical Analysis Plan
Effective Date: 13-Jul-2020/Version 2.0
Sponsor: Actelion Pharmaceuticals US, Inc.
Protocol no: AC-055-205
PRS 005 T 17 E
Page 46 of 50
Strictly Confidential.  © 2004-2014, PRA Health Sciences.  All rights reserved.
Bone marrow necrosis
Bone marrow toxicity
Cardiac haemolytic anaemia
Cold type haemolytic anaemia
Congenital anaemia
Congenital aplastic anaemia
Coombs negative haemolytic anaemia
Coombs positive haemolytic anaemia
Cytopenia
Deficiency anaemia
Erythroblast count abnormal
Erythroblast count decreased
Erythroid maturation arrest
Erythropenia
Erythropoiesis abnormal
Febrile bone marrow aplasia
Foetal anaemia
Full blood count decreased
Haematocrit abnormal
Haematocrit decreased
Haematotoxicity
Haemoglobin abnormal
Haemoglobin decreased
Haemolytic anaemia
Haemolytic anaemia enzyme specific
Haemolytic icteroanaemia
Haemorrhagic anaemia
Hand and foot syndrome secondary to sickle cell anaemia
Hereditary haemolytic anaemia
Hereditary sideroblastic anaemia
Hexokinase deficiency anaemia
Hyperchromic anaemia
Hypochromic anaemia
Hypoplastic anaemia
Iron deficiency anaemia


Statistical Analysis Plan
Effective Date: 13-Jul-2020/Version 2.0
Sponsor: Actelion Pharmaceuticals US, Inc.
Protocol no: AC-055-205
PRS 005 T 17 E
Page 47 of 50
Strictly Confidential.  © 2004-2014, PRA Health Sciences.  All rights reserved.
Leukoerythroblastic anaemia
Melanaemia
Microangiopathic haemolytic anaemia
Microcytic anaemia
Myelodysplastic syndrome
Myelodysplastic syndrome transformation
Myelofibrosis
Myeloid metaplasia
Nephrogenic anaemia
Normochromic normocytic anaemia
Pancytopenia
Panmyelopathy
Pernicious anaemia
Plasmablast count decreased
Primary myelofibrosis
Proerythroblast count abnormal
Proerythroblast count decreased
Protein deficiency anaemia
Pyruvate kinase deficiency anaemia
Red blood cell count abnormal
Red blood cell count decreased
Refractory anaemia with an excess of blasts
Refractory anaemia with ringed sideroblasts
Reticulocyte count abnormal
Reticulocyte count decreased
Reticulocyte percentage decreased
Reticulocytopenia
Scan bone marrow abnormal
Sickle cell anaemia
Sickle cell anaemia with crisis
Sideroblastic anaemia
Spherocytic anaemia
Spur cell anaemia
Warm type haemolytic anaemia


Statistical Analysis Plan
Effective Date: 13-Jul-2020/Version 2.0
Sponsor: Actelion Pharmaceuticals US, Inc.
Protocol no: AC-055-205
PRS 005 T 17 E
Page 48 of 50
Strictly Confidential.  © 2004-2014, PRA Health Sciences.  All rights reserved.
Hypotension: 
Blood pressure ambulatory decreased
Blood pressure decreased
Blood pressure diastolic decreased
Blood pressure orthostatic decreased
Blood pressure systolic decreased
Diastolic hypotension
Hypotension
Mean arterial pressure decreased
Orthostatic hypotension
Procedural hypotension
Oedema/fluid retention:
The case will be included in this subgroup if it contains an event with the MedDRA Preferred Term 
"Pulmonary congestion" or if within the SMQ "Haemodynamic oedema, effusions and fluid overload (SMQ)" 
with the exception of PTs containing "site". In addition to pulmonary congestion, this includes the following
preferred terms in MedDRA:
Acute pulmonary oedema
Amyloid related imaging abnormalities
Ascites
Bone marrow oedema
Bone marrow oedema syndrome
Bone swelling
Brain oedema
Bronchial oedema
Capillary leak syndrome
Cerebral oedema management
Cervix oedema
Compression stockings application
Cytotoxic oedema
Effusion
Elephantiasis nostras verrucosa
Extensive swelling of vaccinated limb
Fluid overload
Fluid retention
Gallbladder oedema
Gastrointestinal oedema


Statistical Analysis Plan
Effective Date: 13-Jul-2020/Version 2.0
Sponsor: Actelion Pharmaceuticals US, Inc.
Protocol no: AC-055-205
PRS 005 T 17 E
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Strictly Confidential.  © 2004-2014, PRA Health Sciences.  All rights reserved.
Generalised oedema
Gestational oedema
Gravitational oedema
Heat oedema
Hydraemia
Hydrothorax
Hypervolaemia
Hypoosmolar state
Joint effusion
Joint swelling
Lipoedema
Local swelling
Localised oedema
Lymphoedema
Mouth swelling
Muscle oedema
Muscle swelling
Myocardial oedema
Non-cardiogenic pulmonary oedema
Oedema
Oedema due to cardiac disease
Oedema due to hepatic disease
Oedema due to renal disease
Oedema mucosal
Oedema neonatal
Oedema peripheral
Oedematous kidney
Oesophageal oedema
Pelvic fluid collection
Pericardial effusion
Perinephric effusion
Peripheral oedema neonatal
Peripheral swelling
Pleural effusion
Prevertebral soft tissue swelling of cervical space


Statistical Analysis Plan
Effective Date: 13-Jul-2020/Version 2.0
Sponsor: Actelion Pharmaceuticals US, Inc.
Protocol no: AC-055-205
PRS 005 T 17 E
Page 50 of 50
Strictly Confidential.  © 2004-2014, PRA Health Sciences.  All rights reserved.
Pulmonary congestion
Pulmonary oedema
Pulmonary oedema neonatal
Reexpansion pulmonary oedema
Retroperitoneal effusion
Retroperitoneal oedema
Scleroedema
Skin oedema
Skin swelling
Spinal cord oedema
Subdural effusion
Swelling
Testicular swelling
Vasogenic cerebral oedema
Visceral oedema
Appendix 7 Prohibited Medication List
The prohibited medication list is a living document and will be updated by the sponsor as needed. It 
includes PAH-specific therapy, inhaled nitric oxide, strong CYP3A4 inhibitors and inducers, inotropes, 
vasopressors, and diuretics.