Clinical trial NCT03714815
Conditions: Heart Failure With Preserved Ejection Fraction and Pulmonary Vascular Disease
Keywords: pulmonary vascular disease macitentan heart failure with preserved ejection fraction
Sponsor: Actelion
Start date: 2018-12-07; Completion date: 2021-10-12
Enrollment: 91 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The aim of this open-label (OL) extension trial is to study the long-term safety and efficacy of macitentan in subjects with heart failure with preserved ejection fraction (HFpEF) and pulmonary vascular disease (PVD) beyond the treatment in the double-blind parent SERENADE study (AC-055G202, NCT03153111). Furthermore, this OL extension study will give eligible subjects of the main study (SERENADE/AC-055G202, NCT03153111) an opportunity to continue or start receiving macitentan.

Detailed description:

Arms: arm 1: oral administration of 10 mg macitentan once daily
Interventions: intervention 1: macitentan 10 mg
Intervention descriptions: intervention 1: macitentan 10 mg, film-coated tablet, oral use

Protocol documents:
Prot_000.pdf: 
Actelion Pharmaceuticals Ltd. *
(a Janssen Pharmaceutical Company of Johnson & Johnson)
CONFIDENTIAL – FOIA Exemptions Apply in U.S.  
1
Macitentan / ACT-064992
Heart failure with preserved ejection fraction and pulmonary 
vascular disease 
Protocol AC-055G203
SERENADE OL
A long-term, multicenter, single-arm, open-label extension of the SERENADE 
study, to assess the safety and efficacy of macitentan in subjects with heart failure 
with preserved ejection fraction and pulmonary vascular disease 
*Actelion Pharmaceuticals Ltd (“Actelion”) is a global organization that operates through different legal
entities in various countries. Therefore, the legal entity acting as the sponsor for Actelion studies may vary,
such as, but not limited to Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; 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.
Study Phase:
2b
EudraCT Number:
2018-001603-37
Status and version:
Final Version 6
Date:
26 November 2020
Document type:
Global Amended Protocol 
Document number (Doc No.):
EDMS-RIM-263261, 1.0
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.
NCT03714815


Macitentan / ACT-064992
HFpEF and pulmonary vascular disease 
Protocol AC-055G203 / SERENADE OL
Amendment 5 Version 6, 26 November 2020
EudraCT 2018-001603-37
Doc No EDMS-RIM-263261
CONFIDENTIAL – FOIA Exemptions Apply in U.S.  
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
Toll phone number: [number]
Site-specific toll telephone numbers and toll-free 
numbers for the Medical Emergency Hotline can be 
found in the Investigator Site File


Macitentan / ACT-064992
HFpEF and pulmonary vascular disease 
Protocol AC-055G203 / SERENADE OL
Amendment 5 Version 6, 26 November 2020
EudraCT 2018-001603-37
Doc No EDMS-RIM-263261
CONFIDENTIAL – FOIA Exemptions Apply in U.S.  
3
CONTRACT RESEARCH ORGANIZATION INFORMATION
CENTRAL LABORATORY
Covance 
8211 SciCorDrive
Indianapolis, IN 46214 
USA
ECHOCADIOGRAPHY 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
CENTRAL STUDY 
TREATMENT 
ALLOCATION/IxRS
Almac Clinical Technologies
20 Seagoe Industrial Estate
Craigavon BT63 5UA
United Kingdom 
A list of site-specific contact details for Contract Research Organizations (CROs) can 
be found in the Investigator Site File.




Macitentan / ACT-064992
HFpEF and pulmonary vascular disease 
Protocol AC-055G203 / SERENADE OL
Amendment 5 Version 6, 26 November 2020
EudraCT 2018-001603-37
Doc No EDMS-RIM-263261
CONFIDENTIAL – FOIA Exemptions Apply in U.S.  
5
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-055G203, SERENADE OL: A long-term, multicenter, single-arm, open-label 
extension of the SERENADE study, to assess the safety and efficacy 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 
well-being 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
Town
Date
Signature
Principal 
Investigator


Macitentan / ACT-064992
HFpEF and pulmonary vascular disease 
Protocol AC-055G203 / SERENADE OL
Amendment 5 Version 6, 26 November 2020
EudraCT 2018-001603-37
Doc No EDMS-RIM-263261
CONFIDENTIAL – FOIA Exemptions Apply in U.S.  
6
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 5, Version 6
26-November-2020
Amendment 4, Version 5
16-July-2020
Amendment 3, Version 4
06-February-2020
Amendment 2, Version 3
16-May-2019
Amendment 1, Version 2
02-August-2018
Original Protocol, Version 1
14-May-2018
Amendment 5 (26-Nov-2020)
Overall Rationale for the Amendment: 
The overall reasons to issue this protocol amendment are to adapt to changed internal safety 
language and reporting processes to align with TransCelerate template, to update 
information about posttreatment access program, study treatment storage conditions, 
forbidden medications, Actelion’s policy for study data disclosure, and to make minor 
editorial revisions and corrections.
A Protocol Amendment Summary of Changes Table for current amendment is provided below. 
The updates are indicated in bold text and strike-through for the deleted text.
Section number
and Name
Description of Change
Brief Rationale
Title Page
Legal name of the organization is 
updated along with a note.
Logistical updates.
Synopsis; 
3.1.1 Study periods;
7.1 General information; 
8.1 Study completion as per 
protocol
Following statement is added: 
‘The safety follow-up visit will 
be waived in case the subject 
moves to a continued access 
program and in that case EOT 
will be the last visit in the study.’
To update about the waiver of safety 
follow-up visit in case the subject 
moves to post treatment access.
5.1.5.2
Study 
treatment 
distribution and storage
Highly detailed study treatment 
storage conditions are deleted.
The text is revised to make the study 
treatment label as a primary reference
source 
for 
storage
conditions 
requirement and to remove the details
from  protocol.
5.1.5.4
Study 
treatment 
return and destruction
Information 
regarding 
proper 
handling, storage  and destruction 
of 
unused 
and 
used 
study 
treatment at the authorized study 
sites as well as the corresponding 
documentation is updated.
To align with Janssen processes.


Macitentan / ACT-064992
HFpEF and pulmonary vascular disease 
Protocol AC-055G203 / SERENADE OL
Amendment 5 Version 6, 26 November 2020
EudraCT 2018-001603-37
Doc No EDMS-RIM-263261
CONFIDENTIAL – FOIA Exemptions Apply in U.S.  
7
Section number
and Name
Description of Change
Brief Rationale
5.1.9.4 Pregnancy
"Pregnancy Form" updated to 
"Pregnancy Notification Form"
Updated to align with Janssen 
processes.
5.1.10
Study 
treatment 
overdose and treatment
A new section is added.
To 
provide 
information 
about 
overdose and treatment.
5.2.4
Forbidden 
concomitant therapy
Following information related to 
forbidden medication is updated:
‘Endothelin 
receptor 
antagonists 
(other 
than 
macitentan 10 mg).’
‘PAH specific 
drugs 
(ERAs, 
prostanoids, PDE 5 inhibitors, 
guanylate cyclase stimulators).’
PH-specific therapies (eg, PDE-5 
inhibitors) are not approved for the 
treatment of HFpEF-PVD; however,
their use in an individual patient is 
based on the investigator's judgement.
8.4
Medical care of 
subjects 
after 
study 
completion / withdrawal 
from study
Information about post study 
continued access program and the 
subjects eligible for receiving it is 
updated.
To describe the continued access 
options 
after 
completion 
of 
SERENADE OL.
9.1.5 Follow-up of adverse 
events
Additional information regarding 
investigator’s 
obligations 
to 
perform or arrange supplemental 
measurements and evaluations is 
added.:
‘The investigator is obligated to 
perform or arrange for the 
conduct 
of 
supplemental 
measurements and evaluations 
as 
medically 
indicated 
to 
elucidate 
the 
nature 
and 
causality of the AE, SAE, or 
product 
quality 
compliant 
(PQC) as fully as possible. This 
may 
include 
additional 
laboratory 
tests 
or 
investigations, histopathological 
examinations, or consultation 
with 
other 
health 
care 
professionals.’
To align with Janssen processes.
9.2.1 Definition of serious 
adverse events
Following statement is added.
‘• Is a suspected transmission 
of any infectious agent via a 
medicinal product’.
To align with TransCelerate Protocol 
Template.
9.2.2 Reporting of serious 
adverse events
Inclusion 
of 
product 
quality 
complaints (PQCs) as reportable 
events in addition to SAEs.
PQCs
included to comply with 
Janssen processes.


Macitentan / ACT-064992
HFpEF and pulmonary vascular disease 
Protocol AC-055G203 / SERENADE OL
Amendment 5 Version 6, 26 November 2020
EudraCT 2018-001603-37
Doc No EDMS-RIM-263261
CONFIDENTIAL – FOIA Exemptions Apply in U.S.  
8
Section number
and Name
Description of Change
Brief Rationale
9.2.3 Follow-up of serious 
adverse events; 
9.2.4
After the 30-day 
follow-up period; 
9.2.5 Reporting procedures
The ‘Actelion Global Drug Safety 
department’ and ‘Actelion’ are
updated as ‘Sponsor’.
Updated reporting and follow-up 
procedures for serious adverse events 
(SAEs).as part of Actelion and 
Janssen integration.
9.2.5 Reporting procedures
Information about Sponsor’s and 
investigator’s responsibility in 
reporting all suspected unexpected 
serious 
adverse 
reactions 
(SUSARs) is updated.
Updated reporting
procedures
for 
SUSARs as part of Actelion and 
Janssen integration.
9.3.1
Reporting 
of 
pregnancy; 
9.3.2
Follow-up 
of 
pregnancy
Information about reporting and 
follow-up 
procedures 
for 
pregnancy is updated.
To reflect the standard Janssen
wording and include monitoring of 
pregnant partners of male patients per 
Janssen safety reporting procedures 
as part of the ongoing integration of 
Actelion into the Janssen ecosystem.
9.4 
Product 
quality 
complaint handling
A new section on PQC handling 
and reporting is added.
PQC
handling section added to 
comply with internal procedures due 
to Actelion and Janssen safety 
process integration.
9.5 
Special 
reporting 
situations
A new section is included to 
define 
special 
reporting 
situations.
To be consistent with Janssen safety 
integration processes.
12.12 Reporting of study 
results and publication
Statement regarding Actelion's 
policy for study data disclosure is 
revised 
as: 
‘Janssen 
Pharmaceutical 
Companies 
(Actelion) will post results from
Phase 1-4 clinical studies on 
external registries as required 
by law and from interventional 
studies in patients for marketed 
products.’
To follow Janssen’s
policy on 
scientific publications.
Throughout the protocol
Minor corrections and editorial 
revisions.
To maintain consistency throughout
and to improve clarity of the content.


Macitentan / ACT-064992
HFpEF and pulmonary vascular disease 
Protocol AC-055G203 / SERENADE OL
Amendment 5 Version 6, 26 November 2020
EudraCT 2018-001603-37
Doc No EDMS-RIM-263261
CONFIDENTIAL – FOIA Exemptions Apply in U.S.  
9
TABLE OF CONTENTS
SPONSOR CONTACT DETAILS......................................................................................2
CONTRACT RESEARCH ORGANIZATION INFORMATION......................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE................................6
TABLE OF CONTENTS.....................................................................................................9
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................15
PROTOCOL SYNOPSIS AC-055G203............................................................................18
PROTOCOL ......................................................................................................................24
1
BACKGROUND.........................................................................................................24
1.1
Indication......................................................................................................24
1.2
Study treatment(s).........................................................................................25
1.3
Purpose and rationale of the study................................................................25
1.4
Summary of known and potential risks and benefits....................................26
2
STUDY OBJECTIVES...............................................................................................27
2.1
Main objective ..............................................................................................27
2.2
Secondary objective......................................................................................27
3
OVERALL STUDY DESIGN AND PLAN ...............................................................27
3.1
Study design and rationale............................................................................27
3.1.1
Study periods ....................................................................................27
3.1.2
Study duration...................................................................................28
3.2
Study committees .........................................................................................29
4
SUBJECT POPULATION..........................................................................................29
4.1
Subject population description and rationale................................................29
4.2
Inclusion criteria...........................................................................................30
4.3
Exclusion criteria..........................................................................................30
4.4
Criteria for women of childbearing potential ...............................................32
4.4.1
Definition of childbearing potential..................................................32
4.4.2
Acceptable methods of contraception...............................................32
4.4.2.1
Countries where macitentan is approved.................................32
4.4.2.2
North America and countries where macitentan is not 
approved ..................................................................................32


Macitentan / ACT-064992
HFpEF and pulmonary vascular disease 
Protocol AC-055G203 / SERENADE OL
Amendment 5 Version 6, 26 November 2020
EudraCT 2018-001603-37
Doc No EDMS-RIM-263261
CONFIDENTIAL – FOIA Exemptions Apply in U.S.  
10
5
TREATMENTS ..........................................................................................................34
5.1
Study treatment.............................................................................................34
5.1.1
Investigational treatment: Description and rationale........................34
5.1.2
Study Treatment Administration ......................................................34
5.1.3
Treatment assignment.......................................................................34
5.1.4
Blinding ............................................................................................34
5.1.5
Study treatment supply .....................................................................34
5.1.5.1
Study treatment packaging and labeling .................................35
5.1.5.2
Study treatment distribution and storage.................................35
5.1.5.3
Study treatment dispensing .....................................................35
5.1.5.4
Study treatment return and destruction ...................................35
5.1.6
Study treatment accountability and compliance with study 
treatment ...........................................................................................35
5.1.6.1
Study treatment accountability................................................35
5.1.6.2
Study treatment compliance ....................................................36
5.1.7
Study treatment dose adjustments and interruptions ........................36
5.1.8
Premature discontinuation of study treatment ..................................37
5.1.9
Study-specific criteria for interruption / premature 
discontinuation of study treatment....................................................37
5.1.9.1
Liver, aminotransferase abnormalities ....................................37
5.1.9.2
Hemoglobin abnormalities ......................................................38
5.1.9.3
Initiation of prohibited medications ........................................39
5.1.9.4
Pregnancy................................................................................39
5.1.10
Study treatment overdose and treatment...........................................39
5.2
Previous and concomitant medications ........................................................40
5.2.1
Definitions ........................................................................................40
5.2.2
Reporting of previous/concomitant medications in the CRF............40
5.2.3
Allowed concomitant therapy...........................................................40
5.2.4
Forbidden concomitant therapy ........................................................40
6
STUDY ENDPOINTS ................................................................................................41
6.1
Efficacy endpoints ........................................................................................41
6.1.1
Primary efficacy endpoint(s) ............................................................41
6.1.2
Exploratory efficacy endpoints.........................................................41
6.2
Safety endpoints ...........................................................................................41
7
VISIT SCHEDULE AND STUDY ASSESSMENTS................................................41
7.1
General information......................................................................................41
7.1.1
Transition to SERENADE OL..........................................................42
7.1.2
Informed consent ..............................................................................42


Macitentan / ACT-064992
HFpEF and pulmonary vascular disease 
Protocol AC-055G203 / SERENADE OL
Amendment 5 Version 6, 26 November 2020
EudraCT 2018-001603-37
Doc No EDMS-RIM-263261
CONFIDENTIAL – FOIA Exemptions Apply in U.S.  
11
7.1.3
Unscheduled visits............................................................................43
7.2
Study assessments.........................................................................................46
7.2.1
Demographics / baseline characteristics...........................................46
7.2.2
Efficacy assessments.........................................................................47
7.2.2.1
Assessment of WHF event ......................................................47
7.2.2.2
NYHA FC................................................................................49
7.2.3
Safety assessments............................................................................49
7.2.3.1
Vital Status ..............................................................................49
7.2.3.2
Physical examination...............................................................49
7.2.3.3
Vital signs................................................................................50
7.2.3.4
Weight .....................................................................................50
7.2.3.5
Home body weight monitoring................................................50
7.2.4
Laboratory assessments ....................................................................50
7.2.4.1
Type of laboratory...................................................................50
7.2.4.2
Laboratory tests .......................................................................51
8
STUDY COMPLETION AND POST-STUDY TREATMENT / MEDICAL 
CARE ..........................................................................................................................52
8.1
Study completion as per protocol .................................................................52
8.2
Premature withdrawal from study ................................................................53
8.3
Premature termination or suspension of the study........................................53
8.4
Medical care of subjects after study completion / withdrawal from 
study..............................................................................................................54
9
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS...........................55
9.1
Adverse events..............................................................................................55
9.1.1
Definition of adverse events .............................................................55
9.1.2
Intensity of adverse events................................................................55
9.1.3
Relationship to study treatment ........................................................56
9.1.4
Reporting of adverse events..............................................................56
9.1.5
Follow-up of adverse events.............................................................57
9.2
Serious adverse events..................................................................................57
9.2.1
Definitions of serious adverse events ...............................................57
9.2.2
Reporting of serious adverse events .................................................58
9.2.3
Follow-up of serious adverse events.................................................58
9.2.4
After the 30-day follow-up period....................................................58
9.2.5
Reporting procedures........................................................................58
9.3
Pregnancy .....................................................................................................59
9.3.1
Reporting of pregnancy ....................................................................59
9.3.2
Follow-up of pregnancy....................................................................59
9.4
Product quality complaints handling............................................................60


Macitentan / ACT-064992
HFpEF and pulmonary vascular disease 
Protocol AC-055G203 / SERENADE OL
Amendment 5 Version 6, 26 November 2020
EudraCT 2018-001603-37
Doc No EDMS-RIM-263261
CONFIDENTIAL – FOIA Exemptions Apply in U.S.  
12
9.4.1
Definition..........................................................................................60
9.4.2
Procedures.........................................................................................60
9.5
Special reporting situations ..........................................................................60
9.6
Study safety monitoring................................................................................61
10 STATISTICAL METHODS .......................................................................................61
10.1
Analysis sets .................................................................................................61
10.1.1
Full Analysis Set...............................................................................61
10.1.2
Per-protocol Analysis Set .................................................................61
10.1.3
Safety Set ..........................................................................................61
10.1.4
Safety Initiated Set............................................................................61
10.1.5
Open-label Extension Enrolled Set...................................................62
10.1.6
Usage of the analysis sets .................................................................62
10.2
Variables.......................................................................................................62
10.2.1
Primary efficacy variable(s)..............................................................62
10.2.2
Exploratory efficacy variables..........................................................62
10.2.2.1
Time to first occurrence of WHF event...................................62
10.2.2.2
Time to first occurrence of a composite of HF death or HF 
hospitalization .........................................................................63
10.2.2.3
Time to first occurrence of a composite of CV death or CV 
hospitalization .........................................................................63
10.2.2.4
NYHA FC (improved/worsened/stable) at each post-baseline 
assessment ...............................................................................63
10.2.3
Safety variables.................................................................................64
10.2.4
Other variables..................................................................................64
10.2.4.1
Exposure to study drug............................................................64
10.2.4.2
Discontinuation of SERENADE OL.......................................64
10.3
Description of statistical analyses.................................................................64
10.3.1
Overall testing strategy.....................................................................64
10.3.2
Analysis of the primary efficacy variable(s).....................................65
10.3.3
Analysis of exploratory efficacy variable(s).....................................65
10.3.3.1
Time to event...........................................................................65
10.3.3.2
NYHA FC (improved/worsened/stable) at each post-baseline 
assessment ...............................................................................65
10.3.4
Sub-group analyses...........................................................................65
10.3.5
Analysis of the safety variable(s)......................................................65
10.3.5.1
All-cause death up to 30 days after study treatment 
discontinuation ........................................................................66
10.3.5.2
Number of all-cause hospital admissions up to 30 days after 
study treatment discontinuation...............................................66
10.3.5.3
Adverse events ........................................................................66


Macitentan / ACT-064992
HFpEF and pulmonary vascular disease 
Protocol AC-055G203 / SERENADE OL
Amendment 5 Version 6, 26 November 2020
EudraCT 2018-001603-37
Doc No EDMS-RIM-263261
CONFIDENTIAL – FOIA Exemptions Apply in U.S.  
13
10.3.5.4
Adjusted incidence rates..........................................................66
10.3.5.5
Vital signs and body weight ....................................................66
10.3.5.6
Laboratory variables................................................................67
10.3.5.7
Glomerular Filtration Rate ......................................................67
10.3.6
Analysis of other variables ...............................................................67
10.4
Interim analyses............................................................................................67
10.5
Sample size...................................................................................................67
11 DATA HANDLING....................................................................................................68
11.1
Data collection..............................................................................................68
11.2
Maintenance of data confidentiality .............................................................68
11.3
Database management and quality control...................................................68
12 PROCEDURES AND GOOD CLINICAL PRACTICE.............................................69
12.1
Ethics and Good Clinical Practice................................................................69
12.2
Independent Ethics Committee / Institutional Review Board ......................69
12.3
Informed consent ..........................................................................................70
12.4
Indemnification, compensation and refund of expenses to subjects and 
investigators..................................................................................................71
12.5
Protocol adherence/compliance....................................................................71
12.6
Protocol amendments ...................................................................................71
12.7
Essential documents and retention of documents.........................................72
12.8
Monitoring....................................................................................................73
12.9
Investigator Site File.....................................................................................74
12.10
Audit .............................................................................................................74
12.11
Inspections....................................................................................................74
12.12
Reporting of study results and publication...................................................75
13 REFERENCES............................................................................................................76
14 APPENDICES.............................................................................................................79


Macitentan / ACT-064992
HFpEF and pulmonary vascular disease 
Protocol AC-055G203 / SERENADE OL
Amendment 5 Version 6, 26 November 2020
EudraCT 2018-001603-37
Doc No EDMS-RIM-263261
CONFIDENTIAL – FOIA Exemptions Apply in U.S.  
14
LIST OF TABLES
Table 1
Visit and assessment schedule ........................................................................44
Table 2
WHF event definition......................................................................................48
LIST OF FIGURES
Figure 1
Study design....................................................................................................28
Figure 2
Acceptable birth control options.....................................................................33
LIST OF APPENDICES
Appendix 1Marked laboratory abnormalities....................................................................79
Appendix 2Central laboratory alert flags...........................................................................80
Appendix 3Worsening Heart Failure Event definitions [ACC/AHA2015].......................81
Appendix 4Classification of cause of death ......................................................................83
Appendix 5Definition of HF and CV hospitalization........................................................85
Appendix 6Protocol amendment history ...........................................................................85


Macitentan / ACT-064992
HFpEF and pulmonary vascular disease 
Protocol AC-055G203 / SERENADE OL
Amendment 5 Version 6, 26 November 2020
EudraCT 2018-001603-37
Doc No EDMS-RIM-263261
CONFIDENTIAL – FOIA Exemptions Apply in U.S.  
15
LIST OF ABBREVIATIONS AND ACRONYMS
6MWT
6-minute walk test
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BNP
Brain natriuretic peptide
BP
Blood pressure
BUN
Blood urea nitrogen
CEC
Clinical Event Committee
CFR
Code of Federal Regulations (US)
CI
Confidence interval
CL
Confidence limit
CRA
Clinical Research Associate
CRF
Case Report Form 
CRO
Contract Research Organization
CSR
Clinical Study Report
CV
Cardiovascular
CYP3A4
Cytochrome P450 3A4
DAOH
Days alive and out of the hospital
DBP
Diastolic blood pressure
ECG
Electrocardiogram
eGFR
estimated Glomerular Filtration Rate
EOS
End-of-Study
EOT
End-of-Treatment
ERA
Endothelin receptor antagonist
FAS
Full Analysis Set
FC
Functional class
FOIA
Freedom of Information Act
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
HF
Heart failure
HFpEF
Heart failure with preserved ejection fraction


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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
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
KCCQ
Kansas City Cardiomyopathy Questionnaire
LFT
Liver Function Test
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
MR-proANP
Mid-regional pro-atrial natriuretic peptide
NT-pro-BNP
N-terminal pro-brain natriuretic peptide
NYHA
New York Heart Association
OL
Open-label
OLE
Open-label Extension Enrolled Set
PAD
Peripheral artery disease
PAH
Pulmonary arterial hypertension
PDE-5
Phosphodiesterase-5
PH
Pulmonary hypertension
PI
Principal Investigator
PQC
Product Quality Complaint
PTOP
Post-treatment observation period
PVD
Pulmonary Vascular Disease
RSI
Reference safety information 
RVD
Right ventricular dysfunction
SAE
Serious adverse event
SAP
Statistical Analysis Plan


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SBP
Systolic blood pressure
SCL
Study Closure
SpO2
Oxygen saturation
SI
International system of units
SIV
Site Initiation Visit
SUSAR
Suspected unexpected serious adverse reaction
ULN
Upper limit of normal
USA
United States of America
VHP
Voluntary Harmonization Procedure
VSFU
Vital Status Follow-Up
WHF
Worsening heart failure


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HFpEF and pulmonary vascular disease 
Protocol AC-055G203 / SERENADE OL
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PROTOCOL SYNOPSIS AC-055G203
TITLE
A long-term, multicenter, single-arm, open-label extension of the 
SERENADE study, to assess the safety and efficacy of macitentan 
in subjects with heart failure with preserved ejection fraction and 
pulmonary vascular disease 
ACRONYM
SERENADE OL
Macitentan in heart failure with preSERved ejEction fractioN and 
pulmonAry vascular DiseasE Open Label
OBJECTIVES
Main objective(s)
To evaluate the long-term safety of macitentan 10 mg in subjects with 
heart failure due to preserved ejection fraction and pulmonary 
vascular disease. 
Secondary objective(s)
To explore the long-term efficacy of macitentan 10 mg.
DESIGN
A multi-center, single-arm, open-label (OL) Phase 2b extension 
study. 
All subjects will receive the same study treatment. 
PERIODS
Pre-OL treatment period: Starts with the signature of the Informed 
Consent Form (ICF) and ends with the administration of the first dose 
of OL study treatment.
Treatment period: Starts with the administration of the first dose of 
OL study treatment and ends on the day of the last dose of OL study 
treatment.
Follow-up period: Starts on the day after the last dose of OL study 
treatment and ends 30 days thereafter with the End-of-Study (EOS) 
Visit. The safety follow-up visit will be waived in case the subject 
moves to a continued access program and in that case EOT will be the 
last visit in the study. 
PLANNED 
DURATION
SERENADE OL starts with the first act of recruitment (i.e., first ICF 
signed) and ends with the last visit of the last subject.
SERENADE OL will continue at each site until all subjects have left 
the study, or until Actelion decides to stop the study (e.g., if the results 
of the main study show that the use of macitentan in this patient 
population is either not safe or not effective), whichever occurs first. 


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Per request from VHP, the following applies for VHP countries:
For each subject, the OL treatment duration will last up to 260 weeks 
(5 years) from his/her enrollment (Visit 1). The study may end earlier 
if all subjects have left the study, or if Actelion decides to stop the 
study (e.g., if the results of the main study show that the use of 
macitentan in this patient population is either not safe or not 
effective).
Likewise, if during the course of the OL study, the Independent Data 
Monitoring Committee (IDMC) concludes that the use of macitentan 
in this patient population is either not safe or not effective, the main 
study (if still ongoing) and the OL study will be stopped.
SITE(S)
/ COUNTRY(IES)
Approximately 77 sites in 17 countries 
SUBJECTS / 
GROUPS
Approximately 112 subjects in 1 group (Macitentan open-label)
INCLUSION 
CRITERIA
1. Signed and dated ICF.
2. Subject remained in the main study (SERENADE / AC-055G202)
for:    
a.
52 weeks after randomization if entered this OL extension 
study prior to protocol Version 4 [see Section 4.1].
b. At least 24 weeks after randomization if entering this OL 
extension study under protocol Version 4 [see 
Section 4.1].
3. A woman of childbearing potential [see definition in 
Section 4.4.1] is eligible only if the following applies:

Negative pre-treatment serum pregnancy test. 

Agreement to undertake monthly pregnancy tests from the 
enrollment visit up to at least 30 days after study treatment 
discontinuation.

Agreement to use reliable contraception [Section 4.4.2] from 
at least 30 days prior to the enrollment visit up to at least 
30 days after study treatment discontinuation.
EXCLUSION 
CRITERIA
1. Premature discontinuation of study treatment in the main study 
due to an adverse event related to: 
a. Edema or fluid retention 
b. Worsening of heart failure
c. Liver aminotransferase elevation
d. Study treatment, based on investigators’ discretion


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2. Liver aminotransferase elevations, at the enrollment visit1,
fulfilling the following criteria:
a.
Alanine aminotransferase (ALT) / aspartate aminotransferase 
(AST) 8 the upper limit of normal range (ULN)
b. ALT/AST 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)
c.
ALT/AST 3 ULN and associated increase in total bilirubin 
to 2 ULN
3. Criteria modified per Amendment 4 
3.1 Treatment with the following forbidden medications within 
1 month prior to the enrollment visit:
a. Treatments that may interfere with the assessment of efficacy 
(i.e., 
endothelin 
receptor 
antagonists, 
prostanoids, 
phosphodiesterase-5 inhibitors, guanylate cyclase stimulators)
b. Strong cytochrome P-450 3A4 (CYP3A4) inducers such as 
rifabutin, rifampin, rifampicin, rifapentin, carbamazepine, 
phenobarbital, phenytoin, or St. John’s wort 
c. Strong CYP3A4 inhibitors such as ketoconazole, itraconazole, 
voriconazole, clarithromycin, telithromycin, nefazodone, 
ritonavir, 
and 
saquinavir
or 
a 
moderate 
dual 
CYP3A4/CYP2C9 inhibitor (eg, fluconazole or amiodarone) 
or co-administration of a combination of moderate CYP3A4 
(eg, ciprofloxacin, cyclosporine, diltiazem, erythromycin, 
verapamil) and moderate CYP2C9 inhibitors (eg, miconazole, 
piperine), in the 1-month period prior to baseline. This will not 
necessarily apply to subjects who are already well-managed 
on such an ongoing combination.
d. any other investigational treatment.
4. Pregnant, planning to be become pregnant or lactating.
5. 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.
                                                
1 In case the central laboratory results at enrollment show ALT/AST elevations 3 ULN, study treatment must not be 
initiated until the values return to pre-enrollment levels or within normal range. Please follow the instructions in 
Section 5.1.9.1.


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6. Known hypersensitivity to macitentan or drugs of the same class, 
or any of the study drug excipients (e.g., soy lecithin, lactose).
STUDY 
TREATMENTS
Investigational treatment
Macitentan oral tablet, 10 mg once daily
ENDPOINTS
Primary efficacy endpoint(s)
No primary efficacy endpoint has been defined for this study.
Exploratory efficacy endpoints

Time to worsening heart failure event Time to first occurrence of 
a composite of heart failure (HF) death or HF hospitalization 

Time to first occurrence of a composite of cardiovascular (CV)
death or CV hospitalization 

New York Heart Association class (improved/worsened/
stable) at each post-baseline assessment
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 adverse events (AEs) and serious adverse 
events 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 all assessed timepoints 
during the study

Treatment-emergent marked laboratory abnormalities up to 
30 days after study treatment discontinuation

Change in laboratory parameters from baseline to all assessed 
timepoints during the study 

Change from baseline in estimated glomerular filtration rate 
(eGFR) to all assessed timepoints during the study.
ASSESSMENTS
Refer to the schedule of assessments in Table 1.
STATISTICAL 
METHODOLOGY
The analyses will combine data from the main study with additional 
data from this open label extension to provide long-term follow-up 
data, in subjects who were exposed to macitentan in the double-blind 
phase of the main study and/or in SERENADE OL. Analyses will be 
conducted to assess the long-term safety and efficacy of macitentan 


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in subjects with heart failure with preserved ejection fraction and 
pulmonary vascular disease.
The SERENADE OL study will contain analyses related to 
exploratory efficacy and safety endpoints. No formal hypothesis 
testing will be performed as all efficacy analyses are considered 
exploratory. Data will be summarized using descriptive statistics. In 
addition, plots of profiles over time will be displayed for continuous 
outcomes. Any p-values are presented for information only. No 
multiplicity adjustment will be made. 
Efficacy will be analyzed including data from both SERENADE and 
SERENADE OL and presented by randomized treatment group in the 
main study. Full details of the analyses will be described in the SAP.
The Safety Set will be used for the analyses of the safety variables 
and includes all subjects who received at least one dose of open-label 
treatment in the study. The results will be presented overall and by 
previous double-blind treatment group in the main study. Baseline 
value will be the last non-missing assessment obtained prior to the 
start of study drug intake in SERENADE OL.
Safety will also be evaluated on the Safety initiated Set including 
subjects who received macitentan treatment in the main study and/or 
macitentan treatment in SERENADE OL. Baseline will be the last 
non-missing value obtained prior to the start of macitentan intake in 
the main study or SERENADE OL, respectively. 
The Open-label Extension Enrolled Set (OLE) includes all subjects 
who enrolled into SERENADE OL. The OLE Set is used for the 
description of subject disposition in the OL extension, as well as the 
description of this study population at baseline.
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.


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A Steering Committee has contributed to the study design and will be 
consulted prior to and during the study for relevant medical issues and 
study publications.
External to the study, 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 any macitentan study as per the ILSDRB charter. 


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Protocol AC-055G203 / SERENADE OL
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PROTOCOL
1
BACKGROUND
1.1
Indication 
Heart failure (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]. 
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 HF 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; and c) evidence of 
abnormal left ventricular 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 HF with reduced 
ejection fraction [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, 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].


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1.2
Study treatment(s)
Macitentan (ACT-064992, Opsumit®) is an orally active, non-peptide, potent dual 
endothelin A (ETA) and endothelin B (ETB) endothelin receptor antagonist (ERA), which 
has been approved for the treatment of pulmonary arterial hypertension (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].
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
The rationale for SERENADE/AC-055G202, hereinafter referred to as the ‘main study,’
relies on the hypothesis that patients with HFpEF and pulmonary vascular disease may 
benefit from treatment with macitentan because of its mechanism of action. Pre-clinical 
data suggest that dual ET receptor blockade can directly improve cardiac remodeling, and 
especially decrease fibrosis, leading to an improvement of the filling capacity of the left 
ventricle. The subset of HFpEF patients with pulmonary vascular disease (PVD) with or 
without Right ventricular dysfunction (RVD) is most likely to benefit from treatment with 
an ERA. ERAs, including macitentan, demonstrated efficacy and are generally well 
tolerated in subjects with PAH with a varied degree of RVD. Furthermore, in a small, 
exploratory phase 2 study of macitentan in combined pre-and post-capillary pulmonary 
hypertension, AC-055G201/MELODY-1 [Vachiéry 2018], evaluation of pulmonary 
hemodynamics showed an increase in cardiac output that was not associated with elevated 
cardiac filling pressures. Furthermore, a 23% reduction in N-terminal pro-brain natriuretic 
peptide (NT-proBNP) compared to placebo was observed. Although the study was not 
powered to assess efficacy, the observed improvements suggest a potential benefit of 
macitentan in those subjects who are able to tolerate macitentan (i.e., who do not develop 
significant fluid retention). The aim of the main study is to confirm these exploratory 
findings, and to evaluate whether they translate into a clinically meaningful benefit. 


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The purpose of this open-label (OL) extension study is to gather additional longer-term 
safety and efficacy data with macitentan 10 mg in subjects with HFpEF and PVD beyond 
24 weeks2 of treatment in the double-blind SERENADE study (AC-055G202). 
Furthermore, this OL extension study will give eligible subjects who have completed the 
main study an opportunity to continue or start receiving macitentan 10 mg.
1.4
Summary of known and potential risks and benefits 
The SERENADE OL study will start while the main study (SERENADE / AC-055G202) 
is still ongoing, i.e., at the time of entry into the OL extension, the treatment allocation in 
the main study will still be blinded.
Previous studies with ERAs in HF have consistently shown increased incidences of early 
fluid retention events [Section 1.3]. To mitigate the risks associated with fluid retention 
events, the SERENADE study was designed to include a 4-week placebo run-in period to 
ensure the subjects’ clinical stability, followed by a 5-week macitentan run-in period to 
identify those subjects who were unable to tolerate macitentan because of an increased 
susceptibility to developing macitentan-induced fluid retention events. To ensure that only 
subjects able to tolerate macitentan entered the double-blind treatment period, the 
SERENADE protocol pre-specified strict run-in failure criteria which, if met, required 
premature discontinuation of the subject from the study. 
Although the results of the main study are not available at the time of entry into the OL 
extension, the risks of participating in the OL extension study are mitigated by the 
above-mentioned strict criteria for entering the double-blind period of the main study. In 
addition, a subject who experienced an adverse event (AE) leading to study treatment 
discontinuation related to edema/fluid retention, worsening heart failure (WHF), or liver 
aminotransferase elevations in the main study, will not be eligible for safety reasons. 
To ensure the safety of subjects who have been on placebo in the main study, all subjects 
will return for a safety visit 1 week (±2 days) after the start of open-label study treatment.
It is the investigator’s responsibility to monitor the risk-benefit 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’ wellbeing.
                                                
2 If subjects entered this OL extension study prior to protocol Version 4, then transition to this OL extension study was 
only allowed from 52 weeks post-randomization.


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2
STUDY OBJECTIVES
2.1
Main objective
To describe the long-term safety of macitentan 10 mg in subjects with HFpEF and 
pulmonary vascular disease.
2.2
Secondary objective
To explore the long-term efficacy of macitentan 10 mg.
3
OVERALL STUDY DESIGN AND PLAN
3.1
Study design and rationale
This is a multi-center, single-arm, OL Phase 2b extension study [Figure 1]. 
Subjects who remained in main study for at least 24 weeks3 after randomization and who 
meet the eligibility criteria described in Sections 4.2 and 4.3 will be eligible to enter this 
OL study. Assuming a 20% discontinuation from the main study, approximately
112 subjects are expected to enter the OL study, which will be conducted at the sites 
participating in the main study (i.e., 77 sites in 17 countries).
3.1.1
Study periods
The SERENADE OL study comprises the following consecutive periods:
Pre-OL treatment period: Starts with the signature of the informed consent and ends with 
the administration of the first dose of OL study treatment.
Treatment period: Starts with the administration of the first dose of OL study treatment 
and ends on the day of the last dose of OL study treatment.
Follow-up period: Starts on the day after the last dose of OL study treatment and ends 
30 days thereafter with the End-of-Study (EOS) Visit. The safety follow-up visit will be
waived in case the subject moves to a continued access program and in that case EOT will 
be the last visit in the study. 
The transition from the main study to SERENADE OL is described in Section 7.1.1. The 
visit schedule and protocol-mandated procedures are performed according to the table of 
assessments [Table 1] and are described in Section 7.
The overall study design is depicted in [Figure 1].
                                                
3 If subjects entered this OL extension study prior to protocol Version 4, then transition to this OL extension study was 
only allowed from 52 weeks post randomization.


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Figure 1
Study design
EOS = End-of-Study; EOT = End-of-Treatment
3.1.2
Study duration
SERENADE OL starts with the first act of recruitment (i.e., first Informed Consent Form 
[ICF] signed) and ends with the last visit of the last subject.
SERENADE OL will continue at each site until all subjects leave the study, or until 
Actelion decides to stop the study (e.g., if the results of the main study show that the use 
of macitentan in this patient population is either not safe or not effective), whichever occurs 
first. 
Per request from VHP, the following applies for VHP countries: For each subject, the 
OL treatment duration will last up to 260 weeks (5 years) from his/her enrollment (Visit 1). 
The study may end earlier if all subjects have left the study, or if Actelion decides to stop 
the study (e.g., if the results of the main study show that the use of macitentan in this patient 
population is either not safe or not effective).
Study Closure (SCL) will be announced by the sponsor when all subjects have discontinued 
study treatment. For an individual subject, the study is completed with the EOS Visit;
however, for subjects who have had their EOS visit more than 8 weeks prior to the SCL 
announcement, a vital status follow-up (VSFU) will be performed within 4 weeks after the 
SCL announcement to determine each subject’s vital status at this time, unless already 
known (i.e., subject died, withdrew consent, or is lost to follow-up). This information will 
be collected in the CRF after the sponsor announces SCL. 
The SCL will occur when the EOS Visit of the last subject and all VSFUs have been 
performed/attempted.4
                                                
4 Apply lost to follow-up rules [Section 8.2] for attempts on VSFU 
at least 24 weeks 
post randomization in 
AC-055G202
EOT
Visit
Macitentan 10 mg 
Safety 
follow-
up 
EOS
Visit
Week                     1        4           8            16         24         36            52    every 26 weeks       30 days
Enrollment
Visit


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3.2
Study committees
The same committees as in the main study will be used:
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.
A Steering Committee has contributed to the study design and will be consulted prior to 
and during the study for relevant medical issues and study publications
External to the study, 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 any macitentan study as per the ILSDRB charter. 
4
SUBJECT POPULATION
4.1
Subject population description and rationale 
The study will enroll male and female subjects with an established diagnosis of HFpEF 
and pulmonary vascular disease with or without overt RVD. As this is an OL extension of 
study AC-055G202 (SERENADE), only subjects who were randomized in the main study, 
remained in the main study for at least 24 weeks5 after randomization, and who meet the 
criteria described in Sections 4.2 and 4.3, are eligible for participation.
Remaining in the main study is defined as follows:

Subjects who completed the treatment period (Core and Extension phase) as per main 
study protocol and had their End-of Treatment (EOT) Visit at Week 52 (–8 days) if 
entering this study prior to SERENADE OL protocol Version 4.

Subjects who completed the Core treatment period as per main study protocol and 
had their EOT Visit at Week 24 (–8 days) or later if entering this study under 
SERENADE OL protocol Version 4.
                                                
5If subjects entered this OL extension study prior to global protocol version 4 then transition to this OL extension study 
was only allowed following 52 weeks post randomization.


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
Subjects who prematurely discontinued study treatment but participated in the 
Post-treatment observation period (PTOP) until Week 52 / PTOP4 (–14 days). Only 
applicable for subjects who have transitioned to the OL extension study prior to
SERENADE OL protocol Version 4.

Subjects who prematurely discontinued study treatment but participated in the PTOP 
until at least Week 24 / PTOP2 (±14 days) if entering under SERENADE OL
protocol Version 4.
4.2
Inclusion criteria
For inclusion in the study, all of the following inclusion criteria must be fulfilled. It is not 
permitted to waive any of the criteria for any subject:
1. Signed and dated informed consent form.
2. Subject remained in the main study (SERENADE/AC-055G202) for:
a.
52 weeks after randomization if entered this OL extension study prior to protocol 
Version 4 [see Section 4.1].
b. At least 24 weeks after randomization if entering this OL extension study under 
protocol Version 4 [see Section 4.1].
3. A woman of childbearing potential [see definition in Section 4.4.1] is eligible only if 
all of the following apply:

Negative pre-treatment serum pregnancy test. 

Agreement to undertake monthly pregnancy tests from the enrollment visit up to 
at least 30 days after study treatment discontinuation.

Agreement to use reliable contraception [Section 4.4.2] from at least 30 days prior 
to the enrollment visit up to at least 30 days after study treatment discontinuation.
4.3
Exclusion criteria
Subjects must not fulfill any of the following exclusion criteria. It is not permitted to waive 
any of the criteria for any subject:
1. Premature discontinuation of study treatment in the main study due to an adverse event
related to:
a. Edema or fluid retention 
b. Worsening of HF
c. Liver aminotransferase elevations.
d. Study treatment, based on investigators’ discretion


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2. Liver aminotransferase elevations, at the enrollment visit6, fulfilling the following 
criteria:
a.
Alanine amino transferase (ALT) / aspartate aminotransferase (AST) 8 the 
upper limit of normal (ULN)
b. ALT/AST 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)
c.
ALT/AST 3 ULN and associated increase in total bilirubin to 2 ULN.
3. Criteria modified per Amendment 4 
3.1Treatment with the following forbidden medications within 1 month prior to the 
enrollment visit:
a.
Treatments that may interfere with the assessment of efficacy (i.e., ERAs, 
prostanoids, 
phosphodiesterase-5 
(PDE-5)
inhibitors, 
guanylate 
cyclase 
stimulators)
b. Strong cytochrome P450 3A4 (CYP3A4) inducers such as rifabutin, rifampin, 
rifampicin, rifapentin, carbamazepine, phenobarbital, phenytoin, or St. John’s wort 
c. Strong CYP3A4 inhibitors such as ketoconazole, itraconazole, voriconazole, 
clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir or a moderate 
dual CYP3A4/CYP2C9 inhibitor (e.g. fluconazole or amiodarone) or co-
administration of a combination of moderate CYP3A4 (eg, ciprofloxacin, 
cyclosporine, diltiazem, erythromycin, verapamil) and moderate CYP2C9 
inhibitors (eg, miconazole, piperine), in the 1-month period prior to baseline. This 
will not necessarily apply to subjects who are already well-managed on such an 
ongoing combination.
d. any other investigational treatment.
4. Pregnant, planning to be become pregnant or lactating.
5. 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.
6. Known hypersensitivity to macitentan or drugs of the same class, or any of the study 
drug excipients (e.g., soy lecithin, lactose).
                                                
6 If there is a known AST/ALT elevation, the site should not initiate OL treatment. In case the central laboratory results 
from enrollment visit show ALT/AST elevations 3 × ULN, study treatment must be interrupted until the values 
return to pre-enrollment levels or within normal range. Please follow the instructions in Section 5.1.9.1.


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4.4
Criteria for women of childbearing potential
4.4.1
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]),

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).
4.4.2
Acceptable methods of contraception
Women of childbearing potential [see definition in Section 4.4.1] must use acceptable birth 
control from enrollment to at least 30 days after study treatment discontinuation. Reliable 
contraception must be used for at least 30 days prior to the enrollment visit.
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. 
4.4.2.1
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. 
4.4.2.2
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. 


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The investigator must counsel patients on pregnancy planning and prevention, including 
emergency contraception, or designate counseling by another healthcare provider trained 
in contraceptive measures.
Figure 2
Acceptable birth control options
Per request from VHP, the following applies for VHP countries:
The sole use of double-barrier methods (Option 3) can only be accepted when the use of 
highly effective measures is medically contraindicated. The contraindication must be 
documented in the patient chart. 


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5
TREATMENTS
5.1
Study treatment
5.1.1
Investigational treatment: Description and rationale
The investigational treatment is macitentan (ACT-064992, Opsumit®), tested at the same 
dose (i.e., 10 mg) as in the main study.
Macitentan is provided as film-coated tablets debossed with ‘10’ on both sides. One tablet 
must be taken orally once a day. 
5.1.2
Study Treatment Administration
The first intake of study treatment will take place at site, during Visit 1 (enrollment). 
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 2, where the study treatment is taken from the bottle dispensed at 
Visit 1).
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 two doses to make up for a missed dose.
5.1.3
Treatment assignment
After having verified that the subject meets all inclusion criteria and none of the exclusion 
criteria, the investigator/delegate contacts the Interactive Response Technology (IRT)
system at the enrollment visit to enroll the subject. All subjects will retain the subject 
number they were assigned in the main study. The IRT assigns the study treatment bottle
number(s).
5.1.4
Blinding
Not applicable, as this is an OL extension study. 
The treatment assignment in the main study will remain blinded until the time of unblinding 
for final data analysis of the main study. Subjects will therefore enter the OL extension 
without knowledge of their treatment assignment in the main study. 
5.1.5
Study treatment supply 
Manufacturing, 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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5.1.5.1
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.
5.1.5.2
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.
5.1.5.3
Study treatment dispensing
The subjects will receive sufficient study treatment (i.e., up to 6 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 doesn’t 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.
5.1.5.4
Study treatment return and destruction
Study treatment must be handled in strict accordance with the protocol and the container 
label, and must be stored at the study site in a limited-access area or in a locked cabinet 
under appropriate environmental conditions. Unused study treatment and study treatment 
returned by the subject must be available for verification by the sponsor’s study site 
monitor during on-site monitoring visits. The return to the sponsor of unused study 
treatment or used returned study treatment for destruction will be documented on the 
intervention return form. When the study site is an authorized destruction unit and study 
treatment supplies are destroyed on-site, this must also be documented on the intervention 
return form.
5.1.6
Study treatment accountability and compliance with study treatment 
5.1.6.1
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 
Clinical Research Associate (CRA) during site visits and at the end of the study. The study 


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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.
5.1.6.2
Study treatment compliance
Study treatment compliance is based on study treatment accountability. Study treatment 
compliance will be calculated by site personnel at each study treatment dispensing visit 
and EOT using the below formula and entered in the CRF:
Compliance = [(number of tablets dispensed number of tablets returned) / Total number 
of tablets that should have been taken between 2 regular study treatment dispensing visits*] 
100
*The number of tablets that should have been taken is derived from the number of days 
between the corresponding regular visits.
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.
5.1.7
Study treatment dose adjustments and interruptions 
Study dosage 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 5.1.9.
If study treatment is interrupted by the subject for any reason, she/he must immediately 
inform the investigator.


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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 5.1.8].
Study treatment interruptions must be recorded in the CRF.
5.1.8
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., AE or lack of efficacy), the investigator (e.g., 
due to pre-specified study treatment discontinuation criteria, an AE or lack of efficacy), or 
Actelion (e.g., study termination) must be documented in the CRF.
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.
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 5.1.9.
A subject who prematurely discontinues study treatment is NOT considered withdrawn 
from the study and will be followed up until EOS, provided that the subject’s consent for 
this limited participation in the study has not been withdrawn.
A subject who prematurely discontinues study treatment and withdraws consent to 
participate in any further study assessments is considered withdrawn from the study. 
Subjects who die or are lost to follow-up are also considered 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.
5.1.9
Study-specific criteria for interruption / premature discontinuation of study 
treatment
5.1.9.1
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


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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 
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.
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:

ALT/AST 8 ULN

ALT/AST 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 medications or other substances) should be 
considered and ruled out by performing the appropriate tests.
All aminotransferase abnormalities leading to study treatment interruption or 
discontinuation must be recorded as AEs [see Section 9].
5.1.9.2
Hemoglobin abnormalities
If there is a decrease in hemoglobin from baseline7 of 20 g/L during the first 6 months of 
OL study treatment (i.e., up to Visit 6 / Week 24), a re-test must be performed within 
                                                
7 Baseline hemoglobin refers to the hemoglobin value obtained at Visit 1 (enrollment visit).


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10 days, with additional laboratory evaluations that may include, but are not limited to, any 
of the following:

Red blood cell cellular indices (mean corpuscular volume, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration), peripheral blood smear, 
reticulocyte count, iron status (iron level, serum ferritin, total iron binding capacity, 
transferrin saturation), lactate dehydrogenase, indirect bilirubin.
If hemoglobin remains > 20 g/L below baseline value at subsequent visits, or if hemoglobin 
decreases > 20g/L below baseline value after Visit 6 / Week 24, 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. 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. Interruption of study medication must not last longer than 4 consecutive weeks; 
longer interruption must lead to permanent discontinuation of study drug. 
5.1.9.3
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 as detailed in Section 5.2.4 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.
5.1.9.4
Pregnancy
If a female subject becomes pregnant while on study treatment, study treatment must be 
permanently discontinued immediately, and a Pregnancy Notification Form must be 
completed [see Section 9.3.1]. 
5.1.10 Study treatment overdose and treatment
For this study, any dose of study medication higher than the planned total daily dose in a 
single day will be considered an overdose. 
In the event of an overdose, standard supportive measures must be taken, as required.


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5.2
Previous and concomitant medications 
5.2.1
Definitions 
A previous medication is any treatment for which the end date is prior to the enrollment
visit.
A medication that is study-concomitant is any treatment that is ongoing or initiated after 
the enrollment visit or initiated up to 30 days after study treatment discontinuation.
5.2.2
Reporting of previous/concomitant medications in the CRF 
The use of all study-concomitant medications (including contraceptives and traditional and 
alternative medicines, e.g., plant-, animal-, or mineral-based medicines) will be recorded 
in the CRF. The generic name, start/end dates of administration (as well as whether it was 
ongoing at start of treatment and/or EOS), route, dose, frequency and indication will be 
recorded in the CRF.
5.2.3
Allowed concomitant therapy

Standard oral therapy for HF, including beta-blockers, ACE inhibitors or ARBs, and 
diuretics will be continued and adjusted as medically indicated.

For subjects with a systolic blood pressure (SBP) > 150 mmHg, treatment with 
antihypertensives according to local guidelines [ESC Guidelines 2013, James 2014] to 
achieve their target blood pressure (BP) is recommended.
5.2.4
Forbidden concomitant therapy
The following concomitant medications are forbidden within 1 month prior to the 
enrollment visit and up to 30 days after study treatment discontinuation:

Endothelin receptor antagonists (other than macitentan 10 mg) 

Strong 
CYP3A4 
inducers 
(eg, 
carbamazepine, 
phenytoin, 
phenobarbital, 
rifampin/rifampicin, rifabutin, rifapentin, St. John’s wort).

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 [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.


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
Any other investigational drug.
6
STUDY ENDPOINTS
6.1
Efficacy endpoints
6.1.1
Primary efficacy endpoint(s)
No primary efficacy endpoint has been defined for this study.
6.1.2
Exploratory efficacy endpoints

Time to WHF event

Time to first occurrence of a composite of HF death8 or HF hospitalization8

Time to first occurrence of a composite of cardiovascular (CV) death8 or CV 
hospitalization8

New York Heart Association functional class (NYHA FC) (improved/worsened/stable) 
at each post-baseline assessment
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 serious AEs (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 all assessed timepoints during the study

Treatment-emergent marked laboratory abnormalities up to 30 days after study 
treatment discontinuation

Change in laboratory parameters from baseline to all assessed timepoints during the 
study 

Change from baseline in estimated glomerular filtration rate (eGFR) to all assessed 
timepoints during the study
7
VISIT SCHEDULE AND STUDY ASSESSMENTS
7.1
General information
The study visits are listed in Table 1. For all visits, the subjects must be seen on the 
designated day with the allowed visit window. A follow-up safety visit must be performed 
                                                
8 See definition of HF death and CV death in Appendix 4; See definition of HF hospitalization and CV hospitalization 
in Appendix 5.


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30 + 5 days after intake of the last dose of OL study treatment. If it is not possible to 
complete all assessments on the same day, a visit may extend over more than 1 day within 
the allowed time window. The safety follow-up visit will be waived in case the subject 
moves to a continued access program and in that case EOT will be the last visit in the study. 
(see Section 8.4).
In case of premature discontinuation of study treatment, the EOT Visit must take place as 
soon as possible and no later than 7 days after making the decision to stop study treatment. 
7.1.1
Transition to SERENADE OL
A subject may transition to the OL extension study after having remained in the main study 
for at least 24 weeks9 after randomization.
The enrollment visit will be combined with the EOT Visit of the main study. If combination 
of the visits is not possible, the OL enrollment visit may be done separately up to 30 days 
after intake of the last dose of study treatment. This transition period may be extended if 
full approval of the SERENADE OL protocol is not obtained on time. For subjects who 
prematurely discontinued study treatment and do not meet any of the exclusion criteria 
listed in Section 4.3, the enrollment visit will be combined with the corresponding PTOP 
or EOS visit9. 
7.1.2
Informed consent
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 this SERENADE OL study and the investigator/delegate must sign the ICF 
prior to any study-related assessment or procedure. Informed consent to participate in 
SERENADE OL may be obtained before or after completion of the main study. The time 
between signature of the ICF and the SERENADE OL enrollment visit should not exceed 
1 month. 
The pre-OL treatment period starts with the signature of the informed consent. The date on 
which the first SERENADE OL protocol-mandated assessment is performed corresponds 
to the date of the enrollment visit.
Subjects will be consented to SERENADE OL Version 4 at the next regular visit. 
                                                
9 If subjects entered this OL extension study prior to protocol version 4, then transition to this OL extension study was 
only allowed following 52 weeks post randomization or post PTOP4 visit at 52 weeks in case of premature 
discontinuation from double-blind treatment.


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7.1.3
Unscheduled visits
Unscheduled visits may be performed at any time during the study. Vital signs and body 
weight will be measured at each unscheduled visit and recorded in the CRF. In addition, 
concomitant medication and AEs will be recorded, as applicable. Depending on the reason 
for the unscheduled visit (e.g., AE), appropriate assessments 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.


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Table 1
Visit and assessment schedule
PERIODS
Name
OPEN LABEL TREATMENT
FOLLOW-UP
VISITS1
Number
1
2
3
4
5
6, 7, 8, 
9-x5
Name
Enrollment3
Week 1
Week 4
Week 8
Week 16
Week 24, 36, 52 
Week 78, 104, 130
EOT5
EOS4
Time
SD 1
SD 7
(± 2)
SD 28
(± 4 d)
SD 56
(± 7 d)
SD 112
(± 14 d)
SDs 168, 252, 364 
(±14 d)
Every 26 (±14 d)
Within 7 d 
after last dose
30 (+ 5 d) days 
after last dose
Informed consent2
X
Eligibility
X
Concomitant therapy
X#
X
X
X
X
X
X
X
X
Physical examination
X#
X
X
X
X
X
X
X
X
Vital signs (BP, HR)
X#
X
X
X
X
X
X
X
X
Body weight
X#
X
X
X
X
X
X
X
X
Home body weight monitoring
 Weekly
NYHA FC
X#
X
X
X
X
X
X
X
X
WHF
X#
X
X
X
X
X
X
X
X
Hematology/Clinical chemistry/ 
serum pregnancy test*6,7
X#
X
X8
X8
X8
X8
X
X
Urine pregnancy test9
Monthly in-between visits
Study treatment dispensing
X
X
X
X
X
X
SAEs/AEs10
X
X
X
X
X
X
X
X
X
*Transferred electronically by an external service provider
# If the EOT (or corresponding PTOP/EOS) Visit of the main study and the enrollment visit of the OL extension are combined, the results of these assessments and 
corresponding actions, as applicable, need to be reported in the CRFs of the main study only. 
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 Informed consent may be signed prior to Visit 1 or at Visit 1.
3 During enrollment, if it is not possible to perform all assessments in one day, the procedures can be done any time prior to Visit 2.
4 For subjects who had their EOS Visit more than 8 weeks prior to study closure (SCL) announcement, a vital status follow-up visit (VSFU) will be performed by the site 
within 4 weeks after the SCL announcement. VSFU does NOT need to be performed if the subject’s vital status is known (i.e., loss to follow-up, death, withdrawal of 
consent) In addition to the VSFU at the time of SCL, the sponsor may request this information be obtained at any time during the study.


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5 Per request from VHP, the following applies for VHP countries: Visits 9 through 15 only, occurring at weeks 78, 104, 130, 156, 182, 208, 234, respectively. EOT 
Visit will be at Week 260 (±14 days). In case of premature discontinuation, the EOT Visit must be within 7 days after the last dose.
6 Sent to the central laboratory.
7 For women of childbearing potential only.
8 Monthly AST/ALT monitoring is recommended. It is at the investigator’s discretion to decide (taking into account the subject’s medical history and AEs) if those 
monthly tests are required/justified. Local laboratory may be used. Per request from VHP, the following applies for VHP countries: monthly AST/ALT 
monitoring is required. Local laboratory may be used for monthly AST/ALT monitoring in between visits.
9 For women of childbearing potential only: Urine pregnancy test will be performed by the subject on a monthly basis, in-between visits. The site will follow-up on the 
results with a telephone call. 
10 All AEs and SAEs that occur after intake of the first dose of OL study treatment and up to 30 days after study treatment discontinuation must be reported [see also 
Section 9].
AE = adverse event; BP = blood pressure; SD = Study Day; d = days; EOS = End-of-Study; EOT = End-of-Treatment; FC = functional class; HR = heart rate; 
NYHA = New York Heart Association; SAE = serious adverse event; SCL= study closure; VHP = voluntary harmonization procedure; VSFU = vital status follow-
up visit; W = Week; w = weeks; WHF = worsening heart failure; PTOP = post-treatment observation period.


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7.2
Study assessments
The study assessments are listed in Table 1. 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 is recommended: 

Physical examination (including assessment of AEs/SAEs), vital signs, NYHA FC, 
body weight, concomitant therapy, WHF)

Blood sampling
If the Principal Investigator (PI) delegates any study procedure/assessment for a subject, 
e.g., 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 enrollment of 
the first subject. Calibration certificates of other equipment must be available as per local 
requirements.

Temperature measurement devices for study treatment storage area 

Body-weight scale 
7.2.1
Demographics / baseline characteristics
Demographic data (sex, race and ethnicity), baseline disease characteristics and medical 
history recorded in the database of the main study will be used.
Where possible, diagnoses and not symptoms will be recorded.
For subjects who were not eligible to enter SERENADE OL, the following data will be 
recorded in the CRF if available:

Date/Time of ICF signature

Reason for non-eligibility and associated assessments, if applicable.


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7.2.2
Efficacy assessments
7.2.2.1
Assessment of WHF event
Occurrence of a WHF event will be assessed by the investigator using the 2015 American 
College of Cardiology / American Heart Association definition [ACC/AHA2015, 
Appendix 3].
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]
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]
*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 2
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
Non-invasive 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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7.2.2.2
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.
7.2.3
Safety assessments
The definitions, reporting and follow-up of AEs, SAEs and pregnancies are described in 
Section 9.
7.2.3.1
Vital Status
For subjects who had their EOS Visit more than 8 weeks prior to SCL announcement, a
VSFU will be performed by the site within 4 weeks after the SCL announcement to 
determine each subject’s vital status (alive, dead, or unknown) at this time.
In addition to the VSFU at the time of SCL, the sponsor may request that this information 
be obtained at any time during the study.
This VSFU will be performed by the investigational site via a contact with the subject or 
legal representatives/caregivers (phone call or any other means allowed per local 
regulations, e.g., access to public registries).
The outcome of the VSFU is reported in the CRF.
7.2.3.2
Physical examination
Physical examination 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 the investigator’s discretion.


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It is recommended that evidence of pulmonary congestion is sought if clinically indicated 
(e.g., chest X-ray, pulmonary ultrasound).
Results of all physical examinations must be documented in the patient’s chart at the study 
site. Significant physical examination findings made after enrollment, 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 diastolic BP (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 
Body weight will be measured at the site at all visits. It is recommended to always weigh 
individual subjects under similar conditions, i.e., indoor clothing without shoes, same 
scale, similar interval between weighing and last meal.
7.2.3.5
Home body weight monitoring
Subjects will be instructed to monitor their body weight at home on a weekly basis from 
enrollment until Week 16, 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. 
7.2.4
Laboratory assessments
7.2.4.1
Type of laboratory
Hematology and chemistry tests will be performed at the visits indicated in Table 1. 
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.
Monthly AST/ALT monitoring is recommended. It is at the investigator’s discretion to 
decide (taking into account the subject’s medical history and AEs) if those monthly tests 
are required/justified. Local laboratories may be used.
If monthly AST/ALT monitoring in between visits is performed, a local laboratory can be 
used. The results from the local AST/ALT tests that are within normal range do not need 
to be reported in the CRF. If the local laboratory results show an increase in AST/ALT 


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≥3 ULN, the results must be reported in the CRF, the subject must return to the site and 
the AST/ALT re-test must be performed centrally.
Per request from VHP, monthly AST/ALT monitoring is required in all VHP 
countries. Local laboratories may be used for monthly AST/ALT monitoring in between 
visits. The results from the local AST/ALT tests that are within normal range do not need 
to be reported in the CRF. If the local laboratory results show an increase in AST/ALT 
≥3 ULN, the results must be reported in the CRF, the subject must return to the site and 
the AST/ALT re-test must be performed centrally.
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. Any clinically relevant laboratory abnormalities 
detected after administration of the first dose of OL study treatment 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
The amount of blood collected from an individual subject is approximately 10 mL at each 
visit which only collects hematology/clinical chemistry, including pregnancy test, if 
applicable. For details, please refer to the laboratory manual. 
Hematology

Hemoglobin (International system of units [SI]: g/L; Conventional unit: g/dL)

Hematocrit (SI Unit: L/L; Conventional unit: %)


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
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)

BUN (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 MDRD formula
Pregnancy test
Women of childbearing potential must have monthly pregnancy tests up to EOS. 
At regular, scheduled visits, a serum pregnancy test will be performed [Table 1]. After 
Week 8, when the interval between visits exceeds 1 month, women of childbearing 
potential must perform urine pregnancy tests at home in between visits on a monthly basis
in addition to the serum pregnancy tests 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.
8
STUDY COMPLETION AND POST-STUDY TREATMENT / 
MEDICAL CARE
8.1
Study completion as per protocol 
A subject who completes the safety follow-up period and EOS Visit is considered to have 
completed the study as per protocol. The safety follow-up visit will be waived in case the 
subject moves to a continued access program and in that case EOT will be the last visit in 
the study.
The VSFU will be collected in the CRF and is performed after study completion.


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8.2
Premature withdrawal from study
Subjects may voluntarily withdraw from the study (including VSFU) 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 
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 wellbeing 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 Independent Ethics Committees (IECs) / Institutional Review Boards 


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(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 
and Steering Committee.
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.
Local regulations on continued access will always take precedence. Plans for continued 
access stated in this protocol may change if new information on the benefit-risk profile of 
macitentan becomes available during the study or program.
At the end of their participation in the study, subjects who have completed the study and 
are benefiting from the study treatment, as determined by their investigator, will be able to 
receive continued access via an another open-label extension study or via post-study 
independent requests from their investigators. 


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9
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS
9.1
Adverse events
9.1.1
Definition of adverse events 
An AE is any adverse change from the subject’s baseline condition10, 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,
whether or not it is 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 of the study treatment and study treatment errors will be reported as an AE when
associated with signs or symptoms.
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.
The three categories of intensity are defined as follows:
                                                
10 Subject's condition prior to initiating the OL study treatment.


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
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 OL study treatment and reported as either related 
or not related. 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 administration of the first dose of OL study treatment and 
up to 30 days after OL study treatment discontinuation must be recorded on specific AE 
pages of the CRF. If the intensity of such an AE worsens, only the worst intensity needs to 
be reported on the AE form of the CRF. 
Adverse events occurring prior to the administration of the first dose of OL study treatment 
are to be reported in the main study. 
Ongoing AEs/SAEs:
AEs/SAEs that started during the main study and are still ongoing at the time of the first 
dose of OL study treatment will also be reported in the CRF of the SERENADE OL study.
If a non-serious, ongoing AE becomes serious during SERENADE OL, a new SAE must
be reported in the SERENADE OL CRF. If a serious, ongoing AE becomes non-serious in 
SERENADE OL, no change is required to be reported.


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If the intensity of an ongoing AE/SAE worsens during SERENADE OL, a new AE/SAE
must be reported in the SERENADE OL CRF. Lessening of intensity of an ongoing 
AE/SAE during SERENADE OL does not need to be reported.
9.1.5
Follow-up of adverse events 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and evaluations as medically indicated to elucidate the nature and causality 
of the AE, SAE, or product quality complaint (PQC) as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
AEs still ongoing more than 30 days after OL study treatment discontinuation must be 
followed up until they are no longer considered clinically relevant or until stabilization. 
The follow-up information obtained after the subject’s EOS Visit / telephone call 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

Is a suspected transmission of any infectious agent via a medicinal product 

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 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.


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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 as well as PQCs, occurring after administration of the first dose of OL study 
treatment and up to 30 days after OL 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.
For reporting of SAEs that are ongoing from the main study, please refer to Section 9.1.4.
An SAE is defined as related to protocol-mandated procedures if it appears to have a 
reasonable possibility of a causal relationship either to the study design or to 
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 / telephone call must be 
reported to Sponsor, 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 Sponsor 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 procedures
All SAEs must be reported by the investigator to Sponsor 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 Sponsor (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. Sponsor 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 the Sponsor in the reference 
safety information (RSI) section provided in the most recent version of the IB.
The Sponsor assumes responsibility for appropriate reporting of AEs to the regulatory 
authorities. The Sponsor will also report to the investigator (and the head of the 
investigational institute where required) all suspected unexpected serious adverse reactions 
(SUSARs). The investigator (or sponsor where required) must report SUSARs to the 
appropriate Independent Ethics Committee/Institutional Review Board (IEC/IRB) that 
approved the protocol unless otherwise required and documented by the IEC/IRB. A 
SUSAR will be reported to regulatory authorities unblinded. Participating investigators and 
IEC/IRB will receive a blinded SUSAR summary, unless otherwise specified.
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
All initial reports of pregnancy in female subjects or partners of male subjects must be 
reported to the Sponsor by the study-site personnel within 24 hours of their knowledge of 
the event using the appropriate Pregnancy Notification Form. Any subject who becomes 
pregnant during the study must discontinue further study treatment (see Section 5.1.9.4).
9.3.2
Follow-up of pregnancy
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae 
in the infant will be required.
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. Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs and must be 
reported on a SAE form as described in Section 9.2.5.


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9.4
Product quality complaints handling
9.4.1
Definition
Product quality complaint is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, 
quality, durability, reliability, or performance of a distributed product, including its 
labeling, drug delivery system, or package integrity. A PQC may have an impact on the 
safety and efficacy of the product. In addition, it includes any technical complaints, defined 
as any complaint that indicates a potential quality issue during manufacturing, packaging, 
release testing, stability monitoring, dose preparation, storage or distribution of the product 
or the drug delivery system.
9.4.2
Procedures
All initial PQCs must be reported to the Sponsor by the study site personnel within 24 
hours after being made aware of the event.
A sample of the suspected product should be maintained under the correct storage 
conditions until a shipment request is received from the Sponsor.
9.5
Special reporting situations
Safety events of interest on a sponsor study treatment in an interventional study that may 
require expedited reporting or safety evaluation include, but are not limited to:

Overdose of a sponsor study treatment

Suspected abuse/misuse of a sponsor study treatment

Accidental or occupational exposure to a sponsor study treatment

Any failure of expected pharmacologic action (ie, lack of effect) of a sponsor study 
treatment

Unexpected therapeutic or clinical benefit from use of a sponsor study treatment

Medication error, intercepted medication error, or potential medication error involving 
a sponsor medicinal product (with or without patient exposure to the sponsor medicinal 
product, eg, product name confusion, product label confusion, intercepted prescribing 
or dispensing errors)

Exposure to a sponsor study intervention from breastfeeding.
Special reporting situations should be recorded in the CRF. Any special reporting situation 
that meets the criteria of a serious adverse event should be recorded on the serious adverse 
event page of the CRF.


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9.6
Study safety monitoring
Study safety information (AEs, SAEs, laboratory values, 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 quality). In addition, 
an IDMC is monitoring safety data [see Section 3.2]. Actelion may request additional 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 Contract Research 
Organizations (CROs) supervised by Actelion.
The analyses will combine data from the main study with additional data from this open 
label extension to provide long-term follow-up data, in subjects who were exposed to 
macitentan in the double-blind phase of the main study and/or in SERENADE OL. 
Analyses will be conducted to assess the long-term safety and efficacy of macitentan in 
subjects with HFpEF and pulmonary vascular disease.
A Statistical Analysis Plan (SAP) will provide full details of the analyses, data displays, 
and algorithms to be used for data derivations.
10.1 Analysis sets
10.1.1 Full Analysis Set
The Full Analysis Set (FAS) includes all subjects randomized in the main double-blind
study regardless of enrollment to SERENADE OL. Following the intent-to-treat principle, 
subjects are evaluated according to the study treatment they have been assigned to at 
randomization (which may be different from the study treatment they have received). The 
analyses of long-term efficacy may be further explored based on select cohorts within this 
analysis set. Full details will be described in the SAP.
10.1.2 Per-protocol Analysis Set
No Per-protocol analysis set is defined for SERENADE OL.
10.1.3 Safety Set
The Safety Set for SERENADE OL study includes all subjects who received at least one 
dose of OL treatment in the study. 
10.1.4 Safety Initiated Set
All subjects who received any macitentan treatment in the main study and/or macitentan
treatment in SERENADE OL. The main purpose of this cohort is to assess adverse events 
during treatment with macitentan.


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10.1.5 Open-label Extension Enrolled Set
The Open-label Extension Enrolled (OLE) Set includes all subjects who enrolled into 
SERENADE OL.
10.1.6 Usage of the analysis sets 
The FAS is used for the basis of the analysis of the exploratory efficacy variables [see 
Section 10.1.1].
The Safety Set is used for the analyses of the safety and efficacy variables in the OL study.
The results will be presented overall and by previous double-blind treatment group in the 
main study. Baseline value will be the last non-missing assessment obtained prior to the 
start of study drug intake in SERENADE OL (OL Baseline). The main purpose of these 
analyses is to assess long-term safety and efficacy during OL study treatment regardless of 
randomized treatment in the main study.
The Safety Initiated Set is used for the analyses of adverse events and other select safety 
variables during treatment with macitentan. Baseline will be the last non-missing value 
obtained prior to the start of macitentan intake in the main study or SERENADE OL, 
respectively.
The OLE Set is used for the description of subject disposition in SERENADE OL as well 
as the description of this study population at baseline. Baseline for this will be the last non-
missing assessment obtained prior to the start of study drug intake in SERENADE OL.
Unless specified otherwise, individual listings are prepared on the OLE Set including any 
sub-study data (6MWD and Borg Dyspnea Index).
10.2 Variables
All variables described hereafter are related to the endpoints defined in Section 6.
10.2.1 Primary efficacy variable(s)
There are no primary or secondary efficacy variables defined for SERENADE OL. 
10.2.2 Exploratory efficacy variables 
This section contains definitions of the variables related to the exploratory efficacy 
endpoints outlined in Section 6.1.2.
10.2.2.1
Time to first occurrence of WHF event 
The time to first occurrence of WHF event.
All WHF events occurring until EOS are considered, irrespective of subjects’ compliance 
to assigned therapies.
Subjects without any WHF event up to EOS are right-censored at their time of EOS.


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Time to first occurrence of WHF event is expressed in days and calculated as the onset date 
of the first WHF event minus reference date plus 1 or, for censored subjects, as EOS date
minus reference date plus 1. Where the analysis includes data combined with the main 
study the reference is the date of randomization, otherwise the reference is the date of 
enrollment in SERENADE OL. 
10.2.2.2
Time to first occurrence of a composite of HF death or HF hospitalization 
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 EOS are considered, irrespective of 
subjects’ compliance to assigned therapies.
Subjects still alive at EOS and without any HF hospitalizations up to EOS are 
right-censored at their time of 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 reference date 
plus 1 or, for censored subjects, as EOS date minus reference date plus 1, where the 
reference date is applied as defined in Section 10.2.2.1.
10.2.2.3
Time to first occurrence of a composite of CV death or CV hospitalization
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 EOS are considered, irrespective of 
subjects’ compliance to assigned therapies.
Subjects still alive at EOS and without any CV hospitalizations up to EOS are 
right-censored at their time of 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 reference 
date plus 1 or, for censored subjects, as EOS date minus reference date plus 1, where the 
reference date is applied as defined in Section 10.2.2.1.
10.2.2.4
NYHA FC (improved/worsened/stable) at each post-baseline assessment
The NYHA FC value is categorized as improved, worsened or stable at every post-baseline 
assessment.
An improvement corresponds to a decrease in NYHA FC by at least one level, whereas a 
worsening corresponds to an increase in NYHA FC by at least one level. Subjects 
remaining in the same NYHA FC as the one reported at baseline are categorized as stable.


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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 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 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 all assessed timepoints during the study

Treatment-emergent marked laboratory abnormalities up all assessed timepoints during 
the study

Change in laboratory parameters from baseline to all assessed timepoints during the 
study 

Change from baseline in eGFR up to all assessed timepoints during the study
10.2.4 Other variables
10.2.4.1
Exposure to study drug
The duration of exposure is defined as the time elapsing between study drug initiation and 
discontinuation, inclusive. This will be determined for exposure to macitentan in 
SERENADE OL and for exposure to macitentan for combined main study and 
SERENADE OL periods.
10.2.4.2
Discontinuation of SERENADE OL
The reasons leading to premature discontinuation of SERENADE OL study treatment and 
withdrawal from SERENADE OL study will be described.
10.3 Description of statistical analyses
10.3.1 Overall testing strategy
This SERENADE OL study will contain analyses related to exploratory efficacy and safety 
endpoints. No formal hypothesis testing will be performed as all efficacy analyses are 
considered exploratory. As such, all confidence intervals (CIs) will be presented as 2-sided 
90% CIs which is consistent with the main study where the sample size was based on alpha 


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= 0.1. Data will be summarized using descriptive statistics. In addition, plots of profiles 
over time will be displayed for continuous outcomes. Any p-values are presented for 
information only. No multiplicity adjustment will be made. 
Efficacy will be analyzed (including data from SERENADE OL) on the FAS by 
randomized treatment group in main study. It is planned that the baseline for efficacy 
analysis will be the same as described for the main study Clinical Study Report (CSR). 
Safety will be similarly analyzed using the Safety Set.
10.3.2 Analysis of the primary efficacy variable(s)
Not applicable.
10.3.3 Analysis of exploratory efficacy variable(s)
10.3.3.1
Time to event 
The analyses of time-to-event variables [Sections 10.2.2.1, , 10.2.2.2, and 10.2.2.3] will be 
conducted using Kaplan-Meier estimates of events over time including graphical 
representation. 
Kaplan-Meier estimates will be calculated with 2-sided 90% CIs at relevant timepoints 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 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 timepoint. 
Further details for the time-to-event variables will be described in the SAP.
10.3.3.2
NYHA FC (improved/worsened/stable) at each post-baseline assessment
The proportion (with 90% confidence limits [CLs]) of subjects having improved, having 
worsened or being stable at each post baseline visit will be summarized overall and by 
double-blind treatment group and may also presented as plots over time.
Handling of missing values will be detailed in the SAP.
10.3.4 Sub-group analyses
None planned.
10.3.5 Analysis of the safety variable(s)
All safety endpoints will be analyzed on the Safety Set and Safety Initiated Set as described 
in Section 10.1.6. Analyses on the safety set will be summarized by double-blind treatment 
group received in the main study.


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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 summarized by:

System Organ Class and Preferred Term within System Organ Class, in descending 
order of incidence

Preferred Term, in descending order of incidence
10.3.5.2
Number of all-cause hospital admissions up to 30 days after study treatment 
discontinuation
The number and frequency of all-cause hospital admissions will be summarized.
10.3.5.3
Adverse events
All AEs will be coded using the latest available version of the MedDRA dictionary.
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/ with at least on AE with fatal outcome, will be tabulated by:

System Organ Class and Preferred Term within System Organ Class, in descending 
order of incidence;

Preferred Term, in descending order of incidence.
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 SAE, for all AEs leading to premature discontinuation of 
study treatment, and for all AEs with fatal outcome.
10.3.5.4
Adjusted incidence rates
In order to account for differences in the duration of exposure of study treatment among 
the subjects, incidence rates of AEs, SAEs, AEs leading to discontinuation, deaths, and 
hospitalizations will be presented as adjusted for patient-years exposure.
Methods for adjustment will be detailed in the SAP.
10.3.5.5
Vital signs and body weight
Descriptive summary statistics by visit will be provided for observed values and absolute 
changes from baseline in SBP, DBP, heart rate, and body weight.


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10.3.5.6
Laboratory variables
Descriptive summary statistics by visit will be provided for observed values and absolute 
changes from baseline for laboratory variables. Data will be displayed in SI units as 
provided by the central laboratory. 
Marked laboratory abnormalities will be summarized for each laboratory variable 
providing their counts and percentages of subjects with at least one treatment-emergent 
marked laboratory abnormality for each parameter for which the marked laboratory 
abnormality is defined.
All hematology and chemistry parameters provided by the central and local laboratory, will 
be displayed in subject listings in original and SI units, including those from unscheduled 
visits. Treatment-emergent marked abnormalities are flagged. 
10.3.5.7
Glomerular Filtration Rate
Descriptive summary statistics by visit will be provided for observed values and absolute 
changes from baseline in GFR.
10.3.6 Analysis of other variables
Demographics and baseline characteristics, exposure to macitentan and subject disposition
will be summarized overall and by treatment group in the main study. Sub-study (6MWD 
and Borg Dyspnea Index) data will be listed.  
10.4 Interim analyses
No interim analyses are planned for the study. 
Periodic review of the efficacy data in parallel to the safety data will be performed, 
allowing an assessment of risk/benefit by the IDMC [see Section 3.2]. An independent 
statistical analysis center (Frontier Science and Technology Research Foundation), 
involved in the main study but not otherwise involved in the design, conduct and analysis 
of the study, will prepare reports for review by the IDMC (for IDMC review meetings 
during the course of the trial) in accordance with the charter. There is no limit to the number 
of reviews meetings or reports, which have the aim of guaranteeing the safety of the 
subjects.
10.5 Sample size
The sample size for the SERENADE OL is expected to be approximately 112 subjects 
assuming 140 subjects randomized in the main study with a study discontinuation rate of 
20% in the double-blind period of the main study.


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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, 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 (refer to US 21 Code of Federal 
Regulations [CFR] Part 11).
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-specific 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.
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 timepoint 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 


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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.
As NT-ProBNP and MR-proANP are potentially unblinding variables, appropriate data 
processes will be implemented to ensure the blind is preserved and integrity of the main 
study maintained. Therefore, individual subject NT-proBNP and MR-proANP central 
laboratory data for subjects from whom NT-proBNP and MR-proANP samples were 
collected for SERENADE OL will not be shared with the site staff and the Sponsor’s study
team until closure of the main study. 
AEs are coded according to the latest Medical Dictionary for Regulatory Activities
(MedDRA) used by Actelion.
After the database has been declared complete and accurate, the database will be closed. 
Any changes to the database after that time may only be made as described in the 
appropriate Actelion Quality System 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.


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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
Only patients able to give their informed consent can be included in this study. 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. 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 shall be verified that the subject has understood the 
information (e.g., by asking the subject to explain what is going to happen). This must be 
demonstrated by means of a personally signed and dated informed consent document 
indicating that the subject has been informed of and understood all pertinent aspects of the 
study.  
The ICF will be provided in the country local language(s).
Site personnel (according to local regulation) authorized to participate in the consent 
process and/or to obtain consent from the subject 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 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; 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 


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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.
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 Indemnification, compensation and refund of expenses 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 indemnification of the subject in the event of study-related injuries will comply with 
applicable regulations.
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 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.


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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: the 
Investigator Site File (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.
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 


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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 enrolling 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 
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.


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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.
12.10 Audit
Actelion’s Global Quality Management representatives may audit the investigator site 
(during the study or after its completion). The purpose of this visit will be to determine the 
investigator’s adherence to ICH-GCP, the protocol, and applicable regulations; adherence 
to Actelion’s requirements (e.g., standard operating procedures [SOPs]) will also be 
verified. Prior to initiating this audit, the investigator will be contacted by Actelion to 
arrange a time for the audit.
The investigator and 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.


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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.
Janssen Pharmaceutical Companies (Actelion) will post results from Phase 1–4 clinical 
studies on external registries, as required by law and from interventional studies in patients 
for marketed products. 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

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.


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13 REFERENCES
[ACC/AHA2015] ACC/AHA Key Data Elements and Definitions for Cardiovascular 
Endpoint Events in Clinical Trials. A Report of the American College of 
Cardiology/American Heart Association Task Force on Clinical Data Standards. J 
Am Coll Cardiol. 2015;66(4):403-469. 
[ATS Statement 2002] ATS Statement: Guidelines for the Six-Minute Walk Test. Am J 
Respir Crit Care Med 2002;166:111-7.
[Bishu 2013] Bishu K, Redfield MM. Acute Heart Failure with Preserved Ejection 
Fraction: Unique Patient Characteristics and Targets for Therapy. Curr Heart Fail 
Rep. 2013 September;10(3):190-7. 
[Borlaug 2014] Borlaug BA. The pathophysiology of heart failure with preserved ejection 
fraction. Nat Rev Cardiol. 2014 Sep;11(9):507-15. 
[Brouwers 2013] Brouwers FP, de Boer RA, van der Harst P, Voors AA, Gansevoort RT, 
Bakker SJ, et al. Incidence and epidemiology of new onset heart failure with 
preserved vs. reduced ejection fraction in a community-based cohort: 11-year 
follow-up of PREVEND. Eur Heart J. 2013 May;34(19):1424-31. 
[Bui 2011] Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile of heart 
failure. Nat Rev Cardiol. 2011 Jan;8(1):30-41.
[CTCAE 2010] Common Terminology Criteria for Adverse Events (CTCAE) Version 
4.0 Published: May 28, 2009 (v4.03: June 14, 2010) U.S. Department Of Health 
And Human Services. National Institutes of Health National Cancer Institute.
[ESC Guidelines 2013] 2013 ESH/ESC Guidelines for the management of arterial 
hypertension. European Heart Journal. 2013;34:2159-2219.
[FDA 2020] Food and Drug Administration. Drug Development and Drug Interactions: 
Table 
of 
Substrates, 
Inhibitors 
and 
Inducers 
(Table 
2-2). 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers. Accessed 09 July 2020.
[Gorter 2018] Gorter TM, Obokata M, Reddy YNV, et al. Exercise unmasks distinct 
pathophysiologic features in heart failure with preserved ejection fraction and 
pulmonary vascular disease. European Heart Journal, 2018; 39(30): 2825–2835.
[ICH M3] ICH M3 Guidelines: Guidance on Nonclinical Safety Studies for the Conduct of 
Human Clinical Trials and Marketing Authorization for Pharmaceuticals; 
June 2009.


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[James 2014] James PA, Oparil S, Carter BL, et al. Evidence-Based Guideline for the 
Management of High Blood Pressure in Adults. JAMA. 2014;311(5):507-520.
[Macitentan IB] Investigator’s Brochure. ACT-064992. Endothelin receptor antagonist. 
Version 15. Actelion Pharmaceuticals Ltd, October 2017.
[McMurray 1998] McMurray JJ, Petrie MC, Murdoch DR, Davie AP. Clinical 
epidemiology of heart failure: public and private health burden. Eur Heart J. 
1998;19(Suppl P):P9-P16.
[McMurray 2012] McMurray JJV, et al. ESC Guidelines for the diagnosis and treatment 
of acute and chronic heart failure 2012. The Task Force for the Diagnosis and 
Treatment of Acute and Chronic Heart Failure 2012 of the European Society of 
Cardiology. Developed in collaboration with the Heart Failure Association (HFA) 
of the ESC. European Heart Journal. 2012;33:1787-1847.
[Melenovsky 2014] Melenovsky V, Hwang SJ, Lin G, Redfield MM, Borlaug BA. Right 
heart dysfunction in heart failure with preserved ejection fraction. Eur Heart J. 
2014;35:3452-62. 
[Mosterd 2007] Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart. 2007 
Sep;93(9):1137-46. 
[Mozaffarian 2015] Mozaffarian D, Benjamin EJ, Go AS, Arnett D, et al. American Heart 
Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease 
and stroke statistics-2015 update: a report from the American Heart Association. 
Circulation. 2015 Jan 27;131(4):e29-322.
[Oktay 2013] Oktay AA, Rich JD, Shah SJ. The emerging epidemic of heart failure with 
preserved ejection fraction. Curr Heart Fail Rep. 2013 Dec;10(4):401-10.
[Reddy 2017] Yogesh N.V. Reddy, Mads J. Andersen, Masaru Obokata, Katlyn E. Koepp, 
et al. Arterial Stiffening with Exercise in Patients with Heart failure and Preserved
Ejection Fraction. JACC. 2017; 70 (2) 136-148.
[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.
[Tiller 2013] Tiller D, Russ M, Greiser KH, Nuding S, Ebelt H, et al. Prevalence of 
Symptomatic Heart Failure with Reduced and with Normal Ejection Fraction in an 
Elderly General Population–The CARLA Study. PLoS ONE. 2013;8(3):e59225. 
[Vachiéry 2018] Vachiéry J-L, Delcroix M, Al-Hiti H, et al. Macitentan in pulmonary 
hypertension due to left ventricular dysfunction. Eur Respir J 2018; 51: 1701886


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[Vasan 2000] Vasan RS, Levy D. Defining diastolic heart failure: a call for standardized 
diagnostic criteria. Circulation. 2000 May 2;101(17):2118-21.
[Zakeri 2015b] Zakeri R, Mohammed SF. Epidemiology of Right Ventricular Dysfunction 
in Heart Failure with Preserved Ejection Fraction. Curr Heart Fail Rep. 2015 
Oct;12(5):295-301.


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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
> 0.55 
For Females
> 0.60 
For males
> 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 ULN
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
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
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. 
Total bilirubin flag alert value - all visits: Please refer to the study protocol for action 
regarding study medication (i.e., interruption or permanent discontinuation) in case of:

Total bilirubin ≥ 2 ×ULN (In combination with ALT and/or AST ≥3 × ULN, study 
treatment must be stopped)
Interruption or permanent discontinuation of study medication - All visits except
EOT and EOS: Please refer to the study protocol for action regarding study medication 
(i.e., interruption or permanent discontinuation) [see Section 5.1.9] in case of the 
following laboratory abnormalities:

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 test alert value - all visits except EOS: Please refer to the study protocol for 
action regarding study medication (i.e., study treatment interruption or permanent 
discontinuation)

AST ≥ 3 × ULN

ALT ≥ 3 × ULN

Hemoglobin > 20 g/L decrease from baseline

Hemoglobin < 80 g/L

Hemoglobin > 50 g/L decrease from baseline


Macitentan / ACT-064992
HFpEF and pulmonary vascular disease 
Protocol AC-055G203 / SERENADE OL
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Appendix 3
Worsening Heart Failure Event definitions [ACC/AHA2015]
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” should 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; S3 = third 
heart sound; TVI = time velocity integral.


Macitentan / ACT-064992
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Appendix 4
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/AHA2015]
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 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 
implantable cardioverter-defibrillator [ICD] review)

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 


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a specific noncardiovascular 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 nonischemic 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., pulmonary embolism, PAD).
CABG = coronary artery bypass graft; CV = cardiovascular; d = days; HF = heart failure; ICD = implantable 
cardioverter-defibrillator; MI = myocardial infarction; PAD = peripheral artery disease; PCI = percutaneous 
coronary intervention.


Macitentan / ACT-064992
HFpEF and pulmonary vascular disease 
Protocol AC-055G203 / SERENADE OL
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EudraCT 2018-001603-37
Doc No EDMS-RIM-263261
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Appendix 5
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., pulmonary embolism, PAD).

Length of stay is at least 24 h (or extends over a calendar date).
Appendix 6
Protocol amendment history
The Protocol Amendment Summary of Changes Table for current amendment is located
just before the Table of Contents. Summary of previous amendments is provided below.
Amendment
Date
Main reason(s)
1
02 August 2018
To introduce the 6MWT sub-study to maximize knowledge gain and 
continue this efficacy assessment from the main study. Additionally, 
to include collection of MR proANP, research biomarker (optional), 
and NT-proBNP at prespecified visits and events.
2
16 May 2019
To correct the description of the Investigational Medicinal Product 
used in this study.
3
06 February 2020

To align the strategy for subject enrollment into this open-label 
(OL) extension study due to premature termination of 
recruitment into the AC-055G202 SERENADE main study:

Eligible subjects may enroll into this OL extension study after 
remaining in the main study (AC-055G202) for at least 24 weeks 

To remove evaluation of the efficacy assessments (i.e., Kansas 
City 
Cardiomyopathy 
Questionnaire, 
accelerometry, 
echocardiography, and blood sample collection for N terminal 
pro-brain natriuretic peptide [NT-proBNP], mid-regional pro-
atrial natriuretic peptide [MR-proANP], and biomarkers) in an 
effort to simplify the study and reduce assessment burden for 
subjects and study site personnel. 


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HFpEF and pulmonary vascular disease 
Protocol AC-055G203 / SERENADE OL
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Amendment
Date
Main reason(s)

To stop the 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.

To remove Clinical Event Committee (CEC) adjudication in line 
with AC-055G202 SERENADE main study global protocol 
Version 6. The CEC was appointed to review and adjudicate in 
a blinded fashion worsening heart failure (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 with the low occurrence of 
clinical events, which will not allow 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 create a single version of the SERENADE OL AC-055G203 
protocol by incorporating Voluntary Harmonisation Procedure 
(VHP)-mandated changes into the global protocol version. 
VHP-mandated additions will only affect VHP countries and 
include the following:

Study termination at 5 years as one option described in Section 
3.1.2; required monthly Liver Function Tests (LFTs) monitoring 
described in Section 7.2.4.1; and use of double-barrier 
contraception methods only when the use of highly effective 
measures, as described in Section 4.4.2, is medically 
contraindicated.
4
16 July 2020

To update the exclusion criteria and 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.


CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
1 
Status: Approved, Date: 2 July 2020 
Actelion Pharmaceuticals Ltd 
Janssen Research & Development * 
Clinical Protocol 
COVID-19 Appendix 
Protocol Title 
A long-term, multicenter, single-arm, open-label extension of the SERENADE study, to 
assess the safety and efficacy of macitentan in subjects with heart failure with preserved 
ejection fraction and pulmonary vascular disease 
 SERENADE OL 
Macitentan in heart failure with preserved ejection fraction and pulmonary vascular 
disease  
Protocol AC-055G203; 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: 20118-001603-37 
Status: 
Approved 
Date: 
2 July 2020 
Prepared by: Janssen Research & Development, LLC  
EDMS number: 
D-20.204  
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL 
[AC-055G203 
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. 
NCT03714815


COVID-19 Appendix  
JNJ-67896062/ACT-064992 Macitentan 
Clinical Protocol AC-055G203  
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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. Missed assessments/visits will be captured in the 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 case report form (CRF).   
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-055G203  
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3 
Status: Approved, Date: 2 July 2020 
ADDITIONAL ELEMENTS, WHERE APPLICABLE: 
•
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
o
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 to be applied under exceptional circumstances (section
5.1.5.3), direct-to-subject shipments are not considered to be a protocol deviation.
o
laboratory assessments using a suitably accredited local laboratory; for selected
measures (eg, urine pregnancy tests), home testing may be applied. Safety laboratory
testing should include AST/ALT and hemoglobin at minimum. 
o
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 perform 
all assessments that have been missed. 
•
Missed assessments/visits will be captured in the 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.
o
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.


COVID-19 Appendix  
JNJ-67896062/ACT-064992 Macitentan 
Clinical Protocol AC-055G203  
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Status: Approved, Date: 2 July 2020 
•
The sponsor will evaluate the totality of impact of COVID-19 on collection or absence 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.4 (core ICF v.3) 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.



SAP_001.pdf: 
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Status: Approved, Date: 2 November 2021
Janssen Research & Development
Statistical Analysis Plan
A long-term, multicenter, single-arm, open-label extension of the SERENADE study, to 
assess the safety and efficacy of macitentan in subjects with heart failure with preserved 
ejection fraction and pulmonary vascular disease
Protocol AC-055G203/ SERENADE-OL; Phase 2b
JNJ-67896062/ACT-064992 (macitentan)
Status:
Approved
Date:
2 November 2021
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS-RIM-574620, 1.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
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..
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Statistical Analysis Plan AC-055G203/ SERENADE-OL
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Status: Approved, Date: 2 November 2021
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
VERSION HISTORY..................................................................................................................................... 4
1.
INTRODUCTION.................................................................................................................................. 5
1.1.
Objectives ........................................................................................................................................ 5
1.2.
Study Design.................................................................................................................................... 5
2.
STATISTICAL HYPOTHESES............................................................................................................ 7
3.
SAMPLE SIZE DETERMINATION...................................................................................................... 8
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS....................................................................... 8
5.
STATISTICAL ANALYSES................................................................................................................. 9
5.1.
General Considerations ................................................................................................................... 9
5.1.1.
Visit Windows ............................................................................................................................... 9
5.1.2.
Relevant time points, baseline and analyses periods ................................................................ 10
5.1.2.1.
Signed informed consent......................................................................................................... 10
5.1.2.2.
Enrollment date ....................................................................................................................... 10
5.1.2.3.
OL Study treatment start date ................................................................................................. 10
5.1.2.4.
Study treatment end (EOT) date ............................................................................................. 11
5.1.2.5.
End of study (EOS) date.......................................................................................................... 11
5.1.2.6.
Baseline................................................................................................................................... 11
5.1.2.7.
Treatment Day, DB+OL Day and Macitentan Day .................................................................. 12
5.1.2.8.
Open-label treatment-emergent period (OL period)................................................................ 12
5.1.2.9.
Macitentan treatment-emergent period (MRI+DB+OL period) ................................................ 12
5.1.2.10.
Double-blind plus open-label treatment-emergent period (DB+OL period)............................. 12
5.1.3.
Conversion rules......................................................................................................................... 13
5.1.4.
Imputation Rules for missing/incomplete date and time fields ................................................... 13
5.1.5.
General rules for data presentations .......................................................................................... 14
5.2.
Participant Dispositions.................................................................................................................. 15
5.2.1.
Screened subjects and screening failures.................................................................................. 15
5.2.2.
Study and Study treatment disposition....................................................................................... 15
5.2.2.1.
Study treatment discontinuation .............................................................................................. 15
5.2.2.2.
Study discontinuation .............................................................................................................. 16
5.3.
Primary Endpoint Analysis ............................................................................................................. 16
5.3.1.
Definition of Endpoints................................................................................................................ 17
5.3.1.1.
All cause-deaths up to 30 days after study treatment discontinuation.................................... 17
5.3.1.2.
Number of all-cause hospital admissions up to 30 days after study treatment 
discontinuation......................................................................................................................... 17
5.3.1.3.
Adverse events........................................................................................................................ 17
5.3.1.3.1.
Treatment-emergent adverse events................................................................................... 18
5.3.1.3.2.
Serious adverse events........................................................................................................ 18
5.3.1.3.3.
Adverse events leading to discontinuation of study treatment............................................. 18
5.3.1.4.
Clinical Laboratory Tests......................................................................................................... 18
5.3.1.4.1.
Marked laboratory abnormalities (MLAs) ............................................................................. 19
5.3.1.5.
Change from baseline in Glomerular Filtration Rate (eGFR) up to 30 days after study 
treatment discontinuation ........................................................................................................ 21
5.3.1.6.
Vital signs ................................................................................................................................ 21
5.3.2.
Estimand..................................................................................................................................... 21
5.3.3.
Analysis Methods........................................................................................................................ 22
5.3.3.1.
All cause-deaths up to 30 days after study treatment discontinuation.................................... 22
5.3.3.2.
Number of all-cause hospital admissions up to 30 days after study treatment 
discontinuation......................................................................................................................... 22


JNJ-67896062/ACT-064992
Statistical Analysis Plan AC-055G203/ SERENADE-OL
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Status: Approved, Date: 2 November 2021
5.3.3.3.
Adverse events........................................................................................................................ 22
5.3.3.3.1.
Treatment-emergent adverse events................................................................................... 23
5.3.3.3.2.
Serious adverse events........................................................................................................ 23
5.3.3.3.3.
Adverse events leading to premature discontinuations of study treatment ......................... 23
5.3.3.4.
Clinical Laboratory Tests......................................................................................................... 24
5.3.3.4.1.
Marked Laboratory Abnormalities (MLAs) ........................................................................... 24
5.3.3.5.
Change from baseline in Glomerular Filtration Rate (eGFR) up to 30 days after study 
treatment discontinuation ........................................................................................................ 25
5.3.3.6.
Vital signs ................................................................................................................................ 25
5.4.
Exploratory Efficacy Endpoints Analysis........................................................................................ 26
5.4.1.
Definition of Endpoint(s) ............................................................................................................. 26
5.4.1.1.
Time to first occurrence of worsening of heart failure (WHF) event........................................ 26
5.4.1.2.
Time to first occurrence of heart failure (HF) death or HF hospitalization............................... 27
5.4.1.3.
Time to first occurrence of cardiovascular (CV) death or CV hospitalization.......................... 27
5.4.1.4.
NYHA FC (improved/worsened/stable) at each post baseline assessment............................ 28
5.4.2.
Estimand..................................................................................................................................... 29
5.4.3.
Analysis Methods........................................................................................................................ 29
5.4.3.1.1.
Time to first occurrence of worsening heart failure.............................................................. 29
5.4.3.1.2.
Time to first occurrence of HF death or HF hospitalization.................................................. 30
5.4.3.1.3.
Time to first occurrence of CV death or CV hospitalization ................................................. 30
5.4.3.1.4.
NYHA FC (improved/worsened/stable) at each post baseline assessment ........................ 30
5.5.
Other Safety Analyses ................................................................................................................... 31
5.5.1.
Other significant adverse events ................................................................................................ 31
5.5.1.1.
AEs with fatal outcome............................................................................................................ 31
5.5.1.2.
AEs of special interest (AESI) ................................................................................................. 31
5.5.1.3.
AEs continuing from AC-055G202 (SERENADE)................................................................... 31
5.5.1.4.
Other AEs of Interest ............................................................................................................... 31
5.5.2.
Additional Safety Assessments .................................................................................................. 32
5.5.2.1.1.
Additional liver test abnormalities......................................................................................... 32
5.5.2.1.2.
Physical Examination Findings ............................................................................................ 32
5.5.2.1.3.
Electrocardiogram ................................................................................................................ 32
5.6.
Other Analyses............................................................................................................................... 33
5.6.1.
Extent of Exposure ..................................................................................................................... 33
5.7.
Interim Analyses............................................................................................................................. 35
5.7.1.
Data Monitoring Committee (DMC) or Other Review Board ...................................................... 35
6.
SUPPORTING DOCUMENTATION .................................................................................................. 36
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 36
6.2.
Appendix 2 Changes to Protocol-Planned Analyses ..................................................................... 37
6.2.1.
Changes to the analyses planned in the study protocol............................................................. 37
6.2.1.1.
Baseline................................................................................................................................... 37
6.2.1.2.
Usage of the analysis sets....................................................................................................... 37
6.2.2.
Changes in the conduct of the study / data collection................................................................ 38
6.2.3.
Clarifications concerning endpoint definitions and related variables or statistical 
methods ...................................................................................................................................... 39
6.2.3.1.
Previous and concomitant medications................................................................................... 39
6.2.3.2.
Exploratory efficacy variables, time to event analysis............................................................. 40
6.2.3.3.
Sub-study assessments (6MWD and Borg Dyspnea Index)................................................... 40
6.3.
Appendix 3 Demographics and Baseline Characteristics.............................................................. 40
6.4.
Appendix 4 Protocol Deviations ..................................................................................................... 42
6.5.
Appendix 5 Prior and Concomitant Medications............................................................................ 43
6.6.
Appendix 6 Medical History ........................................................................................................... 44
6.7.
Appendix 7 Intervention Compliance ............................................................................................. 44
6.8.
Appendix 8 Adverse Events of Special Interest............................................................................. 44
7.
REFERENCES................................................................................................................................... 47


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VERSION HISTORY
Table 1:
SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1
2 November 2021
Not Applicable
Initial release




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Approximately 112 subjects were expected to enter the OL study, which was conducted at the sites 
participating in the main study (ie, 77 sites in 17 countries).
See the protocol for further details on study design, visits and assessment schedule. 
The SERENADE OL study comprises the following consecutive periods: 
Pre-OL treatment period: Starts with the signature of the informed consent and ends with the 
administration of the first dose of OL study treatment (excluded). 
Treatment period: Starts with the administration of the first dose of OL study treatment and ends 
on the day of the last dose of OL study treatment. 
Follow-up period: Starts on the day after the last dose of OL study treatment and ends 30 days 
thereafter with the End-of-Study (EOS) Visit. 
The transition from the main study to SERENADE OL is described in section 7.1.1. of the protocol. 
The overall study design is depicted in Figure 1.
Figure 1:
Study design
EOS = End-of-Study; EOT = End-of-Treatment
The schedule of visits and assessments can be found in the Table 3 below.


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Table 3:
Visit and assessment schedule
*Transferred electronically by an external service provider
# If the EOT (or corresponding PTOP/EOS) Visit of the main study and the enrollment visit of the OL extension are 
combined, the results of these assessments and corresponding actions, as applicable, need to be reported in the CRFs 
of the main study only.
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 Informed consent may be signed prior to Visit 1 or at Visit 1.
3 During enrollment, if it is not possible to perform all assessments in one day, the procedures can be done any time 
prior to Visit 2.
4 For subjects who had their EOS Visit more than 8 weeks prior to study closure (SCL) announcement, a vital status 
follow-up visit (VSFU) will be performed by the site within 4 weeks after the SCL announcement. VSFU does NOT 
need to be performed if the subject’s vital status is known (ie, loss to follow-up, death, withdrawal of consent) In 
addition to the VSFU at the time of SCL, the sponsor may request this information be obtained at any time during the 
study. 
5 Per request from VHP, the following applies for VHP countries: Visits 9 through 15 only, occurring at weeks 
78, 104, 130, 156, 182, 208, 234 respectively. EOT Visit will be at Week 260 (±14 days). In case of premature 
discontinuation, the EOT Visit must be within 7 days after the last dose. 
6 Sent to the central laboratory. 
7 For women of childbearing potential only. 
8 Monthly AST/ALT monitoring is recommended. It is at the investigator’s discretion to decide (taking into account 
the subject’s medical history and AEs) if those monthly tests are required/justified. Local laboratory may be used. Per 
request from VHP, the following applies for VHP countries: monthly AST/ALT monitoring is required. Local 
laboratory may be used for monthly AST/ALT monitoring in between visits. 
9 For women of childbearing potential only: Urine pregnancy test will be performed by the subject on a monthly basis, 
in-between visits. The site will follow-up on the results with a telephone call. 
10 All AEs and SAEs that occur after intake of the first dose of OL study treatment and up to 30 days after study 
treatment discontinuation must be reported [see also protocol section 9]. 
AE = adverse event; BP = blood pressure; SD = Study Day; d = days; EOS = End-of-Study; EOT = End-of-Treatment; 
FC = functional class; HR = heart rate; NYHA = New York Heart Association; SAE = serious adverse event; SCL= 
study closure; VHP = voluntary harmonization procedure; VSFU = vital status follow-up visit; W = Week; w = weeks; 
WHF = worsening heart failure; PTOP = post-treatment observation period. 
2.
STATISTICAL HYPOTHESES
This SERENADE OL study will contain analyses related to exploratory efficacy and safety 
endpoints. No formal hypothesis testing will be performed as all efficacy analyses are considered 
exploratory. As such, all confidence intervals (CIs) will be presented as 2-sided 90% which is 
consistent with the main study where the sample size was based on alpha = 0.1. Data will be 
summarized using descriptive statistics. In addition, plots of profiles over time will be displayed 


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for continuous outcomes. Any p-values are presented for information only. No multiplicity 
adjustment will be made.
The long-term efficacy will be explored based on select cohorts within FAS by randomized 
treatment group in main study. It is planned that the baseline for efficacy analysis will be the same 
as described for the main SERENADE study Clinical Study Report (CSR).
Safety variables will be analyzed using the Safety Set for the OL study. Adverse events and other 
selected safety variables during treatment with macitentan (eg, exposure and the following 
laboratory parameters: erythrocytes, hemoglobin, hematocrit, leukocytes, lymphocytes, 
neutrophils, platelets, AST, ALT, total bilirubin, alkaline phosphatase, MLAs and eGFR) will be 
analyzed on the Safety Initiated Set (all subjects who received double-blind macitentan treatment 
in the main study and/or in SERENADE OL).
3.
SAMPLE SIZE DETERMINATION
The sample size for the SERENADE OL is 91 subjects.
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
All the analysis sets are described in the protocol section 10.1.
Analysis Sets
Description
Open-Label Extension Enrolled Set (OLE)
The Open Label Extension enrolled (OLE) Set includes 
all subjects who were enrolled into the SERENADE OL
(with answer ‘YES’ to the question ‘Was the subject 
enrolled?’ in the “Enrollment” form of the eCRF).
Full Analysis Set (FAS)
The Full Analysis Set includes all subjects randomized in 
the main double-blind study regardless of enrollment to 
SERENADE OL. 
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 at 
randomization (which may be different from the study 
treatment they have received). 
SERENADE OL Safety Analysis Set (Safety Set)
All subjects who received at least one dose of OL 
treatment. 
Safety Initiated Set 
The Safety Initiated Set includes all subjects who 
received macitentan treatment in the DB period of the 
main study and/or macitentan treatment in SERENADE 
OL. 
The main purpose of this cohort is to assess adverse 
events during treatment with macitentan.


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5.
STATISTICAL ANALYSES
5.1.
General Considerations
5.1.1.
Visit Windows
To allow analysis of data at the relevant planned (scheduled) visits during the treatment period,
recorded assessments, including unscheduled ones, are re-assigned to the most appropriate visit 
according to the best fitting time window for that visit (see Table 4 and Table 5 below). Note that 
the visit windows are contiguous in order to retain all values in the analysis by time point.
Assessments for the analysis of the combined period MRI+DB+OL or DB+OL are reassigned 
according to the Table 5 time windows (based on MT Day and DB+OL Day respectively, see 
Section 5.1.2.7) while assessments performed during SERENADE OL study are reassigned, for 
the analysis of the OL period only, according to Table 4 (based on Treatment Day, see 
Section 5.1.2.7). 
Table 4:
Visit Windows for the OL period
Parameter
Scheduled 
Visit Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time Point 
(Day)
Safety and efficacy 
parameters
-
Baseline
<=1
1
30
Week 4
2 to 42
28
40
Week 8
43 to 84
56
50
Week 16
85 to 140
112
60
Week 24
141 to 210
168
70
Week 36
211 to 308
252
80
Week 52 - EOT
309 to 395
365
Safety and efficacy 
parameters (applicable 
only to VHP 
countries)
80
Week 52
309 to 454
365
90
Week 78
455 to 636
546
100
Week 104
637 to 818
728
110
Week 130
819 to 1000
910
120
Week 156
1001 to 1182
1092
130
Week 182
1183 to 1364
1274
140
Week 208
1365 to 1546
1456
150
Week 234
1547 to 1728
1638
160
Week 260 - EOT
>=1729
1820
*Number of days from the study treatment start date in OL.


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Table 5:
Visit Windows for the MRI+DB+OL/DB+OL period
Parameter
Scheduled 
Visit Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time Point 
(MT/DB+OL Day)
Safety and efficacy 
parameters
-
Baseline
<=1
1
-
Week 4
2 to 70
28
-
Week 16
71 to 140
112
-
Week 24
141 to 267
168
-
Week 52 
268 to 454
365
-
Week 78
455 to 636
546
-
Week 104
637 to 818
728
-
Week 130
819 to 1000
910
-
Week 156
1001 to 1182
1092
-
Week 182
1183 to 1364
1274
-
Week 208
1365 to 1546
1456
-
Week 234
1547 to 1728
1638
-
Week 260 - EOT
>=1729
1820
*Number of days from the MRI/DB treatment start date in the main study.
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.
Based on the SERENADE DB study results indicating no evidence of benefit of macitentan 10 mg 
treatment in patients with HFpEF and pulmonary vascular disease the Sponsor decided to stop the 
SERENADE OL study without option for continued access. For this reason, it is expected that 
follow-up will be varied across subjects with a few participants in the VHP countries (see 
Section 6.3, Appendix 3 for details) with data beyond Week 52. All subjects visit assessment 
information available will be considered up to their last follow-up visit. 
5.1.2.
Relevant time points, baseline and analyses periods
5.1.2.1.
Signed informed consent
It is the date of signed informed consent collected in the “Informed Consent” CRF.
5.1.2.2.
Enrollment date
For all the enrolled subjects (all subjects with answer ‘YES’ to the question ‘Was the subject 
enrolled?’ in the “Enrollment” CRF), it is the date of the Visit 1 / Enrollment.
5.1.2.3.
OL Study treatment start date
It is the study treatment start date in OL, ie, the first day of intake of study treatment during the 
SERENADE OL. It is derived from the first treatment start date (in chronological order) in the 
‘Study Treatment Log’.


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5.1.2.4.
Study treatment end (EOT) date 
For participants in the SERENADE main study not enrolled in the SERENADE OL, it is the EOT 
date in the SERENADE main study.
For subjects enrolled in the SERENADE OL, this is the “Treatment end date” from the last interval, 
in chronological order, recorded in the ‘Study Treatment Log’ where the reason for treatment end 
is not temporary interrupted due/not due to an AE.
If missing or incomplete, rules in Section 5.1.4 are followed.
5.1.2.5.
End of study (EOS) date
Subjects completing the EOS visit, the date of the visit is the EOS date.
For subjects who died during the study, the EOS date is “Date of death” collected in “Death” form.
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.
5.1.2.6.
Baseline
Baseline for the SERENADE OL
The baseline for a given measurement in the SERENADE OL is the last value assessed ≤to the 
start date of treatment in the SERENADE OL. If unscheduled/re-test visits are performed on the 
day of treatment start, the available value of the last unscheduled/re-test visit on treatment start 
date is considered as baseline.
Baseline of the SERENADE main study (for the analysis in the DB+OL period)
The baseline for a given measurement in the SERENADE main study was the last value assessed 
≤to the start date of double-blind treatment in the SERENADE main study. If unscheduled/re-test 
visits were performed on the day of treatment start, the available value of the last unscheduled/re-
test visit on treatment start date were considered as baseline.
Macitentan baseline (for the analysis in the MRI+DB+OL period)
The macitentan baseline is defined as the last assessment prior to macitentan initiation, ie:
- for patients who received macitentan already in the double-blind period of the 
SERENADE main study, baseline is the last available assessment performed on or prior to 
the macitentan run-in period start date.


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- for patients who received placebo in the double-blind period of the SERENADE main 
study and received macitentan in the SERENADE OL, baseline is the last available 
assessment performed on or prior to SERENADE OL treatment start date.
Macitentan baseline is the last non-missing value obtained ≤ to the start of macitentan intake in the 
main study or SERENADE OL, ie, ≤ MT Day 1.
5.1.2.7.
Treatment Day, DB+OL Day and Macitentan Day
The Treatment Day (Day) is the number of days elapsed since the treatment start date in the 
SERENADE OL plus 1 (as treatment start date in OL is considered Day 1). 
The Double-blind plus open-label treatment Day (DB+OL Day) is the number of days elapsed 
since the double-blind treatment start date in the SERENADE main study plus 1 (double-blind 
treatment start date is considered Day 1). 
The Macitentan Day (MT Day) is the number of days elapsed since the day of first dose of 
macitentan, ie:
- for patients who received macitentan already in the double-blind period of the SERENADE main 
study is the number of days elapsed since the macitentan run-in treatment start date plus 1 (as 
macitentan run-in treatment start date is considered MT Day 1).
- for patients who who received placebo in the double-blind period of the main study and entered 
SERENADE OL, it is the number of days elapsed since the OL treatment start date plus 1 (as OL 
treatment start date is considered MT Day 1). For these patients, MT Day = Treatment Day. 
Therefore, the treatment day, the double-blind plus open-label treatment day and the macitentan 
day are always different from 0.
5.1.2.8.
Open-label treatment-emergent period (OL period)
Is the period between the study treatment start date in OL (see definition in Section 5.1.2.3) 
excluded up to the EOT date (see definition in Section 5.1.2.4) + 30 days.
5.1.2.9.
Macitentan treatment-emergent period (MRI+DB+OL period)
The macitentan treatment-emergent period is defined as the period from the first intake of 
macitentan (for subjects who received macitentan already in the double-blind period of the 
SERENADE main study this is the date of their first dose of macitentan run-in treatment whereas, 
in all the other cases, this is the study treatment start date in the SERENADE OL, Section 5.1.2.3) 
excluded up to EOT + 30 days. 
5.1.2.10.
Double-blind plus open-label treatment-emergent period (DB+OL 
period)
The double-blind plus open-label treatment-emergent period is defined as the period between the 
double-blind treatment start date in the SERENADE main study (excluded) up to the EOS 
(Section 5.1.2.5) date in the SERENADE OL study.






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
Number of non-missing observations, mean, standard deviation (SD), minimum, Q1, median, 
Q3 and maximum for continuous variables.

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 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% confidence intervals
will be displayed for time-to-event variables.

Where appropriate the efficacy and safety analyses will be performed presenting summaries 
overall and by DB study treatment received (DB-macitentan or DB-placebo. 

When applicable, in summary tables, columns will be presented in the following order from 
left to right: “DB-Placebo”, “DB-Macitentan” and “Total”.
5.2.
Participant Dispositions
The following definitions are relevant to the disposition information:
5.2.1.
Screened subjects and screening failures
No screening will be performed in the SERENADE OL study.
5.2.2.
Study and Study treatment disposition
5.2.2.1.
Study treatment discontinuation
Premature discontinuation will be collected in the “Study Treatment Log” CRF and identified as 
those with a treatment end date and associated reason ‘What was the reason for treatment end?’
answered ‘Premature Discontinuation’. 
The reason for study treatment discontinuation will be taken from 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

Subject decision (AE, Lack of efficacy, No reason provided, Other)

Physician decision (AE, Lack of efficacy, Other)

Sponsor decision (Study termination, Other).
Subjects are evaluated by the investigator for completion of treatment via the CRF (“Study 
Treatment Log”) where the question ‘What was the reason for treatment end?’ is answered 
‘Completed as per protocol’.


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5.2.2.2.
Study discontinuation
Subjects who prematurely discontinued the study are those with some entry in the “Study 
Discontinuation” eCRF form.
For subjects who prematurely discontinued the study, the reasons for study discontinuation are 
reported on the same “Study Discontinuation” CRF form and are as follows:

Death

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.   
Disposition information analysis
The following disposition information will be summarized, presenting the number and percent of 
subjects:

Enrolled

Enrolled in VHP countries (see Appendix 3)

Received OL treatment

Completed treatment

Completed Study.
Listings of subjects will be provided for the following categories:

unmet eligibility criteria

prematurely withdrawn from the treatment (with reasons for premature treatment 
withdrawal)

prematurely withdrawn from the study (with reasons for premature study withdrawal).
The number of subjects in each analysis set will be summarized by “DB-Placebo”, “DB-
Macitentan” treatment groups and overall. Subject membership in the different analysis sets will 
be provided in a listing. 
5.3.
Primary Endpoint Analysis
To describe the long-term safety of macitentan 10 mg in subjects with HFpEF and pulmonary 
vascular disease.


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5.3.1.
Definition of Endpoints
Safety endpoints are defined in section 6.2 of the protocol as:

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 AEs (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 
all assessed time-points during the study

Treatment-emergent marked laboratory abnormalities (MLAs) up to 30 days after study 
treatment discontinuation

Change in laboratory parameters from baseline to all assessed time-points during the study 

Change from baseline in estimated glomerular filtration rate (eGFR) to all assessed time-points 
during the study.
All safety endpoints will be analyzed on the Safety Set during the open-label treatment-emergent
period (OL period, see definition in Section 5.1.2.8) and when specified on the Safety Initiated Set 
during the macitentan treatment-emergent period (MRI+DB+OL period, see definition in 
Section 5.1.2.9). 
5.3.1.1.
All cause-deaths up to 30 days after study treatment discontinuation
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 (ie, primary cause of death) are 
assigned PTs for classification and tabulation using latest implemented version of MedDRA. 
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 any death occurred during the open-label/macitentan treatment-
emergent period.
5.3.1.2.
Number of all-cause hospital admissions up to 30 days after study 
treatment discontinuation
All-cause hospitalizations as reported in the dedicated eCRF form “Hospitalization”.
Treatment-emergent hospitalizations are those occurred during the open-label/macitentan
treatment-emergent period.
5.3.1.3.
Adverse events
An adverse event (AE) is defined as any event reported by the investigator in the “Adverse Event”
CRF form. All AEs that occur after signing of the ICF and up to 30 days after study treatment 


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discontinuation or worsening in intensity of AEs started in the SERENADE main study are 
reported in the CRF “Adverse Event”. 
Note: events reported in the “Ongoing Adverse Event from AC-055G202” CRF form will be 
analyzed separately (Section 5.5.1.3).
The original terms used by the investigators to describe AEs are assigned preferred terms (PT) for 
classification and tabulation using the latest implemented version of MedDRA.
5.3.1.3.1.
Treatment-emergent adverse events
Treatment-emergent AEs are defined as any AE that started during the open-label/macitentan
treatment-emergent period, including the treatment start date.
5.3.1.3.2.
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 (TESAE) are determined as TEAEs (Section 5.3.1.3.1).
5.3.1.3.3.
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.
5.3.1.4.
Clinical Laboratory Tests
Hematology and chemistry tests are performed at Visit 1/Enrollment, Visit 3/W4, EOT and EOS. 
In between Visit 4/W8 and EOT, monthly 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 International system of units (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 (Section 5.3.1.4.1). All assessments recorded after study treatment start date in 
SERENADE OL (Section 5.1.2.3) up to EOT (Section 5.1.2.4) + 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 5.1.1. 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 


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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)
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)

Sodium, potassium, chloride, calcium, magnesium (mmol/L)

Total protein, albumin (SI unit: g/L; conventional unit: g/L)

Albumin / Globulins ratio

estimated Glomerular Filtration Rate (mL/min/1.73m2) using the Modification of Diet in Renal 
Disease formula.
The absolute observed value (during the OL period, during the MRI+DB+OL period and during 
the DB+OL period separately) and the change from baseline (see Section 5.1.2.6) to each 
post-baseline visit for some selected laboratory parameters (ie, erythrocytes, hemoglobin, 
hematocrit, leukocytes, lymphocytes, neutrophils, platelets, AST, ALT, total bilirubin and alkaline 
phosphatase) are defined as:
Change from baseline = value at Visit X - (value at baseline).
5.3.1.4.1.
Marked laboratory abnormalities (MLAs)
MLAs are all marked laboratory abnormalities which occur during the open-label treatment-
emergent period (on Safety Set) and during the macitentan treatment-emergent period (on Safety 
Initiated Set), that were not present at baseline (see Section 5.1.2.6).
The following marked laboratory abnormalities (MLA) are derived according to the protocol.


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Table 6:
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 
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


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Parameter 
LL marked
LLL 
marked
HH marked
HHH marked
Potassium
< 3.2 mmol/L
< 3.0 mmol/L
> 5.5 mmol/L
> 6.0 mmol/L
Magnesium
< 0.5 mmol/L
< 0.4 mmol/L
NA
> 1.23 mmol/L
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.
5.3.1.5.
Change from baseline in Glomerular Filtration Rate (eGFR) up to 30 
days after study treatment discontinuation
The estimated Glomerular Filtration Rate (mL/min/1.73m2) using the Modification of Diet in 
Renal Disease formula is assessed at all visits with laboratory test (see Section 5.3.1.4). 
Unscheduled visits may be performed at any time during the study if appropriate based on the 
investigator judgment.
As described in laboratory Section 5.3.1.4, 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 baseline to each visit is defined as: value at Visit X - (value at baseline).
5.3.1.6.
Vital signs
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] will be used for the analysis.
5.3.2.
Estimand

Primary Trial Objective: To describe the long-term safety of macitentan 10 mg in subjects 
with HFpEF and pulmonary vascular disease.

Population: Safety Set (for the analysis of the OL treatment-emergent period) and Safety 
Initiated Set (for the analysis of the macitentan treatment-emergent period).

Study Intervention: macitentan oral tablet, 10 mg once daily.

Variables: safety endpoints defined in Section 5.3.1 up to 30 days after study treatment 
discontinuation.


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
Population-level Summary Measure: 
o
total number and frequency for count variables; absolute changes from baseline for
continuous variables.
o
Absolute change from baseline for continuous variables.

Intercurrent Events: study treatment and study discontinuation (for any reason). Treatment 
policy strategy (the occurrence of the intercurrent event is irrelevant in defining the treatment 
event of interest). 
5.3.3.
Analysis Methods
The analysis of the primary endpoints will be performed on the Safety Initiated Set for the MRI + 
DB + OL period and on the Safety Set for the OL period only.
5.3.3.1.
All cause-deaths up to 30 days after study treatment discontinuation
All-cause death cases will be reported in a subject listing. Treatment-emergent deaths will be 
flagged accordingly.
A summary table reporting the incidence of treatment-emergent deaths will be provided. Number
and percentages of deaths will be summarized together with the primary reason for death in 
descending order of incidence.
5.3.3.2.
Number of all-cause hospital admissions up to 30 days after study 
treatment discontinuation
The number and frequency of all-cause hospital admissions will be summarized.
Individual listings will also be provided.
5.3.3.3.
Adverse events
The following definitions are relevant for analyzing the adverse events occurred during the study:

Frequency of adverse events. AEs reported more than once (as qualified by the same PT) for a 
participant are counted only once in the frequency table. 

Intensity of adverse events. For AEs reported more than once (as qualified by the same PT) for 
a participant with different intensities, the worst intensity is considered. In case of missing 
intensity, “severe” is imputed.

Relationship of 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 
participant, the worst relationship (ie, ‘related’) is considered. Adverse events with missing 
relationship are considered in any analysis as ‘related’.
An overall summary table of AEs will be provided, containing number and percentages of 
participants having experienced at least 1 occurrence of the following categories of AEs:

Treatment-emergent AEs


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
Severe treatment-emergent AEs 

Treatment-emergent AEs related to study treatment

AEs with fatal outcome 

Treatment-emergent serious AEs (SAEs)

Treatment-emergent SAEs (TESAEs) related to study treatment

AEs leading to premature discontinuation of study treatment.
5.3.3.3.1.
Treatment-emergent adverse events
The number and percentage of subjects with at least one treatment-emergent AE will be tabulated 
separately on the Safety Set (for the OL period) and the Safety Initiated Set (for the combined MRI 
+ DB + OL period) by: 
• System Organ Class and Preferred Term within System Organ Class; 
• Preferred Term. 
The summary tables will be presented by DB study treatment received (“DB-macitentan” or “DB-
placebo” and “Total”) in descending order (eg, SOC and PT within each SOC with the highest 
number of occurrences appears first) in the “DB-macitentan” treatment group. Equal frequency of 
different SOC/PTs will be sorted in alphabetical order of the SOC/PT. NOT Classified terms will 
be ordered last, verbatim terms will be included in the listing only
Similarly, tables by PT will be provided by DB study treatment received in descending order of 
incidence in the “DB-macitentan” treatment group. Equal frequency of different SOC/PTs will be
sorted in alphabetical order of PT.
Listings will be provided for all reported AEs including a flag for the treatment-emergent ones.
5.3.3.3.2.
Serious adverse events
SAEs will be listed in the general AE listing and in a separate listing. Treatment-emergent SAEs 
will be flagged accordingly.
Treatment-emergent SAEs will be summarized by SOC and PT within each SOC and by PT.
5.3.3.3.3.
Adverse events leading to premature discontinuations of study 
treatment
All AEs leading to premature discontinuation of study treatment will be included in the general 
AE listing and in a separate listing on the Safety Initiated Set. 
All AEs leading to premature discontinuation of study treatment will be summarized similarly to 
treatment-emergent AEs by SOC and PT within each SOC and by PT. 


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5.3.3.4.
Clinical Laboratory Tests
All hematology and chemistry parameters provided by the central and local laboratory will be 
displayed in listings, including those from unscheduled visits. Marked laboratory abnormalities 
will be flagged accordingly.
For Week 4, Week 8, Week 16, Week 24, Week 36, Week 52 in the OL period (Table 4 of 
Section 5.1.1), the selected laboratory test parameters defined in Section 5.3.1.4 will be
summarized displaying descriptive statistics (if at least 10 participants are available) for:

observed value at each visit specified 

absolute change from baseline to each visit. 
In each evaluation, will be included only participants who had both the assessments at baseline 
and post baseline visit, on the Safety Set. 
Similarly, the selected laboratory tests defined in Section 5.3.1.4 will be summarized by treatment 
group (and total) in the MRI+DB+OL period (Table 5 of Section 5.1.1) on the Safety Initiated Set
and in the DB+OL period (Table 5 of Section 5.1.1) on the FAS.
5.3.3.4.1.
Marked Laboratory Abnormalities (MLAs)
Marked laboratory abnormalities will be summarized for the OL period (on the Safety Set) and for 
the MRI+DB+OL period (on the Safety Initiated Set) providing their counts and percentages and 
number of participants with at least one treatment-emergent marked laboratory abnormality, for 
each parameter for which the marked laboratory abnormality is defined.
Percentages will be calculated as number of participants with at least one treatment-emergent MLA 
for the parameter under consideration divided by the number of participants with any post-baseline 
laboratory measurement.  
Shifts from baseline to worst post-baseline abnormality category (during the OL period and the 
MRI+DB+OL period separately) up to EOT + 30 days will be summarized with frequencies of 
participants 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. Participants experiencing a worsening from baseline in two 
different directions (eg, 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 participants with at least one post-baseline 
assessment in the considered period.
For the below selected parameters, values over time in the OL period, in the MRI+DB+OL period 
and in the DB+OL period will be summarized and plot on the Safety Set, on the Safety Initiated 
Set and on the FAS, respectively:


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
Hematology:

Hemoglobin

Hematocrit

Erythrocytes 

Leukocytes

Lymphocytes

Neutrophils

Platelets.

Chemistry:

Alanine aminotransferase (ALT)

Aspartate aminotransferase (AST)

Alkaline phosphatase

Total bilirubin.
Summaries and plots will be provided by “DB-Placebo” and “DB-Macitentan” treatment groups.
5.3.3.5.
Change from baseline in Glomerular Filtration Rate (eGFR) up to 30 
days after study treatment discontinuation
Descriptive summary statistics by visit will be provided for observed values and absolute changes 
in eGFR from baseline to each post-baseline visit in the OL period and the MRI+DB+OL period 
separately (on the Safety Initiated Set).
Individual subject’s listing will be provided on the Safety Initiated Set by “DB-Placebo”, 
“DB-Macitentan” treatment groups.
5.3.3.6.
Vital signs
Vital signs (blood pressure measurements, pulse rate) and body weight will be reported in a listing.
Position (supine or sitting) and location (left or right arm) will be included in the listing.
SBP, DBP, pulse rate, and body weight will be summarized displaying descriptive statistics in the 
SERENADE OL on the Safety Set and the MRI+DB+OL period on the Safety Initiated Set for:

observed value at each visit up to EOT + 30 days

absolute change from baseline to each visit up to EOT + 30 days.
In each evaluation, only participants who had both the assessments at baseline and the considered 
post-baseline assessment will be included.
Vitals signs parameters will be analyzed regardless of the measurement position.


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5.4.
Exploratory Efficacy Endpoints Analysis
5.4.1.
Definition of Endpoint(s)
There are no primary or secondary efficacy variables defined for SERENADE OL; exploratory 
efficacy variables as described in protocol section 10.2.2 are:

Time to first occurrence of worsening of heart failure (WHF) event

Time to first occurrence of a composite of heart failure (HF) death or HF hospitalization

Time to first occurrence of a composite of cardiovascular (CV) death or CV hospitalization

NYHA FC (improved/worsened/stable) at each post-baseline assessment
The exploratory efficacy variables will be analyzed in the DB+OL period on the FAS.
Baseline (Section 5.1.2.6) for efficacy variables is defined as the last non-missing value observed 
among all measures, including the unscheduled ones, collected up to and including the 
double-blind treatment in the SERENADE main study. 
All assessments recorded after the start of study treatment, including the unscheduled ones, will 
be assigned to the most appropriate study visit according to the best fitting time-window for that 
assessment as detailed in Section 5.1.1. 
5.4.1.1.
Time to first occurrence of worsening of heart failure (WHF) event
Occurrence of a WHF event is assessed by the investigator using the 2015 ACC/AHA definition
[see protocol section 7.2.2.1 and protocol appendix 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 weeks and calculated as the onset date of 
the first WHF event minus the double-blind treatment start date plus 1 or, for censored participants, 
as the censoring date (see below) minus the study treatment start date 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 are considered, irrespective of participants’
compliance to assigned therapies.


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Participants without any worsening of heart failure event up to EOS are right-censored at EOS or 
if they are enrolled in the VHP countries at the earliest between the EOS date (see Section 5.1.2.5) 
and the upper limit of the Week 52 time window (see Section 5.1.1).
5.4.1.2.
Time to first occurrence of heart failure (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).
HF deaths are all deaths with a primary reason of ‘HF’ entered into the ‘Death’ CRF. 
HF hospitalization is defined per appendix 5 of the protocol as: 

Participant 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 study treatment 
start date are considered, irrespective of participants’ compliance to assigned therapies.
Participants without any HF hospitalization or HF death up to EOS are right-censored at EOS or 
if they are enrolled in the VHP countries at the earliest between the EOS date (see Section 5.1.2.5) 
and the upper limit of the Week 52 time window (see Section 5.1.1).  
Time to first occurrence of HF death or HF hospitalization is expressed in weeks and calculated as 
the onset date of the first HF death or HF hospitalization minus the double-blind treatment start 
date plus 1 or, for censored participants, as the censoring date (defined above) minus the 
double-blind treatment start date plus 1.
5.4.1.3.
Time to first occurrence of cardiovascular (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).


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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. 
CV hospitalization is defined per appendix 5 of the protocol as: 

Participant 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 (eg, PE, PAD).

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 the study 
treatment start date are considered, irrespective of participants’ compliance to assigned therapies.
Participants without any CV hospitalization or CV death up to EOS are right-censored at EOS or 
if they are enrolled in the VHP countries at the earliest between the EOS date (see Section 5.1.2.5) 
and the upper limit of the Week 52 time window (see Section 5.1.1).
Time to first occurrence of CV death or CV hospitalization is expressed in weeks and calculated 
as the onset date of the first CV death or CV hospitalization minus the double-blind treatment start 
date plus 1 or, for censored participants, as the censoring date (defined above) minus the double-
blind treatment start date plus 1.
5.4.1.4.
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 (see Section 5.1.2.6 for definition) 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. Participants remaining 
in the same NYHA class as the one reported at baseline are categorized as stable.
The proportion of participants in each category is calculated at each post-baseline assessment 
based on the number of participants with non-missing data (ie, those having a reported value of I 
through IV).
Participants who died (any cause) are classified as worsened (NYHA FC = V).


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5.4.2.
Estimand

Exploratory Trial Objective: To explore the long-term efficacy of macitentan 10 mg. 

Population: Full Analysis Set.

Intervention: Macitentan oral tablet, 10 mg once daily.

Variables: 
o
Time to first occurrence of worsening of heart failure event
o
The time to first occurrence of HF death or HF hospitalization.
o
The time to first occurrence of cardiovascular (CV) death or CV hospitalization.
o
NYHA FC (improved/worsened/stable) at each post baseline assessment.

Population-level Summary Measure:
o
Kaplan-Meier estimates of events over time with 2-sided 90% CIs at relevant time-
points for time-to-event variables. 
o
NYHA FC: proportion (with 90% confidence limits [CLs]) of participants having 
improved, having worsened or being stable at each post-baseline visit.

Intercurrent Events: study treatment and study discontinuation (for any reason). Treatment
policy strategy (the occurrence of the inter-current event is irrelevant in defining the treatment 
event of interest). 
5.4.3.
Analysis Methods
The analysis of the exploratory efficacy variables will be performed on the FAS for the DB+OL 
period.
5.4.3.1.1.
Time to first occurrence of worsening heart failure
All WHF events (see Section 5.4.1.1) and the time to first occurrence of WHF will be listed, 
irrespective of participants’ compliance to assigned therapies on the FAS by “DB-Placebo”, “DB-
Macitentan” treatment groups. 
If at least 10 participants will experience a WHF event, a summary table will be provided 
displaying the number of participants with WHF overall and by type of WHF. Results will be
displayed overall and by randomized treatment group in the main SERENADE study.
The analyses will be conducted using Kaplan-Meier estimates of events over time including 
graphical representation. 
The graphical representation follows the recommendations from Pocock (Pocock 2002). Two-
sided 90% CIs at specific time points will be constructed, with confidence limits 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 two-sided CIs 
calculated using the method of Brookmeyer (Brookmeyer 1982).


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Kaplan-Meier estimates will be calculated with 2-sided 90% CIs at timepoints (12, 24, 36 and 52 
weeks) and displayed in both a graphical (where the number of participants at risk is at least 10% 
of the total number of participants in the analysis set) and a tabular form. In addition, the number 
of participants at risk, the number of participants censored and the number of participants with 
event will be computed at each time-point. 
5.4.3.1.2.
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 based on 
investigator assessment (see Section 5.4.1.2 for details). 
As described in the previous section, Kaplan-Meier estimates will be calculated with 2-sided 90% 
CIs at time points (12, 24, 36 and 52 weeks) and displayed in both a graphical (where the number 
of participants at risk is at least 10% of the total number of participants in the analysis set) and a 
tabular form. In addition, the number of participants at risk, the number of participants censored 
and the number of participants with event will be computed at each time point. Results will be
displayed overall and by randomized treatment group in the main SERENADE study.
Time to first occurrence of HF death or hospitalization will be presented in a listing on the FAS
by “DB-Placebo”, “DB-Macitentan” treatment groups.
5.4.3.1.3.
Time to first occurrence of CV death or CV hospitalization
The variable of interest is the time to first occurrence of CV death or CV hospitalization based on 
investigator assessment (see Section 5.4.1.3 for details). 
As described in Section 5.4.3.1.1, Kaplan-Meier estimates will be calculated with 2-sided 90% CIs 
at time points (12, 24, 36 and 52 weeks) and displayed in both a graphical (where the number of 
participants at risk is at least 10% of the total number of participants in the analysis set) and a 
tabular form. In addition, the number of participants at risk, the number of participants censored 
and the number of participants with event will be computed at each time point. Results will be
displayed overall and by randomized treatment group in the main SERENADE study.
Time to first occurrence of CV death or hospitalization will be presented in a listing on the FAS
by “DB-Placebo”, “DB-Macitentan” treatment groups.
5.4.3.1.4.
NYHA 
FC 
(improved/worsened/stable) 
at 
each 
post 
baseline 
assessment
A shift table will present the participants scores at baseline and any shift to the worst-case post 
baseline during the DB+OL period to determine any change (see Section 5.4.1.4) on the FAS. 
The proportion of participants in each category will be calculated based on the number of 
participants in the analysis set.
All NYHA FC data (including unscheduled assessments) will be listed on the FAS by double-blind 
treatment group.


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The proportion of participants having improved, having worsened or being stable at each post 
baseline visit will be summarized overall and by double-blind treatment group. 
5.5.
Other Safety Analyses
5.5.1.
Other significant adverse events
5.5.1.1.
AEs with fatal outcome
An AE with fatal outcome is any AE with Outcome = “Fatal” in CRF.
Treatment-emergent AEs with fatal outcome will be included in the AE listing. A separate listing 
will be provided for all participant AEs with fatal outcome.
Treatment-emergent AEs with fatal outcome will be summarized for the Safety Set and the Safety 
Initiated Set separately by SOC and PT within each SOC.
5.5.1.2.
AEs of special interest (AESI)
All AESI and HAESI (see Section 6.8 for definition) will be summarized by PT.
For each area of clinical interest, treatment-emergent AEs of special interest will be summarized 
for the Safety Set and the Safety Initiated Set, presenting counts and percentages of participants 
having experienced at least one treatment-emergent AE of special interest by frequency of PT 
within each AESI/HAESI group. Separate listings will be provided for all AEs of special interest
on the Safety Set and the Safety Initiated Set.
5.5.1.3.
AEs continuing from AC-055G202 (SERENADE)
Adverse Events started in AC-055G202 (SERENADE) but still ongoing at Enrollment in 
AC-055G203 (SERENADE OL) are reported in the CRF form “Ongoing Adverse Event from 
AC-055G202”.
AEs continuing from SERENADE will be summarized separately from the AE occurred during 
SERENADE OL by SOC and PT within each SOC and by PT, for the Safety Set.
A separate listing will be provided for all AEs ongoing from SERENADE study.
5.5.1.4.
Other AEs of Interest
Treatment-emergent thrombocytopenia and leukopenia will be summarized for the Safety Set and 
the Safety Initiated Set.
Cases with events of ‘thrombocytopenia/platelets decrease’ are defined as any event PT within 
either of the following MedDRA SMQs: ‘Haematopoietic thrombocytopenia’, or ‘Haematopoietic 
cytopenias affecting more than one type of blood cell’ (with the exception of 2 unspecific PTs: 
‘Blood disorder’, ‘Blood count abnormal’) or if they contain an event with any MedDRA PT 
containing the text ‘thrombocytopenia’ or ‘thrombocytopenic’.


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Cases with events of leukopenia are defined as any event PT within either of the following 
MedDRA SMQs: ‘Haematopoietic leukopenia’, or ‘Haematopoietic cytopenias affecting more 
than one type of blood cell’ (with the exception of two unspecific PTs: ‘blood disorder’, ‘blood 
count abnormal’).
5.5.2.
Additional Safety Assessments
5.5.2.1.1.
Additional liver test abnormalities
The following summaries will be conducted for liver tests and hemoglobin based on the OL period 
(the Safety Set) and the MRI+DB+OL period (the Safety Initiated Set):
-
ALT and / or AST > 3 × ULN
-
ALT and / or AST > 5 × ULN
-
ALT and / or AST > 8 × ULN
-
ALT and / or AST > 3 and ≤5 × ULN
-
ALT and / or AST > 5 and ≤8 × ULN
-
Total Bilirubin > 2 × ULN
-
ALT and/or AST > 3 × ULN and associated (ie, at the same visit) increase in total bilirubin > 
2 × ULN
-
Hemoglobin ≥ 80 g/L and < 100 g/L
-
Hemoglobin < 100 g/L and a decrease from baseline > 20 g/L 
-
A decrease in hemoglobin from baseline of > 20 g/L
-
A decrease in hemoglobin from baseline of > 20 g/L and ≤ 50 g/L
-
A decrease in hemoglobin from baseline of > 50 g/L
The categories “ALT and / or AST > 3 × ULN”, “ALT and / or AST > 5 × ULN”, “ALT and / or 
AST > 8 × ULN” are not mutually exclusive and participants 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. The hemoglobin values will be summarized 
similarly, considering for the evaluation of the categories the lowest hemoglobin value at any 
time point in the period. 
For the evaluation of liver test and hemoglobin abnormalities, measurements from unscheduled 
visits will be included. All participant with at least one treatment-emergent abnormality will be 
provided in a separate participant listing.
Treatment-emergent liver test and hemoglobin abnormalities will be summarized similarly to the 
MLAs (Section 5.3.3.4.1).
5.5.2.1.2.
Physical Examination Findings
Physical examination is performed at all scheduled visits and any post baseline abnormalities or 
baseline conditions that worsened post baseline should be reported on the Adverse Events/Serious 
AEs forms.
5.5.2.1.3.
Electrocardiogram
A standard 12-lead ECG is performed at Visit 1/Enrollment, Visit 6/W24, Visit 7/W36, EOT.


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All assessments recorded after start of treatment (Section 5.1.2.3) will be assigned to the most 
appropriate study visit according to the best fitting time-window for that assessment as detailed in 
Section 5.1.1. 
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 OL period. Defined as 
any finding and separately for each type.  
Atrial fibrillation / flutter (AF) is defined as presence of any atrial finding (atrial fibrillation or 
atrial flutter).
If atrial fibrillation = yes or atrial flutter = yes then AF = yes. If both are missing then AF is 
missing, otherwise AF= No.
Note a participant cannot have sinus rhythm = Yes if AF= yes at a visit assessment. However, a 
participant may be assessed at a visit as having neither presence of AF nor sinus rhythm (SR), in 
this case the finding is categorized as “other”. In the rare event any case of both SR and AF is 
found, AF will be chosen considering that SR is not a negative finding. Therefore, the findings at 
a visit are categorized as AF, SR or other.
The count and percentage of participants with presence of treatment-emergent qualitative finding 
(atrial fibrillation/atrial flutter) will be summarized in a shift table, for the Safety Set. These will 
be presented as shift from baseline. A listing will be also provided.
5.6.
Other Analyses
5.6.1.
Extent of Exposure
The exposure in the SERENADE OL study 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 data are recorded in the “Study Treatment Log” CRF. 
Study treatment interruptions in SERENADE OL: a participant 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’. 
Duration of treatment (weeks) in SERENADE OL: time (in days) elapsed between the treatment 
start date (Section 5.1.2.3) and the treatment end date (Section 5.1.2.4) + 1 day divided by 7, 
regardless of any treatment interruptions, ie, [(treatment end - treatment start +1)/7].


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In the case that the treatment end date is missing or a reason other than ‘Premature discontinuation’
or ‘Completed as per protocol’ is reported, then the duration of treatment is calculated applying 
the general rules in Section 5.1.4.
Exposure to macitentan treatment (weeks) in SERENADE OL: treatment duration adjusted for 
interruptions defined as:
Duration of treatment - Total Duration of Interruptions (TDI),
where TDI is defined as the sum of the durations of interruptions.
The duration of interruption (days) is the 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 Treatment Log’ End Date with corresponding reason for treatment end 
being ‘temporarily interrupted’. Interruption End Date is the next chronological ‘Study Treatment
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 Treatment Log’ entry the exposure is missing. 
Participant year exposure in SERENADE OL: is calculated by summing the duration of study
treatment for all participants (days) divided by 365.25.
For the combined MRI+DB+OL period, the below variables are derived:
Cumulative duration of treatment (weeks): time (in days) elapsed between the macitentan 
treatment start date and end date + 1 day divided by 7, regardless of any treatment interruptions,
ie, [(treatment end - treatment start +1)/7].
Cumulative participant year exposure: is calculated by summing the cumulative duration of 
treatment for all participants (days), then divided by 365.25.
The duration of treatment (including interruptions) as well as the study treatment exposure 
(excluding interruptions) and the exposure (patient years) in SERENADE OL will be summarized 
on the Safety Set. The treatment duration will be also summarized as a categorical variable, 
presenting the distribution of treatment duration by class interval (i.e., at least 4, 8, 16, 24, 32, 52 
weeks) and displaying frequency counts and percentages of participants in each class interval if at 
least 10 participants are available.
Similarly, the cumulative duration of macitentan treatment (in the combined MRI+DB+OL period) 
will be summarized both as continuous and categorical variable using descriptive statistics on the 
Safety Initiated Set. Results will be displayed overall and by randomized treatment group in the 
main SERENADE study.
A listing of exposure and study treatment interruptions will be provided for the Safety Initiated Set 
by DB study treatment received (DB-macitentan or DB-placebo).


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5.7.
Interim Analyses
5.7.1.
Data Monitoring Committee (DMC) or Other Review Board
No interim analyses are planned for the study. 
An Independent Data Monitoring Committee (IDMC) will not be utilized for the SERENADE OL 
study. 
A Steering Committee has contributed to the study design and will be consulted prior to and during 
the study for relevant medical issues and study publications.
External to the study, 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 any 
macitentan study as per the ILSDRB charter.


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6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
6-MWD
6-minute walk distance
6-MWT
6-minute walk test
AE
Adverse event
ALT
Alanine Transaminase
AST
Aspartate Transaminase
ATC
Anatomic Therapeutic Chemical
bpm
Beats per minute
BP
Blood pressure
BUN
Blood Urea Nitrogen
CEC
Clinical Event Committee
CDDM
Clinical Development Data Management
CRF
Case report form
CI
Confidence interval
CRO
Contract research organization
CLs
Confidence limit(s)
CSR
Clinical study report
CV
Cardiovascular
CYP3A4
Cytochrome P450 3A4
DBP
Diastolic Blood Pressure
ECG
Electrocardiogram
EF
Ejection Fraction
eGFR
estimated Glomerular Filtration Rate
EMA
European Medicines Agency
EOS
End-of-study
EOT
End-of-treatment
ERA
Endothelin receptor antagonist
ESRD
End Stage Renal Disease
EudraCT
European Clinical Trial Database
FAS
Full Analysis Set
FC 
Functional Class
FDA
(US) Food and Drug Administration
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
HDL
High-Density Lipoprotein
HF
Heart Failure
HFpEF
Heart failure with preserved ejection fraction 
ICF
Informed Consent Form
ICH
International Council on Harmonisation
IDMC
Independent Data Monitoring Committee
ILSDRB
Independent Liver Safety Data Review Board
IxRS
Interactive voice/web Recognition System
KM
Kaplan-Meier
LAV
Left Atrial Volume
LVEF
Left Ventricular Ejection Fraction
LDL
Low-Density Lipoprotein
MedDRA
Medical Dictionary for Regulatory Activities
MDRD
Modification of Diet in Renal Disease
MLA
Marked Laboratory Abnormalities
MR-proANP
Mid-Regional pro-Atrial Natriuretic Peptide
NYHA
New York Heart Association
OL
Open-label
OLE
Open-label Extension Enrolled Set 
PAD
Peripheral artery disease 
PAH
Pulmonary arterial hypertension 


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PDE-5
Phosphodiesterase-5 
PASP
Pulmonary Artery Systolic Pressure
PD
Protocol Deviation
PGA
Patient Global Assessment
PT
Preferred Term
PTOP
PVD
Post-Treatment Observation Period
Pulmonary Vascular Disease 
SAE
Serious adverse event
SAP
Statistical analysis plan
SBP
Systolic Blood Pressure
SCR
Screened analysis set
SD
Standard Deviation
SDTM
Study Data Tabulation Model 
SI
International system of units
SMQ
Standardised MedDRA Query
SOC
System organ class
TEAE
Treatment-Emergent Adverse Event
TESAE
Treatment-Emergent Serious Adverse Event
ULN
Upper limit of the normal range
USA
United States of America
VHP
Voluntary Harmonization Procedure
WHF
Worsening of Hearth Failure
WHO
World Health Organization
WHO DDE
World Health Organization Drug Dictionary Enhanced
6.2.
Appendix 2 Changes to Protocol-Planned Analyses
6.2.1.
Changes to the analyses planned in the study protocol
6.2.1.1.
Baseline
Section 10.1.6 of the protocol defines: 

baseline as the last non-missing assessment obtained prior to the start of study drug intake 
in SERENADE OL (OL Baseline)

macitentan baseline as the last non-missing assessment obtained prior to the start of 
macitentan intake in the main study or SERENADE OL, respectively.
For both baselines, the definition used in this SAP is the last non-missing assessment obtained before 
or on the day of the start of macitentan treatment. This is to capture changes in safety after the 
first intake of macitentan and is in line with the approach followed with the main SERENADE 
CSR study.
6.2.1.2.
Usage of the analysis sets
In protocol section 10.1.6 is stated ‘The Safety Initiated Set is used for the analyses of adverse 
events and other select safety variables during treatment with macitentan’. The selected safety 
variables analyzed on this set will be exposure and the following laboratory parameters: 
erythrocytes, hemoglobin, hematocrit, leukocytes, lymphocytes, neutrophils, platelets, AST, ALT, 
total bilirubin, alkaline phosphatase, MLAs and eGFR.


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6.2.2.
Changes in the conduct of the study / data collection
The following protocol amendments were performed:
Protocol AC-055G203 Version 2, amendment 1 - 2 August 2018:

To correct the description of the Investigational Medicinal Product used in this study.
Protocol AC-055G203 Version 3, amendment 2 - 16 May 2019:

To introduce a new efficacy endpoint, the 6-minute walk distance (6MWD), assessed by 
the 6-minute walk test (6MWT), as part of a sub-study to assess the change from baseline 
in exercise capacity. This to maximize the knowledge gain from Phase 2 development, by 
informing on the potential benefits of macitentan treatment in a HFpEF subset that tolerates 
macitentan. The Borg Dyspnea Index was assessed after each 6MWT. 

To include the collection of mid-regional pro-atrial natriuretic peptide and a research 
biomarker (optional) sample at scheduled visits and at the time of a fluid retention or 
worsening heart failure event to continue the analysis from the main study. 

To include the collection of N-terminal pro-brain natriuretic peptide at the time of fluid 
retention or worsening heart failure event to support the Clinical Event Committee review.
Protocol AC-055G203 Version 4, amendment 3 - 6 February 2020:

To align the strategy for participant enrollment into this open-label (OL) extension study 
due to premature termination of recruitment into the AC-055G202 SERENADE main 
study: 
– Eligible participants may enroll into this OL extension study after remaining in the main 
study (AC-055G202) for at least 24 weeks;

To remove evaluation of the efficacy assessments (ie, Kansas City Cardiomyopathy 
Questionnaire, accelerometry, echocardiography, and blood sample collection for 
N-terminal pro-brain natriuretic peptide [NT-proBNP], mid-regional pro-atrial natriuretic 
peptide [MR-proANP], and biomarkers) in an effort to simplify the study and reduce 
assessment burden for participants and study site personnel;

To stop the 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;

To remove the Clinical Event Committee (CEC) adjudication in line with AC-055G202 
SERENADE main study global protocol Version 6. The rationale is based on the reduction 
of the double-blind treatment period from 52 weeks to 24 weeks coupled with the low 
occurrence of clinical events, which will not allow 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). 

To create a single version of the SERENADE OL AC-055G203 protocol by incorporating 
Voluntary Harmonisation Procedure (VHP) mandated changes into the global protocol 


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version. VHP-mandated additions will only affect VHP countries and include the 
following: 
– Study termination at 5 years as one option described in section 3.1.2 of the protocol; 
required monthly Liver Function Tests (LFTs) monitoring described in section 7.2.4.1 of 
the protocol; use of double-barrier contraception methods only when the use of highly 
effective measures, as described in section 4.4.2 of the Global Protocol Version 4, is 
medically contraindicated.
Protocol AC-055G203 Version 5, amendment 4 - 16 July 2020:
The purpose of this amendment was to update the exclusion criteria and 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.
Protocol AC-055G203 Version 6, amendment 5 - 26 November 2020:
The overall reasons to issue this protocol amendment were:

to adapt to changed internal safety language and reporting processes, 

to align with TransCelerate template, 

to update information about post-treatment access program, study treatment storage 
conditions, forbidden medications, Actelion’s policy for study data disclosure, 

to make minor editorial revisions and corrections. 
Note: Only the main reasons for the protocol amendments are described.
6.2.3.
Clarifications concerning endpoint definitions and related variables 
or statistical methods
6.2.3.1.
Previous and concomitant medications
Section 5.2.1 of the protocol specifies definitions for a previous therapy and a study-concomitant 
therapy for the purpose of capturing these in the CRF. The definitions for previous therapy and 
treatment concomitant therapy are adapted in this SAP for the purpose of presenting summaries 
for reporting and interpreting the results in the CSR. 
The SAP changes to the protocol are, in line with the analysis performed in the main SERENADE 
study CSR, as follows:


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
Previous therapy is relative to first dose rather than enrollment visit.

Treatment-concomitant therapy is considered with respect to the study treatment start 
instead of the enrollment visit.

Study-concomitant therapy is not required for reporting of results in the CSR. 
6.2.3.2.
Exploratory efficacy variables, time to event analysis
Regarding the time to event analysis of the exploratory efficacy variables, the protocol states 
‘Participants without any event up to EOS are right-censored at their time of EOS’. It has been 
specified that, for the participants enrolled in the VHP countries (see Section 6.3), the censoring 
date will be the earliest between the EOS and the upper limit of the Week 52 time window (see 
Section 5.1.1). It is expected that the follow up will be varied across participants (from 52 Weeks 
up to 260 weeks in the VHP countries), thus this correction has been introduced to provide 
unbiased survival estimates.
6.2.3.3.
Sub-study assessments (6MWD and Borg Dyspnea Index)
Under global protocol Version 3, participants could continue the participation in the SERENADE 
sub-study, designed to evaluate the long-term effect of macitentan on 6-minute walk distance 
(6MWD). Under global protocol version 4 the sub-study assessments were stopped as the number 
of subjects participating in the sub-study was too low to allow for meaningful interpretation of 
results. Data regarding the sub-study will not be part of this CSR reporting.
6.3.
Appendix 3 Demographics and Baseline Characteristics
Demographic data at screening comprise age (years; continuous and categorical), sex, ethnicity, 
race, race and geographical region. Data are provided in the SDTM.DM dataset (for re-screened 
participants they are taken from the latest re-screening).
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.

Race (Black or African American / American Indian or Alaska Native / Native Hawaiian or 
Other Pacific Islander / Asian / White / Other / Not applicable)

Geographical region: 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; 
– Eastern Europe: Bulgaria, Czech Republic, Hungary, Poland, Romania, Russia. 


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VHP countries for which the study termination was scheduled at 5 years are the following:
– Denmark, Germany, Hungary, Poland, Sweden, United Kingdom.
Table 7 presents the list of demographic variables that will be summarized, using descriptive 
statistics.
Table 7:
Demographic Variables
Continuous Variables:
Summary Type
Age (years)
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and 
range 
[minimum 
and 
maximum], and IQ range).
Categorical Variables
Age (18-64 years, 65-84 years and >=85 years)
Frequency distribution with the 
number 
and 
percentage 
of 
participants in each category.
Race (Black or African American / American Indian or Alaska Native / 
Native Hawaiian or Other Pacific Islander / Asian / White / Other / Not 
applicable)
Geographical region
The SERENADE OL baseline disease characteristics are listed below:
New York Heart Association Functional Class - NYHA FC (“NYHA Functional Class” CRF).
Echocardiography (provided by central echocardiographic laboratory):

Left Ventricular Ejection Fraction (LVEF) [%]: classified as ≥ 40 - <50 and ≥ 50%. 
These categories represent the mid-range 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:

Creatinine (μmol/L, SI units)

Estimated Glomerular Filtration Rate (mL/min/1.73m2) using the Modification of Diet 
in Renal Disease formula [see Section 5.1.3].
Other baseline characteristics include the following:

Renal function: the following categories are defined for renal function based on the 
estimated glomerular filtration rate [eGFR (mL/min/1.73m2)] from the abbreviated 
modification of diet in renal disease (MDRD) study:
o
Normal: ≥ 90
o
Mild Decrease: 60 – <90 
o
Moderate Decrease: 30 – <60
o
Severe Decrease: 15 – <30
o
End Stage Renal Disease (ESRD): <15.


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Table 8 presents the list of baseline disease characteristics variables that will be summarized using 
descriptive statistics.
Table 8:
Baseline Disease Characteristics Variables
Continuous Variables
Summary Type
Left Ventricular Ejection Fraction (LVEF) [%]
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and 
range 
[minimum 
and 
maximum], and IQ range).
Left Atrial Volume Index (LAVI) [mL/m2] 
Lateral E/e’
Pulmonary Artery Systolic Pressure (PASP) [mmHg]
Creatinine (μmol/L, SI units)
Estimated Glomerular Filtration Rate (mL/min/1.73m2)
Categorical Variables
NYHA FC
Frequency distribution with the 
number 
and 
percentage 
of 
participants in each category.
Renal function
Renal function based on the eGFR (mL/min/1.73m2) is summarized as both continuous and 
categorical.
Echocardiography summaries will be presented on the OLE set only in case there are at least 70% 
of the participants in the OLE set with available data. 
6.4.
Appendix 4 Protocol Deviations
In general, the following list of major protocol deviations may have the potential to impact 
participants’ rights, safety or well-being, or the integrity and/or result of the clinical study. 
Participants with major protocol deviations will be identified prior to database lock and the 
participants with major protocol deviations will be summarized by category:

Protocol Deviation prior to and at enrollment

Protocol Deviation during treatment period and follow-up

Protocol Deviation related to COVID-19.
The analyses of PDs will be based on the OLE.
Major protocol deviations will be summarized by category, displaying counts and percentages of 
participants with at least one PD. The summary table will be sorted by category and frequency in 
descending order; if a tie occurs, the tied characteristics will be sorted alphabetically.
All reported PDs will be reported in a listing. Major PDs will be flagged accordingly. 


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6.5.
Appendix 5 Prior and Concomitant Medications
All medications as collected in the “Previous / Concomitant Medication” CRF. 
The original terms used by the investigators to describe medications are assigned preferred terms 
and anatomic therapeutic chemical (ATC) classification code using the latest version of the WHO 
Drug dictionary enhanced (WHO DDE).
Previous medication is defined as any medication that was started prior to start date of open-label 
study treatment (see definition in Section 5.1.2.3) and with an end date prior to the start date of 
study treatment or end date equal to the start date of study treatment with the flag ‘Ongoing at start 
of OLE enrollment?’ ticked “No”.  
If the end date is missing and the start date is prior to the date of open-label study treatment start, 
then the medication is considered as previous if ‘Ongoing at start of OLE enrollment?’ is ticked 
“No”.
Study-treatment concomitant medications are all the medications that are ongoing at start of 
open-label study treatment or initiated on or after study treatment start date and up to study 
treatment end (EOT) date [Section 5.1.2.4] + 30 days (inclusive).
Rules for handling missing and partial dates are detailed in Section 5.1.4.
Diruetics are determined as detailed in the main SERENADE study CSR SAP (section 5.2.5.7), 
from all medications as collected on “Previous / Concomitant Medication” CRF. 
Number and percentages of participants having taken at least one medication will be presented by 
Anatomic Therapeutic Chemical (ATC) class (level 4) and PT within each ATC class. All 
medications will be tabulated by ATC class, and individual preferred terms within each ATC class, 
for the OLE Set. ATC classes will be sorted by descending order of frequency; if the frequencies 
of ATC class are the same, alphabetical order will be used. The same rule applies for preferred 
terms within ATC class. Verbatim terms will be included in the listing only.
Previous medications and study-treatment concomitant medications will be summarized separately 
using descriptive statistics for categorical data. 
All medications will be reported in a listing for the OLE Set, with flags to identify previous and 
study-treatment concomitant ones accordingly. 
Diuretics will be listed in a separate listing.


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6.6.
Appendix 6 Medical History
Medical history is not applicable as this information (including specific medical history) is not 
collected in this SERENADE OL study. 
Medical history data recorded in the database of the main SERENADE study will be used for listings 
on the OLE Set.
6.7.
Appendix 7 Intervention Compliance
Study treatment compliance is based on the “Study Treatment Dispensing & Accountability” form. 
Study treatment compliance was calculated by site personnel at each study treatment dispensing 
visit and EOT using the below formula and entered in the CRF: 
Compliance = [(number of tablets dispensed − number of tablets returned) / Total number of tablets 
that should have been taken between 2 regular study treatment dispensing visits*] × 100. 
*The number of tablets that should have been taken is derived from the number of days between 
the corresponding regular visits. 
During the study, compliance is expected to be between 80% and 120%. 
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. 
Study-treatment compliance in the SERENADE OL study will be summarized on the Safety Set, 
displaying counts and percentages of participants with compliance < 80%, 80%-120% and 
> 120%. 
A listing of compliance for each visit will be also provided, containing the compliance values 
directly collected in “Study Treatment Dispensing & Accountability” form in CRF.
6.8.
Appendix 8 Adverse Events of Special Interest
AEs of special interest (AESI) are identified below. 
The definitions are based on a combination of MedDRA preferred terms (PTs) and SMQs 
(Standardized MedDRA Queries) 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”

excluding events with PTs containing “site”


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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 MedDRA PT containing the text “anaemia”.
Hepatic AEs of special interest (HAESI):

Any AE with PT, SOC or HLGT containing the text specified in Table 9.
Table 9:
Hepatic AE Terms
Term
Type
Acute graft versus host disease in liver
MedDRA PTs
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
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


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Status: Approved, Date: 2 November 2021
Hepatic infiltration eosinophilic
Hepatic necrosis
Hepatic steato-fibrosis
Hepatitis
Hepatitis acute
Hepatitis alcoholic
Hepatitis cholestatic
Hepatitis chronic active
Hepatitis chronic persistent
Hepatitis toxic
Hepatocellular injury
Hepatopulmonary syndrome
Hepatorenal failure
Hepatorenal syndrome
Hepatotoxicity
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
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
Hepatobiliary disorders
SOC Terms
Hepatobiliary investigations
HLGT Terms


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7.
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