Clinical trial NCT03153111
Conditions: Heart Failure With Preserved Ejection Fraction
Sponsor: Actelion
Start date: 2017-07-11; Completion date: 2021-03-12
Enrollment: 143 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study to evaluate whether macitentan is an effective and safe treatment for patients with heart failure with preserved ejection fraction (HFpEF) and pulmonary vascular disease.

The primary objective is to evaluate whether macitentan 10 mg reduces N-terminal pro-brain natriuretic peptide (NT-pro-BNP) as compared to placebo in these patients.

Detailed description:

Arms: arm 1: Subjects randomized to the macitentan arm receives one tablet of macitentan 10 mg every day for at least 24 to maximum 52 weeks. arm 2: Subjects randomized to the placebo arm received one tablet of placebo every day for at least 24 to maximum 52 weeks.
Interventions: intervention 1: Macitentan intervention 2: Placebo
Intervention descriptions: intervention 1: macitentan 10 mg; film-coated tablet; oral use intervention 2: film-coated tablet (identical to the macitentan tablet); oral use

Protocol documents:
Prot_000.pdf: 
 
 
Macitentan / ACT-064992 
Heart failure with preserved ejection fraction and pulmonary 
vascular disease  
Protocol AC-055G202 
 
SERENADE 
A multi-center, double-blind, placebo-controlled Phase 2b study to evaluate the 
efficacy and safety of macitentan in subjects with heart failure with preserved 
ejection fraction and pulmonary vascular disease  
Study Phase: 
2b 
EudraCT Number: 
2016-003653-15 
Status and version: 
Final Version 7 
Date:  
16 July 2020 
Document type 
Global Amended Protocol 
Actelion document number 
(Doc No.): 
D-20.252 
 
Confidentiality statement 
The information provided herein contains Company trade secrets, commercial or financial information that 
the Company customarily holds close and treats as confidential. The information is being provided under the 
assurance that the recipient will maintain the confidentiality of the information under applicable statutes, 
regulations, rules, protective orders or otherwise. 
 
NCT03153111


Macitentan / ACT-064992 
HFpEF and pulmonary vascular disease  
Protocol AC-055G202 / SERENADE 
Version 7 
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EudraCT 2016-003653-15 
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2 
SPONSOR CONTACT DETAILS 
Sponsor 
 
Actelion Pharmaceuticals Ltd 
Gewerbestrasse 16 
CH-4123 Allschwil 
Switzerland 
 
+41 61 565 65 65 
Clinical Trial Physician  
Contact details of the Clinical Trial Physician can 
be found in the Investigator Site File 
Medical Emergency Hotline 
 
Site-specific toll telephone numbers and toll-free 
numbers for the Medical Emergency Hotline can be 
found in the Investigator Site File 
 
 
 
 


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HFpEF and pulmonary vascular disease  
Protocol AC-055G202 / SERENADE 
Version 7 
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CONTRACT RESEARCH ORGANIZATIONS INFORMATION 
 
CENTRAL RANDOMIZATION 
 
Almac Clinical Technologies 
20 Seagoe Industrial Estate 
Craigavon BT63 5UA 
United Kingdom 
 
CENTRAL LABORATORY 
 
Covance 
8211 SciCor Drive 
Indianapolis, IN 46214 
 
ECHOCARDIOGRAPHY CORE 
LABORATORY 
WorldCare Clinical, LLC 
7 Bulfinch Place, P.O. Box 8908 
Boston, MA 02114  
USA 
 
ACCELEROMETRY 
Actigraph  
49 E Chase Street  
Pensacola, FL 32502  
USA 
 
A list of site-specific contact details for Contract Research Organizations (CROs) can 
be found in the Investigator Site File. 
 
 
 


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HFpEF and pulmonary vascular disease 
Protocol AC-055G202 / SERENADE
Version 7
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Doc No D-20.252
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4
SIGNATURE PAGE FOR ACTELION PHARMACEUTICALS LTD
Hereinafter called Actelion
Treatment name / number
Macitentan / ACT-064992
Indication
Heart failure with preserved ejection fraction and pulmonary vascular disease 
Protocol number, study acronym, study title
AC-055G202, SERENADE: A multi-center, double-blind, placebo-controlled Phase 2b 
study to evaluate the efficacy and safety of macitentan in subjects with heart failure with 
preserved ejection fraction and pulmonary vascular disease 
I approve the design of this study.
Title
Name
Date
Signature
PPD


Macitentan / ACT-064992 
HFpEF and pulmonary vascular disease  
Protocol AC-055G202 / SERENADE 
Version 7 
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INVESTIGATOR SIGNATURE PAGE 
Treatment name / number 
Macitentan / ACT-064992 
Indication 
Heart failure with preserved ejection fraction and pulmonary vascular disease  
Protocol number, study acronym, study title 
AC-055G202, SERENADE: A multi-center, double-blind, placebo-controlled Phase 2b 
study to evaluate the efficacy and safety of macitentan in subjects with heart failure with 
preserved ejection fraction and pulmonary vascular disease  
I agree to the terms and conditions relating to this study as defined in this protocol, the 
Case Report Form (CRF), and any other protocol-related documents. I fully understand 
that any changes instituted by the investigator(s) without previous agreement with the 
sponsor would constitute a 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 independent ethics 
committee or institutional review board (IEC/IRB) 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 IEC/IRB and ensure approval by regulatory 
authorities has been obtained before the implementation of changes described in the 
amendment, and I will re-consent the subjects (if applicable). I will allow direct access to 
source documents and study facilities to sponsor representative(s), particularly Clinical 
Research Associate(s) (CRA[s]) and auditor(s), and agree to inspection by regulatory 
authorities or IEC/IRB representative(s). I will ensure that the study treatment(s) supplied 
by the sponsor is/are being used only as described in this protocol. I will ensure that all 
subjects or legally designated representatives have understood the nature, objectives, 
benefits, implications, risks and inconveniences for participating in this study. During the 
conduct of the study, I will constantly monitor the risk/benefit balance for an individual 
subject. 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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HFpEF and pulmonary vascular disease  
Protocol AC-055G202 / SERENADE 
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6 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
  
DOCUMENT HISTORY 
Document 
Date 
Amendment 6, Version 7 
16-July-2020 
Amendment 5, Version 6 
06-February-2020 
Amendment 4, Version 5 
08-March-2019 
Amendment 3, Version 4 
10-April-2018 
Amendment 2, Version 3 
12-April-2017 
Amendment 1, Version 2 
08-February-2017 
Original Protocol, Version 1 
07-September-2016 
Amendment 6 (16-Jul-2020) 
Overall Rationale for the Amendment: The purpose of this amendment is to update the 
concomitant therapy sections pertaining to new information regarding a drug-drug-
interaction of macitentan with moderate dual CYP3A4 and CYP2C9 inhibitors or co-
administration of a combination of moderate CYP3A4 inhibitors and moderate CYP2C9 
inhibitors. 
Data from clinical trials with macitentan 10 mg were reviewed, identifying cases where 
macitentan 10 mg was administered concomitantly with dual CYP3A4 / CYP2C9 
inhibitors, such as fluconazole and amiodarone. The review indicated that co-
administration of fluconazole or amiodarone with macitentan was not common (between 
1-3% of patients). No safety concerns were identified with concurrent administration of 
fluconazole or amiodarone and macitentan 10 mg.  
A Protocol Amendment Summary of Changes Table for current amendment is provided 
below.  


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Section number 
and Name 
Description of Change 
Brief Rationale 
5.2.5 
Forbidden 
concomitant therapy 
Further 
information 
on 
concomitant 
administration of CYP34A and CYP2C9 
inhibitors was added. 
•     Strong CYP3A4 inhibitors (eg, 
itraconazole, ketoconazole, 
voriconazole, clarithromycin, 
telithromycin, nefazodone, ritonavir, 
and saquinavir) or moderate dual 
CYP3A4/CYP2C9 inhibitors (e.g., 
fluconazole, amiodarone) or co-
administration of a combination of 
moderate CYP3A4 (e.g., 
ciprofloxacin, cyclosporine, 
diltiazem, erythromycin, 
verapamil) and moderate CYP2C9 
inhibitors (e.g., miconazole, 
piperine) until study intervention 
discontinuation 
To add moderate dual 
CYP3A4/CYP2C9 inhibitors or 
co-administration of a 
combination of moderate 
CYP3A4- and moderate 
CYP2C9 inhibitors to the list of 
forbidden medications. 
 
• 
If subjects are currently stable on a 
moderate dual CYP3A4/CYP2C9 
inhibitors 
(e.g. 
fluconazole, 
amiodarone) or co-administration of 
a combination of moderate CYP3A4 
(e.g. 
ciprofloxacin, 
cyclosporine, 
diltiazem, erythromycin, verapamil) 
and moderate CYP2C9 inhibitors 
(e.g. 
miconazole, 
piperine), 
the 
subject may remain on current 
treatment per the investigator's 
discretion, based on his/her clinical 
judgement 
and 
risk-benefit 
assessment. 
As we are adding on a new 
group of forbidden therapy 
during the study, it will not 
necessarily apply to subjects 
who are already well managed 
on such an ongoing 
combination. 
 
5.2.5 Forbidden 
concomitant therapy;  
13 References 
A new reference was added to Section 
5.2.5 and updated in the reference list. 
To provide investigators with 
examples 
of 
CYP3A4 
and 
CYP2C9 inhibitors 


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TABLE OF CONTENTS 
SPONSOR CONTACT DETAILS ......................................................................................2 
CONTRACT RESEARCH ORGANIZATIONS INFORMATION ...................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ................................6 
PROTOCOL SYNOPSIS AC-055G202 ............................................................................20 
PROTOCOL ......................................................................................................................33 
1 
BACKGROUND .........................................................................................................33 
1.1 
Indication ......................................................................................................33 
1.2 
Study treatment(s) .........................................................................................34 
1.3 
Purpose and rationale of the study ................................................................35 
1.4 
Summary of known and potential risks and benefits ....................................36 
2 
STUDY OBJECTIVES ...............................................................................................37 
2.1 
Primary objective ..........................................................................................37 
2.2 
Secondary objectives ....................................................................................37 
2.3 
Other objectives ............................................................................................37 
2.4 
Safety objective ............................................................................................37 
3 
OVERALL STUDY DESIGN AND PLAN ...............................................................38 
3.1 
Study design .................................................................................................38 
3.1.1 
Study periods ....................................................................................38 
3.1.1.1 
Screening period ...................................................................... 38 
3.1.1.2 
Run-in period ........................................................................... 38 
3.1.1.3 
Treatment period ..................................................................... 38 
3.1.1.4 
Post-treatment observation period ........................................... 39 
3.1.1.5 
Safety follow-up period ........................................................... 39 
3.1.1.6 
End-of-Study ........................................................................... 39 
3.1.1.7 
SERENADE OL extension (study AC-055G203) .................. 39 
3.1.1.8 
Change in duration of double-blind treatment period per 
Global protocol Version 6 ....................................................... 40 
3.1.2 
Study duration ...................................................................................42 
3.2 
Study design rationale ..................................................................................42 
3.2.1 
Rationale for the use of placebo .......................................................42 
3.2.2 
Placebo- and macitentan treatment run-in period .............................43 


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3.2.3 
Rationale for the post-treatment observation period .........................43 
3.2.4 
Rationale for the duration of the double-blind treatment period ......44 
3.3 
Study committees .........................................................................................44 
4 
SUBJECT POPULATION ..........................................................................................45 
4.1 
Subject population description .....................................................................45 
4.2 
Rationale for the selection of the study population ......................................45 
4.3 
Inclusion criteria ...........................................................................................46 
4.4 
Exclusion criteria ..........................................................................................47 
4.5 
Run-in failure criteria ...................................................................................50 
4.6 
Criteria for women of childbearing potential ...............................................50 
4.6.1 
Definition of childbearing potential ..................................................50 
4.6.2 
Acceptable methods of contraception ...............................................51 
4.6.2.1 
Countries where macitentan is approved ................................. 51 
4.6.2.2 
North America and countries where macitentan is not 
approved .................................................................................. 51 
5 
TREATMENTS ..........................................................................................................52 
5.1 
Study treatment .............................................................................................52 
5.1.1 
Investigational treatment and matching placebo: Description 
and rationale ......................................................................................52 
5.1.2 
Study treatment administration .........................................................53 
5.1.3 
Treatment assignment .......................................................................53 
5.1.4 
Blinding ............................................................................................54 
5.1.4.1 
Single-blind run-in period ....................................................... 54 
5.1.4.2 
Double-blind treatment period ................................................ 54 
5.1.5 
Unblinding ........................................................................................55 
5.1.5.1 
Unblinding for final analyses .................................................. 55 
5.1.5.2 
Unblinding for interim analyses .............................................. 55 
5.1.5.3 
Unblinding for suspected unexpected serious adverse 
reactions ................................................................................... 55 
5.1.5.4 
Emergency procedure for unblinding ...................................... 55 
5.1.6 
Study treatment supply .....................................................................55 
5.1.6.1 
Study treatment packaging and labeling ................................. 56 
5.1.6.2 
Study treatment distribution and storage ................................. 56 
5.1.6.3 
Study treatment dispensing ..................................................... 56 
5.1.6.4 
Study treatment return and destruction ................................... 56 
5.1.7 
Study treatment accountability and compliance with study 
treatment ...........................................................................................57 
5.1.7.1 
Study treatment accountability ................................................ 57 


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5.1.7.2 
Study treatment compliance .................................................... 57 
5.1.8 
Study treatment dose adjustments and interruptions ........................58 
5.1.9 
Premature discontinuation of study treatment ..................................58 
5.1.10 
Study-specific criteria for interruption / premature 
discontinuation of study treatment ....................................................59 
5.1.10.1 
Liver aminotransferase abnormalities ..................................... 59 
5.1.10.2 
Hemoglobin abnormalities ...................................................... 60 
5.1.10.3 
Initiation of prohibited medications ........................................ 61 
5.2 
Previous and concomitant therapy ................................................................61 
5.2.1 
Definitions ........................................................................................61 
5.2.2 
Reporting of previous/concomitant therapy / auxiliary 
medicinal products in the CRF .........................................................62 
5.2.3 
Auxiliary medicinal products ............................................................62 
5.2.4 
Allowed concomitant therapy ...........................................................62 
5.2.5 
Forbidden concomitant therapy ........................................................62 
6 
STUDY ENDPOINTS ................................................................................................63 
6.1 
Efficacy endpoints ........................................................................................63 
6.1.1 
Primary efficacy endpoint .................................................................63 
6.1.2 
Key secondary efficacy endpoints ....................................................64 
6.1.3 
Other efficacy endpoints ...................................................................65 
6.2 
Safety endpoints ...........................................................................................67 
6.3 
Quality of life endpoints ...............................................................................67 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS ................................................67 
7.1 
Study visits ...................................................................................................67 
7.1.1 
Screening/re-screening ......................................................................68 
7.1.2 
Unscheduled visits ............................................................................68 
7.1.3 
EOT and EOS in case of transition to the SERENADE OL 
study ..................................................................................................68 
7.2 
Study assessments .........................................................................................77 
7.2.1 
Demographics / baseline characteristics ...........................................77 
7.2.2 
Efficacy assessments .........................................................................79 
7.2.2.1 
NT-proBNP ............................................................................. 79 
7.2.2.2 
Accelerometry ......................................................................... 79 
7.2.2.3 
Assessment of worsening heart failure event .......................... 80 
7.2.2.4 
Clinical composite outcome measure ...................................... 82 
7.2.2.5 
Echocardiography .................................................................... 82 
7.2.2.6 
Right heart catheterization ....................................................... 83 
7.2.3 
Safety assessments ............................................................................83 


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7.2.3.1 
Safety phone calls during the run-in period ............................ 83 
7.2.3.2 
Physical examination ............................................................... 84 
7.2.3.3 
Vital signs ................................................................................ 84 
7.2.3.4 
Weight and height ................................................................... 84 
7.2.3.5 
Home body weight monitoring ................................................ 85 
7.2.3.6 
Pulmonary function tests ......................................................... 85 
7.2.3.7 
ECG assessment ...................................................................... 85 
7.2.4 
Laboratory assessments ....................................................................85 
7.2.4.1 
Type of laboratory ................................................................... 85 
7.2.4.2 
Laboratory tests ....................................................................... 86 
7.2.5 
Quality of life assessments ...............................................................88 
7.2.6 
Biomarkers ........................................................................................88 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / MEDICAL 
CARE ..........................................................................................................................89 
8.1 
Study completion as per protocol .................................................................89 
8.2 
Premature withdrawal from study ................................................................89 
8.3 
Premature termination or suspension of the study ........................................90 
8.4 
Medical care of subjects after study completion / withdrawal from 
study ..............................................................................................................91 
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ...........................91 
9.1 
Adverse events ..............................................................................................91 
9.1.1 
Definition of adverse events .............................................................91 
9.1.2 
Intensity of adverse events ................................................................91 
9.1.3 
Relationship to study treatment ........................................................92 
9.1.4 
Reporting of adverse events ..............................................................92 
9.1.5 
Follow-up of adverse events .............................................................92 
9.2 
Serious adverse events ..................................................................................93 
9.2.1 
Definitions of serious adverse events ...............................................93 
9.2.2 
Reporting of serious adverse events .................................................93 
9.2.3 
Follow-up of serious adverse events .................................................94 
9.2.4 
After the 30-day follow-up period ....................................................94 
9.2.5 
Reporting and follow-up of SAEs during the PTOP ........................94 
9.2.6 
Reporting procedures ........................................................................94 
9.3 
Pregnancy .....................................................................................................95 
9.3.1 
Reporting of pregnancy ....................................................................95 
9.3.2 
Follow-up of pregnancy ....................................................................95 
9.4 
Study safety monitoring ................................................................................95 


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10 STATISTICAL METHODS .......................................................................................96 
10.1 
Analysis sets .................................................................................................96 
10.1.1 
Screened Analysis Set .......................................................................96 
10.1.2 
Placebo run-in Set .............................................................................96 
10.1.3 
Macitentan run-in Set ........................................................................96 
10.1.4 
Full Analysis Set ...............................................................................96 
10.1.5 
Per-protocol Analysis Set .................................................................96 
10.1.6 
Safety Set ..........................................................................................97 
10.1.7 
Sub-study Analysis Set .....................................................................97 
10.1.8 
Usage of the analysis sets .................................................................97 
10.2 
Variables .......................................................................................................97 
10.2.1 
Primary efficacy variable(s) ..............................................................97 
10.2.2 
Key secondary efficacy variables .....................................................98 
10.2.2.1 
Quality of life at Week 24 ....................................................... 98 
10.2.2.2 
Accelerometer-assessed physical activity at Week 24 ............ 98 
10.2.2.3 
Time to first occurrence of worsening of heart failure 
event over 52 weeks ................................................................ 98 
10.2.3 
Other efficacy variables ....................................................................99 
10.2.3.1 
Number of days alive and out of the hospital .......................... 99 
10.2.3.2 
Time to first occurrence of HF death or HF 
hospitalization over 52 weeks ................................................. 99 
10.2.3.3 
Time to first occurrence of CV death or CV 
hospitalization over 52 weeks ............................................... 100 
10.2.3.4 
Number of HF hospital admissions over 52 weeks ............... 100 
10.2.3.5 
NYHA FC (improved/worsened/stable) at each 
post-baseline assessment ....................................................... 100 
10.2.3.6 
Clinical composite outcome (‘worsened’, ‘unchanged’, 
‘improved’) ............................................................................ 100 
10.2.3.7 
Quality of life scores over time ............................................. 101 
10.2.3.8 
Percent of baseline in NT-proBNP over time ....................... 101 
10.2.3.9 
Percent of baseline in MR-proANP at Week 24 and over 
time ........................................................................................ 101 
10.2.3.10 
Change from baseline in accelerometer-assessed physical 
activity over time ................................................................... 102 
10.2.3.11 
Change from baseline in echocardiography left and right 
heart function at Week 24 and Week 52 ............................... 102 
10.2.4 
Safety variables ...............................................................................102 
10.2.5 
Other variables ................................................................................103 
10.2.5.1 
Discontinuation of placebo run-in ......................................... 103 
10.2.5.2 
Discontinuation of macitentan run-in .................................... 103 


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10.3 
Description of statistical analyses ...............................................................103 
10.3.1 
Overall testing strategy ...................................................................103 
10.3.2 
Analysis of the primary efficacy variable .......................................103 
10.3.2.1 
Hypotheses and statistical model .......................................... 104 
10.3.2.2 
Handling of missing data ....................................................... 105 
10.3.2.3 
Main analysis ......................................................................... 105 
10.3.2.4 
Supportive/sensitivity analyses ............................................. 105 
10.3.2.5 
Subgroup analyses ................................................................. 106 
10.3.3 
Analysis of key secondary efficacy variable(s) ..............................106 
10.3.3.1 
Quality of life at Week 24 ..................................................... 106 
10.3.3.2 
Accelerometer-assessed physical activity at Week 24 .......... 107 
10.3.3.3 
Time to first occurrence of worsening heart failure over 
52 weeks ................................................................................ 107 
10.3.4 
Analysis of other efficacy variable(s) .............................................107 
10.3.4.1 
Number of days alive and out of the hospital ........................ 107 
10.3.4.2 
Time to first occurrence of HF death or HF 
hospitalization over 52 weeks ............................................... 107 
10.3.4.3 
Time to first occurrence of CV death or CV 
hospitalization over 52 weeks ............................................... 108 
10.3.4.4 
Number of HF hospital admissions over 52 weeks ............... 108 
10.3.4.5 
NYHA FC (improved/worsened/stable) at each 
post-baseline assessment ....................................................... 108 
10.3.4.6 
Clinical composite outcome (‘worsened’, ‘unchanged’, 
‘improved’) ............................................................................ 108 
10.3.4.7 
Quality of life scores over time ............................................. 108 
10.3.4.8 
Percent of baseline in NT-proBNP over time ....................... 109 
10.3.4.9 
Percent of baseline in MR-proANP over time ...................... 110 
10.3.4.10 
Change from baseline in accelerometer-assessed physical 
activity over time ................................................................... 110 
10.3.4.11 
Change from baseline in echocardiography left and right 
heart function at Week 24 and Week 52 ............................... 110 
10.3.5 
Analysis of the safety variable(s) ....................................................110 
10.3.5.1 
All-cause death up to 30 days after study treatment 
discontinuation ...................................................................... 111 
10.3.5.2 
Number of all-cause hospital admissions up to 30 days 
after study treatment discontinuation .................................... 111 
10.3.5.3 
Adverse events ...................................................................... 111 
10.3.5.4 
Vital signs and body weight .................................................. 111 
10.3.5.5 
Laboratory variables .............................................................. 112 
10.3.5.6 
Glomerular Filtration Rate .................................................... 112 


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10.3.5.7 
Decrease from baseline in SBP of ≥ 5% and SBP < 100 
mmHg (yes/no) ...................................................................... 112 
10.3.6 
Analysis of the Other variable(s) ....................................................112 
10.3.6.1 
Discontinuation of placebo run-in ......................................... 112 
10.3.6.2 
Discontinuation of macitentan run-in .................................... 112 
10.4 
Interim analyses ..........................................................................................112 
10.5 
Sample size .................................................................................................113 
11 DATA HANDLING ..................................................................................................114 
11.1 
Data collection ............................................................................................114 
11.2 
Maintenance of data confidentiality ...........................................................114 
11.3 
Database management and quality control .................................................115 
12 PROCEDURES AND GOOD CLINICAL PRACTICE ...........................................116 
12.1 
Ethics and Good Clinical Practice ..............................................................116 
12.2 
Independent Ethics Committee / Institutional Review Board ....................116 
12.3 
Informed consent ........................................................................................116 
12.4 
Compensation to subjects and investigators ...............................................117 
12.5 
Protocol adherence/compliance ..................................................................118 
12.6 
Protocol amendments .................................................................................118 
12.7 
Essential documents and retention of documents .......................................118 
12.8 
Monitoring ..................................................................................................119 
12.9 
Investigator Site File ...................................................................................120 
12.10 
Audit ...........................................................................................................121 
12.11 
Inspections ..................................................................................................121 
12.12 
Reporting of study results and publication .................................................121 
13 REFERENCES ..........................................................................................................123 
14 APPENDICES ...........................................................................................................131 
 
 


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LIST OF TABLES 
 
Table 1 
Visit and assessment schedule during the run-in period ............................... 70 
Table 2 
Visit and assessment schedule during the double-blind treatment 
period ............................................................................................................ 72 
Table 3 
Laboratory assessments ................................................................................ 74 
Table 4 
Visit and assessment schedule for subjects entering the PTOP .................... 75 
Table 5 
WHF event definition ................................................................................... 81 
 
 
LIST OF FIGURES 
 
Figure 1 
Study design ................................................................................................. 41 
Figure 2 
Acceptable birth control options ................................................................... 52 
 
 
LIST OF APPENDICES 
 
 
Appendix 1 Marked laboratory abnormalities ................................................................ 131 
Appendix 2 Central laboratory alert flags ...................................................................... 133 
Appendix 3 Kansas City Cardiomyopathy questionnaire (KCCQ) ................................ 134 
Appendix 4 Worsening Heart Failure Event definitions [ACC/AHA 2015] ................. 139 
Appendix 5 Classification of cause of death .................................................................. 141 
Appendix 6 Definition of HF and CV hospitalization ................................................... 143 
Appendix 7 Protocol amendment history ....................................................................... 143 
 
 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
 
6MWD  
6-minute walk distance 
AE  
Adverse event 
AF  
Atrial fibrillation 
ALT  
Alanine aminotransferase 
ANCOVA  
Analysis of covariance 
ANOVA  
Analysis of variance 
AST  
Aspartate aminotransferase 
BCRP  
Breast-cancer resistant protein 
BMI  
Body mass index 
BNP  
Brain natriuretic peptide 
BUN  
Blood urea nitrogen 
CABG  
Coronary artery bypass graft 
CAD  
Coronary artery disease 
CEC  
Clinical Event Committee 
CFR  
Code of Federal Regulations (US) 
CHF  
Chronic heart failure 
CI  
Confidence interval 
CL  
Confidence limit 
CO  
Cardiac Output 
COPD  
Chronic obstructive pulmonary disease 
CpcPH  
Combined post- and pre-capillary pulmonary hypertension 
CRA  
Clinical Research Associate 
CRF  
Case Report Form  
CRO  
Contract Research Organization 
CSR  
Clinical Study Report 
CT  
Computed tomography 
CTA  
Computed tomography angiography 
CTT  
Clinical Trial Team 
CV  
Cardiovascular 


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CYP3A4  
Cytochrome P-450 3A4 
DAOH  
Days alive and out of the hospital 
DBP  
Diastolic blood pressure 
DPG  
Diastolic Pulmonary Vascular Pressure Gradient 
ECG  
Electrocardiogram 
eGFR  
estimated Glomerular Filtration Rate 
EOS  
End-of-Study 
EOT  
End-of-Treatment 
ERA  
Endothelin receptor antagonist 
ET-1  
Endothelin-1 
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 
GFR  
Glomerular Filtration Rate 
GQM  
Global Quality Management 
HDL  
High-density lipoprotein 
HF  
Heart failure 
HFpEF  
Heart failure with preserved ejection fraction 
HFrEF  
Heart failure with reduced ejection fraction 
HR  
Heart rate 
i.v.  
Intravenous 
IB  
Investigator’s Brochure 
ICD  
Implantable cardioverter-defibrillator 
ICF  
Informed Consent Form 
ICH  
International Council for Harmonisation 
IDMC  
Independent Data Monitoring Committee 
IEC  
Independent Ethics Committee 
ILSDRB  
Independent Liver Safety Data Review Board 


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IRB  
Institutional Review Board 
IRT  
Interactive Response Technology 
ISF  
Investigator Site File 
KCCQ  
Kansas City Cardiomyopathy Questionnaire 
LA  
Left atrial 
LAV  
Left atrial volume 
LAVI  
Left atrial volume index 
LDL  
Low-density lipoprotein 
LV  
Left ventricular 
LVD  
Left ventricular dysfunction 
LVEDP  
Left ventricular end-diastolic pressure 
LVEF  
Left ventricular ejection fraction 
MDRD  
Modification of Diet in Renal Disease 
MedDRA  
Medical Dictionary for Regulatory Activities 
MI  
Myocardial infarction 
MR-proANP  
Mid-regional pro-atrial natriuretic peptide 
NSTEMI  
Non-ST-segment elevation myocardial infarction 
NT-pro-BNP  
N-terminal pro-brain natriuretic peptide 
NYHA  
New York Heart Association 
OLE  
Open-label enrollment 
PAD  
Peripheral artery disease 
PAH  
Pulmonary arterial hypertension 
PASP  
Pulmonary artery systolic pressure 
PAWP  
Pulmonary artery wedge pressure 
PCI  
Percutaneous coronary intervention 
PDE-5  
Phosphodiesterase-5 
PE  
Pulmonary embolism 
PGA  
Patient’s global assessment 
PH  
Pulmonary hypertension 
PI  
Principal Investigator 
PPS  
Per-protocol Analysis Set 


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PTOP  
Post-treatment observation period 
PVD  
Pulmonary vascular disease 
PVR  
Pulmonary vascular resistance 
QS  
Quality System 
RA  
Right atrial 
RAAS  
Renin-angiotensin-aldosterone system 
RHC  
Right heart catheterization 
RSI  
Reference safety information  
RV  
Right ventricular 
RVD  
Right ventricular dysfunction 
SAE  
Serious adverse event 
SBP  
Systolic blood pressure 
SD  
Standard deviation 
SIV  
Site initiation visit 
SpO2  
Oxygen saturation 
STEMI  
ST-segment elevation myocardial infarction 
SUSAR  
Suspected unexpected serious adverse reaction 
TAPSE  
Tricuspid annular plane systolic excursion 
TIA  
Transient ischemic attack 
TLC  
Total lung capacity 
TR  
Tricuspid regurgitation 
TSH  
Thyroid stimulating hormone 
ULN  
Upper limit of normal 
V/Q  
Ventilation/perfusion 
VLDL  
Very low-density lipoprotein 
WHF  
Worsening heart failure 
WHO  
World Health Organization 
 
 


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PROTOCOL SYNOPSIS AC-055G202 
TITLE 
A multi-center, double-blind, placebo-controlled Phase 2b 
study to evaluate the efficacy and safety of macitentan in 
subjects with heart failure with preserved ejection fraction and 
pulmonary vascular disease  
ACRONYM 
SERENADE 
Macitentan in heart failure with preSERved ejEction 
fractioN and pulmonAry vascular DiseasE 
 
OBJECTIVES 
 
Primary objective 
To evaluate whether macitentan 10 mg reduces n-terminal 
pro-brain natriuretic peptide (NT-pro-BNP) versus placebo at 
Week 24 in subjects with heart failure with preserved ejection 
fraction (HFpEF) and pulmonary vascular disease.  
Secondary objectives 
To evaluate the effect of macitentan 10 mg as compared to 
placebo on: 
• Quality of life  
• Daily physical activity  
• Worsening of heart failure 
Other objectives 
Other objectives are described in Section 2.3. 
DESIGN 
A prospective, multi-center, double-blind, randomized, 
placebo-controlled, parallel-group design Phase 2b study. 
Subjects will be randomized in a 1:1 ratio to either macitentan 
or placebo. Treatment allocation will be stratified by 
NT-proBNP level (< 1000 pg/mL and ≥ 1000 pg/mL) at 
macitentan run-in entry. 
PERIODS 
Screening period: Lasts up to 30 days; starts with the 
signature of the Informed Consent Form at Visit 1 and ends 
prior to administration of the first dose of study treatment at 
Visit 2. 
Run-in period: 9-week run-in period consisting of a 
single-blind placebo run-in of 4 weeks, followed by a 
single-blind macitentan run-in of 5 weeks.  


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The placebo run-in starts with administration of the first dose 
of placebo at Visit 2 and ends on the day before Visit 4. The 
macitentan run-in starts with the administration of the first dose 
of macitentan at Visit 4 and ends with the subject’s 
randomization at Visit 6.  
Double-blind treatment period: The double-blind treatment 
period consists of 2 phases:  
Core phase: The double-blind core phase will last for 
24 weeks. It starts with the administration of the first dose of 
double-blind study treatment and ends on the day before 
Visit 11 (Week 24). Subjects who are still in the core phase at 
the time of global protocol Version 6 approval will end 
treatment at 24 weeks and will not proceed to the extension 
phase [see Section 3.1.1.8]. 
Extension phase: The double-blind extension phase will last 
for 28 weeks. It starts on the day of Visit 11 (Week 24) and 
ends on the day of last study treatment intake.  
Subjects who are in the extension phase at the global protocol 
Version 6 approval will return for an EOT visit within 60 days, 
but no later than Week 52.  
Post-treatment 
observation 
period: 
Subjects 
who 
prematurely discontinue double-blind study treatment (core or 
extension phase) will be asked to enter a post-treatment 
observation period (PTOP), which ends 52 weeks after 
randomization. The PTOP starts with visit PTOP1, which 
corresponds to the safety follow-up visit. Thereafter, visits are 
scheduled at Week 24 (PTOP2), Week 36 (PTOP3) and 
Week 52 (PTOP4), depending on time point of premature 
discontinuation. Subjects who have not completed Week 24 at 
the time of global protocol Version 6 approval, will end PTOP 
at 24 weeks (PTOP2) [see Section 3.1.1.8]. 
Safety follow-up period: The safety follow-up period starts 
on the day after the last dose of study treatment and ends 
30 days thereafter with the End-of-Study (EOS) visit, or 
PTOP1 visit for those subjects who prematurely discontinue 
study treatment. 


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End-of-Study: EOS is reached when the safety follow-up 
period or, if applicable, PTOP have been completed. 
For an individual subject, the study is completed with the EOS 
visit, which is either Visit 14 (safety follow-up visit) for 
subjects who completed the treatment period as per protocol, 
or PTOP4 for subjects who prematurely discontinued.  
Transition to the SERENADE OL extension study 
(AC-055G203): 
Subjects who remain in the SERENADE study for 52 weeks 
after randomization may transition to the SERENADE OL 
(AC-055G203) study if they meet the eligibility criteria 
defined in the SERENADE OL protocol. Eligible subjects 
who are consented to global protocol Version 6 will be 
allowed to transition to the SERENADE OL study if they 
remained in the SERENADE study for 24 weeks after 
randomization [see Section 3.1.1.8].  
PLANNED DURATION 
Approximately 2.5 years from first subject, first visit to last 
subject, last visit. 
SITE(S) 
/ COUNTRY(IES) 
77  sites in 17 countries. 
SUBJECTS / GROUPS 
It was planned to enroll 300 subjects in 2 groups; randomized 
in a 1:1 ratio (150 subjects per group) by an interactive 
Voice/Web System to macitentan or placebo using the NT-
proBNP value observed before entry in macitentan run-in as a 
stratification factor. 
Following closure of Screening on 27 December 2019, it is 
expected that approximately 140 subjects will be randomized. 
INCLUSION CRITERIA 
1. Signed informed consent prior to any study-mandated 
procedure 
2. Male or female subjects ≥ 18 years of age 
3. Signs or symptoms of heart failure (HF) requiring 
treatment with at least one oral diuretic (any type)  
4. Left ventricular ejection fraction (LVEF) ≥ 40% (by 
echocardiography at Screening) 
5. New York Heart Association (NYHA) functional class 
(FC) II to III 


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6. Criterion removed (see footnote1) 
7. Patients with HFpEF defined as either one of the following 
by echocardiography at Screening: 
a. Left atrial (LA) enlargement: 
i. 
Left atrial volume > 58 mL (male) / > 52 mL 
(female) or 
ii. 
Left atrial volume index ≥ 28 mL/m2, or 
iii. 
LA area > 20 cm2, or 
iv. 
LA diameter > 4.0 cm (male) / > 3.8 cm 
(female) 
b. Left ventricular septal thickness or posterior wall 
thickness ≥ 1.1 cm 
8. Elevated NT-proBNP / BNP ≥ 200 / 60 pg/mL for subjects 
in sinus rhythm or ≥ 500 / 150 pg/mL for subjects with 
atrial fibrillation (AF) at any time within 3 months prior to 
Screening or at Screening 
9. Pulmonary vascular disease or right ventricular (RV) 
dysfunction meeting at least one of the following for 
echocardiographic (at Screening) and/or right heart 
catheterization (RHC) parameters (at Screening or from 
any RHC previously performed): 
a. Echocardiographic peak TR velocity > 2.8 m/s or 
invasive mean pulmonary artery pressure ≥ 25 mmHg 
(RHC) or PASP > 40 mmHg and evidence of RV 
dysfunction (TAPSE < 17 mm or RV fractional area 
change < 35% or RV tissue Doppler s’ velocity < 9.5 
cm/s)  
b. Diastolic Pulmonary Vascular Pressure Gradient 
(DPG) > 5 mmHg (RHC) 
c. Pulmonary vascular resistance (PVR) > 3 Wood Units 
(RHC) 
10. A woman of childbearing potential must have a negative 
pre-treatment serum pregnancy test, agree to use reliable 
contraception from at least 30 days prior to Visit 2 up to at 
least 30 days after study treatment discontinuation, and 
 
1 Inclusion criterion 6 (HF hospitalization within 12 months prior to Screening or RHC within 6 months prior to 
Screening showing PAWP/LVEDP > 15mmHg) was removed in Global Protocol v.4. 


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agree to undertake monthly pregnancy tests from Screening 
up to at least 30 days after study treatment discontinuation. 
EXCLUSION CRITERIA 
Disease-related 
1. 
Any prior valid measurement of LVEF < 40%  
Cardiovascular comorbidities: 
2. 
Significant unrepaired structural valvular heart 
disease (i.e., greater than mild aortic or mitral 
stenosis, and greater than moderate aortic or mitral 
regurgitation) 
3. 
Hypertrophic, 
restrictive, 
and 
infiltrative 
cardiomyopathies 
4. 
Pericardial disease  
5. 
Acute coronary syndrome, including ST-segment 
elevation myocardial infarction (STEMI), non-ST-
segment elevation myocardial infarction (NSTEMI) 
or unstable coronary artery disease or has undergone 
coronary artery bypass graft (CABG) or percutaneous 
coronary intervention (PCI) within 3 months of 
screening. 
6. 
Known indication for PCI or CABG 
7. 
Uncontrolled heart rate (HR) from atrial fibrillation or 
atrial flutter (> 110 beats per minute) as assessed by 
ECG 
8. 
History 
of 
serious 
life-threatening 
or 
hemodynamically significant arrhythmias, including 
symptomatic or sustained ventricular tachycardia or 
defibrillator shock within 12 month(s) of Screening 
9. 
History of or anticipated heart transplant or 
anticipated/implanted ventricular assist device  
10. 
Transient ischemic attack (TIA) or stroke within 
3 months of Screening 
11. 
Systolic blood pressure (SBP) ≥ 180 mmHg or 
diastolic blood pressure (DBP) ≥ 110 mmHg  
Other causes of right heart failure not associated with left 
ventricular dysfunction: 
12. 
Significant parenchymal lung disease fulfilling any of 
the following:  


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a. 
Forced expiratory volume in 1 second / forced 
vital capacity (FEV1/FVC ratio) < 0.7 associated 
with FEV1 < 50% of predicted value after 
bronchodilator administration in subjects with a 
known or suspected history of significant lung 
disease. 
b. Known moderate or severe restrictive lung 
disease, e.g., total lung capacity (TLC) < 60% 
(predicted)  
c. 
Clinical suspicion of diffuse interstitial fibrosis 
or alveolitis, unless excluded by high resolution 
computed tomography (CT) 
d. Clinical 
suspicion 
of 
pulmonary 
thromboembolism within 12 months prior to 
Screening, 
unless 
excluded 
by 
ventilation/perfusion (V/Q) scan or computed 
tomography angiography (CTA)  
13. 
Criterion removed (see footnote2) 
14. 
Clinically significant congenital heart disease that 
could be the cause of the patient’s symptoms and 
signs of HF. 
Criteria related to macitentan use: 
15. 
Administration of pulmonary arterial hypertension-
specific therapy (i.e., endothelin receptor antagonists, 
prostanoids, phosphodiesterase-5 [PDE-5] inhibitors, 
guanylate cyclase stimulators) within 1 month prior to 
Screening 
16. 
Hypotension, i.e., SBP < 90 mmHg or DBP < 50 
mmHg  
17. 
Severe 
renal 
dysfunction 
with 
an 
estimated 
Glomerular Filtration Rate (eGFR) < 30 mL/min per 
1.73 m2 using the Modification of Diet in Renal 
Disease (MDRD) formula  
18. 
Known 
and 
documented 
severe 
hepatic 
impairment, e.g., Child-Pugh Class C  
 
2 Exclusion criterion 13 (BMI ≥ 45 kg/m2) was removed in Global protocol v.4. 


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19. 
Serum aspartate aminotransferase (AST) and/or 
alanine aminotransferase (ALT) ≥ 3 × the upper limit 
of normal at Screening 
20. 
Hemoglobin < 100 g/L (< 10 g/dl) at Screening 
21. 
Plan to become pregnant or lactating 
22. 
Treatment with strong cytochrome P-450 3A4 
(CYP3A4) inducers such as rifabutin, rifampin, 
rifampicin, rifapentin, carbamazepine, phenobarbital, 
phenytoin, or St. John’s wort within 1 month prior to 
Screening 
Treatment with strong CYP3A4 inhibitors such as 
ketoconazole, 
itraconazole, 
voriconazole, 
clarithromycin, telithromycin, nefazodone, ritonavir, 
and saquinavir within 1 month prior to Screening 
23. 
Criterion removed (see footnote3) 
24. 
Known hypersensitivity to macitentan or drugs of the 
same class, or any of the excipients (e.g., soy lecithin, 
lactose) 
General criteria: 
25. 
Planned 
or 
current 
treatment 
with 
another 
investigational treatment within 2 months prior to 
screening 
26. 
Inadequate control of comorbidities according to 
current standards of care, as per judgment of the 
investigator 
27. 
Any known factor or disease that might interfere with 
treatment 
compliance, 
study 
conduct, 
or 
interpretation of the results, such as drug or alcohol 
dependence or psychiatric disease 
28. 
Known concomitant life-threatening disease with a 
life expectancy < 12 months. 
 
3 Exclusion criterion 24 (treatment with BCRP substrates) was removed in Global protocol v.4. 


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RUN-IN FAILURE 
CRITERIA 
A subject must be discontinued from the study in case any of 
the following criteria is fulfilled at any time during the run-in 
period: 
1. 
Study treatment compliance < 80%  
2. 
Central laboratory results showing a decrease in 
hemoglobin by > 50 g/L from Screening or hemoglobin 
< 80 g/L or need for transfusion 
3. 
Significant fluid retention / worsening of HF as evidenced 
by one of the following: 
a. Administration of i.v. diuretics due to fluid retention 
b. Addition 
of 
high 
potency 
thiazide 
diuretic 
(metolazone, indapamide), ≥ 100% increase in loop 
diuretic to a total oral dose ≥ 120 mg of furosemide 
equivalents/day [see Section 4.5]. 
c. Increase in body weight by ≥ 5% or ≥ 5 kg from the 
value at the start of the corresponding run-in period 
(i.e., Visit 2 and Visit 4 for the placebo and 
macitentan run-in, respectively) due to fluid overload 
d. Worsening in NYHA FC 
e. Hospitalization for worsening of HF 
4. 
Any adverse events (AEs) that preclude continuation 
based on the investigator’s judgment.  
STUDY TREATMENTS 
Investigational treatment 
Macitentan oral tablet, 10 mg once daily. 
Comparator  
Matching placebo, once daily. 
AUXILIARY MEDICINAL 
PRODUCTS  
All subjects must be on oral diuretic therapy (any type). 
ENDPOINTS 
Primary efficacy endpoint 
• Percent of baseline NT-proBNP assessed at Week 24  
Secondary efficacy endpoints 
• Change from baseline to Week 24 in the clinical summary 
score (as assessed by the Kansas City Cardiomyopathy 
Questionnaire [KCCQ]) 
• Change from baseline to Week 24 in accelerometer-
assessed proportion of time spent in light to vigorous 


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physical activity based on a threshold of > 100 activity 
counts per minute 
• Time to worsening heart failure (WHF) event over 
52 weeks.  
• Other efficacy endpoints 
Other efficacy endpoints are described in Section 6.1.3. 
Safety endpoints 
• All-cause death up to 30 days after study treatment 
discontinuation 
• Number of all-cause hospital admissions up to 30 days after 
study treatment discontinuation 
• Treatment-emergent AEs and serious adverse events 
(SAEs) up to 30 days after study treatment discontinuation 
• AEs leading to premature discontinuation of study 
treatment 
• Change in vital signs (systolic and diastolic arterial blood 
pressure and pulse rate) and body weight up to 30 days after 
study treatment discontinuation 
• Treatment-emergent marked laboratory abnormalities up to 
30 days after study treatment discontinuation 
• Change from baseline in eGFR up to 30 days after study 
treatment discontinuation 
• Decrease from baseline in SBP of ≥ 5% and SBP 
< 100 mmHg up to 30 days after study treatment 
discontinuation. 
ASSESSMENTS 
Refer to the schedule of assessments in Table 1, Table 2, 
Table 3, and Table 4. 
STATISTICAL 
METHODOLOGY 
Analysis sets 
The Screened Analysis Set includes all subjects who are 
screened and have a subject identification number. 
The placebo run-in Set includes all screened subjects who enter 
the placebo run-in and receive at least one dose of study 
treatment in single-blind placebo run-in. 
The macitentan run-in Set includes all subjects who have 
completed the placebo run-in, enter the macitentan run-in and 


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receive at least one dose of study treatment in single-blind 
macitentan run-in. 
The Full Analysis Set (FAS) includes all subjects randomized 
to double-blind study treatment.  
The Per-protocol Analysis Set comprises all randomized 
subjects who received double-blind study treatment and who 
complied with the protocol sufficiently to allow a reliable 
assessment of the treatment effect on the primary efficacy 
endpoint. 
The Safety Set includes all subjects who received at least one 
dose of double-blind study treatment. 
Primary efficacy variable 
The primary efficacy variable is the percent of baseline in 
NT-proBNP at Week 24. 
For subjects without available NT-proBNP value at Week 24, 
the last available value observed before Week 24 will be 
carried forward and considered for the main analysis. 
Percent of baseline is calculated as the ratio of the Week 24 
NT-proBNP value over baseline value, expressed in 
percentage. 
Null and alternative hypotheses 
Due to the underlying log-normal distribution of the primary 
efficacy variable, an analysis of covariance (ANCOVA) will 
be applied on log-transformed data. 
The null hypothesis is that macitentan and placebo effects on 
NT-proBNP are the same. The alternative hypothesis is that the 
effect of macitentan on NT-proBNP differs from placebo 
effect. 
The null hypothesis will be tested by a 2-sided Wald test with 
a 2-sided significance level of 0.10. 
Primary statistical analysis 
The main analysis will be performed on subjects of the FAS, 
according to the intent-to-treat principle. 
The main analysis of the primary efficacy variable will be 
carried out after log-transformation using ANCOVA, adjusting 


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for the log of the ratio: baseline NT-proBNP over NT-proBNP 
value as per Interactive Response Technology system [IRT] 
with an overall type I error of 10% 2-sided. 
The treatment effect expressed as geometric means ratio and 
its associated 90% 2-sided confidence interval (CI) will be 
estimated based on the same model by inversely transforming, 
using the exponential function, the Least Squares Mean and 
90% CI obtained in log scale. 
Key secondary efficacy variables 
The three key secondary efficacy variables will be tested using 
a hierarchical testing approach to address multiplicity concern. 
The change from baseline to Week 24 in KCCQ clinical 
summary score and accelerometer-assessed physical activity 
will be analyzed by means of an ANCOVA adjusting for the 
variable baseline value and for the log of the ratio: baseline 
NT-proBNP over NT-proBNP value as per IRT. Least Squares 
Estimates within each treatment group and between treatment 
groups will be displayed along with 90% 2-sided CIs and p-
values. 
The analysis of time to first occurrence of WHF event will be 
explored using a proportional hazards Cox model adjusting for 
the log of the ratio: baseline NT-proBNP over NT-proBNP 
value as per IRT. Estimate of HR and its associated 90% CI 
and p-value will be displayed. Kaplan-Meier estimates will be 
calculated with 2-sided 90% CIs at relevant time points for 
each treatment group and displayed in both a graphical and a 
tabular form.  
Safety variables 
The number and percentage of: 
• All-cause deaths occurring up to 30 days after study 
treatment discontinuation 
• Subjects with at least one treatment-emergent AE 
occurring up to 30 days after study treatment 
discontinuation 
• Subjects with at least one SAE occurring up to 30 days after 
study treatment discontinuation 
• Subjects with at least one AE leading to premature 
discontinuation of study treatment 


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will be tabulated by treatment group and by System Organ 
Class and Preferred Term.  
The number of recurrent all-cause hospital admissions will be 
estimated using a Negative binomial regression model.  
Marked laboratory abnormalities will be summarized for each 
laboratory variable by treatment group providing their 
incidence and frequency. For selected laboratory variables 
(erythrocytes, hemoglobin, hematocrit, AST, ALT, total 
bilirubin and alkaline phosphatase), absolute values and 
changes from baseline will be summarized over time up to 
30 days after study treatment discontinuation. 
Vital signs, body weight and GFR will be described over time 
up to 30 days after study treatment discontinuation by means 
of random coefficient regression models. 
Decreases in SBP will be summarized by treatment group 
providing the number and percentage of subjects with, for at 
least one post-baseline assessment and up to 30 days after study 
treatment discontinuation, a percent change from baseline  
≤ −5% and an SBP < 100 mmHg at the time of assessment. 
Sample size 
A number of 300 randomized subjects is adequate to detect a 
geometric means ratio of 0.75 (macitentan over placebo, 
−0.288 in log scale) corresponding to a 25% improvement with 
a power of 80% and a type I error of 0.10 2-sided, when 
considering a standard deviation of 1 in log scale and using the 
Wald test. The critical value expressed as geometric means 
ratio is 0.83. 
Following closure of Screening on 27 December 2019, it is 
expected that approximately 140 subjects will be randomized. 
With the same assumptions as above for the reduced sample 
size of 140, the critical value expressed as geometric means 
ratio is 0.76. 
STUDY COMMITTEES 
An Independent Data Monitoring Committee (IDMC) has 
overall responsibility for safeguarding the interests of subjects 
by monitoring benefit-risk ratio and making appropriate 
recommendations based on all the reported data and thus 


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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. 
Both a Scientific Advisory Board and a Steering Committee 
are involved in the study design and will be consulted prior to 
and during the study for relevant medical issues and study 
publications. 
An Independent Liver Safety Data Review Board (ILSDRB, an 
external expert committee of hepatologists) has been appointed 
to provide ongoing assessment and advice regarding serious 
hepatic AEs of special interest that require further evaluation 
during the study as per the ILSDRB charter. 
 
 
 


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PROTOCOL 
1 
BACKGROUND 
Endothelin-1 (ET-1), a 21 amino acid peptide, is one of the most potent vasoconstrictors, 
and plays a key role in vascular tone and pathophysiology of cardiovascular disease  
[Inoue 1989, Levin 1996, Galiè 2004]. The two ET-1 receptors, ETA and ETB, 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 on endothelial, epithelial, endocrine and nerve 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]. 
The endothelin system has been shown to be activated in chronic heart failure (CHF), 
among other neurohumoral systems, such as the sympathetic and RAAS [Jessup 2003]. 
Plasma big ET-1 and ET-1 levels were found to be elevated and inversely correlated with 
clinical and hemodynamic measures of prognosis in patients with CHF, including patients 
with stable CHF [Kiowski 1995, Pacher 1996, Wei 1994, Parker 2004, Hulsmann 1998]. 
Big ET-1 and C-terminal pro-ET-1 have been shown to independently predict mortality 
and morbidity in CHF [Masson 2006, Jankowska 2011].  
In nonclinical studies in animal models of experimental heart failure (HF) treatment with 
dual or ETA selective antagonists significantly improved left ventricular dysfunction, 
prevented ventricular remodeling and prolonged survival [Cowburn 2001, Wada 1997]. 
Several endothelin receptor antagonist (ERAs) have been shown to improve pulmonary 
hemodynamics, exercise capacity, functional status, and clinical outcome in pulmonary 
arterial hypertension (PAH) and are approved for PAH treatment [Galiè 2015]; however, 
ERAs tested in acute and chronic HF have not consistently shown clinical benefit and new 
studies are warranted [Kaoukis 2013]. 
1.1 Indication 
HF is a common, disabling and potentially fatal condition, which is the leading cause of 
hospitalization in persons over 65 years of age. HF is a major public health issue, with an 
estimated prevalence of over 5.8 million in the USA, and over 23 million worldwide 
[Bui 2011, McMurray 1998]. Approximately 1% to 2% of the adult population in the 
developed countries has HF, and rising to ≥ 10% among persons of 70 years of age or older 
[McMurray 2012, Mosterd 2007].  


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In the USA, projections show that the prevalence of HF will increase 46% from 2012 to 
2030, resulting in > 8 million people ≥ 18 years of age with HF. It is estimated that 
870,000 new cases of HF are diagnosed every year in the USA. The incidence of HF is 
nearly 10 per 1000 population over 65 years of age. Nearly 300,000 deaths occur annually 
that are directly attributable to HF [Mozaffarian 2015].  
The estimated prevalence of heart failure with preserved ejection fraction (HFpEF) among 
all HF patients ranges from 40% to 71% in different studies [Bishu 2013, Oktay 2013, 
Bui 2011, Brouwers 2013, Tiller 2013]. With increasing prevalence in recent years, HFpEF 
may become the predominant form of HF in the coming decades [Oktay 2013]. HFpEF has 
been variably classified as ejection fraction > 40%, > 45%, > 50%, and ≥ 55%. The criteria 
proposed to define the syndrome of HFpEF include a) clinical signs or symptoms of HF; 
b) evidence of preserved or normal left ventricular ejection fraction (LVEF); and 
c) evidence of abnormal left ventricular (LV) diastolic dysfunction (the filling of the left 
heart) that can be determined by Doppler echocardiography or cardiac catheterization 
[Vasan 2000]. HFpEF seems to have a different epidemiological and etiological profile 
from heart failure with reduced ejection fraction (HFrEF) [McMurray 2012]. Patients with 
HFpEF are predominantly elderly, more likely to be female than male, and have a high 
prevalence of comorbidities such as hypertension, coronary artery disease (CAD), diabetes 
mellitus, obesity, anemia, chronic kidney disease, atrial fibrillation, and chronic obstructive 
pulmonary disease [Bishu 2013, Oktay 2013, Bui 2011, Borlaug 2014].  
Dysfunction of the right ventricular-pulmonary vascular unit is a common entity in HFpEF 
and is recognized to confer poor outcomes in these patients, including increased HF 
hospitalization and higher overall cardiovascular mortality. Right ventricular dysfunction 
(RVD) develops in response to elevated afterload and pulmonary vascular dysfunction, and 
is evolving to be a significant modifier of both natural history and prognosis in patients 
with HFpEF. The prognostic significance of RVD in HFpEF has been shown to be 
independent of, and additive to, the severity of pulmonary hypertension (PH)  
[Zakeri 2015b] and was the strongest predictor, more predictive than severity of PH, of 
death in 96 HFpEF patients [Melenovsky 2014]. 
1.2 Study treatment(s)  
Macitentan (ACT-064992, Opsumit®) is an orally active, non-peptide, potent dual 
endothelin ETA and ETB ERA which has been approved for the treatment of PAH. ERAs 
are being developed for a variety of diseases associated with the deleterious effects of ET, 
particularly in the pulmonary and cardiovascular fields.  
For detailed information on macitentan, please see the most recent version of the 
macitentan Investigator’s Brochure (IB) [Macitentan IB]. 


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For detailed information on ‘Special warnings and precautions’ and ‘General precautions’, 
please see sections 1.7 and 1.8 of the most recent version of the macitentan IB 
[Macitentan IB]. 
1.3 Purpose and rationale of the study 
Current HF therapy is largely based on digitalis and diuretics associated with various 
combinations of renin-angiotensin-aldosterone system (RAAS)- and beta blockers. In 
contrast to HFrEF, there is no approved therapy for HFpEF patients despite several 
attempts to mitigate the diastolic dysfunction through blockade of the RAAS, beta blockade 
and phosphodiesterase-5 (PDE-5) inhibitors [Yancy 2013, Shah 2013, Pfeffer 2015]. 
Today, HFpEF patients, particularly those with associated PH, are empirically treated for 
their underlying condition (e.g., hypertension, diabetes) and with diuretics for fluid 
retention.  
The HFpEF population presents a high prevalence of comorbidities that are associated with 
increased ET-1 production, e.g., sleep apnea, metabolic syndrome, diabetes, obesity and 
age. Nonclinical studies demonstrated that ERAs were effective in preventing or 
attenuating the cardiovascular complications (hypertension, endothelial dysfunction, renal 
failure, cardiac remodeling) of these risk factors [Mulder 1976, Maczewski 2000, 
Belaidi 2009, Iglarz 2008]. Cardiac remodeling can be attributed in part to ET-1, based on 
its known profibrotic and hypertrophic properties [Schwarz 2002]. Recent preliminary data 
demonstrated efficacy of ET receptor blockade with macitentan on LV remodeling without 
significantly affecting systemic blood pressure (BP) [Richard V, et al. Actelion data on 
file; Sam 2015]. Taken together, these data suggest that dual ET receptor blockade can 
directly improve LV remodeling, and especially decrease fibrosis, leading to an 
improvement of the filling capacity of the left ventricle. 
Most studies with ERAs did not demonstrate clinical benefit in chronic HF; treatment with 
ERAs has been associated with fluid retention, which may worsen HF symptoms  
[B-166849, B-02.005, D-05.036, Lüscher 2002, Anand 2004, Abraham 2001]. Treatment 
with ERAs has been also associated with increased incidence of edema in PAH patients 
[Aversa 2015]. However, in patients with HFpEF, treatment with sitaxentan for 6 months 
significantly increased exercise tolerance as measured by treadmill time. There was no 
significant difference in the overall occurrence of adverse events (AEs) between sitaxentan 
and placebo, while peripheral edema was reported for 19.7% and 15.6% in the sitaxentan 
and placebo groups, respectively, over 6 months of treatment [Zile 2014]. 
In a Phase 2 exploratory study in 63 subjects with combined post- and pre-capillary 
pulmonary hypertension (CpcPH), AC-055G201/MELODY-1 [Vachiéry 2018], the main 
composite safety endpoint, i.e., the proportion of subjects experiencing either significant 
fluid retention (defined as an increase in body weight due to fluid overload by≥ 5kg or 
≥ 5%, or intravenous (i.v.) administration of diuretics) or a worsening in New York Heart 


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Association (NYHA) functional class (FC) up to End-of-Treatment (EOT), was more 
frequently met in the macitentan group: 7 subjects on macitentan (23%) compared to 
4 subjects on placebo (13%). Occurrence of edema was observed early in the course of this 
trial in patients treated with macitentan and was generally well managed by diuretic 
enhancement. The occurrence of a fluid retention event was more frequent in the 
macitentan group (6.4%) compared to the placebo group (1.6%) during the first 4 weeks 
from the start of study treatment, while it was similar in both treatment groups beyond 
4 weeks of study treatment (5.1% on macitentan versus 4.8% on placebo). This observation 
suggests that the susceptibility to fluid retention manifested early and stabilized over time.  
A higher number of subjects on macitentan experienced at least one serious adverse event 
(SAE) (11 subjects [35%] on macitentan; 6 subjects [18.8%] on placebo), discontinued 
study treatment prematurely (7 subjects [22.6%] on macitentan; 4 subjects [12.5%] on 
placebo), or were hospitalized for worsening of HF (5 subjects [16.1%] on macitentan; 
2 subjects [6.3%] on placebo). This difference was driven by the subjects who met the main 
safety point. 
Although the MELODY-1 study was not powered to assess the efficacy of macitentan, the 
improvements observed in cardiac output (CO) (Hodges-Lehmann’s median treatment 
difference of 0.6 L/min, 95% confidence limit [CL] 0.20, 1.10 at Week 12) and n-terminal 
pro-brain natriuretic peptide (NT-pro-BNP) (23% reduction compared to placebo at Week 
12) may indicate a potential benefit with macitentan in the explored indication. The results 
of the study also showed that the hemodynamic characteristics of subjects with CpcPH 
included in the MELODY-1 study are similar to those with HFpEF and pulmonary vascular 
disease, therefore macitentan may present a potential benefit for subjects with HF, 
specifically HFpEF and pulmonary vascular disease with or without overt RVD whereby 
the increased right ventricular afterload could be mitigated by ERA treatment.  
The purpose of this present study is to confirm the MELODY-1 findings on NT-proBNP 
and evaluate whether favorable findings from this earlier study translate into a clinically 
meaningful benefit in a subset of HFpEF patients with pulmonary vascular disease and who 
tolerate macitentan lending support for the further development in this indication.  
1.4 Summary of known and potential risks and benefits  
The results of the MELODY-1 study have shown that treatment with macitentan reduces 
NT-proBNP, a marker reflecting cardiac load and LV wall stress, and improves CO. These 
findings suggest that macitentan may have a beneficial effect in subjects with HFpEF and 
pulmonary vascular disease. However, the MELODY-1 results also showed an increased 
incidence of fluid retention events which led to worsening of HF in the macitentan group 
[Section 1.3]. The timing of these events suggests that fluid retention under macitentan 
therapy manifests early and stabilizes over time. To mitigate adverse effects caused by 
fluid retention, the study contains a placebo run-in phase to ensure that subjects are stable 


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and on optimal background therapy, and a macitentan run-in during which subjects are 
closely monitored and discontinued from the study if pre-defined criteria indicative of poor 
tolerability are met [see Section 4.5].  
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 
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. 
2 
STUDY OBJECTIVES 
2.1 Primary objective 
The primary objective of the study is to evaluate whether macitentan 10 mg reduces 
NT-pro-BNP versus placebo at Week 24 in subjects with HFpEF and pulmonary vascular 
disease. 
2.2 Secondary objectives 
The secondary objective of the study is to evaluate the effect of macitentan 10 mg as 
compared to placebo on: 
• Quality of life  
• Daily physical activity  
• Worsening of heart failure.  
2.3 Other objectives 
• To evaluate the effects of macitentan 10 mg as compared to placebo on:  
− Cardiovascular deaths and hospitalizations 
− NYHA FC 
− Clinical composite outcome measure 
− Echocardiographic measures of cardiac function and structure.  
2.4 Safety objective 
To evaluate the safety and tolerability of macitentan 10 mg in subjects with HFpEF and 
pulmonary vascular disease. 


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3 
OVERALL STUDY DESIGN AND PLAN 
3.1 Study design 
This is a prospective, multi-center, double-blind, randomized, placebo-controlled, parallel-
group Phase 2b study [Figure 1]. 
It was planned that approximately 300 subjects would be randomized in a 1:1 ratio to either 
macitentan or placebo. Treatment allocation will be stratified by NT-proBNP level at 
macitentan run-in entry. The study is being conducted in 77 sites in 17 countries. 
Following closure of Screening on 27 December 2019, it is expected that approximately 
140 subjects will be randomized [see Section 3.1.1.8]. 
3.1.1 Study periods 
The study comprises the following consecutive periods. 
3.1.1.1 Screening period 
Lasts up to 30 days; starts with the signature of the Informed Consent Form (ICF) at Visit 1 
and ends prior to administration of the first dose of study treatment at Visit 2. 
3.1.1.2 Run-in period 
The run-in period consists of 2 parts: a placebo run-in and a macitentan run-in. 
The run-in period starts with a single-blind placebo run-in of 4 weeks which starts with 
administration of the first dose of placebo at Visit 2 and ends on the day before Visit 4 
(macitentan run-in start).  
The placebo run-in is followed by a single-blind macitentan run-in of 5 weeks, which starts 
with administration of the first dose of macitentan at Visit 4 and ends with the subject’s 
randomization at Visit 6.  
3.1.1.3 Treatment period 
The double-blind treatment period consists of 2 phases:  
Core phase: The double-blind core phase will last for 24 weeks. It starts with the 
administration of the first dose of double-blind study treatment and ends on the day before 
Visit 11 (Week 24). The main aim of the core phase is to determine the 24-week effect of 
macitentan on the primary efficacy endpoint, NT-proBNP. 
Subjects who are in core phase at the time of global protocol version 6 approval, will end 
treatment at 24 weeks and will not proceed to the extension phase of the study [see 
Section 3.1.1.8]. 


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Extension phase: The double-blind extension phase will last for 28 weeks. It starts on the 
day of Visit 11 (Week 24) and ends on the day of last study treatment intake. The main aim 
of the extension phase is to collect further morbidity and mortality data.  
Subjects who are in the extension phase at the global protocol Version 6 approval will 
return for an EOT visit within 2 months, but no later than Week 52.  
3.1.1.4 Post-treatment observation period 
Subjects who prematurely discontinue double-blind study treatment (core or extension 
phase) will be asked to enter a post-treatment observation period (PTOP), which ends 
52 weeks after randomization. The PTOP starts with visit PTOP1, which corresponds to 
the safety follow-up visit. Thereafter, visits are scheduled at Week 24 (PTOP2), Week 36 
(PTOP3) and Week 52 (PTOP4), depending on time point of premature discontinuation. If 
the safety follow-up visit (PTOP1) falls within the time-window of any of the other PTOP 
visits, then the corresponding PTOP visit and the safety follow-up visit can be combined. 
The assessments that are performed at each visit are described in the visit and assessment 
schedule [Table 4] for subjects entering the PTOP. Subjects who have not completed Week 
24 at the time of global protocol Version 6 approval, will end the PTOP at Week 24 
(PTOP2). Subjects who are past Week 24 at the time of consenting to global protocol 
Version 6 will return for an EOT visit within 2 months but no later than Week 52 and will 
then proceed to enroll in the OL study, if eligible, or complete EOS, if not eligible to enter 
SERENADE OL [see Section 3.1.1.8]. 
3.1.1.5 Safety follow-up period 
The safety follow-up period starts on the day after the last dose of study treatment and ends 
30 days thereafter with the End-of-Study (EOS) visit, or PTOP1 visit for those subjects 
who prematurely discontinue study treatment. 
The visit schedule and protocol-mandated procedures will be performed according to the 
table of assessments [Table 2, Table 3, and Table 4] and are described in Section 7. 
3.1.1.6 End-of-Study 
EOS is reached when the safety follow-up period or, if applicable, PTOP have been 
completed. For an individual subject, the study is completed with the EOS visit, which is 
either Visit 14 (safety follow-up visit) for subjects who completed the treatment period as 
per protocol, or PTOP4 for subjects who prematurely discontinued study treatment. 
3.1.1.7 SERENADE OL extension (study AC-055G203)  
Subjects who remained in SERENADE (main study) for 52 weeks after randomization may 
be eligible for transition to the SERENADE OL study. Subjects who consented to global 
protocol Version 6, are eligible to transition to SERENADE OL if they remained in the 
main study for at least 24 weeks [see Section 3.1.1.8]. 


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3.1.1.8 Change in duration of double-blind treatment period per Global protocol 
Version 6 
Applicable to subjects who consented to global protocol version 6. 
With global protocol Version 6, subjects will stop study treatment at Week 24 (Visit 11) 
and may be eligible to transition to SERENADE OL at this timepoint. Subjects who have 
passed Week 24 at the time of consenting to global protocol Version 6 will be scheduled 
to come back for an EOT visit within 2 months but no later than Week 52 and will then 
proceed to enroll in the OL study, if eligible, or complete EOS, if not eligible to enter 
SERENADE OL.  
The reason for treatment discontinuation to be recorded in the eCRF for these subjects will 
be ‘sponsor decision’, unless an additional reason led to discontinuation of study treatment 
(e.g., AE). 
Subjects who prematurely discontinue study treatment will remain in PTOP up to Week 24 
(PTOP 2) and may transition to SERENADE OL if the eligibility criteria are met. Subjects 
who are past PTOP2 at the time of consenting to global protocol Version 6 will return for 
an EOS visit within 60 days  but no later than Week 52 and may transition to SERENADE 
OL at this timepoint, if the eligibility criteria are met.  
The overall study design is depicted in Figure 1. 


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Figure 1 
Study design  
A) Study treatment completed as per protocol: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Macitentan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
Visit 1                2    3 3a() 4   5 5a()      6  7()  8          9          10         11              12                  13             
 
 
Time       30 d           4 w                 5 w        D1  W1  W4        W8      W16     W24          W36           W52    30 d 
Screening   
period 
Placebo 
run-in 
Macitentan 
 run-in 
Core phase 
Extension phase 
Follow-up 
period 
 
 
 
 
D = Day; d = days; EOT = End-of-Treatment; EOS = End-of-Study; W = Week; w = weeks. 
 
 
 
B) Premature discontinuation of study treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Macitentan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
Visit 1          2    3 3a() 4    5  5a()           6                     EOT    PTOP1   PTOP2      PTOP3      PTOP4 
 
 
 
 
 
Time       30 d           4 w            5 w               D1                              Safety FU   W24          W36           W52     
Screening   
period 
Placebo 
run-in 
 
Macitentan 
 run-in 
 
 
 
 
D = Day; d = days; EOT = End-of-Treatment; EOS = End-of-Study; W = Week; w = weeks. 
 
*PTOP visits to be performed depending on the time point of premature discontinuation of study treatment. Patients 
who had not passed Week 24 will remain in PTOP until Week 24. 
Premature discontinuation 
Randomization 
EOT 
EOS 
14 
Double-blind treatment period 
EOS 
Enrollment in 
SERENADE 
OL (optional) 
Enrollment in 
SERENADE 
OL (optional) 
Post-treatment observation period* 


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C) Discontinuation of double- blind treatment period at Week 24 or beyond, per Global 
protocol Version 6 
 
  
 
 
 
 
 
 
D = Day; d = days; EOT = End-of-Treatment; EOS = End-of-Study; W = Week; w = weeks. 
 
3.1.2 Study duration 
The study starts with the first act of recruitment (i.e., ICF signed) and ends with the last 
visit of the last subject. 
The subjects will be treated for 52 weeks in addition to the run-in period of 9 weeks. 
Subjects who prematurely discontinue study treatment will enter a PTOP, which ends 
52 weeks after randomization. For an individual subject, the study is completed with the 
EOS visit. The duration of participation in the study of a subject will be up to 17 months 
[see Section 3.1.1.8]. 
3.2 Study design rationale 
3.2.1 Rationale for the use of placebo 
No medical treatments have currently been approved for the treatment of HFpEF. Current 
practice guidelines are aimed at treating fluid retention, aggressively controlling 
hypertension, and treating comorbid conditions that contribute to decompensation. In this 
study, subjects are allowed to stay on their usual HF treatment; therefore, the addition of a 
placebo arm to the standard-of-care is considered acceptable. Furthermore, since fluid 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Macitentan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
Visit 1         2    3 3a() 4   5 5a()      6  7()  8           9          10        11                             
 
 
 
 
 
Time       30 d           4 w                 5 w  D1  W1  W4       W8      W16     W24          60 d                30 d 
Screening   
period 
Placebo 
run-in 
Macitentan 
 run-in 
Core phase                
Time-window 
for performing 
EOT 
Follow-up period 
Enrollment in SERENADE OL 
(optional) 
Randomization 
14 
EOT
      EOS 


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retention is also a feature of HF itself, it is difficult to distinguish whether fluid retention 
is attributable to the natural progression of disease or to an effect of active treatment. 
Inclusion of a placebo group is the only way to reliably interpret the potential effect of 
macitentan on fluid retention. A placebo-controlled trial conducted in a randomized and 
double-blind fashion also provides the most rigorous method for evaluating the efficacy 
and safety of a medical treatment. 
3.2.2 Placebo- and macitentan treatment run-in period 
Studies with ERAs in HF have consistently shown issues with fluid retention. These events 
were more frequently observed early in the course of these studies, i.e., mainly within 
4 weeks of treatment initiation [D-16.139, B-02.005, Mann 2010, Bakris 2010]. The early 
timing of fluid related AEs and HF exacerbation observed with ERAs in HF studies is not 
unique to this class of compounds. The beta-blocker carvedilol, for example, has been 
known to worsen HF in up to 44% of patients during the initiation of therapy [Krum 1995]. 
To mitigate these risks, some HF trials have employed a pre-randomization run-in period 
to exclude subjects who do not tolerate or do not respond to the study drug or are 
noncompliant [ANZ 1995, SOLVD 1991, Packer 1996, McMurray 2013]. Accordingly, 
the aim of introducing a placebo- and a macitentan run-in period in this study is thus to 
maximize the number of randomized subjects able to tolerate macitentan. The run-ins will 
also serve to exclude noncompliant subjects as medication noncompliance is a notorious 
precipitant of fluid decompensation in HF patients. 
Placebo run-in period: Subjects who are not on optimal diuretic therapy may be more prone 
to developing fluid retention. During the placebo run-in period, which lasts for 4 weeks, 
the clinical stability of the subject will be established. If necessary, HF or other 
cardiovascular medications may be adapted to optimize treatment. The subjects must be on 
stable HF- and/or cardiovascular therapy for at least 1 week immediately prior to entering 
the macitentan run-in. 
Macitentan run-in period: The purpose of the macitentan run-in is to identify and exclude 
subjects who are unable to tolerate macitentan as per criteria defined in Section 4.5, based 
on investigator judgment. Dose adjustment of oral diuretics and other cardiovascular 
medications is allowed, provided that the subject remains on stable therapy for at least 
1 week immediately prior to randomization. The macitentan run-in will last for 5 weeks. 
3.2.3 Rationale for the post-treatment observation period 
In order to comply with the intent-to-treat principle, subjects who prematurely discontinue 
study treatment will be followed until Week 52 to collect information pertaining to 
hospitalization and mortality [see Section 3.1.1.8]. 


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3.2.4 Rationale for the duration of the double-blind treatment period  
The results of the MELODY-1 study (AC-055G201) showed a decrease in NT-proBNP of 
13% compared to placebo after 8 weeks of treatment, and a further decrease to 23% 
compared to placebo after 12 weeks despite a relatively small sample size and absence of 
a minimum natriuretic peptide level requirement at study entry. Results from MELODY-1 
are in line with other studies with other HF treatments which have shown that the effect on 
NT-proBNP occurs early, i.e., within 12 weeks after start of treatment [Solomon 2012, 
Rosenberg 2008]. As wall stress is the mechanical stimulus influencing BNP release, the 
improvement in NT-proBNP is expected to be attained by 24 weeks, reflecting 
improvements in cardiac structural remodeling which are likely to start manifesting by this 
time. Therefore, a study duration of 24 weeks is considered to be sufficient to observe an 
effect on NT-pro-BNP.  
A treatment duration of 24 weeks is also considered to be sufficient to assess a change in 
key secondary endpoints such as daily physical activity and quality of life. 
Originally, the double-blind treatment duration was 52 weeks in order to allow for an 
estimation of the potential effect size on morbidity and mortality for a potential Phase 3 
study in this indication. However, due to early termination of recruitment and consequently 
reduced sample size, the number of WHF events is expected to be too low for a meaningful 
analysis of time to WHF. Furthermore, the primary endpoint (change in NT-proBNP) and 
the key secondary endpoints of KCCQ clinical summary score and change in physical 
activity assessed by accelerometry are all assessed at Week 24. Therefore, the double-blind 
treatment duration was reduced to 24 weeks [see Section 3.1.1.8].  
3.3 Study committees 
An Independent Data Monitoring Committee (IDMC) has overall responsibility for 
safeguarding the interests of subjects by monitoring the benefit-risk ratio and making 
appropriate recommendations based on all the reported data and 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. 
An Independent Statistical Analysis Center (not otherwise involved with study conduct or 
statistical analysis) will have exclusive access to the randomization list and will generate 
the monitoring reports exclusively for review by the IDMC. 
Both a Scientific Advisory Board and a Steering Committee are involved in the study 
design and will be consulted prior to and during the study for relevant medical issues and 
study publications. 


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An Independent Liver Safety Data Review Board (ILSDRB, an external expert committee 
of hepatologists) has been appointed to provide ongoing assessment and advice regarding 
serious hepatic AEs of special interest that require further evaluation during the study as 
per the ILSDRB charter.  
4 
SUBJECT POPULATION 
4.1 Subject population description 
The study will enroll male and female subjects aged 18 years or older with an established 
diagnosis of HFpEF and pulmonary vascular disease with or without overt RVD. The 
subjects must have signs and symptoms of HF requiring treatment with at least 1 diuretic 
of any type, and they must be in NYHA FC II or III. In order to assess the effect of 
macitentan on the physical activity of subjects, subjects must be ambulatory (i.e., subjects 
in NYHA FC IV are excluded).  
To minimize the number of screening failures, it is recommended to only screen subjects 
who have had the diagnosis of HFpEF confirmed by a previous echocardiography. 
Eligible subjects must be able and willing to give informed consent for participation in the 
clinical study.  
4.2 Rationale for the selection of the study population 
The improvements in CO and NT-proBNP observed in MELODY-1 [see Section 1.3] 
indicate a potential benefit of macitentan in subjects with CpcPH due to left ventricular 
dysfuntion (LVD). ERAs have been previously tested in HFrEF and have not consistently 
shown clinical benefit [Kaoukis 2013]. As subjects with HFpEF comprised the majority of 
the MELODY-1 population, macitentan may present a potential benefit for this indication 
with a high unmet need due to lack of approved therapies.  
Similarly to HFrEF, RVD may accompany HFpEF and this phenotype portends a poorer 
prognosis, including higher HF hospitalization rate, cardiovascular mortality, and all-cause 
mortality, irrespective of severity of PH or comorbid conditions [Zakeri 2015a]. In the 
subset of HFpEF patients with secondary RVD, increased right ventricular afterload could 
be mitigated by ERA treatment. A decrease in pulmonary vascular resistance (PVR) with 
macitentan is expected to alleviate right ventricular (RV) burden and consequently improve 
RV-pulmonary artery coupling.  
ERAs, including macitentan, demonstrated efficacy and are generally well tolerated in 
subjects with PAH with a varied degree of RVD. In a Phase 3 study in subjects with PAH 
(AC-055-302 / SERAPHIN), macitentan reduced the risk of a morbidity or mortality event, 
improved exercise capacity, WHO FC and pulmonary hemodynamics, and reduced 
NT-proBNP, compared to placebo. In SERAPHIN, the presence of clinical signs of RVD 
did not negatively impact the treatment effect of macitentan. On the contrary, the treatment 


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effect of macitentan on the morbidity/mortality endpoint was greater in subjects with signs 
and symptoms of right HF (or mean right atrial pressure [mRAP] ≥ 12 mmHg) at baseline. 
Subjects with a more pronounced degree of RVD had an overall higher morbidity/mortality 
event rate.  
It is currently unclear whether macitentan would be beneficial in patients with pulmonary 
vascular disease associated with advanced left heart disease, as increased PVR could be a 
protective mechanism against blood overflow in the lungs. This mechanism is thought to 
be the cause of early aggravation of patients with left HF who received epoprostenol 
[Califf 1997]. However, post hoc analyses conducted for a subset of SERAPHIN PAH 
patients with clinical traits compatible with a possibility of concomitant LVD reported a 
similar treatment effect compared to the overall SERAPHIN PAH population on the 
primary morbidity/mortality efficacy endpoint, as well as the combined endpoint of death 
and hospitalization due to PAH, and a similar effect on 6-minute walk test, without specific 
safety concerns in this patient subset. Similarly, patients with PAH and LV dysfunction in 
the AMBITION study with ambrisentan did not differ from the selected PAH population 
on the primary efficacy endpoint [Galiè 2015]. 
Subject selection in AC-055G202 is aimed to identify subjects with HFpEF and associated 
pulmonary vascular disease with and without overt RVD and tolerating macitentan, which 
will optimize evaluation of potential efficacy of macitentan as assessed by NT-proBNP, 
symptom burden and patient related outcomes in a Phase 2 study over 52 weeks of 
treatment.  
4.3 Inclusion criteria 
For inclusion in the study, all of the following inclusion criteria must be fulfilled at 
Screening. It is not permitted to waive any of the criteria for any subject: 
1. Signed informed consent prior to any study-mandated procedure 
2. Male or female subjects ≥ 18 years of age 
3. Signs or symptoms of HF requiring treatment with at least one oral diuretic (any type)  
4. LVEF ≥ 40% (by echocardiography at screening) 
5. NYHA FC II to III 
6. Criterion removed (see footnote4) 
7. Patients with HFpEF defined as either one of the following by echocardiography at 
Screening: 
a. Left atrial (LA) enlargement: 
 
4 Inclusion criterion 6 (HF hospitalization within 12 months prior to Screening or RHC within 6 months prior to 
Screening showing PAWP/LVEDP > 15mmHg) was removed in Global protocol v.4. 


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i. 
Left atrial volume (LAV) > 58 mL (male) / > 52 mL (female), or 
ii. 
Left atrial volume index (LAVI) ≥ 28 mL/m2, or 
iii. 
LA area > 20 cm2, or 
iv. 
LA diameter > 4.0 cm (male) / > 3.8 cm (female) 
b. Left ventricular septal thickness or posterior wall thickness ≥ 1.1 cm 
8. Elevated NT-proBNP / BNP: ≥ 200 / 60 pg/mL for subjects in sinus rhythm or ≥ 500 / 
150 pg/mL for subjects with atrial fibrillation (AF) at any time within 3 months prior 
to Screening or at Screening 
9. Pulmonary vascular disease or RV dysfunction meeting at least one of the following 
echocardiographic (at Screening) and/or RHC parameters (at Screening or from any 
RHC previously performed): 
a. Echocardiographic peak TR velocity > 2.8 m/s or invasive mean pulmonary artery 
pressure ≥ 25 mmHg (RHC) or PASP > 40 mmHg and evidence of RV 
dysfunction (TAPSE < 17 mm or RV fractional area change < 35% or RV tissue 
Doppler s’ velocity < 9.5 cm/s)  
b. Diastolic Pulmonary Vascular Pressure Gradient (DPG) > 5 mmHg (RHC) 
c. PVR > 3 Wood Units (RHC) 
10. A woman of childbearing potential [see definition in Section 4.6.1] is eligible only if 
the following applies: 
a. Negative pre-treatment serum pregnancy test.  
b. Agreement to undertake monthly pregnancy tests from Screening up to at least 
30 days after study treatment discontinuation. 
c. Agreement to use reliable contraception [Section 4.6.2] from at least 30 days prior 
to Visit 2 up to at least 30 days after study treatment discontinuation 
4.4 Exclusion criteria 
Subjects must not fulfill any of the following exclusion criteria at any time during 
Screening, unless specified otherwise for individual criteria. It is not permitted to waive 
any of the criteria for any subject: 
Disease-related 
1. Any prior valid5 measurement of LVEF < 40% 
 
5 An echocardiogram is considered valid if its quality is sufficient to allow accurate assessment of LVEF and if it is 
reflective of the true status of the subject (the investigator may use his judgement to disregard echocardiogram 
obtained during acute events such as AF with a rapid ventricular response, acute ischemia, etc.). 


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Cardiovascular comorbidities: 
2. Significant unrepaired structural valvular heart disease (i.e., greater than mild aortic 
or mitral stenosis, and greater than moderate aortic or mitral regurgitation). 
3. Hypertrophic, restrictive, and infiltrative cardiomyopathies. 
4. Pericardial disease.  
5. Acute coronary syndrome, including ST-segment elevation myocardial infarction 
(STEMI), non-ST-segment elevation myocardial infarction (NSTEMI) or unstable 
coronary artery disease or has undergone coronary artery bypass graft (CABG) or 
percutaneous coronary intervention (PCI) within 3 months of Screening. 
6. Known indication for PCI or CABG. 
7. Uncontrolled heart rate (HR) from atrial fibrillation or atrial flutter (> 110 beats per 
minute) as assessed by ECG. 
8. History of serious life-threatening or hemodynamically significant arrhythmias, 
including symptomatic or sustained ventricular tachycardia or defibrillator shock 
within 12 month(s) of Screening. 
9. History of or anticipated heart transplant or anticipated/implanted ventricular assist 
device.  
10. Transient ischemic attack (TIA) or stroke within 3 months of Screening. 
11. Systolic blood pressure (SBP) ≥ 180 mmHg6 or diastolic blood pressure (DBP) 
≥ 110 mmHg. 
Other causes of right heart failure not associated with left ventricular dysfunction: 
12. Significant parenchymal lung disease fulfilling any of the following:  
a. Forced expiratory volume in 1 second / forced vital capacity (FEV1/FVC ratio) 
< 0.7 associated with FEV1 < 50% of predicted value after bronchodilator 
administration in subjects with a known or suspected history of significant lung 
diseases. 
b. Known moderate or severe restrictive lung disease, e.g., total lung capacity 
(TLC) < 60% (predicted)  
c. Clinical suspicion of diffuse interstitial fibrosis or alveolitis, unless excluded by 
high resolution computed tomography (CT) 
d. Clinical suspicion of pulmonary thromboembolism within 12 months prior to 
Screening, unless excluded by ventilation/perfusion (V/Q) scan or computed 
tomography angiography (CTA)  
13. Criterion removed (see footnote7) 
 
6 For subjects with an SBP > 150 mmHg prior to randomization, the recommendations provided in Section 5.2.4 should 
be followed. 
7 Exclusion criterion 13 (BMI ≥ 45 kg/m2) was removed in Global protocol Version 4. 


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14. Clinically significant congenital heart disease that could be the cause of the patient’s 
symptoms and signs of HF. 
Criteria related to macitentan use: 
15. Administration of PAH-specific therapy (i.e., ERAs, prostanoids, PDE-5 inhibitors, 
guanylate cyclase stimulators) within 1 month prior to Screening. 
16. Hypotension, i.e., SBP < 90 mmHg or DBP < 50 mmHg  
17. Severe renal dysfunction with an estimated Glomerular Filtration Rate (eGFR) 
< 30 mL/min per 1.73 m2 using the Modification of Diet in Renal Disease (MDRD) 
formula  
18. Known and documented severe hepatic impairment, e.g., Child-Pugh Class C. 
19. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
≥ 3 × the upper limit of normal (ULN). 
20. Hemoglobin < 100g/L (< 10 g/dL). 
21. Plan to become pregnant or lactating. 
22. Treatment with strong cytochrome P-450 3A4 (CYP3A4) inducers such as rifabutin, 
rifampin, rifampicin, rifapentin, carbamazepine, phenobarbital, phenytoin, or St. 
John’s wort within 1 month prior to screening. 
Treatment with strong CYP3A4 inhibitors such as ketoconazole, itraconazole, 
voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir 
within 1 month prior to Screening. 
23. Criterion removed (see footnote8) 
24. Known hypersensitivity to macitentan or drugs of the same class, or any of the 
excipients (e.g., soy lecithin, lactose). 
General criteria: 
25. Planned or current treatment with another investigational treatment within 2 months 
prior to screening. 
26. Inadequate control of comorbidities according to current standards of care, as per 
judgment of the investigator. 
27. Any known factor or disease that might interfere with treatment compliance, study 
conduct, or interpretation of the results, such as drug or alcohol dependence or 
psychiatric disease. 
28. Known concomitant life-threatening disease with a life expectancy < 12 months. 
 
8 Exclusion criterion 24 (treatment with BCRP substrates) was removed in Global protocol v.4. 


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4.5 Run-in failure criteria 
A subject must be discontinued from the study in case any of the following criteria is 
fulfilled at any time during the run-in period: 
1. 
Study treatment compliance < 80%.  
2. 
Central laboratory results showing a decrease in hemoglobin by > 50 g/L from 
Screening or hemoglobin < 80 g/L, or need for transfusion. 
3. 
Significant fluid retention / worsening of HF as evidenced by one of the following: 
a. Administration of i.v. diuretics due to fluid retention 
b. Addition of high potency thiazide diuretic (metolazone, indapamide), or ≥ 100% 
increase in loop diuretic to a total oral dose ≥ 120 mg of furosemide 
equivalents/day9 
c. Increase in body weight by ≥ 5% or ≥ 5 kg from the value at the start of the 
corresponding run-in period (i.e., Visit 2 and Visit 4 for the placebo and 
macitentan run-in, respectively) due to fluid overload 
d. Worsening in NYHA FC 
e. Hospitalization for worsening of HF 
4. 
Any AEs that preclude continuation based on investigator’s judgment.  
4.6 Criteria for women of childbearing potential  
4.6.1 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, 
• Postmenopausal (defined as 12 consecutive months with no menses without an 
alternative medical cause [ICH M3 definition]), 
• Premature ovarian failure (confirmed by a specialist), XY genotype, Turner 
syndrome, uterine agenesis. 
The reason for not being of childbearing potential will be recorded in the Case Report Form 
(CRF). 
 
9 Furosemide equivalents: furosemide 40 mg: torasemide 20 mg: bumetanide 1 mg; ethacrynic acid 50 mg. 


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4.6.2 Acceptable methods of contraception 
Women of childbearing potential [see definition in Section 4.6.1] must use acceptable birth 
control from Screening up to at least 30 days after study treatment discontinuation. Reliable 
contraception must be started at least 30 days prior to Visit 2. 
The methods of birth control used (including non-pharmacological methods) must be 
recorded in the CRF. 
To ensure compliance, the study personnel must remind women of childbearing potential 
at each visit to use the methods of contraception defined for this study. The reminders must 
be documented in the hospital chart.  
If subjects decide that they want to change the form of birth control being used, they need 
to talk with the treating physician to be sure that another acceptable form of birth control 
is chosen.  
4.6.2.1 Countries where macitentan is approved 
In countries where macitentan is approved, the macitentan label can be followed with 
respect to acceptable methods of contraception. It must be ensured that a female counselor 
is available to discuss this topic, if requested.  
4.6.2.2 North America and countries where macitentan is not approved 
Subjects may choose one highly effective form of contraception (intrauterine devices, 
contraceptive implants or tubal sterilization) or a combination of methods (hormone 
method with a barrier method or two barrier methods) [Figure 2]. If a partner’s vasectomy 
is the chosen method of contraception, a hormone or barrier method must be used along 
with this method.  
The investigator must counsel patients on pregnancy planning and prevention, including 
emergency contraception, or designate counseling by another healthcare provider trained 
in contraceptive measures. 


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Figure 2 
Acceptable birth control options 
 
5 
TREATMENTS 
5.1 Study treatment 
5.1.1 Investigational treatment and matching placebo: Description and rationale 
Macitentan 10 mg and placebo will be provided as identical film-coated tablets debossed 
with ‘10’ on one side. One tablet must be taken orally once a day.  
Macitentan doses of 3 mg and 10 mg were investigated in the AC-055-302 / SERAPHIN 
study in subjects with PAH [Pulido 2013]. Based on the results of this trial, macitentan, at 
both the 3 mg and 10 mg doses, decreased the risk of a morbidity/mortality event over the 
treatment period versus placebo. A dose-response was identified, with the greatest efficacy 
demonstrated in the 10 mg dose group. Macitentan was well tolerated in this subject 
population. The number of AEs reported and subjects discontinuing treatment due to AEs 


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was similar across all groups. No differences were observed between macitentan and 
placebo on fluid retention (edema). For more detailed information, see the macitentan IB 
[Macitentan IB].  
Based on these results, a dose of 10 mg was selected for the AC-055G201 / MELODY-1 
study in subjects with CpcPH due to LVD. In MELODY-1, an improvement in CO and 
NT-pro-BNP was observed. The safety observations were consistent with the known safety 
profile of macitentan in other populations, and no new safety signal was detected. 
Therefore, a dose of macitentan 10 mg was selected as the dose for study AC-055G202. 
5.1.2 Study treatment administration  
The first intake of study treatment will take place at site, during Visit 2 (start of the placebo-
run-in). Thereafter, one tablet must be taken orally every morning irrespective of food 
intake. 
The subjects must be instructed not to take study treatment in the morning of study visit 
days. After all study assessments have been performed, a tablet from the newly dispensed 
bottle is taken (except at Visit 3, where the study treatment is taken from the bottle 
dispensed at Visit 2). 
If a dose has been missed, the subject must be instructed to take it as soon as possible on 
the same day, and to take the next dose at the regular time. The subject must be instructed 
not to take 2 doses to make up for a missed dose.  
5.1.3 Treatment assignment 
After informed consent has been signed, the investigator/delegate contacts the Interactive 
Response Technology system (IRT) at Visit 1 (Screening) to obtain a subject number.  
In case of re-screening, the subject number attributed at the time of first screening will also 
be used for the re-screened subject. 
At Visit 2 (start of the placebo run-in), after having confirmed the eligibility of the subject, 
the investigator/delegate contacts the IRT to receive the bottle number for the placebo run-
in period. At the end of the placebo run-in period (Visit 4), after having confirmed the 
eligibility of the subject, the investigator/delegate contacts the IRT to obtain the bottle 
numbers for the macitentan run-in. At the end of the macitentan run-in (Visit 6, 
Randomization), after having confirmed the eligibility of the subject, the IRT is contacted 
again by the investigator/delegate to randomize the subject. The IRT assigns a 
randomization number to the subject and assigns bottle number(s), which match the 
treatment arm assigned by the randomization list to the randomization number. 


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At each visit during the double-blind treatment period (except Visit 7 [telephone call], EOT 
and EOS), the IRT is contacted to obtain new bottle number(s). At EOT, the IRT is 
contacted to register the visit. 
The randomization list is generated by an independent Contract Research Organization 
(CRO), Almac Clinical Technologies, using SAS® version 9.3. 
Treatment allocation will be stratified by NT-proBNP level (≤/> 1000 pg/mL) prior to 
administration of the first dose of macitentan; i.e., the NT-proBNP value measured at 
macitentan run-in entry will be used. If the NT-proBNP value at macitentan run-in entry is 
not available, the NT-proBNP value measured at V1 (Screening) will be used instead. 
NT-proBNP is chosen as a stratification variable as it is associated with many other factors 
that determine outcome such as age, sex, body mass index (BMI), atrial fibrillation and 
chronic kidney disease.  
5.1.4 Blinding 
5.1.4.1 Single-blind run-in period 
The placebo- and macitentan run-in periods will be performed in a single-blind fashion, 
i.e., only the subject is blinded to the identity of the treatment.  
The investigator and site staff must exercise caution when discussing the study procedures 
and study treatment with the subject to keep the subject blinded to the identity of the study 
treatment. 
5.1.4.2 Double-blind treatment period 
After randomization of the subject, the study will be performed in a double-blind fashion. 
The investigator and study personnel, the subjects, the Clinical Research Associates 
(CRAs), Actelion personnel, and CRO personnel involved in the conduct of the study will 
remain blinded to the study treatment until study closure. Actelion personnel responsible 
for clinical study supply distribution will need to be unblinded to ensure adequate supply 
of study treatment. These persons will be clearly identified, their unblinding will be 
documented in the trial master file and they will not take part in any Clinical Trial Team 
(CTT) meetings after study set-up has been completed. 
Until the time of unblinding for final data analysis, the randomization list is kept strictly 
confidential, and accessible only to authorized persons (i.e., Global Quality Management 
[GQM], independent statistical analysis center and Clinical Trials Supplies Group) who 
are not involved in the conduct of the study. 
The investigational treatment and its matching placebo are indistinguishable, and will be 
packaged in the same way. 


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5.1.5 Unblinding 
5.1.5.1 Unblinding for final analyses 
Full randomization information will be made available for data analysis only after database 
closure, in accordance with Actelion Quality System (QS) documents. 
5.1.5.2 Unblinding for interim analyses 
Not applicable. 
5.1.5.3 Unblinding for suspected unexpected serious adverse reactions 
If 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 treatment assignment will not be communicated to site 
personnel or to the Actelion CTT. Unblinded SUSAR information will be provided to 
respective health authorities and independent ethics committees (IECs) or institutional 
review board (IRBs) only. SUSARs will be reported to investigators in a blinded fashion. 
5.1.5.4 Emergency procedure for unblinding 
The investigator, study personnel and Actelion personnel 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 treatment assignment through the IRT. 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 unblinding with Actelion personnel. 
The occurrence of any unblinding during the study must be clearly justified and explained 
by the investigator. In all cases, Actelion personnel must be informed as soon as possible 
before or after the unblinding. 
The circumstances leading to unblinding must be documented in the Investigator Site File 
(ISF) and CRF. 
5.1.6 Study treatment supply  
Manufacture, labeling, packaging, and supply of study treatment will be conducted 
according to Good Manufacturing Practice, Good Clinical Practice (GCP), and any local 
or national regulatory requirements. 
All study treatment supplies are to be used only in accordance with this protocol, and not 
for any other purpose. 


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5.1.6.1 Study treatment packaging and labeling 
Study treatment is provided as tablets and supplied in childproof bottles containing 
36 tablets each. 
Study treatment is labeled to comply with the applicable laws and regulations of the 
countries in which the study sites are located. 
5.1.6.2 Study treatment distribution and storage 
Study treatment supplies must be kept in an appropriate, secure area and stored according 
to the conditions specified on the label. 
Unopened, sealed study treatment bottles may be stored in the refrigerator (above +2 °C 
[36 °F]). Storage below +2 °C / 36 °F (e.g., in the freezer) is not permitted. Opened bottles 
must not be stored in the refrigerator. 
5.1.6.3 Study treatment dispensing 
The subjects will receive sufficient study treatment (i.e., up to 4 bottles) to cover the period 
up to the next scheduled visit. If the study treatment is lost or damaged, a replacement 
bottle can be requested through the Treatment Replacement module via IRT. Subjects are 
asked to return all opened and unopened study treatment bottles at each visit. The protocol-
mandated study-treatment dispensing procedures may not be altered without prior written 
approval from Actelion. Under exceptional circumstances, e.g., if study treatment is lost or 
damaged, or if a subject cannot return to a site within the defined time-window for a visit 
and does not have enough study treatment at home, the site may request permission from 
Actelion to send study treatment to the subject. An accurate record of the date and amount 
of study treatment dispensed to each subject must be available for inspection at any time. 
5.1.6.4 Study treatment return and destruction 
The protocol-mandated study treatment return procedures may not be altered without prior 
written approval from Actelion. Procedures for local destruction or for return and 
destruction by an external vendor are described in the study-specific Site Investigational 
Product Procedures Manual. On an ongoing basis and/or on termination of the study, the 
CRA will collect used and unused treatment bottles which will be sent to the warehouse, 
where Actelion personnel or a deputy will check treatment reconciliation. In certain 
circumstances, used and unused study treatment containers may be destroyed at the site 
once study treatment accountability is finalized and has been checked by Actelion 
personnel or the deputy, and written permission for destruction has been obtained from 
Actelion. 


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5.1.7 Study treatment accountability and compliance with study treatment  
5.1.7.1 Study treatment accountability 
The inventory of study treatment dispensed to and returned by the subject 
(i.e., study-treatment accountability) must be performed by site personnel on the day of the 
visit and before dispensing further study treatment. It is to be recorded by site personnel on 
the study-treatment dispensing and accountability log and in the CRF, and checked by the 
CRA during site visits and at the end of the study. The study treatment accountability log 
in the CRF will include at least the following information for each study treatment bottle 
dispensed to the subject: 
• Dispensed bottle number(s) 
• Date dispensed / number of bottles 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 tablets from the remaining study treatment bottle and to return it 
at the next visit. 
5.1.7.2 Study treatment compliance 
Study treatment compliance is based on study treatment accountability. Study treatment 
compliance will be calculated by site personnel using the below formulas and entered in 
the eCRF. 
Study treatment compliance calculation during the run-in period:  
Placebo run-in: 
𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 (%) = 
36 −𝑛𝑛 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑎𝑎𝑎𝑎 𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉 4
𝑛𝑛 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑡𝑡ℎ𝑎𝑎𝑎𝑎 𝑠𝑠ℎ𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜 ℎ𝑎𝑎𝑎𝑎𝑎𝑎 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉 2 𝑎𝑎𝑎𝑎𝑎𝑎 4 × 100 
Macitentan run-in:  
𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶  (%) = 72 −(𝑛𝑛 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑎𝑎𝑎𝑎 𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉 5 + 𝑛𝑛 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑎𝑎𝑎𝑎 𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉 6)
𝑛𝑛 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑡𝑡ℎ𝑎𝑎𝑎𝑎 𝑠𝑠ℎ𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜 ℎ𝑎𝑎𝑎𝑎𝑎𝑎 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉 4 𝑎𝑎𝑎𝑎𝑎𝑎 6  
× 100 
 
Study treatment compliance calculation during the double-blind treatment period between 
2 regular consecutive visits:  
𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 (%) = 
𝑛𝑛 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑  −𝑛𝑛 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 
𝑛𝑛 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑡𝑡ℎ𝑎𝑎𝑎𝑎 𝑠𝑠ℎ𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜 ℎ𝑎𝑎𝑎𝑎𝑎𝑎 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏  2 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑎𝑎𝑎𝑎 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 × 100 


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The number of tablets that should have been taken is derived from the number of days 
between the day of the visit on which study treatment is dispensed (included) and the next 
regular visit (day of visit not included). 
During the study, compliance is expected to be between 80% and 120%. Compliance 
values outside of this range will be considered as a protocol deviation, which will be 
reported in the CRF by the CRA. The investigator or delegate must discuss the 
non-compliance with the subject to clarify the reasons and to take appropriate actions to 
avoid reoccurrence. This discussion and its outcome must be documented in the source 
documents. 
5.1.8 Study treatment dose adjustments and interruptions 
Study treatment dose adjustments are not permitted. 
Study treatment may be temporarily interrupted in response to an AE, a diagnostic or 
therapeutic procedure, a laboratory abnormality, or for administrative reasons. 
Study-specific criteria for interruption of study treatment are described in Section 5.1.10. 
If study treatment is interrupted by the subject for any reason, she/he must immediately 
inform the investigator. 
Interruptions of study treatment must be kept as short as possible. If treatment is stopped 
for more than 4 consecutive weeks, re-introduction is not permitted, and treatment must be 
permanently discontinued [see Section 5.1.9]. 
Study treatment interruptions must be recorded in the CRF. 
5.1.9 Premature discontinuation of study treatment  
The decision to prematurely discontinue study treatment may be made by the subject, the 
investigator, or Actelion personnel. The main reason and whether discontinuation of study 
treatment is the decision of the subject (e.g., tolerability- or efficacy-related), the 
investigator (e.g., due to pre-specified study treatment discontinuation criteria, an AE or 
lack of efficacy), or Actelion (e.g., study terminated) must be documented in the CRF. 
Refer to Section 3.1.1.8 for guidance on reporting the reason for study treatment 
discontinuation of subjects who consented to global protocol Version 6.  
A subject has the right to prematurely discontinue study treatment at any time, without any 
justification, 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 8.2]). 
Although a subject is not obliged to give his/her reason for prematurely withdrawing from 
the treatment or the study, it is recommended that the investigator makes a reasonable effort 
to ascertain the reason(s), while fully respecting the subject’s rights. 


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The investigator must 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-specific criteria for discontinuation of study treatment are described in 
Section 5.1.10. 
A subject who prematurely discontinues study treatment is NOT considered as withdrawn 
from the study and will be asked to enter a PTOP which lasts until Week 52, provided that 
the subject’s consent for this limited participation in the study has not been withdrawn. 
(The duration of PTOP for subjects who consented to global protocol Version 6 is described 
in  Section 3.1.1.8.) 
The subject will be asked to return for an EOT visit within 7 days after taking the decision 
to stop study treatment and for a safety follow-up visit 30 (+5) days after the last intake of 
study treatment (PTOP1). At the premature EOT visit, the assessments described for the 
regular EOT visit (Visit 13) are to be performed [Table 1]. If the premature EOT- or safety 
follow-up visit falls within the time-window of any of the PTOP visits, the visits can be 
combined.  
A subject who prematurely discontinues study treatment and withdraws consent to 
participate in any further study assessments is considered as withdrawn from the study. 
Subjects who die or are lost to follow-up are also considered as withdrawn from the study. 
Withdrawal from the study and follow-up medical care of subjects withdrawn from the 
study is described in Sections 8.2 and 8.4, respectively. 
Subjects who choose not to enter or complete the PTOP but who did not withdraw consent 
[see definition in Section 8.2] will be contacted by telephone at Week 52  
(+/−14 days) by the site, and their vital status will be recorded in the CRF. 
This does not apply to subjects who consented to global protocol Version 6. 
5.1.10 Study-specific criteria for interruption / premature discontinuation of study 
treatment 
5.1.10.1 Liver aminotransferase abnormalities 
Interruption of study treatment 
Study treatment must be interrupted in the following cases: 
• Aminotransferases (i.e., ALT and/or AST) ≥ 3 and < 8 × ULN 
 
Perform a re-test of aminotransferases (ALT and AST), total and direct bilirubin, and 
alkaline phosphatase within one week. If AST and/or ALT elevation is confirmed, continue 
to weekly monitor aminotransferases, total and direct bilirubin, and alkaline phosphatase 
levels until values return to pre-treatment levels or within normal ranges. If the 


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aminotransferase values return to pre-treatment levels or within normal ranges, and if the 
potential benefits outweigh the risks, re-introduction of study treatment can be considered. 
The advice of a hepatologist is recommended. Interruptions must be for less than 
4 consecutive weeks; longer interruptions must lead to permanent discontinuation of study 
treatment. 
Liver aminotransferase levels must then be checked within 3 days after re-introduction, 
then again after a further 2 weeks and thereafter according to the recommendations in 
Section 7.2.4 (i.e., at monthly intervals). 
Permanent discontinuation of study treatment 
Study treatment must be stopped and its re-introduction 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 to ≥ 2 × ULN 
 
Perform a re-test of aminotransferases (ALT and AST), total and direct bilirubin, and 
alkaline phosphatase. 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, 
alcoholic hepatitis, non-alcoholic steatohepatitis, autoimmune disease) and/or etiologies 
(e.g., hepatic toxicity of concomitant medication[s] or other substances) should be 
considered and ruled out by performing the appropriate tests. 
All liver aminotransferase abnormalities leading to study treatment interruption or 
discontinuation must be recorded as AEs [see Section 9]. 
5.1.10.2 Hemoglobin abnormalities 
Hemoglobin abnormalities leading to run-in failure are described in Section 4.5. 
If there is a decrease in hemoglobin from baseline10 of > 20 g/L during the run-in or 
double-blind treatment period, 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: 
 
10 Baseline hemoglobin refers to the last hemoglobin value obtained prior to the start of the placebo run-in. 


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• 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. 
If hemoglobin remains > 20 g/L below baseline value at subsequent visits, further re-tests 
are to be performed as per investigator’s judgment. 
This work-up should not result in study treatment interruption or discontinuation, unless 
clinically mandated based on the investigator’s judgment, or in the following situation:  
A decrease in hemoglobin to < 80.0 g/L, a decrease in hemoglobin from baseline of 
> 50 g/L, or the need for transfusion must result in temporary interruption of study 
medication, except during the run-in period where the subject must be permanently 
discontinued. Re-introduction of study medication can be considered if hemoglobin 
recovery, defined as a return of hemoglobin to within 20 g/L of the baseline value, is 
achieved.  
Study treatment interruptions exceeding 4 consecutive weeks must lead to permanent 
discontinuation of study treatment. 
5.1.10.3 Initiation of prohibited medications  
Study treatment must be permanently discontinued if any other investigational treatments 
are started during the treatment period.  
Treatment with strong CYP3A4 inducers and inhibitors and PAH specific drugs as detailed 
in Section 5.2.5 must lead to interruption of study treatment for the duration of their 
administration. Re-initiation of study treatment can be considered if the interruption does 
not exceed 4 consecutive weeks. 
5.2 Previous and concomitant therapy 
5.2.1 Definitions  
A previous therapy is any treatment for which the end date is prior to signing of informed 
consent. 
A therapy that is study-concomitant is any treatment that is ongoing or initiated after 
signing of informed consent, or initiated up to 30 days after study treatment 
discontinuation. 
A therapy that is study treatment-concomitant is any treatment that is either ongoing at the 
start of study treatment or is initiated during the treatment period. 


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An auxiliary medicinal product is a medicinal product used for the purpose of the clinical 
study but not as an investigational medicinal product (e.g., a mandatory background 
therapy or a medicinal product used for a study-mandated procedure). 
5.2.2 Reporting of previous/concomitant therapy / auxiliary medicinal products in 
the CRF 
The use of all study-concomitant therapy (including contraceptives and traditional and 
alternative medicines, e.g., plant-, animal-, or mineral-based medicines) will be recorded 
in the CRF. Previous therapy must be recorded in the CRF if discontinued less than 30 days 
prior to signing of the informed consent. 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 CRF. 
5.2.3 Auxiliary medicinal products  
All subjects must be on oral diuretic therapy (any type). On the day of the study visit, 
subjects will be requested to withhold their morning dose of diuretic(s) until after the blood 
sampling.  
5.2.4 Allowed concomitant therapy 
Subjects are allowed to continue with their usual HF therapy. However, HF or other 
cardiovascular medications must be administered at a stable dose for at least 1 consecutive 
week prior to entering the macitentan run-in (Visit 4) and prior to Randomization (Visit 6).  
For subjects with a SBP > 150 mmHg, treatment with antihypertensives according to local 
guidelines [e.g., ESC Guidelines 2013, James 2014] to achieve their target BP is 
recommended. 
After the start of the double-blind treatment period, the investigator is encouraged to keep 
the subject’s cardiovascular medications stable, unless a change is required for medical 
reasons. Any change has to be recorded in the CRF as described in Section 5.2.2. 
5.2.5 Forbidden concomitant therapy 
The following concomitant medications are forbidden within 1 month prior to Screening 
and up to 30 days after study treatment discontinuation: 
• PAH-specific drugs (ERAs, prostanoids, PDE-5 inhibitors, guanylate cyclase 
stimulators).  
• Strong 
CYP3A4 
inducers 
(e.g., 
carbamazepine, 
phenytoin, 
phenobarbital, 
rifampin/rifampicin, rifabutin, rifapentin, St. John’s wort). 
• Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, voriconazole, 
clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) or moderate dual 
CYP3A4/CYP2C9 inhibitors (e.g. fluconazole, amiodarone) or co-administration of a 


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combination of moderate CYP3A4 (e.g. ciprofloxacin, cyclosporine, diltiazem, 
erythromycin, verapamil) and moderate CYP2C9 inhibitors (e.g., miconazole, 
piperine) until study intervention discontinuation [FDA 2020]. 
If subjects are currently stable on a moderate dual CYP3A4/CYP2C9 inhibitors (e.g. 
fluconazole, amiodarone) or co-administration of a combination of moderate CYP3A4 
(e.g. ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) and moderate 
CYP2C9 inhibitors (e.g. miconazole, piperine), the subject may remain on current 
treatment per the investigator's discretion based on his/her clinical judgement and risk-
benefit assessment. However, the subject will not be eligible to enter the OL study 
unless the forbidden medication is discontinued 1-month prior to OL enrollment. 
• Any other investigational drug. 
Initiation of ENTRESTO® (sacubitril/valsartan) is forbidden during the core phase of the 
double-blind treatment period.  
6 
STUDY ENDPOINTS 
6.1 Efficacy endpoints 
6.1.1 Primary efficacy endpoint 
• Percent of baseline NT-proBNP assessed at Week 24. 
Rationale:  
NT-proBNP is one of the best established cardiovascular response markers among all 
available surrogates in HF. Changes in this marker may reflect reduction in cardiac load 
and LV wall stress and reductions in NT-proBNP have been associated with improved 
outcomes in HF [Januzzi 2013, Grewal 2008]. NT-proBNP is a suitable endpoint for a 
Phase 2b, non-registration study in this indication, provided it is accompanied by an 
improvement in symptom burden and/or patient related outcomes (key secondary 
endpoints) and well characterized cardiovascular safety. NT-proBNP is simple to assess, it 
allows shorter study duration. Percent change in NT-proBNP was the most objective 
endpoint in MELODY-1 (decrease in NT-proBNP of 13% compared to placebo after 
8 weeks of treatment with 10 mg macitentan once daily, and a further decrease to 23% 
compared to placebo after 12 weeks) despite a relatively small sample size in MELODY-1 
and without minimum natriuretic peptide level requirement at study entry. This effect was 
commensurate with increased CO without increases in PAWP or HR. In addition, 
NT-proBNP has been used as the primary endpoint in a study in HFpEF (PARAMOUNT 
study [Solomon 2012]) of similar size and duration as study AC-055G202. 
As wall stress is the mechanical stimulus influencing BNP release, the maximum 
improvement in NT-proBNP is expected to be attained by 24 weeks, reflecting 
improvements in cardiac structural remodeling which are likely to manifest by this time. 


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Therefore, a study duration of 24 weeks is considered to be sufficient to observe an effect 
on NT-pro-BNP. 
The statistical method used to analyze the primary efficacy variable takes into account the 
expected underlying log normal distribution of NT-proBNP [Solomon 2012]. As a 
consequence, the treatment effect will be tested on a log-scale using a classical general 
linear model for normally distributed variables and expressed, on the original scale, as the 
ratio between treatment groups of the geometric means of individual percent of baseline at 
Week 24 (macitentan over placebo). As a consequence, the primary endpoint is defined for 
each subject as percent of baseline at Week 24. 
6.1.2 Key secondary efficacy endpoints 
• Change from baseline to Week 24 in the clinical summary score (as assessed by the 
Kansas City Cardiomyopathy Questionnaire [KCCQ]). 
• Change from baseline to Week 24 in accelerometer-assessed proportion of time spent 
in light to vigorous physical activity based on a threshold of > 100 activity counts per 
minute.  
• Time to WHF event over 52 weeks. 
Rationale for the choice of key secondary endpoints:  
The effect on NT-proBNP needs to be accompanied by improvements in clinically relevant 
measures, such as quality of life, functional capacity, and delay in first occurrence WHF.  
The KCCQ is a valid, reliable and responsive health status measure for patients with CHF 
and may serve as a clinically meaningful outcome in cardiovascular (CV) clinical research, 
patient management and quality assessment [Green 2000]. The HF symptoms and physical 
limitation domains scores show the best the correlation for improvements following a CHF 
exacerbation [Green 2000]. Thus, the key secondary endpoint is the clinical summary score 
(mean of physical limitation and total symptoms scores) of the KCCQ at 24 weeks. All 
other domains will be analyzed as other endpoints, as the instrument will be administered 
in its entirety. 
Patients with chronic HF are characterized by a poor exercise tolerance prohibiting them 
to manage activities of daily living without limitation [Belardinelli 1999]. The amount of 
daily physical activity, as well as the intensity with which this habitual activity is performed 
seems important in determining functional capacity and disease severity. Accelerometer-
assessed activity is a novel end point, that provides high-density quantitative data from 
continuous assessment of physical activity in the real-life setting, enabling a more detailed 
analysis of activity. With accelerometry, “every step counts” as ubiquitous walking 
associated with daily living seems to play a contributing role in terms of clinical prognosis. 
Physical activity assessed by accelerometer is significantly associated with exercise 


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capacity in patients with HF and is predictive of disease severity discriminating patients 
with mild (NYHA I) from more advanced stages (NYHA III) of HF [Jehn 2011a].  
Accelerometry circumvents limitations of “targeted walking” assessed by measures such 
as the six-minute walk test which provides an intermittent evaluation of submaximal 
exercise capacity and which therefore can underestimate the true burden of HF.  
Accelerometry has already been used in HF studies. The NEAT-HFpEF study represents 
the first study within a dedicated HFpEF population to use accelerometer-assessed physical 
activity as a primary end point [Redfield 2015]. Recent studies in patients with HFrEF have 
demonstrated correlations between accelerometer data and NYHA FC, six-minute walk 
distance (6MWD), peak oxygen consumption, and estimated (Seattle Heart Failure Model) 
or observed mortality risks. Studies have also shown increases in accelerometer-assessed 
activity after cardiac resynchronization therapy, confirming its ability to reflect therapeutic 
response [Zakeri 2015a]. 
Validity, analytic issues, and compliance with externally worn accelerometer devices have 
been addressed in clinical trials for patients with chronic obstructive pulmonary disease, 
among whom age and activity level are likely comparable with elderly patients with HFpEF 
[Lores 2006, Hecht 2009, Jehn 2011b]. In addition, physical daily activity assessed by 
accelerometry has been shown to correlate with 6MWD in adult PAH patients and is 
significantly lower in patients with WHO FC III/IV as compared to WHO FC I/II 
[Pugh 2012, Ulrich 2013].  
WHF event is defined as an event that includes HF death, WHF hospitalization or an urgent 
WHF visit during which a subject exhibits new or worsening symptoms of HF, has 
objective evidence of WHF, and receives initiation or intensification of HF treatment 
[ACC/AHA 2015]. Accurate recognition of WHF events is important as they are associated 
with the poor outcomes and societal burden. The 2015 ACC/AHA definitions of a HF event 
and a HF death will ensure accurate and consistent reporting of WHF events during the 
study, independent of whether the exacerbation of HF results in hospitalization, 
recognizing that exacerbation of HF can often be managed on an outpatient basis such as 
with an urgent or unscheduled outpatient office/practice or emergency room visit 
[ACC/AHA 2015]. Using a standardized definition of a WHF event is particularly 
important in a global clinical trial, as standard-of-care may significantly differ across 
participating countries and sites. For the purposes of this study, HF death is included in the 
definition of WHF, in order to ensure that relevant fatal events without preceding 
hospitalization or an urgent/unscheduled/emergency visit are also captured. 
6.1.3 Other efficacy endpoints 
• Number of days alive and out of the hospital (DAOH) assessed over 52 weeks 


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• Time to first occurrence of the composite endpoint, which is defined as either HF death 
or HF hospitalization11 over 52 weeks 
• Time to first occurrence of a composite of CV death12 or CV hospitalization13 over 
52 weeks 
• Number of hospital admissions (for HF) over 52 weeks 
• NYHA FC (improved/worsened/stable) at each post-baseline assessment 
• Clinical composite outcome measure (‘worsened’, ‘unchanged’, ‘improved’) based on 
NYHA class, patient global assessment and occurrence of death or HF hospitalization 
at each post-baseline assessment 
• Change from baseline in the KCCQ overall summary score as well as clinical summary 
score and physical limitations score over time 
• Percent of baseline NT-proBNP over time 
• Percent of baseline mid-regional pro-atrial natriuretic peptide (MR-proANP) over time 
• Change from baseline in accelerometer-assessed physical activity variables over time: 
− Proportion of time spent in light to vigorous physical activity based on a threshold 
of > 100 activity counts per minute 
− Mean daily number of episodes of activity over 100 activity counts per minute of 
at least 1-minute duration 
− Mean count per minute of daily activity 
− Mean daily number of episodes of activity over 100 activity counts per minute of 
at least 5 minutes duration 
− Mean daily accelerometer units 
• Proportion of time spent in: 
− Sedentary physical activity  
− Light physical activity  
− Moderate physical activity  
− Vigorous physical activity  
- at each time assessment. 
• Change from baseline in echocardiography left and right heart function at Weeks 24 
and 52 (e.g., TAPSE, LAV, septal e’ velocity, PASP, E/e’ ratio). 
 
11 See definition in Appendix 6. 
12 See definition in Appendix 5. 
13 See definition in Appendix 6. 


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6.2 Safety endpoints 
• All-cause death up to 30 days after study treatment discontinuation 
• Number of all-cause hospital admissions up to 30 days after study treatment 
discontinuation 
• Treatment-emergent AEs and SAEs up to 30 days after study treatment discontinuation 
• AEs leading to premature discontinuation of study treatment 
• Change in vital signs (systolic and diastolic arterial BP and pulse rate) and body weight 
up to 30 days after study treatment discontinuation 
• Treatment-emergent marked laboratory abnormalities up to 30 days after study 
treatment discontinuation 
• Change from baseline in eGFR up to 30 days after study treatment discontinuation 
• Decrease from baseline in SBP of ≥ 5% and SBP < 100 mmHg up to 30 days after 
study treatment discontinuation. 
6.3 Quality of life endpoints 
See key secondary endpoints [Section 6.1.2]. 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS 
7.1 Study visits  
The study visits are listed in Table 1, Table 2 and Table 4. For all visits, the subjects must 
be seen on the designated day with the allowed visit window indicated in Table 1, Table 2 
and Table 4. If it is not possible to complete all assessments on the same day, a visit may 
extend to more than 1 day within the allowed time-window.  
Visits 1 (Screening) and 2 (placebo run-in start) may be combined, if a local laboratory test 
confirms eligibility of the subject, and the locally read echocardiographic parameters meet 
the eligibility criteria. However, if the results from the central laboratory and central 
echocardiography reader do not confirm eligibility, then the subject must be discontinued 
from the study. 
During the run-in period, 2 safety visits and 2 safety phone calls will be performed. Visits 
3 and 3a (phone call) are performed 1 and 2 weeks (±2 days), respectively, after the start 
of the placebo run-in. Visits 5 and 5a (phone call) are performed 1 and 2 weeks (±2 days), 
respectively after the start of the macitentan run-in. A follow-up safety visit must be 
performed 30 (+5) days after intake of the last dose of study treatment, unless the subject 
transitions to the SERENADE OL study. 
The EOT visit only applies to randomized subjects. In case of premature discontinuation 
of study treatment, the EOT visit must take place as soon as possible and no later than 7 


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days after taking the decision to stop study treatment. Subjects who prematurely 
discontinue study treatment or withdraw consent from further participation in the study 
will not be replaced. 
7.1.1 Screening/re-screening 
Screening starts with the first screening assessment. The date of the first screening 
assessment corresponds to the date of the Screening visit. 
It is the responsibility of the investigator/delegate 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 and the investigator/delegate must sign the ICF prior to any 
study-related assessment or procedure. 
Subjects who are in Screening when the enrollment target has been met may still be 
randomized. 
It is permitted to re-screen subjects twice, if the reason for non-eligibility is transient 
(e.g., abnormal laboratory test, insufficient wash-out period of a forbidden medication). All 
screening assessments except pulmonary function tests (PFTs) must be repeated at the time 
of re-screening. If the screening echocardiography was done within 2 months of the 
re-screening visit, it does not need to be repeated.  
7.1.2 Unscheduled visits 
Unscheduled visits may be performed at any time during the study. Vital signs (BP and 
HR) and body weight will be measured at each unscheduled visit and recorded in the CRF. 
In addition, concomitant medications and AEs will be recorded, as applicable. Depending 
on the reason for the unscheduled visit (e.g., AE), appropriate assessments (including 
laboratory assessments as necessary) will be performed based on the judgment of the 
investigator and the results will be recorded in the CRF. After an unscheduled visit, the 
regular scheduled study visits must continue according to the planned visit and assessment 
schedule. 
7.1.3 EOT and EOS in case of transition to the SERENADE OL study 
The SERENADE OL enrollment visit is combined with Visit 11 (Week 24) or the EOT 
visit, and the EOS (safety follow-up) visit of the main study will not be performed.  
In case the EOT- and SERENADE OL enrollment visit cannot be combined, subjects will 
enter the safety follow-up period in the main study. In this scenario, the EOT visit of the 
main study and the SERENADE OL enrollment visit will be 2 separate visits. The 
transition to SERENADE OL occurs within 30 days of the intake of the last dose of 
double-blind study treatment, and the EOS visit will not be performed.  If transition within 


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30 days of intake of the last dose is not possible, then the EOS visit will be performed and 
eligible subjects may transition into SERENADE OL when feasible. 
For subjects in PTOP, the OL enrollment visit will be combined with the corresponding 
visit (EOS, PTOP 2 or PTOP4, as applicable). Results of assessments applicable to both 
EOT (or EOS, PTOP 2 or 4) and OL enrollment visits and corresponding actions, as 
applicable, must be reported in the CRF of the main study. 


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Table 1 
Visit and assessment schedule during the run-in period 
PERIODS 
SCREEN- 
ING 
SINGLE-BLIND RUN-IN 
Rando--
mization 2 
Placebo run-in 
Macitentan run-in 
Duration Up to 30 d 
4 w 
5 w 
VISITS1 
 
Number 
1 
2 
3 
3a  
4 
5 
5a  
6 
Time 
 
D1-R 
W1-R (±2 d) W-2R (±2 d) W4-R (±4 d) 
W5-R (±2 d) 
W6-R (±2 d) W9-R (±4 d) 
Informed consent 
X 
 
 
 
 
 
 
 
Eligibility 
X 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
Medical history 
X 
 
 
 
 
 
 
 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
X 
 
X 
X 
 
X 
Vital signs (BP, HR) 
X 
X 
X 
 
X 
X 
 
X 
Body weight, height4 
X 
X 
X 
 
X 
X 
 
X 
Home body weight monitoring5 
 
Daily 
PFTs6 
X 
 
 
 
 
 
 
 
12-lead ECG7 
X 
 
 
 
X 
 
 
X 
Echocardiography 
X 
 
 
 
 
 
 
 
RHC (optional) 
X 
 
 
 
 
 
 
 
Accelerometry 
 
X8 
X9 
 
 
X9 
 
 
NYHA FC 
X 
X 
X 
 
X 
X 
 
X 
WHF 
 
 
 
 
 
 
 
X 
PGA / KCCQ 
 
 
 
 
 
 
 
X 
Study trt dispensing 
 
X 
 
 
X 
X 
 
X 
SAEs/AEs10 
X 
X 
X 
X 
X 
X 
X 
X 
Signs indicative of a fluid retention /HF event11 
 
 
 
X 
 
 
X 
 
 


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1 Unscheduled visits may be performed at any time during the study. Body weight and vital signs (BP, HR) must be performed at each unscheduled visit. 
Other assessments are performed at the discretion of the investigator. 
2 Subjects who are not randomized (i.e., run-in failures) must perform a safety follow-up visit 30 (+5) days after intake of the last dose of study treatment. 
3 Run-in eligibility criteria defined in Section 4.5. 
4 Body weight is measured at each visit. Height is only measured at Screening.  
5 Subjects will be instructed to monitor their body weight at home on a daily basis during the run-in period, and to contact the study site if they notice any 
unusual weight increase (i.e., ≥ 2 kg / 4.4 lbs) after start of study treatment. 
6 Historical PFTs accepted if performed within 1 year prior to Screening and judged reliable by the investigator, provided the subject’s pulmonary status 
remained unchanged during this time. Only necessary for subjects with a known or suspected history of significant lung disease. 
7 ECGs are read locally only. 
8 Accelerometry will be performed from Visit 2 until Visit 3. 
9 Accelerometry will be performed during 9 days following the visit.  
10 All AEs and SAEs that occur after signing the Informed Consent Form and up to 30 days after study treatment discontinuation must be reported [see also 
Section 9].  
11 During the phone calls, the investigator must inquire about signs and symptoms that may be indicative of a fluid retention- or HF event. Outcome of the 
phone call may trigger unscheduled visits per investigator’s discretion. 
 
AE 
= 
adverse 
event; 
BP 
= 
blood 
pressure; 
D 
= 
Day; 
d 
= 
days; 
ECG 
= 
electrocardiogram; 
FC 
= 
functional 
class;  
HR = heart rate; KCCQ = Kansas City Cardiomyopathy Questionnaire; NYHA = New York Heart Association; PGA = patient’s global assessment;  
PFT = pulmonary function test; R = Run-in; RHC = right heart catheterization; SAE = serious adverse event; trt = treatment; W = Week; w = weeks; WHF = worsening 
heart failure. 
 


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Table 2 
Visit and assessment schedule during the double-blind treatment period 
PERIODS 
DOUBLE-BLIND TREATMENT  
FOLLOW-
UP  
Rando- 
mization 
Core phase 
Extension phase 
Duration 
24 w 
28 w 
30 d 
VISITS1 
 
Number 
6 
7 
8 
9 
10 
11 
 12 
13 (EOT) 8 
14 (EOS) 
Time 
D 1 
(±4 d) 
W1 
2  
(± 2 d) 
W4 
(± 4 
d) 
 W8  
(± 4 d) 
 W 16 
(± 8 d) 
W 24 
(± 8 d) 
W 36 
(± 8 d) 
W 52 
(± 8 d) 
30 (+5) d 
after last 
dose  
Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital signs (BP, HR) 
X 
 
X 
X 
X 
X 
X 
X 
X 
Body weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
Home body weight monitoring3 
Weekly 
 
12-lead ECG4 
X 
 
X 
 
X 
X 
 
X 
 
Echocardiography 
 
 
 
 
 
X 
 
X 
 
Accelerometry5 
 
 
X 
  
X 
X 
 
 
 
NYHA FC 
X 
 
X 
X 
X 
X 
X 
X 
X 
WHF 
X 
 
X 
X 
X 
X 
X 
X 
X 
PGA / KCCQ 
X 
 
 
X 
X 
X 
X 
X 
 
Study trt dispensing 
X 
 
X 
X 
X 
X 
X 
 
 
SAEs/AEs6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 Unscheduled visits may be performed at any time during the study. Body weight and vital signs (BP, HR) must be performed at each unscheduled visit. Other 
assessments are performed at the discretion of the investigator. 
2 Telephone call only. 
3 Subjects will be instructed to monitor their body weight at home on a weekly basis during the double-blind treatment period, and to contact the study site if they notice 
any unusual weight increase (i.e., ≥ 2 kg / 4.4 lbs) after start of study treatment. 
4 ECGs are read locally only. 
5 Accelerometry will be performed during 9 days following Visits 8 and 10.   
6 All AEs and SAEs that occur after signing the Informed Consent Form and up to 30 days after study treatment discontinuation must be reported [see also Section 9].  


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7 Under global protocol Version 6, accelerometry will be performed during the 9 days prior to Visit 11 (Week 24 visit).   
8  Subjects who have passed Week 24 at the time of approval of global protocol Version 6 will have their EOT visit within 60 days but no later than Week 52.  
 
AE = adverse event; BP = blood pressure; D = Day; d = days; ECG = electrocardiogram; EOS = end-of-study; EOT = end-of-treatment; FC = functional class;  
HR = heart rate; KCCQ = Kansas City Cardiomyopathy Questionnaire; NYHA = New York Heart Association; PGA = patient’s global assessment;  
PFT = pulmonary function test; R = Run-in; RHC = right heart catheterization; SAE = serious adverse event; trt = treatment; W = Week; w = weeks; WHF = worsening 
heart failure; V = Visit. 
 
 


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Table 3 
Laboratory assessments  
PERIODS 
SCREENING 
SINGLE-BLIND RUN-IN 
DOUBLE-BLIND TREATMENT  
FOLLOW
-UP  
Anytime 
 
Placebo run-
in 
Macitentan 
run-in 
Core phase 
Extension phase 
Duration 
Up to 30 d 
4 w 
5 w 
24 w 
28 w 
30 d 
NA 
VISITS 
 
Number 
1 
2 
3 
4 
5 
6 
8 
9 
10 
11 
 12 
13 (EOT) 8 14 (EOS) 
Fluid 
retention/ 
WHF event 
(any visit) 
Time 
 
D1-R W1-R 
(±2 d) 
W4-R 
(+/−4 d) 
W5-R 
(±2 d) 
W9-R 
/ D 1 
(±4 d) 
W4 
(± 4 
d) 
 W8,  
(± 4 
d) 
 W 16 
(± 8 
d) 
W 24 
(± 8 d) 
W 36 
(± 8 d) 
W 52 
(± 8 d) 
30 (+5) d 
after last 
dose  
Central laboratory 
tests1 
X2 
 
 
X 
 
X 
X 
X3 
X3 
X3 
X3 
X 
X 
 
Local laboratory 
test 
 
 
 
 
 
X4 
 
 
 
 
 
 
 
 
Serum Pregnancy 
test5 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urine Pregnancy 
test5 
 
 
 
 
 
 
 
W 12 W20 
 
W 28, 32, 
40, 44, 486 
 
 
 
NT-proBNP 
X 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
X 
MR-proANP 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
Biomarker 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X7 
Note: Table does not display phone calls. 
1 Hematology and clinical chemistry. 
2 Laboratory test at Screening must be performed in fasted state. Includes measurement of glucose, lipid profile and TSH levels. 
3 Monthly AST/ALT monitoring recommended. Local laboratory can be used. 
4 Hemoglobin to be measured locally at randomization to confirm run-in failure criteria not met. 
5 For women of childbearing potential only. 
6 Urine pregnancy test will be performed by the subject. The site will follow-up on the results with a telephone call. 
7 For patients who gave their consent for this blood sample only. To be drawn at the time of a fluid retention - or WHF event (any visit, including unscheduled, as 
applicable). 
8 Applicable to subjects who have completed Week 24 prior to global protocol Version 6 approval.  
 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; D = Day; d = days; EOS = end-of-study; EOT = end-of-treatment; MR-proANP = mid-regional pro-
atrial natriuretic peptide; NA = not applicable; NT-proBNP = n-terminal pro-brain natriuretic peptide; R = Run-in; TSH = thyroid stimulating hormone; W = Week; 
w = weeks; WHF = worsening heart failure; V = Visit. 


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Table 4 
Visit and assessment schedule for subjects entering the PTOP 
PERIODS 
Name 
POST-TREATMENT OBSERVATION PERIOD (PTOP) 
 
Duration 
Up to 52 Weeks 
VISITS 
Number 
PTOP1  
PTOP2 
PTOP37 
PTOP47 
 
Name 
Safety follow-up 
 
 
EOS 
 
Time 
30 (+5) d after last dose1 
Week 242 (±14 d)  
Week 362 (± 14 d) 
Week 522 (± 14 d) 
Concomitant therapy 
X 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
Vital signs (BP, HR) 
X 
X 
X 
X 
Body weight 
X 
X 
X 
X 
12-lead ECG 
 
X3 
 
X 
Echocardiography 
 
X 
 
X 
Central laboratory tests 
X4 
 
 
 
NT-proBNP / MR-proANP / Biomarker 
 
X 
 
X 
NYHA functional class 
X 
X 
X 
X 
WHF 
X 
X 
X 
X 
PGA 
 
X 
X 
X 
KCCQ 
 
X 
X 
X 
Accelerometry 
 
X6 
 
 
AEs 
X 
 
 
 
SAEs 
X 
X 
X 
X 
1 If the safety follow-up visit falls within the time-window any of the PTOP visits, the visits can be combined. 
2 From randomization. 
3 ECGs are read locally only. 
4 Hematology and clinical chemistry, including serum pregnancy test for women of childbearing potential. 
6  Under Global protocol Version 6, accelerometry will be performed during the 9 days prior to PTOP2 (Week 24). 
7  Subjects who have passed Week 24 at the time of approval of global protocol Version 6 will have their EOS visit within 60 days but no later than Week 52. 


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AE = adverse event; BP = blood pressure; d = days; ECG = electrocardiogram; EOS = end-of-study; HR = heart rate; KCCQ = Kansas City Cardiomyopathy Questionnaire; 
NT-proBNP 
= 
n-terminal 
pro-brain 
natriuretic 
peptide; 
NYHA 
= 
New 
York 
Heart 
Association; 
PGA 
= 
patient’s 
global 
assessment;  
PTOP = post-treatment observation period; SAE = serious adverse event; WHF = worsening heart failure. 


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7.2 Study assessments 
The study assessments are listed in Table 1 to Table 4. The assessments that are mandatory 
during a visit are marked with an ‘X’.  
All study assessments are performed by qualified study personnel (medical, nursing, or 
specialist technical personnel) and are recorded in the CRF, unless otherwise specified. 
Study assessments performed during unscheduled visits will also be recorded in the CRF. 
The following order of assessments (if applicable) is recommended:  
• KCCQ 
• Patient’s global assessment (PGA) 
• Physical examination (including assessment of AEs/SAEs), vital signs, NYHA FC 
• PFTs  
• ECG 
• Echocardiography 
• Blood sampling. 
If the Principal Investigator (PI) delegates any study procedure/assessment for a subject, 
e.g., ECG, echocardiography, blood sampling to an external facility, he/she should inform 
Actelion to whom these tasks are delegated. The set-up and oversight will be agreed upon 
with Actelion. The supervision of any external facilities remains the responsibility of the 
PI. 
Calibration certificates / evidence of equipment maintenance for the below-listed 
equipment used to perform study assessments must be available prior to the screening of 
the first subject. Calibration certificates of other equipment must be available as per local 
requirements. 
• 
Temperature measurement devices for study treatment storage area and freezer 
• 
Evidence of maintenance of echocardiography equipment 
• 
Body-weight scale.  
7.2.1 Demographics / baseline characteristics 
Demographic and baseline characteristic data to be collected on all subjects include: age, 
sex, race and ethnicity. Previous hospitalization for HF (including date of last 
hospitalization) and number of HF hospitalizations in previous year will be recorded in the 
CRF. 
Relevant medical history/current medical conditions (e.g., chronic and ongoing acute 
conditions, serious past conditions) present before signing informed consent will be 
recorded on the medical history page. Where possible, diagnoses and not symptoms will 
be recorded. 


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The following medical history will be captured in the CRF at Screening: 
• Date of most recent HF hospitalization  
• Number of HF hospitalizations within the last 12 months 
• Atrial fibrillation or flutter (if present, indicate whether paroxysmal, persistent or 
permanent) 
• Hypertension 
• Diabetes mellitus type 1 and 2 
• Chronic kidney disease 
• Chronic obstructive pulmonary disease (COPD) 
• Myocardial ischemia 
• Coronary artery disease 
• Sleep apnea 
• Anemia.  
The following signs/symptoms of special interest will be assessed at every visit as part of 
the physical examination: 
• Peripheral edema (defined as increased tissue fluid indicated by perceptible pitting 
indentation on lower leg, foot, or sacrum after palpation) 
• Pulmonary rales/crackles/crepitations 
• Abdominal distention or ascites (in the absence of primary hepatic disease) 
• S3 gallop 
• Nocturia 
• Orthopnea 
• Paroxysmal nocturnal dyspnea 
• Nocturnal cough 
• Jugular venous distention  
• Hepatojugular reflux. 
For subjects who failed Screening, the following data will be recorded in the CRF if 
available: 
• Date/Time of ICF signature 
• Demographics (age, sex, race and ethnicity) 
• Reason for screen failure and associated assessments, if applicable (e.g., PFT data 
in case exclusion criterion 12a is met). 


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7.2.2 Efficacy assessments 
7.2.2.1 NT-proBNP 
NT-proBNP is the primary endpoint of this study. NT-proBNP blood samples will be 
drawn using the central laboratory kit at the visits listed in Table 3 and Table 4. The 
presence of atrial fibrillation must be assessed with standard 12-lead ECGs on the day of 
NT-proBNP sampling, and recorded in the CRF. 
The subjects will be instructed to avoid high-sodium meals and to not modify their usual 
diet, if possible, within 3 days prior to their visit.  
Further details regarding collection, storage and shipment of the NT-proBNP blood 
samples are provided in the central laboratory manual.  
7.2.2.2 Accelerometry 
The physical activity (counts/min) of the subject is assessed via accelerometer. The 
accelerometer is given to the subject at Visit 2 (start of placebo run-in) and the subject will 
wear the device daily during waking hours until Visit 3. The period between Visits 2 and 
3 is considered to be a training period, and the data collected will only be used for analysis 
if data collected at Visit 3 are incomplete or missing. Subsequently, the subject is instructed 
to wear the accelerometer for 9 consecutive days during waking hours following Visit 3, 
Visit 5 (macitentan run-in safety visit), Visit 8 (Week 4), and Visit 10 (Week 16), as well 
as for 9 consecutive days during waking hours prior to Visit 11 (Week 24; see 
Section 3.1.1.8). This will allow for the inclusion of data during week days and weekend 
days and will provide a reliable estimate of the usual physical activity of the subject. Only 
data collected during these periods will be used for the analysis of physical activity. 
Subjects will receive a reminder from the site staff (e.g., telephone call, text message) to 
ensure that they are wearing the accelerometer during these periods. The subject will 
receive a reminder prior to Week 24 to ensure the device is charged and ready to be worn 
9 days prior to Week 24. The site will send the reminder to subjects to keep the device 
charged. The accelerometers are pre-programmed to minimize patient handling and do not 
display the collected data, i.e., the subjects do not have access to their activity 
measurements since this could influence their behavior. The investigator (or delegate) 
instructs subjects on how and when to wear the accelerometer (refer to the AC-055G202 
Accelerometry Manual). The subjects return the device to the study site and the investigator 
(or delegate) transfers the data to the accelerometry central lab as described in the 
AC-055G202 Accelerometry Manual.  
The central laboratory will read daily counts/min and will analyze duration of daytime 
activity and time (minutes) spent in sedentary, light, moderate, vigorous physical activity. 
These data are transferred to Actelion. 


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Accelerometer devices will be provided to the investigational site before the start of the 
study. 
7.2.2.3 Assessment of worsening heart failure event 
Occurrence of a WHF event will be assessed by the investigator using the 2015 ACC/AHA 
definition [ACC/AHA 2015, Appendix 4]. 
A WHF event includes HF death, hospitalization or an urgent visit for WHF and is defined 
as follows: 
HF death:  
Death associated with clinically worsening symptoms and/or signs of HF, regardless of HF 
etiology (note: deaths due to HF can have various etiologies, including single or recurrent 
myocardial infarctions [MIs], ischemic or non-ischemic cardiomyopathy, hypertension, or 
valvular disease). 
WHF hospitalization: 
• 
Subject is admitted to the hospital with a primary diagnosis of HF 
• 
Length of stay is at least 24 h (or extends over a calendar date) 
• 
Subject has A, B, and C [Table 2 and Table 4]. 
Urgent WHF visit: 
• 
Subject has an urgent, unscheduled office/practice or emergency department visit for 
a primary diagnosis of HF but is not admitted to the hospital 
• 
Subject has A, B, and C* [Table 2 and Table 4]. 
*changes to oral diuretic therapy only in case of addition of high potency thiazide diuretic 
(metolazone, indapamide), or ≥ 100% increase in loop diuretic to a total oral dose ≥ 120 
mg of furosemide equivalents/day. 


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Table 5 
WHF event definition 
A WHF event is defined as HF death, WHF hospitalization or urgent WHF visit (see definition above) and A, B and C 
A) New or worsening HF 
symptoms - At least one of 
the following symptoms must 
be new or have worsened: 
B) Objective evidence of WHF  
At least 2 new or worsening PE findings or 1 new or worsening PE 
finding and 1 new or worsening laboratory criterion 
C) Initiation or Intensification of 
Treatment specifically for HF  
Including at least 1 of the following 
• Dyspnea 
• Decreased exercise 
tolerance 
• Fatigue 
• Worsened end-organ 
perfusion 
• 
Kidney 
• 
Lung 
• 
Heart 
• 
Brain 
• 
Liver 
• Other symptoms of volume 
overload 
 
Physical examination (PE) findings: 
• Peripheral edema 
• Increasing abdominal distention or ascites (in the absence of 
primary hepatic disease 
• Pulmonary rales/crackles/crepitations 
• Increased jugular venous pressure and/or hepato-jugular reflux 
• S3 gallop 
• Clinically significant or rapid weight gain thought to be related to 
fluid retention 
New or worsened laboratory evidence of WHF; obtained within 
24 hours of presentation: 
• Increased BNP or NT-proBNP concentrations.   
• Radiological evidence of pulmonary congestion 
• Noninvasive diagnostic evidence of HF (echocardiography, cardiac 
MRI, cardiac PET scan, and nuclear imaging) 
• Invasive diagnostic evidence of HF (right-sided and/or left-sided 
heart catheterization) 
• Augmentation in oral diuretic therapy 
(increase in oral diuretic dose or addition 
of another oral diuretic) 
• I.v. diuretic or i.v. vasoactive therapy.  
o Vasoactive therapy may include an i.v. 
inotrope, vasodilator, or vasopressor. 
• Mechanical or surgical intervention, 
including: 
o Mechanical circulatory support (e.g., 
intra-aortic balloon pump, ventricular 
assist device, extracorporeal membrane 
oxygenation, total artificial heart). 
o Mechanical 
fluid 
removal 
(e.g., 
ultrafiltration, hemofiltration, dialysis). 
BNP = brain natriuretic peptide; HF = heart failure; i.v. = intravenous; MRI = magnetic resonance imaging; NT-proBNP = n-terminal pro-brain natriuretic peptide; 
PE = physical examination; PET = positron emission tomography; WHF = worsening heart failure. 


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7.2.2.4 Clinical composite outcome measure 
The variable related to this assessment will be derived by Actelion from the data reported 
for NYHA class and patient global assessment including death and HF hospitalization. The 
patient global assessment and the NYHA class are assessed as described below. The 
reporting of HF hospitalization is described in Appendix 6. 
7.2.2.4.1 Patient global assessment 
The PGA is a seven-point patient self-evaluation scale, which will be conducted at visits 
described in Table 2 and Table 4. At Visit 6 (randomization), the investigator/delegate will 
ask the subject how he/she feels about his/her condition at that time, and explains that 
he/she will be asked periodically to rate how he/she feels compared to this point in the 
study. Subsequently, subjects will be asked to rate how well they feel compared to Visit 6 
(randomization/baseline); i.e., by indicating whether their clinical status has markedly, 
moderately or slightly improved, remained unchanged, or had slightly, moderately or 
markedly worsened since the start of the double-blind treatment period at Visit 6.  
7.2.2.4.2 NYHA FC 
The NYHA FC is one of the most reliable instruments for rating HF subjects’ functionality. 
NYHA FC is evaluated at all scheduled visits. 
NYHA class Symptoms 
I 
No symptoms and no limitation in ordinary physical activity, e.g., 
shortness of breath when walking, climbing stairs, etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight 
limitation during ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during 
less-than ordinary activity, e.g., walking short distances (20–100 m). 
Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients. 
7.2.2.5 Echocardiography 
Standard 2D/Doppler echocardiography is performed at the visits listed in Table 1, Table 2, 
and Table 4. 
All echocardiographies will be submitted to a central echocardiography laboratory for 
evaluation of echocardiographic parameters outlined in the echocardiography imaging 
manual.  


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All echocardiographic parameters will be read centrally by the echocardiography 
laboratory and will be transferred electronically to Actelion’s clinical database.  
The LVEF, LA enlargement parameters, LV septal/posterior wall thickness, parameters of 
RV dysfunction (see inclusion criterion 9) measured centrally at Screening will determine 
the subject’s eligibility to enter the study. If the results from the central reader cannot be 
awaited for logistical reasons and the locally read echocardiographic parameters meet the 
eligibility requirements, the subject may start the placebo run-in. However, if the locally-
read results are not confirmed by the central reading results when they become available, 
the subject must be discontinued from the study as soon as possible as long as he/she is 
still in run-in. All efforts must be made to confirm eligibility before the subject enters the 
macitentan run-in. 
If the quality of the echocardiography does not allow assessment of critical measurements 
(i.e., measurements listed in inclusion criteria 4, 7 and 9, septal E/e’ ratio, lateral e’ 
velocity, septal e’ velocity), it may be repeated during Screening or placebo-run-in (if the 
subject entered run-in at risk).  
All echocardiography assessments performed for the study must be reviewed by the 
investigator or delegate, and appropriate action must be taken in the event of safety-related 
findings (e.g., reporting the finding in the medical history or as an AE). Incidental findings 
unrelated to HF identified by central reading will be communicated to the investigator who 
is responsible for taking appropriate action. Subjects with clinically relevant 
echocardiographic findings unrelated to HF will be followed up until the final diagnosis is 
established and managed as per local medical practice. Detailed instructions on how to 
perform echocardiography and how to transfer data to the central echocardiography 
laboratory are provided in a separate manual.  
7.2.2.6 Right heart catheterization 
In order to establish the diagnosis of pulmonary vascular disease, a RHC may be performed 
during the Screening period, if deemed necessary by the investigator. Local guidelines will 
be followed.  
7.2.3 Safety assessments 
The definitions, reporting and follow-up of AEs, SAEs and pregnancies are described in 
Section 9. 
7.2.3.1 Safety phone calls during the run-in period 
A safety phone call will be performed 2 weeks after the start of each run-in period (i.e., 
Run-in Weeks 2 and 6). During this phone call, the investigator or delegate will ask the 
subject if he/she experienced any signs and symptoms (e.g., increase in body weight, 
presence of extra fluid in the body, swelling of legs, feet and ankles, increase in dyspnea 


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or difficulties in breathing, or increase in exercise intolerance and other cardiac symptoms 
[chest pain, palpitations]) that could be indicative of fluid retention or heart failure 
worsening. If any new signs or symptoms are reported by the subject, or if a body weight 
increase ≥ 2 kg / 4.4 lbs is noted, it is recommended to perform an unscheduled visit to do 
a medical assessment.  
7.2.3.2 Physical examination 
Physical examination at Screening and EOT includes the examination of the general 
appearance, heart, lungs, abdomen, skin, extremities/peripheral vascular assessment, eyes, 
ears, nose, throat, neck (including thyroid), and lymph nodes. At interim visits, a more 
focused/shorter physical exam will include the examination of general appearance, heart, 
lungs, abdomen and extremities. If indicated, based on medical history and/or symptoms, 
additional exams may be performed as per investigator’s discretion. 
It is recommended that evidence of pulmonary congestion is sought if clinically indicated 
(e.g., chest X-ray, pulmonary ultrasound). 
Information for all physical examinations must be included in the source documentation at 
the study site. The observations should be reported according to body system in the CRF 
as either normal or abnormal. If an abnormality is found it should be specified on the 
corresponding CRF page (except for abnormalities already reported on the specific 
signs/symptoms form), describing the signs related to the abnormality (e.g., fever) and not 
the diagnosis (e.g., pneumonia). Clinically relevant findings (other than those related to left 
HF and RVD) that are present prior to signing of informed consent must be recorded on 
the Medical History CRF form. Significant physical examination findings made after 
signing of informed consent, which meet the definition of an AE [Section 9.1.1], must be 
recorded on the AE form of the CRF. 
7.2.3.3 Vital signs 
Vital signs are measured at all visits. Triplicate SBP and DBP and radial pulse 
measurements will be measured in a supine or sitting position. It is recommended to allow 
the subject to rest for at least 5 minutes prior to the first reading, to perform the triplicate 
measurements at least 2 minutes apart, and to use the same device, same position (supine 
or sitting), same arm, same operator and appropriate cuff size throughout the study for an 
individual subject. 
7.2.3.4 Weight and height 
Height will be measured at Screening for BMI calculations. Body weight will be measured 
at the site at all visits. It is recommended to always weigh individual subject under similar 
conditions, i.e., indoor clothing without shoes, same scale, similar interval between 
weighing and last meal. 


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7.2.3.5 Home body weight monitoring 
Subjects will be instructed to monitor their body weight at home on a daily basis during 
the entire run-in period and on a weekly basis during the double-blind treatment period, 
and to contact the study site if they notice a weight increase of ≥ 2 kg / 4.4 lbs after the 
start of treatment. It is recommended that the subjects always weigh themselves under 
similar conditions, e.g., every morning before breakfast. The subjects will receive a weight 
card on which body weight measurements can be recorded manually and must be instructed 
to bring the card along at each visit.  
7.2.3.6 Pulmonary function tests 
Post-bronchodilator PFTs (FEV1 and FVC) will be performed at Screening for subjects 
with a known or suspected history of significant lung disease. Historical PFT data obtained 
within 12 months prior to Screening are accepted, provided there is evidence in the source 
documentation that the subject’s pulmonary status has been stable/unchanged during this 
time and the results are considered to be reliable by the investigator.  
Predicted normal values for FEV1 and FVC will be used to determine eligibility.  
Measured FEV1 and FVC values (including historical) will be collected in the CRF. 
Calculated FEV1/FVC and FEV1 % of predicted value used by the site to assess subjects’ 
eligibility will also be collected in the CRF.  
7.2.3.7 ECG assessment 
A standard 12-lead ECG is performed as indicated in Table 1, Table 2, and Table 4. 
The ECG will be interpreted locally, and the presence of atrial fibrillation or atrial flutter 
(i.e., atrial fibrillation, atrial flutter or sinus rhythm) will be recorded in the CRF. 
7.2.4 Laboratory assessments 
7.2.4.1 Type of laboratory 
Hematology and chemistry tests will be performed at the visits indicated in Table 3 and 
Table 4. Monthly AST/ALT monitoring is recommended.  
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.  
If monthly AST/ALT monitoring in between visits is performed, a local laboratory can be 
used. If the local laboratory results show an increase in AST/ALT ≥ 3 × ULN, the subject 
must return to the site and the AST/ALT re-test must be performed centrally. 


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If the results from the central laboratory sample drawn at Screening are not available at the 
time of starting the placebo run-in phase, an additional blood sample may be drawn to 
verify eligibility based on a local laboratory test. The local laboratory results (with the 
corresponding normal ranges) must be recorded in the CRF. 
At randomization, hemoglobin (run-in failure criterion, see Section 4.5) will be assessed 
locally to confirm eligibility of the subject. 
Other exceptional circumstances that will require recording of local laboratory results of 
the parameters listed in Section 7.2.4.2 (with corresponding normal ranges) include 
hospitalization of the subject due to a medical emergency and missing central laboratory 
results from a scheduled or unscheduled visit. 
If two or more consecutive central laboratory samples are lost 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 personnel and the 
concerned site personnel. Alert flags that will trigger such notifications are displayed in 
Appendix 2. 
All laboratory reports must be reviewed, signed and dated by the investigator or delegate 
within 10 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 signing of informed consent must be recorded on the Medical History page 
of the CRF. Any clinically relevant laboratory abnormalities detected after signing of 
informed consent must be reported as an AE or SAE as appropriate [see Section 9], 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. 
Details about the collection, sampling, storage, shipment procedures, and reporting of 
results and abnormal findings can be found in the laboratory manual. 
7.2.4.2 Laboratory tests 
At Screening, the laboratory tests will be performed in fasted state in order to characterize 
the subjects in terms of their glucose levels and lipid profiles. At subsequent visits, the 
subjects do not need to be fasted prior to the laboratory tests.  
The amount of blood collected during the study from an individual subject is approximately 
150 mL (10 mL for hematology/clinical chemistry, including pregnancy test, if applicable; 


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3 mL for NT-proBNP, 3 mL for MR-proANP and 3 mL for the biomarker sample). For 
details, please refer to the laboratory manual.  
Hematology 
• Hemoglobin (SI Unit: g/L; Conventional unit: g/dL) 
• Hematocrit (SI Unit: L/L; Conventional unit: %) 
• Erythrocyte count (reticulocyte count) (SI Unit: 1012/L; Conventional unit: 
106/μL) 
• Leukocyte count with differential counts (SI Unit: 109/L; Conventional unit: 
103/μL) 
• Platelet count (SI Unit: 109/L; Conventional unit: 103/μL) 
Clinical chemistry 
• ALT (U/L) 
• AST (U/L) 
• Alkaline phosphatase (U/L) 
• Total and direct bilirubin (SI unit: μmol/L; Conventional unit: mg/dL) 
• Creatinine (SI unit: μmol/L; Conventional unit: mg/dL) 
• Blood urea nitrogen, BUN (SI unit: mmol/L; Conventional unit: mg/dL) 
• Uric acid (SI unit: μmol/L; Conventional unit: mg/dL) 
• Glucose (SI unit: mmol/L; Conventional unit: mg/dL)14 
• Thyroid stimulating hormone, TSH (SI unit: mIU/L; Conventional unit: 
μIU/mL) 14 
• T3, T414 
• Lipid profile (SI unit: μmol/L; Conventional unit: mg/dL) 14: 
o low-density lipoprotein (LDL) cholesterol 
o high-density lipoprotein (HDL) cholesterol 
o very low-density lipoprotein (VLDL) cholesterol 
o total cholesterol  
o triglycerides  
• Sodium, potassium, chloride, calcium, magnesium (mmol/L) 
• Total protein, albumin (SI unit: g/L; conventional unit: g/L) 
• Albumin / Globulins ratio 
• GFR (mL/min/1.73m2), using the MDRD formula 
Cardiac biomarkers 
• MR-proANP 
 
14 Only measured at Screening; screening labs are measured in fasted state. 
 


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Pregnancy test 
A serum pregnancy test for women of childbearing potential will be performed at Visits 1 
(Screening), 4, and 6 (Randomization) and at all regular post-randomization visits  
[Table 3]. During the double-blind treatment period, women of childbearing potential must 
perform urine pregnancy tests at home in between visits at Weeks 12, 20, 28, 32, 40, 44, 
and 48 in addition to the serum pregnancy test during site visits. The subjects will be 
provided with validated urine pregnancy tests kits by the site. The investigator/delegate 
will follow-up on the results of the urine pregnancy test with a telephone call and records 
the result of the test in the CRF. If pregnancy is suspected during the study, a serum 
pregnancy test must be performed immediately. 
7.2.5 Quality of life assessments 
The KCCQ will be completed at the visits indicated in Table 1, Table 2, and Table 4. It is 
recommended that the KCCQ be completed prior to any other clinical assessment or 
interaction with site staff to avoid potential bias in the subject’s responses.  
The KCCQ is a 23-item, self-administered instrument that quantifies physical function, 
symptoms (frequency, severity and recent change), social function, self-efficacy and 
knowledge, and quality of life. On average, it requires 4–6 minutes to complete.  
The KCCQ is available in a number of validated translations. The questionnaire will not 
be administered if it is not available in a language that can easily be understood by the 
subject. The paper questionnaire completed by the subject is considered to be the source 
document. The data from the paper questionnaire will be manually entered in the CRF by 
site staff.  
Actelion Pharmaceuticals Ltd has been granted a license agreement for the use of the 
KCCQ. 
7.2.6 Biomarkers 
A blood sample for analysis of additional exploratory protein biomarkers related to 
modulation of heart function and target engagement and markers which are important for 
the regulation of the fluid status will be collected from subjects who gave their consent for 
this blood sample. 
The biomarker analysis will be performed after study closure and will not be included in 
the study report. The aim of this analysis is to investigate the effect of macitentan on 
proteins involved in the pathophysiology of HFpEF and pulmonary vascular disease, and 
to gain a better understanding of the mechanism by which ERAs contribute to fluid 
retention. Such markers may include, but are not limited to, galectin-3, co-peptin and 
biomarkers related to the renin-angiotensin system (additional biomarkers may be included 
in the analysis, if scientific rationale has become available through new research). 


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The biomarker blood samples will be drawn using the central laboratory kit at the 
timepoints indicated in Table 3, as well as at the time of a fluid retention - or WHF event. 
This includes fluid retention15- or WHF events16 detected at regular or unscheduled study 
visits at the site. 
Blood sampling procedures, storage and shipment of the biomarker samples are described 
in the central laboratory manual. The biomarker samples will be transferred to an Actelion 
designated biobank when the study is closed and may be stored there for a maximum of 
15 years. Subjects may request that these samples be destroyed at any time during or after 
the study. 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / 
MEDICAL CARE 
8.1 Study completion as per protocol  
A subject who completes 52 weeks of follow-up (± time-window indicated in Table 2 or 
Table 4) including the safety follow-up period is considered to have completed the study 
as per protocol, regardless of whether he/she has completed the double-blind treatment 
period as per protocol. Subjects who die are considered to have completed the study.  
8.2 Premature withdrawal from study  
Subjects may voluntarily withdraw from the study without justification 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 (i.e., withdrawal of consent), die, or are lost to 
follow-up. If a subject withdraws consent, no further data will be collected in the CRF from 
the date of withdrawal onward. The investigator may withdraw a subject from the study 
(without regard to the subject’s consent) if, on balance, he/she believes 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. 
Subjects are considered as lost to follow-up if all reasonable attempts by the investigator 
to communicate with the individual failed. The site must take preventive measures to avoid 
a subject being lost to follow-up (e.g., document different ways of contact such as 
telephone number, home address, email address, person to be contacted in case the subject 
cannot be reached). If the subject cannot be reached, the site must make a reasonable effort 
to contact the subject, document all attempts, and enter the loss of follow-up information 
into the CRF. The following methods must be used: at least three telephone calls must be 
placed to the last available telephone number and one registered letter must be sent by post 
 
15 A fluid retention event refers to an AE related to edema or fluid overload. 
16 See definition in Section 7.2.2.3. 


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to the last available home address. Additional methods may be acceptable if they are 
compliant with local rules/regulations (e.g., a visit by site personnel 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 (if known) for premature 
withdrawal from the study, along with who made the decision (subject, investigator, or 
Actelion personnel) must be recorded in the CRF, if known. 
If for whatever reason (except death or loss-to-follow-up) a subject is withdrawn from the 
study, the investigator should make efforts to schedule a last appointment / telephone call 
to assess the safety and well-being of the subject, collect unused study treatment and 
discuss follow-up medical care. Data obtained during this last appointment / telephone call 
will be recorded in the subjects’ medical records but it will not be collected in the CRF. 
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 8.4. 
8.3 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 the study is prematurely suspended or terminated, Actelion will promptly inform the 
investigators, the IECs/IRBs, and health authorities, as appropriate, and provide the reasons 
for the suspension or termination. 
If the study is suspended or prematurely terminated for any reason, the investigator – in 
agreement with Actelion – must promptly inform all enrolled subjects and ensure their 
appropriate treatment and follow-up, as described in Section 8.4. 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 the study without prior agreement 
from Actelion, the investigator must promptly inform Actelion personnel and the IEC/IRB, 
and provide both with a detailed written explanation of the termination or suspension. 
If the IEC/IRB suspends or terminates its approval / favorable opinion of the study, the 
investigator must promptly notify Actelion personnel 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. 


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8.4 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.  
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
9.1 Adverse events 
9.1.1 Definition of adverse events 
An AE is any untoward medical occurrence, i.e., any unfavorable and unintended sign, 
including an abnormal laboratory finding, symptom, or disease that occurs in a subject 
during the course of the study, whether or not considered by the investigator as related to 
study treatment. 
A treatment-emergent AE is any AE temporally associated with the use of study treatment 
(from study treatment initiation until 30 days after study treatment discontinuation) 
whether or not considered by the investigator as related to study treatment. 
AEs include: 
• Exacerbation of a pre-existing disease. 
• Increase in frequency or intensity of a pre-existing episodic disease or medical 
condition. 
• Disease or medical condition detected or diagnosed during the course of the study 
even though it may have been present prior to the start of the study. 
• Continuous persistent disease or symptoms present at study start that worsen 
following the 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. 
Overdose, misuse, abuse of the study treatment and study treatment errors will be reported 
as an AE. 
9.1.2 Intensity of adverse events  
The intensity of clinical AEs is graded on a three-point scale – mild, moderate, severe – 
and is reported on specific AE pages of the CRF. 


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If the intensity of an AE worsens within a study period, the worst intensity should be 
reported on the AE page. If the AE lessens in intensity, no change in the severity is required 
to be reported. If there is a worsening in intensity occurring during a subsequent study 
period (i.e., placebo run-in, macitentan run-in or double-blind treatment period), this must 
be reported in the CRF. 
The three categories of intensity are defined as follows: 
 Mild 
The event may be noticeable to the subject. It does not usually influence daily activities, 
and normally does not require intervention. 
 Moderate 
The event may make the subject uncomfortable. Performance of daily activities may be 
influenced, and intervention may be needed. 
 Severe 
The event may cause noticeable discomfort and usually interferes with daily activities. The 
subject may not be able to continue in the study, and treatment or intervention is usually 
needed. 
A mild, moderate, or severe AE may or may not be serious [see Section 9.2.1]. 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 intensity assessment, determines the regulatory reporting 
obligations. 
9.1.3 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 the investigator. 
9.1.4 Reporting of adverse events  
All AEs with an onset date after signing of informed consent and up to 30 days after study 
treatment discontinuation must be recorded on specific AE pages of the CRF. 
9.1.5 Follow-up of adverse events  
AEs still ongoing more than 30 days after study treatment discontinuation must be followed 
up until they are no longer considered clinically relevant or until stabilization. The 


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follow-up information obtained after the subject’s EOS visit will not be collected by 
Actelion. 
9.2 Serious adverse events  
9.2.1 Definitions of 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 in-patient 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 not considered as SAEs: 
• 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 (e.g., if a 
complication prolongs hospitalization). 
9.2.2 Reporting of serious adverse events 
All SAEs occurring after signing of informed consent up to 30 days after study treatment 
discontinuation must be reported on AE pages in the CRF and on an SAE form, regardless 
of the investigator-attributed causal relationship with study treatment or study-mandated 
procedures. 
An SAE is defined as related to protocol-mandated procedures if it appears to have a 
reasonable possibility of a causal relationship to either the study design or to 


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protocol-mandated procedures (e.g., discontinuation of a subject’s previous treatment 
during a washout period, leading to exacerbation of underlying disease). 
9.2.3 Follow-up of serious adverse events 
SAEs still ongoing more than 30 days after study treatment discontinuation must be 
followed up until resolution or stabilization, or until the event outcome is provided. The 
follow-up information obtained after the subject’s EOS visit must be reported to Actelion 
Global Drug Safety, but it is not recorded in the CRF. 
9.2.4 After the 30-day follow-up period 
New SAEs occurring after the 30-day follow-up period must be reported to Actelion Global 
Drug Safety within 24 hours 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. 
9.2.5 Reporting and follow-up of SAEs during the PTOP 
All SAEs, regardless of investigator-attributed causal relationship, that occur during the 
PTOP period must be reported on AE pages in the CRF and on an SAE form. 
These SAEs must be followed up until resolution or stabilization, or until the event 
outcome is provided. The follow-up information obtained after the end of the PTOP must 
be reported to Actelion Global Drug Safety, but it is not recorded in the CRF. 
New SAEs occurring after the end of the PTOP must be reported to Actelion Global Drug 
Safety within 24 hours 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. 
9.2.6 Reporting procedures 
All SAEs must be reported by the investigator to Actelion Global Drug Safety within 
24 hours of the investigator’s first knowledge of the event. 
All SAEs must be recorded on an SAE form, irrespective of the study treatment received 
by the subject, and whether or not this event is considered by the investigator to be related 
to study treatment. 
The SAE forms must be sent to Actelion Global Drug Safety (contact details are provided 
on the SAE form). The investigator must complete the SAE form in English, and must 
assess the event’s causal relationship to the study treatment. 
Any relevant information from source documents regarding the SAE, e.g., hospital notes 
or discharge summaries, etc., must be summarized on the SAE form. 


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Follow-up information about a previously reported SAE must also be reported within 
24 hours of receiving it. Actelion Global Drug Safety personnel 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 expectedness of an adverse reaction is determined by Actelion in the reference safety 
information (RSI) section provided in the most recent version of the IB. Any SAE that is 
assessed as related and unexpected against the RSI is known as a SUSAR and must be 
reported by Actelion to concerned health authorities (including the EudraVigilance 
database if the study is conducted in Europe), IECs/IRBs and investigators. 
9.3 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. 
9.3.1 Reporting of pregnancy 
Irrespective of the treatment received by the subject, any pregnancy occurring after study 
start (i.e., signing of informed consent) up to 30 days following study treatment 
discontinuation must be reported within 24 hours of the investigator’s knowledge of the 
event. 
Pregnancies must be reported on the Actelion Pregnancy form, which is faxed to Actelion 
Global Drug Safety (see contact details provided on the Pregnancy form), and on an AE 
page in the CRF. 
9.3.2 Follow-up of pregnancy 
Any pregnancies must be followed up to their conclusion and the outcome must be reported 
to Actelion Global Drug Safety. 
Any AE associated with the pregnancy occurring during the follow-up period after study 
treatment discontinuation must be reported on separate AE pages in the CRF. Any SAE 
occurring during the pregnancy must be reported on an SAE form as described in 
Section 9.2.2. 
9.4 Study safety monitoring  
Study safety information (AEs, SAEs, laboratory values, ECGs, vital signs, and 
study-specific 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 


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quality). In addition, an IDMC is monitoring safety data [see Section 3.3]. Actelion may 
request additional anonymized data pertaining to the diagnostic work-up of an AE or SAE 
(e.g., ECGs, medical imaging, local laboratory values) for the purpose of safety 
monitoring. Such additional data may be shared with external experts.  
10 STATISTICAL METHODS 
All statistical analyses will be conducted by Actelion or by designated CROs supervised 
by Actelion. 
A Statistical Analysis Plan will provide full details of the analyses, data displays, and 
algorithms to be used for data derivations. 
10.1 Analysis sets 
10.1.1 Screened Analysis Set 
The Screened Analysis Set includes all subjects who are screened and have a subject 
number. 
10.1.2 Placebo run-in Set 
The placebo run-in Set includes all screened subjects who enter the placebo run-in and 
receive at least one dose of study treatment in the single-blind placebo run-in. 
10.1.3 Macitentan run-in Set 
The macitentan run-in Set includes all subjects who have completed the placebo run-in, 
enter the macitentan run-in and receive at least one dose of study treatment in the single-
blind macitentan run-in. 
10.1.4 Full Analysis Set 
The Full Analysis Set (FAS) includes all subjects randomized to double-blind study 
treatment. In order to adhere to the intention-to-treat principle as much as possible: 
• Subjects are evaluated according to the study treatment they have been assigned 
to (which may be different from the study treatment they have received), 
• All available data are taken into account. 
10.1.5 Per-protocol Analysis Set 
The Per-protocol Analysis Set (PPS) comprises all randomized subjects who received 
double-blind study treatment and who complied with the protocol sufficiently to allow 
reliable assessment of the treatment effect on the primary efficacy endpoint. Subjects are 
evaluated according to the study treatment they have been assigned to. 
Criteria for exclusion include: 


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• Insufficient compliance or exposure to study drug, 
• Non-protocol compliant assessment of NT-proBNP at baseline or at Week 24, 
• Presence of any protocol deviation questioning the diagnosis of the studied disease. 
10.1.6 Safety Set 
The Safety Set includes all subjects who received at least one dose of double-blind study 
treatment. Subjects are evaluated according to the study treatment they actually received. 
10.1.7 Sub-study Analysis Set 
The Sub-study Analysis Set (SAS) includes all subjects randomized to double-blind study 
treatment and enrolled into the sub-study (under global protocol Version 5). 
10.1.8 Usage of the analysis sets  
The FAS is used for the analyses of all the efficacy variables as well as for the description 
of the study population at baseline [see Section 10.3.1 for baseline definition]. Unless 
specified otherwise, individual listings are prepared on the FAS. 
The PPS is used to perform specific sensitivity analysis on the primary efficacy variable. 
The Safety Set is used for the analyses of the safety variables.  
The Screened Analysis Set is used for the description of subject disposition.  
The placebo run-in Set is used to document the reasons leading to discontinuation of 
placebo run-in. 
The macitentan run-in Set is used to document the reasons leading to discontinuation of 
macitentan run-in. 
The Sub-study Analysis Set is used for presenting listings and descriptive summaries of 
the sub-study data (6-minute walk test and Borg Dyspnea Index). Details of the analyses 
will be described in the SAP.  
10.2 Variables 
All variables described thereafter are related to the endpoints defined in Section 6. 
10.2.1 Primary efficacy variable(s) 
The primary efficacy variable described here below is related to the primary efficacy 
endpoint described in Section 6.1.1. 
The primary efficacy variable is the percent of baseline [see Section 10.3.1 for baseline 
definition] in NT-proBNP at Week 24. 


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For subjects without an available NT-proBNP value at Week 24, the last available value 
observed before Week 24 will be carried forward and considered for the main analysis. 
Percent of baseline is calculated as the ratio of the Week 24 NT-proBNP value over 
baseline value, expressed in percentage. 
10.2.2 Key secondary efficacy variables 
Key secondary efficacy variables described here below are related to the key secondary 
efficacy endpoints described in Section 6.1.2. 
10.2.2.1 Quality of life at Week 24 
The first key secondary efficacy variable is the clinical summary score derived from the 
KCCQ, expressed as change from baseline to Week 24. 
For subjects deceased before Week 24, the scores will be set to 0. 
10.2.2.2 Accelerometer-assessed physical activity at Week 24 
The second key secondary efficacy variable is the proportion of time spent in light to 
vigorous physical activity based on a threshold of > 100 activity counts per minute, 
expressed as change from Baseline to Week 24.  
To be considered evaluable, physical activity should have been measured for at least 
4 complete days at a specific time point of assessment. A complete day is defined as a 
record of at least 7 hours of data (after excluding the periods when the device was 
apparently not worn). These limitations allow for obtaining reliable results 
[Robertson 2011]. 
10.2.2.3 Time to first occurrence of worsening of heart failure event over 52 weeks 
The third key secondary efficacy variable is the time to first occurrence of WHF event. 
All worsening of heart failure events occurring until EOS / open-label enrollment (OLE) 
are considered, irrespective of subjects compliance to assigned therapies. 
Subjects without any worsening of heart failure event up to EOS / OLE are right-censored 
at their time of EOS or OLE. 
Time to first occurrence of WHF event is expressed in days and calculated as the onset date 
of the first WHF event minus date of randomization plus 1 or, for censored subjects, as 
OLE / EOS date minus date of randomization plus 1. 
Prior to global protocol Version 6 subjects were followed up to Week 52 (except where 
subjects prematurely discontinue study). Under global protocol Version 6, subjects are 
followed up to at least Week 24. For the time to first occurrence of WHF event, all events 


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up to the EOS / OLE for each subject are considered, regardless of their duration of follow-
up. 
10.2.3 Other efficacy variables 
This section contains definitions of the variables related to the other efficacy endpoints 
outlined in Section 6.1.3. 
10.2.3.1 Number of days alive and out of the hospital 
The number of DAOH is calculated for each subject based on total expected follow-up 
time, days in hospital and days dead as follows: 
The total expected follow-up time is determined as the number of days from randomization 
until the OLE / EOS date (for alive subjects) or until the randomization date plus 52 weeks 
(or plus 24 weeks [see Section 3.1.1.8]) for subjects who die during the study.  
The days in hospital are obtained by adding the durations of each individual hospital stay. 
The days dead are calculated for subjects who die during the study as the number of days 
from their death to the end of the expected follow-up (randomization date plus 52 weeks 
[or 24 weeks; see Section 3.1.1.8]). 
Days in hospital and days dead are then subtracted from total expected follow-up time to 
derive DAOH for each subject.  
The percentage of DAOH (%DAOH) is also calculated for each subject by dividing DAOH 
by total potential follow-up time. 
10.2.3.2 Time to first occurrence of HF death or HF hospitalization over 52 weeks 
The variable of interest is the time to first occurrence of HF death or HF hospitalization 
based on investigator assessment. 
All HF hospitalizations and HF deaths occurring until OLE / EOS are considered, 
irrespective of subjects compliance to assigned therapies. 
Subjects still alive at OLE / EOS and without any HF hospitalizations up to OLE / EOS 
are right-censored at their time of OLE / EOS. 
Time to first occurrence of HF death or HF hospitalization is expressed in days and 
calculated as the onset date of the first HF death or HF hospitalization minus date of 
randomization plus 1 or, for censored subjects, as OLE / EOS date minus date of 
randomization plus 1. 


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10.2.3.3 Time to first occurrence of CV death or CV hospitalization over 52 weeks 
The variable of interest is the time to first occurrence of CV death or CV hospitalization 
based on investigator assessment. 
All CV hospitalizations and CV deaths occurring until OLE / EOS are considered, 
irrespective of subjects compliance to assigned therapies. 
Subjects still alive at OLE / EOS and without any CV hospitalizations up to OLE / EOS 
are right-censored at their time of OLE / EOS. 
Time to first occurrence of CV death or CV hospitalization is expressed in days and 
calculated as the onset date of the first CV death or CV hospitalization minus date of 
randomization plus 1 or, for censored subjects, as OLE / EOS date minus date of 
randomization plus 1. 
10.2.3.4 Number of HF hospital admissions over 52 weeks 
The total number of recurrent HF hospitalizations is considered for each subject, based on 
investigator assessment. 
All hospitalizations occurring until OLE / EOS are considered, irrespective of subjects 
compliance to assigned therapies. 
Subjects who do not experience any HF hospitalization before OLE / EOS will be 
considered as having 0 HF hospitalization. 
10.2.3.5 NYHA FC (improved/worsened/stable) at each post-baseline assessment 
It is the NYHA FC value categorized as improved, worsened or stable at every 
post-baseline assessment. 
An improvement corresponds to a decrease in NYHA class by at least one level whereas a 
worsening corresponds to an increase in NYHA class by at least one level. Subjects 
remaining in the same NYHA class as the one reported at baseline are categorized as stable. 
The proportion of subjects in each category is calculated at each post-baseline assessment 
based on the number of subjects with non-missing data (i.e., those having a reported value 
of I through IV). 
10.2.3.6 Clinical composite outcome (‘worsened’, ‘unchanged’, ‘improved’)  
The clinical composite outcome measure provides an overall evaluation of whether a 
subject’s condition is considered to have improved, worsened, or unchanged after a 
pre-specified period of time defined as follows [Packer 2001]: 


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• Improved: experienced a favorable change in NYHA class or in the patient global 
assessment by at least one class from the baseline but did not experience death or HF 
hospitalization during the planned duration of treatment. 
• Worsened: experienced death or HF hospitalization during the planned duration of 
treatment or reported worsening of their NYHA class or patient global assessment by 
at least one class compared to baseline. 
• Unchanged: neither improved nor worsened compared to baseline. 
The clinical composite outcome will be calculated and described for the different following 
periods of time: 
• Over 8 weeks 
• Over 16 weeks 
• Over 24 weeks 
• Over 36 weeks 
• Over 52 weeks 
For a given period, only the deaths and hospitalizations occurring during the studied period 
will be taken into account in the clinical composite outcome calculation. Similarly, the last 
non-missing NYHA and PGA assessments performed before or at the end of the studied 
period will be considered. 
10.2.3.7 Quality of life scores over time 
The KCCQ is used and the quality of life variables of interest are: 
• Overall summary score 
• Clinical summary score  
• Physical limitations score 
Longitudinally collected over time and expressed as changes from baseline. 
For deceased subjects during the study, the scores will be set to 0 after death date. 
10.2.3.8 Percent of baseline in NT-proBNP over time 
The variable of interest is NT-proBNP collected longitudinally over time and expressed as 
percent of baseline. 
10.2.3.9 Percent of baseline in MR-proANP at Week 24 and over time 
The variable of interest is MR-proANP collected longitudinally over time and expressed 
as percent of baseline. 


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10.2.3.10 Change from baseline in accelerometer-assessed physical activity over time 
The other accelerometer variables of interest are:  
− Proportion of time spent in light to vigorous physical activity based on a threshold of 
> 100 activity counts per minute 
− Mean daily number of episodes of activity over 100 activity counts per minute of at 
least 1-minute duration 
− Mean count per minute of daily activity 
− Mean daily number of episodes of activity over 100 activity counts per minute of at 
least 5 minutes duration 
− Mean daily accelerometer units 
Longitudinally collected over time and expressed as changes from baseline. 
In addition, the proportion of time spent in: 
− Sedentary physical activity  
− Light physical activity  
− Moderate physical activity  
− Vigorous physical activity  
at each time point of assessment. 
10.2.3.11 Change from baseline in echocardiography left and right heart function at 
Week 24 and Week 52 
The variables of interest are listed in Section 6.1.3.  
For every variable the change from baseline to Week 24 and Week 52 will be described. 
10.2.4 Safety variables  
Safety variables described here below are related to the safety endpoints described in 
Section 6.2. 
The safety variables are the following: 
• All-cause death up to 30 days after study treatment discontinuation 
• Number of all-cause hospital admissions up to 30 days after study treatment 
discontinuation 
• Treatment-emergent AEs up to 30 days after study drug discontinuation 
• SAEs up to 30 days after study treatment discontinuation 
• AEs leading to premature discontinuation of study treatment 


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• Change in vital signs and body weight up to 30 days after study treatment 
discontinuation 
• Treatment-emergent marked laboratory abnormalities up to 30 days after study 
treatment discontinuation 
• Change from baseline in eGFR up to 30 days after study treatment discontinuation 
• Decrease from baseline in SBP of ≥ 5% and SBP < 100 mmHg (yes/no) up to 30 days 
after study treatment discontinuation. 
10.2.5 Other variables  
10.2.5.1 Discontinuation of placebo run-in 
The reasons leading to early discontinuation of placebo run-in will be described. 
10.2.5.2 Discontinuation of macitentan run-in 
The reasons leading to early discontinuation of macitentan run-in will be described. 
10.3 Description of statistical analyses 
10.3.1 Overall testing strategy 
The effect of macitentan as compared to placebo will be tested using a mixed-models 
analysis of covariance (ANCOVA) adjusting for the NT-proBNP evolution observed 
during the macitentan run-in. 
The resulting p-value will be compared to an overall 2-sided type I error of 10%. 
The primary and three key secondary efficacy variables will be tested at two-sided 
α = 0.10, using a hierarchical testing approach to address multiplicity concern in the FAS. 
The secondary efficacy variables will be tested in a sequential conditional manner 
following the order of Section 6.1.2. 
Baseline is defined as the last non-missing value observed among all measures collected 
during placebo and macitentan run-ins, up to the day of randomization (Visit 6). As a 
consequence, for the majority of subjects, it is expected to be the value observed the day 
of randomization (Visit 6). 
10.3.2 Analysis of the primary efficacy variable 
The statistical method used to analyze the primary efficacy variable takes into account the 
expected underlying log normal distribution of NT-proBNP [Solomon 2012]. As a 
consequence, the treatment effect will be tested on a log-scale using an ANCOVA and 
expressed, on the original scale, as the ratio between treatment groups of the geometric 
means of individual percent of baseline at Week 24 (macitentan over placebo). 


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The model is adjusting for the log of the ratio: baseline NT-proBNP over NT-proBNP value 
as per IRT stratification, with the aim to better control the potential unbalance between 
treatment groups of the NT-proBNP levels observed before entering the macitentan run-in. 
Such unbalance may not be fully captured by the baseline NT-proBNP value, which is 
expected to be the value observed on the day of randomization for the majority of subjects, 
and thus already influenced by macitentan. Despite the randomization stratification based 
on the NT-proBNP value collected at subject’s entry into macitentan run-in, a continuous 
covariate quantifying individual NT-proBNP evolution during the macitentan run-in is 
deemed more sensitive and therefore more appropriate than a binary covariate based 
uniquely on the stratification factor.  
10.3.2.1 Hypotheses and statistical model 
Due to the underlying log-normal distribution of the primary efficacy variable, an analysis 
of covariance will be applied on log-transformed data. 
yij 
denotes the log-transformed percent of baseline in NT-proBNP at Week 24 for 
subject j in treatment group i 
xij 
denotes the log-transformed ratio: baseline NT-proBNP over NT-proBNP value as 
per IRT stratification, for subject j in treatment group i 
TRTi 
denotes for each subject the treatment group i he/she belongs to. Equal 1 for 
macitentan and 0 for placebo  
α 
denotes the common intercept 
eij 
denotes the random error term, assumed to follow a normal distribution with mean 
0 and standard error σ 
The model could be written: 
𝑦𝑦𝑖𝑖𝑖𝑖= 𝛼𝛼+ 𝛽𝛽1𝑇𝑇𝑇𝑇𝑇𝑇𝑖𝑖+ 𝛽𝛽2𝑥𝑥𝑖𝑖𝑖𝑖+ 𝑒𝑒𝑖𝑖𝑖𝑖 
2-sided hypotheses are focusing on the model coefficient β1. The null hypothesis is that 
macitentan and placebo effects on NT-proBNP are the same. The alternative hypothesis is 
that the effect of macitentan on NT-proBNP differs from placebo effect. 
H0 β1 = 0 
vs 
H1 β1 ≠ 0 
The null hypothesis will be tested by a 2-sided Wald test with a 2-sided significance level 
of 0.10.  


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10.3.2.2 Handling of missing data  
For subjects without available NT-proBNP value at Week 24, the last available value 
observed before Week 24 will be carried forward and considered for the main analysis. 
This approach is chosen as it is commonly used for this specific parameter [Solomon 2012] 
and in order to facilitate the clinical interpretation across study publications in the same 
indication. 
A sensitivity analysis will be performed by imputing missing NT-proBNP values at 
Week 24 according to the reason for drop-out. In particular, subjects who died or were 
hospitalized for HF before Week 24 will be assigned a value significantly higher than the 
one assigned to subjects who have a missing value at Week 24 due to 
technical/administrative reason. 
10.3.2.3 Main analysis 
The main analysis will be performed on subjects of the FAS, according to the intent-to-
treat principle. 
The main analysis of the primary efficacy variable will be carried out after 
log-transformation using an ANCOVA adjusting for the log of the ratio: baseline 
NT-proBNP over NT-proBNP value as per IRT with an overall type I error of 10% 2-sided. 
The treatment effect expressed as geometric means ratio and its associated 90% 2-sided 
confidence interval (CI) will be estimated based on the same model by inversely 
transforming using the exponential function the least squares mean and 90% CIs obtained 
in log scale. 
10.3.2.4 Supportive/sensitivity analyses  
The following supportive analyses are planned: 
• Main analysis on PPS, 
• Analysis of variance (ANOVA) on FAS without adjustment for the NT-proBNP 
evolution observed during the macitentan run-in, 
• Main analysis imputing missing NT-proBNP values at Week 24 according to the reason 
for drop-out. 


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10.3.2.5 Subgroup analyses 
In order to assess the consistency of the treatment effect across different subject subgroups 
for the primary endpoint, subgroup analyses are performed in the FAS according to the 
following demographic and baseline disease characteristics: 
• Geographical area (North America, South America, Western Europe, Eastern Europe) 
• Gender (Male versus Female) 
• NYHA FC (II versus III) 
• Atrial Fibrillation (yes/no) 
• NT-proBNP (< 1000 pg/mL and ≥ 1000 pg/mL) as per IRT stratification based on 
macitentan run-in entry 
Subgroup analyses are performed with a separate analysis for each subgroup variable using 
a two factor ANOVA model with treatment, subgroup and treatment-by-subgroup 
interaction terms. 
The test of interaction is performed with ‘n-1’ degrees of freedom, where ‘n’ is the number 
of subgroup categories. The treatment effect, measured as a geometric means ratio, will be 
estimated within each level of the subgroup variable based on the ANOVA including the 
interaction term. Significance of the interaction terms will be tested at a 0.01 level.  
Treatment effect geometric means ratio and corresponding 90% CIs for the different levels 
of each subgroup are presented in a forest-plot. The forest-plot is prepared as described in 
[Cuzick 2005] with a vertical reference line displayed at the level of the overall treatment 
effect for macitentan versus placebo and a vertical reference line at geometric means ratio 
= 1. The p-value for the interaction test is displayed on the plot for each subgroup along 
with the number of patients in macitentan and the number of patients in placebo within 
each subgroup level. 
Some of the pre-specified subgroup analyses will not be conducted or categories will be 
combined when it is determined that there is an insufficient number of subjects in a 
subgroup category to produce a valid result. 
Further subgroups will be added for analysis if deemed appropriate.  
No multiplicity adjustment is introduced; the subgroup analysis is descriptive in nature. 
10.3.3 Analysis of key secondary efficacy variable(s) 
10.3.3.1 Quality of life at Week 24 
The change from baseline to Week 24 in the clinical summary score will be analyzed by 
means of an ANCOVA adjusting for the score baseline value and for the log of the ratio: 


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NT-proBNP at Baseline (randomization) over NT-proBNP value before entering 
macitentan run-in (as per IRT). 
Least Squares Estimates within each treatment group and between treatment groups will 
be displayed along with 2-sided 90% CIs and p-values. 
10.3.3.2 Accelerometer-assessed physical activity at Week 24 
The change from baseline to Week 24 in the proportion of time spent in light to vigorous 
physical activity will be analyzed by means of an ANCOVA adjusting for the variable 
baseline value and for the log of the ratio: NT-proBNP at Baseline (randomization) over 
NT-proBNP value before entering macitentan run-in (as per IRT). 
Least Squares Estimates within each treatment group and between treatment groups will 
be displayed along with 2-sided 90% CIs and p-values. 
10.3.3.3 Time to first occurrence of worsening heart failure over 52 weeks 
The analysis of time to first occurrence of WHF will be carried out using a proportional 
hazards Cox model adjusting for the log of the ratio: NT-proBNP at Baseline 
(randomization) over NT-proBNP value before entering macitentan run-in (as per IRT).  
Estimate of Hazard Ratio and its associated 90% CI and p-value will be displayed. 
Kaplan-Meier estimates will be calculated with 2-sided 90% CIs at relevant time points for 
each treatment group and displayed in both a graphical (where the number of subjects at 
risk is at least 10% of the total number of subjects in the analysis set) and a tabular form. 
In addition, the number of subjects at risk, the number of subjects censored and the number 
of subjects with event will be computed at each time point and for each treatment group. 
10.3.4 Analysis of other efficacy variable(s) 
10.3.4.1 Number of days alive and out of the hospital 
For both DAOH and %DAOH, the treatment effect will be assessed by means of an 
ANCOVA adjusting for the log of the ratio: NT-proBNP at Baseline (randomization) over 
NT-proBNP value before entering macitentan run-in (as per IRT). 
Least Squares Estimates within each treatment group and between treatment groups will 
be displayed along with 90% 2-sided CIs. 
10.3.4.2 Time to first occurrence of HF death or HF hospitalization over 52 weeks 
The analysis of time to first occurrence of HF death or HF hospitalization will be carried 
out using a proportional hazards Cox model adjusting for the log of the ratio: NT-proBNP 
at Baseline (randomization) over NT-proBNP value before entering macitentan run-in (as 
per IRT).  


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Estimate of Hazard Ratio and its associated 90% CI will be displayed. 
Kaplan-Meier estimates will be calculated with 2-sided 90% CIs at relevant time points for 
each treatment group and displayed in both a graphical (where the number of subjects at 
risk is at least 10% of the total number of subjects in the analysis set) and a tabular form. 
In addition, the number of subjects at risk, the number of subjects censored and the number 
of subjects with event will be computed at each time point and for each treatment group. 
10.3.4.3 Time to first occurrence of CV death or CV hospitalization over 52 weeks 
The analysis of time to first occurrence of CV death or CV hospitalization will be carried 
out using a proportional hazards Cox model adjusting for the log of the ratio: NT-proBNP 
at Baseline (randomization) over NT-proBNP value before entering macitentan run-in (as 
per IRT).  
Estimate of Hazard Ratio and its associated 90% CI will be displayed. 
Kaplan-Meier estimates will be calculated with 2-sided 90% CIs at relevant time points for 
each treatment group and displayed in both a graphical (where the number of subjects at 
risk is at least 10% of the total number of subjects in the analysis set) and a tabular form. 
In addition, the number of subjects at risk, the number of subjects censored and the number 
of subjects with event will be computed at each time point and for each treatment group. 
10.3.4.4 Number of HF hospital admissions over 52 weeks 
The number of recurrent HF hospital admissions will be analyzed using a Negative 
binomial regression model adjusting for the log of the ratio: NT-proBNP at Baseline 
(randomization) over NT-proBNP value before entering macitentan run-in (as per IRT).  
Adjusted Estimates within each treatment group and between treatment groups will be 
displayed along with 2-sided 90% CIs, after inverse transformation using the exponential 
function. 
10.3.4.5 NYHA FC (improved/worsened/stable) at each post-baseline assessment 
The proportion of subjects having improved, having worsened or being stable will be 
calculated at each post-baseline assessment by treatment group. The relative risk 
(macitentan over placebo) will be displayed with 2-sided 90% CIs. 
10.3.4.6 Clinical composite outcome (‘worsened’, ‘unchanged’, ‘improved’)  
The proportion of subjects having improved, having worsened or being unchanged will be 
calculated for each period of time by treatment group. The relative risk (macitentan over 
placebo) will be displayed with 2-sided 90% CIs. 
10.3.4.7 Quality of life scores over time 
For each variable: 


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• Overall score 
• Clinical summary score  
• Physical limitations score 
the change over time is evaluated, assuming a linear pattern over time, with the use of a 
random coefficient regression model (with random slopes and intercepts) that 
includes treatment, time and time-by-treatment as factors and the score baseline value as a 
covariate.  
The random variables for this model are the subject-intercept and the subject-by-time 
interaction. The error term is assumed to follow a Normal distribution and the vector of the 
two correlated random effects is assumed to follow a bivariate Normal distribution, each 
with mean 0 and unstructured covariance matrix. 
The treatment effect is determined by using estimated slopes for each study treatment group 
on the basis of the time-by-treatment interaction term. Estimates within each treatment 
group and between treatment groups will be displayed overall and for each study visit along 
with their corresponding 90% 2-sided CIs.  
No imputation of missing values is planned. 
Modelling adjustments, such as addition of a quadratic term or a different covariance 
pattern within subject, will be made in case of meaningful conflict between the predicted 
and the observed data.  
10.3.4.8 Percent of baseline in NT-proBNP over time 
The percent of baseline in NT-proBNP over time is evaluated after log-transformation, 
assuming a linear pattern over time, with the use of a random coefficient regression model 
(with random slopes and intercepts) that includes treatment, time and time-by-treatment as 
factors and the log of the ratio: NT-proBNP at Baseline (randomization) over NT-proBNP 
value before entering macitentan run-in (as per IRT) as a covariate.  
The random variables for this model are the subject-intercept and the subject-by-time 
interaction. The error term is assumed to follow a Normal distribution and the vector of the 
two correlated random effects is assumed to follow a bivariate Normal distribution, each 
with mean 0 and unstructured covariance matrix. 
The treatment effect expressed as geometric means ratio and its associated 90% 2-sided 
CIs will be estimated based on the same model by inversely transforming using the 
exponential function of the least squares means and 90% CIs obtained in log scale. 
Estimates within each treatment group and between treatment groups will be displayed 
overall and for each study visit along with their corresponding 90% 2-sided CIs. 


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No imputation of missing values is planned.  
Modelling adjustments, such as addition of a quadratic term or a different covariance 
pattern within subject, will be made in case of meaningful conflict between the predicted 
and the observed data. 
10.3.4.9 Percent of baseline in MR-proANP over time 
The percent of baseline in MR-proANP over time is evaluated after log transformation, 
assuming a linear pattern over time, with the use of a random coefficient regression model 
(with random slopes and intercepts) as described in Section 10.3.4.7. 
10.3.4.10 Change from baseline in accelerometer-assessed physical activity over time 
For each variable: 
− Proportion of time spent in light to vigorous physical activity based on a threshold of 
> 100 activity counts per minut   
− Mean daily number of episodes of activity over 100 activity counts per minute of at 
least 1-minute duration 
− Mean count per minute of daily activity 
− Mean daily number of episodes of activity over 100 activity counts per minute of at 
least 5 minutes duration 
− Mean daily accelerometer units 
the change over time is evaluated with the use of a random coefficient regression model 
(with random slopes and intercepts) as described in Section 10.3.4.7. 
In addition, the proportion of time spent in: 
− Sedentary physical activity 
− Light physical activity 
− Moderate physical activity 
− Vigorous physical activity 
will be described at each time point of assessment by calculating for each treatment group 
the average time spent in each category and will be displayed in both a graphical (bar plots) 
and a tabular form. 
10.3.4.11 Change from baseline in echocardiography left and right heart function at 
Week 24 and Week 52 
For each variable, the change over time is summarized.  
10.3.5 Analysis of the safety variable(s)  
All safety endpoints will be analyzed on the Safety Set. All AEs are coded with MedDRA. 


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10.3.5.1 All-cause death up to 30 days after study treatment discontinuation 
The number and percentage of all-cause deaths occurring up to 30 days after study 
treatment discontinuation will be tabulated by treatment group and by: 
• System Organ Class and Preferred Term within System Organ Class, in descending 
order of incidence within the macitentan treatment group 
• Preferred Term, in descending order of incidence within the macitentan treatment 
group 
10.3.5.2 Number of all-cause hospital admissions up to 30 days after study treatment 
discontinuation 
The number of recurrent all-cause hospital admissions will be analyzed using a Negative 
binomial regression model. 
Estimates within each treatment group will be displayed, after inverse transformation using 
the exponential function. 
10.3.5.3 Adverse events 
The number and percentage of subjects with at least one treatment-emergent AE / with at 
least one SAE / with at least one AE leading to premature discontinuation of study 
treatment, occurring up to 30 days after study treatment discontinuation will be tabulated 
by treatment group and by: 
• System Organ Class and Preferred Term within System Organ Class, in descending 
order of incidence within the macitentan treatment group 
• Preferred Term, in descending order of incidence within the macitentan treatment 
group 
The same analysis will be performed considering the maximum intensity of reported AEs 
and relationship to study treatment. 
Listings will be provided for all reported AEs, including SAEs. In addition, separate 
listings will be provided for all AEs leading to premature discontinuation of study 
treatment, and for all AEs leading to death. 
10.3.5.4 Vital signs and body weight 
Vital signs and body weight will be described over time up to 30 days after study treatment 
discontinuation by means of a random coefficient regression model as described in 
Section 10.3.4.7. 


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10.3.5.5 Laboratory variables 
All laboratory data transferred are taken into account regardless of whether they correspond 
to scheduled or unscheduled assessments. All recorded assessments will be assigned to the 
most appropriate study visit according to the best fitting time-window for that assessment 
using the usual location and scale summary statistics by treatment group. 
Marked laboratory abnormalities will be summarized for each laboratory variable by 
treatment group providing their incidence and frequency. 
Absolute values and changes from baseline will be summarized over time up to 30 days 
after study treatment discontinuation for selected laboratory variables (erythrocytes, 
hemoglobin, hematocrit, AST, ALT, total bilirubin, and alkaline phosphatase). 
10.3.5.6 Glomerular Filtration Rate 
GFR will be described over time up to 30 days after study treatment discontinuation by 
means of a random coefficient regression model as described in Section 10.3.4.7. 
10.3.5.7 Decrease from baseline in SBP of ≥ 5% and SBP < 100 mmHg (yes/no) 
Decreases in SBP will be summarized by treatment group providing the number and 
percentage of subjects with, for at least one post-baseline assessment and up to 30 days 
after study treatment discontinuation, a percent change from baseline ≤ −5% and a SBP 
< 100 mmHg at the time of assessment. 
10.3.6 Analysis of the Other variable(s)  
10.3.6.1 Discontinuation of placebo run-in 
The number and percentage of subjects who discontinued during the placebo run-in / who 
completed the placebo run-in will be calculated on the placebo run-in Set. 
In addition, for subjects who discontinued, the main reasons for discontinuation will be 
displayed in descending order of incidence. All adverse events occurring during the 
placebo run-in will be described. 
10.3.6.2 Discontinuation of macitentan run-in 
The number and percentage of subjects who discontinued during the macitentan run-in / 
who completed the macitentan run-in will be calculated on the macitentan run-in Set. 
In addition, for subjects who discontinued, the main reasons for discontinuation will be 
displayed in descending order of incidence. All AEs occurring during the macitentan run-in 
will be described. 
10.4 Interim analyses 
No interim analysis will be performed. 


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10.5 Sample size 
The sample size calculation was performed using EAST version 6.4, based on the change 
from baseline to Week 24 in NT-proBNP, expressed as the ratio of 24-week NT-proBNP 
over baseline NT-proBNP due to the lognormal nature of its underlying distribution 
[Solomon 2012]. 
A number of 300 randomized subjects is adequate to detect a geometric means ratio of 0.75 
(macitentan over placebo, −0.288 in log scale) corresponding to a 25% improvement with 
a power of 80% and a type I error of 0.10 2-sided, when considering a standard deviation 
(SD) of 1 in log scale and using the Wald test. The critical value expressed as geometric 
means ratio is 0.83. 
Following closure of Screening on 27 December 2019, it is expected that approximately 
140 subjects will be randomized. With a reduced sample size of 140 and the same 
assumptions as above, the critical value expressed as geometric means ratio is 0.76. 
The originally planned sample size calculations and assumptions are presented below, with 
SD ranging from 0.8 to 1 and a geometric means ratio of 0.8 or 0.75. 
Power 
2-sided alpha 
Treatment effect 
(ratio of geometric means) 
SD 
(log 
scale) 
Total number of 
subjects 
80% 
0.10 
0.8 
0.8 
318 
0.85 
359 
0.9 
403 
0.95 
449 
1 
497 
0.75 
0.8 
192 
0.85 
216 
0.9 
243 
0.95 
270 
1 
299 
The scenario highlighted in grey corresponds to the originally chosen sample size of 
300 randomized subjects for this study. 
The 2-sided type I error has been fixed to 0.10 due to the Phase 2b nature of this study.  
The SD of 1 has been conservatively fixed based on: 
• PARAMOUNT study in which the observed SD vary between 0.91 and 0.99 (baseline 
and Week 12) 
• MELODY-1 study for which the SD is equal to 0.82 in subjects with a NT-proBNP 
baseline ≥ 300 pg/mL. 


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The targeted treatment effect of 0.75 has been chosen based on MELODY-1 study results. 
11 DATA HANDLING  
11.1 Data collection 
The investigator/delegate is responsible for ensuring the accuracy, completeness and 
timelines 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 CRF derived from 
source documents must be consistent with the source documents. 
CRF data will be captured via electronic data capture (using the Rave system provided by 
Medidata Solutions, Inc., a web-based tool). The investigator and site personnel will be 
trained to enter and edit the data via a secure network, with secure access features 
(username, password, and identification – an electronic password system). A complete 
electronic audit trail will be maintained. The investigator/delegate will approve the data 
(i.e., confirm the accuracy of the data recorded) using an electronic signature (ref. to US 
21 CFR Part 11). 
Entries recorded by the subject in the KCCQ as well as the physician-reported global 
assessment are considered source data. Site personnel will review and ensure completeness 
and readability of the subjects’ entries. 
Subject screening and enrollment data will be completed for all subjects (i.e., eligible and 
non-eligible) through the IRT system and CRF. 
For each subject enrolled, regardless of study treatment initiation, a CRF must be 
completed and signed by the investigator/delegate. This also applies to those subjects who 
fail to complete the study. If a subject withdraws from the study, the reason must be noted 
on the CRF. 
11.2 Maintenance of data confidentiality 
The investigator/delegate must ensure that data confidentiality is maintained. On CRFs or 
other documents (e.g., documents attached to SAE forms / Pregnancy forms) submitted to 
Actelion and any CROs, subjects must be identified only by number and never by their 
name or initials, date of birth, hospital numbers, or any other identifier. The 
investigator/delegate must keep a subject identification code list at the site, showing the 
subject/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. 


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11.3 Database management and quality control 
CRFs will be used for all subjects. The investigators will have access to the site CRF data 
until the database is closed. Thereafter, they will have read-only access. The CRF must be 
kept current to reflect subject status at any time point during the course of the study. 
While entering the data, the investigator/delegate will be instantly alerted to data queries 
by validated programmed checks. Additional data review will be performed by Actelion 
personnel on an ongoing basis to look for unexpected patterns in data and for study 
monitoring. If discrepant data are detected, a query specifying the problem and requesting 
clarification will be issued and visible to the investigator/delegate via the CRF. All 
electronic queries visible in the system either require a data correction (when applicable) 
and a response from the investigator/delegate to clarify the queried data directly in the 
CRF, or simply a data correction in the CRF. The investigator/delegate must, on request, 
supply Actelion with any required background data from the study documentation or 
clinical records. This is particularly important when errors in data transcription are 
suspected. In the case of health authority queries, it is also necessary to have access to the 
complete study records, provided that 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 
electronically sent to Actelion. If local laboratory data are obtained, they must be entered 
in the CRF by the site, as defined in Section 7.2.4.1. 
NT-proBNP samples will be processed through the central laboratory and the results will 
be sent electronically to Actelion.  
As NT-proBNP is a potentially unblinding variable, appropriate data processes will be 
implemented to ensure the blind is preserved and integrity of the study maintained. 
Individual subject NT-proBNP data assessed during the double-blind phase will not be 
shared with the site staff and the Sponsor’s study team. There are no restrictions on 
NT-proBNP data up to and including Visit 6. 
MR-proANP data also have the potential to unblind treatment allocation and will therefore 
not be shared with the site staff and the Sponsor’s study team until after data base closure. 
Echocardiographies are read centrally and the results are transferred electronically to 
Actelion.  
AEs are coded according to the latest Medical Dictionary for Regulatory Activities 
(MedDRA) used by Actelion. 


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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 Actelion QS docs. After database closure, the investigator will receive the 
CRFs of the subjects of his/her site (including all data changes made) on electronic media 
or as a paper copy. 
12 PROCEDURES AND GOOD CLINICAL PRACTICE  
12.1 Ethics and Good Clinical Practice 
Actelion personnel 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 study is conducted. 
12.2 Independent Ethics Committee / Institutional Review Board 
The investigator will submit this protocol and any related document(s) provided to the 
subject (such as the ICF) to an IEC/IRB. Approval from the committee/board 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 the ICF after receipt of the approval must also be 
submitted as amendments by the investigator to the IEC/IRB in accordance with local 
procedures and regulations [see Section 12.6]. 
A list of members participating in the IEC/IRB 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 member of the study personnel was present during an IEC/IRB meeting, it must be 
clear that this person did not vote. 
12.3 Informed consent 
It is the responsibility of the investigator/delegate to obtain informed consent according to 
ICH-GCP and Declaration of Helsinki guidelines and local regulations from each 
individual participating in this study and/or legally designated representative. The 
investigator/delegate must explain to subjects that they are completely free to refuse to 
enter the study, or to voluntarily withdraw from the study at any time for any reason without 
having to provide any justification. Special attention shall be paid to the information needs 
of specific subject populations and of individual subjects, as well as to the methods used 
to give the information. Adequate time shall be given for the subject and/or legally 
designated representative to consider his or her decision to participate in the study and it 


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shall be verified that the subject has understood the information (e.g., by asking the subject 
to explain what is going to happen). 
The ICF will be provided in the country local language(s). 
Site personnel authorized (according to local regulation) to participate in the consent 
process and/or to obtain consent from the subject and/or legally designated representative 
will be listed on the Delegation of Authority form supplied by Actelion. A study physician 
must always be involved in the consent process. 
The subject and/or legally designated representative and authorized site personnel listed on 
the Delegation of Authority form supplied by Actelion must sign, personally date, and time 
(if the first study-mandated procedure is to be performed on the same day informed consent 
is obtained) the ICF before any study-related procedures (i.e., any procedures required by 
the protocol) begin.  
A copy of the signed and dated ICF is given to the subject and/or legally designated 
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 at a minimum 
the study reference, the subject number, the date and, if applicable, time when the subject 
was first introduced to the 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’s family member[s]), and the 
information that a copy of the signed ICF was given to the subject / legally designated 
representative. 
If the site intends 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 IEC/IRB 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 IEC/IRB, according to 
procedures and before subjects are recruited. 
12.4 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. 


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12.5 Protocol adherence/compliance 
The investigator must conduct the study in compliance with the IEC/IRB and/or the 
regulatory authority-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 
ICH-GCP must be reported to the IEC/IRB and regulatory authorities according to Actelion 
or (overruling) local requirements. 
All protocol deviations will be reported in the Clinical Study Report (CSR). IECs/IRBs 
will be provided with listings of protocol deviations as per local requirements. 
12.6 Protocol amendments 
Any change to the protocol can only be made through a written protocol amendment. An 
amended protocol must be submitted to the IEC/IRB and regulatory authorities, according 
to their requirements. 
12.7 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 
subjects’ 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. 


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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 CRA has been provided personal and restricted access to 
study subjects only, to verify consistency between electronic source data and the CRF 
during monitoring visits. 
If the site is using an electronic/computerized system to store subject medical records but 
it could not be confirmed that the system is validated or if the CRA 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 CRA. The print-outs must be numbered, stapled together with a 
coversheet, signed and dated by the investigator/delegate to confirm that these certified 
copies are exact copies having the same information as the original source data. The 
printouts will be considered as the official clinical study records and must be filed either 
with the subject’s medical records or with the subject’s CRF. 
In order to verify that the process the site uses to prepare certified copies is reliable, the 
CRA 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 CRA 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 
CRA 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. 
12.8 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 SIV. 
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 CRA 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 CRFs and other protocol-related documents. Actelion monitoring standards 
require full verification that informed consent has been provided, verification of adherence 


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to the inclusion/exclusion criteria, documentation of SAEs, and the recording of the main 
efficacy, safety, and tolerability endpoints. Additional checks of the consistency of the 
source data with the CRFs will be performed according to the study-specific monitoring 
guidelines. The frequency of the monitoring visits will be based on subject recruitment rate 
and critical data-collection times. 
The PI must ensure that the CRF is completed after a subject’s visit (site visit or telephone 
call), and that all requested subject files (e.g., ICFs, medical notes/charts, other 
documentation verifying the activities conducted for the study) are available for review by 
the CRA. The required site personnel must be available during monitoring visits and allow 
adequate time to meet with the CRA to discuss study-related issues. 
The investigator agrees to cooperate with the CRA(s) to ensure that any issues detected in 
the course of these monitoring visits are resolved. If the subject is hospitalized or dies in a 
hospital other than the study 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. 
12.9 Investigator Site File 
Each site will be provided with an ISF prior to the SIV. It will contain all the essential 
documents that are required to be up-to-date and filed at site as per ICH-GCP section 8. 
The ISF will include a table of content listing the essential documents. All study-related 
documentation must be maintained in the ISF. 
In some cases, exceptions can be discussed with the CRA 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 
immediately inform Actelion. 
If the PI will change, or if the site will relocate, the CRA must be notified as soon as 
possible. 


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12.10 Audit 
Actelion’s GQM 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., standard operating procedures) 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 site personnel must cooperate with the auditor(s) and allow access to 
all study documentation (e.g., subject records) and facilities. 
12.11 Inspections 
Health authorities and/or IEC/IRB may also conduct an inspection of this study (during the 
study or after its completion) at the site. 
Should an inspection be announced by a health authority and/or IEC/IRB, the investigator 
must immediately inform Actelion (usually via the CRA) that such a request has been 
made. 
The investigator and site personnel must cooperate with inspector(s) and allow access to 
all study documentation (e.g., subject records) and study facilities. 
12.12 Reporting of study results and publication 
Actelion will post the key elements of this protocol and the summary of results on 
Actelion’s Clinical Trial Register and within the required timelines on publicly accessible 
databases (e.g., clinicaltrials.gov, EU database), as required by law and regulation. 
Study results will be documented in a CSR that will be signed by Actelion representatives 
and the Coordinating Investigator (or PI for single-center studies). 
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 submission to a peer-reviewed journal. 
The Coordinating Investigator and the Steering Committee, if any, will have the 
opportunity to review the analysis of the data and to discuss the interpretation of the study 
results with Actelion personnel prior to submission to a peer-reviewed journal or 
presentation at a congress. 
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 


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


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14 APPENDICES 
Appendix 1 
Marked laboratory abnormalities 
Laboratory abnormalities according to the most updated version of the Common 
Terminology Criteria for Adverse Events [CTCAE 2010]. 
A marked abnormality is defined based on the following list (SI units). 
Parameter 
LL 
LLL 
HH 
HHH 
HHHH 
Hemoglobin 
(g/L) 
< 100 
< 80 
Increase of > 20 g/L 
above ULN or above 
baseline if baseline 
is above ULN 
Increase 
of> 40 g/L above 
ULN or above 
baseline if baseline 
is above ULN 
 
Hematocrit 
(L/L) 
< 0.28 for 
females 
< 0.32 for 
males 
< 0.20 
> 0.60 in men 
> 0.55 in women 
> 0.65 
 
Platelet count 
(109 /L) 
< 75 
< 50 
> 600 
> 999 
 
Leucocytes 
(× 109 /L) 
< 3.0 
< 2.0 
> 20.0 
> 100.0 
 
Neutrophils 
(109/L) 
< 1.5 
< 1.0 
NA 
NA 
 
Eosinophils 
 
 
> 5.0 × 109 or > 5% 
NA 
 
Lymphocyte 
(109/L) 
< 0.8 
< 0.5 
> 4.0 
> 20.0 
 
AST (U/L) 
NA 
NA 
> 3 ULN 
> 5 ULN 
> 8 
ULN 
ALT (U/L) 
NA 
NA 
> 3 ULN 
> 5 ULN 
> 8 UL
N 
AP (U/L) 
NA 
NA 
> 2.5 ULN 
> 5 ULN 
 
Total 
bilirubin 
(μmol/L) 
NA 
NA 
> 2 ULN 
> 5 ULN 
 
Creatinine 
(μmol/L) 
NA 
NA 
> 1.5 ULN or 
1.5 × baseline 
> 3 ULN or 
> 3× baseline 
 
Glucose 
(mmol / L) 
< 3.0 
< 2.2 
> 8.9 
> 13.9 
 
Calcium 
(mmol/L) 
< 2.0 
< 1.75 
> 2.9 
> 3.1 
 


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Parameter 
LL 
LLL 
HH 
HHH 
HHHH 
Sodium 
(mmol/L) 
 
< 130 
> 150 
> 155 
 
Potassium 
(mmol/L) 
< 3.2 
< 3.0 
> 5.5 
> 6.0 
 
Magnesium 
(mmol/L) 
< 0.5 
< 0.4 
- 
> 1.23 
 
Uric acid 
(μmol/L) 
- 
- 
> 590 
> 720 
 
Albumin (g/L) 
< 30 
< 20 
- 
- 
 
BUN 
(mmol/L) 
- 
- 
> 2.5 ULN 
> 5 ULN 
 
AP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea 
nitrogen; ULN = upper limit of normal. 
 
 
 


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Appendix 2 
Central laboratory alert flags 
Central laboratory alert flags  
• On top of the flags described below, at a minimum, results above the upper limit or 
below the lower limit of the reference range for normal subjects will be flagged.  
• Exclusionary alert value - at Screening (Visit 1): The result is outside the study 
specific defined limit for inclusion in the study. 
Hemoglobin < 100 g/L 
AST ≥ 3 × ULN 
ALT ≥ 3 × ULN 
Serum pregnancy test positive 
• Exclusionary alert value - during Run-in (Visits 2–5): The result is outside the study 
specific defined limit for inclusion in the study. 
Decrease in hemoglobin by > 50 g/L from Screening 
Hemoglobin < 80 g/L 
Serum pregnancy test positive 
• Total bilirubin flag alert value - all visits: In combination with ALT and/or AST ≥ 3 × 
ULN, study treatment should be stopped or not initiated. 
Total bilirubin ≥ 2 ×ULN 
• Interruption or permanent discontinuation of study medication - All visits except 
Screening (Visit 1), EOT and EOS: Please refer to the study protocol; study 
medication must be interrupted or stopped [see Section 5.1.10]. 
• AST ≥ 3 × ULN 
• ALT ≥ 3 × ULN 
AST ≥ 8 × ULN 
ALT ≥ 8 × ULN 
Serum pregnancy test positive 
Hemoglobin < 80 g/L 
Hemoglobin > 50 g/L decrease from baseline 
• Repeat alert value - all visits except Screening (Visit 1), Visit 2, and EOS: Repeat 
testing is needed (+ interrupt study medication in case of ALT and/or AST ≥ 3 × ULN). 
AST ≥ 3 × ULN 
ALT ≥ 3 × ULN 
Hemoglobin > 20 g/L decrease from baseline 
 


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Appendix 3 
Kansas City Cardiomyopathy questionnaire (KCCQ) 
 
 


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Appendix 4 
Worsening Heart Failure Event definitions [ACC/AHA 2015] 
New or worsening symptoms - definitions 
Dyspnea 
Includes dyspnea on exertion, dyspnea at rest, orthopnea, 
and paroxysmal nocturnal dyspnea. 
Decreased exercise 
tolerance 
Decreased exercise tolerance: reduced ability to withstand 
or participate in activities that induce physical or mental 
exertion. 
Fatigue 
Unusual tiredness and inability to perform usual activities. 
Worsened end-organ 
perfusion 
Decreased blood supply to the vital organs (kidney, liver, 
lungs, heart, and brain).  
Volume overload 
Excessive accumulation of intravascular fluid resulting 
from compromised regulatory mechanisms.  
 
New or worsening Physical Examination findings - definitions 
Peripheral edema 
Increased tissue fluid indicated by perceptible pitting 
indentation on lower leg, foot, or sacrum after palpation. 
Increasing abdominal 
distention or ascites 
Intra-abdominal fluid accumulation as determined by 
physical examination (in the absence of primary hepatic 
disease). 
Pulmonary rales/crackles/ 
crepitations 
Pulmonary rales/crackles/crepitations: Abnormal breath 
sounds caused by the accumulation of fluid in the lungs. 
Increased jugular venous 
pressure and/or 
hepatojugular reflux 
Increase in the estimated height of the mean jugular 
venous waveform above the right atrium in centimeters. 
Note: When expressed as centimeters without further 
description, the number should be recorded as written. 
When it is expressed as centimeters above the sternal 
angle, 5 cm should be added to the number recorded. In 
the absence 
of a numerical estimate of jugular venous pressure, 
“JVD”, “distended neck veins,” and “halfway to the jaw” 
or “to the angle of the jaw” would be recorded as positive 
for elevated jugular venous pressure. 
S3 gallop 
Presence of an S3 mid-diastolic heart sound. 
 
Clinically significant 
or rapid weight gain 
Weight gain thought to be related to fluid retention. 
 
 


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New or worsening laboratory data - definitions 
Increase in HF biomarker 
Biomarker increase BNP/NT-pro BNP with 
decompensation of HF (such as BNP > 500 pg/mL or NT-
proBNP > 2000 pg/mL). In patients with chronically 
elevated natriuretic peptides, a significant increase above 
baseline is required. 
Radiological evidence of 
pulmonary congestion 
Radiological evidence of pulmonary congestion: imaging 
findings consistent with increased intravascular blood 
volume in the lungs. 
Noninvasive diagnostic 
evidence of HF 
Noninvasive diagnostic evidence of HF: Noninvasive 
diagnostic evidence of clinically significant elevated left 
or 
right-sided ventricular filling pressure or low cardiac 
output. For example, echocardiographic criteria could 
include E/e’ > 15 or D-dominant pulmonary venous inflow 
pattern, plethoric inferior vena cava with minimal collapse 
on inspiration, or decreased LVOT minute stroke distance 
(TVI). 
Invasive diagnostic 
evidence of HF 
Invasive diagnostic evidence with right-sided 
catheterization of heart showing a PAWP (pulmonary 
artery wedge pressure) ≥ 18 mmHg, central venous 
pressure ≥ 12 mmHg, or a cardiac index < 2.2 L/min/m2. 
 
HF event treatment intensification - definitions 
Augmentation of oral 
diuretic therapy 
Initiation or intensification of orally administered 
medication(s) that promote diuresis to treat HF. 
Intravenous diuretic, 
inotrope, vasopressor, or 
vasodilator therapy 
Initiation or intensification of medication(s) administered 
by vein to treat HF, increase production of urine, increase 
cardiac performance, and/or reduce cardiac preload or 
afterload. 
Mechanical or surgical 
intervention 
Mechanical circulatory support (e.g., intra-aortic balloon 
pump, ventricular assist device, extracorporeal membrane 
oxygenation, total artificial heart) or mechanical fluid 
removal (e.g., ultrafiltration, hemofiltration, dialysis). 
BNP = brain natriuretic peptide; HF = heart failure; JVD = jugular venous distension; LVOT = left ventricular outflow 
tract; NT-proBNP = n-terminal pro-brain natriuretic peptide; PAWP = pulmonary artery wedge pressure; TVI = 
time velocity integral. 
 
 
 


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Appendix 5 
Classification of cause of death 
Definitions of cardiovascular death: 
Since Cardiovascular (CV) death is part of a composite efficacy endpoint, it is important 
to accurately classify the cause of death. CV death is defined as death with the following 
primary cause [ACC/AHA 2015]:  
 
Acute MI 
Death by any cardiovascular mechanism (arrhythmia, 
sudden death, HF, stroke, pulmonary embolus, PAD) within 
30 d after an acute MI, related to the immediate 
consequences of the MI, such as progressive HF or 
recalcitrant 
arrhythmia. 
There 
may 
be 
assessable 
(attributable) mechanisms of cardiovascular death during 
this time period, but for simplicity, if the cardiovascular 
death occurs within 30 d of an acute MI, it will be 
considered a death due to MI. Note: Acute MI should be 
verified to the extent possible by the diagnostic criteria 
outlined for acute MI or by autopsy findings showing recent 
MI or recent coronary thrombosis. Death resulting from a 
procedure to treat an MI (PCI or CABG), or to treat a 
complication resulting from MI, should also be considered 
death due to acute MI. Death resulting from an elective 
coronary 
procedure 
to 
treat 
myocardial 
ischemia 
(i.e., chronic stable angina) or death due to an MI that 
occurs as a direct consequence of a cardiovascular 
investigation/procedure/operation should be considered as a 
death due to a cardiovascular procedure. 
Sudden cardiac death 
Death that occurs unexpectedly and not within 30 d of an 
acute MI. Note: Sudden cardiac death includes the 
following scenarios:  
• Death witnessed and occurring without new or 
worsening symptoms 
• Death witnessed within 60 min of the onset of new or 
worsening cardiac symptoms unless the symptoms 
suggest acute MI 
• Death witnessed and attributed to an identified 
arrhythmia (e.g., captured on an electrocardiographic 
recording, witnessed on a monitor, or unwitnessed but 
found on ICD review) 


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• Death after unsuccessful resuscitation from cardiac 
arrest (e.g., ICD unresponsive sudden cardiac death, 
pulseless electrical activity arrest) 
• Death after successful resuscitation from cardiac arrest 
and without identification of a specific cardiac or 
noncardiac etiology 
• Unwitnessed death in a subject seen alive and clinically 
stable ≤ 24 h before being found dead without any 
evidence supporting a specific non-cardiovascular 
cause of death (information about the patient’s clinical 
status preceding death should be provided if available) 
Unless additional information suggests an alternate specific 
cause of death (e.g., Death due to Other Cardiovascular 
Causes), if a patient is seen alive ≤ 24 h before being found 
dead, sudden cardiac death (criterion 2f) should be 
recorded. For patients who were not observed alive within 
24 h of death, undetermined cause of death should be 
recorded (e.g., a subject found dead in bed but who had not 
been seen by family members for > 24 h). 
HF 
Death associated with clinically worsening symptoms 
and/or signs of HF, regardless of HF etiology.  
Note: Deaths due to HF can have various etiologies, 
including single or recurrent MIs, ischemic or non-ischemic 
cardiomyopathy, hypertension, or valvular disease. 
Stroke 
Death after a stroke that is either a direct consequence of the 
stroke or a complication of the stroke.  
Note: Acute stroke should be verified to the extent possible 
by the diagnostic criteria outlined for stroke. 
CV procedure 
Death caused by the immediate complication(s) of a 
Cardiovascular procedure. 
CV hemorrhage 
Death related to hemorrhage such as a nonstroke 
intracranial 
hemorrhage 
(e.g., 
subdural 
hematoma) 
nonprocedural or nontraumatic vascular rupture (e.g., aortic 
aneurysm), or hemorrhage causing cardiac tamponade. 
CV: other 
Cardiovascular death not included in the above categories 
but with specific, known cause (e.g., PE, PAD). 
CABG indicates coronary artery bypass graft; CV, cardiovascular; HF, heart failure; ICD, implantable cardioverter-
defibrillator; MI, myocardial infarction; PAD, peripheral artery disease; PCI, percutaneous coronary intervention 
and PE, pulmonary embolism. 
 


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Appendix 6 
Definition of HF and CV hospitalization 
HF hospitalization is defined as: 
• 
Subject is admitted to the hospital with a primary diagnosis of HF. 
• 
Length of stay is at least 24 h (or extends over a calendar date). 
CV hospitalization is defined as:  
• 
Subject is admitted to the hospital with a primary diagnosis of HF, MI, stroke, 
resuscitated sudden death, CV procedure, CV hemorrhage or cardiovascular 
hospitalization not included in the above categories but with specific, known cause 
(e.g., PE, PAD). 
• 
Length of stay is at least 24 h (or extends over a calendar date). 
 
Appendix 7 
Protocol amendment history 
The Protocol Amendment Summary of Changes Table for the current amendment is  
directly before the Table of Contents. Summary of previous amendment is provided 
below. 
 
Amendment 
Date 
Main reason(s) 
1 
08 February 2017 
Implementation of additional safety monitoring measures post-
macitentan first dose, as requested by the FDA. 
2 
12 April 2017 
Addition of medications mainly transported by BCRP to the list of 
forbidden medications, as requested by the FDA. 
3 
10 April 2018 
 Description of the transition to the SERENADE OL extension 
study, revision of the eligibility and run-in failure criteria and 
introduction of a Clinical Event Committee. 
4 
08 March 2019 
Addition of the 6-minute walk distance sub study to assess the 
change in exercise capacity from baseline and the removal of the 8-
hour post-macitentan first dose safety monitoring period at the start 
of macitentan run-in. Addition of 2 phone calls to ensure adequate 
safety follow-up is established during the run-in phase. In addition, 
the testing hierarchy of the key secondary efficacy endpoints was 
changed. 
5 
06 February 2020 • 
The early termination of recruitment into the study since the 
study failed to meet subject recruitment targets and completion 
of the study within reasonable timeline is not realistic. The 


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EudraCT 2016-003653-15 
Doc No D-20.252 
 
 
 CONFIDENTIAL – FOIA Exemptions Apply in U.S.   
144 
Amendment 
Date 
Main reason(s) 
sample size was updated to reflect the early termination of 
recruitment. 
• 
To reduce the length of the double-blind treatment period to 24 
weeks. The rationale for this change is that Week 24 is the pre-
defined timepoint for assessing the primary endpoint, as well as 
the key secondary endpoints. The secondary endpoint of time to 
worsening heart failure (WHF) event however was planned to 
be assessed up to Week 52 to gather meaningful information for 
the preparation of a pivotal clinical trial development program. 
Due to the reduced sample size, the number of WHF events is 
expected to be too low for a meaningful analysis of time to 
WHF. The double-blind treatment period will thus be stopped at 
Week 24, and eligible subjects will be able to transition to 
SERENADE OL at this timepoint. Subjects who have already 
completed the Week 24 visit, will be scheduled to come back for 
an EOT visit within 60 days  and will proceed to enroll in the 
OL study, if eligible.  
• 
To remove the CEC which was appointed to review and 
adjudicate in a blinded fashion WHF events, the reasons for 
hospitalization and causes of death. The rationale is based on the 
reduction of the double-blind treatment period from 52 weeks to 
24 weeks, coupled by the low occurrence of WHF events which 
will not allow for meaningful conclusions to be drawn. 
However, the investigator assessment of WHF events will 
continue. Removal of the CEC does not affect safety monitoring 
and therefore the decision was also endorsed by the Independent 
Data Monitoring Committee (IDMC).  
• 
To re-schedule accelerometry to be performed 9 consecutive 
days prior to Week 24 (Visit 11/PTOP2) for subjects completing 
week 24 (Visit 11) under Amendment 5 to ensure assessment 
performed on double-blind treatment.  
• 
To stop sub-study assessments (6-minute walk test and Borg 
Dyspnea Index), as number of subjects participating in the sub-
study is too low to allow for meaningful interpretation of results. 
The planned analysis of sub-study data is amended to reflect the 
above amendment to the protocol.   
 
 


Actelion Pharmaceuticals Ltd 
Janssen Research & Development * 
 
Clinical Protocol 
 
COVID-19 Appendix 
 
Protocol Title 
A multi-center, double-blind, placebo-controlled Phase 2b study to evaluate the efficacy 
and safety of macitentan in subjects with heart failure with preserved ejection fraction and 
pulmonary vascular disease 
 
 SERENADE  
 
Macitentan in heart failure with preserved ejection fraction and pulmonary vascular disease 
 
Protocol AC-055G202; Phase 2b 
 
JNJ-67896062/ACT-064992 Macitentan  
 
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Actelion Pharmaceuticals Ltd; Janssen Biotech, Inc.; Janssen 
Products, LP; Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica 
NV; Janssen Sciences Ireland UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. 
The term “sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is 
identified on the Contact Information page that accompanies the protocol. 
 
United States (US) sites of this study will be conducted under US Food & Drug Administration 
Investigational New Drug (IND) regulations (21 CFR Part 312). 
 
EudraCT NUMBER: 2016-003653-15 
 
 
Status: 
Approved 
Date: 
2 July 2020 
Prepared by: Janssen Research & Development, LLC   
EDMS number: 
D-20.203  
 
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL 
[AC-055G202] 
 
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements.  
Confidentiality Statement 
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential. The information is being provided under the assurance that the recipient will 
maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or otherwise. 
NCT03153111


COVID-19 Appendix  
 
JNJ-67896062/ACT-064992 Macitentan  
Clinical Protocol AC-055G202  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
2 
Status: Approved, Date: 2 July 2020 
COVID-19 APPENDIX 
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC 
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants and 
study-site personnel; travel restrictions/limited access to public places, including hospitals; study 
site personnel being reassigned to critical tasks.  
In alignment with recent health authority guidance, the sponsor is providing options for 
study-related participant management in the event of disruption to the conduct of the study. This 
guidance does not supersede any local or government guidelines or requirements or the clinical 
judgement of the investigator to protect the health and well-being of participants and site staff. If, 
at any time, a participant’s safety is considered to be at risk, study intervention will be 
discontinued, and study follow-up will be conducted. 
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent 
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each 
contact, participants will be interviewed to collect safety data. Key efficacy endpoint assessments 
should be performed if required and as feasible. Participants will also be questioned regarding 
general health status to fulfill any physical examination requirement.  
Every effort should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow-up. Modifications to protocol-required assessments may be 
permitted via COVID-19 Appendix after consultation with the participant, investigator, and the 
sponsor.  
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance. 
If a participant has tested positive for COVID-19, the investigator should contact the sponsor’s 
responsible medical officer to discuss plans for study intervention and follow-up. Modifications 
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the 
clinical study report. 
 
 
 


COVID-19 Appendix  
 
JNJ-67896062/ACT-064992 Macitentan  
Clinical Protocol AC-055G202  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
3 
Status: Approved, Date: 2 July 2020 
GUIDANCE SPECIFIC TO THIS PROTOCOL:  
• Certain protocol-mandated visits to the study site may not be possible during the COVID-19 
outbreak. Therefore, temporary measures may be implemented if considered appropriate by 
the sponsor and investigator to maintain continuity of participant care and study integrity. 
Certain measures, such as those listed below, may be necessary and should be instituted in 
accordance with applicable (including local) laws, regulations, guidelines, and procedures: 
o remote (eg, by phone / telemedicine) or in-person, off-site (eg, in-home) interactions 
between site staff (or designees) and participants for study procedures, eg, those related 
to safety monitoring / efficacy evaluation / study intervention storage and 
administration (including training where pertinent). The following assessments should 
be made and documented in the eCRF and source documents: 
• Weekly body weight measurements 
• Follow-up on ongoing AEs, recording of new AEs 
• Changes in concomitant medications 
• Results from urine pregnancy test, as applicable 
Wherever possible, the following efficacy assessments should be performed and recorded in 
the eCRF if they would have been assessed at the missed visit: 
• 
Kansas City Cardiomyopathy Questionnaire: the site should administer the KCCQ by 
interview over the phone. When administering the KCCQ, the following points should be 
considered: 
o The participant should be interviewed without others in attendance. This will 
not only make the participant more comfortable, but also ensure that the 
answers are those of the participant. 
o The instructions and each part (the question and available responses) of the 
questionnaire should be read exactly as written. 
o If the participant does not understand the question, it should not be interpreted 
for them. Participants should merely be reassured that there are no right or 
wrong answers and that they should answer the questions as best they can. The 
question can be reread to the participant. 
• Patient Global Assessment (PGA): The PGA can be administered by interview over the phone. 
• Accelerometry: if the participant still has an accelerometer at home, he/she will be instructed 
to keep the device charged and to start wearing it as per ‘visit and assessment schedule’ of the 
SERENADE protocol. If the participant doesn’t have an accelerometer at home, the site will 
send an accelerometer to the participant. 
 


COVID-19 Appendix  
 
JNJ-67896062/ACT-064992 Macitentan  
Clinical Protocol AC-055G202  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
4 
Status: Approved, Date: 2 July 2020 
• Procurement of study intervention by participants (or designee) or shipment of study 
intervention from the study site directly to participants for at home administration (including 
the potential for self-administration of study intervention). Since this is pre-planned in the 
protocol under exceptional circumstances (section 5.1.6.3), direct-to-subject shipments are not 
considered to be a protocol deviation. 
• Laboratory assessments using a suitably accredited local laboratory: for selected measures 
(eg, urine pregnancy tests), home testing may be employed. Safety laboratory testing should 
include AST/ALT and hemoglobin at minimum. NT-proBNP should be measured if a visit 
which includes NT-proBNP sampling is missed. 
• Other procedures, eg, imaging, may be conducted at an appropriate facility. 
Once the restrictions are lifted, the subject should return to the site within 4 weeks to start to 
perform all safety and efficacy assessments that have been missed. 
o Missed assessments/visits will be captured in Rave, electronic data capture system for 
protocol deviations. Discontinuations of study interventions and withdrawal from the 
study should be documented with the prefix “COVID-19-related” in the eCRF. Other 
relevant study data elements impacted by the pandemic should also be documented / 
labeled as “COVID-19-related” in CRFs, per addendum to the eCRF completion 
guidelines. These may include missed / delayed / modified study visits / assessments / 
dosing, and instances where temporary measures such as those above are implemented.   
• The sponsor will evaluate the totality of impact of COVID-19 on collection of key study 
data and additional data analyses will be outlined in study SAP(s).  
Guidance for re-consenting and monitoring 
• Re-consenting to protocol v.6 (core ICF v.6) can be done over the phone and/or mail; provided 
local regulations allow this mode of consenting.  
• Remote monitoring will be performed if this can be implemented at the site, per local 
requirements. 
 
 
 


 
PPD

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
FOR THE CLINICAL STUDY REPORT  
SERENADE 
 
A multi-center, double-blind, placebo-controlled Phase 2b study to evaluate the 
efficacy and safety of macitentan in subjects with heart failure with preserved 
ejection fraction and pulmonary vascular disease  
 
Purpose of Analysis 
Clinical Study Report 
Investigational Drug 
Macitentan / ACT-064992 
Protocol Number 
AC-055G202/ SERENADE 
Actelion Document Number 
D-17.528 
Document Status/Version Number 
Final Version 1.0  
Date 
2 April 2020 
 
Author 
, Statistician  
, CRO Statistician (Valos) 
 
Reviewer 
, Project Statistician 
Reviewer 
 CRO Lead Expert 
Statistician (Valos) 
Reviewer 
 Clinical Project Physician 
Reviewer 
 Clinical Trial Scientist 
Reviewer 
 Medical Safety Officer 
Reviewer 
 Senior Clinical Scientist 
 
Confidential 
 
Property of Actelion Pharmaceuticals Ltd. May not be used, divulged, published or 
otherwise disclosed without the consent of Actelion Pharmaceuticals Ltd. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
NCT03153111


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND ACRONYMS.............................................. 10 
1 
INTRODUCTION ....................................................................................... 15 
2 
STUDY DESIGN AND FLOW.................................................................... 15 
2.1 
Study design .................................................................................. 15 
2.2 
Study visit and assessment schedule ............................................... 19 
3 
OBJECTIVES ............................................................................................. 19 
3.1 
Primary objective(s) ....................................................................... 19 
3.2 
Secondary objectives...................................................................... 19 
3.3 
Other objectives ............................................................................. 20 
3.4 
Safety objective ............................................................................. 20 
4 
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE 
STUDY PROTOCOL .................................................................................. 20 
4.1 
Changes to the analyses planned in the study protocol ..................... 20 
4.1.1 
Geographical regions and other subgroup analyses ............... 20 
4.1.2 
Baseline.............................................................................. 20 
4.1.3 
Percent of baseline in MR-proANP over time....................... 21 
4.1.4 
Display of listings ............................................................... 21 
4.2 
Changes in the conduct of the study / data collection ....................... 22 
4.2.1 
The following protocol amendments were performed: .......... 22 
4.3 
Clarifications concerning endpoint definitions and related variables  
or statistical methods ...................................................................... 24 
4.3.1 
Previous and concomitant medications................................. 24 
4.3.2 
Efficacy endpoints evaluated over 52 weeks......................... 24 
5 
DEFINITIONS OF VARIABLES ................................................................ 25 
5.1 
Screening and run-in failures and disposition .................................. 25 
5.1.1 
Screening failure ................................................................. 25 
5.1.1.1 
Unmet eligibility criteria for Placebo Run-in ............... 25 
5.1.2 
Single-blind placebo run-in disposition and failures ............. 26 
5.1.2.1 
Unmet eligibility criteria for Macitentan Run-in .......... 26 
5.1.3 
Single-blind macitentan run-in disposition and failures......... 26 
5.1.3.1 
Unmet eligibility criteria for Double blind treatment 
period ........................................................................ 26 


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5.2 
Subject characteristics .................................................................... 27 
5.2.1 
Demographics ..................................................................... 27 
5.2.2 
Baseline disease characteristics............................................ 28 
5.2.3 
Other baseline characteristics .............................................. 30 
5.2.4 
Medical history ................................................................... 31 
5.2.4.1 
Specific medical history ............................................. 31 
5.2.5 
Previous and concomitant therapies ..................................... 31 
5.2.5.1 
Previous therapies ...................................................... 31 
5.2.5.2 
Baseline therapies ...................................................... 32 
5.2.5.3 
Study-concomitant therapies....................................... 32 
5.2.5.4 
Study-treatment concomitant therapies........................ 32 
5.2.5.5 
Post Study-treatment therapies.................................... 32 
5.2.5.6 
Therapies of special interest ....................................... 32 
5.2.5.7 
Diuretics .................................................................... 33 
5.2.6 
Other subject characteristics ................................................ 35 
5.3 
Study treatment exposure and compliance....................................... 35 
5.3.1 
Exposure ............................................................................ 35 
5.3.2 
Compliance with study treatment......................................... 37 
5.3.3 
Study treatment discontinuation........................................... 37 
5.3.4 
Study treatment adjustments or interruptions ........................ 39 
5.4 
Study discontinuation ..................................................................... 39 
5.4.1 
Study disposition by visit .................................................... 40 
5.5 
Efficacy variables .......................................................................... 41 
5.5.1 
Primary efficacy variable(s)................................................. 42 
5.5.2 
Secondary efficacy variables ............................................... 43 
5.5.2.1 
Quality of life: KCCQ Clinical summary score at  
Week 24 .................................................................... 43 
5.5.2.2 
Accelerometer-assessed light to vigorous physical 
activity at Week 24 .................................................... 43 
5.5.2.3 
Time to first occurrence of worsening of heart failure 
event.......................................................................... 45 
5.5.3 
Other efficacy variables....................................................... 46 
5.5.3.1 
Number of days alive and out of the hospital ............... 46 
5.5.3.2 
Time to first occurrence of HF death or HF 
hospitalization............................................................ 46 
5.5.3.3 
Time to first occurrence of CV death or CV 
hospitalization............................................................ 47 
5.5.3.4 
Number of HF hospital admissions over 52 weeks....... 48 
5.5.3.5 
NYHA FC (improved/worsened/stable) at each 
post-baseline assessment ............................................ 49 


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5.5.3.6 
Clinical composite outcome (‘worsened’, ‘unchanged’, 
‘improved’)................................................................ 49 
5.5.3.7 
Change from baseline in the KCCQ overall summary 
score and KCCQ scores over time .............................. 50 
5.5.3.8 
Percent of baseline in NT-pro-BNP over time ............. 50 
5.5.3.9 
Change from baseline in accelerometer-assessed  
physical activity variables over time ........................... 51 
5.5.3.10 
Proportion of time spent in physical activity at each  
time assessment ......................................................... 51 
5.5.3.11 
Change from baseline in echocardiography left and  
right heart function at Week 24 and Week 52. ............. 52 
5.5.3.12 
Percent of baseline in MR-proANP over time.............. 52 
5.5.3.13 
Patient Global Assessment ......................................... 52 
5.6 
Safety variables.............................................................................. 52 
5.6.1 
Adverse events.................................................................... 54 
5.6.1.1 
Treatment-emergent adverse events ............................ 54 
5.6.1.2 
Frequency of treatment-emergent adverse events......... 56 
5.6.1.3 
Intensity of treatment-emergent adverse events ........... 56 
5.6.1.4 
Relationship of treatment-emergent adverse events ..... 56 
5.6.2 
Deaths ................................................................................ 56 
5.6.3 
Serious adverse events ........................................................ 57 
5.6.4 
Adverse events leading to discontinuation of study  
treatment ............................................................................ 57 
5.6.5 
Other significant adverse events .......................................... 57 
5.6.5.1 
AEs with fatal outcome .............................................. 57 
5.6.5.2 
AEs of special interest ................................................ 57 
5.6.6 
Vital signs and body weight................................................. 58 
5.6.6.1 
Decrease in SBP ........................................................ 59 
5.6.7 
Electrocardiogram............................................................... 59 
5.6.8 
Laboratory .......................................................................... 60 
5.6.8.1 
Fasted state laboratory values ..................................... 61 
5.6.8.2 
Marked laboratory abnormalities ................................ 61 
5.6.8.3 
Additional liver laboratory abnormalities .................... 64 
5.6.9 
Other safety variables.......................................................... 65 
5.6.9.1 
Number of all-cause hospital admissions up to 30 days 
after study treatment discontinuation........................... 65 
5.6.9.2 
Change from baseline in Glomerular Filtration Rate  
up to 30 days after study treatment discontinuation ..... 65 
5.6.9.3 
Physical examination ................................................. 65 
5.6.9.4 
Heart failure sign and symptoms of special interest ..... 65 
5.7 
Sub-study ...................................................................................... 66 


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5.8 
Quality of life variables .................................................................. 67 
6 
DEFINITION OF PROTOCOL DEVIATIONS ............................................ 68 
7 
ANALYSIS SETS ....................................................................................... 68 
7.1 
Definitions of analysis sets ............................................................. 68 
7.1.1 
Screened Analysis Set ......................................................... 68 
7.1.2 
Placebo run-in Set ............................................................... 68 
7.1.3 
Macitentan run-in Set .......................................................... 68 
7.1.4 
Full analysis Set .................................................................. 69 
7.1.5 
Per-Protocol analysis Set ..................................................... 69 
7.1.6 
Safety Set ........................................................................... 71 
7.1.7 
Sub-study Analysis Set........................................................ 71 
7.2 
Usage of the analysis sets ............................................................... 72 
8 
DEFINITION OF SUBGROUPS ................................................................. 73 
9 
GENERAL STATISTICAL METHODOLOGY ........................................... 73 
9.1 
Statistical methods for ANCOVA analysis ...................................... 74 
9.2 
Statistical methods for time-to-event data........................................ 76 
9.3 
Statistical methods for count variables ............................................ 77 
9.4 
Statistical methods for categorical variables .................................... 77 
9.5 
ANCOVA model for repeated measurements .................................. 77 
10 STATISTICAL ANALYSES ....................................................................... 78 
10.1 
Overall testing strategy................................................................... 78 
10.2 
General rules for data presentations ................................................ 79 
10.3 
Display of subject disposition, protocol deviations and analysis  
sets ................................................................................................ 80 
10.3.1 
Screening failures and run-in disposition and failures ........... 80 
10.3.2 
Subject disposition .............................................................. 81 
10.3.3 
Protocol deviations.............................................................. 82 
10.3.4 
Analysis sets ....................................................................... 82 
10.4 
Analyses of subject characteristics .................................................. 82 
10.4.1 
Demographics ..................................................................... 83 
10.4.2 
Baseline disease characteristics............................................ 83 
10.4.3 
Other baseline characteristics .............................................. 83 
10.4.4 
Medical history ................................................................... 83 
10.4.5 
Previous and concomitant therapies ..................................... 84 
10.4.6 
Baseline therapies of special interest .................................... 84 


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10.4.7 
Changes in Diuretics ........................................................... 84 
10.4.8 
Other subject characteristics ................................................ 85 
10.4.8.1 
Contraceptive methods ............................................... 85 
10.5 
Analysis of study treatment exposure and compliance ..................... 85 
10.5.1 
Exposure ............................................................................ 85 
10.5.2 
Compliance with study treatment......................................... 85 
10.5.3 
Study treatment discontinuation........................................... 86 
10.5.4 
Study treatment adjustments or interruptions ........................ 86 
10.6 
Analysis of the primary efficacy variable(s) .................................... 86 
10.6.1 
Hypothesis and statistical model .......................................... 87 
10.6.2 
Handling of missing data ..................................................... 87 
10.6.3 
Main analysis...................................................................... 88 
10.6.4 
Supportive/sensitivity analyses ............................................ 89 
10.6.5 
Subgroup analyses .............................................................. 89 
10.6.6 
Additional supportive analyses ............................................ 90 
10.7 
Analysis of the secondary efficacy variables ................................... 90 
10.7.1 
Quality of life: KCCQ Clinical Summary score at Week 24 .. 90 
10.7.1.1 
Hypothesis and statistical model ................................. 90 
10.7.1.2 
Handling of missing data ............................................ 91 
10.7.1.3 
Statistical analysis ...................................................... 91 
10.7.1.4 
Supportive/sensitivity analyses ................................... 91 
10.7.1.5 
Subgroup analyses ..................................................... 91 
10.7.2 
Accelerometer-assessed light to vigorous physical activity  
at Week 24.......................................................................... 91 
10.7.2.1 
Hypothesis and statistical model ................................. 91 
10.7.2.2 
Handling of missing data ............................................ 92 
10.7.2.3 
Statistical analysis ...................................................... 92 
10.7.2.4 
Supportive/sensitivity analyses ................................... 92 
10.7.2.5 
Subgroup analyses ..................................................... 92 
10.7.3 
Time to first occurrence of worsening heart failure over 52 
weeks (up to EOS / OLE) .................................................... 92 
10.7.3.1 
Hypothesis and statistical model ................................. 92 
10.8 
Analysis of other efficacy variables ................................................ 93 
10.8.1 
Number of days alive and out of the hospital ........................ 93 
10.8.2 
Time to first occurrence of HF death or HF hospitalization 
over 52 weeks (up to EOS/ OLE)......................................... 93 
10.8.3 
Time to first occurrence of CV death or CV hospitalization 
over 52 weeks (up to EOS/ OLE)......................................... 94 
10.8.4 
Number of HF hospital admissions over 52 weeks................ 94 
10.8.5 
NYHA FC (improved/worsened/stable) at each post-baseline 
assessment .......................................................................... 94 


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10.8.6 
Clinical composite outcome (‘worsened’, ‘unchanged’, 
‘improved’)......................................................................... 95 
10.8.7 
Quality of life KCCQ scores over time................................. 95 
10.8.8 
Percent of baseline NT-pro-BNP over time .......................... 96 
10.8.9 
Change from baseline in accelerometer-assessed physical 
activity over time ................................................................ 97 
10.8.10 
Change from baseline in echocardiography left and right  
heart function at Week 24 and Week 52 ............................... 97 
10.8.11 
Percent of baseline MR-proANP over time .......................... 97 
10.8.12 
NT-pro-BNP over time........................................................ 98 
10.8.13 
Patient global assessment .................................................... 98 
10.9 
Analysis of safety variables ............................................................ 98 
10.9.1 
Adverse events.................................................................... 98 
10.9.1.1 
Treatment emergent adverse events .......................... 100 
10.9.2 
Deaths, other serious adverse events .................................. 101 
10.9.2.1 
Deaths ..................................................................... 101 
10.9.2.2 
Serious adverse events ............................................. 101 
10.9.2.3 
Adverse events leading to study treatment 
discontinuation......................................................... 101 
10.9.2.4 
Other significant adverse events ............................... 102 
10.9.2.5 
Eudract and CTgov summaries ................................. 102 
10.9.3 
Electrocardiogram............................................................. 103 
10.9.4 
Laboratory tests ................................................................ 103 
10.9.4.1 
Fasted state laboratory values ................................... 103 
10.9.4.2 
Marked laboratory abnormalities .............................. 104 
10.9.4.3 
Additional liver laboratory abnormalities .................. 105 
10.9.5 
Vital signs and body weight............................................... 105 
10.9.6 
Other safety variables........................................................ 106 
10.9.6.1 
Number of all-cause hospital admissions up to 30 days 
after study treatment discontinuation......................... 106 
10.9.6.2 
Glomerular Filtration Rate........................................ 106 
10.9.6.3 
Physical examination ............................................... 106 
10.9.6.4 
Heart failure signs and symptoms of special interest .. 106 
10.10 
Analysis of quality of life variables............................................... 107 
10.11 
Analysis of sub-study variables .................................................... 107 
11 GENERAL DEFINITIONS AND DERIVATIONS .................................... 107 
11.1 
Time windows ............................................................................. 107 
11.2 
Dates ........................................................................................... 108 
11.2.1 
Signed informed consent ................................................... 108 
11.2.2 
Screening date .................................................................. 108 


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11.2.3 
Randomization date........................................................... 109 
11.2.4 
Study treatment start date .................................................. 109 
11.2.5 
Study treatment end (EOT) date......................................... 109 
11.2.6 
Single-blind placebo run-in start date ................................. 109 
11.2.7 
Single-blind placebo run-in end date .................................. 109 
11.2.8 
Single-blind Macitentan run-in start date............................ 109 
11.2.9 
Single-blind Macitentan run-in end date............................. 109 
11.2.10 
Double-blind treatment start date ....................................... 109 
11.2.11 
Double-blind treatment end date ........................................ 110 
11.2.12 
End of study (EOS) date .................................................... 110 
11.3 
Baseline....................................................................................... 110 
11.3.1 
Macitentan run-in Baseline ................................................ 111 
11.4 
Study day..................................................................................... 111 
11.5 
Treatment emergent periods ......................................................... 111 
11.5.1 
Study treatment period ...................................................... 111 
11.5.2 
Double-blind treatment period ........................................... 111 
11.5.3 
Placebo run-in period ........................................................ 111 
11.5.4 
Macitentan run-in period ................................................... 111 
11.5.5 
Combined macitentan treatment period .............................. 112 
11.5.6 
Safety follow-up period ..................................................... 112 
11.5.7 
PTOP period ..................................................................... 112 
11.5.8 
End of Study (EOS) visit ................................................... 112 
11.5.9 
Duration of time on study .................................................. 112 
11.5.10 
Duration of PTOP ............................................................. 112 
11.6 
Subjects in Run-in........................................................................ 113 
11.7 
Run-in failures ............................................................................. 113 
11.8 
Randomized subjects.................................................................... 113 
11.9 
Conversion rules .......................................................................... 113 
12 HANDLING OF MISSING/INCOMPLETE DATE AND TIME FIELDS ... 114 
13 LIST OF SUMMARY TABLES, LISTINGS AND FIGURES .................... 118 
14 REFERENCES .......................................................................................... 118 
15 APPENDICES........................................................................................... 120 
 
 


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LIST OF TABLES 
 
Table 1 
Efficacy endpoints .............................................................. 41 
Table 2 
Definition of marked laboratory abnormalities ..................... 62 
Table 3 
Exclusions from Per-Protocol analysis Set ........................... 70 
Table 4 
Overview of the different analysis sets and their usage ......... 72 
Table 5 
Overview of summary tables for AEs .................................. 99 
Table 6 
Visit time windows NT-pro-BNP....................................... 107 
Table 7 
Safety Visit time windows and efficacy with similar  
schedule............................................................................ 108 
 
LIST OF FIGURES 
 
Figure 1 
Study design ....................................................................... 17 
Figure 2 
Study design in case of premature discontinuation of DB 
treatment ............................................................................ 18 
Figure 3 
Discontinuation of double- blind treatment period at  
Week 24 or beyond, per global protocol Version 6 ............... 19 
Figure 4 
Hierarchical testing strategy ................................................ 79 
 
LIST OF APPENDICES 
 
Appendix A 
Protocol synopsis, and schedule from Protocol version 6  
(6 February 2020) ............................................................. 120 
Appendix B 
Diuretics identified from Standard drug grouping* ............. 138 
Appendix C 
The Kansas City Cardiomyopathy Questionnaire Scoring 
Instructions ....................................................................... 140 
Appendix D 
PTs and SOCs for identification of HAESI ........................ 144 
 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
6-MWD  
6-minute walk distance 
6-MWT  
6-minute walk test 
ACE  
Angiotensin converting enzyme inhibitors 
AE  
Adverse event 
ALT  
Alanine transaminase 
ANCOVA  
Analysis of covariance 
ANOVA  
Analysis of variance 
ARB  
Angiotensin Receptor Blockers 
AST  
Aspartate transaminase 
ATC  
Anatomic Therapeutic Chemical 
BCRP  
Breast-Cancer Resistant Protein 
BMI  
Body Mass Index 
bpm  
Beats per minute 
CDDM  
Clinical Development Data Management 
CEC  
Clinical Event Committee 
CI  
Confidence interval 
CL  
Confidence limit(s) 
CO  
Cardiac Output 
COPD  
Chronic obstructive pulmonary disease 
CRF  
Case report form 
CRO  
Contract research organization 
CSR  
Clinical study report 
CV  
Cardiovascular  
DAOH  
Days Alive and Out of the Hospital 
DAU  
Daily accelerometer units 
DBP  
Diastolic Blood Pressure 
dPAP  
diastolic Pulmonary Arterial Pressure 


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DPG  
Diastolic Pulmonary Vascular Pressure Gradient 
DPS  
Data presentation specification 
dSAP  
diastolic Systemic Arterial Pressure 
DTS  
Data Transfer Specifications 
ECG  
Electrocardiogram 
ECSC  
European Community for Steel and Coal 
EF  
Ejection Fraction 
eGFR  
estimated Glomerular Filtration Rate 
EMA  
European Medicines Agency 
EOS  
End-of-study 
EOT  
End-of-treatment 
ESRD  
End Stage Renal Disease 
EudraCT  
European Clinical Trial Database 
FAS  
Full Analysis Set 
FC   
Functional Class 
FDA  
(US) Food and Drug Administration 
FEV  
Forced Expiratory Volume 
FVC  
Forced Vital Capacity 
GCP  
Good Clinical Practice 
HAESI  
Hepatic adverse events of special interest 
HDL  
High-Density Lipoprotein 
HF  
Heart Failure 
HFpEF  
Heart failure with preserved ejection fraction  
HLGT  
High Level Group Term 
ICE  
Integrated Computer Environment 
ICF  
Informed Consent Form 
ICH  
International Council on Harmonisation 
IDMC  
Independent Data Monitoring Committee 


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IxRS  
Interactive voice/web Recognition System 
IRT  
Interactive Response Technology 
IV  
Intravenous 
KCCQ  
Kansas City Cardiomyopathy Questionnaire 
KM  
Kaplan-Meier 
LAV  
Left Atrial Volume 
LAVI  
Left Atrial Volume Index 
LDL  
Low-Density Lipoprotein 
LTA  
liver test abnormality 
LVPA  
Light to vigorous physical activity 
LVEDP  
Left Ventricular End Diastolic Pressure 
LVEF  
Left Ventricular Ejection Fraction 
MDRD  
Modification of diet in renal disease 
MedDRA  
Medical Dictionary for Regulatory Activities 
MI  
Myocardial infarction 
MLA  
Marked laboratory abnormality 
mPAP  
mean Pulmonary Arterial Pressure 
MRA  
Mineralocorticoid receptor antagonists 
mRAP  
mean Right Arterial Pressure 
MRI  
Macitentan Run-In 
MR-proANP  
Mid-Regional pro-Atrial Natriuretic Peptide 
mSvO2  
mixed venus Oxygen Saturation 
NDD  
Number of days dead 
NDH  
Number of days in hospital 
NT-pro-BNP  
n-terminal pro-Brain Natriuretic Peptide 
NYHA  
New York Heart Association 
OL  
Open-label 
OLE  
Open-label enrollment 


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PAP  
Pulmonary Arterial Pressure 
PASP  
Pulmonary Artery Systolic Pressure 
PAWP  
Pulmonary Artery Wedge Pressure 
PD  
Protocol Deviation 
PGA  
Patient Global Assessment 
PFT  
Pulmonary Function Test 
PPS  
Per-Protocol analysis set 
PRI  
Placebo Run-In 
PT  
Preferred Term 
PTOP  
Post-Treatment Observation Period 
PVR  
Pulmonary Vascular Resistance 
RHC  
Right heart catheterization 
SAE  
Serious adverse event 
SAF  
Safety set 
SAP  
Statistical analysis plan 
SAS®  
Statistical Analysis Software 
SBP  
Systolic Blood Pressure 
SCR  
Screened analysis set 
SDTM  
Study Data Tabulation Model  
SI  
International system of units 
SMQ  
Standardised MedDRA Query 
SOC  
System organ class 
sPAP  
systolic Pulmonary Arterial Pressure 
SpO2  
Oxygen saturation 
sSAP  
systolic Systemic Arterial Pressure 
SSAS  
Sub-study Analysis Set 
TAPSE  
Tricuspid Annular Plane Systolic Excursion 
TDD  
Total Daily Dose 


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TDI  
Total Duration of Interruptions 
TEAE  
Treatment-Emergent Adverse Event 
TFU  
Total Expected follow-up time 
TSH  
Thyroid Stimulating Hormone 
ULN  
Upper limit of the normal range 
USA  
United States of America 
VLDL  
Very Low-Density Lipoprotein 
V/Q  
Ventilation/perfusion 
WHF  
Worsening of Heart Failure 
WHO  
World Health Organization 
WHO DDE  
World Health Organization Drug Dictionary Enhanced 
 


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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP), for study AC-055G202 / SERENADE, 
describes in detail the methods, conduct and content of statistical analyses of efficacy, 
safety and quality of life endpoints planned for the final Clinical Study Report (CSR). 
Source data for the analyses are provided as Statistical Analysis Software (SAS®) 
data sets according to Clinical Data Interchange Standards Consortium Study Data 
Tabulation Model (SDTM). Source data are those provided by Actelion Clinical 
Development Data Management (CDDM) via the Integrated Computer Environment 
(ICE) system. 
A separate programming specification and conventions document is prepared in line 
with this SAP to provide programming details necessary to implement the statistical 
analysis. 
2 
STUDY DESIGN AND FLOW 
Protocol version 6 (6 February 2020, D-20.020) is used as a reference and the 
synopsis can be found in Appendix A.  
2.1 Study design 
This is a prospective, multi-center, double-blind, randomized, placebo-controlled, 
parallel-group Phase 2b study designed to evaluate whether macitentan 10 mg reduces 
n-terminal pro-Brain Natriuretic Peptide (NT-pro-BNP) versus placebo at Week 24 
in subjects with heart failure with preserved ejection fraction (HFpEF) and pulmonary 
vascular disease. 
It was planned that approximately 300 subjects would be randomized in a 1:1 ratio to 
either macitentan or placebo. Treatment allocation is stratified by NT-pro-BNP level 
at macitentan run-in entry (< 1000 pg/mL and ≥ 1000 pg/mL). The study is being 
conducted in 77 sites in 17 countries. 
Following closure of Screening on 27 December 2019, it is expected that 
approximately 140 subjects will be randomized. 
The study comprises of a screening period, a single-blind run-in period, a 
double-blind treatment period and a safety follow-up period as described below and 
depicted in Figure 1. 
Run-in period: 
The run-in period starts with a single-blind placebo run-in of 4 weeks (Visit 2 to the 
day before Visit 4), followed by a single-blind macitentan run-in of 5 weeks, from 
the first dose of macitentan at Visit 4 to the subject’s randomization at Visit 6. The 


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placebo and macitentan run-in periods are single-blind as only the subject is blinded 
to the identity of the treatment. 
Treatment period: 
The double-blind treatment period consists of a core phase up to Week 24 (Visit 11), 
followed by an extension phase lasting for 28 weeks, and ending on the day of last 
study treatment intake.  
Subjects who are in core phase at the time of global protocol version 6 approval will 
stop study treatment at Week 24 (Visit 11), will not proceed to the extension phase of 
the study and may be eligible to transition to SERENADE OL (AC-055G203) at this 
time point. 
Subjects who have passed Week 24, i.e., are in the extension phase at the global 
protocol version 6 approval, will return for an end-of-treatment (EOT) visit within 
2 months, but no later than Week 52 and will then proceed to enroll in the 
SERENADE OL study, if eligible, or complete end-of-study (EOS), if not eligible to 
enter SERENADE OL. 
Safety follow-up period: 
The safety follow-up period starts on the day after the last dose of study treatment 
and ends 30 days thereafter with the EOS visit, or Post-Treatment Observation Period 
(PTOP) PTOP1 visit for those subjects who prematurely discontinue study treatment 
(see the definition later in this section). 
End-of-study: 
EOS is reached when the safety follow-up period or, if applicable, PTOP have been 
completed. For an individual subject, the study is completed with the EOS visit, which 
is either Visit 14 (safety follow-up visit) for subjects who completed the treatment 
period as per protocol, or PTOP4 for subjects who prematurely discontinued study 
treatment (see also section “Post-treatment observation period” below) / PTOP2 
(applicable for subjects who consented to global protocol version 6).  
SERENADE OL extension (study AC-055G203): 
Subjects who remained in SERENADE (main study) for 52 weeks after 
randomization may be eligible for transition to the SERENADE OL study. Subjects 
who consented to global protocol version 6, are eligible to transition to SERENADE 
OL if they remained in the main study for at least 24 weeks. 
The overall study design is depicted in Figure 1. 
 
 


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Figure 1 
Study design  
 
 
A) Study treatment completed as per protocol: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Macitentan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
Visit 1                2    3 3a() 4   5 5a()      6  7()  8          9          10         11              12                  13             
 
 
Time       30 d           4 w                 5 w        D1  W1  W4        W8      W16     W24          W36           W52    30 d 
Screening   
period 
Placebo 
run-in 
Macitentan 
 run-in 
Core phase 
Extension phase 
Follow-up 
period 
 
 
 
D = Day; d = days, EOT = End-of-treatment, EOS = End-of-study; W = Week; w = weeks. 
Post-treatment observation period: 
Subjects who prematurely discontinue double-blind study treatment are asked to enter 
a PTOP, which ends 52 weeks after randomization. The PTOP starts with visit 
PTOP1, which corresponds to the safety follow-up visit. Thereafter, visits are 
scheduled at Week 24 (PTOP2), Week 36 (PTOP3) and Week 52 (PTOP4), 
depending on time point of premature discontinuation. If the safety follow-up visit 
(PTOP1) falls within the time-window of any of the other PTOP visits, then the 
corresponding PTOP visit and the safety follow-up visit can be combined (see 
protocol Table 4 Visit and assessment schedule for subjects entering the PTOP). 
Subjects who have not completed Week 24 at the time of global protocol version 6 
approval, will end the PTOP at Week 24 (PTOP2). Subjects who are past Week 24 at 
the time of consenting to global protocol Version 6 will return for an EOT visit within 
2 months but no later than Week 52 and will then proceed to enroll in the OL study, 
if eligible, or complete EOS, if not eligible to enter SERENADE OL. 
In Figure 2, an example of PTOP is shown for subject prematurely discontinuing the 
double-blind study treatment at Week 8 (Visit 9). 
Randomization 
EOT 
EOS 
14 
Double-blind treatment period 
Enrollment in 
SERENADE 
OL (optional) 


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Figure 2 
Study design in case of premature discontinuation of double-
blind treatment  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Macitentan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
Visit 1          2    3 3a() 4    5  5a()           6                     EOT    PTOP1   PTOP2      PTOP3      PTOP4 
 
 
 
 
 
Time       30 d           4 w            5 w               D1                              Safety FU   W24          W36           W52     
Screening   
period 
Placebo 
run-in 
 
Macitentan 
 run-in 
 
 
 
 
D = Day; d = days, EOT = End-of-treatment, EOS = End-of-study; W = Week; w = weeks, PTOP = Post-Treatment 
Observation Period. 
*PTOP visits to be performed depending on the time point of premature discontinuation of study treatment. 
Patients who had not passed Week 24 will remain in PTOP until Week 24. 
 
In Figure 3, an example of discontinuation of double-blind treatment period at Week 
24 or beyond, per global protocol version 6. 
 
 
 
 
 
Premature discontinuation 
EOS 
Post-treatment observation period* 
Enrollment in 
SERENADE 
OL (optional) 


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Figure 3 
Discontinuation of double-blind treatment period at Week 24 or 
beyond, per global protocol version 6 
 
  
 
 
 
 
 
 
D = Day; d = days; EOT = End-of-Treatment; EOS = End-of-Study; W = Week; w = weeks. 
2.2 Study visit and assessment schedule 
The schedule of visits and assessments together with the protocol synopsis can be 
found in Appendix A (protocol Table 1, Table 2, Table 3, and Table 4). 
3 
OBJECTIVES 
3.1 Primary objective(s) 
The primary objective of the study is to evaluate whether macitentan 10 mg reduces 
NT-pro-BNP versus placebo at Week 24 in subjects with HFpEF and pulmonary 
vascular disease. 
3.2 Secondary objectives 
The secondary objective of the study is to evaluate the effect of macitentan 10 mg as 
compared to placebo on: 
• Quality of life  
• Daily physical activity  
• Worsening of heart failure.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Macitentan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
Visit 1         2    3 3a() 4   5 5a()      6  7()  8           9          10        11                             
 
 
 
 
 
Time       30 d           4 w                 5 w  D1  W1  W4       W8      W16     W24          60 d                30 d 
Screening   
period 
Placebo 
run-in 
Macitentan 
 run-in 
Core phase                
Time-window 
for performing 
EOT 
Follow-up period 
Enrollment in SERENADE OL 
(optional) 
Randomization 
14 
EOT
      EOS 


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3.3 Other objectives 
The other objectives are: 
• To evaluate the effects of macitentan 10 mg as compared to placebo on:  
− Cardiovascular deaths and hospitalizations 
− New York Heart Association (NYHA) functional class (FC) 
− Clinical composite outcome measure 
− Echocardiographic measures of cardiac function and structure.  
3.4 Safety objective 
To evaluate the safety and tolerability of macitentan 10 mg in subjects with HFpEF 
and pulmonary vascular disease. 
4 
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN 
THE STUDY PROTOCOL  
4.1 Changes to the analyses planned in the study protocol 
4.1.1 Geographical regions and other subgroup analyses 
Section 10.3.2.5 (subgroup analyses) in the protocol describes four geographical 
regions (North America, South America, Western Europe, Eastern Europe). 
Considering the closure of Screening on 27 December 2019, the following three 
geographical regions are applicable: Americas (merge of North and South America 
subjects), Western Europe, Eastern Europe. 
The following subgroups were added with respect to the protocol section 10.3.2.5: 
• Age (18–64, 65–84, ≥ 85 years)  
• Renal function at Baseline: normal, mild decrease, moderate decrease, severe 
decrease / end stage renal disease (ESRD) 
• Obesity (body mass index [BMI] ≥ 30 vs < 30).  
4.1.2 Baseline 
Section 10.3.1 of the protocol defines Baseline as the last non-missing value observed 
among all measures collected during placebo and macitentan run-ins, up to the day of 
randomization (Visit 6).  
• For accelerometry however, evaluable measures are observed among data 
collected over 9 days following a visit. Therefore, the last non-missing value 


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observed up to day of Visit 6 would result in using the assessment following 
Visit 5, i.e., 9 days starting after 1 week of single-blind macitentan treatment. 
Instead the following will apply: 
− Accelerometry Baseline [Section 5.5.2.2] is defined as the evaluable 
measures observed among data collected over 9 days following Visit 3 
(during placebo run-in).   
− Visit 3 is selected because these data are obtained while the subject is still 
on placebo. Visit 3 data are preferred to data collected at Visit 2 (placebo 
run-in) as any potential changes in heart failure (HF) treatment are 
expected to occur at the beginning of the placebo run-in, and so the 
clinical stability of subjects is expected to be better established at Visit 3 
as compared to Visit 2.  
− In case of missing evaluable data during placebo run-in following Visit 3, 
the training period following Visit 2 (placebo run-in) will be used.  
− In the rare event accelerometer data are not evaluable both at/after Visit 2 
(placebo run-in) and Visit 3, then accelerometer data collected during the 
9 days following Visit 5 will be used.  
− Further details for defining accelerometry Baseline are described in 
Section 5.5.2.2.  
• For safety variables [Section 5.6] the baseline is the last non-missing assessment 
obtained before or on the day of the start of macitentan single-blind run-in 
treatment. This is to capture changes in safety after first intake of macitentan and 
is referred to as the macitentan run-in baseline. 
4.1.3 Percent of baseline in MR-proANP over time 
Mid-Regional pro-Atrial Natriuretic Peptide (MR-proANP) is collected at Week 24 
and Week 52 post baseline. Fewer subjects are expected to have a Week 52 
assessment following the protocol amendment (global protocol version 6) to reduce 
the duration of the study to 24 weeks. Therefore, the random coefficient regression 
model scheduled in the protocol section 10.3.4.9 will be replaced by an analysis of 
covariance (ANCOVA) model at Week 24 adjusting for the log of the variable 
baseline value.  
4.1.4 Display of listings  
Section 10.1.8 of the protocol specifies that listings will be prepared on the Full 
Analysis Set (FAS). In order to include all subjects’ data, including data from subjects 


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discontinuing during the single-blind run-in periods and screening failures, listings 
will be presented using the Screened (SCR) Set or PRI set where applicable [see 
Section 7.2]. 
4.2 Changes in the conduct of the study / data collection 
4.2.1 The following protocol amendments were performed:  
Protocol Version 2, amendment 1 - 8 February 2017 
• Implementation of additional safety monitoring measures post-macitentan first 
dose, as requested by the FDA. 
Protocol Version 3, amendment 2 - 12 April 2017 
• Update of exclusion criteria and forbidden medication to address FDA request to 
avoid co-administration of macitentan with breast-cancer resistant protein 
(BCRP) substrate medications. 
Protocol Version 4, amendment 3 - 10 April 2018 
• To define EOS for subjects who are eligible to enter the SERENADE OL 
extension study (AC-055G203)  
• To establish a Clinical Event Committee (CEC) to review and adjudicate 
worsening of heart failure events, as well as all reasons for hospitalization and 
death.  
• 
To revise the inclusion and exclusion criteria and run-in failure criterion 3b. 
• Changes made to statistical methods section to account for: subjects entering the 
SERENADE OL; the introduction of CEC; and the amendment to allow  
NT-pro-BNP values measure at screening to be used for stratification at the time 
of treatment assignment 
• Change to definition of placebo run-in analysis set and macitentan analysis set. 
Protocol Version 5, amendment 4 - 8 March 2019 
• To introduce a new efficacy endpoint, the 6-minute walk test (6-MWT), as part 
of a sub-study to assess the change from baseline in exercise capacity [see 
Section 5.7].   
• To remove the 8-hour post-macitentan first-dose safety monitoring period at the 
start of macitentan run-in and add 2 safety phone calls during the run-in period. 
• To change the testing hierarchy of the key secondary efficacy endpoints. The 
Kansas City Cardiomyopathy Questionnaire (KCCQ) was moved to the first 


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secondary endpoint in the hierarchy, with accelerometry (which used to be the 
first secondary endpoint) moved then to the second position, followed by ‘time to 
worsening HF events’. 
• To introduce a new hierarchical composite exploratory efficacy endpoint which 
combines hard (death, hospitalizations) and soft (functional capacity, quality of 
life) endpoints to allow for a more complete and broader assessment of clinical 
benefit of macitentan in HFpEF. The composite endpoint will be analyzed using 
the win ratio approach that accounts for clinical priorities [Pocock 2012]. This 
was subsequently removed in protocol Version 6 due to the reduced sample size, 
and stopping assessment of functional capacity (6MWD). 
Protocol Version 6, amendment 5 - 6 February 2020 
• The early termination of recruitment into the study since the study failed to meet 
subject recruitment targets and completion of the study within reasonable timeline 
is not realistic. The sample size was updated to reflect the early termination of 
recruitment. 
• To reduce the length of the double-blind treatment period to 24 weeks. The 
rationale for this change is that Week 24 is the pre-defined time point for assessing 
the primary endpoint, as well as the key secondary endpoints. The secondary 
endpoint of time to worsening heart failure (WHF) event however was planned to 
be assessed up to Week 52 to gather meaningful information for the preparation 
of a pivotal clinical trial development program. Due to the reduced sample size, 
the number of WHF events is expected to be too low for a meaningful analysis of 
time to WHF. The double-blind treatment period will thus be stopped at Week 24, 
and eligible subjects will be able to transition to SERENADE OL at this 
time point. Subjects who have already completed the Week 24 visit, will be 
scheduled to come back for an EOT visit within 60 days and will proceed to enroll 
in the OL study, if eligible.  
• To remove the CEC which was appointed to review and adjudicate in a blinded 
fashion WHF events, the reasons for hospitalization and causes of death. The 
rationale is based on the reduction of the double-blind treatment period from 
52 weeks to 24 weeks, coupled by the low occurrence of WHF events which will 
not allow for meaningful conclusions to be drawn. Removal of the CEC does not 
affect safety monitoring and therefore the decision was also endorsed by the 
Independent Data Monitoring Committee (IDMC).  


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• To re-schedule accelerometry to be performed 9 consecutive days prior to Week 
24 (Visit 11/PTOP2) for subjects completing Week 24 (Visit 11) under 
Amendment 5 to ensure assessment performed on double-blind treatment.  
• To stop sub-study assessments (6-MWT and Borg Dyspnea Index), as number of 
subjects participating in the sub-study is too low to allow for meaningful 
interpretation of results. 
Note: Only the main reasons for the protocol amendments are described. No subjects 
were enrolled prior to amendments 1 and 2. 
4.3 Clarifications concerning endpoint definitions and related variables 
or statistical methods 
4.3.1 Previous and concomitant medications  
Section 5.2.1 of the protocol specifies definitions for a previous therapy, a 
study-concomitant therapy and a study treatment-concomitant therapy for the purpose 
of capturing these in the case report form (CRF). The definitions for previous therapy 
and treatment concomitant therapy are adapted in this SAP Section 5.2.5 for the 
purpose of presenting summaries for reporting and interpreting the results in the CSR.  
The SAP changes to the protocol are as follows: 
• Previous therapy is relative to first dose rather than signing of informed consent. 
• Treatment concomitant therapy period is extended up to 30 days after study 
treatment end. 
• Study-concomitant therapy is not required for reporting of results in the CSR.  
4.3.2 Efficacy endpoints evaluated over 52 weeks 
Sections 6.1.2 and 6.1.3 of the protocol specify efficacy event endpoints as evaluated 
over 52 weeks. Prior to global protocol version 6 subjects were followed up to 
Week 52, except where subjects prematurely discontinue study. Under global 
protocol version 6 the follow-up period was reduced to 24 weeks, except where 
subjects had already passed Week 24 (Visit 11). Therefore, it is expected that the 
follow-up will be varied across subjects. All subjects visit assessment information 
available will be considered up to Week 52. 
The time to event variables in sections 10.2.2.3 and 10.2.3 of the protocol are defined 
as events occurring until EOS/ open-label enrollment (OLE). In order not to lose any 
information and reduce risk of bias or informative censoring and due to the shorter 


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follow-up time for subjects enrolled under global protocol version 6, the approach to 
EOS/ OLE is applied consistently where applicable in the CSR SAP. 
5 
DEFINITIONS OF VARIABLES 
This section provides the definitions and sources for all variables used in the analyses, 
including specifications for the derivations. 
General recurrent definitions (e.g., study treatment start date, baseline) or unit 
conversion are described in detail in Section 11. 
5.1 Screening and run-in failures and disposition 
5.1.1 Screening failure  
Screening failures are all subjects with answer ‘NO’ to the question ‘Did the subject 
enter the single-blind run-in period?’ in the “Eligibility for Placebo Run-in” CRF. 
The primary reason for screening failure is provided in the same CRF (‘Subject 
withdrew consent’, ‘Not eligible as per inclusion/exclusion criteria’, ‘Lost to follow-
up’ or ‘Other’). In the rare case that the reason for screening failure is not provided 
in the CRF for a subject considered a screening failure, the reason is categorized as 
‘Unknown’.  
It is permitted to re-screen subjects twice, if the reason for non-eligibility is transient 
(e.g., abnormal laboratory test, insufficient wash-out period for a forbidden 
medication). All screening assessments except pulmonary function tests (PFTs) must 
be repeated at the time of re-screening. If the screening echocardiography was done 
within 2 months of the re-screening visit, it doesn’t need to be repeated. 
Subjects who failed screening more than once will be counted only once (and only 
the reason for the last screening failure will be included in the summary table). If a 
subject is screened more than once and subsequently enters the single-blind placebo 
run-in period, the subject is not considered a screening failure. 
5.1.1.1 Unmet eligibility criteria for Placebo Run-in 
Inclusion criteria not met, and exclusion criteria met are collected in the CRF for 
subjects who are not eligible for placebo run-in as per the inclusion/Exclusion criteria 
(CRF; Eligibility for Placebo Run-in). For re-screened subjects it is taken from the 
latest re-screening. Note a subject may have multiple criteria which are reported 
separately to the primary reason for screening failure described above in 
Section 5.1.1.  


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5.1.2 Single-blind placebo run-in disposition and failures 
A subject is considered to have withdrawn during placebo run-in / not entered into 
macitentan run-in if he/she entered the single-blind placebo run-in period but 
eventually did not enter the single-blind macitentan run-in period as identified from 
the answer to the CRF question “Did the subject enter the macitentan run-in period?” 
(CRF; Eligibility - Macitentan Run-in).  
If the answer to this question is “No”, the reasons provided in the CRF: ‘Subject 
withdrew consent’, ‘Not eligible as per inclusion/exclusion criteria’, ‘Placebo run-in 
failure’, ‘Lost to follow-up’ or ‘Other’ (CRF; Eligibility - Macitentan Run-in) are 
used as the primary reason for not entering macitentan run-in period.  
Run-in failure criteria are collected on the CRF for subjects who met any run-in 
failure criteria during the placebo run-in (CRF; Eligibility - Macitentan Run-in). 
5.1.2.1 Unmet eligibility criteria for Macitentan Run-in 
Exclusion criteria are collected on the CRF for subjects who met any of the exclusion 
criteria during the placebo run-in (CRF; Eligibility - Macitentan Run-in). Note a 
subject may have multiple criteria which are reported separately to the primary reason 
for not entering macitentan run-in described above in Section 5.1.2. 
In addition, subjects on a stable dose of heart failure (or cardiovascular) medication 
for 7 days prior to the Macitentan Run-in Visit 4 are captured on the same CRF (as 
“yes” /” no”).  
5.1.3 Single-blind macitentan run-in disposition and failures 
A subject is considered to have withdrawn during macitentan run-in / not entered into 
double-blind if he/she entered the single-blind macitentan run-in period but 
eventually was not randomized as identified from the answer to the question “Was 
the subject randomized?”. If the answer to this question is “No”, the reasons provided 
in the CRF: ‘Subject withdrew consent’, ‘Not eligible as per inclusion/exclusion 
criteria’, ‘Macitentan run-in failure’, ‘Lost to follow-up’ or ‘Other’ (CRF; 
Randomization) are used as the primary reason for not entering double-blind period.  
Run-in failure criteria are collected on the CRF for subjects who met any run-in 
failure criteria during the macitentan run-in (CRF; Eligibility - Double-blind 
Treatment Period). 
5.1.3.1 Unmet eligibility criteria for Double blind treatment period 
Exclusion criteria are collected on the CRF for subjects who met any of the exclusion 
criteria during the macitentan run-in (CRF; Eligibility - Double-blind Treatment 


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Period). Note a subject may have multiple criteria which are reported separately to 
the primary reason for not entering double-blind described above in Section 5.1.3. 
In addition, a subject on stable cardiovascular medication for 7 days prior to Visit 6 
(randomization) is captured on the same CRF (as “yes” /” no”). 
5.2 Subject characteristics 
If a subject is screened more than once, only the data assessed during the latest 
successful re-screening attempt (subject did not fail screening / entered placebo run-
in) are displayed and included in any analysis. Exceptions to this rule are applied 
where data from earlier visits may be used if not available at the latest successful re-
screening attempt as follows:  
• Historical data such as right heart catheterization (RHC) and PFTs, the data 
coming from an earlier screening are included in the corresponding analysis if not 
available at the successful (re-)screening attempt.  
• For echocardiography, the data coming from an earlier screening visit are 
considered. 
• NT-pro-BNP (from central laboratory only). 
• Characteristics that will not change including sex, race, ethnicity and height may 
be used from previous screening visits.  
5.2.1 Demographics 
Demographic data at screening comprise age (years; continuous and categorical), sex, 
ethnicity, race, height (cm), weight (kg) and BMI (kg/m2; continuous and 
categorical). Demographics of the subjects are taken from the Screening visit (Visit 1) 
or Re-Screening visit (age, weight, height, BMI) where subject is re-screened. 
The following categories are defined for demographic variables: 
• Age (years): 18–64, 65–84, ≥ 85  
Note the above categories for age are the same as those required for disclosure to 
EudraCT and ClinicalTrials.gov. 
• BMI (kg/m2): < 18.5; ≥ 18.5 – < 25; > 25 – < 30; > 30 – < 40; > 40 
• BMI (kg/m2): < 30; ≥ 30, for the obesity evaluation 
• Race (Black or African American / American Indian or Alaska Native / Native 
Hawaiian or Other Pacific Islander / Asian / White / Other / Not applicable) 


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• Geographical region: considering the closure of Screening on 27 December 
2019, the following geographical regions are applicable: 
− Americas: North America (USA), South America (Argentina and Brazil) 
− Western Europe: Austria, Denmark, France, Germany, Spain, Sweden, 
United Kingdom. In addition, Israel is also considered part of this region 
− Eastern Europe: Bulgaria, Czech Republic, Hungary, Poland, Romania, 
Russia. 
Age, sex, race, and ethnicity are collected in the “Demographics” CRF. Country is 
determined from the site number and provide in the SDTM.DM dataset. 
The values of height, weight and BMI are recorded in the “Height, Body Weight & 
BMI” CRF. Conversion from imperial units to metric (international system of units 
[SI]) units is performed automatically in the CRF applying the conversion rules 
detailed in Section 11.9.  
BMI is calculated automatically in the CRF using the formula specified in 
Section 11.9 and will not be (re-) calculated for the analysis.  
5.2.2 Baseline disease characteristics  
The baseline disease characteristics are listed below: 
Specific Medical History (“Specific Medical History” CRF): 
• Time since most recent hospitalization for heart failure (years): expressed in 
number of years and determined in relation to the date of screening. It is calculated 
by firstly taking the difference between the date of screening and the date of most 
recent HF hospitalization, and secondly by dividing the result by 365.25. 
• Number of heart failure hospitalizations within the last 12 months 
• Anemia (Yes / No)   
• Hypertension (Yes / No)   
• Diabetes mellitus type II (Yes / No)   
• Chronic obstructive pulmonary disease (COPD; Yes / No) 
• Atrial fibrillation/flutter (Yes / No): subject is classified as having atrial 
fibrillation/flutter (Yes) if atrial fibrillation = Yes or atrial flutter = Yes, regardless 
if ongoing at screening or not. If both atrial fibrillation and atrial flutter are 
missing then atrial fibrillation/flutter is classified as missing, otherwise = No.  


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• Ischemic heart disease (Yes / No) 
New York Heart Association Functional Class - NYHA FC (“NYHA Functional 
Class” CRF): only Class II and III are allowed per inclusion criteria. 
Echocardiography (provided by central echocardiographic laboratory): 
• Left Ventricular Ejection Fraction (LVEF) [%]: classified as ≥ 40 - <50 and ≥ 
50%. These categories represent the mid-range Ejection Fraction (EF) and 
preserved EF. In the unexpected case we have LVEF < 40%, this sub-category 
will also be displayed.  
• Left Atrial Volume Index (LAVI) [mL/m2]  
• Lateral E/e’  
• Pulmonary Artery Systolic Pressure (PASP) [mmHg]. 
Laboratory: 
• NT-pro-BNP (pg/mL): value at screening from central laboratory only 
• NT-pro-BNP used as stratification factor as per the Interactive voice/web 
Recognition System (IxRS) value provided as continuous and categorical 
(< 1000 pg/mL and ≥ 1000 pg/mL) 
• Creatinine (μmol/L, SI units) 
• Estimated Glomerular Filtration Rate(eGFR) (mL/min/1.73m2) using the 
Modification of Diet in Renal Disease formula [see Section 11.9]. 
Presence of valvular disease (“Medical History” CRF):  
Any disease or diagnosis corresponding to one of the following preferred terms (PTs): 
‘Mitral Valve Repair’, ‘Mitral Valve Replacement’, ‘Mitral Valve Valvotomy’, 
‘Mitral 
Valve Commissurotomy’, ‘Aortic Valve Repair’, ‘Aortic Valve 
Replacement’, ‘Aortic Valve Valvotomy’. The definitions are based on a combination 
of MedDRA PTs) and Standardized MedDRA Queries (SMQs) which can be updated 
according to MedDRA version / SMQs updates and documented in the data 
presentation specification (DPS). 
Signs and symptoms of special interest (“Signs/Symptoms of special interest” 
CRF): 
• Peripheral edema (Yes / No / Not assessed) 
• 
Jugular venous distension (Yes / No / Not assessed). 


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5.2.3 Other baseline characteristics 
Other baseline characteristics include the following: 
• Pulmonary function tests (“Pulmonary Function Tests” CRF), including results 
of test performed during screening and historical PFT performed within 
12 months prior to Screening:  
o FEV1 (L)  
o FEV1 predicted (L) 
o FEV1 percent of predicted value (%)* 
o Forced Vital Capacity (FVC) (L) 
o FEV1/FVC (ratio)*, equations are those from the European Community 
for Steel and Coal (ECSC) [Quanjer 1993].   
*Calculated values provided in the CRF are not (re-) calculated. 
• Right heart catheterization (“Right Heart Catheterization” CRF) - where 
historical RHC values are available these are collected at Screening on the 
CRF form: 
o Heart rate (bpm) 
o Cardiac Output (CO) [L/min] 
o Systolic Pulmonary Arterial Pressure (sPAP) [mmHg]  
o Diastolic Pulmonary Arterial Pressure (dPAP) [mmHg] 
o Mean Pulmonary Arterial Pressure (mPAP)[mmHg] 
o Mean Right Atrial Pressure (mRAP)[mmHg] 
o Pulmonary Artery Wedge Pressure (PAWP)[mmHg] 
o Left Ventricular End Diastolic Pressure (LVEDP)[mmHg] 
o Systolic Systemic Arterial Pressure (sSAP) [mmHg]  
o Diastolic Systemic Arterial Pressure (dSAP) [mmHg]  
o Mixed Venus Oxygen Saturation (mSvO2) at rest [%] 
 
The following RHC values are calculated automatically within the CRF according to 
the algorithm in Section 11.9: 
o Pulmonary Vascular Resistance (PVR) [wood units]* 
o Diastolic Pulmonary Vascular Pressure Gradient (DPG) [mmHg]*. 
 
*Calculated values provided in the CRF are not (re-) calculated.  
 
• Renal function: the following categories are defined for renal function based 
on the eGFR (mL/min/1.73m2) from the abbreviated modification of diet in 
renal disease (MDRD) study [FDA 2010]:  
o Normal: ≥ 90 


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o Mild Decrease: 60 – < 90  
o Moderate Decrease: 30 – < 60 
o Severe Decrease: 15 – < 30 
o ESRD: < 15. 
5.2.4 Medical history 
Medical history is collected during the Screening visit (Visit 1, or re-screening visit 
where subject is re-screened) on the “Medical History” CRF. The original terms 
reported by the investigators are coded using the latest implemented version of 
MedDRA. 
Note: specific medical history [Section 5.2.4.1] are not collected on the main medical 
history CRF. Therefore, both sources of information are used in the general summary 
of medical history using the coded terms. 
5.2.4.1 Specific medical history  
Pre-defined specific medical history, including current medical conditions of special 
interest, for this population are collected during the Screening visit (Visit 1) on the 
“Specific Medical History” CRF. These predefined terms are also coded according to 
MedDRA.  
5.2.5 Previous and concomitant therapies 
All therapies as collected in the “Previous / Concomitant Medication” CRF including 
the therapies collected for subjects entering the PTOP.  
The original terms used by the investigators to describe therapies are assigned PTs 
and anatomic therapeutic chemical (ATC) classification code using the latest version 
of the WHO Drug dictionary enhanced (WHO DDE). 
Start and end dates that are incomplete or missing are handled according to the rules 
in Section 12. 
5.2.5.1 Previous therapies 
Previous therapy is defined as any therapy that was started prior to start date of study 
treatment and with an end date prior to the start date of study treatment (i.e., first dose 
of single-blind placebo run-in treatment, see definition in Section 11.2.4) or end date 
equal to start of study treatment with the flag ‘Ongoing at start of treatment?’ ticked 
“No”.  
If the end date is missing and the start date is prior to the date of study treatment start, 
then the therapy is considered as previous if ‘Ongoing at start of treatment?’ is ticked 
“No”. 


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Rules for handling missing and partial dates are detailed in Section 12. 
5.2.5.2 Baseline therapies  
Baseline therapy is defined as any therapy that was started prior to start date of study 
treatment with an end date after start date of study treatment or the end date is missing 
and ‘Ongoing at start of treatment?’ ≠’No’. It is used in describing therapies of special 
interest [see Section 5.2.5.6.]. 
5.2.5.3 Study-concomitant therapies 
Not applicable, not required for presentation of therapies. 
5.2.5.4 Study-treatment concomitant therapies 
Study-treatment concomitant therapy considers study treatment overall periods 
including single-blind placebo and macitentan run-in periods and double-blind 
treatment period.  
Study-treatment concomitant therapies are all the therapies that are ongoing at start 
of study treatment or initiated on or after study treatment start date and up to study 
treatment end (EOT) date [Section 11.2.5] + 30 days (inclusive).  
5.2.5.5 Post Study-treatment therapies 
Post study-treatment concomitant therapies are all the therapies that are initiated after 
the EOT date + 30 days.  
5.2.5.6 Therapies of special interest  
Therapies of special interest are based on recommendations for treatment of patients 
with HFpEF and include the following:  
• Loop diuretics, thiazides, other diuretics [see definition in Appendix B]  
• Beta blockers (Level 2 text: Beta blocking agents / ATC code: C07A) 
• Calcium channel blockers (Level 2 text: calcium channel blockers / ATC code: 
C08C and C08D) 
• ACE inhibitors or ARB (one category) (Level 2 text: AGENTS ACTING ON 
THE RENIN-ANGIOTENSIN SYSTEM / ATC codes: C09A, B, C and D) 
• MRAs (Level 2 text: POTASSIUM-SPARING AGENTS / ATC code: C03D) 
• Cardiac glycosides (ATC code: C01A). 
The definitions above can be updated according to WHO DDE updates. 


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5.2.5.7 Diuretics 
Diuretics are determined from all therapies as collected on “Previous / Concomitant 
Medication” CRF with ATC code starting with C03 (DIURETICS) and where 
ingredients include the diuretics listed in Appendix B [Subset of ingredients selected 
from Standardised Drug Groupings (Diuretics)]. These selected diuretic therapies are 
then coded according to the ingredient so that for example “Furosemide sodium” and 
“Furosemide” are both assigned type = “Furosemide”.   
Note for combination diuretics each component will be entered in the CRF separately 
together with the respective dose of each component so that the diuretic type and 
corresponding total daily dose (TDD) can be determined and to avoid double 
counting. 
Diuretics are further partitioned for placebo run-in, macitentan run-in and 
double-blind treatment periods to determine frequency of changes within a period. 
They are defined as: 
Placebo run-in concomitant diuretics: diuretic therapy initiated during the placebo 
run-in period [see definition in Section 11.5.3]. 
Macitentan run-in concomitant diuretics: diuretic therapy initiated during the 
macitentan run-in period [see definition in Section 11.5.4]. 
Double-blind treatment concomitant diuretics: diuretic therapy initiated during the 
double-blind treatment period [see definition in Section 11.5.2]. 
Baseline diuretics for placebo run-in: includes diuretic(s) taken on day prior to first 
dose of placebo run-in treatment [see Section 11.2.6].  
Baseline diuretics for macitentan run-in: includes diuretic(s) taken on day prior to 
first dose of macitentan run-in treatment [see Section 11.2.8].  
Baseline diuretics for double-blind treatment: includes diuretic(s) taken on day 
prior to first dose of double-blind treatment [see Section 11.2.10].  
Changes (increase / decrease) in diuretics in a period compared to the respective 
baseline are derived for the placebo run-in, macitentan run-in and double-blind 
concomitant diuretics as follows:  


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Increases in diuretic categorized as:  
• Increase total daily dose (TDD): TDD (at the time of new diuretic prescription) > 
baseline TDD. Calculated for oral diuretics only. Each time this happens is 
considered as an increase; 
• New diuretic where the diuretic type(s) ≠ baseline diuretic type(s) (each time this 
happens is considered as an increase); 
• New IV diuretic where route = INTRAVENOUS (each time this happens is 
considered as an increase). 
Decreases in diuretic: 
• TDD: TDD at the time of new diuretic prescription < baseline TDD. Each time 
this happens is considered as a decrease.  
Note any interruption of a diuretic and its re-introduction at the same dose is not 
considered as a change. 
TDD mg/day: is calculated for all oral diuretics according to frequency and the dose 
(mg). Where dose units are recorded as g or ug, the dose is converted to mg by 
multiplying or dividing by a factor of 1000, respectively. Other reported units cannot 
be converted to mg and therefore TDD cannot be derived and is set to zero. TDD 
(mg/day) is derived for each oral diuretic using coded values as follows: 
Frequency (coded)a 
Total daily dose (mg / day) 
Once a day 
Dose 
Twice per day  
2 × dose 
<X> times per day 
<X> × dose 
Every other day 
Dose / 2 
Twice per week  
2 × dose / 7 
<X> times per week 
<X> × dose / 7 
Every week  
dose / 7 
Every <X> weeks 
Dose /(7 × <X>) 
Every month 
Dose / 30.5 
Every year 
Dose / 365 
Missing, other codes  
0 
a: values coded to CONTINUOUS, ONCE, AS NEEDED, UNKNOWN and OTHER 
cannot be used to determine TDD and therefore TTD will be set to zero.  
Diuretics given via any other route (or where missing route) are not used in deriving 
TDD. TDD is set to zero if the above frequency coded terms are not assigned or if 
either frequency or dose are missing or not coded. Where more than one diuretic of 
the same type is taken in the same period / overlapping period then these are additive. 


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Diuretics of different types may not be summed for the TDD, i.e., furosemide 80 mg 
TDD should not be combined with Spironolactone 100 mg TDD. 
The start / end date of the diuretic flagged as a change identifies the duration of the 
change in the diuretic therapy. The start date is used to determine number of changes 
in the defined periods below. The end date is used in determining proximity timing 
of change relative to other study assessment including NT-pro-BNP at wWeek 24.  
5.2.6 Other subject characteristics  
• Women of childbearing potential (Yes / No): collected on the “Demographics / 
Re-Screening Demographics” CRFs together with reason for not being of 
childbearing potential. Any change in status is collected on the “Women of 
Childbearing Potential - Status Change” CRF. 
• Contraceptive methods: For females of child bearing potential, the 
contraceptive method used is recorded on dedicated “Contraception methods” 
CRF. Options include hormonal contraceptives as well as other birth control 
methods. The original terms used to describe hormonal contraceptives are coded 
using PTs from the most recent version of the WHO Drug dictionary. 
All contraceptive methods are listed together with the data for women of childbearing 
potential.  
5.3 Study treatment exposure and compliance 
5.3.1 Exposure 
The exposure is evaluated in terms of study treatment duration including study 
treatment interruptions and then in terms of actual weeks exposed to study treatment, 
excluding any interruptions. The double-blind treatment is the main period of interest 
to be evaluated. Other treatment periods are defined to evaluate the total exposure to 
macitentan for all subjects during the study and to assess compliance during 
macitentan run-in period. The data are recorded in the “Study Drug Log” CRF. See 
Section 11.2 for the definitions of treatment start / end date.  
Duration of double-blind treatment (weeks): time (in days) elapsed between the 
double-blind treatment start date and the double-blind study treatment end date + 1 
day divided by 7, regardless of any treatment interruptions, i.e., [(Double-blind 
treatment end - Double-blind treatment start +1)/7]. 


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Exposure of double-blind treatment (weeks): treatment duration adjusted for 
interruption defined as: 
Duration of double-blind treatment - Total Duration of Interruptions (TDI), 
where TDI is defined as the sum of duration of interruption over all interruption 
periods in double-blind treatment. For a single period, the duration of interruption 
(days) is time elapsed between the Interruption Start Date and the Interruption End 
Date, i.e., (Interruption End Date - Interruption Start Date), where Interruption Start 
Date is the Study Drug Log End Date with corresponding reason for treatment end 
being temporarily interrupted. Interruption End Date is the next chronological Study 
Drug Log Start Date after Interruption Start Date. In the event of partial or missing 
treatment start or end date, exposure is missing. If Interruption End Date cannot be 
derived as there is no next chronological Study Drug Log entry the exposure is 
missing.  
Exposure of double-blind treatment up to Week 24 (weeks): is derived in the same 
way as above except double-blind treatment end date is replaced by Week 24 
(Visit 11) date for subjects who continue treatment beyond Week 24. This exposure 
is adjusted only for interruptions occurring prior to Week 24 (Visit 11) date. If an 
interruption has start date < Visit 11 date and end date > Visit 11 date, then only the 
difference between Visit 11 date and start date is used for that interruption. 
Cumulative subject year exposure (years): is calculated by summing the duration 
of double-blind treatment for all subjects divided by 52. 
Total duration of macitentan treatment (weeks): is calculated, for all subjects who 
receive at least 1 dose of macitentan, as the time (in days) elapsed between the 
single-blind macitentan treatment start date and the last dose date of macitentan 
(double-blind or single-blind) + 1 day divided by 7, regardless of any treatment 
interruptions.  
Duration of singe-blind placebo run-in treatment (weeks): is the time (in days) 
elapsed between the single-blind placebo treatment start date and the single-blind 
study treatment end date + 1 day divided by 7, regardless of any treatment 
interruptions. 
Duration of singe-blind macitentan run-in treatment (weeks): is the time (in days) 
elapsed between the single-blind macitentan treatment start date and the single-blind 
macitentan treatment end date + 1 day divided by 7, regardless of any treatment 
interruptions. 


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5.3.2 Compliance with study treatment 
Double-blind study treatment compliance (%) is based on the study drug 
dispensing and accountability data recorded in the CRF “Study Drug Dispensing & 
Accountability”. It is determined using drug accountability data for the double-blind 
treatment, calculated as the total tablets dispensed at any time from Visits 6 - Visit 12 
minus total tablets returned for the corresponding bottle dispensed: 
Double-blind study-treatment compliance =  
[(total number of tablets dispensed at any time from Visit 6 onward− total number of 
tablets returned from Visit 8 onward) / Total number of tablets that should have been 
taken during double-blind period] × 100. 
The number of capsules that should have been taken during the double-blind 
treatment period is double-blind treatment duration (in days) as defined in 
Section 5.3.1, since macitentan 10 mg is taken once daily. 
Double-blind study treatment compliance (%) up to Week 24 is similarly 
calculated. 
Double-blind study-treatment compliance up to Week 24 =  
[(total number of tablets dispensed from Visit 6 to Visit 10 − total number of tablets 
returned from Visit 8 to Visit 11) / Total number of tablets that should have been 
taken during double-blind period within Week 24] × 100. 
The number of capsules that should have been taken during the double-blind 
treatment period up to Week 24 is double-blind treatment duration up to Week 24 (in 
days) as defined in Section 5.3.1. 
Compliance assessed at each visit by site personnel is calculated and entered in the 
CRF and is not (re-) calculated. The reasons for non-compliance since last visit are 
also collected in the CRF.  
Compliance to macitentan single-blind treatment during run-in period: is 
calculated in the CRF to assess this run-in criterion and will not be (re-) calculated 
for the analysis. 
5.3.3 Study treatment discontinuation  
Study treatment discontinuation for each period are identified in CRF as occurring 
during the single-blind placebo run-in, single-blind macitentan run-in, or during the 
double-blind treatment period. Premature discontinuation are collected in the “Study 
Drug Log” CRF are identified as those with a treatment end date and associated 


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reason ‘What was the reason for treatment end?’ answered ‘Premature 
Discontinuation’. For example, a subject is considered to have prematurely 
discontinued double-blind study treatment if the ‘reason for treatment end’ in the 
Study drug Log CRF is ‘PREMATURE DISCONTINUATION’ and the ‘Study 
Period’ is ‘DOUBLE-BLIND TREATMENT’.  
Reason for study treatment discontinuation are collected in the “Premature 
Discontinuation of Study Treatment’ CRF, full list of reasons is as follows: 
• 
Death 
• 
Lost to follow-up 
• 
Pre-specified study treatment discontinuation criteria 
• 
Exclusion criteria met during run-in 
• 
Run-in failure 
• 
Subject decision (adverse event [AE], Lack of efficacy, No reason provided, 
Other) 
• 
Physician decision (AE, Lack of efficacy, Other) 
• 
Sponsor decision (Study termination, Other). 
Note: with global protocol version 6, subjects will stop study treatment at Week 24 
(Visit 11) and may be eligible to transition to SERENADE OL at this time point. 
Subjects who have passed Week 24 at the time of consenting to global protocol 
version 6 will be scheduled to come back for an EOS visit within 2 months but no 
later than Week 52 and will then proceed to enroll in the OL study, if eligible.  
The reason for treatment discontinuation to be recorded in the eCRF for these subjects 
is ‘sponsor decision’, unless an additional reason led to discontinuation of study 
treatment (e.g., AE). 
Note: a subject should prematurely discontinue treatment only once during the study, 
i.e., should not enter subsequent treatment periods following a premature 
discontinuation. 
Subjects are evaluated by the investigator for completion of treatment within each 
treatment period via the CRF where the question ‘What was the reason for treatment 
end?’ is answered ‘Completed as per protocol’.  


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5.3.4 Study treatment adjustments or interruptions 
Study treatment dose adjustments are not permitted.  
A subject is considered to have had a study treatment interruption if the reason for 
treatment end is either ‘Temporarily interrupted due to an AE’ or ‘Temporarily 
interrupted not due to an AE’ (CRF; “Study Drug Log”). Study treatment 
interruptions are identified in CRF for the treatment period: single-blind placebo run-
in, single-blind macitentan run-in or double-blind treatment. 
5.4 Study discontinuation 
As per Section 8 of the protocol, a subject who completes 52 weeks of follow-up 
including the safety follow-up period is considered to have completed the study as 
per protocol, regardless of whether he/she has completed the double-blind treatment 
period as per protocol (subjects who prematurely discontinue double-blind study 
treatment are asked to enter the post-treatment observation period identified with 
available PTOP visit date).  
Therefore: 
• subjects entering the double-blind treatment period who did not prematurely 
discontinue the treatment [Section 5.3.3] with available EOS / Visit 14 
[Section 11.5.8] are considered completers; 
• subjects prematurely discontinuing the double-blind study treatment who entered 
PTOP with available PTOP4 Visit are considered completers; 
• subjects who enter the SERENADE OL are considered completers, except where 
a subject has a protocol deviation assigned (PD226) indicating that the subject did 
not complete the 52 weeks of follow-up before entering the SERENADE OL (this 
deviation is not applicable to subjects who signed the Informed Consent Form 
(ICF) v6 prior to entering OL extension) or, if the subject signed the ICF v6, 
he/she has a protocol deviation assigned (PD336) indicating that entered the 
SERENADE OL prior to Week 24 (i.e., Visit 11 or PTOP2); 
• subjects who do not enter the double-blind treatment period / are not randomized 
should continue with safety follow-up and complete EOS / Visit 14. These 
subjects are not considered completers in the summary of disposition. 
For subjects who prematurely discontinue the study, the reasons for study 
discontinuation are reported on a dedicated “Study Discontinuation” CRF and are as 
follows: 
• Death 


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• Lost to follow-up 
• Subject decision/Withdrawal of consent (AE, Lack of efficacy, No reason 
provided, Other) 
• Physician decision (AE, Lack of efficacy, Other) 
• Sponsor decision (Study termination, Other). 
The date of study discontinuation corresponds to the reason; date of death (as entered 
in the “Death” CRF); date of last successful contact for subjects lost to follow-up; 
date of subject decision, physician decision or when the subject was informed of 
sponsor decision as reported in the CRF “Study Discontinuation”.    
In the rare event a subject does not complete the study according to the definition 
above and there is no entry in the “Study Discontinuation” CRF, the subject is 
classified as a prematurely discontinuation with reason given as “unknown”.  
5.4.1 Study disposition by visit  
With the change in duration of double-blind treatment period per global protocol 
version 6 (see protocol section 3.1.1.8) subject follow-up will be more varied as:    
1. Subjects will stop study treatment at Week 24 (Visit 11). 
2. Subjects who have passed Week 24 at the time of consenting to global protocol 
version 6 will be scheduled to come back for an EOT visit within 2 months but 
no later than Week 52. 
3. Subjects previously completed study treatment at Week 52 (Visit 13), protocol 
version 5 or earlier. 
4. Subjects may prematurely discontinue study at any time. 
Therefore, subject meeting criteria 1 above will have visit assessments up to Week 24. 
Subjects meeting criteria 2 will have assessments performed up to at least Week 24 
and subsequent visit assessments will depend on the timing of the subject enrollment 
and approval of the protocol amendment at their local level.  
The disposition of subjects in the double-blind period will be determined by visit 
based on time of discontinuation and randomization.   


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5.5 Efficacy variables 
Efficacy endpoints of the study are summarized below: 
Table 1 
Efficacy endpoints 
Efficacy endpoints 
Planned in 
the protocol 
Primary efficacy endpoint 
 
• 
Percent of baseline NT-pro-BNP assessed at Week 24. 
Yes 
Secondary efficacy endpoints 
 
• 
Change from baseline to Week 24 in the clinical summary score (as 
assessed by the Kansas City Cardiomyopathy Questionnaire [KCCQ]).  
Yes 
• 
Change from baseline to Week 24 in accelerometer-assessed proportion of 
time spent in light to vigorous physical activity based on a threshold of > 
100 activity counts per minute.  
Yes 
• 
Time to worsening heart failure (WHF) event over 52 weeks (Up to EOS / 
OLE) 
Yes 
Other efficacy endpoints 
 
• 
Number of days alive and out of the hospital (DAOH) assessed over 52 
weeks (up to EOS / OLE)  
Yes 
• 
Time to first occurrence of the composite endpoint, which is defined as 
either HF death or HF hospitalization over 52 weeks (up to EOS / OLE)  
Yes 
• 
Time to first occurrence of a composite of CV death or CV hospitalization 
over 52 weeks (up to EOS / OLE) 
Yes 
• 
Number of hospital admissions (for HF) over 52 weeks (up to EOS / OLE) 
Yes 
• 
NYHA FC (improved/worsened/stable) at each post-baseline assessment 
Yes 
• 
Clinical composite outcome measure (‘worsened’, ‘unchanged’, 
‘improved’) based on NYHA class, patient global assessment and 
occurrence of death or HF hospitalization at each post-baseline assessment 
Yes 
• 
Change from baseline in the KCCQ overall summary score as well as 
clinical summary score and physical limitations score over time 
Yes 
• 
Percent of baseline NT-pro-BNP over time 
Yes 
• 
Change from baseline in accelerometer-assessed physical activity variables 
over time 
Yes 
• 
Proportion of time spent in physical activity at each time assessment 
Yes 
• 
Change from baseline in echocardiography left and right heart function at 
Weeks 24 and 52 
Yes 


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Efficacy endpoints 
Planned in 
the protocol 
• 
Percent of baseline MR-proANP over time 
Yes 
• 
Patient global assessment (PGA) 
No 
CV ꞊ Cardiovascular; DAOH ꞊ Number of days alive and out of the hospital; EOS ꞊ End-of-study; FC ꞊ Functional 
Class; HF ꞊ Heart Failure; KCCQ ꞊ Kansas City Cardiomyopathy Questionnaire; MR-proANP ꞊ Mid-Regional 
pro-Atrial Natriuretic Peptide; NT-pro-BNP ꞊n-terminal pro-Brain Natriuretic Peptide; NYHA ꞊ New York Heart 
Association; OLE ꞊ Open-label enrollment; PGA ꞊ Patient global assessment; WHF ꞊ worsening heart failure. 
Prior to global protocol version 6 subjects were followed up to Week 52, except where 
subjects prematurely discontinue study. Under global protocol version 6 the 
follow-up period was reduced to 24 weeks, except where subjects had already passed 
Week 24 (Visit 11). Therefore, it is expected that the follow-up will be varied across 
subjects. All subjects efficacy assessment information available will be considered up 
to Week 52. 
Except where otherwise specified, baseline [Section 11.3] for efficacy variables is 
defined as the last non-missing value observed among all measures collected during 
placebo and macitentan run-ins, up to and including the start of double-blind 
treatment date [Section 11.2.10]. Therefore, the baseline is expected to be the Visit 6 
(Randomization Day 1) assessment unless missing or as specified otherwise for 
accelerometer data [Section 5.5.2.2] or as determined by the scheduled visit 
assessments (Screening for echocardiography, see Appendix A, protocol Table 1).   
Efficacy data for NT-pro-BNP are provided via a central laboratory (Covance). The 
results of the NT-pro-BNP are considered to be potentially un-blinding. As per 
protocol Section 11.3, the clinical trial team are blinded to the NT-pro-BNP results 
from all visits post randomization Visit 6, until un-blinding of the study post-database 
lock.  
All assessments recorded after start of double-blind treatment [Section 11.2.10] will 
be assigned to the most appropriate study visit according to the best fitting 
time-window for that assessment as detailed in Section 11.1. Assessments recorded 
before or on double-blind treatment start date (i.e., Visit 1/Screening, Visit 4/W4-R, 
Visit 6/W9-R/D1) will not be assigned with the same criteria, but evaluated according 
to the scheduled visit assigned. 
5.5.1 Primary efficacy variable(s) 
The primary efficacy variable is the percent of baseline NT-pro-BNP at Week 24. It 
is calculated as the ratio of the Week 24 NT-pro-BNP value over baseline value, 
expressed in percentage, i.e., as 100 times the Week 24 value divided by the baseline 


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value. Reduction in NT-pro-BNP (ratio < 100) is associated with a clinical 
improvement. 
For subjects without an available NT-pro-BNP value at Week 24, the last available 
value observed before Week 24 (including baseline) will be carried forward and 
considered for the main analysis [see Section 10.6.2].   
5.5.2 Secondary efficacy variables 
5.5.2.1 Quality of life: KCCQ Clinical summary score at Week 24  
The first key secondary efficacy variable is the clinical summary score as assessed by 
the Kansas City Cardiomyopathy Questionnaire (KCCQ), expressed as change from 
baseline to Week 24: 
• KCCQ clinical summary score at Week 24 - Baseline KCCQ score. 
Baseline score is the Visit 6 value (according to the schedule of assessment this is the 
first time KCCQ is assessed). Hence, if value at Visit 6 is missing then baseline is 
missing and change from baseline cannot be determined for this subject.  
For subjects who died before Week 24, the missing score at Week 24 will be set to 0: 
otherwise, the last available value observed before Week 24 (including baseline) is 
carried forward and considered for the analysis. 
The algorithm for the derivation of the KCCQ clinical summary scores is detailed in 
Appendix C.  
5.5.2.2 Accelerometer-assessed light to vigorous physical activity at Week 24 
The second key secondary efficacy variable is the proportion of time spent in light to 
vigorous physical activity (LVPA) based on a threshold of > 100 activity counts per 
minute, expressed as change from Baseline to Week 24.  
Physical activity is assessed via accelerometer device. The accelerometer is given to 
the subject at Visit 2 (D1-R start of placebo run-in) and the subject will wear the 
device daily during waking hours until Visit 3 (W1-R). This period is considered a 
training period. Subsequent assessments via accelerometry are performed for 9 
consecutive days following the visit [Week 1-R placebo; Week 5-R macitentan; Week 
4; Week 16; Week 24] as well as for 9 consecutive days during waking hours prior to 
Visit 11 (Week 24) for subjects enrolled under global protocol version 6. 
Baseline is defined as the non-missing, evaluable measures observed among data 
collected over 9 days following Visit 3 (during placebo run-in), because these data 
are obtained while the subject is still on placebo. Visit 3 data are preferred to data 
collected at Visit 2 as any potential changes in HF treatment are expected to occur at 


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the beginning of the placebo run-in, and so the clinical stability of subjects is expected 
to be better established at Visit 3 as compared to Visit 2. However, in case of missing 
non-evaluable data during placebo run-in, the training period following Visit 2 
(during placebo run-in) may be used. In the rare event accelerometer data is not 
evaluable at Visit 2 and Visit 3 then accelerometer data collected during Visit 5 is 
used. The data obtained during the 9 days following Visit 5 is the least favored choice 
since the subject is already on single-blind macitentan during this period. However, 
using this data is considered acceptable for the Baseline definition, as the recently 
initiated single-blind macitentan treatment would have then only no or limited impact 
on the accelerometer parameters.  
Daily time spent in LVPA is determined as the sum of time (minutes) in light, 
moderate or vigorous (including very vigorous) activity per day.  
• Proportion of time in LVPA = sum of daily time in LVPA / sum weartime 
Derivations are determined using only complete days. To be considered evaluable, 
physical activity should have been measured for at least 4 complete days (out of the 
9 consecutive days) at a specific time point of assessment.  
The 9-day time period is selected by taking the first (in chronological order) interval 
of 9 consecutive days with at least 4 complete daily time periods following the visit 
(or the last 9 consecutive days preceding Week 24 visit for assessment according to 
protocol version 6) and not including the midpoint of the day-interval between the 
visit and the following one. 
A complete day is defined as a record of at least 7 hours of data, i.e., if “WearMinutes” 
>=7*60 (after excluding the periods when the device was apparently not worn). These 
limitations allow for obtaining reliable results [Robertson 2011]. 
Accelerometry data 
Efficacy data for accelerometry are collected electronically and are transferred to 
Actelion by the vendor (Actigraph).  
The data are processed and provided by ActiGraph. Data are provided as “Minute 
epochs” (60 seconds) and “Day epochs” (24 hours) including activity counts in 
3 dimensions (X, Y and Z axis); vector magnitude (square root of the sum of the 
squares of X, Y and Z axis); and “wear time” (minutes) calculated using the Troiano 
2008 approach [Troiano 2008]. The time (minutes) spent in sedentary, light, moderate 
and vigorous (including very vigorous) activity is provided for the “Day epoch” 
according to the algorithm of Freedson 1998 [Freedson 1998], excluding time where 
the device was not worn (“WearFilteredCutpoints”). The cutpoints are based on the 
activity counts on the vertical Y axis. In addition, ActiGraph provide the daily LVPA 
and daily activity accounts including non-wear time. Physical activity is evaluated 


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according to wear time unless specified otherwise. Actigraph also provide the 
SERENADE specific parameters for the Day epoch: (1) number of episodes of 
activity > 100 activity counts per minute of at least 1 minute duration and; (2) number 
of episodes of activity > 100 activity counts per minute of at least 5 minute duration. 
Derivations for physical activity (mean daily activity and proportions of time) are 
determined in the analyses using evaluable days at each visit.  
[Note according to current literature and standard of care: for wear-time and valid day criteria, 
this would entail the subject wearing the device for a minimum of 4 days, and to have a 
minimum of 10 hours of wear time per day. The protocol listed valid day as 7 hours per day 
and will be applied for the analyses unless specified otherwise]. 
5.5.2.3 Time to first occurrence of worsening of heart failure event 
The third key secondary efficacy variable is the time to first occurrence of WHF 
event. 
Occurrence of a WHF event is assessed by the investigator using the 2015 ACC/AHA 
definition (see protocol section 7.2.2.3 for details).  
A WHF event includes HF death, hospitalization for WHF or an urgent visit for WHF. 
WHF events determined by the investigator are reported in the CRF.  
Time to first occurrence of WHF event is expressed in days and calculated as the 
onset date of the first WHF event minus date of randomization plus 1 or, for censored 
subjects, as EOS date minus date of randomization plus 1. The onset date of the first 
WHF event is the earliest between the following three dates: 
• the date of death reported on the ‘Death’ form in the CRF where classification of 
primary cause of death is ‘HF’; 
• the earliest date of WHF hospitalization entered on a ‘WHF Event’ CRF for a 
WHF event type of ‘WHF Hospitalization’; 
• the earliest date of urgent WHF visit entered on a ‘WHF Event’ CRF for a WHF 
event type of ‘Urgent WHF Visit’. 
All worsening of heart failure events occurring until EOS / OLE are considered, 
irrespective of subjects’ compliance to assigned therapies. 
Subjects without any worsening of heart failure event up to EOS / OLE are right-
censored at their EOS / OLE date [Section 11.2.12]. 
Prior to global protocol version 6 subjects were followed up to Week 52 (except 
where subjects prematurely discontinue study). Under global protocol version 6, 
subjects are followed up to at least Week 24. For the time to first occurrence of WHF 


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event, all events up to the EOS / OLE for each subject are considered, regardless of 
their duration of follow-up. 
5.5.3 Other efficacy variables 
5.5.3.1 Number of days alive and out of the hospital   
The number of days alive and out of the hospital (DAOH) is calculated for each 
randomized subject based on the total expected follow-up time, (TFU) the number of 
days in hospital and the time elapsed between death date and expected follow-up time 
(number of days dead). 
The TFU is determined as the number of days elapsed between the randomization 
date and the EOS (EOS - randomization date + 1) for the alive subjects or TFU=395 
days (52 weeks × 7 days + 30 days safety follow-up + 1 day) for subjects who die 
during the study / OLE date. Under global protocol version 6 TFU=199 days (24 
weeks × 7 days + 30 days safety follow-up + 1 day). For further details see Section 
11.2.12.  
The number of days in hospital (NDH) is obtained by adding the durations 
(discharge date - admission date + 1) of each individual hospital stay for which the 
admission date is on or after the randomization date. Subjects never hospitalized have 
0 days in hospital.   
The number of days dead (NDD) are calculated for subjects who die during the 
study as the number of days elapsed between their death date and what would have 
been their expected study duration if they did not die. It is calculated as: 
𝑁𝑁𝑁𝑁𝑁𝑁= 395 −(𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑ℎ 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑−𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑+ 1) 
The NDH and NDD are then subtracted from the TFU to derive DAOH for each 
subject: 
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷= 𝑇𝑇𝑇𝑇𝑇𝑇−𝑁𝑁𝑁𝑁𝑁𝑁−𝑁𝑁𝑁𝑁𝑁𝑁 
The percentage of DAOH (%DAOH) is also calculated for each subject by dividing 
DAOH by the TFU. 
5.5.3.2 Time to first occurrence of HF death or HF hospitalization 
The variable of interest is the time to first occurrence of HF death or HF 
hospitalization.  
Occurrence of HF death and hospitalization events are assessed by the investigator 
and recorded in the CRF (“Death” form and “Hospitalization” form respectively).  


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HF deaths are all deaths with a primary reason of ‘HF’ entered into the ‘Death’ CRF.  
HF hospitalization is defined per appendix 6 of the protocol as:  
• 
Subject is admitted to the hospital with a primary diagnosis of HF 
• 
Length of stay is at least 24 h (or extends over a calendar date). 
HF hospitalization are defined as the hospitalizations recorded on the 
‘Hospitalization’ CRF where length of stay ≥ 1 day (end date - start date ≥ 1) AND 
primary diagnosis of HF determined as the following criterion selected in the CRF: 
‘HF’ is specified where the main reason for hospitalization is cardiovascular = ‘Yes’. 
All HF hospitalizations and HF deaths with an admission / death date on or after 
randomization until EOS / OLE are considered, irrespective of subjects’ compliance 
to assigned therapies. 
Subjects without any HF hospitalization or HF death up to EOS / OLE are 
right-censored at their EOS / OLE date [Section 11.2.12].   
Time to first occurrence of HF death or HF hospitalization is expressed in days and 
calculated as the onset date of the first HF death or HF hospitalization minus the date 
of randomization plus 1 or, for censored subjects, as the EOS / OLE date minus the 
date of randomization plus 1. 
Prior to global protocol version 6 subjects were followed up to Week 52 (except 
where subjects prematurely discontinue study). Under global protocol version 6, 
subjects are followed up to at least Week 24. For the time to first occurrence of HF 
death or HF hospitalization, all events up to the EOS / OLE for each subject are 
considered, regardless of their duration of follow-up. 
5.5.3.3 Time to first occurrence of CV death or CV hospitalization  
The variable of interest is the time to first occurrence of cardiovascular (CV) death or 
CV hospitalization. 
Occurrence of CV death and hospitalization events are assessed by the investigator 
and recorded in the CRF (“Death” form and “Hospitalization” form respectively). 
CV deaths are all deaths with a primary reason of ‘CV: Acute MI’, ‘CV: Sudden 
cardiac death’, ‘CV: HF’, ‘CV: Stroke’, ‘CV: Procedure’, ‘CV: Hemorrhage’, or ‘CV: 
Other’ entered into the ‘Death’ CRF.  


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CV hospitalization is defined per appendix 6 of the protocol as:  
• 
Subject is admitted to the hospital with a primary diagnosis of HF, MI, stroke, 
resuscitated sudden death, CV procedure, CV hemorrhage or cardiovascular 
hospitalization not included in the above categories but with specific, known 
cause. 
• 
Length of stay is at least 24 h (or extends over a calendar date). 
CV Hospitalization are the hospitalizations recorded on the ‘Hospitalization’ CRF 
where length of stay ≥ 1 day (end date - start date ≥ 1) AND the primary diagnosis 
CV determined as the question ‘Was the main reason for hospitalization 
cardiovascular?’ ticked ‘Yes’. 
All CV hospitalizations and CV deaths with an admission / death date on or after 
randomization until EOS date are considered, irrespective of subjects’ compliance to 
assigned therapies. 
Subjects without any CV hospitalization or CV death up to EOS / OLE are 
right-censored at their date of EOS / OLE date [Section 11.2.12]. 
Time to first occurrence of CV death or CV hospitalization is expressed in days and 
calculated as the onset date of the first CV death or CV hospitalization minus the date 
of randomization plus 1 or, for censored subjects, as the EOS / OLE date minus the 
date of randomization plus 1. 
Prior to global protocol version 6 subjects were followed up to Week 52 (except 
where subjects prematurely discontinue study). Under global protocol version 6, 
subjects are followed up to at least Week 24. For the time to first occurrence of CV 
death or CV hospitalization, all events up to the EOS / OLE for each subject are 
considered, regardless of their duration of follow-up. 
5.5.3.4 Number of HF hospital admissions over 52 weeks 
The total number of recurrent HF hospitalizations, i.e., the cumulative number of 
distinct HF hospitalization episodes (different admission dates) as defined in 
Section 5.5.3.2, is computed for each subject, based on investigator assessment.  
All hospitalizations occurring until EOS / OLE date are considered, irrespective of 
subjects’ compliance to assigned therapies. 
Subjects who do not experience any HF hospitalization before EOS / OLE date will 
be considered as having 0 HF hospitalization. 
Prior to global protocol version 6 subjects were followed up to Week 52 (except 
where subjects prematurely discontinue study). Under global protocol version 6, 


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subjects are followed up to at least Week 24. For the analysis of the number of HF 
hospital admissions over 52 weeks all events up to the EOS / OLE for each subject 
are considered, regardless of their duration of follow-up. 
5.5.3.5 NYHA FC (improved/worsened/stable) at each post-baseline assessment 
Changes from baseline in NYHA FC values (I=1, II=2, III=3, IV=4) are categorized 
as improved, worsened or stable at every post-baseline assessment according to the 
following rules: 
An improvement corresponds to a decrease in NYHA class by at least one level 
whereas a worsening corresponds to an increase in NYHA class by at least one level. 
Subjects remaining in the same NYHA class as the one reported at baseline are 
categorized as stable. 
The proportion of subjects in each category is calculated at each post-baseline 
assessment based on the number of subjects with non-missing data (i.e., those having 
a reported value of I through IV). 
Subjects who died (any cause) are classified as worsened (NYHA FC = V). 
5.5.3.6 Clinical composite outcome (‘worsened’, ‘unchanged’, ‘improved’)  
The clinical composite outcome measure provides an overall evaluation of whether a 
subject’s condition is considered to have improved, worsened, or unchanged after a 
pre-specified period of time [Packer 2001]. 
The clinical composite outcome measure is derived based on NYHA FC, patient 
global assessment (PGA) and occurrence of death or HF hospitalization [see 
definition in Section 5.5.3.2] at each post-baseline assessment.  
PGA is a seven-point patient self-evaluation scale rating compared to Visit 6, 
collected in the CRF pages ‘Patient Global Assessment (PGA)’. Favorable changes 
are ‘MARKEDLY IMPROVED’, ‘MODERATELY IMPROVED’, ‘SLIGHTLY 
IMPROVED’ responses. ‘REMAINED UNCHANGED’ implies an unchanged 
condition. Other responses consist of an unfavorable change. 
Improved, worsened, or unchanged conditions are defined as below: 
• Improved: experienced a favorable change in NYHA class [see Section 5.5.3.5 
for definition] or in the PGA from the baseline and did not experience death or 
HF hospitalization during the planned duration of treatment. 


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• Worsened: experienced death or HF hospitalization during the planned duration 
of treatment or reported worsening of their NYHA class or an unfavorable change 
in PGA compared to baseline. 
• Unchanged: neither improved nor worsened compared to baseline, as defined 
above. 
The clinical composite outcome will be calculated and described for the different 
following periods of time: 
• Over 8 weeks (Day 2 up to Day 56 (+ 4 day window for Week 8 assessment) 
• Over 16 weeks (Day 2 up to Day 112 (+ 8 day window for Week 16 assessment) 
• Over 24 weeks (Day 2 up to Day 168 (+ 8 day window for Week 24 assessment) 
For a given period, only the deaths and hospitalizations occurring during the studied 
period will be taken into account in the clinical composite outcome calculation. 
Similarly, the last non-missing NYHA and PGA assessments performed during the 
studied period will be considered. To allow for the assessment schedule window, + 4 
days and + 8 days will be added to each period according to the visit schedule [see 
Appendix A, protocol Table 2]. 
5.5.3.7 Change from baseline in the KCCQ overall summary score and KCCQ 
scores over time 
Changes from baseline are derived at each visit for the following KCCQ summary 
scores: 
• Total score 
• Clinical summary score  
• Physical limitations score. 
For subjects who died during the study, the scores will be set to 0 after the date of 
death. 
The algorithm for the derivation of the summary scores is detailed in Appendix C. 
5.5.3.8 Percent of baseline in NT-pro-BNP over time 
The percent of baseline NT-pro-BNP is calculated at each post-baseline visit using 
the same calculation described for the primary efficacy variable [see Section 5.5.1]. 
No imputation for missing data will be performed. 


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5.5.3.9 Change from baseline in accelerometer-assessed physical activity 
variables over time 
The accelerometer-assessed variables of interest are:  
− Proportion of time spent in light to vigorous (including very vigorous) physical 
activity (LVPA) based on a threshold of > 100 activity counts per minute [see 
Section 5.5.2.2]. 
− Mean daily number of episodes of activity > 100 activity counts per minute of at 
least 1 minute duration*. The mean daily number of episodes is derived for each 
visit as the sum of episodes over complete days divided by number of complete 
days. 
− Mean count per minute of daily activity, derived at each visit taking the total 
activity counts in the Y axis (Day epoch - “WearFilteredTotalAxisYCounts”) for 
a complete day and divided by the total wear minutes in that day (“WearMinutes” 
variable in Data Transfer Specifications [DTS]) across all complete days (at least 
4 days out of 9 days). In summary, to compute the mean counts per minute of 
daily activity, it is necessary to identify all complete days; if less than 4 complete 
days out of 9 are identified then the endpoint is missing, otherwise, if at least 4 
complete days out of 9 are identified before a visit, then calculate the endpoint on 
the complete days only. 
− Mean daily number of episodes of activity > 100 counts per minute of at least 
5 minutes duration* is derived for each visit as the sum of episodes over complete 
days divided by number of complete days. 
− Mean daily accelerometer units (DAU) is derived at each visit based on the total 
vector magnitude (Day epoch - variable “WearfilteredTotalVectorMagnitude” in 
DTS) and dividing by total wear minutes. Mean DAU is then derived for each 
visit for the complete days. 
[*Actigraph provides the number of episodes for each day (Day epoch) that accelerometry is performed 
for 9 days following each visit]. 
Longitudinally collected over time and expressed as changes from baseline. 
5.5.3.10 Proportion of time spent in physical activity at each time assessment 
The proportion of time spent in each category of physical activity [Section 5.5.2.2] is 
calculated for each category and assessment time using evaluable days.  
Proportion time = total time spent in the category / total wear time: 
− Sedentary physical activity (< 100 activity counts per minute) 
− Light physical activity (100 to ≤ 1951 activity counts per minute) 
− Moderate physical activity (1952–5724 activity counts per minute) 


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− Vigorous (including very vigorous) physical activity (≥ 5725 activity counts 
per minute). 
5.5.3.11 Change from baseline in echocardiography left and right heart function 
at Week 24 and Week 52. 
Standard 2D/Doppler echocardiography is performed at screening (Visit 1), Week 24 
(Visit 11/PTOP2) and Week 52 (Visit 13/EOT). The change is defined as 
post-baseline value minus baseline value. 
Echocardiographies are read centrally and echocardiography parameters are provided 
by the echocardiography laboratory. 
The variables of interest for the analyses include the following: 
• Tricuspid annular plane systolic excursion (TAPSE) [mm] 
• Left atrial volume (LAV) [mL]  
• Septal e’ velocity [cm/sec] 
• Pulmonary artery systolic pressure (PASP) [mmHg] 
• Lateral E/e’ ratio 
• Septal E/e’ ratio 
Note: other echocardiographic parameters provided by the echocardiography 
laboratory will be listed.  
5.5.3.12 Percent of baseline in MR-proANP over time 
The percent of baseline MR-proANP is calculated at each post-baseline visit using 
the same methodology described for the primary efficacy variable [see Section 5.5.1]. 
5.5.3.13 Patient Global Assessment 
PGA is performed at Randomization (Visit 6), Week 8 (Visit 9), Week 16 (Visit 10), 
Week 24 (Visit 11/PTOP2), Week 36 (Visit 12/PTOP3) and Week 52 (Visit 13/EOT). 
The assessment is based on a 7-point patient self-evaluation as detailed in 
Section 5.5.3.6. 
5.6 Safety variables 
For the safety and tolerability endpoints, the main analyses are based on comparison 
of the double-blind treatment groups, placebo versus macitentan for subjects included 
in the safety set [Section 7.1.6]. Longitudinal safety data collected for subjects 


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included in the safety set will be described over time from screening to the end of 
study.  
As the safety set includes a pre-selected population of subjects tolerating the run-in 
periods, a few analyses are presented separately including subjects who do not enter 
the double-blind period, i.e., on PRI and MRI analysis sets [Sections 7.1.2 and 7.1.3]. 
For analyses related to change during the double-blind treatment period, the 
macitentan run-in baseline [Section 11.3.1] is used, i.e., the last non-missing 
assessment obtained before or on the day of the start of macitentan single-blind run-in 
treatment.   
Subjects who discontinue treatment early or complete the treatment period as per 
protocol enter a 30 days safety follow-up period on the day after the last dose of study 
treatment. The main analysis of safety variables considers the time from first dose of 
double-blind treatment to end of double-blind treatment period plus 30 days [see 
definition in Section 11.5]. Selected analyses are defined separately for the 
single-blind placebo [Section 11.5.3] and macitentan run-in [Section 11.5.4] periods 
as well as for the combined macitentan treatment period [Section 11.5.5]. The periods 
are defined in Section 11.5 and are inclusive of start and end dates. 
 
 


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Safety endpoints are defined in section 6.2 of the protocol as: 
Safety endpoints 
Planned in the 
protocol 
• 
All-cause death up to 30 days after study treatment 
discontinuation 
Yes 
• 
Number of all-cause hospital admissions up to 30 
days after study treatment discontinuation 
Yes 
• 
Treatment-emergent AEs/ SAEs up to 30 days after 
study treatment discontinuation 
Yes 
• 
AEs leading to premature discontinuation of study 
treatment 
Yes 
• 
Change in vital signs (systolic and diastolic arterial 
blood pressure and pulse rate) and body weight up 
to 30 days after study treatment discontinuation 
Yes 
• 
Treatment-emergent marked laboratory 
abnormalities up to 30 days after study treatment 
discontinuation 
Yes 
• 
Change in laboratory parameters from baseline to 
all assessed time points during the study 
No 
• 
Change from baseline in eGFR up to 30 days after 
study treatment discontinuation 
Yes 
• 
Decrease from baseline in SBP of ≥ 5% and SBP 
< 100 mmHg up to 30 days after study treatment 
discontinuation. 
Yes 
• 
Treatment emergent ECG findings 
No 
5.6.1 Adverse events 
An AE is defined as any event reported by the investigator in the “Adverse Event” 
CRF. All AEs that occur after signing of the ICF and up to 30 days after study 
treatment discontinuation are reported in the CRF “Adverse Event”. For subjects 
entering the PTOP, serious adverse events (SAEs) are reported until the end of the 
PTOP period. The original terms used by the investigators to describe AEs are 
assigned PT for classification and tabulation using the latest implemented version of 
MedDRA. 
5.6.1.1 Treatment-emergent adverse events 
Treatment-emergent AEs (TEAEs) are defined as any AE that started during the study 
treatment period (i.e., from first dose of single-blind placebo treatment, see 
Section 11.5.1), or any worsening of AE (see below for definition) that started prior 


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to the study treatment period with an “Intensity change date” reported during the 
study treatment period.  
Double-blind TEAEs are defined for the double-blind treatment period as any AE that 
started, or intensity worsened during the double-blind period. This will be used as the 
main period for presenting summaries for comparison of treatment groups.  
Treatment-emergent AEs are also defined for the placebo run-in and macitentan run-
in periods as well as combined macitentan treatment period (single-blind plus double-
blind macitentan treatment period [see Section 11.5.5]). These latter periods are used 
for a few selected presentations of AE and SAE summaries.   
A change in intensity of an AE is documented in the adverse event CRF together with 
the intensity change date. A worsening () in intensity is determined according to the 
following table for intensity change in AE: 
Previous 
intensity 
New intensity 
Mild 
Moderate 
Severe 
Missing 
Mild 
 
 
 
 
Moderate 
 
 
 
 
Severe 
 
 
 
 
Missing 
 
 
 
 
 
Double-blind TEAEs: 
• any AE with an onset date during double-blind treatment period, start and end 
dates of period included [see definition in Section 11.5.2]. 
• any worsening of AE that started prior to the start of double-blind treatment with 
an “Intensity change date” reported during the double-blind treatment period 
(start and end dates included) [see definition in Section 11.5.2]. 
Placebo run-in TEAEs: 
• any AE with an onset date between the start and end dates (included) of the 
placebo run-in period [see definition in Section 11.5.3]. 
• any worsening of AE that started prior to the placebo run-in start date with an 
“Intensity change date” reported between the start and end dates (included) of the 
placebo run-in period [see definition in Section 11.5.3]. 


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Macitentan run-in TEAEs: 
• any AE with an onset date between the start and end dates (included) of the 
macitentan run-in period [see definition in Section 11.5.4]. 
• any worsening of AE that started prior to the macitentan run-in start date with an 
“Intensity change date” reported between the start and end dates (included) of the 
macitentan run-in period [see definition in Section 11.5.4]. 
Combined macitentan TEAEs: 
• any AE with an onset date between the start and end dates (included) of the 
combined macitentan treatment period [Section 11.5.5]. 
• any worsening AE that started prior to the combined macitentan treatment period 
start date with an “Intensity change date” reported between the start and end dates 
(included) of the combined macitentan treatment period [Section 11.5.5]. 
5.6.1.2 Frequency of treatment-emergent adverse events 
TEAEs reported more than once (as qualified by the same PT) for a subject within a 
study period are counted only once in the frequency table for the given study period.  
5.6.1.3 Intensity of treatment-emergent adverse events 
For treatment-emergent AEs reported more than once (as qualified by the same PT) 
for a subject within a study period with different intensities, the worst intensity is 
considered for the given study period. In case of missing intensity, “severe” is 
imputed. 
5.6.1.4 Relationship of treatment-emergent adverse events 
Relationship to study treatment is defined as ‘related’ or ‘not related’. An AE is 
considered related if the causality is checked as ‘related’ by the investigator. For 
treatment-emergent AEs reported more than once (as qualified by the same PT) for a 
subject within a study period, the worst relationship (i.e., ‘related’) is considered. AEs 
with missing relationship are considered in any analysis as ‘related’. 
5.6.2 Deaths 
The date/time of death and associated primary cause are recorded in the CRF “Death” 
form.  
The original terms used by the investigator to describe death (i.e., primary cause of 
death) are assigned PTs for classification and tabulation using latest implemented 
version of MedDRA.  


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Additional classification of primary cause of death is performed by the investigator 
based on pre-specified causes (CV vs non-CV) available in the same CRF.    
Treatment-emergent deaths are assigned to periods (double-blind treatment, placebo 
and macitentan run-in, combined macitentan) in the same way as for TEAEs 
according to the date of death.  
5.6.3 Serious adverse events 
An AE is considered serious if the tick box ‘Yes’ for ‘Serious?’ is checked on the AE 
CRF. If the information on seriousness is missing, the AE is assumed to be a SAE for 
the purpose of the summaries. 
Treatment-emergent SAEs are assigned to study treatment periods as for AEs 
[Section 5.6.1.1]. SAEs collected during PTOP are reported on the same CRF as other 
AEs / SAEs and handled the same way as SAEs collected during the double-blind 
treatment period.  
5.6.4 Adverse events leading to discontinuation of study treatment 
An AE is considered as leading to discontinuation of study treatment if the tick box 
‘Drug withdrawn’ of ‘Action taken with study treatment’ is checked on the “Adverse 
Event” CRF.   
5.6.5 Other significant adverse events 
5.6.5.1 AEs with fatal outcome 
An AE with fatal outcome is any AE with Outcome = “Fatal” in CRF. 
TEAEs with fatal outcome are presented for subjects in the safety set [see 
Section 10.9.2.4].  
5.6.5.2 AEs of special interest  
AEs of special interest identified are given below. The definitions are based on a 
combination of MedDRA PTs and SMQs which can be updated according to 
MedDRA version / SMQs updates. 
Oedema and fluid retention: 
• Any AE with PTs listed in the SMQ “Haemodynamic oedema, effusions and fluid 
overload (SMQ)” OR 
• Any AE with PTs containing “Pulmonary congestion” 


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• excluding events with PTs containing “site” 
Anaemia: 
• Any AE with a PT within the SMQ “Haematopoietic erythropenia” OR 
• Any AE with a PT within the SMQ “Haematopoietic cytopenias affecting more 
than one type of blood cell “ (excluding two unspecific PTs: “blood disorder”, 
“blood count abnormal”) OR 
• an event with any PT containing the text “anaemia”. 
Hepatic AEs of special interest (HAESI): 
• Any AE with PT, system organ class (SOC) or HLGT containing the text specified 
in Appendix D. 
The latest version of the MedDRA dictionary will be applied and hence any PTs that 
change or are no longer applicable will be documented in the DPS. 
5.6.6 Vital signs and body weight 
Vital signs (systolic and diastolic blood pressures [SBP and DBP], pulse rate) and 
body weight are measured pre-dose at all visits and reported in the “Vital Signs” CRF. 
Triplicate SBP and DBP and radial pulse measurements are measured in a supine or 
sitting position. The average of the triplicate values [provided in SDTM] are used for 
the analysis. 
At Visit 4/W4-R, SBP, DBP and pulse rate are also monitored 4 hours post-
macitentan first dose, and 8-hours post-macitentan first dose. These assessments are 
listed and not included in any summaries. At this visit, the SpO2 (%) is also monitored 
pre-dose, 4-hours post macitentan first-dose, 8-hours post-macitentan first dose and 
at additional time points during visit 4, if needed by the investigator. These 
assessments are only listed. Note these first-dose safety monitoring assessments 
(4 and 8-hour post-macitentan first-dose) are no longer applicable for subjects 
enrolled under protocol version 5 or later. 
All assessments recorded during double-blind treatment period [Section 11.5.2] 
excluding Visit 6/W9-R/D1 will be assigned to the most appropriate study visit 
according to the best fitting time-window for that assessment as detailed in 
Section 11. If more than one value falls on the same date and time (and parameter) 
then the one with the last sequential number in SDTM will be used. Assessments 
recorded before or on double-blind treatment start date (i.e., Visit 1/Screening, Visit 
2/D1-R, Visit 3/W1-R, Visit 4/W4-R, Visit 6/W9-R/D1) will not be assigned with the 
same criteria, but reported according to scheduled visit. 


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Absolute change from macitentan run-in baseline [Section 11.3.1] to each visit in 
SBP, DBP, pulse rate, and body weight defined as: 
(Value at visit (Visit 6 - Visit 13)) - (value at macitentan run-in baseline) 
is evaluated. 
5.6.6.1 Decrease in SBP 
The decrease from baseline during double blind-period in SBP ≥ 5% and SBP < 100 
mmHg (both conditions must occur at the same time) at any time point of assessment 
starting from one day after start of double-blind study treatment up to EOT + 30 days 
will be derived. 
Similarly, decrease from baseline during macitentan run-in period is determined from 
one day after single-blind macitentan run-in start date [see definition in 
Section 11.2.8] and up to start date of double-blind treatment (inclusive). If 
double blind treatment was not received, then the period is up to 30 days after the end 
of the single-blind macitentan run-in date [see definition in Section 11.2.9]. 
5.6.7 Electrocardiogram 
A standard 12-lead ECG is performed at Visit 1/Screening, Visit 4/W4-R, Visit 6/W9-
R/D 1, Visit 8/W4, Visit 10/W16, Visit 11/W24 and Visit 13/W52-EOT. 
All assessments recorded after start of double-blind treatment [Section 11.2.10] will 
be assigned to the most appropriate study visit according to the best fitting time-
window for that assessment as detailed in Section 11.1. Assessments recorded before 
or on double-blind treatment start date (i.e., Visit 1/Screening, Visit 4/W4-R, Visit 
6/W9-R/D1) will not be assigned with the same criteria, but evaluated according to 
the scheduled visit assigned. 
The ECGs are interpreted locally, and the presence of ‘atrial fibrillation’ or ‘atrial 
flutter’ or ‘sinus rhythm’ are recorded in the CRF (“12-Lead ECG” form). 
Unscheduled assessments may be performed at any time during the study if 
appropriate based on the investigator judgment.   
The following variable is also defined: 
Treatment-emergent qualitative ECG abnormalities (findings): defined as 
presence (yes/ no) of any finding (atrial fibrillation or atrial flutter or sinus rhythm) 
during the double-blind treatment period [see Section 11.5.2]. Defined as any finding 
and separately for each type.    


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5.6.8 Laboratory 
Hematology and chemistry tests are performed at Visit 1/Screening, Visit 4/W4-R, 
Visit 6/W9-R/D1, Visit 8/W4, Visit 9/W8, Visit 10/W16, Visit 11/W24, Visit 
12/W36, Visit 13/W52-EOT, Visit 14/EOS, Visit PTOP1. In between Visit 9/W8 and 
Visit 12/W36, monthly aspartate transaminase / alanine transaminase (AST/ALT) 
monitoring is recommended. Unscheduled assessments may be performed at any time 
during the study if appropriate based on the investigator judgment. 
Data are evaluated in SI units unless specified otherwise as provided by the central 
laboratory. In case of local laboratory, values are provided in conventional units and 
converted to SI units. The tests converted to SI are available in SDTM for the analysis.  
Note: Laboratory results recorded as ‘< xxxʼ (or similar with ≤, >, or ≥) will be 
considered as ‘xxx’ for analysis, e.g., a result for ALT of ‘< 1’ is considered as 1 for 
the analysis. The values are listed including the < or > sign.  
For the analysis, local laboratory values are included in the calculation of marked 
laboratory abnormalities (MLAs) [Section 5.6.8.2]. All assessments recorded after 
double-blind treatment start date [Section 11.2.10] up to EOT + 30 days will be 
assigned to the most appropriate study visit according to the best fitting time-window 
for that assessment as detailed in Section 11.1. If more than one value for a laboratory 
parameter is assessed on the same day, from central and local laboratory, the value 
from the central laboratory is considered for the analysis. If more than one value falls 
on the same date and time (and laboratory) then the one with the last sequential number 
in SDTM will be used. 
Laboratory parameters include: 
Hematology: 
• 
Hemoglobin (SI Unit: g/L; Conventional unit: g/dL) 
• 
Hematocrit (SI Unit: L/L; Conventional unit: %) 
• 
Erythrocyte count (reticulocyte count) (SI Unit: 1012/L; Conventional unit: 
106/μL) 
• 
Leukocytes count (SI Unit: 109/L; Conventional unit: 103/μL) 
• 
Neutrophils count (SI Unit: 109/L; Conventional unit: 103/μL) 
• 
Lymphocytes count (SI Unit: 109/L; Conventional unit: 103/μL) 
• 
Monocytes count (SI Unit: 109/L; Conventional unit: 103/μL) 
• 
Eosinophils count (SI Unit: 109/L; Conventional unit: 103/μL) 
• 
Basophils count (SI Unit: 109/L; Conventional unit: 103/μL) 
• 
Platelet count (SI Unit: 109/L; Conventional unit: 103/μL) 
 


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Chemistry: 
• ALT (U/L) 
• AST (U/L) 
• Alkaline phosphatase (U/L) 
• Total and direct bilirubin (SI unit: μmol/L; Conventional unit: mg/dL) 
• Creatinine (SI unit: μmol/L; Conventional unit: mg/dL) 
• Blood urea nitrogen (SI unit: mmol/L; Conventional unit: mg/dL) 
• Uric acid (SI unit: μmol/L; Conventional unit: mg/dL) 
• Sodium, potassium, chloride, calcium, magnesium (mmol/L) 
• Total protein, albumin (SI unit: g/L; conventional unit: g/L) 
• Albumin / Globulins ratio 
• eGFR (mL/min/1.73m2) using the Modification of Diet in Renal Disease 
formula 
The absolute observed value and change from baseline to each visit for selected 
laboratory parameters (i.e., erythrocytes, hemoglobin, hematocrit, AST, ALT, total 
bilirubin and alkaline phosphatase) are defined as: 
Values at visit (Visit 8 to Visit 13) - (value at macitentan run-in baseline). 
5.6.8.1 Fasted state laboratory values 
Laboratory values at screening / re-screening are collected only in fasted state. The 
value at the latest successful (re-) screening are used: 
• Glucose (SI unit: mmol/L; Conventional unit: mg/dL) 
• Thyroid stimulating hormone (TSH; SI unit: mIU/L; Conventional unit: μIU/mL)  
• T3, T4 
• Lipid profile (SI unit: μmol/L; Conventional unit: mg/dL): 
o low-density lipoprotein (LDL) cholesterol 
o high-density lipoprotein (HDL) cholesterol 
o very low-density lipoprotein (VLDL) cholesterol 
o total cholesterol  
o triglycerides. 
5.6.8.2 Marked laboratory abnormalities 
The following MLA are derived according to the protocol. 
Double-blind MLAs are all marked laboratory abnormalities occurring from one day 
after the double-blind study treatment start [see definition in Section 11.2.10] and up 
to 30 days after the end of double-blind treatment date [see definition in 
Section 11.2.11]. 


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Double-blind treatment-emergent MLAs are double-blind MLAs that were not 
present at macitentan run-in baseline.  
Macitentan run-in MLAs are all marked laboratory abnormalities occurring from one 
day after the single-blind macitentan run-in start date [see definition in 
Section 11.2.8] and up to start date of double-blind treatment (inclusive). If 
double-blind treatment was not received, then period is up to 30 days after the end of 
single-blind macitentan run-in date [see definition in Section 11.2.9].  
Macitentan run-in treatment emergent MLAs are macitentan run-in MLAs that were 
not present at macitentan run-in baseline [see Section 11.3.1]. 
Placebo run-in MLAs are all marked laboratory abnormalities occurring from one day 
after the single-blind placebo run-in start date [see definition in Section 11.2.6] and 
up to start date of single-blind macitentan treatment (inclusive). If single-blind 
macitentan treatment was not received, then period is up to 30 days after the end of 
single-blind placebo run-in date [see definition in Section 11.2.7].  
Placebo run-in treatment emergent MLAs are placebo run-in MLAs that were not 
present at Screening. 
Table 2 
Definition of marked laboratory abnormalities 
Parameter  
LL 
marked 
LLL 
marked 
HH marked 
HHH marked 
Hematology 
 
 
 
 
Hemoglobin 
(baseline value 
within normal 
range or below 
LLN) 
< 100 g/L 
< 80 g/L 
> 20 g/L above 
ULN  
> 40 g/L above 
ULN 
Hemoglobin 
(baseline value > 
ULN) 
< 100 g/L 
< 80 g/L 
> 20 g/L above 
baseline 
> 40 g/L above 
baseline 
Hematocrit 
< 0.28 L/L 
for females  
< 0.32 L/L 
for males 
< 0.20 L/L 
 
> 0.55 L/L for 
females 
> 0.60 L/L for 
males 
> 0.65 L/L  
 


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Parameter  
LL 
marked 
LLL 
marked 
HH marked 
HHH marked 
Leukocytes 
< 3.0 × 
109/L 
< 2.0 × 
109/L 
> 20.0 × 109/L 
> 100.0 × 109/L 
Neutrophils 
< 1.5 × 
109/L 
< 1.0 × 
109/L 
NA 
NA 
Lymphocytes 
< 0.8 × 
109/L  
< 0.5 × 
109/L  
> 4.0 × 109/L  
> 20.0 × 109/L  
Eosinophils 
NA 
NA 
> 5x109/L 
NA 
Platelets  
< 75 × 
109/L 
< 50 × 
109/L 
> 600 × 109/L  
> 999 × 109/L  
Chemistry 
 
 
 
 
ALT*  
NA 
NA 
> 3 × ULN 
> 5 × ULN 
AST*  
NA 
NA 
> 3 × ULN 
> 5 × ULN 
Alkaline 
phosphatase 
NA 
NA 
> 2.5 × ULN 
> 5 × ULN 
Total bilirubin 
NA 
NA 
> 2 × ULN 
> 5 × ULN 
Creatinine  
(baseline value 
within normal 
range or below 
LLN) 
NA 
NA 
> 1.5 × ULN 
> 3 × ULN 
Creatinine 
(baseline value > 
ULN) 
NA 
NA 
> 1.5 × above 
baseline 
> 3 × above 
baseline 
BUN 
NA 
NA 
> 2.5 × ULN 
> 5 × ULN 
Uric acid 
NA 
NA 
> 590 µmol/L 
> 720 µmol/L 
Sodium 
NA 
< 130 
mmol/L 
> 150 mmol/L 
> 155 mmol/L 
Potassium 
< 3.2 
mmol/L 
< 3.0 
mmol/L 
> 5.5 mmol/L 
> 6.0 mmol/L 


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Parameter  
LL 
marked 
LLL 
marked 
HH marked 
HHH marked 
Magnesium 
< 0.5 
mmol/L 
< 0.4 
mmol/L 
NA 
> 1.23 mmol/L 
Calcium 
< 2.0 
mmol/L 
< 1.75 
mmol/L 
> 2.9 mmol/L 
> 3.1 mmol/L 
Albumin 
< 30 g/L 
< 20 g/L 
NA 
NA 
 
 
 
 
 
* For ALT and AST, additional threshold (HHHH) are reported namely > 8 × ULN 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea 
nitrogen; LLN = lower limit of the normal range; NA = not applicable; ULN = upper limit of the 
normal range 
5.6.8.3 Additional liver laboratory abnormalities 
The following liver test abnormalities (LTAs) are defined for MRI and double-blind 
periods: 
- 
(ALT > 3 ×  ULN) OR (AST > 3 × ULN) 
- 
(ALT > 5 × ULN) OR (AST > 5 × ULN) 
- 
 (ALT > 8 × ULN) OR (AST > 8 × ULN) 
- 
Total Bilirubin > 2 × ULN 
- 
{(ALT > 3 × ULN) OR (AST > 3 × ULN)} AND (Total Bilirubin > 2 × ULN at 
any time). 
Double-blind LTAs and macitentan run-in LTAs are derived in the same way as for 
the double-blind MLAs and macitentan run-in MLAs respectively [Section 5.6.8.2].   
The categories “ALT or AST > 3 × ULN”, “ALT or AST > 5 × ULN”, “ALT or AST 
> 8 × ULN” are not mutually exclusive and subjects may be counted in more than 
one category. The highest ALT or AST value at any time point in the period is 
considered in the evaluation of these categories, as defined above. 


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5.6.9 Other safety variables 
5.6.9.1 Number of all-cause hospital admissions up to 30 days after study 
treatment discontinuation 
All-cause hospitalizations are reported in the dedicated CRF “Hospitalization”. 
The total number of events for each subject (e.g., all-cause hospitalizations) is 
calculated for the run-in periods [see definition in Sections 11.5.3 and 11.5.4] and for 
the double-blind treatment period [see definition in Section 11.5.2]. 
5.6.9.2 Change from baseline in Glomerular Filtration Rate up to 30 days after 
study treatment discontinuation 
The eGFR (mL/min/1.73m2) using the Modification of Diet in Renal Disease formula 
is assessed at all visits with laboratory test [see Section 5.6.8].  
Unscheduled visits may be performed at any time during the study if appropriate 
based on the investigator judgment. 
As described in laboratory Section 5.6.8, the assessments will be assigned to the most 
appropriate study visit. 
Data are evaluated as provided by the central laboratory. 
The change in eGFR from macitentan run-in baseline to each visit is defined as: 
Value at visit (Visit 6/ Visit 8/ Visit 13) - (value at macitentan run-in baseline). 
5.6.9.3 Physical examination 
Physical examination is performed at all scheduled visits, collected in the CRF 
“Physical Examination” with general assessment performed. If an abnormality is 
found (i.e., Result = “Abnormal”), further details describing the signs and symptoms 
related to the abnormality are specified. The abnormality is clinically significant if 
the question “Clinically significant” is answered “Yes”.  
Physical examination includes the examination of the general appearance, head, eyes, 
ears, nose, throat, neck (including thyroid), cardiovascular, respiratory, 
gastrointestinal, lymphatic, genitourinary, rectal, extremities, neurologic, psychiatric, 
skin, musculoskeletal. 
5.6.9.4 Heart failure sign and symptoms of special interest  
The following signs and symptoms of special interest are assessed at every visit as 
part of the physical examination (CRF “Signs/Symptoms of Special Interest”): 


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• Peripheral edema (defined as increased tissue fluid indicated by perceptible 
pitting indentation on lower leg, foot, or sacrum after palpation) 
• Pulmonary rales/crackles/crepitations 
• Abdominal distention or ascites (in the absence of primary hepatic disease) 
• S3 gallop 
• Orthopnea 
• Nocturia 
• Paroxysmal nocturnal dyspnea 
• Nocturnal cough 
• Jugular venous distention 
• Hepatojugular reflux. 
 
The above are collected in CRF as ‘Present at visit’ = ‘Yes /No /Not assessed’.  
5.7 Sub-study  
Sub-study endpoints defined in this section are applicable only to subjects who were 
enrolled under protocol version 5 and eligible for the sub-study. Data of the sub-study 
assessments (6-MWT and Borg Dyspnea Index) will be described presenting listings 
and descriptive summaries (only in the case of at least 20 subjects with available 
baseline / post baseline assessments). 
A training 6-MWT was conducted at Visit 2 and a qualifying 6-MWT conducted at 
Visit 3. To obtain meaningful results for the 6-MWT, additional eligibility criteria 
were defined as listed below. Subjects who met these eligibility criteria were included 
in the 6-MWT sub-study and 6-MWT was performed at subsequent visits (Visit 4/ 
W4-R, Visit 6/W9-R/D1, Visit 8/W4, Visit 9/W8, Visit 10/W16, Visit 11/W24 and 
Visit 13/W52-EOT). Subjects who were included in the 6-MWT sub-study were 
allowed to withdraw (e.g., if a subject becomes wheelchair bound) from participation 
in the sub-study while remaining in the main study.  
Eligibility criteria for participation in the 6-MWT sub-study were: 
• 
6-minute walk distance (6-MWD) ≥100 m AND ≤ 450 m at Visit 3  
• 
Ambulatory (not wheelchair / scooter dependent) 
The efficacy variable is defined as follows:  
• 
The observed and absolute change (meters) from baseline over time in 6-MWD, 
as measured by the 6-MWT 


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Where baseline is defined as the last non-missing value observed among all measures 
collected during placebo run-in and macitentan run-in, up to and including the start 
of double-blind treatment date [Section 11.2.10]. Therefore, the baseline is expected 
to be the Visit 6 (Randomization Day 1) assessment. All assessments, including 
unscheduled if any, will be assigned to the most appropriate visit time point according 
to the best fitting time window for the assessment [see Section 11.1, Table 7]. 
The Borg Dyspnea Index is assessed after each 6-MWT rating dyspnea on a scale 
from 0 to 10. 
5.8 Quality of life variables 
The KCCQ is a validated health related quality of life measure for heart failure. The 
KCCQ is a 23-item, self-administered instrument that quantifies physical function, 
symptoms (frequency, severity and recent change), social function, self-efficacy and 
knowledge, and quality of life [see appendix 3 of the protocol for questionnaire]. It is 
assessed at Visit 6/W9-R/D1, Visit 9/W8, Visit 10/W16, Visit 11/W24, Visit 12/W36, 
Visit 13/W52 and PTOP2/PTOP3/PTOP4. 
All assessments recorded during double-blind treatment period [Section 11.5.2] 
excluding Visit 6/W9-R/D1 will be assigned to the most appropriate study visit 
according to the best fitting time-window for that assessment as detailed in 
Section 11.1. 
For subjects who died during the study after randomization, the scores will be set to 
0 for the visits after the time-window that includes death date. For the visit whose 
time-window include death date, the scores will be set to 0 only in case there is no 
KCCQ assessment included in its time-window. 
Questions refer to subjects’ heart failure and how it may affect their life with reference 
to a period of “over the past 2 weeks”. 
In the KCCQ, different scores can be derived, in which higher scores reflect better 
health status. KCCQ scoring instructions are provided in Appendix C. 
The quality of life variables of interest derived from KCCQ that will be summarized 
are: 
• Physical limitations score 
• Clinical summary score  
• Overall summary score. 


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6 
DEFINITION OF PROTOCOL DEVIATIONS 
The description of each protocol deviation (PD) is agreed in the sponsor protocol 
deviation code list. According to this document, each PD is classified as important or 
not and categorized into periods as follows: 
• PDs at screening and during run-in (for subjects who entered run-in only) 
• PDs during double-blind treatment period and follow-up (including PTOP) 
• PDs applicable to all study periods.  
The data are available in SDTM. 
Protocol deviation PD_MM.329 ‘Administration of incorrect study treatment (i.e., 
subject did not get the medication bottle assigned by IXRS)’ will be classified to 
‘Incorrect bottle received: treatment received different from assigned treatment’ 
(PD_MM.3291) or ‘Incorrect bottle received: assigned treatment received’ 
(PD_MM.3292).  
The PDs which lead to exclusion from the Per-Protocol analysis set (PPS) are in 
Section 7.1.5. 
7 
ANALYSIS SETS  
7.1 Definitions of analysis sets 
7.1.1 Screened Analysis Set 
The SCR analysis set includes all subjects who are screened and have a subject 
number. 
7.1.2 Placebo run-in Set 
The placebo run-in (PRI) Set includes all screened subjects who enter the placebo 
run-in and receive at least one dose of study treatment in single-blind placebo run-in. 
7.1.3 Macitentan run-in Set 
The macitentan run-in (MRI) Set includes all subjects who have completed the 
placebo run-in, enter the macitentan run-in and receive at least one dose of study 
treatment in single-blind macitentan run-in. 


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7.1.4 Full analysis Set  
The FAS includes all subjects randomized to double-blind study treatment [see 
definition in Section 11.8]. In order to adhere to the intention-to-treat principle as 
much as possible: 
• Subjects are evaluated according to the study treatment they have been assigned 
to (which may be different from the study treatment they have received), 
• All available data are taken into account. 
7.1.5 Per-Protocol analysis Set  
The PPS comprises all subjects from the FAS who received double-blind study 
treatment and who complied with the protocol sufficiently to allow reliable 
assessment of the treatment effect on the primary efficacy endpoint. Subjects are 
evaluated according to the study treatment they have been assigned to. 
Criteria for exclusion from PPS include: 
Insufficient compliance to study drug in the first 24 Weeks determined from 
PD_PP.223 (Study treatment compliance during the core phase of the double-blind 
treatment period duration < 80% or >120%) 
Insufficient exposure to study drug in the first 24 Weeks determined from 1 or more 
of the following: 
• PD_PM.225 (Interruption of double-blind study treatment for more than  
4 consecutive weeks without permanent study treatment discontinuation up to and 
including Week 24 (core phase)).  
• Study drug discontinued (or interrupted) more than 7 consecutive days prior to 
Week 24 assessment of NT-pro-BNP. 
Non-protocol compliant assessment of NT-pro-BNP at baseline or Week 24: 
determined from one of more of the following: 
• PD_PM.215 (NT-pro-BNP sample not collected or not evaluable at Visit 11). 
• PD_PM.152 [(At least 1 visit with missing or non-evaluable NT-pro-BNP sample 
during Screening (Visit 1) and/or Run-in (Visit 4, Visit 6)]. Where PD is applied 
to all 3 Visits.   
Presence of any protocol deviation questioning the diagnosis of the studied 
disease and other PDS affecting the assessment of the primary efficacy are presented 
in Table 3.   


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Table 3 
Exclusions from Per-Protocol analysis Set  
PD Code 
Description / Condition 
Additional 
PD_PP.101 
No informed consent signed and dated by subject 
 
PD_PP.109 
NYHA class I or IV or missing at Visit 1 
 
PD_PP.111 
Subjects without structural heart disease (left atrial enlargement or Left 
ventricular hypertrophy) assessed by echocardiography 
 
PD_PP.112 
No NT-pro-BNP / BNP value fulfilling the protocol criteria within 3 
months prior to Screening or at Screening 
 
PD_PP.113 
Subject does not meet the criteria for pulmonary vascular disease or 
right ventricular dysfunction 
 
PD_PM.116 
Any prior measurement of LVEF < 40% 
 
PD_PP.117 
Significant unrepaired structural valvular heart disease 
 
PD_PP.118 
Hypertrophic, restrictive, or infiltrative cardiomyopathy 
 
PD_PP.119 
Pericardial disease 
 
PD_PP.120 
Acute coronary syndrome or unstable coronary artery disease or has 
undergone coronary artery bypass graft (CABG) or percutaneous 
coronary intervention (PCI) within 3 months of screening. 
 
PD_PP.121 
Known indication for PCI or CABG 
 
PD_PP.124 
History of or anticipated heart transplant or anticipated/implanted 
ventricular assist device 
 
PD_PP.125 
Transient ischemic attack (TIA) or stroke within 3 months of Screening 
 
PD_PP.126 
Systolic blood pressure (SBP) ≥180 mmHg or diastolic blood pressure 
(DBP) ≥110 mmHg  
If present in all 3 
periods: Screening, 
placebo 
run-in, 
macitentan run-in 
PD_PM.127 
Significant parenchymal lung disease 
 
PD_PP.129 
Clinically significant congenital heart disease that could be the cause 
of the patient’s symptoms and signs of heart failure. 
 
PD_PP.142 
Any known factor or disease that might interfere with treatment 
compliance, study conduct, or interpretation of the results, such as drug 
or alcohol dependence or psychiatric disease. 
 
PD_PP.143 
Known concomitant life-threatening disease with a life expectancy < 
12 months. 
 
PD_PM.160 
Subject not on stable Heart Failure/cardiovascular therapy during a 
minimum of 7 consecutive days immediately prior to randomization 
(Visit 6) 
 
PD_PM.201 
Subject met at least one run-in failure criterion but was randomized 
 
PD_PP.221 
Not on at least one oral diuretic (any type) at time of randomization 
(visit 6) 
 


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PD Code 
Description / Condition 
Additional 
PD_PM.310 
Subject received a PAH specific therapy (i.e., ERA, PDE-5 inhibitors, 
prostanoids, IP receptor agonists, guanylate cyclase stimulators) 
between Screening and EOS 
Except 
therapies 
starting after Week 
24 NT-pro-BNP 
PD_PM.314 
Subject received investigational product other than study treatment 
between Screening and EOS 
Except 
therapies 
starting after Week 
24 NT-pro-BNP 
PD_MM.329 
Administration of incorrect study treatment (i.e., subject did not get the 
medication bottle assigned by IxRS). Plus, additional condition that 
treatment received is different from assigned treatment. 
Except 
study 
treatment 
dispensed 
after 
Week 24 NT-pro-
BNP.  
BNP ꞊ Brain Natriuretic Peptide; CABG ꞊ coronary artery bypass graft; DBP ꞊ diastolic blood pressure;  
EOS 
꞊ 
End-of-study; ERA 
꞊ 
endothelin 
receptor 
antagonist; 
FC 
꞊ 
Functional 
Class;  
IxRS ꞊ Interactive voice/web Recognition System; LVEF ꞊ Left Ventricular Ejection Fraction;  
NT-pro-BNP ꞊ n-terminal pro-Brain Natriuretic Peptide; NYHA ꞊ New York Heart Association; OLE ꞊ Open-
label enrollment; PAH ꞊ pulmonary arterial hypertension; PCI ꞊ percutaneous coronary intervention;  
PDE-5 ꞊ phosphodiesterase-5; SBP Systolic blood pressure; TIA ꞊ Transient ischemic attack. 
7.1.6 Safety Set  
The Safety Set (SAF) includes all subjects from FAS who received at least one dose 
of double-blind study treatment. Subjects are evaluated according to the study 
treatment received. The treatment received may be different from the treatment 
assigned at randomization (randomized treatment) only in the case of a dispensing 
error that was sustained throughout the subject`s entire double-blind treatment period. 
Short-term dispensing errors will not qualify for a change from the randomized 
treatment group.   
7.1.7 Sub-study Analysis Set 
Applicable only to subjects who were enrolled under protocol version 5. 
The Sub-study Analysis Set (SSAS) includes all subjects randomized to double-blind 
study treatment and eligible to enter the Sub-study [see Section 5.7]. In order to the 
intention-to-treat principle, subjects are evaluated according to the study treatment 
they have been assigned to (which may be different from the study treatment they 
have received). 


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7.2 Usage of the analysis sets 
Table 4 
Overview of the different analysis sets and their usage 
Analyses/Data 
Displays 
Screened 
analysis 
set 
(SCR) 
Placebo 
Run-in 
set 
(PRI) 
Macitentan 
Run-in set 
(MRI) 
Full 
analysis 
set 
(FAS) 
Safety 
set 
(SAF) 
  
Per 
protocol 
analysis 
seta 
(PPS) 
Sub-
study 
Analysis 
set 
(SSAS) 
 
Disposition 
 
 
 
 
 
 
 
Inclusion /exclusion 
criteria 
 
 
 
 
 
 
 
Demographic 
characteristics 
  
 
 
 
  
 
 
Baseline 
characteristics 
 
 
 
 
  
 
 
Medical history 
  
 
 
 
 
 
 
Previous 
/concomitant 
medications 
 
 
 
 
 
 
 
Treatment exposure 
 
 
 
 
 
 
 
Primary endpoint 
 
 
 
  
 
   
 
Subgroup Analyses 
 
 
 
 
 
 
 
Secondary endpoints 
 
 
 
 
 
* 
 
Exploratory 
endpoints 
  
 
 
 
 
 
 
Safety endpoints 
 
 
 
 
 
 
 
Sub-study  
 
 
 
 
 
 
 
Subject listings 
** 
 
 
 
 
 
 
a Main analysis of the primary and secondary efficacy endpoints is based on the full analysis set. Demographics, 
baseline characteristics and treatment exposure are presented for the PPS only when the PSS differs from the FAS 
by more than 15 subjects in both randomized treatment groups (≥ 10%).   
* selected main analyses for physical activity and quality of life.   
** select listings including screening failure information  
The FAS is used for the analyses of all the efficacy variables as well as for the 
description of the study population at baseline.  
The PPS is used to perform specific sensitivity analysis on the primary efficacy 
variable. 
The SAF is used for the analyses of the safety variables.  


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The SCR set is used for the description of subject disposition and some select listings. 
Unless specified otherwise, individual listings are prepared on the PRI or FAS. 
The PRI set is used to present the reasons leading to discontinuation of placebo run-
in as well as a few select safety analyses. 
The MRI set is used to document the reasons leading to discontinuation of macitentan 
run-in as well as a few select safety analyses. 
The SSAS is used for presenting listings and descriptive summaries of the sub-study 
data (6-MWT and Borg Dyspnea Index) assessed for subjects included in the 
sub-study (applicable only to subjects enrolled under global protocol version 5). 
8 
DEFINITION OF SUBGROUPS 
The category in bold type is the reference category used in the statistical analysis of 
these subgroups.  
The following subgroups are defined according to the protocol. 
• Geographical region (Americas, Western Europe, Eastern Europe as defined in 
Section 5.2.1] 
• Sex (Male versus Female) 
• NYHA FC (II versus III) at screening as defined in Section 5.2.2 
• Atrial Fibrillation (yes versus no) as collected on Specific MH CRF 
• NT-pro-BNP (< 1000 pg/mL versus ≥ 1000 pg/mL) as per the IxRS stratification 
• Age (18–64, 65–84, ≥ 85 years)  
• Renal function at Baseline: Normal, mild decrease, moderate decrease, severe 
decrease / ESRD 
• Obesity (BMI ≥ 30 vs < 30).  
 
9 
GENERAL STATISTICAL METHODOLOGY  
SAS (Statistical Analysis System®) version 9.4 is used for all the statistical analysis. 
This section describes in general terms the statistical analysis methods which are 
applied in the subsequent sections. Specific details will be addressed in Section 10. 
In addition, all efficacy data will be summarized for observed and change from 
baseline using descriptive statistics by visit time point where applicable. 


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9.1 Statistical methods for ANCOVA analysis 
The statistical method used to analyze the primary efficacy variable takes into account 
the expected underlying log normal distribution of NT-pro-BNP [Solomon 2012]. As 
a consequence, the treatment effect will be tested on a log-scale using an ANCOVA 
and expressed, on the original scale, as the ratio between treatment groups of the 
geometric means of individual percent of baseline at Week 24 (macitentan over 
placebo). 
The model is adjusting for the log of the ratio: baseline NT-pro-BNP over  
NT-pro-BNP value at subject’s entry into macitentan run-in (as per Interactive 
Response Technology [IRT]), with the aim to better control the potential unbalance 
between treatment groups of the NT-pro-BNP levels observed before entering the 
macitentan run-in. Such unbalance may not be fully captured by the baseline  
NT-pro-BNP value, which is expected to be the value observed the day of 
randomization for the majority of subjects, and thus already influenced by macitentan. 
Despite the randomization stratification based on the NT-pro-BNP value collected at 
subject’s entry into macitentan run-in, a continuous covariate quantifying individual 
NT-pro-BNP evolution during the macitentan run-in is deemed more sensitive and 
therefore more appropriate than a binary covariate based uniquely on the stratification 
factor.  
Due to the underlying log-normal distribution of the primary efficacy variable, an 
analysis of covariance will be applied on log-transformed data. 
yij 
denotes the log-transformed percent of baseline in NT-pro-BNP at Week 24 
for subject j in treatment group i 
xij 
denotes the log-transformed ratio: baseline NT-pro-BNP over NT-pro-BNP 
value at subject’s entry into macitentan run-in, for subject j in treatment group i 
TRTi 
denotes for each subject the treatment group i he/she belongs to. Equal 1 for 
macitentan and 0 for placebo  
α 
denotes the common intercept 
eij 
denotes the random error term, assumed to follow a normal distribution with 
mean 0 and standard error σ 
The model could be written: 
𝑦𝑦𝑖𝑖𝑖𝑖= 𝛼𝛼+ 𝛽𝛽1𝑇𝑇𝑇𝑇𝑇𝑇𝑖𝑖+ 𝛽𝛽2𝑥𝑥𝑖𝑖𝑖𝑖+ 𝑒𝑒𝑖𝑖𝑖𝑖 
2-sided hypotheses are focusing on the model coefficient β1.  


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The null hypothesis is that macitentan and placebo effects on NT-pro-BNP are the 
same. The alternative hypothesis is that the effect of macitentan on NT-pro-BNP 
differs from placebo effect. 
H0: β1 = 0 
vs 
H1: β1 ≠ 0. 
The null hypothesis will be tested by a 2-sided Wald test with a 2-sided significance 
level of 0.10. 
For primary endpoint, the statistical model will be implemented by the SAS® code 
detailed in the DPS Part 1 document. 
ANCOVA is also applied (under assumptions of normal distribution) for secondary 
and others efficacy analysis specified below: 
• Change from baseline to Week 24 in the clinical summary score (as assessed by 
the KCCQ). Adjusting for the variable baseline value and for the log of the ratio 
(baseline NT-pro-BNP over NT-pro-BNP value at subject’s entry into macitentan 
run-in (as per IRT). 
• Change from baseline to Week 24 in accelerometer-assessed proportion of time 
spent in light to vigorous (including very vigorous) physical activity (LVPA) 
based on a threshold of > 100 activity counts per minute. Adjusting for the 
variable baseline value and for the 
log 
of the 
ratio 
(baseline  
NT-pro-BNP over NT-pro-BNP value at subject’s entry into macitentan run-in 
(as per IRT)). 
• Number of days alive and out of the hospital (DAOH and %DAOH) assessed over 
52 weeks. Adjusting need to be for the log of the ratio only (baseline  
NT-pro-BNP over NT-pro-BNP value at subject’s entry into macitentan run-in 
[as per IRT]). 
The validity of classical parametric ANCOVA depends on several assumptions, 
including normality of error terms, equality of error variances for different treatments, 
equality of slopes for the different treatment regression lines and linearity of 
regression. For the primary and secondary endpoints analyzed with an ANCOVA 
model the assumptions will be assessed (creating diagnostic plots) and where they 
will not be valid, a non-parametric ANCOVA similar to that described in section 7.7 
of Stokes [Stokes 2000] will be performed. 


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Details on the procedure described in Stokes [Stokes 2000] are given in the DPS Part 
1 document. 
9.2 Statistical methods for time-to-event data 
The analysis of time to first occurrence of WHF will be carried out using a Cox 
proportional hazards model adjusting for the log of the ratio: baseline NT-pro-BNP 
over NT-pro-BNP value per IRT.  
Data will be listed and summarized in tables and figures, including: number of events, 
number of censored observations, number of subjects at risk, and Kaplan-Meier (KM) 
estimates of the survival function for time-to-event variables, hazard ratios and 
corresponding 90% confidence intervals (CIs). The null hypothesis, tested by means 
of the log-rank test comparing macitentan 10 mg versus placebo, is rejected upon 
achieving a statistically significant difference at a 2-sided significance level such that 
the log-rank p-value is lower than α = 0.10. 
The graphical representation follows the recommendations from Pocock 
[Pocock 2002]. Two-sided CIs at specific time points will be constructed, with 
confidence limits (CLs) calculated using Greenwood’s formula for the estimate of the 
standard error. Median time to event (as well as 25th and 75th percentiles) for each 
group will be provided with the corresponding 2-sided CIs calculated using the 
method of Brookmeyer [Brookmeyer 1982]. 
KM estimates of the survival function are presented at the following relevant 
time points: Weeks 16, 24, 36, and 52. 
The statistical models will be implemented by the SAS® code described in the DPS 
Part 1 document.  
This statistical method with the same adjustment will be also applied on other efficacy 
variables: 
• Time to first occurrence of HF death or HF hospitalization over 52 weeks (up to 
EOS / OLE); 
• Time to first occurrence of CV death or CV hospitalization over 52 weeks (up to 
EOS / OLE). 
An investigation into the assumption of proportional hazards for treatment will be 
performed informally using a plot of the complementary log-log of the survival 
against the log of time (for each group). If the hazards are proportional, the lines 
should be approximately parallel. 


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9.3 Statistical methods for count variables 
The number of recurrent HF hospital admissions will be analyzed using a Negative 
binomial regression model adjusting for the log of the ratio: baseline NT-pro-BNP 
over NT-pro-BNP value per IRT. The time on treatment will also be considered and 
included as an offset variable. 
Adjusted Estimates within each treatment group and between treatment groups will 
be displayed along with 2-sided 90% CIs, after inverse transformation using the 
exponential function. 
The statistical models will be implemented by the SAS® code detailed in the DPS Part 
1 document. 
9.4 Statistical methods for categorical variables 
The proportion of subjects having NYHA FC and clinical composite outcome 
improved, having worsened or being stable and the proportion of subjects in each of 
the 3 PGA categories of favorable change, unfavorable change and unchanged 
[Section 5.5.3.6] will be calculated at each post-baseline assessment by treatment 
group. The relative risk (macitentan over placebo) of subjects having worsened will 
be displayed with 2-sided 90% CIs. 
The statistical models will be implemented by the SAS® code detailed in the DPS 
Paret 1 document. 
NYHA FC: to calculate the relative risk, “stable” and “improved” categories will be 
put together as a single category “not worsened”. 
Clinical composite outcome: to calculate the relative risk, “unchanged” and 
“improved” categories will be put together as a single category “not worsened”. 
PGA: to calculate the relative risk, “unchanged” and “favorable change” categories 
will be put together as a single category “not worsened”. 
9.5 ANCOVA model for repeated measurements 
The efficacy endpoints where this model will be implemented are: Quality of life 
scores over time, Percent of baseline in NT-pro-BNP over time, change from baseline 
in accelerometer-assessed physical activity over time, change from baseline in 
Glomerular Filtration Rate. 
A random coefficient regression model (with random slopes and intercepts) will be 
applied. It includes treatment, time (expressed in weeks from the start of double-blind 
treatment) and time-by-treatment as factors and the baseline value as a covariate. For 
NT-pro-BNP analysis only, the model includes treatment, time and time-by-treatment 


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as factors and the log of the ratio: baseline NT-pro-BNP over NT-pro-BNP value per 
IRT as a covariate. 
The choice of the random coefficient regression model instead of the traditional 
repeated measures analysis of variance (fixed coefficient model assuming that 
everybody changes at the same rate) was justified by the advantages of using a method 
allowing for individual differences in the initial status and rate of change (slope) and 
allowing the analysis of unbalanced data (subjects are not required to have the same 
number of observations or to be observed at the same time points). 
For NT-pro-BNP analysis, the treatment effect expressed as geometric means ratio 
and its associated 90% 2-sided CIs will be estimated based on the same model by 
inversely transforming using the exponential function the least squares means and 
90% CIs obtained in log scale.  
No imputation of missing values is planned. 
The statistical models will be implemented by the SAS® code detailed in the DPS Part 
1 document. 
10 STATISTICAL ANALYSES 
10.1 Overall testing strategy 
The effect of macitentan as compared to placebo will be tested using a mixed-models 
ANCOVA adjusting for the NT-pro-BNP evolution observed during the macitentan 
run-in. 
The resulting p-value will be compared to an overall 2-sided type I error of 10%. 
The primary and three secondary efficacy variables will be tested at 2-sided  
α = 0.10, using a hierarchical testing approach to address multiplicity concern in the 
FAS. The secondary efficacy variables will be tested in a sequential manner following 
the order listed in Section 5.5.2.  
The hierarchical strategy will be applied to control the experiment-wise α level 
[Dmitrienko 2010] with overall 2-sided α = 0.10. Where a test null hypothesis cannot 
be rejected in favor of macitentan 10 mg, then the test p value and subsequent test p 
values in the hierarchical order will be presented for information only.  


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Figure 4 
Hierarchical testing strategy 
 
KCCQ CS = Kansas City Cardiomyopathy Questionnaire Clinical Summary score; CHGcs(t) = Change from 
baseline in KCCQ Clinical Summary score; CHGlvpa(t) = Change from baseline in proportion of time spent in 
light to vigorous physical activity based on a threshold of > 100 activity counts per minute;WHF = worsening 
heart failure; S(t) = WHF survival function. 
10.2 General rules for data presentations 
This section describes the general rules applied for all data displays. 
Unless otherwise specified in this document: 
• All listings will be sorted by randomized treatment group (or not-randomized), 
then by geographical region (order according to Section 5.2.1), country 
(alphabetical order), site, subject number and when appropriate by visit / date of 
assessment. The order site/ subjects within the not-randomized subset will be 
according to the latest run-in period achieved: MRI, PRI and screening failures 
last. All data collected will be displayed, including unscheduled visits (if any). 
Listings will be presented on the SCR set  unless specified otherwise.  
• In summary tables and graphical representations, subjects will be grouped by 
randomized treatment group. All scheduled visits for a variable will be displayed 
including assessments during run-in periods.   
Difference between treatments in percent of baseline NT-ProBNP at Week 24 - FAS
H0(1): β1 = 0 vs. H1(1): β1 ≠ 0
Change from baseline in KCCQ CS score at Week 24 - FAS
H0(2): CHGcs_m(t) = CHGcs_p(t) vs. H1(2): CHGcs_m(t) ≠ CHGcs_p(t)
Time to WHF - FAS
H0(4): S_m(t) = S_p(t) vs. H1(4): S_m(t) ≠ S_p(t)
Change from baseline in proportion time in LVPA at Week 24 - FAS
H0(3): CHGlvpa_m(t) = CHGlvpa_p(t) vs. H1(3): CHGlvpa_m(t)≠ 
CHGlvpa_p(t)


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• In summary tables presented for the FAS or SAF, “macitentan” treatment group 
is displayed as first column from the left. “Placebo” is the second/last column 
from the left. A third column (i.e., “Total”) with the pool across the treatment 
groups (macitentan+placebo) is added for subject disposition, demographic and 
baseline characteristics.  
• The absolute change from baseline to Visit/Week X is defined as the difference 
between the post-baseline Visit X value and the baseline value. 
• Selected summary tables presented for run-in treatment periods: placebo run-in is 
displayed first followed by macitentan run-in to reflect the order of the run-
periods. 
• Data will be summarized in tables including: number of non-missing 
observations, frequency with percentage per category (percentages based on the 
number of non-missing observations) for categorical safety variables, 
• Data will be summarized in tables including: number of missing observations and 
frequency with percentage per category (percentages based on the total number 
of observations) for categorical variables other than safety variables. 
• Number of events, number of censored observations, number of subjects at risk, 
and KM estimates of the survival function, hazard ratios and corresponding 90% 
CIs will be displayed for time-to-event variables. 
• Geometric means and coefficients of variation  will also be displayed for  
NT-pro-BNP analysis. 
10.3 Display of subject disposition, protocol deviations and analysis sets 
Subject disposition, PDs and analysis sets will be displayed in accordance with the 
ICH E3 guidelines [ICH 1995] and the sponsor CSR template. 
10.3.1 Screening failures and run-in disposition and failures 
Counts and percentages of screening failures [see definition in Section 5.1.1] and 
associated reason will be presented in a summary table. For subjects that fail 
screening more than once, only the reason of the last failure will be reported in the 
summary table. All screening failure reasons will be included in the listings. 
Counts and percentages of single-blind placebo and macitentan run-in withdrawals 
[see definitions in Sections 5.1.2 and 5.1.3] will be presented overall and by reason. 
A subject listing of withdrawals and associated reasons according to period is 
provided by geographical region, country and site. 


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The number and percentage of subjects with 1 or more criterion for placebo run-in 
failure [Section 5.1.2] or macitentan run-in failure [Section 5.1.3] will be presented 
overall and per criterion. For subjects who failed placebo run-in and then entered and 
failed macitentan run-in, the summary will include only their first failure during the 
placebo run-in. Listings will include all run-in failure criteria met, sorted by 
geographical region, country, site and subject.  
The number and percentage of subjects with 1 or more unmet eligibility criterion for 
placebo run-in [see definition in Section 5.1.1.1], macitentan run-in [see definition in 
Section 5.1.2.1] and double-blind treatment period [see definition in Section 5.1.3.1] 
will be presented by period overall and per criterion.  
All subjects with unmet eligibility criteria will be listed by geographical region, 
country and site. Subjects randomized with unmet criteria will be flagged in the 
listing. 
10.3.2 Subject disposition 
The number of subjects randomized, treated (received at least one dose of double-
blind study treatment), completed treatment, entered in PTOP, completed the study 
will be all summarized by treatment group and overall for the FAS. 
Subjects prematurely withdrawn from the study (post randomization) with reasons 
for premature study withdrawal will be summarized by treatment group and overall 
for the FAS.  
The following information is summarized, presenting the number and percent of 
subjects overall for the SCR set: 
• Screened  
• Entered the single-blind placebo run-in 
• Treated with single-blind placebo 
• Entered the single-blind macitentan run-in  
• Treated with single-blind macitentan 
• Eligible for the double blind  
• Randomized  
• Received double-blind treatment 
• Completed treatment 
• Completed study 
• Eligible for the sub-study 
• Participated in the sub-study 
All subject disposition variables will be listed. 


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In addition, the disposition of subjects in the double-blind period will be summarized 
by visit on the FAS. 
Subjects’ randomization is summarized by geographical region, country and site. 
Randomization information (number, date, stratification factor, planned and actual 
treatment group) will be provided in a subject listing for the FAS. The listing will also 
include the NT-pro-BNP observed value used in the randomization stratification 
factor and also at entry into MRI period (with flags for different values). 
If any randomization code is broken before database closure, the event that triggered 
the request as well as the action taken following the unblinding are collected in the 
CRF “Subject Unblinding” and will be provided in a subject listing. 
10.3.3 Protocol deviations 
Protocol deviations [as defined in Section 6] will be summarized by category, 
displaying counts and percentages of subjects with at least one PD by treatment group 
and overall for the FAS. A similar table is presented for important protocol deviations. 
This summary table is sorted, within each category, by overall frequency, in 
descending order; if a tie occurs, the tied characteristics will be sorted alphabetically. 
All reported PDs will be reported in a subject listing. Important PDs are flagged 
accordingly.  
10.3.4 Analysis sets 
The number and percentage of subjects in each analysis set will be summarized in a 
table, by treatment group and overall on the SCR set. Subject participation in each 
analysis set will be listed. 
Reasons for excluding subjects from the PPS will be listed and summarized in a table 
on the FAS. 
10.4 Analyses of subject characteristics 
This section provides the statistical analyses performed to describe subject 
characteristics defined in the corresponding section above. 
Summaries for demographic and baseline characteristics will be performed on the 
FAS. 
All data will be reported in subject listings. 


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10.4.1 Demographics 
Continuous and categorical demographics [see definition in Section 5.2.1] will be 
summarized, by treatment group and overall, using descriptive statistics. 
Demographic characteristics are also summarized by subgroups of geographical 
region as defined in Section 8. 
Demographics will also be summarized for subjects in each of the PRI and MRI 
analysis sets split by those who enter / don’t qualify for the next period. 
10.4.2 Baseline disease characteristics 
Continuous and categorical baseline disease characteristics [see definition in 
Section 5.2.2] will be summarized, by treatment group and overall, using descriptive 
statistics on the FAS. NT-pro-BNP is partitioned by subjects with / without atrial 
fibrillation according to ECG at screening. 
Baseline disease characteristics will also be summarized by subgroups of 
geographical regions as defined in Section 8.  
Baseline disease characteristics are also summarized for subjects in each of the PRI 
and MRI analysis sets split by those who enter / don’t qualify for the next period. 
In addition, NT-pro-BNP values as per IxRS are displayed together with values 
assessed at subject’s entry into macitentan run-in and displayed in a shift table if any 
mis-strata occurred. 
All the baseline data collected in the “Specific Medical History” CRF and 
“Signs/Symptoms of special interest” CRF will be provided in a subject listing. 
10.4.3 Other baseline characteristics 
Other baseline characteristics (RHC and PFTs in Section 5.2.3) will be listed only. 
Renal function [Section 5.2.3] based on the eGFR (mL/min/1.73m2) is summarized 
as both continuous and categorical. 
10.4.4  Medical history 
All medical history [see definition in Sections 5.2.4 and 5.2.4.1] will be summarized 
together by treatment group and overall for the FAS, displaying counts and 
percentages of subjects having been diagnosed with at least one disease. Counts and 
percentages of subjects having been diagnosed with at least one disease will be 
presented by SOC and PT within each SOC as well as by PT. The summary tables 
will be presented in descending order according to the incidence in the macitentan 


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treatment group (e.g., SOC and PT within each SOC with the highest number of 
occurrences appears first). If the frequencies of SOC/PTs are the same, alphabetical 
order will be used. 
Subjects with two or more occurrences of the same disease (as qualified by the same 
PT) are counted only once. 
Separate listings of medical history and specific medical history [Section 5.2.4.1] are 
provided. 
10.4.5 Previous and concomitant therapies 
Number and percentages of subjects having taken at least one therapy will be 
presented by ATC class (level 4) and PT within each ATC class. All summaries will 
be tabulated by ATC class, and individual PTs within each ATC class, for the FAS. 
ATC classes will be sorted by descending order of frequency in the macitentan 
treatment group. If the frequencies of ATC class are the same, alphabetical order will 
be used. The same rule applies for PTs within ATC class.  
Previous therapies [Section 5.2.5.1], study-treatment concomitant therapies 
[Section 5.2.5.4], and post-study treatment therapies [Section 5.2.5.5] will be 
summarized separately, by treatment group and overall, using descriptive statistics 
for categorical data.  
All therapies will be reported in a subject listing for all subjects flagging previous, 
study-treatment concomitant and post-study treatment therapies accordingly.  
10.4.6 Baseline therapies of special interest  
Baseline therapies of special interest [Sections 5.2.5.2 and 5.2.5.6] will be 
summarized separately, by treatment group and overall, using descriptive statistics 
for categorical data as above in Section 10.4.5.  
All therapies of special interest will be reported separately in a subject listing flagging 
baseline therapies accordingly. 
10.4.7 Changes in Diuretics 
Details for calculating TDD and deriving changes in diuretics intake are described in 
Section 5.2.5.7. The number and percentage of subjects with a change (increase/ 
decrease) in diuretic therapy: during placebo run-in period will be summarized on 
PRI set; during macitentan run-in period will be summarized on MRI set, while those 
with a change during double-blind treatment period will be summarized on FAS. 


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Summaries of increase in diuretic therapy will be presented overall and by category 
(increase TDD, new diuretic, IV) [Section 5.2.5.7]. 
Diuretics [Section 5.2.5.7] will be listed in a separate listing including description of 
changes (increases and decreases) when applicable. 
10.4.8 Other subject characteristics 
10.4.8.1 Contraceptive methods 
For female of childbearing potential only, contraceptive methods [as defined in 
Section 5.2.6] together with serum pregnancy tests data (i.e., choriogonadotropin 
beta) will be provided in separate subject listings. 
10.5 Analysis of study treatment exposure and compliance 
Exposure data as well as drug accountability will be provided in subject listings. 
10.5.1 Exposure 
The duration of study treatment (including interruptions, see definition in 
Section 5.3.1) as well as the study treatment exposure (excluding interruptions) and 
the cumulative exposure (patient years) for the double-blind treatment period is 
summarized per treatment group using descriptive statistics for the FAS and SAF. 
The study treatment duration is also summarized as a categorical variable, presenting 
the cumulative distribution of treatment duration by class interval (i.e., at least 
4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at 
least 24 weeks, at least 36 weeks and at least 52 weeks) and displaying counts and 
percentages of subjects in each class interval.  
Study treatment exposure (excluding interruptions) up to Week 24 is summarized per 
treatment group using descriptive statistics for the FAS and PPS. 
The total exposure to macitentan treatment (see definition in Section 5.3.1) is 
summarized using descriptive statistics for the MRI set.  
A listing of exposure and study treatment interruptions is provided for the PRI. 
10.5.2 Compliance with study treatment 
Double-blind study-treatment compliance [see definition in Section 5.3.2] is 
summarized overall per treatment group on the FAS, displaying counts and 
percentages of subjects with compliance < 80%, 80%–120% and > 120%. In the same 
manner, also the double-blind study-treatment compliance up to Week 24 is 


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summarized per treatment group on the FAS and PPS. Compliance during macitentan 
run-in period is summarized on the MRI set. 
A listing of compliance for each visit and compliance during macitentan run-in is also 
provided, containing the compliance values directly collected in “Study Drug 
Dispensing & Accountability” form in CRF. 
10.5.3 Study treatment discontinuation  
A summary table is provided on the SAF to display, for each treatment group, and 
overall, counts and percentages of subjects who prematurely discontinued study 
treatment during double-blind treatment period together with reason associated with 
study treatment discontinuation [see definition in Section 5.3.3]. 
A subject listing with all study treatment premature discontinuations and related 
reasons is provided. 
A summary table to display counts and percentages of subjects who prematurely 
discontinued study treatment during the two run-in treatment periods is provided on 
the PRI set and MRI set respectively, together with reasons for discontinuation.  
10.5.4 Study treatment adjustments or interruptions 
Subjects with study treatment interruption and corresponding reasons for 
interruption(s) [defined in Section 5.3.4] will be summarized per treatment group for 
the double-blind study treatment period using the number and percentages of subjects 
with at least one interruption on the FAS. The numbers in the categories may sum to 
a number greater than the number of subjects with an interruption as a single subject 
could have multiple interruptions for multiple reasons. 
Multiple interruptions of the same type (reason) are only counted once per subject.  
All subject treatment interruptions are presented in the listing of exposure described 
in Section 10.5.1 above. 
10.6 Analysis of the primary efficacy variable(s) 
Percent of baseline in NT-pro-BNP at Week 24 [defined in Section 5.5.1] will be 
analyzed using ANCOVA as described in Section 9.1. NT-pro-BNP is assumed to 
follow a log-normal distribution. Therefore, data is log transformed before analysis. 
The following covariate will also be used for the statistical analyses of the primary 
endpoint: 
• log of the ratio between baseline NT-pro-BNP and the NT-pro-BNP value as per 
IRT stratification. 


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The main analysis will be performed on subjects of the FAS, according to the intent-
to-treat principle. The PPS analysis will be used to perform specific sensitivity 
analysis on the primary efficacy variable. 
10.6.1 Hypothesis and statistical model 
Due to the underlying log-normal distribution of the primary efficacy variable, an 
analysis of covariance will be applied on log-transformed data. 
𝑦𝑦𝑖𝑖𝑖𝑖= 𝛼𝛼+ 𝛽𝛽1𝑇𝑇𝑇𝑇𝑇𝑇𝑖𝑖+ 𝛽𝛽2𝑥𝑥𝑖𝑖𝑖𝑖+ 𝑒𝑒𝑖𝑖𝑖𝑖 
The null hypothesis is that macitentan and placebo effects on NT-pro-BNP are the 
same. The alternative hypothesis is that the effect of macitentan on NT-pro-BNP 
differs from placebo effect. 
H0: M macitentan 10 mg = M placebo versus 
H1: M macitentan 10 mg ≠ M placebo  
The null hypothesis will be tested by a 2-sided Wald test with a 2-sided significance 
level of 0.10. 
Assuming normal distribution of the primary variable, the null hypothesis will be 
tested by geometrical means of an ANCOVA model on percent of baseline  
NT-pro-BNP assessed at Week 24. 
The ANCOVA model as described in Section 9.1 will be applied where 𝑦𝑦𝑖𝑖𝑖𝑖 denotes 
log-transformed percent of baseline in NT-pro-BNP at Week 24 and 𝑥𝑥𝑖𝑖𝑖𝑖 denotes the 
log-transformed ratio for subject 𝑗𝑗 under treatment 𝑖𝑖, respectively. 
Log-transformed percent of baseline in NT-pro-BNP at Week 24 will be used to test 
the null hypothesis of equality of treatment effects. According to the model notation, 
null and alternative hypotheses above conform to H0: β1 = 0 versus H1: β1 ≠ 0.  
10.6.2 Handling of missing data 
The primary efficacy variable is the percent of baseline NT-pro-BNP at Week 24 
(Visit 11). Baseline is defined as the last non missing value among all measures 
collected during placebo and macitentan run-ins, up to and including the day of 
double-blind treatment start (Visit 6). Therefore, no subject will have a missing value 
for baseline because the subject cannot be randomized via IRT in case of missing 
values at both pre-macitentan run-in (Visit 4) & screening (Visit 1).  
During the conduct of the study, all efforts will be made to avoid missing values in 
NT-pro-BNP at Week 24. For Week 24, the time window interval [see Section 11.1] 
is applied. 


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Furthermore, if a subject prematurely discontinues study treatment the subject will be 
asked to return for a visit within 7 days of EOT where NT-pro-BNP assessments is 
performed. If treatment is discontinued prior to Week 24, and the subject enters the 
PTOP, it is requested that the subject return for a NT-pro-BNP assessment at 
Week 24. Any unscheduled assessment or local laboratory assessment will also be 
mapped to a time window.  
However, if missing values still occur in NT-pro-BNP at Week 24 the following 
approach for imputation will be applied: 
Imputation for Main Analysis 
For randomized subjects without available NT-pro-BNP value at Week 24, the last 
available value observed before Week 24 (including baseline) is carried forward and 
considered for the main analysis. 
This approach is chosen as it is commonly used for this specific parameter  
[Solomon 2012] and in order to facilitate the clinical interpretation across study 
publications in the same indication. 
Imputation for Sensitivity analysis 
A sensitivity analysis will be performed by imputing missing NT-pro-BNP values at 
Week 24 according to the reason for drop-out. In particular, randomized subjects 
who died or were hospitalized for HF before Week 24 will be assigned a value 
significantly higher than the one assigned to subjects who have a missing value at 
Week 24 due to technical/administrative reason. In details the following rules will be 
applied: 
i) 
Subjects who died or were hospitalized for HF before Week 24: for each 
subject, their highest available value (worst case) observed from all visits 
from Visit 6 onwards (up to Week 24) will be imputed.  
ii) 
Subjects who are known to be alive, were not hospitalized for HF and 
with a missing value at Week 24: the mean of their available values from 
Visit 6 onwards (up to Week 24) will be imputed. 
iii) 
Subjects Lost to follow-up: their highest available value (worst case) 
observed from Visit 6 onwards (up to Week 24) will be imputed. 
10.6.3 Main analysis 
The main analysis will be performed on subjects in the FAS, according to the 
intent-to-treat principle. 


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The main analysis of the primary efficacy variable will be carried out after 
log-transformation using an ANCOVA adjusting for the log of the ratio: baseline 
NT-pro-BNP over NT-pro-BNP value as per IRT with an overall type I error of 10% 
2-sided. 
The treatment effect expressed as geometric means ratio and its associated 90% 
2-sided CI will be estimated based on the same model by inversely transforming using 
the exponential function the least squares mean and 90% CIs obtained in log scale. 
A listing of NT-pro-BNP values overtime will be provided for the FAS. 
10.6.4 Supportive/sensitivity analyses 
The following supportive analyses are planned: 
• Main analysis on the PPS, 
• Analysis of variance (ANOVA) on the FAS without adjustment for the  
NT-pro-BNP evolution observed during the macitentan run-in, 
• Main analysis imputing missing NT-pro-BNP values at Week 24 according to the 
reason for drop-out. 
10.6.5 Subgroup analyses 
Subgroup analyses will be performed with a separate analysis for each subgroup 
variable [see Section 8] using a two factor ANOVA model with treatment, subgroup 
and treatment-by-subgroup interaction terms. 
The test of interaction is performed with ‘n-1’ degrees of freedom, where ‘n’ is the 
number of subgroup categories. The treatment effect, measured as a geometric means 
ratio, will be estimated within each level of the subgroup variable based on the 
ANOVA including the interaction term. Significance of the interaction terms will be 
tested at a 0.01.  
Treatment effect geometric means ratio and corresponding 90% CIs for the different 
levels of each subgroup will be presented in a forest-plot. The forest-plot will be 
prepared as described in Cuzick [Cuzick 2005] with a vertical reference line displayed 
at the level of the overall treatment effect for macitentan versus placebo and a vertical 
reference line at geometric means ratio = 1. The p-value for the interaction test is 
displayed on the plot for each subgroup along with the number of patients in 
macitentan and the number of patients in placebo within each subgroup level. 
Some of the pre-specified subgroup analyses will not be conducted or categories will 
be combined when it is determined that there is insufficient number of subjects in a 
subgroup category to produce a valid result. 


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Further subgroups will be added for analysis if deemed appropriate.  
No multiplicity adjustment is introduced; the subgroup analysis is descriptive in 
nature. 
10.6.6 Additional supportive analyses 
• NT-pro-BNP vs MR-proANP   
A scatter plot of NT-pro-BNP observed values versus MR-proANP concentrations at 
Week 24 will be presented including a linear regression fitted line and 90% CLs for 
the fitted line. If a linear model does not fit the data, then alternative models may be 
explored (including a log-transformation of both variables). 
• NT-pro-BNP at Week 24 (as observed) vs increase in diuretics 
NT-pro-BNP is summarized partitioned by those with increase in diuretics (Yes/ No) 
and by type of increase new drug, increase TDD and IV. 
10.7 Analysis of the secondary efficacy variables 
The analysis of secondary efficacy variables will be performed on subjects in the 
FAS. 
10.7.1 Quality of life: KCCQ Clinical Summary score at Week 24 
10.7.1.1 Hypothesis and statistical model  
The change from baseline to Week 24 in the clinical summary score will be analyzed 
by means of an ANCOVA adjusting for the score baseline value and for the log of 
the ratio: baseline NT-pro-BNP over NT-pro-BNP value per IRT.  
The statistical hypotheses for this secondary endpoint is similar to statistical 
hypotheses of the primary endpoint. 
H0: M macitentan 10 mg = M placebo versus 
H1: M macitentan 10 mg ≠ M placebo  
Least Squares Estimates within each treatment group and between treatment groups 
will be displayed along with 2-sided 90% CIs and p-values. 
More details regarding the model and SAS code are presented in the DPS Part 1 
document. 


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10.7.1.2 Handling of missing data  
The last available value observed before Week 24 (including baseline) is carried 
forward and considered for the analysis. 
10.7.1.3 Statistical analysis 
An ANCOVA on the change from baseline to Week 24 in the clinical summary score, 
adjusting for the score baseline value and for the log of the ratio: baseline  
NT-pro-BNP over NT-pro-BNP value per IRT will be applied on the FAS. The 
treatment effect and its associated 90% 2-sided CI will be estimated based on the 
model. 
An individual subject listing of the KCCQ scores overtime will be provided on the 
FAS. 
10.7.1.4 Supportive/sensitivity analyses 
Not applicable. 
10.7.1.5 Subgroup analyses 
Not applicable.  
10.7.2 Accelerometer-assessed light to vigorous physical activity at Week 24 
10.7.2.1 Hypothesis and statistical model  
The change from baseline to Week 24 in the proportion of time spent in light to 
vigorous (including very vigorous) physical activity will be analyzed by means of an 
ANCOVA adjusting for the variable baseline value and for the log of the ratio: 
baseline NT-pro-BNP over NT-pro-BNP value per IRT.  
The statistical hypotheses for this secondary endpoint is similar to statistical 
hypotheses of the primary endpoint. 
H0: M macitentan 10 mg = M placebo versus 
H1: M macitentan 10 mg ≠ M placebo  
Least Squares Estimates within each treatment group and between treatment groups 
will be displayed along with 90% 2-sided CIs and p-values. 
More details regarding the model and SAS code are presented in the DPS Part 1 
document. 


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10.7.2.2 Handling of missing data  
To be considered evaluable, physical activity should have been measured for at least 
4 complete days at a specific time point of assessment. A complete day is defined as 
a record of at least 7 hours of data (after excluding the periods when the device was 
apparently not worn). 
Subjects received a reminder from the site staff (e.g., telephone call, text message) to 
ensure that they were wearing the accelerometer during interest periods. 
If the baseline value measured after Visit 3 is missing or not evaluable then the data 
collected following Visit 2 (training visit) or Visit 5 may be used [see Section 5.5.2.2]. 
No imputation of missing values is planned. 
10.7.2.3 Statistical analysis 
 An ANCOVA on the change from baseline to Week 24 in the proportion of time 
spent in light to vigorous (including very vigorous) physical activity, adjusting for the 
variable baseline value and for the log of the ratio: baseline NT-pro-BNP over  
NT-pro-BNP value per IRT will be applied on the FAS. The treatment effect and its 
associated 90% 2-sided CI will be estimated based on the model. 
10.7.2.4 Supportive/sensitivity analyses 
Not applicable. 
10.7.2.5 Subgroup analyses 
Not applicable.  
10.7.3 Time to first occurrence of worsening heart failure over 52 weeks (up to 
EOS / OLE) 
10.7.3.1 Hypothesis and statistical model  
The analysis of time to first occurrence of WHF will be carried out using a 
proportional hazards Cox model adjusting for the log of the ratio: baseline  
NT-pro-BNP over NT-pro-BNP value per IRT.  
Subjects without any worsening of heart failure event up to EOS will be right-
censored at their time of EOS. Estimate of Hazard Ratio and its associated 90% CI 
and p-value will be displayed. 
KM estimates will be calculated with 2-sided 90% CIs at time points (16, 24, 36, and 
52 weeks) for each treatment group and displayed in both a graphical (where the 
number of subjects at risk is at least 10% of the total number of subjects in the analysis 


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set) and a tabular form. In addition, the number of subjects at risk, the number of 
subjects censored and the number of subjects with event will be computed at each 
time point and for each treatment group. 
Time to first occurrence of WHF will be presented in a subject listing on the FAS. 
10.8 Analysis of other efficacy variables 
Exploratory analysis of other efficacy variables will be conducted on the FAS. 
Missing values will not be imputed. 
10.8.1 Number of days alive and out of the hospital 
For both DAOH and %DAOH [see Section 5.5.3.1], the treatment effect will be 
assessed by means of an ANCOVA adjusting for the log of the ratio: baseline  
NT-pro-BNP over NT-pro-BNP value per IRT. 
Least Squares Estimates within each treatment group and between treatment groups 
will be displayed along with 90% 2-sided CIs. 
More details regarding the model and SAS code are presented in the DPS Part 1 
document. 
Data regarding DAOH and %DAOH will be reported in an individual subject listing 
on the FAS. 
10.8.2 Time to first occurrence of HF death or HF hospitalization over 52 
weeks (up to EOS/ OLE) 
The analysis of time to first occurrence of HF death or HF hospitalization will be 
carried out using a proportional hazards Cox model adjusting for the log of the ratio: 
baseline NT-pro-BNP over NT-pro-BNP value per IRT.  
Estimate of Hazard Ratio and its associated 90% CI will be displayed. 
KM estimates will be calculated with 2-sided 90% CIs at time points (12, 24, 36, and 
52 weeks) for each treatment group and displayed in both a graphical (where the 
number of subjects at risk is at least 10% of the total number of subjects in the analysis 
set) and a tabular form. In addition, the number of subjects at risk, the number of 
subjects censored and the number of subjects with event will be computed at each 
time point and for each treatment group. 
More details regarding the model and SAS code are presented in the DPS Part 1 
document. 


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Time to first occurrence of HF death or hospitalization will be presented in a subject 
listing on the FAS. 
10.8.3 Time to first occurrence of CV death or CV hospitalization over 52 weeks 
(up to EOS/ OLE) 
The analysis of time to first occurrence of CV death or CV hospitalization will be 
carried out using a proportional hazards Cox model adjusting for the log of the ratio: 
baseline NT-pro-BNP over NT-pro-BNP value per IRT.  
Estimate of Hazard Ratio and its associated 90% CI will be displayed. 
KM estimates will be calculated with 2-sided 90% CIs at time points (12, 24, 36, and 
52 weeks) for each treatment group and displayed in both a graphical (where the 
number of subjects at risk is at least 10% of the total number of subjects in the analysis 
set) and a tabular form. In addition, the number of subjects at risk, the number of 
subjects censored and the number of subjects with event will be computed at each 
time point and for each treatment group. 
More details regarding the model and SAS code are presented in the DPS Part 1 
document. 
Time to first occurrence of CV death or hospitalization will be presented in a subject 
listing on the FAS. 
10.8.4 Number of HF hospital admissions over 52 weeks 
The number of recurrent HF hospital admissions will be analyzed using a Negative 
binomial regression model adjusting for the log of the ratio: baseline NT-pro-BNP 
over NT-pro-BNP value per IRT. 
Adjusted Estimates within each treatment group and between treatment groups will 
be displayed along with 2-sided 90% CIs, after inverse transformation using the 
exponential function. 
More details regarding the model and SAS code are presented in the DPS Part 1 
document. 
10.8.5 NYHA FC (improved/worsened/stable) at each post-baseline assessment 
The proportion of subjects having improved, having worsened or being stable will be 
calculated at each post-baseline assessment by treatment group. The relative risk 
(macitentan over placebo) will be displayed with 2-sided 90% CIs. 


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To calculate the relative risk, “stable” and “improved” categories will be put together 
as a single category “not worsened”.  
More details regarding the model and SAS code are presented in the DPS Part 1 
document. 
A listing of NYHA FC change overtime will be presented on the FAS. 
10.8.6 Clinical composite outcome (‘worsened’, ‘unchanged’, ‘improved’)  
The proportion of subjects having improved, having worsened or being unchanged 
will be calculated for each period of time by treatment group. The relative risk 
(macitentan over placebo) will be displayed with 2-sided 90% CIs. 
To calculate the relative risk, “unchanged” and “improved” categories will be put 
together as a single category “not worsened”. 
More details regarding the model and SAS code are presented in the DPS Part 1 
document. 
A listing of clinical composite outcome will be presented on the FAS. 
10.8.7 Quality of life KCCQ scores over time 
For each variable: 
• Overall summary score 
• Clinical summary score  
• Physical limitations score 
the change over time is evaluated, assuming a linear pattern over time, with the use 
of a random coefficient regression model (with random slopes and intercepts) that 
includes treatment, time and time-by-treatment as factors and the score baseline value 
as a covariate.  
The random variables for this model will be the subject-intercept and the subject-by-
time interaction. The error term is assumed to follow a Normal distribution and the 
vector of the two correlated random effects is assumed to follow a bivariate Normal 
distribution, each with mean 0 and unstructured covariance matrix. 
The treatment effect is determined by using estimated slopes for each study treatment 
group on the basis of the time-by-treatment interaction term. Estimates within each 
treatment group and between treatment groups will be displayed overall and for each 
study visit along with their corresponding 90% 2-sided CIs.  
No imputation of missing values is planned.  


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Modelling adjustments, such as addition of a quadratic term (both in the model and 
in the random effect) or a different covariance pattern within subject, will be made in 
case of meaningful conflict between the predicted and the observed data (via a review 
of the predicted and observed residuals plot).  
More details regarding the model and SAS code are presented in the DPS Part 1 
document. 
A listing of KCCQ scores and changes overtime will be presented on the FAS. 
10.8.8 Percent of baseline NT-pro-BNP over time 
The percent of baseline NT-pro-BNP over time is evaluated after log-transformation 
with the use of a random coefficient regression model (with random slopes and 
intercepts) that includes treatment, time and time-by-treatment as factors and the log 
of the ratio: baseline NT-pro-BNP over NT-pro-BNP value per IRT as a covariate.  
The random variables for this model will be the subject-intercept and the subject-by-
time interaction. The error term is assumed to follow a Normal distribution and the 
vector of the two correlated random effects is assumed to follow a bivariate Normal 
distribution, each with mean 0 and unstructured covariance matrix. 
The treatment effect expressed as geometric means ratio and its associated 90% 
2-sided CIs will be estimated based on the same model by inversely transforming 
using the exponential function the least squares means and 90% CIs obtained in log 
scale. Estimates within each treatment group and between treatment groups will be 
displayed overall and for each study visit along with their corresponding 90% 2-sided 
CIs. 
No imputation of missing values is planned.  
Modelling adjustments, such as addition of a quadratic term or a different covariance 
pattern within subject, will be made in case of meaningful conflict between the 
predicted and the observed data. 
More details regarding the model and SAS code are presented in the DPS Part 1 
document. 
A listing of NT-pro-BNP values overtime will be presented on the FAS. 


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10.8.9 Change from baseline in accelerometer-assessed physical activity over 
time 
For each variable as described in Sections 5.5.2.2 and 5.5.3.9: 
− Proportion of time spent in light to vigorous physical activity based on a threshold 
of > 100 activity counts per minute 
− Mean daily number of episodes of activity over 100 activity counts per minute of 
at least 1 minute duration 
− Mean count per minute of daily activity 
− Mean daily number of episodes of activity over 100 activity counts per minute of 
at least 5 minutes duration 
− Mean daily accelerometer units 
the change over time is evaluated with the use of a random coefficient regression 
model (with random slopes and intercepts) as described in Section 9.5. 
In addition, the proportion of time spent in: 
− Sedentary physical activity 
− Light physical activity 
− Moderate physical activity 
− Vigorous physical activity 
will be described at each time point of assessment by calculating for each treatment 
group the mean proportion of time spent in each category and will be displayed in 
both a graphical (bar plots) and a tabular form. 
More details regarding the model and SAS code are presented in the DPS Part 1 
document.  
A listing of accelerometer-assessed physical activity data will be presented on the 
FAS. 
10.8.10 Change from baseline in echocardiography left and right heart function 
at Week 24 and Week 52 
For each variable listed in Section 5.5.3.11, the change over time is summarized. 
A listing of echocardiography data will be presented on the FAS. 
10.8.11 Percent of baseline MR-proANP over time 
The percent of baseline MR-proANP over time is analyzed by means of an ANCOVA 
at Week 24 adjusting for the log of the variable baseline value.  


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A listing of MR-proANP values overtime will be presented on the FAS. 
10.8.12 NT-pro-BNP over time 
Summary statistics of NT-pro-BNP over time will be presented per treatment group 
for the FAS for all assessments from screening, through run-in and double-blind 
periods. In addition, summaries will be presented on the MRI and PRI sets. 
A listing of NT-pro-BNP values overtime will be presented on the FAS. 
10.8.13 Patient global assessment 
Summary statistics of PGA 7-point scale over time will be presented per treatment 
group for the FAS. 
The proportion of subjects having favorable, unchanged or unfavorable ratings will 
be calculated at each post-baseline assessment by treatment group.  
The relative risk (macitentan over placebo) will be displayed at each time point with 
2-sided 90% CIs. To calculate the relative risk, “unchanged” and “favorable changes” 
categories will be put together as a single category “not worsened”. 
A listing of all PGA data will be presented on the FAS. 
10.9 Analysis of safety variables 
10.9.1 Adverse events 
All AEs collected from signing of informed consent up to EOS will be reported in the 
subject listings together with the assigned PT/SOC. The SAEs collected during PTOP 
will be included in these subject listings. Treatment-emergent AEs during the placebo 
run-in, macitentan run-in and double-blind treatment periods [see definition in 
Section 5.6.1] will be flagged accordingly. Missing intensity is reported in listings 
and is replaced with the worst case only for the summary tables. 
AE summaries will be presented for the safety set (i.e., subjects received double-blind 
treatment) and by double-blind treatment group unless specified otherwise. A few 
select summary tables, will be presented for the PRI and MRI sets as in Table 5 and 
detailed in the sections below: 


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Table 5 
Overview of summary tables for AEs 
Summary  
Period * 
Analysis 
set 
Overview of AEs 
Study treatment 
Double-blind 
SAF 
SAF 
TEAEs  
Study treatment 
PRI, MRI, double-blind  
Double-blind, related to study treatment  
Double-blind, by maximum intensity  
Placebo run-in (overall) 
Macitentan run-in (overall) 
Combined macitentan (overall) 
Combined macitentan, related to study 
treatment (overall) 
Combined macitentan, by maximum 
intensity (overall) 
SAF 
SAF 
SAF 
SAF 
PRI 
MRI 
MRI 
MRI 
 
MRI 
Serious TEAEs 
Study treatment 
PRI, MRI, double-blind  
Placebo run-in (overall) 
Macitentan run-in (overall) 
Combined macitentan (overall) 
SAF 
SAF 
PRI 
MRI 
MRI 
AE leading to treatment 
discontinuation ** 
Double-blind 
Double-blind TEAE 
Placebo run-in (overall) 
Macitentan run-in (overall) 
SAF 
SAF 
PRI 
MRI 
AE with fatal outcome ** 
Double-blind  
Combined macitentan (overall) 
SAF 
MRI 
Deaths 
Double-blind  
SAF 
TEAEs of special interest 
Double-blind  
Combined macitentan (overall) 
SAF 
MRI 
*presented by treatment group unless specified otherwise as overall 
** Period of discontinuation/fatality may include AEs started and worsened in previous periods, therefore a 
separate table is included for double blind treatment-emergent AEs leading to discontinuation.  
AE ꞊ adverse event; MRI ꞊ Macitentan Run-In; PRI ꞊ Placebo Run-In; SAF ꞊ Safety ; TEAE ꞊ Treatment-Emergent 
Adverse Event. 


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A summary table with an overview of TEAEs is provided displaying, for each 
treatment group, counts and percentages of subjects having experienced at least a 
TEAE, a severe AE, a study-treatment related AE, an AE leading to study treatment 
discontinuation, a non-serious frequent AE [see Section 10.9.2.5], a serious AE, a 
study-treatment related serious AE, a fatal SAE. The overview is also repeated for 
double-blind TEAEs. 
10.9.1.1 Treatment emergent adverse events 
Treatment-emergent AEs will be summarized presenting counts and percentages of 
subjects having experienced at least one TEAE by SOC and PT within each SOC as 
well as by PT. The summary tables will be presented in descending order according 
to the incidence in double-blind macitentan treatment group (e.g., SOC and PT within 
each SOC with the highest number of occurrences appears first). If frequencies of 
SOC/PTs are the same, alphabetical order will be used. The summaries will be 
presented split by treatment emergent period (PRI, MRI and for the double-blind 
TEAEs) within each treatment group.  
Double-blind TEAEs related to study treatment will be summarized similarly by 
SOC/ PT. Double-blind TEAEs by maximum intensity will be summarized similarly 
by PT, only. 
A graphical display of the relative risk (macitentan over placebo) together with the 
2-sided 95% CLs for the most common double-blind TEAEs in either treatment 
groups (i.e., in at least 5 subjects [~ 3%] in either treatment groups) is provided by 
PT. The graph is presented in descending order according to the incidence in the 
macitentan treatment group. The choice to use 95% CLs instead of 90% CLs (as done 
for the efficacy analysis) is to be in line with FDA guidance for QT/QTc studies. 
Placebo run-in TEAEs and macitentan run-in TEAEs and combined macitentan 
TEAEs will be summarized for the placebo run-in set and macitentan run-in set, 
respectively. Number and percentages of subjects having experienced at least a TEAE 
will be presented by SOC and PT within each SOC. The summary tables will be 
presented in descending order (e.g., SOC and PT within each SOC with the highest 
number of occurrences appears first). If frequencies of SOC/PTs are the same, 
alphabetical order will be used. 
Combined macitentan TEAEs related to study treatment will be summarized similarly 
by SOC and PT. Macitentan TEAEs by maximum intensity will be summarized 
similarly by PT, only. 


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10.9.2 Deaths, other serious adverse events 
10.9.2.1 Deaths 
All-cause death cases will be reported in the subject listing. Treatment-emergent 
deaths during the placebo run-in, macitentan run-in, and double-blind treatment 
periods [see definition in Section 5.6.2] will be flagged accordingly. 
A summary table reporting the incidence of deaths in the double-blind treatment 
period will be provided for the safety set. Number and percentages of deaths will be 
summarized together with the primary reason for death in descending order according 
to the incidence in double-blind macitentan treatment group.  
10.9.2.2 Serious adverse events 
All SAEs will be reported in a separate subject listing. Treatment-emergent SAEs 
during the placebo run-in, macitentan run-in and double-blind treatment periods [see 
definition in Section 5.6.3] will be flagged accordingly. SAEs reported during PTOP 
will also be included in the listing. 
Treatment-emergent SAEs will be summarized by SOC and PT within each SOC 
similarly to AEs [see Section 10.9.1]. The summaries will be presented split by 
treatment emergent period (PRI, MRI and for the double-blind TEAEs) within 
treatment group. 
Placebo run-in treatment-emergent SAEs, macitentan run-in treatment-emergent 
SAEs and combined macitentan treatment-emergent SAEs will be summarized for 
the placebo run-in set and macitentan run-in set, respectively. Counts and percentages 
of subjects having experienced at least one treatment-emergent SAE will be presented 
by SOC and PT within each SOC.  
10.9.2.3 Adverse events leading to study treatment discontinuation 
A separate subject listing is provided for all AEs leading to discontinuation of study 
treatment indicating the treatment period discontinued.  
AEs leading to premature discontinuation of study treatment will be summarized 
similarly to TEAEs [see Section 10.9.1.1], by SOC and PT within each SOC, on the 
double-blind safety set (SAF)*.  
*Note the above summary will include all AEs leading to discontinuation of double-blind treatment 
and by definition may include AEs that were emergent and worsened during the run-in periods. This 
is considered an appropriate conservative approach in comparison of double-blind treatment groups. 
In this summary of AEs, the action of withdrawing the treatment is considered as a worsening in the 
double-blind treatment period in the absence of any worsening of intensity for AEs that were emergent 
in the run-in period. 


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The summary of AEs leading to discontinuation is repeated for the double-blind 
TEAEs on the SAF. In addition, AEs leading to discontinuation of study treatment 
during the run-in periods are presented on the PRI and MRI analyses sets respectively. 
10.9.2.4 Other significant adverse events 
Treatment-emergent AEs with fatal outcome will be summarized for the safety set 
and for the combined macitentan period on the MRI set by SOC and PT within each 
SOC. Note this summary will include any AEs that are emergent or worsened in the 
run-in periods but with fatal outcome occurring after double-blind treatment start for 
these subjects in the safety set.  
A separate subject listing is provided for all subject AEs with fatal outcome. Deaths 
occurring during the run-in periods will be included in the listing. 
For each area of clinical interest, double-blind TEAEs and macitentan TEAEs of 
special interest [see definition in Section 5.6.5.2] will be summarized for the safety 
set and MRI set respectively, presenting counts and percentages of subjects having 
experienced at least one TEAE of special interest by frequency of PT within each 
AESI group. Separate subject listings will be provided for all AEs of special interest. 
10.9.2.5 Eudract and CTgov summaries 
For the disclosure of the results to EudraCT and ClinicalTrials.gov (and not for the 
purpose of the CSR), separate similar summary tables are provided by SOC and PT 
within each SOC for: 
• treatment-emergent SAEs related to study treatment during the double-blind 
treatment period 
• treatment-emergent SAEs with fatal outcome during the double-blind treatment 
period 
• treatment-emergent SAEs related to study treatment with fatal outcome during 
double-blind treatment period. 
In addition, for the disclosure of the results to VICTOR, treatment-emergent SAEs 
during double-blind treatment period are summarized displaying, for each treatment 
group, counts and percentages of subjects with at least a treatment-emergent SAE 
plus the number of events (counted exactly the number of times they occurred also 
within a subject) by SOC and PT. The summary table is presented in descending order 
according to the incidence in the macitentan treatment group (i.e., SOC and PT within 
each SOC with the highest number of occurrences appears first). Equal frequency of 
different PTs is sorted in alphabetical order of the PT. 


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Double-blind treatment-emergent non-serious AEs (any AE not classed as serious) with 
frequencies ≥ 5% in at least one treatment arm (referred to as non-serious frequent 
AEs) are  summarized displaying, for each treatment group, counts and percentages of 
subjects with at least a treatment-emergent non-serious frequent AE plus the number 
of events (counted exactly the number of times they occurred also within a subject) by 
SOC and individual preferred. The summary table is presented in descending order 
according to the number of events in the macitentan treatment group (i.e., SOC and 
individual PT within each SOC with the highest number of occurrences appears first). 
Equal frequency of different individual PTs is sorted in alphabetical order of the 
individual PT. 
10.9.3 Electrocardiogram 
The count and percentage of subjects with presence of treatment emergent qualitative 
finding [Section 5.6.7, atrial fibrillation/atrial flutter] during the double-blind study 
treatment period will be summarized in a shift table, for the safety set. These will be 
presented as shift from macitentan run-in baseline.  
In addition, shift for ECG findings will be presented by history of atrial fibrillation or 
atrial flutter (yes/no), as reported in the specific medical history CRF [see 
Section 5.2.2]. 
10.9.4 Laboratory tests 
All hematology and chemistry parameters [see Section 5.6.8] provided by the central 
and local laboratory will be displayed in subject listings, including those from 
unscheduled visits. MLAs will be flagged accordingly. 
For Week 4, Week 8, Week 16, Week 24, Week 36, Week 52, the selected laboratory 
test parameters [Section 10.9.4.2] will be summarized by treatment group displaying 
descriptive statistics for: 
• observed value at each visit specified  
• absolute change from macitentan run-in baseline to each visit.  
In each evaluation, will be included only subjects who had both the assessments at 
macitentan run-in baseline and post baseline visit.  
10.9.4.1 Fasted state laboratory values 
Laboratory values collected at screening / re-screening in fasted state 
[Section 5.6.8.1] will be summarized on FAS. Only assessments from central lab will 
be considered. 


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10.9.4.2 Marked laboratory abnormalities 
For the evaluation of MLAs, separate summaries will be presented for hematology 
and chemistry laboratory tests. 
A dictionary listing of definitions of MLA (LL, LLL, HH, HHH) is provided for each 
parameter. 
For each category (i.e., LL, LLL, HH, HHH, HHHH), double-blind treatment-
emergent MLAs [see definition in Section 5.6.8.2] will be summarized by treatment 
group, displaying counts and percentages of subjects with at least one treatment-
emergent MLA for each parameter for which the marked abnormality is defined. 
Percentages will be calculated as number of subjects with at least one treatment-
emergent MLA for the parameter under consideration divided by the number of 
subjects with any post-baseline laboratory measurement. The summary will be 
partitioned to include macitentan run-in emergent MLAs and placebo run-in emergent 
MLAs occurring in the same safety set. 
Macitentan run-in emergent MLAs will be summarized in the same way on MRI set. 
Shifts from macitentan run-in baseline to worst post-baseline abnormality category 
(during double-blind period) up to EOT + 30 days will be summarized with 
frequencies of subjects and percentages per category of shift. Categories considered 
are LLL, LL, L (L = below LLN), normal (between LLN and ULN), H (H = above 
ULN), HH, HHH. For baseline the category ‘Missing’ is also considered. Subjects 
experiencing a worsening from baseline in two different directions (e.g., going from 
normal at baseline once to H and once to L post-baseline) are counted in both 
directions.  
The denominator for percentages is the number of subjects with at least one 
post-baseline assessment. 
In-text tables will be provided for the following parameters: 
• 
Hematology: 
• 
Hemoglobin 
• 
Hematocrit 
• 
Erythrocytes  
• 
Chemistry: 
• 
ALT 
• 
AST 
• 
Alkaline phosphatase 
• 
Total bilirubin 


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For the above selected parameters, values over time from Screening visit will be 
plotted.  
10.9.4.3 Additional liver laboratory abnormalities 
For the evaluation of liver laboratory abnormalities, measurements from unscheduled 
visits will be included. All subject with at least one treatment-emergent LTA will be 
provided in a separate subject listing. 
Double-blind treatment-emergent LTAs [see definition in Section 5.6.8.3] will be 
summarized similarly to the MLAs [see Section 10.9.4.2].  
A similar summary is created also for single-blind macitentan run-in emergent liver 
abnormalities. 
10.9.5 Vital signs and body weight 
Vital signs (blood pressure measurements, pulse rate) and body weight [see 
Section 5.6.6] will be reported in a subject listing. 
SBP, DBP, pulse rate, and body weight will be summarized, by treatment group, 
displaying descriptive statistics for: 
• observed value at each visit up to Week 52 
• absolute change from macitentan run-in baseline to each visit up to Week 52. 
Vitals signs parameters will be analyzed regardless of the measurement position. 
The number and percent of subjects with a decrease from baseline during 
double-blind period in SBP [see definition in Section 5.6.6.1] will be summarized by 
treatment group on the safety set, by displaying frequency and percentages of subjects 
together with 2-sided 90% CLs. Similar summary is presented for decrease in SBP 
during single-blind macitentan run-in period on the MRI set. 
Vital signs and body weight will be described over time up to EOT + 30 days by 
means of a random coefficient regression model as described in Section 9.5. 
The change in SBP and DBP, pulse rate and body weight over time is evaluated by 
means of a random coefficient (9.5) regression model (with random slopes and 
intercepts). The dependent variable of the model is the change from baseline. 
Randomized study treatment visit (i.e., Week 4/Week 8/Week 16/Week 24/Week 
36/Week 52), treatment-by-visit interaction terms, and baseline value will be included 
as fixed effects in the model. The random variables for this model will be both the 
subject-intercept and the subject-by-time interaction. The error term is assumed to 
follow a normal distribution and the vector of the two correlated random effects is 


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assumed to follow a bivariate normal distribution, each with mean 0 and unstructured 
covariance matrix. This statistical model allows for missing data, assuming they are 
missing at random. Therefore, no imputation of missing values is planned. 
The treatment effect is determined by using estimated slopes for each study treatment 
group on the basis of the treatment-by-time interaction term from the mixed model.  
The results will be presented in a summary table displaying: 
• For each visit, the adjusted least squares means and 2-sided 90% CLs for each 
treatment group as well as the adjusted least squares means difference macitentan 
vs placebo with 2-sided 90% CLs. 
10.9.6 Other safety variables 
10.9.6.1 Number of all-cause hospital admissions up to 30 days after study 
treatment discontinuation 
A negative binomial model as described in Section 9.3 is used for the statistical 
analysis. The null hypothesis of no treatment effect is tested by a 2-sided Wald-type 
test. 2-sided 90% Wald CLs is calculated for the relative reduction in mean annualized 
hospitalization rate for macitentan compared to placebo. 
10.9.6.2 Glomerular Filtration Rate 
Estimated GFR [see definition in Section 11.9] is summarized on the SAF, by 
treatment group, displaying descriptive statistics for: 
• observed value at each visit up to Week 52 
• absolute change from macitentan run-in baseline to each post baseline visit.  
GFR will be described over time up to 30 days after study treatment discontinuation 
by means of a random coefficient regression model as described in Section 9.5. 
10.9.6.3 Physical examination 
Physical examinations [as defined in Section 5.6.9.3] performed during the course of 
the study will be reported in a subject listing.  
10.9.6.4 Heart failure signs and symptoms of special interest  
Heart failure signs and symptoms of special interest [as defined in Section 5.6.9.4] 
assessed during the course of the study will be reported in a subject listing. 


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10.10 Analysis of quality of life variables 
The three scores derived from KCCQ will be summarized on the FAS, by treatment 
group, displaying descriptive statistics for: 
• observed value at each visit  
• absolute change from baseline to each visit. 
10.11 Analysis of sub-study variables  
The 6-MWD will be summarized on the SSAS by treatment group, displaying 
descriptive statistics for: 
• observed value at each visit  
• absolute change from baseline to each visit. 
Sub-study data including 6-MWD and Borg Dyspnea Index will be listed. 
11 GENERAL DEFINITIONS AND DERIVATIONS 
11.1 Time windows  
To allow analysis of data at the relevant planned (scheduled) visits during the 
double-blind period, recorded assessments, including PTOP and unscheduled ones, 
are re-assigned to the most appropriate visit according to the best fitting time window 
for that visit [see Table 6 and Table 7]. Note that the visit windows are contiguous in 
order to retain all values in the analysis by time point.  
Table 6 
Visit time windows NT-pro-BNP 
Visits  
Target day* 
Min. day  
Max. day 
Baseline 
1 
No limit 
1 
Week 4  
28 
2 
70 
Week 16 
112 
71 
140 
Week 24 
168 
141 
267 
Week 52 
365 
268 
No upper limit 
* Number of days from start of double-blind treatment. 


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Table 7 
Safety Visit time windows and efficacy with similar schedule 
Visits  
Target day* 
Min. day  
Max. day 
Week 4^ 
28 
2 
42 
Week 8 
56 
43 
84 
Week 16 
112 
85 
140 
Week 24 
168 
141 
210 
Week 36 
252 
211 
308 
Week 52  
365 
309 
No upper limit 
* Number of days from start of double-blind treatment. 
^ For KCCQ / PGA assessments this visit is not present and Visit 9 - Week 8 min. day = 2. 
Echocardiographic measures, MR-ProANP presented at Week 24 and Week 52 only. 
KCCQ ꞊ Kansas City Cardiomyopathy Questionnaire; MR-proANP ꞊ Mid-Regional pro-Atrial Natriuretic 
Peptide; PGA ꞊ Patient global assessment 
In the event that there is more than one value within the same time window, the value 
closest to the planned assessment date will be taken. In the event of equidistant values 
from the planned time point, the last assessment will be considered for the analyses. 
Where multiple assessments fall on the same day the latest is then used.  
For laboratory values the central laboratory values are always selected in favor of any 
local laboratory value. If more than one value falls on the same date and time (and 
laboratory) then the one with the last sequential number in SDTM will be used. 
11.2 Dates 
11.2.1  Signed informed consent 
It is the date of signed informed consent collected in the “Informed Consent” CRF. 
11.2.2 Screening date 
It is the date of screening visit collected in the “Visit Summary” CRF. If the subject 
is screened once, it is the visit date associated with the first screening attempt. For 
subjects screened more than once, the date of screening is the visit date associated 
with the latest re-screening attempt, regardless if the subject is entered into the run-in. 


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11.2.3 Randomization date 
It is the date of subject randomization in the study from IVRS. 
11.2.4 Study treatment start date 
This is the “Treatment start date” from the first interval, in chronological order, 
recorded in the study drug log CRF and is equivalent to start date of Single-blind 
placebo run-in. 
11.2.5 Study treatment end (EOT) date  
Also known as the date of end of treatment or treatment discontinuation, this is the 
“Treatment end date” from the last interval, in chronological order, recorded in the 
study drug log CRF. If missing or incomplete, rules in Section 12 are followed. 
11.2.6 Single-blind placebo run-in start date  
It is the first day of intake of single-blind placebo. It is derived as the first treatment 
start date (in chronological order) in the “Study Drug Log” CRF if ‘Treatment period’ 
is flagged as ‘Single-blind placebo run-in’. 
11.2.7 Single-blind placebo run-in end date  
It is the last day of intake of single-blind placebo. It is derived as the last treatment 
end date (in chronological order) in the “Study Drug Log” CRF if ‘Treatment period’ 
is flagged as ‘Single-blind placebo run-in’.  
11.2.8 Single-blind Macitentan run-in start date  
It is the first day of intake of single-blind macitentan. It is derived as the first treatment 
start date (in chronological order) in the “Study Drug Log” CRF if ‘Treatment period’ 
is flagged as ‘Single-blind Macitentan run-in’. 
11.2.9 Single-blind Macitentan run-in end date  
It is the last day of intake of single-blind macitentan. It is derived as the last treatment 
end date (in chronological order) in the “Study Drug Log” CRF if ‘Treatment period’ 
is flagged as ‘Single-blind Macitentan run-in’.  
11.2.10 Double-blind treatment start date 
It is the first day of intake of double-blind treatment. It is derived as the first treatment 
start date (in chronological order) in the “Study Drug Log” CRF if ‘Treatment period’ 
is flagged as ‘Double-blind treatment’. 


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11.2.11 Double-blind treatment end date 
It is the last day of intake of double-blind treatment. It is derived as the last treatment 
end date (in chronological order) in the “Study Drug Log” CRF if ‘Treatment period’ 
is flagged as ‘Double-blind treatment’ and the reason for treatment end is ≠ 
“TEMPORARILY 
INTERRUPTED 
DUE TO AN AE” or “TEMPORARILY 
INTERRUPTED NOT DUE TO AN AE”. 
Rules for handling incomplete/missing dates are detailed in Section 12.  
11.2.12 End of study (EOS) date 
For subjects not entering the placebo run-in period, EOS date is the “Date of subject’s 
End of Study” collected in “Eligibility for Placebo Run-in” CRF form. 
For subjects who died during the study, the EOS date is “Date of death” collected in 
“Death” form. 
Subjects completing the EOS visit (Visit 14 or PTOP4), the date of the visit is the 
EOS date. Note subjects who have not completed Week 24 at the time of global 
protocol version 6 approval, will end PTOP at 24 weeks (PTOP2). Subjects that 
already completed PTOP2 or PTOP 3 visits at the time of global protocol version 6 
approval will end PTOP at the next PTOP visit. 
For all subjects who enter the SERENADE OL, the EOS date is the ‘Date of first dose 
in OL study’ - 1 (if the date is available) or the ‘Date of enrollment in OL study’ - 1, 
as collected in the “Open-label enrollment” CRF. 
Otherwise for all other subjects, the EOS date is collected in “Study discontinuation” 
CRF form according to the reason for discontinuation as follows:  
• Lost to follow-up = date of last successful contact. 
• Subject decision/ withdrawal of consent = date of subject decision 
• Physician decision = date of physician decision 
• Sponsor decision = Date subject was informed of sponsor decision 
11.3 Baseline  
Except where otherwise specified, the baseline for a given measurement is the last 
value assessed ≤ the start date of double-blind treatment. If unscheduled/re-test visits 
are performed on the day of double-blind treatment start, the available value of the 
last unscheduled/re-test visit on double-blind treatment start date is considered as 
baseline. 


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11.3.1 Macitentan run-in Baseline 
The macitentan run-in baseline for a given measurement is the last value assessed 
≤ the start date of single-blind macitentan run-in treatment [Section 11.2.8]. 
11.4 Study day  
The study day (for the double-blind period) is the number of days elapsed since the 
day of first double-blind treatment plus 1 (start of double-blind treatment is 
considered Day 1). For dates prior to Day 1, study day is the negative number of days 
between the date under consideration and the date of first double-blind treatment. 
Therefore, the study day is always different from zero. 
11.5 Treatment emergent periods  
Note: the periods below refer to the treatment emergent periods for reporting safety 
and other variables as appropriate.  
11.5.1 Study treatment period 
Start date is the date of first dose of single-blind placebo run-in treatment and end 
date is the EOT date + 30 days. 
11.5.2 Double-blind treatment period 
Start date is the date of first dose of double-blind treatment and end date is the last 
dose date + 30 days. 
11.5.3 Placebo run-in period 
Start date is the first dose of single-blind placebo treatment and end date is the day 
prior to first dose of macitentan in the run-in period. Subjects that entered this period 
and who do not receive macitentan in the single-blind macitentan run-in period, the 
end date is the last dose date + 30 days. 
11.5.4 Macitentan run-in period 
Start date is the first dose of single-blind macitentan treatment and end date is the day 
prior to first dose of treatment in the double-blind treatment period. Subjects that 
entered this period and who do not receive double-blind treatment, the end date is the 
last dose date + 30 days. 


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11.5.5 Combined macitentan treatment period 
Start date is the first dose of single-blind macitentan run-in treatment and end date is 
the date of the last dose of any macitentan treatment (single-blind or double-blind)+ 
30 days.   
11.5.6 Safety follow-up period 
The safety follow-up period starts the day after the EOT date [see definition in 
Section 11.2.5] and ends 30 days thereafter with the End-of-Study visit, or PTOP1 
visit for those subjects who prematurely discontinue double-blind study treatment and 
enter PTOP.  
Duration of FU (days) is defined as the time elapsing between date of last study drug 
intake + 1 day and the safety follow-up (FU) visit + 1 (in days). 
11.5.7 PTOP period 
The PTOP period starts the day of visit PTOP1 and ends at day of the last PTOP visit 
(or EOS date if discontinued early - see Section 11.2.12). 
11.5.8 End of Study (EOS) visit 
The EOS is reached when the safety follow-up period or, if applicable, PTOP have 
been completed. For an individual subject, the study is completed with the EOS visit, 
which is either Visit 14 (safety follow-up visit) for subjects who completed the 
treatment period as per protocol, or PTOP4 for subjects entering PTOP (or PTOP1 
depending on time point of premature treatment discontinuation). Subjects who are 
past PTOP2 at the time of consenting to global protocol version 6 will return for an 
EOS visit within 60 days but no later than Week 52. 
Hence EOS visit and safety follow-up visit may differ when subject enters PTOP. 
11.5.9 Duration of time on study 
Duration on study (weeks) is defined as the time elapsing between date of Screening 
/ re-screening and the EOS visit + 1 (in days) / 7. 
11.5.10 Duration of PTOP 
Duration of PTOP (weeks) is defined as the time elapsing between date of PTOP1 
and the last PTOP visit (or study discontinuation) + 1 (in days) / 7. 


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11.6 Subjects in Run-in 
A subject is considered as entered in placebo run-in if answer =‘Yes’ to the question 
‘Did the subject enter the single-blind run-in period?’ in the “Eligibility for Placebo 
Run-in” CRF. A subject is considered as entered in macitentan run-in if answer 
=‘Yes’ to the question ‘Did the subject enter the single-blind run-in period?’ in the 
“Eligibility - Macitentan Run-in” CRF. 
11.7 Run-in failures 
Includes all subjects defined as placebo run-in failures [see Section 5.1.2] or 
macitentan run-in failures [see Section 5.1.3].  
11.8 Randomized subjects 
A subject is randomized into the study when he/she is assigned with a randomization 
number in the IVRS. 
11.9 Conversion rules 
• BMI (kg/m2) = weight (kg) / (height (cm) / 100)2 
In case height is measured in “inch” and body weight in “lbs” the following 
conversion rules are applied in CRF: 
o Height (cm) = height (inch) × 2.54  
o Weight (kg) = weight (lbs) × 0.4536  
• PVR (wood units) = [(mPAP – PAWP)-CO]*80, if PAWP is missing then 
substitute with LVDEP 
• DPG (mmHg) = diastolic PAP – PAWP 
• eGFR =175 x (SCr)-1.154 x(age)-0.203 x0.742 [if female] x1.212 [if Black] 
where Scr (standardized serum creatinine) in mg/dL, age in years. 
 
 


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12 HANDLING OF MISSING/INCOMPLETE DATE AND TIME 
FIELDS 
This section describes some general principles to be followed in the case of missing 
or incomplete dates/times.  
The dates in these types that are missing or incomplete are derived as follows: 
• Dates are split in 3 parts: year, month and day. Year is the top-level, month is 
medium level and day is low level. If a part expected to contain a number is 
numeric but the value is outside a valid range, the complete date is handled as 
missing. For example, if date = 44Nov2000 the whole date is considered to be 
missing. 
• If a Part is missing, all other parts of a lower level are considered to be missing. 
This means that a ddmmyy date ‘21--99’ is considered as ‘----99’. 
• Missing parts are changed into acceptable non-missing values in a way depending 
on the type of date to be replaced. 
Missing parts for specific dates/times are changed into acceptable non-missing values 
as described in the table below. 
In the following, ‘lower limit’ and ‘upper limit’ refer to the minimum or maximum, 
respectively, of a possible date. For example, if the day is missing, the lowest limit is 
the first day of the given month and the upper limit is the last day of the given month. 
If the day and month are missing, the lower limit refers to the first day of the given 
year and the upper limit to the last day of the given year. The earliest and the latest 
dates refer to the first or last date, respectively, when ordered in sequence. Other 
sources should be considered for possible dates including death date and date of 
withdrawal from study when determining possible dates.  
Type of date/time  Date/time is incomplete 
Date/time is missing 
Single-blind 
placebo run-in end 
date 
Use the earliest date between the: 
start of macitentan run-in minus 1 day (when 
applicable) 
upper limit 
date of Visit 13 
EOS 
date of death 
date of last successful contact 
Use the earliest date between the: 
start of macitentan run-in minus 1 
day (when applicable) 
date of Visit 13 
EOS 
date of death 
date of last successful contact 


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Type of date/time  Date/time is incomplete 
Date/time is missing 
Single-blind 
macitentan run-in 
end date 
Use the earliest date between the: 
start of double-blind treatment minus 1 day 
(when applicable) 
upper limit 
date of Visit 13 
EOS 
date of death 
date of last successful contact 
Use the earliest date between the: 
start of double-blind treatment minus 
1 day (when applicable) 
date of Visit 13 
EOS 
date of death 
date of last successful contact 
Double-blind 
treatment start date 
- Day missing: Replaced by day of the 
randomization date. In case the day of 
randomization is in the previous month, replace 
the day by 1 
- Day and month are missing: replace entirely 
by the randomization date 
Replace 
entirely 
by 
the 
randomization date, if evidence the 
subject was treated in the double-
blind. Otherwise is considered not 
treated.   
Evidence includes Visit > Visit 6 
other than study discontinuation. 
Double-blind treatment end date 
present. Other information may be 
available during the programming 
should be considered and updated in 
the programming specifications. 
EOT 
Use the earliest date between the: 
upper limit 
date of Visit 13 
EOS 
date of death 
date of last successful contact 
 
Use the earliest date between the: 
Date of Visit 13 
EOS 
date of death 
date of last successful contact 
 
AE resolution date The upper limit 
No approximation, the AE is 
considered as ongoing in the analysis 


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Type of date/time  Date/time is incomplete 
Date/time is missing 
AE onset date 
If the resolution date of the AE is before the 
single-blind placebo run-in start date: the 
lower limit. 
If the resolution date of the AE is on or after 
the single-blind placebo run-in start date 
and before the single-blind macitentan run-
in start date (or macitentan run-in start date 
is missing): if the single-blind placebo run-in 
start falls in the range of possible dates, this 
date is used. Otherwise, the lower limit is used. 
If the resolution date of the AE is on or after 
the single-blind macitentan run-in start date 
and before the double-blind treatment start 
date (or double-blind treatment start date is 
missing): if the single-blind macitentan run-in 
start falls in the range of possible dates, this 
date is used. Otherwise, the lower limit is used. 
If the resolution date of the AE is on or after 
the double-blind treatment start date: if the 
double-blind treatment start falls in the range 
of possible dates, this date is used. Otherwise, 
the lower limit is used. 
If the resolution date of the AE is missing: if 
the start date of the last period accessed by the 
subject (i.e., double-blind, macitentan run-in, 
placebo run-in) falls in the range of possible 
dates, this date is used. Otherwise, the lower 
limit is used. 
If the end date of the AE is before 
the single-blind placebo run-in 
start date: the date of AE resolution. 
If the end date of the AE is on or 
after the single-blind placebo run-
in start date and before the single-
blind macitentan run-in start date: 
the single-blind placebo run-in start. 
If the end date of the AE is on or 
after the single-blind macitentan 
run-in start date and before the 
double-blind treatment start date: 
the single-blind macitentan run-in 
start 
If the end date of the AE is on or 
after the double-blind treatment 
start 
date: 
the 
double-blind 
treatment start 
If the resolution date of the AE is 
missing: the start date of the last 
period accessed by the subject (i.e., 
double-blind, macitentan run-in, 
placebo run-in) is used. 
AE intensity 
change date 
If the start date of the next period following the 
AE onset period / accessed by the subject (i.e., 
double-blind, macitentan run-in, placebo run-
in) falls in the range of possible dates, this date 
is used. Otherwise, the lower limit is used. 
Start date of the next period 
following the AE onset period / 
accessed by the subject  


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Type of date/time  Date/time is incomplete 
Date/time is missing 
Concomitant 
medication end 
date 
The upper limit unless: 
 the medication started prior to placebo run-in 
start date 
and  
- upper limit is after the placebo run-in start 
and 
‘Ongoing at start of treatment?’ is ticked ‘No’,  
 
in which case it is 1 day before the placebo run-
in start date. 
No replacement.  
Concomitant 
medication start 
date 
If the end date of the medication is not before 
the informed consent signature date and if the 
informed consent date falls in the range of 
possible dates, the informed consent date is 
used. 
If the end date of the medication is not before 
the placebo run-in start date and if the placebo 
run-in start date falls in the range of possible 
dates, the placebo run-in start date is used.  
In all the other cases, the lower limit is used. 
No replacement, the medication is 
considered to have started before 
the date of consent. 
EOS 
Upper limit 
Data extract date (after dblock). 
Death 
date 
(Investigator 
assessment) 
Use the lower limit 
No replacement. 
WHF/HF/CV 
hospitalization 
date (Investigator 
assessment) 
If the onset date of the AE leading to 
hospitalization falls in the range of possible 
dates, it is the onset date of the AE. In all the 
other cases, it is the lower limit. 
The onset date of the AE leading to 
hospitalization. 
 
 
 


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13 LIST OF SUMMARY TABLES, LISTINGS AND FIGURES 
This list and the mock layouts are provided in the DPS Part 1 document. 
14 REFERENCES 
[Brookmeyer 1982] Brookmeyer R, Crowley JA. CI for the median survival time. 
Biometrics. 1982;38:29-41. 
[Cuzick 2005] Cuzick J. Forest plots and the interpretation of subgroups. Lancet. 
2005 Apr 9-15;365(9467):1308. 
[Dmitrienko 2010] Dmitrienko A, Tamhane AC, Bretz F. Multiple testing problems 
in pharmaceutical statistics. CRC Press;2010. 
[FDA 2010] Guidance for Industry: Pharmacokinetics in Patients with Impaired 
Renal Function — Study Design, Data Analysis, and Impact on Dosing and 
Labeling. March 2010. 
[Freedson 1998] Freedson PS, Melanson E, Sirard J. Calibration of the computer 
science and applications, Inc. Accelerometer. Med Sci Sports Exerc. 1998, 
30;777-781. 
[ICH 1995] ICH harmonized tripartite guideline E3: Structure and content of Clinical 
study reports CPMP/ICH/137/95 November 1995.  
[ICH 1998] ICH harmonized tripartite guideline E9: statistical principles for clinical 
trials CPMP/ICH/363/96 September 1998. 
[Packer 2001] Packer M. Proposal for a new clinical end point to evaluate the efficacy 
of drugs and devices in the treatment of chronic heart failure. J Cardiac Fail. 
2001;7(2):176-182. 
[Pocock 2002] Pocock SJ, Clayton TC, Altman DG. Survival plots of time-to-event 
outcomes in clinical trials: good practice and pitfalls. The Lancet 
2002;359:1686-9. 
[Pocock 2012] Pocock S, Ariti C, Collier T, Wang D. The Win Ratio: a new approach 
to the analysis of composite endpoints in clinical trials based on clinical 
priorities. European Heart J. 2012;33:176-182. 
[Quanjer 1993] Quanjer PH, et al. Lung volumes and forced ventilatory flows. Report 
Working Party Standardization of Lung Function Tests, European Community 
for Steel and Coal. Official Statement of the European Respiratory Society. Eur 
Respir J Suppl. 1993 Mar;16:5-40. 


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[Robertson 2011] Robertson W, Stewart-Brown S, Wilcock E, Oldfield M, 
Thorogood M. Utility of Accelerometers to Measure Physical Activity in 
Children Attending an Obesity Treatment Intervention. J Obes. 2011:1-8. 
[Solomon 2012] Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor 
neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a 
phase 2 double-blind randomised controlled trial. Lancet. 2012;380:1387-95. 
[Stokes 2000] Stokes ME, Davis CS, Koch GG. Categorical data analysis using the 
SAS® system, 2nd Edition. SAS Institute Inc. 
[Troiano 2008] Troiano RP, et al. Physical Activity in the United States Measured by 
Accelerometer. American College of Sports Medicine. 2008. 
 
 


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15 APPENDICES 
Appendix A 
Protocol synopsis, and schedule from Protocol version 6 (6 
February 2020) 
TITLE 
A multi-center, double-blind, placebo-controlled Phase 2b 
study to evaluate the efficacy and safety of macitentan in 
subjects with heart failure with preserved ejection fraction 
and pulmonary vascular disease  
ACRONYM 
SERENADE 
Macitentan in heart failure with preSERved ejEction 
fractioN and pulmonAry vascular DiseasE 
OBJECTIVES 
 
Primary objective 
To evaluate whether macitentan 10 mg reduces n-terminal 
pro-brain natriuretic peptide (NT-pro-BNP) versus placebo 
at Week 24 in subjects with heart failure with preserved 
ejection fraction (HFpEF) and pulmonary vascular disease.  
Secondary objectives 
To evaluate the effect of macitentan 10 mg as compared to 
placebo on: 
• Quality of life  
• Daily physical activity  
• Worsening of heart failure 
Other objectives 
Other objectives are described in Section 2.3. 
DESIGN 
A prospective, multi-center, double-blind, randomized, 
placebo-controlled, parallel-group design Phase 2b study. 
Subjects will be randomized in a 1:1 ratio to either 
macitentan or placebo. Treatment allocation will be 
stratified by NT-proBNP level (< 1000 pg/mL and 
≥ 1000 pg/mL) at macitentan run-in entry. 
PERIODS 
Screening period: Lasts up to 30 days; starts with the 
signature of the Informed Consent Form at Visit 1 and ends 
prior to administration of the first dose of study treatment 
at Visit 2. 


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Run-in period: 9-week run-in period consisting of a 
single-blind placebo run-in of 4 weeks, followed by a 
single-blind macitentan run-in of 5 weeks.  
The placebo run-in starts with administration of the first 
dose of placebo at Visit 2 and ends on the day before Visit 
4. The macitentan run-in starts with the administration of 
the first dose of macitentan at Visit 4 and ends with the 
subject’s randomization at Visit 6.  
Double-blind treatment period: The double-blind 
treatment period consists of 2 phases:  
Core phase: The double-blind core phase will last for 
24 weeks. It starts with the administration of the first dose 
of double-blind study treatment and ends on the day before 
Visit 11 (Week 24). Subjects who are still in the core phase 
at the time of global protocol Version 6 approval will end 
treatment at 24 weeks and will not proceed to the extension 
phase [see Section 3.1.1.8]. 
Extension phase: The double-blind extension phase will 
last for 28 weeks. It starts on the day of Visit 11 (Week 24) 
and ends on the day of last study treatment intake.  
Subjects who are in the extension phase at the global 
protocol Version 6 approval will return for an EOT visit 
within 60 days, but no later than Week 52.  
Post-treatment observation period: Subjects who 
prematurely discontinue double-blind study treatment 
(core or extension phase) will be asked to enter a post-
treatment observation period (PTOP), which ends 52 
weeks after randomization. The PTOP starts with visit 
PTOP1, which corresponds to the safety follow-up visit. 
Thereafter, visits are scheduled at Week 24 (PTOP2), 
Week 36 (PTOP3) and Week 52 (PTOP4), depending on 
time point of premature discontinuation. Subjects who 
have not completed Week 24 at the time of global protocol 
Version 6 approval, will end PTOP at 24 weeks (PTOP2) 
[see Section 3.1.1.8]. 
Safety follow-up period: The safety follow-up period 
starts on the day after the last dose of study treatment and 


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ends 30 days thereafter with the End-of-Study (EOS) 
visit, or PTOP1 visit for those subjects who prematurely 
discontinue study treatment. 
End-of-Study: EOS is reached when the safety follow-up 
period or, if applicable, PTOP have been completed. 
For an individual subject, the study is completed with the 
EOS visit, which is either Visit 14 (safety follow-up visit) 
for subjects who completed the treatment period as per 
protocol, or PTOP4 for subjects who prematurely 
discontinued.  
Transition to the SERENADE OL extension study 
(AC-055G203): 
Subjects who remain in the SERENADE study for 52 
weeks after randomization may transition to the 
SERENADE OL (AC-055G203) study if they meet the 
eligibility criteria defined in the SERENADE OL 
protocol. Eligible subjects who are consented to global 
protocol Version 6 will be allowed to transition to the 
SERENADE OL study if they remained in the 
SERENADE study for 24 weeks after randomization [see 
Section 3.1.1.8].  
PLANNED DURATION Approximately 2.5 years from first subject, first visit to last 
subject, last visit. 
SITE(S) 
/ COUNTRY(IES) 
77 sites in 17 countries. 
SUBJECTS / GROUPS It was planned to enroll 300 subjects in 2 groups; 
randomized in a 1:1 ratio (150 subjects per group) by an 
interactive Voice/Web System to macitentan or placebo 
using the NT-proBNP value observed before entry in 
macitentan run-in as a stratification factor. 
Following closure of Screening on 27 December 2019, it is 
expected that approximately 140 subjects will be 
randomized. 
INCLUSION 
CRITERIA 
1. Signed informed consent prior to any study-mandated 
procedure 
2. Male or female subjects ≥ 18 years of age 


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3. Signs or symptoms of heart failure (HF) requiring 
treatment with at least one oral diuretic (any type)  
4. Left ventricular ejection fraction (LVEF) ≥ 40% (by 
echocardiography at Screening) 
5. New York Heart Association (NYHA) functional class 
(FC) II to III 
6. Criterion removed (see footnote1) 
7. Patients with HFpEF defined as either one of the 
following by echocardiography at Screening: 
a. Left atrial (LA) enlargement: 
i. 
Left atrial volume > 58 mL (male) / > 52 
mL (female) or 
ii. 
Left atrial volume index ≥ 28 mL/m2, or 
iii. 
LA area > 20 cm2, or 
iv. 
LA diameter > 4.0 cm (male) / > 3.8 cm 
(female) 
b. Left ventricular septal thickness or posterior wall 
thickness ≥ 1.1 cm 
8. Elevated NT-proBNP / BNP ≥ 200 / 60 pg/mL for 
subjects in sinus rhythm or ≥ 500 / 150 pg/mL for 
subjects with atrial fibrillation (AF) at any time within 
3 months prior to Screening or at Screening 
9. Pulmonary vascular disease or right ventricular (RV) 
dysfunction meeting at least one of the following for 
echocardiographic (at Screening) and/or right heart 
catheterization (RHC) parameters (at Screening or 
from any RHC previously performed): 
a. Echocardiographic peak TR velocity > 2.8 m/s or 
invasive mean pulmonary artery pressure ≥ 25 
mmHg (RHC) or PASP > 40 mmHg and evidence 
of RV dysfunction (TAPSE < 17 mm or RV 
fractional area change < 35% or RV tissue Doppler 
s’ velocity < 9.5 cm/s)  
 
1 Inclusion criterion 6 (HF hospitalization within 12 months prior to Screening or RHC within 6 months prior to 
Screening showing PAWP/LVEDP > 15mmHg) was removed in global protocol v.4. 


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b. Diastolic Pulmonary Vascular Pressure Gradient 
(DPG) > 5 mmHg (RHC) 
c. Pulmonary vascular resistance (PVR) > 3 Wood 
Units (RHC) 
10. A woman of childbearing potential must have a 
negative pre-treatment serum pregnancy test, agree to 
use reliable contraception from at least 30 days prior to 
Visit 2 up to at least 30 days after study treatment 
discontinuation, and agree to undertake monthly 
pregnancy tests from Screening up to at least 30 days 
after study treatment discontinuation. 
EXCLUSION 
CRITERIA 
Disease-related 
1. 
Any prior valid measurement of LVEF < 40%  
Cardiovascular comorbidities: 
2. 
Significant unrepaired structural valvular heart 
disease (i.e., greater than mild aortic or mitral 
stenosis, and greater than moderate aortic or 
mitral regurgitation) 
3. 
Hypertrophic, 
restrictive, 
and 
infiltrative 
cardiomyopathies 
4. 
Pericardial disease  
5. 
Acute coronary syndrome, including ST-segment 
elevation myocardial infarction (STEMI), non-
ST-segment elevation myocardial infarction 
(NSTEMI) or unstable coronary artery disease or 
has undergone coronary artery bypass graft 
(CABG) or percutaneous coronary intervention 
(PCI) within 3 months of screening. 
6. 
Known indication for PCI or CABG 
7. 
Uncontrolled heart rate (HR) from atrial 
fibrillation or atrial flutter (> 110 beats per 
minute) as assessed by ECG 
8. 
History 
of 
serious 
life-threatening 
or 
hemodynamically 
significant 
arrhythmias, 
including symptomatic or sustained ventricular 


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tachycardia or defibrillator shock within 12 
month(s) of Screening 
9. 
History of or anticipated heart transplant or 
anticipated/implanted ventricular assist device  
10. 
Transient ischemic attack (TIA) or stroke within 
3 months of Screening 
11. 
Systolic blood pressure (SBP) ≥ 180 mmHg or 
diastolic blood pressure (DBP) ≥ 110 mmHg  
Other causes of right heart failure not associated with 
left ventricular dysfunction: 
12. 
Significant parenchymal lung disease fulfilling 
any of the following:  
a. 
Forced expiratory volume in 1 second / 
forced vital capacity (FEV1/FVC ratio) < 0.7 
associated with FEV1 < 50% of predicted 
value after bronchodilator administration in 
subjects with a known or suspected history of 
significant lung disease. 
b. 
Known moderate or severe restrictive lung 
disease, e.g., total lung capacity (TLC) < 
60% (predicted)  
c. 
Clinical suspicion of diffuse interstitial 
fibrosis or alveolitis, unless excluded by high 
resolution computed tomography (CT) 
d. 
Clinical 
suspicion 
of 
pulmonary 
thromboembolism within 12 months prior to 
Screening, 
unless 
excluded 
by 
ventilation/perfusion 
(V/Q) 
scan 
or 
computed tomography angiography (CTA)  
13. 
Criterion removed (see footnote2) 
14. 
Clinically significant congenital heart disease that 
could be the cause of the patient’s symptoms and 
signs of HF. 
Criteria related to macitentan use: 
15. 
Administration 
of 
pulmonary 
arterial 
hypertension-specific therapy (i.e., endothelin 
 
2 Exclusion criterion 13 (BMI ≥ 45 kg/m2) was removed in global protocol v.4. 


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receptor 
antagonists, 
prostanoids, 
phosphodiesterase-5 
[PDE-5] 
inhibitors, 
guanylate cyclase stimulators) within 1 month 
prior to Screening 
16. 
Hypotension, i.e., SBP < 90 mmHg or DBP < 50 
mmHg  
17. 
Severe renal dysfunction with an estimated 
Glomerular Filtration Rate (eGFR) < 30 mL/min 
per 1.73 m2 using the Modification of Diet in 
Renal Disease (MDRD) formula  
18. 
Known 
and 
documented 
severe 
hepatic 
impairment, e.g., Child-Pugh Class C  
19. 
Serum aspartate aminotransferase (AST) and/or 
alanine aminotransferase (ALT) ≥ 3 × the upper 
limit of normal at Screening 
20. 
Hemoglobin < 100 g/L (< 10 g/dl) at Screening 
21. 
Plan to become pregnant or lactating 
22. 
Treatment with strong cytochrome P-450 3A4 
(CYP3A4) inducers such as rifabutin, rifampin, 
rifampicin, 
rifapentin, 
carbamazepine, 
phenobarbital, phenytoin, or St. John’s wort 
within 1 month prior to Screening 
23. 
Treatment with strong CYP3A4 inhibitors such as 
ketoconazole, 
itraconazole, 
voriconazole, 
clarithromycin, 
telithromycin, 
nefazodone, 
ritonavir, and saquinavir within 1 month prior to 
Screening 
24. 
Criterion removed (see footnote3) 
25. 
Known hypersensitivity to macitentan or drugs of 
the same class, or any of the excipients (e.g., soy 
lecithin, lactose) 
 
3 Exclusion criterion 24 (treatment with BCRP substrates) was removed in global protocol v.4. 


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General criteria: 
26. 
Planned or current treatment with another 
investigational treatment within 2 months prior to 
screening 
27. 
Inadequate control of comorbidities according to 
current standards of care, as per judgment of the 
investigator 
28. 
Any known factor or disease that might interfere 
with treatment compliance, study conduct, or 
interpretation of the results, such as drug or 
alcohol dependence or psychiatric disease 
29. 
Known concomitant life-threatening disease with 
a life expectancy < 12 months. 
RUN-IN FAILURE 
CRITERIA 
A subject must be discontinued from the study in case any 
of the following criteria is fulfilled at any time during the 
run-in period: 
1. 
Study treatment compliance < 80%  
2. 
Central laboratory results showing a decrease in 
hemoglobin by > 50 g/L from Screening or 
hemoglobin < 80 g/L or need for transfusion 
3. 
Significant fluid retention / worsening of HF as 
evidenced by one of the following: 
a. Administration of i.v. diuretics due to fluid 
retention 
b. Addition of high potency thiazide diuretic 
(metolazone, indapamide), ≥ 100% increase in 
loop diuretic to a total oral dose ≥ 120 mg of 
furosemide equivalents/day [see Section 4.5]. 
c. Increase in body weight by ≥ 5% or ≥ 5 kg from 
the value at the start of the corresponding run-in 
period (i.e., Visit 2 and Visit 4 for the placebo and 
macitentan run-in, respectively) due to fluid 
overload 
d. Worsening in NYHA FC 
e. Hospitalization for worsening of HF 


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4. 
Any adverse events (AEs) that preclude continuation 
based on the investigator’s judgment.  
STUDY 
TREATMENTS 
Investigational treatment 
Macitentan oral tablet, 10 mg once daily. 
Comparator  
Matching placebo, once daily. 
AUXILIARY 
MEDICINAL 
PRODUCTS  
All subjects must be on oral diuretic therapy (any type). 
ENDPOINTS 
Primary efficacy endpoint 
• Percent of baseline NT-proBNP assessed at Week 24  
Secondary efficacy endpoints 
• Change from baseline to Week 24 in the clinical 
summary score (as assessed by the Kansas City 
Cardiomyopathy Questionnaire [KCCQ]) 
• Change from baseline to Week 24 in accelerometer-
assessed proportion of time spent in light to vigorous 
physical activity based on a threshold of > 100 activity 
counts per minute 
• Time to worsening heart failure (WHF) event over 
52 weeks.  
• Other efficacy endpoints 
Other efficacy endpoints are described in Section 6.1.3. 
Safety endpoints 
• All-cause death up to 30 days after study treatment 
discontinuation 
• Number of all-cause hospital admissions up to 30 days 
after study treatment discontinuation 
• Treatment-emergent AEs and serious adverse events 
(SAEs) up to 30 days after study treatment 
discontinuation 
• AEs leading to premature discontinuation of study 
treatment 


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• Change in vital signs (systolic and diastolic arterial 
blood pressure and pulse rate) and body weight up to 
30 days after study treatment discontinuation 
• Treatment-emergent marked laboratory abnormalities 
up to 30 days after study treatment discontinuation 
• Change from baseline in eGFR up to 30 days after 
study treatment discontinuation 
• Decrease from baseline in SBP of ≥ 5% and SBP 
< 100 mmHg up to 30 days after study treatment 
discontinuation. 
ASSESSMENTS 
Refer to the schedule of assessments in Table 1, Table 2, 
Table 3, and Table 4. 
STATISTICAL 
METHODOLOGY 
Analysis sets 
The Screened Analysis Set includes all subjects who are 
screened and have a subject identification number. 
The placebo run-in Set includes all screened subjects who 
enter the placebo run-in and receive at least one dose of 
study treatment in single-blind placebo run-in. 
The macitentan run-in Set includes all subjects who have 
completed the placebo run-in, enter the macitentan run-in 
and receive at least one dose of study treatment in single-
blind macitentan run-in. 
The Full Analysis Set (FAS) includes all subjects 
randomized to double-blind study treatment.  
The Per-protocol Analysis Set comprises all randomized 
subjects who received double-blind study treatment and 
who complied with the protocol sufficiently to allow a 
reliable assessment of the treatment effect on the primary 
efficacy endpoint. 
The Safety Set includes all subjects who received at least 
one dose of double-blind study treatment. 
Primary efficacy variable 
The primary efficacy variable is the percent of baseline in 
NT-proBNP at Week 24. 


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For subjects without available NT-proBNP value at Week 
24, the last available value observed before Week 24 will 
be carried forward and considered for the main analysis. 
Percent of baseline is calculated as the ratio of the Week 
24 NT-proBNP value over baseline value, expressed in 
percentage. 
Null and alternative hypotheses 
Due to the underlying log-normal distribution of the 
primary efficacy variable, an analysis of covariance 
(ANCOVA) will be applied on log-transformed data. 
The null hypothesis is that macitentan and placebo effects 
on NT-proBNP are the same. The alternative hypothesis is 
that the effect of macitentan on NT-proBNP differs from 
placebo effect. 
The null hypothesis will be tested by a 2-sided Wald test 
with a 2-sided significance level of 0.10. 
Primary statistical analysis 
The main analysis will be performed on subjects of the 
FAS, according to the intent-to-treat principle. 
The main analysis of the primary efficacy variable will be 
carried out after log-transformation using ANCOVA, 
adjusting for the log of the ratio: baseline NT-proBNP over 
NT-proBNP value as per Interactive Response Technology 
system [IRT] with an overall type I error of 10% 2-sided. 
The treatment effect expressed as geometric means ratio 
and its associated 90% 2-sided confidence interval (CI) 
will be estimated based on the same model by inversely 
transforming, using the exponential function, the Least 
Squares Mean and 90% CI obtained in log scale. 
Key secondary efficacy variables 
The three key secondary efficacy variables will be tested 
using a hierarchical testing approach to address 
multiplicity concern. 
The change from baseline to Week 24 in KCCQ clinical 
summary score and accelerometer-assessed physical 
activity will be analyzed by means of an ANCOVA 
adjusting for the variable baseline value and for the log of 


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the ratio: baseline NT-proBNP over NT-proBNP value as 
per IRT. Least Squares Estimates within each treatment 
group and between treatment groups will be displayed 
along with 90% 2-sided CIs and p-values. 
The analysis of time to first occurrence of WHF event will 
be explored using a proportional hazards Cox model 
adjusting for the log of the ratio: baseline NT-proBNP over 
NT-proBNP value as per IRT. Estimate of HR and its 
associated 90% CI and p-value will be displayed. Kaplan-
Meier estimates will be calculated with 2-sided 90% CIs at 
relevant time points for each treatment group and displayed 
in both a graphical and a tabular form.  
Safety variables 
The number and percentage of: 
• All-cause deaths occurring up to 30 days after study 
treatment discontinuation 
• Subjects with at least one treatment-emergent AE 
occurring up to 30 days after study treatment 
discontinuation 
• Subjects with at least one SAE occurring up to 30 days 
after study treatment discontinuation 
• Subjects with at least one AE leading to premature 
discontinuation of study treatment 
will be tabulated by treatment group and by System Organ 
Class and Preferred Term.  
The number of recurrent all-cause hospital admissions will 
be estimated using a Negative binomial regression model.  
Marked laboratory abnormalities will be summarized for 
each laboratory variable by treatment group providing their 
incidence and frequency. For selected laboratory variables 
(erythrocytes, hemoglobin, hematocrit, AST, ALT, total 
bilirubin and alkaline phosphatase), absolute values and 
changes from baseline will be summarized over time up to 
30 days after study treatment discontinuation. 
Vital signs, body weight and GFR will be described over 
time up to 30 days after study treatment discontinuation by 
means of random coefficient regression models. 


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Decreases in SBP will be summarized by treatment group 
providing the number and percentage of subjects with, for 
at least one post-baseline assessment and up to 30 days 
after study treatment discontinuation, a percent change 
from 
baseline  
≤ −5% and an SBP < 100 mmHg at the time of assessment. 
Sample size 
A number of 300 randomized subjects is adequate to detect 
a geometric means ratio of 0.75 (macitentan over placebo, 
−0.288 in log scale) corresponding to a 25% improvement 
with a power of 80% and a type I error of 0.10 2-sided, 
when considering a standard deviation of 1 in log scale and 
using the Wald test. The critical value expressed as 
geometric means ratio is 0.83. 
Following closure of Screening on 27 December 2019, it is 
expected that approximately 140 subjects will be 
randomized. With the same assumptions as above for the 
reduced sample size of 140, the critical value expressed as 
geometric means ratio is 0.76. 
STUDY COMMITTEES An Independent Data Monitoring Committee (IDMC) has 
overall responsibility for safeguarding the interests of 
subjects by monitoring benefit-risk ratio and making 
appropriate recommendations based on all the reported 
data and 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. 
Both a Scientific Advisory Board and a Steering 
Committee are involved in the study design and will be 
consulted prior to and during the study for relevant medical 
issues and study publications. 
An Independent Liver Safety Data Review Board 
(ILSDRB, an external expert committee of hepatologists) 
has been appointed to provide ongoing assessment and 
advice regarding serious hepatic AEs of special interest 


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that require further evaluation during the study as per the 
ILSDRB charter. 


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Table 1 
Visit and assessment schedule during the run-in period 
 
 
1 Unscheduled visits may be performed at any time during the study. Body weight and vital signs (BP, HR) 
must be performed at each unscheduled visit. Other assessments are performed at the discretion of the 
investigator. 
2 Subjects who are not randomized (i.e., run-in failures) must perform a safety follow-up visit 30 (+5) days 
after intake of the last dose of study treatment. 
3 Run-in eligibility criteria defined in Section 4.5 of the protocol. 
4 Body weight is measured at each visit. Height is only measured at Screening.  
5 Subjects will be instructed to monitor their body weight at home on a daily basis during the run-in period, 
and to contact the study site if they notice any unusual weight increase (i.e., ≥ 2 kg / 4.4 lbs) after start of 
study treatment. 
6 Historical PFTs accepted if performed within 1 year prior to Screening and judged reliable by the 
investigator, provided the subject’s pulmonary status remained unchanged during this time. Only 
necessary for subjects with a known or suspected history of significant lung disease. 
7 ECGs are read locally only. 
8 Accelerometry will be performed from Visit 2 until Visit 3. 
9 Accelerometry will be performed during 9 days following the visit.  
10 All AEs and SAEs that occur after signing the Informed Consent Form and up to 30 days after study 
treatment discontinuation must be reported [see also Section 9 of the protocol].  
11 During the phone calls, the investigator must inquire about signs and symptoms that may be indicative of 
a fluid retention- or HF event. Outcome of the phone call may trigger unscheduled visits per investigator’s 
discretion. 
AE = adverse event; BP = blood pressure; D = Day; d = days; ECG = electrocardiogram; FC = functional class;  
HR = heart rate; KCCQ = Kansas City Cardiomyopathy Questionnaire; NYHA = New York Heart Association; PGA 
= patient’s global assessment; 
PFT = pulmonary function test; R = Run-in; RHC = right heart catheterization; SAE = serious adverse event; trt = 
treatment; W = Week; w = weeks; WHF = worsening heart failure. 
 
 


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Table 2 
Visit and assessment schedule during the double-blind treatment period 
 
 
1 Unscheduled visits may be performed at any time during the study. Body weight and vital signs (BP, HR) must be 
performed at each unscheduled visit. Other assessments are performed at the discretion of the investigator. 
2 Telephone call only. 
3 Subjects will be instructed to monitor their body weight at home on a weekly basis during the double-blind treatment 
period, and to contact the study site if they notice any unusual weight increase (i.e., ≥ 2 kg / 4.4 lbs) after start of 
study treatment. 
4 ECGs are read locally only. 
5 Accelerometry will be performed during 9 days following Visits 8 and 10.   
6 All AEs and SAEs that occur after signing the Informed Consent Form and up to 30 days after study treatment 
discontinuation must be reported [see also Section 9 of the protocol].  
7 Under global protocol Version 6, accelerometry will be performed during the 9 days prior to Visit 11 (Week 24 visit).   
8 Subjects who have passed Week 24 at the time of approval of global protocol Version 6 will have their EOT visit 
within 60 days but no later than Week 52.  
 
AE = adverse event; BP = blood pressure; D = Day; d = days; ECG = electrocardiogram; EOS = end-of-study; EOT = 
end-of-treatment; FC = functional class; HR = heart rate; KCCQ = Kansas City Cardiomyopathy Questionnaire; 
NYHA = New York Heart Association; PGA = patient’s global assessment; PFT = pulmonary function test; R = Run-
in; RHC = right heart catheterization; SAE = serious adverse event; trt = treatment; W = Week; w = weeks; WHF = 
worsening heart failure; V = Visit. 
 
 
 


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Table 3 
Laboratory assessments 
Note: Table does not display phone calls. 
1 Hematology and clinical chemistry. 
2 Laboratory test at Screening must be performed in fasted state. Includes measurement of glucose, lipid profile and TSH 
levels. 
3 Monthly AST/ALT monitoring recommended. Local laboratory can be used. 
4 Hemoglobin to be measured locally at randomization to confirm run-in failure criteria not met. 
5 For women of childbearing potential only. 
6 Urine pregnancy test will be performed by the subject. The site will follow-up on the results with a telephone call. 
7 For patients who gave their consent for this blood sample only. To be drawn at the time of a fluid retention - or WHF 
event (any visit, including unscheduled, as applicable). 
8 Applicable to subjects who have completed Week 24 prior to global protocol Version 6 approval.  
 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; D = Day; d = days; EOS = end-of-study; EOT = 
end-of-treatment; MR-proANP = mid-regional pro-atrial natriuretic peptide; NA = not applicable; NT-proBNP = n-
terminal pro-brain natriuretic peptide; R = Run-in; TSH = thyroid stimulating hormone; W = Week; w = weeks; WHF 
= worsening heart failure; V = Visit. 
 


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Table 4 
Visit and assessment schedule for subjects entering the PTOP 
PERIODS 
Name 
POST-TREATMENT OBSERVATION PERIOD (PTOP) 
 
Duration 
Up to 52 Weeks 
VISITS 
Number 
PTOP1  
PTOP2 
PTOP37 
PTOP47 
 
Name 
Safety follow-up 
 
 
EOS 
 
Time 
30 (+5) d after last 
dose1 
Week 242 (±14 d)  
Week 362 (± 14 
d) 
Week 522 (± 14 
d) 
Concomitant therapy 
X 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
Vital signs (BP, HR) 
X 
X 
X 
X 
Body weight 
X 
X 
X 
X 
12-lead ECG 
 
X3 
 
X 
Echocardiography 
 
X 
 
X 
Central laboratory tests 
X4 
 
 
 
NT-proBNP / MR-proANP / 
Biomarker 
 
X 
 
X 
NYHA functional class 
X 
X 
X 
X 
WHF 
X 
X 
X 
X 
PGA 
 
X 
X 
X 
KCCQ 
 
X 
X 
X 
Accelerometry 
 
X6 
 
 
AEs 
X 
 
 
 
SAEs 
X 
X 
X 
X 
1 If the safety follow-up visit falls within the time-window any of the PTOP visits, the visits can be combined. 
2 From randomization. 
3 ECGs are read locally only. 
4 Hematology and clinical chemistry, including serum pregnancy test for women of childbearing potential. 
 
 
 


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Appendix B 
Diuretics identified from Standard drug grouping*   
 
Ingredient / Diuretics* 
High ceiling Sulfonamides 
(LOOP) 
 
furosemide  
bumetanide  
piretanide  
torasemide  
etacrynic acid  
tienilic acid  
azosemide 
etozolin 
Low ceiling, thiazides 
(THIAZIDES) 
bendroflumethiazide  
hydroflumethiazide  
hydrochlorothiazide  
chlorothiazide  
polythiazide  
trichlormethiazide  
cyclopenthiazide  
methyclothiazide  
cyclothiazide  
mebutizide  
epitizide 
altizide  
bemetizide 
benzthiazide 
butizide 
benzylhydrochlorothiazide 
Low ceiling, excl. thiazides 
 
quinethazone  
clopamide  
chlortalidone  
mefruside  
clofenamide  
metolazone  
meticrane  
xipamide  
indapamide  
clorexolone  
fenquizone  
cicletanine 
Potassium sparing 
 
spironolactone  
potassium canrenoate  
canrenoic acid 
canrenone  
finerenone 
eplerenone 
amiloride  


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* Identified diuretics starting with ATC code = C03 
 
 
triamterene  
Vasopressin antagonists 
tolvaptan  
conivaptan  
mozavaptan 
ribuvaptan 
lixivaptan 
satavaptan 
Carbonic anhydrase inhibitors 
acetazolamide 
 
chlorazanil 
 
demeclocycline 
 
diurgin 
 
esaxerenone 
 
ethiazide 
 
flumethiazide 
 
hydrobentizide 
 
methalthiazide 
 
metipamid 
 
paraflutizide 
 
penflutizide 
 
rolofylline 
 
teclothiazide 
 
tiamizide 
 
tripamide 


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Appendix C 
The Kansas City Cardiomyopathy Questionnaire Scoring 
Instructions 
There are 10 summary scores within the KCCQ, which are calculated as follows: 
1. Physical limitations score 
After coding the questions 1a-f collected in CRF as follows: 
• 
Extremely limited = 1 
• 
Quite a bit limited = 2 
• 
Moderately limited = 3 
• 
Slightly limited = 4 
• 
Not at all limited = 5 
• 
Limited for other reasons or did not do = <missing value> 
If at least three of questions 1a-f are not missing: 
Physical Limitation Score = 100*[(Mean of Questions 1a-f answered) -1] /4 
where the mean is calculated on non-missing values. 
2. Symptom Stability 
Code the response to Question 2 as follows: 
• 
Much worse = 1 
• 
Slightly worse = 2 
• 
Not changed = 3 
• 
Slightly better = 4 
• 
Much better = 5 
• 
I’ve had no symptoms over the last 2 weeks = 3 
If Question 2 is not missing, then compute 
Symptom Stability Score = 100*[(Question 2) – 1]/4 
3. Symptom Frequency score 
After coding the questions 3, 5, 7 and 9 collected in CRF as follows: 
Question 3 
• 
Every morning = 1 
• 
3 or more times a week but not every day = 2 
• 
1-2 times a week = 3 
• 
Less than once a week = 4 
• 
Never over the past 2 weeks = 5 


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Questions 5 and 7 
• 
All of the time = 1 
• 
Several times a day = 2 
• 
At least once a day = 3 
• 
3 or more times a week but not every day = 4 
• 
1-2 times a week = 5 
• 
Less than once a week = 6 
• 
Never over the past 2 weeks = 7 
Question 9 
• 
Every night = 1 
• 
3 or more times a week but not every day = 2 
• 
1-2 times a week = 3 
• 
Less than once a week = 4 
• 
Never over the past 2 weeks = 5 
If at least two of Questions 3, 5, 7 and 9 are not missing, then compute: 
• 
S3 = [(Question 3) – 1]/4 
• 
S5 = [(Question 5) – 1]/6 
• 
S7 = [(Question 7) – 1]/6 
• 
S9 = [(Question 9) – 1]/4 
Symptom Frequency Score = 100*(mean of S3, S5, S7 and S9) 
4. Symptom Burden score 
Code responses to each of questions 4, 6, and 8 as follows: 
• 
Extremely bothersome = 1 
• 
Quite a bit bothersome = 2 
• 
Moderately bothersome = 3 
• 
Slightly bothersome = 4 
• 
Not at all bothersome = 5 
• 
I’ve had no swelling/fatigue/shortness of breath = 5 
If at least one of Questions 4, 6 and 8 is not missing, then compute: 
Symptom Burden Score = 100*[(mean of Questions 4, 6 and 8)-1]/4 
5. Total Symptom score 
It is the mean of the following available summary scores: 
• 
Symptom Frequency score 
• 
Symptom Burden score 
 
6. Self-Efficacy 
Code responses to Questions 10 and 11 as follows: 
Question 10 


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• Not at all sure = 1 
• Not very sure = 2 
• Somewhat sure = 3 
• Mostly sure = 4 
• Completely sure = 5 
Question 11 
• Do not understand at all = 1 
• Do not understand very well = 2 
• Somewhat understand = 3 
• Mostly understand = 4 
• Completely understand = 5 
If at least one of Questions 10 and 11 is not missing, then compute: 
Self-Efficacy Score = 100*[(mean of Questions 10 and 11 actually answered) – 1]/4 
7. Quality of Life score 
Code responses to the questions 12, 13 and 14 as follows: 
Question 12 
• 
It has extremely limited my enjoyment of life = 1 
• 
It has limited my enjoyment of life quite a bit = 2 
• 
It has moderately limited my enjoyment of life = 3 
• 
It has slightly limited my enjoyment of life = 4 
• 
It has not limited my enjoyment of life at all = 5 
Question 13 
• 
Not at all satisfied = 1 
• 
Mostly dissatisfied = 2 
• 
Somewhat satisfied = 3 
• 
Mostly satisfied = 4 
• 
Completely satisfied = 5 
Question 14 
• 
I felt that way all of the time = 1 
• 
I felt that way most of the time = 2 
• 
I occasionally felt that way = 3 
• 
I rarely felt that way = 4 
• 
I never felt that way = 5 
If at least one of Questions 12, 13 and 14 is not missing, then compute: 
Quality of Life Score = 100*[(mean of Questions 12, 13 and 14)-1]/4 
8. Social Limitation score 
After coding the questions 15a-d as follows: 
• 
Severely limited = 1 


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• 
Limited quite a bit = 2 
• 
Moderately limited = 3 
• 
Slightly limited = 4 
• 
Did not limit at all = 5 
• 
Does not apply or did not do for other reasons = <missing value> 
If at least two of Questions 15a-d is not missing, then compute: 
Social Limitation Score = 100*[(mean of Questions 15a-d)-1]/4 
9. Overall Summary score 
It is the mean of the following available summary scores:  
• Physical limitations 
• Total Symptom Score  
• Quality of life Score 
• Social Limitation Score   
10. Clinical Summary score 
It is the mean of the following available summary scores 
• Physical limitations score 
• Total Symptom score 
 
 


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Appendix D 
PTs and SOCs for identification of HAESI 
MedDRA PTs 
Acute graft versus host disease in liver 
Acute hepatic failure 
Acute on chronic liver failure 
Alanine aminotransferase 
Alanine aminotransferase abnormal 
Alanine aminotransferase increased 
Allergic hepatitis 
Alloimmune hepatitis 
Aspartate aminotransferase 
Aspartate aminotransferase abnormal 
Aspartate aminotransferase increased 
Asterixis 
Autoimmune hepatitis 
Biliary cirrhosis 
Bilirubin conjugated 
Bilirubin conjugated abnormal 
Bilirubin conjugated increased 
Blood bilirubin 
Blood bilirubin abnormal 
Blood bilirubin increased 
Cardiohepatic syndrome 
Cholestatic liver injury 
Chronic graft versus host disease in liver 
Chronic hepatic failure 


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Chronic hepatitis 
Cirrhosis alcoholic 
Coma hepatic 
Cryptogenic cirrhosis 
Drug-induced liver injury 
Graft versus host disease in liver 
Hepatic cirrhosis 
Hepatic encephalopathy 
Hepatic encephalopathy prophylaxis 
Hepatic enzyme 
Hepatic enzyme abnormal 
Hepatic enzyme increased 
Hepatic failure 
Hepatic fibrosis 
Hepatic function abnormal 
Hepatic infiltration eosinophilic 
Hepatic necrosis 
Hepatic steato-fibrosis 
Hepatitis 
Hepatitis acute 
Hepatitis alcoholic 
Hepatitis cholestatic 
Hepatitis chronic active 
Hepatitis chronic persistent 
Hepatitis fulminant 
Hepatitis toxic 


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Hepatocellular injury 
Hepatopulmonary syndrome 
Hepatorenal failure 
Hepatorenal syndrome 
Hepatotoxicity 
Hyperbilirubinaemia 
Hyperbilirubinaemia 
Hypertransaminasaemia 
Increased liver stiffness 
Ischaemic hepatitis 
Jaundice 
Jaundice cholestatic 
Jaundice hepatocellular 
Liver function test 
Liver function test abnormal 
Liver function test increased 
Liver injury 
Liver operation 
Liver transplant 
Lupoid hepatic cirrhosis 
Lupus hepatitis 
Minimal hepatic encephalopathy 
Mixed liver injury 
Multivisceral transplantation 
Nodular regenerative hyperplasia 
Non-alcoholic steatohepatitis 


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Ocular icterus 
Portal fibrosis 
Primary biliary cholangitis 
Pseudocirrhosis 
Radiation hepatitis 
Renal and liver transplant 
Reye’s syndrome 
Reynold’s syndrome 
Steatohepatitis 
Subacute hepatic failure 
Transaminases 
Transaminases abnormal 
Transaminases increased 
Withdrawal hepatitis 
Yellow skin 
SOC terms 
Hepatobiliary disorders 
HLGT terms 
Hepatobiliary investigations